ARTICLE OPEN ACCESS

Neurologic syndromes related to anti-GAD65Clinical and serologic response to treatment

Amaia Muntildeoz-Lopetegi MD Marienke AAM de Bruijn MD Sanae Boukhrissi BSc

Anna EM Bastiaansen MD Mariska MP Nagtzaam BSc Esther SP Hulsenboom BSc

Agnita JW Boon MD PhD Rinze F Neuteboom MD PhD Juna M de Vries MD PhD

Peter AE Sillevis Smitt MD PhD Marco WJ Schreurs PhD and Maarten J Titulaer MD PhD

Neurol Neuroimmunol Neuroinflamm 20207e696 doi101212NXI0000000000000696

Correspondence

Dr Titulaer

mtitulaererasmusmcnl

AbstractObjectiveAntibodies against glutamic acid decarboxylase 65 (anti-GAD65) are associated with a numberof neurologic syndromes However their pathogenic role is controversial Our objective was todescribe clinical and paraclinical characteristics of anti-GAD65 patients and analyze their re-sponse to immunotherapy

MethodsRetrospectively we studied patients (n = 56) with positive anti-GAD65 and any neurologicsymptom We tested serum and CSF with ELISA immunohistochemistry and cell-based assayAccordingly we set a cutoff value of 10000 IUmL in serum by ELISA to group patients intohigh-concentration (n = 36) and low-concentration (n = 20) groups We compared clinical andimmunologic features and analyzed response to immunotherapy

ResultsClassical antindashGAD65-associated syndromes were seen in 3436 patients with high concen-tration (94) stiff-person syndrome (7) cerebellar ataxia (3) chronic epilepsy (9) limbicencephalitis (9) or an overlap of 2 or more of the former (6) Patients with low concentrationshad a broad heterogeneous symptom spectrum Immunotherapy was effective in 1927 treatedpatients (70) although none of them completely recovered Antibody concentration re-duction occurred in 1517 patients with available pre- and post-treatment samples (medianreduction 69 range 27ndash99) of which 14 improved clinically The 2 patients with un-changed concentrations showed no clinical improvement No differences in treatmentresponses were observed between specific syndromes

ConclusionMost patients with high anti-GAD65 concentrations (gt10000 IUmL) showed some im-provement after immunotherapy unfortunately without complete recovery Serum antibodyconcentrationsrsquo course might be useful to monitor response In patients with low anti-GAD65concentrations especially in those without typical clinical phenotypes diagnostic alternativesare more likely

From the Department of Neurology (AM-L MAAMdB AEMB MMPN ESPH AJWB RFN JMdV PAESS MJT) and Department of Immunology (SB MWJS)Erasmus MC University Medical Center Department of Neurology (AM-L) IDIBAPS Barcelona Spain and Health Care Provider of the European Reference Network on Immu-nodeficiency Autoinflammatory and Autoimmune Diseases (ERN-RITA) (MJT) Rotterdam the Netherlands

Go to NeurologyorgNN for full disclosures Funding information is provided at the end of the article

The Article Processing Charge was funded by Erasmus University

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

Autoantibodies against glutamic acid decarboxylase (GAD)65 have been linked to different types of syndromes Theseantibodies are widely used as biomarkers for diabetes mel-litus type 1 (DM1) diagnosis because they are present in80 of patients at diagnosis12 However it is well knownthat anti-GAD65 can also be associated with specific neu-rologic disorders including stiff-person syndrome (SPS)cerebellar ataxia (CA) epilepsy (Ep) and limbic encepha-litis (LE)3ndash6

The pathophysiologic role of anti-GAD65 in neuro-inflammation is still unclear It is hard to understand whetherthere is a direct antibody-associated pathogenic effect be-cause the target antigen is located intracellularly Moreoverresponses to immunotherapy seem to be poorer than inpatients with neurologic disorders caused by most otherantineuronal antibodies78

In studies evaluating treatment effects in antindashGAD65-positive patients methods used are variable and patientcohorts are often restricted to one of the specific clinicalphenotypes9ndash11 In addition some studies describing patientswith neurologic symptoms and anti-GAD65 also includepatients with low antibody concentrations In these patients

clinical relevance of anti-GAD65 is questionable because lowantibody concentrations are regularly found among patientswith DM1 (without neurologic symptoms) and rarely inhealthy individuals1212

The aim of this cohort study is to evaluate the clinical rele-vance of low and high anti-GAD65 concentrations in patientswith neurologic symptoms to establish clinically relevantcutoff values (in serum and CSF) and to evaluate clinical andserologic treatment responses

MethodsPatientsWe retrospectively included patients with neurologicsymptoms and an increased anti-GAD65 concentrationdetected in serum andor CSF from January 2015 until June2018 Anti-GAD65 was routinely detected at the De-partment of Immunology (Laboratory Medical Immunol-ogy) of the Erasmus University Medical Center by usingELISA and reported as negative or positive Clinical in-formation was obtained from medical files Thirty of 56patients (54) were seen by one of the authors

GlossaryCA = cerebellar ataxia CBA = cell-based assay Ep = epilepsy GAD = glutamic acid decarboxylase IHC =immunohistochemistry IVIg = IV immunoglobulin LE = limbic encephalitis mRS = modified Rankin Scale SARA = Scalefor the Assessment and Rating of Ataxia SPS = stiff-person syndrome

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Standard protocol approvals registrationsand patient consentsThe institutional review board of the Erasmus UniversityMedical Center approved the study protocol Written in-formed consent was obtained from all patients

Laboratory testsAnti-GAD65 was determined in serum and CSF when availableusing 3 assays Paired serum and CSF samples were used ifpossible Otherwise serum samples drawn closest to the CSF tapwere used provided they were preimmunotherapy samples Firstautomated quantitative ELISA was performed according to themanufacturerrsquos instructions (Medizym anti-GAD MedipanBerlin Germany) Calibration curves based on 5 calibrators (518 35 120 and 250 IUmL) were used to infer antibody con-centrations Samples were considered positive with anti-GAD65concentrations above 5 IUmL When concentrations were over250 IUmL we tested serial dilutions (110 1100 11000 110000) and chose the most reliable result (ie optical densityvalue in the linear part of the calibration curve) to determine theIUmL end concentration Second immunohistochemistry(IHC) was used as a screening method to determine immuno-reactivity of patientsrsquo serum (diluted 1200) or CSF (diluted 12)against rat hippocampal brain tissue A detailed description can befound elsewhere13 GAD65 antibody binding causes a character-istic staining pattern13 Finally cell-based assay (CBA) (Euro-immun Lubeck Germany REF FA 1022-1005-50) wasperformed according to the manufacturerrsquos instructions usinghuman embryonal kidney cells (HEK293) expressing recombi-nant GAD65 Serum was diluted 110 and CSF was usedundiluted

ELISA provided quantitative results IHC and CBA were usedas confirmatory qualitative techniques to determine clinicallyrelevant cutoff values for serum and CSF Samples positive byELISA and confirmed with positive IHC and CBA were con-sidered high-concentration samples14 Samples showing a pos-itive staining pattern on IHC but no typical GADpattern weretested more extensively with commercial and in-house CBAsusing fixed or live cells (Euroimmun kits and in-house CBAs)

Defining clinical phenotypes and clinicalrelevance of anti-GAD65Patients were allocated into 6 groups based on the clinicalphenotypes described in the literature (1) SPS (2) CA (3)Ep (4) LE (5) overlap and (6) other The overlap categoryconsisted of patients who had developed more than 1 antindashGAD65-associated neurologic syndrome over the diseasecourse Patients with LE presenting with seizures or de-veloping seizures following LE were not considered asoverlap syndromes and were all classified as LE

After determining cutoff values patients were classified intoa high-concentration or low-concentration group Patients inthe high-concentration group were studied more thoroughly toassess clinical and serologic response to immunotherapy

Immunotherapy responses were evaluated by one of theauthors during follow-up or were retrospectively assessed frommedical files A seizure frequency reduction of at least 50 wasconsidered as improvement in patients with Ep For the otherclinical phenotypes the modified Rankin Scale (mRS) scoreand the Scale for the Assessment and Rating of Ataxia (SARA)score were used1516 when available One-point improvementin the mRS score or 3 points at the SARA score was consideredclinically relevant In the absence of absolute scores patientsrsquoand physiciansrsquo evaluations as measured by the clinical globalimpressionmdashimprovement scale17 were taken into account

Serologic response to treatment was measured comparingpre- and post-immunotherapy ELISA antibody concen-trations A reduction of at least 25 following immunother-apy was considered a relevant concentration reduction

Patients with isolated DM1To explore the spectrum of concentrations of anti-GAD65antibodies we also assessed patients with DM1 without neu-rologic symptoms At the Department of Immunology of theErasmus University Medical Center sera from 669 patientswere tested for anti-GAD65 between January 2018 and De-cember 2018 As the reason for testing was often unknownfiltering based on additional antibody testing for Islet CellCytoplasmic Autoantibodies (ICA) or tyrosine phosphataseantibodies (anti-IA2) was performed This way we selectedsamples from 198 patients that were sent specifically for a sus-picion of insulin-dependent diabetes mellitus because neurol-ogists would not request additional islet antigen antibodiesSeventy-three samples (37) tested positive for anti-GAD65Of these 37 were analyzed more extensively with quantitativeELISA IHC and CBA Patients with high concentrations andpositive IHC and CBA (n = 3) were approached to identifyassociated neurologic disorders of whom 2 could be traced

StatisticsThe Fisher exact test was used to compare categorical varia-bles between the high-concentration and low-concentrationgroups Age CSF cell count and protein count were com-pared with the Mann-Whitney U test To compare antibodytests theMcNemar test was used pValues less than 005 wereconsidered significantWe used SPSS 240 and Graph Path 70for analysis and data visualization

Data availabilityAny data not published within this article are available at theErasmus University Medical Center Patient-related data willbe shared on request from any qualified investigator main-taining anonymization of the individual patients

ResultsLaboratory testsWe identified 71 patients with neurologic symptoms and atleast 1 positive serum or CSF anti-GAD65 test result of

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whom 56 were included in our study Eleven patients couldnot be reached to collect informed consent and 4 patientsrefused to participate

The median serum concentration measured with ELISAwas 74700 IUmL (n = 54 interquartal range [IQR]1350ndash612500 IUmL range 6ndash2130000 IUmL) and themedian CSF concentration was 2430 IUmL (n = 43 IQR6ndash8810 IUmL range 0ndash83800 IUmL) Serum and CSFsamples were drawn a median of 25 months (IQR 6ndash69months) and 19 months (IQR 1ndash69 months) after symptomonset respectively

IHC and CBA showed a high concordance (figure 1) A cutoffof 100 IUmL showed a 100 concordance among tests inCSF For serum with a cutoff value of 10000 IUmL 100 oflow-concentration samples had a negative IHC and 97 ofhigh-concentration samples had a positive IHC Similarly100 of high-concentration samples were positive with CBAand 96 of low-concentration samples were negative AllCBAs and IHCs corresponded except 3 diabetes sampleswith positive CBA and negative IHC In those 3 samples

ELISA concentrations were between 6220 and 15400 IUmL Samples with an unspecific neuropil staining on IHCwere excluded for calculations Other antibodies were foundin 1 patient in the high anti-GAD65 concentration (anti-gamma-aminobutyric acid B receptor [GABAbR]) and 2patients with low anti-GAD65 concentration (1 anti-GABAbR and 1 anti-GlyR)

In the DM1 group without overt neurologic symptoms themedian serum concentration of 68 patients with DM1 (35of 192 samples) was 86 IUmL (IQR 51ndash3670 IUmL range15ndash145400 IUmL) Three samples (16) showed an anti-GAD65 concentration gt10000 IUmL and also tested posi-tive by IHC and CBA The 2 patients traceable had DM1Onealso had multiple other autoimmunities (vitiligo idiopathicthrombocytopenic purpura and thyroiditis) but in bothpatients no neurologic or psychiatric symptoms were present

PatientsThirty-six patients were allocated into the high-concentrationgroup (serum concentration gt10000 IUmL or CSF con-centration gt100 IUmL) and 20 patients into the low-

Figure 1 Comparison of laboratory techniques

ELISA concentrations of serum (A and B) and CSF (A and D) of patients with neurologic disorders in comparison to IHC and CBA Patients identified with darkgray and yellow squares in A showed a neuropil staining on IHC instead of the typical GAD pattern Samples with a neuropil staining and high ELISAconcentration had a positive GAD65-CBA result whereas CBA was negative for low-concentration samples (A) In B and D dark gray and yellow dots are usedin both IHC and CBA columns to identify these samples In the dark gray dotted patients a different antibody was found Serum or CSF of the yellow dottedpatients showed a neuropil staining but no known antibody was found Serum results from patients with antibody testing for diabetes (DM-1) are shown (C)Logarithmic transformationwas used for charts Concordance rates for ELISA IHC and CBA are provided for serumandCSF (E) CBA = cell-based assay GAD =glutamic acid decarboxylase IHC = immunohistochemistry

4 Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 3 | May 2020 NeurologyorgNN

concentration group Clinical characteristics are shown intable 1

In the high-concentration group 3436 (94) patients hada typical antindashGAD-associated neurologic syndrome SPS (n= 7) CA (n = 3) Ep (n = 9) LE (n = 9) or an overlapsyndrome (n = 6) In the overlap group 4 patients initially haddrug-resistant focal Ep and developed CA SPS or a combi-nation of both between 2 and 7 years after seizure onset(figure 2) One patient initially had CA and developed SPS 5years later and 1 SPS patient developed prominent cerebellarsymptoms 7 years after onset One patient with LE no seiz-ures and associated extralimbic involvement in MRI hadconcomitant GABAbR antibodies without a tumor Of the

remaining 2 patients both with DM type 2 one had a pseudo-orthostatic tremor and the other one had optic neuropathy

In the low-concentration group 1220 patients had an al-ternative diagnosis including 1 LE with anti-GABAbR anda pancreatic adenocarcinoma and 1 progressive encephalo-myelitis with rigidity and myoclonus with anti-GlyR withoutan associated tumor different variants of subacute or chronicpolyradiculoneuropathies and other nonndashimmune-mediateddiseases (glioblastoma hemispastic syndrome after brainsurgery multiple system atrophy or functional disorder) Theremaining 8 patients had chronic Ep otherwise seronegativeLE or nonspecific ataxia and gait disorder (see table e-1 linkslwwcomNXIA209)

Table 1 Clinical and paraclinical characteristics of the high-concentration and low-concentration groups

High concentration (n = 36) Low concentration (n = 20) p Value

Age at onset median (IQR range) 29 (33 11ndash80) 52 (22 5ndash72) 023

Women n () 29 (81) 9 (45) 002a

Autoimmune disorders n () 1832 (56) 1418 (77) 021

DM1 n () 1435 (40) 818 (44) 078

Other autoimmune disorders n () 1132 (34) 1218 (67) 004a

Tumorsb n () 420 (20) 210 (20) 100

Clinical syndrome

Typical n () 34 (94) 11 (55) 00008cd

SPS n () 7 (19) 2 (10)

CA n () 3 (8) 2 (10)

Ep n () 9 (25) 3 (15)

LE n () 9 (25) 4 (20)

Overlap n () 6 (17) 0 (0)

Other n () 2 (6) 9 (45)

CSF

Pleocytosis n () 627 (22) 714 (50) 009

Cell count median (IQR range) 31 (128 6ndash310) 18 (102 11ndash366) 066

Proteins increased n () 824 (33) 712 (58) 0175

Protein count median (IQR range) 038 (020 020ndash113) 055 (054 031ndash124) 001a

Oligoclonal bands n () 1218 (67) 35 (60) 038

MRI (brain) abnormalities n () 1532 (46) 516 (31) 038

Other antibodies n ()e 135 (3) 217 (12) 020

Immunotherapy use n () 2735 (77) 819 (42) 002a

Abbreviations CA = cerebellar ataxia DM1 = diabetes mellitus type 1 Ep = epilepsy IQR = interquartal range LE = limbic encephalitis SPS = stiff-personsyndromea p lt 005b Tumors in the high-concentration group intestinal lymphoma (1) breast cancer (1) prostate adenocarcinoma (1) and testicular tumor (pathology unknown)(1) Tumors in the low-concentration group glioblastoma (1) and pancreatic carcinoma (1)c p lt 0005d Comparing the frequency of typical vs other syndromes between patients with high-concentration or low-concentration samplese One patient in the high-concentration group had anti-GABAbR In the low-concentration group 1 patient had anti-GlyR and 1 patient had anti-GABAbR

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 3 | May 2020 5

Figure 3 shows patients distributed according to their clinicalphenotype and antibody concentration in serum and CSFThe median concentrations of the different clinical pheno-types (in the high-concentration group) were comparable inserum (p = 0210) and CSF (p = 0067) No association wasfound between concentration levels and clinical severity be-tween patients (data not shown)

Within the high-concentration group the median serumCSFanti-GAD65 ratio was 53 (IQR 171 range 7ndash1761 n = 28)After excluding overlaps there were no significant ratio dif-ferences between the clinical syndromes (p = 029) althoughthe median ratio of SPS was more than 2-fold that of the otherphenotypes (figure 3C)

Twenty-seven patients from the high-concentration group weretreated with immunotherapy of them 26 (96) received IVimmunoglobulins (IVIg) in different treatment regimes Mostused regime was 04 gkg for 5 days repeated monthly for atleast 2 more times to assess response Eight patients (30)were treated with IV methylprednisolone and 3 patients re-ceived plasma exchange Four patients were additionally treatedwith second-line immunotherapy including rituximab (n = 3)and cyclophosphamide (n = 1) Chronic immunosuppressionwas given in 11 patients consisting of combinations of azathi-oprine (n = 9) oral steroids (n = 8) mycophenolate mofetil (n= 5) and cyclosporine (n = 1) Figure 2 shows individualtimelines of the high-concentration group patients treated withimmunotherapy Nineteen patients (70) improved Eight of

10 patients with SPS (including patients with overlap syn-dromes) improved according to themselves and their physi-cians accompanied by the mRS score decrease in 7 of them(table 2) All patients with CA (including patients with overlapsyndromes) except one felt better and obtained a reduction inthe mRS score SARA scores improved ge3 points in the only 2patients in whom scores were available In patients with chronicEp gt50 seizure frequency reduction was obtained in 4 of 7patients Immunotherapy was efficacious in 5 of 7 patients withLE and 2 of them had relapses despite chronic treatmentThose 2 responded to more intensive therapies Four typicalpatient examples are provided in figure 4

In 1736 high concentration patients pre- and post-treatmentsamples were available for comparison Antibody concentrationsshowed a median concentration reduction of 69 (range27ndash99) and decrease was over 25 in 15 of the 17 serumsamples after immunotherapy (figure 5) A clear clinical responsewas observed in 14 of these 15 treated patients The 2 patientswithout consistent decrease in concentration showed no clinicalimprovement Both had focal Ep for years

In none of the patients complete recovery was reachedSimilarly in none of the patients antibodies disappeared inserum In 617 patients with pre- and post-treatment samplesserum concentrations became lower than 10000 IUmLDespite periodic or chronic immunotherapy a stagnationboth clinically and serologically was observed after initialimprovement However after withdrawal or tapering of

Figure 2 Patients treated with immunotherapy

Disease courses and treatment regimens of the 27 patients that were treated with immunotherapy In patients with overlapping syndromes the specificsyndromes are indicated below the gy bar with the corresponding color at the relative time when they were diagnosed Symbols inside the color bars showspecific treatments or the moment they were initiated A line with the same color is used for chronic (continuous line) and periodic (discontinuous line)treatments to show their duration Symbols on the left side correspond to those in Figure 5

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 3 | May 2020 NeurologyorgNN

immunotherapy symptoms deteriorated syndromes relapsedor concentrations increased in 6 patients (figure 2 and figure 4)Four patients also had relapses or clinical worsening despitestable chronic or periodic immunotherapy

DiscussionThis study aimed to determine the clinical relevance ofGAD65 antibodies in patients with neurologic syndromesand evaluate their responses to immunotherapy We showedthat patients with high anti-GAD65 concentrations pre-sented with a limited number of specific neurologic syn-dromes whereas the neurologic symptoms observed inpatients with low concentrations were less specific neces-sitating additional investigations The laboratory tests usedshowed a high concordance and a clear cutoff value for thehigh and low antibody concentrations Around two thirds ofthe patients responded to immunotherapy although all in-completely The clinical improvement was reflected in thereduction of anti-GAD65 concentrations in both serumand CSF

Patients with high antibody concentrations had well-definedclinical phenotypes that have been classically associated withGAD65 antibodies such as stiff-person syndrome CA Ep or

LE In addition 1 of 5 patients had overlap syndromes Re-markably in these patients the relapse tended to present withdifferent phenotypes Another interesting feature was a dif-ferent not previously described phenotype including pseudo-orthostatic tremor and optic neuropathy in 2 patients in thehigh-concentration group Unfortunately these 2 patientswere not seen by one of the authors so diagnosis and absenceof more typical symptoms should be taken with caution

From a different perspective patients with low antibodyconcentrations presented with a diversity of neurologic syn-dromes Some of them had a phenotype that is similar to theclassically antindashGAD65-associated syndromes which wasprobably the reason why anti-GAD65 was requested in thesepatients However frequently other diagnoses were identifiedin the workup or during the follow-up like neurodegenerativediseases or tumors In these cases positive ELISA was notconfirmed by IHC or CBA and concentrations were low andcomparable to those seen in samples tested for type 1 diabetesmellitus In these patients extensive workup to identify otherdiseases is warranted including requesting other antibodiesAnti-GABAbR antibodies were identified in a few patientswith high and low concentrations of GAD65 antibodies inline with previous studies18 Around 40 of the patients inboth high- and low-concentration groups had been diagnosed

Figure 3 Antibody concentrations and clinical syndromes

Patients were grouped according to their clinical phenotype into 1 of the 4 classical antindashGAD65-associated syndrome categories in the overlap or othercategory Serum (A) and CSF (B) ELISA concentrations are shown in a logarithmic scale Small black dots represent patients with low antibody concentrationsThe specific symptoms of these patients are listed in the supplementary material Orange dots in the SPS column were patients with progressive enceph-alomyelitis with rigidity and myoclonus which is considered an extended form of SPS (C) SerumCSF ratio of anti-GAD65 ELISA values within the differentsyndromes in the high-concentration group The blue ribbon represents the ratio-frame where intrathecal antibody synthesis would be expected to start CA= cerebellar ataxia Ep = epilepsy GAD = glutamic acid decarboxylase LE = limbic encephalitis SPS = stiff-person syndrome

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Table 2 Effects of immunotherapy in patients with high antiglutamic acid decarboxylase 65 concentrations

ID Condition ImprovedBeforetreatment

Best aftertreatment

ImprovedmRSscoreSARAscore

Subjectiveimprovement CGI-S CGI-I

8 SPS Yes Walked with a walkerlimited by painful spasmsthat worsened withmovement mRS score 3

Cycles and walksindependent or sometimeswith walker mRS score 2

Yes 3 to2NA

Yes muchbetter

4moderate

2 muchimproved

5 SPS Yes Stiff-leg syndrome Couldwalk without assistancemRS score 2

Much better with IVIg butstill increased tonus mRSscore 1

Yes 2 to1NA

Yes muchbetter

4moderate

2 muchimproved

33 SPS Yes Stiff-leg syndromeUnassisted in shortdistances wheelchair andwalker for longer walksoutside home mRS score 3

Mild stiffness Verysatisfied ldquoSometimesforgets that she is illrdquo mRSscore 1

Yes 3 to1NA

Yes muchbetter

4moderate

2 muchimproved

13 SPS No Walked unassistedindependent for dailyactivities of life but limitedby leg stiffness painfulcramps and lower backpain mRS score 2

Progression halted but noimprovement mRS score 2

NoNA No 3 mild 4 notimproved

22 CA Yes Walked without assistancebut tandem impossibleDiplopia and dysmetriamRS score 2

Diplopia and handdysmetria solvedsubjectively ataxia 50improved (still needsassistance) mR 2

Noyes11 to 8

Yes improved 4moderate

2 muchimproved

9 CA Yes Moderate ataxiadysarthria and dysmetriaOnly short distances witha walker mRS score 4

Ataxia improved able towalk 30 m with a stick mRSscore 3

Yes 4 to3unknown

Yes 4moderate

3 mildlyimproved

30 CA Yes Ataxia dysarthrianystagmus and dysmetrianeeds a walker mRS score3

Objective improvement ofstatic and dynamic stabilitymeasured by a physicaltherapist mRS score 2

Yes 3 to2unknown

Yes 4moderate

2 muchimproved

18 Ep Yes 7 seizuresd FOA-deja-vu-FOIA)

Clusters of days with 1ndash3seizuresd days withoutseizures

NANA Yes mildly 4moderate

3 mildlyimproved

6 Ep Yes 40 seizuresmo (FOIA FOAand bilateral tonic-clonic)

2ndash4 seizuresmo (lessintense)

NANA Yes muchbetter

4moderate

2 muchimproved

32 Ep Yes Clusters of 1ndash3 seizuresd every 3 wk (FOIA)

1ndash2 seizuresmo (FOIA) NANA Yes muchbetter

3 mild 2 muchimproved

3 Ep Yes 5ndash10 seizuresmo (FOIA andFOA)

2 seizuresmo (FOA) NANA Yes improved 3 mild 2 muchimproved

36 Ep No Daily seizures (FOIA dailyand bilateral tonic-clonicoften)

No improvement NANA No 4moderate

4 notimproved

23 Ep No Daily FOA (deja-vu) 9 tonic-clonic seizuresmo

Improved (deja-vu 2ndash5wk5 tonic-clonic seizuresmo)but less than 50

NANA Yes mildly(insufficient)

4moderate

3 mildlyimproved

16 Ep No 50ndash60 seizuresmo (FOIA) No improvement NANA No 4moderate

4 notimproved

34 LE Yes Severe cognitive declinememory severely impairedand unable to recognizefamily members

Initial improvementrecognized familymembers Able to live athomewith serious cognitiveimpairment Relapse 9 molater withoutimprovement

Yes 5 to4NA

Yes 6 verysevere

3 mildlyimproved

Continued

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 3 | May 2020 NeurologyorgNN

Table 2 Effects of immunotherapy in patients with high antiglutamic acid decarboxylase 65 concentrations (continued)

ID Condition ImprovedBeforetreatment

Best aftertreatment

ImprovedmRSscoreSARAscore

Subjectiveimprovement CGI-S CGI-I

4 LE Yes Debut seizures andcognition (FOA-deja-vu-FOIA bilateral tonic-clonicstatus epilepticus)Relapses seizure frequencyincrease status epilepticusand cognition

Clear improvement seizurefrequency reduced (almostall FOA) cognitionimproved Worsens withimmunotherapy reduction

Yes 5 to2NA

Yes improved 4moderate

2 muchimproved

21 LE Yes Debut memoryimpairment panic attacksseizures (FOA and bilateraltonic-clonic) and statusepilepticus Then chronicEp Relapses seizurefrequency to 1ndash2 daily

Seizures and memoryimproved during firstadmission Seizures almostdisappeared with chronicimmunotherapy(occasional FOIA)

Yes 5 to1NA

Yes muchbetter

4moderate

2 muchimproved

24 LE Yes Chronic Ep with relapsesRelapses seizure frequencyincrease (almost daily)behavioral symptomstwice status epilepticus

1 seizurewk lately stablefor 15 mo

Yes 5 to2NA

Yes muchbetter

4moderate

2 muchimproved

26 LE Yes Memory impairment andseizures clinicaldeterioration unable towalk or feed herself

No seizures walks assistedand able to eat(immunotherapy surgeryand chemotherapy)

Yes 5 to3NA

Yes improved 5 severe 3 mildlyimproved

29 LE No Seizures (FOIA) andbehavioral symptomsAdmitted with statusepilepticus

Chronic treatment-refractory Ep noimprovement withimmunotherapy

NoNA No 4moderate

4 notimproved

12 LE No Memory impairment andseizures (FOA-deja-vu- 2dbilateral tonic-clonic twice)

2 seizureswk (FOA)memory normalized

Yes 3 to1NA

Yes muchbetter

4moderate

2 muchimproved

7 Ep + SPS Yes Seizures (FOA-musicogenic- bilateral tonic-clonic) hadvariable frequencyStiffness in legs walkerSerious progression afterimmunotherapywithdrawal (falls hipfracture and continuedspasm) became bedboundmRS score 5

Initially became seizurefree not muchimprovement in stiffnessTreatment stoppedRestarted afterprogression with seriousimprovement Needswalker mRS score 3

Yes 5 to3NA

Yes muchbetter

5 severe 2 muchimproved

1 Ep + SPS Yes Seizures 15wk (FOIA)Wheelchair due to stiffnessand pain mRS score 4

Seizures 1ndash4wk (FOIA)Able to cycle 5 km andrecovered someindependence mRS score2

Yes 4 to2NA

Yes improved 4moderate

2 muchimproved

2 Ep + SPS +CA

Yes 4 seizuresmo Because ofataxia and stiffness unableto walk at all WheelchairSARA score 22 mRS score 4

No seizures SARA score 17Can walk 12 m with 2people mRS score 4 Butsubjectively somewhatbetter than beforetreatment

Noyes22 to 17

Yes improved 5 severe 3 mildlyimproved

28 Ep + SPS Yes Seizures 1mo (FOIA) Mildstiffness in the right leg andarm walked withassistance mRS score 3

Seizures unchanged (1mo)Clear but short-lastingimprovement in stiffnessand spasms after IVIginfusions Able to walkwithout assistance mRSscore 2

Yes 3 to2NA

Yes improved 4moderate

2 muchimproved

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 3 | May 2020 9

with type 1 DM before the onset of neurologic symptomswhich is also in line with previous studies19ndash22

To define which antibody concentration should be consid-ered high and relevant we compared 3 different laboratorytechniques and found highly concordant results ELISAconcentrations above 10000 IUmL for serum and 100 IUmL for CSF can be detected by IHC and CBA with com-parable results CBA as expected is more specific especially if

a different antibody is concomitantly present in the testedsample (leading to an unspecific IHC staining pattern) An-other cutoff value (of 2000) has been suggested before1323

but these studies used a radioimmunoassay with different testcalibration currently not widely used anymore

The role of GAD65 antibodies in neuroinflammation is de-batable and still unknown An obvious theory would be thatantibodies block GAD65 interfering with GABA synthesis

Table 2 Effects of immunotherapy in patients with high antiglutamic acid decarboxylase 65 concentrations (continued)

ID Condition ImprovedBeforetreatment

Best aftertreatment

ImprovedmRSscoreSARAscore

Subjectiveimprovement CGI-S CGI-I

14 CA + SPS Yes Ataxia and dysmetria anddizziness (SARA score 115)and stiffness Neededa stick at home and awalkerfor long distances mRSscore 4

Dizziness disappearedSpeech Ataxia clearlyimproved stiffness mildlyimproved SARA score 7stick to go out unassisted athome mRS score 2

Yes 4 to2NA

Yes muchbetter

4moderate

3 mildlyimproved

15 SPS + CA No Severe cerebellarsyndrome bedbound mostof the time mRS score 5

Never improved Nounknown

No 6 verysevere

4 notimproved

Abbreviations CA = cerebellar ataxia CGI-I = Clinical Global ImpressionndashImprovement scale improvement of disease after immunotherapy rated bya clinician (1mdashvery much improved to 7mdashvery much worse) CGI-S = Clinical Global ImpressionmdashSeverity scale severity of the patientrsquos illness beforeimmunotherapy rated by a clinician (1mdashnormal to 7mdashmost extremely ill) Ep = epilepsy FOA = focal onset preserved awareness seizures FOIA = focal onsetimpaired awareness seizures IVIg = IV immunoglobulin LE = limbic encephalitis mRS = modified Rankin Scale NA = not applicable SARA = Scale for theAssessment and Rating of Ataxia SPS = stiff-person syndromeSARA scores are only provided in patients with ataxia whereas mRS scores are omitted for patients having Ep only

Figure 4 Disease course and treatment response of 4 patients in the high-concentration group

Horizontal bars containing treatment abbreviations represent the time periods of the corresponding treatments Blue vertical lines represent seizurefrequency over time Green discontinuous line connected by green circles shows evolution of serum anti-GAD65 concentration Thick dark-blue lineconnected by rhomboids represents functional status over time according to the visual score at the rightmost part of the charts AED= antiepileptic drug AZA= azathioprine GAD = glutamic acid decarboxylase IVIg = IV immunoglobulin IVMP = IV methylprednisolone MMF = mycophenolate mofetil PDN =prednisone RTX rituximab

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 3 | May 2020 NeurologyorgNN

and impairing the inhibitory GABAergic circuits This wouldresult in a hyperexcitability state of the CNS There are studiessupporting this theory demonstrating a reduced GABAconcentration in the CSF and in the cerebral cortex of patientswith SPS2425 However GAD65 is located intracellularly andas such not accessible for extracellular antibodies As an ex-planation it has been hypothesized that GAD65 might tran-siently appear on the cell surface in the synaptic cleft duringthe process of neurotransmission and exocytosis26 In rats invivo injection of GAD65 antibodies from patients with SPSinduced electrophysiologic changes in myelinated neuronswhereas GAD65 antibodies from patients with DM1 didnot27 On the other hand injection of GAD65-specific T cellsin mice caused death even in mice without B cells28 Thissuggests that the mechanism might be comparable to para-neoplastic syndromes in which T cellndashmediated responsesprimarily lead to symptoms29 Similarly despite severalefforts there are no convincing successful animal models tosupport the pathogenicity of GAD65 antibodies

Moreover studies report poor responses to immunotherapytargeting different GAD syndromes61130 as compared toother neurologic disorders caused by antibodies targeted toextracellular neuronal structures again questioning the directpathogenic role of anti-GAD65 Although the mechanismsremain questionable our results revealed that many patientsshow improvement after immunotherapy (mostly IVIg)coupled to a simultaneous concentration decrease Manypatients improve not immediately after initiating treatmentsbut might need some months of treatment before improve-ment This might explain some lack of treatment responsefrom the literature Repeated doses or combinations of dif-ferent treatments might be considered before classifyinga patient as a nonresponder Nevertheless some of thepatients do not respond at all to immunotherapy In addition

it is humbling that even in responders improvement is gen-erally incomplete and often patients have stagnation in boththe clinical and the serologic response after a few months withchronic immunotherapy Unfortunately no patient com-pletely recovered A possible explanation might be a combi-nation of functional and structural neuronal damage asdifferent research groups have demonstrated in CA93031

Immunotherapy helps to restore cell function but cell death isnonreversible

Despite clinical stabilization with immunotherapy treatmentintensity reductions or withdrawals frequently result in clini-cal progression (in CA) or relapses (in SPS LE and Ep) Afew patients have relapses despite stable chronic immuno-therapy Fortunately these patients usually respond to moreintense treatments

The limitations of this study are mainly linked to its retro-spective design In addition not all patients were seen by oneof the authors Accordingly it was sometimes difficult to as-sess outcome after treatment Objective parameters such asmRS score SARA score and seizure frequency were usedwhen applicable As treatments were open label a placeboeffect or regression to the mean could explain part of theresults However most patients had stable (or slowly pro-gressive) disease for a longer period and showed a seriousdeviation from the time course before Similarly the asso-ciation with concentrations also suggests some real effectsFor future studies it would be of additional value to studytreatment outcome prospectively by using standardizedquestionnaires examinations serologic follow-up and neu-ropsychological assessments

To summarize in patients with classical syndromes (stiff-person CA and encephalitis with seizures) detection of high

Figure 5 Antibody concentration response to immunotherapy

Concentration responses to treatment of the 17patients of whom pretreatment and posttreat-ment samples were available Red lines representthe patients lacking clinical improvement Theblue dashed line in the right graph represent CSFsamples obtained pretreatment and at clinicalrelapse A reduction of at least 25 following im-munotherapy was considered a relevant concen-tration reduction GAD = glutamic aciddecarboxylase

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 3 | May 2020 11

concentrations of anti-GAD65 is practically diagnostic of anantindashGAD65-related syndrome However depending on thesyndrome (eg LE) physicians should consider the possi-bility of concurrent antibodies such as GABAbR Theseclassical syndromes should be treated with prolonged im-munotherapy (as the current study suggests) On the otherhand the presence of atypical syndromes (or nonspecificencephalitic syndromes with seizures) or a typical syndromebut with low-concentration anti-GAD65 should raise concernfor another underlying disease (anti-GAD65 as bystanders)In these patients more extensive investigations for alternativediagnoses should be considered

AcknowledgmentThe authors thank all patients for their participation Theythank all referring physicians A Muntildeoz-Lopetegi receiveda Research Experience Fellowship grant from the EuropeanAcademy of Neurology (EAN) for this research projectAuthors RF Neuteboom JM de Vries MWJ SchreursPAE Sillevis Smitt and MJ Titulaer of this publication aremembers of the European Reference Network for RareImmunodeficiency Autoinflammatory and AutoimmuneDiseasesndashProject ID No 739543

Study fundingA Muntildeoz-Lopetegi was supported by the EAN ExperienceFellowship from the European Academy of Neurology MJTitulaer was supported by an Erasmus MC fellowship and hasreceived funding from the Netherlands Organization forScientific Research (NWO Veni incentive) from the DutchEpilepsy Foundation (NEF project 14-19) and from ZonMw(Memorabel program)

DisclosureA Muntildeoz-Lopetegi MAAM de Bruijn S BoukhrissiAEM Bastiaansen MMP Nagtzaam ESP Hulsen-boom AJW Boon RF Neuteboom JM de Vries andMWJ Schreurs report no disclosures relevant to themanuscript PAE Sillevis Smitt holds a patent for thedetection of anti-DNER and received research supportfrom Euroimmun MJ Titulaer received research funds forserving on a scientific advisory board of MedImmune LLCand a travel grant for lecturing in India from Sun PharmaIndia MJ Titulaer has filed a patent for methods for typingneurologic disorders and cancer and devices for usetherein and has received research funds for serving ona scientific advisory board of MedImmune LLC for con-sultation at Guidepoint Global LLC and an unrestrictedresearch grant from Euroimmun AG Go to NeurologyorgNN for full disclosures

Publication historyReceived by Neurology Neuroimmunology amp NeuroinflammationNovember 25 2019 Accepted in final form January 13 2020

Appendix Authors

Name Location Role Contribution

AmaiaMuntildeoz-Lopetegi MD

Department ofNeurology ErasmusMC UniversityMedical CenterRotterdam TheNetherlandsCurrentlyemployed atNeurology ServiceUniversitat deBarcelona IDIBAPS

Author Study designacquisition of datastatistical analysisinterpretation ofdata and drafting ofthe manuscript

MarienkeAAM deBruijn MD

Department ofNeurology ErasmusMC UniversityMedical CenterRotterdam TheNetherlands

Author Study designacquisition of datainterpretation ofdata and revision ofthe manuscriptcontent

SanaeBoukhrissiBSc

Department ofImmunoologyErasmus MCUniversity MedicalCenter RotterdamThe Netherlands

Author Technical assistanceand revision of themanuscript forcontent

Anna EMBastiaansenMD

Department ofNeurology ErasmusMC UniversityMedical CenterRotterdam TheNetherlands

Author Acquisition of dataand revision of themanuscript forcontent

Mariska MPNagtzaamBSc

Department ofNeurology ErasmusMC UniversityMedical CenterRotterdam TheNetherlands

Author Technical assistanceand revision of themanuscript forcontent

Esther SPHulsenboomBSc

Department ofNeurology ErasmusMC UniversityMedical CenterRotterdam TheNetherlands

Author Technical assistanceand revision of themanuscript forcontent

Agnita JWBoon MDPhD

Department ofNeurology ErasmusMC UniversityMedical CenterRotterdam TheNetherlands

Author Acquisition of dataand revision of themanuscript forcontent

Rinze FNeuteboomMD PhD

Department ofNeurology ErasmusMC UniversityMedical CenterRotterdam TheNetherlands

Author Acquisition of dataand revision of themanuscript forcontent

Juna M deVries MDPhD

Department ofNeurology ErasmusMC UniversityMedical CenterRotterdam TheNetherlands

Author Acquisition of dataand revision of themanuscript forcontent

Peter AESillevis SmittMD PhD

Department ofNeurology ErasmusMC UniversityMedical CenterRotterdam TheNetherlands

Author Acquisition of dataand revision of themanuscript forcontent

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 3 | May 2020 NeurologyorgNN

References1 Solimena M de Camilli P Blake R et al Autoimmunity to glutamic acid decarbox-

ylase (GAD) in Stiff-Man syndrome and insulin-dependent diabetes mellitus TrendsNeurosci 199114452ndash457

2 Sigurdsson E Baekkeskov S The 64-kDa beta cell membrane autoantigen and othertarget molecules of humoral autoimmunity in insulin-dependent diabetes mellitusCurr Top Microbiol Immunol 1990164143ndash168

3 Giometto B Miotto D Faresin F Argentiero V Scaravilli T Tavolato B Anti-GABAergic neuron autoantibodies in a patient with stiff-man syndrome and ataxiaJ Neurol Sci 199614357ndash59

4 Peltola J Kulmala P Isojarvi J et al Autoantibodies to glutamic acid decarboxylase inpatients with therapy-resistant epilepsy Neurology 20005546ndash50

5 Honnorat J Saiz A Giometto B et al Cerebellar ataxia with antindashglutamic aciddecarboxylase antibodies Arch Neurol 200158225

6 MalterMPHelmstaedter C UrbachH Vincent A BienCG Antibodies to glutamic aciddecarboxylase define a form of limbic encephalitis Ann Neurol 201067470ndash478

7 Mckeon A RobinsonMTMcevoy KM et al Stiff-man syndrome and variants clinicalcourse treatments and outcomes Arch Neurol 201269230ndash238

8 Martinez-Hernandez E Arintildeo H McKeon A et al Clinical and immunologic inves-tigations in patients with stiff-person spectrum disorder JAMA Neurol 201673714ndash720

9 Arintildeo H Gresa-Arribas N Blanco Y et al Cerebellar ataxia and glutamic aciddecarboxylase antibodies immunologic profile and long-term effect of immuno-therapy JAMA Neurol 2014711009ndash1016

10 Dalakas MC Rakocevic G Dambrosia JM Alexopoulos H McElroy B A double-blind placebo-controlled study of rituximab in patients with stiff person syndromeAnn Neurol 201782217ndash277

11 Malter MP Frisch C Zeitler H et al Treatment of immune-mediated temporal lobeepilepsy with GAD antibodies Seizure 20153057ndash63

12 Baekkeskov S Aanstoot H Christgau S et al Identification of the 64K autoantigen ininsulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decar-boxylase Nature 1900347151ndash156

13 Saiz A Arpa J Sagasta A et al Autoantibodies to glutamic acid decarboxylase in threepatients with cerebellar ataxia late-onset insulin-dependent diabetes mellitus andpolyendocrine autoimmunity Neurology 1997491026ndash1030

14 Saiz A Blanco Y Sabater L et al Spectrum of neurological syndromes associated withglutamic acid decarboxylase antibodies diagnostic clues for this association Brain20081312553ndash2563

15 Quinn TJ Dawson J Walters MR Lees KR Functional outcome measures in con-temporary stroke trials Int J Stroke 20094200ndash205

16 Weyer A Abele M Schmitz-Hubsch T et al Reliability and validity of the scale for theassessment and rating of ataxia a study in 64 ataxia patients Mov Disord 2007221633ndash1637

17 Guy W ECDEU Assessment Manual for Psychopharmacology Rockville US De-partment of Health Education and Welfare Public Health Service Alcohol DrugAbuse and Mental Health Administration National Institute of Mental HealthPsychopharmacology Research Branch Division of Extramural Research Programs1976

18 Hoftberger R Titulaer MJ Sabater L et al Encephalitis and GABA B receptorantibodies Novel findings in a new case series of 20 patients Neurology 2013811500ndash1506

19 Solimena M Folli F Aparisi R Pozza G De Camilli P Autoantibodies to GABA-ergicneurons and pancreatic beta cells in Stiff-Man syndrome N Engl J Med 19903221555ndash1560

20 Dalakas MC Fujii M Li M McElroy B The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome Neurology 2000551531ndash1535

21 Meinck HM Thompson PD Stiffman syndrome and related conditions Mov Disord200217853ndash866

22 RakocevicGRajuRDalakasMCAntindashglutamic acid decarboxylase antibodies in the serumand cerebrospinal fluid of patients with stiff-person syndrome Arch Neurol 200461902

23 Pittock SJ Yoshikawa H Ahlskog JE et al Glutamic acid decarboxylase autoimmunitywith brainstem extrapyramidal and spinal cord dysfunction Mayo Clin Proc 2006811207ndash1214

24 Dalakas MC Li M Fujii M Jacobowitz DM Stiff person syndrome quantificationspecificity and intrathecal synthesis of GAD65 antibodies Neurology 200157780ndash784

25 Levy LM Levy-Reis I Fujii M Dalakas MC Brain γ-aminobutyric acid changes instiff-person syndrome Arch Neurol 200562970ndash974

26 Dalakas MC Progress and stiff challenges in understanding the role of GAD-antibodies in stiff-person syndrome Exp Neurol 2013247303ndash307

27 Manto M-U Laute M-A Aguera M Rogemond V Pandolfo M Honnorat J Effects ofanti-glutamic acid decarboxylase antibodies associated with neurological diseases AnnNeurol 200761544ndash551

28 Burton AR Baquet Z Eisenbarth GS et al Central nervous system destructionmediated by glutamic acid decarboxylase-specific CD4+ T cells J Immunol 20101844863ndash4870

29 Bien CG Vincent A Barnett MH et al Immunopathology of autoantibody-associatedencephalitides clues for pathogenesis Brain 20121351622ndash1638

30 Mitoma H Hadjivassiliou M Honnorat J Guidelines for treatment of immune-mediated cerebellar ataxias Cerebellum Ataxias 201521ndash10

31 MitomaHMantoM Hampe CS Immune-mediated cerebellar ataxias from bench tobedside Cerebellum Ataxias 201742ndash14

Appendix (continued)

Name Location Role Contribution

Marco WJSchreurs PhD

Department ofImmunoologyErasmus MCUniversity MedicalCenter RotterdamThe Netherlands

Author Acquisition of dataand revision of themanuscript forcontent

Maarten JTitulaer MDPhD

Department ofNeurology ErasmusMC UniversityMedical CenterRotterdam TheNetherlands

Author Study design studysupervisioninterpretation ofdata statisticalanalysis and revisionof the manuscript forcontent

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 3 | May 2020 13

DOI 101212NXI000000000000069620207 Neurol Neuroimmunol Neuroinflamm

Amaia Muntildeoz-Lopetegi Marienke AAM de Bruijn Sanae Boukhrissi et al treatment

Neurologic syndromes related to anti-GAD65 Clinical and serologic response to

This information is current as of March 2 2020

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

ServicesUpdated Information amp

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Subspecialty Collections

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httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the

Errata

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nextAn erratum has been published regarding this article Please see

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httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

ServicesUpdated Information amp

httpnnneurologyorgcontent73e696fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent73e696fullhtmlref-list-1

This article cites 30 articles 1 of which you can access for free at

Citations httpnnneurologyorgcontent73e696fullhtmlotherarticles

This article has been cited by 3 HighWire-hosted articles

Subspecialty Collections

httpnnneurologyorgcgicollectionstiff_person_syndromeStiff person syndrome

httpnnneurologyorgcgicollectiongait_disorders_ataxiaGait disordersataxia

httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the

Errata

content74e733fullpdf or page

nextAn erratum has been published regarding this article Please see

Permissions amp Licensing

httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

CORRECTION

Neurologic syndromes related to anti-GAD65 Clinical and serologicresponse to treatmentNeurol Neuroimmunol Neuroinflamm 20207e733 doi101212NXI0000000000000733

In the article ldquoNeurologic syndromes related to anti-GAD65 Clinical and serologic response totreatmentrdquo byMuntildeoz-Lopetegi et al1 published onlineMarch 2 2020 the y-axis label for figure5rsquos right graph should be ldquoCSF anti-GAD65 concentration (IUmL)rdquo The editorial officeregrets the error

Reference1 Muntildeoz-Lopetegi A de Bruijn MAAM Boukhrissi S et al Neurologic syndromes related to anti-GAD65 Clinical and serologic response

to treatment Neurol Neuroimmunol Neuroinflamm 20207e696 doi 101212NXI0000000000000696

Copyright copy 2020 American Academy of Neurology 1

Copyright copy 2020 American Academy of Neurology Unauthorized reproduction of this article is prohibited