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Stiff Person Syndrome: A Case Report with Sudden Onset and Coexistence of Sero-Positive Antibodies to Glutamic Acid Decarboxylase and Anti-SOX1 Antibodies.

ABSTRACT: Stiff Person Syndrome (SPS) is an extremely rare neurological condition characterized by muscle stiffness and painful muscle spasms. The symptoms often progress slowly and can cause disability. Antibodies to glutamic acid decarboxylase (anti-GAD) have been reported in up to 80% of the classic type of SPS. Paraneoplastic syndrome comprises 5% of SPS cases. These patients present with different malignancies including lung, thymus, breast, colon, and lymph nodes. In this paper, we report a case of a 25-year-old Vietnamese female patient with SPS presenting with unusual clinical manifestations of sudden onset, rapidly progressive spinal, abdominal, and lower limb rigidity accompanied by painful spasms, autonomic disorders, and severe, multiple bone fractures. Serologic tests detected high-titer anti-GAD, combined with anti-SOX1 antibodies, suggesting paraneoplastic SPS. Intravenous immunoglobulin has been employed as the main treatment therapy, and the patient has had a complete remission.

SUBMITTER: Nguyen PM

PROVIDER: S-EPMC9210011 | biostudies-literature | 2022 May-Aug

REPOSITORIES: biostudies-literature

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Stiff Person Syndrome: A Case Report with Sudden Onset and Coexistence of Sero-Positive Antibodies to Glutamic Acid Decarboxylase and Anti-SOX1 Antibodies.

Nguyen Phuong Minh PM Vu Dung Duy DD Vu Kien Dung KD Nguyen Hai Thanh HT Nguyen Dinh Van DV

Case reports in neurology 20220510 2

Stiff Person Syndrome (SPS) is an extremely rare neurological condition characterized by muscle stiffness and painful muscle spasms. The symptoms often progress slowly and can cause disability. Antibodies to glutamic acid decarboxylase (anti-GAD) have been reported in up to 80% of the classic type of SPS. Paraneoplastic syndrome comprises 5% of SPS cases. These patients present with different malignancies including lung, thymus, breast, colon, and lymph nodes. In this paper, we report a case of ...[more]

PMID: 35815107

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Project description:IMPORTANCE:High titers of autoantibodies to glutamic acid decarboxylase (GAD) are well documented in association with stiff person syndrome (SPS). Glutamic acid decarboxylase is the rate-limiting enzyme in the synthesis of ?-aminobutyric acid (GABA), and impaired function of GABAergic neurons has been implicated in the pathogenesis of SPS. Autoantibodies to GAD might be the causative agent or a disease marker. OBJECTIVE:To investigate the characteristics and potential pathogenicity of GAD autoantibodies in patients with SPS and related disorders. DESIGN:Retrospective cohort study and laboratory investigation. SETTING:Weatherall Institute of Molecular Medicine, University of Oxford. PARTICIPANTS:Twenty-five patients with SPS and related conditions identified from the Neuroimmunology Service. EXPOSURES:Neurological examination, serological characterization and experimental studies. MAIN OUTCOMES AND MEASURES:Characterization of serum GAD antibodies from patients with SPS and evidence for potential pathogenicity. RESULTS:We detected GAD autoantibodies at a very high titer (median, 7500 U/mL) in 19 patients (76%), including all 12 patients with classic SPS. The GAD autoantibodies were high affinity (antibody dissociation constant, 0.06-0.78 nmol) and predominantly IgG1 subclass. The patients’ autoantibodies co-localized with GAD on immunohistochemistry and in permeabilized cultured cerebellar GABAergic neurons, as expected, but they also bound to the cell surface of unpermeabilized GABAergic neurons. Adsorption of the highest titer (700 000 U/mL) serum with recombinant GAD indicated that these neuronal surface antibodies were not directed against GAD itself. Although intraperitoneal injection of IgG purified from the 2 available GAD autoantibody–ositive purified IgG preparations did not produce clinical or pathological evidence of disease, SPS and control IgG were detected in specific regions of the mouse central nervous system, particularly around the lateral and fourth ventricles. CONCLUSIONS AND RELEVANCE:Autoantibodies to GAD are associated with antibodies that bind to the surface of GABAergic neurons and that could be pathogenic. Moreover, in mice, human IgG from the periphery gained access to relevant areas in the hippocampus and brainstem. Identification of the target of the non-GAD antibodies and peripheral and intrathecal transfer protocols, combined with adsorption studies, should be used to demonstrate the role of the non-GAD IgG in SPS.

Project description:ImportanceLittle 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.ObjectiveTo report the clinical and immunological features of patients with paraneoplastic neurological syndromes (PNS) and GAD-abs.Design, setting, and participantsRetrospective 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.Main outcomes and measuresAnalysis 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.ResultsEight 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 < .001), and had more often coexisting neuronal cell-surface antibodies, mainly against γ-aminobutyric acid receptors (53% vs 11%; P < .001). The tumors more frequently involved were lung (n = 6) and thymic neoplasms (n = 4). The risk for an underlying tumor was higher if the presentation was a classic PNS, if it was different from stiff-person syndrome or cerebellar ataxia (odds ratio, 10.5; 95% CI, 3.2-34.5), or if the patient had coexisting neuronal cell-surface antibodies (odds ratio, 6.8; 95% CI, 1.1-40.5). Compared with the current series, the 19 previously reported cases had more frequent stiff-person syndrome (74% vs 13%; P = .001) and better responses to treatment (79% vs 27%; P = .005). Predictors of improvement in the 34 patients (current and previously reported) included presentation with stiff-person syndrome and the presence of a thymic tumor.Conclusions and relevancePatients with GAD-abs must be screened for an underlying cancer if they have clinical presentations different from those typically associated with this autoimmunity or develop classic PNS. The risk for cancer increases with age, male sex, and the presence of coexisting neuronal cell-surface antibodies.

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.

Dataset Information

Stiff Person Syndrome: A Case Report with Sudden Onset and Coexistence of Sero-Positive Antibodies to Glutamic Acid Decarboxylase and Anti-SOX1 Antibodies.

Publications

Stiff Person Syndrome: A Case Report with Sudden Onset and Coexistence of Sero-Positive Antibodies to Glutamic Acid Decarboxylase and Anti-SOX1 Antibodies.

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