Free On-line Access

SPCI - Sociedade Portuguesa de Cuidados Intensivos

Revista Brasileira de Terapia Intensiva

AMIB - Associação de Medicina Intensiva Brasileira


ISSN: 0103-507X
Online ISSN: 1982-4335

Ícone Fechar

How to Cite


Welling LC, Rabelo NN, Yoshikawa MH, Telles JPM, Teixeira MJ, Figueiredo EG. Eficácia do topiramato como terapia adicional em pacientes com estado epiléptico refratário: uma breve revisão sistemática. Rev Bras Ter Intensiva. 2021;0(0):020221





Efficacy of topiramate as an add-on therapy in patients with refractory status epilepticus: a short systematic review

Eficácia do topiramato como terapia adicional em pacientes com estado epiléptico refratário: uma breve revisão sistemática

Leonardo Christiaan Welling1, Nícollas Nunes Rabelo2, Marcia Harumy Yoshikawa2, João Paulo Mota Telles2, Manoel Jacobsen Teixeira2, Eberval Gadelha Figueiredo2

1 Department of Neurological Surgery, Universidade Estadual de Ponta Grossa - Ponta Grossa (PR), Brazil.
2 Department of Neurological Surgery, Universidade de São Paulo - São Paulo (SP), Brazil.

Conflicts of interest: None.

Responsible editor: Viviane Cordeiro Veiga

Submitted on September 17, 2020
Accepted on December 19, 2020

Corresponding author: Eberval Gadelha Figueiredo, Universidade de São Paulo, Avenida Dr. Enéas de Carvalho Aguiar, 255, Zip code: 01246-903 - São Paulo (SP), Brazil. E-mail: [email protected]



OBJECTIVE: To identify current evidence on the use of topiramate for refractory status epilepticus.
METHODS: We reviewed the literature to investigate the efficacy of topiramate in the treatment of refractory status epilepticus. The search terms used were “status epilepticus”, “refractory”, “treatment” and “topiramate”. No restrictions were used.
RESULTS: The search yielded 487 articles that reported using topiramate as a treatment for refractory status epilepticus and its outcomes. Case reports, review articles, and animal experiments were excluded. After excluding duplicates and applying inclusion and exclusion criteria, nine studies were included for analyses. Descriptive and qualitative analyses were performed, and the results were as follows: response rates (defined as termination in-hospital until 72 hours after the administration of topiramate) varied from 27% to 100%. The mortality rate varied from 5.9% to 68%. Positive functional long-term outcomes, defined as discharge, back to baseline or rehabilitation, were documented by seven studies, and the rates ranged between 4% and 55%. Most studies reported no or mild adverse effects.
CONCLUSION: Topiramate was effective in terminating refractory status epilepticus, presented relatively low mortality and was well tolerated. Therefore, topiramate could be a good option as a third-line therapy for refractory status epilepticus, but further studies are necessary.

Keywords: Status epilepticus; Topiramate; Seizure.



Status epilepticus (SE) is defined by the League Against Epilepsy (ILAE) Task Force as “a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures”.(1) It is a medical emergency associated with high mortality that demands immediate medical care and prolonged hospital stay, incurring high health care costs.(2-6) The American Epilepsy Society establishes benzodiazepines as first-line treatment and fosphenytoin, valproic acid, levetiracetam, or intravenous phenobarbital as second-line.(7) The state of refractory disease is characterized by the failure of first- and second-line therapies. Currently, there are few controlled or randomized studies about refractory status epilepticus (RSE) and no drug with clear evidence to be useful as a third-line treatment, so therapeutic management often includes repeating second-line therapy or anesthetic doses of either thiopental, midazolam, pentobarbital, or propofol.(7)

Topiramate (TPM) is being studied as an option in these refractory patients. It is a second-generation drug with an action mechanism against various epileptic syndromes with pleiotropic effects on different receptors and ion channels. Pathophysiological studies demonstrate that topiramate potentiates gamma-aminobutyric acid (GABA) through modulation of its GABAA receptor independent of benzodiazepines. This means that topiramate can help to overcome the benzodiazepine resistance observed in refractory epileptic patients.(8)

Given the importance of clear evidence to guide RSE therapy and the lack of studies in this area, the purpose of this systematic review is to investigate the efficacy of TPM as an add-on therapy to patients with RSE compared with those who did not use it. Addressing this question is fundamental to instruct medical conduct, improve health care, and reduce costs of treatment. We carried out a systematic review to identify current evidence on the use of topiramate for RSE.


To investigate the efficacy of topiramate as an add-on therapy to patients with RSE compared with those who did not use it, electronic searches were performed by two reviewers independently in March 2020 in four different databases: MEDLINE, Embase, Cochrane Library and Web of Science. The search terms were “status epilepticus”, “refractory”, “treatment,” and “topiramate”. No restrictions were used. The inclusion criteria were as follows: studies reporting the use of topiramate as a treatment for RSE and its outcomes (response rate, mortality rate, or long-term outcomes). Case reports, review articles, letters, conference abstracts and animal experiments were excluded. After the study selection, we performed descriptive and qualitative analyses. For each study, we evaluated the study design, the number of participants, the dose of topiramate administered, response rate 72 hours after the administration of TPM, the mortality rate in-hospital, and favorable long-term outcomes (i.e., discharge, back to baseline or rehabilitation). Only the data of patients who had TPM as the last drug were included.


The search returned 487 articles, including 82 duplicates. We screened 405 studies, resulting in 25 manuscripts eligible for full text assessment; among those, 16 studies were excluded due to lack of information about topiramate treatment outcomes and publication type. Nine studies were included in this review (Figure 1).

Figure 1 - Study selection flow diagram for the systematic review.
RSE - refractory status epilepticus.

Eight studies were retrospective, and one was prospective.(9) Madzar et al.(10) was the only one that retrospectively compared episodes treated with and without TPM in terms of demographics, RSE characteristics, clinical course, and outcome; the others only analyzed cases treated with TPM. No studies were controlled or randomized. The total number of patients included was 261, with the number of participants in each study varying from 6 to 106 (Table 1).

Table 1 - Studies included
Author Study design Nº of cases Daily dose Response* (%) Mortality (%) Favorable long-term outcome† (%)
Asadi-Pooya et al. (9) Prospective 20 400mg 80 35 55
Madzar et al. (10) Retrospective 17 50mg - 1,000mg 100 5.9 4
Akyildiz et al. (11) Retrospective 14 5mg/kg - 25mg/kg 85 7 21
Fechner et al. (12) Retrospective 106 100mg - 400mg 27 22.6 21.7
Synowiec et al. (13) Retrospective 27 400mg - 600mg 48 18.5 NA
Hottinger et al. (14) Retrospective 27 < 400mg - 800mg 81.4 33 66
Towne et al. (15) Retrospective 6 300mg - 1,600mg 66 NA NA
Stojanova et al. (16) Retrospective 11 50mg - 800mg 27 36 9
Kim et al. (17) Retrospective 16 300mg - 1,000mg 81 68 25

NA - not assessed.

* Response defined as termination in hospital stay until 72 hours after the administration of topiramate; † favorable long-term outcome defined as discharge, back to baseline or rehabilitation.

Table 1 - Studies included

There was no significant difference in the population between the studies concerning gender and age, except for one study(11) that included only pediatric patients. Most studies included participants with different types of seizures, including generalized clonic, generalized tonic-clonic, simple partial, complex partial, nonconvulsive, and focal motor seizures. Fechner et al.(12) did not report the type of seizure of patients, and Asadi-Pooya et al.(9) only included patients with generalized convulsive status epilepticus. Synowiec et al.,(13) Hottinger et al.,(14) and Asadi-Pooya et al.(9) documented a history of epilepsy among 45.7%, 31.4%, and 20% of patients, respectively.

Refractory status epilepticus etiology was diverse within and between studies and included infection, intracranial hemorrhage, low antiepileptic drug (AED) level, metabolic abnormality, drug or alcohol overdose or withdrawal, trauma, stroke, anoxia/hypoxia, brain tumor, congenital brain malformation, myocardial infarction, Dandy-Walker syndrome, and Lennox Gestaut syndrome.

Refractory status epilepticus severity was assessed with the Status Epilepticus Severity Score (STESS) by two studies: Madzar et al.(10) and Fechner et al.(12) The former reported STESS ≥ 3 in 7% of patients treated with TPM and in 36% of patients not treated with TPM; the latter reported STESS 0 - 3 in 64.2% of the patients included and STESS 4 - 6 in 35.8%.

The maximum daily dose of TPM used in each study had considerable variation, ranging between 400mg and 1,600mg, while the minimum daily dose varied from 50mg to 400mg. Even within studies, the dose administered for each patient showed remarkable variation (Table 1).

The response rates, here defined as termination in-hospital until 72 hours after the administration of TPM, varied from 27% to 100%. The mortality rate varied from 5.9% to 68%. One study(15) did not report the mortality rate. Positive functional long-term outcome - defined as discharge, back to baseline, or rehabilitation - was documented by seven studies, and the rates ranged between 4% and 55%. The study performed with pediatric patients reported 21% discharge without neurological sequelae in the follow-up.

Most studies reported no or slight adverse effects that involved metabolic acidosis, hyperammonemia, later nephrolithiasis (occurring in one patient 63 days after TPM introduction and leading to sepsis), and lethargy. However, Fechner et al.(12) observed a significant rate of hyperammonemia during treatment with TPM - 35.8% of the patients developed that disturbance.


Topiramate demonstrated response rates similar or even superior to those documented by the current third-line options to RSE (pentobarbital 4% - 43%, propofol 46% - 62%, or midazolam 63% - 100%).(18,19) Moreover, a study that compared episodes treated with and without TPM(10) reported that the likelihood of RSE termination was significantly higher when TPM was part of the baseline AED regimen.

Intriguingly, in studies with more significant variability in TPM doses,(15,16) lower doses seem to be associated with higher response rates. However, the heterogeneous RSE etiologies and TPM cotherapy are significant biases that disallow the association of lower doses with higher response rates. Concerning etiologies, previous studies demonstrated that epilepsy and previous diagnosis of epilepsy offer a favorable prognosis, while coma and RSE caused by anoxia/hypoxia were unfavorable factors.(19-23)

Mortality seems to be lower than that observed in other antiepileptic drugs,(19,21) which could be associated with the characteristics of the patients chosen to receive TPM therapy. Madzar et al.(10) documented that TPM seemed to be administered to younger and healthier patients in association with higher doses of AEDs. It is essential to note that younger age alone is not a predictor of better outcomes in RSE, but the worse clinical course of older patients is most strongly correlated with underlying etiologies and comorbidities.(19,21-26)

The study’s significant limitations were the heterogeneity of the population studied (i.e., the varying etiologies and severity levels of RSE, variance in the protocol of administration of TPM, and the use of different doses and cotherapies). Most importantly, these limitations demonstrate the lack of high-quality evidence on this topic, particularly in comparing topiramate to other treatments for RSE.

Despite these limitations, our study demonstrates the likely efficacy of TPM in RSE episodes and the necessity of large, controlled, and randomized trials that could provide clear evidence. Furthermore, the formulation of intravenous solutions of TPM is essential to increase its use in situations of SE, although oral TPM has good bioavailability, little protein binding, and rapid absorption.(27) Fortunately, intravenous solutions are under development for clinical practice.(28)


Topiramate was effective in terminating refractory status epilepticus. Its response rate seems similar or even superior to those documented by the current third-line options for refractory status epilepticus, while mortality seems lower. Despite the difficulty of evaluating adverse events associated with add-on medications in critically ill patients, topiramate was well tolerated and promoted no severe side effects, so it can be considered a good option as third-line therapy for refractory status epilepticus. Further studies are needed to directly compare topiramate with other currently recommended drugs.


Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar S, et al. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515-23. Link DOI
Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol. 2015;14(6):615-24. Link DOI
Strzelczyk A, Knake S, Oertel WH, Rosenow F, Hamer HM. Inpatient treatment costs of status epilepticus in adults in Germany. Seizure. 2013;22(10):882-5. Link DOI
Strzelczyk A, Ansorge S, Hapfelmeier J, Bonthapally V, Erder MH, Rosenow F. Costs, length of stay, and mortality of super refractory status epilepticus: a population based study from Germany. Epilepsia. 2017;58(9):1533-41. Link DOI
Schubert Bast S, Zöllner JP, Ansorge S, Hapfelmeier J, Bonthapally V, Eldar-Lissai A, et al. Burden and epidemiology of status epilepticus in infants, children, and adolescents: a population based study on German health insurance data. Epilepsia. 2019;60(5):911-20. Link DOI
Kellinghaus C, Rossetti AO, Trinka E, Lang N, May TW, Unterberger I, et al. Factors predicting cessation of status epilepticus in clinical practice: data from a prospective observational registry (SENSE). Ann Neurol. 2019;85(3):421-32.
Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61. Link DOI
Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia. 2000;41(S1):3-9. Link DOI
Asadi-Pooya AA, Jahromi MJ, Izadi S, Emami Y. Treatment of refractory generalized convulsive status epilepticus with enteral topiramate in resource limited settings. Seizure. 2015;24:114-7. Link DOI
Madžar D, Kuramatsu JB, Gerner ST, Huttner HB. Assessing the value of topiramate in refractory status epilepticus. Seizure. 2016;38:7-10. Link DOI
Akyildiz BN, Kumandaş S. Treatment of pediatric refractory status epilepticus with topiramate. Childs Nerv Syst. 2011;27(9):1425-30. Link DOI
Fechner A, Hubert K, Jahnke K, Knake S, Konczalla J, Menzler K, et al. Treatment of refractory and superrefractory status epilepticus with topiramate: a cohort study of 106 patients and a review of the literature. Epilepsia. 2019;60(12):2448-58. Link DOI
Synowiec AS, Yandora KA, Yenugadhati V, Valeriano JP, Schramke CJ, Kelly KM. The efficacy of topiramate in adult refractory status epilepticus: experience of a tertiary care center. Epilepsy Res. 2012;98(2-3):232-7. Link DOI
Hottinger A, Sutter R, Marsch S, Rüegg S. Topiramate as an adjunctive treatment in patients with refractory status epilepticus: an observational cohort study. CNS Drugs. 2012;26(9):761-72. Link DOI
Towne AR, Garnett LK, Waterhouse EJ, Morton LD, DeLorenzo RJ. The use of topiramate in refractory status epilepticus. Neurology. 2003;60(2):332-4. Link DOI
Stojanova V, Rossetti AO. Oral topiramate as an add-on treatment for refractory status epilepticus. Acta Neurol Scand. 2012;125(2):e7-e11. Link DOI
Kim W, Kwon SY, Cho AH, Lim SC, Kim YI, Shon YM. Effectiveness of topiramate in medically complicated patients with status epilepticus or acute refractory seizures. J Epilepsy Res. 2011;1(2):52-6. Link DOI
Rai S, Drislane FW. Treatment of refractory and super-refractory status epilepticus. Neurotherapeutics. 2018;15(3):697-712. Link DOI
Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia. 2002;43(2):146-53. Link DOI
Drislane FW, Blum AS, Lopez MR, Gautam S, Schomer DL. Duration of refractory status epilepticus and outcome: loss of prognostic utility after several hours. Epilepsia. 2009;50(6):1566-71. Link DOI
Lai A, Outin HD, Jabot J, Mégarbane B, Gaudry S, Coudroy R, et al. Functional outcome of prolonged refractory status epilepticus. Crit Care. 2015;19(1):199. Link DOI
Kilbride RD, Reynolds AS, Szaflarski JP, Hirsch LJ. Clinical outcomes following prolonged refractory status epilepticus (PRSE). Neurocrit Care. 2013;18(3):374-85. Link DOI
Drislane FW, Lopez MR, Blum AS, Schomer DL. Survivors and nonsurvivors of very prolonged status epilepticus. Epilepsy Behav. 2011;22(2):342-5. Link DOI
Kudin AP, Debska-Vielhaber G, Vielhaber S, Elger CE, Kunz WS. The mechanism of neuroprotection by topiramate in an animal model of epilepsy. Epilepsia. 2004;45(12):1478-87. Link DOI
Edmonds Jr HL, Jiang YD, Zhang PY, Shank R. Topiramate as a neuroprotectant in a rat model of global ischemia-induced neurodegeneration. Life Sci. 2001;69(19):2265-77. Link DOI
Rossetti AO, Hurwitz S, Logroscino G, Bromfield EB. Prognosis of status epilepticus: role of aetiology, age, and consciousness impairment at presentation. J Neurol Neurosurg Psychiatry. 2006;77(5):611-5. Link DOI
Niebauer M, Gruenthal M. Topiramate reduces neuronal injury after experimental status epilepticus. Brain Res. 1999;837(1-2):263-9. Link DOI
Clark AM, Kriel RL, Leppik IE, White JR, Henry TR, Brundage RC, et al. Intravenous topiramate: safety and pharmacokinetics following a single dose in patients with epilepsy or migraines taking oral topiramate. Epilepsia. 2013;54(6):1106-11. Link DOI

Submission On-line

Indexed in




Associação de Medicina Intensiva Brasileira - AMIB

Rua Arminda nº 93 - 7º andar - Vila Olímpia - São Paulo, SP, Brasil - Tel./Fax: (55 11) 5089-2642 | e-mail: [email protected]

Cookie Policy

GN1 - Systems and Publications