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CNS Abstracts
401. Predictive Value of Electroencephalogram for
Neurological Outcome and Epilepsy After Neonatal
Seizures
Els L. Ortibus, john M . Sum. and Jin S. Hahn, Stanford, CA
This study aims at determining the electroencephalographic
(EEG) variables that are predictive for outcome and epilepsy
following neonatal seizures. W e identified all neonates with
EEG-proven seizures (81) admitted to the intensive care
nurseries berween 1987 and 1793. In the 81 ictal EEGs and
60 interictal EEGs (obtained within 1 week of the ictal record), we scored the background on a 6-point scale and quantified the seizure activity. The EEG analysis further included
the presence of sharp waves, runs of sharp waves, and 8-a
bursts. The medical records were reviewed for clinical variables. We then correlated the EEG and clinical variables with
epilepsy and outcome. The outcome was normal in 18 cases
( 2 2 q ), mildly abnormal in 11 (14% ), and severely abnormal
in 29 (36%). Twenty-three patients (28%) died. Unfavorable
outcome was significantly correlated with poor background
scores in both ictal and interictal EEGs ( p < 0.03) and the
presence of electrographic status epilepticus ( p < 0.01). The
absence of 0-abursts had a clear association with a severely
abnormal outcome or death ( p < 0.002). Relevant clinical
variables were the neurological exam ( p < 0.0001) and the
etiology ( p < 0.015). Seizures due to cerebral dysgenesis ( 5
cases) were invariably associated with a poor outcome. Patients with hypoxic-ischemic encephalopathy (30) or central
nervous system infection (7) tended to have severe outcome,
while those with arterial stroke ( 7 ) or parenchymal hemorrhage (4) were likely to be normal or mildly abnormal. Postneonatal epilepsy occurred in 17 patients (21%). Of the EEG
variables, the absence of 8-a bursts was associated with epilepsy ( p < 0.05). Other variables, such as the background
score and status epilepticus, did not show any correlation.
Cerebral dysgenesis was invariably followed by epilepsy,
while other etiologies had no clear association. In conclusion,
neurological outcome following neonatal seizures can be predicted by the background activity of both ictal and interictal
neonatal EEG and by the presence of status epilepticus.
However, these EEG variables do not necessarily predict the
development of epilepsy. The data further suggest that the
absence of 0-a bursts is unfavorable with regard to both outcome and development of epilepsy.
402. Phenobarbital and Phenytoin Treatment of
Neonatal Seizures
Mirhael/. Painter. iCiurk S. Srher, Nigrl S. Paneth.
Zhiviing Wang, A yeb D. Stein. Joseph Gardiner. and
John D. Ahin, Pittsburgh, PA. and East Lansing. MI
We studied the relative efficacy of phenobarbital (PB) and
phenytoin (IT
in)treating neonatal seizures. Neonates with
electrically documented seizures were randomly assigned to
PB (,n = 21) or FT
' (n = 20) treatment, and continuous
electroencephalographic (EEG) monitoring was performed
for 24 hours. Free (unbound) plasma concentrations of 25
mgiL for PB and 3 mg/L for PT were maintained. Of the 41
neonates, 15 experienced no further seizures with desired
plasma concentrations (PB, 8 of 21; FT,7 of 20; p = 0.84).
The maximum efficacy of either agent was no greater than
38% and appears less when accounting for natural history.
Neither PB nor PT was effective in preventing seizure recur-
486
Annals of Neurology
Vol 36 No 3
rence in severe seizures (severity score, >15,000 lead seci
hr; calculated by seizure duration in seconds x number of
electrodes involved, maximum 11). Utilizing least square regression analysis comparing pretreatment recording to posttreatment, no predictable alteration in seizure intensity slope
was affected by either drug in seizures of all severities.
Among treatment failures, the median time to subsequent
seizure was 0.71 hours for PB and 0.90 hours for FT (rank
sum test, p = 0.96). The median severity score for the first
recurrence was 720 for P B and 560 for PT (rank sum test,
p = 0.45). Based on these data, the two drugs did not differ
in their ability to prevent the onset of subsequent seizures,
to delay the time to onset of recurrent seizure, or to attenuate
the severity of recurrence. Neither drug was effective in preventing seizure recurrence in most neonates and both were
least effective in neonates with severe seizures. (Funded by
N S 26746.)
403. Role of Inositol-Triphosphate and Intracellular
Calcium Stores i n Kainic Acid-induced Hippocampal
Damage
L. Carmant, Z. Liu, S. Warner. M. A. Mikati.
and G , L. Ho17ne,., Boston,M A
While immature rats have severe seizures with kainic acid
(KA), hippocampal damage is much less than in adult rats.
Immature animals thus appear protected from excitotoxic cell
damage. Neuroprotective mechanisms operating in immature
animals remain unclear. W e report the effects of prolonged
seizures on inositol-triphosphate (IP3) levels, a second messenger that controls many cellular processes through internal
calcium signals, in immature and mature rats. KA seizures
were induced in 3 groups, 10- (n = 29). 20- (n = 26), and
60-day-old (n = 12) rats. Test animals received 12 mgikg
KA intraperitoneally; matched controls received saline. Animals were decapitated at 0.5, L,2, and 4 hours after injection.
Hippocampi were immediately dissected and IP3 levels measured after homogenization using a radioimmunoassay test.
A ninefold increase in IP3 levels was found in adult rats
following KA, peaking 1 hour after injection and followed
by slow decline over the next 3 hours. Despite more severe
seizures, no increase in IP3 was seen in immature animals.
Time profile of IP3 release is similar to that reported in
other models. IP3 pathway is not activated in immature rats
subjected to KA seizures. This likely prevents release of intracellular calcium stores and might play a critical role in
preventing cell damage.
404. Induction of Brain-derived Neurotrophic Factor
m R N A b y Seizures i n Neonatal Rat Brain
HarLey I. Kortzblum. Raman Sankar. Donald Shin.
Claude G. Wasterlain, and Chri.rtine M . Gull,
Los Angeles and Iwine. C A
Prior studies have demonstrated that seizures induce a rise
in mRNAs for nerve growth factor and brain-derived neurotrophic factor (BDNF) within the adult rat brain. Other studies have indicated that seizures prior to 2 weeks of life do
not produce a similar enhancement of hybridization. In the
present study, using two different experimental models we
demonstrate that limbic seizures dramatically enhance hybridization densities for B D N F mRNA in developing rat
brain. Rats from 7 to 60 days of age were pretreated with
lithium chloride (3 mEqikg), followed 16 hours later by 100
September 1994
mg/kg pilocarpine or were treated with kainic acid (3 mg/
kg). Controls were treated with vehicle. Some animals were
pretreated with diazepam, 25 mgikg, to prevent seizures.
Some animals were implanted with cortical and hippocampal
electrodes to verify electrographic seizures. Animals were
killed 1, 2, 4 , or 8 hours postinjection. Brains were then
processed for in situ hybridization using %-labeled cRNA
probes. Both treatments induced electrographic and clinical
seizures at all ages studied. At postnatal day 12 and older,
pilocarpine-induced seizures resulted in dramatic elevations
of hybridization densities in multiple brain areas including
neocortex; hippocampus; piriform, cingulate and entorhinal
cortices; and amygdala. Maximal effects were observed between 2 and 4 hours postinjection, and these effects were
prevented by pretreatment with diazepam. Pilocarpineinduced seizures led to significantly elevated hybridization
within cingulate, piriform, and entorhinal cortex at postnatal
day 7. Kainate-induced seizures led to markedly enhanced
hybridization only within the CA3 subfield of the hippocampus of 9-day-old rats. The present study demonstrates that
neurotrophin expression can be dramatically altered by seizures within the developing brain, at ages when significant
maturational events are taking place. Furthermore, different
models of limbic seizures produce different effects on neurotrophin expression. Further studies will be necessary to determine if altered neurotrophin expression leads to structural
or functional change within the developing brain.
405. Corticotropin-releasing Hormone Receptor
Antagonist Is Effective for Febrile Seizures i n the
Infant Rat
Tallie Z. Baram and Linda Srhultz, Los Angeles. C A
Febrile seizures (FS) are a common, age-specific entity observed in 3 to 5 q Jof infants and young children. Despite the
frequency of FS, the mechanisms and potential endogenous
convulsants involved in their generation are poorly understood. Corticotropin-releasing hormone (CRH) is a neuropeptide, inducing age-specific seizures when administered
into the cerebral ventricles of infant rats in picomolar
amounts. Endogenous CRH, found in the hypothalamus and
limbic system, has been found to participate in certain mechanisms of hyperthermia. W e tested the hypothesis that endogenous C R H may contribute to febrile seizures in an infant
rat paradigm. Infant rats (n = 43) were implanted with a
chronic cannula in the lateral cerebral ventricle (icv) on postnatal day 9.O n day 10, a-helical-(9-41)-CRH, a competitive
antagonist of the C R H receptor, was infused icv (0.9 x
mol) to half the animals. Hyperthermia was induced 30 minutes later to 2 rats at a time, 1 of which was treated and the
other used as a control. Seizure onset was assessed by an
investigator blinded to treatment; rectal temperature was
measured immediately (Thermistor probe, Omega Engineering, Stamford, CT). Mean temperature at onset of FS
was 43.16"C + 0.46 for controls, and 44.47"C + 0.46 for
rats pretreated with C R H antagonist ( p < 0.05). C R H antagonist increased temperature required for hyperthermic seizures in infant rats by 1.31"C. In the same paradigm, phenobarbital raised FS-inducing temperature by 1"C, while
phenytoin did not affect seizure threshold, similar to effects
on FS in human infants (Olson JE, Scher MS, Holtzman D.
Effects of anticonvulsants on hyperthermia-induced seizures
in the rat pup. Epilepsia 1984;25:96-99). W e conclude that
C R H antagonist may be effective for human FS, via alteration
of CRH-mediated convulsive mechanisms. (Supported by
NS28912.)
406. Developmental Neuropathology in Children with
Intractable Partial Epilepsy
A. Simon Harvey, Michael S. Ducboic*ny.Rita Goldrteiti.
Jocelyn Bruce, Prasanna Jayakar. Tveiior R. Resnick.
Luis A. Aharez, and Nolan Altnzari, Miami. FL
Although the majority of children with intractable epilepsy
are believed to have developmental lesions, the neuropathology of childhood epilepsy has yet to be adequately described.
We report the neuropathological findings in 125 children (70
boys, 55 girls), mean age 9.0 years (age range, 1 month to
18 years; SD, 5.2), who underwent either hemispherectomy
(20) or focal cortical resection (temporal, 45; frontal, 36;
parietal, 5; occipital, 2; multilobar, 17) for intractable partial
epilepsy at our center between 1985 and 1994. Histological
examination of resected cerebral cortex revealed cortical dysplasia in 85, atrophic or sclerotic lesions in 17, tumor in
21, Rasmussen's encephalitis in 5, and no abnormality in 12;
multiple pathology was present in 14. Hippocampal sclerosis
was seen in only 8 children and was always in association
with developmental pathology; however, hippocampal tissue
was not always available for pathological examination. Cortical dysplasia in children with single pathology was characterized by the following hierarchy: ectopic neurons in white
matter (group I = 28); additional cortical architectural abnormalities with either disrupted horizontal lamination or
columnar orientation of neurons (group I1 = 21); and additional morphologically abnormal neurons (group 111 = 23).
In 20 of 2 1 tumors, the cortical position, mixed glial-neuronal
content, surrounding cortical dysplasia, lack of malignant features, and absence of regrowth following surgery suggested
the tumors were developmental in origin. In contrast to the
predominance of atrophic, sclerotic, and neoplastic lesions
in adults with partial epilepsy, the underlying pathology in
children with intractable partial epilepsy is overwhelmingly
developmental in origin. Thus, the etiological substrate of
intractable partial epilepsy in the majority of children is established during the second to fifth months of gestation, during
the period of neuronal proliferation, differentiation, and migration.
407. Neurological Correlates of Fetal Cocaine
Exposure: Transient Hypertonia of Infancy and Early
Childhood
Claudia A . Cbiriboga. Martha Vibbert, Renee' Malouk
Maria S. Suarez, Elaine J . Abranis, Margaret C . Heagarty.
John C. M . Brust, and W. Allen Hauser, Neul York, N Y
To determine long-term neurodevelopmental consequences
of cocaine exposure, we prospectively evaluated 80 children
drawn from a cohort at risk for perinatal HIV infection up
to age 24 months. Examiners were blinded to drug exposure
and H I V status. A positive urine toxicology for cocaine at
birth defined exposure in 35 infants.
Age
CocainePositive
CocaineNegative
OR
95% CI
OR
(LR)
6 moa
19/35 (56)
14/45 (31)
2.6
1.1-6.5
1.7"
12 moa
18 mod
24 mo
14/34 (41)
6/24 (25)
1/17 (7)
7/38 (18) 3.1
2/33 (6)
4.2
0113 ( 0 )
1.1-8.9
1.1-28
1.7a
2.3"
-
Number with hypertonia (HTYtotal (percent).
y;p
< 0.05.
Program and Abstracts, Child Neurology Society 487
Cocaine-positive infants were 4 times more likely at age 6
months to show hypertonic tetraparesis (HTP) than cocainenegative infants (OR = 3.9; CI = 1.5-10.5). Cocaine (6,
12, and 18 months) and gestational age (6 months only) were
independently associated with HT in logistic (LR) models
that controlled for perinatal confounders; HIV infection was
not linked to HT at 6 months. Hypertonia diminished over
time in both groups, and resolved in 94% of affected infants
by 24 months. Arm HT abated first; leg HT remained in
some children up to age 18 months. There were no differences in development scores between the 2 groups at any
age interval. Among cocaine-positive infants, however, we
noted lower mean scores, especially mental (MDI), at all ages
in infants with early H T P compared to infants without HTP.
Fetal cocaine exposure is associated with transient hypertonia
that resolves by age 24 months. Among cocaine-positive infants, H T P may be a marker for later developmental impairments.
408. Transplacental Cocaine Exposure: A Mouse
Model Demonstrating Growth and Behavioral
Abnormalities
Bawy E . Kosofky and Aaron S. Wifkins,Boston, M A
Using mice, we have developed an animal model of prenatal
cocaine exposure that has allowed us to dissociate the direct
effects of cocaine in altering fetal development from the indirect effects associated with cocaine-induced malnutrition. Primiparous pregnant dams (SW) were separated into 3 prenatal
treatment groups: 1 to receive cocaine (COC: 20 mg/kg, sc,
bid), 1 to receive saline and to be pair-fed with the cocaine
animal (SPF), and 1 to receive saline with food available ad
libitum (SAL). O n P1, each litter was fostered to an untreated
surrogate dam. Pup weight, sex, and biparietal diameter were
also recorded on P1, as well as on behavioral testing day P9.
We observed a tiered effect of prenatal treatment on P1
weight (F[2,384] = 141.34; p < 0.0001), in which COC
pups weighed the least and SAL pups the most. O n F'9, SAL
pups weighed significantly more than both SPF and COC pups
(F[2,66] = 4.26; p < 0.02); but, COC and SPF pup weights
did not significantly differ. As with P1 weights, there was a
tiered effect of prenatal treatment on P1 biparietal diameter
(F[2,269] = 79.11; p < 0.0001). SPF pups had the narrowest, and SAL pups the widest, biparietal diameters. By P9,
we observed no significant differences in biparietal diameter
berween COC and SPF pups, and SAL pups still displayed
wider biparietal diameters than SPF and COC pups (F[2,36]
= 20.67; p < 0.0001). A total of 65 animals (COC, n =
26; SPF, n = 17; SAL, n = 22) were tested for first-order
conditioning on P9. An ANOVA on P9 conditioned avoidance data revealed significant main effects of both treatment
(F[2,59] = 8.19; p < 0.001) and test conditions (F[1,59] =
50.15; p < 0.0001), wherein COC pups did not demonstrate
first-order aversive conditioning. We find that transplacental
cocaine exposure independently impairs fetal brain and body
growth and results in impairment in first-order aversive conditioning on P9.
409. Neurological Outcome of 102 Extracorporeal
Membrane Oxygenation-treated Neonates at 5 Years
of A g e
Lucy Ciuiteffo. Penny Glass, A n n Wagner.
Shrrsila Rajasingham. and Billie Short. Washington, DC
Extracorporeal membrane oxygenation (ECMO) is used to
treat term or near-term neonates with severe pulmonary dis-
ease who fail maximal conventional therapy and who meet
criteria for 20% or less chance of survival. ECMO survivors
are at high risk for neurological morbidity. A total of 102
ECMO-treated neonates have been evaluated at 5 years of
age with formal neuropsychological testing and neuromotor
and neurological examinations. In addition, 38 5-year-old
controls with benign neonatal courses have had identical evaluations. Major handicaps were not seen in controls, but they
were seen in 15%' of ECMO-treated patients. Handicaps include mild mental retardation (MR) (6), moderate MR (21,
profound MR (l), and mild-to-moderate cerebral palsy ( 5 ) ,
with all 5 patients being ambulatory, paraplegia (1), bilateral
sensorineuronal hearing loss ( l ) , epilepsy (2),and cortical
visual deficit (1). Significant gross motor delay (>2 years) was
seen in 89% of ECMO patients, but not in controls. Microcephaly was noted in 9 ECMO patients. The most common
abnormality on neurological examination in both populations
was hypotonia, seen in 75?4 of ECMO patients and 89g of
controls ( p = 0.56). The hypotonia was functionally significant in 6 of 77 (85%) of ECMO patients, but not in any
controls. Four ECMO patients had focal findings (2 with left
hemiparesis and 2 with right hemiparesis). Mean full-scale
IQ of ECMO patients was 96 (SD, 10.6); mean full-scale IQ
was 115 in controls (SD, 15.6), p < 0.05. A total of 5776
of ECMO patients and 49% of controls with normal IQs
had 1 or more neuropsychological deficits (language, memory, visual perception, visual motor integration, executive
functioning and/or academic screening). In summary, most
ECMO patients appear to have normal global function at 5
years of age; the incidence of major handicap is 15Tt; and
focal neurological deficits are rare.
410. The Monozygotic Preterm T w i n Weighing Less
T h a n 1,250 Grams Is at Increased Risk for Severe
Neurological Injury
Jej,frty Perlman and R. Sue Broyfes, DalluJ. T X
Increasing evidence indicates that twins contribute substantially to neonatal mortality and long-term neurological morbidity. Potential mechanisms for brain injury include the
twin-to-twin transfusion syndrome and a fetal-disruptive syndrome secondary to the death of a co-twin. We hypothesized
that the preterm Mz twin set, because of vascular anastomosis, would be at increased risk for brain injury, compared to
the dizygotic (Dz) twin set or singletons weighing less than
1,250 gm. Zygosity was determined by placental report. Between January 1992 and December 1993, 23 sets of twins
were studied. A total of 12 were Mz of birth weight (BW)
955 gm, gestational age (GA) 28 weeks. Of 24, 11 (45%)
died, i.e., in utero (n = 1) (with holoprosencephaly), at birth
(n = 2) (both with severe cystic encephalomalacia), postnatal
(n = 8). Severe intraventricular hemorrhage (IVH) (i.e.,
grade 111 2 intraparenchymal echogenicity) developed in 7
(33%,), with onset ranging from 12 to 72 hours. Of 7 infants
with severe IVH, 6 died. O n e infant whose co-twin died in
utero had loss of cerebellar hemisphere noted at birth. One
infant developed moderate ventriculomegaly without IVH.
Eleven of the twin sets were Dz of BW 323 gm, G A 27
weeks. Of 22, 4 (18%) died (all postnatal). Severe IVH developed in 3 of 22 (lo%,)(2 of 3 with severe IVH died).
During the concurrent period, severe I V H developed in 31
of 258 (12%) weighing less than 1,250 gm, specifically in
17% of infants weighing less than 1,000 gm. Singletons with
severe IVH were of comparable BW, but lesser GA, i.e., 26
weeks ( p < 0.05). At follow-up ranging from 6 to 15 months,
in Mz infants, 3 had severe developmental delay, 1 had se-
488 Annals of Neurology Vol 36 No 3 September 1994
vere hearing loss, and 3 were normal; in 12 Dz infants, 4
had mild developmental delay, 1 was blind, and 7 were normal. These data indicate the Mz preterm twin is at increased
risk for brain injury, which contributes substantially to neonatal mortality and long-term morbidity. The preterm Dz twin
appears to be at comparable risk for severe brain injury as
singletons weighing less than 1,250 gm. An increase in Mz
preterm twin survival will likely contribute to more children
with cerebral palsy.
41 1. Incidence a n d Management of Posthemorrhagic
Hydrocephalus i n Premature Newborns
Adnan Y . Manzur, Brian A . Lupton. Elke H . Roland,
Paul Steinbok. and Alan Hill, Vancouver, British Columbia.
Canada
Optimal management of posthemorrhagic hydrocephalus
( P H H ) following intraventricular hemorrhage (IVH) has not
been defined. We report trends in incidence and management of P H H during the last decade. W e reviewed the records of premature newborns with IVH (body weight <1,500
gm) admitted between 1783 and 1773 (N= 424). Diagnosis
of P H H was based on rapid increase in head circumference
or ventriculomegaly on cranial ultrasonography, associated
with clinical signs of raised intracranial pressure. Of 424 infants with IVH, 42 developed P H H (7.7%) (mean age of
onset, 14 days; range, 2-85 days). The yearly incidence of
IVH (excluding germinal matrix hemorrhage alone) decreased from 2 1 % to 8%. The incidence of P H H increased
from l O q , to 16g in infants with IVH. Management of
P H H is summarized below.
Complete clinical, HUS, and follow-up data were available
for 295 outborn preemies (168 boys, 127 girls; mean EGA,
30 weeks) enrolled from January 1984 to December 1786.
A subset of 101 premature babies had detailed, semiquantitative serial EEGs at mean postnatal ages 7, 15, and 25 days.
There was no difference in these 101 patients with EEGs
compared to the 174 without EEGs with respect to their
IVH grades. However, those with EEGs were significantly
younger and had more frequent clinical diagnoses of asphyxia, coma, inactivity, and seizures. T h e survival rate in
the EEG subset (67 of 101; 68%) was significantly lower
than the non-EEG group (168 of 174; 87%*)( p < 0.0005).
Measurements of the duration of the interburst interval (IBI)
were performed on the 209 EEGs recorded from members
of the EEG subset. Measurements of the IBI durations were
summarized from a representative 10-minute segment of discontinuous EEG as “longest,” “mean,” and “median” IBIS.
All 3 summaries of IBIS at first measurement (mean age of
7 days), and in a repeated measures analysis using all available
repeats of EEG (maximum of 3 per patient), showed a significant relation between postconceptual age (PCA) and IBI
such that older PCA infants had briefer IBI durations than
younger ones. Furthermore, nonsurviving infants had longer
measures of IBI than survivors. Measures of IBI duration
were not related to I V H grade. Among survivors with good
outcome (i.e., normal development at 2-year follow-up),
there was a strong relationship between advancing PCA and
the expected shortening of IBI measures than among survivors with adverse outcome. A repeated measures analysis
based on serial EEG examinations performed at mean legal
ages of 7, 15, and 25 days showed a consistent relation between IBI and PCA and no relation to IVH grade. The IVH
P H H Stabilized
Age at Onset of Treatment
Treatment Modality
Mean
Range (days)
Serial lumbar punctures (n = 30)
Ventricular access device (n = 2 5 )
Ventriculoperitoneal shunt (n = 28)
24
13-60
14-71
3 1-205
33
28
These data demonstrate increased yearly incidence of
PHH, despite decrease in IVH. The low success rate of serial
lumbar punctures suggests initial use of a ventricular access
device for repeated cerebrospinal fluid drainage, and later
ventriculoperitoneal shunting, if necessary.
412. Survival Outcome Prediction by
Electroencephalogram and Intraventricdar
Hemorrhage Grade in Premature Infants
Robert R . Claniy, Henrietta Rosenberg, Judy Bernbaum.
Marsha Gerdes, Hee Jung Chung. John P. Temple,
Linda Corzoraii.JoAnn D’Agostino,Sharon Zirin.
Huaqing Zhao. and Atital Cnaan, Philadelphia. PA
We conducted a prospective study of survival outcome in
premature infants transferred to the Children’s Hospital of
Philadelphia. Survival outcome was examined as a function
of the patient’s clinical characteristics, I V H grade by cranial
ultrasonography, and serial EEG examinations. We hypothesized that the EEG examination, a sensitive measure of functional cortical integrity, may provide a more accurate prediction of prognosis than knowledge of IVH grade alone.
Number
4
7
28
Percent
13
28
100
grade was grouped as lout (grade 0 , 1, or 2 IVH) versus high
(grade 3 or 4 IVH) and was not associated significantly with
survival in either the entire group (N = 275) or the EEG
subset (n = 101). A logistic regression model showed that
survival was best predicted by the rank of the most abnormal
EEG (judged as normal or mildly, moderately, or markedly
abnormal) and PCA, with a positive predictive value of 77%
and a negative predictive value of 100%. Knowledge of the
IVH grouping did not improve predictive values. We conclude that EEG examinations and PCA in this high-risk patient population provide potentially useful information to
predict survival. (This study was funded in part by the United
Cerebral Palsy Research Foundation and the CRC of the
Children’s Hospital of Philadelphia.)
413. Frequent Deletions of the LISl G e n e in Classic
Lissencephal y
William B . Dobyns. Romeo Carrozzo. and David H . Ledbetter.
Minneapolis. M N . and Bethesda, M D
A gene on chromosome 17p associated with lissencephaly
(agyria-pachygyria) was recently cloned and named LIS 1
Program and Abstracts, Child Neurology Society 489
(Reiner et al, Nature 1993;364:717-721). We studied 38
patients with Miller-Dieker syndrome (MDS) and 59 patients
with isolated lissencephaly (ILS) using chromosome analysis, and fluorescence in situ hybridization (FISH) with 3
sets of overlapping cosmid probes from the 5' end, the middle, and the 3' end of the gene. Among the MDS patients,
cytogenetic analysis showed visible deletions or other rearrangements in 25 of 38 patients (66%), while the remainder were normal. FISH showed deletions in 24 of 26 patients
(92%) tested. Among ILS patients, deletions were found in
22 of 59 patients (37%) tested; but, some patients were
tested with only one or two probes. Deletions were found
in 11 of 25 patients (44%))tested with all three FISH probes.
Deletions of the 5' end of the gene were detected in 24 of
26 MDS patients, but in only 2 of 30 ILS patients tested.
We conclude that MDS results from large deletions of the
LlSl gene, particularly those involving the 5' end of the
gene. ILS results from smaller deletions of the LISl gene,
which rarely involve the 5' end, in at least 44% of patients.
We expect future studies to show deletions of the LISl gene
in well over half of all patients with classic, generalized lissencephaly.
414. Mutational Analysis in the Norrie Disease Gene:
A n Expanding Phenotype
Katherine B. Sims, Deborah Si-huback, Zheiig Y i Chen,
Ian W . Craig, and Xaiidra 0. Breakefeld, Boston, M A ,
and Oxford, UK
Norrie disease ( N D ) is an X-linked recessive disorder characterized by congenital blindness secondary to a retinal dysplasia, mental retardation, and a progressive sensorineural hearing loss. This disease is an excellent model for the molecular
genetic and biological study of a neurodevelopmental disorder whose defect is critical to early retinal development (ganglion cell aplasia), and where variable effect on cognitive
development and hearing are produced by disease gene mutation. To confirm the etiological role of a candidate gene
we isolated for Norrie disease, and to gain insight into the
regions of the predicted protein presumably critical to neurobiological function, we studied 30 kindred with Norrie disease. The entire coding region, as well as the 5' and 3' untranslated regions of the norrin mRNA, have been analyzed
by PCR-based SSCP and direct symmetric PCR sequencing
of genomic DNA. In addition to previously described submicroscopic deletions, we have identified 6 intragenic deletions
and 17 point mutations, including 1 expanded dinucleotide
repeat present in the untranslated first exon promoter region.
Mutations cluster in the coding region of the third exon,
which has apparent significant homology with 2 groups of
proteins, the immediate early genes CEF-10 and CYR-6, and
the 3' cysteine-rich domain of mucins. Each of these identified mutations is unique with the exception of 2 apparently
unrelated kindred, in whom the clinical phenotype is surprisingly disparate. Although the classic phenotype is considered
relatively rare, our mutational analysis has allowed expansion
of the recognized N D phenotype to include that of psychotic
mental retardation, depression, variable degree of visual loss,
and recognition of clinical expression in female carriers.
Identification of the disease-associated mutation in greater
than 709; of N D kindred tested to date makes available
D N A diagnostic testing for prenatal and carrier analysis as
well as diagnostic confirmation.
415. Microphthalmia w i t h Linear Skin Defects
Syndrome: Characterization of the Critical Region
and Isolation of Expressed Sequences
Laura Schaefer, Martin C . Wfapenaar, Andrea Ballabia.
and Huda Y. Zoghbi. Houston. T X
Microphthalmia with linear skin defects syndrome (MLS) is
an X-linked male-lethal disorder characterized by abnormalities in the development of the brain, skin, and eye. Features
include microphthalmia, linear skin defects, agenesis of the
corpus callosum, retinal abnormalities, mental retardation,
and skeletal abnormalities. Some of these features are observed in two other X-linked male-lethal disorders, Aicardi's
and Goltz syndromes. The overlap in the phenotype suggests
that the same gene or genes are involved in all three disorders. Patients with MLS have X chromosome rearrangements
leading to the loss of Xpter-Xp22. Recently we defined the
MLS critical region through analysis of hybrid cell lines from
17 female patients who showed features of MLS and had
various deletion breakpoints in Xp22. Using D N A markers
in the Xp22 region, we developed a 1.7-Mb yeast artificial
chromosome (YAC) contig spanning the region. Long-range
restriction analysis of the YACs allowed us to estimate the
size of the MLS candidate region to be 450 to 550 kb. To
identify candidate genes in the critical region, two strategies
have been used. The first is aimed at isolating transcribed
portions of D N A (exons), and the second involves identifying sequences that are conserved through evolution, and
are thus likely to code for functional genes. Using the exon
trapping method, 54 putative exons have been isolated and
are currently being characterized to determine the genes
from which they derive. In addition, an evolutionarily conserved sequence has been identified within the critical region
and has been used to isolate several overlapping cDNAs
from a human embryo library. Northern analysis of this gene
shows expression of a 5.2-kb transcript in all tissues examined. Sequence analysis revealed a 7 7 7 base-pair open reading frame encoding a putative 258 amino acid protein. This
gene is currently being analyzed as a possible candidate for
MLS and Aicardi's and Goltz syndromes.
416. Congenital Fibrosis of the Extraocular Muscles
Maps to the Centromeric Region of Chromosome 12
i n Multiple Families
Elizabeth C. Engle, Linda A. Specht, Louis M . Kunkel,
and Alan H . Beggs. Boston, M A
Congenital fibrosis of the extraocular muscles (CFEOM) is
an autosomal dominant, ocular disorder characterized by congenital, nonprogressive, bilateral ptosis and external ophthalmoplegia, with a compensatory backward tilt of the head.
Due to tissue specificity, large family sizes, and clear-cut pattern of inheritance, CFEOM is an ideal candidate to be studied at the molecular genetic level. Elucidation of the abnormal gene and its product will provide insight into the
development and biology of extraocular muscles and may
help to explain the basis of selectivity of muscle involvement
in neuromuscular disorders. We report linkage of this disorder in two unrelated families to markers in the centromeric
region of human chromosome 12. D12S59 does not recombine with the disease, giving a two-point lod score of 12.5
(0 = 0.00). D12S87 and GATA5A09 flank the CFEOM
locus with two-point lod scores of 8.9 (0 = 0.03) and 9.7
(0 = 0.021, respectively, defining a region of 3.7 cm. These
data establish a map location for CFEOM. Through multiple
collaborations, we are currently obtaining blood samples
from over 20 additional families to further define the genetic
490 Annals of Neurology Vol 36 No 3 September 1994
homogeneity/heterogeneity of the disorder and to decrease
the interval within which the CFEOM gene is located.
417. Pyruvate Dehydrogenase Deficiency: Molecular
Mechanisms Contributing to Phenotypic
Heterogeneity
Tatsuya Fujii, Marcela Garcia-Aharez, Kwan-Fu Sheu.
Pamela Kranz-Eble, and Dawy/ C . De Vivo. Neui York. NY
Phenotypic heterogeneity is common with pyruvate dehydrogenase complex (PDC) deficiency. We have investigated 7
patients (5 boys) with PDC deficiency caused by PDH-E,
a-subunit mutations. Three different phenotypes were evident in this group: congenital lactic acidosis and early death
( 5 patients); recurrent ataxia, weakness, and cramps (1 patient); and chronic progressive spinocerebellar ataxia with
ophthalmoplegia (1 patient). Seven different mutations ( 5 being novel) were found, all located in the downscream region
involving exons 10 or 11. Four patients had insertions, 2 had
point mutations, and 1 had a microdeletion. The El a-subunit
and El P-subunit were deficient by immunoblot analysis in
every patient. Two patients with gene insertion showed altered electrophoretic mobility of the residual El a-subunit.
Pulse-labeling studies demonstrated normal synthesis of the
mutant E l a-subunit in every patient. Posttranslational degradation was accelerated (48 hours). The coordinate posttranslational degradation of the El @-subunitwas more variable,
with a normal amount of residual subunit at 96 hours in 1
patient. This finding indicates that the E, P-subunit deficiency
is secondary to the primary E l a-subunit gene mutation; and
the rate of El 6-subunit posttranslational degradation is determined by the nature of the mutation and the resulting instability of the E l a-subunit. This observation provides insight
into a mechanism contributing to phenotypic heterogeneity
in this X-linked disorder. (Supported in part by the Colleen
Giblin Foundation for Pediatric Neurology Research and
Sigma-Tau Pharmaceuticals, Inc.)
418. Glucose Transporter Protein Deficiency: A n
Emerging Syndrome with Therapeutic Implications
Duwyl C . De Vico. Christopher Burke, RoJ.aria Trifletti,
Francis Filoux. Joseph Dooley. Geojjrej Shewood.
Marcela Garciu-Aharez, and Sami Harik. New York, N Y
In 1991, we described 2 children with defective glucose
transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay
( N Engl J Med 1991;325:703-709). We have evaluated 7
additional children with this syndrome. The 9 patients (6
boys, 3 girls) ranged in age from 2 to 20 years and had
varying degrees of psychomotor retardation. Seizures were
present in every case and responded promptly to the ketogenic diet. The electroencephalograms frequently were normal, and neuroimaging was unremarkable. The CSF glucose
values (30.6
2.7 mg/dl), CSF/blood glucose ratios (0.33
2 0.03), and CSF lactate values (0.71
0.11 mM/L) were
significantly lower in the group, compared to data from a
population of patients evaluated for other neurological conditions. The dominant clinical features include infantile-onset
seizures, delayed motor and mental development, developmental clumsiness, impaired language and behavioral skills,
and inconstant deceleration of head growth with acquired
microcephaly. Erythrocyte uptake rates of glucose in vitro
were approximately 50’2 of patients’ values in all cases studied. Parents’ clinical and laboratory findings were normal, and
no family had more than 1 affected child. These observations
suggest that the condition represents a spontaneous muta-
*
*
tion, and patients are symptomatic heterozygotes. The condition is partly treatable with a ketogenic diet, and diagnosis
requires measurement of CSF metabolites. A lumbar puncture is recommended to evaluate infantile-onset seizures of
undetermined etiology. (Supported in part by the Colleen
Giblin Foundation for Pediatric Neurology Research.)
419. Positive Neuropsychological Outcome After Bone
Marrow Transplantation in Hurler Syndrome
Elsa G . Shapiro, Lawrence A . Lockman, Michael J . Bulthazor.
Chester B. Whitley, and William Krizit, from the Storage
Disease Collaborative Study Group, Minneapolis, M N
Bone marrow transplantation (BMT) alters the natural course
of Hurler syndrome (MPS-I). Preservation of neurological
function is one potential benefit of the procedure. Of 53
transplanted and engrafted children with MPS-I from our
database (pacients from institutions participating in the Consortium to Study the Value of Bone Marrow Trarisplantacion
for Storage Diseases), a total of 20 children (Set-T) were
selected for study who had an IQ of 70 or greater at BMT
and at least 1 year follow-up. Only 12 of the children (Set-Y)
met our current criterion of transplant age 24 months or
younger. The older 8 patients (Set-0) were transplanted
between ages 24 and 36 months. Donors included HLAand related donors
identical siblings (7); unrelated donors (9);
(4).At entry, the Bayley Scales of Mental Development
(BSMD) was administered to all patients. The mean I Q was
87 (SD = 11) for Set-T and 89 (SD = 12) for Set-Y. Mean
age at transplant was 22 months (SD = 9)for Set-T and 16
months (SD = 6 ) for Set-Y. At follow-up, either the BSMD
or Stanford Binec Intelligence Composite Score, Wechsler
Preschool and Primary Scales of Intelligence Full-Scale IQ, or
McCarthy General Cognitive Index was used. Mean length of
follow-up was 38 months ( S D = 27) for Set-T and 28
months (SD = 14) for Set-Y. Six patients were considered
failures on the basis of poor intellectual outcome; in 4 patients, 1Q scores dropped below 50, and 2 patients were
untestable. In these 6 failures, 4 were in Set-0. Overall, 14
of 20 (70%) Set-T patients and 10 of 12 ( 8 3 % ) of Set-Y
patients had good intellectual outcome and were considered
successes. The mean I Q at follow-up was 75 (SD = 18) for
Set-T and 79 (SD = 13) for Set-Y. For children in Set-0,
the mean I Q at follow-up was 62. For the children in Set-Y,
the I Q decrement was 5.6 points per year (SD = 7.5). This
decrement reflects slowing of skill acquisition, rather than
loss of abilities. We conclude that for MPS-I patients transplanted at under 24 months of age with an IQ of 70 or
greater, neuropsychological function is preserved after BMT.
420. Transplantation of P-Glucuronidase-expressing
Immortalized Neural Progenitors for G e n e
Transfer into t h e Central Nervous System of the
Mucopolysaccaridosis VII Mouse: A Prototype of a
Genetic Neurovisceral Lysosomal Storage Disease
Euan Y . Snyder, Rosanne M . Taylor, and John H . Wolfe,
Boston, MA, and Philadelphiu. PA
The C17-2 multipotent immortalized neural progenitor cell
line has been demonstrated previously by us to engraft and
participate in development of the mouse central nervous system (CNS) in a nontumorigenic, cytoarchitecturally appropriate manner. Furthermore, engrafted cells could stably and
robustly express an exogenous reporter gene (lurz).These
data suggested that using such immortalized progenitors as
transduction agents for exogenous gene products as integral
members of the C N S cytoarchitecture may be feasible for
Program and Abstracts, Child Neurology Society 491
clinical and research applications. The MPS VII mouse,
which lacks the secreted enzyme GUSB, is an ideal model
for neurovisceral lysosomal storage diseases where a single
gene defect has been defined and where CNS manifestations
remain prominent and insignificantly influenced by peripheral therapy. W e report diffuse integration within the MPS
VII mouse brain of C17-2 cells expressing GUSB. W e
developed techniques for diffuse engraftment of GUSBexpressing cells throughout the neuroaxis of newborn mutants. At maturity, recipient brains were analyzed for lac2
and GUSB expression, GUSB enzymatic activity, and reduction in lysosomal storage in neural tissue. A total of 93% of
transplanted MPS VII mutants successfully engrafted, and,
of animals successfully engrafted, all had evidence of GUSB
activity diffusely throughout the brain. In all animals, activity
was at least 2 to 12% of normal levels in various regions,
and, in some regions of some animals, at virtually carrier
levels (-40% of normal). Engraftment and expression could
be detected at least 8 months posttransplant. These enzyme
levels were sufficient to decrease or forestall accumulation of
lysosomal storage in neural tissue. Because the blood-brain
barrier may impose restrictions to entry of enzyme supplied
peripherally (either directly or through genetically engineered somatic or bone marrow cells), and because bone
marrow transplantation entails irradiation, which may be inimical to developing CNS, the approach of transplanting neural precursors constituitively secreting missing gene products,
or genetically engineered to do so, may provide an adjunctive
strategy for sustained therapy of the C N S manifestations of
other neurovisceral diseases. Furthermore, this study provides a paradigm for using transplantation of immortalized
neural progenitors for the transfer of other types of exogenous genes or factors into the CNS.
421. New Diagnostic Screening Test for Neuronal
Ceroid Lipofuscinoses Patients
K. E. Wisnieuaki. W . Kanmarski, A . A . Golabek.
and E. Kida, Staten Island. N Y
Subunit c of mitochondrial ATP synthase is a component of
the lysosomal storage material in the brain and other tissues
of various forms of NCL, except for infantile neuronal ceroid
lipofuscinoses (INCL). In searching for an easily available
diagnostic test for NCL using Western blot analysis and
ELISA technique, we screened urine from 8 late infantile
neuronal ceroid lipofuscinoses (LINCL), 12 juvenile neuronal ceroid lipofuscinoses (JNCL), 8 obligate heterozygotes,
and 16 control cases for the presence of subunit c. W e have
found significantly higher levels of subunit c in the urine of
LINCL and some JNCL patients (Wisniewski et al, 1994, in
press). To develop a new diagnostic test for NCL, we have
studied urine samples from 20 LINCL, 3 INCL, 17 JNCL,
30 heterozygotes, and 70 controls by modified blotting procedure. Samples from patients with adult form of NCL were
not available. The rapid blotting technique used, providing
results within hours, confirmed our previously obtained data.
This rapid technique represents a new diagnostic screening
test for NCL using noninvasive, readily available material.
422. Molecular Genetics of Adrenoleukodystrophy
Fernando Kok. Syliiia Neirniann, Siqun Zheng. He-Ming Wei.
James Bergin, Hugo Moser. and Kirby Smith. Baltimore, M D
Adrenoleukodystrophy (ALD) is an X-linked disorder characterized by deficient peroxisomal metabolism of very long
chain fatty acids (VLCFA) and reduced activity of VLCFA-
492
Annals of Neurology
CoA ligase. The most frequent clinical manifestation of ALD
is a generalized and rapidly progressive demyelination of the
brain, associated with perivascular inflammation. A putative
gene for ALD (ALDP) recently was isolated that, surprisingly, codes for a protein that belongs to a family of transmembrane transporters regulated or activated by adenosine
triphosphate. It appears to be a half-transporter, with a coding sequence of 2238 base pairs (bp). We have assayed for
mutations in the putative ALDP gene in ALD patients. We
detected large deletion in the carboxyl terminal portion of
the gene in 4 of 100 patients. Twenty-three patients with
intact ALDP genes were surveyed for mutations by singlestrand conformation polymorphism (SSCP) procedures.
SSCP variants were detected in 16, while 7 were normal for
all exons and the promoter region. No variants were found
in 28 normal ALD genes. Mutations within the variant SSCP
fragments were determined by D N A sequence analysis. The
mutations were distributed throughout the gene; most were
missense mutation, except for an unusual cluster of small
insertions and deletions in the 96 bp exon 5 detected in 6
patients. These data strongly support the notion that mutations in this putative ALD gene result in ALD. The possibility
that VLCFA-CoA ligase mutations can cause ALD awaits the
completion of D N A sequence analysis of the ALDP genes
that appear normal by SSCP.
423. Biochemical a n d Clinical Distinction Between
Peroxisomal Bifunctional Enzyme Deficiency a n d
Acyl-CoA Oxidase Deficiency
P . A . Watkins, M . C . McGuinness, G. V . Raymond,
M. Rasmussen, A. B. Moser. and H . W. Moser,
Baltimore, M D
The clinical distinction between patients who have a disorder
of peroxisome biogenesis (e.g., Zellweger syndrome) and the
10% of these patients who, in actuality, have a single-enzyme
defect in the peroxisomal fatty acid P-oxidation pathway, can
be difficult. Peroxisomal P-oxidation requires three enzymes:
Acyl-CoA oxidase (AOx), bifunctional enzyme (Bif), and 3oxoacyl-CoA thiolase. W e studied 29 patients suspected of
being deficient in one of these enzymes. Using complementation analysis, 24 were found to be Bif-deficient, and 5 had
AOx deficiency. Biochemical abnormalities (e.g., elevated
plasma very long chain fatty acid [VLCFA] levels and impaired fibroblast VLCFA P-oxidation) were more severe in
Bif-deficient patients than in those patients with AOx deficiency. Similarly, the clinical course in Bif deficiency (profound hypotonia, neonatal seizures, dysmorphic features, age
at death -9 months) was more severe than in AOx deficiency
(moderate hypotonia, seizures after neonatal period, no
dysmorphism, development of a leukodystrophy, age at
death -4 years). Based on these findings, accurate diagnosis
of Bif and AOx deficiency is thus possible, improving the
reliability of prenatal diagnosis and consequent genetic counseling. (Supported in part by USPHS grant RR00052.)
424. Fatty Acid Oxidation Abnormalities in
Childhood-Onset Spinal Muscular Atrophy: Primary
or Secondary Defect(s)?
lngrid Tein. Awil E. Sloane. Elizabeth Donner.
Dennis C . Lehotay. David S. Mil(ington.
and Richard 1. Kelhy, Toronto. Ontario. Canada.
Durham, N C . and Bahimore. M D
Evidence is emerging that there are abnormalities in fatty
acid oxidation (FAO) in spinal muscular atrophy (SMA) that
Vol 36 N o 3 September 1994
may respond to F A 0 dietary therapy. The purpose of this
study was to further identify and quantify these abnormalities, correlate these with disease severity, and identify specific
underlying defect(s). We studied 15 children with SMA (3,
type I; 8, type 11; 4, type 111) who were classified according
to maximum function attained: SMA I, never sat unsupported; SMA 11, sat unsupported, but never stood unaided;
SMA 111, stood unaided and walked at some time. The serum
carnitine totalIfree concentrations demonstrated a tendency
toward an increased esterified fraction ranging from 35 to
5897 of total carnitine (normal, 2 5 4 0 % of total) in younger
children with SMA I and SMA 11. Over 23 months of age
at the time of sampling, the remaining SMA I1 and SMA I11
patients had normal esterified carnitine levels. Urinary organic acid analysis demonstrated a range of abnormalities including mild to moderate medium-chain dicarboxylicaciduria
(DCA) in SMA I patients and normal to moderate increases
in short-chain and medium-chain organic acids in SMA I1
patients. In the SMA 111 group, the organic acids were
normal except for a mild medium-chain DCA in one patient. W e also measured muscle intramitochondrial P-oxidation in 5 children (2 SMA I, 2 SMA 11, and 1 SMA 111)
and found a significant reduction in the activities of shortchain L-3-hydroxyacyl-CoA dehydrogenase, long-chain L-3hydroxyacyl-CoA dehydrogenase, acetoacetyl-CoA thiolase
and 3-ketoacyl CoA thiolase, yet normal crotonase activity.
Most strikingly, there was a marked increase (three- to fivefold) in the activity ratios of crotonase to L-3-hydroxyacylCoA dehydrogenase and thiolase activities with both the
short- and long-chain substrates. The organic acid abnormalities combined with documented abnormalities in the L-3hydroxyacyl-CoA dehydrogenase and thiolase activities suggest a defect in a mitochondria1 multifunctional enzyme, such
as the trifunctional enzyme (Hashimoto et al, 1992). The
mechanism by which an abnormality of F A 0 may cause the
combined muscle and neuronal picture is unknown, but
could include altered bioenergetics in both, abnormal muscle
nutrition, retrograde axoplasmic transport of toxic muscle
metabolites to motor neurons, limited flow of trophic factors
to anterior horn cells and muscle, local toxic effects of fatty
acids, or abnormal mono- and dicarboxylic fatty acid composition of complex lipids. The F A 0 abnormalities may be primary or secondary.
425. H u m a n Homologues of the M 6 Neuronal
Proteins: Definition of the PLPIDM20 Gene Family
V. Narayanan. B. Ripepi, S. Olinsky. A . DeKosky, Y. Yan,
and C . Lagenaur, Pittsburgh. P A
As part of a program to identify neuronal molecules that
are of importance in early central nervous system (CNS)
developmental events, such as migration and neurite outgrowth, one of us (Lagenaur et al, J Neurobiol 1992;23:7182) had prepared monoclonal antibodies against partially purified membrane fractions of mouse brain homogenates. O n e
of these antibodies, designated M6, recognized a 35 kDa
glycoprotein distributed throughout the CNS, found primarily on the surface of neuronal cell bodies and their nonmyelinated processes, as well as the choroid plexus and proximal
renal tubules. The M6 antibody interferes with neurite outgrowth when added to cultured cerebellar neurons. We used
an expression cloning approach to identify 2 murine cDNAs
(M6A and M6B) that encoded proteins, at least 1 of which
corresponds to the purified M6 antigen (Yan et al, Neuron
1993;11:423-431). In siru hybridization studies suggest that
the M6A mRNA is found primarily in neurons, whereas the
M6B mRNA is found in white matter tracts, as well. These
cDNAs are highly homologous to the myelin proteolipid
protein, PLP/DM2O. This result, together with results of a
homology screening approach used by Colman et al (Neuron
1993;11:433-448), has led to the realization that PLPIDM20
belongs to a large gene family, whose ancestor may have
been a pore-forming protein. We have used the murine M6A
and M6B cDNAs to isolate several corresponding human
cDNAs from a human spinal cord cDNA library. The sequences of these cDNAs, as well as their map position within
the human genome, is being determined. This will allow a
better definition of the extent of the PLP/DM20 gene family.
Study of these homologues of PLP that are expressed in
neurons may lead to novel ideas about PLP and M6 protein
function.
426. Multiple Guidance Cues Are Involved i n the
Segregation of Pioneering Pathways i n the Cortex and
Internal Capsule: Evidence from Reeler
A. R. Bicknese, W . Wang. and A. Sharma. Stony Brook, N Y
W e compared pathway formation during cortical development in normal and Reeler mutant mice using the carbocyanine dyes Dil and DiA to trace axons in fixed tissue, and
immunolabeling with antibodies to chondroitin sulfate proteoglycans (CSPG) to identify the extracellular matrix
(ECM). By embryonic day (E)11, neurons begin extending
axons from the preplate zone (PPZ), which has intense CSPG
labeling. By E12, cortical plate (CP) neurons begin splitting
the PPZ into the marginal zone (MZ) and subplate (SP),
which retain dense CSPG labeling. C P axons traverse the SP,
turn and then obliquely cross the intermediate zone (IZ),
exiting the cortex close to the VZ. Reelers retain the PPZ,
and their IZ and C P are mixed in one layer. Axons of “CP’
neurons extend obliquely across this layer and exit near the
VZ. In both normal and Reeler, pioneer efferents hesitate in
a zone above the forming striatum. If later arriving (E12-13)
thalamic axons encounter the waiting cfferents, they fasciculate. The time period of co-extension is brief. In normal neocortex, thalamic axons selectively extend within the subplate
and its CSPG. As the striatum matures, thalamic axons extend laterally around expanding striatum, to enter the subplate and its CSPG. C P axons continue to exit the cortex
near the VZ. Thus the two systems are physically separated
and axons do not encounter each other after E14. Reeler E l 4
“CP’ develops streaks of CSPG intermingled with efferent
neurons and axons, allowing Reeler thalamic afferents to encounter cortical axons. Thalamic axons selectively extend
within the streaks of CSPG, rarely fasciculating with cortical
axons. Our evidence indicates that if thalamic and cortical
axons guide each other in development, it occurs in a limited
number of axons. Multiple guidance cues produce pathway
segregation in the forming cortex and internal capsule.
427. Ontogenetic Changes in N-Type Calcium
Channels of H u m a n Cerebellum, Hippocampus, and
Frontal Cortex
FranciJ M . Filloux. J . Michael Mclntosh.
Baldomero M . Olitiera, and Kimberley R. Ward.
Salt Lake City, U T
N-type presynaptic calcium channels modulate neuronal migration, synaptogenesis, and growth-cone function. Furthermore, we have recently described substantive alterations in
N-type channel expression occurring during brain development in the rat (Filloux et al, Dev Brain Res 1994;78:131-
Program and Abstracts, Child Neurology Society 493
136). W e have now applied similar receptor autoradiographic
techniques to describe ontogenetic changes in N-type calcium channels in the human brain. The brains of l l infants
(aged 1-6 months) and 8 adults (aged 26-66 years) were
obtained within 24 hours of death; samples were frozen on
dry ice and stored at - 70°C. Slide-mounted tissue sections,
10-pm thick, from the lateral cerebellar hemisphere, the hippocampal region, and the prefrontal cortex were labeled with
the selective N-channel antagonist [ ‘”Ilo-conotoxin GVIA
(“GVIA). Autoradiograms generated from these labeled sections were quantitated using image analysis. The qualitative
pattern of ‘GVIA binding in cerebellum does not differ between the 2 age groups: Binding is denser in the molecular
layer than in the granular cell layer, and binding in the white
matter approaches background. The pattern of N-channel
expression in frontal cortex, however, differs markedly between infant and adult brains. Specifically, in the mature cerebral cortex, binding in gray matter is much higher than in
white matter (1.69 -+ 0.128 vs 0.25 2 0.043 fmollmg tissue). In contrast, in the immature cortex, discrimination between gray and white matter is difficult (1.83 t 0.126 vs
1.60 ? 0.130 fmol/mg tissue). Consequently, N channels
appear to be transiently expressed in the cerebrocortical
white matter. Similar transient N-channel binding is evident
in the white matter of the hippocampal region. These findings
indicate that the expression of N-type calcium channels
changes as a function of development in the human. The
temporary appearance of N channels in forebrain white matter in early infancy may correspond to a transitory role for
such channels in certain neurodevelopmental phenomena.
428. ACPD-induced Long-Term Depression i n
Immature CA1 Requires Both m G l u R and N M D A R
Activation
Barbara L. Trommer. Linda S . Lundin. N. Trararse Slater.
Jeffrey W . Cozzens. and Joseph F . Pasternak. Evanston. IL
Long-term depression (LTD), an activity-dependent decrease
in synaptic efficacy, is a candidate mechanism by which an
excess of neuronal elements and synaptic connections may
be eliminated during development. In immature rat hippocampal area CA1, activation of the metabotropic glutamate
receptor (mGluR) with bath-applied lS,3R-ACPD (10 bM,
20 min) induces LTD, and this effect is blocked by the
mGluR antagonist MCPG (500 pM). To investigate the
mechanism underlying mGluR-induced LTD, we studied
the effects of N-methyI-L>-aspartate receptor (NMDAR)
blockade on ACPD-induced LTD. Recordings of extracellular field EPSP were made in the striatum radiatum of CA1
in response to stimulation of the Schaffer collateral path in
hippocampal slices from 9- to 12-day-old rats (n = 13). In
the presence of the NMDAR antagonist AP5 (20 pM),bath
application of ACPD (10 p.M, 20 min) failed to produce
LTD, although a reversible depression ( - 187%) of EPSP
slope was seen in 8 slices. After ACPD wash, EPSP slope
remained near baseline (n = 8) or showed a persistent increase ( + 27%,, n = 5 ) . With subsequent AP5 wash (20, 60,
or 120 minutes following ACPD wash), a persistent decrease
( - 20%) in EPSP slope occurred in all slices. Subsequent
bath application of ACPD ( 10 p M , 20 min) produced a further decrease in EPSP slope (-25?4), whereas subsequent
tetanus reversed L I D and/or produced LTP ( + 3 1%). Our
results indicate that the modulation of synaptic neurotransmission by mGluR activation is complex. Potentiation of
neurotransmission, the dominant effect in mature CA1, is
seen in immature CA1 only with NMDAR blockade; when
both mGluR and NMDAR are active in immature CAI,
LTD is produced. Moreover, the depression of synaptic activity in immature CA1 consists of 2 components: one that is
reversible and depends only on m G h R activation, and a second that is long-lasting and requires concomitant, but not
necessarily coincident, NMDAR activation. Finally, it appears that mGluR activation alone creates a “depressionprimed” state that is subsequently expressed as LTD after
return of the NMDAR-associated current produced by background synaptic activity. It is likely that this “priming” effect
results from activation of second messenger systems by
mGluR, and the consequent production of a long-lasting
change in the intracellular environment.
429. Adverse Effects of Excitatory Amino Antagonists
o n the Developing Brain
Gregovy L. Holmes, Suzanne Werner. Zhao L h ,
Lionel Carmant. and Mohamad Mzkati. Boston, MA
Because of the role of excitatory amino acids (EAAs) in epileptogenesis and seizure-induced brain damage, EAA antagonists are now being considered as possible therapy for seizures. However, during development, EAAs play a pivotal
role in learning, memory, and brain plasticity. To evaluate
the long-term effects of a short course of EAA antagonists
on the developing brain, a non-N-methyhaspartate (nonNMDA) antagonist, N B Q X , or NMDA antagonist, MK801, was administered over 7 days by osmotic pumps stereotaxically implanted into the lateral ventricles in normal
20-day-old rats. Control rats received osmotic pumps and
were administered the vehicle. Following surgery, rats were
intermittently videotaped to monitor spontaneous seizures.
One month later, the N B Q X (n = 23), MK-801 ( n = lo),
and controls ( n = 18) underwent a series of behavioral studies: handling test, open-field, and Morris water maze. Finally,
flurothyl inhalation was used to test seizure susceptibility. A
high mortality rate was noted in both the N B Q X (65%) and
MK-801 (5457) when compared to controls (,27%). Spontaneous seizures were seen in both the N B Q X and MK-801
groups. In the open field, both the N B Q X and MK-80 1 rats
were significantly more active than controls ( p = 0.049).
While the N B Q X group was slower to find the escape platform than the controls on all 4 days of testing, this difference
was not significant. No differences in handling test scores in
the 3 groups were noted. The NBQX, but not the MK-801,
group demonstrated an increased susceptibility to flurothylinduced seizures, with reduced latencies to seizure onset ( p
= 0.0049). Even when used for short periods of time, EAA
antagonists may have significant adverse effects on the developing brain. These detrimental effects must be considered
when designing strategies to treat seizures in the young child.
430. Phenobarbital Inhibits Dendritic Development in
Cultured Sympathetic Neurons
Michael B. Loegering and Mary I . Johnson. Trirson. AZ
Phenobarbital is utilized as an anticonvulsant in both pregnant mothers and neonates with seizures. Concern has been
raised, however, over potential adverse effects on the development of the nervous system. In this study, an in vitro
model of neuronal development is utilized by which dendritic
development can be analyzed separately from axonal growth.
Dissociated rat sympathetic neurons are plated in low density
onto glass coverslips. Schwann cells are allowed to proliferate
and induce dendrites to develop. Control cultures were
treated with defined medium. Treatment groups were exposed to 15 to 16 bg/ml of phenobarbital, beginning at 2 to
494 Annals of Neurology Vol 36 No 3 September 1994
3 days in vitro. In 4 experiments after 5 to 7 weeks, 50
to 80% of neurons in control cultures developed dendrites.
Phenobarbital at 30 pg/ml reduced the percentage of neurons with dendrites to 20 to 50% of the controls. The number of primary dendrites per neuron, the average length per
dendrite, and the total dendritic length per neuron were all
significantly reduced by 30 pg/ml ( p < 0.003 to < 0.0001).
At 60 kg/ml of phenobarbital, the neurons remained very
immature and extended only axons. Phenobarbital at 15 p.g/
ml had little effect. The number of neurons was reduced to
50% of control by 30 p.g/ml of phenobarbital ( p < 0.05)
and to less than 10% by 60 pg/ml. Schwann cell numbers
were also reduced. Our current hypothesis is that phenobarbital interferes with the normal interaction (cell adhesion or
trophic) between the neurons and their glia necessary for
neuronal survival, Schwann cell proliferation, and induction
of dendrites. (Supported by ADC 82-2689.)
43 1. Proliferative Behavior of Glial Cell Progenitors
in the Developing Cerebral Wall
T . Takahashi and Verne S . CauinesJ,Jr. Tokyo,Japan. and
Boston. M A
Neurons and glial cells of the neocortex and underlying cerebral wall arise from two distinct proliferative populations: the
pseudostratified ventricular epithelium, at the margin of the
ventricle (PVE, a source of the majority of neocortical neurons), and the secondary proliferative population (SPP, the
progenitor population of glial cells) (Takahashi T , Nowakowski RS, Caviness Jr VS, Cell cycle parameters and patterns
of nuclear movement in the neocortical proliferative zone of
the fetal mouse, J Neurosci 1993;13:820-833; Takahashi T ,
Nowakowski RS, Caviness Jr VS, Mode of cell proliferation
in the developing mouse neocortex, Proc Natl Acad Sci USA
1994;91:375-377). The SPP arises from the PVE and then
expands rapidly. After the completion of neuronogenesis
when the PVE is replaced by the nonproliferative ependymal
cell layer, the SPP becomes the only proliferative population
In the cerebral wall, retaining its proliferative activity life
long. We present here the first quantitative characterization
of 1. the size and distribution, 2. cell cycle parameters, and
3. the rate of cell production of the SPP of the cerebral wall.
The analysis is based upon double S-phase labeling paradigms, using both bromodeoxyuridine (BUdR) and jHthymidine (Takahashi et al, 1994), in the mouse cerebral wall
on embryonic days 14 to 16 (E14-E16), the earliest phase
of glial cell ontogeny in this species. From its earliest origin
between E l 3 and E14, the SPP is intermixed with the proliferative PVE and also with nonproliferative cells, including
postmitotic neurons, radial glial cells, and other cells of glial
lineage. The SPP becomes widely spread through the subcortical cerebral wall and increases nearly 6-fold within the 48hour experimental interval. In the course of the SPP expansion, the density of these cells remains relatively uniform
across the width of the subcortical cerebral wall, even as the
width of the wall expands. The cell cycle length of the SPP,
estimated by the labeled mitosis method with BUdR, is constant at 15 hours from E l 4 to El6. Thus, the SPP undergoes
3.2 cycles in the course of this 48-hour period. From these
observations, it may be estimated that between E l 4 and E l 6
only about 10% of daughter cells of the SPP leave the cell
cycle to differentiate into glial cells after each cell division,
whereas 90% continue to proliferate actively. This proliferative behavior assures the necessary massive expansion of the
SPP antecedent to the explosive diffusion of glial cells
through the neocortex and subjacent cerebral wall, which
occurs subsequent to the completion of neuronal migration.
432. H u m a n Oligodendrocytes Derive from Precursor
Cells Found Early in Prenatal Development
M. J . Rivkin. J . Flax. R. Osathaizoiidh.J . J . Volpe.
and L. Villa-Komaroff;Boston, M A
The predominant occurrence of periventricular leukomalacia
(PVL) in premature infants implies a developmentally dependent mechanism for this cerebral injury. Widespread reduction of oligodendrocyte number, but comparatively little necrosis, in PVL implies that oligodendroglial development
may be disrupted. Little inquiry has been made regarding
human oligodendroglial development. W e have successfully
established primary mixed glial cell cultures prepared from
individual fetal human brains (15-20 weeks gestation in age).
Cultures were maintained for as long as 3 months in either
10% fetal calf serum or serum-free chemically defined medium. Using morphological criteria and immunohistochemical techniques, we have identified the precursor cell for human oligodendrocytes ( 0 - 2 A cell) from developing human
fetal brain. This cell bears the bipolar morphology and
A2B5 immunoreactivity typical of the 0 - 2 A precursor cell.
As these cultures aged, cells possessing a stellate morphology
appeared, some of which stained with the 0 4 antibody, indicating cell differentiation committed to the oligodendroglial
lineage. At yet older culture age, highly arborized cells with
morphological characteristics typical of oligodendrocytes
were found that clearly harbored the 0 1 (GC) immunohistochemical marker, confirming more advanced oligodendroglial
identity. T o complement these observations, double immunofluorescent studies were performed on parietal sections
from human fetal brains, 19 to 20 gestational weeks in age.
Bipolar A2B5 +, multipolar A2B5'/04+, and arborized
A 2 B 5 - / O l C cells were found, thus confirming for the first
time the presence of oligodendrocyte maturation in human
fetal brain at this stage of prenatal development. Currently,
studies are being conducted to isolate human oligodendrocyte precursor cells and to identify conditions leading to cell
death or cell survival, respectively.
+
433. Platelet-activating Factor as a Retrograde
Messenger i n Hippocampal Excitatory Synaptic
Transmission
Gavy D. Clark. Ty Ovella. Rachel McAllister. Leo T . Happel.
Kiinio Kato. and Charles F . Zoruniski, N K UOrleans.
~
LA,and
S t Louis, M O
Platelet-activating factor (PAF) is a presynaptic facilitator of
excitatory synaptic transmission and is a candidate retrograde
messenger in hippocampal long-term potentiation. W e have
used patch clamp recording techniques in rat postnatal hippocampal culture to examine the effects of intracellular instillation of c-PAF ( 2 pM), a nonhydrolizable form of the PAF
molecule, upon miniature excitatory synaptic currents
(mepscs). Since mepscs are the result of spontaneous release
of excitatory transmitter from neighboring neurons, they are
influenced by presynaptic mechanisms. c-PAF instillation resulted in a 1,021 -t 72%' (mean ? SE) increase in the frequency of mepscs over that observed in other neurons in the
same or sister cultures (n = 10).This increase was noted to
develop over 1 to 2 minutes of recording in some cells, with
as much as a 507%' increase in frequency of mepscs from
the first 30-second epoch to the third 30-second epoch. FB0502, a PAF receptor antagonist, did block the observed
increase in frequency (n = 2). Voltage-dependent calcium
currents were recorded using the nystatin patch technique,
and no observed increase in current amplitude was noted.
Pertussis toxin (1.3 p.g/ml) was placed in cultures for 6 hours
prior to recording and 2 observations were made. First, there
Program and Abstracts, Child Neurology Society 495
was a paucity of mepscs over that observed in sister cultures
(0.55Isec ? 0.27 vs 8.8/sec _t 0.9; n = 5 pertussis vs 10
not pertussis); second, there was no PAF effect on mepscs.
These data support a role for PAF as a transynaptic modulator of excitatory synaptic transmission. PAF presynaptic receptor activation modulates mepscs via a pertussis toxin G ,
protein-mediated process.
434. Mechanism of ICAM-1 Up-Regulation in H u m a n
Brain Endothelial Cells
James E. Carroll, David C . Hess. Kenneth Buchanan.
and Mike McEachin, Augusta. G A
Intercellular adhesion molecule-1 (ICAM-I) mediates neutrophil infiltration into brain. We showed that hypoxia with
subsequent reoxygenation causes up-regulation of ICAM-1
in human brain endothelial cells (HBMEC) and that N-acetylr-cysteine (NAC), a free radical inhibitor and glutathione
donor, inhibits this up-regulation (Stroke, in press). Interleukin-lp (IL-1p) and tumor necrosis factor (TNF) also produce
up-regulation of ICAM-1 in HBMEC (Neurosci Lett 1994;
168:201-204). We hypothesized that low intracellular glutathione levels lead to up-regulation of ICAM-1 in cytokinemediated processes. Utilizing primary cultures of HBMEC
obtained from epilepsy surgery specimens, we examined
ICAM-I up-regulation as produced by T N F or IL-1p. The
cells were incubated with IL-lP or T N F (both 100 U/ml) in
combination with preincubations of NAC (20 mM), pyrrolidone dithiocarbamate (PDTC) (50 FM), which also increases
glutathione levels, or dimethylthiourea (DMTU) (10 mM),
which is a free radical scavenger, but does not affect glutathione metabolism. ICAM-1 mRNA was measured by Northern blots, and ICAM-1 protein was measured by ELISA.
PDTC completely blocked up-regulation of ICAM-1 mRNA
and reduced ICAM- 1 protein below basal levels. NAC produced little change, while DMTU actually enhanced ICAM-1
mRNA levels. These findings suggest that cytokines and
possibly hypoxia/reoxygenation
up-regulate ICAM-1
through a pathway mediated by decreased glutathione levels.
435. Efficacy of Chemotherapy for Children with
Newly Diagnosed Progressive Low-Grade Gliomas
Roger J . Packer, Jeffery C. Allen, Peter Phillips,
Regina Jakacki. Joann L. Ater, J . Russell Geyer,
Jonathan Finlay, H. Stacy Nichohon. Elizabeth Kurnynski,
James Boyett, and The Low Grade Glioma Studjl Group,
Washington, DC
Low-grade gliomas (LGGs), the most common tumors of
childhood, are often very extensive and not amenable to extensive resections, especially in young children. Due to the
potential long-term deleterious effects of radiotherapy, chemotherapy has been increasingly employed for subtotally resected LGGs, with variable results. In a multi-institution
study begun in 1988, 76 consecutive children with newly
diagnosed progressive LGGs were treated with carboplatin
and vincristine. Following a 10-week induction phase, ten
4-week cycles of maintenance chemotherapy were planned
in responding patients. Children were a median of 3.0 years
of age (mean, 3.5 years; range, 0.25-16 years); 25 were less
than 3 years and 6 were older than 7 years. Fifteen had
neurofibromatosis. Tumor location was the chiasm/hypothalamus in 55, the brainstem in 10, the cortex in 4, the leptomeninges in 4, and other sites in 3. In 70 patients evaluated
for response, 40 (57q))had measurable tumor shrinkage (22
with greater than 5076 shrinkage and 18 with 25-49%1
shrinkage); 27 (39%) had stable disease, and 3 progressed.
Of 40 responding patients, 15 had further tumor shrinkage
during maintenance. Objective responses were seen in brainstem, thalamic, cortical, and leptomeningeal lesions. The
majority of children with the diencephalic syndrome responded to treatment. Children with neurofibromatosis were
as likely to respond as those without. Age was not a determinant of response, as 13 of 24 patients less than 2 years had
an objective response, compared to 19 of 32 older children.
Progression-free survival at 1 year was 85 +- 5%,; at 2 years,
it was 76 t 8%. Thirty-one children are off all treatment
and are stable, 20 for more than 2 years. Thirteen children
developed progressive disease, 8 while on treatment and 5
off treatment. Therapy was well-tolerated except for treatment limiting allergy to carboplatin in 6 and overwhelming
sepsis (and death) in 1. Carboplatin and vincristine are very
effective in progressive LGGs and are associated with arrest
of progression in the majority of patients (96%), with objective shrinkage in nearly 60%. Therapy can successfully delay
the need for radiotherapy, even in children with nonchiasmatic (e.g., brainstem, cortical) lesions and in those with diencephalic syndrome, with many having a long-term response
to treatment.
436. Apoptosis Is t h e Mechanism of Neuronal Cell
Death and Retinal Degeneration i n Batten Disease
Rose-Mary N . Boustany. Steven C . Lane, and Wei-Hua Qian,
Durham, NC
The main features of the late infantile (LINCL) and the juvenile (JNCL) forms of neuronal ceroid lipofuscinosis, or Batten disease, are retinal degeneration, progressive neuronal
cell death, seizures, and, ultimately, death. We have established that apoptosis is the mechanism of retinal degeneration
and neuronal loss in these disorders. Brain cortex sections
obtained from LINCL and JNCL autopsies, as well as dog
and sheep models, stained positively with terminal deoxynucleotide transferase (TdT) to label free 3’-OH D N A ends
generated in the nuclei of apotosed cells due to intranucleosoma1 cleavage. Also, serum-starved fibroblast cell lines
treated with glucocorticoids showed the characteristic D N A
laddering, a hallmark of apoptosis. In addition, we demonstrated a threefold increase in thymidine release in LINCLand JNCL-derived lymphoblasts over control lymphoblasts.
We also demonstrated overexpression of the Bcl-2 protooncogene in those same brain sections by immunocytochemistry. This protooncogene, normally protective against
apoptosis in dividing cells, has an opposite effect when overexpressed in postmitotic cells such as neurons. These findings
strongly suggest that apoptosis is indeed the molecular process leading to this form of genetic death. Delineating its
specific pathways will elucidate mechanisms of cell death, in
general, and neurodegenerative disease, in particular. Targeted therapeutic intervention for Batten disease and other
neurodegenerative disorders to halt disease progression has
now become possible.
437. Near Infrared Spectroscopic Estimations of
Cerebral Blood Flow i n N e w b o r n Piglets
Jan Goddard-Finegold,Penelope T . Louis, Diana L. Rodriguez.
and Peter Rolf. Houston, T X , and Stoke-on-Trent, UK
We compared cerebral blood flow estimated using near infrared spectroscopy (NIRS) and a modification of the Fick principle to quantitations by radioactive microspheres (MS).
Piglets 1 to 2 days old were anesthetized and ventilated.
Catheters were placed into the aorta from a femoral artery
and into the left cardiac ventricle via the right carotid artery.
496 Annals of Neurology Vol 36 No 3 September 1994
The NIRS optodes were placed at the parietotemporal regions. Blood pressure and arterial blood gases were monitored, and a pulse oximeter was placed at the axilla. After
infusion of MS into the left ventricle, withdrawal of the reference sample, and replacement of blood, a modest decrease
in O2 saturation was instituted by a change in Fio, over 6 to
8 seconds. The changes in oxyhemoglobin and deoxyhemoglobin concentrations (mmol.cm/L) were recorded by NIRS.
Using centrally measured arterial hemoglobin (mmol/ml),
the measured interoptode distance (cm) and the pathlength
factor for preterm human infants (4.39), and correcting to per
100 gm tissue mass, flows were obtained by the following:
where K = 0.89. Results are shown in the Table.
SS
Hypovolemrd
Reflow Period 1 Reflow Period 2
MS
39 c 6
4 2 c 10
14
lr
27
2
NIRS
16
12
32 c 9
2 9
32
34
f
21
2
10
3
(allmllrnin/lOOgm)
(allml/rnin/lOOgm)
Five pigs were studied during steady state, hypovolemia, and
during two reflow periods. NIRS and MS flows were very
close during steady state and the first reflow period; during
hypovolemia, flows were more variable in both groups. During the second reflow period, there was not as close a correlation as during the first reflow period. The near infrared spectroscopic blood flows all changed in the same direction as
the microsphere quantitations. NIRS flows correlated best
with cortical flows quantitated by MS. We speculate that the
differences seen in the blood flows may have been due to
the modest differences in timing of the MS and NIRS flow
estimations. Future studies will utilize simultaneous Fio, increases, NIRS quantitations, and MS infusions. Nevertheless,
the NIRS estimations were well within the same range and
showed the same directional changes as those quantitated by
microspheres. (Support to J. G. F. from the United Cerebral
Palsy Foundation.)
438. Cerebral Ischemia Increases Nonheme Iron in
Brain Nuclear Fractions of Newborn Piglets
Lisa M. Adcock, Yoshiro Yamashita. Jan Goddzrd-Finegold,
and Charles V . Smith, Houston. TX
Studies on the mechanisms involved in the damaging effects
of ischemia and reflow in brain tissue indicate significant contributions from reactive oxygen species (Halliwell B, Oxidants and human disease: some new concepts, FASEB J
1987;1:358-364; Traystman RJ, Kirsch JR, Koehler RC,
Oxygen radical mechanisms of brain injury following ischemia and reperfusion, J Appl Physiol 1991;71:1185-1195;
Ayene IS, Dodia C, Fisher AB, Role of oxygen in oxidation
of lipid and protein during ischemialreperfusion in isolated
perfused rat lung, Arch Biochem Biophys 1992;296:183189);loss of homeostatic control of intracellular iron appears
to be a significant determinant of oxidant-mediated damage
(Babbs CF, Role of iron ions in the genesis of reperfusion
injury following successful cardiopulmonary resuscitation:
preliminary data and a biochemical hypothesis, Ann Emerg
Med 1985;14:777-783; Komara JS, Nayini NR, Bialick HA,
et al, Brain iron delocalization and lipid peroxidation following cardiac arrest, Ann Emerg Med 1986;15:384-389; Braughler JM, Duncan LA, Chase RL, The involvement of iron
in lipid peroxidation, J Biol Chem 1986;261:10282-10289;
Aruoma 01, Halliwell B, Gajewski E, Dizdaroglu M, Damage to the bases in D N A induced by hydrogen peroxide and
ferric ion chelates, J Biol Chem 1989;264:20509-205 12;
Palmer C, Pavlick G, Karley D, et al, The regional localization of iron in the cerebral cortex of the immature rat: relationship to hypoxic-ischemic (HI) injury, Pediatr Res 1993;
33:2224A). We therefore investigated the effects of cerebral
ischemia and reflow on the redistribution of nonheme iron
in newborn piglets. Anesthetized newborn piglets were subjected to reductions in cerebral blood flow (measured by
microspheres) by hemorrhage and cervical cuff compression
(Goddard-Finegold J, Michael LH, Brain vasoactive effects
of phenobarbital during hypertension and hypoxia in newborn pigs, Pediatr Res 1992,32:103-106; Yamashita Y ,
Goddard-Finegold J, Contant CF, et al, Phenobarbital and
cerebral blood flow during hypotension in newborn pigs,
Pediatr Res 1933;33:59-60). Control animals were shamoperated. Reflow was achieved, when indicated, by cuff release and restoration of blood volume. Arterial Po, and Pco,
did not change. Subcellular fractions were isolated from brain
tissue homogenates by differential centrifugation and nonheme iron contents of these fractions measured wirh ferene-S
(Artiss JD, Vingradov S, Zak B, Spectrophotometric study
of several sensitive reagents for serum iron, Clin Biochem
1981;14:311-315). Iron contents in the total homogenates
0.10 nmol/mg
and in the mitochondria1 fractions (0.59
pro) were not altered. However, iron contents of the purified
nuclear fractions of animals subjected to 30 minutes of ischemia increased ("p < 0.01; ANOVA); 120 minutes of reflow caused no further changes (Table).
*
~
~~~~~~~~~~~~~
Cerebral Blood Flow
(ml/min/ 100 gm)
Experimental
Group
Initial
Control ( 5 )
Ischemia (7)
Reflow ( 7 )
47 t 4 48 ? 4
43 t 6 12 ? 2
44 t 9 15 -+ 2
Ischemia Reflow
45 t 3
NA
43 t 7
Nuclear Fraction
(Fe) (nmol/mg pro)
0.47 -+ 0.18
0.89 ? 0.20"
0.89 -+ 0.20"
We conclude that cerebral ischemia causes a redistribution
of iron to the nuclear subcellular fractions of the brains of
newborn piglets; if the iron is present as redox-active chelates, it could potentiate damage by reactive oxygen species
during reflow.
439. Glucose Transporter Gene Expression in
Immature Rat Brain: Effect of Hypoxia-Ischemia
Susan J . Vannucci, Lisa B. Seaman, Richard Reinhardt.
Ian A. Simpson, and Carolyn A. Bandy, Hershey. PA,
and Bethesda, M 0
Cerebral hypoxia-ischemia (H-I) produces major alterations
in glucose uptake and utilization by the immature brain.
These changes begin during the insult and proceed well into
the recovery period. The passage of glucose from the blood
into the brain requires transport across the endothelid cells
of the blood-brain barrier (BBB) and into the neurons and
glia. As for most mammalian cells, these processes are mediated by the facilitative glucose transporter proteins (GLUT).
GLUT1 is in the BBB and also glia; GLUT3 is the primary
neuronal transporter; and GLUT5 is in microglia. The expression of these proteins is low in the immature rat brain
and appears to be limiting to cerebral glucose utilization
(CGU). To determine the relationship between the expression of the GLUT proteins and glucose metabolism following
H-I, we examined GLUT1, GLUT3, and GLUT5 gene expression by in situ hybridization at 24 and 48 hours following
Program and Abstracts, Child Neurology Society 497
unilateral cerebral H-I in the immature rat. Seven-day postnatal rats underwent unilateral common artery ligation, followed by exposure to hypoxia (857 0,)for 2.5 hours at 37°C.
At 24 hours of recovery, GLUTl mRNA was elevated in the
damaged, relative to the contralateral, hemisphere, consistent
with previously observed increases in BBB GLUTl protein
at this time. GLUT3 mRNA was decreased in the cerebral
cortex and CA 1 hippocampus, consistent with selective neuronal necrosis; GLUT5 was not evident in either hemisphere.
At 48 hours, GLUTl and GLUT3 mRNA were decreased
in the injured tissue; GLUT5 mRNA was sharply increased,
consistent with the microglial response to the insult. The
alterations in GLUTl and GLUT3 reflect changes in glucose
metabolism. The widespread increase in GLUTS, coincident
with a decrease in CGU, suggests an alternate function for
GLUT5 in microglia.
440. MK-801 Treatment Increases N M D A Receptor
Subunit m R N A Expression in Rats
Stephen L. Kinsman. Mary Ann Wilson.
and Michael V .Johnston, Baltimore, M D
N-methybaspartate (NMDA) is an analog of the excitatory
neurotransmitter glutamate and a potent neurotoxin. Experimental models using NMDA have been helpful in characterizing the pathophysiology of neuronal excitotoxicity. The
NMDA receptor antagonist MK-801 reduces brain injury if
administered during excitotoxin exposure or hypoxiaischemia, status epilepticus, or hypoglycemia. This has raised
hopes that clinical interventions based on NMDA receptor
blockade might be effective in ameliorating brain in j y y .
However, McDonald and colleagues (Neuroscience 38: 103)
have shown that pretreating the young rat with MK-801 enhances NMDA-mediated brain in jury. This hypersensitivity
to injury is associated with a rapid increase in NMDA binding within several regions of the rat brain. One important
component of the NMDA receptor complex is encoded by
the N R 1 gene. T o determine whether the observed increase
in NMDA binding is associated with a change in the mRNA
level for this NMDA receptor subunit, we performed in situ
hybridization using an oligonucleotide probe specific for the
N R I receptor subunit. Seven-day-old rats were killed 2 or
24 hours after MK-801 ( I mg/kg) administration. In situ
hybridization was used to compare NR1 subunit expression
in treated and saline-injected control rats. MK-801 treatment
produced an approximately 357% increase in NR1 subunit
mRNA in regions previously found to have increased binding (hippocampus, striatum and cortex). These results suggest
that the rapid increase in NMDA receptor binding induced
by MK-801 is regulated, at least in part, at the transcriptional
level. These observations provide new information about the
regulation of the NMDA receptor complex in response to
the binding of this important neuroprotective agent. A more
complete understanding of the regulation of the NMDA receptor complex is needed if we are to exploit the properties
of this set of channel receptors in clinical therapeutic strategies.
44 1. Effect of Status Epilepticus on Hypoxic-Ischemic
Brain Damage in the Immature Rat
Ogirz Cataltepe, Robert C Vanniiiir.Jaiad Toiufighz. arid
Dnnirl F Heit;mn, HevJhey, PA
T o ascertain whether seizures superimposed upon cerebral
hypoxia-ischemia (HI) accentuate perinatal brain damage, 7day postnatal rats were subjected to unilateral common ca-
498
Annals of Neurology
rotid artery ligation, 3 hours following which they were exposed to hypoxia with 8% 0, at 37°C for 2.5 hours.
Thereafter, they received single or multiple sc injections(s)
of bicuculline (6 mg/kg), adequate to produce seizures lasting
more than 1 hour. A single episode of status epilepticus (SE)
at 24 hours of recovery from HI was associated with a mortality rate of 15%; neuropathological analysis of the survivors at
30 days of age revealed no accentuation of H I brain damage,
compared to nonconvulsing HI control littermates. Repeated
episodes of SE at 2, 6, and 12 hours of recovery produced
a mortality rate of 58%. Among the survivors, there was
no statistically significant difference in the severity of brain
damage between convulsing and nonconvulsing HI controls
when analyzed at 30 days of age. Furthermore, neuropathological examination for the presence of acute lesions during
early recovery also indicated no difference in the severity of
brain damage between expired and surviving rat pups subjected to SE, indicating that mortality was not related to the
severity of prior HI brain damage. Immature rats that died
during SE exhibited lower blood glucose concentrations
( 1.75 mmol/L) compared to surviving, convulsing animals
(4.25 mmol/L; p = 0.02). Glucose supplementation (0.1 ml
50% glucose) early during SE improved survival and significantly prolonged seizure activity, although glucose treatment
did not increase the extent of brain damage compared to
nonglucose-treated convulsing littermates. The findings indicate that even repetitive episodes of SE in immature rats
previously subjected t o cerebral HI does not accentuate
brain damage, despite a substantial mortality.
442. Felbamate Effects o n Hypoxic Cultures of Mixed
Neurons and Glia as Assessed by Propidium Iodide
Fluorescence
Jan 6. WoILack and Roger M . Collins. .Jr, Baltimore, M D
Felbamate is a new dicarbamate anticonvulsant that appears
to also display some ability to protect neurons against hypoxia
and ischemia (Wallis et al, Stroke 1092;23:547-551; Wasterlain et al, Neurology 1993;43:2303-2310). To further delineate this apparent neuroprotective action, felbamate’s effects in a cell-culture model of cerebral hypoxia were
investigated. Mixed cultures of neurons and glia were derived
from embryonic day-15 mice as described by Choi and colleagues Neurosci 1987;7:357-368) and grown in 96 well
microplates. After 14 to 17 days in vitro, the culture medium
was replaced by a salt solution containing various concentrations of felbamate, ranging from 10 pM to 2 mM. The cultures were then exposed to an atmosphere of 88%, N2, 7C7
H,, and 5%) CO, for up to 4 hours, after which the cultures
were returned to their normoxic incubator. After 24 hours,
loss of the integrity of cell membranes, a sign of cellular
injury or death, was assessed by the ability of the fluorescent
dye, propidium iodide, to permeate the membranes and bind
to nucleic acids within the cell. The resulting fluorescence of
the bound dye was then measured using a microplate capable
fluorimeter (Cytofluor, Millipore Inc) and expressed as a percentage of the total fluorescence observed after all the cells
were killed by freezing and thawing. This assay was adopted
as previous work in the laboratory had demonstrated interference by valproic acid and some other neuroactive substances
with the release of lactate dehydrogenase from injured cells,
the assay classically used to evaluate neuronal injury. A doserelated decrease in fluorescence was noted for cultures
treated with felbamate. For example, cultures treated with 1
mM felbamate and exposed to 3 hours of hypoxia showed
33% less fluorescence than did untreated cultures (3 separate
Vol 36 No 3 September 1994
u
experiments, each with n = 8, p < 0.01). These results
suggest that felbamate does have a protective effect on neurons exposed to hypoxia.
443. Modest Hypothermia Reduces Brain
Energy Utilization
A. R. kzptook, R. J . T.Corbett, R. Sterret, D. Garcia,
and G . Tollefsbol, DaLlas, T X
In neonatal and adult animals, modest reduction in brain temperature (Th,2-3°C) during ischemia and hypoxia-ischemia
provides partial or complete neuroprotection. One potential
mechanism for this effect is a decrease in brain energy utilization rate with consequent preservation of brain adenosine
triphosphate, as occurs with profound hypothermia. To determine if modest hypothermia is associated with a decrease
in brain energy utilization rate, in vivo 31Pand 'H magnetic
resonance spectroscopy (MRS) were used in 11 piglets (8-16
days) to measure the rate of change in brain concentration of
phosphocreatine (PCr), nucleoside triphosphate, and lactate
following complete ischemia induced by cardiac arrest. Preischemia metabolite concentrations and MRS-determined
rate constants were used to calculate the initial flux of highenergy phosphate equivalents (df-P]/dt, brain energy utilization rate). Baseline measurements were obtained at 38.2"C,
and were repeated after Th was adjusted so that d[-PJ/dt
was acquired at 1 to 2 "C increments between 28 and 41°C.
Adjusting T, did not alter any systemic variable except for
heart rate, which correlated with T, ( r = 0.95; p < 0.001).
Prior to ischemia, Tb inversely correlated with PCr ( r =
-0.89; p < 0.001), and reflected changes in the PCr-ATP
equilibrium, since T, inversely correlated with intracellular
p H ( r = -0.77; p = 0.005). T, and d[-P]/dt were directly
correlated and described by a linear relationship (slope =
0.61; intercept = - 12; r = 0.92; p < 0.001). Slopes and
intercepts for T, versus d[-P)/dt for animals of different
ages were similar. A reduction in Th is associated with a
decline in d[-P]/dt of 5.396 per degree centigrade; therefore, decreases in df-PJidt during modest hypothermia
represent a potential mechanism contributing to neuroprotection.
444. Carbon Dioxide Protects the Perinatal Brain from
Hypoxic-lschemic Damage
Robert C. Vannucci,Javad Towfighi, Daniel F . Heitjan,
and Robert M . Brucklacher, Hershey, PA
Clinical investigations suggest that premature infants who require mechanical ventilation from respiratory distress syndrome are at increased risk for PVL if hypocapnia occurs
during respiratory management. The question remains as to
the contribution of hypocapnia to hypoxic-ischemic (H-I)
brain damage. Seven-day postnatal rats underwent unilateral
common carotid artery ligation, followed by exposure to hypoxia with 896 O,, combined with either O%, 393, 6%, or
9% CO, for 2 hours at 37°C. Blood C 0 2 tensions averaged
26, 42, 54, and 71 mm Hg in the O%, 396, 6%, and 9%
C0,-exposed animals, respectively, during systemic hypoxia.
Survivors underwent neuropathological examination at 30
days of age; their brains were categorized as follows: 0 =
normal, 1 = mild atrophy, 2 = moderate atrophy, 3 =
atrophy with cystic cavitation less than 3 mm; 4 = cystic
cavitation more than 3 mm. Results showed that 30 of 38
(79%) rats exposed to 3% COz showed either no or mild
brain damage, compared to 13 of 33 (39%) controls (0%
CO,). Cystic infarction occurred in only 4 C0,-exposed rat
pups, compared to 14 controls ( p = 0.004). At 69% CO,
exposure, 20 of 20 rat pups showed either no damage or
mild atrophy, compared to controls ( p < 0.0001); and at 9%
CO,, 19 of 23 (83%) rat pups showed no or mild damage,
compared to controls ( p = 0.0001). The data also showed
that the greatest reduction in brain damage occurred in immature rats exposed to 6% CO, ( p < 0.001) compared to
3%, with slightly less protection at 9% CO,, the latter comparable to brain damage sustained by animals inhaling 3%
CO,. Thus, normocapnic cerebral H-I is associated with less
severe brain damage than in hypocapnic H-I, and mild hypercapnia is more protective than normocapnia. The findings in
an experimental model dictate a clinical reexamination of the
ventilatory management of sick newborn human infants.
445. Magnesium Protects Neonatal Mouse Brain from
Posthypoxic-like Damage Induced by Ibotenate in
Mouse Pups
S. Marret, R. Mukendi, J.-F. Gadisseux, P. Gressens,
and P. Evrard, Brussels, Belgium
The protective effect of magnesium sulfate (Mg), an antagonist of N-methyla-aspartate, was tested in a mouse model
of excitotoxicity induced by ibotenate (Ibo). Jbo was injected
in the right hemisphere (5 pg/injection) at postnatal day 5.
A dosage of 0.03 mg (6 mg/kg), 0.3 mg (60 mg/kg), or 3
mg (600 mgikg) of Mg was injected twice intraperitoneally,
2 hours and 10 minutes before Ibo injection. A fourth group
of animals received only 3 mg Mg 10 minutes after Ibo.
Controls received Ibo alone. All controls displayed tonicclonic seizures a few minutes after Ibo injection. Clinical
signs were suppressed (0.3 or 3 mg) or decreased (0.03 mg)
after Mg injections. Five days after Ibo injection, cortical
plate lesions and porencephalic cysts of the white matter
were classified into 4 groups: 1. absence of histological lesion;
2. microlesion (rostro-caudal axis of the lesion <lo0 pm,
neuronal depopulation in infragranular layers, and diameter
of the white matter cyst <50 pm); 3. intermediary lesion; and
4. extensive lesion (rostro-caudal axis >300 pm, neuronal
depopulation in infra- and supragranular layers, diameter of
the cyst > l o 0 pm). Controls (8 of 8) and animals injected
with 0.03 mg Mg (7 of 7) had intermediary or extensive
histological damages. Conversely, 7596 (6 of 8) of pups injected with 3 mg Mg before Ibo, 50% (4 of 8) of pups
injected with 0.3 mg Mg before Ibo, and 80% (4 of 5) of
pups injected with 3 mg Mg after Ibo displayed only minor
or no lesions, demonstrating a protective effect of Mg in
neonatal rodent brains subjected to excitotoxic insult. A controlled study of the effect of Mg in human perinatal asphyxia
seems relevant.
446. Can Magnesium Sulfate Reduce the Risk of
Cerebral Palsy in Infants with Very Low Birth
Weight?
Karin B. Nelson and Judith K. Grether, Bethesda, M D ,
and Emeyville, CA
Infants born weighing less than 1,500 gm (very low birth
weight, VLBW) are at relatively high risk for cerebral palsy
(CP). Kuban and co-workers (J Child Neurol 1992;7:70) reported that VLBW infants exposed in utero to magnesium
sulfate demonstrated a lower frequency of germinal matrix
or intraventricular hemorrhage, a risk factor for CP. We in-
Program and Abstracts, Child Neurology Society 433
vestigated whether magnesium sulfate (MgSO,J, administered to the mothers as an anticonvulsant in preeclampsia or
as a tocolytic agent, was associated with lower rate of C P in
infants weighing less than 1,500 gm. Singleton VLBW infants
born 1983 through 1985 in 4 California counties and surviving to 3 years with moderate or severe congenital C P were
identified in a birth cohort of 155,636. VLBW children with
CP were compared with randomly selected VLBW control
survivors with respect to receipt of MgSO, and other information abstracted from labor and delivery records. During
the admission for delivery, 7.1% of the 42 VLBW infants
with later CP and 3 6 p of the 7 5 VLBW controls were exposed to MgSO, (OR, 0.14,959L CI 0.05,0.50). Infants with
CP were less often exposed antenatally to MgSO, whether
or not mothers were preeclamptic (OR, 0.11, CI 0.01, 2.4,
preeclampsia; OR, 0.25, CI 0.08, 0.97, nonpreeclampsia),
or there was cotreatment with non-MgS04 tocolytics (other
tocolytics administered, OR for MgSO.., exposure 0.19, CI
0.05, 1.0; n o other tocolytics, OR for MgSOl 0.12, CI 0.03,
1.0) or antenatal steroids (steroids given, OR for MgSO,
exposure 0.23, C1 0.06, 1.2; steroids not given, OR for
MgSO, 0.09 C1 0.02, 0.80). In this exploratory study, in
utero exposure to MgSO,! was more frequent in controls than
in children with CP, consistent with a protective effect of
MgSO.<against C P in these VLBW infants.
447. Nitric Oxide Inhibition Reduces Infarct Volume
During Transient Neonatal Focal Cerebral Ischemia i n
Spontaneously Hypertensive Rats
Stephen Ashwal. Daniel/. Cole, Suzzanne Orbornee
Terrill N . Osborne. and WilliamJ . Pearce. Lorna Linda,C A
Nitric oxide (NO) may serve a dual role during focal cerebral
ischemic injury. The majority of adult studies have suggested
that N O is neurotoxic, although N O is a vasodilator and
could improve cerebral blood flow and reduce injury. The
current study examined whether N O is neurotoxic in a
unique “string” model of middle cerebral artery occlusion
(MCAO) in the newborn rat. We developed a reproducible
transient MCAO stroke model in 3-week-old spontaneously
hypertensive rats (SHR; 35 gm; adult weight = 400 gm) by
passing a number 6-0 (0.07 mm) nylon filament via the carotid artery to transiently occlude the MCA for 4 hours under conditions of normoxia. After removal of the filament
and reperfusion for 24 hours, we determined infarct volume
using the mitochondrial stain 2,3,5-triphenyltetrazolium
chloride (TTC). NO synthesis was inhibited using NG-nitroL-arginine methyl ester (L-NAME)at a dose of 3 mg/kg IP,
1 hour before MCAO. We measured infarct volume in control (n = 4 ) and L-NAME ( n = 4 ) groups. L-NAME reduced
infarct volume by 56%, from 237.5 mm’ ( ? 14.8 mm3) in
2
in the experithe control group to 104.3 mm’ ( ~ 4 9 . mm’)
mental group ( p < 0.002). These findings suggest an important neurotoxic role for NO during focal cerebral ischemia
in the newborn.
448. Nerve Growth Factor Markedly Protects
Against Hypoxic-Ischemic-Induced Injury in t h e
Developing Brain
Daisid M . Holtzman. Wyatt Jajje, R. Anne Sheidon.
and Donna F. Frrriero. San Francisco. C A
Nerve growth factor (NGF) has been shown to protect specific neurons from a variety of insults in the developing and
adult brain. We asked whether N G F would protect against
CNS damage in a neonatal model of hypoxia-ischemia. Post-
500 Annals of Neurology
Vol 36
natal day (PD) 7 rat pups received a right carotid ligation
and were then exposed to hypoxic conditions for 2.5 hours
(modified Levine procedure). Prior to carotid ligation and 48
hours later, pups received an intraventricular injection of either 15 kg of N G F in vehicle (PBS) or vehicle alone. Coronal
sections (40 p.) of the 4(-/c paraformaldehyde-fixed brains
were morphometrically assessed at P D 2 1. In vehicle-treated
animals (n = 231, there was a 30 to 35% decrease in the
volume of both the right striatum and cortex compared to
the undamaged left hemisphere. In contrast, NGF-treated
animals (n = 22) showed only a 10F decrease in volume of
both the right striatum ( p = 0.003) and cortex ( p = 0.01).
Thus, N G F prevented 75% of the hypoxia-ischemiainduced tissue loss. Further studies are underway to determine effects on specific neuronal populations and the mechanism of the protective effects. These results suggest that
N G F may prove useful in diminishing neonatal hypoxiaischemia-induced brain injury.
449. Long-term Outcomes of
a Cohort of Children
Prospectively Followed from the T i m e of Their First
Unprovoked Seizure
Shlomo Shinnar, Anne T . Berg, Solomon L. Moshe,
Harriet Kang. Karen R. Ballaban-Gilt Christine O’Dell.
Marta Alemany, David Neustein. and W . Allen Hauser.
Bronx and New York, N Y . and Dekalb, I L
A cohort of 407 children and adolescents were recruited
prospectively at the time of their first unprovoked seizure
and followed for a mean of 69 months. To date, 168 (41%)
of the children have experienced a recurrence. The overall
recurrence risk was 0.29, 0.37, 0.42, 0.43, and 0.43 at 1, 2.
4, 6, and 8 years, respectively. A remote symptomatic etiology, an abnormal EEG, and the occurrence of the initial seizure during sleep were associated with an increased risk of
seizure recurrence. Of those who have had more than 1 seizure, 5 1 (30%) have had 2, 26 (15%) have had 3, 14 (8%’)
have had 4, and 77 (46:/0) have had 5 or more seizures. In
the 3 7 3 children who have been followed for more than 2
years, the probability of attaining 2-year terminal remission
on or off medications was 0.79 by 5 years and 0.85 at 8
years. For remission off medications, the probability was 0.72
and 0.77 at 5 and 8 years. For the 139 children with 2 or
more seizures on whom sufficient subsequent follow-up was
available, the probability of 2-year terminal remission was
0.63 and 0.73 at 5 and 8 years. The probability of remission
off antiepileptic drugs in this group was 0.47 and 0.55 at 5
and 8 years. An idiopathic etiology ( p < 0.00 1 ) and a normal
EEG in idiopathic cases ( p < 0.001) were associated with a
higher probability of attaining remission. Age at first seizure
and duration of the first seizure did not affect the probability
of attaining remission. The majority of these children have
favorable long-term outcomes. Continued follow-up of this
pediatric cohort identified at the time of their first seizure will
provide valuable information on the prognosis of childhood
seizures.
450. Seizure Recurrence After Discontinuing
Anticonvulsant T h e r a p y i n Children W h o A r e Seizure
Free for One Year
J . Dooley, K. Gordon. P. Camfield. C . Camfield, E. Smith.
and J . MacSween, Hal;fax. N o w Scotia, Canada
Between March 1, 1989, and February 28, 1993, all consenting patients on antiepileptic drug (AED) monotherapy
No 3 September 1994
free for 12 to 13 months were weaned from their
2y over 4 to 6 weeks. Follow-up was 12 to 57
,,ms (mean, 32 months). A total of 13 patients refused
discontinuation because of physician (2) or family (1 1) concerns. One patient was lost to follow-up. The data on the
remaining 97 patients were analyzed using Kaplan-Meier survival analysis with Cox’s model for multivariate analysis. The
overall recurrence rate was 3957 (95%, CI: 29%, 49%) at
24 months. Lnivariate analysis of an incomplete sample was
previously presented (Ann Neurol 1992;32:430). Multivariate analysis of the complete group showed that the following
factors were associated with an increased risk of seizure recurrence: (1) female sex, with an increased risk of 3.8 (955%
CI: 1.7, 8.4); (2) age at seizure onset over 10 years, with an
increased risk of 5.6 (95% CI: 2.4, 13.3); and (3) neurological abnormality, with an increased risk of 2.98 (959%CI: 1.3,
6.6). When seizure types were compared with benign rolandic epilepsy (always discontinued successfully), generalized
seizures had an increased risk of 2.99 (95% CI: 1.4,6.5) and
partial seizures had an increased risk of 8.9 (9557 CI: 4.1,
19.3). Using these data, for selected children, prolonged
AED therapy is unnecessary. Antiepileptic medication may
be successfully discontinued after 1 year without seizure.
45 1. Methylphenidate for Children with Epilepsy
and Attention Deficit Hyperactivity Disorder
Varda Gross-Tsur.Ruth Shalezi, Orb Manor.
and Naonzi Amir. Jerusalem, Israel
Methylphcnidate (MPH) has been implicated in lowering the
convulsive threshold, but the PDR discourages its use in children with the dual diagnosis of epilepsy and attention deficit
hyperactivity disorder (ADHD). We studied the safety of
MPH in 9 boys and 8 girls, aged 6.6 to 16.4 years. A total
of 10 had complex partial seizures, 4 had primary tonic-clonic
seizures, and 3 had true absences. A total of 15 children were
seizure free and 2 had 1 to 2 seizures weekly; 16 were on
monotherapy and 1 was on a combination of antiepileptic
drugs (AEDs). The children were tested while on AEDs and
placebo at the end of the 1-month MPH-free period and a
second time after 1 month on M P H (0.3 mglkg). All underwent neurological assessment and brain C T prior to MPH;
EEG, AED levels (trough and 2 hours after ingestion), and
Conners’ questionnaire were done at both sessions. None of
the 15 seizure-free children developed attacks while on
MPH; a moderate increase in seizure frequency was noted
in the 2 children who had seizures. N o major changes in
EEG epileptiform features were seen. AED levels were in
the therapeutic range during the placebo and MPH conditions. For tegretol (n = 5 ) , the mean difference between
trough and 2-hour levels for placebo-MPH was 0.3 t 0.7;
for valproic acid (n = l l ) , the mean difference was 4.6 2
9.1. Clinical improvement in A D H D symptomatology was
noted in 12 cases. N o side effects appeared that required
withdrawal of MPH. In conclusion, MPH in therapeutic
doses is safe for children with seizures and concurrent
ADHD. Caution is warranted in children with active seizure
disorder.
452. Redefining Therapeutic Levels of Valproic Acid
Radhakrishna Rao. Patricia Beierwaltes. and Michael Nigro,
Detroit, MI
We prospectively evaluated 100 children who were receiving
valproic acid (VPA), mono- and polytherapy, to define the
relationship between total and free VPA levels and the correlation with seizure control, liver function, complete hemogram, and symptoms of toxicity. Increasing free levels of
VPA relative to total levels greater than 100 p.g/ml has been
described as an explanation for enhanced VPA effectiveness
at supratherapeutic levels, and may account for toxicity, as
well. In our patients with total VPA levels of 50 to 100, the
totallfree ratio averaged 0.12. With 1 exception, children
tolerated total VPA levels up to 140, and free VPA levels
up to 30 p,g/ml, with a totallfree ratio of up to 0.25 without
thrombocytopenia or symptoms of toxicity. Only 3 children
had thrombocytopenia (platelet count less than 100,000), and
each of these had total VPA levels ranging from 102 to 158
and free VPA levels ranging from 19.6 to 70.6. Reduction
in VPA dose resulted in resolution of the thrombocytopenia,
as expected. A totallfree ratio over 0.3 correlated with
thrombocytopenia. No pancytopenia or elevation in liver
function tests was found. Better seizure control was observed
with free VPA levels between 15 and 30 pg/ml. There was
no relationship of maximum tolerated dose to therapeutic
benefit. The type of seizure being treated with VPA influences the VPA level needed to obtain seizure control.
Polytherapy was typically associated with higher VPA dose
necessary to maintain therapeutic levels. Our data suggest
that, on the basis of safety and effectiveness, the total VPA
level should be increased to 140 &ml and the free VPA
level should be increased to 30 pg/ml.
453. A r e Children W h o A r e Receiving Monotherapy
for Idiopathic Epilepsy at Risk for Osteoporosis?
Yes, If Therapy Is w i t h Valproate
Raj D. Sheth, Carl A. Wesolou?rki,J . C. Jacob. Sharon Penney.
and Gerald R. Hobbs, Morgantouln, WV. and St John’s,
Newfoundland, Canada
Reduced bone mineralization in childhood is a significant risk
factor for osteoporotic fractures in the elderly. Children with
idiopathic epilepsy frequently receive prolonged carbamazepine (CBZ) or valproate (VPA) monotherapy at a time of
rapid bone mineralization. It is not clear if the alteration in
serum markers of calcium and vitamin D metabolism reported to occur with antiepileptic medications actually reduces bone mineralization. Institutional review board approval and informed consent were obtained for this
cross-sectional study. Subjects were normal, except for idiopathic epilepsy, and had received uninterrupted CBZ or
VPA monotherapy for more than 1.5 years. Controls were
healthy school-age children. Bone mineral density was measured by dual photon absorptiometry (Lunar DP-3) at the
distal one third of the radius and L2-4 lumbar spine. An
analysis of covariance was performed using age and gender
(a dummy variable) as covariates, and medication as the treatment variable. A total of 26 controls (mean age, 13.4 ? 2.8
years) were compared with 13 subjects receiving CBZ (age,
13.2 t 4.1 years; dose, 9.9 t 3.7 mg/kg/day; serum CBZ
level, 6.88 ? 2 pglml) and 13 subjects receiving VPA (age,
15.4 t 3.3 years; dose, 15.1 t 7 . 2 mg/kg/day; serum VPA
level, 72.04 2 45.6 p,g/ml) for 3.5 2 2 years (range, 1.5-9
years). Calcium intake was similar for both groups. In VPAtreated subjects, calcium content was reduced by 10%)at the
distal one third radius ( p = 0.008), and by 13% at lumbar
spine 2-4 ( p = 0.017). The longer the duration of VPA
therapy, the greater the reduction in bone density. Subjects
receiving C B Z did not show a significant decrease in bone
density. VPA therapy, even in low doses, reduces bone min-
Program and Abstracts, Child Neurology Society 501
eralization in childhood. These children may be at significantly increased risk of osteoporosis in later life.
454. Free Radical Enzyme Deficiency Syndrome
William D. Graf. Tracy A. Glauser. and
Charles E. Pippenger. Seattle, WA. Cincinnati. OH,
and Redniond, W A
The number of fatalities from valproic acid (VPA)-associated
hepatotoxicity has decreased in the last 10 years by avoiding
or monitoring certain high-risk patients; but potentially severe idiosyncratic, dose-related, teratogenic, and chronic
toxic effects from VPA are still experienced in some patients.
Thus, there is a need for identification of individuals at greatest risk to develop idiosyncratic drug reactions (IDR) prior
to VPA therapy to facilitate the beneficial effects and clinical
application of this commonly used medication. We measured
erythrocytic free radical scavenging enzyme activitiesglutathione peroxidase (GSH-Px), glutathione reductase, glutathione-S-transferase, catalase, and superoxide dismutaseand their plasma cofactor trace elements-Se, Zn, Cu, and
Mn-in a series of patients who presented clinically with
VPA-associated IDR. All children in this series (mean age,
6.5 years) had pronounced deficiency in erythrocytic
GSH-Px activity (reported in mean, 2 SD; normal range,
30.3-44.1 IU/gm Hb). Patients were categorized clinically
as follows: group I, acute or subacute VPA-related IDR ( 3
children) included signs of nausea/vomiting, lethargy, increased seizures, allergic rash, or marked behavioral changes
after initial doses of VPA (17.1 ? 1.9 IUlgm Hb); group
11, chronic VPA-related IDR, occurring after long-term therapy (6 children), included signs of nauseaivomiting, lethargy,
pancreatitis, thrombocytopenia, hepatotoxicity, with improvement on discontinuation of VPA or selenium supple3.2 IU/gm Hb); or group 111,
mentation or both (19.3
rapid unexplained deterioration, leading to death with critically low GSH-Px activity at the time of death (2 children)
and no other apparent cause for death (such as carnitine deficiency, mitochondrial cycopathy, or organic aciduria) (13.9
2 0.5 IU/gm Hb). These data support the hypothesis that
defects in the antioxidant enzyme system that protect cellular
membranes from excessive lipid peroxidation play a role in
the pathogenesis of VPA-associated IDR. We speculate that a
primary (group I ) or secondary (group 11) free radical enzyme
deficiency syndrome is present in these patients. Other factors, such as acute febrile illness (group HI),could possibly
potentiate both neuronal excitotoxicity and oxidative stress
in at-risk patients. Further follow-up studies are in progress.
*
45 5. Evidence for the Barbiturate-like Actions
of t h e Dicarbamates Felbamate and Meprobamate
Jong M . Rho. Sean D . Donetvan. and Michael A. Rogauski.
Bethe~da.M D
Felbamate (FBM) and meprobamate (MBM) are structurally
related dicarbamates that exhibit distinct clinical profiles:
FBM is a broad-spectrum anticonvulsant with a high protective index, whereas MBM is a strong sedative-anxiolytic. Previously, we reported that FBM potentiates GABA-activated
currents and inhibits N-methybaspartate (NMDAkactivated currents (Ann Neurol 1994;35:229-234). We now
provide evidence that FBM and MBM are barbiturate-like
modulators of the GABA, receptor. Whole-cell voltage
clamp and single-channel recordings were obtained from cultured rat hippocampal neurons. MBM, but not FBM, directly
activated CI- current responses in the same manner as the
anesthetic barbiturate pentobarbital (PB). W e compared the
kinetic properties of channel activation by barbiturates and
GABA by measuring the rates of deactivation of the wholecell current following termination of agonist perfusion. Deactivation rates for 300 pmol PB and 10 mmol MBM were
similar (110 ? 10 msec [n = 101 and 112 ? 7 msec [n =
91, respectively), whereas for 1 to 10 pnol GABA the offrates were higher (==170 msec), and still higher for 10 mmol
MBM
1 kmol GABA (490
70 msec; n = 5 ) , 3 mmol
FBM + 3 kmol GABA (470 2 45 msec; n = 4),and 300
kmol PB + 1 p n o l GABA (440 ? 30 msec; n = 5). We
further examined the single-channel currents activated by
GABA alone and by GABA plus MBM, FBM, o r PB. Both
MBM and FBM produced an increase in the mean burst
duration similar to that obtained with pentobarbital. MBM
and FBM exhibit barbiturate-like effects on GABA, receptors, both in their ability to modulate responses to GABA,
and, in the case of MBM, to activate the receptor directly.
The low toxicity of felbamate could relate, in part, to its
failure to produce this latter effect.
+
*
456. y-Hydroxybutyric Acid and GABA, Antagonists:
Potential Antiabsence Drugs
0. Carter Snrad 111. Los Angele,. CA
y-Hydroxybutyric acid (GHB) is a naturally occurring compound that has the ability to induce generalized absence seizures when given to animals, a phenomenon shown to be
blocked by the specific GABAB antagonist, CGP35348
( h e a d , Eur J Pharmacol 1992;213:343-349). The object of
these experiments was to determine the effect of a range of
other GABA, receptor antagonists and agonists as well as
a specific G H B antagonist on generalized absence seizures.
Experimental absence seizures were induced in freely moving
rats by the administration of either G H B or pentylenetctrazole after the administration of the GABA, antagonists, phaclofen and 2-hydroxy-saclofen, the GABA, agonists ( - )
baclofen and 3-amino-propylphosphinic acid, the inactive
( ) isomer of baclofen, or the specific G H B receptor antagonist, NCS 382. All GABA, antagonists, as well as the G H B
antagonist, produced blockade or significant ( p < 0.05) attenuation of the duration of experimental absence seizures in
both models, while pretreatment with GABA, agonists resulted in generalized absence status epilepticus lasting for
hours. The inactive isomer ( + ) baclofen had no effect. The
more potent of the GABA, antagonists produced increased
sharp activity on the electroencephalogram and some clonic
seizure activity at doses 30 to 5096 in excess of the ED,, for
absence seizure control. These data confirm that GABAB
antagonist properties confer antiabsence activity and suggest
that the same may hold for GHB antagonists. Both G H B
and GABA, antagonist drugs may have the potential to be
useful therapeutic agents in the treatment of generalized absence seizures.
+
457. Paraneoplastic Autoantibody Anti-Hu Is
Cytotoxic to Cultured H u m a n Fetal Brain Neurons
Identified by Immunohistochemistry: Implications
for Opsoclonus-Myoclonus
Michael R. Pranzatelli, N . Suzun Nadi, Su//y A. Moody.
Eugene 0. Major. Bruno A. Chirmpztazi. and
Michael F . Marusick. Washington. DC. Bethesda, M D ,
and Eugene, OR
Childhood opsoclonus-myoclonus syndrome (OMS) is an autoimmune disorder associated with remote neural crest-
502 Annals of Neurology Vol 36 No 3 September 1994
derived tumors or certain viral infections. The mechanism
of immunological injury is unknown. Anti-Hu is a putative
autoantibody that has been found in some neuroblastoma
cases and has been implicated in the pathophysiology of paraneoplastic syndromes such as OMS. H u proteins are expressed early in all neurons, just prior to overt neuronal
differentiation, and continue to be expressed in mature neurons. However, no causal relation between anti-Hu and brain
injury has been demonstrated, and no animal model of OMS
is available. As an in vitro model, we studied the effect of
anti-Hu monoclonal antibodies (MAb 1 6 A l l ) in primary cultures of human fetal brain cells. Cultures grown from fetal
brains of gestational ages ranging from 17 to 22 weeks were
observed to have a dense layer of astroglia of varying morphologies (defined by staining with a polyclonal antibody to
glial fibrillary acidic protein [GFAP]), overlaid by a neuronal
population (defined by staining with a monoclonal antibody
to a neuron-specific isotype of P-tubulin, c P4 TuJ 1) of varying sizes and shapes with extensive processes. After 48 hours
of exposure to anti-Hu 10 pg/ml, there was widespread loss
of processes and death of neurons identified with TuJl and
immunostained with FITC- or Texas Red-labeled secondary
antibodies. Glia identified with GFAP were relatively spared.
The cell populations were also immunostained for neurotransmitter content (5-HT, GABA, Glu) and colabeling with
anti-Hu, tested for trypan blue exclusion, and time-course
and dose-response studies were performed. These data suggest that primary cultures of human fetal brain are a model
system for in vitro studies of cytotoxicity in OMS. Studies
on apoptosis as the mechanism of anti-Hu-mediated cell
death are in progress.
458. Autoimmune Demyelination Induced i n Mice
at Different Stages of Central Nervous System
Maturation
M . E . Smith. M . K . Racke, C. S. Raine, and
H . F . McFarland. Bethesda, M D . and Bronx, N Y
We studied the effect of age at time of exposure to encephalitogenic T cells on the development of experimental allergic
encephalomyelitis (EAE), a model for multiple sclerosis. Myelin basic protein-specific encephalitogenic T cells were
adoptively transferred into SJL mice of various ages (2-10
weeks). Daily clinical examination and histopathology were
performed on recipient mice. Animals at 2 weeks of life
failed to develop typical acute EAE, while 10-week-old mice
developed clinical signs at the anticipated time (7-10 days
posttransfer [dpt}). The 4- to 6-week-old group showed delayed onset of EAE. Interestingly, by histology, both 2- and
10-week-old mice demonstrated comparable degrees of demyelination and inflammation at 7 dpt, while mice sensitized
at intermediate ages (4-6 weeks) demonstrated minimal disease. Ultimately, after delays that varied inversely with age at
transfer, all mice (including the original 2-week-olds) showed
clinical disease by 11 weeks of life. Levels of myelination,
programmed cell death, and antigen presentation to T cells
were found to vary with increasing maturity and susceptibility
to clinical disease. W e conclude that a process of autoimmune
demyelination can be initiated and persist throughout development without significant clinical manifestation until maturity. This suggests that in the development of clinical and
pathological signs of EAE, both encephalitogenic T cells and
additional host factors linked to maturation interact in the
expression of disease.
459. Long-Term Experience w i t h Gamma Globulin
Treatment of Childhood Chronic Relapsing
Idiopathic Polyneuropathy
Jay D . Cook. Galzieston, T X
Pulse gamma globulin (GG) was used to treat 10 children ( 4
girls, 6 boys; aged 6-18 years) who met the criteria for childhood chronic relapsing idiopathic polyneuropathy (CRIDP).
Pulse GG was used in 1 of 3 clinical settings: 1. dependent
on chronic pulse methylprednisolone (PMP), n = 1; 2. rapid
reduction of immunotherapy because of significant side effects, n = 4; and 3. nonambulatory or respiratory failure
refractory to PMP or plasma exchange, n = 5. All 10 patients
responded. The beneficial effects of GG pulsing occurred
within hours to days of the first dose. The beneficial responses were documented by Austin scores, hand grasp, and
timed ambulation. Post-GG Austin scores were improved
compared to pre-GG scores ( p < 0.05: median pre-GG =
5; post-GG = 2). Pre-GG scores were statistically improved
compared to post-GG for hand grasp ( p < 0.01) and timed
ambulation ( p < 0.001). Patients experienced minimal side
effects. Follow-up has ranged from 3 to 6 years (mean, 5.6
-+ 1.9 years). Three children no longer require medication,
4 receive GG only, and 3 require a combination of pulse
GG and immunosuppressant medication to maintain their
improved state. The complete remission in 30% of these
difficult CRIDP children indicates that initiating GG pulsing
does not evolve into continuous treatment dependency.
460. High-Dose Intravenous Serum Gamma Globulins
A r e Effective i n Severe Pediatric Guillain-Barre
Syndrome: A Prospective Follow-up Study of 23 Cases
Eli M. Shahar, Chaim M . Roifman. Zamir Shover,
Zohar Banilay, Yaacot. hi Natan Brand.
and E . Gordon Murphy. Beer Sheba, Israel,
and Toronto, Ontario, Canada
The effect of high-dose intravenous serum gamma globulins
(IVSG) was evaluated in an open prospective multicenter
study of 23 children with severe Guillain-Barre syndrome
(GBS). The patients presented at ages of 3 to 16 years with
mild-moderate flaccid weakness of extremities, along with
cranial nerve involvement in 18 and sensory nerve impairment in 20. All children rapidly deteriorated over a period
of 2 to 16 days (mean, 6 ) to become bedridden; 2 of them
also developed respiratory failure, requiring artificial ventilation (thus representing grades 4-5 of the GBS disability
grading scale). IVSG was then administered at a total dose
of 2 grn/kg, commonly over 2 consecutive days, without any
serious adverse effects requiring cessation of IVSG. Marked
and rapid improvement was noted in 22 children, improving
by 1 to 2 disability grade scales within 2 weeks after the
infusion. Eighteen were able to walk independently by 1
week, and 1 could be weaned from the ventilator. Sixteen
children recovered by 2 weeks, and the remainder recovered
within a period of up to 4 months. One patient temporarily
improved on IVSG, but then relapsed, requiring artificial
ventilation for 4 weeks. This child, who received a second
dose of IVSG, started walking independently after 2 months
and recovered by 4 months. The uniform, rapid improvement and recovery associated with IVSG therapy in 22 of
23 children with severe GBS seem to intercept the slow
natural course of recovery recorded in severe cases. We conclude that IVSG is an effective and harmless mode of therapy
in severe pediatric GBS, and, therefore, may serve as the
treatment of choice.
Program and Abstracts, Child Neurology Society
503
461. Localization of Semantic Processing Using
Functional Magnetic Resonance Imaging
B. A . Shaywitz, K. R. Pugh. R. T . Constable, S. E. Shaywitz.
R. T . Bronen. R. K. Fulbright, D . P. Shankuieiler, L. Katz.
J . M . Fletcher. P. Skudlarski. andJ. C. Gore,
New Haven. C T
The relationship between the functional components of language and the anatomic foci of their neural systems represents a central issue in cognitive neuroscience. Conflicting
results from a number of laboratories using positron emission
tomography have led to a significant controversy over the
specific neuroanatomic sites engaged by semantic processing-that is, whether semantic processing activates temporal or frontal regions. In these experiments, we used specifically designed cognitive tasks together with functional
magnetic resonance imaging to examine the neuroanatomic
loci of phonologic compared to lexical-semantic processing.
We studied 9 right-handed men performing 2 silent generation tasks: rhyme and semantic category. The former focuses
on word form (phonologic information), while the latter focuses on word meaning (semantic information). This study
represents the first functional imaging investigation of lexicalsemantic processing designed to equate the semantic and
control tasks on both memory search and response generation components. As such, it circumvents the limitations of
previous functional imaging studies of lexical-semantic processing, which tended to confound semantic processing with
other cognitive operations. Semantic processing makes demands on and activates widespread areas within the brain,
including the inferior frontal regions bilaterally and the left
posterior temporal region. Phonologic processing engages a
more restricted neuroanatomic assembly involving primarily
anterior left temporal lobe sites.
462. Identification of Cortical Language Areas Using
1.5 T Functional Magnetic Resonance Imaging
in Children with Epilepsy
W . D . Gaillard, L. Hertz-Pannier, S. Mott. S. Weinstein.
J . Coniy. M . Kolodgie, W . H . Theodore. and D . LeBihan,
Bethesda. M D . and Washington. DC
W e investigated the use of conventional 1.5 T magnetic resonance imaging (MRI) to identify language areas during cortical activation in 10 right-handed children (mean age, 12
years; 6 boys), 7 with partial epilepsy and 1 with juvenile
absence. We acquired 3 to 5 coronal 5-mm thick slices with
echo-planar imaging (TR = 4 sec; TE = 40 msec; flip angle,
90"; FOV, 16 cm; 64 x 6 4 matrix). Images were acquired
continuously, during periods of rest alternating with silent
word generation, and then reregistered to correct for motion.
Activated regions were identified by cross-correlation between signal time-course and a reference waveform. Five patients had a localized ictal electroencephalographic focus ( 3
left, 2 right). FMRI studies (75 minutes) were well-tolerated.
One subject had lateralized left inferior frontal gyms (IFG,
Broca) activation, confirmed by Wada test and surgery. Two
had no detected activation (secondary to motion), 7 had bilateral IFG activation, but more extensive in IFG of the presumed dominant hemisphere; 10 had premotor and cingulate
activation. FMRI is feasible and safe in children, and demonstrates regions of language activation. Bilateral activation may
be age or task dependent, or a result of language reorganization. FMRI is a promising tool, with minimal risk and discomfort, to study language and its development in children.
504 Annals of Neurology
463. Epilepsy Surgery in Children with Normal
or Nonspecific Neuroimaging Studies
Prasanna Jayakar. Michael Duchmc~ny,Tretior Resnick.
Luis Aloarez. and Glen Morrison, Miami. F L
Children with chronic epilepsy that is lesional in origin often
benefit from surgical therapy; but the outcome of surgery in
children who are nonlesional is less clear. We present 3 1
children (16 boys, 15 girls), aged 3 months to 11.4 years
(mean age, 4.7 years), with intractable seizures of temporal
( l l ) ,frontal (131, centroparietal ( 5 ) , or occipital ( 2 ) origin,
who had normal or nonspecific computed tomographic/magnetic resonance imaging scans. Positron emission tomographic scans revealed focal hypometabolism in 5 of 6 patients. Corticectomies (7) or Iobectomies ( 2 4 )were tailored
on the basis of the extraoperative subdural electroencephalographic evaluation and functional cortical mapping. In 19 patients, it was possible to excise the entire ictal and intericral
epileptogenic region. O f these, 14 are now seizure free, 1 is
90% improved, and 4 are less than 509; improved or are
unchanged at follow-up of 1.5 to 8 years. In 12 patients, the
ictal focus was removed, but involvement of critical cortex
prevented complete resection of the entire epileptogenic
zone. None of these patients is seizure free, and only 4 obtained even a partial reduction in seizure frequency. Our
findings suggest that children with chronic nonlesional epilepsy benefit from surgery only if the entire epileptogenic
region is removed. Involvement of eloquent cortex is, therefore, an important determinant of outcome, and cannot be
established preoperatively.
464. Dopamine Transporter Reuptake Sites
i n Tourette's Syndrome
Harvey S. Singer, Dean F . Wong.Janice Brown.
Stefan Marenco. Babbington Yung, Fuji Yokoi, Boon Chan.
Haya'en Rauert, William Matthews, John Miisachio.
and Robert F . Dannals. Baltimore. M D
The underlying pathophysiological mechanism in Tourette's
syndrome (TS) remains undetermined. In postmortem tissue
from 3 patients with TS we have previously identified increased numbers of striatal presynaptic dopamine (DA) carrier sites in the caudate and putamen using ['Hlmazindol
binding (Singer HS, Hahn I-H, Moran T, Abnormal dopamine uptake sites in postmortem striatum from patients with
Tourette's syndrome, Ann Neurol 1991;30:558). In an attempt to confirm this finding, we measured DA transporter
reuptake sites with ["CIWIN 35,428 positron emission tomography (PET). Ten men with T S (mean age, 30.9 years;
age range, 8-57 years) underwent a PET scan after receiving
approximately 20 mCi W I N 35,428 administered inrravenously. For each region of interest (caudate, putamen. cerebellum), images of D A transporter binding acquired 8 0 to 70
minutes after injection of tracer were obtained; an estimate of
specific binding was achieved by measuring caudate (CA)/
cerebellum (CB) and putamen (PUVCB ratios. Mean CAI
CB (TS, 3.7 t 0.2; control, 3.3 t 0.2) and PU/CB (Tourette's syndrome, 3.3 5 0.3; control, 3.4 t 0.3) ratios did
not differ between TS and age-matched controls. However,
when data were stratified based on age (less or greater than
28 years) those patients less than 28 years old (n = 5 ) had
a significant elevation in the CA/CB ratio (TS, 4.2 -C 0.3;
control, 3.2 ? 0.3; p < 0.05),and there was a higher trend
in the PU/CB ratio (TS, 4.8 t 0.4; control, 3.6 t 0.4).
Values were not influenced by age of onset of tics, tic severity, presence of obsessive-compulsive symptoms, or use of
Vol 36 N o 3 September 1994
tic-suppressing medications. This preliminary study suggests
that some adults, especially those less then age 28 years, have
a dopaminergic abnormality involving a significant alteration
of uptake sites.
465. Single-Photon Emission Computed Tomography
of Pediatric Brain Tumors: A Comparative Study of
Thallium-201 Chloride, 18F Fluorodeoxyglucose, and
q c Hexamethylpropyleneamineoxime
Bernard L. Maria and Walter E. Drane, Gainesville, FL
Thallium-20 1 chloride uptake is imaged with triple-headed
single-photon emission computed tomography (SPECT) in
histologically and anatomically diverse pediatric brain tumors
(Pediatr Neurosurg 1994;20: 11- 18). ‘*F Fluorodeoxyglucose (FDG) is the most common radiotracer used to assess
the value of positron emission tomographic scanning in grading and prognosticating human brain tumors. Because FDG
and thallium can be taken up by neoplastic cells, but FDG
is also taken up by normal brain cells, we hypothesized that
thallium-201 is a superior radiotracer to “F FDG in imaging
brain tumors. We developed a methodology for performing
FDG-SPECT of brain (Radiology, in press); the primary aim
of this study was to determine the comparative value of thallium-SPECT, FDG-SPECT, and 9 T c hexamethylpropyleneamineoxime (HMPAObSPECT for tumor and brain imaging. Each of the 13 patients with thallium-positive tumors
and 6 patients with thallium-negative tumors were injected
with 3 to 6 mCi of FDG and 5 to 15 mCi of HMPAO. FDG
tumor uptake was increased in 3 of 13 (23%) thalliumpositive tumors and 0 of 6 thallium-negative tumors. Magnetic resonance imaging was required to localize the neoplasm in the 3 FDG-positive cases, but not in any of the 13
thallium-positive cases. HMPAO tumor uptake was increased in 4 of 13 (31%) thallium-positive cases, and none
of these cases accumulated FDG. FDG uptake in brain surrounding tumor was decreased in 9 of 13 (6.396) thalliumpositive cases, including 6 of 7 (67%) who had received cranial irradiation. These results indicate that 1. thallium-SPECT
is superior to FDG-SPECT or HMPAO-SPECT in imaging
brain tumors, and 2. FDG-SPECT can detect alterations in
brain glucose metabolism surrounding the tumor that may
result from cranial irradiation. High-resolution thalliumSPECT is an important imaging adjunct to magnetic resonance imaging in the assessment of brain tumors. FDGSPECT may provide measures of brain metabolism in
patients undergoing therapy.
466. Evaluation of Optic Pathway Tumors: Natural
History and Treatment. Pediatric Oncology G r o u p
Study Preliminary Report
Michael E. Cohen, Donald H . Mahoney,Jr,
Patricia K. Duffner. Linda Gemer, Rita Linggood,
Hector E. James.James W. Lungston,Jonathan Sbuster,
John Fontanesi, Henry S. Friedman, and the Pediatric
Oncology Grorip, Buflalo, N Y
Between July 1789 and April 1994, the Pediatric Oncology
Group (POG)conducted a study (#8935136) with twogoals:
1. to evaluate the time to progression in untreated children
identified as having optic pathway tumors (OPT);and 2. to
determine treatment efficacy in those patients with OPT who
either developed progressive visual loss or increased tumor
size on sequential neuroimaging. A total of 107 patients were
registered. Sixty-two (57%) had neurofibromatosis. Thirty-
nine patients continue to be studied without progressive disease. Of these, 33 (73%) have neurofibromatosis. Seventy
patients were treated for progressive disease, of whom 29
(41%) have neurofibromatosis. At the time of progression,
where possible, patients had surgery. Pathology was a lowgrade astrocytoma in all cases (37). Patients less than 5 years
of age were treated with carboplatinum (560 mg/m2) for 18
months, and those children over 5 years received local radiation. Fifty-one children received chemotherapy (CT) and 19
received radiation therapy (RT). Of the 5 1 patients receiving
CT, 3 were over 5 years of age and received C T off protocol.
Of the 51 patients treated with CT, 19 had tumors of the
chiasm exceeding 3 x 3 cm in size. Of the 19 children who
received R T without CT, 1 developed progressive disease.
Of the 5 1 patients, 17 developed progressive disease on CT.
Four had completed 18 cycles of treatment. Seven went on
to R T at the time of progressive disease. The mean time to
progression in the failed group was 6 months (range, 1-31
months). Four patients have died. A partial response was
seen in 2 patients treated with CT. All the others have stable
disease. In patients with optic pathway tumors, those with
neurofibromatosis appear to have a more benign course than
patients without neurofibromatosis. In the presence of progressive disease of the optic pathway, carboplatinum in the
young and RT in the older child may be effective in delaying
further progression.
467. Improved Prognosis of Malignant Intracranial
Nongerminoma G e r m Cell T u m o r s
with Multimodality T h e r a p y
P . L. Robertson, R. C. DaRoJso. andJ. C. Allen.
Ann Arbor, M I , and Npw York. N Y
The 5-year survival for patients with malignant intracranial
nongerminoma germ cell tumors (NGGCT), which include
endodermal sinus tumors, embryonal carcinomas, choriocarcinomas, and immature teratomas, is less than 2 5 g following
a small resection and radiotherapy (XRT). In an effort to
improve therapy for these patients, an approach using an
attempt at radical resection, where feasible, followed by
multimodality “sandwich therapy (chemotherapy-XRTchemotherapy) was used to treat 17 newly diagnosed patients
between 1986 and 1992 in a multi-institutional study. Fourteen patients had histologically proven NGGCT, and 3 were
presumed N G G C T because of marked elevations of both
serumlcerebrospinal fluid a-fetoprotein and P-human chorionic gonadotropin. The primary tumor was confined to the
pineal region in 11 patients, to the suprasellar region in 5
patients, and in a cerebral hemisphere in 1 patient. Radical
surgical resection was performed in 11 (GTR, 6; PR, 5);
4 had bx and 2 had no surgery. All patients then received 3
or 4 cycles of neoadjuvant chemotherapy with cisplatin (100
mg/m2/cycle) and VP-16 (500 mg/m2/cycle). Of the 12 patients with evaluable disease, there were 9 responses to the
neoadjuvant chemotherapy (5 CR; 4 PR); 1 had stable disease and 2 progressed during chemotherapy; 5 patients with
no evaluable disease after a GTR had a continuous CR. Sixteen patients received XRT (local, 9; local + CS-XRT, 6;
local + whole brain, 1). Twelve patients received 4 cycles
post-XRT chemotherapy with vinblastine, bleomycin,
VP-16, and carboplatin; 2 patients died before receiving postXRT chemotherapy; and 3 patients refused it. A total of
4 patients have died (3, PD; 1, metabolic). Five-year progression-free and total survivals are 81% and 76%. The
combination of radical surgery and multimodality adjuvant
therapy appears to dramatically improve the outcome of malignant intracranial NGGCT.
Program and Abstracts, Child Neurology Society 505
468. Apoptosis Versus Differentiation: Subclone
Dependence of the Response of SK-N-SH Human
Neuroblastoma Cells to Enediyne Anticancer Drugs
Nina F . Schor. Pittsburgh. PA
We have previously shown that the enediyne anticancer drug,
neocarzinostatin (NCS) induces one of two changes in human
SK-N-SH neuroblastoma cells (Falcione et al, Biochem Pharmacol 1993;46:731-738). Within 6 to 24 hours after a 1hour exposure to NCS, 505% of the cells die. The surviving
cells undergo stable Schwann cell-like morphological change
and remain viable for at least two weeks after NCS treatment.
Our more recent studies demonstrate 1. that the cell death
seen in 50%’ of the SK-N-SH cells represents apoptosis;
2. that the cells that undergo apoptosis belong to the neuronlike SH-SY5Y subclone of SK-N-SH cells, while the cells
that undergo morphological differentiation belong to the epithelioid SH-EP1 subclone of SK-N-SH cells; and 3. that both
of these effects occur after exposure to any of the reactive
enediynes and can be obviated by continuous exposure of the
cells to nerve growth factor (NGF). Cells that are destined to
die after exposure to NCS and related reactive enediynes
fragment while maintaining membrane integrity; demonstrate nuclear chromatin condensation and fragmentation; can
be “rescued” by incubation with cycloheximide or aurintricarboxylic acid; and demonstrate fragmentation of cellular D N A
into internucleosomal-sized fragments ( 180 base pair multiples). Treatment of the isolated subclones of SK-N-SH cells
with NCS results in 100% apoptosis in the case of SH-SY5Y
cells, and 10Oq Schwann cell-like morphological change in
the case of SH-EP1 cells. Similar results have been obtained
with the enediynes enediyne-5, dynemicin, and calicheamicin, demonstrating that these effects are not unique to NCS.
Furthermore, treatment of SK-N-SH cells with N G F before,
during, and after NCS treatment results in prevention of
both apoptosis and Schwann cell-like differentiation.
469. Adenovirus-mediated Gene Transfer for
Treatment of Experimental Medulloblastoma
and Glioma
P. C. Phillips. Y. Yao. H. Huang. J . Wilson, a n d L. Sutton.
Philadelphia, PA
Transfection of the herpes thymidine kinase gene (HSVtk)
increases tumor sensitivity to gancyclovir (GCV) more than
1,000-fold. Retrovirus-mediated HSVtk transfection followed by GCV causes regression of murine and human gliomas; but this vector has poor infectivity, requires cotreatment with producer cells, and risks insertional
mutagenesis. To circumvent these problems, we used a replication-defective adenovirus (ADS) vector containing HSVtk
to evaluate in vitro and in vivo cytotoxicity in experimental
models of human medulloblastoma (DAOY) and 6 malignant
gliomas. Vector transfection efficiency was estimated with
AD5 containing the lacZ reporter gene. At infection ratios
of 100 viral particles per cell, P-galactosidase nuclear staining
was detected in 48 to 70% of cells. For in vitro cytotoxicity
studies (MTT or clonogenic assay), 50% of AD5tk-infected
medulloblastoma cells were killed (LD,,,) by 16 nM GCV,
whereas LD,, values for untransfected or ADJlacZtransfected controls were 290 and 300 mM, respectively.
For AD5tk-transfected glioblastoma cells, LD,, values ranged
from 10 to 200 nmol versus 200 to 650 mM for untransfected or AD5lacZ-transfected controls. Decreasing the
ratio of AD5tk-infected to uninfected DAOY or U25 1 cells
did not significantly reduce GCV cytotoxicity until the ratio
of infected:uninfected cells exceeded 1:20, confirming a by-
stander effect. In vivo experimenrs in nude mice bearing
subcutaneous xenografts showed tumor volume regression
or disappearance in 100% of D A O Y medulloblastoma and
92% of U251 glioma treated by AD5tk intratumoral injection followed by intraperitoneal (ip) GCV. Similarly treated
nude mice bearing intracranial (ic) DAOY or U25 1 showed
a mean increased life span (ILS) of 154% or 122‘3, respectively, versus untreated controls ( p < 0.001). A significant
survival advantage (ILS) was also observed when ic tumor
AD5tk-treated mice were compared to ic tumor-bearing
mice treated with ip BCNU, &-platinum, or cyclophosphamide. The impressive antitumor activity demonstrated by
these studies, against experimental brain tumor models that
have shown predictive utility in other preclinical evaluations,
justifies clinical trials with AD5tk + GCV for local control
of medulloblastoma and glioma.
470. Calcification of the Basal Ganglia in Children
with HIV Infection
Lucy Civitello, Pim Brouwers, Charles DeCavli,
and Phillip Pizzo, Washington. DC. and Bethesda. M D
The prevalence of neurodevelopmental abnormalities in children with symptomatic HIV infection ranges from 40 to
90%. A total of 85% of children with P2 disease have structural abnormalities on computed tomography (CT) scans.
One of the more characteristic findings is calcification (Ca)
of the basal ganglia, presumably related to the calcific vasculopathy seen at autopsy. Qualitative analysis of the most recent C T scans of 116 symptomatic HIV-infected children
was performed by 2 neurologists. When the presence of Ca
was noted, the patient’s age when Ca first appeared was determined through retrospective evaluation. All patients also underwent neuropsychological evaluations. Calcification was
seen in 21 of 58 patients (36%’)with vertical acquisition. In
these patients, Ca was first detected between 6 months and
6 years of age (mean, 1.9 years). All of these patients were
encephalopathic. Calcification was seen in 5 of 36 children
(14%) who acquired H I V through transfusions in the first
year of life. This rate is significantly different from the vertically infected patients, p < 0.02. Ca was first noted between
5.5 and 10.5 years (mean, 7.6 years) in this transfused group
of patients. Of 5 patients, 4 were transfused as premature
infants (25-33 weeks) and 1 was transfused at 6 months of
age. All were classified as encephalopathic. None of the 13
hemophiliacs and none of the 9 patients who acquired HIV
through transfusions after the first year of life had Ca. In
summary, 1. Ca occurred predominantly in children with vertical transmission, and less frequently in those who were
transfused within the first 6 months of life, particularly premature infants; 2. Ca tended to develop later in children with
transfusion-acquired disease; and 3. Ca may be a marker for
encephalopathy. This study suggests a selective vulnerability
of the basal ganglia blood vessels in the developing brain to
the effects of the human immunodeficiency virus.
47 1. TNFa-mediated Apoptosis in SK-N-MC
Neuroblastoma Cells: A Model for Neuronal
Cell Loss i n HIV-1-associated Dementia
Angela Tally, Seth Perryt Leon G . Epstein.
and Harrif A. Gelbard, Rochester. NY
An important feature of the neuropathogenesis of H1V-Iassociated dementia is neuronal loss in discrete areas of the
cortex and subcortical regions. No evidence for HIV-1 infection of neurons exists; but soluble neurotoxic factors may
mediate neuronal cell death. HIV-1-infected macrophages
produce high levels of the cytokine tumor necrosis factor
506 Annals of Neurology Vol 36 N o 3 September 1994
alpha (TNFa), and increased levels of mRNA for T N F a in
cortex and basal ganglia correlate with HIV- 1-associated dementia. We have demonstrated that T N F a is neurotoxic to
cultures of human fetal cortical neurons in a dose-dependent
fashion (0.2-1 ng/ml). Because T N F a has been implicated
in apoptotic cell death for other neural cells, we tested the
hypothesis that T N F a could induce programmed cell death
(apoptosis) in a neuroblastoma cell line (SK-N-MC) differentiated to a neuronal phenotype with 5 FM retinoic acid.
Apoptotic nuclei in SK-N-MC cells were identified by an in
situ method that uses terminal deoxynucleotidyl transferase
to bind digoxigenin-dUTP to free 3’-OH ends of newly
cleaved nuclear DNA. At a dose of 0.2 ng/ml, T N F a induces
apoptosis in SK-N-MC cells by 6 hours, reaching a maximum
at 48 hours. At a dose of 0.05 ng/ml TNFa, approximately
10% of SK-N-MC cells have apoptotic nuclei. At a dose of
25 ng/ml T N F a approximately 66% of SK-N-MC cells have
apoptotic nuclei. This dose-dependent increase in apoptotic
nuclei correlates well with a dose-dependent (same dose
range) decrease in cell viability, as measured by trypan blue
exclusion and enzymatic conversion of 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide. These studies
suggest that T N F a may induce apoptosis in neurons as a
possible mechanism for HIV- 1 neuropathogenesis. Current
experiments are focusing on interfering with signal transduction of T N F a to prevent neuronal apoptosis.
All children had been treated with prior radiation therapy
(conventional fractionation schedules: median dose, 54.5 Gy;
range, 54-60 Gy) and chemotherapy (nitrosoureas, 4 ; carboplatin, 8). Tumor recurrence was documented by radiographic tumor enlargement utilizing brain magnetic resonance imaging (MRI) with gadolinium enhancement (12
children) and clinical neurological deterioration ( 8 children).
Each cycle of therapy consisted of 2 1 days of VP-16 (50 mg/
m2/day), followed by 14 days of rest, followed by an additional 21 days of VP-16 (50 mg/m2/day). Complete blood
counts were followed biweekly and a neurological examination and MR scan were performed prior to initiation of each
cycle of therapy. Treatment-related complications included
partial alopecia (6), diarrhea (4),weight loss (3), neutropenia
( 3 ) , and thrombocytopenia ( 3 ) . Three children required
transfusion (3 red blood cell; 3 platelet) and 1 child required
antibiotic treatment of neutropenic fever. There were no
treatment-related deaths. All children were evaluated, of
whom 6 demonstrated a radiographic response ( 2 partial; 4
stable disease), with a median duration of response of 7
months. In summary, oral VP-16 is a well-tolerated and relatively nontoxic chemotherapeutic agent with apparent activity in this small cohort of children with recurrent, previously
treated cerebellar astrocytomas.
472. Apoptotic Neurons Are Present in Brains
from Children with HIV-1 Encephalitis
Harris A. Gelbard. Leroy Sharer, Harold James. Seth Pewy,
and Leon G. Epstein. Rochester, N Y . and Newark, NJ
Twenty children, aged 4 to 28 months (median, 12 months),
with medically refractory infantile spasms (IS) or the LennoxGastaut syndrome (LGS) were treated with the investigational oral benzodiazepine, nitrazepam (NTZ). Of 10 children with IS, 2 had cryptogenic spasms and the remaining 8
had symptomatic spasms. All children with IS had been
treated with ACTH (median dose, 60 units), resulting in
either no response (NR; 6 children) or a partial response
(PR; 4 children). All 10 children with LGS had symptomatic
etiologies, and all had been treated with high-dose valproic
acid (VPA) monotherapy (median dose, 100 mgikglday),
with either N R ( 4 ) or PR (6). Additional agents used both
in combination and as monotherapy included clonazepam
( 5 children), phenytoin (4),
and carbamazepine (4). Dose of
N T Z ranged from 0.5 to 3.5 mg/kg/day, with a median dose
of 1.5 mg/kg/day, divided twice per day. Side effects included sedation ( 6 children) and sialorrhea ( 1 2 ) ;however, no
serious adverse side effects were seen. All children with IS
were treated with single-agent NTZ, as were 3 children with
LGS. The remaining 7 children with LGS were treated with
combination therapy (NTZ and VPA). Responses to NTZ
were as follows: 5 complete responses (cessation of all seizures); 7 PR (>50% reduction of seizures), and 8 NR. In
conclusion, NTZ is an effective anticonvulsant in this small
cohort of children with medically refractory IS and LGS,
resulting in a 25% complete response rate and only modest
side effects.
Postmortem examination of brain tissue from patients with
HIV- 1-associated dementia demonstrates multinucleated giant cell formation, astrocyte proliferation, and neuronal cell
loss in discrete areas of the neocortex and subcortical regions.
The mechanism for this neuronal cell loss remains poorly
understood, but it is not due to direct viral infection of neurons. Soluble factors, including gene products from HIV-1,
cytokines, and arachidonic acid metabolites, have been implicated as neurotoxins. Using a light microscopic in situ
method to identify newly cleaved 3’-OHends of D N A with
antibody directed at digoxigenin-dUTP, we have identified
apoptotic nuclei in basal ganglia neurons from postmortem
tissue of children with HIV- 1 encephalitis and progressive
encephalopathy. In contrast, light microscopic analysis of cerebral cortex from postmortem tissue of children who are
HIV-1 seronegative (1 child with Duchenne’s muscular dystrophy and 1 child with a cerebral aneurysm and a DandyWalker cyst) revealed no apoptotic nuclei in neurons or other
neural cells, including astrocytes and microglia. These findings suggest that HIV-I infection of the central nervous
system in children may involve an apoptotic mechanism for
neuronal cell death. These findings may be important in designing therapeutic strategies directed at preventing neuronal
apoptosis.
473. Recurrent Cerebellar Gliomas: Salvage Therapy
with Oral VP-16
Marc C. Chamderluin. Sun Diego. CA
Twelve children (8 boys, 4 girls) with recurrent cerebellar
gliomas were treated with the oral topoisomerase inhibitor
VP-16 (etoposide). Patients ranged in age from 5 to 15 years,
with a median age of 7 years. Tumor histologies included 10
juvenile pilocytic astrocytomas and 2 anaplastic astrocytomas.
474. Nitrazepam for Refractory Infantile Spasms
and the Lennox-Gastaut Syndrome
Marc C. Chamberlain, San Diego. C A
475. Radical Surgery as the Sole Therapy
for Intracranial Low-Grade Ependymoma
Yasser Awaad, J e f f y Allen. DougIas C. Miller,
and Fred Epstein, New York, N Y
The optimum management of totally resected intracranial
low-grade ependymoma is controversial, but may include
postoperative radiotherapy and chemotherapy. The benefits
of additional therapy are uncertain, and its side effects may
be serious and long-lasting. Since 1989, our institution has
recommended deferral of adjuvant treatment when a radio-
Program and Abstracts, Child Neurology Society
507
logically confirmed total resection has been accomplished.
Seven patients, with a median age at diagnosis of 7 years
(range, 3-16 years), are in follow-up and are closely monitored with biannual magnetic resonance imaging (MRI).
There are 5 boys and 2 girls. The primary tumor was located
in the cerebrum (6) and cerebellum (1). Their prodromes
were short, averaging 1 month (range, 0.5-4 months), and
their initial symptoms reflected increased intracranial pressure (3), a seizure disorder (3), or speech difficulty (1).Postoperative MRI of the brain and spine confirmed totally resected disease without central nervous system metastasis. Of
the 7 patients, 6 remain in continuous remission after a median follow-up of 15 months (range, 3-46 months). The 1
patient who recurred at 11 months had a second total resection and remains in remission 12 months later. After a limited
period of follow-up, radical surgery alone seems to be an
acceptable method of treatment for intracranial low-grade
ependymoma. The management of low-grade intracranial
ependymoma is similar to that of other pediatric low-grade
gliomas; that is, radical surgery may be sufficient therapy.
476. A Negative Correlation of Soluble Interleukin-2
Receptor and T i t e r of Antibody to H u m a n
Acetylcholine Receptor
Masatoshi Hayashi, Tomohiko Takaoka, Kohji Manabe.
Itarti Yamada.Juiiji Yoshinaga. and Kaichi Kidu.
Ehime and Hirmhima.Japan
Myasthenia gravis (MG) is an autoimmune disease in which
autoreactive lymphocytes and autoantibody would occur, and
control of cytokine level would be deteriorated. Various autoimmune diseases were reported to have increased interleukin(IL)-2 or soluble IL-2 receptors (sIL-~R),which is associated with cellular immunity. To elucidate the balance of
immune response in MG, we studied slL-2R and antibody
to human acetylcholine receptor (AChR) in the clinical
course, as well as at onset. sIL-2R and AChR Ab were measured in 34 M G patients who had not yet received immunosuppressive therapy, and in 12 MG patients who received
immunosuppressive therapy, such as steroid or thymectomy,
to study the change in their clinical courses. Of 12 patients,
6 patients received only thymectomy, 5 patients were administered only steroid hormone, and 1 patient received both of
them. There was a good negative correlation between sIL-2R
and Ab titer to human AChR (n = 34; p < 0.01). Patients
with low AChR Ab titer had a high level of sIL-2R. Patients
treated with steroid showed a decrease in sIL-2R in parallel
to clinical improvement; patients with thymectomy showed
a transient increase and then decrease in sIL-2R. Of patients
with thymectomy, those with low titer of AChR Ab had good
responses to treatment, showing a decrease in both sIL-2R
and AChR Ab titer; but those with high titer of AChR Ab
showed a decrease in sIL-2R and, in contrast, an increase in
AChR Ab titer after thymectomy. This indicates that there
may be a heterogeneity of pathogenesis in M G where some
are associated with T h l and others with Th2, and that thymectomy induces clinical improvement in M G with a different mechanism from steroid hormone.
Fever sometimes induces seizures in patients with febrile
convulsions or epilepsy. Blood gas changes caused by hyper-
Vol 36 No 3
+
478. Cerebrospinal Fluid Kynurenine Metabolism in
Epileptic Children
Hitoshi Yamamoto, Bunsei Egauia, Kumiko Horiguchi. and
Hiroshi Murakami, Kawasaki. Japan
Recent studies have revealed that the kynurenines, metabolites of tryptophan, may moderate excitatory amino acid
transmission and may act as neuroactive agents in several
neurological diseases. In the present study, the levels of kynurenic acid (KYA) and 3-hydroxy-kynurenine (3-OHKY)
were measured in the cerebrospinal fluid (CSF) of epileptic
children and age-matched controls to determine the relationship between seizures and kynurenine metabolite levels. CSF
samples from 6 patients with West syndrome (WS), 4 patients with generalized epilepsy, and 4 patients with localization-related epilepsy were collected by lumbar puncture. The
concentrations of CSF kynurenine metabolites were analyzed
by HPLC with electrochemical detection and were compared
with those of age-matched controls. The levels of CSF KYA
were significantly lower in patients with WS, compared with
controls. In contrast, the levels of CSF 3-OHKY were significantly higher in WS than in controls. The levels of CSF
KYA and 3-OHKY in patients with generalized epilepsy and
with localization-related epilepsy did not differ significantly
from control levels. These results suggest that the presence
of seizures in WS is associated with altered turnover in the
direction of KYA to 3-OHKY. The possibility that seizures
in these epileptic children may be related to altered production of kynurenine metabolites is discussed.
479. Demyelinating Neuropathy as a Feature of
Mitochondrial Encephalomyopathy
James W. Teener and John T . Sladky, Philadelphia. PA
477. Effects of Blood Gas Changes on
Hyperthermia-induced Seizures
Takehiko Morinzoto. Kaichi Kidu. Hideo Nagao.
and Mitsunzasa Fukuda, Ehime, Japan
508 Annals of Neurology
ventilation accompanying fever, in addition to elevation of
the brain temperature itself, may contribute to the occurrence of seizures. Electrical seizure discharges were induced
by subjecting the brain to infrared irradiation in developing
rats (20-22 days of age), which were paralyzed with pancronium bromide and supported with an artificial ventilator. The
seizure threshold (ST; seconds), defined as the latency from
the start of heating until the appearance of seizure discharges
on electroencephalography (EEG), and seizure duration (SD;
seconds) were measured at various respiratory rates, and C 0 2
and 0, concentrations in the inspired air. Blood samples
were taken from the carotid artery immediately after seizure
induction and blood gases were analyzed. There was a positive correlation between Pcoz and ST: ST = 1.84 Pcoz
3.0 ( r = 0.82, R2 = 0.67, n = 9);there was a negative
correlation between Pcoz and SD: SD = 4788 Pcoz-'.'
( r = 0.84, R2 = 0.85, n = 9) at Po, levels ranging from
82 to 123 mm Hg. No significant correlation between Po,
and SD, and a negative correlation between Po, and ST
(ST = 8010 Po2-'.04 [ r - -0.57, R2 = 0.39, n = 111)
were recognized at Pcoz levels ranging from 39 to 49 mm
Hg. These results suggest that hyperventilation caused by
fever facilitates the occurrence of fever-induced seizures by
lowering the Pco, level. The suppression of ventilation during seizures probably plays a role in seizure arrest by increasing Pco, and lowering the Po, level.
Peripheral neuropathy is an occasionally mentioned, but
poorly described, feature of the mitochondrial encephalomyopathies. Four patients from three families with demyelinating neuropathy as a prominent feature of their mitochondrial
cytopathy are presented. In 2 patients, the electrophysiology,
September 1994
clinical signs and symptoms, and histopathology mimicked an
acquired demyelinating neuropathy to the extent that these
patients were treated with immunosuppression. Features of
demyelination, including myelin debris, thinly myelinated
fibers, onion bulbs, and demyelinated axons, are seen in the
nerve biopsies. Endoneurial and perineurial edema are also
present. In 2 patients, nerve conduction velocities are slowed
to the point of meeting diagnostic criteria for demyelinating
neuropathy. In the other patients, the velocities are slowed
to suspicious, but not diagnostic, levels. In all patients, needle
electromyographic examination demonstrates small polyphasic units with early full recruitment, consistent with myopathy. The electrophysiological finding of myopathic units
in combination with moderate to severe slowing of conduction velocities can be a feature of the mitochondrial encephalomyopathies, and should prompt further evaluation for
these disorders.
480. Pyridoxine-dependent Epilepsy: The Need for
Repeated Trials and the Risk of Electrocerebral
Silence with Intravenous Infusion
Nancy E. Bass. Elaine Wyliie. Bruce Cohen.
and S. Anne Joseph, Cleveland, OH
Most authors suggest that failure to stop seizures with a single
intravenous injection of pyridoxine, 50 to 100 mg, eliminates
the possibility of pyridoxine-dependent seizures. We report
an infant with persistent seizures until the third trial. She first
had left and right clonic seizures at 6 days old after a normal
pregnancy and delivery. She was given 100 mg of pyridoxine
IV on day 6 of life with no change in her electroencephalogram (EEG) or seizures. Seizures and recurrent status epilepticus continued despite phenobarbital (150 mg/L) and phenytoin (60 mg/L). EEG showed multifocal spikes and seizures
arising from the left and right parietal regions. Pyridoxine,
100 mg IV, was again given at 3 months during an episode
of status epilepticus, again with no change in the EEG or
seizures. The patient was challenged a third time at 8 months
during status epilepticus, 50 mg of pyridoxine by slow IV
drip. Four minutes after infusion, the EEG changed from
continual generalized spikes to electrocerebral silence for 15
hours. One day after infusion, the patient had a single focal
seizure for 10 minutes; but, she had no seizures since then
for 6 months on pyridoxine 8 mg/kg/day PO, off all other
antiepileptic medications. At 1 year old, she has made dramatic developmental progress. This case illustrates that failure to respond to a single trial of IV pyridoxine does not
rule out the possibility of pyridoxine-dependent seizures.
The occurrence of an isoelectric EEG after IV pyridoxine
has been rarely reported, and may be due to a sudden
massive increase in the inhibitory neurotransmitter yaminobutyric acid following abrupt activation ofglutamic acid
decarboxylation by infusion of its coenzyme. Because of this
potential complication, oral pyridoxine trials may be safer,
for example, 100 to 300 mg/day for 3 days. Repeated trials
may be appropriate for infants with refractory seizures if an
initial trial has failed.
481. TcwmHMPAO-Single-Photon Emission
Computed Tomography in Patients w i t h Migrational
Disorders
Sarenur Tutuncuoglu, Hasan Tekgiil, Yusuf Duman, and
Nuri Sener. Izmir, Turkey
Neuronal migration is one of the central nervous system
developmental periods that occurs between 3 and 5 months
of gestation. Neurons located at ventricular and subventricu-
lar zones move toward the cortical area, where they will reside along life (Volpe JJ, Neurology of the newborn, 2nd ed,
Philadelphia, WB Saunders, 1987:33-49). Any insult to the
brain during this period results in a migration anomaly. The
cerebral cortex is usually thickened due to disorganized layers of neurons whose migration has been prematurely halted.
Chromosomal anomalies, infections, and vascular insults are
considered to be responsible for the pathogenesis of these
anomalies. The idea of genetic factors and genetic susceptibility to the pathogenesis is emphasized in some disorders (Barkovich AJ, Chwang SH, Norman D , MR of neuronal migration anomalies, AJR 1988;150:179-187; Byrd SE, Osborn
RE, Bohan TP, Naidich TP, The C T and MR evaluation of
migrational disorders of the brain (part I), Pediatr Radio1
1989;19:151-156). W e present 7 patients with neuronal migration disorders studied by MRI and brain single-photon
emission computed tomography (SPECT). Microcephaly, developmental delay, epilepsy, and spasticity were the clinical
findings, as reported in the literature (Aniskiewicz AS, Frumkin NL, Brady DE, et al, Magnetic resonance imaging and
neurobehavioral correlates in schizencephaly, Arch Neurol
1990;47:911-916; Barkovich AJ, Norman D. MR imaging
of schizencephaly, AJR 1988;150:1391-1396). The rate of
consanguineous marriage in our study group was 42%, which
exceeds the average rate in Turkey (20%).This finding suggests that genetic factors may play a role in migrational disorders. MRI and T C ~ ~
HMPAO-SPECT
"'
were performed for
all patients. Migrational disorders detected by MRI were:
schizencephaly in 2 patients, hemimegalencephaly in 1 patient, and pachygyria in 4 patients. Brain SPECT showed
perfusion loss on the cleft side in schizencephalic patients.
In hemimegalencephalic patients, SPECT revealed hypoperfusion on the opposite side of megalencephaly. The patients
with pachygyria prominently displayed hypoperfusion on the
frontal and parieto-occipital areas, which were consistent with
the findings detected by MRI. We conclude that brain
SPECT demonstrated more widespread areas of cortical dysplasia than revealed by MRI.
482. Complicated "Migraine-like'' Headaches in
Children Following Cranial Irradiation and
Chemotherapy
Roger J . Packer, Gilbert Vezina. H . Stacy Niiholson,
and Deborah LaFond, Washington. DC
A multitude of neurological sequelae may occur months to
years following cranial irradiation. Children are especially
prone to neurological compromise; the vascular endothelium
has been implicated as the site of primary damage, with resultant strokes, hemorrhages, and necrosis. Over a two-year period, 4 patients with brain tumors, a median of 11 years at
diagnosis (range, 6.5- 11.5 years) developed severe intermittent unilateral headaches associated with nausea ( 4 ) ,episodic
visual loss ( 3 ) , hemiparesis (3), aphasia ( 4 ) ,and/or hemisensory loss ( 4 ) .Symptoms and signs varied during attacks, alternating between hemispheres and lasting 2 to 24 hours. Symptoms began between 1.2 and 2.8 years from diagnosis, when
all had stable disease and were off of treatment. All patients
had posterior fossa tumors (3 primitive neuroectodermal and
1 ependymoma) and had previously received whole brain
(2,400-3,600 cGy) and local boost (5,400 cGy) cranial irradiation and cisplatin, CCNU, and vincristine containing chemotherapy regimens. N o patients had previous similar headaches or a family history of migraine. Evaluations in all
included unchanged magnetic resonance (MR) scans and normal cerebrospinal fluid cytologies, electroencephalograms
(except for focal slowing), MR angiograms, and echocardio-
Program and Abstracts, Child Neurology Society 5 0 9
grams. Three patients had cerebral angiograms, which were
normal, but precipitated severe unilateral or posterior headaches and focal neurological deficits (hemiparesis in 1 and
visual loss in 2), resolving over 24 and 48 hours. Response
to treatment with aspirin, propranolol, and/or verapamil was
variable, although the overall frequency and severity of spells
decreased over the ensuing 3- to 6-month period. Autopsy
in 1 child, who subsequently died from tumor recurrence,
demonstrated no vascular disease. W e conclude that 1. complicated migraine-like episodes may occur in children after
cranial irradiation and chemotherapy and are a sequelae of
therapy; 2. these headaches may not be the harbinger of
impending strokes, severe intracranial vasculitis, or tumor
recurrence; 3. they may spontaneously improve; and 4. these
patients may transiently worsen after cerebral angiography.
483. The Use of Invasive Chronic Intracranial
Monitoring from Bilateral Subdural Strip Electrodes to
Lateralize Epileptogenic Foci in Children Undergoing
Epilepsy Surgery
0. C . Snead Ill. 5’. R. Kongelbeck, W. G. Mitchel(.
L. S. Chen, and C. Raffel. Los Angeles. C A
The epileptogenic zone in children undergoing evaluation
for epilepsy surgery is often extratemporal and requires ictal
recording from chronically implanted subdural electrode
grids for localization. We report 6 children, ranging in age
from 6 months to 12 years (mean. 6.6 years), in whom
chronic recording from bilateral subdural strips was required
to lateralize the epileptogenic zone preparatory to placement
of a subdural electrode grid for localization and subsequent
excision. All children demonstrated clinical evidence of partial seizures, but had discordant electroencephalogram, neuroimaging, and clinical data, which made lateralization of the
focus, and, therefore, selection of the appropriate side for
grid placement, impossible. All children had 4 contact silastic
electrode strips placed bilaterally through burr holes over the
lateral, mesial, and subfrontal regions, as well as over the
lateral and mesial temporal areas. Seizures were recorded
extraoperatively over a period of 3 to 8 days, and the strips
were then removed. One child was rejected for further surgery because of bilateral seizure discharges. Five children
returned to surgery for subdural grid placement over the side
lateralized by the subdural strip recordings with subsequent
focal cortical resection of the epileptogenic zone. This technique makes surgery an option for those children with intractable seizures who would otherwise be excluded from surgical consideration because of an inability to lateralize the
seizure focus by noninvasive means.
484. Does Fluid Restriction Improve t h e Outcome of
Acute Meningitis?
Prutibha D. Singhi, S. C . Singhi. B. Srinivas.
11. P. Narakesari. N.K . Ganguly, R. Sialy. R. Prasad.
and 8.N.S . Walia, Chandigarh, India
Fluid restriction is routinely recommended in acute meningitis. No controlled study exists to support this. We evaluated
the role of restricted fluid therapy in 2 groups of 50 consecutively hospitalized children with acute meningitis: 1. with and
2. without SIADH. They were randomly assigned to receive
either maintenance (M) or restricted (R) (60-70P of M)
fluids during the first 48 hours. Total body water (TBW),
extracellular water (ECW), serum sodium (SNa), and osmolality were measured at admission and after 48 hours. The
mean TBW and ECW showed a significant decrease in children on R fluids, whereas they remained unchanged in those
510 Annals of Neurology
Vol 36 No 3
on M fluids. The outcome did not differ significantly in the
2 groups. For further analysis, the data were divided into 2
groups: 1. those patients with 3% or more and 2. those
patients with less than 3% or no reduction of ECW in 48
hours. In group 1, the intact survival (10 of 28; 36T) was
significantly lower than that of group 2 (14 of 22; 6 4 p ) ( p
< 0.05), and the mortality (7 of 28; 25%) higher than that
of group 2 (2 of 22; 9%). The 2 groups were similar in their
clinical characteristics, including severity of the illness. We
conclude that fluid restriction does not improve the outcome
of acute meningitis.
485. Ethical Issues i n Managed and Rationed Care for
Children with Severe Neurological Disabilities: Results
of a Questionnaire Sent to Members of the Child
Neurology Society
The CNS Ethics Committee: Dasid L. Coulter.
Stephen Ashwal, Bhuwan P. Garg. Carol R. Leicher.
D. Alan Shewmom Theodore R. Sunder, and
M a 0 Zupanc
A total of 246 Child Neurology Society members (222 active, 18 junior, 5 retired, 1 NA) returned a questionnaire
mailed in September 1993 to all members. Respondents
were about equally divided between academic and private
practice, and averaged 14.8 years of child neurology practice.
Four questions explored what care is medically indicated, 6
questions explored whether all medically indicated care
should always be provided, and 5 questions explored how
this care should be managed or rationed. Narrative comments were encouraged to amplify a yesino response. In
general, respondents felt that medically indicated care should
be demonstrably effective and should enhance functioning,
but noted the lack of good data in this regard. Cardiopulmonary resuscitation was not felt to be indicated late in the
course of degenerative diseases or in PVS. Respondents felt
that provision of care should be influenced by cost, quality
of life, and family wishes; but how to assess and respond to
these influences was not at all clear. Most respondents felt
that making these decisions should be a team process involving the child neurologist, primary care physician, and family.
Managing care for these children might be helped by practice
guidelines or service coordinators; but most respondents rejected caps or financial limits. A total of 8 2 2 felt the Child
Neurology Society should take a position on these ethical
issues.
486. Carnitine Deficiency in Neonatal Seizures
David L. Coulter, Boston. M A
Carnitine facilitates energy metabolism by shuttling acyl
groups into and out of the mitochondrion and maintaining
the availability of free coenzyme A within the mitochondrion. Some neonatal disorders (such as asphyxia) impair mitochondrial function, while neonatal seizures increase metabolic demand. This prospective study tested the hypothesis
that plasma carnitine deficiency is associated with neonatal
seizure activity. Plasma total and free carnitine levels were
measured in 18 neonates with seizures (gestational age.
27-41 weeks at birth). Infants with known or suspected metabolic disease were excluded. Ten infmts had birth asphyxia,
and 5 infants were receiving TPN. Mean total carnitine level
was 2 1.1 ? 12.8, and mean free carnicine level was 15.7 t
9.4 pmol/L in those infants with seizures. Total and free
carnitine levels were significantly lower ( p < 0.0 1) in infants
with seizures than in laboratory normals and in 5 neonatal
intensive care unit control infants without seizures (mean
September I994
total carnitine, 49.2 2 13.7; mean free carnitine, 39.4 k
10.8). Carnitine deficiency (free carnitine less than 2 S D below the mean for controls) was present in 13 infants with
seizures and in none of the controls. The data indicate that
plasma carnitine deficiency is a common finding in neonates
with seizures. I t may reflect a state of metabolic insufficiency
that increases the risk of seizure activity. This state may be
treatable or preventable.
487. T h e Value of Brain Imaging in Children
with Headaches
Joseph Maytal, Theresa Amigo, and Lydia Eviatar.
N m Hyde Park, N Y
Headache is a common problem in pediatric patients. With
the increasing practice of “defensive medicine,” neuroimaging is widely used to evaluate headache. Our objective was
to study the value of brain imaging in the form of computed
tomographic (CT) or magnetic resonance imaging (MRI)
scans in children with normal neurological exam referred for
evaluation of headaches. The charts of all children referred
to the pediatric neurology clinic for evaluation of headaches
over a period of 1 year (1992-1993) were reviewed. The
records for each child were evaluated for headache characteristics and results of brain imaging. A total of 101 patients
was included. Ages ranged from 3 to 16 years. Migraine
was diagnosed in 5 5 patients (54%); muscular tension was
diagnosed in 15 patients ( 1 5 % ) ; 1 patient’s headache was
related to prednisone; 1 patient’s headache was related to
sinus infection; and 1 headache was judged psychogenic. In
28 patients (28%), headaches remained unclassified. Neurological examination was assessed as normal in all patients. A
total of 40 patients (39%))had brain imaging: 24 had MRI,
9 had CT, 7 patients had both. One C T and 4 MRI studies
were abnormal, 2 showed an arachnoid cyst, and 3 showed
chronic sinus inflammation. All imaging findings were
deemed incidental. Many physicians feel uncomfortable
when dealing with headaches in children. This anxiety, coupled with parental concern about the headaches, may influence the decision regarding the need for brain imaging. Neuroimaging studies, while relatively safe, are expensive, and
also carry the additional risk of deep sedation. These should
be limited to headache patients with clinical evidence of an
underlying structural lesion and to patients with atypical
headache patterns.
in utero or in the perinatal period. Two surviving sons had
normal MFU scans and were clinically normal. This family
has inherited NMD with sex-linked phenotypes, supporting
X-linked dominant inheritance. Familial N M D with lissencephaly in surviving male offspring has been described,
but presumably affected men in this family were nonviable.
Awareness of the sex-linked dominant inheritance of this
disorder is of major importance because mildly affected
women may not be recognized, and the serious genetic implications may be overlooked. This family affords the opportunity to identify a gene critical to normal neuronal migration.
489. O n the Wisdom of High-Dose Steroids During
Circulatory Arrest for Infant Open-Heart Surgery
Jean Holowacb Thurston and Richard E. Hauhart.
St Louis, MO
A major concern in infants undergoing hypothermic circulatory arrest or low-flow cardiopulmonary bypass for heart surgery is the risk of hypoxic/ischemic brain damage and abnormal neurological sequelae. In a recent study (NewburgerJW,
et al, A comparison of the perioperative neurological effects
of hypothermic circulatory arrest versus low-flow cardiopulmonary bypass in infant heart surgery, N Engl J Med 1993;
3291057-1064), young infants (all aged <3 months; most
aged < 1 month) received 30 mg/kg of methylprednisolone
(Meth-Pred) at onset of bypass. W e found this practice disturbing, since pretreatment ( 2 hours) of 16 normal 5- to
9-day-old mice with 20 mg/kg of dexamethasone (DXM) sc
reduced their time of survival in pure N2 gas 43CX, 5.22 2
0.72 minutes versus 9.16 t 1.07 minutes in controls (Thurston JH, Hauhart RE,Dirgo JA, A single dose of dexamerhasone increases the brain carbohydrate reserve but decreases
anoxic survival of developing mice: a most unexpected adverse complication, Clin Res 1993;41(3):626A). Pretreatment with D X M also increased mortality during anoxia in
adult rats (Plum F, Alvord EC Jr, Posner PB, Effect of steroids on experimental cerebral infarction, Arch Neurol 1963;
9571-573) and cerebral hypoxia/ischemia in infant rats (Altman DI, Young RSK, Yagel SK, Effects of dexamethasone
in hypoxic-ischemic brain injury in the neonatal rat, Biol
Neonate 1984;46:149- 156). I t seemed important to exclude
a similar ill effect of Meth-Pred on anoxic tolerance. Eighteen
9-day-old mice were exposed to N2gas 3 hours after sc injection of 30 mglkg of Meth-Pred or 0.9% NaCl. Duration
0.61 minutes in
of anoxic survival was unchanged, 5.15
steroid-treated mice versus 5.64 2 0.43 minutes in controls.
However, the real issue is potential steroid-induced longterm neurological deficits. It is highly relevant that even treatment of normal nonhypoxic 6-day-old rats with a single injection of 0.8 mg of Meth-Pred decreased brain weight and
delayed myelination (Gumbinas M, Oda M, Huttenlocher P,
The effects of corticosteroids on myelination of the developing rat brain, Biol Neonate 1973;22:355-366). The data
suggest a need for a comparison of the neurological outcome
of infants who do, or do not, receive high doses ofglucocorticoids during hypothermic circulatory arrest or low-flow cardiopulmonary bypass for cardiac surgery.
*
488. Familial Band Heterotopias: A n X-Linked
Dominant Disorder with Variable Severity
Ingrid E. Scheffer. L. Anne Mitchell, R. Anne Howell,
Gregovy Fitt, Ari Syngeniotis, Michael Saling, and
Samuel F. Berkozic, Melbourne, Australia
A spectrum of generalized neuronal migration disorders
(NMD) associated with epilepsy has been recently identified
incorporating periventricular heterotopias, band heterotopias
(“double cortex”), pachygyria, and lissencephaly. These malformations are usually sporadic, although maternal transmission has been reported. We describe a family whose pedigree
lends further support to X-linked dominant inheritance of
NMD. The proband presented with intractable partial epilepsy and severe cognitive impairment. H e r mother was of
borderline intellect with partial epilepsy, and her sister had
learning difficulties. MRI scans on all three women showed
bilateral band heterotopias, predominantly in the frontal and
occipital regions, with pachygyria centrally. The severity of
cognitive impairment correlated with more extensive pachygyria. There was a maternal history of loss of 3 male offspring
430. Clinical Correlation of Cranial Magnetic
Resonance i n Children with Developmental Delay
Maurine Packard, Rick Risser, and Nancy K . Rollins.
Dallas, T X
Magnetic resonance (MR) studies of 100 children with developmental delay were correlated with history and physical
Program and Abstracts, Child Neurology Society 511
findings to determine specific indications for MR in this setting. MR scans were reviewed blinded to clinical findings for
presence and distribution of gliosis, ventriculomegaly, brainstem/basal ganglia (BSBG) abnormalities, thin corpus callosum (CC), and myelination. Sixty-three scans were abnormal.
Increased DTRs and increased muscle tone correlated with
gliosis, ventriculomegaly, BSBG abnormalities, and thin CC
(range, p < 0.001-0.039). Very delayed motor skills correlated with ventriculomegaly, BSBG abnormalities, and thin
CC (range, p = 0.006-0.035). Paresis correlated with ventriculomegaly, BSBG abnormalities, and thin CC (range,
p < 0.003-0.04 1). Prematurity correlated with ventriculomegaly, gliosis, and thin CC (range,p < 0.001-0.031). Perinatal asphyxia or stroke correlated with thin CC and BSBG
abnormalities (range, p = 0.0014-0.024). Delay in myelination correlated with age under 2 years ( p = 0.006), failure
to thrive ( p = 0.0016), and seizures ( p = 0.043). Delay in
language, hypotonia, sensory deficits, dysmorphic features,
chronic medical problems, and maternal drug use did not
correlate with any MR findings. In conclusion, physical findings suggestive of upper motor neuron dysfunction, severe
motor delays, and birth history correlate best with abnormalities on MR scans; language delays or hypotonia are less likely
to yield abnormal MRIs.
491. Brain Glucose Metabolism in Children with
Arachnoid Cysts
Anne G . De Volder. Christian Michel, Christran Thauzioy.
Ge'rard Fewiire. Marie C. Belpaire. and Philippe Eward.
Louziain-la-Neuw, Belgium
Regional brain glucose utilization was investigated for the
first time in 4 children before and after shunting of an intracranial arachnoid cyst. Studies were carried out with positron
emission tomography (PET), using an ECAT 111 tomograph
and the fluorodeoxyglucose (FDG)autoradiographic method.
In 3 patients (aged 10, 2, and 6 years), a middle fossa arachnoid cyst was associated with acquired epileptic aphasia, developmental d ysphasia with hemiparesis, and refractory headache, respectively. In a fourth patient (aged 13), who was
affected by epilepsy, the cyst location was frontal. Although
magnetic resonance imaging failed to disclose any tendency
toward expansion, the local patterns of glucose utilization
displayed drastic alterations in all cortical regions surrounding
the cyst, suggesting chronic compression of the developing
brain. Extradural pressure monitoring gave high values in 1
patient and doubtful results in 2 other patients. A subsequent
cyst-peritoneal shunting led to diminished cyst size and
marked clinical improvement. The postoperative PET studies
demonstrated a significant increase in glucose utilization in
all previously affected areas. These data suggest that PET/
FDG are able to evaluate the functional disturbances associated with expanding arachnoid cysts and to follow the neurological improvement after drainage. They might offer superior diagnostic information to determine whether surgery is
necessary.
492. Value Of E1ectroencephalographic
Television Monitoring i n Pediatric Neurological
Practice
S h a d Thirumlai. Bassel Abou-KhaliL and Toufc Fakhoury,
Nashzdle, T N
We evaluated the utility of electroencephalographic closedcircuit television (EEG-CCTV) monitoring in 193 consecutive pediatric patients referred to our Epilepsy Unit for un-
512
Annals of Neurology
usual o r refractory attacks. Both outpatient short studies
(2-8 hours) and inpatient long studies (24 hours or longer)
were performed. An attack was captured in the first study in
two thirds of the patients. Short studies were successful in
585% of patients; long studies were successful in all patients.
The yield of short studies was higher under age 12 years.
EEG-CCTV was repeated in 25% of those patients without
a recorded attack, and was successful in 7 5 9 . Among those
patients with attacks recorded on the first study, 49qt had
nonepilepric seizures, 2 1V had generalized seizures, and
34% had partial seizures. Implications for management were
present in 97% of those patients with documented attacks.
A favorable influence on outcome was seen in 759;) of those
with follow-up data. W e conclude that EEG-CCTV is of considerable value in definitive diagnosis and rational management of seizures in children.
493. Treatment of Patients w i t h Both Migraine
Headaches and Tourette's Complex
Diana L. Ross, Cinrinnati. OH
In the past 2 years, I have treated 46 children with both
migraine headaches and at least 2 features of Tourette's complex. Eighty-three percent were boys, with a median age of
10 years at first contact. The median age in girls was 8 years.
The most frequent presenting complaint was headache; but,
some patients presented with tic, attention deficit hyperactivity disorder (ADHD), or other problems, such as seizure or
tremor. The majority had had no prior treatment. All ,i6
children had headaches compatible with migraine, and most
had a positive family history for migraine. Thirty-eight (83%)
had multiple tics. Thirty (65%) had significant attentional
deficit, and several others had mild indications of attention
deficit disorder ( A D D ) or positive family history. Twentynine (635%) had obsessive-compulsive habits (mainly touching or chewing behaviors); but morbid fears, excessive perfectionism, and obesity related to compulsive eating were
also noted. Two other subjects were significantly obese; but,
compulsive habits were not elicited. Five children had a myoclonic disorder: 1 infantile myoclonus, 1 action myoclonus,
2 massive myoclonic movement disorder who also had tics
at separate times, and 1 juvenile myoclonic epilepsy. Four
children had seizure disorders, 2 with motor arrests and absence with synchronous polyspikes and 2 with benign rolandic epilepsy. Five children had enuresis beyond age 10. Migraine headaches were treated with Inderal in doses from 60
to 120 mg/day with full control in most patients. All subjects
who were treated with Inderal and who also had mild to
moderate (1-3 + 1 tics showed substantial improvement in
the tic, from 80 to 1007; controlled, generally within the
first month of treatment, and without any undesirable side
effects. Two subjects with more active tic (4 and 5 + ) were
also significantly improved; but, 1 patient achieved better
control with the addition of a small dose of clonidine. No
subject who was treated with Ritalin in doses up to 20 mg
SR BID showed any worsening of preexisting tics. Ten subjects had thyroid functions (T4, TSH) checked. -Dartlv. due
to the reporied association of thyroid receptor disorder with
A D H D (Ciarenello RD, Attention deficit-hyperactivity diSorder and resistance to thyroid hormone-a new idea? N
Engl J Med 1993;328:1038-1039). All were normal. My
main purpose in reporting this experience is to suggest the
effectiveness of Inderal in the management of multide tics.
especially in milder severity, where treatment with sedative
medications is commonly withheld. From family histories
obtained, I do not believe the association of migraine and
Vol 36 No 3 September 1994
+
Tourette's complex to represent genetic linkage between the
disorders, but rather, a common chemical substrate that can
be affected by beta blockade. Choreoathetosis, a movement
disorder that resembles multiple tics, can be a presenting
manifestation of thyrotoxicosis and is effectively treated with
beta blockade (Tonner DR, Schlechte JA, Neurologic complications of thyroid disease and parathyroid disease, Med
Clin North Am 1993;77;251-263). It has been suggested
that the movement disorder occurs through catecholamine
augmentation by thyroxine at the receptor or up-regulation
of the receptor. Similar receptor mechanisms may apply to
migraine and Tourette's complex.
494. Clinical Correlation of Periodic Lateralized
Epileptiform Discharges i n Children
Bhuuian P . Garg and Nema Patel. Indianapolis, IN
in neuronal cultures, where neural activity, growth factors,
neuromodulators, and neurotransmitter agonists and antagonists can be experimentally varied, free from the complexity
in vivo. Such studies will give insight into regulation of neural
genes and interactions with learning and diseases. Epilepsy is
an obvious example for K + channel genes; but most diseases
of the brain must involve primary or secondary changes in
gene expression, suggesting the possibility of novel therapies.
496. Psychogenic Seizures i n Children
and Adolescents
Christine O'Dell. Linda Lightstone. Karen Ballaban-Gif,
Harriet Kang, Bernard Wyszynski, Kathleen Maloney-Lutz,
Solomon L. Moshe. and Shlomo Shinnar, Bronx, N Y
Periodic lateralized epileptiform discharges (PLEDs) are electroencephalographic phenomena characterized by lateralited
or focal moderate- to high-voltage, spike-wave complexes
occurring in a periodic or pseudoperiodic pattern. Bilateral
periodic lateral epileptiform discharges (BIPLEDs) are usually independent, but rarely synchronous, over the two hemispheres. Limited information is available about the clinical
significance of PLEDs in children. We report 15 children
with PLEDs (age range, 3 months to 17 years). Of the I 5
children, 11 had PLEDs and 4 had BIPLEDs. Clinical diagnoses were: prior epilepsy, 6; viral encephalitis, 2 (1 with a
history of epilepsy); leukemia, 3; congenital heart disease, 2;
and 1 each with acute liver failure, heat stroke with anoxia,
and postinfectious encephalitis. Though all patients had seizures, 6 had status epilepticus. Overall, 8 of 15 patients died
(2 of 6 patients with prior epilepsy and 6 of 9 patients with
new-onset seizures). Of the 7 surviving patients, 4 had neurological deficit ( 3 had preexisting and 1 had new-onset deficit).
Of the remaining 3 survivors with no neurological deficit, 2
have partial seizures. Only 1 of our 15 patients in this series
has no sequelae. Patients with BIPLEDs had no worse outcome than those with PLEDs. We conclude that PLEDs children have a poor prognosis with a high mortality and morbidity.
From June 1991 to March 1994, 17 children and adolescents
under 21 years of age with video-EEG monitoring documented psychogenic seizures were evaluated in our inpatient
epilepsy unit. They comprised 6 p of all pediatric admissions
to the unit during that time period. The mean age was 13.6
years (range, 8-19 years). I n contrast to the strong female
preponderance seen in adult series including our own adult
patients, there were 8 (47%) boys and 9 ( 5 3 % ) girls. Among
the 4 children under 12 years of age, there were 3 boys and
1 girl. A history of prior or concurrent epileptic seizures was
present in 8 (47%) children. EEGs were normal in 9 ( 5 3 % ) ,
epileptiform in 5 (29%), and contained nonepileptiform abnormalities in 3 (18%). There was a history of documented
(n = 6) or suspected (n = 5) abuse in 11 children (65%),
including both physical (n = 4), sexual ( n = 3), and emotional ( n = 4 ) abuse. Follow-up was available in 14 (82Y)
at 2 to 30 months following their stay in the epilepsy unit.
S i x children (43%))were no longer having psychogenic seizures, 3 (21%) were having fewer episodes, and 5 i36C4,)
had experienced no improvement. No child developed other
somatic complaints. Of the patients, 10 (59'7) were not o n
antiepileptic drugs. Psychogenic seizures in children are increasingly recognized. They are often associated with abuse.
They may also be associated with epilepsy. The proper diagnosis of these disorders and recognition of associated risk
factors are essential for proper treatment.
495. Regulation of Gene Expression i n Developing
Cerebellum: K + Channel Polypeptides
N. J . Lenn. M . Maletic-SazJatir,and J . Trimmer,
Stony Brook, N Y
497. Use of Botulinum Toxin for Adductor Spasticity
in Cerebral Palsy
Balbir Singh, Saad A. Shahuian. V a n S. Miller. and
Anthony R. Riela, Dallas, T X , and Riyadh. Saudi Arabia
Functionally important alterations of gene expression are induced by experience and pathology. Undetermined putative
factors act on the numerous neural genes, often differently
for each gene in each class of neuron, to produce such
changes. We are studying these issues quantitatively by Western blots and irnmunostaining of two slow-inactivating (delayed rectifier-type) Kf channel polypeptides, Kvl.5 and
Kv2.1, at postnatal day (P) 1, 5 , 7, 9, 12, and adult. Kvl.5
is barely detectable by Western blot until adulthood, while
Kv2.1 is seen as two bands at P1, increasing steadily to adulthood. Immunostaining shows both channels present in all
neuron cell bodies and main dendrites. Plasma membrane
accentuation is continuous with Kvl.5, and patch-like with
Kv2.1. These patterns contrast with fast-inactivating (A-type)
K+ channel polypeptides, which are expressed at interrnediate ages (Maletic-Savatic M, et al, unpublished data) and
are localized to distal axons or distal dendrites of particular
neurons: mossy afferents and Purkinje's cells, respectively
(Sheng et al, Neuron 1992;9:271). These patterns are seen
Hip adductor spasticity is common in children with cerebral
palsy and can interfere with ambulation and perineal hygiene.
Effective treatment is currently limited to surgical intervention, which may be risky in these children. We used a single
course of botulinum toxin type A injection (Botox, Allergan)
in 8 consecutive children with severe adductor spasm (age
range, 3-10 years; mean age, 6.4 years). Each child received
4 injections into each hip adductor group, with a total dose
of 2 to 2.5 U/kg/leg. Physiotherapists and parents evaluated
each child weekly before and after the injections for 12
weeks. Six patients had an increase in passive abduction of
the lower extremities of 40 to 70 degrees (mean, 5 1 degrees);
2 patients were unchanged. improvement was maximal 2 to
4 weeks after the injections, and was maintained for over 12
weeks in 3 patients and for 4 to 10 weeks in 5 patients.
Parents reported improved diaper care in 7 patients. No adverse effects were observed. Thus, botulinum toxin injection
may be an effective and well-tolerated medical therapy for
children with disabling adductor spasticity.
Program and Abstracts, Child Neurology Society 513
498. Risk Factors for Recurrence of Status Epilepticus
Lisa S.Leuis, Tracy A. Glauser, Kristen A . Ebner,
and Melanie K . Titanic, Cincinnati, OH
Although the first episode of pediatric status epilepticus (SE)
cannot be predicted, we hypothesized that children at risk
for recurrent SE could be recognized by characteristics identifiable in the emergency department at the time of the first
SE. The medical records of 54 children who presented to a
pediatric emergency department with ongoing SE (continuous seizure lasting at least 30 minutes) between January 1 ,
1990, and July 1, 1993, were retrospectively reviewed. Patients were subdivided into 2 groups for analysis: l. patients
with a single episode of SE (single SE, n = 33), and 2.
patients with more than one episode of SE (multiple SE,
n = 2 1). Children in the multiple SE group had 103 episodes
of SE (average, 4.9 SEipatient). The time to second SE in
the multiple SE group (14 ? 24 months) was not different
than the time elapsed between the single SE group’s sole SE
and January 1, 1094 ( 2 3 2 13 months). At the time of
the first SE, children in the multiple SE group had a higher
frequency of a diagnosis of epilepsy (multiple 48%, versus
single 21%,; p < 0.05; relative risk [RR} = 2.24; 95%’ CI
1.01 < RR < 4.98), developmental delay (S19fJversus 30%;
p < 0.001; RR = 2.43, 955% CI 1.41 < RR < 4.20), and
symptomatic etiologies (67Cfversus 33%; p < 0.001; RR
= 3.25, 95% CI 1.52 < RR < 6.93). The most common
etiology in the multiple SE group was brain malformations
or genetic syndromes, while idiopathic SE with or without
fever was predominant in the single SE group. There was no
difference between the groups on the basis of race, gender,
age at first SE, family history of epilepsy, duration of first
SE, length of SE, medications used to treat the first SE, need
for assisted ventilation during first SE, or length of subsequent hospitalization. Children with a diagnosis of epilepsy,
developmental delay, or identifiable central nervous system
abnormality or genetic syndromes at the time of their first
SE are at higher risk for recurrent SE. We recommend that
these patients and parents receive additional education in
seizure recognition and home seizure management to prevent, terminate, or reduce morbidity from future SE episodes.
499. Preliminary Results: Recurrent Intrinsic
Brainstem Gliomas of Childhood Respond to
Tamoxifen
M . Pons, M . Hetherington, V . Massey, E . J. Hanson,
aging. Of 5 children, 4 demonstrated objective shrinkage
with tamoxifen, that is, greater than 50% shrinkage either in
two-dimensional or three-dimensional measurements. The 4
patients continue in remission from 6 to 30 months, continue
receiving tamoxifen, and are in good neurological and functional status. The side effects were minimal: hot flashes, irregular menses, amenorrhea, oligomenorrhea, abdominal
cramps, and musculoskeletal pain. Preliminary findings indicate that tamoxifen is an effective agent in brainstem gliomas.
500. Pediatric AIDS Encephalopathy: Quantitative
Magnetic Resonance Imaging Analysis
A . Rozenstein, V. Scarmato. Y . Frank. D . Lzi. R. Gould.
R. Hyman, and S. Pavlakis. Manhasset, N Y
Our purpose was to study the pattern of cerebral atrophy in
pediatric AIDS encephalopathy. W e studied 26 children with
AIDS encephalopathy (7 with progressive encephalopathy,
or “plateau,” and 19 with static encephalopathy), and 36 normal children, aged 1 to 18 years. T1- and T2-weighted MRl
images were obtained (GE, 1.5 tesla). Ventricular-brain ratio
(VBR), a measure of general atrophy, bifrontal ratio (BFR),
a measure of frontal horn enlargement, and bicaudate ratio
(BCR), a measure of atrophy in the caudate nucleus region,
were measured in the axial plane. There was no significant
change of VBR, BFR, or BCR with age. VBR was higher in
the AIDS group (unpaired t test, p < 0.005); BFR was higher
in the normal group, but the difference was not significant;
and BCR was higher in the AIDS group ( p < 0.05). When
the progressive-plateau (PP) and static encephalopathy (SE)
patients were studied separately, BCR was significantly
higher in the PP children ( p < 0.05). We conclude that,
1. pediatric AIDS encephalopathy is associated with brain
atrophy, and 2. BCR may differentiate PP from SE patients.
501. ‘H Magnetic Resonance Spectroscopic Imaging
in Patients with Childhood Ataxia with Central
Nervous System Hypomyelination
Raphael Schifimann, Gioacchino Tedeschi. Hen y H.-L. Shih,
Jefirty R. Alger, Colette C . Parker. Roscoe 0. Brady,
Giovanni D i Chiro. and Norman W . Barton, Bethesda. MD,
and La Anneles. C A
J . Egelhoff; D . Zwick. L. Conz,y. and A . Freeman.
Kansas city. M O
Our objective was to determine the effects of tamoxifen in
brainstem gliomas. Diffuse intrinsic brainstem gliomas have
a poor prognosis. Most children with these gliomas are dead
2 years following diagnosis. The standard of therapy is radiation, and it provides benefit for a short period. Chemotherapy has, at best, been of marginal value. Tamoxifen is a
nonsteroidal compound that has both antiestrogen and estrogen-agonist activity. The mechanism of action of tamoxifen
in gliomas is unclear, but there are several theories. It has
been found in recent studies that tamoxifen inhibits angiogenesis and the protein kinase C (PKC). Tumor growth
depends on active angiogenesis and the PKC enzyme may
mediate cell proliferation of malignant glial tumors in vitro.
In the last 30 months, we treated 4 children with diffuse
intrinsic brainstem gliomas and 1 with a cervicomedullary
glioma with oral tamoxifen at a dose of 80 mg/m2. All have
been closely evaluated with brain magnetic resonance im-
514 Annals of Neurology
Vol 36 No 3
September 1994
‘H magnetic resonance spectroscopic imaging (‘HMRSI)
allows measurement of the spatial distribution of metabolites
within entire sections of brain with minimal partial-volume
effects and, therefore, is superior to single-volume spectroscopic studies. We describe ‘HMRSI of 6 patients, aged 2
to 13 years with childhood ataxia with central nervous system
hypomyelination (CACH) (Ann Neurol 1994;35:33 1-340).
Four unrelated girls and 2 brothers from 5 families were
studied. Head magnetic resonance imaging of all patients
showed diffuse white matter abnormality without atrophy.
‘HMRSI was performed o n a 1.5-T GE Signa imager using
a pulse sequence with TE of 272 msec. A 15-mm-thick slice
above the lateral ventricles was chosen. Spectra was obtained
from 1,024 volume elements of 0.84-ml each. Color-coded
signal maps for each metabolite were obtained. Age-matched
controls were used. All patients showed significant reductions
in choline, creatine and N-acetyl-aspartate, in white matter
only, that paralleled clinical severity. Deep and posterior areas were most affected. Three patients with advanced disease
had elevated lactate in the most affected regions. We conclude that CACH is not limited to girls, and may involve a
defect in energy metabolism causing hypomyelination with
secondary axonal loss.
504. Diagnostic Yield of the Neurological
Assessment of the Globally Delayed Child
Annette Majnemer and Michael 1. Shwell,
Montreal, Quebec, Canada
502. Thermal Effects on Myoclonus: A Rat P u p Model
Rosario R. Trifiletti and Elizabeth A. Bolan, New York, N Y
As with seizures, clinical experience suggests that elevation
of body temperature increases myoclonus. Rat pups display
spontaneous developmental myoclonus (SDM) and provide
an ideal animal model in which to explore the effects of
temperature upon myoclonus. Sprague-Dawley rat pups of
various ages were placed in thermostat chambers. Skin and
rectal temperatures were determined. Several hundred thousand SDM events were scored using a human-guided, computer-assisted system. Myoclonic rate increases linearly with
temperature over the range 30 to 42°C. Myoclonic rate increases 0.38 events/min/"C on DOL #2; temperature sensitivity peaks on DOL #7 at 0.76 events/min/"C, and declines
rapidly thereafter. Developmental profile of thermal sensitivity closely parallels that of SDM rate. Previous studies in
our laboratory have dissected SDM into three distinct subprocesses: myoclonic threshold, myoclonic facilitation, and
myoclonic suppression (Ann Neurol 1993;34:491). The
marked increase of myoclonic rate with body temperature is
due almost entirely to an increase in myoclonic facilitation.
We conclude that, in the rat pup model, body temperature
has a powerful and developmentally sensitive influence upon
myoclonus. The rat pup model is an ideal system for exploring the neurochemical basis of these developmental changes.
503. Studies of Spatial Skills i n Children with
Attention Deficit Hyperactivity Disorder
Doris A . Traiiner. Alan Graham. Thomas Gould.
and Angela Ballantyne, La Jolla. CA
There has been recent speculation that children with attention deficit hyperactivity disorder (ADHD) may have right
hemisphere (RH) dysfunction as a cause of their attentional
difficulties. If this is true, then children with A D H D should
have difficulty with spatial tasks, since it has previously been
demonstrated that children with early R H damage do more
poorly than controls on spatial tasks. Twenty-seven children
with A D H D and 25 age-, sex-, and SES-matched controls
have been enrolled in the study to date. Age range was 5.4
to 16.5 years. The diagnosis of A D H D was made by a physician based on DSM-IIIR criteria, as well as on results of
the Connors Parent Rating Scale and the Test of Variable
Attention. All children received a cluster of visual spatial
and perceptual tests, which included the Motor-Free Visual
Perception Test, the Facial Recognition Test (Benton), mazes
from the Wechsler Intelligence Scale for Children-Revised,
spatial relations from the Woodcock-Johnson PsychoEducational Battery, and trailmaking from the HalstedReitan. They also received a test of simple motor speed (finger-tapping from the Halsted-Reitan) and the Token Test, a
test of language comprehension. Results to date do not provide strong evidence for R H dysfunction in children with
ADHD. There were no significant differences between controls and A D H D subjects on any of the visual perceptual/
spatial tests administered. Differences in performance on the
spatial relations test merely approached significance ( p =
0.093).There was a significant difference in the performance
on the test of language comprehension, however, with the
A D H D group scoring significantly lower than controls ( p
= 0.003). Future data analyses will compare A D H D and
focal lesion groups directly.
Developmental delay is a common reason for referral to a
pediatric neurologist; yet, little data exist regarding the diagnostic yield of such an evaluation. A retrospective chart
review was carried out on all patients referred to a single
university-based neurologist for evaluation of global developmental delay from July 1991 to December 1993. Patients
referred for isolated speech or motor delay, autism, or those
who had been previously evaluated by a neurologist were
excluded. A total of 7 1 patients were identified; 47 were
boys, and 62 were referred by a pediatrician. Neurological
evaluation did not confirm global delay in 10, and 8 did
not complete diagnostic evaluation. Of the remaining 59, an
etiological diagnosis was suspected in 13 by the referring
physician at the time of referral. Although parents suspected
a delay at a mean age of 0.66 years ( +0.69 years), children
were only evaluated by the neurologist at a mean of 3.58
years ( +- 2.44 years). Diagnostic work-up (history, physical,
and investigations, including metabolic screens, karyotype,
fragile X testing, electroencephalography, and neuroimaging)
yielded an etiological diagnosis in 37 of 59 patients (62.7%).
Etiological categories included cerebral dysgenesis ( 1 7 % ) ,
hypoxic-ischemic encephalopathy (10.1 ), chromosomal abnormalities (8.5%), toxins ( 8 . 5 9 ), metabolic disorders (55%),
neurocutaneous (3.4c/(), neuromuscular (3.4?6), genetic/
dysmorphic (3.4%), and epileptic (3.4%) syndromes. Referral to a pediatric neurologist and application of a battery of
investigations yields an etiology in a significant portion of
globally delayed children, having important implications with
respect to management, prognosis, and recurrence risk estimate.
505. Basal Ganglia Damage After Perinatal
Hypoxia-Ischemia
Rowena Korobkin and Jerome Barakos, San Francisco, CA
Our objective was to correlate specific clinical findings in
cerebral palsy children with imaging abnormalities of basal
ganglia and relate the imaging abnormalities to timing of
study. Although discrete lesions of basal ganglia and thalamus
are considered to be an unusual form of selective injury after
hypoxia-ischemia in the term infant, we have seen discrete
bilateral basal ganglia signal abnormalities on magnetic resonance (MR) brain scan in a large majority of scans in such
cases. Imaging studies done in early infancy may not show
these lesions or correlate with outcome. We reviewed the
clinical, prenatal, perinatal, and postnatal course of 10 children with cerebral palsy, perinatal hypoxic-ischemic insult at
term, and bilateral lesions in basal ganglia and/or thalami on
MR scan. W e then correlated imaging findings with clinical
outcome and sequential imaging studies when present. All
the children had deep white matter signal abnormalities in
the perirolandic region, in addition to the basal ganglia lesions. The more severely affected children also had perirolandic cortical atrophy, and a few had diffuse cortical atrophy as
well. Clinical findings correlated with the severity of the lesions. Those with milder lesions had significant choreoathetosis. Those with more severe white matter damage in the perirolandic regions lost hand function, particularly midline hand
use. When there was cortical atrophy, spastic quadriplegia
became the predominant clinical finding, and choreoathetosis
was not appreciated. Those children were cortically blind as
well. Those with more severe injury tended to have signs of
Program and Abstracts, Child Neurology Society 515
diffuse cerebral edema in the neonatal period; but basal ganglia and white matter lesions were difficult to appreciate with
MR in the first months of life or o n computed tomographic
scan even later. Damage to basal ganglia and deep white
matter in areas of early myelination is a very common accompaniment to perinatal hypoxic-ischemic injury, even before
neuronal loss can be appreciated, and is of clinical significance, particularly in terms of hand use. Choreoathetosis is
appreciated clinically only when there is some hand use. The
type and extent of lesions cannot be appreciated on early
imaging studies.
506. Use of Felbamate for Refractory Infantile Spasms
Daniel L. H u n t and Tewy D. Rolan. Lubbock. T X
Based on the initial successful use of felbamate for infantile
spasms in an infant with tuberous sclerosis, an additional 3
infants with infantile spasms of different etiologies, who also
had failed conventional therapies, were treated with felbamate. Of the 4 patients, 3 have shown complete resolution
of infantile spasms. AIL responding patients did so within 1
week of starting felbamate. The 1 treatment failure had an
initial reduction of seizure frequency and severity, but has
not maintained that response long term. Controlled studies
will be needed to establish firmly that felbamate is both safe
and effective for the treatment of infantile spasms. To our
knowledge, these are the first reported cases of infantile
spasms associated with symptomatic causes, tuberous sclerosis, Down’s syndrome, and cerebral heterotopias to be
treated successfully with felbamate after unsuccessful standard therapies. As these cases document, felbamate, with its
low side-effect profile, is currently available for empiric use
in infantile spasms. The frequent conversion of infantile
spasms to Lennox-Gastaut syndrome (for which felbamate is
approved) makes its use in infantile spasms logical.
507. Brain Injury D u e to Amniocentesis
R. S. Kandt and G . R. DeLong, Winston-Salem
and Durham, NC
In the past, abnormalities of brain function in infancy were
often blamed on birth difficulties. However, accumulated evidence suggests that mental retardation is often related to
factors that are present prior to birth. Furthermore, brain
malformations previously thought to be due to primary neuronal migration problems (e.g., schizencephaly), are now often thought to result from primary destructive processes
causing abnormal migration. We present 4 children with neurological deficits associated with amniocentesis, all of whom
have historical or neuroimaging characteristics consistent
with damage by the amniocentesis needle. All 4 children
underwent amniocentesis at 16 to 19 weeks gestation because of advanced maternal age, and all have hemiparesis and
focal signs consistent with their cavitary brain lesions. None
had difficulties at birth. Features supportive of amniocentesis
as the cause of the brain lesions included: multiple passes of
the amniocentesis needle (4 of 4 patients); lesions passing
through several intracranial structures in a line (3 of 4 ) ; lack
of midline lesions such as encephaloceles (4 of 4 ) ; lack of a
vascular distribution for the lesions ( 4 of 4);a subcutaneous,
lateral parietal scalp nodule containing central nervous system tissue without meninges, and overlying a porencephalic
cleft partially lined by gray matter ( 1 of 4 ) ;intracranial placement of the amniocentesis needle followed by in utero “unilateral hydrocephalus” by ultrasound, and postnatal unilateral
porencephaly ( 1 of 4);a cavitary lesion passing across the
brain and into the contralateral optic nerve (1 of 4 ) ; and a
516 Annals of Neurology
Vol 36 No 3
tubular defect connecting a hypoplastic caudate with temporal porencephaly (1 of 4). Because hemiparesis is often not
evident at birth, the relationship of the amniocentesis to the
hemiparesis may be missed. These examples highlight a prenatal cause for brain dysfunction, as well as abnormal neuronal migration secondary to a destructive process. Finally,
these cases suggest that cerebral injury secondary to perforation of the fetal cerebrum at amniocentesis may not be rare.
508. Spinal Cord Compression as the Initial
Manifestation of Osseous, Cartilaginous, and
Soft-Tissue Sarcomas
Thomas J . Geller and Suresh Kotagal. St Louis. MO
Sarcomas in children generally manifest with nonneurological
symptoms at the onset. We have observed a rather common
occurrence of spinal cord compressive syndrome as the initial
manifestation of chondrosarcoma, Ewing’s sarcoma, rhabdomyosarcoma, and undifferentiated sarcomas in our institutions. Though these tumors make up only a small percentage
of tumors that invade the spinal canal, we have observed 5
cases of primary spinal cord compromise among a total of 33
newly diagnosed tumors of this type in the interval from
1988 to 1993. Our retrospective analysis of these patients is
designed to elucidate the salient features of sarcomas with
neurological presentations. The study population consisted
of 5 newly diagnosed sarcomas, including 2 Ewing’s sarcoma,
1 chondrosarcoma, and 2 undifferentiated sarcoma. The
mean age at presentation was 10.4 years (age range, 5.75-15
years). Of the 5 patients, 4 were boys and 1 was a girl. Progressive lower-extremity weakness was present at the onset
in 4 of 5 , radicular pain or paresthetic symptoms were present in 4 of 5 , bladder dysfunction was present in 3 of 5 , and
back pain was present in 4 of 5. One of the patients with
girdle-like radicular pain was initially mistaken to have an
acute intraabdominal disorder. The mean duration of symptoms prior to presentation was 15 days (range, 2-21 days).
Extradural spinal canal mass lesions were detected using myelography in 1 patient and by magnetic resonance imaging in
4 patients. The location of the lesions varied from thoracic
5 to sacral 2 vertebral levels. Emergency decompressive laminectomy was carried out in 4 of 5 patients, and biopsy with
immediate, aggressive chemotherapy and radiation therapy in
the other patient. All patients achieved excellent neurological
recovery, including eventual independent ambulation, following these therapies. Follow-up varied from 5 to 71
months, limited only by survival duration, which averaged
only 3 1 months. Despite radiotherapy and chemotherapy, 4
of 5 died from metastatic recurrences. Two of the deceased
patients presented again with recurrent spinal cord or radicular disease, which responded to surgical or radiation treatment. They died of diffuse metastatic disease involving the
bone marrow. The 1 surviving patient has had a recurrence
of rib and pleural tumor. The 15% incidence of childhood
sarcomas with primary neurological presentation in our series
is higher than that reported in one other series (Lewis DW,
Packer RJ, et al, Incidence, presentation and outcome of
spinal cord disease in children with systemic cancer, Pediatrics 1986;78:438-443). In contrast to the more common
group of childhood solid tumors that present with spinal cord
compression (neuroblastomas), patients with sarcomas who
manifest spinal cord symptoms at the onset are generally
older. The primary myelopathic sarcomas appear to have
good initial recovery of neurological function following decompression, but succumb to systemic relapses and have a
high ultimate mortality rate. Because myelopathic signs and
symptoms in the preteen are frequently associated with pri-
September 1994
mary osseous and cartilaginous tumors, sarcoma should
strongly be considered in the older child with myelopathy
and any radicular features.
509. Neurological Status of HIV' and HIVHemophiliacs: Longitudinal Three-Year Follow-up
Wendy G. Mitchell, Margaret A. Maeder, James F . Bale. Jr?
Timothy P. Bohan, A n n Tilton. Bhuuiari P. Garg,
Mamiin 0. Nelson, and John K. Willis, Los Angeles. C A .
Watertown, MA. Iowa City, IA, Houston. T X .
N e u ~Orleans. LA. and Indianapolis. IN
We report the results of a three-year longitudinal evaluation
of hemophilic boys, 6 to 19 years old at enrollment. The
original cohort consisted of 333 subjects, 207 H I V + and 126
HIV-. T o date, 19 have died of AIDS, 8 in the last year.
Among the 8, evaluation at year 2 noted abnormal coordination or gait (C/G) in 75(rr', hyperreflexia (HR) in 25%, and
nonhemophilia-related muscle atrophy (NHRMA) in 12.5%.
In contrast, year 2 exam in surviving H I V + subjects noted
abnormal C / G in 2 2 . 9 9 , H R in 1.9%, and NHRMA in
3.2%, virtually identical to HIV- survivors (abnormal C/G,
2 5 . 5 p ; HR, 4.6%; NHRMA, 1.8%). At year 3, 104 HIVand 145 HIV' subjects were examined: 51 H I V + with
CD4+ less than 200/ul, 94 HIV with CD4+ 200/ul or
more. HR, not present at the previous examination, was
found in 6 of 137 HIV' subjects and 2 of 93 H I V subjects
for whom all 4 exams were completed. H R resolved in 1
HIV and 3 HIV- subjects in whom it had been recorded
at the previous exam. NHRMA was newly noted in 5 of 136
H l V + and 1 of 93 HIV- subjects, and resolved in 1 H I V +
and 1 HIV- subject. Abnormal C / G was newly noted in 17
of 136 H I V + and 11 of 94 HIV- subjects, and resolved in
16 HIV' and 10 H I V - subjects. Seizures were infrequent
(1 H I V + , CD4' < 200 subjects), as were intracranial bleeds
(2 H I V ' , CD4+ < 200 subjects, and 1 H I V + , CD4+ 2
200 subjects). Head injuries were reported in 2 HIV',
CD4' less than 200, 1 H I V + , CD4' 200 or more, and 10
H I T subjects. Increased sleep or rest was newly noted in
17 of 143 H I V + and 3 of 74 H I V subjects; permanent
personality change was newly noted in 15 of 143 H I V + and
5 of 92 H I V - subjects. At the third annual exam, overt
neurological manifestations of HIV are still infrequent. Certain neurological features, particularly HR, abnormal C/G,
and report of increased sleep/rest or personality changes may
be indicators of disease progression. NHRMA, associated
with advanced HIV at earlier exams, is infrequent at year
3, possibly reflecting aggressive treatment of nutritional and
systemic complications of AIDS.
+
+
5 10. Environmental Manipulation in t h e Infant Rat:
A Model for Child Abuse?
Elizabeth E. GilleJ-,Su-Jin Yi. Sarit Aiiishai-Eliner,
and Tallie Z. Baram. Los Angeles, C A
Neurobehavioral correlates of childhood abuse and neglect
(A&N) are now known. A&N involve repetitive-chronic
stress. Developmental aspects of the normal neuroendocrine
stress response, specifically corticotropin-releasing hormone
(CRH) and the regulation of plasma corticosteroids, and their
potential perturbations by A&N have not been elucidated.
The central nervous system (CNS) components of stress response of infant human and rat pup, specifically CRH, are
identical. Creation of an infant rat model of human A&N
and investigation of alterations in the stress response are the
focus of this study. Sprague-Dawley rats (N = 82) born in
our facility were assigned to 3 treatment groups on postnatal
day (PND) 2: NH, not handled, but permitted access to
bedding; N H N B , not handled, no access to bedding; H ,
handled daily (for 15 minutes). Cold-separation challenge was
performed on P N D 7, as previously described (Yi SJ, Schultz
L, Baram T Z , Plasma corticosterone is significantly increased
by cold stress in 3-day-old neonatal rats, SOCNeurosci 1992;
abst (423.5)). N H N B rats had poor weight gain: O n P N D
7, mean weight of N H N B rats was 14.82 gm, mean weight
of NH rats was 2 1.17 gm, and mean weight of H rats was
20.08 gm. Basal morning plasma corticosterone (CORT) was
significantly higher in N H N B rats ( N H N B = 1.63 + 0.3
pg/dl; H = 1.23 + 0.1 pg/dl; NH = 1.07 + 0.15 pgldl).
Cold challenge resulted in plasma CORT elevation at 1.5
hours in all groups. By 4 hours, N H N B plasma CORT continued to rise significantly, while H and N H groups were
declining ( N H N B = 4.59 pg/dl; H = 2.51 pg/dl; N H =
2.56 pg/dl). Infant rats subjected to environmental manipulation (e.g., bedding deprivation) gained weight poorly and had
high basal CORT, compatible with a chronically stressed
state. With acute stress challenge (cold), they had an exaggerated stress response, with pronounced elevation of CORT
by 4 hours. Chronic stress, specifically prolonged elevation
of plasma CORT, is known to result in hippocampal neuronal
death. Infants with A&N-induced chronic stress may have
long-term, as well as short-term, alterations in CNS function.
(Supported by NS28912.)
5 11. Don't Rush to Surgery for Children with Partial
Complex Seizures: Intractability Cannot Be Predicted
i n t h e First Year of T r e a t m e n t
Carol Camfield, Peter Camfield, Keo'in Gordon, and
Joseph DooleypHalifax. Nova Scotia, Canada
W e identified all children with epilepsy beginning in 1977
to 1985 in a regional population of 850,000. A total of 70
had normal intelligence, complex partial seizures, and follow-up greater than 5 years. O f the 70, I4 had intractable
epilepsy defined as more than 1 seizure every 2 months during the last year of follow-up after unsuccessful treatment
with more than 2 medications. During year 1 of treatment,
2 of 14 intractables were seizure free versus 28 of 76 of
nonintractables ( p = ns); 12 of 14 intractables had more
than 4 seizures versus 29 of 76 nonintractables ( p = 0.002);
11 of 14 intractables had more than 9 seizures versus 19 of
76 nontractables ( p = 0.0002). Numbers of seizures were
the same or greater for the second 6 months of treatment
compared to the first 6 months in 75% intractables and 31Q
nonintractables ( p = 0.007). Despite thesep values, the positive predictive value of more than 7 seizures in the first year
of treatment was 3696, negative predictive value 95%, with
24% misclassified. We conclude that confident identification
of childhood intractable complex partial seizures must await
more than 1 year of treatment.
5 12. Epileptic Blindness i n Children: A Localizing
Sign of Various Epileptic Disorders
Eli M. Sbahar, Howard Desatnik. Natan Brand.
Rachel Straussberg. and Paul A . Huiang, Tel Avizi, Israel.
and Toronto. Ontario, Canada
lctal manifestations, EEG, CT, and MRI correlates, as well
as management and outcome of 11 children with epileptic
blindness, are presented. A total of 7 boys and 4 girls presented at age 3 months to 13 years with single or recurrent
episodes of acute obscured vision. Ictal blindness was the
solitary epileptic manifestation in only 2 patients. The remainder had either focal or generalized motor perturbations,
accompanied in a few patients with loss of consciousness. Six
Program and Abstracts, Child Neurology Society 517
children had either focal epileptic manifestations or unilateral
occipitoparietal EEG disturbances in lieu of a normal head
CT. Drug of choice in this group was carbamazepine, and
all became asymptomatic. Two additional children had focal
epileptic phenomena secondary to structural abnormalities of
the brain. One had a low-grade occipital astrocytoma, which
was resected. Another infant suffered from focal cortical dysplasia responsible for status epilepticus amauroticus, requiring cortical resection using electrocorticography. Following
the diagnosis and initiation of antiepileptic treatment, the
episodic blindness abated, as well as other epileptic manifestations in 7 children, and following focal cortical resection
in the patient with dysplasia. Three additional children with
freezing episodes had generalized epileptiform discharges on
EEG, induced by photic stimulation in 2 of them. Two boys
in this group have low-normal intelligence, with attention
deficit disorders. Valproate was the most effective drug in
these children, who have fully recovered. Our data suggest
a relatively benign nature and favorable outcome of children
with epileptic blindness. Resection of secondary temporoparietal foci that originate in the occipital area, as occurred in
our patient, may result in complete cessation of seizures and
subsequent visual recovery.
513. Cerebral Palsy and T w i n Pregnancy
D. 1. Zafeiriou and I . Tsikorrlas, Thessaloniki. Greece
A total of 37 children with cerebral palsy (CP) (20 boys,
17 girls; aged 3-13 years), who were the products of twin
pregnancies, were studied in terms of risk factors, zygosity,
concordance, clinical patterns, radiological findings, associated impairments, and disabilities. Of the cases, 37.5% were
monozygotic (MZ) and 62.5% were dizygotic (DZ). I n
85.7% of the cases, both twins were of the same sex; in
14.3%#,they were of different sex. A total of 86.5% were
born preterm and 13.5% were born at term; 48.6% were
A-twins and 51.4% were B-twins; 55.9% weighed less than
1,500 gm, 29.4q' weighed between 1,500 and 2,500 gm,
and 14.7% weighed more than 2,500 gm. The main types
of CP were spastic diplegia (40.5'%), spastic tetraplegia
(35.1@), hemiplegia (21.6%), and athetoid diplegia (2.7%).
Regarding impairments and disabilities, 43.2% were mentally retarded (IQ < 70), 37.8% had speech impairment,
5.4% had hearing impairment, 24.3% had visual defects,
8.1F had myoskeletal impairment, and 10.8$X had epilepsy.
Computed tomography or magnetic resonance imaging was
carried out in 81.1% of the cases, and showed atrophy in
50.0%, focal findings in 26.7%, hydrocephalus in 16.796,
and congenital anomalies in 6.75%.Regarding the fate of the
co-twin, in 51.3% of the cases, the co-twin was normal; in
24.3%, the co-twin had CP; in 8.1536, the co-twin was stillborn; and in 16.2%, the co-twin died postnatally. Our findings suggest that 1. twin order at birth does not seem to
affect the overall incidence of C P in rwins, 2. M Z twins may
be at higher risk for CP than DZ twins, and so are DZ SGA
twins; 3. the rate of CP is eight times higher among twins
compared with singletons; 4. the male:female ratio in C P
twins does not differ from that found in singletons; and 5 . a
genetic basis for C P is not supported.
5 14. Provoked Seizures: A Variant
of Febrile Seizures Without Fever
Wei Ling Lee, Kulok Chan Lun, Poh Sim LOZCI.
and Uma Raja,, Singapore
Seizures are a nonspecific symptom of brain dysfunction, not
a homogeneous disease. Epileptic seizures are due to brain
518 Annals of Neurology
Vol 36 No 3
pathology and may recur spontaneously. Acute symptomatic
seizures may be caused in normal subjects by certain diseases,
such as hypoglycemia; the outcome depends on the underlying disease and whether it has caused permanent brain damage. Certain triggers may provoke seizures in susceptible individuals without causing brain damage, for instance, fever
in young children causing febrile seizures (FS). A less wellrecognized entity is provoked afebrile seizures (PS) occurring
during an infection that does not affect the brain, such as an
upper respiratory infection. During an epidemiological study
of seizure disorders in Singapore, 1,208 patients were hospitalized at the time of their first seizure and had welldocumented records. Of the patients, 875 had FS, 208 had
afebrile seizures during an infection not involving the brain
(PS), and 125 had unprovoked afebrile seizures. The patients
were followed for an average of 7 years. The clinical features
of PS were very similar to FS except for the absence of fever.
There was a male preponderance: the ma1e:female ratio was
1.4 in FS, and 1.2 in PS. The median age at first seizure was
18 months in FS and 19 months in PS. Family history of FS
was present in 3357 and 25% of patients with FS and PS,
respectively. O f patients presenting with PS, 4 6 q also had
FS at some other time. The Kaplan-Meier estimate of risk
of subsequent unprovoked seizures at 5 years was 2%, 8%;,
and 68% for those presenting with FS, PS, and unprovoked
afebrile seizures, respectively ( p < .0001). For both FS and
PS, developmental delay and family history of epilepsy were
significant predictive risk factors, while family history of FS
was not. FS and PS are reactive seizures resulting from
age-related lowering of seizure threshold to systemic infection. Both have very low risk of subsequent epilepsy,
and are distinctly different from unprovoked afebrile seizures.
515. Ineffectiveness of Acetaminophen and
Diazepam in Preventing Febrile Seizures
Heikki Rantala, Matti Uhari. Lena Vainionpaz.
and Rita Kurttila. Oulu. Finland
A randomized double-blind trial of both acetaminophen and
diazepam in preventing febrile seizures was conducted at the
Department of Pediatrics, University of Oulu, between November 1986 and September 1990, for 180 consecutive children who needed medical help following their first febrile
seizure. The patients were randomly allocated to receive either diazepam (0.6 mglkgiday, divided in 3 doses) or placebo
during all their feverish episodes. For the first feverish episode, the children were randomly allocated to receive either
placebo or acetaminophen (40 mg/kg/day, divided in 4
doses); thereafter, they received placebo or acetaminophen,
alternating for every other feverish episode. Thus, the different treatment regimens for each feverish episode were:
( 1 ) diazepam and acetaminophen; (2) diazepam and placebo;
( 3 ) placebo and acetaminophen; and ( 4 )placebo and placebo.
A total of 160 children were followed for 2 years; 1 5 3 of
them had at least 1 feverish episode; the number of feverish
episodes totaled 641. Of the 1 5 3 children, 38 (24.8%) had
at least 1 recurrent febrile seizure. The recurrences in the 4
treatment groups were: (1) 10 of 39 (25.6%'); ( 2 ) 11 of 3 5
(31.4%));( 3 ) 6 of 40 (15.0%); and ( 4 ) 11 of 39 (28.2%).
All the differences between the treatment regimens were
statistically insignificant. Both acetaminophen and diazepam
appeared to be ineffective in preventing febrile seizures.
Acetaminophen was ineffective in reducing temperature in
children apt to recurrences of febrile seizure.
September 1994
5 16. Modulation of Extracellular Concentration of
Glutamate and G A B A i n Thalamus in Experimental
Absence Seizures
0. C. Snead 111 and P . K . Banerjee, Los Angeles, CA
The ventrobasal relay nuclei of thalamus (VB) are considered
to be critical to the genesis of experimental absence-like seizures. The inhibitory and excitatory neurotransmitters that
modulate thalamocortical neurotransmission are GABA and
glutamate, respectively. In the present study, we investigated
the release patterns of glutamate and GABA in the VB in the
y-hydroxybutyric acid (GHB) model of generalized absence
seizures. Dialysis and electroencephalographic recordings
were performed simultaneously in freely moving rats by the
technique of a combined bipolar recording electrode-looptype dialysis probe unit inserted into VB nucleus of thalamus.
G H B (250 mM and 1 mM) applied locally into VB through
the dialysis probe significantly reduced the basal extracellular
concentrations of GABA, but not glutamate. However,
G H B in both concentrations inhibited K+-evoked increases
in glutamate concentration by 50% to 70% ( p < 0.05). but
had no appreciable effect on K+-stimulated GABA levels.
The basal GABA levels in VB did not change during the
course of GHB-induced generalized spike-wave discharges;
but, K’ stimulated glutamate release in VB was decreased
significantly ( p < 0.05) compared to control after the onset
of GHB-induced SWD. These results suggest that by selectively inhibiting basal GABA release and K’-stimulated glutamate release in the thalamus, G H B creates a subtle imbalance of inhibition and excitation in favor of the latter, but
with preservation of inhibition. This marginally increased excitatory environment in thalamus creates an environment optimal for the generation of absence seizures.
5 17. Validity of Postconcussive Symptoms i n Children
with Traumatic Brain Injury
ChriJtine T . Barry, Susan K. Klein, and H . G e T Taylor,
Cleveland, OH
Headache, dizziness, inattention, and other behavioral
changes are postconcussive symptoms commonly observed
in children recovering from traumatic brain injuries (TBI). I t
is not clear, however, if these symptoms distinguish children
with TBI from children with other traumatic injuries, or if
these symptoms predict the neurobehavioral consequences
of TBI. As part of a longitudinal study of recovery from TBI,
we assessed the frequency of postconcussive symptoms in 2
groups of 6- to 12-year-old children: 41 with moderate-tosevere TBI and 40 with orthopedic injuries (01) only. Parents rated their children on a 30-item postconcussive symptom scale both immediately after injury (baseline) and at a
6-month follow-up. Concurrent measures of behavioral adjustment and neuropsychological functioning were administered. Injury severity was assessed at baseline. Children with
TBI exhibited more postconcussive symptoms than the 0 1
group both at baseline (t = 5.23; p < 0.001) and at 6 months
(t = 4.71; p < 0.001), even when preinjury behavioral ratings were taken into account. Children who had initial loss
of consciousness (t = 2.77; df = 38; p < 0.01) or Glasgow
Coma Scale score less than 9 (t = -2.77; df = 41; p <
0.05) had more postconcussive symptoms. Controlling for
sociodemographic factors, the number of symptoms were
also related to baseline performance on Token Test (R’
change = 0.15; p < 0.001), Test of Nonverbal intelligence
(R’ change = 0.19;p < 0.01),and the Children’s Depression
Inventory (R2 change = 0.11; p < 0.05). Lesion site was not
related to postconcussive symptoms. These data document
the validity of postconcussive symptoms as markers of severity and as predictors of outcomes.
518. Abnormal Nerve Conduction i n
Insulin-dependent Diabetes Mellitus
Herbert SuJick,Catherine Allen. Guangheng Shen,
and Donn D’Alessio for the Wiscoonsin Diabetes Registv,
M iluaukee, WI
Longitudinal studies of neurological function and glycemic
control were done in a population-based incident cohort of
children and young adults with newly diagnosed insulindependent diabetes mellitus (IDDM). Neurological status
was assessed near the time of diagnosis and again during the
fourth year of diabetes. Mean age at follow-up was 15.0 years
( f6.1 years). After having diabetes for 4 years, 8.69: (2 1 of
243) had hypoactive Achilles’ reflexes and 11.1%) (27 of 243)
had paresthesias; but, only 2 subjects had symptomatic neuropathy. To date, 189 subjects have had nerve conduction
velocity (NCV) measured in at least 2 nerves (median motor
and sensory, peroneal, sural). N C V was abnormal in at least
2 nerves in 20.6%. Logistic regression analysis demonstrated
that abnormal N C V was related both to age ( p = 0.01) and
to mean glycosylated hemoglobin ( p = 0.002). Abnormal
velocities occurred most frequently in the peroneal ( 3 7 . 1 9 )
and median motor (24.3%) nerves. Abnormal N C V was rare
in subjects less than 10 years of age. (See Table.)
Age (years)
6-9
10-14
215
Total
Abnormal
v
30
69
90
2
13
24
6.7
18.8
26.7
189
39
20.6
Normal
In a substantial number of young people with IDDM, abnormal NCV occurs early in the disease and is related both to
age and to control of diabetes.
5 19. Electroclinical, Neuroradiological, and Prognostic
Features i n Childhood Tuberous Sclerosis
Raffaella Cusmai, Catherine Chiron, IsabelleJambaqui.
Stefan0 Ricci, Federico Vigetiano, and Olivier Dulac.
Rome, Italy, and Paris, France
Epilepsy is a common symptom of tuberous sclerosis; it may
have different clinical features and its prognosis is difficult to
predict. To correlate clinical and neuroradiological features
with mental and epilepsy outcome, we studied 37 epileptic
patients with tuberous sclerosis followed in 2 neuropediatric
departments (Paris, Saint Vincent de Paul Hospital; Rome,
Bambino Gesti Hospital). A total of 22 children presented
infantile spasms. In 12, partial seizures were preceded or
followed by a cluster of spasms; in the other 10 patients,
spasms were asymmetrical or showed focal signs. Age at onset ranged from 1 to 6 months. The remaining 15 children
presented with partial seizures at onset. Seizures occurred in
the first year of life in 10 patients, in the second year of life
in 3 patients, and in the following years in 2 patients. Only 8
of 37 children had no seizure relapse: 5 of these had infantile
spasms that stopped with vigabatrin; the other 3 exhibited
late-onset partial seizures. The remaining 29 patients with
relapses developed partial epilepsy. Magnetic resonance imaging showed cortical tubers in all. The patients with favor-
Program and Abstracts, Child Neurology Society
519
able mental and epilepsy outcome showed fewer and smaller
cortical lesions, while patients with severe epilepsy showed
multiple cortical tubers. Mental outcome was favorable in
patients presenting a single type of seizure (spasms or partial
seizures) responsive to therapy. In the group of children with
epilepsy, cognitive and behavioral deficits had various degrees of severity. Our data suggest that 1. in tuberous sclerosis, epilepsy is partial; and 2. new therapeutic approaches
using vigabatrin to control seizures may change mental outcome in a considerable number of patients.
520. Broad Utility of Intrathecal Baclofen in t h e
Treatment of Spasticity: Initial Findings
Richard Gilmartin. Patrire Rawlins. William Shapiro,
and Cindy Lewis. Wichita. I;cT
Penn (N Engl J Med 1989;320:1517-1521) determined the
efficacy of Lioresal intrathecal baclofen (IB) for spinal spasticity and associated muscle spasms. Albright UAMA 1993;
270:2457-2477) extended the observation of this treatment
to spasticity of cerebral origin. The purpose of our project
is to demonstrate the broad utility of IB delivered by a programmable. implantable pump in disorders of muscle tone.
Thus far, 2 1 patients with either cerebral palsy (CP), primary
lateral sclerosis, multiple sclerosis, near drowning, spinal
trauma, aneurysm, or Brown-Sgquard syndrome with continuous focal myoclonus have been evaluated with a standard
bolus of IB. Those with C P participate in a double-blind
protocol. Participants with a greater than 1 point reduction
of spasticity on the 5-point Ashworth scale during the trial
are implanted with the pump for continuous infusion of IB.
The pump may be programmed to meet individual changing
needs for tone throughout the day. Documented in each
patient were reduced spasticity, elimination of spasms, and
improved function, as measured by the Ashworth Scale,
Gross Motor Function Measure, Functional Independence
Measure, or Functional Independence Measure for Children.
Continuous infusion of IB via an implanted pump improves
the quality of life of patients with disabling spasticity.
521. Management and Prognosis of Alternating
Hemiplegia
Tina M . Narayan, Houston, T X
Alternating hemiplegia ( A H ) is a rarely diagnosed disorder,
usually presenting below the age of 18 months with episodic
unilateral or bilateral weakness, often associated with global
neurological deficits. Over a 9-year period (1985-1994), 9
patients with A H were diagnosed and managed in our practice, representing the largest reported experience with this
condition. The age of onset ranged from 7 to 48 months.
The clinical features were variable and occurred with the
following frequency: unilateral weakness with bilateral episodes, 9; identifiable trigger factors, 7; delayed language, 9;
oromotor hypotonia, 9; generalized hypotonia, 8 ; motor delay, 8; seizure disorder, 6; abnormal eye movements, 7; autonomic phenomena, 6; paroxysmal movements, 4 ; hypoxic
encephalopathy, 1; and spastic cerebral palsy, 1. All patients
underwent detailed evaluation, including EEG, MRI of the
head, and metabolic and chromosomal studies. One patient
demonstrated a 47 XY mosaic chromosome; a second patient
had ethyl malonic ADPIC aciduria with short-chain Acyl C
A dehydrogenase deficiency. One other patient had a static
encephalopathy with history of birth hypoxia. These 3 patients with identifiable abnormalities did not respond to flunarizine. Furthermore, these 3 patients were severely de-
layed, with inability to walk or speak. In contrast, the 6
patients with no identifiable structural, metabolic. or chromosomal abnormality have been better controlled with flunarizine, and have shown better developmental progress. Treatment with Aunarizine, a calcium channel blocker, was found
to be maximally effective in preventing hemiplegic spells,
with lorazepam as a useful adjunct in some cases. In conclusion, there appear to be two subsets of AH, one with a
distinctly better prognosis than the other. The clinical features of management and prognosis of this intriguing entity
will be further discussed.
522. Electrographic Seizures and the Distribution and
Severity of Neuronal Loss Following Repeated
Asphyxia in Fetal Sheep
Suzanne L. Dazfis,Carina Mallard, Christopher E. Williams.
Barbara M .Johnrton. and Peter 0. Glzickman. Auckland.
New Zealand
W e subjected 10 chronically instrumented fetal sheep to 4
episodes of 5-minute asphyxia, each 30 minutes apart. Asphyxia was induced by occlusion of the umbilical cord. The
ECoG recorded from the parasagittal cortcx (PSCx) was
monitored from 30 mintues preinsult to 36 hours postinsult.
ECoG seizures (SZ)were paroxysmal high-voltage (>1 mV)
sharp, slow, or spike discharges, of more than 30 seconds
duration. Neuronal death (ND) was estimated from acidfuchsin-stained sections of the striatum (ST), hippocampus,
(HC) and PSCx. Hypoxia and acidosis developed with each
occlusion; increasing hypotension developed with successive
occlusions. A total of 3 animals died during occlusion. ECoG
amplitude attenuated with the first insult and for 5 hours
postinsult. SZ occurred in 5 of 7 surviving animals. No SZ
occurred in 2 of 3 and 1 SZ (of 1-minute duration) was
recorded at 5 hours postinsult in 1 of 3 with mild injury (ND
< 20%) restricted to the ST. O n e of 2 had 19 SZ (7 > 5
minutes) 5 to 16 hours postinsult, and 1 of 2 had no SZ with
moderate ST injury (ND > 20% < 707;). One animal had
13 SZ (<1 minute) 15 to 30 hours postinsult with severe ST
injury ( N D > 70%) and moderate H C injury. One had 6
SZ (<3 minutes) 5 to 13 hours postinsult with severe ST
injury and mild HC and PSCx injury. We conclude that in
moderate to severe brain injury from repeated asphyxia1 insults, the frequency and duration of seizures do not predict
the distribution or severity of neuronal loss.
523. Congenital Fiber-type Dysproportion with
Fibrillation Potentials o n Electromyographic
Examination: A Diagnostic Pitfall
T . S. Edgar. B. Latz, A . Wucluwzk, and R. S.Rust,
Madison. WI
Congenital fiber-type dysproportion (CETD) myopathy is
classically characterized by type 1 fiber predominance, with
relatively small type 1 fibers and large type 2 fibers. Typically,
the children are hypotonic and weak, with a nonprogressive
clinical course. Electromyographic (EMG) findings are described as normal or myopathic, but very rarely neurogenic.
We present 3 patients with C I T D who demonstrated very
prominent neurogenic changes in the electromyogram. All 3
patients presented with hypotonia and weakness emphasized
in the legs. Two had preserved muscle stretch reflexes and
2 had upper-extremity micropolymyoclonus. EMG changes
were significant for fibrillation potentials, reduced recruitment, and long-duration high-amplitude motor unit potentials, strongly suggesting active anterior horn cell disease.
520 Annals of Neurology Vol 36 No 3 September 1994
Muscle histology showed type 1 fiber atrophy and preponderance consistent with CFTD myopathy. There was no evidence for denervation changes (eg., angular fibers or fibertype grouping). Of 3 patients, 2 have experienced clinical
improvement, consistent with CFTD. These cases emphasize
the need for confirmatory muscle biopsy in suspected spinal
muscle atrophy, and further allude to the influence of neuronal activity in the maintenance of histochemical fiber types
and their growth.
524. Ophthalmoplegic Migraine
R. S. Rust and H . S. Schutta, Madison, WI
Ophthalmoplegic migraine (OM) is perhaps the rarest form
of complicated migraine, and confusion exists concerning the
diagnostic criteria. Four cases of O M cared for at our institution during the last 18 years represent less than 0.1% of
children with migraine. In each of these 4 cases, the first
episode occurred before 5 years of age, and recurred thereafter at intervals of 4 to 13 months. In each case, the episodes
were confined to one third nerve, always recurring on the
same side, with cumulative permanent ptosis, meiosis, and
limitation of upgaze. Between episodes, general health was
excellent and the frequency of other migrainous complaints
was low. None had evidence for etiological vascular or inflammatory disease, and prophylactic antimigrainous therapy
provided little benefit; but, 3 of 4 were responsive to abortive
steroid therapy, particularly high-dose intravenous methylprednisolone (15 mg/kg). A critical review of these and all
186 previously reported cases (1884-1994) suggests that diagnostic criteria should include: 1. idiopathic childhood onset; 2. pain preceding ophthalmoparesis by less than 6 days,
followed by days to weeks of paresis; 3. recurrences invariabh confined to one eye and one cranial nerve (CNIII in
94%' of cases); 4. four or more attacks by age 20; and 5. no
better diagnosis. Of the 81 of 186 reported cases that meet
these criteria, only 4 proved to have an alternative diagnosis
(tumor, AVM, or granuloma). The remainder of the reported
cases can be divided into three additional diagnostic classes.
Multiple cranial nerve involvement, variability of side, and
older age at onset suggest Tolosa-Hunt syndrome, tumor,
AVM, or inflammatory diseases as the etiology of painful
ophthalmoplegia.
tives with epilepsy. More than half had greater than 3 Prensky criteria for migraine. Twenty-six percent had syncopal
episodes and 44% were adjudged depressed. Only 19%
achieved significant headache relief with analgesics. Phenytoin therapy ( n = 30) provided complete relief in 1 1 F and
partial relief in 33% of cases, compared to 30% and 0%
with phenobarbital (PB) (n = 33), and 40'i: and 4057 with
valproate (n = 20). Ethosuximide (ESX) provided no relief.
Headache worsened in 22%' of patients treated with PB and
66% of those treated with ESX. Of 18 patients treated with
propranolol, 86% experienced complete headache relief, as
did 66% of 15 patients treated with amitriptyline. None of
these patients experienced exacerbation of seizures. Headache is an important cause of discomfort in children with
complex-partial and absence epilepsy, and may be effectively
treated with adjunctive antimigraine therapy.
526. Congenital Muscular Dystrophy Distinguished
Pathologically b y Specific Patterns of Alkaline
Phosphatase and Acid Phosphatase Staining
Anne M . Connolly and Alan Pestronk. St Louis. MO
Congenital muscular dystrophy (CMD) is often difficult to
diagnose. Clinically and pathologically, it may resemble other
inherited or acquired myopathies. W e report a pattern of
alkaline (AIkP) and acid phosphatase (AcP) staining on muscle biopsy, which usually distinguishes C M D from other myopathies. W e reviewed muscle biopsies of 11 children with
a clinical diagnosis of C M D (mean age, 2.5 2 2.0 years), 7
with Duchenne's muscular dystrophy (DMD) (mean age, 5.4
2.3 years), and 15 normal biopsies (mean age, 5.2 2 4.5
years). We compared 1. numbers of muscle fibers with AlkP
staining, 2. numbers of AcP-positive cells, and 3. dystrophin
staining. A ratio of AcP:AlkP was calculated for each biopsy.
In CMD, the mean ratio was 0.09 2 0.08. In DMD, the
mean ratio was 1.67 2 1.26 ( p < 0.001). Normal controls
showed no AlkP fiber or AcP staining. This relative increase
in AlkP staining was independent of the age at which the
biopsy was taken. The AlkP staining probably reflects persistent immatdrity of muscle fibers. A pattern of increased AlkP
staining of muscle fibers compared to AcP staining has specificity for CMD, and provides histopathological support for
the diagnosis.
*
527. Central Nervous System Growth Factors
525. Epilepsy and Migraine i n Children
R. S. Rust and A. L. Prensky, Madison, WI,
and S t Louis, MO
in Autism
Basil T . Dawas, Zhen Ye. Qing Liu. and
Glenn B. Mannheim. Boston. M A , and Silver Spring, M D
Migrainous headache occurs commonly in certain forms of
childhood epilepsy; but the association is little studied and
treatment is often neglected. As part of a retrospective study
of more than 4,000 children with headache, we identified 92
children who also had epilepsy and migraine. A total of 13%
had classic absence; 23%) had atypical absence; 20% had
complex-partial; 20% had complex-partial with secondary
generalization; lo%>had generalized tonic-clonic; 7%, had
reflexive; and 7% had partial-simple epilepsy. Of the children
we identified, 40% were girls and 60% were boys, with an
age range of 2.5 to 14 years of age at presentation. A total
of 16.7% had seizure onset before developing migraine
(mean, 7.4; 3.5 years); 43.3% had migraine before developing seizures (mean, 8.5; 3.2 years); and 40% had simultaneous onset. In 63%, most headaches occurred independently from seizures, while 4% had headache mostly before
and 3395 had headache mostly after seizures. A total of 60%
had a family history of migraine; 33% had first-degree rela-
We elected to study central nervous system (CNS) growth
factors as candidate genes in autism for several reasons, but,
most importantly, because of the reported preponderance of
neuropathological changes in the limbic system and cerebellum of autistic persons, areas of brain where the known CNS
growth factors are predominantly expressed. We have analyzed the nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) genes,
utilizing a combination of single-stranded conformation polymorphism analysis and direct sequencing, in conjunction with
Southern blotting and pulsed-field-gel electrophoresis. Molecular analysis of D N A derived from 73 autistic individuals
disclosed no mutations in the NGF, BDNF, and NT-3 genes.
Therefore, it seems that mutations in the major CNS growth
factors are not operative in the pathogenesis of autism. We
have identified a polymorphism within the coding region of
the BDNF gene, but its significance in terms of behavioral/
neuropsychiatric disease phenotype remains to be deter-
Program and Abstracts, Child Neurology Society
521
mined. Because BDNF is expressed in critical areas of the
hippocampus (CA2, CA3 sectors and dentate gyms), the
BDNF polymorphism may prove very useful in analysis of
associations between alleles at this locus with either neuropsychiatric disease states or simply behavioral traits.
528. The Horizontal Dipole: A Reliable Marker for
Benign Rolandic Epilepsy?
Mark H . Libenson. Boston, MA
A correct diagnosis of benign childhood epilepsy with centrotemporal spikes (BCECTS) has important implications for
the additional testing needed (limited) and long-term (excellent) prognosis. The centrotemporal spike with horizontal
(tangentially oriented) dipole (HD) is felt to be the hallmark
of BCECTS. Three patients with centrotemporal spikes and
an H D , but with nonrolandic seizures, are described. The
first patient is a 6-year-old boy with a history of a single
generalized febrile seizure at age 3 years and again 4 months
later. The EEG showed classic rolandic spikes, maximal in
the right midtemporal area with positivity anteriorly (HD).
The second patient is a 7-year-old developmentally delayed
boy with a left hemiparesis and a history of left-sided, then
secondarily generalized, seizures following bilateral subdural
hematomas in the first year of life. The EEG showed left
midtemporal-maximum spike-wave discharges with positivities over the right hemisphere and vertex (HD). The third
patient is an 8-year-old girl with a left Babinski’s sign who
experienced a generalized seizure at 4 years, followed by
a left-sided Todd’s hemiparesis. Sporadic left-sided seizures
followed, including some with a “Jacksonian march,” beginning with clonic movements of the left hand. The EEG
showed frequent right midtemporal spike-wave discharges
with positivity anteriorly (HD). Skepticism about the diagnosis of BCECTS is warranted even when rolandic spikes manifest an HD.
529. Ten-Year Follow-up of Bone-Marrow
Transplantation for Treatment of Metachromatic
Leukodystrophy
Lawrence A . Lorkman. Elsa G. Shapiro, and William Krizit,
M inmapolis. M N
In 1984, a 4Y2-year-old girl with metachromatic leukodystrophy (MLD) received a bone-marrow transplant from her
HLA identical, unaffected, younger
sibling. An older sibling
.
died of MLD at age 9, following 4 years i n a vegetative state.
W e report the current status of the recipient who is now
14Ih years old. At the time of transplant, she had shown early
motor deterioration with roe-walking, increased tone at the
ankles. and mild intention tremor. H e r Wechsler Preschool
and Primary Scale of Intelligence scores were 106 full scale
(116 verbal; 95 performance). Ten years after transplantarion, her motor handicap is severe, consisting primarily of
ataxia and incoordination. Magnetic resonance imaging shows
improvement in the cerebral abnormality and no abnormality
in the brainstem, cerebellum, or spinal cord. H e r motor
problems are primarily attributable to peripheral disease as
the nerve-conduction velocities have continued to decrease.
Endocrine abnormalities include slowed growth rate from
the age of 8’12 years, with no response to growth hormone
stimulation and unresponsiveness to exogenous growth hormone, primary ovarian failure, and normal thyroid function.
Neuropsychologically, she shows normal receptive vocabulary, comprehension, and reading. Expressive vocabulary is
in the borderline impaired, math in the mildly impaired, and
visual perception in the severely impaired range. She has
522 Annals of Neurology
well-developed social skills and is emotionally stable. In this
patient, although there has been continued deterioration of
peripheral motor function, cerebral function has been preserved.
530. Bilateral Striatal Necrosis with a Novel Point
Mutation i n t h e Mitochondrial ATPase 6 Gene
Linda De Medeir. Sara Seneca, Wi@yLissens. Erik Schorntjes,
Marc Bruyland, Brigitte Desprechins, and lnge Lzrbaers,
Brussels, Belgiuni
A 2.5-year-old boy was admitted because of developmental
delay. After an initial normal development, he started to fall
frequently at the age of 18 months. When he was 2.5 years
old, he suffered a generalized hypotonia and was not able to
walk without falling. Intermittent choreoathetotic movements of the trunk and limbs occurred at rest and were reduced by voluntary movement. There was no dysmetria. The
tendon reflexes were normal in the upper and lower limbs.
Babinski’s sign was bilateral in extension. Speech was markedly delayed. Blood gases, liver tests, B U N , and electrolytes
were normal. Lactate and pyruvate (fasting and postprandial)
were normal. Serum and urinary amino acids and urinary
organic acids were normal. Cerebrospinal fluid lactate and
pyruvate levels were mildly elevated. Flash ERG revealed a
response with diminished amplitude, both photo- and scotopically, indicating reduced retinal conduction. Echocardiography was normal. A needle muscle biopsy revealed normal
morphology, no red ragged fibers, normal oxidative histochemistry, and large mitochondria. Magnetic resonance imaging of the brain showed lesions in the basal ganglia, consisting of a prolongation of both T1- and T2-weighted signals
in the caudate nucleus and putamen, while the midbrain and
brainstem appeared normal. Because of the similarities with
NARP and Leigh‘s disease, and the absence of the common
ATPase 8893 mutation, another molecular investigation was
done. Using PCR-SSCP analysis and direct D N A sequencing, we identified a novel point mutation (T+C) at nucleotide 8851 of the mitochondrial DNA. The mutation alters a
highly conserved amino acid in subunit 6 of the mtATPase
gene. The mutation was nearly homoplasmic and maternally
inherited. These data suggest that mutations in the ATPase
6 gene, and possibly in other subunits, could account for
more cases of bilateral striatal degeneration of unknown
origin.
53 1. Leber-associated Dystonia w i t h Putamen Necrosis
R. V a n Cojter,J.-P. Misson, F . Meire, and
B. Obermaier-Kusser,Ghent and Liege. Belgium.
and Munich. Germany
Propositus is a boy born from nonconsanguineous parents.
His mental and motor development was normal until the age
of 11 years. At thar age, he presented with mental and motor
regression and subacute onset of vision failure. Neurological
examination at the age of 16 years revealed walking difficulties, muscular weakness, axial hypotonia, dystonia, ankle clonus, brisk deep tendon reflexes bilaterally, and nystagmus.
Lactate and pyruvate were borderline increased, but increased abnormally after physical effort. Ophthalmological
examination showed optic atrophy. Putamen necrosis bilaterally was demonstrated by magnetic resonance imaging. No
ragged-red fibers were found by LM, but subsarcolemmal
accumulations of mitochondria were seen by EM. Partial deficiency of cytochrome c oxidase, succinate cytochrome c reductase, and complex I were found in mitochondrial subfractions of skeletal muscle. At the age of 26 years his brother
Vol 36 No 3 September 1994
presented with rapidly progressive loss of vision and hearing.
Ophthalmological examination was compatible with Leber’s
hereditary optic neuropathy (LHON). Cranial magnetic
resonance imaging was normal. Morphological and biochemical examination of skeletal muscle showed the same abnormalities as in his brother. Patients with subacute visual loss
and bilateral putamen necrosis were previously reported in
the literature (Marsden CD, Lang AE, Quinn NP, et al, Familial dystonia and visual failure with striatal CT lucencies, J
Neurol Neurosurg Psych 1986;49:500-509; Novotny EJ,
Singh G, Wallace DC, et al, Leber’s disease and dystonia: a
mitochondrial disease, Neurology 1986;36: 1053-1060;
Bruyn GW, Vielvoye GJ, Went LN, Hereditary spastic dystonia: a new mitochondrial encephalopathy? Putaminal necrosis as a diagnostic sign, J Neurol Sci 1991;103:195-202;
Leuzzi V, Bertini E, De Negri AM, et al, Bilateral striatal
necrosis, dystonia and optic atrophy in two siblings,J Neurol
Neurosurg Psych 1992;55:16-19). Either dystonia or optic
atrophy is the presenting feature, and different members of
the same family may have either anomaly or both. The authors consider these patients as representing atypical LHON
or Leigh‘s disease. Our hypothesis is that a mitochondrial
DNA mutation is responsible for the progressive encephalopathy with subacute vision failure in 1 patient and the rapidly progressive loss of vision in his brother. Thirteen point
mutations associated with LHON (11.778, 4.160, 3460,
13.708, 15.257, 15.812, 5244, 7.444, 14.484, 4216, 4917,
3.394, 4.136) were excluded by PCR. Further research is
being conducted to detect one or more mitochondrial point
mutations.
(i.e., sleep architecture, continuity, and EEG spectral, phasic,
and autonomic measures), utilizing 129 studies on 51 infants
between 28 and 43.5 weeks postconceptional age (PCA).
Spearman correlations assessed individual relationships within physiological groupings with PCA; nonparametric regression was used to investigate a summated effect of multiple
measures within and across groupings. Final analyses ranked
the best variables as explanatory of maturation: 5 measures
(i.e., a energy during quiet sleep, heart-rate variance, total
EEG energy and spectral edge for EKG during active sleep,
and percentage of EEG discontinuity) best explained maturational effect in neonates less than 36 weeks PCA. Three
variables (i.e., 0 and p energies during active sleep and a
energy during quiet sleep) were explanatory of maturation
in the neonatal group older than 36 weeks PCA. While individual sleep measures within each physiological group may
also reflect brain maturation, spectral EEG energies were
stronger indicators of maturation compared to autonomic and
phasic measures, particularly in preterm neonates. Sleep organization exists in the preterm infant and maturational
trends that are specific for different sleep behaviors. Thirtysix weeks PCA is a pivotal age around which specific changes
in sleep behavior occur. (Supported by NSOl110, NS26793,
and MOlRR00084.)
534. Unexpected Declines i n Spectral
Electroencephalographic Energies for Healthy
Preterm Neonates Prior to T e r m Ages
M. S. Scher, D. A. Steppe, and D. L. Banks, Pittsburgh, PA
We previously reported state-specific rectal temperature
changes that are unique to preterm infants compared to fullterm infants at postconceptional term ages (PCA) (Ped Neurol 1994, in press). We now present analyses of maturational
trends in EEG-sleep state-specific rectal temperature in preterm infants between 28 and 43 weeks PCA. A total of 28
continuous 3-hour studies were obtained on preterm infants,
using a 24-channel computerized monitoring system in which
minutes were assigned EEG state by traditional criteria. Using Spearman correlations and nonparametric regression
analyses, no significant association of rectal temperature was
noted with sleep states under 35 weeks gestation. After 36
weeks PCA, average rectal temperature was significantly correlated during both active and quiet sleep ( r = 0.55 and
0.62, with p < 0.02 and 0.01, respectively). EEG statespecific changes in rectal temperature display maturational
effects only after 36 weeks PCA. Functional brain maturation
involving pathways subserving both sleep and thermoregulation occur during late gestation and contribute to the differences noted at corrected full-term ages. (Supported in part
by NS26793.)
Maturational trends in spectral EEG energies (6 through p)
were studied in 54 3-hour studies between 28 and 43 postconceptional age (PCA). In the younger age group (<36
weeks), significant negative Spearman correlation coefficients
for total EEG spectral energy were seen during active sleep
( r = -0.71; p < 0.001) and quiet sleep ( r = -0.63; p <
0.001). A negative correlation for spectral 6 energy was
noted only during active sleep ( r = -0.54; p < 0.001).
Alpha and p spectral energies both significantly increased
during active sleep ( r = 0.43; p < 0.001). Theta energy did
not change significantly with increasing gestational age before
36 weeks. Spearman correlations for spectral EEG energies
between 36 and 43 weeks were different. Total spectral EEG
and 6 energies did not significantly change with increasing
PCA. Theta spectral energy significantly increased ( r = 0.31;
p < 0.02) during active sleep; but, a and p energies now
showed decreasing trends with increasing PCA during quiet
sleep (Y = -0.77 and -0.74; p < 0.0001). This decrease
in faster EEG frequencies for preterm infants after 36 weeks
is contrary to what is expected for brain maturation in older
infants. We reported lowered spectral EEG energies during
specific sleep state segments at term ages in preterm infants
(Sleep 1994;17:47), and our present data suggest that altered
brain maturation occurs because of adaptation to conditions
associated with prematurity in asymptomatic neonates. (Supported in part by NS26793.)
533. Maturational Trends o f
Electroencephalographic-Sleep Parameters
in t h e Healthy Preterm Neonate
M . S. Scher, D. A . Steppe, D. L. Banks, S. G . Dokianakis,
R. D. Guthrie, and R. J . Sclabassi, Pittsburgh, PA
535. Screening for Seizures with Serial
Electroencephalographic Recordings in an Inborn
Neonatal Population
M . S. Scher, J . Alvin, L. Gaus, B. Minnigh,
and M. J. Painter, Pittsburgh, PA
Maturational trends of sleep were assessed in preterm neonates. Five physiological groupings of 66 EEG-sleep parameters were tabulated from 24-channel EEG-sleep recordings
A total of 47 neonates had EEG-confirmed seizures prior to
antiepileptic drug (AED) treatment as part of a prospective
study of AED efficacy over a 42-month period. This group
5 32. Maturational Trends in Rectal Temperature
During Specific Electroencephalographic-Sleep States
M . S. Scher, D. A. Steppe, and D. L. Banks, Pittsburgh, PA
Program and Abstracts, Child Neurology Society 523
was 35% of an inborn neonatal population (47 of 135 neonates) who were initially entered into a screening protocol
consisting of EEG recordings for up to 3 consecutive days
based on 7 inclusion criteria: 57% (77) for suspicious movements; 24% (33) for asphyxia (ix., base deficit > - 10); 16%
for drug exposure or infection (15 and 7 , respectively); only
3% ( 3 )of studies because of central nervous system trauma,
malformation, or during pharmacological paralysis. Fiftythree percent (40 of 77) with suspicious movements had EEG
confirmation; of these, 55% (22 of 40) were only confirmed
o n the second or third day of EEG screening. Only 19% (6
of 3 2 ) with asphyxia had EEG-confirmed seizures, with 81%
(4 of 6) diagnosed on the second or third day. Systematic
screening of neonates prior to AED administration who are
at risk for seizures will confirm seizures in one third of infants, but not unless EEG recordings are performed for 3
consecutive days. (Supported in part by NS26793 and
NS26946.)
536. Periodic Epileptiform Discharges i n Acutely 111
Children: Relationship to Outcome
Todd F. Barron and John DellaBadia, Jr, Hershey, P A
Fifteen children, ages 4 months to 15 years, were identified
by EEG with periodic epileptiform discharges (PEDs) and
followed clinically. Of the 15 patients, 12 presented with
prolonged seizures and altered mental status and 3 presented
with altered mental status alone. Only 2 of 15 had a prior
history of seizures. Of the 15, 14 were treated with one or
more antiepileptic drugs (AEDs). Nine of the 15 patients had
primary C N S disease, while the remainder had neurological
complications of systemic illness. Neurological examinations
Sensitivity
Specificity
Total predictive power
Alphabet
Cancellation
0.81
0.85
0.83
537. Diagnostic Efficiency of Attention
Deficit Hyperactivity Disorder Tests
K . K. S. Voeller, K . M . Heilman. P. Edge,
and A . Alexander. Gaineszille. F L
Attention deficit hyperactivity disorder ( A D H D ) is a heterogeneous disorder of self-regulation consisting of inattention,
impulsivity, and, sometimes, hyperactivity. These deficits can
be operationally defined as impaired stimulus detection and
response inhibition, impersistence, and increased activity.
We have developed simple neurological tasks that do not
show learning effects and can be used to monitor drug response. Group mean comparisons ( A D H D to controls) reveal group differences for each task. However, this does not
indicate how many subjects would be correctly classified as
A D H D or controls by a given task. Subjects are 22, 8- to
10-year-old A D H D boys, meeting DSM IIIIIII-R diagnostic
criteria, and 14 age-matched and IQ-matched controls. Tasks
consisted of alphahet cancellation, impersistence, ocular and
tactile response inhibition, and activity level. The sensitivity,
specificity, and total predictive power of each task was calculated using a - 1.5 S D cutoff (see Table).
Impersistence
Ocular
Response
Inhibition
Tactile
Response
Inhibition
0.4 1
0.86
0.58
0.79
0.93
0.67
0.64
demonstrated coma in 9, obtundation in 5, and a confusional
state in 1; 1 patient could not be examined secondary to
neuromuscular blockade. EEGs were obtained within 7 2
hours of admission, with most performed within 24 hours.
Bilateral PEDs were noted in 8 patients (2 synchronous, 6
asynchronous), unilateral in 7 , with 1 demonstrating bilateral
PEDs on repeat EEG. PEDs were associated with electrographic seizures in 6 patients. EEGs demonstrated persistent
PEDs or worsened background changes in 8 of 15, 7 of
whom had bilateral discharges initially. Of the 15, 12 had
one or more neuroimaging studies ( C T or MRI). In those
with unilateral discharges, 3 were normal or unchanged from
previous studies, with the remainder demonstrating diffuse,
multifocal abnormalities. In those with bilateral discharges, 3
had normal initial scans, which, when repeated, were diffusely abnormal; the other 3 patients had scans demonstrating diffuse. multifocal changes. Clinical follow-up ranged
from 1 month to 2 years, 1 patient was lost to follow-up, but
was normal at discharge. Eight of 9 patients with bilateral
PEDs, compared with 3 of 6 patients with unilateral discharges, had a poor outcome (3 of 9 died). Two of 6 patients
with unilateral discharges, compared with 1 of 9 with bilateral
discharges, were normal or at baseline at the time of
524 Annals of Neurology
follow-up. These 2 children had normal neuroimaging studies. One with unilateral discharges was mildly impaired. Of
the surviving patients, 8 of 12 continued to require AEDs at
the time of follow-up. The presence of PEDs on EEG in
children correlates with acute, diffuse neurological dysfunction that may precede changes on CT. PEDs, especially if
bilateral and if associated with abnormal neuroimaging studies, predicts a poor neurological outcome.
0.78
0.69
Activity
0.42
0.86
0.47
Certain of these simple tasks measuring specific deficits
associated with A D H D show good sensitivity and specificity.
The sensitivity of hyperactivity was low because not all
A D H D subjects have this trait. Future studies with larger
subject numbers may serve to further increase diagnostic efficiency.
538. Postnatally Acquired Microcephaly and
Prediction of Later Development
N. Paul Rosnlan, illichaef J . Rirmkin, Christie Enzjgh.
and Glenti B. Mannheim. Boston, M A
In 53 children with acquired microcephaly, the causes were:
destructive 15; dysgenetic 14; idiopathic, low developmental
quotient (LDQ) 13; idiopathic, normal developmental quotient ( N D Q ) 6; Rett’s syndrome 5. Mean follow-ups (in
months) were: destructive, 38; dysgenetic, 42; idiopathic,
LDQ, 36; idiopathic, NDQ, 29; Rett’s syndrome, 102, with
serial body weights (BW), head circumferences (HC), and
DQs. Mean DQs were: destructive, 0.38 (0.02-1.0); dysgenetic, 0.26 (0.05-0.7); idiopathic, LDQ, 0.39 (0.03-0.7); idiopathic, N D Q , 1.06 (1.0-1.2); Rett’s syndrome, 0.08
Vol 36 No 3 September 1994
(0.05-0.1). Mean birth BW for all groups were 33 to 48%.
Mean birth H C percentiles were: destructive, 38%; dysgenetic, 29%,; idiopathic, LDQ, 41%; idiopathic, N D Q , 75%;
Rett's syndrome, 43%. By 15 months, those mean HCs
were: I%, 39%,2$6, 2$6, and 696, respectively, representing
as percentages of mean birth HCs: destructive, 3%; dysgenetic, 10%; idiopathic, LDQ, 5%; idiopathic, NDQ, 29%;
Rett's syndrome, 14%. Except for the Rett's syndrome
group, body growth was quite good, with last BW as a percentage of birth BW: destructive, 35%; dysgenetic, 31%;
idiopathic, LDQ, 32%; idiopathic, N D Q , 48%; but only 2%
in the Rett's syndrome group (the group with the lowest
DQ). Thus, particularly with idiopathic acquired microcephaly, even with a small H C at birth, the child's developmental
outcome may be normal, particularly if the decline in H C
during the first 15 months of life is modest, and body growth
is reasonably well-maintained.
539. Hemangioendotheliomatosis:A Reversible Cause
of Multiple Lesions of the Central Nervous System
Donna M . Capin, N.Paul Rosman, R. Alan B. Ezekowitz,
and Elizabeth Yang, Boston, M A , and St Louis, MO
Capillary hemangioendotheliomas, the most common vascular tumor in children, are usually solitary, involve skin, and
involute by 1.5 to 8 years. They can also involve the head,
eyes, neck, heart, liver, adrenal glands, and, rarely, the central
nervous system. Newborn 1, with red amniotic fluid and
melena, had 30 cutaneous hemangiomas. MRI showed 1 lesion in the liver, 4 in the cerebrum, and 1 in the spinal
epidural space. After a failed trial of prednisone, interferon-a
was begun at 1 month; by 7 months, the liver lesion was
smaller and the brain and spinal lesions were gone. At 3
years, the skin lesions have resolved and development is normal. Newborn 2, with fever, had a 7 x 10-cm hemangioma
attached to the liver; it was resected. Because of macrocrania,
MRI of the brain was done; this showed 4 cerebral lesions
with some gadolinium enhancement. Urine assay of basic
fibroblast growth factor (bFGF) (a protein elevated by hemangioma proliferation and lowered by involution), was 16
times elevated. Two months of steroid therapy resulted in
no MRI change. Development has been normal except for
mild gross motor delay. Urine bFGF assay can now replace
diagnostic biopsy of these lesions, which can also be complicated by bleeding. The diagnosis of hemangioendotheliomatosis should be considered in children with multiple lesions of the meninges, brain, or spinal cord, particularly when
associated with hemangiomas of the skin or elsewhere.
540. Fibronectin Expression i n Developmental
Brain Injury
D. C . Chugani. H . Shamoto, M.-L. Lee, and H . T . Chugani,
Detroit, MI
In developmental brain injury studied in the rat, the relationship between lesion size and recovery of function is such that
small lesions are associated with compensation mediated by
brain regions ipsilateral to the side of injury, whereas large
lesions trigger compensatory changes in the contralateral
hemisphere. Further, functional recovery following large lesions is better when the lesion occurs early in life. The neurobiological and molecular mechanisms that govern intrahemispheric versus interhemispheric reorganization are poorly
understood, but are highly relevant to our understanding of
recovery following pediatric brain injury and epilepsy surgery. Fibronectin is an extracellular matrix glycoprotein that
plays a role in neuronal guidance and neurite outgrowth during development, and may play a role in repair following
brain injury. W e examined fibronectin expression by immunofluorescence in rats following unilateral frontal cortical lesions and hemidecortication. Differences in fibronectin expression were seen with lesion type and age. Staining with
antifibronectin antibody in lesioned animals revealed predominantly staining at the edge of the lesion. The intensity
of staining following the lesions was different at each of the
ages studied. Unilateral cortical lesions in postnatal day 1 rats
produced the largest increase in fibronectin staining, while
in rats lesioned at postnatal day 10, the fibronectin increase
was smaller. Adult operates showed increased fibronectin immunoreactivity only at the rim of the lesion. An understanding of the role of fibronectin, as well as other extracellular
matrix glycoproteins, in brain reorganization following lesions may lead to the development of interventions to aid in
neuronal plasticity and functional recovery following brain
injury.
541. Growth Inhibition of Glioblastoma Multiforme
w i t h Sodium Phenylbutyrate: I n Vitro and Xenograft
Investigations
Hawey S. Singer, Daniel Martinie, John Hilton, and
Michael Colvin. Baltimore, M D
Glioblastoma multiforme (GBM) is an extremely malignant
astrocytoma with patient survival of less than 6 months. Sodium phenylbutyrate (NaPB) is a phenyl derivative of butyric
acid, an effective inducer of cytodifferentiation. Using a human GBM cell line (U373), we investigated the effect of
NaPB o n in vitro cultures and U373 xenografts in nude mice.
U373 cells incubated with NaPB, 0.5 to 10 mM produced
dose-related reductions in growth rate; 10 mM reduced cell
counts by 855% and diminished BUdR incorporation. Studies
of cell division showed interruption in the G o / G l and G2/M
phases with 99% of cells remaining viable. NaPB treatment
increased several neurochemical markers, compared to untreated cells; choline acetyltransferase (ChAT) activities
(159% of control), glutamate receptor binding (131-440%),
serotonin, (286%), 5-HIAA (168%), and measures of adenylyl cyclase activity (threefold-fivefold). Tumors established
in mice retain characteristics similar to in vitro cultures for
ChAT, glutamate, and phorbol receptor binding. Mice with
U37 3 xenografts were administered intraperitoneal NaPB in
doses ranging from 250 to 1,000 mg/kg bid. After nontoxic
doses of 750 mg/kg were given for 2 weeks, the slope of
tumor growth was flatter in treated mice (0.062), compared
to that in controls (0.16). Although the mechanism by which
NaPB arrests cell growth and induces differentiation is unknown, our study suggests that this agent may deserve consideration as a potential treatment in humans.
542. (L'C]Flumazenil Positron Emission Tomography
i n Children with Intractable Epilepsy
D . C . Chugani. T .J . Mangner. 0. Muzik, P. K . Chakroborty,
D. B. Behrendt, and H . T . Chugani, Detroit. MI
[''C]Flumazenil (FMZ) positron emission tomography (PET)
measurements of central benzodiazepine receptors have been
demonstrated previously to be useful in localization of epileptic foci in adults with partial complex epilepsy. In the
present study, we have employed FMZ PET in children
whose epileptic foci were either not defined or poorly defined by ['8F)fluoro-2-deoxy-~-g~ucose
(FDG) PET. Dynamic
scans were performed in 8 children o n a Siemens EXACT
Program and Abstracts, Child Neurology Society
525
HR, and arterial blood samples were obtained for measurement of plasma FMZ and metabolites in 4 of the children.
EEG was monitored during the scan. Patients were maintained on their regular anticonvulsants, with the exception of
benzodiazepines, which were discontinued at least 3 weeks
prior to the procedure. Sedation with chloral hydrate was
necessary in 6 of the 8 patients. Values for receptor concentration (dv) were calculated using the method of Koeppe et a1
(1991). Receptor concentrations measured in children were
higher than reported previously in adults. For example, the
dv in cortex was 9.51 ? 0.60 SD. In 3 children with mild
cortical glucose hypometabolism, FMZ was also decreased in
the same area and provided additional evidence for a focus.
One patient with a normal FDG scan and EEG evidence of
epileptogenicity in the left hemisphere displayed decreased
FMZ in right frontal and left temporal cortex. The FMZ
pattern was more restricted than glucose hypometabolism in
2 patients. FMZ is a potentially useful PET probe in the
study of epilepsy in children, and may be particularly valuable
when FDG PET fails to define a focus.
543. Morphology of Corpus Callosum in Children
with Tourette’s Syndrome
Harvq S. Singer, Mkhael T . Abram,
Thomas L. Baunigardner, Michael J . Colli.
and Allan L. Reiss, Baltimore. M D
The corpus callosum (CC) contains commissural fibers interconnecting the two cerebral hemispheres. It has been suggested that structural lateralizations previously identified in
the putamen and the lenticular region (Singer HS, Reiss AL,
Brown J, et al, Volumetric changes in basal ganglia in children with Tourette’s syndrome, Neurology 1993;43:950956) are also reflected in the CC. To further analyze this
possibility, area determinations were obtained on midsagittal
magnetic resonance images from Tourette’s syndrome (TS)
subjects who also had significant volumetric changes affecting
their basal ganglia. Area CC measures from 34 outpatients
with TS (30 boys, 4 girls; age range, 7-16 years; mean age,
11.7 years) were compared to those from 26 controls (20
men, 6 women) of similar age. A comorbid diagnosis of attention deficit hyperactivity disorder (ADHD) was present in
19 of 34 TS patients. All TS and control subjects had normal
IQs. Using established analysis techniques, the CC was circumscribed manually and the overall area in the midsagittal
plane was determined. Interrater reliability was 0.98. Initial
analyses, which covaried for the effects of age and intracranial
area (IC), showed no significant difference (F, 3.22;p < 0.08)
between TS (6.7 1 & 0.17) and control (6.17 2 0.16) groups.
Significant differences ( p < 0.005) were identified for the
ratio of CCiIC with the TS group (0.043 2 0.001) being
larger than controls (0.038 2 0.001). Results were not influenced by the presence of ADHD. The results of this study
suggest that anatomical variations of the basal ganglia are not
paralleled by reductions of interhemispheric connectivity.
544. Alternating Hemiplegia of Childhood:
CJinical Manifestations
U . Kramer. M . A. Mikati, R. Shunahan. and The United
States Alternating Hemiplegia Grordp?Boston. M A . and
Oakland, C A
The clinical manifestations of 3 5 American patients with alternating hemiplegia of childhood were investigated. Standardized questionnaires were completed by family members
and by treating physicians. A total of 11 patients were seen
in our center. The ma1e:femaIe ratio was 20:15; age of onset
ranged from birth to 54 months (mean age, 7.4 months).
Initial symptoms were abnormal eye movements in 69%,
dystonia in 58%,, and hemiplegia in 33%. Some patients had
a combination of 2 symptoms as the initial manifestation.
When hemiplegia was not the presenting symptom, the mean
time from disease onset to first hemiplegic episode was 6.6
months (range, 1-34 months). Hemiplegic events lasted
from minutes to 14 days. Provoking factors, noted in 78%,
include excitement, activity, hot bath, menstruation, and fatigue. In 9 l % , quadriplegic episodes during which they were
unable to eat or talk also occurred. Dyspnea was a major
complication in 1. A total of 89% had mental retardation.
Of the 4 considered to be cognitively normal, 2 had lateonset disease. A third had only few hemiplegic episodes.
Reported physical findings included ataxia in 63%, and choreoathetosis in 43%. Epileptic seizures occurred in 20%,
and were usually infrequent. Flunarizine reduced the severity
and/or frequency of the hemiplegic attacks in 769C ( p <
0.01). The degree of retardation is correlated with age at
disease onset ( r == 0.50; p = 0.0068), and at onset of hemiplegic episodes (t. = 0.51; p = 0.0072).
545. Evaluation of Ictal Brain Single-Photon Emission
Computed Tomography Using Tc-99m-Bicisate i n
Children with Partial Epilepsy
R. Dazis, L. Carmant, A . B . Packard. P . 1 . Roach,
L. A. O’Tuama, S . T . Trwes, and J . J . Riviello. Boston. MA
Ictal brain single-photon emission computed tomography
(SPECT) is superior to both interictal and postictal SPECT
in localizing either a temporal or extratemporal focus in patients with partial seizures. However, ictal studies may be
difficult to obtain due to the short half-life of Tc-99mHMPAO, which must be reconstituted at seizure onset. In
this study we assessed the chemically more stable perfusion
agent Tc-99m-bicisate (Neurolite) as a new brain SPECT
agent. We enrolled 15 patients and obtained ictal studies in
6 patients over 4 months. Injections were done within a
minute of seizure onset. Image acquisition was performed
with a Siemens MultiSPECT-3 system. Interictal SPECT was
performed on all. Images were reviewed blindly by three
physicians. Ictal studies demonstrated focal areas by hyperperfusion in all. while cwo interictal studies showed focal
perfusion abnormalities. The region of hyperperfusion always
corresponded to surface and invasive electroencephalographic findings. Magnetic resonance imaging was lateralizing
on only 1 patient. Valid surgical follow-up data is not yet
available. We conclude that ictal brain SPECT can be obtained more readily in children with Tc-79m-bicisate and is
significantly more informative than interictal SPECT. In certain circumstances, ictal SPECT might obviate the need for
invasive recording.
546. Effect of Hyperthermia on Chronic Hippocampal
Stimulation in Immature and A d u l t Rats
L. Cawtiant. Z . Liu, S. Warner, M . A . Mikati.
and G. L. Holmes, BoJton. M A
Continuous hippocampal stimulation (CHS) shows that
younger rats have more severe seizures than adults, but are
exempt from hippocampal
sclerosis seen in older animals.
.Similar experiments using hyperthermia demonstrate that
rats are susceptible to hyperthermic seizures at a young age
only; but associated lesions are diffuse, with no propensity
for temporal lobe. W e combined CHS with hyperthermia to
526 Annals of Neurology Vol 36 No 3 September 1994
study how temperature affects seizure-induced brain damage.
Male rats 18 to 20 days old (n = 33) and 60 days old (n =
5 ) were implanted with a bipolar stimulating electrode in the
ventral hippocampus. On the following day, half the immature rats received 45 minutes of CHS when rectal temperature reached 40°C, and half received similar treatment, but
on 3 consecutive days, starting on day 18. Adult animals
received a single stimulation course. Animals were sacrificed
10 days later. All animals had clinical seizures characterized
by staring, salivation, and facial clonus. A total of 13 immature rats survived, with no gross histological lesions; but, cell
counts revealed a reduction of hilar cells compared to controls ( p = 0.04). Adults showed bilateral hilar lesions and
ipsilateral CA3 involvement. Hyperthermia potentiates the
effects of CHS. While less dramatic than in mature animals,
cell loss in immature animals may also lead to synaptic reorganization and changes in neuroexcitability.
547. Preoperative Predictors of Outcome for
Corpus Callosotomy
L. Carmant, G. L. Holmes. M . A. Mikati, J . J . Riziiello, and
S . L. Helniers, Boston, M A
Fifty years after Van Wagenen and Herren introduced callosotomy, its indications and results remain controversial. We
reviewed the Children's Hospital experience to try to determine who benefits from callosotomy. A total of 28 patients,
aged 2 to 26 years at surgery and of whom 79% were retarded and 18% had lateralizing signs, were included. They
were followed for more than 1 year postoperatively and were
available at the time of the study. Age of onset, duration of
epilepsy, seizure type, surgical approach, focal deficits, mental retardation, and electroencephalographic findings were
evaluated as predictors of outcome. W e assessed the presence or absence of global improvement in the level of functioning following surgery. Seizure type was the only predictor
of outcome. Tonic or myoclonic drop attacks were most responsive, with significant improvement in 80%, followed by
atonic drops (7796), atypical absences (73%), generalized
tonic-clonic (55%,), and partial seizures (13%). Worsening
or appearance of partial seizures occurred in 50%. Only 50%
of families reported significant global improvement. Our results suggest that, even in mentally retarded individuals, drop
attacks of all types respond favorably. But, global improvement occurs less often than predicted b,y seizure control. This
probably relates to the persistence of other seizure types and
exacerbation of partial seizures.
548. Outcome of Temporal Lobectomy i n Children
M . Sotero. M. Connofly, C . T . Lombroso. S . L. Helmers,
J . J . Riiiello. G. L. Holmes. P. McL. Black. J . Madsen.
and M . A. Mikati. Boston, M A
The factors predictive of outcome in temporal lobectomy are
not well-established in children. We assessed the outcome of
patients 18 years and younger who had temporal lobectomy
and were followed for a minimum of 1 year after surgery.
The study population was comprised of 40 patients who had
temporal lobectomy. We evaluated the clinical, neuropsychological profiles, structural and functional neuroimaging, interictal and ictal electroencephalograms, and pathological
data. The most common pathological diagnoses were hippocampal sclerosis, tumors, neocortical gliosis, and dysplasia.
The postoperative seizure outcome was classified according
to Engel, classes I to IV. Statistical analysis was performed
using a two-tailed paired t test. The follow-up ranged from
12 to 136 months. Of the 40 patients, 26 had a good outcome (Engel class I, 11) and 14 had a poor outcome (Engel
111, IV). Overall, patients with tumors had a better outcome
following surgery ( p c 0.01).
549. Neurocognitive and Behavioral Assessment of
Children w i t h Hypothalamic Tumors: A Pilot Study
P. T . Molloy. H . A. Sernyak. L. N . Sutton, J . Radcliffe.
M . N . Needle. J . W. Goldwein, and P. C . Phillips.
Philadelphia , P A
The long-term cognitive, behavioral and psychological outcome of children with brain tumors of the hypothalamus
has not been well-characterized. A total of 8 1 patients with
chiasmatic-hypothalamic tumors were identified by medical
chart review and neuroimaging studies. The Child Behavior
Checklist (CBCL), consisting of two scales (Parent Rated
Competence Scale and Internaliting/Externalizing Scale),
evaluated behavioral, emotional, and social adjustment. A
parental questionnaire assessed academic performance. A total of 35 patients have been evaluated (21 boys, 14 girls).
Mean age was 9.2 years (age range, 3-19 years). All patients
received surgery, chemotherapy, and radiation therapy alone
or in some combination. Of 32 patients, 19 (59%) required
special education or remedial instruction ( 3 cases were excluded; age < 4 not evaluable by CBCL). Patients were abnormal (clinical range) on the Parent Rated Competence
Scale in the following categories: school performance (31%'),
social skills (31%), activities of daily living (13%). Abnormal
factors noted on Internalizing/Externalizing (I/E) Scale include: somatic complaints (41%), social problems (34%), attentional problems (199r,), withdrawn behavior (16%), anxiousldepressed mood (16$%), thought problems (16%),
aggressivity (13%), and delinquency (35%). The combined
I/E Scale revealed that 9 of 32 (28%) were abnormal (4,
borderline; 5, clinical range). Children surviving hypothalamic tumors demonstrate neurocognitive problems measured
by poor academic performance and need for remedial instruction. Social and behavioral ad juscment problems were
noted on CBCL and warrant further clinical investigation.
550. Neuromuscular Asymmetries in Newborns and
the Ballard Maturational Score
August0 Morales. Springfield, IL
Asymmetries in 116 apparently healthy newborns (54 girls;
mean gestational age, 39.37 weeks; SD, 1.25; range, 36-42
weeks) were studied by performing a bilateral examination
using neuromuscular items of the Ballard Maturational Score
(BMS). The degree of asymmetry (mild = 1 point; moderate
= 2 points; marked = 3 points) and number of asymmetrical
items were recorded. Descriptive statistics and correlations
were used for analysis. Left and right asymmetries were noted
in 57%; these were mild in 50%, moderate in 6%, and
marked in 1%. One asymmetrical BMS item was found in
28%, 2 items were found in 23%, 3 items were found in
4%, and 4 items were found in 1%. The correlation between
the left and right raw neuromuscular scores was r = 0.81.
Upper/lower asymmetries on the posture item were noted
in 48%; mild asymmetries were noted in 37%, moderate
asymmetries were noted in lo%, and marked asymmetries
were noted in 1%. The neuromuscular asymmetries affected
gestational age assessment by 1 week in 28% and by 2 weeks
in 396. The correlation between gestational age assessment
by examination (physical and neuromuscular) and by dates
using the left-side neuromuscular examination was r = 0.43,
Program and Abstracts, Child Neurology Society
527
using the right-side neuromuscular examination was r =
0.22, and using the whole body, r = 0.43. We conclude that
neuromuscular asymmetries can be detected by BMS items.
Despite high correlations between left- and rightneuromuscular scores, considerable variance is still unaccounted for. The significance of these asymmetries is unknown. They could affect gestational age assessment. A
one-side neuromuscular assessment should not be used in
determining the total BMS.
CMVs indicated 6 strain patterns for a sequence, 5 patterns
for gB, and 13 patterns for MIE. Combined analysis through
the 3 regions revealed 3 sets of 2 infants each with indistinguishable strain patterns; each had some common epidemiological features. The remainder were distinct by PCR analysis. These data indicate considerable diversity of CMV
strains. Indistinguishable strain patterns may suggest common epidemiological sources for some congenitally infected
infants. PCR analysis provides new insights regarding the
characteristics of CMV strains.
551. T h e Child Neurologist as Expert Witness: Results
of the Child Neurology Society Questionnaire
James F. Bale. Jr. Stephen Ashoal. Michael L. Goldstein. and
the members of the Child Neurology Society Ethics and Practice
Committees, Iowa City. IA, Loma Linda, C A .
and Salt Lake City. U T
5 5 3 . Thyroid Studies i n Children with Attention
Deficit Hyperactivity Disorder
G a y B. Bobele and Janeth Todd, Oklahorna City, OK
To assess the role and opinions of the Child Neurology Society (CNS) membership regarding expert witness activity, a
detailed questionnaire was circulated to CNS members in
late 1993. A total of 285 questionnaires was completed and
returned, a response rate of 25.3%. Of the respondents,
89% were senior (active) members, 52% were in universitybased, academic practices, and 3 2 Y were in private practice.
Forty-eight percent of respondents practiced in cities with
populations greater than 1,000,000,43r/c had practiced more
than 15 years, and 48% saw 31 or more patients per week.
With respect to medical-legal activities, 86% had testified
or been deposed as a treating physician, and 42% had been
the object of a medical liability lawsuit. Approximately 91%
of respondents reviewed cases for attorneys, and 37% of
these reviewed 5 or more cases in an average year; 7296
had testified in court as an expert witness. Nearly 90%) of
respondents indicated that the current legal system should
be reformed, and only 30% believed that the current system
was fair. Slightly more than half (56%) of the respondents
believed that the CNS should monitor the expert witness
activities of child neurologists, and 66% believed that there
should be a mechanism for peer review of these activities.
More than 909; agreed with the statement prepared by the
American Academy of Neurology for expert witness activities. These results indicate that child neurologists play a substantial role as medical experts and have an unfavorable view
of the current medical liability system.
552. Epidemiology of Congenital
Cytomegalovirus Infection
lnara E. Souza, Patricia Benson. Marsha E. O’Neill.
Jody R. Murph. and Janies F . Bale. Jr. Iouia City, IA
Our objective was to determine the incidence of congenital
cytomegalovirus (CMV) infection, the most common cause
of virus-induced mental retardation, in eastern Iowa, to characterize CMV strain patterns, and to identify epidemiological
factors for infection. Between October 1989 and January
1994, 7,972 infants born at 4 hospitals were prospectively
surveyed for congenital CMV infection by culturing urine
obtained in the first 2 weeks of life. The polymerase chain
reaction (PCR) and primers for a sequence, glycoprotein B,
(gB), and major immediate early (MIE) regions of the CMV
genome were used to characterize CMV isolates. CMV
strains were compared with regard to date and hospital of
birth, and parental residence. A total of 31 infants excreted
CMV, a 0.4% incidence of congenital infection. Infants were
born to parents living in communities ranging in size from
less than 1,000 to more than 100,000. PCR analysis of 27
Attention deficit hyperactivity disorder ( A D H D ) is reported
to be associated with mutations in the thyroid receptor beta
gene that cause generalized resistance to thyroid hormone
(GRTH), a condition characterized by elevated serum T ,
levels and normal or elevated thyrotropin (TSH) levels, goiter, and clinical euthyroid or hypothyroid states. To further
investigate this association, we studied patients referred to
the Pediatric Behavioral Neurology Clinic at the Children’s
Hospital of Oklahoma. Data on 5 5 patients with A D H D
and 48 patients with other neurobehavioral disorders were
reviewed. Of the A D H D parients, 85% were boys, mean
age was 9.9 t 0.4 (all data 2 1 SEMI years, and the Connor’s
Hyperkinetic Index ( C H I ) was 2.05 2 0.05. Of the patients
without ADHD, 76% were boys, mean age was 10.5 2 0.4
years, and the C H I was 1.57 t 0.10. No patient had a goiter
or clinical hypothyroidism; 1 patient with A D H D had known
Grave’s disease. All other patients had normal serum T, levels, and none had elevated TSH levels. W e conclude that the
association of A D H D and mutations of the thyroid betareceptor gene are rare.
With A D H D
Without A D H D
Serum T.i ng/dl
Serum T S H Uiml
1.15 t 0.09
1.73 t 0.30
2.49 t 0.18
2.43 2 0.21
5 5 4 . Do Gender, Laterality of Cerebral Insult, and
A g e of Seizure Onset Modulate Intellectual Outcome?
Karhiyti A. Selby. Keiin Faryell. Esther H . Strauss.
Joseph Zaide. and Michael Hunter. Vancorriier and
Victoria. British Columbia. Conada
Functional reorganization (plasticity) of the brain varies according to the age at the time of injury. Gender and lateralization of the lesion may also play a role in intellectual outcome. In a retrospective study of children with partial
seizures, the influence of gender, age at seizure onset, and
lateralization of hemispheric dysfunction o n cognitive and
behavioral outcome was studied. W e identified 40 children
with clear lateralization of the seizure focus. Comprehensive
neuropsychological evaluation was performed in all children.
Age at seizure onset was an important predictor of intellectual outcome ( p < 0.03). The average full-scale I Q was 76
in those with seizure onset before 12 months, and 94 in
those with seizure onset after 12 months. The laterality of
dysfunction and gender appeared to modulate the relationship between age of seizure onset and intellectual outcome.
Males with left-hemispheric dysfunction demonstrated the
highest correlation. This study suggests that age at seizure
5 2 8 Annals of Neurology Vol 36 No 3 September 1994
onset correlates with intellectual outcome, and that gender
and lateralization of the seizure focus modulate this relationship.
555. Increasing Incidence of Cystic Periventricular
Leukomalacia: Possible Etiological Factors
Adnan Y . Manzur, Brian A . Lupton, Elke H . Roland. and
Alan Hill<Vancouver, Britijh Columbia. Canadu
Recent observations have demonstrated increased incidence
of cystic periventricular leukomalacia (PVL). The precise
cause of such increase is not entirely clear. We reviewed the
records of all 2,149 premature newborns (body weight <
1,500 gm) admitted between 1983 and 1993. A total of 51
infants (excluding infants with major I V H and hemorrhagic
parenchymal involvement) had cystic PVL on serial ultrasound scans. Prior to 1991, the incidence of cystic PVL was
2 to 4 per year (295), which rose sharply to 8 in 1992 and
12 in 1993 (6%), without change in imaging surveillance.
The mortality rate decreased from 24% (1986) to 115%
(1993). Cystic PVL was detected prior to 1 week of age in 8
infants, suggesting antenatal onset. Other possible etiological
factors include: multiple pregnancy, 17 (33%); maternal urinary tract infection and chorioamnionitis, 28 (55%); bronchopulmonary dysplasia, 37 (73%); surfactant therapy, 18
(3595), and dexamethasone treatment, 15 (29%). These data
demonstrate that recent observation of increased incidence
of cystic PVL may be explained on the basis of decreasing
mortality rate in premature newborns. In addition, the increasing incidence of multiple pregnancy, in which fetal compromise may be more common, may contribute to the patients with cysts of presumed antenatal onset. Further studies
are needed to evaluate the possible etiological role of other
factors.
556. Serum Ionized Magnesium Levels in Infants
Exposed to Cocaine In Utero
J . C . Marcus. G . Valenria. B . T . Altura, D . Jean-Baptiste,
K. Sinha, and B . M . Altura. Brooklyn, NY
The association of premature labor, neonatal stroke, and
in utero cocaine exposure has been well-established. Experimentally, it has been shown in intact brain and cultured cells
that cocaine reduces magnesium (Mg) concentration. Ionized
magnesium (IMg) is a more sensitive indicator of Mg metabolism than standard serum total Mg (TMg). Having recently
established IMg levels in neonates of different gestational
ages and weights, we examined serum IMg levels in cocaineexposed infants for comparison. A total of 15 infants with
cocaine or metabolites in the urine, or a strong history of
maternal drug abuse, ranging from 33 to 40 weeks gestation,
and weighing 1.7 to 3.1 kg, were matched with nonexposed
infants. Serum IMg and ionized calcium (ICA) levels were
measured with ion-specific electrodes, and, in addition, ratios
of ionized calcium to TMg were calculated. No statistical
difference between the 2 groups could be established for
serum 1Mg levels (ANOVA, p = 0.859) or for 1Ca:IMg
(ANOVA, p = 0.503). This is not in keeping with experimental data in tissues and cells, suggesting that blood IMg
may not reflect the activity in intact brain.
557. Morbidity i n Children After Status Epilepticus
John M . Pellock, Carolyn A. Fortner, Susan M . Driscoll,
and Robert J . DeLorenzo, Richmond, V A
Childhood morbidity following status epilepticus (SE) has
been estimated to range from 9 to 50% The mortality, how-
ever, is quite low, approximately 4 to 11%. A retrospective
study of SE in children was performed at the Medical College
of Virginia for the years 1980 to 1989. Of the 313 episodes
observed, 169 were first time SE. Neurological state was
ascertained before and after SE in all but 7 patients. Children
with known seizures (sz hx) prior to SE comprised 5 2 q of
the patients. Of the children with no SZ hx, 80% were normal
before SE, compared to 19% of children with sz hx. Previously normal children who had sz hx before their SE deteriorated 1% of the time, in contrast to those without sz hx,
where deterioration occurred in 29.6%. Patients who were
neurologically abnormal and had sz hx before their SE deteriorated 7.9% of the time, in contrast to those without
sz hx, where deterioration occurred in 6%. Length of followup of these children ranged from discharge date to 11 years.
Prior neurological abnormalities included a variety of problems ranging from cerebral palsy to mental retardation. Deterioration after SE included hemiparesis, speech and memory
deficits, mental retardation, and epilepsy.
558. Status Epilepticus in Virginia-born T w i n s and
Their Families: Possible Familial Association?
John M . Pellock, Linda A . Corey, Marsha Gaudin,
Libbie L. Miller, and Robert J . DeLorenzo, Richmond, V A
Although genetic epilepsies most frequently occur in children and adolescents, different ages of onset and symptoms
can be seen within a family. To date, our studies of status
epilepticus (SE) involving twins contained within the population-based Virginia Twin Registry (11,392 twin pairs) identified 9 families containing 2 or more individuals positive for
a history of SE. These findings suggest that SE may have a
familial basis in some cases, independent of the seizure or
epilepsy type. Although SE presented in both childhood and
adulthood in our sample, this observation was not randomly
distributed across families. In 1 case of monozygotic twins,
SE presented at the same age in both pair members, while
in another monozygotic pair, SE occurred at 11 and 18 years
of age, even though the epilepsy and seizure types were identical. Of the 7 remaining multiplex SE families in the study,
3 contain SE-affected sibling pairs, and, in 4, the affected
relatives were parents and offspring. Seizure and epilepsy
types included both familial and symptomatic forms. SEaffected individuals within a family, furthermore, sometimes
differed in seizure and epilepsy type. Age-of-SE occurrence
also differed among affected family members. These results
suggest that the occurrence of SE within families may not
strictly be a manifestation of the epilepsy syndrome, but
might represent separate familial predisposition.
559. Use of a Continuous Performance Task
as a Measure of Sleepiness
Michael H . Kohman, David W . Shucard, Gregory L. Ciupak,
and Lori Monte, Bufialo, N Y
Objective measures of excessive daytime sleepiness and severity of apnea in children have yet to be developed. A total
of 34 consecutive subjects, aged 6 to 18 years, presenting
for clinical polysomnography, were given a continuous performance task to assess the task as a measure of sleepiness.
Eight patients with sleep apnea (mean apnea hypopnea index,
8 & 12 evendhour) and 6 patients with normal polysomnograms were identified from this group (mean age, apneic
group, 13.7
2.6 years; mean age, normal group, 11.5 2
1.2 years). A visual continuous performance task (A-X) was
administered prior to the polysomnogram (prestudy) and on
*
Program and Abstracts, Child Neurology Society 529
arising in the morning (poststudy). Average sleep time during
the polysomnograms was 5.0 2 2. Group reaction time for
the apneic patients was 454 2 132 msec prestudy and 566
2 157 msec poststudy. For the normal, nonapneic group,
reaction time was 487 2 5 5 msec prestudy and 519 -+ 40
msec poststudy. There was no significant difference in reaction times between prestudy and poststudy in the normal
subjects and between prestudy reaction time in both groups.
Nonapneic patients had somewhat longer reaction times than
apneic patients for the prestudy session. The reaction times
were significantly prolonged prestudy to poststudy in the apneic patients ( p = 0.05 tt). The intertest prolongation of
reaction time in the apneic group suggests that this measure
may correlate with excessive sleepiness. Additional subjects
are needed to evaluate this hypothesis.
560. Use of EEG i n Tiagabine Therapy
ues. Brain weight in RS subjects (range, 700-1,240 gm) was
lower than in controls (range, 1,204-1.379 gm) and did not
show age-related changes. In the age range of our autopsies,
the brain and kidneys were the first organs to fall from the
normal growth pattern. The kidneys, however, unlike the
brain, continued to grow. The heart, liver, and spleen were
similar to controls until 10 to 12 years; but, thereafter, the
rate of growth declined. The adrenal glands were the same
weight as controls. These observations support the hypothesis that the decreased brain weight in RS is related to a developmental arrest, rather than to a progressive process. Also,
the pattern of brain growth failure appears to occur early,
and is different from somatic and other organ growth failure
that occurs later, but is associated with continued growth.
This information may be of value in planning for nutrition
in RS, and it is hoped that it may help to characterize a factor
that may be responsible for the unique abnormality of brain
growth in RS.
Roy D . Elterman. David B . Owen, and Steuen L. Linder.
Dallas. T X
Tiagabine hydrochloride (HCI), a potent inhibitor of GABA
re-uptake, is currently being evaluated in the United States
and Europe for the treatment of epilepsy. Double-blind,
placebo-controlled studies show Tiagabine to be effective in
the treatment of complex-partial seizures. We report a clinical syndrome in patients on Tiagabine that can lead to confusion as to whether the patient is drug intoxicated or experiencing clinical partial seizures. Of 19 patients treated with
Tiagabine for refractory epilepsy, 6 developed bouts of sleepiness, confusion, ataxia, impaired responsiveness, and impaired abilities to produce spoken language, associated with
jerkiness and twitching of the eyes and extremities. In 2
patients, this behavioral syndrome was initially interpreted
as drug intoxication. Continuous closed-circuit television
electroencephalographic (CCTV-EEG) recording in these 2
patients demonstrated that these were complex-partial seizures. The Tiagabine dose was increased in both patients,
with significant improvement in their seizure frequency. In
4 patients, these episodes were assessed as being seizure activity. Increasing Tiagabine doses failed to result in any improvement. CCTV-EEG recording showed no epileptiform
activity associated with these events in these 4 patients. Reduction of Tiagabine doses resulted in resolution of this
symptomatology. All 6 patients have remained on Tiagabine
therapy with improved seizure control over baseline. The
occurrence of this striking clinical syndrome in patients with
partial seizures and secondarily generalized seizures on Tiagabine can create a management dilemma wherein drug toxici t y cannot be distinguished from seizures. CCTV-EEG or
ambulatory electroencephalogram can clarify this situation.
561. Pattern of Brain and O r g a n Growth in
Rett’s Syndrome Supports Hypothesis of
Cerebral Developmental Arrest
D. Arnistvot~g~
R. P. Tviwdi. and D . Glaze, Houston. T X
Rett’s syndrome (RS) is a disease of unknown etiology.
Growth failure is a recognized feature of RS, and cerebral
developmental arrest has been postulated as an explanation
for the decreased brain size and the mental and motor handicaps. This hypothesis implies a defect in normal growth regulation. We have reported in RS a pattern of early deceleration
of head growth followed by somatic (heightlweight) growth
failure. To further characterize growth failure in RS, we report the brain and organ weights of 31 autopsy cases of RS
(ages 4-35 years), compared to normative age-matched val-
562. Children Who Won’t Walk: Analysis of 35
Consecutive Cases
S. Robert Snodgrars,Jackson. MS
Children who are not seriously ill, and yet will not walk, are
difficult diagnostic problems: Most are small and uncooperative. A total of 35 consecutive acute cases, seen personally
by the author in Los Angeles and Mississippi over a six-year
period, without a chronic neurological history are reviewed.
All had been seen by other physicians and, sometimes, by
multiple consultants. A total of 20 were hospitalized and 15
were sent home. Of the 15, 2 failed to return, but were
eventually tracked by telephone. The oldest was 13, but most
were under age 5, especially those without a diagnosis. The
most common diagnoses were Guillain-Barre syndrome
(GBS) and no diagnosis but rapid recovery. Two patients had
spinal cord tumors, one of whom was initially misdiagnosed
because of evidence of child abuse. Three patients were
wrongly diagnosed as GBS: 1 who walked out the next day,
1 with intrathecal leukemia, and 1 with neuroblastoma. The
second patient became totally flaccid with normal lumbosacral MR and only mildly abnormal CSF (malignant cells were
sought and not found). Four G B S patients had diagnoses of
acute ataxia, even though all were areflexic.
Diagnosis
No. Patients
Guillain-Barre syndrome
Recovered-no diagnosis
Musculoskeletal syndrome
Acute cord syndrome
Cerebral disorders
Spinal cord tumor
Miscellaneous
11
7
5
3
3
2
4
Afebrile patients who were eating could usually be sent
home; but, 2 did not return and had to be tracked down
by telephone. No diagnostic errors were due to failure to
hospitalize parients. Emergency MR scans were necessary in
a minority of patients, and there was a tendency to overread
them. Two patients with spinal inflammatory disease had no
MR abnormality of the cord, but had trouble walking and
voiding. Only 1 case was believed to be due to a behavioral
problem. Findings, diagnosis, and therapy in each major subgroup are presented and the frequency of GBS and its misdi-
530 Annals of Neurology Vol 36 No 3 September 1994
agnosis is emphasized. Outcomes were generally good; only
4 patients had residuals.
563. Rett’s Syndrome: Cerebrospinal Fluid Biogenic
Amine Levels Correlate with Motor Dysfunction
D . G. Glaze. A.K . Percy. R. J. Schultz, R. P. Trioedi.
H . Zoghbi. I . J . Butler, E. C . Myer, D . Williamson.
J . J . Jankovic, andJ. D . Frost,Jr. Houston, T X ,
Birmingham, AL, and Richmond, VA
While there is no biological marker for Rett’s syndrome (RS),
alterations in CSF biogenic amine metabolites (BA) and Bendorphins (B-ENDS) have been reported. We report the
relationship of changes to clinical manifestations of RS. In 66
females meeting strict criteria for RS (aged 1.4-21.4 years;
median age, 4.8 years), 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), homovanillic acid (HVA), and 5hydroxyindoleacetic acid (5-HIAA) were measured. CSF BE N D levels were determined in 44 patients. Clinical parameters included Bayley Scales, scores for motor characteristics,
awake breathing abnormalities, stereotyped hand movement,
and FOC 2 scores. In comparison to controls, H V A and
MHPG CSF levels were lower in RS ( p < 0.001); MHPG,
5-HIAA, and HVA showed expected age-related changes.
Lower levels of 5-HIAA were correlated with lower Bayley
Psychomotor Scores ( p = 0.01; r = 0.40). Greater motor
disability correlated with lower levels of HVA ( p = 0.03;
r = 0.35) and 5-HIAA ( p = 0.03; r = 0.37);and H V A
with increased hand movements ( p = 0.017; r = 0.405).
There was no significant correlation noted between BA or
B-END levels and the respiratory parameters or FOC Z
score. These findings implicate dopamine and serotonin pathways in motor abnormalities of RS. However, normal agerelated changes in BA and lack of correlation of BA and
B-ENDS with other clinical parameters indicate these are not
the only or primary defect in RS.
564. Periventricular Leukomalacia i n the Premature
Infant: Is It Preventable?
Jeffrty Perlman, Dallas, T X
Bilateral cystic periventricular leukomalacia (PVL), the principal ischemic lesion of the premature infant, refers to necrosis of white matter in areas that represent arterial border
zones adjacent to the external angles of the lateral ventricles.
Prevention is a major goal because of the major motor deficits observed with this lesion. Although the etiology is not
clear, a decrease in cerebral blood flow secondary to systemic
hypotension is considered to be of paramount importance.
The study objective was to determine whether premature
infants who evolve to cystic PVL could be identified by clinical markers, i.e., systemic hypotension prior to development
of the lesion. Between January 1992 and December 1993,
14 of 61 1 premature infants (2.3%) less than 1,750gm developed cystic PVL; the incidence was 3.8% for infants less than
1,500 gm, 4.796 for infants less than 1,250 gm, and 4.29%
for infants less than 1,000 gm. Mean body weight was 1,290
gm, G A 29 weeks. Cysts developed “early,” i.e., by 7 to 10
postnatal days (n = lo), and later, i.e., after 21 days (n =
4). Perinatal risk factors associated with PVL included 1. prolonged rupture of membranes, 4 of 14 versus 34 of 611 for
infants without PVL ( p < 0.0002; odds ratio, 6.78); sensitivity -10%); 2. chorioamnionitis, which occurred in 3 of 14
versus 21 of 611 ( p < 0.0003; odds ratio, 7.66; sensitivity
- 10%’);and 3. systemic hypotension (mean blood pressure,
<30 mm Hg) occurred in 3 infants (2 1 %). No differences
in severe fetal acidemia (i.e., cord p H < 7.00), 5-minute
apgar score less than 5 , mean blood pressure, or overt sepsis
was noted in infants with or without PVL. Seven of the infants have been followed beyond 1 year and have severe
developmental delay. These data indicate 1. cystic PVL remains a significant problem affecting 4% of infants less than
1,500 gm; 2. overt perinatal/postnatal hypotension is an uncommon event, suggesting that other factors, possibly by inducing excitotoxic neurotransmitter release or oxidantinduced iniurv,
,
.. mav, be more important; and 3. since most
infants who evolve to PVL canno; be readily identified clinically, selective prophylactic measures of susceptible infants
may not be possible.
565. Limitations of Clinical Observations in
Infantile Seizures
Carl W . B a d . Douglas R. Nordli. Jr, Tinlothy A.Pedley.
and Mark L. Scheuer, Neu York, NY
Seizures in infancy are common, but often difficult to characterize and classify. We analyzed 39 seizures in 20 infants
(aged 4 months-2 years) recorded during inpatient monitoring using closed-circuit television/EEG (CCTV-EEG). EEGs
and videotapes of all seizures were independently reviewed
by two epileptologists who were blinded to clinical histories.
Videotapes of each seizure were reviewed without benefit of
the simultaneous EEG (phase I), and printouts of ictal EEGs
were assessed without clinical correlates (phase 11). The two
observers recorded detailed observations of both phases on
worksheets specifically developed for this project. A total of
72%, of interpretable ictal EEGs were judged to be of partial
onset. Of these, approximately one third were localized to
the temporal lobe. In contrast to older children and adults,
well-developed automatisms and lateralizing signs were rare:
Fewer than 10% had limb automatisms, 3% had oral automatisms, and focal dystonic posturing occurred in less than 5%
of all seizures. As a result, seizures were correctly assigned
to the temporal lobe in only 1 patient, and none of the temporal lobe seizures could be accurately lateralized by clinical
criteria alone. Furthermore, observers could not reliably distinguish partial from generalized seizures based on phase I
analysis. These findings underscore the limitations of
applying clinical criteria developed from the analysis of adult
seizures to infants. Further study of the clinical characteristics
of infantile seizures and their EEG correlates is warranted,
and a more appropriate classification scheme tailored to the
special circumstances of infants is needed.
566. New Observations i n Patients w i t h
Kugelberg-Welander Disease
Bawy S. Russman, C . Ralph Buncher, Michael L. White.
Susan T . lannaccone, and Fred J . Samaha. Neuington*C T .
Cincinnati, OH, and Dallas, T X
Hausmanowa-Petrusewicz recently published a long-term
follow-up of patients with Kugelberg-Welander (K-W) disease (patients with spinal muscular atrophy whose onset of
weakness begins after they have developed independent
walking) (Hausmanowa-Petrusewicz I, Badurska B, Ryniewicz B, The natural history of proximal chronic childhood
spinal muscular atrophy (forms 2 and 3), Acta Cardiobiol
1992;4:19-33). Using repeat muscle biopsy and EMG evidence, they suggested that patients with this entity have pro-
Program and Abstracts, Child Neurology Society 531
gressive loss of anterior horn cells, explaining their loss of
function. We evaluated 14 K-W patients, a mean of 8 times
over a 3- to 5-year period, and normal controls (aged 6-30
years) 1 time. The K-W patients ranged in age from 5 to 31
years and included 5 males and 9 females. Quantitative
strength (QS) of 14 muscle groups, functional assessment
(FA), and forced vital capacity (FVC) were measured. Three
patients lost function by FA during the observation period.
One patient, aged 7 , lost independent ambulation without
change in QS, and 2 patients, aged 14 and 30, lost function
associated with a decrease in QS. Of 7 patients, 6, aged 5 to
12, showed an increase in QS, while 4 , aged 14 to 31, had
no change in QS. FVC decreased, but not significantly, in 1
of 3 who lost function, and in 4 of 5 patients aged 11 to 31.
Untrained normal individuals gained strength until age 2 0 ,
at which time a plateau seemed to develop. We conclude
that K-W patients gain strength similar to "normal" individuals, but plateau earlier, by age 13. Furthermore, function loss
in K-W patients may not be explained by progressive loss of
strength. W e suggest that loss of function by FA in K-W
patients may be caused by complications of static weakness,
such as flexion contracture, rather than by degeneration of
motor neurons.
567. Repetitive Motor Movements Do Not Increase
Total Daily Energy Expenditure i n Rett's Syndrome
R. J . Schultz, K . J . Motil. and D. G . Glaze. Houston, T X
Features of Rett's syndrome (RS), a neurological disorder
affecting females, are repetitive motor movements and
growth abnormalities. Poor linear growth and weight gain
may be caused by increased total daily energy expenditure
(TDEE) as a result of these repetitive movements. W e examined TDEE and growth in 7 girls with RS (clinical stage IIIV). TDEE was measured by the 'H2 I8O dilution method.
Each subject received an oral bolus dose of 'Hz, 100 mg/kg
body weight, and "0, 125 mg/kg body weight, in the form
of water. Urine samples were collected prior to isotope ingestion and once daily for the next 10 days. All foods were preand postweighed for 48 hours to measure energy intake (EI).
Lean body mass (LBM) was measured by anthropometry and
total body electrical conductivity. Energy expenditures were
compared to published data (Fontvielle AM, et al, J Pediatr
1993) for healthy girls. Results (means t- SD) are shown in
the Table.
Variable
Age (yr)
Weight (kg)
Lean body mass (kg)
P,body weight
TDEE (kcalid)
EI tkcalid)
RS (n =
7)
6.7 t 1.7
15.3 t 4.1
13 4 t 5.8
87.0 2 3
7 7 8 0 t 88
1218.0 t 2 3 8
Reference
( n = 13)
5.5 2
18.9 t
14.6 2
77.0 t
1364.0 2
1500.0"
p value
0.4
2.5
0.7
5
188
NS
NS
NS
~0.05
cO.05
'RDA N A S N R C Washington, DC. 1389.
Despite similar LBM between groups, TDEE was significantly lower in RS girls than in reference girls. These data
suggest that repetitive movements do not raise TDEE in this
RS age group. The reduced dietary energy intakes relative to
recommended allowances suggest that dietary insufficiencies
may lead to a compensatory reduction of TDEE in RS girls.
532 Annals of Neurology
Vol 36 N o 3
Therefore, long-standing dietary energy deficits relative to
needs may account for growth failure in these girls.
568. Relationship of Attention and Adaptive
Functioning in Tourette's Syndrome
P. Cirino, L. Chapieski. M . Hiscock,
and D. Glaze, Houston. T X
Children with Tourette's syndrome (TS) have been considered at risk for behavior and attentional difficulties. The purpose of this study was to examine the relationship of adaptive
functioning and behavioral problems to attention and impulsivity in 30 TS subjects (27 male), compared to a demographically similar control group of 22 individuals (17 male). Fifteen of the TS subjects were receiving medication for
attention (tricyclics or clonidine); none were receiving stimulants. The T S group had significantly lower scores than controls on measures of externalizing behavioral problems, adaptive skills ( p < 0.0008),and inattention ( p < 0.03); they did
not differ on impulse control. Both groups were impaired
on a sustained attention measure; both groups performed
within normal limits in terms of impulse control. Difficulties
in adaptive skills or externalizing behavioral problems were
not related to either sustained attention or impulse control.
The 15 TS subjects receiving medication showed greater externalizing behavior problems than the 15 nonmedicated TS
subjects ( p < 0.002), who did not differ from controls on
this measure. Otherwise, the 2 TS groups did not perform
differently. Although difficulties in behavior and attention
were found in the present investigation, they were not significantly related to one another. These findings suggest that
there may be little agreement between laboratory measures
and parent report measures of attention and impulse control.
569. Blood Lead Concentrations i n Children with
Attention Deficit Hyperactivity Disorder
0. Papazian. A. Towes. 1. Alfnso. and
B . Carrillo, Miami. FL
Recent data suggest a relationship between poor school
achievement and hyperactive behavior with blood lead concentrations between 10 and 25 pg/dl. T h e objective of this
study is to determine if there is an association between abnormal blood lead concentrations and attention deficit hyperactivity disorder (ADHD), with or without learning disability
(LD). We evaluated 100 children, 73 boys and 27 girls, aged
4 to 13 years, with A D H D according to DSM-111-R criteria.
Of the 100 children, 7 2 had LD. Fasting blood lead concentrations were determined. A blood lead level less than 10
(*g/dl is not considered to be indicative of lead poisoning.
None of the children were at high risk for lead exposure by
Centers for Disease Control questionnaire criteria. The
blood lead concentrations in all the children were below 10
pg/dl. Even though the sample is small compared to the
incidence of A D H D (9%), LD (4.8%'),and blood lead level
at or above 10 pg/dl(l5.5%), the findings have a significant
negative correlation. In conclusion, our findings suggest that
A D H D with or without LD is not associated with blood lead
levels at or above 10 pg/dl. Therefore, we do not recommend routine determination of blood lead in children with
ADHD, with or without LD, and negative history of exposure to lead as defined by Centers for Disease Control questionnaire criteria.
September 1994
570. Proton Magnetic Resonance Spectroscopy in
Childhood Central Nervous System Infections
Stephen A s b u d . Kathleen L. Auld3Barbara A . Hohhouser,
Ronald M . Perkin. and David B. Hinshaio, Jr,
Loma Linda, C A
Proton magnetic resonance spectroscopy ('H-MRS) can examine neuronal activity (N-acetylaspartate, NA), cerebral glycolytic (lactate) and energy metabolism (creatine, Cr), and
membrane integrity (choline-containing compounds, Ch).
We studied 'H-MRS in 8 infants and children (aged 1
month-9 years) with central nervous system infections. Five
patients had bacterial meningitis (2 with subdural empyemas);
3 patients had viral encephalitis. Single voxel 'H-MRS was
determined in the midsagittal position of occipital gray and
parietal white matter (8-ml volume) using a STEAM sequence with TE = 20 msec, T R = 3,000 msec, 128 scans,
T M = 30 msec. Cerebral lactate was elevated in 2 of 5
patients with meningitis, but did not correlate with outcome.
None of the patients with encephalitis had increased lactate.
Although several patients were neurologically impaired and
encephalopathic at the time of study, their spectroscopy studies (NAICr, ChlCr, NAlCh ratios) were normal and correlated with good recovery. 'H-MRS is an emerging technology that may be useful in evaluating children with severe
childhood infections. Our preliminary data suggest that cerebral lactate production is increased in bacterial meningitis.
Spin resonance ratios may serve as an indicator of the potential for recovery.
571. Proton Magnetic Resonance Spectroscopy i n
Children with Acute Central Nervous System
Ischemic Injury
Kathleen L. Auld, Stephen Ashuial, Barbara A . Holshouser,
and D a d B. Hinshaw, Jr. Loma Linah, C A
Proton magnetic resonance spectroscopy ('H-MRS) noninvasively measures cerebral metabolites that are predictably altered during ischemic injury. N-acetylaspartate (NA), creatine (Cr), choline (Ch), glutaminelglutamate (Glx), lactate
(Lac), and myoinositol (Ins) reflect neuronal injury, energy
metabolism, membrane integrity, excitatory neurotransmitters and glycolysis, respectively. W e studied 12 patients (aged
2 weeks-5 years; mean age, 1.5 years) after acute cerebral
hypoxic-ischemic in jury (4 near-drowning, 2 cardiac arrest,
3 nonaccidental injury, 2 near-SIDS, 1 birth asphyxia). Single
voxel 'H-MRS (STEAM sequence TE, 20 msec; TR, 3,000
msec; 128 scans; TM, 30 msec) measurements from occipital
gray and parietal white matter were obtained and peak amplitude ratios were determined. Poor outcome (severe disability, persistent vegetative state, and death) was associated with
age-dependent decreased NAlCh, increased ChICr, and Lac
compared to published normals (Kreiss et al, MRM 1993;30:
424-437), and abnormal clinical variables. 'H-MRS is useful
in evaluating the extent of brain injury and potential for recovery in children suffering hypoxic-ischemic injury. Data
interpretation depends on the timing of study after injury
and the age of the patient.
572. Excitotoxic Injury Impairs Mitochondrial
Respiratory Chain Function in the Neonatal Rat
P u p by a Nitric Oxide-dependent Mechanism
Ayele N.Bandele. Elizabeth A. Bolan. and
Rosario R. Trifiletti. Neui York, N Y
Our laboratory previously found that injury to the 7-day-old
rat striatum produced by the pure NMDA-agonist quinolinic
acid (QA) is mediated by nitric oxide (Ann Neurol 1993;34:
444). W e explored whether nitric oxide production attending
intrastriatal Q A administration results in impaired respiratory
chain function. Activities of total NADH-dehydrogenase
(NADH-d), NADH-cytochrome c reductase (NCCR), and
cytochrome c oxidase (COX) were determined in the (L)
and (R) striata at varying times following intrastriatal QA
administration. We found that total NADH-d and N A D H
CCR activities were transiently reduced by 40 to 50% in
striata ipsilateral (but not contralateral) to lesion, the effect
peaking at 20 minutes postlesion, and returning to baseline
by 180 minutes. In contrast, ipsilateral striatal C O X activity
is rapidly and profoundly depressed (to 1 5 q 1to 25% of control) for up to 24 hours after lesion. Pharmacological blockade of de novo nitric oxide (NO) synthesis mitigates the
QA-induced reduction in C O X activity. Exposure of striatal
homogenates to N O gas in vitro results in profound depression of C O X activity. Taken together, these results suggest
that N O generation can potentially impair striatal respiratory
chain activity, especially at the level of COX. These effects
might be direct effects of NO and/or the results of free
radicals whose formation is triggered by NO.
573. Cerebrospinal Fluid Findings in Infants
Evaluated for Possible Sepsis
Marcela Garcia-Alvarez. Darryl C . DeVivo. and
Rosario R. Trifiletti, New York, N Y
There is a paucity of recent quantitative data on cerebrospinal
fluid (CSF) composition in normal infants. W e obtained normative data at our institution, with special reference to CSF/
blood glucose ratio (CSF/BGR). A total of 5 11 lumbar punctures were performed at the Babies Hospital (New York,
NY) on infants with an admitting diagnosis of possible sepsis
during the period January 1, 1991 to May 1, 1993. Data on
CSF protein, glucose, cell count and CSF culture (positive in
3 cases), blood culture (positive in 20 cases), and concomitant
blood glucose were examined. W e stratified patients into 4
groups according to age at lumbar puncture (<31 days,
31-60 days, 61-90 days, and >90 days). CSF protein decreases with age and is multimodally distributed in all age
groups. Blood glucose was normally distributed with values
of 95 2 2, 102 2 , 1 0 3 5 , and 11 1 5 mgldl (mean 2
SEM) in each of the 4 age groups. CSF glucose was likewise
normally distributed with values of 55 ? 1, 56 2 1, 65 2
3, and 71 -t- 3 mgldl in each of the age groups. The CSF/
BGR is a function of the blood glucose; but the functional
relationship varies continuously with age. Our findings suggest that glucose transport is age-dependent in young infants;
this finding has important implications for the early diagnosis
of the recently described type I glucose transporter deficiency syndrome (GLUT1 deficiency) ( N Engl J Med 1991;
32 5 1703-707).
*
*
*
574. GYKI 52466 Neuroprotection in Excitatory
Amino Acid-induced Injury i n Neonatal Rat Brain
William H . Trescher and Michael V .Johnston. Baltimore. M D
GYKI 52466, a 2,3-benzodiazepine, selectively antagonizes
AMPAlkainate responses in a -noncompetitive manner. It
also has anticonvulsant activity in a variety of seizure models.
We investigated the neuroprotective effects of GYKI 52466
in an in vivo model of selective excitatory amino acidinduced hippocampal injury in the immature rat brain. Anesthetized, postnatal day 7 rat pups were subjected to a stereotaxic microinjection of S-AMPA (5 nmol),'kainate (10 nmol)
or N-methybaspartate (NMDA) (10 nmol) directed into
the dorsal hippocampus. Fifteen minutes after intracerebral
Program and Abstracts, Child Neurology Society 533
injection of excitotoxin, the animals received an intraperitoneal (ip) injection of GYKI 52466 (20 mg/kg) followed by
three 10 mglkg ip injections administered at 1-hour intervals.
One week later, the brains were removed, and selected coronal brain sections were prepared for Nissl staining. The severity of brain injury was expressed as $% damage = 100x(Cl)/C, by comparison of the hippocampal cross-sectional areas
ipsilateral (I) and contralateral (C) to the injection. Data are
presented as mean & SEM. GYKI 52466 did not protect
against S-AMPA-induced hippocampal injury (GYKI
52466, 50.2 t 4.6%; control, 53.0 t_ 4.7%), or against
kainate-induced hippocampal injury (GYKI 52466, 20.1 2
3.3%; control, 24.7 t 3.3%); however, it did provide partial
protection against NMDA-induced hippocampal injury
(GYKI 52466, 27.7 ? 3.2%);control, 57.3 5 5.296; p =
0.0002, Student's t test). The data suggest that GYKI 52466
neuroprotection may be partially through an NMDAdependent mechanism.
575. Writing H a n d Posture i n Developmental
Disorders of Attention and Right
Hemispheric Dysfunction
Drake D. Duane. Michelle Clark, and Larry Gottlob.
Srottsdule and Tempe?AZ
Hand posture in holding a writing instrument typically
evolves with development. A spectrum of writing hand postures occur in the general population (Ziviani J, Qualitative
changes in dynamic tripod grip between seven and 14 years
of age, Dev Med Child Neurol 1983;25:778-782). Whether
anomalous hand posture itself correlates with motor speed
or specific disorders of academic achievement or of attention
is unclear. This pilot report is from a large longitudinal study
of school-age children, adolescents, and adults referred for
behavioral neurological assessment (Duane DD, Clark M,
Brennan ME, Bryan T, Later life neuropsychiatric concomitants of developmental right hemisphere dysfunction, Neurology 1994;44[supp12]:376).Retrospective analysis included 25 control children (18 boys; mean age, 12 years;
age range, 6-12 years), 29 children with attention deficit
hyperactivity disorder (ADHD) (25 boys of similar age), and
2 1 children with right hemisyndrome dysfunction ( 1 3 boys of
similar age). Compared were writing wrist posture (inverted,
partial inverted or noninverted) and writing hand posture
(normal, tight, grasp, and brush stroke). All subjects were
photographed while writing. Results for wrist posture: pediatric control, 12%) partial inverted, 88% noninverted;
ADHD, 48c/('partial inverted, 52% noninverted; and right
hemisyndrome, 43'3 partial inverted, 52% noninverted;
p = 0.1 control versus each of the above. Hand posture
(normal, tight, grasp, brush) pediatric control, SO'%, 12%,
874,O; ADHD, 2 4 q . 28%, 1 0 9 , 38%' ( p = 0.005 vs control); right hemisyndrome, 2476, 24%, 38%, 1 4 9 ( p =
0.005 vs control). Anomalous hand and wrist posture is more
prevalent in children with disorders of attention or right
hemisphere function and may persist into adulthood. The
correlates of this observation and its etiology are under investigation.
576. Computerized Pedigree Analysis (SIMLINK) in
Families with Febrile Seizures
Steoen L. Kugler, Edulard S. Sienroos, Dasid E. Mandelbaunr,
Marc Meulener. and William G.Johnson, Neiu Brunsuick, NJ
Febrile seizures occur with a prevalence of 3 to 4%, and
genetic factors have long been implicated. We identified 32
children with febrile seizures ascertained to have at least 1
other family member with a febrile seizure. Of the 32
multicase pedigrees, 3 families had 6 affected individuals, 1
had 5 , 2 had 4 , 14 had 3, and 12 had 2 affected pedigree
members. There were 20 male and 12 female probands.
Among secondary cases, there were 35 males and 32 females.
The pedigrees were compatible with autosomal dominant inheritance with reduced penetrance. The pedigrees were analyzed with the computer program SIMLINK (Am J Hum
Genet 1989;44:543-55 I), which allows for estimating the
power of a proposed linkage study for a genetic trait. We
used a gene frequency of 1.5%1,4alleles each with frequency
0.25, penetrance of 0.5 and 1,000 replicants. Assuming homogeneity, the average lod score for the combined pedigrees
was 11.60, with a maximum of 16.80 at 0 = 0; the average
lod score was 2.96, with a maximum of 12.29 at 0 = 0.15.
For heterogeneity with a = 0.5, the average lod score was
2.93, and the maximum was 11.03 at 0 = 0; the average lod
score was 0.94, and the maximum was 7.12 at 0 = 0.15. A
lod score of 3.0 means that the likelihood that the data results
from genetic linkage versus chance is 1,000:1. These pedigrees support the hypothesis that the tendency for febrile
seizures is inherited as an autosomal dominant trait. The
SIMLINK analysis indicates chat these kindreds will be helpful for linkage studies directed toward localizing and cloning
the gene or genes involved.
577. Do Children w i t h Migraine or Epilepsy Differ in
T h e i r Cognitive Functioning?
K. M . Fiano, S. R. Legarda. E. B . Fenndl, and B. L. Maria,
Gairresidle. FL
Adults with migraine have been shown to perform significantly worse on verbal and nonverbal memory tasks than
their age-matched controls (Kohler S, Fennell EB, Learning
and memory functioning in migraine headache sufferers,
1992). Although children represent a substantial percentage
of the migraine population (Hockaday JM, Migraine in childhood, London: Butterworth, 1988), no comparable research
exists to date regarding pediatric migraine. In well-controlled
seizure disorders, there is little evidence for global deterioration in cognitive functioning (Brown ER, Interictal cognitive
changes in epilepsy, Sem Neurol 1991;11(2):167-174).
Most studies on children with epilepsy have not controlled
for subject baseline variables such as global IQ, seizure type,
and drug therapy (Legarda SB, Booth MP, Fennell EB, Maria
BL, Cognitive effects of valproate monotherapy in children
with epilepsy-a review, 1994 [in press)). Using an agematched control group of normal children (aged 7- 17 years),
we compared the findings in neuropsychological functioning
between 15 children with migraine and 1 1 children with idiopathic epilepsy prior to initiation of drug treatment. Based
on I Q screening ( 4 subtests from WISC-R) all subjects fell
within a normal range of intellectual functioning (within 1
standard deviation). Children with idiopathic epilepsy performed worse on measures of verbal memory ( p = 0.033)
and attention ( p = 0.033) than either children with migraine
or normal controls; children with migraine performed similarly to controls. Unlike adults with migraine, children with
migraine may perform as well as their normal peers in cognitive measures. Children with idiopathic epilepsy can have
significant differences in cognitive functioning, not contributed to by antiepileptic drugs.
534 Annals of Neurology Vol 36 N o 3 September 1994
578. Primidone in Intractable Pediatric Epilepsy
S. B. Legardz. M . Kraisinger, and D. Ringdahl.
Gainesville, FL
Primidone has lost popularity among the major anticonvulsants prescribed today because of its barbiturate side effects.
It is metabolized to phenobarbital and phenylethylmalonamide, both of which have added anticonvulsant activity. From
September 1992 through October 1993, 18 children with
intractable epilepsy (aged 6 months- 15 years) received primidone as substitutive therapy replacing one of their medications in combination therapy. (All 18 had failed phenobarbital, tegretol, dilantin, and valproate in monotherapy or in
various combinations of polytherapy.) Although seizures
were reportedly improved, intolerable behavioral changes (in
5) and oversedation (in 1) led to discontinuation of primidone in 6 children. After 6 months on primidone, 9 reported
a greater than 95% reduction in seizure frequency (SF) and
3 enjoyed a significant improvement in quality of life (>75%
reduction in SF). Of 6 children initially referred for epilepsy
surgery, 3 remain well-controlled (>95’% reduction in SF),
1 of them on primidone monotherapy. Primidone’s adverse
influences, not lack of seizure control, led to its discontinuation in a third of our patients. Primidone should remain an
important resource in the management of intractable epilepsy
in children.
579. Increased Levels of Alternatively Spliced
Proteolipid Protein i n Two Atypical
Pelizaeus-Merzbacher Disease Brothers Carrying
an Insertion i n the 5’ UTR of T h e i r Proteolipid
Protein Gene
Paul Carango, Vicky L. Funanage, and Harold G . Markr,
Wilmington, DE
Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder. The genetic defect involves one of the major
myelin proteins, the proteolipid protein (PLP). The classic
form of PMD presents in early infancy with arrhythmic nystagmus. Subsequently, children develop optic atrophy, mental retardation, bradylalia, and progressive paraparesis. The
arms are ataxic and hypotonic. W e evaluated 2 brothers with
PMD, atypical in that arms were severely spastic and, at age
15 years, one brother was first found to have nystagmus only
on upward gaze. Mutations in 5’ UTR of exon I of the PLP
gene were found in the brothers. Skin fibroblast RNA shows
an increase in 2 previously undescribed alternate transcripts
of the PLP gene. These transcripts result from the removal
of 165 bp and 133 bp, respectively, from exon I1 of the
transcribed PLP message. Analogous to the phenomenon of
“phenotypic rescue” described by Morisaki et al (J Clin Invest 1993;91:2275-2280) for individuals with adenosine monophosphate deaminase deficiency and by Chelly et al (J
Clin Invest 1991,88:1161-1166) for Duchenne’s muscular
dystrophy, we postulate that the mutation in the 5’ UTR may
be forcing the PLP message down minor splicing pathways,
resulting in the increased levels of these alternately spliced
PLP transcripts.
580. New Mutation of Proteolipid Protein i n
Complicated Form of X-Linked Spastic Paraplegia
Harold G. Marks, Hisashi Kobayashi, and Eric P. Hoffman.
Wilmington, DE, and Pittsburgh, PA
Johnson and McKusick (Am J Hum Genet 1962;14:83-94)
were the first to describe a sex-linked recessive form of (complicated) spastic paraplegia (XLCSP). Saugier-Veber et a1
(Nat Genet 1994;6:257-262) reported a family with XLCSP
and a point mutation (His 139 Tyr) in the third exon of the
proteolipid protein (PLP) gene, suggesting that PelizaeusMerzbacher disease (PMD) and XLCSP are allelic disorders
at the PLP locus. We evaluated 3 affected members (2 children and l adult) of the original XLCSP family and found a
point mutation (A’IT to ACT) in exon 4 that alters an amino
acid at residue 186. The 2 children presented at age 2 with
gait ataxia, hypotonia, and global developmental delay, and,
over the last 3 years, have developed a mild spastic paraparesis. The maternal uncle presently has a pure spastic paraplegia. Magnetic resonance imaging scans in the uncle and 1
child were normal. In the uncle, BAERs demonstrated prolonged I11 to V interwave latency and VERs demonstrated
prolonged latency of P100. This report confirms that PMD
and XLCSP are allelic disorders, and will review the phenotype of the 2 XLCSP families.
581. Relapse of Herpes Simplex Encephalitis After
Adequate Acyclovir Therapy
Agustin Legido, Daniel K. Miles, Catherine M . Foley,
Harold Lischner. Sarah Long, Richard Whitley.
Fred Lakeman, and Warren D. Grover, Philade&hza, PA.
and Bimingham, A L
Recently, relapse of herpes simplex virus (HSV) encephalitis
following acyclovir therapy has been reported in children.
The pathogenic mechanism of the recurrence is not fully
understood. It has been explained on the basis of postinfectious encephalomyelitis, short duration of acyclovir treatment, acyclovir resistance, or persistence of HSV infection.
W e report 2 new cases that support a mechanism of persistent HSV infection. Patient 1 was 2 years old and Patient 2
was 8 months old. Both presented with fever, lethargy, focal
seizures, and focal motor findings. Cerebrospinal fluid (CSF)
had mild elevation of protein (5 1-58 mg/dl) and white blood
cells (WBCs) (36-52). Electroencephalogram (EEG) showed
asymmetric slowing. Magnetic resonance imaging (MRI) displayed focal changes. Serum HSV antibodies (Abs) were negative. Qualitative CSF Abs were low. CSF polymerase chain
reaction (PCR) in Patient 1 was not done; in Patient 2, PCR
was negative. Patients were treated with acyclovir and corticosteroids for 14 and 2 1 days, respectively. Their neurological examination improved, and was normal at discharge in
Patient 1, and showed mild hemiparesis in Patient 2. Patients
were readmitted at 1 month, and 4 days after discharge, respectively. They presented with lethargy, seizures and choreoathetoid movements. CSF showed mild elevation of protein and WBCs. MRI displayed bilateral changes. Serum and
CSF HSV Abs were significantly increased. CSF PCR was
positive. Patient 2 had a brain biopsy; the culture grew HSV,
sensitive to acyclovir. Both patients were treated with
acyclovir, but progressed to a neurovegetative status. The
duration of acyclovir treatment was adequate; CSF andlor
biopsy studies demonstrated the presence of HSV; in Patient
2, HSV was sensitive to acyclovir. In these 2 cases, persistent
HSV infection is the most likely explanation for recurrent
encephalitis. Patients with clinical signs of HSV, who have
negative serological or PCR studies, should be considered
for brain biopsy before stopping treatment with acyclovir. If
positive, the treatment should be continued. Although it is
unclear if corticosteroids facilitate the relapse, they may be
a risk for prolonging HSV infection.
582. Benign Epilepsy with Multifocal Spikes
Anne E. Anderson and Peter Kellau)ay, Houston, T X
The presence of multiple foci of spike discharge in a single
electroencephalogram (EEG) is currently viewed as evidence
Program and Abstracts, Child Neurology Society 535
of “diffuse bilateral cerebral disease” (Daly and Pedley,
1770).A prospective and retrospective study of 550 children
with 2 or more foci of spike discharge in the same, or in
nonhomologous (homologous foci were excluded to avoid
the problem of mirror foci), regions of both hemispheres
revealed 1. that 40% had no antecedent history of brain
disease or injury; 2. normal neurological findings; and 3. normal or slightly slow background EEGs. The other 60% had
evidence of neurological abnormality, ranging from learning
disability to severe encephalopathy of varying etiology. The
age distribution curve on the first group was similar to that
of children with benign rolandic epilepsy, while, in the second group with neurological dysfunction, the curve was
shifted to the left. There is evidence that children with benign
rolandic epilepsy at different times will show multiple foci in
the same or opposite hemisphere and, although the centrotemporal region is the most common site for presence of
benign focal spikes, there is a proclivity for such spikes to
occur at multiple sites, even at a single point in time (Kellaway P, Cortical epileptogenesis in the developing human
brain, In: Mody I, Gurwick M, eds, The Cortical Neuron,
New York: Oxford University Press, 1974: [in press)).
583. Gratification Phenomena: A Common b u t
Infrequently Recognized Movement Disorder in
Childhood
L. Matthew Frank, Norfolk, V A
Gratification phenomena (GP) (Brett EM, Paediatric neurology, Edinburgh: Churchill-Livingstone, 1983; Aicardi J, Diseases of the nervous system in childhood, London: Mac Keith
Press, New York: Cambridge University Press, 1992) is an
uncommonly recognized movement disorder not falling into
the usual categories of abnormal involuntary movements.
Nine children were referred in the past 5 years with complaints ranging from seizures to athetosis. These movements
consist of very specific posturing of the upper extremities,
torso, and face. Movements of the hands or fingers occur in
a highly stereotyped fashion. The duration of each event may
range from 2 to 3 seconds to as long as 1 minute. Episodes
tend to occur during times of heightened emotions; but, they
also occur with boredom. Self-consciousness and embarrassment often cause the child to leave the room or hide
behind furniture, distinguishing G P from the usual selfstimulatory stereotypes of childhood. Children with GP are
remarkably unable to describe what they do during these
events, and are unable to spontaneously mimic their behaviors afterward. They can be distracted from G P by a word or
touch. Electroencephalogram during these events is normal.
There is an increased incidence of LD, OCD, and attention
deficit disorder in these children. Pharmacological intervention has been completely unrewarding, including antiepileptics, stimulants, tricyclics and SSRIs. Counseling has been of
little value, with symptoms persisting in all patients over 5
years of observation.
584. A New Progressive Storage Disease with
Endothelial Lysosornal Inclusions, Myoclonus, Focal
Dermal Atrophy, Mental Retardation, and Rigidity
L. Matthem Frank, Ralph S . Northam, and Thomas Reagan,
Norfolk and Newport News. VA
A new lysosomal storage disease is presented. Unique features include endothelial lysosomal inclusions, progressive
rash, peripheral neuropathy, mental retardation, and stimulus-sensitive myoclonus. A 4-year-old girl presented at 6
months with developmental delay and increased tone. She
had a dramatic acoustical startle response, hyperreflexia, and
ankle clonus; fundi were normal. At 2 years old, a rash, consisting of diffuse, atrophic, depressed 2- to 10-mm lesions
with hyperpigmented cobblestoned base, appeared. By 4
years of age, DTRs were hypoactive and nystagmus appeared. Chromosomes, amino acids, organic acids, urinary
sialic acid, lysosomal enzymes, lactate, and T O R C H titers
were normal at 6 months, as was MRI. At 17 months, MRI
showed mild diffuse atrophy. BAER was normal. Motor and
sensory nerve conduction velocities had been normal at 12
months, but had slowed to the 30-msec range by age 3. Biopsies of conjunctiva, rectum, rash, and sural nerve all had unusual cytoplasmic membrane-bound inclusions in capillary
pericytes on electromyogram. Schwann cells and axons were
intact. Literature review and neuropathological consultations
failed to identify the nature of the lysosomal inclusions or
any previously reported similar disease. A newly described
progressive lysosomal storage disease affecting capillary pericytes and having unique electromyographic, dermal, and neurological features is presented.
585. Differential Sleep Diagnoses in Traumatically
Brain-injured Children
Beth Kurdunowicz. Edward Dabrowski, Rashmi Gupta,
Robert Rothemel, Ron Thomas, and Michael Nigro.
Detroit, MI
Parents of 42 traumatically brain-injured (TBI) children completed a questionnaire (QUEST-T) to describe their child’s
current sleep-wake behavior during routine outpatient visits.
The children (23 boys; 19 girls), aged 2 to 18 years (mean
age, 7.6 years) had sustained their injuries 3 to 75 months
(mean, 30.7 months) earlier. Children were described by severity of injury using the Glasgow outcome scale (GOS):
good recovery = 20; moderate disability = 13; severe disability = 7; and persistent vegetative state = 0. Of the 42
children, 36 (85%) had symptoms consistent with sleep disorders. Predominant sleep complaints ( 2 2 5 % of childrenj
were difficulty falling asleep (15), difficulty with arousal ( 17),
daytime sleepiness (14), not rested when awoken (20), night
waking (17). nightmares/terrors (14), restless sleep (15),
jerking/kicking/thrashing(17), sleeptalking ( 15), and snoring
a lot (10).Twenty parents reported that sleep quality affected
the child’s daytime functioning. A pediatric neurologist with
expertise in sleep disorders utilized QUEST-T data to classify
all patients by differential sleep diagnosis: disorder of initiating and maintaining sleep (DIMS) = 18; disorder of excessive sleep (DOES) = 7; and parasomnias (PARA) = 23. In
this sample, DIMS was more common with decreasing age,
irrespective of severity of disability. There may be a peak in
the occurrence of DIMS 1 to 2 years postinjury. DOES occurred in lowest incidence among school-age children, particularly among patients closer to the time of injury and in those
with greater disability. PARA had an overall incidence of
54%, with no trends among age groups or time since injury;
however, it was more common among the less disabled. All
10 children who snored fell within 1 or more of these groups;
9 of them had 2 or more symptoms consistent with PARA.
Three children had significant sleep schedule disruption,
which was primarily a result of poor sleep hygiene, and did
not sufficiently meet group criteria. Of 2 1 children who were
beyond 2 years postinjury, 16 (76%) had sleep disorders.
The data suggest that sleep disorders are a common problem
in TBI children and an important issue in long-term clinical
management. Given the range of sleep disturbances experi-
536 Annals of Neurology Vol 36 No 3 September 1994
enced, it is likely many neurological and nonneurological factors are involved in the evolution of these disorders.
586. Functional Outcome of Patients with Acucel
Chronic Inflammatory Demyelinating Polyneuropathy
E . R. Dabrowski, A . M . Michon, K. Maearherin, S. Stewart,
P. Peel, S . Fistler, M . B . Archambauit, R. Thomas, and
M . A . Nigro, Detroit, MI
Chronic inflammatory demyelinating polyneuropathy (CIDP)
and Guillain-Barre syndrome (GBS) are both characterized
by inflammation of the peripheral myelin with subsequent
motor, sensory, and autonomic sequelae. Weakness, as well
as long-term functional disability, is a hallmark feature of
both conditions. The perceived and actual functional abilities
of patients with CIDP and GBS have never been extensively
studied within the pediatric population. W e prospectively
evaluated the functional abilities of patients with CIDP and
GBS in 10 children and young adults (aged 5-21 years; mean
age, 17 years). There were 4 boys and 6 girls. Each parent
and/or young adult completed the extensive 197-item Pediatric Evaluation Disabilities Inventory (PEDI) questionnaire
examining his or her perception of the patient’s functional
abilities in the areas of self-care, motor/mobility, social interaction, communication, and cognition. A complete neurological examination was conducted on each patient. The Functional Independence Measure (FIM) tool, which is composed
of 18 items exploring the self-care, motor/mobility, social
interaction, communication, and cognitive domains, was then
administered to reflect objectively the functional status of
each patient. Of the 10 patients studied, there were no statistical variations on the PEDI questionnaire. Each parent and/
or young adult perceived that the patient was capable of
performing and accomplishing the functional abilities in the
previously mentioned domain. The neurological examinations revealed decreased or absent DTRs, vibratory sensation, and balance; poor tandem gait; distal weakness; tremor;
and sweaty palms and feet. The summary scores from the
FIM indicated little variation in the 13 subitem categories
comprising the motor skill domain. However, values obtained from the remaining 5 categories compiling the FIM
cognitive domain revealed lower mean scores, particularly in
areas of social interaction, problem solving, and memory.
This preliminary study suggests that 1. the perceptual abilities
of pediatric patients affected with CIDP or GBS are as accurate as objective/actual functional abilities measured; 2. functional outcome in patients with either of these disorders is
favorable; 3. the memorylcognition subcategory suggested
difficulties with short-term memory and information processing; and 4. the neurological examination remains the
most sensitive indicator of overall neurological function.
587. Functional Outcome in Newborns with
Panplexopathy Brachial Plexus Injuries
Neal Alpiner, Mary Ruehle, Kristen Daniels,
Edward DabrowJki. and Michael Nigro, Detroit, MI
Prognosis for newborns with brachial plexus injuries has, in
large part, been determined by initial and short-term clinical
and electrophysiological exams. Traditionally, patients with
upper trunk, C5-6 stretch (Erbs) injuries have the best prognosis, and panplexopathies have poor outcome. It has been
noted in our institution that newborns with birth plexus injuries have a greater incidence of panplexopathy, with a significant percentage having only mild residual impairment. W e
present the initial findings of a prospective study to define
the population accurately. A total of 13 newborns and infants, ranging in age from 1 month to 14 months, seen in the
last year met criteria for newborn plexus injuries. Historical
characteristics included birth weight, clavicular fractures, in
utero position, and delivery complications. Clinical examination was restricted to only involved personnel to increase
interrater reliability. Electromyogram (EMG) was performed
within 2 weeks of initial evaluation. Four patients had a birth
weight between 6.8 and 8 pounds, and 9 patients had a birth
weight greater than 9.3 pounds. Four clavicular fractures
were documented. Initial clinical examinations revealed 7 patients with evidence of panplexopathy and 6 patients with
Erbs patterning. EMG testing on 9 patients revealed 5 with
panplexopathy and 4 with Erbs or upper trunk C5, C 6 patterns. Of those patients with clinical and/or EMG evidence
of panplexopathy (n = 7), serial examination revealed 3 patients had complete distal resolution, 2 patients were beginning to show distal greater than proximal symptom resolution, and 2 patients remained full panplexopathies. The initial
results of this prospective study reveals that a significant number of newborns with brachial plexus injuries diagnosed as
panplexopathy have potential for good functional recovery,
contradictory to previous reports. The pathophysiology of
these injuries most likely represents a neuropraxia of the
lower trunk and an axonotmesis of the upper trunk. Of interest is the high incidence (30%))of newborns who were of
normal birth weight and developed plexus injuries.
588. Relationship of Neurotrophin-3 Receptor
Expression and Disease Progression in
Medulloblastoma
S. L. Pomeroy. L. C. Goumnerova, Y . K. Kwon. C. D. Stiles,
and R . A . Segal, Boston, MA
Medulloblastoma is the most common malignant brain tumor
of childhood. Although the tumor has a variable prognosis,
there have been no reliable markers of biological behavior
to date. Since medulloblastomas are believed to arise from
external granule cells of the cerebellum, we have examined
tumor expression of neurotrophins, which have an important
role in granule cell development, to determine if these molecules might influence tumor growth. Northern and Western
blot analyses were performed on tumor samples (n = 11)
that were snap-frozen in the operating room to preserve
R N A and protein integrity. All of the tumor samples were
found to express neurotrophin-3, as well as its high-affinity
receptor, trk C. The level of trk C expression was variable,
but was highest in patients with less aggressive disease. Using
Kaplan-Meier analysis, patients with high levels of trk C expression had significantly longer progression-free survival
than those with low levels of expression. Levels of trk A or
B expression were not significantly associated with disease
behavior.
589. Early Presentation of Narcolepsy in
Preteenaged Children
Yong D. Park, Morris J . Cohen, Josh L. Hal/, Czndi Riccio,
and Bashir A . Chaudhary, Augusta, G A
Narcolepsy is rarely diagnosed in preteenaged children. A
total of 8 subjects, 15 years of age or younger (mean age, 9.2
years), were observed prospectively for 2.5 years (between
October 1991 and April 1994) at the Medical College of
Georgia. Excessive daytime sleepiness (EDS) was the main
Program and Abstracts, Child Neurology Society 537
groups was modestly increased from the general population
of epileptics.
clinical feature in all patients; but visual hallucination with
personality change and clumsiness with frequent falls were
the reasons for referral in each case. A careful history elicited
cataplexy symptoms in all patients. Nocturnal polysomnogram was obtained and was followed the next day by multiple
sleep latency test. A great degree of daytime sleepiness
(mean sleep latency from 1.5-8 minutes) was documented
in 7 patients; an increased frequency (more than two) of
sleep-onset rapid eye movement periods was documented in
6 subjects. All patients underwent human leukocyte antigen
typing. S i x patients were positive for both DRwl5(DR2) and
DQw6(DQwl). One patient had only DQw6, another patient had neither DQw6 nor DRwl5. Neuropsychological
tests were performed in all 8 patients. WISC Ill vocabulary
and block design subtests revealed low average-to-borderline
ranges (85 ? 17.2 and 76 5 13.9, respectively). Both visual
and auditory continuous performance testings were significantly impaired. The Conners parent rating scale was significant for attention deficit disorder and anxiety-passivity, but
not conduction disorder. Conners teacher rating scales did
not demonstrate abnormal scores, which might reflect the
effect of medication while in school. These findings indicate
that cataplexy, in addition to EDS, is an early clinical manifestation in narcoleptic children. Further, narcoleptic children
are at risk for neuropsychological dysfunction. Therefore,
early identification and treatment are critical.
591. Changes in Valproic Acid Concentrations and
Dose/Level Ratios by Felbamate Coadministration in
Children
Mauricio R. Delgado, Dallas, T X
Felbamate (FBM) was introduced as adjunctive therapy in 10
epileptic children ( 5 boys and 5 girls; 2-14 years old). These
patients were on valproic acid (VPA) treatment for more
than 3 months, but failed to achieve satisfactory seizure control. The influence of FBM initiation (240-600 mg/day;
18.51 4.50 mgikglday; mean 2 SD) on blood VPA concentrations and VPA dose/level ratios was investigated. The
VPA baseline daily dose in these patients was from 400 to
2,400 mg (39.45 t 18.72 mgikgiday), and was decreased
by 26.32 -t 2.98% as FBM was introduced. Serial morning
trough VPA concentrations before and after the initiation of
FBM were investigated prospectively. During the first week
of FBM initiation. FBM caused an increase in VPA concentrations (from 108.33 ? 19.79 pg/ml to 125.67 ? 31.92
pg/ml), despite the decrease in VPA dose. The VPA dose/
level ratios were significantly decreased after the initiation
of FBM (from 7.74 t 5.84 to 6.12 ? 5.72; p < 0.005).
Additionally, some individual patients experienced dramatic
changes in VPA concentrations after FBM was added (from
100 p,g/ml increasing to 160 p,g/ml, with a free fraction increasing from 15 to 38$), even though the VPA dose was
already decreased by 3 0 g ' . These results suggest that children have a stronger drug interaction of FBM on VPA than
adults, and may need a more aggressive reduction of VPA
doses when FBM is initiated. Close patient monitoring
should be done when FBM is added to children on VPA
treatment, together with appropriate VPA dose adjustments,
to avoid the potential risk of VPA toxicity that may be caused
by this drug interaction.
*
590. Long-Term Epilepsy Prognosis in
Institutionalized Epileptics with Onset
of Neurological Disability in Infancy
or Early Childhood
Stmen A. Phillips. Judith E. Hogg, Euti-Kyu Lee.
and Conrad Pappas*Sacramento. CA
We examined the long-term epilepsy outcome in clients at
the Lubbock State School. Etiology was determined by a
review of past records, neurological examination, and genetic
evaluation. Outcome was assessed as controlled if clients had
less than 3 seizures per month and their epilepsy had minimal
or no effect on daily function. Uncontrolled assignment was
made when either or both of the above criteria were not
met. A total of 202 epileptic clients were identified with
onset of neurological disability in infancy or early childhood.
Of the clients, 63% were males and 37% were females; their
ages ranged from 11 to 48 years, with an average age of 31
years. Etiologies included idiopathic, 35%; C N S infections
(CNS-ID), 20%; hypoxic-ischemic encephalopathy (HIE),
13 g 8 ;neurocutaneous disorders and syndromes (NCDIS),
9%; closed head injury (CHI), 9%; and others, 14%. Epilepsy outcome was compared to etiology in the Table below.
592. Effect of Felbamate a n d Valproic Acid
on Carbamazepine and Its Major Metabolites
i n Epileptic Children
Hua Liu and Mauricio R . Delgado, Dallas. T X
The metabolism of carbamazepine (CBZ) has been reported
to be influenced by both felbamate (FBM) and valproic acid
(VPA). The purpose of this study is to investigate further
the effect of FBM and VPA on C B Z and its metabolites in
patients receiving VPA, CBZ, and FBM. Participating in this
study were 5 children on both VPA and CBZ (period I).
VPA doses were then gradually decreased, while FBM therapy was initiated (period 11). Finally, VPA was withdrawn,
Outcome
Idiopathic
CNS-ID
HIE
NCDlS
CHI
Others
Controlled
Uncontrolled
38W27)
62%(44)
70%(28)
3056(12)
73Nl9)
27%( 7)
79%( 15)
21%( 4 )
82F(14)
1 8 7 8 3)
724(21)
28W 8)
A significantly different ( p < 0.01) outcome was noted in
the idiopathic group, compared to other groups. We conclude that the long-term epilepsy prognosis is worse in the
idiopathic group of institutionalized epileptic clients. There
was n o major difference in outcome in other etiological
groups, and the percentage of uncontrolled clients in these
538 Annals of Neurology
leaving patients on FBM and C B Z only (period 111). The
doses of C B Z were unchanged during the entire study. Serial
blood samples before the morning dose of the medications
were collected and analyzed by high-performance liquid
chromatography. Compared with period 1, patients in period
I1 had a 22.14% decrease in C B Z level (10.30 z 4.82
Vol 36 No 3 September 1994
*
pg/ml vs 8.12
3.65 pg/ml; mean 2 SD) and 46.40%
decrease in CBZ-l0,ll-epoxide (CBZ-E) level (5.70 5 2.85
vs 2.70 ? 1.11; p = 0.05), while trans-l0,lI-dihydroxy10,ll-dihydro-CBZ (CBZ-H) level was increased (5.46 5
3.48 vs 6.05 ? 1.78; +20.12%); the concentration ratios
of CBZ-H/CBZ-E and CBZ-H/CBZ were significantly
increased (0.86 5 0.12 vs 2.14 2 0.20; +126.71’%; p
< 0.0001 and 0.40
0.12 vs 0.67 2 0.07; +74.60%;
p = 0.005, respectively), while the concentration ratio of
CBZ-E/CBZ was decreased (0.45 2 0.08 vs 0.31 ? 0.04;
- 23.57%). There was no appreciable effect of FBM on C B Z
and its major metabolites during period 111, except a ten3.65 vs
dency of further decrease in CBZ level (8.12
6.52 ? 1.40; - 17.51%). These results suggested that the
biotransformation of CBZ-E to CBZ-H was increased during
period 11, presumably due to the release of the inhibitory
effect on liver epoxide-hydrolase when withdrawing VPA.
*
*
573. Clinical Trial of Felbamate in Children
with Refractory Infantile Spasms
Lukthrni Nagarajan, Deborah Carson, Gail Solomon,
and Douglas R. Labar, New York. N Y
Infantile spasms (IS) are one of the most intractable seizure
types in children, often resulting in significant psychomotor
handicap. Felbamate (FBM) is an antiepileptic drug with
proven benefit in adults with multiple seizure types and in
patients with Lennox-Gastaut syndrome. We studied the efficacy of FBM in children with symptomatic IS refractory to
multiple medications. A total of 8 children with refractory
IS (symptomatic in all), aged 6 to 45 months, were treated
with FBM as an add-on drug. The dosage range was 30 to
70 mg/kg/day; the duration of follow-up was 2 to 8 months.
FBM was generally well-tolerated with mild, transient adverse effects in 2 infants. Increased alertness occurred in 5
children. An infant with severe perinatal brain injury and
almost continuous IS who had several seizure-free hours a
day on FBM, died during sleep with cause undetermined.
Seizure frequency was recorded and reported by parent/
guardian and seizure counts were recorded on a 24-hour
basis. Video-EEG monitoring prior to and approximately 3
months after starting FBM was used to assess the efficacy of
FBM. One child with tuberous sclerosis became seizure free.
Seizures decreased by more than 90% in 3 patients, by more
than 75% in 2 patients, and by more than 50% in 1 patient.
Seizure frequency was unchanged, and FBM was discontinued after 2 months in 1 child. Thus, the efficacy of FBM
in symptomatic refractory IS, known to carry a bad prognosis,
is promising.
594. Not-So-Benign Behavior of Spinal Myxopapillary
Ependymomas of Childhood
Atiya Khan, Jeffrty Allen, and Fred Epstein, N e u ~York. N Y
Myxopapillary ependymomas of the spinal cord are unique
in several respects: rare occurrence, cauda equina origin, and
indolent course. The optimum management has yet to be
defined. A retrospective analysis was made of all intra- and
extramedullary primary spinal cord tumors in pediatric patients (<2 l years old) at our institution over an 8-year period
(1785-1994). Of the 219 tumors, 32 (14%) were ependymomas, of which 6 (3%) were of the myxopapillary type.
Three children were seen at diagnosis and 3 children were
seen at recurrence. Their average age at initial surgery was
13 years, with an average prodrome of 2.5 years. The male:
female ratio was 2:4. The primary site was the cauda equina
region in all; none had metastatic disease at presentation. The
presenting symptoms were low-back pain (6), paraparesis (3),
and loss of bladder and bowel control (1). The initial surgical
procedure was partial resection (2) and total resection (4).
Adjuvant radiation therapy was given to 1 child who had
a partial resection. The median progression-free and total
survivals were 4.2 and 13 years, respectively. All patients
are alive; but, 3 have developed local recurrences, 2 of whom
have intracranial leptomeningeal metastases. In conclusion,
children with spinal myxopapillary ependymomas must be
followed indefinitely, as they remain at continued risk for
late recurrences. Total resection confers the longest progression-free survival.
+
595. Clinical Algorithmic Analysis of High-Intensity
T2-Weighted Signals on Magnetic Resonance Imaging
in Young Children w i t h Neurofibromatosis T y p e 1
Correlating with Cognitive Scores
Stephen H. Mott, Cynthia 0. Brasseux,
Carole A.Samango-Sprouse, L. Gilbert Vezina,
Roger J . Packer, and Kenneth N . Rosenbaum.
Washington, DC
UBOs are common MR findings in children with neurofibromatosis type 1 (NF-1). Although it has been difficult to
show a correlation between UBOs and neurodevelopmental/
cognitive status (NCS), our previous work suggested a relationship between NCS and increasing numbers of UBOs in
the neurophysiological anatomic pathways that affect the left
corticospinal tract. To further refine these findings, we developed an algorithm to rank each patient’s MRI according to
the numbers and specific locations within defined left-sided
pathways of UBOs and correlated the severity of the UBO
involvement to the NCS. Since previous work has suggested
an age-dependent distribution of UBOs in the rostro-caudal
axis, a second U B O algorithm was developed to rank each
patient by their U B O number appearing along this axis, and
correlated these findings to the NCS. These algorithms were
applied to 33 patients (age range, 11-76 months) with NF-1.
U B O characteristics utilizing left-sided pathway occurrence
and NCS showed an inverse relationship between numbers
of UBOs and NCS ( r = -0.54). Greater numbers of caudal
UBOs were related to poorer NCS ( r = - 0.5 1). This algorithmic approach is useful in categorizing UBOs in NF-1
patients less than 7 years old. Increasing left neurophysiological pathway and more caudal anatomical structure UBO
involvement is correlated to lower NCS.
576. Prediction of Morbidity and Mortality
in Perinatal Asphyxia
M . Gaty Karlowicz. Lawy White, and Donald W. Leumis,
NoYflk, V A
Our objective was to evaluate a neonaral asphyxia scale in
predicting neurological morbidity. Portman and colleagues
developed an asphyxia1 scoring system that accurately predicted multisystem dysfunction in term infants within 1 hour
of age using 3 parameters: fetal heart rate, 5-minute Apgar,
and base deficit. Neonates older than 36 weeks were retrospectively scored. Group 1 included scores greater than 6;
Group 2 included scores less than 5. The 6 6 infants (33 in
each group) were comparable in gestational age and weight.
Seizures occurred in 63%) of Group 1 versus 24% of Group
2 ( p < 0.01). Hypotonia occurred in 81% of Group 1 versus
24% of Group 2 ( p < 0.001). Systemic effects were as follows (Group 1 versus Group 2): acute renal failure (60% vs
Program and Abstracts, Child Neurology Society 539
0%; p < 0.001) and hypotension (80% vs 50%; p < 0.01).
Mortalities were equal (19% vs 17%). Among survivors in
group 1, over 80Y have multiple disabilities (cerebral palsy,
mental retardation), whereas in Group 2, disabilities predominated in those who had superimposed postnatal asphyxia
(MAS, PPH). This asphyxia score is a valuable tool in the
immediate perinatal period to predict high risk rapidly for
both acute encephalopathy and neurological sequelae.
597. A Cost-Effective Approach to Outpatient
Evaluation of Excessive Daytime Sleepiness i n Children
O’Neill F . D’Cruz. Chapel Hill, N C
Excessive daytime sleepiness (EDS) results from an increase
in inherent sleep tendency. Sleep diaries were used as a
screening tool for ourpatient evaluation of patients with EDS.
The average daily sleep time was calculated from a two-week
diary. Sleep phase (sleep period in relation to time of day)
was also plotted on 16 patients who were evaluated by this
approach. Six patients had normal total sleep time for age
and were found to have sleep phase abnormalities that accounted for EDS. Their symptoms resolved with sleep phase
correction and/or rearrangement of schedules. In 10 patients
with increased total sleep time, further investigations were
performed. One patient maintained a sleep diary for two
months and was diagnosed with Kleine-Levin syndrome. The
other 9 patients had EDS related to epilepsy ( 4 ) ,postencephalitic hypersomnia ( l), narcolepsy (I), sleep-related respiratory disturbance ( 2 ) ,and hypothyroidism (1). In children presenting with EDS, the sleep diary is a simple and effective
screening tool to assess etiology and determine need for further investigation.
598. Protective Effects of Fasting and Ketone Body
Supplementation on Hypoxic-Ischemic Brain Damage
in t h e Immature Rat
Jerome Y . Yager. Sashtoon. Saskatcbhewan, Canada
Prolonged fasting protects the immature brain from hypoxicischemic (H-I) damage (Yager JY, Heijan DF, Towfighi J,
Vannucci RC, Effects of insulin-induced and fasting hypoglycemia on perinatal hypoxic-ischemic brain damage, Ped Res
1992;3 1:138- 142 ). To determine the mechanisms underlying the protective effects of fasting, 7-day rat pups underwent
unilateral common carotid artery ligation under halothane
anesthesia (4% induction; 1% maintenance) and exposure to
H-I in 8% oxygen/nitrogen for 2 hours. Temperature was
maintained at 37 & 0.5”C. Rat pups fasted for 12 hours were
compared to those given 0.1 ml subcutaneous injections of
either 2, 5 , or 10 mmol/kg of beta-hydroxybutyrate o r 0.9%’
saline (fasted and controls). In separate groups, either highenergy compounds and glycolytic intermediates were measured at 0, 60, 90, and 120 minutes of H-I; or rat pups
recovered with their dams to 30 days of age and were assessed neuropathologically. Fasting, as well as supplementation of 5 or 10 mmolikg beta-hydroxybutyrate was protective
to the brain ( p < 0.05), despite higher concentrations of
brain lactate in the latter 2 groups ( p < 0.05). Only fasting
significantly preserved brain adenosine triphosphate levels
during H-I ( p < 0.05). The current study clearly shows 1. an
equally protective effect of both fasting and ketone body
supplementation; and 2. that different mechanisms underly
the protective effects of ketone body supplementation and
fasting.
540 Annals of Neurology
599. Respiratory Sinus Arrhythmia i n Children with
Severe Breath-Holding Spells
Franris J . DiMario, Jr, Lance Bauer, arid Jana Volpe.
Farniington. CT
Breath-holding spells (BHS) in children are a common and
dramatic clinical phenomenon. They have been wellrecognized for several hundred years, and are diagnosed on
the basis of a distinctive stereotypical sequence of events.
This typically incorporates a provocation that causes the child
to cry or display emotional upset resulting in noiseless expiration. The face and trunk ultimately become cyanotic or pallid.
In severe spells, the child will appear dazed and eventually
lose consciousness. Prior research concerning the underlying
pathophysiological mechanisms involved in breath-holding
spells has implicated a heterogeneous autonomic nervous system dysregulation, whereby children with pallid BHS have
parasympathetic excess, and those with cyanotic BHS probably do not (DiMario FJ, AJDC 1992;146:125). In this study,
we sought to investigate further parasympathetic dysregulation among children with cyanotic BHS by examining respiratory sinus arrhythmia (RSA). Since there are vagal efferents
to the heart that influence its rate relative to inspiratory depth
and rate, then there is a parallel between overall vagal tone
and heart-rate variability. RSA has been established as a purer
measure of vagal tone than heart-rate variability alone. The
validity of RSA has been demonstrated by studying the effects of vagotomy and of agonist/antagonist drugs. RSA was
evaluated in 2 groups of patients: 16 cyanotic BHS subjects
( 5 boys, 11 girls; mean age, 37.5 months) and 17 controls (8
boys, 9 girls; mean age, 37.7 months). Subjects were children
clinically diagnosed with recurrent (>3) severe BHS. Each
participant had normal general and neurological examinations. Evaluations were done in a quiet laboratory room. Each
subject’s electrocardiogram was recorded and digitized by an
80/386 personal computer during five 1-minute periods. R-R
intervals within each period were converted to heart rate in
120 successive 0.5-second intervals. The resultant heart-rate
time series was ultimately converted to its underlying frequency composition. RSA was defined as the variability in
the time series over a frequency range (0.096-0.48 Hz) corresponding to the range of respiratory rates 6 to 30 breaths/
min. ANCOVA adjusting for age and sex was conducted
with subject group and frequency bin as dependent measures. Cyanotic BHS subjects had similar variability in their
heart rates, as did controls (group x frequency bin: F =
0.74; p = 0.71). This study supports the hypothesis that
autonomic dysregulation in cyanotic BHS is not due to primary parasympathetic excess.
600. Clinical Correlates of Giant
Interhemispheric Cysts
M. L. Griebel and C. M . Glasier. Little Rock, AR
Giant interhemispheric cysts have been known for years. Yet
few reports, with limited numbers of patients and contradictory outcomes, detail neurodevelopmental status associated
with such lesions. We report clinical outcomes of 11 children
with giant interhemispheric cysts identified from Arkansas
Children’s Hospital radiology files in the past 5 years. The
11 children, 9 boys and 2 girls, range in age from 7 months to
5 years. Anomalies in 5 were discovered by routine prenatal
ultrasounds. Five presented with hydrocephalus at birth or
with increasing head size; 1 presented with seizures. Eight
have undergone ventriculoperitoneal shunting. OFC in the
unshunted children is normal. Seven have had seizures, with
2 of these now off antiepileptic drugs and 2 seizure free on
Vol 36 No 3 September 1994
medication. One developed focal status epilepticus of 4
hours, with residual mild hemiparesis. One has intractable
gelastic seizures, but also has a hamartoma of the tuber cinereum. Of the 11, 6 are assessed as developmentally normal,
4 are mildly delayed, and the child with gelastic seizures
is moderately delayed. Six have normal examinations, with
abnormalities in others ranging from low tone to frank hemiparesis. All 3 children with normal OFC are normal. Although l child with schizencephaly is normal, generally neurodevelopmental outcome correlates with the number and
severity of associated CNS anomalies. While these CNS lesions appear spectacular, the prognosis is good for normal or
only mildly delayed neurodevelopmental outcome.
601. Hyperkalemic Periodic Paralysis with Cardiac
Dysrhythmia: A Novel Sodium Channel Mutation
Jaime L. Baquero, Ricardo A. Ayala,Jianzhou Wang,
Richard G. Curlels. W. Gregory Ferro, Eric P. Hoffnlan,
and Mackram R. Ebeid, Miami, FL. and Pittsburgh. PA
Hyperkalemic periodic paralysis (HyperPP), a hereditary defect of the sarcolemmal membrane, has been reported with
four different point mutations in the adult skeletal-muscle
sodium channel. We present an additional case with HyperPP and a life-threatening cardiac dysrhythmia. Clinical
findings and results of oral potassium loading were diagnostic
of HyperPP. At age 11, 2 episodes of presyncope during
nonstrenuous activity prompted a cardiological evaluation.
Electrocardiogram revealed ventricular tachycardia and multiform ventricular ectopy. Therapy with oral verapamil was
instituted, with subsequent improvement of cardiac symptoms. Molecular analysis using single-strand conformation
polymorphism (SSCP) technique demonstrated an amino
acid substitution (Val78311e) in the adult skeletal muscle sodium channel gene on chromosome 17q. Due to lack of
family members available for linkage testing, we could not
determine if the Val83 llle substitution co-segregated with
HyperPP, cardiac dysrhythmia, or both. Several lines of evidence support the hypothesis that at least HyperPP is caused
by the Val78311e mutation. First, nearly all patients with HyperPP show point mutations of this gene and this was the
only change detected. Second, the Va178311e change is localized in a highly conserved region in the sodium channel.
To date all sodium channel genes sequenced from different
species and different mammalian tissues show valine at position 783, implying functional importance of this amino acid.
Finally, the change was not found in 120 unrelated normal
individuals, so that benign polymorphism is unlikely. In conclusion, we have demonstrated an amino acid substitution in
the adult skeletal muscle sodium channel gene of a patient
with both HyperPP and cardiac dysrhythmia. Further clinical
and molecular studies are warranted in patients with HyperPP and cardiac dysrhythmia.
602. Severe Choreoathetosis Associated with
Presumed Encephalitis: A Series of Five Cases
Elizabeth A. Thiele, Mary E. Sutton. Joao 0. Siffert,
Ronald G. Davis, and Karl C. K. Kuban, Boston, M A
We report a regional cluster of 5 cases in a 3-year period
in which choreoathetosis and severe oromotor dysfunction
developed in the setting of presumed encephalitis. Five previously healthy children, aged 2.5 to 7.5 years, presented with
focal seizures and impairment of consciousness. Three of the
patients had a prodromal illness. Cerebrospinal fluid (CSF)
analysis on presentation in all cases had white blood cell
counts ranging from 6 to 80, wirh a lymphocytic predominance. All CSF samples had normal or slightly elevated protein levels, and normal glucose concentrations. Viral, bacterial, fungal, and mycobacterial cultures from CSF, blood, and
urine were negative in all patients; 1 patient had a positive
stool adenovirus culture. Herpes simplex virus (HSV) polymerase chain reaction performed on CSF samples in 4 patients was negative. Serum HSV antibody titers were positive
for recent infection in 1 patient (CSF PCR negative). All
patients were treated with acyclovir and antibiotics. Anticonvulsants provided good control of seizure activity. All had
persistent alteration of consciousness and developed choreoathetosis and hemiballismus in the second week of illness. In
every case, the movement disorder had a major oromotor
component, necessitating nasogastric tube feeding or gastrostomy. Pharmacological control of the movements was difficult. Reserpine was ultimately used successfully in 2 patients.
Initial and follow-up magnetic resonance imaging studies
were normal, with the exception of generalized brain atrophy
on follow-up in 2 of the more severely affected patients. The
outcome was generally poor: 3 patients suffered moderate to
severe motor and cognitive disability, and 2 of these had
continued choreoathetosis. One patient’s symptoms largely
resolved, and 1 was improving at discharge. Choreoathetosis
is an unusual manifestation of encephalitis in children. The
likely cause in these children was infectious, although we
could not exclude parainfectious inflammatory illness. Clinical features suggest basal ganglia and subthalamic nuclei dysfunction. Reserpine may be valuable in controlling severe
choreoathetosis.
603. Development of a and f3 Cah4 Kinase I1
in the Cerebellum of Jaundiced and Nonjaundiced
G u n n Rats
John W . Conlee, Stetten M. Shapiro. and Setmern B. Churn,
Salt Lake City.U T . and Richmond, V A
Calcium/calmodulin-dependent protein kinase I1 (CaMKII)
is a neuronally-enriched enzyme that mediates many important cellular processes (Shulman H, The multifunctional calcium/calmodulin-dependent protein kinase, In: Greengard P,
Robison GA, eds, Advances in second messenger and phosphoprotein research, vol 22, New York: Raven Press, 1988:
39-112). Abnormalities in CaMKII activity could lead to
the prominent loss of Purkinje’s cells in the cerebellum of
jaundiced animals. Therefore, the developmental expression
of the a and p subunits of CaMKII was studied in the cerebellum of heterozygous nonjaundiced (Nj) and homozygous
jaundiced ( j j ) Gunn rats. Rats were examined at postnatal
days 4 , 8, 18, and 30, using monoclonal antibodies against
the a and p subunits of CaMKII with horseradish peroxidase
immunohistochemistry. Alternating serial sections were
stained for a and p CaMKII subunits or Nissl substance. The
p subunit of CaMKII was detected at all ages in both N j
(n = 9) and j j (n = 10) animals. Immunoreaction product
appeared to fill completely somata and dendrites of Purkinje’s, granule, and Golgi type I1 cells, and the deep cerebellar nuclei. At 4 and 8 days, Purkinje’s cells had primitive
dendrites that reached only as far as the external granule cell
layer. Interestingly, the only granule cells stained were those
migrating through the molecular layer and those in the internal granule cell layer. External granule cells were completely
negative, suggesting that synaptogenesis with Purkinje’s cells
may induce the expression of p CaMKIl in granule cells. By
18 days, dendrites of Purkinje’s cells extended close to the
pial surface, and the distribution of the p subunit appeared to
Program and Abstracts, Child Neurology Society
541
reach adult levels. The number (mean ? SD) of Nissl-stained
Purkinje’s cells was significantly reduced in j j adults (20.3 +2.9 j j vs 26.7 f 1.3 Nj; n = 4 each;p = 0.007, Student’s
t test), but the ratio of p CaMKII/Nissl-stained cells was no
different, suggesting that all surviving j j Purkinje’s cells were
stained with the p subunit. Immunostaining for the a subunit
was found onb in the Purkinje’s cells. At 4 days of age, the
a subunit was not detected in either group; by 8 days, only
the Nj animals expressed this subunit. Purkinje’s cells appeared strongly immunoreactive by 18 days in both groups.
Somata and dendrites appeared normal in the Nj rats, while
the affected Purkinje’s cells were withered and much less
arborized in the j j rats. The results indicate that the a and p
subunits of CaMKII have different distributions in the cerebellum, and that the expression of the a subunit may be
affected in the j j Gunn rats. Studies are in progress to determine whether the absence of the a subunit in the Purkinje’s
cells of the 8-day j j rats represents a delay in developmental
expressions, or foreshadows eventual Purkin je’s cell death.
mg/kg/day in infants less than 3 months of age without clini-
604. Bilirubin Exposure Results in a Calcium-specific
Inhibition of Multifunctional Calcium/
Calmodulindependent Kinase I1
Sealern B . Churn, Adam M . Gray. Robert J . DeLorenzo,
and Steven M . Shapiro, Richmond, VA
Excessive bilirubin levels in newborn infants result in longterm neurological deficits that remain after bilirubin levels
return to normal. Much of the observed neurological deficits
can be attributed to bilirubin-induced, delayed neuronal cell
death. Inhibition of CaM kinase 11 activity that precedes cell
death is observed in conditions such as seizure activity
(Churn SB, Anderson WW, DeLorenzo, RJ, Exposure of
hippocampal slices to magnesium-free medium produces epileptiform activity and simultaneously decreases calcium and
calmodulin-dependent protein kinase I1 activity, Epilepsy
Res 1991;9:211-217), stroke (Churn SB, Taft WC, Billingsley MS, et al, Global forebrain ischemia induces a
posttranslational modification of multifunctional calcium/
calmodulin-dependent kinase 11, J Neurochem 1992;59:
1221-1232), and glutamate excitotoxicity (Churn SB, Sombati S, Taft WC, DeLorenzo RJ, Excitotoxicity affects membrane potential and calmodulin kinase 11 activity in cultured
rat cortical neurons, Stroke 1?93;24:27 1-278). Since neonatal bilirubin exposure results in neuronal loss in developing
brain systems (Schutta HS, Johnson L, Bilirubin encephalopathy in the Gunn rat: a fine structure study of the cerebellar
cortex, J Neuropathol Exp Neurol 1967;26:377), we tested
whether bilirubin exposure would induce an immediate inhibition of CaM kinase I1 activity in vitro. P-81 filtration assay
of basal and calcium-stimulated kinase activity was performed
under standard kinase assay conditions. Bilirubin and/or albumin was added to the reaction vessels to determine the
effect of these agents on kinase activity. Bilirubin exposure
resulted in a concentration-dependent inhibition of CaM kinase 11 activity (IC>”= 16.78 (LM).At concentrations above
50 pM, bilirubin exposure resulted in a 71 t 8% (mean t
SD) inhibition of kinase activity ( p < 0.001, Student’s t test;
n = 10). Bilirubin exposure did not result in kinase inhibition if excessive bilirubin was removed by albumin binding
prior to stimulation of kinase activity (106.9 t 9.6% control
activity; n = 5). However, removal of bilirubin by binding
with albumin following calcium addition did not restore kinase activity (36.1 5 3.8% control activity; n = 5). Thus,
once inhibition was observed, the activity could not be re-
stored by addition of albumin. The data suggest that bilirubin
exposure resulted in a calcium-dependent inhibition of CaM
kinase I1 activity that, once induced, was not reversible by
removing bilirubin by the addition of albumin. Since inhibition of CaM kinase I1 activity has been correlated with delayed neuronal cell death in many neuropathological conditions, bilirubin-induced inhibition of this enzyme may be a
cellular mechanism by which bilirubin exposure results in
delayed neuronal cell death in developing brain. (Supported
by NIH-NIDCD R01-DC00369.)
605. Free Radical Scavenging Enzymes i n Children
with Spinal Muscular Atrophy
Harold G. Marks, Judith A. Childs, Tracy A. Glauser.
and C. E. Pippenger, Wilmington. DE, Cincinnati, OH. and
Redmond, WA
Oxidative cytotoxicity resulting from mutations in free radical scavenging enzyme genes may underlie certain progressive neurological disorders, such as amyotrophic lateral sclerosis (ALS) (Rosen DR, Siddique T , Patterson D , et al,
Mutations in CulZn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis, Nature 1993;
362:59-62). Patients with familial ALS who are heterozygous for superoxide dismutase (SOD) mutations have less
than 50% the red blood cell (RBC) SOD activity of controls
(Deng H-X, Hentati A, Tainer JA, et al, Amyotrophic lateral
sclerosis and structural defects in Cu,Zn superoxide dismutase, Science 19?3;261: 1047-105 1). Spinal muscular atrophy (SMA), like ALS, is a motor neuron disease; a feature
in common to both is the progressive degeneration of anterior horn cells. This pilot study examined 5 children with
type I1 SMA and 1 child with type 1 SMA for activities of
several free radical scavenging enzymes: RBC and plasma
SOD, glutathione peroxidase and catalase, as well as RBC
glutathione reductase and glutathione transferase. In addition, values for plasma trace elements, including Cu, Mn, Zn,
and Se were obtained. Results were compared to those of 6
age-matched controls. There were no significant differences
in the activities of any of the enzymes between these 2
groups. There was a 43% increase ( p 5 0.008) in Mn in the
SMA children, compared to controls; however, values of
both groups were well within the lab’s normal range. Selenium was somewhat reduced in 1 child receiving enteral feedings; he is currently receiving supplemental selenium. Although the sample size was small, our results suggest that the
activities of the free radical scavenging enzymes investigated
are not significantly altered in children with SMA.
606. Naproxen for Migraine Prophylaxis
Donald W. Lewis. Margaret Middlebrook. Lika Mehallick.
and Carole Deline, No$olk and Portsmouth. VA
Our objective was to assess the efficacy of naproxen prophylaxis for childhood migraine. Migraine is the most frequent
chronic headache syndrome in children; 30 to 50Q of patients warrant prophylaxis. Naproxen, a potent inhibitor of
platelet aggregation and prostaglandin synthesis, is effective
in adult migraine at 550 mg bid (Welch KMA, Ellis DJ,
Keenan PA, Successful migraine prophylaxis with naproxen
sodium, Neurology 1985;35:1304-1310; Ziegler DK, Ellis
DJ, Naproxen in prophylaxis of migraine, Arch Neurol 1985;
42:582-584). Our study was a double-blind, placebocontrolled, crossover. Adolescents with more than 2 migraines/wk began 4 weeks of placebo, then randomized to 6
weeks of naproxen 250 mg bid or placebo, 1 week washout,
542 Annals of Neurology Vol 36 No 3 September 1994
then 6 weeks on the alternate arm. All recorded headache
logs. A total of 19 patients enrolled and 10 (8 boys, 2 girls;
aged 11-16 years) have completed the 17-week protocol.
Six reported improved frequency and severity (3-50%,2 >
70@, 1 > 90% decreased frequency). Three reported mild
gastric irritation. Naproxen is an effective prophylactic agent
for childhood migraine, with over half of patients reporting
a 50% or greater reduction in headache frequency and
severity.
607. Positron Emission Tomography i n Children
with Neurofibromatosis-1
Allen M . Kaplan, Michael A . Lawson, Charles T . Bonstelle,
and David L. Wodrich. Phoenix. AZ
Neurofibromatosis-1 (NF-1) is a genetic disorder commonly
associated with central nervous system (CNS) neoplasms and
cognitive disorders. Magnetic resonance imaging (MRI) has
detected abnormal focal areas of high signal intensity (FASI)
on T2-weighted images in 60 to 70% of children with NF-1.
These lesions are poorly defined and may represent glial nodules, hamartomas, heterotopias, or neoplastic tissues. We
studied 10 children berween the ages of 4 and 15 years with
confirmed NF-1 ( N I H criteria). All patients had MRI scans
demonstrating FASI. Positron emission tomography (PET)
scans were performed on a Siemens 951/31 ECAT scanner
utilizing [ '8F}fluoro-2-deoxy-~-g~ucose
(FDG) and were coregistered with MRI. Formal psychometric studies were performed on all patients. The aims of the study were to correlate MRI abnormalities (FASI) with PET, to determine the
metabolic activity of FASI, and to investigate potential CNS
metabolic or physiological PET changes in NF-1. We conclude 1. small FASI were not resolved by PET, but larger
MRI lesions were either metabolically inactive or hypoactive;
2. all patients showed decreased uptake of FDG in thalamic
structures; 3. visual inspection of the PET images demonstrated a greater degree of inhomogeneity in cortical distribution of FDG in NF-1 patients compared to normal reference
subjects; and 4. mean full-scale I Q testing in the NF-1 group
was nearly 1 standard deviation below a representative sample of children, suggesting an association berween I Q and
cortical FDG changes.
608. Leigh Disease D u e to Complex I Deficiency
Presenting as Leukodystrophy
Carsten G. Bonnemann, Talh Lerman-Sagie,
Barry E . Kosofky. Brian H . Robinson, Ana Sotrel,
Francis E. Dougherty, and Katherine B. Sims,
Boston, MA. and Toronto. Ontario, Canadu
Leigh disease (LD) is a mitochondrial syndrome defined by a
characteristic neuropathology. The clinical phenotype is very
variable and may correlate poorly with the several identified
biochemical defects, including the rare N A D H C o Q reductase (complex I) deficiency. W e report 4 patients in 2 families
with complex I deficiency. Three had progressive white matter degeneration as the leading feature, an unusual presentation for both complex I deficiency and LD. Family 1: Patient
1, a 5-month-old girl, became acutely ill after immunization
with loss of tone, weakness, and subsequent spasticity. Neurological decline was steadily progressive, except for normal
eye movements. Computed tomography showed a generalized leukodystrophy. She died of hypoventilation at age 13.5
months. Autopsy showed widespread cavitary destruction of
white matter, spongy degeneration with axonal sparing, and
vascular proliferation in basal ganglia, periaqueductal gray,
and other areas. Patient 2, an 18-month-old girl, deteriorated
at 13 months after a heavy table fell on top of her. She
developed rapidly progressive ataxia, hypotonia, and spasticity, but retained normal eye movements and respiratory
pattern. Magnetic resonance imaging (MRI) showed generalized white matter disease and abnormal periaqueducral signal.
Basal ganglia appeared normal. Family 2: Patient 3, a 32month-old boy, presented at 2 years with ataxia and decreased upward gaze. MRI showed basal ganglia and brainstem abnormalities and normal white matter. Patient 4 , a
16-month-old girl, developed at 10 months of age rapid onset
of lethargy and hypotonia, and progressed to spasticity and
dystonia, retaining normal eye movements. MRI showed
generalized white matter disease and abnormalities in basal
ganglia and midbrain. Blood lactate was elevated in all 4 patients; cerebrospinal fluid lactate was elevated in 3 of 3 patients. Muscle biopsies in 3 of 3 patients did not show ragged
red fibers. Complex I deficiency was found in all patients in
either muscle tissue or fibroblasts. Mitochondria1 D N A studies have failed to identify mutations. These cases expand the
phenotype of LD due to complex I deficiency, emphasize
intrafamilial heterogeneity, and establish a presentation of
progressive leukoencephalopathy.
609. A n Innovative Approach to the Problem of
Sedating Children w i t h Opsoclonus-Myoclonus
Syndrome: Effects on Myoclonus and CSF
Monoamine Metabolites
Elizabeth D. Tate, Michael R. Pranzatelli. Yung-yu Huang,
and Richard Kaplan, Washington, DC. and New York, N Y
The opsoclonus-myoclonus syndrome (OMS) is a neurological syndrome with involuntary myoclonic jerks of the head,
trunk, and limbs; ataxia; opsoclonus; developmental delay;
and behavioral problems. Children with OMS are difficult to
sedate for procedures necessary to rule out a neuroblastoma
(CT scan, MRI, lumbar puncture, MIBG). Conventional
drugs used for sedation have been associated with lack of
efficacy, despite high doses, increased myoclonus, paradoxical responses, and cancellations of the needed procedures.
Propofol, an intravenous anesthetic that does not require
intubation, is an ideal drug for short diagnostic procedures
because of its short mechanism of action and rapid return to
wakefulness. O u r study compared the effectiveness of propofol with other sedatives 1. to sedate patients with OMS and
abate myoclonus; and 2 . to determine if metabolites of serotonin or dopamine in the CSF were changed. Following IRB
approval, a total of 22 patients were given midazolam (0.5
mg/kg), fentanyl (1 pg/kg), chloral hydrate (100 mgikg),
and/or pentobarbital (5 mg/kg) (n = 14); or propofol was
administered 2 mg/kg with additional boluses of 1 mg/kg
(n = 2), or infusion 100 to 500 (*g/kg/min (n = 6). Neurotransmitter metabolites 5-hydroxyindoleacetic acid ( 5 HIAA) and homovanillic acid (HVA) were analyzed by highpressure liquid chromatography. All 8 patients were effectively sedated using propofol, with cessation of myoclonus
except in 1 who had transiently increased myoclonus. No
patient developed postsedation increased myoclonus. Other
standard sedative agents were associated with a high rate (9
out of 14) of complications: inadequate sedation (7 out of
14) and/or paradoxical agitation (2 out of 14) ( p = 0.08 x2).
Propofol or midazolam alone did not significantly change
CSF 5-HIAA ( p = 0.20) o r H V A ( p = O.66), compared
to patients who were not sedated (ANOVA). Propofol is an
effective sedative in children with OMS because of its quick
Program and Abstracts, Child Neurology Society 543
onset of action, decreased adverse effects, and rapid return
to wakefulness.
610. Juvenile Autoimmune Myasthenia Gravis
Michael A . Nigro, Edward Dabrowski. Anne Marie Micbon,
and Aijuz Kbalid, Detroit, MI
Autoimmune neurological disease management has been significantly affected by the use of intravenous immunoglobulin
(IVIG) over the past 8 years. Venous access, readily available
IgG, and relative lack of identifiable complications has
prompted its use in myasthenia gravis (MG). In adults, its
effectiveness has been inconsistent with variable acetylchoLine receptor (AChR) antibody responses. We evaluated 4
children for clinical responses to and complications of IVIG,
and, in 2, we obtained weekly AChR antibody titers. All 4
children were receiving maximal tolerated doses of acetylcholinesterase inhibitors and no other medication. IVIG was infused at variable rates: 2 gmlkgll day, 660 mglkgldayl3
days, and 500 mglkgldayl4 days. All were infused over 12
hours, with the exception of 24-hour infusion in 1 case of 2
gmlkg single infusion. In all but 1 case, repeat infusions were
done at monthly intervals. The first patient was initially
treated at 15 years of age with a modest (15-30%) improvement in strength, and only required 1 infusion 2 years later,
when she was ventilator-dependent 2 days postpartum and
2 years postthymectomy. She responded 24 hours after an
infusion of 500 mg/kg/day/4 days with 25% improvement
in strength, and was extubated in 36 hours and at prenatal
strength within 1 week. A 3-year-old boy exhibited a 25 to
50%)improvement in strength beginning 5 to 7 days following completion of 660 mglkgldayl3 days, with increasing
weakness 3 weeks later. AChR antibodies were reduced by
30 to 50% 1 to 2 weeks postinfusion, and gradually returned
to pre-IVIG levels. After 3 months, the benefit of IVIG was
less significant. A 14-year-old boy with ophthalmoplegia and
generalized M G had a 20 to 30% improvement in strength
and 30 to 50% reduction in AChR antibodies after 660 mg/
kgldayl3 days for 2 months, but had insignificant response
afterward. A 16-year-old girl had a similar clinical response
after her initial infusion of 660 mglkgldayl3 days. All children tolerated IVIG without complications. Decreasing response to IVIG was evident after 3 monthly infusions, suggesting tolerance. WIG can be considered safe and effective
in the short-term management of MG, but appears to be of
limited long-term benefit. Suppression of IgG AChR antibodies and a postsynaptic protective effect could explain the
limited benefit of IVIG.
611. Brain Single-Photon Emission Computed
Tomography Imaging in Fragile-X Syndrome
Marilisa Guerreiro,M . Valeriana Moura-Ribeiro. M e V Kato,
Edwaldo Camargo. and Antonia P. Marques de Faria,
.
Campinas. SZo Paulo. Brazil
Fragile-X syndrome (FXS) is a biological model to study
autism, since almost all FXS patients exhibit autistic characteristics. W e present 7 male patients, aged 8 to 19 years old,
with the cytogenetic diagnosis of FXS. All patients received
HMPAO intravenously while
20 mCi (740 MBq) of '"Tc
awake, and were imaged using a camera-computer system.
Single-photon emission computed tomography (SPECT) revealed alterations in all cases: hypoperfusion of the inferior
portions of the frontal lobes occurred in 6 examinations;
cerebellar hypoperfusion was found in 2 examinations; and
hypoperfusion of parietal lobes was found in 2 examinations.
Neuropsychological assessment demonstrated poor attention
skills in all of them. Attention difficulties are considered frontal deficits, since the frontal lobe seems to be the one cortical
region most intimately related to the maintenance of the attentional matrix. Other investigators have noted that the positron emission tomographic abnormalities in autism involve
the neural circuitry for attention. Our findings in the FXS
agree with the literature in autism. We conclude that brain
SPECT imaging is a useful laboratory adjunct to contribute
to the understanding of the neurobiology of the FXS.
612. The Lumbar Puncture: Factors Affecting
Success Rate
Glen Fenton. Marsha Steffen. Elizabeth Sugarbaker.
Karen Miller. Barbara Suit, Pat Green, and Rebecca Charlton,
St Louis, MO
The lumbar puncture (LP) is one of the more common diagnostic procedures; yet, little information exists regarding the
spinal tap itself. How often is cerebrospinal fluid (CSF) obtained on the first attempt and what factors impact this success rate? In attempts to answer these questions, a survey of
LPs performed between June 30, 1993, and December 6,
1993, was undertaken. A total of 165 spinal taps were performed on children aged 1 day to 16.5 years (mean age, 32
months), with males and females being equally represented.
Patients were divided into age categories of 0 to 2 months
(69 of 165; 42%), 2 to 12 months (26 of 165; 16%), 1 to 5
years (36 of 165; 22951, 5 to 10 years (22 of 165; 13%), and
more than 10 years (12 of 165; 7%). The procedure was
carried out in the emergency department (87 of 165; 54%),
oncology clinic (36 of 165; 22%), intensive care units (19 of
165; 11%), medical wards (18 of 165; 1 I%), operating room
(2 of 165; I%), and neurology clinic (1 of 165; 1%). Attending physicians, residents/fellows-in-training,and, rarely,
medical students performed the spinal taps for a variety of
indications, including evaluation for central nervous system
(CNS) infection (97 of 165; 59%'0),administration of intrathecal chemotherapy (39 of 165; 24%), new-onset seizures (8
of 165; 5%), intraventricular hemorrhage with hydrocephalus ( 3 of 165; 2%), headache (2 of 165; l%), neurodegenerative disease (2 of 165; l%), and unspecified (14 of 165; 8%).
Anesthetic agent (local or systemic) was used in 6 9 of 165
(42%) cases overall. Only 9 of 95 patients (9%,)under 12
months of age were anesthetized, whereas 60 of 70 (86%)
patients over 12 months and 34 of 34 (1OOV) of patients
over 5 years were anesthetized. No particular problems with
equipment (LP traylneedles, table, lighting) were identified.
The mean overall number of sticks per patient (stick being
defined as a break in the skin) was 1.70, with 64%)of patients
requiring 1 stick, 18% requiring 2 sticks, 11% requiring 3
sticks, 2% each requiring 4, 5, and 6 sticks, and 1% requiring
7 sticks. N o patient required fluoroscopy-guided LP. Comparisons were made between age groups and sites. The
younger patients (less than 12 months) required a greater
number of attempts (reaching statistical significance [ p <
0.051 when all 165 patients were included, but not when only
single-site comparisons were made). Patients in the oncology
clinic required the lowest number of attempts, with a 97%
I-stick rate (significant at p < 0.01). No conclusion could be
made regarding the utility of anesthetic. This study of the
procedural analysis of the LP in a pediatric population has
shown differences in patient groups regarding the ease of
obtaining CSF by this method. The infant required the greatest number of attempts, probably due to a number of factors,
including lack of cooperation, need to perform on an emer-
544 Annals of Neurology Vol 36 No 3 September 1994
gent basis to exclude CNS infection, and lack of familiarity
with relational anatomy in the growing infant. It is not known
whether routine use of local anesthetic would impact on the
success rate in this population. Patients in this study who had
the greatest likelihood of requiring only 1 stick were older
children, who did not require the procedure on an emergent
basis, received local and/or systemic anesthetic, and had the
LP performed by an attending physician.
graphic pattern showed 2 to 2.5 H z generalized spike-wave
discharges. Intravenous lorazepam was the initial anticonvulsant used in most cases; but, it was successful in only a few
patients. Nonconvulsive status epilepticus in children thus is
most commonly complex-partial in type, and is often difficult
to recognize and treat.
615. Blood Lead Levels in Children with
613. Early Infantile Opsoclonus: Clinical Categories,
Etiology, and Outcome
Joao 0. Siffert and Karl C. K. Kuban, Boston, M A
Opsoclonus in the infant is a dramatic clinical finding. Few
studies have analyzed the etiology, particularly in relation
to neuroblastoma, and the outcome of opsoclonus in young
infants. This study investigates clinical features, etiology, and
outcome in 7 infants presenting with opsoclonus diagnosed
at less than 4 months of age. We retrospectively analyzed
charts and magnetic resonance imaging and computed tomography scans of these infants. Myoclonus or ataxia was not
observed in any patient. All patients were subjected to extensive work-up for neuroblastoma, including laparotomy in 2;
but, evaluations were negative uniformly. This observation
is similar to the 15 previously reported infants with opsoclonus who were also not found to have neuroblastoma. Definite
etiology was identified in only 1 infant with a Dandy-Walker
malformation and hydrocephalus. Another infant had electrophysiological signs of brainstem dysfunction (abnormal brainstem evoked responses), but no definable structural pathology. Outcome was of considerable interest. Thus, opsoclonus
resolved within 2 months of presentation in 3 patients, within
2 years in 3 patients, and persists in 1 patient at age 12 years.
In 2 children, opsoclonus evolved into nystagmus. Notably,
4 patients had serious visual impairment on follow-up (16
months- 13 years). W e hypothesize that visual impairment is
related to the pathophysiological mechanisms of opsoclonus
in some infants. O n the basis of the 15 cases previously reported and our 7 cases, we propose to divide children with
opsoclonus into four clinical groups: 1. healthy neonates with
transient benign opsoclonus; 2. infants with isolated visual
impairment; 3. infants with clinical manifestations of encephalopathy, with or without visual impairment; and 4. children
with the syndrome of opsoclonus-myoclonus.
614. Nonconvulsive Status Epilepticus in Children
Van S. Miller, Louise Anderson, Anthony R. Riela,
and Balbir Singh, Dalhs, TX
Nonconvulsive status epilepticus has not been described often in children. W e retrospectively reviewed 17 children presenting with nonconvulsive status (age range, 13 months-15
years; mean age, 7.5 years), defined as at least 30 minutes of
continuous (or serial without recovery) behavioral impairment without major motor activity, confirmed by continuous
rhythmic epileptiform discharges on electroencephalogram.
Complex-partial status occurred in 16 children, 1 of whom
had absence status. Average status duration was prolonged
(mean duration, 6.5 days; range, 40 minutes-30 days), and
the time from diagnosis to resolution of status averaged 2.8
days (range, 0-7 days). Time from status onset to recognition
averaged 4.7 days (range immediate, 30 days). Only 10 children had a prior history of seizures; 7 had nonconvulsive
status as their first seizure. Almost all children required multiple anticonvulsants as treatment, with several receiving 4 or
5 anticonvulsants. The most common ictal electroencephalo-
Neurobehavioral Disorders
Gary B. Bobele, Oklahoma City, OK
Lead exposure in early childhood has been associated with
lower intelligence and academic achievement, poorer motor
development, and inattention and hyperactivity. Lead levels
in the blood can remain elevated for years after exposure.
To evaluate the utility of screening for lead exposure in children with attention deficit hyperactivity disorder (ADHD)
and other neurobehavioral disorders, a prospective evaluation of children referred to the Pediatric Behavioral Neurology Clinic at the Children’s Hospital of Oklahoma was performed. Blood lead levels obtained by venipuncture were
available on 84 children (67 boys, 17 girls), ranging in age
from 4 to 23 years (mean age, 10.2 ? 0.4 years). The diagnoses in these children were: A D H D , 49;Tourette’s syndrome
(TS), 11; and other behavioral disorders, 24. Lead levels in
all patients were less than 9 (*.g/dland there were no differences in lead levels among the three groups (Table). These
data suggest that lead exposure is a rare cause of neurobehavioral disorders in children in our population.
Diagnosis
Number
Blood lead,
pg/dl,
(mean t SEM)
ADHD
TS
49
11
2.00
1.86 t 0.20
Other
?
0.50
24
2.46
2
0.38
616. Comparison of Polarography and
Spectrophotometry Data in the Diagnosis
of Mitochondrial Cytopathies
W. D. Grover, L. Salganicoff; F . Kohler, C. M . Foley,
A . Legido. D. Miles, K. Bierbrauer, E . Hobdellq
and M . Grossman, Philadelghia, P A
A defect in oxidative phosphorylation (Ox-Phos) is critical in
the diagnosis of mitochondrial cytopathy (MTC). The measurement by polarography (Pa) of oxygen consumption in
states 3 and 4 and the cytochrome concentrations is the only
method for determining the kinetics of electron transport
(ET), turnover number and adenosine triphosphate (ATP)
synthesis of complexes 1 to 5. The Pa of fresh mitochondria
(mt) isolated by subcellular fractionation was compared to
spectrophotometry (Spm) of complexes 1 to 4 in the muscle
biopsies of 21 patients with clinical and/or features suggesting MTC. Decreased complex 1 function noted by Pa
not detected by Spm occurred in 3 of 2 1 patients. Normal
function by Pa was documented in 3 of 21 patients with
abnormal activity in complexes 1 (2) and 4 (1) by Spm. Of
the 21 patients, 5 had abnormalities by both techniques, 2
of 5 at the same site. Ten patients had normal values. Patients
with abnormal values by both techniques had encephalopathy, lactic acidosis, a family history, and MRI abnormalities,
but no higher incidence of abnormal mt morphology or mu-
Program and Abstracts, Child Neurology Society 545
tations. Pa is a superior method of measuring Ox-Phos because it detects changes in respiratory control, dynamics of
ET, including ATP synthesis, and substrate transport into mt.
617. Outcome of Periodic Lateralized Epileptiform
Discharges in a Pediatric Population
Cynthia V. Stack and Michael S. Hammer. Chicago, IL
Electroencephalographic reports from our laboratory for the
last 10 years were reviewed, uncovering 44 cases of periodic
lateralized epileptiform discharges (PLEDs). Retrospective
chart review produced clinical follow-up data in 29 patients.
The age range of these patients was 7 days to 18.75 years.
Clinical diagnosis and outcome in each patient was recorded
(Table).
0ut come
Normal
Unknown
Developmental delay
(unknown severity)
Moderate mental
retardation
Neurological devastation
Death
Number of
Patienrs
6 children
Mean Age
(months)
1 child
97
17 1
1 child
4
3 children
8 children
10 children
11
40
50
In this population, adverse outcome of PLEDs appears to be
related to clinical diagnosis. Patients with diffuse insults, i.e.,
anoxia, meningitis, encephalitis, degenerative disorders, fared
worse than those with discrete central nervous system lesions, i.e., stroke, tumor, hemorrhage. Patient age at the time
of the PLEDs also predicated a dire outcome.
618. Adverse Outcome of Children with
Opsoclonus-Myoclonus Associated
with Neuroblastoma
Michael S. Hamnier. Marianne B. Lursen. Cynthia V . Stack,
and Charles N . Swisher, Chicago. IL
We reviewed the medical records from 1983 to 1993 of
all patients admitted to Children’s Memorial Hospital for
opsoclonus and myoclonus associated with neuroblastoma.
Eight children were found to meet these criteria. The neuroblastoma ( N B ) was surgically resected in all 8 children, with
residual opsoclonus-myoclonus (OM) and/or ataxia postsurgically. In all 8 children OM and/or ataxia was the presenting
symptom that led to the detection of the NB. All 8 children
initially were treated with ACTH. Only 1 of the children has
normal development. H e was only symptomatic with O M
for 2 months; he has had no recurrences and has remained
asymptomatic for the past 11 months. The remaining 7 children were symptomatic from 13 to 37 months. Those 7 children had recurrences of symptoms while tapering ACTH or
after it had been discontinued. Often the ACTH had to be
restarted or increased; but, several times the episodes were
brief and self-limited, not requiring treatment. In 2 of the 8
children, prednisone was used to treat the recurrences of
O M after ACTH had been tapered. The patients exhibited
minimal or no improvement on prednisone and required further treatment with ACTH to eliminate symptoms. Of the
8 children, 7 have delayed development. These 7 have gross
and fine motor incoordination and have speech delay. Of the
546 Annals of Neurology
7, 3 have experienced behavioral problems. O n e of these 7
children has borderline intelligence, the remaining 6 children
have IQs ranging from 56 to 75. W e found that prednisone
was ineffective in controlling OM. The majority of children
with O M had more severe developmental delays and at a
higher rate than previously reported by Senelick (J Ped Surg,
1973) and Telander (J Ped Surg, 1989). Tumor removal did
not improve the symptomatology in any of the children. The
1 child with normal development had resolution of symptoms within 2 months and remained asymptomatic, suggesting quick response to therapy indicates a better prognosis. The remaining 7 patients showed no correlation between
neurological outcome and the number of recurrences, response rate, length of time symptoms took to resolve, or age
of child at time of symptomatic presentation.
619. Clusters of Children with Infratentorial
Glial T u m o r s
F. H . Gilles. E . Sobel. C. J . Taimari, A. Leviton,
and E. T . Hedlq-Whyte, for the Childhood Brain
Tumor Consortium, Los Angeles, C A
Abnormal proliferation of “normal” glial cells or their progenitors generates glial tumors with characteristic histological
patterns. Predominant cell type usually determines diagnosis.
However, cellular heterogeneity is common in childhood tumors, and can lead to significant heterogeneity in subjects
chosen for therapeutic trials by diagnostic names only. W e
devised a new strategy to cope with this problem. First, we
grouped 26 reliably identified histological features using factor analysis on 1,068 children. We found 5 uncorrelated
groups of histological features, or “factors,” that we called
spongy, proliferative, ring, jibrillaty, and nuclear. The score
(“strength”) of each factor in each tumor provided the basis
for identifying 11 clusters of children. Some tumors in these
clusters were subsets of traditional diagnostic categories; others had characteristics of more than one diagnosis. Three
child clusters were subsets of ependymomas; 2 were pilocytic
astrocytomas; 4 were primitive neuroectodermal tumors
(PNET) (medulloblastomas); and 2 contained features of
astrocytoma, anaplastic astrocytoma, and PNET. Within
these subsets, one or more histological factor scores differed
significantly from the others, e.g., subsets within the diagnosis of pilocytic astrocytoma differed on nuclear factor scores.
These differences identified child clusters with statistically
significant different survival probabilities. We propose that
this strategy be employed to ensure homogeneous subsets
for therapeutic clinical trials. (Supported by CA495 32.)
620. D N A Analysis in G r o u p A Xeroderma
Pigmentosum by Polymerase Chain Reaction Method
Naoyuki Tanuma..Jun Kohyama. Masayuki Shimohira.
Takeshi Hasegawa, Masahiro Ito. and Yoshihide lu~akawa.
Tokyo, Japan
Xeroderma pigmentosum (XP) is an autosomal recessive human genetic disorder manifested as extreme sensitivity to
sunlight, resulting in a very high incidence of skin cancer,
and frequent neurological abnormalities. We tried polymerase chain reaction (PCR) diagnosis on genomic D N A from
14 Japanese patients of Group A XP. The molecular basis of
Group A XP was investigated by restriction fragment length
polymorphism analysis of PCR-amplified D N A sequences
using the 3 restriction enzymes, endonuclease Alui NI, Hph
I, and Mse I. Of the 14 patients, 11 were homozygous for the
G to C transition mutation of X P Group A complementing
Vol 36 N o 3 September 1994
(XPAC) gene at the 3’ splice acceptor site of intron 3. They
had typical neurological symptoms of Group A XP, and this
mutation is the most common in Japanese Group A XP patients. Two typical Group A X P patients were heterozygous
for the nonsense mutation of exon 3: 1 was a compound
heterozygote for this mutation and for the splicing mutation;
1 was homozygous for the splicing mutation. An atypical
Group A patient with minimal neurological abnormalities
showed compound heterozygote for the splicing mutation
and the nonsense mutation of exon 6. Our results suggest
that the clinical heterogeneity in Group A XP is partially
caused by different mutations in the XPAC gene.
height of 163.9 2 5.4 cm. The height in boys (n = 105)
was 182.0 ? 7.2 cm, with a target height of 177.6 t 4.7
cm. The duration of therapy was 10.9
5.2 years (boys)
and 9.9 & 4.9 years (girls). The height of our patients was
normal when compared to the German standards reported
by Reinken (1992) (boys, 180.1 cm; girls, 167.9 cm). The
difference between actual height and target height is due to
the secular acceleration of growth. Neither the form of epilepsy, the onset of therapy, or the kind of therapy had any
influence on adult height. Children with epilepsy and AEDs
have a normal adult height, when compared with target
height or the population standard.
621. Brainstem Auditory and Visual Evoked
Responses in Congenital Heart Disease
Gulbis Deda, Semra Ataky, Uiur Karagol, Ayten Imamoglu,
Senay Kukner, and Erdal Ince, Ankara, Turkey
623. Pharmacotherapy in Childhood Narcolepsy
Mewill S. Wise and AnnJobnson, Birmingham, AL
Delayed developmental milestones in infants and children
with congenital heart disease, especially cyanotic heart disease, appears mainly to be a result of undernutrition or
chronic hypoxemia affecting the cerebral cortex. However,
this retardation may be partially due to delayed brainstem
maturation. In our study, we have detected both brainstem
auditory evoked response (BAER) and visual evoked response (VER) in cyanotic and acyanotic patients with congenital heart disease in order to evaluate the influence of chronic
hypoxemia on myelinization and brainstem maturation. We
examined 58 children with cyanotic or acyanotic congenital
heart disease. The patients were divided into two groups
according to their ages: 18 patients were between 1 and 24
months, with a mean age of 7 months (10 with cyanotic and
8 with acyanotic heart disease); 40 patients were between 2
and 16 years, with a mean age of 5.1 years (19 with cyanotic
and 21 with acyanotic heart disease). The results of both
BAERs and VERs were compared with age-matched controls. There was no significant difference between the peak
and interpeak latencies of BAER among cyanotic, acyanotic,
and control subjects in both age groups. The N2 latencies
of VERs in children with cyanotic and acyanotic heart disease
whose ages were between 2 and 16 years were significantly
prolonged when compared with the control group. Although
this is a preliminary report of an ongoing study, chronic congenital heart disease, both cyanotic and acyanotic, seems to
prolong the N2 latencies of VER, which may be due to delayed myelinization in these children.
622. Adult Height and Target Height i n 133 Boys
and Girls with Epilepsy and Antiepileptic Drugs
G. Kurlemann, T h . Benner, P. VoJscbulte, P. Heyen,
J . H . Branuwig, and D. G. Palm, Munster, Germany
Body height contributes considerably to social acceptance.
Therefore, the question of growth impairment due to antiepileptic drugs (AEDs) is important for children with epilepsy.
Only a few investigations, with inconsistent results, have
been reported up to now. A total of 179 patients (74 girls,
105 boys) had been treated for epilepsy in childhood over
many years. At the time of investigation, all patients were 18
years or older. Height was measured at visits to the clinic or
at home, according to detailed instructions mailed to them.
In addition, height of the parents was determined and target
height calculated according to the method of Tanner. Onset,
duration of therapy, the kind of epileptic treatment, and the
form of epilepsy were documented. The adult height in girls
(n = 94) was 167.4 2 8.2 cm (mean ? SD), with a target
Narcolepsy is a chronic neurological disorder that causes
sleepiness and impaired sleep/wake regulation. The sleepiness disrupts cognitive function, places the individual at risk
for accidents, and is highly stigmatizing. A previous report
by us (Ann Neurol 1993;34:378) emphasized the severe
sleepiness among children with narcolepsy. This report focuses on the therapeutic response of 13 children and adolescents (average age, 15.6 years) who have been followed longitudinally (average duration of follow-up, 27.6 months). Nine
patients presently receive methylphenidate and 4 receive
dextroamphetamine. Dosage varies from 15 to 90 mg per
day of methylphenidate, and from 10 to 60 mg per day of
dextroamphetamine. The 4 patients on dextroamphetamine
previously took methylphenidate, but experienced unacceptable side effects or little improvement. Improvement in
sleepiness was scored by the authors based on clinical observation and reports from patients, parents, and teachers. Improvement in sleepiness is “good” in 2 patients, “fair” in 10
patients, and “poor” in 1 patient. Ascertainment of response
was difficult at times, as highlighted by frequent discrepancies
between reports from patients, parents, and teachers. Our
experience with this group indicates that: 1. children and
adolescents with narcolepsy often exhibit a suboptimal response to stimulant medications, even in relatively high
doses; 2. better instruments are needed to quantify precisely
improvement in sleepiness during the day; and 3. children
and adolescents should be given access to clinical trials for
newer stimulants. Presently, we are working to establish correlations between certain HLA subtypes and response to
stimulants, thereby moving toward a pharmacogenetic approach to rational selection of stimulants in narcolepsy.
624. Quantitative Magnetic Resonance Imaging
of Dysmyelination in the 18q- Syndrome
Charles T . Gay, Jack L. Lancaster,Jean L. Floyd,
Hope Marcotte, Celza I. Kaye, and Peter T . Fox,
San Antonio, T X
The 18q- syndrome-one of the most common chromosomal deletion syndromes-consists of mental retardation,
short stature, a variety of dysmorphic features (Miller G,
Mowrey PN, Hopper KD, et al, Neurologic manifestations
in 18q- syndrome, Am J Med Genet 1990;37:128-132),
and dysmyelination of cerebral white matter (Vogel H , Urich
H, Horoupian DS, Wertelecki W, The Brain in the 18qsyndrome, Dev Med Child Neurol 1990;32:732-737).
These patients may be hemizygous for the myelin basic protein gene (Weiss BJ, Kamholz J, Ritter A, et al, Segmental
spinal muscular atrophy and dermatological findings in a patient with chromosome 18q deletion, Ann Neurol 1991;30:
Program and Abstracts, Child Neurology Society 547
419-423; Kamholz J, Spielman R, Gogolin K, et al, The
human myelin basic protein gene: chromosomal localization
and RFLP analysis, Am J Hum Genet 1987;40:365-373),
and many are growth hormone deficient (unpublished data).
We have studied the brains of 3 children, aged 3 to 6 years,
with the 18q - syndrome using quantitative magnetic resonance imaging on an Elscint 1.9-tesla magnet (SE T1weighted 500/20, TZ-weighted 3400/80/20; 5-mrn thick,
1-mm gap). From the digitized raw image data, we calculated
T I and T2 images of the whole brain. W e then analyzed T I
and T2 relaxation times in selected gray and white matter
regions of interest. Two patients had abnormal deep cerebral
white matter by visual inspection (increased signal intensity
on T2-weighted images). In all 3 subjects, gray and white
matter relaxation times were longer than reported age-related
norms derived from images obtained at 0.35 tesla (Holland
BA, Haas DK, Norman D, et al, MRI of normal brain maturation, AJNR 1986;7:201-208). More importantly, the relaxation times in our patients (e.g., frontal gray T1, 14751525 msec; frontal white T1, 1100-1300 msec) were longer
than those obtained from a normal 5-year-old child (frontal
gray T1, 1375 msec; frontal white T1, 825 msec) and from a
normal 40-year-old adult (frontal gray T1, 1300 rnsec; frontal
white T1, 775 msec) using the same 1.9-tesla magnet. Furthermore, the MRI scan of a 6-year-old child with 18qwas normal to visual inspection, but exhibited quantitative
differences (prolonged TI and T2 relaxation times for gray
and white matter) compared to the scan of a normal 5-yearold child studied with the same 1.9-tesla magnet. W e analyzed numerous gray and white matter regions ( 4 of each)
from every patient and control. There was very little intrasubject variability, suggesting that the differences between subjects were not due merely to sampling error. Quantitative
MRI demonstrates tissue relaxation properties characteristic
of normal and abnormal myelination in vivo. We have used
quantitative MRI to demonstrate abnormalities not apparent
with standard visual inspection in patients with the 18q- syndrome. This technique-more sensitive to white matter abnormalities than is visual inspection of MR imagesfacilitates investigation of disturbed myelination in genetic
and acquired disorders of white matter.
625. Sumatriptan Therapy of Pediatric Migraines
Michelle Hoerlein. Gail McMonigle. and David Neal Franz.
Cincinnati, OH
Sumatriptan is a novel drug approved for treatment of acute
migraines in adults. This drug acts as a 5HT-type IC receptor
agonist that mediates vasoconstriction of cranial blood vessels
in animals and human models producing pain relief. Sumatriptan also works by decreasing neurogenically mediated extravasation of plasma proteins, thus preventing pain associated with neurogenic inflammation. The safety and efficacy
of Sumatriptan over placebo has been demonstrated in
adults; no data exist for the pediatric population. We present
our experience with Sumatriptan in 17 children, aged 7 to
18 years, over the last 12 months. All patients had diagnoses
of migraine, atypical migraine, complicated migraine, intractable migraine, or headache. Of 17 patients, 15 were on migraine prophylaxis, including amitriptyline, cyproheptadine,
and nonsteroidal antiinflammatory drugs or ergot derivatives.
Children and their parents were informed of the availability
of Sumatriptan and elected to receive the drug on a voluntary
basis for moderate to severe headache. Patients were asked
to rank their headache on a visual analog scale of 1 to 10
before receiving Sumatriptan. Vital signs, including blood
548 Annals of Neurology
pressure, were taken prior to injection doses, given subcutaneously, of either 3 mg or 6 mg and every 15 minutes thereafter for 45 minutes. Patients were then asked to rank their
headaches again on a visual analog scale. Good to excellent
relief was subjectively determined as a decrease in pain on
the visual analog scale of one half or more of initial pain
intensity. Good to excellent relief of headache was attained
in 12 of 17 patients (71%) after 4 5 minutes. In 2 patients
(129%), no relief was seen; in 3 patients ( 18p6), headache
actually worsened. Side effects were minor, transient, and
had been eliminated in all patients by 45 minutes after injection. The side effects include flushing (3), nausea andlor vomiting (2), tightening in throat ( l ) , dizziness ( 1 ), diaphoresis
(I), fatigue ( l ) , stomach ache ( l ) , dry throat (I), and pallor
(1). Patients with basilar artery migraine are felt to be at
increased risk of stroke with Sumatriptan. We treated no
such individuals. Our experience with Sumatriptan suggests
that its safety, efficacy, and side effects profile in children
parallel that of the adult population. The major contraindications to use of Sumatriptan-angina, hypertension, and coronary artery disease-are rarely found in the pediatric population.
626. Testing Linkage Between Familial Neural T u b e
Defects and the Pax-3Gene
S. Chatkupt, F. A. Hol, Y . Y . Shugart. M . P. H . Geurds.
E. S. Stenroos, M . R. Koenigsberger. B. C . J . Hamel,
E. C. M . Mariman, and W. G.Johnson.
Newark and New Brunswick, NJ. Nijmrgen.
The Netherlands, and New York, N Y
Neural tube defects (NTDs) are among the most common
and disabling birth defects. The etiology of NTDs is unknown and its genetics are complex. The majority of NTD
cases are sporadic, isolated, nonsyndromic, and generally
considered to be multifactorial in origin. Recently, HuP2
(the human homologue of mouse Pax-3 ), on chromosome
2q35-37, was s u s e s t e d as a candidate gene for NTDs because mutations of Pax-3 cause mouse mutant Splotch ( S p ) ,
an animal model for human NTDs. Mutations in HuP2 were
also identified in patients with Waardenburg’s syndrome type
1 (WS1). At least 3 patients with both WSI and myelomeningocele have been described, suggesting possible pleiotropy
or contiguous gene syndrome. A total of 194 individuals (SO
affecteds) from 17 1J.S. families and 14 Dutch families with
more than 1 affected individual with NTDs were genotyped
using the Pax-3 polymorphic marker. The data were analyzed
using affecteds-only linkage analysis. The lod scores were
- 7.30 (U.S.), - 3.?4 (Dutch), and - 11.04 (combined) at
6 = 0.0, under the assumption of the autosomal dominanr
model. For the recessive model, the lod scores were - 3.30
(US.), - 1.46 (Dutch), and -4.76 (combined) at 8 = 0.0.
Linkage between Pax-3 and familial NTDs was excluded to
19.8 cM for the dominant model and to 7.26 cM for the
recessive model in the families studied. No evidence of heterogeneity was found using the H O M O G program.
627. Thyroid H o r m o n e Regulates Gene Transcription
of Transforming Growth Factor Alpha in the
Developing Brain
Kenneth R. Huff and Fatima Rrrsso. Torrance, CA
Thyroid hormone (TH) has profound developmental effects,
including effects on neuronal number; but its mediation is
unknown. Transforming growth factor alpha (TGF-a) functions in developmental processes, including DNA synthesis
Vol 36 No 3 September 1994
stimulation, and accelerates some developmental effects delayed in a hypothyroid state. W e have studied TH treatment
effects on TGF-a levels and TGF-a gene expression in the
rat brain at a developmental stage when hormone levels are
naturally low. Brains were assayed for TGF-a with a specific
radioimmunoassay or were homogenized for R N A isolation,
which was reverse transcribed into cDNA and amplified by
polymerase chain reaction. Message levels detectable at 12
days of gestation were made undetectable postnatally after
TH treatment and growth factor levels were lowered markedly to that of a later stage. We conclude that TH “matures”
TGF-a gene expression in the developing brain. As
astrocytes are known to respond to TGF-a with increased
D N A synthesis, perhaps TH effects on neuronal number in
development may be mediated through TGF-a levels and
appropriate astrocyte differentiation for migratory guidance
or trophic support of neurons.
628. Genetic Mapping of Borjeson-Forssman-Lehmann
Syndrome
Katherine Mathms, Kerty Wiles. Tita Scberpbier-Heddem,
Ken Buetow, and Jefirq Murray, Iowa City, IA, and
Philadelphia, PA
Borjeson-Forssman-Lehmann syndrome (BFLS) is a form of
X-linked recessive mental retardation characterized by dysmorphic craniofacial features (supraorbital ridges, ptosis,
large ears), obesity, hypogonadism, short stature, and microcephaly. The degree of mental retardation is variable in the
reported cases. Heterozygous females may have mild features of the syndrome or may be entirely normal. BFLS was
originally mapped to Xq25-Xq26 by us (Am J Med Genet
1989;34:470-474) and by Turner et a1 (Am J Med Genet
1989;34:463-469). The recombination events defining the
proximal boundary of the region of interest could not be
confirmed as additional markers have become available. We
have studied our original family and 2 additional BFLS families with microsatellite markers spanning approximately
Xq24-Xq27. We have confirmed the original localization,
with a maximal 2-point lod score of 6.28 at 0 = 0 for
DXS144. The most centromeric recombinant in our families
thus far is with DXS1212. One female with subtle clinical
features of BFLS is recombinant with DXS1047 (more telomeric); however, she has been scored as unaffected in the
formal analysis. The telomeric boundary of the BFLS interval
is at CDRl3. The identification of the BFLS gene will depend
on additional families to refine the region of interest or identification of candidate genes in distal Xq. One such candidate
gene (SOX3) has recently been described by Stefanovic et
a1 (Hum Molec Genet 1993;2:2013-2018) and will be studied for a possible role in BFLS.
629. Brainstem Mass Lesions in Neurofibromatosis
Type I: A Distinct Clinical Entity
P . T . Molloy, L. Bilaniuk. M . Needle, S. N . Vaughan,
E . Zackai, and P . C. Phillips, Philadelphia, P A
The natural history of brainstem mass lesions in patients with
neurofibromatosis type I (NF-I) is variable and less benign
than the typical brainstem high-intensity foci of NF-I seen
on T2-weighted MRI. We characterized the clinical presentation, radiographic evaluation, treatment, and overall outcome
of these lesions and report the largest series of brainstem
masses in NF-I to date. A total of 17 patients with both
NF-I and brainstem masses were identified from a large NF-I
population from 1984 to 1994. A brainstem mass was de-
fined as any focal or diffuse enlargement of the midbrain,
pons, or medulla. All patient charts and 73 neuroimaging
studies (51 head MRI scans, 3 spine MRI scans, and 19 head
C T scans) were reviewed. The most common clinical presentation was headache (5396). Neurological examination revealed cranial neuropathies (35% ), gross motor incoordination (4 1% ), dysarthrias (29% ), papilledema ( 1 2 P ),
hemiparesis (12%), ataxia (12%), and seizures (6%)). On
neuroimaging studies, 14 (82%) had an enlarged medulla, 7
(41%) had an enlarged pons, and 6 (35%) had a thickened
tectum. Seven (41%) had an exophytic nodule, 6 ( 3 5 g ’ )
exhibited mass effect, and 7 (4 1%) had hydrocephalus. Seven
(41%) required surgical intervention, 6 required VP shunts,
2 required partial tumor resections (Path: fibrillary astrocytoma), 1 with reoperation for medullary hemorrhage (Path:
anaplastic astrocytoma). Three ( 18% ) received radiation
therapy, chemotherapy, or both. Two patients (12%’)died,
and 15 (88%) are alive (mean follow-up = 51 months).
Brainstem masses in NF-I are a clinically distinct entity whose
prognosis is intermediate between T2WI high-intensity foci
and brainstem gliomas. Despite prolonged survival, the high
incidence of hydrocephalus and frequent medullary location
result in a variable clinical course. The role of radiation and
chemotherapy is unknown. Clinical and radiographic follow-up are essential.
630. Neurological Outcome of Premature Babies in
H o n g Kong: A n Analysis of Risk Factors
Virginia C. N.Wong. Pokfulam, Hong Kong
W e report the neurological outcome of children born prematurely from 1971 to 1993 and assessed in The Child Assessment Centre of The Duchess of Kent Children’s Hospital by
the University Department of Paediatrics during the period
1984 to 1994. Of a total of 502 children born before 37
weeks of gestation and assessed in the centre, 264 children
had a birth weight of less than 1,500 gm. The gestational age
at birth ranged from 24 to 35 weeks. T h e neurological outcome consisted of epilepsy (15); microcephaly ( 5 ) ; cerebral
palsy (53); limited intelligence (72); mental retardation (40);
visual handicap (22); hearing impairment (18);hydrocephalus
(11); multiple handicap (14); language problem (32); delayed
development ( 5 1), as assessed according to the real age prior
to full intellectual testing due to young age; behavioral problem ( 5 ) ; and autistic disorder (2). The severity of the children’s mental retardation was graded as mild (23), moderate
(1 11, and severe (6). T h e majority of children with cerebral
palsy had spastic diplegia (n = 3 1). The other types of cerebral palsy, in descending order, consisted of hemiplegia (8:
right in 5, left in 3), spastic tetraplegia (8).bilateral hemiplegia (3), ataxic diplegia ( l ) ,and mixed type (1). None had
dyskinetic or dystonic type of cerebral palsy. Neurological
outcome was analyzed according to the following groups:
(1) extremely low birth weight of 500 to 1,000 gm (n = 67)
versus very low birth weight of 1,000 to 1,500 gm (n =
197); (2) inborn (164 children born under university or government hospital neonatal intensive care unit) versus outborn
(100 born in private hospitals, where resuscitation was followed by transferral to university hospital); (3) neonatal risk
factors: intermittent positive pressure ventilation (n = 145),
perinatal asphyxia (n = 72), apnea (n = 77), convulsion (n =
14), intraventricular hemorrhage (n = 43), severe neonatal
jaundice requiring exchange transfusion (n = 50),meningitis
(n = 3), septicemia (n = 25), and respiratory distress syndrome (n = 138). Only three factors were found to be
related to outcome: outborn group and visual handicap
Program and Abstracts, Child Neurology Society 549
( p < 0.009); perinatal asphyxia and delayed development
( p < 0.005); intraventricular hemorrhage and language disorder ( p = 0.008).
631. Utility of Head Ultrasound in Group B Strep
Meningitis
Lawy E. White. Norfolk, V A
The objective of this study was to determine the usefulness
of head ultrasound (HUS) in infants with Group B Strep
meningitis. Group B Strep is the major cause of meningitis
in young infants. Decreased reliability of clinical findings,
proven efficacy of H U S in younger babies, and accessible
fontanels in this age group make H U S valuable in identifying
brain injury, which may impact morbidity. Over a 24-month
period, 12 infants, aged 6 days to 3 months, with Group B
Strep meningitis (by cerebrospinal fluid culture) were imaged, acutely or within 72 hours of presentation. Two distinct
groups were identified. Group 1 (6 patients) had clinical encephalitis with seizures and abnormal electroencephalogram.
H U S was abnormal in 5 of 6, with diffuse cerebritis in 3,
infarction in 2; cystic encephalomalacia developed in 3,
shunted hydrocephalus developed in 1; 1 died, and the rest
have neurological sequelae. Group 2 (6 patients) had clinical
meningitis with fever and behavior change. H U S was abnormal in 4 of 6, with increased extracerebral fluid in 2, subcortical infarction in 1, and mild hydrocephalus in 1. None died;
4 of the 6 are developing normally with limited follow-up.
HUS is useful in clinical meningoencephalitis to monitor diffuse and focal brain injury; also, it is useful in detecting subclinical injuries, which may affect morbidity, in infants without overt signs of brain involvement.
632. T-cell Receptor (TcR) Vp Repertoire of Muscle
Infiltrating Lymphocytes in Juvenile Dermatomyositis
Giuseppe Marreale, Fabio Ghiotto. Claudio Bruno.
Carlo Minetti. Vito Pistoia, and Giuseppe Cordone,
Genozia. Itah
Juvenile dermatomyositis (JDM) is a rare, chronic multisystem disease, characterized by muscle infiltration with mononuclear cells (MNC).The pathogenesis ofJDM is controversial; both antibod y-dependent and cell-mediated mechanisms
may be involved. Here, were report the results of immunohistochemical and molecular characterization of muscle infiltrating lymphocytes (MILS) in 4 JDM patients and, for comparison, in 4 Duchenne’s muscular dystrophy (DMD)
patients. Serial sections from muscle biopsies were stained
with fluorescein-conjugated monoclonal antibodies and processed for RNA extraction. TcR Vp gene expression was
investigated by a semiquantitative reverse transcriptasepolymerase chain reaction (RT-PCR) using specific primers
that detect 22 V p gene families. MILS were comprised
mainly of T lymphocytes (50-60q)) in all of the JDM patients, with a predominance of CD4’ cells in 3 cases and of
CD8+ cells in 1 case. The proportion of T cells in MILS
from D M D patients was lower than in JDM (10-20% of
total MNC), with a predominance of C D 8 + cells. In JDM,
isolated expression of V p l 5 was observed in 2 patients; in
the 2 remaining cases, V p l 5 was detected together with, but
in higher amounts than, Vp 6, 7, 8, 13.2, and 19. The same
TcR V p families with a similar distribution pattern were detected in DMD. These findings suggest that a skewed usage
of TcR Vp genes occurs in MILs from both JDM and D M D
patients. The mechanisms of the phenomenon are now being
actively investigated.
633. Phenytoin Pharmacology i n the First 3 Months
of Life
Brenda L. Banuiell. Simon Levin, Michael J . Rieder. and
David J . Freeman, London, Ontario. Canadz
Physicians are reluctant to use phenytoin (PHT) in the first 3
months of life because of difficulties in achieving therapeutic
serum levels. Phenytoin pharmacodynamics have not been
systematically studied in this age group. The objective of
our study was to demonstrate the necessity and safety of a
high-dose P H T regimen in a prospective cohort of 8 neonates. We hypothesized that high PHT doses are required
because of poor gastrointestinal absorption and high fecal
losses, rather than increased hepatic metabolism or reduced
serum protein-binding. Measurements of serum total PHT
and free PHT levels, urinary P H T metabolites, and fecal
PHT concentrations were obtained. W e assessed side effects,
seizures, and liver and renal function. Our results show that
therapeutic serum PHT levels (40-80 pmol/L) were
achieved with doses of 15 to 20 mg/kg/day. There was no
toxicity. Free P H T levels were 12% of total PHT levels,
consistent with those seen in adults. W e conclude that therapeutic P H T levels can be achieved with doses of 15 to 20
mg/kg/day in infants less than 3 months of age without clinical toxicity or toxic-free P H T levels.
634. Mitochondrial D N A Studies i n Rett’s Syndrome
S. Naidu, V . Namyanan, D. Johns, F . Castora. and
0. C . Stine, Baltimore. M D . Pittsburgh, PA. Boston, M A , and
Norfolk. V A
Rett’s syndrome (RS) is a neurological disorder commonly
seen in females. A mitochondrial (mt) etiology is proposed,
as some RS patients show abnormal mt morphology and others have mt enzyme deficiencies in muscle. In addition, the
rare familial cases (0.5%) suggest matrilineal transmission.
We analyzed mt D N A for structural abnormalities and investigated an mt enzyme encoded on the X chromosome from
a region proposed for RS involvement. Mitochondrial D N A
from frozen brain tissue of 2 unrelated girls was probed with
a 32P-labeled 3.0-kb mt D N A fragment containing the region
of heavy chain replication, and overlapping regions were amplified by PCR to cover 90%’ of the protein coding region
of the mt genome. N o deletions or insertions were noted
when compared to normal brain mt DNA. To increase the
sensitivity of detecting mutations, we are employing singlestrand conformation polymorphism (SSCP) and denaturing
gradient gel electrophoresis (DGGE) analysis of PCRamplified products. Using SSCP, the 3’ regions of N A D H
5 and N A D H 6 in mr D N A from peripheral leukocytes of
4 RS girls were no different from their normal parents. Previous studies suggest that a gene responsible for RS may be
located in the region of X p 21-22, which contains the gene
encoding E, a-subunit of the mt enzyme pyruvate dehydrogenase (PDH). We, therefore, studied leukocytes in 8 RS
girls using a 1.4-kb PDH E,a-subunit c D N A probe from the
coding region. Though no abnormalities were noted when
compared to their healthy parents, point mutations and the
possibility that mutations may be present in tissues other
than leukocytes cannot be excluded. Major rearrangements
of mt D N A are not the cause of RS. An mt enzyme encoded
in the nuclear D N A considered as a posslble RS locus is
normal. More detailed studies of mt D N A and other nuclear
encoded mt proteins are in progress to determine if mt abnormalities are responsible for RS. (Supported by NIH
grants RR00052 and HD24448.)
550 Annals of Neurology Vol 36 No 3 September 1994
635. Primitive Neuroectodermal Tumors
of the Brainstem
Jeffrty Allen, David Zagzag. Mark Lee, and Fred Epstein,
New Yovk, N Y
The majority (>90%) of primitive neuroectodermal tumors
(PNETs) in children arise in the cerebellar vermis. Less common sites include the cerebrum and pineal region. We described 7 cases of histologically confirmed PNET arising in
the brainstem (pons, 6; medulla, 1). One patient (pt) developed his C N S tumor as a second malignant neoplasm, having
acquired a rhabdoid sarcoma in his skin 4 months previously.
The median age of the pts at diagnosis was 1.5 years (range,
0.5-7.5 years), and the median duration of their prodrome
was 1 month (range, 1-6 months). The male:female ratio
was 2 : 5. The initial symptoms included focal cranioneuropathies (7) and hemiparesis (3). Imaging studies identified intrinsic focal lesions in all, which enhanced in 6. Two tumors
had exophytic components. Neurosurgical intervention consisted of a partial resection ( 5 ) or biopsy (2) and 6 pts required VP shunts. Three pts had leptomeningeal metastases
(LM) at diagnosis (brain and spine). Treatment consisted of
craniospinal radiotherapy and chemotherapy (4)or chemotherapy alone (3). Two had transient responses to therapy.
Four pts have died at 3, 4,8, and 10 months from diagnosis
with local recurrences and diffuse LM. The 3 living pts are
newly diagnosed and are presently receiving chemotherapy.
The recognition of the brainstem as another site of origin of
PNET reflects our institutional preference for resecting focal
brainstem tumors. Younger pts with focal enhancing pontine
lesions and those who present with LM should have histological documentation prior to treatment. Presently, the prognosis of brainstem PNET is poor following conventional therapy, and the pattern of relapse is typical for PNET.
636. Ischemic Cerebral Infarction of the Basal Ganglia
and Internal Capsule i n Children
Mary C. Brwer and E. Stezie Roach, Dalhs, T X
A total of 21 children with ischemic cerebral infarcts limited
primarily to the basal ganglia andlor internal capsule were
identified. Signs and symptoms and radiographic features
were reviewed. The series includes 12 boys and 9 girls, ranging in age from newborn to 10 years. Seventeen children
were evaluated with computed tomography; 18 were evaluated with magnetic resonance imaging; 6 were evaluated with
magnetic resonance angiography, and 9 were evaluated with
conventional cerebral angiography. Nineteen patients had
unilateral lesions (8 right, 11 left), while 2 had bilateral infarcts. Echocardiography was performed in 11 cases, and special blood testing, including determination of coagulation factor levels, organic and amino acid screening, and systemic
inflammatory indicators, were available in some cases. The
most common presenting symptom was hemiplegia (16 of
21). Other major clinical features noted on presentation included aphasia (3 of 21), seizures (3 of 21), diffuse encephalopathy (3 of 21), monoplegia (1 of 21), and chorea (1 of
2 1). The etiologies were: idiopathic ( 5 patients), congenital
heart disease ( 5 ) , infection ( 3 ) , trauma (3), coagulopathy (2),
and carotid vasculopathy, hypoglycemia with dehydration,
and a presumed adverse effect of chemotherapy (1 each).
Lacunar infarction in adults is strongly linked to hypertension
and arteriosclerosis; in children, these lesions more often result from embolism, inflammatory or congenital vasculopathy, or a hypercoagulable state. Accumulation of a larger
series may allow further clarification of this pathophysiologically distinct pediatric lacunar syndrome.
Program and Abstracts, Child Neurology Society 551
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