The use of topiramate in refractory status epilepticus

seems always to be the woman. This probably relates to the X-chromosomal localization of DCX. Our study has important implications for genetic counseling of families with SBH/XLIS patients. Owing to the high rate of mosaicism and based on the possibility of incomplete or nonpenetrance of symptoms (Family C and references 5 and 9), we suggest that parents of affected men or affected women should be analyzed for mutations in the DCX gene. To limit the number of false-negative results obtained by analyzing lymphocyte DNA, we suggest including DNA isolated from ectodermal cells (skin biopsy), hair roots,6 or corticospinal fluid in the analysis. The genetic analysis of patients should take the high incidence of somatic mutations into account. In the case of an early pregnancy in a SBH/XLIS family, prenatal diagnosis of the DCX gene should be considered. Acknowledgment The authors thank all patients and family members who volunteered to participate in the study. They also thank Prof. Dr. Ulrich Bogdahn for continuous support. References 1. des Portes V, Pinard JM, Billuart P, et al. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 1998;92:51– 61. 2. Gleeson JG, Allen KM, Fox JW, et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998;92:63–72. 3. Matsumoto N, Leventer RJ, Kuc JA, et al. Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia. Eur J Hum Genet 2001;9:5–12. 4. Gleeson JG, Luo RF, Grant PE, et al. Genetic and neuroradiological heterogeneity of double cortex syndrome. Ann Neurol 2000;47:265–269. 5. Gleeson JG, Minnerath S, Kuzniecky RI, et al. Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes. Am J Hum Genet 2000;67:574 –581. 6. Kato M, Kanai M, Soma O, et al. Mutation of the doublecortin gene in male patients with double cortex syndrome: somatic mosaicism detected by hair root analysis. Ann Neurol 2001;50:547–551. 7. Pilz DT, Kuc J, Matsumoto N, et al. Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1. Hum Mol Genet 1999;8:1757–1760. 8. Aigner L, Fluegel D, Dietrich J, Ploetz S, Winkler J. Isolated lissencephaly sequence and double-cortex syndrome in a German family with a 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 2001;2:327–330. 10. Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 1992;51:1229 –1239. The use of topiramate in refractory status epilepticus 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 suspension 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 reported. NEUROLOGY 2003;60:332–334 Refractory status epilepticus (RSE) (seizure duration ⱖ 60 minutes) has a ⬎30% mortality, 10 times that of status epilepticus (SE) successfully terminated earlier, underscoring the need for effective intervention.1 The standard definition of SE is 30 minutes of continuous seizure activity or discrete seizures without recovery of consciousness between. However, determining the duration of SE is not always possible Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the January 28 issue to find the title link for this article. because seizure onset may not have been observed. Thus, therapy to terminate SE should be initiated as rapidly and safely as possible, and administration of antiepileptic drugs should begin whenever a seizure has lasted from 5 to 10 minutes. Topiramate is an anticonvulsant with multiple activities at receptors and ion channels that may be more effective than conventional anticonvulsants in treating RSE. Like phenytoin, topiramate exhibits voltage-sensitive, use-dependent, sodium-channel blockade and may have an additive effect at this 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 East Marshall Street, Room 6-013, Box 980599, Richmond, VA 23298-0599; e-mail: [email protected] 332 Copyright © 2003 by AAN Enterprises, Inc. Table Individual cases Case 1 39/M Right and left frontal; partial with secondary generalization FOS, DZP, LZP, PB, VAL, CBZ, PTB drip 38 d* Encephalitis 2 55/F Intermittent complex partial PB, LZP, VAL 2d Remote meningioma resection, decreased AED 400 6 h after dose increased from 25 mg every 4 h to 200 mg bid 3 42/F Focal motor LZP, VAL, FOS 3d Acute stroke, remote brain tumor, decreased AED 300 Seizures stopped within 1 d of TPM initiation 4 46/F Partial with secondary generalization to partial electrographic LZP, DZP, FOS, PB, PTB drip 63 h Encephalitis, remote stroke 1,200 12 h 5 59/F Partial nonconvulsive FOS, CBZ 23 h Encephalitis, remote stroke 1,600 Several hours 6 72/F Complex partial to subtle CBZ, DZP 60 h Remote stroke, infection (pneumonia) Seizure type TPM Cotherapy SE duration (total) Age, y/sex SE etiology Max TPM dose, mg/d 1,600 600 Time to TPM response 10 d on low-dose TPM with efforts to reduce PTB coma; patient weaned from PTB when TPM increased to 400 mg qid 48 h * 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 usedependent blockade of the sodium channel, its effects at other sites more likely underlie its effectiveness in RSE. Topiramate potentiates GABA inhibition independently of the benzodiazepine site on the GABAA receptor and significantly elevates brain GABA levels.3,4 Thus, topiramate may be effective in SE-induced benzodiazepine pharmacoresistance. Another action of topiramate is its ability to antagonize excitatory glutamatergic transmission, providing a mechanism for termination of seizure discharges in RSE.5 Other actions of topiramate that may contribute to its anticonvulsant effect include inhibiting high-voltage–activated calcium channels6 and inhibition of carbonic anhydrase activity that may result in pH modulation.7 Topiramate may have interactions with other anticonvulsants, especially acute effects on protein binding, that potentiate the effects of these agents on RSE.8,9 In addition, topiramate has been shown to reduce neuronal injury after prolonged SE and may prevent delayed neuronal death.10 Because of these multiple mechanisms of action, topiramate was evaluated as an agent to treat RSE. We report our initial experience in using topiramate to treat RSE unresponsive to sequential trials of multiple agents. Methods. The Greater Richmond Status Epilepticus database is a large, population-based, prospectively collected database of SE patients treated at the Medical College of Virginia Hospitals and all community hospitals in the greater Richmond metropolitan area. For this retrospective case review, the database was searched for patients with RSE treated with topiramate. Case records were reviewed for information regarding patient characteristics, SE etiology, type, duration, and treatment history prior to administration of topiramate. All patients were unresponsive to a standard treatment protocol of successive IV courses, typically consisting of loading doses of: Lorazepam (0.1 mg/kg) or diazepam (0.1 to 0.25 mg/kg) Fosphenytoin (15 to 20 mg/kg phenytoin equivalent/kg) or phenytoin (15 to 20 mg/kg) Phenobarbital (20 mg/kg), pentobarbital (3 to 5 mg/kg), valproate (25 to 50 mg/kg), or midazolam (0.1 to 0.3 mg/kg) Or anesthetic doses of phenobarbital, pentobarbital, midazolam, or propofol by continuous infusion after loading. Topiramate tablets were crushed to a powder and mixed with water. The mixture was allowed to sit for several minutes to avoid clumping and then administered via syringe into a nasogastric tube. Dose escalation and maximum dose were individualized by patient; the maximum topiramate dose was 1,600 mg/d. Results. From the database of SE patients, six patients were identified for inclusion in this study. Individual cases are summarized in the table. Seizure activity resolved in all six patients after administration of topiramate, and all were eventually discharged from the hospital. Lethargy was the only reported side effect. Summaries of three cases, representative of the spectrum of SE episodes in this series, appear below. Case 1: Mixed partial seizures with secondary generalization. A 39-year-old man with no history of seizures was admitted to the hospital with fever, headache, and altered mental status. During this admission for encephalitis, he developed simple partial seizures with secondary generalization that progressed to SE. After 10 hours of successive treatment with lorazepam, fosphenytoin, and valproate, the patient was put into a pentobarbital coma to control SE and was maintained on pentobarbital and propofol drips. Over the next 2 weeks, any attempt at weaning the pentobarbital resulted in SE recurrence. On day 30, topiramate was started (100 mg twice daily) and increased to 400 mg four times daily. The patient was successfully weaned from pentobarbital without SE recurrence. He was discharged on phenytoin 300 mg three times daily, phenobarbital 50 mg three times daily, and topiramate 400 mg three times daily. Case 2: Intermittent complex partial seizures. A 55-year-old woman came to the emergency department because of intermittent complex partial seizures for 4 hours. Seizure history included complex partial seizures with secondary generalization prior to and following a right frontal craniotomy for meningioma resection. Over the next 2 days, intermittent seizures continued. Antiepileptic drug noncompliance was suspected, and lorazepam and valproate were administered. Topiramate 25 mg twice daily was also started. Over the next 12 hours, the patient had approximately 14 seizures per hour. Topiramate and lorazepam were increased, reducing seizure frequency. On day 3, valproate and phenobarbital were continued, lorazepam was decreased, and topiramate was increased to 200 mg twice daily. On day 4, the EEG was slow but showed no seizures. There was improvement over the next 6 days. She was weaned off valproate and lorazepam but continued on January (2 of 2) 2003 NEUROLOGY 60 333 topiramate and phenobarbital. On days 11 to 14, she was alert with improved mental status. On day 16, she was discharged on phenobarbital 30 mg twice daily and topiramate 100 mg twice daily. Case 3: Focal motor seizures. A 42-year-old woman with a remote history of astrocytoma with resultant complex partial seizures was hospitalized with respiratory failure secondary to pneumonia. Head CT showed right cerebral middle cerebral artery–posterior cerebral artery watershed strokes. She developed left-sided focal motor SE and was given lorazepam, valproate, and midazolam with temporary seizure control. Two days later, SE recurred and she was given lorazepam, phenytoin, valproate, and fosphenytoin with continued SE. Topamax was started at 100 mg twice daily and increased to 150 mg twice daily with cessation of SE within 24 hours. She was discharged 2 weeks later. Discussion. In this series of six cases, topiramate effectively terminated RSE in a variety of clinical settings. With several mechanisms of action involving different receptors and ion channels, topiramate would be expected to be effective in SE involving different seizure types. Decreased potential for pharmacoresistance compared with agents with a single mechanism of action would also be anticipated. In this series, topiramate was effective against both generalized convulsive SE and nonconvulsive SE. In several cases, SE control achieved by topiramate averted the need for barbiturate coma, mechanical ventilation, and intensive care admission. Further, in three patients given topiramate as a last resort, after pentobarbital infusion failed, topiramate successfully stopped seizures. Effective daily dosages ranged from 300 mg to 1,600 mg. While addi- 334 NEUROLOGY 60 January (2 of 2) 2003 tional research is needed to validate these initial observations, topiramate administered nasogastrically appears to be effective in aborting SE, even after a prolonged period of time. A parenteral formulation would allow topiramate to be used more widely in RSE. Acknowledgment The authors thank Angela Brown, Susan Byers, Julie Bieber, Desiree Slawski, and the VCU Neurology Housestaff and the MCV Hospital Neuroscience ICU staff. References 1. Towne AR, Pellock JM, Ko D, et al. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27–34. 2. DeLorenzo RJ, Sombati S, Coulter DA. Effects of topiramate on sustained repetitive firing and spontaneous recurrent seizure discharges in cultured hippocampal neurons. Epilepsia 2000;41:S40 –S44. 3. White HS, Brown SD, Woodhead JH, Skeen GA, Wolf HH. Topiramate modulates GABA-evoked currents in murine cortical neurons by a nonbenzodiazepine mechanism. Epilepsia 2000;41:S17–S20. 4. Petroff OA, Hyder F, Rothman DL, Mattson RH. Topiramate rapidly raises brain GABA in epilepsy patients. Epilepsia 2001;42:543–548. 5. Gibbs JW, Sombati S, DeLorenzo RJ, Coulter DA. Cellular actions of topiramate: blockade of kainate-evoked inward currents in cultured hippocampal neurons. Epilepsia 2000;41:S10 –S16. 6. Zhang X, Velumian AA, Jones OT, Carlen PL. Modulation of highvoltage-activated calcium channels in dentate granule cells by topiramate. Epilepsia 2000;41:S52–S60. 7. Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 2000;41:S35–S39. 8. Garnett WR. Clinical pharmacology of topiramate: a review. Epilepsia 2000;41:S61–S65. 9. Bourgeois BF. Important pharmacokinetic properties of antiepileptic drugs. Epilepsia 1995;36:S1–S7. 10. Niebauer M, Gruenthal M. Topiramate reduces neuronal injury after experimental status epilepticus. Brain Res 1999;837:263–269. The use of topiramate in refractory status epilepticus A.R. Towne, L.K. Garnett, E.J. Waterhouse, et al. Neurology 2003;60;332-334 DOI 10.1212/01.WNL.0000042783.86439.27 This information is current as of January 28, 2003 Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright . All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X. Updated Information & Services including high resolution figures, can be found at: http://www.neurology.org/content/60/2/332.full.html Supplementary Material Supplementary material can be found at: http://www.neurology.org/content/suppl/2003/01/27/60.2.332.DC1.htm l References This article cites 6 articles, 0 of which you can access for free at: http://www.neurology.org/content/60/2/332.full.html##ref-list-1 Citations This article has been cited by 9 HighWire-hosted articles: http://www.neurology.org/content/60/2/332.full.html##otherarticles Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): All Clinical trials http://www.neurology.org//cgi/collection/all_clinical_trials All Epilepsy/Seizures http://www.neurology.org//cgi/collection/all_epilepsy_seizures Antiepileptic drugs http://www.neurology.org//cgi/collection/antiepileptic_drugs Clinical trials Observational study (Cohort, Case control) http://www.neurology.org//cgi/collection/clinical_trials_observational_ study_cohort_case_control Status epilepticus http://www.neurology.org//cgi/collection/status_epilepticus Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions Reprints Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright . All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.