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Electroclinical signs of benign neonatal familial convulsions.

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Electroclinical Signs of Benign Neonatal
F d a l Convulsions
E. Hirsch, MD," A. Velez, MD," F. Sellal, MD,* B. Maton, MD," A. Grinspan, MD,* A. Malafosse, MD,?
and C. Marescaux, MD"
~~
Benign neonatal familial convulsions comprise a distinct epileptic syndrome with an autosomal mode of transmission.
The electroclinical signs of seimres in this syndrome are not yet well defined. In 3 children from two families
presenting with benign neonatal familial convulsions, 14 seizures were recorded during electroencephalographic
(EEG)-video sessions. All seizures occurred during sleep, after a short arousal reaction. Seizures started with bilateral,
symmetrical flattening of the EEG for 5 to 19 seconds; simultaneously there was apnea and tonic motor activity. The
EEG flattening was followed by a long (l-2-minute) bilateral discharge of spikes and sharp waves; simultaneously,
there were vocalizations, chewing, and focal or generalized clonic activity. The prominence of EEG and motor abnormalities varied between the left and the right from one seizure to the next in any given child. The seizures stopped
without EEG or clinical postictal depression. These electroclinical observations suggest that the convulsions of benign
neonatal familial convulsions are a form of generalized tonic-clonic seizure whose expression may be asymmetrical,
probably because of the immaturity of the corpus callosum or other structures ensuring seizure synchronization.
Hirsch E, V e l a A, Sellal F, Maton B, Grinspan A, Malafosse A, Marescaux C. Electroclinical sgns of
benign neonatal familial convulsions Ann Neurol 1993;34:&35-841
Benign neonatal familial convulsions (BNFCs) have
been recognized as a distinctive epileptic syndrome
since 1964 (1, 21. Seizures start at the second or third
day after birth in children with no prenatal or perinatal
pathological antecedent. The findings on neuroradiological and biochemical examinations are normal. Brief
seizures occur for several days or weeks, then regress
[3-17). Less than 10% of patients subsequently develop seizures, approximately two thirds as adults {12,
17). For some authors, BNFCs may consist of two
different entities: one having a 20% risk of subsequent
epilepsy, and a second that carries no increased risk
(12). For other authors, only one form of BNFC exists,
and all patients with BNFCs have a lower threshold
for seizures 1171.
The syndrome has an autosomal mode of transmission. The gene responsible for BNFCs was recently
localized on the long arm of chromosome 20, at
20q13.3 [18, 191. BNFCs may be genetically heterogeneous: In one family the results were not consistent
with linkage of the disease and marker loci on chromosome 20 E20).
Seizures have seldom been recorded, and the electroclinical signs of BNFCs are not yet well defined.
Here we describe the results of an electroencephalographic (EEG)-video study of 14 seizures in 3 children
from two families.
From the *Service d'Epileptologie Clinique, HBpitaux Universimires
de Strasbourg, Strasbourg, and the tlaboratoire de M6decine Exp&
rimentale, Institut de Biologie, Montpellier, France.
Address correspondence to Dr Hirsch, Service d'Epileptologie Clinique, Cliniquc Ncurologique, HBpitaux Universitaires de Strasbourg, 1 place de l'Hbpital, 67091 Strasbourg Cedex, France.
Observations
In two families presenting with BNFCs, 6 people were
affected (Fig 1). Cell lines have been established for all
living members of the two pedigrees, which have been
included in a collaborative linkage study of BNFCs.
In these two families, linkage analysis with 20q
D N A markers (D20S15, D20S64, D20S20, D20S19,
D20S24) strongly suggest the implication of the chromosome 20q BNFC gene (maximum multipoint lod
score Z = 1.36).The 6 patients, without prenatal or
perinatal pathological antecedents, were all born at
term. None of the neurological examinations between
seizures, the usual clinical biological examinations, or
the neuroradiological examinations (computed tomography [CTf, magnetic resonance imaging [MRI)), revealed abnormalities.
For several days, 4 of the patients were the subject
of EEG recordings (eight bipolar leads according to the
10/20 system, nasal thermistor, electrocardiography
{EKG)) under video control, during 3-hour periods.
Received Dec 28, 1992, and in revised form May 12, 1993. Accepted for publication May 26, 1993.
Copyright 0 1993 by the American Neurological Association
835
day 3. At 18 months, the psychomotor development was
normal.
Patient 4
2
A
The mother of Patients 5 and 6 was born in 1764. O n days
2 and 3 there were seizures described as clonic. No treatment
was given. The interictal EEGs were normal, and no seizure
was recorded. The patient’s psychomotor development was
normal. U p to the age of 28 years, there were no more
seizures. At 28 years old, the EEG was normal with physiological 50- to 100-FV posterior alpha rhythm.
3
O-T-
dr”
m m
5
6
Patient 5
This girl was born on December 12, 1989. Clonic seizures
appeared on day 4.The maximal daily seizure frequency was
10, on day 6. Treatment with phenobarbital, 5 mg . k g - ’ .
d-’, was started on day 6. Seizures stopped by day 14. Initially, on day 4 , the interictal EEG showed sharp alternating
theta rhythms. Thereafter, all interictal EEGs were normal.
No seizure was recorded. Treatment was stopped at 6
months. At 3 years old, the child’s psychomotor development
was normal.
B
F i g 1 Pedzgrees of the two famzlzes. (Ai Famzly T : Patzentj 1 ,
2, and 3. (BI Famzly S: Patzents 4, 5 , and 6.
Patient 2
This woman, born in 1957, mother of Patients 2 and 3,
comes from North Africa. During the first months of life,
she had some rare seizures whose signs have not been identified. No EEG was recorded. She was never treated. Up to
the age of 35 years, there were no more seizures, and the
EEG was normal with larger posterior alpha rhythm.
Putient 6
The brother of Patient 5 was born on January 4 , 1971. Clonic
seizures started on day 2. The maximal daily seizure frequency was 5 to 7, between days 2 to 7. As the outcome of
his untreated mother and of his sister was excellent, and as
every alternative diagnosis had been eliminated, the child was
not treated. The interictal EEGs were normal from days 5 to
90, except on day 7 during which sharp alternating theta
rhythms were recorded. Four electroclinical seizures were
recorded: 1 each on days 5 , 6, 7, and 10. Seizures stopped
on day 11. At 24 months old, the child had a normal development.
Patient 2
This boy was born on June 14, 1790. From day 3, the baby
had seizures with clonia of the four limbs and cyanosis. The
maximal daily seizure frequency was 10, on day 11. Treatment with phenobarbital, 5 mg . kg-l . d-’, was started on
day 8 and stopped at 6 months. Seizures stopped on day 30.
The interictal EEGs were normal between days 3 and 20.
O n days 22 and 29, interictal EEG showed bursts of sharp,
high-amplitude, theta rhythms, alternating with normal lowamplitude background activity. This “theta pointu alternant”
pattern was sometimes asynchronous. Interictal EEGs were
normal thereafter. Six seizures were recorded: 1 on day 3, 2
on day 11, 2 on day 18, and 1 on day 21. At 2% years old,
the psychomotor development was normal.
Patzent 3
The brother of Patient 2 was born on July 15, 1971. O n day
2, the baby had seizures with apnea, cyanosis, tonic contractions, and clonia. The maxlmal d i l y seizure frequency was
4,on day 7. Treatment with phenobarbital, 5 mg kg-’
d-’, was started on day 4 and stopped on day 30. A few
seizures, 1 to 2 per month, persisted until 5 months and then
stopped for good. The interictal EEGs were normal from
days 2 to 120, except on day 45 when there were sharp
alternating theta rhythms Four seizures were recorded on
Seizure Signs and Symptoms
The clinical and EEG signs were very similar for the
14 seizures recorded. The EEG findings are summarized in the Table. Seizures occurred during active
sleep (Figs 2, 3) and were preceded by a short (4to 18second) period of arousal. Seizures started with a brief
generalized EEG flattening for 5 to 19 seconds (Figs
2, 3); simultaneously, there was apnea, tachycardia, and
tonic motor activity, often asymmetrical, with head rotation, abduction or adduction of the upper limbs,
flexion of the hips, and extension of the knees. The
clinical symptoms of the tonic phase varied between
the left and the right from one seizure to the next in
any given child (Fig 4).The EEG flattening was followed by a long generalized discharge, 44 to 146 seconds, of spikes or of sharp waves. In some cases this
discharge started asynchronously; in others it was generalized from the onset (see Figs 2, 3). Simultaneously,
there were vocalizations, chewing, and focal or generalized clonias involving the four limbs, often asymmetrically and asynchronously. Eight of the 14 seizures
ended asymmetrically with unilateral and sometimes
836 Annals of Neurology Vol 34 No 6 December 1993
Electroencephalogruph~cFindings During 14 Seizures in 3 Patients uitb Brnign hleonatal Familial Conzdsions
Patient 2
Patient 3
Patient 6
6
3
4
4
2
2
0
2
No. of EEG seizures recorded
Total EEG-video seizures
Symmetrical EEG seizures
Asymmetrical EEG seizures
R>L
L>R
Mean duration (range) of EEG seizures (sec)
Complete seizure
Flattened EEG
Paroxysmal discharge
1
3
2
1
3
1
2
89.5
(59- 15 5)
14.5
82.5
(62-120)
11.5
(8- 19)
72.5
(47- 105)
R >L
= EEG discharges predominate in the right hemisphere; L > R
EEG = electroencephalographic.
focal spikes; the topography might change from one
seizure to the next in a given child. A stable focus was
never observed (Figs 2, 3). Six seizures ended symmetrically. There was no postictal EEG exhaustion or clinical deficit.
Discussion
In these two families, the development of seizures as
a function of age, and the inherited nature of the condition, identified it as BNFCs. This diagnosis is further
supported by the positive maximum multipoint lod
score calculated with D20S19 and D20S20 (Z = 1.36
at the D20S19 locus).
Our electroclinical observations confirm that the epileptic seizures of BNFCs are very stereotyped, associating successively a brief bilateral flattening of the EEG
with apnea and a tonic phase, then a spike discharge
with a c h i c phase (see Figs 2, 3). By their duration
and by their principal symptoms, the seizures we saw
seem to be identical to those described in the literature
using purely clinical criteria [17, 21, 22). All the seizures we observed started with a tonic phase. This
tonic phase was rarely noted previously; it was so brief,
however, that it might well have been overlooked in
the absence of an EEG-video record.
In our patients, the interictal EEG either was normal
or showed, during one or several days, bursts of sharp
alternating theta rhythms. This “theta pointu alternant”
pattern, which may be present during epileptic seizures
of different etiologies, cannot be considered as specific
to benign idiopathic neonatal convulsions, familial or
nonfamilial { 17, 2 1, 22). Many descriptions of the features of interictal EEG have been reported. Fifty percent of the EEGs were abnormal. Pathological findings,
which included slowing, spike foci, sharp wave discharges, and focal or multifocal abnormalities, were
usually transient 16, 9, 11-15, 17, 21-23]. As yet, no
EEG record of an entire seizure has been published.
(5-19)
78.5
(44-146)
=
11 1.5
(106-137)
12.5
(10-15)
109
(96- 122)
EEG discharges predominate in the left hemisphere
Giroud and colleagues 123) and Camfield and associates 124) recorded the end of a seizure in 2 children
presenting with BNFCs. They noted a rhythmic discharge consisting of sharp waves, focalized or unilateral, which appears to be identical with the discharge
described here in 8 seizures that ended asymmetrically.
In nonfamilial benign idiopathic neonatal convulsions occurring around the fifth day of life, numerous
seizures have been recorded 12 51. The convulsions
were described as clonic and/or apneic but never tonic.
Clonic seizures were often lateralized, starting on one
side, then affecting the other side, and rarely generalized. They lasted from 1 to 3 minutes. The ictal EEG
showed rhythmic spikes or slow waves, lateralized or
generalized. Stable foci were never reported. The lack
of a tonic phase and of initial flattening of the EEG
might be a marker differentiating nonfamilial from familial benign neonatal convulsions. In fact, this initial
phase could be missed: Most of the EEG studies in
nonfamilial neonatal convulsions consisted of longduration recordings at low paper speed (2.5 mmisec)
without video control { 2 5 ) .
From the EEG-video records, are these seizures partial or generalized? The asymmetry of the tonic or clonic motor signs, or both, and the focal or lateralited
EEG abnormalities at the end of some seizures suggest
that they can be diagnosed as partial seizures. The variation, then, of the topography of clinical and EEG
symptoms from one seizure to another in a given child
would imply that the seizures are multifocal. Multifocal
partial seizures are indeed seen during severe symptomatic epilepsies, but also during benign age-related
epilepsies [26, 27).
Other evidence suggests that the seizures are generalized. The initial flattening of the EEG is generalized
from the start, synchronous, and symmetrical. This
flattening is very similar to that seen in certain generalized genetic animal epilepsies [28-30). In these modHirsch et al: Neonatal Familial Convulsions
837
A
1 B 2
Fi g 2. Electroencephalographicseizure recorded in Patient 3 on
day 3 ithe t w o parts of the figure are continuous; 7 secorzds of
clonic seizure were removed between C and DI. A = arousal; B
= tonic seizure onset; C = clonic seizure onset: D = ldt focal
sharp waves (leJt discharge continues for 19 seconds). For explanation of I , 2 , and 3. see behavioral concomitants in Fig 4.
Calibrations: 100 p V , 2 seconds.
838 Annals of Neurology Vol 34 No 6 December 1993
3
FP2C4
c4-02
TM4
CMZ
czx3
C3-T3
FP1-C)
C3-01
ECC
Fig 3. Electroencephalographic seizure recorded in Patient .3 on
day 3. A = arousal; B = tonic seizure onset; C = clonic seizure onset; D = rigbt focal sharp waves (right discharge continues for 56 seconds). For explanation of 4, 5, and 6 , see bebavioral concomitants i n F i g 4. Calibrations: 100 p V , 2 seconds.
els, the flattening of the cortical EEG appears to correspond to the activation of diverse brainstem structures.
The successive symptoms of BNFCs-tonic phase,
apnea, clonic phase-are identical to those described
for generalized tonic-chic seizures recorded in children or adults with generalized idiopathic epilepsy, in
which the initial tonic phase may often be asymmetrical
and induce rotation of the head or the body axis {26,
31). The provocative role of arousal has also been observed in generalized epileptic seizures (grand mal seizures on awakening, benign juvenile myoclonic epilepsy, etc.) 12, 267. If we are dealing with a generalized
epilepsy, the asymmetrical character of some of the
clinical and EEG signs might be explained by the absence of maturation of the corpus callosum during the
first weeks of life [32]. This structure ensures the synchronization of the EEG discharges in numerous human or experimental generalized epilepsies [337.
A final characteristic of BNFCs is the absence of any
postictal phase. This absence of clinical deficit or EEG
exhaustion may perhaps be linked with the fact that
BNFCs do not seem to induce cerebral lesions. Even
a high number of seizures have no effect on the patient’s later development [21, 22). For patients described in the literature, as well as our own, the longterm prospects are usually excellent. The outcome of
our 6 patients was favorable whether or not treatment
was given (see case reports for Patients 1, 4 , and 6).
Similarly, observations made on different animal models of epilepsy have shown that a status epilepticus does
not induce cerebral lesions in the newborn, whereas it
does in the older animal [34, 351. These clinical and
experimental results suggest that there may be little
reason to institute a heavy therapeutic schedule when
BNFCs have been diagnosed with certainty 112, 21,
221.
In conclusion, this study confirms that the epileptic
seizures of BNFCs are very stereotyped. The electroclinical picture argues in favor of the generalized
nature of the seizures and justifies the classlfication of
BNFCs among the generalized idiopathic epilepsies.
The EEG and clinical expression of the seizures can
sometimes be asymmetrical, probably because of the
immaturity of the corpus callosum or other structures
ensuring discharge synchronization.
Hirsch et al: Neonatal Familial Convulsions
839
Fig 4. Behavioral concomitants during two seizures recorded in
Patient 3 on ahy 3 . First seizure (see Fig 2): 1 = arousal reaction; 2 and 3 = tonic bead rotation to the left. Second seizure
(see Fig 3): 4, 5 , and 6 = tonic bead rotation to the right.
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Hirsch et al: Neonatal Familial Convulsions
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