seems always to be the woman. This probably relates to the X-chromosomal localization of DCX.
1. des Portes V, Pinard JM, Billuart P, et al. A novel CNS gene required Our study has important implications for genetic for neuronal migration and involved in X-linked subcortical laminar counseling of families with SBH/XLIS patients. Ow- heterotopia and lissencephaly syndrome. Cell 1998;92:51– 61.
2. Gleeson JG, Allen KM, Fox JW, et al. Doublecortin, a brain-specific ing to the high rate of mosaicism and based on the gene mutated in human X-linked lissencephaly and double cortex syn- possibility of incomplete or nonpenetrance of symptoms drome, encodes a putative signaling protein. Cell 1998;92:63–72.
3. Matsumoto N, Leventer RJ, Kuc JA, et al. Mutation analysis of the (Family C and references 5 and 9), we suggest that DCX gene and genotype/phenotype correlation in subcortical band het- parents of affected men or affected women should be erotopia. Eur J Hum Genet 2001;9:5–12.
4. Gleeson JG, Luo RF, Grant PE, et al. Genetic and neuroradiological analyzed for mutations in the DCX gene. To limit the heterogeneity of double cortex syndrome. Ann Neurol 2000;47:265–269.
number of false-negative results obtained by analyzing 5. Gleeson JG, Minnerath S, Kuzniecky RI, et al. Somatic and germline lymphocyte DNA, we suggest including DNA isolated mosaic mutations in the doublecortin gene are associated with variablephenotypes. Am J Hum Genet 2000;67:574 –581.
from ectodermal cells (skin biopsy), hair roots,6 or corti- 6. Kato M, Kanai M, Soma O, et al. Mutation of the doublecortin gene in cospinal fluid in the analysis. The genetic analysis of male patients with double cortex syndrome: somatic mosaicism detectedby hair root analysis. Ann Neurol 2001;50:547–551.
patients should take the high incidence of somatic mu- 7. Pilz DT, Kuc J, Matsumoto N, et al. Subcortical band heterotopia in tations into account. In the case of an early pregnancy rare affected males can be caused by missense mutations in DCX(XLIS) or LIS1. Hum Mol Genet 1999;8:1757–1760.
in a SBH/XLIS family, prenatal diagnosis of the DCX 8. Aigner L, Fluegel D, Dietrich J, Ploetz S, Winkler J. Isolated lissen- gene should be considered.
cephaly sequence and double-cortex syndrome in a German family witha novel doublecortin mutation. Neuropediatrics 2000;31:195–198.
9. Demelas L, Serra G, Conti M, et al. Incomplete penetrance with normal MRI in a woman with germline mutation of the DCX gene. Neurology 10. Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Meth- The authors thank all patients and family members who volun- ylation of HpaII and HhaI sites near the polymorphic CAG repeat in teered to participate in the study. They also thank Prof. Dr. Ulrich the human androgen-receptor gene correlates with X chromosome inac- Bogdahn for continuous support.
tivation. Am J Hum Genet 1992;51:1229 –1239.
The use of topiramate in refractory
A.R. Towne, MD; L.K. Garnett, RN, MSHA; E.J. Waterhouse, MD; L.D. Morton, MD; and R.J. DeLorenzo, MD, PhD, MPH Abstract—In cases of refractory status epilepticus (RSE) unresponsive to sequential trials of multiple agents, a suspen-
sion of topiramate administered via nasogastric tube was effective in aborting RSE, including one patient in a prolonged
pentobarbital coma. Effective dosages ranged from 300 to 1,600 mg/d. Except for lethargy, no adverse events were
Refractory status epilepticus (RSE) (seizure duration because seizure onset may not have been observed.
ⱖ 60 minutes) has a ⬎30% mortality, 10 times that Thus, therapy to terminate SE should be initiated as of status epilepticus (SE) successfully terminated rapidly and safely as possible, and administration of earlier, underscoring the need for effective interven- antiepileptic drugs should begin whenever a seizure tion.1 The standard definition of SE is 30 minutes of has lasted from 5 to 10 minutes.
continuous seizure activity or discrete seizures with- Topiramate is an anticonvulsant with multiple ac- out recovery of consciousness between. However, de- tivities at receptors and ion channels that may be termining the duration of SE is not always possible more effective than conventional anticonvulsants intreating RSE. Like phenytoin, topiramate exhibits Additional material related to this article can be found on the Neurology voltage-sensitive, use-dependent, sodium-channel Web site. Go to and scroll down the Table of Con- blockade and may have an additive effect at this tents for the January 28 issue to find the title link for this article.
site.2 While topiramate in combination with the use From Virginia Commonwealth University, Richmond, VA.
This research is supported by NIH P01NS525630.
Received April 12, 2002. Accepted in final form October 2, 2002.
Address correspondence and reprint requests to Dr. Alan R. Towne, Virginia Commonwealth University Health System, Department of Neurology, 1101 EastMarshall Street, Room 6-013, Box 980599, Richmond, VA 23298-0599; e-mail: [email protected] Copyright 2003 by AAN Enterprises, Inc.

Table Individual cases
Time to TPM response Right and left frontal; partial 10 d on low-dose TPM with efforts with secondary generalization to reduce PTB coma; patient weaned from PTB when TPM increased to 400 mg qid Intermittent complex partial Remote meningioma 6 h after dose increased from 25 resection, decreased AED mg every 4 h to 200 mg bid Acute stroke, remote brain Seizures stopped within 1 d of tumor, decreased AED Partial with secondary Encephalitis, remote stroke generalization to partial Partial nonconvulsive Encephalitis, remote stroke Complex partial to subtle Remote stroke, infection * Includes period in which PTB coma used to control seizure activity.
CBZ ⫽ carbamazepine; DZP ⫽ diazepam; FOS ⫽ fosphenytoin; LZP ⫽ lorazepam; MDL ⫽ midazolam; PB ⫽ phenobarbital; PTB ⫽ pentobarbital; TPM ⫽topiramate; VAL ⫽ valproate; AED ⫽ antiepileptic.
of conventional agents may produce additional use- Phenobarbital (20 mg/kg), pentobarbital (3 to 5 mg/kg), val- dependent blockade of the sodium channel, its effects proate (25 to 50 mg/kg), or midazolam (0.1 to 0.3 mg/kg) Or anesthetic doses of phenobarbital, pentobarbital, midazo- at other sites more likely underlie its effectiveness in lam, or propofol by continuous infusion after loading.
RSE. Topiramate potentiates GABA inhibition inde- Topiramate tablets were crushed to a powder and mixed with pendently of the benzodiazepine site on the GABA water. The mixture was allowed to sit for several minutes to avoid receptor and significantly elevates brain GABA lev- clumping and then administered via syringe into a nasogastrictube. Dose escalation and maximum dose were individualized by els.3,4 Thus, topiramate may be effective in SE-induced patient; the maximum topiramate dose was 1,600 mg/d.
benzodiazepine pharmacoresistance. Another action oftopiramate is its ability to antagonize excitatory gluta- From the database of SE patients, six patients were matergic transmission, providing a mechanism for ter- identified for inclusion in this study. Individual cases are summa-rized in the table. Seizure activity resolved in all six patients after mination of seizure discharges in RSE.5 Other actions administration of topiramate, and all were eventually discharged of topiramate that may contribute to its anticonvulsant from the hospital. Lethargy was the only reported side effect.
effect include inhibiting high-voltage–activated calcium Summaries of three cases, representative of the spectrum of SE channels6 and inhibition of carbonic anhydrase activity episodes in this series, appear below.
Case 1: Mixed partial seizures with secondary generalization. that may result in pH modulation.7 Topiramate may 39-year-old man with no history of seizures was admitted to the have interactions with other anticonvulsants, espe- hospital with fever, headache, and altered mental status. During this cially acute effects on protein binding, that potentiate admission for encephalitis, he developed simple partial seizures withsecondary generalization that progressed to SE. After 10 hours of the effects of these agents on RSE.8,9 In addition, topi- successive treatment with lorazepam, fosphenytoin, and valproate, ramate has been shown to reduce neuronal injury after the patient was put into a pentobarbital coma to control SE and was prolonged SE and may prevent delayed neuronal maintained on pentobarbital and propofol drips. Over the next 2 death.10 Because of these multiple mechanisms of ac- weeks, any attempt at weaning the pentobarbital resulted in SErecurrence.
tion, topiramate was evaluated as an agent to treat On day 30, topiramate was started (100 mg twice daily) and RSE. We report our initial experience in using topira- increased to 400 mg four times daily. The patient was successfully mate to treat RSE unresponsive to sequential trials of weaned from pentobarbital without SE recurrence. He was dis-charged on phenytoin 300 mg three times daily, phenobarbital 50 multiple agents.
mg three times daily, and topiramate 400 mg three times daily.
Case 2: Intermittent complex partial seizures. The Greater Richmond Status Epilepticus database is woman came to the emergency department because of intermit- a large, population-based, prospectively collected database of SE tent complex partial seizures for 4 hours. Seizure history included patients treated at the Medical College of Virginia Hospitals and complex partial seizures with secondary generalization prior to all community hospitals in the greater Richmond metropolitan and following a right frontal craniotomy for meningioma resection.
area. For this retrospective case review, the database was Over the next 2 days, intermittent seizures continued. Antiepilep- searched for patients with RSE treated with topiramate. Case tic drug noncompliance was suspected, and lorazepam and val- records were reviewed for information regarding patient charac- proate were administered. Topiramate 25 mg twice daily was also teristics, SE etiology, type, duration, and treatment history prior started. Over the next 12 hours, the patient had approximately 14 to administration of topiramate.
seizures per hour. Topiramate and lorazepam were increased, re- All patients were unresponsive to a standard treatment protocol ducing seizure frequency. On day 3, valproate and phenobarbital of successive IV courses, typically consisting of loading doses of: were continued, lorazepam was decreased, and topiramate was Lorazepam (0.1 mg/kg) or diazepam (0.1 to 0.25 mg/kg) increased to 200 mg twice daily. On day 4, the EEG was slow but Fosphenytoin (15 to 20 mg/kg phenytoin equivalent/kg) or phe- showed no seizures. There was improvement over the next 6 days.
nytoin (15 to 20 mg/kg) She was weaned off valproate and lorazepam but continued on January (2 of 2) 2003

topiramate and phenobarbital. On days 11 to 14, she was alert with tional research is needed to validate these initial obser- improved mental status. On day 16, she was discharged on pheno- vations, topiramate administered nasogastrically barbital 30 mg twice daily and topiramate 100 mg twice daily.
Case 3: Focal motor seizures. A 42-year-old woman with a re- appears to be effective in aborting SE, even after a mote history of astrocytoma with resultant complex partial seizures prolonged period of time. A parenteral formulation was hospitalized with respiratory failure secondary to pneumonia.
would allow topiramate to be used more widely in RSE.
Head CT showed right cerebral middle cerebral artery–posteriorcerebral artery watershed strokes. She developed left-sided focalmotor SE and was given lorazepam, valproate, and midazolam with temporary seizure control. Two days later, SE recurred and The authors thank Angela Brown, Susan Byers, Julie Bieber, she was given lorazepam, phenytoin, valproate, and fosphenytoin Desiree Slawski, and the VCU Neurology Housestaff and the MCV with continued SE. Topamax was started at 100 mg twice daily Hospital Neuroscience ICU staff.
and increased to 150 mg twice daily with cessation of SE within24 hours. She was discharged 2 weeks later.
1. Towne AR, Pellock JM, Ko D, et al. Determinants of mortality in status In this series of six cases, topiramate epilepticus. Epilepsia 1994;35:27–34.
2. DeLorenzo RJ, Sombati S, Coulter DA. Effects of topiramate on sus- effectively terminated RSE in a variety of clinical set- tained repetitive firing and spontaneous recurrent seizure discharges in tings. With several mechanisms of action involving dif- cultured hippocampal neurons. Epilepsia 2000;41:S40 –S44.
3. White HS, Brown SD, Woodhead JH, Skeen GA, Wolf HH. Topiramate ferent receptors and ion channels, topiramate would be modulates GABA-evoked currents in murine cortical neurons by a non- expected to be effective in SE involving different sei- benzodiazepine mechanism. Epilepsia 2000;41:S17–S20.
zure types. Decreased potential for pharmacoresistance 4. Petroff OA, Hyder F, Rothman DL, Mattson RH. Topiramate rapidly raises brain GABA in epilepsy patients. Epilepsia 2001;42:543–548.
compared with agents with a single mechanism of ac- 5. Gibbs JW, Sombati S, DeLorenzo RJ, Coulter DA. Cellular actions of tion would also be anticipated. In this series, topira- topiramate: blockade of kainate-evoked inward currents in culturedhippocampal neurons. Epilepsia 2000;41:S10 –S16.
mate was effective against both generalized convulsive 6. Zhang X, Velumian AA, Jones OT, Carlen PL. Modulation of high- SE and nonconvulsive SE. In several cases, SE control voltage-activated calcium channels in dentate granule cells by topira-mate. Epilepsia 2000;41:S52–S60.
achieved by topiramate averted the need for barbitu- 7. Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of rate coma, mechanical ventilation, and intensive care carbonic anhydrase isoenzymes. Epilepsia 2000;41:S35–S39.
admission. Further, in three patients given topiramate 8. Garnett WR. Clinical pharmacology of topiramate: a review. Epilepsia as a last resort, after pentobarbital infusion failed, topi- 9. Bourgeois BF. Important pharmacokinetic properties of antiepileptic ramate successfully stopped seizures. Effective daily drugs. Epilepsia 1995;36:S1–S7.
10. Niebauer M, Gruenthal M. Topiramate reduces neuronal injury after dosages ranged from 300 mg to 1,600 mg. While addi- experimental status epilepticus. Brain Res 1999;837:263–269.
January (2 of 2) 2003


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