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Diagnostic utility of cerebrospinal fluid (CSF) findings in seizures and epilepsy with and without autoimmune-associated disease

  • Lisa Langenbruch
    Affiliations
    Department of Neurology with Institute of Translational Neurology, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany

    Department of Neurology, Klinikum Osnabrück, Am Finkenhügel 1, 49076 Osnabrück, Germany
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  • Heinz Wiendl
    Affiliations
    Department of Neurology with Institute of Translational Neurology, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany
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  • Catharina Groß
    Affiliations
    Department of Neurology with Institute of Translational Neurology, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany
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  • Stjepana Kovac
    Correspondence
    Correspondence to: Stjepana Kovac, Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany, Phone: 0049-251-8344463, Fax: 0049-251-8348199
    Affiliations
    Department of Neurology with Institute of Translational Neurology, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany
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Open ArchivePublished:June 28, 2021DOI:https://doi.org/10.1016/j.seizure.2021.06.030

      Highlights

      • CSF parameters that are frequently altered after seizures but not specific for seizure etiology include CSF protein and lactate.
      • Pleocytosis and CSF specific oligoclonal bands are rare and should be considered as signs of infectious or immune mediated seizures and epilepsy.
      • CSF analysis in new-onset seizures or status epilepticus is of particular importance if autoimmune etiology is suspected.
      • Clinically helpful biomarkers in CSF for refractory epilepsy or for assessment of neuronal damage are not available yet, but are an important area of future research.

      Abstract

      Patients with seizures and epilepsy routinely undergo multiple diagnostic tests, which may include cerebrospinal fluid (CSF) analysis. This review aims to outline different CSF parameters and their alterations in seizures or epilepsy. We then discuss the utility of CSF analysis in seizure patients in different clinical settings in depth.
      Some routine CSF parameters are frequently altered after seizures, but are not specific such as CSF protein and lactate. Pleocytosis and CSF specific oligoclonal bands are rare and should be considered as signs of infectious or immune mediated seizures and epilepsy. Markers of neuronal damage show conflicting results, and are as yet not established in clinical practice. Parameters of neuronal degeneration and more specific immune parameters are less well studied, and are areas of further research.
      CSF analysis in new-onset seizures or status epilepticus serves well in the differential diagnosis of seizure etiology. Here, considerations should include autoimmune-associated seizures. CSF findings in these disorders are a special focus of this review and are summarized in a comprehensive overview. Until now, CSF analysis has not yielded clinically helpful biomarkers for refractory epilepsy or for assessment of neuronal damage which is a subject of further studies.

      Keywords

      Abbreviations:

      ADEM (acute disseminated encephalomyelitis), AIE (autoimmune encephalitis), AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), ASM (antiseizure medication), CASPR2 (contactin-associated protein-like 2), CHI3L1 (chitinase 3 L protein 1), CNS (central nervous system), CSF (cerebrospinal fluid), d (days), DPPX (dipeptidyl-peptidase-like protein 6), GABAAR (γ-amino butyric acid receptor type A), GABABR (γ-amino butyric acid receptor type B), GAD65 (glutamic acid decarboxylase 65 kilodalton isoform), GLUT1 (glucose transporter type 1), GlyR (glycine receptor), h (hours), HS (hippocampal sclerosis), IFNγ (interferon γ), IL (interleukin), IL-1ra (interleukin 1 receptor antagonist), LE (limbic encephalitis), LGI1 (leucine-rich glioma-inactivated 1), mGluR5 (metabotropic glutamate subtype 5 receptor), MOG (myelin oligodendrocyte glycoprotein), MPO (myeloperoxidase), mRS (modified Rankin scale), NMDAR (N-methyl D-aspartate receptor), NORSE (new onset refractory status epilepticus), NSE (neuron-specific enolase), OCB (oligoclonal bands), PNES (psychogenic, non-epileptic seizures), POLG (polymerase gamma), SAH (subarachnoid hemorrhage), SE (status epilepticus), SOD1 (superoxide dismutase 1), TGFβ1 (transforming growth factor β1), TLE (temporal lobe epilepsy), TNFα (tumor necrosis factor α), VGKC (voltage-gated potassium channel), y (years)

      1. Introduction

      Patients with a first seizure or newly established epilepsy undergo routine diagnostics, mainly EEG and neuroimaging. First, these serve to clarify if a diagnosis of epilepsy can be established. Second, they aid in establishing epilepsy classification and etiology. However, test results may not be definite and clinical circumstances may demand additional laboratory tests including cerebrospinal fluid (CSF) analysis. This review aims at exploring the impact of seizures on CSF results and when CSF analysis is useful in (differential) diagnosis of seizures and epilepsy. First, alterations of CSF routine and some additional parameters in seizure patients is covered. Second, different clinical settings are explored with regard to CSF analysis. A special focus is then laid on the differential diagnosis of autoimmune-associated seizures and epilepsy. Seizures in the course of autoimmune encephalitis are increasingly recognized. In these cases, differential diagnosis is often difficult, but diagnosis has major therapeutic consequences, as rapid immune therapy is often more effective than classical antiseizure medication (ASM) [
      • Bruijn Maam de, van Sonderen A.
      • van Coevorden-Hameete M.H.
      • et al.
      Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.
      ].

      2. Routine CSF parameters

      Routine CSF parameters are often examined in first seizures or newly diagnosed epilepsy. Here, differentiation of findings induced or explained by the seizure itself from findings indicating an underlying condition such as meningitis or encephalitis is most important.

      2.1 Leukocyte cell count

      Among routine CSF parameters, leukocyte cell count is certainly most widely studied in seizures and epilepsy. There is a number of cohort studies examining CSF cell count in different clinical settings and varying patient cohorts (Table 1). The reported rates of pleocytosis range from 2 to 30%, even if including only studies in adult and adolescent patients and excluding studies focusing mainly on findings in status epilepticus (SE) [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ,
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ,
      • Devinsky O.
      • Nadi S.
      • Theodore W.H.
      • et al.
      Cerebrospinal fluid pleocytosis following simple, complex partial, and generalized tonic-clonic seizures.
      ,
      • Edwards R.
      • Schmidley J.W.
      • Simon R.P.
      How often does a CSF pleocytosis follow generalized convulsions?.
      ,
      • Lennox W.G.
      • Merritt H.H.
      The Cerebrospinal Fluid in `Essential' Epilepsy.
      ,
      • Prokesch R.C.
      • Rimland D.
      • Petrini J.L.
      • et al.
      Cerebrospinal fluid pleocytosis after seizures.
      ,
      • Zisimopoulou V.
      • Mamali M.
      • Katsavos S.
      • et al.
      Cerebrospinal fluid analysis after unprovoked first seizure.
      ]. Pleocytosis was mostly mild (max. 25 cells/µl) with moderate or marked pleocytosis found only exceptionally.
      Table 1.Overview of studies on CSF leukocyte cell count in seizures and epilepsy.
      Publicationpatient cohortrelevant exclusion criteriaageninterval seizure/CSF samplingleukocyte range per µlelevated CSF cell count% (cut-off)commentary
      Süße 2019
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      single seizures, epilepsy or SEautoimmune or infectious etiologyadults267mean 36–48 hmax. 284 (≥5)no differences comparing seizures semiologies or SE/single seizures
      Scramstad 2017
      • Scramstad C.
      • Jackson A.C.
      Cerebrospinal fluid pleocytosis in critical care patients with seizures.
      ICU patients with a seizure +/- preexisting epilepsyadults51≤ 5 dmax. 11723.5 (>5)all patients with pleocytosis had acute or chronic brain disorder incl. infectious diseases
      Zisimopoulou 2016
      • Zisimopoulou V.
      • Mamali M.
      • Katsavos S.
      • et al.
      Cerebrospinal fluid analysis after unprovoked first seizure.
      unprovoked first seizuresany condition suggesting a provoked seizure> 16 y71< 24 h0–409.9 (>5)35% had at least one pathological CSF parameter
      Tumani 2015
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      epileptic or non-epileptic seizuresCNS inflammation14–97 y319median 1 dmax. 246 (≥5)no correlation with seizure duration; no differences in unprovoked seizures vs. epilepsy
      Li 2013
      • Li Y.-.J.
      • Wang Z.-.H.
      • Zhang B.
      • et al.
      Disruption of the blood-brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels.
      first or recurring bilateral tonic-clonic seizuresacute-symptomatic seizuresadults31< 24 h (mean 6.2 h)not reportednot reportedhigher mean CSF leukocyte cell count compared to control group
      Devinsky 1988
      • Devinsky O.
      • Nadi S.
      • Theodore W.H.
      • et al.
      Cerebrospinal fluid pleocytosis following simple, complex partial, and generalized tonic-clonic seizures.
      epilepsyacute neurologic disease14 – 44 y27 (62 samples)mean 17.6 hmax. 1211.3 (>5)shorter interval to seizure in samples with pleocytosis
      Edwards 1983
      • Edwards R.
      • Schmidley J.W.
      • Simon R.P.
      How often does a CSF pleocytosis follow generalized convulsions?.
      bilateral tonic clonic seizuresacute neurologic diseaseadults91 (98 samples)≤ 72 hmax. 652 (>5)
      Prokesch 1983
      • Prokesch R.C.
      • Rimland D.
      • Petrini J.L.
      • et al.
      Cerebrospinal fluid pleocytosis after seizures.
      seizures or epilepsymeningitis, SAHadults102≤ 48 hmax. 46430 (>5)no differences depending on seizure semiology
      Lennox 1936
      • Lennox W.G.
      • Merritt H.H.
      The Cerebrospinal Fluid in `Essential' Epilepsy.
      epilepsy“organic nervous disease”not reported734not reportedmax. 214 (>5)
      SE, status epilepticus; CNS, central nervous system; CSF, cerebrospinal fluid; SAH, subarachnoid hemorrhage; h, hours; d, days; y, years.
      As most studies did not provide individual patient data, exact frequencies could not be determined. This heterogeneity may result at least in part from different diagnostic means over the decades which would lead to inclusion of different patient groups. Additionally, cell count procedures may have varied. These were not specified in all publications.
      Control groups are often lacking. Those studies that did report a control group (for example of persons undergoing CSF examination for exclusion of acute neurological disease) found a higher mean CSF leukocyte count compared to controls (e.g. 8.2 vs. 2.0/µl) [
      • Li Y.-.J.
      • Wang Z.-.H.
      • Zhang B.
      • et al.
      Disruption of the blood-brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels.
      ].
      Not all studies reported the interval between last seizure and CSF sampling. If reported, results suggest a decrease of leukocyte cell count over time (for example 7% pleocytosis on day 0 or 1 vs. 3.5% with later sampling), although not all results were significant [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ,
      • Devinsky O.
      • Nadi S.
      • Theodore W.H.
      • et al.
      Cerebrospinal fluid pleocytosis following simple, complex partial, and generalized tonic-clonic seizures.
      ,
      • Langenbruch L.
      • Bleß L.
      • Schulte-Mecklenbeck A.
      • et al.
      Blood and cerebrospinal fluid immune cell profiles in patients with temporal lobe epilepsy of different etiologies.
      ]. This is in line with blood leukocytosis after seizures with a similar time course [
      • Nass R.D.
      • Sassen R.
      • Elger C.E.
      • et al.
      The role of postictal laboratory blood analyses in the diagnosis and prognosis of seizures.
      ]. Both point to a transient systemic inflammatory reaction.
      Some findings suggest a higher proportion of CSF pleocytosis in patients with symptomatic epilepsy or alcohol withdrawal seizures [
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ,
      • Prokesch R.C.
      • Rimland D.
      • Petrini J.L.
      • et al.
      Cerebrospinal fluid pleocytosis after seizures.
      ,
      • Zisimopoulou V.
      • Mamali M.
      • Katsavos S.
      • et al.
      Cerebrospinal fluid analysis after unprovoked first seizure.
      ,
      • Scramstad C.
      • Jackson A.C.
      Cerebrospinal fluid pleocytosis in critical care patients with seizures.
      ], but evidence is far from definite as other studies found no difference comparing symptomatic and cryptogenic epilepsy patients, or epilepsy and unprovoked seizures without a definite epilepsy diagnosis [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ].
      Seizure semiology, duration, or number of seizures do not influence CSF leukocyte cell count [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ,
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ,
      • Devinsky O.
      • Nadi S.
      • Theodore W.H.
      • et al.
      Cerebrospinal fluid pleocytosis following simple, complex partial, and generalized tonic-clonic seizures.
      ,
      • Prokesch R.C.
      • Rimland D.
      • Petrini J.L.
      • et al.
      Cerebrospinal fluid pleocytosis after seizures.
      ,
      • Zisimopoulou V.
      • Mamali M.
      • Katsavos S.
      • et al.
      Cerebrospinal fluid analysis after unprovoked first seizure.
      ]. In SE, older studies showed mild CSF pleocytosis of > 5 leukocytes/µl in 8–15% after exclusion of acute symptomatic causes [
      • Aminoff M.J.
      • Simon R.P.
      Status epilepticus. Causes, clinical features and consequences in 98 patients.
      ,
      • Barry E.
      • Hauser W.A.
      Pleocytosis after status epilepticus.
      ]. It must be kept in mind that these studies included patients with seizures of > 30 min as SE. Recent data showed pleocytosis after SE in only 6% and did not find differences in SE versus single seizures [
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ,
      • Malter M.P.
      • Choi S.
      • Fink G.R.
      Cerebrospinal fluid findings in non-infectious status epilepticus.
      ].
      In summary, CSF pleocytosis after seizures is infrequent, but may be found especially in lumbar punctures performed in the first hours/days after a seizure. Given the rarity of this finding, CSF pleocytosis in a seizure patient should always prompt consideration of further diagnostic tests to exclude relevant causes such as meningitis or encephalitis.

      2.2 Total protein and albumin

      In contrast to CSF pleocytosis, elevated CSF protein and/or albumin is a frequent finding in seizures and epilepsy. Again, evidence is heterogenous with an elevated total protein reported in 10 to 61% (Table 2) [
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ,
      • Devinsky O.
      • Nadi S.
      • Theodore W.H.
      • et al.
      Cerebrospinal fluid pleocytosis following simple, complex partial, and generalized tonic-clonic seizures.
      ,
      • Edwards R.
      • Schmidley J.W.
      • Simon R.P.
      How often does a CSF pleocytosis follow generalized convulsions?.
      ,
      • Lennox W.G.
      • Merritt H.H.
      The Cerebrospinal Fluid in `Essential' Epilepsy.
      ,
      • Zisimopoulou V.
      • Mamali M.
      • Katsavos S.
      • et al.
      Cerebrospinal fluid analysis after unprovoked first seizure.
      ,
      • Chatzikonstantinou A.
      • Ebert A.D.
      • Hennerici M.G.
      Cerebrospinal fluid findings after epileptic seizures.
      ]. A frequent elevation of albumin quotient as a marker for blood/CSF barrier impairment or total CSF protein are also found in recent larger studies with careful patient selection and exclusion of patients with infectious or autoimmune epilepsies [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ,
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ].
      Table 2.Overview of studies on CSF protein in seizures or epilepsy.
      Publicationpatient cohortrelevant exclusion criteriaageninterval seizure/CSF samplingelevated CSF protein% (cut-off mg/dl)commentary
      Süße 2019
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      single seizures, epilepsy or SEautoimmune or infectious etiologyadults267mean 36–48 h51 (>50)no differences comparing seizures semiologies or SE/single seizures
      Zisimopoulou 2016
      • Zisimopoulou V.
      • Mamali M.
      • Katsavos S.
      • et al.
      Cerebrospinal fluid analysis after unprovoked first seizure.
      unprovoked first seizuresany condition suggesting a provoked seizure> 16 y71< 24 h31 (≥45)correlation with age, male sex
      Tumani 2015
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      epileptic or non-epileptic seizuresCNS inflammation14–97 y319median 1 dnot reported34% with elevated albumin quotient; correlation with seizure duration
      Chatzi-konstantinou 2015
      • Chatzikonstantinou A.
      • Ebert A.D.
      • Hennerici M.G.
      Cerebrospinal fluid findings after epileptic seizures.
      seizures, epilepsy, or SECSF pleocytosisadults151not reported61 (>40)correlation with age, male sex, bilateral tonic-clonic seizures
      Li 2013
      • Li Y.-.J.
      • Wang Z.-.H.
      • Zhang B.
      • et al.
      Disruption of the blood-brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels.
      first or recurring bilateral tonic-clonic seizuresacute-symptomatic seizuresadults31< 24 h (mean 6.2 h)not reportedhigher albumin quotient in patients vs. control group and in recurring vs. single seizures
      Devinsky 1988
      • Devinsky O.
      • Nadi S.
      • Theodore W.H.
      • et al.
      Cerebrospinal fluid pleocytosis following simple, complex partial, and generalized tonic-clonic seizures.
      epilepsyacute neurologic disease14 – 44 y27 (62 samples)mean 17.6 h26
      Edwards 1983
      • Edwards R.
      • Schmidley J.W.
      • Simon R.P.
      How often does a CSF pleocytosis follow generalized convulsions?.
      bilateral tonic clonic seizuresacute neurologic diseaseadults91 (98 samples)≤ 72 h18 (≥45)
      Lennox 1936
      • Lennox W.G.
      • Merritt H.H.
      The Cerebrospinal Fluid in `Essential' Epilepsy.
      epilepsy“organic nervous disease”not reported793not reported10 (>45)correlation with age
      SE, status epilepticus; CNS, central nervous system; CSF, cerebrospinal fluid; h, hours; d, days; y, years.
      The albumin quotient does not seem to depend on the time interval between last seizure and CSF sampling, although data is scarce [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ]. Increased total protein with older age was frequently seen [
      • Lennox W.G.
      • Merritt H.H.
      The Cerebrospinal Fluid in `Essential' Epilepsy.
      ,
      • Zisimopoulou V.
      • Mamali M.
      • Katsavos S.
      • et al.
      Cerebrospinal fluid analysis after unprovoked first seizure.
      ,
      • Chatzikonstantinou A.
      • Ebert A.D.
      • Hennerici M.G.
      Cerebrospinal fluid findings after epileptic seizures.
      ]. Some studies also found higher total protein in male patients [
      • Zisimopoulou V.
      • Mamali M.
      • Katsavos S.
      • et al.
      Cerebrospinal fluid analysis after unprovoked first seizure.
      ,
      • Chatzikonstantinou A.
      • Ebert A.D.
      • Hennerici M.G.
      Cerebrospinal fluid findings after epileptic seizures.
      ]. Evidence on a dependence of seizure semiology is conflicting and does not permit a clear statement [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ,
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ,
      • Chatzikonstantinou A.
      • Ebert A.D.
      • Hennerici M.G.
      Cerebrospinal fluid findings after epileptic seizures.
      ].
      No differences of CSF albumin quotient were seen comparing patients with structural/symptomatic and cryptogenic epilepsy, or patients with epilepsy and unprovoked seizures without a diagnosis of epilepsy [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ,
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ]. In contrast, another study found higher albumin quotients in patients with recurring seizures compared to patients with a first diagnosis of epilepsy or controls [
      • Li Y.-.J.
      • Wang Z.-.H.
      • Zhang B.
      • et al.
      Disruption of the blood-brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels.
      ]. In SE, elevated protein was found in 44% with an increased likelihood in refractory SE, although some data fail to indicate differential results in SE and single seizures [
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ,
      • Malter M.P.
      • Choi S.
      • Fink G.R.
      Cerebrospinal fluid findings in non-infectious status epilepticus.
      ].
      In summary, elevated CSF protein or albumin may be explained by a seizure in the absence of other CNS disease. It may be cause by seizure-induced blood/CSF barrier leakage, which is supported by recent imaging studies [
      • Marchi N.
      • Banjara M.
      • Janigro D.
      Blood-brain barrier, bulk flow, and interstitial clearance in epilepsy.
      ,
      • Rüber T.
      • David B.
      • Lüchters G.
      • et al.
      Evidence for peri-ictal blood-brain barrier dysfunction in patients with epilepsy.
      ].

      2.3 Intrathecal immunoglobuline synthesis

      Evidence on intrathecal immunoglobuline synthesis and oligoclonal bands (OCB) in epilepsy patients is rare. One study found a surprisingly high percentage of 34% in a mixed epilepsy cohort vs. 3% in controls, with an especially high frequency of intrathecal immunoglobuline synthesis of 45% in cryptogenic focal epilepsy [
      • Kowski A.B.
      • Volz M.S.
      • Holtkamp M.
      • et al.
      High frequency of intrathecal immunoglobulin synthesis in epilepsy so far classified cryptogenic.
      ]. These findings raise the question of underdiagnosed autoimmune diseases and were not replicated in other studies that found intrathecal IgG-synthesis or CSF-specific OCB in 0 to 8%, depending on etiology, and 10% in SE [
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ,
      • Langenbruch L.
      • Bleß L.
      • Schulte-Mecklenbeck A.
      • et al.
      Blood and cerebrospinal fluid immune cell profiles in patients with temporal lobe epilepsy of different etiologies.
      ,
      • Malter M.P.
      • Choi S.
      • Fink G.R.
      Cerebrospinal fluid findings in non-infectious status epilepticus.
      ,
      • Fauser S.
      • Soellner C.
      • Bien C.G.
      • et al.
      Intrathecal immunoglobulin synthesis in patients with symptomatic epilepsy and epilepsy of unknown etiology ('cryptogenic').
      ].

      2.4 Glucose and lactate

      A decreased CSF/serum glucose ratio (<0.4) is a rare finding after seizures (5.9% in a 2015 study) [
      • Chatzikonstantinou A.
      • Ebert A.D.
      • Hennerici M.G.
      Cerebrospinal fluid findings after epileptic seizures.
      ]. No association was found between a pathologic glucose ratio and clinical characteristics [
      • Chatzikonstantinou A.
      • Ebert A.D.
      • Hennerici M.G.
      Cerebrospinal fluid findings after epileptic seizures.
      ]. A negative correlation of higher CSF glucose values and abnormal EEG after unprovoked first seizures has been described, but was not replicated, and glucose ratio or lactate level were not given and thus these finding remains difficult to interpret [
      • Zisimopoulou V.
      • Mamali M.
      • Katsavos S.
      • et al.
      Cerebrospinal fluid analysis after unprovoked first seizure.
      ]. In seizures or epilepsy, CSF-glucose levels are of little diagnostic value. One exception is hereditary GLUT1-transporter-deficiency (GLUT1, glucose transporter type 1). Patients typically show very low CSF glucose levels, but as diagnosis is usually established in childhood, neurologists will rarely make use of this diagnostic means in an adult patient [
      • Koch H.
      • Weber Y.G.
      The glucose transporter type 1 (Glut1) syndromes.
      ].
      An elevated CSF lactate after seizures is found in 14% to 28% [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ,
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ,
      • Chatzikonstantinou A.
      • Ebert A.D.
      • Hennerici M.G.
      Cerebrospinal fluid findings after epileptic seizures.
      ]. Lactate values are time-dependent with regard to the interval between last seizure and CSF sampling with elevated values found in 19% in CSF samples taken on the same day or the following day at the latest vs. 5% in samples taken from day 2 on [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ]. Elevated levels were only found until day 3. No difference was found depending on seizure etiology [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ,
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ] or in patients with established epilepsy compared to patients with a first seizure without an epilepsy diagnosis [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ]. Lactate may be higher after seizures with motor onset compared to non-motor onset, although data are inconclusive [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ,
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ]. Likewise, SE was associated with higher lactate in some, but not all studies [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ,
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ,
      • Chatzikonstantinou A.
      • Ebert A.D.
      • Hennerici M.G.
      Cerebrospinal fluid findings after epileptic seizures.
      ]. One study found significantly increased lactate values in patients after SE with poor outcome in comparison to patients with good outcome [
      • Calabrese V.P.
      • Gruemer H.D.
      • James K.
      • et al.
      Cerebrospinal fluid lactate levels and prognosis in status epilepticus.
      ]. This correlation with outcome of SE could not be replicated in a more recent study in non-infectious SE, although elevated lactate was confirmed in 23% [
      • Malter M.P.
      • Choi S.
      • Fink G.R.
      Cerebrospinal fluid findings in non-infectious status epilepticus.
      ]. Generally, comparison is made difficult due to differing cut-off values. Elevated lactate may be explained by increased neuronal (or peripheral) glycolysis during a seizure, but it remains inconclusive how to interpret this in a clinical setting. Large increases in CSF lactate in a patient with epilepsy with or without direct association to a seizure may be found in mitochondrial disease, where increase in lactate is a direct consequence of the mitochondrial metabolic defect with impaired oxidative phosphorylation and a shift towards glycolysis [
      • Baheerathan A.
      • Pitceathly R.D.
      • Curtis C.
      • et al.
      CSF lactate.
      ]. It is unclear which levels of CSF lactate should prompt evaluation of mitochondrial disease. We would advise to consider this as a differential diagnosis if other clues to a mitochondrial epilepsy are present such as occipital preponderance in both EEG and MRI and clinical features. Of note, mitochondrial disease such as polymerase gamma (POLG) mutation related mitochondrial disease often manifest in status epilepticus [
      • Janssen W.
      • Quaegebeur A.
      • van Goethem G.
      • et al.
      The spectrum of epilepsy caused by POLG mutations.
      ].

      3. Markers of neuronal damage

      Assessing markers of neuronal damage may aim to distinguish seizure severity or to prognosticate disease course and seizure sequelae.

      3.1 Neuron-specific enolase (NSE) and S100B

      NSE as a brain-derived protein has been studied for its diagnostic utility in epilepsy similarly to S100B. Most often, NSE and S100B were evaluated in serum samples. These findings are conflicting: one study found moderately increased serum NSE values in about a third of patients after single seizures [
      • Tumani H.
      • Otto M.
      • Gefeller O.
      • et al.
      Kinetics of serum neuron-specific enolase and prolactin in patients after single epileptic seizures.
      ]. Increased serum NSE in children after seizures is found less frequently [
      • Wong M.
      • Ess K.
      • Landt M.
      Cerebrospinal fluid neuron-specific enolase following seizures in children: role of etiology.
      ,
      • Tanabe T.
      • Suzuki S.
      • Hara K.
      • et al.
      Cerebrospinal fluid and serum neuron-specific enolase levels after febrile seizures.
      ]. Evidence on serum S100B is conflicting with some studies showing increased values after seizures, which were not replicated in other studies [
      • Asadollahi M.
      • Simani L.
      The diagnostic value of serum UCHL-1 and S100-B levels in differentiate epileptic seizures from psychogenic attacks.
      ,
      • Leutmezer F.
      • Wagner O.
      • Baumgartner C.
      Serum s-100 protein is not a suitable seizure marker in temporal lobe epilepsy.
      ,
      • Portela L.V.C.
      • Tort A.B.L.
      • Walz R.
      • et al.
      Interictal serum S100B levels in chronic neurocysticercosis and idiopathic epilepsy.
      ].
      CSF has been examined less often. In a group of patients with unprovoked first seizures, CSF NSE and S100B values did not differ from controls, serum and CSF values did not correlate [
      • Palmio J.
      • Peltola J.
      • Vuorinen P.
      • et al.
      Normal CSF neuron-specific enolase and S-100 protein levels in patients with recent non-complicated tonic-clonic seizures.
      ]. In contrast, in a small group of patients with refractory temporal lobe epilepsy who had been seizure-free for at least one week, cisternal NSE and S100B in CSF gathered from foramen ovale electrodes were increased ipsilateral to the seizure onset zone [
      • Steinhoff B.J.
      • Tumani H.
      • Otto M.
      • et al.
      Cisternal S100 protein and neuron-specific enolase are elevated and site-specific markers in intractable temporal lobe epilepsy.
      ]. After SE, CSF NSE was found to be increased in most patients with a good correlation of CSF and serum NSE values [
      • Correale J.
      • Rabinowicz A.L.
      • Heck C.N.
      • et al.
      Status epilepticus increases CSF levels of neuron-specific enolase and alters the blood-brain barrier.
      ]. In children, findings on correlation of CSF NSE and seizure duration or severity yielded conflicting results [
      • Tanabe T.
      • Suzuki S.
      • Hara K.
      • et al.
      Cerebrospinal fluid and serum neuron-specific enolase levels after febrile seizures.
      ,
      • Shi Ll-M
      • Chen R.-.J.
      • Zhang H.
      • et al.
      Cerebrospinal fluid neuron specific enolase, interleukin-1β and erythropoietin concentrations in children after seizures.
      ,
      • Rodríguez-Núñez A.
      • Cid E.
      • Rodríguez-García J.
      • et al.
      Cerebrospinal fluid purine metabolite and neuron-specific enolase concentrations after febrile seizures.
      ]. A recent meta-analysis found a significant increase of serum and CSF NSE in children with epilepsy, but stressed the heterogeneity of results [
      • Mu R.-.Z.
      • Liu S.
      • Liang K.-.G.
      • et al.
      A meta-analysis of neuron-specific enolase levels in cerebrospinal fluid and serum in children with epilepsy.
      ]. Taken together, neither CSF nor serum NSE or S100B appear to be helpful in a clinical setting in an individual patient with seizures.

      3.2 Tau, amyloid and alpha-synuclein

      Elevated CSF tau protein was found in 36% of patients after epileptic seizures with highest levels after SE [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ]. These findings were not replicated in another study which did not find elevated CSF tau or phospho-tau levels after epileptic seizures [
      • Palmio J.
      • Suhonen J.
      • Keränen T.
      • et al.
      Cerebrospinal fluid tau as a marker of neuronal damage after epileptic seizure.
      ]. Here, a decreased phospho-tau/t-tau ratio was found only in subgroups depending on seizure etiology. Further studies even found decreased t-tau and/or p-tau levels, although partly with very small cohort sizes [
      • Shahim P.
      • Rejdak R.
      • Ksiazek P.
      • et al.
      Cerebrospinal fluid biomarkers of β-amyloid metabolism and neuronal damage in epileptic seizures.
      ,
      • Mo L.
      • Ding X.
      • Tan C.
      • et al.
      Association of cerebrospinal fluid zinc-α2-glycoprotein and tau protein with temporal lobe epilepsy and related white matter impairment.
      ]. In a cohort of patients with SE, CSF tau was elevated in 50% and showed a positive correlation with duration of SE [
      • Monti G.
      • Tondelli M.
      • Giovannini G.
      • et al.
      Cerebrospinal fluid tau proteins in status epilepticus.
      ]. In this study, patients with higher CSF t-tau levels had a worse outcome. Interestingly, increased t-tau was also found if propofol was used as intravenous anesthesia [
      • Monti G.
      • Tondelli M.
      • Giovannini G.
      • et al.
      Cerebrospinal fluid tau proteins in status epilepticus.
      ].
      Amyloid peptides in the CSF have rarely been examined in patients with seizures or epilepsy. One study found similar values in seizure patients in general compared to controls, and some differential values in subgroup analyses [
      • Shahim P.
      • Rejdak R.
      • Ksiazek P.
      • et al.
      Cerebrospinal fluid biomarkers of β-amyloid metabolism and neuronal damage in epileptic seizures.
      ]. The data were limited by small sample sizes and failed to reveal a possible explanation.
      CSF (and serum) alpha-Synuclein was elevated in a small cohort of patients with refractory epilepsy compared to patients who had been seizure free for several months [
      • Rong H.
      • Jin L.
      • Wei W.
      • et al.
      Alpha-synuclein is a potential biomarker in the serum and CSF of patients with intractable epilepsy.
      ]. These data are as yet insufficient for consideration of alpha-synuclein as a biomarker for refractory epilepsy.

      3.3 Neurofilaments

      CSF neurofilament heavy chains were found to be increased in patients with repetitive seizures or SE, but not after single seizures [
      • Rejdak K.
      • Kuhle J.
      • Rüegg S.
      • et al.
      Neurofilament heavy chain and heat shock protein 70 as markers of seizure-related brain injury.
      ]. Neurofilaments have been evaluated as a marker of axonal damage in different neurological disorders and may be of some value in epilepsy. Due to their lack of specificity they are of limited use in differential diagnosis. Data on AIE with or without associated seizures is reviewed below.

      4. Immune parameters

      Since inflammatory mechanisms as a cause or result of epileptic seizures have gained more and more attention, some work has been done on cells and mediators of the immune system and their alterations in blood and CSF.

      4.1 Cytokines

      After tonic-clonic seizures, elevated CSF (and plasma) levels of the proinflammatory interleukin 6 (IL-6) have been found especially with early sampling during the first hours after a seizure [
      • Peltola J.
      • Hurme M.
      • Miettinen A.
      • et al.
      Elevated levels of interleukin-6 may occur in cerebrospinal fluid from patients with recent epileptic seizures.
      ,
      • Peltola J.
      • Palmio J.
      • Korhonen L.
      • et al.
      Interleukin-6 and interleukin-1 receptor antagonist in cerebrospinal fluid from patients with recent tonic-clonic seizures.
      ]. The increase in CSF IL-6 levels seems to be more pronounced with higher seizure severity, i.e. recurring vs. single seizures [
      • Lehtimäki K.A.
      • Keränen T.
      • Huhtala H.
      • et al.
      Regulation of IL-6 system in cerebrospinal fluid and serum compartments by seizures: the effect of seizure type and duration.
      ]. Chemokine CX3CL1 expression was elevated in CSF, serum and resected tissue of epilepsy patients [
      • Xu Y.
      • Zeng K.
      • Han Y.
      • et al.
      Altered expression of CX3CL1 in patients with epilepsy and in a rat model.
      ]. However, not all immune mediators are non-selectively altered after seizures, as for example a significant change of CSF levels of TNFα was not observed [
      • Peltola J.
      • Palmio J.
      • Korhonen L.
      • et al.
      Interleukin-6 and interleukin-1 receptor antagonist in cerebrospinal fluid from patients with recent tonic-clonic seizures.
      ]. CSF IL-1β was found decreased and IL1-ra increased only after recurrent seizures [
      • Lehtimäki K.A.
      • Keränen T.
      • Palmio J.
      • et al.
      Levels of IL-1beta and IL-1ra in cerebrospinal fluid of human patients after single and prolonged seizures.
      ]. Unchanged or decreased CSF levels of IL-1β appear somewhat surprising as there is a sound body of evidence for induction of IL-1β after seizures [
      • Vries EE de
      • van den Munckhof B.
      • Braun K.P.J.
      • et al.
      Inflammatory mediators in human epilepsy: a systematic review and meta-analysis.
      ]. In clinical CSF studies, it may not be possible to confirm these results, either because IL-1β may be found exclusively in brain parenchyma, or because a rapid timeline of induction and suppression of IL-1β may prevent detection at the usual latency of CSF sampling. There is more evidence on CSF cytokines after febrile seizures and on cytokines in serum and brain parenchyma which is beyond the scope of this review. An excellent overview has been published in 2016 [
      • Vries EE de
      • van den Munckhof B.
      • Braun K.P.J.
      • et al.
      Inflammatory mediators in human epilepsy: a systematic review and meta-analysis.
      ].

      4.2 CSF flow cytometry in epilepsy

      Data on CSF immune cell signatures in epilepsy focuses mainly on patients with autoimmune-associated seizures or epilepsy. Our recent study compared CSF immune cell signatures in patients with temporal lobe epilepsy (TLE) of different etiologies (non-lesional TLE, hippocampal sclerosis (HS), and glutamic acid decarboxylase 65 kilodalton isoform (GAD65)-antibody associated limbic encephalitis). Here, all TLE patients showed reduced proportions of CD14lowCD16+ monocytes and increased proportions of HLA-DR-expressing activated CD4+ T-lymphocytes [
      • Langenbruch L.
      • Bleß L.
      • Schulte-Mecklenbeck A.
      • et al.
      Blood and cerebrospinal fluid immune cell profiles in patients with temporal lobe epilepsy of different etiologies.
      ]. Patients with GAD65-LE differed from TLE patients with HS or non-lesional TLE by elevated proportions of CD8+ HLA-DR-expressing T-lymphocytes.
      For individual references, see references given in the text. CSF, cerebrospinal fluid; OCB, oligoclonal bands; NSE, neuron-specific enolase

      5. Clinical settings

      CSF studies may serve different purposes in seizures or epilepsy depending on the clinical setting, as described below. For a summary of CSF parameters in seizure patients, see Table 3.
      Table 3.Overview of CSF parameters in seizure patients.
      CSF parametercommentary
      leukocyte cell countpleocytosis rarely found after seizures (4–10% in recent studies) probably indication of transient inflammatory reaction (time course with decreasing cell count over the first few days) important parameter for evaluation of differential diagnoses, e.g. autoimmune or infectious (meningo-)encephalitis
      CSF proteinfrequently elevated after seizures (10–61%) indication of blood/CSF barrier damage not specific concerning seizure etiology
      CSF lactate and glucosetime-dependent elevation of CSF lactate in 14–28% after seizures differential diagnosis of mitochondrial disease CSF glucose of little use in seizure patients
      OCB/intrathecal immunoglobuline synthesisrare (0–10%) may point towards autoimmune seizure etiology
      markers of neuronal damageCSF NSE and tau protein frequently elevated after SE with unclear diagnostic value conflicting or insufficient data concerning CSF NSE, S100B, tau protein, amyloid, and alpha-synuclein in seizure/epilepsy patients, therefore not established in clinical routine
      neural autoantibodiesCSF examination regarding neural autoantibodies essential in suspected autoimmune seizure etiology, especially in younger patients
      CSF flow cytometryCSF plasma cells or increased CD8+ T-lymphocytes may point towards autoimmune seizure etiology not available in all CSF laboratories
      cytokinesaltered CSF cytokine levels after seizures, e.g. increased interleukin-6 level not established in clinical routine

      5.1 First seizure

      In the setting of a first seizure, CSF sampling is often done as a means to rule out differential diagnoses, especially meningitis and encephalitis. It has been shown that in patients with a first unprovoked seizure, 35% of CSF samples yield a pathologic result in at least one routine parameter, mostly elevated protein [
      • Zisimopoulou V.
      • Mamali M.
      • Katsavos S.
      • et al.
      Cerebrospinal fluid analysis after unprovoked first seizure.
      ]. The same study found a weak correlation of higher CSF leukocyte cell count with pathological imaging. In line with the overall evidence on CSF pleocytosis after seizures, this encourages taking pathological CSF findings, particularly pleocytosis, seriously, and completing a thorough search of differential diagnoses.
      Few studies compared CSF parameters in patients with recurring seizures and those with a first unprovoked seizure without a definite epilepsy diagnosis (“occasional” seizure). These studies showed no differences regarding CSF leukocyte cell count, lactate or albumin quotient [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ,
      • Süße M.
      • Saathoff N.
      • Hannich M.
      • et al.
      Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.
      ]. Based on the existing evidence, CSF is not helpful in distinguishing patients with a first seizure from patients with established epilepsy. Still, this might be an interesting question for future research, especially with regard to assessment of seizure recurrence risk.
      The differential diagnosis of epileptic and non-epileptic seizures including syncopes can be challenging, sometimes even with detailed witness reports. One study found slightly lower CSF leukocyte cell count and tau protein level in a small group of ten patients with psychogenic, non-epileptic seizures compared to patients with epileptic seizures [
      • Tumani H.
      • Jobs C.
      • Brettschneider J.
      • et al.
      Effect of epileptic seizures on the cerebrospinal fluid–A systematic retrospective analysis.
      ]. In the same study, CSF/blood albumin quotient and lactate were lower in psychogenic, non-epileptic seizures (PNES) compared to some, but not all subgroups with epileptic seizures and did not differ significantly compared to the pooled groups of focal, generalized or occasional seizures. A possible use of CSF examination in differentiating epileptic from non-epileptic seizures will have to be confirmed in larger studies. Such a biomarker would be of immense use for the clinician, so that the respective research should be promoted.

      5.2 Biomarkers for refractory epilepsy

      There has been some effort to find biomarkers for refractory epilepsy which may allow early detection and modification of therapeutic strategies in patients with an unfavorable disease course. As mentioned above, certain parameters have been evaluated in cohorts of patients with refractory epilepsy as compared to patients with a seizure-free interval or with single seizures. Single studies with small to moderate numbers of patients showed elevated values of CSF alpha-synuclein, chitinase 3 like protein, and transforming growth factor β1 (TGFβ1), and a decrease of superoxide dismutase 1 (SOD1) and clusterin in refractory epilepsy [
      • Rong H.
      • Jin L.
      • Wei W.
      • et al.
      Alpha-synuclein is a potential biomarker in the serum and CSF of patients with intractable epilepsy.
      ,
      • Zhang H.
      • Tan J.-.Z.
      • Luo J.
      • et al.
      Chitinase-3-like protein 1 may be a potential biomarker in patients with drug-resistant epilepsy.
      ,
      • Chen D.
      • Lu Y.
      • Yu W.
      • et al.
      Clinical value of decreased superoxide dismutase 1 in patients with epilepsy.
      ,
      • Yu W.
      • Chen D.
      • Wang Z.
      • et al.
      Time-dependent decrease of clusterin as a potential cerebrospinal fluid biomarker for drug-resistant epilepsy.
      ,
      • Yu W.
      • Zou Y.
      • Du Y.
      • et al.
      Altered cerebrospinal fluid concentrations of TGFβ1 in patients with drug-resistant epilepsy.
      ]. Confirming studies in larger populations have not been published. Until now, CSF parameters have not gained clinical utility as a biomarker for refractory epilepsy, but this remains an important area of research with potential impact for the individual patient.

      5.3 Status epilepticus

      A detailed coverage of CSF findings in SE is beyond the scope of this review and has been addressed elsewhere [
      • Hanin A.
      • Lambrecq V.
      • Denis J.A.
      • et al.
      Cerebrospinal fluid and blood biomarkers of status epilepticus.
      ]. The clinician will frequently perform CSF analysis in patients with SE mainly for differential diagnosis of infectious or autoimmune meningoencephalitis. Even though, as shown above, 6 to 15% of patients with SE may show pleocytosis, an elevated CSF leukocyte cell count should always prompt further evaluation. There is good evidence for elevation of CSF lactate in or after SE in 14–28%. Evidence about CSF lactate or total tau protein as a negative prognostic marker is inconclusive.
      New onset refractory SE (NORSE) is a clinical scenario in which CSF analysis is of special value. NORSE is a rare condition, but autoimmune etiology is frequent [
      • Langenbruch L.
      • Kovac S.
      Autoimmuner Status epilepticus.
      ]. Evaluation of a broad range of viral and other pathogens as well as neural autoantibodies are warranted. CSF flow cytometry may be of interest in the diagnosis of autoimmune SE, but has not been systematically evaluated.

      5.4 Assessing neuronal damage

      Assessing neuronal damage in epilepsy by measuring CSF proteins or metabolites is difficult due to the dynamic nature of the disease. Seizure duration, frequency, localization of the epileptogenic zone, and spread of seizure activity may influence parameters as well as etiology and comorbid conditions. Tau protein may yield more reliable results than other parameters for its longer half-life, but evidence is still heterogenous. Other parameters with a shorter half-life may provide information on consequences of single or recurring events such as single seizures or SE. None of these parameters has yielded consistent results, though.

      5.5 Differential diagnosis of autoimmune-associated seizures and epilepsy

      In new onset seizures, autoimmune or limbic encephalitis (AIE, LE) as a potential etiology has to be considered because of major therapeutic implications. Symptoms of AIE frequently include seizures, although the proportion in seropositive AIE varies with the different neural autoantibodies (Table 4). High rates of seizures are found in the presence of GABAAR/GABABR (γ-amino butyric acid receptor type A/B), LGI1 (leucine-rich glioma-inactivated 1), or CASPR2 (contactin-associated protein-like 2) antibodies, while in the presence of IGLON5, Hu or Ma2/Ta antibodies, seizures are much less frequent. In addition to seizures, typical symptoms of AIE include cognitive deficits, especially verbal and figural memory deficits in LE, and psychiatric symptoms such as psychosis or mood disorders. Movement disorders or focal neurological deficits may occur, particularly in non-limbic AIE.
      Table 4.Association of neural antibodies with seizures and epilepsy and related CSF findings.
      AntibodyPatients presenting with seizures,%appropriate sample for antibody detectionCSF pleocytosis,%elevated CSF protein,%CSF specific OCB,%male patients,%median age at onset (years)comment on diagnostic utility
      NMDAR50–86 [
      • Bruijn Maam de, van Sonderen A.
      • van Coevorden-Hameete M.H.
      • et al.
      Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.
      ,
      • Wang R.
      • Guan H.-.Z.
      • Ren H.-.T.
      • et al.
      CSF findings in patients with anti-N-methyl-D-aspartate receptor-encephalitis.
      ,
      • Gastaldi M.
      • Mariotto S.
      • Giannoccaro M.P.
      • et al.
      Subgroup comparison according to clinical phenotype and serostatus in autoimmune encephalitis: a multicenter retrospective study.
      ,
      • Dalmau J.
      • Gleichman A.J.
      • Hughes E.G.
      • et al.
      Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
      ,
      • Lim J.-.A.
      • Lee S.-.T.
      • Jung K.-.H.
      • et al.
      Anti-N-methyl-d-aspartate receptor encephalitis in Korea: clinical features, treatment, and outcome.
      ]
      15–63% CSF only
      • 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.
      ,
      • Wang R.
      • Guan H.-.Z.
      • Ren H.-.T.
      • et al.
      CSF findings in patients with anti-N-methyl-D-aspartate receptor-encephalitis.
      ,
      • Bien C.G.
      • Bien C.I.
      • Dogan Onugoren M.
      • et al.
      Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome.
      58–91 [
      • 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.
      ,
      • Wang R.
      • Guan H.-.Z.
      • Ren H.-.T.
      • et al.
      CSF findings in patients with anti-N-methyl-D-aspartate receptor-encephalitis.
      ,
      • Dalmau J.
      • Gleichman A.J.
      • Hughes E.G.
      • et al.
      Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
      ,
      • Lim J.-.A.
      • Lee S.-.T.
      • Jung K.-.H.
      • et al.
      Anti-N-methyl-d-aspartate receptor encephalitis in Korea: clinical features, treatment, and outcome.
      ]
      17–50 [
      • 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.
      ,
      • Wang R.
      • Guan H.-.Z.
      • Ren H.-.T.
      • et al.
      CSF findings in patients with anti-N-methyl-D-aspartate receptor-encephalitis.
      ,
      • Dalmau J.
      • Gleichman A.J.
      • Hughes E.G.
      • et al.
      Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
      ,
      • Lim J.-.A.
      • Lee S.-.T.
      • Jung K.-.H.
      • et al.
      Anti-N-methyl-d-aspartate receptor encephalitis in Korea: clinical features, treatment, and outcome.
      ]
      47–67 [
      • Gastaldi M.
      • Mariotto S.
      • Giannoccaro M.P.
      • et al.
      Subgroup comparison according to clinical phenotype and serostatus in autoimmune encephalitis: a multicenter retrospective study.
      ,
      • Dalmau J.
      • Gleichman A.J.
      • Hughes E.G.
      • et al.
      Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
      ]
      9–53 [
      • Bruijn Maam de, van Sonderen A.
      • van Coevorden-Hameete M.H.
      • et al.
      Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.
      ,
      • 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.
      ,
      • Wang R.
      • Guan H.-.Z.
      • Ren H.-.T.
      • et al.
      CSF findings in patients with anti-N-methyl-D-aspartate receptor-encephalitis.
      ,
      • Gastaldi M.
      • Mariotto S.
      • Giannoccaro M.P.
      • et al.
      Subgroup comparison according to clinical phenotype and serostatus in autoimmune encephalitis: a multicenter retrospective study.
      ,
      • Dalmau J.
      • Gleichman A.J.
      • Hughes E.G.
      • et al.
      Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
      ,
      • Lim J.-.A.
      • Lee S.-.T.
      • Jung K.-.H.
      • et al.
      Anti-N-methyl-d-aspartate receptor encephalitis in Korea: clinical features, treatment, and outcome.
      ]
      15–42 [
      • Bruijn Maam de, van Sonderen A.
      • van Coevorden-Hameete M.H.
      • et al.
      Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.
      ,
      • 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.
      ,
      • Wang R.
      • Guan H.-.Z.
      • Ren H.-.T.
      • et al.
      CSF findings in patients with anti-N-methyl-D-aspartate receptor-encephalitis.
      ,
      • Gastaldi M.
      • Mariotto S.
      • Giannoccaro M.P.
      • et al.
      Subgroup comparison according to clinical phenotype and serostatus in autoimmune encephalitis: a multicenter retrospective study.
      ,
      • Dalmau J.
      • Gleichman A.J.
      • Hughes E.G.
      • et al.
      Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
      ,
      • Lim J.-.A.
      • Lee S.-.T.
      • Jung K.-.H.
      • et al.
      Anti-N-methyl-d-aspartate receptor encephalitis in Korea: clinical features, treatment, and outcome.
      ]
      CSF should always be tested along serum for antibody; low titres of serum only antibodies are without clinical significance
      LGI175–93 [
      • Bruijn Maam de, van Sonderen A.
      • van Coevorden-Hameete M.H.
      • et al.
      Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.
      ,
      • Yang X.
      • Li A.-.N.
      • Zhao X.-.H.
      • et al.
      Clinical features of patients with anti-leucine-rich glioma inactivated-1 protein associated encephalitis: a Chinese case series.
      ,
      • Navarro V.
      • Kas A.
      • Apartis E.
      • et al.
      Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis.
      ,
      • Irani S.R.
      • Alexander S.
      • Waters P.
      • et al.
      Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.
      ,
      • Finke C.
      • Prüss H.
      • Heine J.
      • et al.
      Evaluation of Cognitive Deficits and Structural Hippocampal Damage in Encephalitis With Leucine-Rich, Glioma-Inactivated 1 Antibodies.
      ]
      6–16% serum only [
      • Yang X.
      • Li A.-.N.
      • Zhao X.-.H.
      • et al.
      Clinical features of patients with anti-leucine-rich glioma inactivated-1 protein associated encephalitis: a Chinese case series.
      ,
      • van Sonderen A.
      • Thijs R.D.
      • Coenders E.C.
      • et al.
      Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up.
      ,
      • Gastaldi M.
      • Mariotto S.
      • Giannoccaro M.P.
      • et al.
      Subgroup comparison according to clinical phenotype and serostatus in autoimmune encephalitis: a multicenter retrospective study.
      ]
      0–17 [
      • Yang X.
      • Li A.-.N.
      • Zhao X.-.H.
      • et al.
      Clinical features of patients with anti-leucine-rich glioma inactivated-1 protein associated encephalitis: a Chinese case series.
      ,
      • van Sonderen A.
      • Thijs R.D.
      • Coenders E.C.
      • et al.
      Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up.
      ,
      • Navarro V.
      • Kas A.
      • Apartis E.
      • et al.
      Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis.
      ,
      • Irani S.R.
      • Alexander S.
      • Waters P.
      • et al.
      Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.
      ,
      • Thompson J.
      • Bi M.
      • Murchison A.G.
      • et al.
      The importance of early immunotherapy in patients with faciobrachial dystonic seizures.
      ]
      0–25 [
      • Yang X.
      • Li A.-.N.
      • Zhao X.-.H.
      • et al.
      Clinical features of patients with anti-leucine-rich glioma inactivated-1 protein associated encephalitis: a Chinese case series.
      ,
      • van Sonderen A.
      • Thijs R.D.
      • Coenders E.C.
      • et al.
      Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up.
      ,
      • Irani S.R.
      • Alexander S.
      • Waters P.
      • et al.
      Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.
      ,
      • Thompson J.
      • Bi M.
      • Murchison A.G.
      • et al.
      The importance of early immunotherapy in patients with faciobrachial dystonic seizures.
      ]
      0–5 [
      • Irani S.R.
      • Alexander S.
      • Waters P.
      • et al.
      Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.
      ,
      • Thompson J.
      • Bi M.
      • Murchison A.G.
      • et al.
      The importance of early immunotherapy in patients with faciobrachial dystonic seizures.
      ,
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ]
      56–83 [
      • Bruijn Maam de, van Sonderen A.
      • van Coevorden-Hameete M.H.
      • et al.
      Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.
      ,
      • Yang X.
      • Li A.-.N.
      • Zhao X.-.H.
      • et al.
      Clinical features of patients with anti-leucine-rich glioma inactivated-1 protein associated encephalitis: a Chinese case series.
      ,
      • Navarro V.
      • Kas A.
      • Apartis E.
      • et al.
      Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis.
      ,
      • Irani S.R.
      • Alexander S.
      • Waters P.
      • et al.
      Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.
      ,
      • Finke C.
      • Prüss H.
      • Heine J.
      • et al.
      Evaluation of Cognitive Deficits and Structural Hippocampal Damage in Encephalitis With Leucine-Rich, Glioma-Inactivated 1 Antibodies.
      ]
      57–65 [
      • Bruijn Maam de, van Sonderen A.
      • van Coevorden-Hameete M.H.
      • et al.
      Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.
      ,
      • Yang X.
      • Li A.-.N.
      • Zhao X.-.H.
      • et al.
      Clinical features of patients with anti-leucine-rich glioma inactivated-1 protein associated encephalitis: a Chinese case series.
      ,
      • Navarro V.
      • Kas A.
      • Apartis E.
      • et al.
      Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis.
      ,
      • Finke C.
      • Prüss H.
      • Heine J.
      • et al.
      Evaluation of Cognitive Deficits and Structural Hippocampal Damage in Encephalitis With Leucine-Rich, Glioma-Inactivated 1 Antibodies.
      ]
      serum testing for antibody sufficient; in typical clinical syndromes (FBDS) start with immune therapy without waiting for test result
      CASPR253–89 [
      • van Sonderen A.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      The clinical spectrum of Caspr2 antibody-associated disease.
      ,
      • Irani S.R.
      • Alexander S.
      • Waters P.
      • et al.
      Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.
      ,
      • Joubert B.
      • Saint-Martin M.
      • Noraz N.
      • et al.
      Characterization of a subtype of autoimmune encephalitis with anti-contactin-associated protein-like 2 antibodies in the cerebrospinal fluid, prominent limbic symptoms, and seizures.
      ,
      • Bien C.G.
      • Mirzadjanova Z.
      • Baumgartner C.
      • et al.
      Anti-contactin-associated protein-2 encephalitis: relevance of antibody titres, presentation and outcome.
      ]
      13–14% serum only [
      • van Sonderen A.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      The clinical spectrum of Caspr2 antibody-associated disease.
      ,
      • Bien C.G.
      • Mirzadjanova Z.
      • Baumgartner C.
      • et al.
      Anti-contactin-associated protein-2 encephalitis: relevance of antibody titres, presentation and outcome.
      ]
      21–67 [
      • van Sonderen A.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      The clinical spectrum of Caspr2 antibody-associated disease.
      ,
      • Joubert B.
      • Saint-Martin M.
      • Noraz N.
      • et al.
      Characterization of a subtype of autoimmune encephalitis with anti-contactin-associated protein-like 2 antibodies in the cerebrospinal fluid, prominent limbic symptoms, and seizures.
      ,
      • Bien C.G.
      • Mirzadjanova Z.
      • Baumgartner C.
      • et al.
      Anti-contactin-associated protein-2 encephalitis: relevance of antibody titres, presentation and outcome.
      ]
      8–26 [
      • van Sonderen A.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      The clinical spectrum of Caspr2 antibody-associated disease.
      ,
      • Joubert B.
      • Saint-Martin M.
      • Noraz N.
      • et al.
      Characterization of a subtype of autoimmune encephalitis with anti-contactin-associated protein-like 2 antibodies in the cerebrospinal fluid, prominent limbic symptoms, and seizures.
      ]
      25–29 [
      • van Sonderen A.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      The clinical spectrum of Caspr2 antibody-associated disease.
      ,
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ]
      84–94 [
      • van Sonderen A.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      The clinical spectrum of Caspr2 antibody-associated disease.
      ,
      • Irani S.R.
      • Alexander S.
      • Waters P.
      • et al.
      Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.
      ,
      • Joubert B.
      • Saint-Martin M.
      • Noraz N.
      • et al.
      Characterization of a subtype of autoimmune encephalitis with anti-contactin-associated protein-like 2 antibodies in the cerebrospinal fluid, prominent limbic symptoms, and seizures.
      ,
      • Bien C.G.
      • Mirzadjanova Z.
      • Baumgartner C.
      • et al.
      Anti-contactin-associated protein-2 encephalitis: relevance of antibody titres, presentation and outcome.
      ]
      64–66 [
      • van Sonderen A.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      The clinical spectrum of Caspr2 antibody-associated disease.
      ,
      • Joubert B.
      • Saint-Martin M.
      • Noraz N.
      • et al.
      Characterization of a subtype of autoimmune encephalitis with anti-contactin-associated protein-like 2 antibodies in the cerebrospinal fluid, prominent limbic symptoms, and seizures.
      ,
      • Bien C.G.
      • Mirzadjanova Z.
      • Baumgartner C.
      • et al.
      Anti-contactin-associated protein-2 encephalitis: relevance of antibody titres, presentation and outcome.
      ]
      low titres (<1:32) not specific; in neuromyotonia up to 100% serum only antibodies
      • Joubert B.
      • Saint-Martin M.
      • Noraz N.
      • et al.
      Characterization of a subtype of autoimmune encephalitis with anti-contactin-associated protein-like 2 antibodies in the cerebrospinal fluid, prominent limbic symptoms, and seizures.
      GABAAR72–100 [
      • Spatola M.
      • Petit-Pedrol M.
      • Simabukuro M.M.
      • et al.
      Investigations in GABAA receptor antibody-associated encephalitis.
      ,
      • 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.
      ,
      • O’Connor K.
      • Waters P.
      • Komorowski L.
      • et al.
      GABAA receptor autoimmunity: a multicenter experience.
      ]
      13% serum only
      • Spatola M.
      • Petit-Pedrol M.
      • Simabukuro M.M.
      • et al.
      Investigations in GABAA receptor antibody-associated encephalitis.
      (up to 100% serum only at low serum titers
      • 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.
      )
      33–40 [
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • 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.
      ]
      18–33 [
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • 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.
      ]
      25–33 [
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • 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.
      ]
      37–67 [
      • Spatola M.
      • Petit-Pedrol M.
      • Simabukuro M.M.
      • et al.
      Investigations in GABAA receptor antibody-associated encephalitis.
      ,
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • 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.
      ,
      • O’Connor K.
      • Waters P.
      • Komorowski L.
      • et al.
      GABAA receptor autoimmunity: a multicenter experience.
      ]
      40–50 with a wide range [
      • Spatola M.
      • Petit-Pedrol M.
      • Simabukuro M.M.
      • et al.
      Investigations in GABAA receptor antibody-associated encephalitis.
      ,
      • 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.
      ,
      • O’Connor K.
      • Waters P.
      • Komorowski L.
      • et al.
      GABAA receptor autoimmunity: a multicenter experience.
      ]
      strong clinical significance of positive antibody result in a seizure patient
      GABABR80–100 [
      • Bruijn Maam de, van Sonderen A.
      • van Coevorden-Hameete M.H.
      • et al.
      Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.
      ,
      • Guan H.-.Z.
      • Ren H.-.T.
      • Yang X.-.Z.
      • et al.
      Limbic Encephalitis Associated with Anti-γ-aminobutyric Acid B Receptor Antibodies: a Case Series from China.
      ,
      • Maureille A.
      • Fenouil T.
      • Joubert B.
      • et al.
      Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis.
      ,
      • Cui J.
      • Bu H.
      • He J.
      • et al.
      The gamma-aminobutyric acid-B receptor (GABAB) encephalitis: clinical manifestations and response to immunotherapy.
      ,
      • Boronat A.
      • Sabater L.
      • Saiz A.
      • et al.
      GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders.
      ,
      • 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.
      ,
      • Dogan Onugoren M.
      • Deuretzbacher D.
      • Haensch C.A.
      • et al.
      Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.
      ,
      • Höftberger R.
      • Titulaer M.J.
      • Sabater L.
      • et al.
      Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients.
      ]
      mostly serum and CSF, rarely serum or CSF only [
      • Guan H.-.Z.
      • Ren H.-.T.
      • Yang X.-.Z.
      • et al.
      Limbic Encephalitis Associated with Anti-γ-aminobutyric Acid B Receptor Antibodies: a Case Series from China.
      ,
      • Maureille A.
      • Fenouil T.
      • Joubert B.
      • et al.
      Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis.
      ]
      36–81 [
      • Guan H.-.Z.
      • Ren H.-.T.
      • Yang X.-.Z.
      • et al.
      Limbic Encephalitis Associated with Anti-γ-aminobutyric Acid B Receptor Antibodies: a Case Series from China.
      ,
      • Maureille A.
      • Fenouil T.
      • Joubert B.
      • et al.
      Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis.
      ,
      • Boronat A.
      • Sabater L.
      • Saiz A.
      • et al.
      GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders.
      ,
      • 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.
      ,
      • Dogan Onugoren M.
      • Deuretzbacher D.
      • Haensch C.A.
      • et al.
      Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.
      ,
      • Höftberger R.
      • Titulaer M.J.
      • Sabater L.
      • et al.
      Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients.
      ]
      28–74 [
      • Guan H.-.Z.
      • Ren H.-.T.
      • Yang X.-.Z.
      • et al.
      Limbic Encephalitis Associated with Anti-γ-aminobutyric Acid B Receptor Antibodies: a Case Series from China.
      ,
      • Maureille A.
      • Fenouil T.
      • Joubert B.
      • et al.
      Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis.
      ,
      • 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.
      ,
      • Höftberger R.
      • Titulaer M.J.
      • Sabater L.
      • et al.
      Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients.
      ]
      27–90 [
      • Guan H.-.Z.
      • Ren H.-.T.
      • Yang X.-.Z.
      • et al.
      Limbic Encephalitis Associated with Anti-γ-aminobutyric Acid B Receptor Antibodies: a Case Series from China.
      ,
      • Maureille A.
      • Fenouil T.
      • Joubert B.
      • et al.
      Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis.
      ,
      • 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.
      ,
      • Dogan Onugoren M.
      • Deuretzbacher D.
      • Haensch C.A.
      • et al.
      Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.
      ]
      48–82 [
      • Bruijn Maam de, van Sonderen A.
      • van Coevorden-Hameete M.H.
      • et al.
      Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.
      ,
      • Guan H.-.Z.
      • Ren H.-.T.
      • Yang X.-.Z.
      • et al.
      Limbic Encephalitis Associated with Anti-γ-aminobutyric Acid B Receptor Antibodies: a Case Series from China.
      ,
      • Maureille A.
      • Fenouil T.
      • Joubert B.
      • et al.
      Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis.
      ,
      • Cui J.
      • Bu H.
      • He J.
      • et al.
      The gamma-aminobutyric acid-B receptor (GABAB) encephalitis: clinical manifestations and response to immunotherapy.
      ,
      • Boronat A.
      • Sabater L.
      • Saiz A.
      • et al.
      GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders.
      ,
      • Dogan Onugoren M.
      • Deuretzbacher D.
      • Haensch C.A.
      • et al.
      Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.
      ,
      • Höftberger R.
      • Titulaer M.J.
      • Sabater L.
      • et al.
      Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients.
      ]
      56–70 [
      • Bruijn Maam de, van Sonderen A.
      • van Coevorden-Hameete M.H.
      • et al.
      Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.
      ,
      • Guan H.-.Z.
      • Ren H.-.T.
      • Yang X.-.Z.
      • et al.
      Limbic Encephalitis Associated with Anti-γ-aminobutyric Acid B Receptor Antibodies: a Case Series from China.
      ,
      • Maureille A.
      • Fenouil T.
      • Joubert B.
      • et al.
      Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis.
      ,
      • Cui J.
      • Bu H.
      • He J.
      • et al.
      The gamma-aminobutyric acid-B receptor (GABAB) encephalitis: clinical manifestations and response to immunotherapy.
      ,
      • Boronat A.
      • Sabater L.
      • Saiz A.
      • et al.
      GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders.
      ,
      • 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.
      ,
      • Dogan Onugoren M.
      • Deuretzbacher D.
      • Haensch C.A.
      • et al.
      Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.
      ,
      • Höftberger R.
      • Titulaer M.J.
      • Sabater L.
      • et al.
      Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients.
      ]
      strong clinical significance of positive antibody result in a seizure patient
      AMPAR0–40 [
      • Höftberger R.
      • van Sonderen A.
      • Leypoldt F.
      • et al.
      Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients.
      ,
      • Dogan Onugoren M.
      • Deuretzbacher D.
      • Haensch C.A.
      • et al.
      Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.
      ,
      • 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.
      ,
      • Lai M.
      • Hughes E.G.
      • Peng X.
      • et al.
      AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location.
      ]
      0–29% CSF only [
      • Höftberger R.
      • van Sonderen A.
      • Leypoldt F.
      • et al.
      Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients.
      ,
      • 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.
      ,
      • Lai M.
      • Hughes E.G.
      • Peng X.
      • et al.
      AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location.
      ,
      • Graus F.
      • Boronat A.
      • Xifró X.
      • et al.
      The expanding clinical profile of anti-AMPA receptor encephalitis.
      ]
      50–90 [
      • Höftberger R.
      • van Sonderen A.
      • Leypoldt F.
      • et al.
      Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients.
      ,
      • Lai M.
      • Hughes E.G.
      • Peng X.
      • et al.
      AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location.
      ]
      47–50 [
      • Höftberger R.
      • van Sonderen A.
      • Leypoldt F.
      • et al.
      Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients.
      ,
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • Lai M.
      • Hughes E.G.
      • Peng X.
      • et al.
      AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location.
      ]
      30–37 [
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • Lai M.
      • Hughes E.G.
      • Peng X.
      • et al.
      AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location.
      ]
      10–43 [
      • Höftberger R.
      • van Sonderen A.
      • Leypoldt F.
      • et al.
      Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients.
      ,
      • 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.
      ,
      • Lai M.
      • Hughes E.G.
      • Peng X.
      • et al.
      AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location.
      ]
      56–62 [
      • Höftberger R.
      • van Sonderen A.
      • Leypoldt F.
      • et al.
      Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients.
      ,
      • Dogan Onugoren M.
      • Deuretzbacher D.
      • Haensch C.A.
      • et al.
      Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.
      ,
      • 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.
      ,
      • Lai M.
      • Hughes E.G.
      • Peng X.
      • et al.
      AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location.
      ,
      • Graus F.
      • Boronat A.
      • Xifró X.
      • et al.
      The expanding clinical profile of anti-AMPA receptor encephalitis.
      ]
      GlyR13, up to 57 in small case series [
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • Swayne A.
      • Tjoa L.
      • Broadley S.
      • et al.
      Antiglycine receptor antibody related disease: a case series and literature review.
      ,
      • Carvajal-González A.
      • Leite M.I.
      • Waters P.
      • et al.
      Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.
      ]
      14% serum only
      • Swayne A.
      • Tjoa L.
      • Broadley S.
      • et al.
      Antiglycine receptor antibody related disease: a case series and literature review.
      22–43 [
      • Swayne A.
      • Tjoa L.
      • Broadley S.
      • et al.
      Antiglycine receptor antibody related disease: a case series and literature review.
      ,
      • Carvajal-González A.
      • Leite M.I.
      • Waters P.
      • et al.
      Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.
      ]
      11–23 [
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • Swayne A.
      • Tjoa L.
      • Broadley S.
      • et al.
      Antiglycine receptor antibody related disease: a case series and literature review.
      ,
      • Carvajal-González A.
      • Leite M.I.
      • Waters P.
      • et al.
      Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.
      ]
      20–33 [
      • Swayne A.
      • Tjoa L.
      • Broadley S.
      • et al.
      Antiglycine receptor antibody related disease: a case series and literature review.
      ,
      • Carvajal-González A.
      • Leite M.I.
      • Waters P.
      • et al.
      Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.
      ]
      21–66
      • Swayne A.
      • Tjoa L.
      • Broadley S.
      • et al.
      Antiglycine receptor antibody related disease: a case series and literature review.
      ,
      • Carvajal-González A.
      • Leite M.I.
      • Waters P.
      • et al.
      Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.
      ,
      • Brenner T.
      • Sills G.J.
      • Hart Y.
      • et al.
      Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy.
      40–60 [
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • Swayne A.
      • Tjoa L.
      • Broadley S.
      • et al.
      Antiglycine receptor antibody related disease: a case series and literature review.
      ,
      • Carvajal-González A.
      • Leite M.I.
      • Waters P.
      • et al.
      Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.
      ,
      • Brenner T.
      • Sills G.J.
      • Hart Y.
      • et al.
      Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy.
      ]
      mGluR555–100 [
      • Spatola M.
      • Sabater L.
      • Planagumà J.
      • et al.
      Encephalitis with mGluR5 antibodies: symptoms and antibody effects.
      ,
      • Lancaster E.
      • Martinez-Hernandez E.
      • Titulaer M.J.
      • et al.
      Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome.
      ]
      not enough dataup to 100, single cases without pleocytosis
      • Spatola M.
      • Sabater L.
      • Planagumà J.
      • et al.
      Encephalitis with mGluR5 antibodies: symptoms and antibody effects.
      ,
      • Lancaster E.
      • Martinez-Hernandez E.
      • Titulaer M.J.
      • et al.
      Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome.
      ,
      • Mat A.
      • Adler H.
      • Merwick A.
      • et al.
      Ophelia syndrome with metabotropic glutamate receptor 5 antibodies in CSF.
      ,
      • Guevara C.
      • Farias G.
      • Silva-Rosas C.
      • et al.
      Encephalitis Associated to Metabotropic Glutamate Receptor 5 (mGluR5) Antibodies in Cerebrospinal Fluid.
      rare
      • Lancaster E.
      • Martinez-Hernandez E.
      • Titulaer M.J.
      • et al.
      Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome.
      ,
      • Mat A.
      • Adler H.
      • Merwick A.
      • et al.
      Ophelia syndrome with metabotropic glutamate receptor 5 antibodies in CSF.
      ,
      • Guevara C.
      • Farias G.
      • Silva-Rosas C.
      • et al.
      Encephalitis Associated to Metabotropic Glutamate Receptor 5 (mGluR5) Antibodies in Cerebrospinal Fluid.
      ,
      • Prüss H.
      • Rothkirch M.
      • Kopp U.
      • et al.
      Limbic encephalitis with mGluR5 antibodies and immunotherapy-responsive prosopagnosia.
      75
      • Spatola M.
      • Sabater L.
      • Planagumà J.
      • et al.
      Encephalitis with mGluR5 antibodies: symptoms and antibody effects.
      ~56
      • Spatola M.
      • Sabater L.
      • Planagumà J.
      • et al.
      Encephalitis with mGluR5 antibodies: symptoms and antibody effects.
      ,
      • Lancaster E.
      • Martinez-Hernandez E.
      • Titulaer M.J.
      • et al.
      Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome.
      ,
      • Mat A.
      • Adler H.
      • Merwick A.
      • et al.
      Ophelia syndrome with metabotropic glutamate receptor 5 antibodies in CSF.
      ,
      • Guevara C.
      • Farias G.
      • Silva-Rosas C.
      • et al.
      Encephalitis Associated to Metabotropic Glutamate Receptor 5 (mGluR5) Antibodies in Cerebrospinal Fluid.
      ,
      • Prüss H.
      • Rothkirch M.
      • Kopp U.
      • et al.
      Limbic encephalitis with mGluR5 antibodies and immunotherapy-responsive prosopagnosia.
      29, single cases 15 – 68
      • Spatola M.
      • Sabater L.
      • Planagumà J.
      • et al.
      Encephalitis with mGluR5 antibodies: symptoms and antibody effects.
      ,
      • Lancaster E.
      • Martinez-Hernandez E.
      • Titulaer M.J.
      • et al.
      Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome.
      ,
      • Mat A.
      • Adler H.
      • Merwick A.
      • et al.
      Ophelia syndrome with metabotropic glutamate receptor 5 antibodies in CSF.
      ,
      • Guevara C.
      • Farias G.
      • Silva-Rosas C.
      • et al.
      Encephalitis Associated to Metabotropic Glutamate Receptor 5 (mGluR5) Antibodies in Cerebrospinal Fluid.
      ,
      • Prüss H.
      • Rothkirch M.
      • Kopp U.
      • et al.
      Limbic encephalitis with mGluR5 antibodies and immunotherapy-responsive prosopagnosia.
      DPPX10–100 in small case series
      • Hara M.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      DPPX antibody-associated encephalitis: main syndrome and antibody effects.
      ,
      • Tobin W.O.
      • Lennon V.A.
      • Komorowski L.
      • et al.
      DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients.
      ,
      • Boronat A.
      • Gelfand J.M.
      • Gresa-Arribas N.
      • et al.
      Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels.
      all serum and CSF positive [
      • Hara M.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      DPPX antibody-associated encephalitis: main syndrome and antibody effects.
      ,
      • Tobin W.O.
      • Lennon V.A.
      • Komorowski L.
      • et al.
      DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients.
      ]
      52–100 [
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • Hara M.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      DPPX antibody-associated encephalitis: main syndrome and antibody effects.
      ,
      • Boronat A.
      • Gelfand J.M.
      • Gresa-Arribas N.
      • et al.
      Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels.
      ]
      38–67 [
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • Boronat A.
      • Gelfand J.M.
      • Gresa-Arribas N.
      • et al.
      Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels.
      ]
      22–67 [
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • Hara M.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      DPPX antibody-associated encephalitis: main syndrome and antibody effects.
      ,
      • Boronat A.
      • Gelfand J.M.
      • Gresa-Arribas N.
      • et al.
      Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels.
      ]
      50–89 [
      • Blinder T.
      • Lewerenz J.
      Cerebrospinal fluid findings in patients with autoimmune encephalitis-A systematic analysis.
      ,
      • Hara M.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      DPPX antibody-associated encephalitis: main syndrome and antibody effects.
      ,
      • Tobin W.O.
      • Lennon V.A.
      • Komorowski L.
      • et al.
      DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients.
      ,
      • Boronat A.
      • Gelfand J.M.
      • Gresa-Arribas N.
      • et al.
      Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels.