Autoimmune Encephalitis–Related Seizures and Epilepsy: Diagnostic and Therapeutic Approaches

More than 50 million people worldwide have epilepsy, and approximately 30% of these patients continue to experience seizures despite management with antiseizure medications (ASMs).1EpilepsyWorld Health Organization website.www.who.int/news-room/fact-sheets/detail/epilepsyDate accessed: November 10, 2020Google Scholar Acute symptomatic seizure secondary to autoimmune encephalitis (ASSAE) is a common symptom in patients with autoimmune encephalitis, particularly when the limbic system is involved. Autoimmune-associated epilepsy (AAE) refers to chronic seizures determined to be secondary to autoimmune brain diseases.2Steriade C. Britton J. Dale R.C. et al.Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions.Epilepsia. 2020; 61: 1341-1351Crossref PubMed Scopus (36) Google Scholar The detection of neural autoantibodies is essential in establishing the diagnosis of autoimmune encephalitis.3Graus F. Titulaer M.J. Balu R. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (1495) Google Scholar Most of these antibodies target neuronal cell surface antigens, including synaptic neurotransmitter receptors, ion channels, or related proteins (eg, glioma inactivated 1 protein [LGI1],4Irani S.R. Michell A.W. Lang B. et al.Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.Ann Neurol. 2011; 69: 892-900Crossref PubMed Scopus (563) Google Scholar,5van Sonderen A. Schreurs M.W. de Bruijn M.A. et al.The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies.Neurology. 2016; 86: 1692-1699Crossref PubMed Scopus (99) Google Scholar N-methyl-d-aspartate receptor [NMDAR],6Titulaer M.J. 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: 157-165Abstract Full Text Full Text PDF PubMed Scopus (1647) Google Scholar,7Dalmau J. Gleichman A.J. Hughes E.G. et al.Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.Lancet Neurol. 2008; 7: 1091-1098Abstract Full Text Full Text PDF PubMed Scopus (2066) Google Scholar γ-aminobutyric acid type A receptor,8Petit-Pedrol M. Armangue T. Peng X. et al.Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies.Lancet Neurol. 2014; 13: 276-286Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar and γ-aminobutyric acid B receptor9Lancaster E. Lai M. Peng X. et al.Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen.Lancet Neurol. 2010; 9: 67-76Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar). Another group of antibodies targets neuronal intranuclear or cytoplasmic antigens (eg, glutamic acid decarboxylase 65-kDa isoform [GAD65]10Malter M.P. Helmstaedter C. Urbach H. Vincent A. Bien C.G. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis.Ann Neurol. 2010; 67: 470-478Crossref PubMed Scopus (332) Google Scholar and Ma1/2).11Dalmau J. Graus F. Villarejo A. et al.Clinical analysis of anti-Ma2-associated encephalitis.Brain. 2004; 127: 1831-1844Crossref PubMed Scopus (492) Google Scholar Table 1 summarizes the best known currently identified antibodies associated with autoimmune encephalitis.12Joubert B. Kerschen P. Zekeridou A. et al.Clinical spectrum of encephalitis associated with antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor: case series and review of the literature.JAMA Neurol. 2015; 72: 1163-1169Crossref PubMed Scopus (66) Google Scholar, 13Lancaster E. Huijbers M.G. Bar V. et al.Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia.Ann Neurol. 2011; 69: 303-311Crossref PubMed Scopus (320) Google Scholar, 14Spatola M. Sabater L. Planagumà J. et al.Encephalitis with mGluR5 antibodies: symptoms and antibody effects.Neurology. 2018; 90: e1964-e1972Crossref PubMed Scopus (47) Google Scholar, 15Carvajal-González A. Leite M.I. Waters P. et al.Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes [published correction appears in Brain. 2014;137(pt 12):e315].Brain. 2014; 137: 2178-2192Crossref PubMed Scopus (256) Google Scholar, 16Graus F. Keime-Guibert F. Reñe R. et al.Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients.Brain. 2001; 124: 1138-1148Crossref PubMed Scopus (661) Google Scholar The true incidence of AAE remains unknown; however, some reports suggest that approximately 6% to 10% of patients with late-onset seizures may have AAE.17von Podewils F. Suesse M. Geithner J. et al.Prevalence and outcome of late-onset seizures due to autoimmune etiology: a prospective observational population-based cohort study.Epilepsia. 2017; 58: 1542-1550Crossref PubMed Scopus (16) Google Scholar Identifying an immune-mediated cause opens up a new avenue of therapy (immunotherapy), which can drastically alter the course of ASM-resistant epilepsy. This commentary is intended to highlight the concept of immune-mediated seizures to primary care, internal medicine, and emergency medicine clinicians.Table 1Autoimmune Encephalitis–Associated Acute Symptomatic Seizures and Autoimmune-Associated EpilepsyAntibody-targeting antigenMost common seizure typeCommon nonseizure symptomAcute symptomatic seizure prevalenceRisk of AAEPrevalence of malignant neoplasmMain type(s) of malignant neoplasmResponse to immunotherapyCell surface antigensNMDAR6Titulaer M.J. 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: 157-165Abstract Full Text Full Text PDF PubMed Scopus (1647) Google Scholar,7Dalmau J. Gleichman A.J. Hughes E.G. et al.Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.Lancet Neurol. 2008; 7: 1091-1098Abstract Full Text Full Text PDF PubMed Scopus (2066) Google Scholar•Tonic-clonic•Focal•EPC•Behavioral and psychiatric changes•Dyskinesia70%-80%<5%Varies with sex30%-40%Ovarian teratomaGoodAMPAR12Joubert B. Kerschen P. Zekeridou A. et al.Clinical spectrum of encephalitis associated with antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor: case series and review of the literature.JAMA Neurol. 2015; 72: 1163-1169Crossref PubMed Scopus (66) Google Scholar•Temporal lobe•Opsoclonus•Cognitive dysfunction30%-40%<5%50%-60%•SCLC•Thymoma•BreastGoodGABAaR8Petit-Pedrol M. Armangue T. Peng X. et al.Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies.Lancet Neurol. 2014; 13: 276-286Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar•Refractory status epilepticus•EPC•Behavioral changes•Cognitive dysfunction80%-90%<5%20%-30%ThymomaGoodGABAbR9Lancaster E. Lai M. Peng X. et al.Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen.Lancet Neurol. 2010; 9: 67-76Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar•Focal onset impaired awareness•Focal to bilateral tonic-clonic seizures•Behavioral changes•Cognitive dysfunction90%-95%20%-30%50%-60%SCLCGoodLGI14Irani S.R. Michell A.W. Lang B. et al.Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.Ann Neurol. 2011; 69: 892-900Crossref PubMed Scopus (563) Google Scholar,5van Sonderen A. Schreurs M.W. de Bruijn M.A. et al.The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies.Neurology. 2016; 86: 1692-1699Crossref PubMed Scopus (99) Google Scholar•Faciobrachial dystonic seizures•Focal aware•Focal to bilateral tonic-clonic seizures•Hyponatremia•Cognitive dysfunction80%15%<5%ThymomaGoodCASPR25van Sonderen A. Schreurs M.W. de Bruijn M.A. et al.The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies.Neurology. 2016; 86: 1692-1699Crossref PubMed Scopus (99) Google Scholar,13Lancaster E. Huijbers M.G. Bar V. et al.Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia.Ann Neurol. 2011; 69: 303-311Crossref PubMed Scopus (320) Google Scholar•Focal onset impaired awareness•Morvan syndrome•Cognitive dysfunction40%-50%<10%<20%ThymomaGoodmGluR514Spatola M. Sabater L. Planagumà J. et al.Encephalitis with mGluR5 antibodies: symptoms and antibody effects.Neurology. 2018; 90: e1964-e1972Crossref PubMed Scopus (47) Google Scholar•Myoclonic•Psychiatric changes•Cognitive dysfunction50%-60%5%50%-60%Hodgkin lymphomaGoodGlyR15Carvajal-González A. Leite M.I. Waters P. et al.Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes [published correction appears in Brain. 2014;137(pt 12):e315].Brain. 2014; 137: 2178-2192Crossref PubMed Scopus (256) Google Scholar•Refractory SE•EPC•Myoclonus•PERM•SPSD-plus phenotype10%-40%Unclear10%-15%•Thymoma•B-cell lymphoma•Hodgkin lymphoma•Breast•MelanomaGoodIntracellular antigensGAD6510Malter M.P. Helmstaedter C. Urbach H. Vincent A. Bien C.G. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis.Ann Neurol. 2010; 67: 470-478Crossref PubMed Scopus (332) Google Scholar•TLE•Stiff person SPSD•Cerebellar ataxia•Cognitive dysfunction10%-50%>80%<10%•Very rare, adenocarcinoma, thymomaPoorMa211Dalmau J. Graus F. Villarejo A. et al.Clinical analysis of anti-Ma2-associated encephalitis.Brain. 2004; 127: 1831-1844Crossref PubMed Scopus (492) Google Scholar•TLE•Cognitive dysfunction hypersomnia•Ataxia40%-50%>60%>90%•Testicular germ cell•SCLC•BreastPoorHu/ANNA-116Graus F. Keime-Guibert F. Reñe R. et al.Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients.Brain. 2001; 124: 1138-1148Crossref PubMed Scopus (661) Google Scholar•TLE•Dysphagia•Dysarthria•Hypoventilation•Ataxia40%-50%>60%>95%•SCLCPoorAAE, autoimmune-associated epilepsy; AMPAR, alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ANNA-1, type 1 antineuronal nuclear antibody; CASPR2, contactin-associated protein 2; EPC, epilepsia partialis continua; GABAaR, γ-aminobutyric acid A receptor; GABAbR, γ-aminobutyric acid B receptor; GAD65, glutamic acid decarboxylase 65-kDa isoform; GlyR, glycine receptor; LGI1, leucine-rich glioma-inactivated 1; mGluR5, metabotropic glutamate receptor 5; NMDAR, N-methyl-d-aspartate receptor; PERM, progressive encephalomyelitis with rigidity and myoclonus (stiff person syndrome with rigidity, stimulus-sensitive spasms, myoclonus, hyperekplexia, autonomic disturbance, plus additional brainstem or other neurological deficits); SCLC, small cell lung cancer; SE, status epilepticus; SPSD, stiff person spectrum disorder; TLE, temporal lobe epilepsy. Open table in a new tab AAE, autoimmune-associated epilepsy; AMPAR, alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ANNA-1, type 1 antineuronal nuclear antibody; CASPR2, contactin-associated protein 2; EPC, epilepsia partialis continua; GABAaR, γ-aminobutyric acid A receptor; GABAbR, γ-aminobutyric acid B receptor; GAD65, glutamic acid decarboxylase 65-kDa isoform; GlyR, glycine receptor; LGI1, leucine-rich glioma-inactivated 1; mGluR5, metabotropic glutamate receptor 5; NMDAR, N-methyl-d-aspartate receptor; PERM, progressive encephalomyelitis with rigidity and myoclonus (stiff person syndrome with rigidity, stimulus-sensitive spasms, myoclonus, hyperekplexia, autonomic disturbance, plus additional brainstem or other neurological deficits); SCLC, small cell lung cancer; SE, status epilepticus; SPSD, stiff person spectrum disorder; TLE, temporal lobe epilepsy. Autoantibodies against surface antigens are hypothesized to directly mediate neurological changes that lead to acute symptomatic seizure development (by antigenic modulation or by recruitment of immune cells or complement activation).18Fang Z. Yang Y. Chen X. et al.Advances in autoimmune epilepsy associated with antibodies, their potential pathogenic molecular mechanisms, and current recommended immunotherapies.Front Immunol. 2017; 8: 395Crossref PubMed Scopus (9) Google Scholar Therefore, cases with these antibodies are often reversible with good immunotherapy response and do not require lifelong ASM. The risk of AAE is generally higher in patients with intracellular neuronal antibodies (suspected to be a T cell–mediated process) than in those with cell surface antibodies (often directly pathogenic). However, in experimental animal models, autoantibodies against surface antigens have exhibited robust effects on the target proteins, resulting in hyperexcitability and impairment of synaptic function and plasticity, leading to ASSAE.19Taraschenko O. Fox H.S. Pittock S.J. et al.A mouse model of seizures in anti-N-methyl-d-aspartate receptor encephalitis.Epilepsia. 2019; 60: 452-463Crossref PubMed Scopus (20) Google Scholar Autoimmune encephalitis–related seizures present with acute or subacute seizures, often frequent from the onset. A history of preceding viral prodrome is common. Frequent seizures can be the first symptom that raises initial suspicion of ASSAE or AAE, especially in patients who do not have a history or risk factors. Seizures are often multifocal and refractory to ASMs. Certain seizure types can be pathognomonic of an underlying immune etiology, for example, faciobrachial dystonic seizures in LGI1 antibody–associated autoimmune encephalitis.4Irani S.R. Michell A.W. Lang B. et al.Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.Ann Neurol. 2011; 69: 892-900Crossref PubMed Scopus (563) Google Scholar Additional neurological symptoms, including autonomic disturbances, neurobehavioral problems, memory decline, and movement disorders, are also common. Some patients may present with new-onset refractory status epilepticus (NORSE) or febrile infection-related epilepsy syndrome (FIRES). Autoimmune encephalitis is the most common cause of NORSE (37%),20Gaspard N. Foreman B.P. Alvarez V. et al.New-onset refractory status epilepticus: etiology, clinical features, and outcome.Neurology. 2015; 85: 1604-1613Crossref PubMed Scopus (200) Google Scholar which is no longer considered a diagnosis but a clinical presentation. When the etiology remains unknown despite extensive work-up, it is labeled as cryptogenic new-onset refractory status epilepticus (cNORSE), which makes up around half of all NORSE cases.21Yanagida A. Kanazawa N. Kaneko J. et al.Clinically based score predicting cryptogenic NORSE at the early stage of status epilepticus.Neurol Neuroimmunol Neuroinflamm. 2020; 7: e849Crossref PubMed Scopus (6) Google Scholar Table 2 summarizes clinical clues that should raise suspicion of ASSAE.Table 2Clues Suggestive of Autoimmune Encephalitis–Related Acute Symptomatic SeizureClinical symptoms and history•Subacute onset (rapid progression of <3 mo) of ≥1 of the following symptoms:○Short-term memory loss○Altered level of consciousness, lethargy, or personality change○Psychiatric symptoms (eg, psychosis and hallucination)○Brainstem symptoms (eg, ataxia, dysarthria, and dysphagia)○Eye movement disorder○Autonomic dysfunction○Exaggerated startle response○Dyskinesia○Dystonia•New focal neurological finding•New seizure (eg, status epilepticus [NORSE] and faciobrachial dystonic seizures) without previously diagnosed seizure disorder•Prodromal symptoms such as headache, fever, or flu-like symptoms•Signs of cancer (eg, unintended weight loss, night sweats, and fatigue)•Personal history of autoimmune condition•Family history of autoimmune or cancerOther supportive laboratory or imaging findings•Cerebrospinal fluid with a white blood cell count of >5 cells/mm3 and protein elevation•Detection of IgG autoantibodies in the cerebrospinal fluid or serum (not IgA or IgM)•Brain MRI showing hyperintensity involving 1 or both medial temporal lobes (limbic encephalitis) on T2-FLAIR or involving multiple foci in the gray matter, white matter, or both that are compatible with demyelination or inflammation•Electroencephalogram showing frequent bilateral temporal lobe seizures or extreme delta brushMRI, magnetic resonance imaging; NORSE, new-onset refractory status epilepticus; T2-FLAIR, T2-weighted fluid-attenuated inversion recovery sequence. Open table in a new tab MRI, magnetic resonance imaging; NORSE, new-onset refractory status epilepticus; T2-FLAIR, T2-weighted fluid-attenuated inversion recovery sequence. A key to ASSAE’s or AAE’s diagnosis is obtaining serum and cerebrospinal fluid (CSF) autoimmune neuronal antibody panel to test for autoantibodies’ presence because the detection of neural autoantibody helps establish the diagnosis.3Graus F. Titulaer M.J. Balu R. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (1495) Google Scholar However, reliance on antibody testing might delay the diagnosis. Recently, an international group developed diagnostic criteria for early diagnosis of autoimmune encephalitis in adults, which require (1) subacute onset over less than 3 months of working memory deficits, altered mental status, or psychiatric symptoms; (2) at least 1 of the following: new focal central nervous system (CNS) findings, seizures not explained by a preexisting disorder, CSF pleocytosis, and/or magnetic resonance imaging (MRI) features suggestive of encephalitis; and (3) reasonable exclusion of alternative cause.3Graus F. Titulaer M.J. Balu R. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (1495) Google Scholar When there is suspicion of ASSAE or AAE, urgent neurology consultation is warranted because antibody testing, diagnosis, and treatment may be esoteric to clinicians without a neuroimmunology background. Generally, panel testing of multiple autoantibodies rather than single antibody testing is recommended. In some cases, antibodies may be present only in the CSF or serum. For instance, anti-LGI1 IgG is more commonly detected in serum whereas up to 15% NMDAR IgG has detectable antibodies only in the CSF.3Graus F. Titulaer M.J. Balu R. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (1495) Google Scholar The electroencephalogram may have variable findings, including normal, focal, or diffuse slowing; epileptiform discharges; or frank seizures. The scalp electroencephalogram may also be normal (including during faciobrachial dystonic seizures) when the epileptic focus is deep or involves too small a neuronal aggregate for a synchronized activity to register on the scalp. Brain MRI can be normal (between 30% and 50%),22Quek A.M. Britton J.W. McKeon A. et al.Autoimmune epilepsy: clinical characteristics and response to immunotherapy.Arch Neurol. 2012; 69: 582-593Crossref PubMed Scopus (239) Google Scholar especially at the onset, but abnormalities, including bilateral and asymmetric mesial temporal lobe or limbic T2 hyperintensity, are commonly seen later. Findings of brain positron emission tomography are nonspecific but may detect focal areas of hyper- or hypometabolism. Tumor screening with whole body computed tomography or positron emission tomography scan is usually warranted, especially if antibodies that are known to be associated with specific tumors are present (Table 1). The modified Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score, a 10-item, 16-point index, primarily based on clinical evaluation (such as new-onset epilepsy, neuropsychiatric manifestations, and autonomic dysfunction) (Table 2), has been developed to predict specific neuronal presence autoantibodies.23Dubey D. Pittock S.J. McKeon A. Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability.Epilepsia. 2019; 60: 367-369Crossref PubMed Scopus (17) Google Scholar The sensitivity and specificity of the APE2 score greater than but not equivalent to 4 in predicting neuronal autoantibody (thereby AAE) were 98% and 84%, respectively.23Dubey D. Pittock S.J. McKeon A. Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability.Epilepsia. 2019; 60: 367-369Crossref PubMed Scopus (17) Google Scholar Most clinicians could easily use this score, even in a primary care setting or emergency departments. However, it should be noted that the APE2 score is likely most useful to pick up ASSAE rather than AAE. Importantly, the score may not be sensitive enough to diagnose patients with chronic epilepsy and underlying intracellular antibodies such as GAD65 antibodies in which features of limbic encephalitis may be lacking. To address these issues, recently, de Bruijn et al24de Bruijn M.A.A.M. Bastiaansen A.E.M. Mojzisova H. et al.Antibodies contributing to focal epilepsy signs and symptoms score.Ann Neurol. 2021; 89: 698-710Crossref PubMed Scopus (10) Google Scholar have created the Antibodies Causing Epilepsy Syndromes (ACES) score, a 6-item (cognitive symptoms, behavioral changes, autonomic symptoms, speech problems, autoimmune diseases, and temporal MRI hyperintensities) and a 6-point index. This score (cutoff ≥ 2) can be used to select patients requiring neuronal antibody screening.24de Bruijn M.A.A.M. Bastiaansen A.E.M. Mojzisova H. et al.Antibodies contributing to focal epilepsy signs and symptoms score.Ann Neurol. 2021; 89: 698-710Crossref PubMed Scopus (10) Google Scholar Although the items for ACES and APE2 scores partially overlap, the ACES score is more sensitive for patients with focal epilepsy without overt encephalitis. Also, because this score assigns a 1 point for each risk factor, it is much easier to score than APE2 (a value-weighted score), thus more likely to be used in clinical settings.24de Bruijn M.A.A.M. Bastiaansen A.E.M. Mojzisova H. et al.Antibodies contributing to focal epilepsy signs and symptoms score.Ann Neurol. 2021; 89: 698-710Crossref PubMed Scopus (10) Google Scholar Treatment recommendation is inferred from the autoimmune encephalitis literature, and currently, little is known about the efficacy of immunotherapy in patients with AAE without signs and symptoms of encephalitis. Observational studies and a clinical trial suggest that early immunotherapy can shorten the time to seizure cessation or reduce and improve long-term outcomes, including cognition.25Thompson J. Bi M. Murchison A.G. et al.Faciobrachial Dystonic Seizures Study GroupThe importance of early immunotherapy in patients with faciobrachial dystonic seizures.Brain. 2018; 141: 348-356Crossref PubMed Scopus (146) Google Scholar Although evidence is still limited, the current recommended first-line management is immunotherapy with either intravenous methylprednisolone (1 g/d for 3-5 days), intravenous immunoglobulin (0.4 g/kg per day for 5 days), or plasmapheresis (plasma exchange [PLEX], every alternate day for 5 sessions).22Quek A.M. Britton J.W. McKeon A. et al.Autoimmune epilepsy: clinical characteristics and response to immunotherapy.Arch Neurol. 2012; 69: 582-593Crossref PubMed Scopus (239) Google Scholar,26Toledano M. Britton J.W. McKeon A. et al.Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.Neurology. 2014; 82: 1578-1586Crossref PubMed Scopus (134) Google Scholar If there is no response, minimal response (<50% of seizure reduction), or subsequent relapse after initial improvement with the first-line treatment, it is reasonable to initiate second-line immunosuppressive therapies such as rituximab or cyclophosphamide.6Titulaer M.J. 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: 157-165Abstract Full Text Full Text PDF PubMed Scopus (1647) Google Scholar,26Toledano M. Britton J.W. McKeon A. et al.Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.Neurology. 2014; 82: 1578-1586Crossref PubMed Scopus (134) Google Scholar Typically, patients with antibodies against surface antigens are more likely to respond to immunotherapy, especially when diagnosed early.26Toledano M. Britton J.W. McKeon A. et al.Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.Neurology. 2014; 82: 1578-1586Crossref PubMed Scopus (134) Google Scholar A recent study by McGinty et al27McGinty R.N. Handel A. Moloney T. et al.Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies.J Neurol Neurosurg Psychiatry. 2021; 92: 291-294Crossref PubMed Scopus (10) Google Scholar suggests that immunotherapy is generally effective in patients with seizures as part of autoimmune encephalitis and not in those with epilepsy related to positive neuronal antibody results (AAE); that is, the clinical phenotype is paramount in guiding the relevance of autoantibody results, including the decision on a trial of immunotherapy. Antiseizure medications should be initiated in adjunct with immunotherapy. It should also be noted that antibody testing may be falsely negative if testing is done after immunotherapy administration, especially PLEX or rituximab. Therefore, it is a good practice to communicate with the laboratory to save initial CSF samples to be used for future testing. This further underscores the need for early neurology or neuroimmunology consultation when ASSAE or AAE is suspected. There are ongoing discussions on the proper terminology, especially surrounding the term epilepsy in autoimmune encephalitis, given many patients who suffer from encephalitis-associated seizures achieve seizure freedom after treatment with immunotherapy.2Steriade C. Britton J. Dale R.C. et al.Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions.Epilepsia. 2020; 61: 1341-1351Crossref PubMed Scopus (36) Google Scholar,26Toledano M. Britton J.W. McKeon A. et al.Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.Neurology. 2014; 82: 1578-1586Crossref PubMed Scopus (134) Google Scholar Although most patients with intracellular antibodies, including GAD65 and Ma1/2 require lifelong ASM therapy, most patients with cell surface antibodies (eg, NMDAR [>80%] and LGI1 [>70%]) require only short-term ASM therapy, typically 6 to 24 months.25Thompson J. Bi M. Murchison A.G. et al.Faciobrachial Dystonic Seizures Study GroupThe importance of early immunotherapy in patients with faciobrachial dystonic seizures.Brain. 2018; 141: 348-356Crossref PubMed Scopus (146) Google Scholar,28Feyissa A.M. López Chiriboga A.S. Britton J.W. Antiepileptic drug therapy in patients with autoimmune epilepsy.Neurol Neuroimmunol Neuroinflamm. 2017; 4: e353Crossref PubMed Scopus (44) Google Scholar, 29Vogrig A. Joubert B. André-Obadia N. Gigli G.L. Rheims S. Honnorat J. Seizure specificities in patients with antibody-mediated autoimmune encephalitis.Epilepsia. 2019; 60: 1508-1525Crossref PubMed Scopus (33) Google Scholar, 30de Bruijn M.A.A.M. van Sonderen A. van Coevorden-Hameete M.H. et al.Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.Neurology. 2019; 92: e2185-e2196Crossref PubMed Scopus (82) Google Scholar The International League Against Epilepsy Autoimmunity and Inflammation Taskforce has recently proposed conceptual definitions for 2 main diagnostic entities: (1) ASSAE and (2) AAE, the latter of which suggests an enduring predisposition to seizures.2Steriade C. Britton J. Dale R.C. et al.Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions.Epilepsia. 2020; 61: 1341-1351Crossref PubMed Scopus (36) Google Scholar Although the previously discussed APE2 and ACES scores were initially designed and validated to predict the likelihood of neural antibody positivity, there is currently no consensus on the established criteria for diagnosing ASSAE or AAE.31Dubey D. Singh J. Britton J.W. et al.Predictive models in the diagnosis and treatment of autoimmune epilepsy.Epilepsia. 2017; 58: 1181-1189Crossref PubMed Scopus (72) Google Scholar Only a small subpopulation with neuronal surface antibody positivity develops intractable AAE. Most patients in this population report an excellent response to immunotherapy and have a better overall prognosis than do patients with antibodies targeting nuclear or cytoplasmic proteins. The resolution of symptoms after immunotherapy for patients with cell surface antibodies might point toward an argument for their pathogenicity. Recently, intracerebroventricular infusion of anti-NMDAR IgG in mice has been found to induce seizures, suggesting a possible direct pathogenic role for surface neuronal antibodies.19Taraschenko O. Fox H.S. Pittock S.J. et al.A mouse model of seizures in anti-N-methyl-d-aspartate receptor encephalitis.Epilepsia. 2019; 60: 452-463Crossref PubMed Scopus (20) Google Scholar To date, there have been mixed findings with regard to intracellular antibodies’ direct pathogenic role.2Steriade C. Britton J. Dale R.C. et al.Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions.Epilepsia. 2020; 61: 1341-1351Crossref PubMed Scopu