Genetic Variation of CACNA1H in IdiopathicGeneralized EpilepsySarah 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 puta-tive mutations in the T-type calcium channel geneCACNA1H in 14 of 118 patients with childhood absenceepilepsy (CAE), and concluded that missense mutations inthis gene may predispose to CAE. To investigate variation ofCACNA1H in our patient population, we screened exons 9to 11, in which 75% of the putative mutations described byChen and colleagues are located, in 192 patients (134 unre-lated) with idiopathic generalized epilepsies or generalizedepilepsy with febrile seizures plus. This group included 34CAE and 15 juvenile absence epilepsy patients.

The study was approved by the ethics committees of theWomen’s and Children’s Hospital and Austin Health. In-formed consent was obtained from participants. DNA wasamplified by polymerase chain reaction and screened for vari-ation by single-stranded conformation analysis. Sequencingwas performed using ABI BigDye v3.0 on the ABI 3700 in-strument. Ninety-six control samples were screened for vari-ants identified in patients. When a variant was present in apatient and not in controls, available members of the pa-tient’s family were tested for the variant.

Four variants were present only in patients. These werec.1438G3A (A480T); c.1853C3T (P618L); c.1857-1858del (V621fsX654), and c.2264G3A (G755D). The in-heritance of these changes in the families is shown in theFigure. None of these variants was found in CAE or juvenileabsence epilepsy patients.

None of the four variants segregate with a specific epilepsyphenotype in each family, nor is their presence associated withany one phenotype. There are two instances in which siblingswith the same phenotype are discordant for a variant, and allfour variants are present in unaffected individuals.

Our failure to replicate the findings of Chen and col-leagues in absence phenotypes in our patient population sug-gests that the significance of CACNA1H variants in the causeof human epilepsy remains unclear. Moreover, functionaldata are required for all CACNA1H variants before their rolein epilepsy is established.

Generalized epilepsies are likely to be polygenic in origin,with variations in multiple ion-channel subunits or othergenes interacting to cause epileptogenesis.2 For example, amutation of GABRG2 has been found previously in threemembers of Family E and it is probable that several genes

Fig. Pedigrees of families with CACNA1H variants. Individ-uals with the variant are indicated by an asterisk, and indi-viduals who tested negative for the variant are indicated by aminus sign. The variants in the families are Family A,A480T; Families B and C, P618L; Family D, c.1857-1858del; Family E, G755D. Members of Family E shownhere are III:21-22, IV:33-37, and V:58-68 on the pedigreedescribed by Harkin and colleagues.3 Twelve other members ofFamily E tested were negative for the G755D variant.

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LETTERS

© 2004 American Neurological Association 595Published by Wiley-Liss, Inc., through Wiley Subscription Services

contribute to the various phenotypes in this family.3 Even ifvariation in CACNA1H is a contributing factor in general-ized epilepsy syndromes, its effect size is likely to be small.

Note Added in ProofKhosravhani and colleagues (“Gating effects of muta-tions in the Cav3.2 T-type calcium channel associatedwith childhood absence epilepsy” J Biol Chem Jan 2004;DOI: 10.1074/jbc.C400006200) recently studied 5 ofthe 12 putative mutations reported by Chen and col-leagues1, finding changes to channel properties in 3 mu-tations which were consistent with epileptogenesis.

The study was supported by National Health and Medical ResearchCouncil 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 andChildren’s Hospital, North Adelaide, South Australia,Australia; 2Department of Neurology, Tel-Aviv SouraskyMedical Center, Tel-Aviv, Israel; 3Epilepsy Research Centreand Department of Medicine (Neurology), University ofMelbourne, Austin Health; and 4Departments of Neurology,Monash Medical Centre and Royal Children’s Hospital,Melbourne, Victoria, Australia

References1. Chen Y, Lu J, Pan H, et al. Association between genetic varia-

tion of CACNA1H and childhood absence epilepsy. Ann Neurol2003;54:239–243.

2. Gargus JJ. Unraveling monogenic channelopathies and their im-plications for complex polygenic disease. Am J Hum Genet2003;72:785–803.

3. Harkin LA, Bowser DN, Dibbens LM, et al. Truncation of theGABAA-receptor �2 subunit in a family with generalized epilepsywith febrile seizures plus. Am J Hum Genet 2002;70:530–536.

DOI: 10.1002/ana.20028

Microdysgenesis in Mesial Temporal LobeEpilepsySofia H. Eriksson, MD, PhD,1,2

Claes Nordborg, MD, PhD,3 Maria Thom, FRCPath,1

and Sanjay M. Sisodiya, MRCP, PhD1

Kasper and colleagues report a study of microdysgenesis inmesial temporal lobe epilepsy.1

The diagnostic criteria for microdysgenesis (MD), and itsfunctional significance, if any, in epileptogenesis have been de-bated since its first description.2–6 This debate highlights theneed for robust reproducible studies. There are importantmethodological points about this study. We appreciate the im-portance of quantification of the findings, but if quantificationis to be more useful than visual inspection alone, it has to beperformed using strict and reproducible methods.6 In the ar-ticle by Kasper and colleagues, and the original article outlin-ing the methods,7 many facts are not stated: (1) the region oftemporal lobe analyzed: there are significant cytoarchitectonic

variations within the temporal lobe and variations in distribu-tion of neurons between deep and subcortical temporal lobewhite matter; (2) the sampling strategy for the area studiedquantitatively: random, or areas containing most or least fre-quent white matter neurons; (3) the number of fields or sec-tions and blocks analyzed in each case; (4) the actual extent ofarea (eg, in square micrometers) studied: the use of the term“high-power field (�400)” is insufficient, the microscope usedis not specified, and the term is not readily translated to othermicroscopes and laboratories; (5) whether the same areas wereassessed by the two neuropathologists; (6) the actual inter- andintrarater count reproducibility; (7) slice thickness (not statedin either article): this will naturally influence the number ofneurons seen per visual field in two dimensions; and (8) whysmaller neurons were not counted (eg, identified using NeuNstaining).

Furthermore, as the diagnosis and significance of MD re-mains controversial, it is important not only to try to delin-eate the malformation accurately, but also to establish validclinical correlations. No correlations were found betweenMD features and clinical parameters, and the authors suggestthat MD is unlikely to play any important role for the de-velopment of hippocampal sclerosis and that MD is not as-sociated with a strong genetic basis. It must, however, bepointed out that the group studied is only 24 patients (fiveof whom had short follow-up), making it unlikely that anystatistically significant differences between fractions of thegroup could be found. In addition, the patients were selectedfrom a group of 200 patients and such selection may intro-duce bias. Finally, 58% of the specimens displayed a distur-bance in neuronal distribution. This is a remarkably highfigure for epilepsy surgery material, which might, contrary towhat the authors claim, indicate that MD might play apathogenetic role in mesial temporal lobe epilepsy.

MD may or may not turn out to have significance in ep-ilepsy, but to establish this future studies must include largerseries examined using stringent morphological and stereologi-cal criteria.

1Department of Clinical and Experimental Epilepsy, Instituteof Neurology, University College London, London, UnitedKingdom; 2 Institute of Clinical Neuroscience, EpilepsyResearch Group; and 3Institute of Laboratory Medicine,Department of Pathology, Sahlgrenska University Hospital,Goteborg, Sweden

References1. Kasper BS, Stefan H, Paulus W. Microdysgenesis in mesial tem-

poral lobe epilepsy: a clinicopathological study. Ann Neurol2003;54:501–506.

2. Meencke H-J, Janz D. Neuropathological findings in primary gen-eralized epilepsy: a study of eight cases. Epilepsia 1984;25:8–21.

3. Lyon G, Gastaut H. Considerations on the significance attrib-uted to unusual cerebral histological findings recently describedin eight patients with primary generalized epilepsy. Epilepsia1985;26:365–367.

4. Opeskin K, Kalnins RM, Halliday G, et al. Idiopathic general-ized epilepsy. Lack of significant microdysgenesis. Neurology2000;55:1101–1106.

5. Bothwell S, Meredith GE, Phillips J, et al. Neuronal hypertrophyin neocortex of patients with temporal lobe epilepsy. J Neurosci2001;21:4789–4800.

596 Annals of Neurology Vol 55 No 4 April 2004

6. Thom M, Sisodiya SM, Harkness W, et al. Microdysgenesis intemporal lobe epilepsy. A quantitative and immunohistochemicalstudy of white matter neurones. Brain 2001;124:2299–2309.

7. Kasper BS, Stefan H, Buchfelder M, et al. Temporal lobe mi-crodysgenesis in epilepsy versus control brains. J NeuropatholExp Neurol 1999;58:22–28.

DOI: 10.1002/ana.20056

ReplyBurkhard S. Kasper, MD

We thank Eriksson and colleagues for their interest in ourstudy.1 We are happy to provide the technical details they re-quest. The material submitted by the neurosurgeon was com-pletely processed, but unequivocal topographical identificationwas not possible. Five to 12 blocks per case were analyzed andmaximum values were used for statistical analysis. The micro-scopic high-power field used encompassed 0.29mm2. Thick-ness of paraffin sections was 5�m. Histological features wereevaluated by two observers using a multiheaded microscope, atechnique that minimizes errors but is not appropriate for cal-culating inter- or intrarater reliabilities. We have counted onlylarge neurons, because they are easily and unequivocally iden-tified using standard hematoxylin and eosin stains. Our origi-nal definitions of microdysgenesis (MD)2 that have been usedhere are based on routine techniques, because more elaboratetechniques are prone to introduce variation within and amonglaboratories.

We are grateful that Eriksson and colleagues have stressedthe primary focus of our study; that is, it is important toanalyze possible clinical correlates of MD. We feel that thisgoal can best be achieved by testing hypotheses after selectinghomogeneous subgroups. In our view, mixing up heteroge-neous patient groups including different epileptogenic lesionsand various topographic cortical areas has been misleading sofar. The highly selected sample of 24 patients with mesialtemporal lobe epilepsy (MTLE) analyzed in our study issmall but homogeneous, and it is larger than in other studiesaddressing the clinical significance of MD, which occasion-ally have been based on a single case.3

The presence of MD is widely used as an argument sup-porting a maldevelopmental hypothesis of hippocampalsclerosis and MTLE. However, we have found that MDfeatures were not linked with each other and did not cor-relate to clinical parameters in MTLE.1 Furthermore, someof the features referred to as MD represent virtually normalcytoarchitectonic findings,2 whereas the remaining tissuefeatures were observed in a minority of our cases.1 We thusdo not understand how the percentage of 58% of caseswith architectonic disturbance was extracted by Erikssonand colleagues from our material. Notwithstanding theseminor inaccuracies, we concur with Eriksson and colleaguesthat current evidence suggests that MD features are seen inMTLE specimens, although their pathogenetic basis andclinical significance are still unknown. No study, includingours, has found convincing evidence that MD does have adysplastic origin. The term microdysgenesis therefore shouldbe used with caution.

Department of Neurology, University of Erlangen EpilepsyCenter, Erlangen, Germany

References1. Kasper BS, Stefan H, Paulus W. Microdysgenesis in mesial tem-

poral lobe epilepsy: a clinicopathological study. Ann Neurol2003;54:501–506.

2. Kasper BS, Stefan H, Buchfelder M, Paulus W. Temporal lobemicrodysgenesis in epilepsy versus control brains. J NeuropatholExp Neurol 1999;58:22–28.

3. Eriksson SH, Rydenhag B, Uvebrant P, et al. Widespread mi-crodysgenesis in therapy-resistant epilepsy—a case report onpost-mortem findings. Acta Neuropathol 2002;103:74–77.

DOI: 10.1002/ana.20067

Meningitis-Associated Hearing Loss: Protection byAdjunctive Antioxidant TherapyDiederik van de Beek, MD, and Jan de Gans, PhD

In the October issue, Klein and colleagues presented dataon adjunctive antioxidant therapy for the prevention ofmeningitis-induced hearing impairment.1 Although the re-sults are interesting, we disagree with their statement thatthe effect of adjunctive dexamethasone on hearing loss isquestionable. A recent Cochrane meta-analysis including1,853 patients showed that corticosteroids reduced severehearing loss in childhood bacterial meningitis caused byHaemophilus influenzae (relative risk, 0.31; 95% confidenceinterval, 0.15– 0.62), as well as in meningitis caused byother bacteria than H. influenzae (relative risk, 0.42; 95%confidence interval, 0.20 – 0.89).2 Although the two mostrecent clinical trials were not included in this meta-analysis,the beneficial effect is not questioned by the results of thesetrials. The Malawian study included mainly children inwhom treatment began late, human immunodeficiency vi-rus–positive children, and children receiving inappropriateantibiotic therapy.3 Therefore, the results are not represen-tative for patients with bacterial meningitis in developedcountries. In the European trial, dexamethasone reducedmortality from 17 of 50 patients (34%) with pneumococcalmeningitis in the placebo group to 8 of 58 patients (14%)in the dexamethasone group (relative risk, 0.41; 95% con-fidence interval, 0.19 – 0.86).4 Although no significant ben-eficial effect on hearing loss was found in patients withpneumococcal meningitis (relative risk, 0.67; 95% confi-dence interval, 0.25–1.69), neurological sequelae, includinghearing loss, were predominately found in the most severelyill patients, and the proportion of severely ill patients whosurvived to be tested was substantially larger in dexameth-asone group than in the placebo group.

Department of Neurology, Academic Medical Center,University of Amsterdam, Amsterdam, The Netherlands

References1. Klein M, Koedel U, Pfister HW, Kastenbauer S. Meningitis-

associated hearing loss: protection by adjunctive antioxidant ther-apy. Ann Neurol 2003;54:451–458.

2. Van de Beek D, de Gans J, McIntyre P, Prasad K. Corticoste-roids in acute bacterial meningitis. The Cochrane Library.Chichester, UK: John Wiley & Sons, Ltd. Issue 4; 2003.

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3. Molyneux EM, Walsh AL, Forsyth H, et al. Dexamethasonetreatment in childhood bacterial meningitis in Malawi: a ran-domised controlled trial. Lancet 2002;360:211–218.

4. De Gans J, Van de Beek D. Dexamethasone in adults with bac-terial meningitis. N Engl J Med 2002;347:1549–1556.

DOI: 10.1002/ana.20059

ReplyStefan 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 discussionabout the role of dexamethasone in the therapy of bacterialmeningitis. Their recent article signaled a substantial progressin the management of bacterial meningitis in adults, because itclearly demonstrated that mortality is reduced by dexametha-sone pretreatment.2 However, there are still several unresolvedproblems, for example, there is no established adjunctive post-treatment regimen (ie, after administration of antibiotics), andthe mortality of pneumococcal meningitis (14%) and theprevalence of long-term focal neurological deficits (22%) andhearing loss (14%) are still unacceptably high despite dexa-methasone pretreatment.2 Therefore, more effective adjunctivepre- and posttreatment regimens are needed and N-acetyl-L-cysteine (NAC) is a promising candidate because five experi-mental studies using different animal models and experimentaldesigns reported a protective effect of NAC against the devel-opment of meningitis-associated cerebral and cochlear compli-cations.1,3–6 Because NAC is well tolerated and in wide clin-ical use, a clinical study evaluating it for the adjunctive therapyof bacterial meningitis appears feasible.

In their letter, van de Beek and de Gans argue that hear-ing loss was predominantly found in the most severely illpatients. In 87 adults with pneumococcal meningitis fromour department,7 hearing loss was detected in 17 of 66 sur-vivors. Even when all fatal cases are excluded from the anal-ysis (because hearing assessment usually was performed onlyafter recovery and thus not in fatal cases), lower GlasgowComa Scores on admission (GCSA) were not associated withhearing loss (mean GCSA � SD: 10.0 � 2.7 in 17 survivorswith hearing loss vs 11.5 � 3.3 in 49 survivors without hear-ing loss, not significant). Furthermore, in their article, deGans and van de Beek did not report how (cerebral vs ex-tracerebral complications) dexamethasone reduced the mor-tality rates.2 A better understanding of the mechanism of ac-tion of adjunctive corticosteroids also would make theinterpretation of their effect on hearing impairment easier.Without the necessary data, however, the statement that thereduction of mortality by dexamethasone masked its benefi-cial effect on hearing because more severely ill patients sur-vived to be tested remains in the realm of speculation.

Department of Neurology, Klinikum Grosshadern,Ludwig-Maximilians University, Munich, Germany

References1. Klein M, Koedel U, Pfister H-W, et al. Meningitis-associated

hearing loss: protection by adjunctive antioxidant therapy. AnnNeurol 2003;54:451–458.

2. De Gans J, van de Beek D. Dexamethasone in adults with bac-terial meningitis. N Engl J Med 2002;347:1549–1556.

3. Koedel U, Pfister HW. Protective effect of the antioxidantN-acetyl-L-cysteine in pneumococcal meningitis in the rat. Neu-rosci Lett 1997;225:33–36.

4. Auer M, Pfister LA, Leppert D, et al. Effects of clinically usedantioxidants in experimental pneumococcal meningitis. J InfectDis 2000;182:347–350.

5. Christen S, Schaper M, Lykkesfeldt J, et al. Oxidative stress inbrain during experimental bacterial meningitis: differential effectsof alpha-phenyl-tert-butyl nitrone and N-acetylcysteine treat-ment. Free Radic Biol Med 2001;31:754–762.

6. Schaper M, Gergely S, Lykkesfeldt J, et al. Cerebral vasculatureis the major target of oxidative protein alterations in bacterialmeningitis. 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 of87 cases. Brain 2003;126:1015–1025.

DOI: 10.1002/ana.20058

Aortogenic Embolism Is a Possible Mechanism ofCryptogenic StrokeKazuo Kitagawa, MD

I read with great interest the recent article by Bang and col-leagues demonstrating the frequency and mechanisms ofstroke recurrence after cryptogenic stroke.1 They suggestedthat occlusive lesions other than significant stenosis of rele-vant artery may play an important role in the stroke recur-rence in patients with cryptogenic stroke, the stroke with nodetermined cause. On the basis of clinical findings, brainmagnetic resonance imaging (MRI) and angiography, carotidduplex, echocardiogram, and routine blood tests, they di-vided patients into large artery disease, cardioembolism,small artery disease, and no determined cause categories. Inthe discussion, they mentioned that more extensive studiesshould be performed to document possible embolism due topatent foramen ovale and paradoxical embolism with trans-esophageal echocardiography (TEE). Although Bang and col-leagues did not mention it, I want to add aortogenic embo-lism as a frequent cause for cryptogenic stroke. Amarencoand colleageus2 and Toyoda and colleageus3 previously dem-onstrated significant incidence of aortic complex lesion, a po-tential embolic source, in ischemic stroke patients with nodetermined cause. In our consecutive 147 patients with isch-emic cerebrovascular disease including ischemic stroke andtransient ischemic attacks, 56 patients had aortic complex le-sion defined as an aortic intimamedia thickness (IMT)greater than 4mm, mobile plaque, and/or ulcers.4 CarotidIMT, evaluated by carotid duplex, was closely associatedwith aortic IMT. Each one standard deviation greater carotidIMT was associated with 4.2-fold higher likelihood of com-plex aortic lesions. Our results together with others’5 clearlydemonstrated that the patients with mild carotid atheroscle-rosis were likely to have aortic complex lesions as an embolicsource. Therefore, I recommend examination of aortic archwith TEE or MRI in patients with cryptogenic stroke espe-cially when mild stenosis (�50%) is found in extracranialand/or intracranial cerebral artery.

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Division of Stroke Research, Department of Internal Medicineand Therapeutics, Osaka University Graduate School ofMedicine, Osaka, Japan

References1. 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 diseaseof the aortic arch and the risk of ischemic stroke. N Engl J Med1994;331:1474–1479.

3. Toyoda K, Yasaka M, Nagata S, Yamaguchi T. Aortogenic em-bolic stroke: a transesophageal echocardiographic approach.Stroke 1992;23:1056–1061.

4. Shimizu Y, Kitagawa K, Nagai Y, et al. Carotid athyerosclerosisas a risk factor for complex aortic lesions in patients with isch-emic cerebrovascular disease. Circ J 2003;67:597–600.

5. Kallikazaros IE, Tsioufis CP, Stefanadis CI, et al. Closed relationbetween carotid and ascending aortic atherosclerosis in cardiacpatients. Circulation 2000;102:III-263–III-268.

DOI: 10.1002/ana.20073

Monitoring �-Hydroxybutyric Acid Levels inSuccinate-Semialdehyde Dehydrogenase DeficiencyPhillip L. Pearl, MD, and Andrea Gropman, MD

We read with interest the report by Ergezinger and col-leagues1 describing successful treatment using low-dose viga-batrin of a 10-year-old girl with succinate-semialdehyde de-hydrogenase (SSADH) deficiency, in parallel with decreased�-hydroxybutyric acid (GHB) levels in physiological fluids.This is a significant issue, because this rare pediatric neuro-transmitter disorder has profound clinical ramifications, andany biomarkers to predict and follow the course of therapywould be most welcome.

We question the authors’ opinion as to the increase inGHB levels between the measurements at ages 7 7/12 and 9years. The levels return to the pathological range and evenexceed the pretreatment range in urine. The case reportshows no change in clinical management, including vigaba-trin dosage, during that interval. The pathological increasesremain throughout the follow-up period.

There appears to be an increasing clinical spectrum toSSADH deficiency,2 as well as structural and functional im-aging abnormalities that may serve as surrogate biomarkers ofdisease progression.3 Although cerebrospinal fluid levels ofGHB have been reported to decrease by as much as 70%from pretreatment levels,4 neither laboratory or clinical ef-fects have been consistent with vigabatrin therapy.5 Whereasclinical improvement was sustained in the authors’ case de-spite return to high elevations of this metabolite, it is diffi-cult to assess the utility of this biomarker as a useful labora-tory parameter. Such efforts are particularly difficult withoutmore information on the natural history of the disorder.

Department of Neurology, Children’s National MedicalCenter, George Washington University School of Medicine,Washington, DC

References1. Ergezinger K, Jeschke R, Frauendienst-Egger G, et al. Monitor-

ing of 4-hydroxybutyric acid levels in body fluids during vigaba-trin treatment in succinic semialdehyde dehydrogenase defi-ciency. Ann Neurol 2003;54:686–689.

2. Pearl PL, Acosta MT, Gibson KM, et al. Clinical spectrum ofsuccinic semialdehyde dehydrogenase deficiency. Neurology2003;60:1413–1417.

3. Pearl PL, Novotny EJ, Acosta MT, et al. Succinic semialdehydedehydrogenase deficiency in children and adults. Ann Neurol2003;54(suppl 6):S73–S80.

4. Jaeken J, Casaer P, deCock P, Francois B. Vigabatrin in GABAmetabolism disorders. Lancet 1989;1:1074.

5. Gropman A. Vigabatrin and newer interventions in succinicsemialdehyde dehydrogenase deficiency. Ann Neurol 2003;54(suppl 6):S66–S72.

DOI: 10.1002/ana.20084

ReplyKatrin Ergezinger, MD,1 and Volker H. Schuster, MD2

We reported successful treatment of a 10-year-old girl withsuccinate-semialdehyde dehydrogenase (SSADH) deficiencyusing low-dose vigabatrin. The authors question our view con-cerning the increase in �-hydroxybutyric acid (GHB) levelsbetween 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 vigabatrinper day. The next measurements were performed 17 monthslater at age 9 years, with the vigabatrin dose held constant. Atthis time, very high levels of GHB in serum and urine wereobserved. Because there had been further clinical improvement,we decided not to alter treatment until a further specimen wasobtained 2 months later. Furthermore, there was the potentialfor noncompliance. After the first seizure in our patient at age 93/12 years, vigabatrin dose was increased to 1,000mg per day.GHB levels in serum and urine decreased markedly within 1month. Still, the GHB levels were high in comparison with thelevels observed in the preceding 3.5 years.

The exact pathophysiology of SSADH deficiency remainsobscure, and it is unknown whether excess GABA and/orGHB contribute to the variable disease phenotype. In somecases, laboratory and clinical effects have been inconsistentwith vigabatrin therapy.1 In our patient, there was a goodcorrelation between the decrease of GHB in physiologicalfluids and clinical improvement during the first 30 monthsof therapy. At this time, we have no rational explanation forthe higher GHB levels in the final year of treatment, but thepotential for enzyme tolerance after long-term application ofvigabatrin remains a possibility.

We appreciate the insightful comments from Drs Pearland Gropman but feel that until such time as other, perhapsmore appropriate, biomarkers are available that it is worth-while to monitor GHB levels in patients with SSADH defi-ciency undergoing vigabatrin intervention.1Allergieklinik Davos, Switzerland; and 2Children’s Hospital,University of Leipzig, Leipzig, Germany

Reference1. Gibson KM, De Vivo DC, Jakobs C. Vigabatrin therapy in pa-

tients with succinic semialdehyde dehydrogenase deficiency. Lan-cet 1989;2:1105–1106.

DOI: 10.1002/ana.20080

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