Download PDF
Semin Neurol 2020; 40(06): 708-718
DOI: 10.1055/s-0040-1719111
Review Article

Immunologic Treatments of Seizures and Status Epilepticus

George W. Culler 
1   Department of Neurology, Northwestern Memorial Hospital, Chicago, Illinois
2   Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
,
Stephen VanHaerents 
1   Department of Neurology, Northwestern Memorial Hospital, Chicago, Illinois
2   Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

An autoimmune etiology for seizures, epilepsy, and status epilepticus is becoming increasingly recognized. The role of autoimmunity in epilepsy has been highlighted in the literature and the International League Against Epilepsy now recognizes autoimmune epilepsy as a distinct entity. An appropriate and thorough work-up of all new-onset seizures and status epilepticus is paramount in determining the likely efficacy of immunotherapeutic agents in treating seizures and status epilepticus. Criteria for the clinical diagnosis of autoimmune mediated epilepsy and encephalitis have been published by expert consensus and validated models to predict response to immunotherapy exist. These guidelines should guide clinicians about when to promptly start immunotherapy. Immunotherapy has been shown to improve outcomes and may reduce relapse rates in autoimmune encephalitis. Treatment algorithms with immunotherapeutic agents have been established by expert opinion and multiple observational retrospective trials in the past 10 years. However, future prospective randomized controlled trials are still needed to better understand the optimal regimen, dosing schedule, and duration of treatment with immunotherapeutic agents.

Keywords

immunotherapy - autoimmune encephalitis - epilepsy - NORSE - FIRES


Publication History

Article published online:
11 November 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Incidence of status epilepticus in Rochester, Minnesota, 1965-1984. Neurology 1998; 50 (03) 735-741
    CrossrefPubMedGoogle Scholar
  • 2 DeLorenzo RJ, Hauser WA, Towne AR. et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996; 46 (04) 1029-1035
    CrossrefPubMedGoogle Scholar
  • 3 Brophy GM, Bell R, Claassen J. Neurocritical Care Society Status Epilepticus Guideline Writing Committee. et al; Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17 (01) 3-23
    CrossrefPubMedGoogle Scholar
  • 4 VanHaerents S, Gerard EE. Epilepsy emergencies: status epilepticus, acute repetitive seizures, and autoimmune encephalitis. Continuum (Minneap Minn) 2019; 25 (02) 454-476
    PubMedGoogle Scholar
  • 5 Tan RYL, Neligan A, Shorvon SD. The uncommon causes of status epilepticus: a systematic review. Epilepsy Res 2010; 91 (2–3): 111-122
    CrossrefPubMedGoogle Scholar
  • 6 Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons B-F. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 2002; 59 (02) 205-210
    CrossrefPubMedGoogle Scholar
  • 7 Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry 2005; 76 (04) 534-539
    CrossrefPubMedGoogle Scholar
  • 8 Gaspard N, Hirsch LJ, Sculier C. et al. New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): state of the art and perspectives. Epilepsia 2018; 59 (04) 745-752
    CrossrefPubMedGoogle Scholar
  • 9 Gaspard N, Foreman BP, Alvarez V. Critical Care EEG Monitoring Research Consortium (CCEMRC). et al; New-onset refractory status epilepticus: etiology, clinical features, and outcome. Neurology 2015; 85 (18) 1604-1613
    CrossrefPubMedGoogle Scholar
  • 10 Sculier C, Gaspard N. New onset refractory status epilepticus (NORSE). Seizure 2019; 68 (68) 72-78
    CrossrefPubMedGoogle Scholar
  • 11 Sakuma H, Awaya Y, Shiomi M. et al. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. Acta Neurol Scand 2010; 121 (04) 251-256
    CrossrefPubMedGoogle Scholar
  • 12 Mikaeloff Y, Jambaqué I, Hertz-Pannier L. et al. Devastating epileptic encephalopathy in school-aged children (DESC): a pseudo encephalitis. Epilepsy Res 2006; 69 (01) 67-79
    CrossrefPubMedGoogle Scholar
  • 13 Kramer U, Chi CS, Lin KL. et al. Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children. Epilepsia 2011; 52 (11) 1956-1965
    CrossrefPubMedGoogle Scholar
  • 14 Sakuma H, Tanuma N, Kuki I, Takahashi Y, Shiomi M, Hayashi M. Intrathecal overproduction of proinflammatory cytokines and chemokines in febrile infection-related refractory status epilepticus. J Neurol Neurosurg Psychiatry 2015; 86 (07) 820-822
    CrossrefPubMedGoogle Scholar
  • 15 Saitoh M, Kobayashi K, Ohmori I. et al. Cytokine-related and sodium channel polymorphism as candidate predisposing factors for childhood encephalopathy FIRES/AERRPS. J Neurol Sci 2016; 368: 272-276
    CrossrefPubMedGoogle Scholar
  • 16 van Baalen A, Vezzani A, Häusler M, Kluger G. Febrile infection-related epilepsy syndrome: clinical review and hypotheses of epileptogenesis. Neuropediatrics 2017; 48 (01) 5-18
    PubMedGoogle Scholar
  • 17 Gall CRE, Jumma O, Mohanraj R. Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy. Seizure 2013; 22 (03) 217-220
    CrossrefPubMedGoogle Scholar
  • 18 Li J, Saldivar C, Maganti RK. Plasma exchange in cryptogenic new onset refractory status epilepticus. Seizure 2013; 22 (01) 70-73
    CrossrefPubMedGoogle Scholar
  • 19 Khawaja AM, DeWolfe JL, Miller DW, Szaflarski JP. New-onset refractory status epilepticus (NORSE)--the potential role for immunotherapy. Epilepsy Behav 2015; 47: 17-23
    CrossrefPubMedGoogle Scholar
  • 20 Irani SR, Stagg CJ, Schott JM. et al. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain 2013; 136 (Pt 10): 3151-3162
    CrossrefPubMedGoogle Scholar
  • 21 Titulaer MJ, McCracken L, Gabilondo I. et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12 (02) 157-165
    CrossrefPubMedGoogle Scholar
  • 22 Toledano M, Britton JW, McKeon A. et al. Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy. Neurology 2014; 82 (18) 1578-1586
    CrossrefPubMedGoogle Scholar
  • 23 Holzer FJ, Seeck M, Korff CM. Autoimmunity and inflammation in status epilepticus: from concepts to therapies. Expert Rev Neurother 2014; 14 (10) 1181-1202
    CrossrefPubMedGoogle Scholar
  • 24 Cabrera Kang CM, Gaspard N, LaRoche SM, Foreman B. Survey of the diagnostic and therapeutic approach to new-onset refractory status epilepticus. Seizure 2017; 46: 24-30
    CrossrefPubMedGoogle Scholar
  • 25 Jun JS, Lee ST, Kim R, Chu K, Lee SK. Tocilizumab treatment for new onset refractory status epilepticus. Ann Neurol 2018; 84 (06) 940-945
    CrossrefPubMedGoogle Scholar
  • 26 van Baalen A, Häusler M, Plecko-Startinig B. et al. Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES. Neuropediatrics 2012; 43 (04) 209-216
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Sato Y, Numata-Uematsu Y, Uematsu M. et al. Acute encephalitis with refractory, repetitive partial seizures: pathological findings and a new therapeutic approach using tacrolimus. Brain Dev 2016; 38 (08) 772-776
    CrossrefPubMedGoogle Scholar
  • 28 Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T. IL-1 receptor/toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav Immun 2011; 25 (07) 1281-1289
    CrossrefPubMedGoogle Scholar
  • 29 Clarkson BDS, LaFrance-Corey RG, Kahoud RJ, Farias-Moeller R, Payne ET, Howe CL. Functional deficiency in endogenous interleukin-1 receptor antagonist in patients with febrile infection-related epilepsy syndrome. Ann Neurol 2019; 85 (04) 526-537
    CrossrefPubMedGoogle Scholar
  • 30 Kenney-Jung DL, Vezzani A, Kahoud RJ. et al. Febrile infection-related epilepsy syndrome treated with anakinra. Ann Neurol 2016; 80 (06) 939-945
    CrossrefPubMedGoogle Scholar
  • 31 Dilena R, Mauri E, Aronica E. et al. Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection-related epilepsy syndrome. Epilepsia Open 2019; 4 (02) 344-350
    CrossrefPubMedGoogle Scholar
  • 32 Jyonouchi H, Geng L. Intractable epilepsy (IE) and responses to Anakinra, a human recombinant IL-1 receptor agonist (IL-1ra): case reports. J Clin Cell Immunol 2016; 7 (05) 3-8
    CrossrefPubMedGoogle Scholar
  • 33 DeSena AD, Do T, Schulert GS. Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade. J Neuroinflammation 2018; 15 (01) 38
    CrossrefPubMedGoogle Scholar
  • 34 Nabbout R, Mazzuca M, Hubert P. et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 2010; 51 (10) 2033-2037
    CrossrefPubMedGoogle Scholar
  • 35 Thakur KT, Probasco JC, Hocker SE. et al. Ketogenic diet for adults in super-refractory status epilepticus. Neurology 2014; 82 (08) 665-670
    CrossrefPubMedGoogle Scholar
  • 36 Dupuis N, Curatolo N, Benoist JF, Auvin S. Ketogenic diet exhibits anti-inflammatory properties. Epilepsia 2015; 56 (07) e95-e98
    CrossrefPubMedGoogle Scholar
  • 37 Gofshteyn JS, Wilfong A, Devinsky O. et al. Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. J Child Neurol 2017; 32 (01) 35-40
    CrossrefPubMedGoogle Scholar
  • 38 Lin JJ, Lin KL, Hsia SH, Wang HS. CHEESE Study Group. Therapeutic hypothermia for febrile infection-related epilepsy syndrome in two patients. Pediatr Neurol 2012; 47 (06) 448-450
    CrossrefPubMedGoogle Scholar
  • 39 Dubey D, Alqallaf A, Hays R. et al. Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol 2017; 74 (04) 397-402
    CrossrefPubMedGoogle Scholar
  • 40 Scheffer IE, Berkovic S, Capovilla G. et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58 (04) 512-521
    CrossrefPubMedGoogle Scholar
  • 41 Byrne S, Walsh C, Hacohen Y. et al. Earlier treatment of NMDAR antibody encephalitis in children results in a better outcome. Neurol Neuroimmunol Neuroinflamm 2015; 2 (04) e130
    CrossrefPubMedGoogle Scholar
  • 42 Thompson J, Bi M, Murchison AG. Faciobrachial Dystonic Seizures Study Group. et al; The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018; 141 (02) 348-356
    CrossrefPubMedGoogle Scholar
  • 43 de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH. et al. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology 2019; 92 (19) e2185-e2196
    CrossrefPubMedGoogle Scholar
  • 44 Dubey D, Britton J, McKeon A. et al. Randomized placebo-controlled trial of intravenous immunoglobulin in autoimmune LGI1/CASPR2 epilepsy. Ann Neurol 2020; 87 (02) 313-323
    CrossrefPubMedGoogle Scholar
  • 45 Dubey D, Samudra N, Gupta P. et al. Retrospective case series of the clinical features, management and outcomes of patients with autoimmune epilepsy. Seizure 2015; 29: 143-147
    CrossrefPubMedGoogle Scholar
  • 46 Dubey D, Singh J, Britton JW. et al. Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia 2017; 58 (07) 1181-1189
    CrossrefPubMedGoogle Scholar
  • 47 Dubey D, Kothapalli N, McKeon A. et al. Predictors of neural-specific autoantibodies and immunotherapy response in patients with cognitive dysfunction. J Neuroimmunol 2018; 323 (June): 62-72
    CrossrefPubMedGoogle Scholar
  • 48 Dubey D, Pittock SJ, McKeon A. Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability. Epilepsia 2019; 60 (02) 367-369
    CrossrefPubMedGoogle Scholar
  • 49 Linnoila J, Pittock SJ. Autoantibody-associated central nervous system neurologic disorders. Semin Neurol 2016; 36 (04) 382-396
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Titulaer MJ, Soffietti R, Dalmau J. European Federation of Neurological Societies. et al; Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol 2011; 18 (01) 19-e3
    CrossrefPubMedGoogle Scholar
  • 51 Graus F, Titulaer MJ, Balu R. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15 (04) 391-404
    CrossrefPubMedGoogle Scholar
  • 52 Husari KS, Dubey D. Autoimmune epilepsy. Neurotherapeutics 2019; 16 (03) 685-702
    CrossrefPubMedGoogle Scholar
  • 53 DeSena AD, Noland DK, Matevosyan K. et al. Intravenous methylprednisolone versus therapeutic plasma exchange for treatment of anti-N-methyl-D-aspartate receptor antibody encephalitis: a retrospective review. J Clin Apher 2015; 30 (04) 212-216
    CrossrefPubMedGoogle Scholar
  • 54 Lee WJ, Lee ST, Byun JI. et al. Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort. Neurology 2016; 86 (18) 1683-1691
    CrossrefPubMedGoogle Scholar
  • 55 Scheibe F, Prüss H, Mengel AM. et al. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology 2017; 88 (04) 366-370
    CrossrefPubMedGoogle Scholar
  • 56 Schroeder C, Back C, Koc Ü. et al. Breakthrough treatment with bortezomib for a patient with anti-NMDAR encephalitis. Clin Neurol Neurosurg 2018; 172 (172) 24-26
    CrossrefPubMedGoogle Scholar
  • 57 Shin YW, Lee ST, Kim TJ, Jun JS, Chu K. Bortezomib treatment for severe refractory anti-NMDA receptor encephalitis. Ann Clin Transl Neurol 2018; 5 (05) 598-605
    CrossrefPubMedGoogle Scholar
  • 58 Cordani R, Micalizzi C, Giacomini T. et al. Bortezomib-responsive refractory anti-N-methyl-D-aspartate receptor encephalitis. Pediatr Neurol 2019; 103: 61-64
    CrossrefPubMedGoogle Scholar
  • 59 Alexander T, Sarfert R, Klotsche J. et al. The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis 2015; 74 (07) 1474-1478
    CrossrefPubMedGoogle Scholar
  • 60 Chavele K-M, Merry E, Ehrenstein MR. Cutting edge: circulating plasmablasts induce the differentiation of human T follicular helper cells via IL-6 production. J Immunol 2015; 194 (06) 2482-2485
    CrossrefPubMedGoogle Scholar
  • 61 Lee WJ, Lee ST, Moon J. et al. Tocilizumab in autoimmune encephalitis refractory to rituximab: an institutional cohort study. Neurotherapeutics 2016; 13 (04) 824-832
    CrossrefPubMedGoogle Scholar
  • 62 Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol 2019; 15 (08) 459-472
    CrossrefPubMedGoogle Scholar
  • 63 Leroy C, Rigot JM, Leroy M. et al. Immunosuppressive drugs and fertility. Orphanet J Rare Dis 2015; 10 (01) 136
    CrossrefPubMedGoogle Scholar
  • 64 Huong DL, Amoura Z, Duhaut P. et al. Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study in 84 patients. J Rheumatol 2002; 29 (12) 2571-2576
    PubMedGoogle Scholar
  • 65 Kim M, Rostas S, Gabardi S. Mycophenolate fetal toxicity and risk evaluation and mitigation strategies. Am J Transplant 2013; 13 (06) 1383-1389
    CrossrefPubMedGoogle Scholar
  • 66 Götestam Skorpen C, Hoeltzenbein M, Tincani A. et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis 2016; 75 (05) 795-810
    CrossrefPubMedGoogle Scholar
  • 67 Das G, Damotte V, Gelfand JM. et al. Rituximab before and during pregnancy: a systematic review, and a case series in MS and NMOSD. Neurol Neuroimmunol Neuroinflamm 2018; 5 (03) e453
    CrossrefPubMedGoogle Scholar
  • 68 Anakinra. In: Specific Lexicomp Online Database. Hudson, OH: Lexicomp Inc.; Available at: http://online.lexi.com/lco/action/api/find/globalid/5645?utd=1. Accessed Nov. 2019
    Google Scholar