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Paraneoplastic Neurological Syndromes and Glutamic Acid Decarboxylase Antibodies.

ABSTRACT: Little is known of glutamic acid decarboxylase antibodies (GAD-abs) in the paraneoplastic context. Clinical recognition of such cases will lead to prompt tumor diagnosis and appropriate treatment.To report the clinical and immunological features of patients with paraneoplastic neurological syndromes (PNS) and GAD-abs.Retrospective case series study and immunological investigations conducted in February 2014 in a center for autoimmune neurological disorders. Fifteen cases with GAD65-abs evaluated between 1995 and 2013 who fulfilled criteria of definite or possible PNS without concomitant onconeural antibodies were included in this study.Analysis of the clinical records of 15 patients and review of 19 previously reported cases. Indirect immunofluorescence with rat hippocampal neuronal cultures and cell-based assays with known neuronal cell-surface antigens were used. One hundred six patients with GAD65-abs and no cancer served as control individuals.Eight of the 15 patients with cancer presented as classic paraneoplastic syndromes (5 limbic encephalitis, 1 paraneoplastic encephalomyelitis, 1 paraneoplastic cerebellar degeneration, and 1 opsoclonus-myoclonus syndrome). When compared with the 106 non-PNS cases, those with PNS were older (median age, 60 years vs 48 years; P?=?.03), more frequently male (60% vs 13%; P?

SUBMITTER: Arino H

PROVIDER: S-EPMC4838033 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Paraneoplastic Neurological Syndromes and Glutamic Acid Decarboxylase Antibodies.

Ariño Helena H Höftberger Romana R Gresa-Arribas Nuria N Martínez-Hernández Eugenia E Armangue Thaís T Kruer Michael C MC Arpa Javier J Domingo Julio J Rojc Bojan B Bataller Luis L Saiz Albert A Dalmau Josep J Graus Francesc F

JAMA neurology 20150801 8

<h4>Importance</h4>Little is known of glutamic acid decarboxylase antibodies (GAD-abs) in the paraneoplastic context. Clinical recognition of such cases will lead to prompt tumor diagnosis and appropriate treatment.<h4>Objective</h4>To report the clinical and immunological features of patients with paraneoplastic neurological syndromes (PNS) and GAD-abs.<h4>Design, setting, and participants</h4>Retrospective case series study and immunological investigations conducted in February 2014 in a cente ...[more]

PMID: 26099072

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Project description:ObjectiveTo describe clinical phenotypes and prognosis of neurological autoimmunity related to glutamic acid decarboxylase 65 (GAD65) antibodies in China.MethodIn this retrospective observational study from Peking Union Medical College Hospital, we identified patients with neurological disorders related to GAD65 antibodies (cell-based assay) from May 2015 to September 2021. Clinical manifestations, immunotherapy responsiveness, and outcomes were collected after obtaining informed consent from all patients.ResultsFifty-five patients were included: 40 (72.73%) were women and initial neurological symptoms developed at 42(34-55) years of age. The median time to the nadir of the disease was 5 months (range from 1 day to 48 months). The clinical syndromes included limbic encephalitis (LE) or epilepsy (Ep) (n = 34, 61.82%), stiff-person syndromes (SPS) (n = 18, 32.73%), autoimmune cerebellar ataxia (ACA) (n = 11, 20%), and overlap syndrome in eight (14.55%) patients. Thirty-two (58.2%) patients had comorbidities of other autoimmune diseases, including Hashimoto thyroiditis (n = 17, 53.13%), T1DM (n = 11, 34.78%), vitiligo (n = 6, 18.75%), and others (n=5, 15.63%). Two (3.64%) patients had tumors, including thymoma and small cell lung cancer. Fifty-one (92.7%) patients received first-line immunotherapy (glucocorticoids and/or IV immunoglobulin), and 4 (7.3%) received second-line immunotherapy (rituximab). Long-term immunotherapy (mycophenolate mofetil) was administered to 23 (41.8%) patients. At the median time of 15 months (IQR 6-33.75 month, range 3-96 month) of follow-up, the patients' median modified Rankin Score (mRS) had declined from 2 to 1. Thirty-eight (70.4%) patients experienced clinical improvement (mRS declined ≥1), 47 (87%) had favorable clinical outcomes (mRS ≤2), and nine were symptom-free (16.7%). The sustained response to immunotherapy ranged from 7/15 (63.63%) in ACA patients and 22/34 (64.7%) in LE/Ep patients to 14/17 (82.35%) in SPS patients.ConclusionsLE/Ep was the most common neurological phenotype of GAD65 antibody neurological autoimmunity in our cohort. Most patients had comorbidities of other autoimmune diseases, but underlying tumors were rare. Most patients responded to immunotherapy. However, the long-term prognosis varied among different clinical phenotypes.

Project description:Current clinical and immunologic knowledge on cerebellar ataxia (CA) with glutamic acid decarboxylase 65 antibodies (GAD65-Abs) is based on case reports and small series with short-term follow-up data.To report the symptoms, additional antibodies, prognostic factors, and long-term outcomes in a cohort of patients with CA and GAD65-Abs.Retrospective cohort study and laboratory investigations at a center for autoimmune neurologic disorders among 34 patients with CA and GAD65-Abs, including 25 with long-term follow-up data (median, 5.4 years; interquartile range, 3.1-10.3 years).Analysis of clinicoimmunologic features and predictors of response to immunotherapy. Immunochemistry on rat brain, cultured neurons, and human embryonic kidney cells expressing GAD65, GAD67, ?1-subunit of the glycine receptor, and a repertoire of known cell surface autoantigens were used to identify additional antibodies. Twenty-eight patients with stiff person syndrome and GAD65-Abs served as controls.The median age of patients was 58 years (range, 33-80 years); 28 of 34 patients (82%) were women. Nine patients (26%) reported episodes of brainstem and cerebellar dysfunction or persistent vertigo several months before developing CA. The clinical presentation was subacute during a period of weeks in 13 patients (38%). Nine patients (26%) had coexisting stiff person syndrome symptoms. Systemic organ-specific autoimmunities (type 1 diabetes mellitus and others) were present in 29 patients (85%). Twenty of 25 patients with long-term follow-up data received immunotherapy (intravenous immunoglobulin in 10 and corticosteroids and intravenous immunoglobulin or other immunosuppressors in 10), and 7 of them (35%) improved. Predictors of clinical response included subacute onset of CA (odds ratio [OR], 0.50; 95% CI, 0.25-0.99; P?=?.047) and prompt immunotherapy (OR, 0.98; 95% CI, 0.96-0.99; P?=?.01). Similar frequencies of serum GAD67-Abs were found in patients with CA (24 of 34 patients [71%]) and in patients with stiff person syndrome (20 of 28 patients [71%]). However, GAD67-Abs were found in all of the cerebrospinal fluid samples examined (22 samples from patients with CA and 17 samples from patients with stiff person syndrome). Glycine receptor antibodies but not other cell surface antibodies were identified in 4 patients with CA. The presence of glycine receptor antibodies did not correlate with any specific clinical feature.In patients with CA and GAD65-Abs, subacute onset of symptoms and prompt immunotherapy are associated with good outcome. Persistent vertigo or brainstem and cerebellar episodes can herald CA and should lead to GAD65-Ab testing, particularly in patients with systemic organ-specific autoimmunities.

Project description:BackgroundIn the current study, seizure semiology and potential predictive factors of seizure outcomes in glutamic acid decarboxylase antibody (GAD Ab)-associated neurological syndrome were investigated.MethodsIn this study, 32 Chinese patients with GAD Ab-associated neurological syndrome who presented with seizures at Peking Union Medical College Hospital from January 2017 to October 2022 were reviewed; 30 had a follow-up duration of more than 1 year.ResultsAmong the 32 patients, 10 presented with epilepsy alone. Concomitant neurological syndromes were observed in 22 patients, including limbic encephalitis (n = 20), stiff-person syndrome (SPS, n = 1), and cerebellar ataxia (n = 1). Bilateral tonic-clonic seizures were observed in 21 patients (65.6%). Focal seizures occurred in 27 patients (84.4%); 17 had focal motor seizures and 18 focal non-motor seizures. Among 30 patients with long-term follow-up, 11 (36.7%) were seizure-free. Acute/subacute onset (p = 0.049) and comorbidity of limbic encephalitis with epilepsy (p = 0.023) led to better seizure outcomes. Patients with persistent epilepsy were more likely to have focal seizure (p = 0.003) and higher frequency of seizure (p = 0.001). Furthermore, these patients tended to have longer intervals from onset to immunomodulatory treatments. Early immunotherapy (within 6 months from onset) was administered in 81.8% of seizure-free patients but only in 42.1% of patients with persistent seizures. However, steroid and immunosuppressant duration did not differ in the two groups. Repeated serum GAD Ab tests during the follow-up showed no association with seizure outcomes.ConclusionsThe seizure manifestations are diverse and variable. Approximately one third of patients achieved seizure remission during long-term follow-up. The type and frequency of seizures may influence the seizure outcomes. Early immunotherapy, especially within 6 months, may lead to better seizure outcomes.

Project description:Background and objectiveParaneoplastic neurological syndromes (PNS) are a group of rare syndromes associated with immunopathological process and tumors. Paraneoplastic autoantibodies are important for the diagnosis of PNS and for searching for underlying tumors. With the development of detection methods and discovery of new autoantibodies, the 2004 guidelines on PNS have recently been updated by a worldwide PNS-Care expert group. For clinicians, proper testing methods and testing results explanation are important for the diagnosis and treatment of PNS. This review aims to review the detection of paraneoplastic autoantibodies and the significance of testing results.MethodsWe summarize the studies on detection methods, association of autoantibodies and PNS or tumors, particularly the guidelines of PNS.Key content and findingsAntibodies are divided into 3 groups in the context of PNS according to the frequency of cancer association regardless of their eventual pathogenic effect. Instead of well-characterized antibodies and partially-characterized antibodies, high-risk antibodies, intermediate risk antibodies and lower risk antibodies were applied. According to the location of recognized antigens, these autoantibodies are divided as anti-intracellular antigen antibodies and neuronal surface antibodies (NSAbs). Tissue-based assays is recommended as screening method for paraneoplastic antibodies. Moreover, this method is helpful to discover new autoantibodies. A combination of a screening method [tissue-based assays (TBA)] and a confirmatory test [immunoblot and cell-based assay (CBA)] can improve sensitivity and specificity of the tests. Many PNSs are associated with specific antineuronal antibodies, but there is considerable diversity. Some autoantibodies are markers of specific neurological syndromes. Paraneoplastic antibodies are often specific for the PNS-associated tumor rather than for a particular neurological syndrome.ConclusionsDiagnosis of PNS depends on integrated analysis of clinical manifestations and auxiliary examinations. During diagnosis, selection of candidate antibodies for testing is challenging due to the varying clinical phenotypes and tumors associated with a given antibody. Broad antibody panels are more likely to capture causative antibodies and should be considered. According to different subtypes of autoantibodies, specific tumors or PNS should be considered. However, antibody titers, including cerebrospinal fluid (CSF) titers, should not be the primary driver of treatment decisions.

Dataset Information

Paraneoplastic Neurological Syndromes and Glutamic Acid Decarboxylase Antibodies.

Publications

Paraneoplastic Neurological Syndromes and Glutamic Acid Decarboxylase Antibodies.

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