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Limbic Encephalitis Associated With GAD65 Antibodies: Brief Review of the Relevant literature

Published online by Cambridge University Press:  31 March 2016

Maude-Marie Gagnon  and
Martin Savard
Maude-Marie Gagnon
Affiliation:
CHU de Québec - Neurological Science, Quebec, Canada.
Martin Savard
Affiliation:
CHU de Québec - Neurological Science, Quebec, Canada.
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Abstract

Recently, many cases of autoimmune limbic encephalitis with positive GAD65 (glutamic acid decarboxylase) antibodies have been described in the scientific literature. However, it remains an understudied topic of great relevance to practicing neurologists. Thus, we report here a review of published cases, in English, of autoimmune limbic encephalitis with this type of antibodies, focusing on presenting symptoms and signs, associated conditions, and findings upon investigation. We also report treatment responses. We aim to offer a better description of the clinical spectrum of autoimmune limbic encephalitis associated with GAD65 antibodies as well as to expose its paraclinical features and outcome.

Résumé

Au cours des dernières années, plusieurs cas d’encéphalite limbique avec anticorps GAD65 (glutamic acid decarboxylase) ont été décrits dans la littérature. Néanmoins, il s’agit d’un sujet relativement peu connu, mais qui s’avère pertinent à bien connaître pour les neurologues praticiens. Ainsi, nous proposons une revue des différents cas publiés, en anglais, d’encéphalite limbique auto-immune associés à cet anticorps. Celle-ci se concentre sur la présentation clinique, les conditions associées de même que les trouvailles à l’investigation. De surcroît, nous proposons une revue des traitements utilisés et de leurs réponses. Cet article a pour objectif premier d’obtenir une meilleure description du spectre clinique de l’encéphalite auto-immune avec anticorps GAD65 et, dans un second temps, d’exposer ses caractéristiques paracliniques ainsi que son évolution.

Keywords

cognitive impairmentCNS inflammationimmune systemneuroimmunologyneuroinflammationneurology – clinicalseizuresstatus epilepticus
Type
Review Articles
Information
Canadian Journal of Neurological Sciences , Volume 43 , Supplement 4 , July 2016 , pp. 486 - 493
Copyright
Copyright © The Canadian Journal of Neurological Sciences Inc. 2016 

Background

Limbic encephalitis (LE) was first described in the 1960s.Reference Brierley, Corsellis, Hierons and Nevin 1 It is a disorder affecting the medial temporal lobe of the brain and can be explained by infective and systemic autoimmune etiologies. It can also be associated with neuronal antibodies related to cancer (in paraneoplastic LE)Reference Dalmau and Rosenfeld 2 or not (in nonparaneoplastic autoimmune LE).Reference Graus, Saiz and Dalmau 3 Recently, an increasing number of valuable autoantibodies have been identified, including glutamic acid decarboxylase 65 (GAD65) antibodies.

LE is characterized by subacute development of short-term memory loss, seizure, or psychiatric symptoms suggestive of limbic involvement. It is combined with inflammatory findings in cerebrospinal fluid (CSF) or temporal abnormalities on magnetic resonance imaging (MRI) or electroencephalogram (EEG). Criteria sets have been suggested, including clinical and radiological findings.Reference Bien and Elger 4 – Reference Graus, Saiz and Dalmau 6

GAD is crucial for the conversion of glutamic acid into gamma aminobutyric acid (GABA), which is the major inhibitory neurotransmitter of the central nervous system. Antibodies against this enzyme possibly cause an imbalance resulting in the outweighing of excitatory neurotransmitters such as glutamic acid and aspartate, which induce a neuronal hyperexcitability.Reference Mitoma, Song, Ishida, Yamakukuni, Kobayashi and Mizusawa 7 They are among the autoantibodies against intracellular components. GAD65 antibodies are markers of type 1 diabetesReference Yoshimoto, Doi and Fukai 8 and are found in high titers (>1000 U/ml) in various neurological pathologies such as stiff-person syndrome (SPS)Reference Solimena, Folli and Denis-Donini 9 pharmacoresistant epilepsy,Reference Vincent, Bien, Irani and Waters 10 cerebellar ataxia,Reference Birand, Cabre and Bonnan 11 and progressive encephalomyelitis with rigidity and myoclonus.Reference Alexopoulos, Akrivou and Dalakas 12 In the literature, characteristics of SPS are well described, whereas autoimmune LE with these type of antibodies remains an understudied topic.

We report here a review of published cases, in English, of autoimmune LE with GAD65 antibodies, focusing on clinical presentation of initial symptoms and signs, associated conditions, and findings upon investigation, including other autoantibodies results. Treatment responses are also reported. The purpose is to better define the clinical spectrum of autoimmune LE associated with GAD65 antibodies to raise awareness of this disease and expose its outcome.

Methods

We conducted a search on Medline for articles published in English between August 1998 and August 2014 and using the keywords “encephalitis” and “GAD” or “glutamic acid decarboxylase.” A back-search of reference lists from retrieved publications was also conducted to identify other potentially relevant articles. The year 1998 was chosen as the starting point because the first relevant case was reported at that time.Reference Giometto, Nicolao and Macucci 36 Titles and abstracts were screened and articles were included according to their relevance to the entry criteria. If an abstract was not available, the entire article was screened. We selected clinical case reports and case series reporting positive GAD65 antibodies using the term “encephalitis” (in titles, abstract, or text). We also included observational studies with prospective or retrospective analysis of sera or CSF of patients with diagnosis of LE if clinical features were available. There were no special requirements for positive CSF GAD65 antibodies in patients with diabetes type 1 or for details concerning clinical features, treatment, or outcome. We included cases from adult and pediatric populations (Table 1).

Table 1 Search process flowchart

Clinical details were extracted and then revised by one reviewer (M-MG). Before review, specific variables were identified as general characteristics, clinical manifestations, MRI and EEG findings, concomitant systemic autoimmune disorders and cancer, and outcome and autoantibodies findings. In regard to clinical manifestations, we assumed that the signs or symptoms that were not mentioned in the case description were absent (as opposed to other variables considered as “not available” when they were not explicitly mentioned). In regard to MRI findings, “abnormalities” referred to T2/fluid attenuated inversion recovery hyperintensities (with or without contrast enhancement). Spikes, sharp waves, electrographic seizures, and status epilepticus or “epileptiform activity” on EEG were included as epileptiform abnormalities. Data were stratified into four groups for outcome, from full recovery to death. The outcome was considered as an “improvement” when improvement of the initial symptoms was observed at the time of the last available follow-up. A relapse was considered if there was a recurrence of symptoms or the appearance of new symptoms related to LE after diagnosis of LE and a period of at least 1 month of significant improvement (after treatment or not). For demographic, clinical, and outcome differences between groups, Fisher’s exact test was used. Finally, we did not contact authors to obtain further information (more details on variables in Supplementary Appendix 1).

Results

We identified a total of 58 cases (from 31 articles) in adult (n=37) and pediatric (n=21) populations.

General Characteristics

Most cases were young adult patients, but a child as young as 1 year oldReference Lin, Lin and Hsia 15 has also been reported. The majority of patients were women (59%, 34/58); however, in the pediatric population, there was a slight predominance of males (57%, 12/21).

Systemic autoimmune disorders appeared to be frequent (48%, 22/46), particularly diabetes (35%, 16/46). Psoriasis,19 common variable immune deficiency,Reference Matà, Muscas and Naldi 22 celiac disease,Reference Marchiori, Vaglia and Vianello 21 , Reference Mazzi, De Roia, Cruciatti, Matà and Catapano 38 and autoimmune thyroiditisReference Petit-Pedrol, Armangue and Peng 14 , Reference Finelli 16 , Reference Marchiori, Vaglia and Vianello 21 , Reference Blanc, Ruppert and Kleitz 28 , Reference Mazzi, De Roia, Cruciatti, Matà and Catapano 38 , Reference Cianci, Labate and Lanza 40 , Reference Saidha, Murphy and Ronayne 41 were also reported. For six cases, more than one autoimmune conditionReference Petit-Pedrol, Armangue and Peng 14 , Reference Marchiori, Vaglia and Vianello 21 , Reference Blanc, Ruppert and Kleitz 28 , Reference Mazzi, De Roia, Cruciatti, Matà and Catapano 38 , Reference Saidha, Murphy and Ronayne 41 was described. Cancer was reported in 10% of cases (10%, 6/58), with cancer workup not explicitly done in 16 casesReference Lin, Lin and Hsia 15 , Reference Garcìa Garcìa, Catrillo and Morales 20 , Reference Matà, Muscas and Naldi 22 , Reference Cikrikçili, Ulusoy and Turan 25 , Reference Olson, Olson and Sandborg 26 , Reference Haberlandt, Bast and Ebner 32 , Reference Korff, Parvez and Cisamoni 35 , Reference Mazzi, De Roia, Cruciatti, Matà and Catapano 38 (14%, 6/42). They were men from 38 to 70 years old with a mean age of 61 years. Malignancies were small-cell lung carcinoma (67%, 4/6)Reference Blanc, Ruppert and Kleitz 28 , Reference Knudsen, Bredholt and Storstein 30 , Reference Boronat, Sabater and Saiz 39 and malignant thymoma (33%, 2/6) (Table 2).Reference Saiz, Blanco and Sabater 29 , Reference Graus, Saiz and Lai 31

Table 2 General characteristicsReference Petit-Pedrol, Armangue and Peng 14 - Reference Mishra, Rodan and Nita 44

* Total of 47 patients with both known age and sex.

† Total of 46 patients with known autoimmune status.

‡ One case had two autoimmune diseases.

Clinical Features

Seizures were the most frequent manifestation (97%, 56/58); they were reported in all cases except for two.Reference Mirabelli-Badenier, Morana and Pinto 17 , Reference Blanc, Ruppert and Kleitz 28 Status epilepticus was reported in 24% (24%, 14/58), which was generally refractory and treated with multiple anticonvulsive drugs,Reference Petit-Pedrol, Armangue and Peng 14 , Reference Lin, Lin and Hsia 15 , Reference Kanter, Huttner and Staykov 18 , Reference Matà, Muscas and Naldi 22 , Reference Malter, Helmstaedter and Urbach 24 , Reference Cikrikçili, Ulusoy and Turan 25 , Reference Monnerat, Velasco and Nakano 37 , Reference Pandit, Ihtisham and Garg 43 and only one had concurrent neuronal antibodies (GABA A receptor [GABAAR], 7%, 1/14).Reference Petit-Pedrol, Armangue and Peng 14 One case reported a certain efficiency of treatment with ketamine in a 21-year-old woman with refractory status epilepticus.Reference Kanter, Huttner and Staykov 18 Opercular myoclonic-anarthric status epilepticus was described in one patient.Reference Monnerat, Velasco and Nakano 37 Epilepsia partialis continua was described in three cases,Reference Petit-Pedrol, Armangue and Peng 14 , Reference Cikrikçili, Ulusoy and Turan 25 , Reference Olson, Olson and Sandborg 26 whereas dysgeusia/dysosmia was described in two.Reference Petit-Pedrol, Armangue and Peng 14 , Reference Mishra, Rodan and Nita 44

Memory impairment was the second most frequent manifestation (59%, 34/58). Impairment of other cognitive functions was also common (40%, 23/58). Disorientation, dysexecutive syndrome, and language problems were reported. Confabulation and apraxia were reported in oneReference Markakis, Alexopoulos and Poulopoulou 42 and two cases, respectively.Reference Haberlandt, Bast and Ebner 32 Psychiatric symptoms were described in 28% of cases (28%, 16/58), with mainly depression and behavior or personality changes. Concerning movement disorders, myoclonusReference Garcìa Garcìa, Catrillo and Morales 20 , Reference Olson, Olson and Sandborg 26 , Reference Monnerat, Velasco and Nakano 37 (three cases) and facial crampsReference Petit-Pedrol, Armangue and Peng 14 (one case) were described. Mild generalized rigidity was described onceReference Malter, Helmstaedter and Urbach 24 and concurrent diagnosis of SPS was made in one patient.Reference Petit-Pedrol, Armangue and Peng 14 Cerebellar manifestations were reported in four cases.Reference Matà, Muscas and Naldi 22 , Reference Malter, Helmstaedter and Urbach 24 , Reference Korff, Parvez and Cisamoni 35 , Reference Monnerat, Velasco and Nakano 37 Headache was rare and described only in pediatric cases.Reference Lin, Lin and Hsia 15 , Reference Mishra, Rodan and Nita 44 Hyperphagia,Reference Mirabelli-Badenier, Morana and Pinto 17 gaze-evoked nystagmus,Reference Finelli 16 and tinnitus with facial crampsReference Petit-Pedrol, Armangue and Peng 14 were manifestations reported in one case each (Table 3).

Table 3 Clinical featuresReference Petit-Pedrol, Armangue and Peng 14 - Reference Mishra, Rodan and Nita 44

* More than one psychiatric symptoms in five cases.

Imaging and Paraclinical Features

Brain MRI was reported abnormal in 78% of cases (78%, 45/58); involvement of temporal lobes was usual and described in 34 cases (59%, 34/58). Multifocal abnormalities were present in nine cases (16%, 9/58). In seven, the initial brain MRI was reported normal.Reference Kanter, Huttner and Staykov 18 , 19 , Reference Marchiori, Vaglia and Vianello 21 , Reference Cikrikçili, Ulusoy and Turan 25 , Reference Korff, Parvez and Cisamoni 35 , Reference Monnerat, Velasco and Nakano 37 , Reference Mazzi, De Roia, Cruciatti, Matà and Catapano 38 EEG results were available for 35 cases. Epileptiform abnormalities were found in 27 cases (77%, 27/35), with temporal involvement most frequent (70%, 19/27). Multifocal (22%, 6/27)Reference Petit-Pedrol, Armangue and Peng 14 , Reference Lin, Lin and Hsia 15 , Reference Cikrikçili, Ulusoy and Turan 25 , Reference Korff, Parvez and Cisamoni 35 , Reference Mishra, Rodan and Nita 44 and generalized (7%, 2/27)Reference Lin, Lin and Hsia 15 , Reference Malter, Helmstaedter and Urbach 24 epileptiform abnormalities were also described. On lumbar puncture, pleocytosis was reported in 11 cases (27%, 11/41), with white blood cells values ranging from 7 to 114/µl.Reference Garcìa Garcìa, Catrillo and Morales 20 Oligoclonal bands were reported in 21 cases. Hyponatremia was rare and reported in only three cases.Reference Finelli 16 , Reference Knudsen, Bredholt and Storstein 30 , Reference Cianci, Labate and Lanza 40 It was severe in one patient, with a value as low as 107 mmol/l.Reference Finelli 16 It was associated with lung cancer in another.Reference Knudsen, Bredholt and Storstein 30 Voltage-gated potassium channels (VGKC) antibodies were negative for the three cases.

GAD65 antibodies were reported positive in serum and CSF in 35 cases (with available index in 19), in serum only in 18, and in CSF only in three.Reference Petit-Pedrol, Armangue and Peng 14 , Reference Pandit, Ihtisham and Garg 43 For two cases, results were not clearly mentioned.Reference Boronat, Sabater and Saiz 39 For three patients with diabetes, a GAD65-positive result was only described for serum.Reference Petit-Pedrol, Armangue and Peng 14 , Reference Malter, Helmstaedter and Urbach 24 , Reference Saidha, Murphy and Ronayne 41 Overall, neuronal antibodies other than GAD65 were explicitly tested in a variable proportion of cases, ranging from 9% to 83% (Table 4)

Table 4 Tested antibodiesReference Petit-Pedrol, Armangue and Peng 14 - Reference Mishra, Rodan and Nita 44

* Number of cases with antibodies explicitly tested.

.

Concurrent antibodies were reported in 11 cases (11/58, 19%, details in Table 5). We did not find significant differences for sex, age, main clinical features, autoimmunity, and association with cancer between cases with and without concurrent antibodies (details in Supplementary Table 9). Antibodies against VGKC were positive in three patients,Reference Mirabelli-Badenier, Morana and Pinto 17 , Reference Haberlandt, Bast and Ebner 32 GABA B receptor (GABABR) antibodies in three,Reference Petit-Pedrol, Armangue and Peng 14 , Reference Boronat, Sabater and Saiz 39 and GABAAR antibodies in five.Reference Petit-Pedrol, Armangue and Peng 14 Testing for N-methyl-D-aspartic receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR), and onconeuronal antibodies were all negative. However, we suspected that one caseReference Graus, Saiz and Lai 31 retrospectively tested positive for AMPAR in an ulterior studyReference Alexopoulos, Akrivou and Dalakas 12 (because of the description of same age, sex, and clinical features). Moreover, in patients with cancer, other antibodies were positive in one-half of the cases (3/6): GABABRReference Boronat, Sabater and Saiz 39 in two SOX-1Reference Boronat, Sabater and Saiz 39 and CRMP3/CRMP4Reference Saiz, Blanco and Sabater 29 in one case each.

Table 5 Cases with concurrent neuronal antibodies (n=11)Reference Petit-Pedrol, Armangue and Peng 14 - Reference Mishra, Rodan and Nita 44

MMF, mycophenolate mofetil; NA, not available.

Treatment and Outcome

In limbic encephalitis associated with GAD65 antibodies, many patients suffered from severe and nonremitting neurologic impairment. Several different treatments were used with variable outcome (Table 6). Duration of follow-up varied from 0 to 96 months. In five cases (9%, 5/58), outcome was unknown (n=53)Reference Petit-Pedrol, Armangue and Peng 14 , Reference Finelli 16 , Reference Akman, Patterson, Rubinstein and Herzog 23 , Reference Boronat, Sabater and Saiz 39 and treatment was not reported in 3 cases (n=55).Reference Petit-Pedrol, Armangue and Peng 14 , Reference Akman, Patterson, Rubinstein and Herzog 23

Table 6 Treatment and outcome (n=55Footnote *)Reference Petit-Pedrol, Armangue and Peng 14 - Reference Mishra, Rodan and Nita 44

MMF, mycophenolate mofetil; NA, not available; PLEX, plasma exchange.

* Table excludes patients without details on treatment.

† Outcome including “full recovery” and “improvement.”

Number of cases placed between () if more than one patients are implied.

Full recovery was reported in four patients (8%, 4/53), with follow-up ranging from 3Reference Malter, Helmstaedter and Urbach 24 ,Reference Cikrikçili, Ulusoy and Turan 25 to about 80 months.Reference Petit-Pedrol, Armangue and Peng 14 , Reference Knudsen, Bredholt and Storstein 30 Three of them received immunotherapy: steroids only,Reference Petit-Pedrol, Armangue and Peng 14 steroids with intravenous immunoglobulin (IVIg)Reference Malter, Helmstaedter and Urbach 24 and steroids, and IVIg with plasma exchange.Reference Cikrikçili, Ulusoy and Turan 25 One patient did not receive any immunosuppressant and had a spontaneous remission (2%, 1/53).Reference Knudsen, Bredholt and Storstein 30 Death was also reported in four cases (8%, 4/53); it was associated with cancer in three.Reference Blanc, Ruppert and Kleitz 28 , Reference Knudsen, Bredholt and Storstein 30 , Reference Boronat, Sabater and Saiz 39 The other case was in the pediatric population.Reference Lin, Lin and Hsia 15 Improvement of initial symptoms on the last available follow-up period was found in 23 cases (43%, 23/53, with follow-up ranging from less than 1 month to 96 months). For 22 cases (42%, 22/53), there was no improvement or worsening of the condition. Relapses were reported in nine cases (17%, 9/53).Reference Kanter, Huttner and Staykov 18 , Reference Marchiori, Vaglia and Vianello 21 , Reference Matà, Muscas and Naldi 22 , Reference Olson, Olson and Sandborg 26 – Reference Blanc, Ruppert and Kleitz 28 , Reference Mazzi, De Roia, Cruciatti, Matà and Catapano 38 , Reference Cianci, Labate and Lanza 40 , Reference Mishra, Rodan and Nita 44

Favorable outcome was described in 24 patients with positive GAD65 antibodies only (24/44, 55%, including full recovery for three patientsReference Malter, Helmstaedter and Urbach 24 , Reference Cikrikçili, Ulusoy and Turan 25 , Reference Knudsen, Bredholt and Storstein 30 [3/44, 7%]) and in three patients with other antibodies against CNS target (3/9, 33%, including full recovery for one caseReference Petit-Pedrol, Armangue and Peng 14 [1/9, 11%]). However, we did not find significant difference for favorable outcome between cases with and without concurrent antibodies (details in Supplementary Table 9). Moreover, in patients with positive CSF GAD65 antibodies, favorable outcome (including patients with “full recovery” and “improvement”) was described in 45% (45%, 17/38) compared with 56% in cases with antibodies only positive in serum (56%, 10/18). There was no significant difference between the two groups according to Fisher’s exact test.

Discussion

We reported 58 cases of autoimmune limbic encephalitis associated with GAD65 antibodies in pediatric and adult populations. Most cases were young adult patients, but age ranged from 1 to 70 years of age. A coexisting systemic autoimmune condition was found in almost half of cases, mainly diabetes. This finding tends to demonstrate that those patients had a propensity to autoimmunity. Cancer was reported in 10%, which is less than for LE associated with VGKC or GABABR antibodies.Reference Rosenfeld and Dalmau 45 For one-half of those patients, however, there were concurrent antibodies. In a recent study, the authors suggested that the probability of an underlying cancer was seven times higher in patients with GAD65 and coexisting antibodies against neuronal cell-surface antigens.Reference Arino, Höftberger and Gresa-Arribas 47 In contrast with ovarian teratoma predicting LE associated with NMDAR antibodies,Reference Dalmau, Tuzun and Wu 48 we found no specific type of cancer (small-cell lung cancer and malignant thymoma reported). Furthermore, seizures and memory impairment were cardinal symptoms. Status epilepticus was frequently reported (almost one of four patients), which suggests that GAD65 antibodies testing could also be helpful in this context. Cognitive impairment other than memory, such as difficulties with orientation, executive functions, and language, were possible. As opposed to LE associated with VGKC or NMDAR antibodies, characteristic movement disorders such as brachiofacial dystonia or orofacial dyskinesia were not reported.Reference Rosenfeld and Dalmau 45 , Reference Andrade, Tai, Dalmau and Wennberg 49 Brain MRI and EEG were usually characterized by temporal abnormalities, but multifocal abnormalities were also found. In a one-quarter of cases, pleocytosis was present, which could be as high as 114 white blood cells per microliter. Hyponatremia was possible (5%), but less frequently than in other autoimmune LE such as LGI1 (up to 60%).Reference Lai, Huijbers and Lancaster 50 Overall, no distinctive patterns of clinical and paraclinical findings were found.

Furthermore, many patients suffered from severe and nonremitting neurologic impairment. Only four cases presented full recovery. Different treatments were used with very variable responses. Here, reporting an aggregate pooled effect concerning treatment could be misleading because of small samples and variable duration and description of follow-up across patients. Consequently, therapeutic strategies cannot be reasonably recommended. Also, we did not find significant difference of outcome between cases whether or not positive GAD65 antibodies were reported in CSF.

SPS is a disorder characterized by progressive muscular rigidity, predominantly of the trunk muscles, and spasms.Reference Hadavi, Noyce, Leslie and Giovannoni 51 A proportion of patients with GAD65 antibodies has a syndrome called SPS plus or progressive encephalomyelitis with rigidity and myoclonus, which is similar to SPS with rigidity with also stimulus-sensitive myoclonus, brainstem signs, and autonomic disturbance.Reference Carvajal-Gonzalez, Leite and Waters 52 In this review, we did not find much overlap among the three syndromes. Clinical spectrum appeared to be fairly different, except for three cases. Muscle stiffness was reported in a 63-year-old female who presented seizures with generalized abnormalities on EEG, disorientation, and dysarthria.Reference Malter, Helmstaedter and Urbach 24 She also had psychiatric manifestations such as social withdrawal, insomnia, episodes of purposeless crying, visual hallucinations, and paranoid delusions. GAD65 antibodies were highly positive in serum, but not explicitly tested in CSF. Oligoclonal bands were found. Brain MRI was normal. At 3 months, full recovery was observed after a treatment with steroids and IVIg. For the second case, a 12-year-old male patient had a diagnosis of SPS 7 years before the episode of LE.Reference Petit-Pedrol, Armangue and Peng 14 He had right temporal seizures. Brain MRI was abnormal with hippocampal high T2/fluid attenuated inversion recovery signal. Partial improvement of SPS symptoms was observed with resolution of seizures with treatment, consisting of anticonvulsants, IVIg, and rituximab. In both cases, there was no cancer, and GAD65 antibodies were positive only in serum, but not explicitly tested in CSF. One had concurrent type 2 diabetes.Reference Malter, Helmstaedter and Urbach 24 Myoclonus were reported in three casesReference Garcìa Garcìa, Catrillo and Morales 20 , Reference Olson, Olson and Sandborg 26 , Reference Monnerat, Velasco and Nakano 37 and appeared to be part of seizure manifestations. In a 23-year-old female, it was associated with diffuse hyperreflexia and brainstem signs.Reference Monnerat, Velasco and Nakano 37 In comparison with SPS, we found that LE with GAD65 antibodies was also associated with systemic autoimmune disorder.Reference Dalmau, Tuzun and Wu 48 Risk of cancer was another similarity.Reference Baizabal-Carvallo and Jankovic 53 Indeed, in this review, patients with cancer were all men with a mean age of 61 years old (median at 68 years of age, age spectrum 38-70 years old) and coexisting neuronal antibodies in 50% (Supplementary Table 8).

Concerning paraclinical features, GAD65 antibodies were positive for almost all cases, mainly in CSF. In about 30% of cases, antibodies were not clearly tested in CSF, including three patients with diabetes. However, the presence of antibodies in the circulation does not mean that they play a pathophysiological role in a brain-related syndrome. A certain rate of transfer can be expected in healthy subjects with an intact blood-brain barrier.Reference Reiber and Peter 54 In a recent study with a focus on some autoantibodies in the serum of healthy and neuropsychiatrically ill subjects, GAD65 antibodies were comparably detectable in both groups studied.Reference Dahm, Steiner and Stepniak 55 Consequently, detection of significant antibodies titers in CSF might be necessary to determine a causal relationship between antibodies and a central nervous system disorder such as encephalitis.Reference Gresa-Arribas, Titulaer and Torrents 56 In addition, some authors proposed that GAD65 antibodies are not the pathogenic key, considering that antibodies for intracellular antigens are rarely thought to be pathogenic.Reference Birand, Cabre and Bonnan 11 , Reference Lai, Hughes and Peng 13 , Reference Petit-Pedrol, Armangue and Peng 14 , Reference Rosenfeld and Dalmau 46 Instead, they suggest that other cell-surface antibodies (such as against AMPAR, GABABR, and more recently GABAAR) coexist in patients with autoimmune LE. In this review, other relevant antibodies were reported in almost one patient of five. For this group, we did not find significant differences for sex, age, clinical features, autoimmunity, association with cancer, and outcome, which is under consideration for a small sample. Most importantly, we found that those relevant antibodies were not tested in every case.

There are several limitations to this work. Obviously, there are inherent limitations of case reviews. Identified cases were diverse in their degree of description of clinical features, investigation, and outcome. This was particularly significant for outcome data. Vocabulary also differed from one article to another and could have led to a certain degree of interpretation. Moreover, primary authors were not contacted to confirm the accuracy of abstracted data or to provide additional relevant data. Another important methodological limitation was that the review was carried out by only one person. Furthermore, only cases in English from the Medline database were considered; it is plausible that published cases were missed. Inclusion of studies with retrospective or prospective immunological analysis increased the sample, but might have caused duplication of cases. Clinical descriptions were also often briefer. There are also limitations associated with the statistical analyses concerning subgroups because of small sample size and statistical power. Finally, reporting bias must be discussed. Overreporting of “exceptional” with more severe clinical features is possible. Status epilepticus, which was reported in 24%, might be an example. Moreover, overreporting of cases with more favorable responses to therapy cannot be excluded.

Conclusion

Our review of the literature demonstrated that LE associated with GAD65 antibodies occur across the age spectrum, and commonly occurs in association with systemic autoimmune disease, particularly diabetes. Limbic encephalitis was frequently refractory to standard immunotherapies, and recovery was often incomplete. Concurrent autoantibodies such as GABABR, GABAAR, and VGKC were described in 19% of tested cases, with recovery (partial or complete) reported in 33% of these patients. Moreover, we found that the vast majority of cases were not tested for all those cell-surface antibodies. The detection of additional disease-associated autoantibodies may further guide treatment, acknowledging that the pathogenicity of GAD65 antibodies has not been convincingly shown. Prospective studies recruiting patients with autoimmune-mediated LE are needed to better elucidate the contributions of GAD65 autoantibodies to LE, and to evaluate treatment and outcomes in this population.

Disclosures

M-MG has received honoraria and served as a medical record reviewer for Grifols Canada. MS served as a speaker for and received speaker fees from UCB Canada and Serono.

Acknowledgments

We are grateful for the contribution of the Clinical Research Platform (CRP) of the CHU de Quebec for the statistical support.

Supplementary Material

To view supplementary material for this article, please visit http://dx.doi.org/10.1017/cjn.2016.13

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Figure 0

Table 1 Search process flowchart

Figure 1

Table 2 General characteristics14-44

Figure 2

Table 3 Clinical features14-44

Figure 3

Table 4 Tested antibodies14-44

Figure 4

Table 5 Cases with concurrent neuronal antibodies (n=11)14-44

Figure 5

Table 6 Treatment and outcome (n=55*)14-44

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