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Aortogenic embolism is a possible mechanism of cryptogenic stroke.

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LETTERS
Genetic Variation of CACNA1H in Idiopathic
Generalized Epilepsy
Sarah E. Heron, BSc (Hons),1 Hilary A. Phillips, BSc,1
John C. Mulley, PhD,1 Aziz Mazarib, MD,2
Miriam Y. Neufeld, MD,2 Samuel F. Berkovic, MD,3
and Ingrid E. Scheffer, MD, PhD3,4
In a recent report, Chen and colleagues1 described 12 putative mutations in the T-type calcium channel gene
CACNA1H in 14 of 118 patients with childhood absence
epilepsy (CAE), and concluded that missense mutations in
this gene may predispose to CAE. To investigate variation of
CACNA1H in our patient population, we screened exons 9
to 11, in which 75% of the putative mutations described by
Chen and colleagues are located, in 192 patients (134 unrelated) with idiopathic generalized epilepsies or generalized
epilepsy with febrile seizures plus. This group included 34
CAE and 15 juvenile absence epilepsy patients.
The study was approved by the ethics committees of the
Women’s and Children’s Hospital and Austin Health. Informed consent was obtained from participants. DNA was
amplified by polymerase chain reaction and screened for variation by single-stranded conformation analysis. Sequencing
was performed using ABI BigDye v3.0 on the ABI 3700 instrument. Ninety-six control samples were screened for variants identified in patients. When a variant was present in a
patient and not in controls, available members of the patient’s family were tested for the variant.
Four variants were present only in patients. These were
c.1438G3 A (A480T); c.1853C3 T (P618L); c.18571858del (V621fsX654), and c.2264G3 A (G755D). The inheritance of these changes in the families is shown in the
Figure. None of these variants was found in CAE or juvenile
absence epilepsy patients.
None of the four variants segregate with a specific epilepsy
phenotype in each family, nor is their presence associated with
any one phenotype. There are two instances in which siblings
with the same phenotype are discordant for a variant, and all
four variants are present in unaffected individuals.
Our failure to replicate the findings of Chen and colleagues in absence phenotypes in our patient population suggests that the significance of CACNA1H variants in the cause
of human epilepsy remains unclear. Moreover, functional
data are required for all CACNA1H variants before their role
in epilepsy is established.
Generalized epilepsies are likely to be polygenic in origin,
with variations in multiple ion-channel subunits or other
genes interacting to cause epileptogenesis.2 For example, a
mutation of GABRG2 has been found previously in three
members of Family E and it is probable that several genes
Fig. Pedigrees of families with CACNA1H variants. Individuals with the variant are indicated by an asterisk, and individuals who tested negative for the variant are indicated by a
minus sign. The variants in the families are Family A,
A480T; Families B and C, P618L; Family D, c.18571858del; Family E, G755D. Members of Family E shown
here are III:21-22, IV:33-37, and V:58-68 on the pedigree
described by Harkin and colleagues.3 Twelve other members of
Family E tested were negative for the G755D variant.
‹
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
595
contribute to the various phenotypes in this family.3 Even if
variation in CACNA1H is a contributing factor in generalized epilepsy syndromes, its effect size is likely to be small.
Note Added in Proof
Khosravhani and colleagues (“Gating effects of mutations in the Cav3.2 T-type calcium channel associated
with childhood absence epilepsy” J Biol Chem Jan 2004;
DOI: 10.1074/jbc.C400006200) recently studied 5 of
the 12 putative mutations reported by Chen and colleagues1, finding changes to channel properties in 3 mutations which were consistent with epileptogenesis.
The study was supported by National Health and Medical Research
Council of Australia Program Grants (207703, J.C.M.; 144105,
S.F.B., I.E.S.).
We thank the patients for their participation.
From the 1Department of Genetic Medicine, Women’s and
Children’s Hospital, North Adelaide, South Australia,
Australia; 2Department of Neurology, Tel-Aviv Sourasky
Medical Center, Tel-Aviv, Israel; 3Epilepsy Research Centre
and Department of Medicine (Neurology), University of
Melbourne, Austin Health; and 4Departments of Neurology,
Monash Medical Centre and Royal Children’s Hospital,
Melbourne, Victoria, Australia
References
1. Chen Y, Lu J, Pan H, et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol
2003;54:239 –243.
2. Gargus JJ. Unraveling monogenic channelopathies and their implications for complex polygenic disease. Am J Hum Genet
2003;72:785– 803.
3. Harkin LA, Bowser DN, Dibbens LM, et al. Truncation of the
GABAA-receptor ␥2 subunit in a family with generalized epilepsy
with febrile seizures plus. Am J Hum Genet 2002;70:530 –536.
variations within the temporal lobe and variations in distribution of neurons between deep and subcortical temporal lobe
white matter; (2) the sampling strategy for the area studied
quantitatively: random, or areas containing most or least frequent white matter neurons; (3) the number of fields or sections and blocks analyzed in each case; (4) the actual extent of
area (eg, in square micrometers) studied: the use of the term
“high-power field (⫻400)” is insufficient, the microscope used
is not specified, and the term is not readily translated to other
microscopes and laboratories; (5) whether the same areas were
assessed by the two neuropathologists; (6) the actual inter- and
intrarater count reproducibility; (7) slice thickness (not stated
in either article): this will naturally influence the number of
neurons seen per visual field in two dimensions; and (8) why
smaller neurons were not counted (eg, identified using NeuN
staining).
Furthermore, as the diagnosis and significance of MD remains controversial, it is important not only to try to delineate the malformation accurately, but also to establish valid
clinical correlations. No correlations were found between
MD features and clinical parameters, and the authors suggest
that MD is unlikely to play any important role for the development of hippocampal sclerosis and that MD is not associated with a strong genetic basis. It must, however, be
pointed out that the group studied is only 24 patients (five
of whom had short follow-up), making it unlikely that any
statistically significant differences between fractions of the
group could be found. In addition, the patients were selected
from a group of 200 patients and such selection may introduce bias. Finally, 58% of the specimens displayed a disturbance in neuronal distribution. This is a remarkably high
figure for epilepsy surgery material, which might, contrary to
what the authors claim, indicate that MD might play a
pathogenetic role in mesial temporal lobe epilepsy.
MD may or may not turn out to have significance in epilepsy, but to establish this future studies must include larger
series examined using stringent morphological and stereological criteria.
1
DOI: 10.1002/ana.20028
Microdysgenesis in Mesial Temporal Lobe
Epilepsy
Department of Clinical and Experimental Epilepsy, Institute
of Neurology, University College London, London, United
Kingdom; 2 Institute of Clinical Neuroscience, Epilepsy
Research Group; and 3Institute of Laboratory Medicine,
Department of Pathology, Sahlgrenska University Hospital,
Göteborg, Sweden
Sofia H. Eriksson, MD, PhD,1,2
Claes Nordborg, MD, PhD,3 Maria Thom, FRCPath,1
and Sanjay M. Sisodiya, MRCP, PhD1
References
Kasper and colleagues report a study of microdysgenesis in
mesial temporal lobe epilepsy.1
The diagnostic criteria for microdysgenesis (MD), and its
functional significance, if any, in epileptogenesis have been debated since its first description.2– 6 This debate highlights the
need for robust reproducible studies. There are important
methodological points about this study. We appreciate the importance of quantification of the findings, but if quantification
is to be more useful than visual inspection alone, it has to be
performed using strict and reproducible methods.6 In the article by Kasper and colleagues, and the original article outlining the methods,7 many facts are not stated: (1) the region of
temporal lobe analyzed: there are significant cytoarchitectonic
1. Kasper BS, Stefan H, Paulus W. Microdysgenesis in mesial temporal lobe epilepsy: a clinicopathological study. Ann Neurol
2003;54:501–506.
2. Meencke H-J, Janz D. Neuropathological findings in primary generalized epilepsy: a study of eight cases. Epilepsia 1984;25:8 –21.
3. Lyon G, Gastaut H. Considerations on the significance attributed to unusual cerebral histological findings recently described
in eight patients with primary generalized epilepsy. Epilepsia
1985;26:365–367.
4. Opeskin K, Kalnins RM, Halliday G, et al. Idiopathic generalized epilepsy. Lack of significant microdysgenesis. Neurology
2000;55:1101–1106.
5. Bothwell S, Meredith GE, Phillips J, et al. Neuronal hypertrophy
in neocortex of patients with temporal lobe epilepsy. J Neurosci
2001;21:4789 – 4800.
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6. Thom M, Sisodiya SM, Harkness W, et al. Microdysgenesis in
temporal lobe epilepsy. A quantitative and immunohistochemical
study of white matter neurones. Brain 2001;124:2299 –2309.
7. Kasper BS, Stefan H, Buchfelder M, et al. Temporal lobe microdysgenesis in epilepsy versus control brains. J Neuropathol
Exp Neurol 1999;58:22–28.
DOI: 10.1002/ana.20056
Reply
Burkhard S. Kasper, MD
We thank Eriksson and colleagues for their interest in our
study.1 We are happy to provide the technical details they request. The material submitted by the neurosurgeon was completely processed, but unequivocal topographical identification
was not possible. Five to 12 blocks per case were analyzed and
maximum values were used for statistical analysis. The microscopic high-power field used encompassed 0.29mm2. Thickness of paraffin sections was 5␮m. Histological features were
evaluated by two observers using a multiheaded microscope, a
technique that minimizes errors but is not appropriate for calculating inter- or intrarater reliabilities. We have counted only
large neurons, because they are easily and unequivocally identified using standard hematoxylin and eosin stains. Our original definitions of microdysgenesis (MD)2 that have been used
here are based on routine techniques, because more elaborate
techniques are prone to introduce variation within and among
laboratories.
We are grateful that Eriksson and colleagues have stressed
the primary focus of our study; that is, it is important to
analyze possible clinical correlates of MD. We feel that this
goal can best be achieved by testing hypotheses after selecting
homogeneous subgroups. In our view, mixing up heterogeneous patient groups including different epileptogenic lesions
and various topographic cortical areas has been misleading so
far. The highly selected sample of 24 patients with mesial
temporal lobe epilepsy (MTLE) analyzed in our study is
small but homogeneous, and it is larger than in other studies
addressing the clinical significance of MD, which occasionally have been based on a single case.3
The presence of MD is widely used as an argument supporting a maldevelopmental hypothesis of hippocampal
sclerosis and MTLE. However, we have found that MD
features were not linked with each other and did not correlate to clinical parameters in MTLE.1 Furthermore, some
of the features referred to as MD represent virtually normal
cytoarchitectonic findings,2 whereas the remaining tissue
features were observed in a minority of our cases.1 We thus
do not understand how the percentage of 58% of cases
with architectonic disturbance was extracted by Eriksson
and colleagues from our material. Notwithstanding these
minor inaccuracies, we concur with Eriksson and colleagues
that current evidence suggests that MD features are seen in
MTLE specimens, although their pathogenetic basis and
clinical significance are still unknown. No study, including
ours, has found convincing evidence that MD does have a
dysplastic origin. The term microdysgenesis therefore should
be used with caution.
Department of Neurology, University of Erlangen Epilepsy
Center, Erlangen, Germany
References
1. Kasper BS, Stefan H, Paulus W. Microdysgenesis in mesial temporal lobe epilepsy: a clinicopathological study. Ann Neurol
2003;54:501–506.
2. Kasper BS, Stefan H, Buchfelder M, Paulus W. Temporal lobe
microdysgenesis in epilepsy versus control brains. J Neuropathol
Exp Neurol 1999;58:22–28.
3. Eriksson SH, Rydenhag B, Uvebrant P, et al. Widespread microdysgenesis in therapy-resistant epilepsy—a case report on
post-mortem findings. Acta Neuropathol 2002;103:74 –77.
DOI: 10.1002/ana.20067
Meningitis-Associated Hearing Loss: Protection by
Adjunctive Antioxidant Therapy
Diederik van de Beek, MD, and Jan de Gans, PhD
In the October issue, Klein and colleagues presented data
on adjunctive antioxidant therapy for the prevention of
meningitis-induced hearing impairment.1 Although the results are interesting, we disagree with their statement that
the effect of adjunctive dexamethasone on hearing loss is
questionable. A recent Cochrane meta-analysis including
1,853 patients showed that corticosteroids reduced severe
hearing loss in childhood bacterial meningitis caused by
Haemophilus influenzae (relative risk, 0.31; 95% confidence
interval, 0.15– 0.62), as well as in meningitis caused by
other bacteria than H. influenzae (relative risk, 0.42; 95%
confidence interval, 0.20 – 0.89).2 Although the two most
recent clinical trials were not included in this meta-analysis,
the beneficial effect is not questioned by the results of these
trials. The Malawian study included mainly children in
whom treatment began late, human immunodeficiency virus–positive children, and children receiving inappropriate
antibiotic therapy.3 Therefore, the results are not representative for patients with bacterial meningitis in developed
countries. In the European trial, dexamethasone reduced
mortality from 17 of 50 patients (34%) with pneumococcal
meningitis in the placebo group to 8 of 58 patients (14%)
in the dexamethasone group (relative risk, 0.41; 95% confidence interval, 0.19 – 0.86).4 Although no significant beneficial effect on hearing loss was found in patients with
pneumococcal meningitis (relative risk, 0.67; 95% confidence interval, 0.25–1.69), neurological sequelae, including
hearing loss, were predominately found in the most severely
ill patients, and the proportion of severely ill patients who
survived to be tested was substantially larger in dexamethasone group than in the placebo group.
Department of Neurology, Academic Medical Center,
University of Amsterdam, Amsterdam, The Netherlands
References
1. Klein M, Koedel U, Pfister HW, Kastenbauer S. Meningitisassociated hearing loss: protection by adjunctive antioxidant therapy. Ann Neurol 2003;54:451– 458.
2. Van de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids in acute bacterial meningitis. The Cochrane Library.
Chichester, UK: John Wiley & Sons, Ltd. Issue 4; 2003.
Annals of Neurology
Vol 55
No 4
April 2004
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3. Molyneux EM, Walsh AL, Forsyth H, et al. Dexamethasone
treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet 2002;360:211–218.
4. De Gans J, Van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549 –1556.
DOI: 10.1002/ana.20059
Reply
Stefan Kastenbauer, MD, Matthias Klein,
Uwe Koedel, MD, and Hans-Walter Pfister, MD
By commenting on the introductory section of our article,1
van de Beek and de Gans have entered into the discussion
about the role of dexamethasone in the therapy of bacterial
meningitis. Their recent article signaled a substantial progress
in the management of bacterial meningitis in adults, because it
clearly demonstrated that mortality is reduced by dexamethasone pretreatment.2 However, there are still several unresolved
problems, for example, there is no established adjunctive posttreatment regimen (ie, after administration of antibiotics), and
the mortality of pneumococcal meningitis (14%) and the
prevalence of long-term focal neurological deficits (22%) and
hearing loss (14%) are still unacceptably high despite dexamethasone pretreatment.2 Therefore, more effective adjunctive
pre- and posttreatment regimens are needed and N-acetyl-Lcysteine (NAC) is a promising candidate because five experimental studies using different animal models and experimental
designs reported a protective effect of NAC against the development of meningitis-associated cerebral and cochlear complications.1,3– 6 Because NAC is well tolerated and in wide clinical use, a clinical study evaluating it for the adjunctive therapy
of bacterial meningitis appears feasible.
In their letter, van de Beek and de Gans argue that hearing loss was predominantly found in the most severely ill
patients. In 87 adults with pneumococcal meningitis from
our department,7 hearing loss was detected in 17 of 66 survivors. Even when all fatal cases are excluded from the analysis (because hearing assessment usually was performed only
after recovery and thus not in fatal cases), lower Glasgow
Coma Scores on admission (GCSA) were not associated with
hearing loss (mean GCSA ⫾ SD: 10.0 ⫾ 2.7 in 17 survivors
with hearing loss vs 11.5 ⫾ 3.3 in 49 survivors without hearing loss, not significant). Furthermore, in their article, de
Gans and van de Beek did not report how (cerebral vs extracerebral complications) dexamethasone reduced the mortality rates.2 A better understanding of the mechanism of action of adjunctive corticosteroids also would make the
interpretation of their effect on hearing impairment easier.
Without the necessary data, however, the statement that the
reduction of mortality by dexamethasone masked its beneficial effect on hearing because more severely ill patients survived to be tested remains in the realm of speculation.
Department of Neurology, Klinikum Grosshadern,
Ludwig-Maximilians University, Munich, Germany
References
1. Klein M, Koedel U, Pfister H-W, et al. Meningitis-associated
hearing loss: protection by adjunctive antioxidant therapy. Ann
Neurol 2003;54:451– 458.
598
Annals of Neurology
Vol 55
No 4
April 2004
2. De Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549 –1556.
3. Koedel U, Pfister HW. Protective effect of the antioxidant
N-acetyl-L-cysteine in pneumococcal meningitis in the rat. Neurosci Lett 1997;225:33–36.
4. Auer M, Pfister LA, Leppert D, et al. Effects of clinically used
antioxidants in experimental pneumococcal meningitis. J Infect
Dis 2000;182:347–350.
5. Christen S, Schaper M, Lykkesfeldt J, et al. Oxidative stress in
brain during experimental bacterial meningitis: differential effects
of alpha-phenyl-tert-butyl nitrone and N-acetylcysteine treatment. Free Radic Biol Med 2001;31:754 –762.
6. Schaper M, Gergely S, Lykkesfeldt J, et al. Cerebral vasculature
is the major target of oxidative protein alterations in bacterial
meningitis. J Neuropathol Exp Neurol 2002;61:605– 613.
7. Kastenbauer S, Pfister HW. Pneumococcal meningitis in adults:
spectrum of complications and prognostic factors in a series of
87 cases. Brain 2003;126:1015–1025.
DOI: 10.1002/ana.20058
Aortogenic Embolism Is a Possible Mechanism of
Cryptogenic Stroke
Kazuo Kitagawa, MD
I read with great interest the recent article by Bang and colleagues demonstrating the frequency and mechanisms of
stroke recurrence after cryptogenic stroke.1 They suggested
that occlusive lesions other than significant stenosis of relevant artery may play an important role in the stroke recurrence in patients with cryptogenic stroke, the stroke with no
determined cause. On the basis of clinical findings, brain
magnetic resonance imaging (MRI) and angiography, carotid
duplex, echocardiogram, and routine blood tests, they divided patients into large artery disease, cardioembolism,
small artery disease, and no determined cause categories. In
the discussion, they mentioned that more extensive studies
should be performed to document possible embolism due to
patent foramen ovale and paradoxical embolism with transesophageal echocardiography (TEE). Although Bang and colleagues did not mention it, I want to add aortogenic embolism as a frequent cause for cryptogenic stroke. Amarenco
and colleageus2 and Toyoda and colleageus3 previously demonstrated significant incidence of aortic complex lesion, a potential embolic source, in ischemic stroke patients with no
determined cause. In our consecutive 147 patients with ischemic cerebrovascular disease including ischemic stroke and
transient ischemic attacks, 56 patients had aortic complex lesion defined as an aortic intimamedia thickness (IMT)
greater than 4mm, mobile plaque, and/or ulcers.4 Carotid
IMT, evaluated by carotid duplex, was closely associated
with aortic IMT. Each one standard deviation greater carotid
IMT was associated with 4.2-fold higher likelihood of complex aortic lesions. Our results together with others’5 clearly
demonstrated that the patients with mild carotid atherosclerosis were likely to have aortic complex lesions as an embolic
source. Therefore, I recommend examination of aortic arch
with TEE or MRI in patients with cryptogenic stroke especially when mild stenosis (⬍50%) is found in extracranial
and/or intracranial cerebral artery.
Division of Stroke Research, Department of Internal Medicine
and Therapeutics, Osaka University Graduate School of
Medicine, Osaka, Japan
References
1. Bang OY, Lee PH, Joo SY, et al. Frequency and mechanisms of
stroke recurrence after cryptogenic stroke. Ann Neurol 2003;54:
227–234.
2. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease
of the aortic arch and the risk of ischemic stroke. N Engl J Med
1994;331:1474 –1479.
3. Toyoda K, Yasaka M, Nagata S, Yamaguchi T. Aortogenic embolic stroke: a transesophageal echocardiographic approach.
Stroke 1992;23:1056 –1061.
4. Shimizu Y, Kitagawa K, Nagai Y, et al. Carotid athyerosclerosis
as a risk factor for complex aortic lesions in patients with ischemic cerebrovascular disease. Circ J 2003;67:597– 600.
5. Kallikazaros IE, Tsioufis CP, Stefanadis CI, et al. Closed relation
between carotid and ascending aortic atherosclerosis in cardiac
patients. Circulation 2000;102:III-263–III-268.
DOI: 10.1002/ana.20073
Monitoring ␥-Hydroxybutyric Acid Levels in
Succinate-Semialdehyde Dehydrogenase Deficiency
Phillip L. Pearl, MD, and Andrea Gropman, MD
We read with interest the report by Ergezinger and colleagues1 describing successful treatment using low-dose vigabatrin of a 10-year-old girl with succinate-semialdehyde dehydrogenase (SSADH) deficiency, in parallel with decreased
␥-hydroxybutyric acid (GHB) levels in physiological fluids.
This is a significant issue, because this rare pediatric neurotransmitter disorder has profound clinical ramifications, and
any biomarkers to predict and follow the course of therapy
would be most welcome.
We question the authors’ opinion as to the increase in
GHB levels between the measurements at ages 7 7/12 and 9
years. The levels return to the pathological range and even
exceed the pretreatment range in urine. The case report
shows no change in clinical management, including vigabatrin dosage, during that interval. The pathological increases
remain throughout the follow-up period.
There appears to be an increasing clinical spectrum to
SSADH deficiency,2 as well as structural and functional imaging abnormalities that may serve as surrogate biomarkers of
disease progression.3 Although cerebrospinal fluid levels of
GHB have been reported to decrease by as much as 70%
from pretreatment levels,4 neither laboratory or clinical effects have been consistent with vigabatrin therapy.5 Whereas
clinical improvement was sustained in the authors’ case despite return to high elevations of this metabolite, it is difficult to assess the utility of this biomarker as a useful laboratory parameter. Such efforts are particularly difficult without
more information on the natural history of the disorder.
Department of Neurology, Children’s National Medical
Center, George Washington University School of Medicine,
Washington, DC
References
1. Ergezinger K, Jeschke R, Frauendienst-Egger G, et al. Monitoring of 4-hydroxybutyric acid levels in body fluids during vigabatrin treatment in succinic semialdehyde dehydrogenase deficiency. Ann Neurol 2003;54:686 – 689.
2. Pearl PL, Acosta MT, Gibson KM, et al. Clinical spectrum of
succinic semialdehyde dehydrogenase deficiency. Neurology
2003;60:1413–1417.
3. Pearl PL, Novotny EJ, Acosta MT, et al. Succinic semialdehyde
dehydrogenase deficiency in children and adults. Ann Neurol
2003;54(suppl 6):S73–S80.
4. Jaeken J, Casaer P, deCock P, Francois B. Vigabatrin in GABA
metabolism disorders. Lancet 1989;1:1074.
5. Gropman A. Vigabatrin and newer interventions in succinic
semialdehyde dehydrogenase deficiency. Ann Neurol 2003;
54(suppl 6):S66 –S72.
DOI: 10.1002/ana.20084
Reply
Katrin Ergezinger, MD,1 and Volker H. Schuster, MD2
We reported successful treatment of a 10-year-old girl with
succinate-semialdehyde dehydrogenase (SSADH) deficiency
using low-dose vigabatrin. The authors question our view concerning the increase in ␥-hydroxybutyric acid (GHB) levels
between the measurements at ages 7 7/12 , 9, and 10 years.
At age 7 7/12 years GHB was at its lowest level in serum,
urine, and cerebrospinal under treatment with 800mg vigabatrin
per day. The next measurements were performed 17 months
later at age 9 years, with the vigabatrin dose held constant. At
this time, very high levels of GHB in serum and urine were
observed. Because there had been further clinical improvement,
we decided not to alter treatment until a further specimen was
obtained 2 months later. Furthermore, there was the potential
for noncompliance. After the first seizure in our patient at age 9
3/12 years, vigabatrin dose was increased to 1,000mg per day.
GHB levels in serum and urine decreased markedly within 1
month. Still, the GHB levels were high in comparison with the
levels observed in the preceding 3.5 years.
The exact pathophysiology of SSADH deficiency remains
obscure, and it is unknown whether excess GABA and/or
GHB contribute to the variable disease phenotype. In some
cases, laboratory and clinical effects have been inconsistent
with vigabatrin therapy.1 In our patient, there was a good
correlation between the decrease of GHB in physiological
fluids and clinical improvement during the first 30 months
of therapy. At this time, we have no rational explanation for
the higher GHB levels in the final year of treatment, but the
potential for enzyme tolerance after long-term application of
vigabatrin remains a possibility.
We appreciate the insightful comments from Drs Pearl
and Gropman but feel that until such time as other, perhaps
more appropriate, biomarkers are available that it is worthwhile to monitor GHB levels in patients with SSADH deficiency undergoing vigabatrin intervention.
1
Allergieklinik Davos, Switzerland; and 2Children’s Hospital,
University of Leipzig, Leipzig, Germany
Reference
1. Gibson KM, De Vivo DC, Jakobs C. Vigabatrin therapy in patients with succinic semialdehyde dehydrogenase deficiency. Lancet 1989;2:1105–1106.
DOI: 10.1002/ana.20080
Annals of Neurology
Vol 55
No 4
April 2004
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