Anti-NMDA Receptor Encephalitis Foundation Newsletter

Psychosomatics. 2015 May-Jun;56(3):227-41. doi: 10.1016/j.psym.2015.01.003. Epub 2015 Feb 4.

 




For people with encephalitis, rapid treatment of their acute brain inflammation is critical for avoiding devastating physical and cognitive deficits. But appropriate treatment requires identifying the culprit causing the symptoms.

 




Annals of Neurology, Volume 83, Issue 4, Page 863-869, April 2018….

 




Objective To determine the frequency and clinical relevance of immunoglobulin (Ig)G, IgA, and IgM N -methyl-d-aspartate receptor (NMDAR) antibodies in several diseases, and whether the IgG antibodies occur in disorders other than anti-NMDAR encephalitis.

 




Eur J Paediatr Neurol. 2018 Jan;22(1):207-208. doi: 10.1016/j.ejpn.2017.09.013. Epub 2017 Nov 24.Letter; Comment…

 




CASE SUMMARY
A 17-year-old female presented with two days of acute psychosis, which progressed to catatonia and unresponsiveness. During the first several da…

 




Front Immunol. 2017 Apr 21;8:442. doi: 10.3389/fimmu.2017.00442. eCollection 2017.Review…

 




A young lady was ventilated on intensive care for a prolonged period with NMDA receptor encephalitis. She had undergone steroid, immunoglobulin, and plasmapheresis with no evidence of recovery. Her main management issue was the control of severe orofacial and limb dyskinesia.

 




Journal of Neurology February 2017, Volume 264, Issue 2, pp 407–415 | Cite as Increased rates of sequelae post-encephalitis in individuals attending primary care practices in the United Kingdom: a population-based retrospective cohort study Authors Authors and affiliations Julia GranerodEmail author Nicholas W. S. Davies Parashar P. Ramanuj Ava Easton David W. G. Brown Sara L. Thomas Neurological Update First Online: 20 October 2016 Received: 06 October 2016 Revised: 12 October 2016 Accepted: 12 October 2016 34 Shares 192 Downloads 1 Citations Abstract The true extent of sequelae in encephalitis survivors relative to rates within the general population is not known. This study aimed to quantify increased risks of epilepsy, depressive disorders, anxiety disorders, psychotic disorders, bipolar disorder, cognitive problems, dementia, headache, and alcohol abuse among encephalitis cases. 2460 exposed individuals diagnosed with incident encephalitis in the Clinical Practice Research Datalink and 47,914 unexposed individuals without a history of encephalitis were included. Multivariable Poisson regression was used to estimate adjusted rate ratios in individuals with encephalitis compared to the general population and to estimate whether the effect of these outcomes varied over time. Individuals with encephalitis had an increased risk of all investigated outcomes. The highest RR was seen for epilepsy (adjusted RR 31.9; 95 % confidence interval 25.38–40.08), whereas the lowest was seen for anxiety disorders (1.46, 1.27–1.68). The second highest RRs were for particular psychiatric illnesses, including bipolar disorder (6.34, 3.34–12.04) and psychotic disorders (3.48, 2.18–5.57). The RR was highest in the first year of follow-up for all outcomes except headache; this was particularly true for epilepsy (adjusted RR in first year of follow-up 139.6, 90.62–215.03). This study shows that sequelae are common in survivors of encephalitis. We confirm the presence of outcomes more commonly linked to encephalitis and describe those less commonly identified as being associated with encephalitis. The results of this study have important implications for the management of encephalitis patients and for the design of tertiary prevention strategies, as many of these sequelae are treatable. Keywords Epidemiology Outcomes Encephalitis Epilepsy Sequelae  This is a preview of subscription content, log in to check access Notes Acknowledgments The authors thank Harriet Forbes for extraction of the data. Compliance with ethical standards Funding This report is independent research commissioned and funded by the Department of Health’s Policy Research Programme (Enhanced Diagnostic and Management Strategies to Improve the Identification and Outcome of Individuals with Encephalitis, 047/1084). The views expressed in this publication are those of the author(s) and not necessarily those of the Department of Health. Ethics This study was approved by the Independent Scientific Advisory Committee of the Medicines and Healthcare Products Regulatory Authority (ISAC_09_061RA2) and the Ethics Committee of the London School of Hygiene and Tropical Medicine. Conflicts of interest The authors declare that they have no conflict of interest. Data sharing No additional data available. Supplementary material 415_2016_8316_MOESM1_ESM.docx (22 kb) Supplementary material 1 (DOCX 21 kb) References 1. Granerod J, Tam CC, Crowcroft NS, Davies NWS, Borchert M, Thomas SL (2010) Challenge of the unknown: a systematic review of acute encephalitis in non-outbreak situations. Neurology 75(10):924–932 CrossRefPubMedGoogle Scholar 2. Irani SR, Alexander S, Waters P et al (2010) 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. Brain 133(9):2734–2748 CrossRefPubMedPubMedCentralGoogle Scholar 3. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R (2011) Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 10(1):63–74 CrossRefPubMedPubMedCentralGoogle Scholar 4. Granerod J, Cousens S, Davies NWS, Crowcroft NS, Thomas SL (2013) New estimates of incidence of encephalitis in England. Emerg Infect Dis. doi: 10.3201/eid1909.130064 PubMedPubMedCentralGoogle Scholar 5. Easton A, Atkin K, Dowell E (2006) Encephalitis, a service orphan: the need for more research and access to neuropsychology. Br J Neurosci Nurs 2:488–492 CrossRefGoogle Scholar 6. Granerod J, Ambrose HE, Davies NW et al (2010) Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 10(12):835–844 CrossRefPubMedGoogle Scholar 7. Easton A (2016) Life after encephalitis: a narrative approach. Routledge, Oxford Google Scholar 8. Hjalmarsson A, Blomqvist P, Skoldenberg B (2007) Herpes simplex encephalitis in Sweden, 1990–2001: incidence, morbidity, and mortality. Clin Infect Dis 45:875–880 CrossRefPubMedGoogle Scholar 9. Fazekas C, Enzinger C, Wallner M et al (2006) Depressive symptoms following herpes simplex encephalitis–an underestimated phenomenon? Gen Hosp Psychiatry 28:403–407 CrossRefPubMedGoogle Scholar 10. Mailles A, De Broucker T, Costanzo P, Martinez-Almoyna L, Vaillant V, Stahl JP, Steering Committee and Investigators Group (2012) Long-term outcome of patients presenting with acute infectious encephalitis of various causes in France. Clin Infect Dis 54(10):1455–1464 CrossRefPubMedGoogle Scholar 11. Herrett E, Gallagher AM, Bhaskaran K, Forbes H, Mathur R, van Staa T et al (2015) Data Resource Profile: Clinical Practice Research Datalink (CPRD). Int J Epidemiol. doi: 10.1093/ije/dyv098 PubMedPubMedCentralGoogle Scholar 12. CPRD website. https://www.cprd.com/intro.asp 13. Herrett E, Thomas SL, Schoonen WM et al (2010) Validation and validity of diagnoses in the General Practice Research Database: a systematic review. Br J Clin Pharmacol 69:4–14 CrossRefPubMedPubMedCentralGoogle Scholar 14. Lewis JD, Bilker WB, Weinstein RB, Strom BL (2005) The relationship between time since registration and measured incidence rates in the General Practice Research Database. Pharmacoepidemiol Drug Saf 14(7):443–451. doi: 10.1002/pds.1115 CrossRefPubMedGoogle Scholar 15. Baumeister H (2012) Inappropriate prescriptions of antidepressant drugs in patients with subthreshold to mild depression: time for the evidence to become practice. J Affect Dis 139:240–243 CrossRefPubMedGoogle Scholar 16. CG90 (2009) Depression in adults: recognition and management. National Institute for Health and Care Excellence Google Scholar 17. Pillai SC, Mohammad SS, Hacohen Y, Tantsis E, Prelog K, Barnes EH, Gill D, Lim MJ, Brilot F, Vincent A, Dale RC (2016) Postencephalitic epilepsy and drug-resistant epilepsy after infectious and antibody-associated encephalitis in childhood: clinical and etiologic risk factors. Epilepsia 57(1):e7–e11 CrossRefPubMedGoogle Scholar 18. Rismanchi N, Gold JJ, Sattar S, Glaser CA, Sheriff H, Proudfoot J, Mower A, Crawford JR, Nespeca M, Wang SG (2015) Epilepsy after resolution of presumed childhood encephalitis. Pediatr Neurol 53(1):65–72 CrossRefPubMedGoogle Scholar 19. Depression after Traumatic Brain Injury was developed by J Fann and T Hart in collaboration with the Model Systems Knowledge Translation Center. http://www.msktc.org/tbi/factsheets/Depression-After-Traumatic-Brain-Injury#sthash.HlR0e0MJ.dpuf 20. Blomström Å, Karlsson H, Svensson A, Frisell T, Lee BK, Dal H, Magnusson C, Dalman C (2014) Hospital admission with infection during childhood and risk for psychotic illness—a population-based cohort study. Schizophr Bull 40(6):1518–1525 CrossRefPubMedGoogle Scholar 21. Avramopoulos D, Pearce BD, McGrath J, Wolyniec P, Wang R, Eckart N, Hatzimanolis A, Goes FS, Nestadt G, Mulle J, Coneely K, Hopkins M, Ruczinski I, Yolken R, Pulver AE (2015) Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation. PLoS One 10(3):e0116696 CrossRefPubMedPubMedCentralGoogle Scholar 22. Hokkanen L, Launes J (1997) Cognitive recovery instead of decline after acute encephalitis: a prospective follow up study. J Neurol Neurosurg Psychiatry 63:222–227 CrossRefPubMedPubMedCentralGoogle Scholar 23. Gatson JW, Stebbins C, Mathews D, Harris TS, Madden C, Batjer H, Diaz-Arrastia R, Minei JP (2015) Evidence of increased brain amyloid in severe TBI survivors at 1, 12, and 24 months after injury: report of 2 cases. J Neurosurg 1–8 Google Scholar 24. Lucas S (2015) Posttraumatic headache: clinical characterization and management. Curr Pain Headache Rep 19(10):48 CrossRefPubMedGoogle Scholar 25. Russo A, D’Onofrio F, Conte F, Petretta V, Tedeschi G, Tessitore A (2014) Post-traumatic headaches: a clinical overview. Neurol Sci 35(1):153–156 CrossRefPubMedGoogle Scholar 26. Neligan A, Sander JW (2009) The incidence and prevalence of epilepsy. In: Sander JW, Rugg-Gunn, FJ, Smalls JE (eds) Epilepsy 2009: from benchside to bedside. A practical guide to epilepsy. Lecture notes from the Twelfth Epilepsy Teaching Weekend, 18–20 September 2009, St. Anne’s College, Oxford. International League Against Epilepsy (UK Chapter) and National Society for Epilepsy: Chalfont St Peter, Bucks, pp 15–21 Google Scholar 27. Rait G, Walters K, Griffin M, Buszewicz M, Petersen I, Nazareth I (2009) Recent trends in the incidence of recorded depression in primary care. Br J Psychiatry 195(6):520–524 CrossRefPubMedGoogle Scholar 28. Frisher M, Collins J, Millson D, Crome I, Croft P (2004) Prevalence of comorbid psychiatric illness and substance misuse in primary care in England and Wales. J Epidemiol Community Health 58(12):1036–1041 CrossRefPubMedPubMedCentralGoogle Scholar 29. Beghi E, Nicolosi A, Kurland LT et al (1984) Encephalitis and aseptic meningitis, Olmsted County, Minnesota, 1950–1981: I. Epidemiology. Ann Neurol 16:283–294 CrossRefPubMedGoogle Scholar 30. Cizman M, Jazbec J (1993) Aetiology of acute encephalitis in childhood in Slovenia. Pediatr Infect Dis J 12:903–908 CrossRefPubMedGoogle Scholar 31. Lee T, Tsai C, Yuan C, Wei C, Tsao W, Lee R, Cheih S, Huang I, Chen K (2003) Encephalitis in Taiwan: a prospective hospital-based study. Jpn J Infect Dis 56:193–199 PubMedGoogle Scholar 32. Studahl M, Bergstrom T, Hagberg L (1998) Acute viral encephalitis in adults: a prospective study. Scand J Infect Dis 30:215–220 CrossRefPubMedGoogle Scholar Copyright information © Springer-Verlag Berlin Heidelberg 2016 Authors and Affiliations Julia Granerod1Email author Nicholas W. S. Davies2 Parashar P. Ramanuj3 Ava Easton4 David W. G. Brown15 Sara L. Thomas6 1.Virus Reference DepartmentPublic Health England, National Infection ServiceLondonUK 2.Department of NeurologyChelsea and Westminster HospitalLondonUK 3.New York State Psychiatric InstituteNew YorkUSA 4.Encephalitis SocietyMaltonUK 5.Influenza LaboratoryOswaldo Cruz Institute/FiocruzRio de JaneiroBrazil 6.London School of Hygiene and Tropical MedicineLondonUK

 




Abstract Objective: Neurologic autoimmune syndromes associated with anti–glutamate acid decarboxylase 65 antibodies (GAD65-Abs) are rare and mostly sporadic. Methods: We describe a niece and her aunt with GAD65-Abs neurologic syndromes. High-resolution HLA typing of Class I and Class II alleles was performed using next-generation sequencing. Results: The proband had cerebellar ataxia and probable limbic encephalitis features, whereas her niece had stiff-person syndrome. Both had a high titer of GAD65-Abs in serum and CSF and showed signs of inflammation in CSF. Both affected members carried the same rare recombinant DRB1*15:01:01∼DQA1*01:02:01∼DQB1*05:02:01 haplotype, which may or may not be involved in disease susceptibility. Of interest, other unaffected members of the family either had the same HLA haplotype but normal serum GAD65-Abs or had different HLA types but a high titer of serum GAD65-Abs without neurologic symptoms, suggesting cumulative effects. Conclusions: This unique association strengthens the concept that hereditary factors, possibly including specific HLA haplotypes, play a role in neurologic syndromes associated with GAD65-Abs. GLOSSARY GAD=glutamic acid decarboxylase; IgG=immunoglobulin G; SPS=stiff-person syndrome; T1DM=type 1 diabetes mellitus; TG=antithyroglobulin; TPO=antithyroperoxidase Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme for the production of γ-aminobutyric acid, the main inhibitory neurotransmitter of the CNS. GAD is also expressed in pancreatic islet β-cells.1 Anti-GAD65 antibodies (GAD65-Abs) have been described as a biological marker in patients with type 1 diabetes mellitus (T1DM), but also in some patients with neurologic diseases, such as stiff-person syndrome (SPS), cerebellar ataxia, or limbic encephalitis.2,–,7 Although rare, the concept of neurologic syndromes with GAD65-Abs is now well established, most cases reported so far being sporadic.8 Few experimental studies suggest a possible pathogenic role of GAD65-Abs.9,–,11 We describe 2 members of the same family with GAD65-Abs neurologic syndromes in combination with a rare recombinant HLA haplotype and 2 other members without the same haplotype and with a high level of GAD65-Abs but no neurologic symptoms. These results suggest that there may be a genetic basis for susceptibility of the development of GAD-antibody autoimmunity. METHODS Written informed consent was obtained from all HLA-tested members, and this study was approved by the Institutional Review Board of University Claude Bernard Lyon 1 and Hospices Civils de Lyon. Samples are deposited in the collection of biological samples named “Neurobiotec” registered as the biobank of the Hospices Civils de Lyon. Full HLA next-generation sequencing–based typing was performed based on long-range PCRs detailed by Wang in 2012.12 RESULTS Cases reports. The first patient (II3, figure), a 68-year-old woman without a medical history, first developed acute dizziness and vomiting. Neurologic clinical examination revealed an ataxic gait with enlargement of the sustentation polygon and nystagmus. The rest of the physical examination was normal. Videonystagmography revealed a left vestibular deficit. Brain MRI showed no cerebellar atrophy, but hypersignal intensity on fluid attenuation inversion recovery sequences restricted to both hippocampi (nevertheless, no acute clinical signs of limbic encephalitis were observed). CSF examination showed elevated protein levels at 0.71 g/L without white blood cells and a normal immunoglobulin G (IgG) index (0.5; normal <0.7), but few oligoclonal bands (<5) were present. GAD65-Abs were positive in CSF at 250 IU/mL as well as in the serum above 1,200 IU/mL (ELISA Medipan, cutoff positivity: 5 IU/mL). Antithyroperoxidase (TPO) and antithyroglobulin (TG) antibodies were also positive (Varelisa; Thermo Fischer Scientific, Waltham, MA) (718 and 283 IU/mL, respectively, cutoff of positivity for both Abs: 60 IU/mL). No other biological abnormalities were detected. Body fluorodeoxyglucose–PET and mammography were also normal. A diagnosis of cerebellar ataxia with GAD65-Abs was proposed, and treatment with monthly IV immunoglobulin was initiated. After 6 months, the patient stabilized, while still exhibiting a mild cerebellar syndrome. GAD65-Abs remained positive during 15 years of follow-up. Brain MRI performed 4 years after onset showed cerebellar and diffuse brain atrophy. The patient developed late-onset T1DM and a progressive dementia without significant clinical progression of cerebellar ataxia. HLA typing revealed the presence of an unusual haplotype DRB5*01:01:01∼DRB1*15:01:01∼DQA1*01:02:01 ∼DQB1*05:02:01, together with a classical type 1 diabetes–associated haplotype DRB1*03:01:01∼DQA1*05:01:01∼DQB1*02:01:01 (figure). DRB5*01:01:01∼DRB1*15:01:01∼DQA1*01:02:01 ∼DQB1*05:02:01 is very unusual. In large samples from north European countries, the frequency is typically below 1 for 1,000 patients. We identified no patient with this haplotype in more than 100 French people. In our estimation, the frequency of this haplotype in France must be less than 1 for 5,000 patients. Figure Family tree with the HLA haplotyping of 6 members of the family The colors indicate the bioclinical characteristics of the patients. Black circle: patients with GAD65-Abs without neurologic syndromes (III3 and III4). Red circle: patient with GAD65-Abs and cerebellar ataxia (II3). Blue circle: patient with GAD65-Abs and stiff-person syndrome (III5). Green circle: patients with TPO-Abs (II3, III3, and III5). Her niece (III5, figure) developed signs of progressive muscular rigidity with superimposed spasms at the age of 42 years. The right leg was first affected, followed by the trunk and the left leg. Her medical history was notable for Hashimoto thyroiditis (with anti-TPO at 1,966 IU/mL and anti-TG-Abs at 12,786 IU/mL). Medullary and brain MRI were normal. The CSF study revealed a normal IgG index (0.61; normal <0.7) with many oligoclonal bands (>5) and GAD65-Abs at 250 IU/mL. Serum GAD65-Abs were also positive with a titer above 2,000 IU/mL. EMG confirmed the suspicion of SPS with continuous motor activity and cocontraction of agonist and antagonist muscles of the thigh, hip, and back muscles. Five years later, no diabetes mellitus was observed and no cancer has been found. The patient has been treated with benzodiazepines, immunoglobulins, and cyclophosphamide and experienced only partial recovery. HLA typing revealed that this patient also carried the unusual DRB5*01:01:01∼DRB1*15:01:01∼DQA1*01:02:01∼DQB1*05:02:01 haplotype, together with DRB3*02:02:01∼DRB1*11:04:01∼DQA1*05:05:01∼DQB1*03:01:01 (figure). Familial history. After identification of these 2 index cases, we reviewed the entire family history and extended HLA typing to 6 other members of the family (figure). The entire family is of Caucasian ethnicity. The father of II3 developed dementia and diabetes mellitus, but we have no more information. Of interest, 2 relatives (III3 and III4) without the rare DRB5*01:01:01∼DRB1*15:01:01∼DQA1*01:02:01, ∼DQB1*05:02:01 haplotype had serum GAD65-Abs titer higher than 250 IU/mL. One (III3), the sister of the patient III5 with SPS, developed pernicious anemia with intrinsic antibodies, breast cancer, and thyroiditis, and her brother (III4) had no particular medical history. All the members of the family were examined by JH and had no abnormalities on neurologic examination. No other disease was reported in the other members of the family. Conversely, 4 other members of the family (III 6, 7, 8, and 9) shared the rare DRB5*01:01:01∼DRB1*15:01:01∼DQA1*01:02:01∼DQB1*05:02:01 haplotype but had no GAD65-Abs and no neurologic symptoms. The father of II3 developed dementia and diabetes mellitus, and his HLA haplotype was not characterized. DISCUSSION Very little is known regarding genetic predisposition to autoimmune neurologic syndromes with GAD65-Abs. HLA genetic predisposition to SPS has been studied only in 1 large study of 18 patients, with unremarkable findings, although weak association with DQB1*02 (DQB1*02:01 and DQB1*02:02) was suggested.13 In this study, however the presence of DQB1*06:02, a strong protective allele for type 1 diabetes, was present in some patients with SPS without type 1 diabetes but in none with cooccurring diabetes.13,14 However, a few familial occurrences of neurologic conditions associated with GAD65-Abs have been previously described, 2 families with multiplex familial SPS15,16 and 1 family with 2 sibling sisters with cerebellar ataxia and GAD65-Abs,17 suggesting that genetic factors may be involved (HLA typing was not performed in these cases). In our 2 cases, DQB1*02 was present only in 1 affected case, but both carried an unusual haplotype HLA-DRB1*15:01∼DQA1*01:02∼DQB1*05:02. This haplotype is likely the result from recombination of HLA DRB1*15:01:01∼DQA1*01:02:01∼DQB1*06:02:01 with DRB1*16:01/2∼DQA1*01:02:02∼DQB1*05:02:01, 2 common Caucasian haplotypes. We can also speculate that the father of II3 who developed dementia and diabetes mellitus may also have had this rare haplotype. Although reported rarely in the literature, except in a few patients of Romani people, Northern Indian, and Chinese origin,18,–,20 this haplotype is extremely rare in US and French Caucasians (<0.1%)21 and thus unlikely to be present by chance in these 2 affected patients.20 The rare haplotype, if involved, is however not the sole determinant of disease, as 4 relatives (III 6, 7, 8, and 9) with the haplotype do not have neurologic symptoms or GAD65-Abs. Surprisingly, we also found 2 other relatives (III3 and III4) having high GAD65-Abs titers without neurologic symptoms. This is also unlikely to be a chance phenomenon, as GAD65-Abs are found only in around 1.7% of the general population with or without neurologic disorders.22,23 Of interest, the presence of GAD65-Abs in the general asymptomatic population (including asymptomatic individuals from families with prevalent type 1 diabetes) also correlates with typical type 1 diabetes–associated HLA DRB1*03:01∼DQA1*05:01∼DQB1*02:01 and DRB1*04∼DQA1*03∼DQB1*03:02, notably when both haplotypes are in trans of each other.23,24 In our family, the 2 asymptomatic patients with high GAD65-Abs do not share the same extended HLA subtypes with both affected patients, suggesting that GAD65-Abs are unlinked with HLA alone and that the sole presence of high titers of GAD65-Abs is insufficient to develop neurologic symptoms. One reason could be that GAD65-Abs in affected vs unaffected patients target different epitopes, as has been shown for type 1 diabetes vs SPS.25,–,27 Of interest, a recent study in 6,556 type 1 diabetes cases has shown strong genetic association for the presence of GAD65-Abs not with an HLA region, but with other genes, notably in IFIH1, a locus associated with positivity for TPO and GAD65-Abs28 and involved in other immune phenotypes.29,30 A similar complex genetic susceptibility has already been discussed in neuromyelitis optica (NMO), another autoimmune neurologic disorder associated with antineural antibodies.31 In NMO, around 3% of patients have a familial occurrence of the disease, and familial NMO is indistinguishable from sporadic NMO.31 Furthermore, the association with a specific HLA haplotyping is also highly debated.32 Our family with GAD65-Abs and all the data of the literature suggest that coincident complex genetic factors in the HLA and non-HLA regions should be carefully studied in autoimmune neurologic disorders associated with antineural antibodies. AUTHOR CONTRIBUTIONs Aude Belbezier contributed to the acquisition of data, analysis, interpretation of the data, drafting the manuscript for intellectual contents. Bastien Joubert contributed to the acquisition of data, analysis, interpretation of the data, critical revision of the manuscript for intellectual content. Gonzalo Montero-Martin contributed to the acquisition of data, analysis, interpretation of the data, critical revision of the manuscript for intellectual content. Marcelo Fernandez-Vina contributed to the acquisition of data, analysis, interpretation of the data, critical revision of the manuscript for intellectual content. Nicole Fabien contributed to the acquisition of data. Véronique Rogemond contributed to the acquisition of data. Emmanuel Mignot contributed to the interpretation of the data and critical revision of the manuscript for intellectual content. Jérôme Honnorat contributed to the study concept and design of the study, critical revision of manuscript for intellectual content, study supervision. STUDY FUNDING This study is supported by research grants from ANR (ANR-14-CE15-0001-MECANO), the Federation pour la recherche sur le cerveau (FRC-Neurodon2014), the Fondation pour la Recherche Médicale (Programme “équipe FRM” DEQ20170336751), and CSL Behring France. DISCLOSURE A. Belbezier, B. Joubert, and G. Montero-Martin report no disclosures. M. Fernandez-Vina serves on the editorial board of Human Immunology and received research support from NIH-NIAID. N. Fabien and V. Rogemond report no disclosures. E. Mignot served on the scientific advisory board of FDA, Kleine-Levin Syndrome Foundation, National Academy of Sciences, Institute of Medicine, Board on Neuroscience and Behavioral Health, Study Task Force on Sleep Research and Member, Membership Committee Section, NIH/NIMH, National Advisory Mental Health Council, Mood Disorders Workgroup, Board of Scientific Counselors, and Restless Leg Syndrome Foundation; served on the editorial board of Journal of Neuropsychopharmacology, Public Library of Sciences—Biology, Sleep, Sleep Medicine, Sleep Research Online, and Molecular Biology; receives publishing royalties from Informa Healthcare; consulted for Jazz Pharmaceuticals; received research support from GlaxoSmithKline, Novo Nordisk, Jazz Pharmaceuticals, NIH, National Institute of Neurological Disorders and Stroke, NSBRI, CORI, NASA, and HHMI; and held stock in ResMed. J. Honnorat served on the scientific advisory board of Bristol-Myers Squibb; holds patent for and receives royalties from licensing fees to Athena Diagnostics, Euroimmun, and Ravo Diagnostika for a patent for the use of CV2/CRMP5 as diagnostic tests; and received research support from CSL Behring France. Go to Neurology.org/nn for full disclosure forms. ACKNOWLEDGMENT The authors thank Dr. Michel Gouttard for his help to collect clinical data. Footnotes Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was funded by the ADR05 INSERM, France. Received May 23, 2017. Accepted in final form October 2, 2017. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. REFERENCES 1.↵Solimena M, Folli F, Aparisi R, et al. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990;322:1555–1560.OpenUrlCrossRefPubMed 2.↵Saiz A, Blanco Y, Sabater L, et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain J Neurol 2008;131:2553–2563.OpenUrlCrossRefPubMed 3.↵Honnorat J, Saiz A, Giometto B, et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol 2001;58:225–230.OpenUrlCrossRefPubMed 4.↵Malter MP, Elger CE, Surges R. 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