REVIEW CPD

Diagnosing autoimmune limbic encephalitis

Adrian Budhram MD, Andrew Leung MD, Michael W. Nicolle MD DPhil, Jorge G. Burneo MD MSPH n Cite as: CMAJ 2019 May 13;191:E529-34. doi: 10.1503/cmaj.181548

utoimmune limbic encephalitis (ALE) is an inflammatory disease involving the medial temporal lobes; it classically KEY POINTS presents with rapid neuropsychiatric decline. Patients with • Autoimmune limbic encephalitis is an inflammatory disease ALEA have, and may present with, a diverse array of neuropsychiatric involving the medial temporal lobes; it classically presents with symptoms, which means that they may initially be assessed by any the subacute onset of short-term memory deficits, seizures or psychiatric symptoms. one of a range of medical practitioners. The condition was first described as a paraneoplastic phenomenon, but subsequently, • Brain magnetic resonance imaging can show medial temporal lobe abnormalities typical of autoimmune limbic encephalitis in with the discovery of disease-causing antibodies, was shown to be suspected cases, but clinicians should be aware of other 1,2 nonparaneoplastic in many cases. Although ALE is uncommon diseases that may have a similar imaging appearance. (an epidemiologic study of encephalitis found the prevalence of • Analysis of both electroencephalogram (EEG) and cerebrospinal ALE without antibody positivity to be only 2 cases per 100 000 peo- fluid can provide supportive evidence of neuro-inflammation in ple), the incidence of autoimmune encephalitides has risen over patients with suspected autoimmune limbic encephalitis, but a the last decade, driven largely by improved antibody detection.3 normal EEG or cerebrospinal fluid profile does not exclude the diagnosis. Autoimmune limbic encephalitis is commonly misdiagnosed, yet early diagnosis and treatment can improve outcomes. • Testing for antibodies to onconeural, cell-surface and synaptic proteins represents a major advancement in the diagnosis of We review the approach to diagnosis of ALE, drawing on find- autoimmune limbic encephalitis, although false-positives are ings of large cohort and case-control studies, which represent possible. the highest level of evidence in this field (Box 1). We discuss diag- nostic criteria for ALE presented in a 2016 position paper by Graus and colleagues (hereafter referred to as the Graus criteria; who presents with sudden-onset neurologic symptoms is more Box 2),4 which aim to prevent overdiagnosis of ALE and are highly likely to have suffered an acute neurologic or systemic insult specific.5 These criteria serve as an excellent resource for both such as a stroke or toxic ingestion. specialists and generalists. The treatment of ALE is best coordin­ However, it is important not to classify a patient’s illness as acute ated by a specialist in autoimmune neurologic diseases and is before questioning family, friends or caregivers about subtle mem- beyond the scope of this review. ory problems or behavioural changes in the preceding days or weeks. Conversely, an individual may seem to have a precipitous What are the clinical features of autoimmune deterioration concerning for ALE, but after further history-taking, it limbic encephalitis? becomes apparent that there has been milder cognitive impairment over many months, or even years. Although certain antibodies have Typical symptoms of ALE reflect dysfunction of the limbic struc- been associated with a more insidious presentation of ALE,10 a pro- tures of the brain and include short-term memory deficits, tracted disease course should alert the physician to the possibility of behavioural changes, anxiety, depression, psychosis and sei- an alternative diagnosis such as a neurodegenerative disease. zures.1,6,7 Autoimmune limbic encephalitis most often occurs in middle-aged adults, but it can affect people of all ages, ranging Involuntary movements from children to older people.1,6–8 Clinicians should ask caregivers about any hemi-body jerking lead- ing up to presentation, which may represent faciobrachial Pace of disease progression dystonic seizures. These involuntary movements consist of brief In retrospective studies of patients with ALE, the median time contractions that affect the ipsilateral face, arm and sometimes from symptom onset to clinical assessment was usually several leg; last a few seconds; can occur up to hundreds of times a day; weeks;6,9 this subacute presentation of the disease is highlighted and are often refractory to treatment with anti-epileptic drugs.11 in the Graus criteria and is a hallmark of the disorder.4 Although They are seen with anti–leucine-rich glioma inactivated 1 (LGI1) ALE should be considered in any patient who presents with rap- antibodies, the most common antibody causing ALE.9 Other symp- idly progressive memory difficulties, behavioural changes, toms likely resulting from focal seizure activity may occur in anti- psychi­atric symptoms or seizures of unclear cause, an individual LGI1 encephalitis, including thermal sensations, piloerection and

© 2019 Joule Inc. or its licensors CMAJ | MAY 13, 2019 | VOLUME 191 | ISSUE 19 E529 REVIEW E530 pathic epilepsy, cerebralischemiaorneurodegeneration. than encephalitis,includingprimary psychiatricdisorders,idio- that two-thirdswereinitiallythought tohaveconditionsother withautoimmuneencephalitidessuch asALEfound 50 patients A retrospectivestudyexamining admissiondiagnosesof Why isprompt,correctdiagnosisessential? monic of this disease. are especiallyhelpfuldiagnosticallyastheynearlypathogno - paroxysmal dizzinessspells,butfaciobrachialdystonicseizures seen onlyintheminority. suade practitioners,ascoincidentepileptiformdischarges are gram (EEG)duringfaciobrachialdystonicseizuresshouldnotdis - typical of ALE in 20 patients (77%); with such seizures found that they preceded cognitive impairment ease inapatientwhoappearstopresentacutely. seizures maybeacluetoprodromalautoimmuneneurologicdis - medial temporal lobes. more sensitive thanMRIto show anincrease inFDGuptake innormal-appearing from studiesfrom thepast5years suggestthat18 F-FDG-PET imagingmightbe †18 Fluorodeoxyglucose (18 F-FDG) PETcanbeusedto fulfil thiscriterion. Results onconeural proteins. can bemadeonly withthedetection ofantibodiesagainst cell-surface, synaptic, or *If oneofthefirst isnotmet, adiagnosisofdefinite 3criteria limbicencephalitis resonance imaging. Note: CSF=cerebrospinal fluid, EEG =electroencephalogram, MRI=magnetic Elsevier. of autoimmune encephalitis. LancetNeurol 2016;15:391–404, from withpermission Reprinted from Graus F, Titulaer MJ, BaluR,etal. A clinicalapproach to diagnosis • • • • been met: Diagnosis canbemadewhenall4*ofthefollowingcriteriahave limbic encephalitis Box 2:Diagnosticcriteriafordefiniteautoimmune the last10years,givenrecentadvancementsinantibodytesting. case-control studiesovercasereports,aswellpublicationswithin publications forpotentialinclusion.Weemphasizedlargercohortand the subject.Wealsoreviewedreferencesofallrelevant mimics, datingbackto1964,andreviewedthosethatwererelevant diagnosis ofautoimmunelimbicencephalitisand/orexclusionits We screenedtitlesofallpublicationsviaPubMed Box 1:Searchstrategyforthisreview Reasonable exclusionofalternativecauses • • At leastoneofthefollowing: Bilateral brainabnormalitiesonT involvement ofthelimbicsystem. memory deficits,seizures,orpsychiatricsymptomssuggesting Subacute onset(rapidprogressionoflessthan3mo)working lobes† inversion recoveryMRIhighlyrestrictedtothemedialtemporal temporal lobes EEG withepilepticorslow-waveactivityinvolvingthe per mm CSF pleocytosis(whitebloodcellcountofmorethan5cells 3 )

11–14 4 Importantly, a normal electroencephalo- 11 A retrospective study of 26 patients Aretrospectivestudyof26 patients 11 2 -weighted fluid-attenuated thus, faciobrachial dystonic CMAJ pertaining to the pertaining tothe | MAY 13,2019 15 Even | VOLUME 191 commonly assumed. sidered, aninfectiousratherthanautoimmunecausewasmore among theone-thirdofpatientsinwhomencephalitiswascon - and likelyeven improved survival. associated withreducedseizure frequency,recoveryofcognition use ofimmunotherapywhich,inobservationalstudies,hasbeen guish betweenaninfectiousandimmune-mediatedcause. tionally infectioussymptomssuchasfeverdidnotreadilydistin - of 203patientswithencephalitis,whichfoundthatmanytradi - these 2diseaseprocesseswashighlightedinaprospective study malignancy may ultimatelydetermineclinicaloutcome. later; bodies thatstronglypredictthe presenceofatumour(discussed gers malignancyscreening,especially amongpatientswithanti- antibodies orwhohave co-existent neuronal cell-surface antibodies(e.g.,anti-GABA **Likelihood oftumourishigherinolder(medianage 60yr)patients withanti-GAD tumours have beenidentified,most commonly non-SCLC. antibodies. Inolderpatients withco-existent anti-Ma1antibodies,avariety ofother ¶Testicular tumourismost likely inyoung (< 45yr)malepatients withanti-Ma2 children withanti-Huantibodiesandmore likely to beneuroblastomas. §SCLC ismost likely inadults withanti-Huantibodies.Tumours are lesscommon in with anti-NMDAR antibodiesandare more likely to becarcinomas. are between theages of12and45years. Tumours are lesscommon inolderpatients ‡Ovarian teratoma ismost likely infemale patients withanti-NMDAR antibodies,who peripheral system nervous hyperexcitability, ordualanti-LGI1/CASPR2 antibodypositivity. †Thymoma ismore likely inpatients withanti-CASPR2antibodies andconcomitant *Antibodies inboldare majordiagnostic considerations inpatients withALE. NMDAR =N glioma inactivated 1,mGluR5=metabotropic glutamate receptor 5,NA=not applicable, γ Amphiphysin GAD Ma2 Hu Antibodies to intracellular proteins Neurexin-3-α mGluR5 NMDAR AMPAR GABA CASPR2 LGI1 Antibodies to extracellular cell surface orsynaptic proteins Antibodies* limbic encephalitis, andtheirtumourassociations Table 1:Antibodiesthat maybefound inautoimmune associated protein-like 2,CRMP5=collapsin response mediator protein 5,GABA α Note: AK5=adenylate kinase5,ALE=autoimmune limbicencephalitis, AMPAR = AK5 CV2/CRMP5 antibodies). -aminobutyric acidBreceptor, GAD =glutamic aciddecarboxylase, LGI-1 =leucine-rich -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidreceptor, CASPR2=contactin- Identification of ALE is important because it facilitates prompt Identification ofALEisimportantbecauseitfacilitatesprompt 8,23 28 24 25 12,14 Table 1). Detection of any occult neoplasm is critical as the B R 18,19 20 6,17 21 10,14 -methyl-d | ISSUE 19 27 22 26 -aspartate receptor, SCLC =small-cell lungcancer. SCLC, thymoma Testicular tumour SCLC None identified Hodgkin’s lymphoma Ovarian teratoma SCLC, thymoma SCLC Thymoma cancers) pancreatic andother breast, thyroid, colon, Various (thymoma, None identified SCLC, thymoma SCLC, breast cancer 15 Thepotentialsymptomoverlapbetween Main tumour association 12,17 Recognitionof ALE also trig- Approximate tumour frequency, % > 90¶ > 90§ 25** > 90 > 90 40‡ 20† NA NA 50 60 50 10 1 B R = R = 16

B R REVIEW - E531 Follow-up Follow-up 33 -hyperintensity 2 Usually, however, EEG shows 9,36 Importantly, EEG abnormalities of Importantly, EEG abnormalities of 37 (Figure 2F). 35 ISSUE 19 ISSUE | ), but early control of seizures with anti-epileptic (Figure 2E), but early control of 34 Seizures can also cause temporal lobe imaging abnormal­ Seizures can also cause drugs alone, lack of prodromal neuropsychiatric symptoms and and symptoms neuropsychiatric prodromal of lack alone, drugs sei of cessation after changes lobe temporal of resolution the supportive of seizure-related MRI changes zure activity are all temporal medial the involving stroke Ischemic ALE. than rather acutely but sometimes causes only mild lobe usually presents patients may delay seeking medical neurocognitive deficits; - is needed to differentiate a sub attention. Careful history-taking from a static neuro- acute progression of symptoms over days MRI, signal abnormality logic insult that occurred days earlier. On distinguish ischemic restricted to a vascular territory helps stroke from ALE slow-wave activity or epileptiform discharges from the temporal discharges epileptiform activity or slow-wave inflammation. In a lobes of patients with ALE — a clue to brain autoimmune encepha- retrospective analysis of 19 patients with EEGs (63%) had sei- litis and seizures, 10 of 16 patients with ictal which closely mirrored zure onset over the temporal lobe region, three- in MRI on seen abnormalities lobe temporal medial the quarters of those studied. Electroencephalography a normal EEG, which Patients with ALE may occasionally have does not rule out the diagnosis. - pres to thought classically Although on. early absent are edema - medial tem series, bilateral in one retrospective ent unilaterally, patients with in 54% cases of involvement was seen poral lobe glioblastoma. ALE who later developed suspected with magnetic resonance imaging is therefore recommended in in is therefore recommended resonance imaging with magnetic atypically, as who progresses ALE possible with patient any indicative of high-grade neoplasm malignant transformation ). may occur (Figure 2C, 2D ities imaging on changes observed any without lobes temporal the ALE in the absence of a are not sufficient to make a diagnosis of VOLUME 191 VOLUME |

4 Other major MAY 13, 2019 MAY | 30,31 CMAJ 30,32 -hyperintensity of the medial temporal lobes is seen (A, arrows). (B) Bilateral T 2 Unilateral rather than bilateral temporal lobe lobe Unilateral rather than bilateral temporal because this modality is not as accessible to is not as accessible to because this modality 30 29 of the medial temporal lobes is also shown on an axial FLAIR image (arrows). Antibodies targeting contactin-associated of the medial temporal lobes is also shown on an axial FLAIR image (arrows). Antibodies targeting protein-like 2 were identified in serum by cell-based assay. Brain magnetic resonance imaging in autoimmune limbic encephalitis. On coronal fluid-attenuated inversion inversion Figure 1: Brain magnetic resonance imaging in autoimmune limbic encephalitis. On coronal fluid-attenuated recovery (FLAIR) image, bilateral T Several noninfectious diseases may involve the temporal the temporal Several noninfectious diseases may involve lobes and be mistaken for ALE. Gliomas may cause diffuse tem- lobes and be mistaken for ALE. Gliomas features of high-grade poral lobe changes on MRI, while imaging and vasogenicneoplasm such as necrosis, irregular enhancement infectious considerations are varicella zoster virus, tuberculosis tuberculosis virus, zoster varicella are considerations infectious these entities should and neurosyphilis; appropriate testing for be considered early in the disease course. changes, insular involvement and absence of basal ganglia of basal ganglia changes, insular involvement and absence suggest herpes simplex involvement are neuroimaging clues that ). virus encephalitis rather than ALE (Figure 2A, 2B

Magnetic resonance imaging Magnetic medial show can the brain of (MRI) imaging resonance Magnetic ) and is rec- the disease (Figure 1 changes typical of temporal lobe cases. in suspected by expert consensus ommended What tests aid in the diagnosis of ALE? of diagnosis aid in the tests What 18-Fluorodeoxyglucose positron emission tomography (18-FDG (18-FDG tomography emission positron 18-Fluorodeoxyglucose be even more sensitive for temporal lobe PET) of the brain may abnormalities; Differential diagnosis of temporal lobe changes on MRI Differential diagnosis of temporal lobe changes cases of encephalitis In a retrospective review of 251 suspected nearly 25% were due with temporal lobe abnormalities on MRI, therefore important to to herpes simplex virus encephalitis; it is in patients with rule out this potentially devastating infection suspected ALE. - MRI remains a first-line neuroim many Canadian practitioners, to imaging abnormalities restricted aging technique. Bilateral lobes are required for a definitive diagnosis the medial temporal to of antibody positivity. It is important of ALE in the absence diseases — such as other infectious and bear in mind that other as well as vascular or neoplastic inflammatory encephalitides, these structures (Appendix 1, available conditions — may involve at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.181548/-/DC1). REVIEW the presenceof leukocytepleocytosisandoligoclonal bandsin brospinal fluidsamples. clonal bandswereeachnoted in onlyabout25%oftestedcere- 205 patients with ALE, however, leukocyte pleocytosis and oligo- cating separation),inkeepingwithacuteinfarctionrestrictedtoavascularterritory. (arrow). Thereisnoextensionofthelesionintomoreanteriororlateraltemporallobesuppliedbyleftmiddlecerebralartery(redlinedemar - diffusion–weighted image,thereisadiffusion-brightlesionoftheleftmedialtemporallobewithinterritoryposteriorcerebralartery E532 ­positive. three-quarters ofsamplestested foroligoclonalbandswere while cells/µL), ­leukocyte pleocytosisincerebrospinalfluid(< 100 50 patientswithparaneoplastic ALE, about50%hada modest mation in patients with possible ALE. In a retrospective study of Analysis ofcerebrospinalfluidcanprovideevidenceneuro-inflam - Cerebrospinal fluidanalysis positive antibody, according to the Graus criteria Figure 2:Magneticresonanceimaging(MRI)mimicsofautoimmunelimbicencephalitis.(A,B)Herpessimplexvirusencephalitis:Onaxial T fuse image, diffuse On axialT lobe abnormalities. sidered, tolookfortheintervaldevelopmentofmedialtemporal the initialMRIisnormal;insuchcases,repeatmaybecon - with possibleALEshouldraisesuspicionoftheconditioneven if or epileptiformdischargesfromthetemporallobesinapatient Box 2.Inclinicalpractice,anEEGthatshowsslow-waveactivity insula (B,arrow)thatsparestheadjacentbasalganglia(redlinedemarcatingseparation).(C,D)Temporallobeglioma:OnaxialT with localedemaonaxialT T 2 -hyperintensity oftherightanteromedialtemporallobeisseen(C,arrow).Onfollow-upMRI6monthslater,thereheterogenousenhancement 2 1 -weighted image,thereisfocalT Inalargerretrospectivepooled-data analysisof T 2 -hyperintensity of the right anteromedial temporal lobe with swelling is seen (A, arrow). There is also 38 1 39 -weighted post-gadoliniumimage,concerningfortransformationintohigh-gradeglioma(D,arrow).(E)Statusepilepticus: Thesefindingssuggestthatalthough 2 -hyperintensity ofthemedialtemporallobesbilaterally(arrows).(F)Acuteischemicstroke:Onaxial CMAJ | MAY 13,2019 4 outlined in | VOLUME 191 abnormalities. encephalitis andautoimmunewithtemporallobe could notreliablydifferentiatebetweenherpessimplexvirus alone (leukocytecount,erythrocyteproteinandglucose) retrospective studyfoundthatthecerebrospinalfluidprofile mimics ofALE,inparticularherpessimplexvirusencephalitis. A nosis ofdefiniteALEevenintheabsenceantibodypositivity. pleocytosis oroligoclonalbandsincerebrospinalfluidforadiag - reflected intheGrauscriteria,whichdonotrequireleukocyte ate clinicalcontext,theirdiagnosticsensitivityislow.This cerebrospinal fluidsupportsadiagnosisofALEintheappropri- repeat PCRtesting iswise. viral treatmentwhileawaiting asecondlumbarpuncturefor remains aconcernclinicallyoron neuroimaging,continuinganti- negative PCRresultbutherpes simplexvirusencephalitis may benegativeearlyinthedisease course. sensitivity andspecificity,but clinicians shouldbeawarethatit pes simplexvirusinthecerebrospinalfluidhashighdiagnostic Testing ofthecerebrospinalfluidisalsohelpfultoexclude | ISSUE 19 30 Polymerasechainreaction(PCR)testingforher- 40 T 2 -hyperintensity of the right 40 2 -weighted image,dif- Ifapatienthas 2 -weighted REVIEW

- . 49 6 51. If aIf E533 195. 48 1500- 10,50 840- 17: 81: 378: 2017; 2013; 2018; Neurology BMC Neurol N Engl J Med Paraneoplastic limbic encephalitis: Paraneoplastic limbic encephalitis: Autoimmune limbic encephalopathy Encephalitis and GABAB receptor anti receptor GABAB and Encephalitis

Investigation of LGI1 as the antigen in Investigation of LGI1 as the antigen in 404. Autoimmune encephalitis epidemiology Autoimmune encephalitis epidemiology et al. et al. et al. et , , , R L et al. E, 391-

A clinical approach to diagnosis of autoimmune , et al. E 15: Voltz CR, et al. , 2016; Sabater R , , MR, Karantoni Kelly MJ Application of the 2016 diagnostic approach for autoimmunefor 2016 diagnostic approach the Application of

A, Lancaster Balu SJ, Antibody-mediated encephalitis. . MJ, MG, et al. et F , R Titulaer Rosenfeld Didelot Lancet Neurol , , R Du

J, ISSUE 19 ISSUE Pittock Graus , | SH, , , L Titulaer J , D Huijbers F , Sun M , L Should 18-fluorodeoxyglucose positron emission tomography positron Should 18-fluorodeoxyglucose suspected autoimmune performed in patients with routinely be magnetic resonance who have a normal limbic encephalitis imaging scan? testing be performed inShould more extensive antibody criteria for definite autoimmunepatients who already meet are negative for the most commonlimbic encephalitis, but this disease?antibodies associated with suspicion for autoimmune limbicWhat is the threshold of antibody testing should be sent, so asencephalitis above which ordering and minimize the risk of false- to avoid indiscriminate positive results? testing be standardized acrossShould methods of antibody Canadian institutions? Höftberger encephalitis from Lancet Neurology to Chinese patients. Dubey and a comparison to infectious encephalitis. Ann Neurol 2018;83:166-77. Graus and anti-Hu antibodies in children without cancer. Neurology 2013;80:2226-32. neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000;123:1481-94. Dalmau Gultekin Lai limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 2010;9:776-85. Honnorat encephalitis. Li bodies: novel findings in a new case series of 20 patients. Box 3: Unanswered questions questions Box 3: Unanswered • • • • . . . . 3. 1. 7. 8. 6 4 2 5

Even if a patient is ultimately determined to have a diagnosis to have a diagnosis Even if a patient is ultimately determined investigation if itother than ALE, a positive antibody still requires (e.g., anti-Hu). strongly associates with an underlying tumour

Conclusion man- appropriate ensure critical to is of ALE diagnosis Accurate the likelihood of a good agement of the disease and to maximize criteria provide a patient outcome. Although recently published is important to under- valuable diagnostic framework for ALE, it diagnostic tools stand the rationale behind using conventional fluid), as well as their (MRI, EEG and analysis of cerebrospinal 3), the ongoing discov- limitations. While questions remain (Box and synaptic pro- ery of antibodies to onconeural, cell-surface the refined diagnosis of teins represents a major advancement in a thoughtful ALE, and, as such testing becomes more accessible, diagnostic approach will help to balance patient care with resource management in Canada. References

Further detail regarding screening for tumours in paraneoplasticFurther detail regarding screening for tumours the scope of this neurologic syndromes such as ALE is beyond published. been has guideline comprehensive a but review, positive antibody is reported in a patient deemed unlikely to havepositive antibody is reported in a patient deemed laboratorymade into whether the testing ALE, inquiry should be false-positives. can perform a confirmatory assay to exclude

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1 In a ret- R, AMPAR, R, AMPAR, 1,41 B -methyl-d These were These were 1 MAY 13, 2019 MAY | R) may be identi be may R) B CMAJ

9 4 Antibody testing is also worth- Antibodies to the intracellular Antibodies to the intracellular 14,17 Antibodies to the N 42,43 46 R) in 16%, α-amino-3-hydroxy-5-methyl-4- 16%, in R) 44 20,47 B These antibodies are variably associated with with These antibodies are variably associated 6,7,45 Onconeural antibodies bind intracellular antigens and are bind intracellular antigens and are Onconeural antibodies More recently, antibodies targeting neuronal cell-surface or or cell-surface neuronal targeting antibodies recently, More The recognition that ALE may be associated with malignancy with malignancy associated ALE may be that The recognition The presence of an antibody with a strong tumour association Of note, antibodies to the voltage-gated potassium channel potassium channel Of note, antibodies to the voltage-gated therefore of unclear pathogenic significance in ALE; they may pathogenic significance in ALE; they may therefore of unclear of a primarily cytotoxic T-cell– simply be an epiphenomenon can lead to irreversible neuronal damage mediated process that and poor clinical outcomes. CASPR2, Hu, Ma2 and GAD) should be considered, to maximize CASPR2, Hu, Ma2 and GAD) should be considered, to maximize diagnostic yield, as some antibodies (e.g., anti-LGI1) are more anti-GABA (e.g., others and serum in sensitive malignancy, and patients often improve with immunotherapy, with immunotherapy, malignancy, and patients often improve neuronal dysfunction. owing to reversal of antibody-mediated synaptic proteins have been discovered in patients with ALE; in patients with ALE; synaptic proteins have been discovered thus more likely to be they bind extracellular antigens and are pathogenic. was followed by the discovery of antineuronal antibodies that discovery of antineuronal antibodies that was followed by the disease mechanism. supported an immune-mediated - ALE, antibodies to neural anti rospective study of paraneoplastic - tumour (referred to as onconeural antibod gens expressed by a in 30 of 50 (60%) of patients. ies) were identified fied only in cerebrospinal fluid.

Approach to antibody testing Both serum and cerebrospinal fluid testing for the most com- monly identified antibodies in ALE (anti-LGI1, GABA Testing for antibodies to onconeural, cell-surface or synaptic synaptic or cell-surface onconeural, to antibodies for Testing disease- ALE, as a positive very helpful in suspected proteins is who would diagnosis in patients can make the specific antibody satisfy Graus criteria. not otherwise Antibody testing Antibody antigen glutamic acid decarboxylase may also be associated with antigen glutamic acid decarboxylase may typically seen in type 1 ALE, but at much higher titres than are diabetes mellitus. while even in a patient who already meets Graus criteria for defi- for criteria Graus meets already who patient a in even while nite ALE, as a positive antibody may indicate the likelihood of a specific tumour (Table 1) and inform malignancy screening. should prompt repeated screening for malignancy if an initial screen is negative, to ensure an occult neoplasm is not missed. were initially reported in ALE but later found to target the associ- were initially reported in ALE but later found than the voltage-gated CASPR2, rather LGI1 and ated proteins potassium channel itself. aspartate receptor (NMDAR) may be identified in ALE, but more in ALE, but more aspartate receptor (NMDAR) may be identified often are found in patients with a normal MRI and a characteris- tic clinical syndrome (anti-NMDAR encephalitis), consisting of abnormal behaviour, speech dysfunction, seizures, dyskinesias or dysautonomia. most often anti-Hu or Ma2 antibodies, which are classically found or Ma2 antibodies, which are classically found most often anti-Hu and testicular tumour, respectively. with small-cell lung cancer isoxazolepropionic acid receptor (AMPAR) in 7%, and contactin- isoxazolepropionic acid receptor (AMPAR) associated protein-like 2 (CASPR2) in 6%. In a retrospective study of 163 patients with ALE, antibodies were In a retrospective study of 163 patients with neuronal cell- found in 93%, the majority of which targeted γ-aminobutyric acid B surface or synaptic proteins: LGI1 in 44%, (GABA receptor REVIEW E534 29. 28. 10. 15. 25. 23. 14. 12. 11. 24. 16. 27. 26. 13. 18. 17. 19. 20. 21. 22. 9 . This articlehasbeenpeerreviewed. other competinginterestsweredeclared. Research Chair),outsidethesubmittedwork.No Chair inEpilepsyResearch(aWesternUniversity sity, andothersupportthroughtheJackCowin the Ontario Brain Institute and Western Univer- ceiving grantsfromtheRickBergLegacyFund, Competing interests: Graus Newey with anti–adenylatekinase5autoantibodies.Neurology2017;88:514-24. Do 146- van Sonderen 2018; Baumgartner among 256LGI1/CASPR2-IgG-positivepatients.AnnNeurol2017;82:79-92. limbic encephalitis tis. AutoimmuneDis2016;:9450452. tomography scanshouldbeobtainedearlyincasesofautoimmuneencephali- of lungcancerandthymoma-relatedautoimmunity. Ariño encephalitis. Graus 2016;86:2235-42. bodies associatewithencephalitisandaltersynapsedevelopment. Gadoth 2017;50:14-7. characterised byfrequent,multifocalclinicalandsubclinicalseizures. van Sonderen antibody limbicencephalitis.AnnNeurol2011;69:892-900. Irani antibody-associated disease.Neurology2016;87:521-8. Dalmau encephalomyelitis: analysisof200patients.Brain2001;124:1138-48. Granerod later diagnosedwithautoimmuneencephalitis.JNeurol2019;266:124-32. Yu neoplastic accompaniments.AnnNeurol2005;58:96-107. Pittock 874- dromes andglutamicaciddecarboxylaseantibodies. Aurangzeb syndrome andlong-termfollow-up.Neurology2016;87:1449-56. Höftberger Neurol encephalitis withseizures:caseseriesandcharacterisationoftheantigen. Lancaster spective study.LancetInfectDis2010;10:835-44. in theirclinicalpresentationsEngland:amulticentre,population-basedpro- Aetiology ofEncephalitisStudyGroup. Laurido-Soto 2403- antibodies: novelfindingsinacaseseriesof22patients. Titulaer associations inAMPAreceptorencephalitis.JNeurol2019;266:450-60. Spatola observational cohortstudy.LancetNeurol2013;12:157-65. for long-termoutcomeinpatientswithanti-NMDAreceptorencephalitis:an Gresa-Arribas symptoms andantibodyeffects.Neurology2018;90:e1964-72. Z L-D, 81. 54. , 25: SR,

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