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

      Abbreviations and Acronyms:

      AAE (autoimmune-associated epilepsy), ACES (Antibodies Causing Epilepsy Syndromes), APE2 (Antibody Prevalence in Epilepsy and Encephalopathy), ASM (antiseizure medication), ASSAE (acute symptomatic seizures secondary to autoimmune encephalitis), cNORSE (cryptogenic new-onset refractory status epilepticus), CNS (central nervous system), CSF (cerebrospinal fluid), GAD65 (glutamic acid decarboxylase 65-kDa isoform), IL (interleukin), LGI1 (leucine-rich glioma-inactivated 1), MRI (magnetic resonance imaging), NMDAR (N-methyl-d-aspartate receptor), NORSE (new-onset refractory status epilepticus), PLEX (plasma exchange), VGKC (voltage-gated potassium channel)
      More than 50 million people worldwide have epilepsy, and approximately 30% of these patients continue to experience seizures despite management with antiseizure medications (ASMs).
      Epilepsy
      World Health Organization website.
      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.
      • Steriade C.
      • Britton J.
      • Dale R.C.
      • et al.
      Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions.
      The detection of neural autoantibodies is essential in establishing the diagnosis of autoimmune encephalitis.
      • Graus F.
      • Titulaer M.J.
      • Balu R.
      • et al.
      A clinical approach to diagnosis of autoimmune encephalitis.
      Most of these antibodies target neuronal cell surface antigens, including synaptic neurotransmitter receptors, ion channels, or related proteins (eg, glioma inactivated 1 protein [LGI1],
      • Irani S.R.
      • Michell A.W.
      • Lang B.
      • et al.
      Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.
      ,
      • van Sonderen A.
      • Schreurs M.W.
      • de Bruijn M.A.
      • et al.
      The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies.
      N-methyl-d-aspartate receptor [NMDAR],
      • Titulaer 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.
      ,
      • Dalmau J.
      • Gleichman A.J.
      • Hughes E.G.
      • et al.
      Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
      γ-aminobutyric acid type A receptor,
      • Petit-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.
      and γ-aminobutyric acid B receptor
      • Lancaster 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.
      ). Another group of antibodies targets neuronal intranuclear or cytoplasmic antigens (eg, glutamic acid decarboxylase 65-kDa isoform [GAD65]
      • Malter M.P.
      • Helmstaedter C.
      • Urbach H.
      • Vincent A.
      • Bien C.G.
      Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis.
      and Ma1/2).
      • Dalmau J.
      • Graus F.
      • Villarejo A.
      • et al.
      Clinical analysis of anti-Ma2-associated encephalitis.
      Table 1 summarizes the best known currently identified antibodies associated with autoimmune encephalitis.
      • Joubert 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.
      • Lancaster E.
      • Huijbers M.G.
      • Bar V.
      • et al.
      Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia.
      • Spatola M.
      • Sabater L.
      • Planagumà J.
      • et al.
      Encephalitis with mGluR5 antibodies: symptoms and antibody effects.
      • Carvajal-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].
      • Graus F.
      • Keime-Guibert F.
      • Reñe R.
      • et al.
      Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients.
      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.
      • von 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.
      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 Epilepsy
      Antibody-targeting antigenMost common seizure typeCommon nonseizure symptomAcute symptomatic seizure prevalenceRisk of AAEPrevalence of malignant neoplasmMain type(s) of malignant neoplasmResponse to immunotherapy
      Cell surface antigensNMDAR
      • Titulaer 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.
      ,
      • Dalmau J.
      • Gleichman A.J.
      • Hughes E.G.
      • et al.
      Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
      • Tonic-clonic
      • Focal
      • EPC
      • Behavioral and psychiatric changes
      • Dyskinesia
      70%-80%<5%Varies with sex

      30%-40%
      Ovarian teratomaGood
      AMPAR
      • Joubert 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.
      • Temporal lobe
      • Opsoclonus
      • Cognitive dysfunction
      30%-40%<5%50%-60%
      • SCLC
      • Thymoma
      • Breast
      Good
      GABAaR
      • Petit-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.
      • Refractory status epilepticus
      • EPC
      • Behavioral changes
      • Cognitive dysfunction
      80%-90%<5%20%-30%ThymomaGood
      GABAbR
      • Lancaster 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.
      • Focal onset impaired awareness
      • Focal to bilateral tonic-clonic seizures
      • Behavioral changes
      • Cognitive dysfunction
      90%-95%20%-30%50%-60%SCLCGood
      LGI1
      • Irani S.R.
      • Michell A.W.
      • Lang B.
      • et al.
      Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.
      ,
      • van Sonderen A.
      • Schreurs M.W.
      • de Bruijn M.A.
      • et al.
      The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies.
      • Faciobrachial dystonic seizures
      • Focal aware
      • Focal to bilateral tonic-clonic seizures
      • Hyponatremia
      • Cognitive dysfunction
      80%15%<5%ThymomaGood
      CASPR2
      • van Sonderen A.
      • Schreurs M.W.
      • de Bruijn M.A.
      • et al.
      The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies.
      ,
      • Lancaster E.
      • Huijbers M.G.
      • Bar V.
      • et al.
      Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia.
      • Focal onset impaired awareness
      • Morvan syndrome
      • Cognitive dysfunction
      40%-50%<10%<20%ThymomaGood
      mGluR5
      • Spatola M.
      • Sabater L.
      • Planagumà J.
      • et al.
      Encephalitis with mGluR5 antibodies: symptoms and antibody effects.
      • Myoclonic
      • Psychiatric changes
      • Cognitive dysfunction
      50%-60%5%50%-60%Hodgkin lymphomaGood
      GlyR
      • Carvajal-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].
      • Refractory SE
      • EPC
      • Myoclonus
      • PERM
      • SPSD-plus phenotype
      10%-40%Unclear10%-15%
      • Thymoma
      • B-cell lymphoma
      • Hodgkin lymphoma
      • Breast
      • Melanoma
      Good
      Intracellular antigensGAD65
      • Malter M.P.
      • Helmstaedter C.
      • Urbach H.
      • Vincent A.
      • Bien C.G.
      Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis.
      • TLE
      • Stiff person SPSD
      • Cerebellar ataxia
      • Cognitive dysfunction
      10%-50%>80%<10%
      • Very rare, adenocarcinoma, thymoma
      Poor
      Ma2
      • Dalmau J.
      • Graus F.
      • Villarejo A.
      • et al.
      Clinical analysis of anti-Ma2-associated encephalitis.
      • TLE
      • Cognitive dysfunction hypersomnia
      • Ataxia
      40%-50%>60%>90%
      • Testicular germ cell
      • SCLC
      • Breast
      Poor
      Hu/ANNA-1
      • Graus F.
      • Keime-Guibert F.
      • Reñe R.
      • et al.
      Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients.
      • TLE
      • Dysphagia
      • Dysarthria
      • Hypoventilation
      • Ataxia
      40%-50%>60%>95%
      • SCLC
      Poor
      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.

      Where Are We Standing?

      Pathophysiology

      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).
      • Fang Z.
      • Yang Y.
      • Chen X.
      • et al.
      Advances in autoimmune epilepsy associated with antibodies, their potential pathogenic molecular mechanisms, and current recommended immunotherapies.
      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.
      • Taraschenko O.
      • Fox H.S.
      • Pittock S.J.
      • et al.
      A mouse model of seizures in anti-N-methyl-d-aspartate receptor encephalitis.

      Clinical Presentation

      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.
      • Irani S.R.
      • Michell A.W.
      • Lang B.
      • et al.
      Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.
      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%),
      • Gaspard N.
      • Foreman B.P.
      • Alvarez V.
      • et al.
      New-onset refractory status epilepticus: etiology, clinical features, and outcome.
      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.
      • Yanagida A.
      • Kanazawa N.
      • Kaneko J.
      • et al.
      Clinically based score predicting cryptogenic NORSE at the early stage of status epilepticus.
      Table 2 summarizes clinical clues that should raise suspicion of ASSAE.
      Table 2Clues Suggestive of Autoimmune Encephalitis–Related Acute Symptomatic Seizure
      Clinical 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 cancer
      Other 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 brush
      MRI, magnetic resonance imaging; NORSE, new-onset refractory status epilepticus; T2-FLAIR, T2-weighted fluid-attenuated inversion recovery sequence.

      Diagnosis

      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.
      • Graus F.
      • Titulaer M.J.
      • Balu R.
      • et al.
      A clinical approach to diagnosis of autoimmune encephalitis.
      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.
      • Graus F.
      • Titulaer M.J.
      • Balu R.
      • et al.
      A clinical approach to diagnosis of autoimmune encephalitis.
      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.
      • Graus F.
      • Titulaer M.J.
      • Balu R.
      • et al.
      A clinical approach to diagnosis of autoimmune encephalitis.
      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%),
      • Quek A.M.
      • Britton J.W.
      • McKeon A.
      • et al.
      Autoimmune epilepsy: clinical characteristics and response to immunotherapy.
      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.
      • Dubey D.
      • Pittock S.J.
      • McKeon A.
      Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability.
      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.
      • Dubey D.
      • Pittock S.J.
      • McKeon A.
      Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability.
      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 al
      • de Bruijn M.A.A.M.
      • Bastiaansen A.E.M.
      • Mojzisova H.
      • et al.
      Antibodies contributing to focal epilepsy signs and symptoms score.
      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.
      • de Bruijn M.A.A.M.
      • Bastiaansen A.E.M.
      • Mojzisova H.
      • et al.
      Antibodies contributing to focal epilepsy signs and symptoms score.
      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.
      • de Bruijn M.A.A.M.
      • Bastiaansen A.E.M.
      • Mojzisova H.
      • et al.
      Antibodies contributing to focal epilepsy signs and symptoms score.

      Treatment

      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.
      • Thompson J.
      • Bi M.
      • Murchison A.G.
      • et al.
      Faciobrachial Dystonic Seizures Study Group
      The importance of early immunotherapy in patients with faciobrachial dystonic seizures.
      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).
      • Quek A.M.
      • Britton J.W.
      • McKeon A.
      • et al.
      Autoimmune epilepsy: clinical characteristics and response to immunotherapy.
      ,
      • Toledano M.
      • Britton J.W.
      • McKeon A.
      • et al.
      Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.
      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.
      • Titulaer 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.
      ,
      • Toledano M.
      • Britton J.W.
      • McKeon A.
      • et al.
      Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.
      Typically, patients with antibodies against surface antigens are more likely to respond to immunotherapy, especially when diagnosed early.
      • Toledano M.
      • Britton J.W.
      • McKeon A.
      • et al.
      Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.
      A recent study by McGinty et al
      • McGinty R.N.
      • Handel A.
      • Moloney T.
      • et al.
      Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies.
      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.

      Where Are We Headed?

      Definition and Diagnostic Criteria

      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.
      • Steriade C.
      • Britton J.
      • Dale R.C.
      • et al.
      Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions.
      ,
      • Toledano M.
      • Britton J.W.
      • McKeon A.
      • et al.
      Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.
      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.
      • Thompson J.
      • Bi M.
      • Murchison A.G.
      • et al.
      Faciobrachial Dystonic Seizures Study Group
      The importance of early immunotherapy in patients with faciobrachial dystonic seizures.
      ,
      • Feyissa A.M.
      • López Chiriboga A.S.
      • Britton J.W.
      Antiepileptic drug therapy in patients with autoimmune epilepsy.
      • Vogrig A.
      • Joubert B.
      • André-Obadia N.
      • Gigli G.L.
      • Rheims S.
      • Honnorat J.
      Seizure specificities in patients with antibody-mediated autoimmune encephalitis.
      • de 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.
      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.
      • Steriade C.
      • Britton J.
      • Dale R.C.
      • et al.
      Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions.
      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.
      • Dubey D.
      • Singh J.
      • Britton J.W.
      • et al.
      Predictive models in the diagnosis and treatment of autoimmune epilepsy.

      Pathogenicity vs Epiphenomenon

      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.
      • Taraschenko O.
      • Fox H.S.
      • Pittock S.J.
      • et al.
      A mouse model of seizures in anti-N-methyl-d-aspartate receptor encephalitis.
      To date, there have been mixed findings with regard to intracellular antibodies’ direct pathogenic role.
      • Steriade C.
      • Britton J.
      • Dale R.C.
      • et al.
      Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions.
      In a recent study, Herdlevaer et al
      • Herdlevaer I.
      • Kråkenes T.
      • Schubert M.
      • Vedeler C.A.
      Localization of CDR2L and CDR2 in paraneoplastic cerebellar degeneration.
      reported that anti-Yo antibodies might have a direct effect on disrupting messenger RNA translation and/or protein synthesis. In contrast, other studies reported conflicting results on whether intracellular antibodies, such as anti-Hu antibodies, have a direct role in neuronal injury.
      • Greenlee J.E.
      • Clawson S.A.
      • Hill K.E.
      • et al.
      Neuronal uptake of anti-Hu antibody, but not anti-Ri antibody, leads to cell death in brain slice cultures.
      The inadequate response to immunotherapy in patients with antibodies against intracellular antigens likely reflects the early cytotoxic response leading to apoptosis or gliosis and may also suggest nonimmune mechanisms.
      • Fang Z.
      • Yang Y.
      • Chen X.
      • et al.
      Advances in autoimmune epilepsy associated with antibodies, their potential pathogenic molecular mechanisms, and current recommended immunotherapies.
      It remains to be determined whether the differences in immunotherapy responsiveness are secondary to innate differences between patients or are secondary to another unidentified pathogenic agent.

      Significance of Antibody Positivity

      With most antibodies, there are currently limited data and evidence supporting their titers having clinical relevance or whether they help predict clinical response to immunotherapy and cancer detection. The detection of nonspecific systemic autoantibodies, including antinuclear antibody and anti–thyroid peroxidase antibodies, does often not implicate ASSAE or AAE (Figure).
      • de Bruijn M.A.A.M.
      • Bastiaansen A.E.M.
      • Mojzisova H.
      • et al.
      Antibodies contributing to focal epilepsy signs and symptoms score.
      ,
      • Muñoz-Lopetegi A.
      • de Bruijn M.A.A.M.
      • Boukhrissi S.
      • et al.
      Neurologic syndromes related to anti-GAD65: clinical and serologic response to treatment [published correction appears in Neurol Neuroimmunol Neuroinflamm. 2020;7(4):e733].
      • Pittock S.J.
      • Yoshikawa H.
      • Ahlskog J.E.
      • et al.
      Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction.
      • Falip M.
      • Rodriguez-Bel L.
      • Castañer S.
      • et al.
      Musicogenic reflex seizures in epilepsy with glutamic acid decarbocylase antibodies.
      We recommend against testing thyroid peroxidase antibodies in patients with suspected AAE because these antibodies are nonspecific and commonly found in the general population, do not cross the blood-brain barrier, and lack pathogenic potential.
      • Mattozzi S.
      • Sabater L.
      • Escudero D.
      • et al.
      Hashimoto encephalopathy in the 21st century.
      However, it is essential to note that the presence of systemic autoimmunity may suggest a predisposition to CNS involvement. For example, GAD65 can be detected in individuals with type 1 diabetes, autoimmune thyroid disease, and pernicious anemia, and around 70% of patients with GAD65 neurological autoimmunity have one of these coexisting disorders.
      • McKeon A.
      • Tracy J.A.
      GAD65 neurological autoimmunity.
      Figure thumbnail gr1
      FigureAlgorithm for autoantibody testing, result interpretation, and risk of autoimmune encephalitis–associated epilepsy. AAE, autoimmune-associated epilepsy; AMPAR, alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ANA, antinuclear antibody; ANNA-1, type 1 antineuronal nuclear antibody; ASM, antiseizure medication; CASPR2, contactin-associated protein 2; CSF, cerebrospinal fluid; cNORSE, cryptogenic new-onset refractory status epilepticus; DM, diabetes mellitus; GABAa/bR, γ-aminobutyric acid A/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; NORSE, new-onset refractory status epilepticus; SCLC, small cell lung cancer; TPO, thyroid peroxidase. aAn anti-GAD65 enzyme-linked immunosorbent assay concentration of >10,000,000 IU/L
      • Muñoz-Lopetegi A.
      • de Bruijn M.A.A.M.
      • Boukhrissi S.
      • et al.
      Neurologic syndromes related to anti-GAD65: clinical and serologic response to treatment [published correction appears in Neurol Neuroimmunol Neuroinflamm. 2020;7(4):e733].
      and an radioimmunoassay titer of 20 nmol/L from the Mayo Clinic Laboratory
      • Pittock S.J.
      • Yoshikawa H.
      • Ahlskog J.E.
      • et al.
      Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction.
      or 2,000,000 U/L from non–Mayo Clinic Laboratories
      • Falip M.
      • Rodriguez-Bel L.
      • Castañer S.
      • et al.
      Musicogenic reflex seizures in epilepsy with glutamic acid decarbocylase antibodies.
      are generally considered clinically relevant.24 bConsider cNORSE for patients with a high cNORSE score.
      • Yanagida A.
      • Kanazawa N.
      • Kaneko J.
      • et al.
      Clinically based score predicting cryptogenic NORSE at the early stage of status epilepticus.
      Voltage-gated potassium channel (VGKC) antibodies, which are nonspecific neuronal antibodies that can bind to the VGKC complex, were previously thought to be likely antigenic targets but were recently found to be common in healthy controls and have no well-defined clinic syndrome.
      • van Sonderen A.
      • Schreurs M.W.
      • de Bruijn M.A.
      • et al.
      The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies.
      ,
      • Michael S.
      • Waters P.
      • Irani S.R.
      Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2.
      ,
      • Lang B.
      • Makuch M.
      • Moloney T.
      • et al.
      Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies.
      The initial radioimmunoassay that discovered the VGKC complex antibody would detect the pathogenic antibodies (that bind to surface-exposed domains of LGI1 and contactin-associated protein 2) and the nonpathogenic antibodies (that bind to the intracellular domains of the VGKC complex). In light of this, several investigators suggest avoiding testing for VGKC autoantibodies and only test for autoantibodies to LGI1 and contactin-associated protein 2 when ASSAE or AAE is suspected.
      • Michael S.
      • Waters P.
      • Irani S.R.
      Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2.
      With the increasing awareness of ASSAE and AAE, there can be mounting pressure on physicians to diagnose and treat this condition quickly. As such, it is critical to keep a broad differential in every case, particularly in antibody-negative patients who do not fulfill the clinical criteria (Table 2). Alternative diagnoses, including genetic and metabolic etiologies, should also be considered before exposing patients to the unnecessary adverse effects of immunotherapies and ASMs. Certainly, screening patients for antibodies irrespective of the clinical presentation, often using a single test, poses a therapeutic dilemma. This single test approach, using serum only and without confirmatory studies, may also explain the extraordinary variability in prevalence in AASSE or AAE among investigators (see Table 1 and Figure). Along the same lines, several studies have challenged the specificity of serum neuronal antibody positivity (eg, NMDAR and GAD65 antibodies) alone because these antibodies have been reported in patients with a wide range of diseases and healthy individuals.
      • Pittock S.J.
      • Yoshikawa H.
      • Ahlskog J.E.
      • et al.
      Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction.
      ,
      • Hara M.
      • Martinez-Hernandez E.
      • Ariño H.
      • et al.
      Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor.
      Antibody positivity should never replace clinical judgment. The Figure details our clinical management approach at Mayo Clinic in Florida.

      Autoantibody-Negative Autoimmune Epilepsy

      If standard commercial antibody testing for commonly identified neural autoantibodies is negative, and the suspicion of AAE or ASSAE remains high, sending samples to a research laboratory to look for potentially unclassified neural autoantibodies is recommended. Initial serum and CSF should be ideally saved for future testing, as subsequent samples might be contaminated by immunotherapy. Clinicians should also be aware that cNORSE cases can present similarly to autoimmune NORSE.
      • Yanagida A.
      • Kanazawa N.
      • Kaneko J.
      • et al.
      Clinically based score predicting cryptogenic NORSE at the early stage of status epilepticus.
      Seronegative ASSAE and cNORSE are generally less likely to receive acute or chronic immunotherapy, more likely to have status epilepticus that lasts longer in duration and potentially die of uncontrolled seizures.
      • Iizuka T.
      • Kanazawa N.
      • Kaneko J.
      • et al.
      Cryptogenic NORSE: Its distinctive clinical features and response to immunotherapy.
      Therefore, once infectious etiology is ruled out, early immunotherapy trials should be considered in patients with clinical features suggestive of ASSAE or cNORSE while waiting for antibody confirmation (Figure).

      Efficacy and Duration of Immunotherapy

      There are currently no data to suggest superiority in efficacy or safety when comparing different immunosuppressive options. There are also not enough data to suggest whether there is a benefit of trying second or third immunotherapy if a patient has no improvement after the administration of the first immunotherapy. Although some reports suggest that second-line immunosuppressive agents are often necessary and may be more effective than current immunosuppressive agents used at initial presentation, it remains unclear whether long-term immunosuppression is a useful treatment.
      • Irani S.R.
      • Gelfand J.M.
      • Bettcher B.M.
      • Singhal N.S.
      • Geschwind M.D.
      Effect of rituximab in patients with leucine-rich, glioma-inactivated 1 antibody-associated encephalopathy.
      ,
      • Xu X.
      • Lu Q.
      • Huang Y.
      • et al.
      Anti-NMDAR encephalitis: a single-center, longitudinal study in China.
      The duration and type of long-term maintenance immunotherapy are also yet to be established. Interestingly, recent studies have found elevated cytokines, including interleukin (IL)-1 and IL-6 in both serum and CSF, and preliminary data indicate that modulators of these cytokines, such as IL-1 (eg, anakinra) or IL-6 (eg, tocilizumab) inhibitors, may be useful.
      • Gofton T.E.
      • Gaspard N.
      • Hocker S.E.
      • Loddenkemper T.
      • Hirsch L.J.
      New onset refractory status epilepticus research: what is on the horizon?.
      • Jun J.S.
      • Lee S.T.
      • Kim R.
      • Chu K.
      • Lee S.K.
      Tocilizumab treatment for new onset refractory status epilepticus.
      • 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.
      However, there is currently insufficient evidence to recommend these agents, even in patients with cNORSE regularly.

      Role of Conventional Epilepsy Therapies

      Antiseizure medications are often used in adjunct with immunotherapy, although their overall efficacy is relatively low.
      • Feyissa A.M.
      • López Chiriboga A.S.
      • Britton J.W.
      Antiepileptic drug therapy in patients with autoimmune epilepsy.
      Nevertheless, some evidence suggests that ASMs with sodium-channel blocking properties (eg, carbamazepine and lacosamide) may be more effective.
      • Feyissa A.M.
      • López Chiriboga A.S.
      • Britton J.W.
      Antiepileptic drug therapy in patients with autoimmune epilepsy.
      Although those with intracellular neuronal antibodies (eg, GAD65) require lifelong ASM therapy, those with neuronal surface antibodies (eg, NMDAR) may require only short-term therapy.
      • Thompson J.
      • Bi M.
      • Murchison A.G.
      • et al.
      Faciobrachial Dystonic Seizures Study Group
      The importance of early immunotherapy in patients with faciobrachial dystonic seizures.
      ,
      • Feyissa A.M.
      • López Chiriboga A.S.
      • Britton J.W.
      Antiepileptic drug therapy in patients with autoimmune epilepsy.
      • Vogrig A.
      • Joubert B.
      • André-Obadia N.
      • Gigli G.L.
      • Rheims S.
      • Honnorat J.
      Seizure specificities in patients with antibody-mediated autoimmune encephalitis.
      • de 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.
      Currently, the exact duration of ASM therapy for the latter group is not known. Many patients with refractory AAE are not surgical candidates because of seizures arising from multiple foci. Indeed, in patients with ASM-resistant AAE who underwent epilepsy surgery, the seizure freedom outcome was much worse than expected in other etiologies.
      • Carreño M.
      • Bien C.G.
      • Asadi-Pooya A.A.
      • et al.
      Epilepsy surgery in drug resistant temporal lobe epilepsy associated with neuronal antibodies.
      However, some patients might be candidates for neuromodulation therapy, including responsive neurostimulation therapy, which has been approved for treating adults with medically refractory focal onset seizures arising from 1 or 2 foci.
      • Feyissa A.M.
      • Mirro E.A.
      • Wabulya A.
      • Tatum W.O.
      • Wilmer-Fierro K.E.
      • Won Shin H.
      Brain-responsive neurostimulation treatment in patients with GAD65 antibody-associated autoimmune mesial temporal lobe epilepsy.
      The primary concern in using chronically implanted devices, including the responsive neurostimulation system, is the risk of device-related infection because some of these patients may be receiving chronic immunosuppressive treatments. Prospective multicenter trials are needed to examine the risks and efficacies of these devices in patients with drug-resistant AAE.

      Conclusion

      The identification of neural autoantibodies in patients with new-onset seizures of unknown etiology has led to the concept of ASSAE and AAE. In these patients, ASM-resistant seizures occur as an early and prominent feature. When combined with other symptoms suggestive of immune-mediated seizures, urgent consultation with neurology is recommended. Early treatment with immunotherapy can drastically alter the course of the disease. First-line immunotherapies include intravenous steroids, intravenous immunoglobulin, and PLEX. In the case of insufficient response, cyclophosphamide and rituximab can be considered appropriate second-line treatments. Treatment also includes adjunct ASM therapy and non-CNS tumor resection (if paraneoplastic etiology is suspected) when found on screening.
      As we continue to advance our knowledge in AAE and ASSAE, we need to clarify its definition and diagnostic criteria and promote recognition of relevant symptoms (detailed in Table 2) that would lead to early neurology referral and timely diagnosis. The recently developed APE2 and ACES scores have helped build a foundation for diagnosing ASSAE and AAE; however, there remains much ambiguity. Studies are needed to identify additional CSF and imaging biomarkers to help guide therapy and long-term monitoring. Future studies should also aim to discover optimal therapeutic agents and define the treatment duration of AAE and ASSAE. The role of long-term immunotherapy, including monoclonal antibodies, needs to be clarified in future prospective multicenter trials. At the molecular level, elucidating the exact pathophysiological mechanism(s) of AAE will help develop more specific and effective therapies. Lastly, insight into genetic risk factors and novel molecular biomarkers will aid the early diagnosis and therapeutic response.

      Supplemental Online Material

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