Clinical spectrum of high-titre GAD65 antibodies

ObjectiveTo determine clinical manifestations, immunotherapy responsiveness and outcomes of glutamic acid decarboxylase-65 (GAD65) neurological autoimmunity.MethodsWe identified 323 Mayo Clinic patients with high-titre (>20 nmol/L in serum) GAD65 antibodies out of 380 514 submitted anti-GAD65 samples (2003–2018). Patients classified as having GAD65 neurological autoimmunity after chart review were analysed to determine disease manifestations, immunotherapy responsiveness and predictors of poor outcome (modified Rankin score >2).ResultsOn review, 108 patients were classified as not having GAD65 neurological autoimmunity and 3 patients had no more likely alternative diagnoses but atypical presentations (hyperkinetic movement disorders). Of remaining 212 patients with GAD65 neurological autoimmunity, median age at symptom onset was 46 years (range: 5–83 years); 163/212 (77%) were female. Stiff-person spectrum disorders (SPSD) (N=71), cerebellar ataxia (N=55), epilepsy (N=35) and limbic encephalitis (N=7) could occur either in isolation or as part of an overlap syndrome (N=44), and were designated core manifestations. Cognitive impairment (N=38), myelopathy (N=23) and brainstem dysfunction (N=22) were only reported as co-occurring phenomena, and were designated secondary manifestations. Sustained response to immunotherapy ranged from 5/20 (25%) in epilepsy to 32/44 (73%) in SPSD (p=0.002). Complete immunotherapy response occurred in 2/142 (1%). Cerebellar ataxia and serum GAD65 antibody titre >500 nmol/L predicted poor outcome.InterpretationHigh-titre GAD65 antibodies were suggestive of, but not pathognomonic for GAD65 neurological autoimmunity, which has discrete core and secondary manifestations. SPSD was most likely to respond to immunotherapy, while epilepsy was least immunotherapy responsive. Complete immunotherapy response was rare. Serum GAD65 antibody titre >500 nmol/L and cerebellar ataxia predicted poor outcome.

Seizures associated with antibodies against cell surface antigens are acute symptomatic and not indicative of epilepsy: insights from long-term data

Background Clinicians have questioned whether any disorder involving seizures and neural antibodies should be called “(auto)immune epilepsy.” The concept of “acute symptomatic seizures” may be more applicable in cases with antibodies against neural cell surface antigens. We aimed at determining the probability of achieving seizure-freedom, the use of anti-seizure medication (ASM), and immunotherapy in patients with either constellation. As a potential pathophysiological correlate, we analyzed antibody titer courses. Methods Retrospective cohort study of 39 patients with seizures and neural antibodies, follow-up ≥ 3 years. Results Patients had surface antibodies against the N-methyl-d-aspartate receptor (NMDAR, n = 6), leucine-rich glioma inactivated protein 1 (LGI1, n = 11), contactin-associated protein-2 (CASPR2, n = 8), or antibodies against the intracellular antigens glutamic acid decarboxylase 65 kDa (GAD65, n = 13) or Ma2 (n = 1). Patients with surface antibodies reached first seizure-freedom (88% vs. 7%, P < 0.001) and terminal seizure-freedom (80% vs. 7%, P < 0.001) more frequently. The time to first and terminal seizure-freedom and the time to freedom from ASM were shorter in the surface antibody group (Kaplan–Meier curves: P < 0.0001 for first seizure-freedom; P < 0.0001 for terminal seizure-freedom; P = 0.0042 for terminal ASM-freedom). Maximum ASM defined daily doses were higher in the groups with intracellular antibodies. Seizure-freedom was achieved after additional immunotherapy, not always accompanied by increased ASM doses. Titers of surface antibodies but not intracellular antibodies decreased over time. Conclusion Seizures with surface antibodies should mostly be considered acute symptomatic and transient and not indicative of epilepsy. This has consequences for ASM prescription and social restrictions. Antibody titers correlate with clinical courses.

Improving accuracy of myasthenia gravis autoantibody testing by reflex algorithm

ObjectiveTo improve myasthenia gravis (MG) autoantibody testing.MethodsMG serologic tests with confirmatory or refuting clinical–electrodiagnostic (EDX) testing and cancer evaluations were reviewed over 4 years (2012–2015). All patients had acetylcholine receptor–binding (AChR-Bi), modulating (AChR-Mo), and striational (STR) autoantibody testing, and negatives reflexed to muscle-specific kinase (MuSK). Thymoma and cancer occurrences were correlated with STR and reflexed glutamic acid decarboxylase 65 (GAD65), ganglionic acetylcholine receptor (α3), collapsin response mediating protein-5, and voltage-gated potassium channel complex autoantibodies.ResultsOf 433 samples tested, 133 (31%) met clinical–EDX criteria for MG. Best sensitivity (90%) occurred at AChR-Bi >0.02 nmol/L, leaving 14 negative (6 ocular MG, 7 generalized MG, 1 MuSK MG) with specificity 90% (31 false-positives). Using AChR-Mo antibodies (>20% loss), specificity was better (92%, 24 false-positives), but sensitivity dropped (85%). Specificity improved (95%) by testing AChR-Mo when AChR-Bi are positive, resulting in 45% reduction of false-positives (31–17), maintaining AChR-Bi 90% sensitivity. Cutoff values recommended by area under the curve analysis did not outperform this approach. AChR-Bi and AChR-Mo values were significantly higher in true-positives. CT evaluations in 121 MG samples revealed 16 thymomas. Historical or subsequent cancers occurred in 22. STR and reflexed autoantibodies were not more common in MG with thymoma or other cancers. Full-body CT (n = 34) was performed in those with STR and reflex autoantibody positivity, but without additional cancers found.ConclusionAccuracy of MG serologic testing is improved by reflexing AChR-Bi–positive cases to AChR-Mo. STR and other reflexed cancer evaluation autoantibodies did not provide value beyond standard CT chest imaging at the time of MG diagnosis. Diagnostic certainty is informed by AChR-Bi and AChR-Mo with higher values increasing specificity.

Anti-GAD65 antibody-associated hemiataxia

Autoimmune and paraneoplastic movement disorders are increasingly recognized as a result of improved methods in detecting antibodies directed against intracellular, membrane, and other antigens.1 High concentrations of anti-glutamic acid decarboxylase 65 (GAD65) antibodies are associated with several neurologic syndromes including stiff-person syndrome, epilepsy, limbic encephalitis, and cerebellar ataxia.2 Anti-GAD65-associated cerebellar ataxia is typically generalized with prominent gait disturbance and eye movement abnormalities.1 Limb ataxia is present in 60-70% of patients.3 Here we present 2 unusual cases of hemiataxia associated with high concentrations of anti-GAD65 antibodies.

Breaking β Cell Tolerance After 100 Years of Life: Intratumoral Immunotherapy–Induced Diabetes Mellitus

Cancer immunotherapies are changing the landscape of cancer care. Intratumoral talimogene iaherparepvec (T-VEC), an oncolytic viral vaccine, has been approved for treatment of unresectable melanoma with minimal toxicity. We describe the first case of a centenarian who developed autoimmune diabetes while on T-VEC immunotherapy. The patient’s high titer of glutamic acid decarboxylase 65 autoantibodies as well as insulin deficiency are consistent with autoimmune diabetes. Autoimmune diabetes has previously been seen following immune checkpoint inhibitor use; however, it has never been reported with T-VEC. This case highlights that autoimmune diabetes can be a rare but morbid complication of intratumoral T-VEC immunotherapy and can occur in the ultra-elderly.

Islet cell and glutamic acid decarboxylase-65 autoantibodies in young diabetic patients attending in a General Hospital in Dhaka City

Background: Immune mediated destruction of pancreatic beta cell in type-I diabetes is well established but its’ role in young type-2 diabetic patients is still not conclusive. These young diabetic patients pass through several stages where they do not need insulin but found to have serum autoantibody against islets cell and even become dependent on insulin for survival in course of time. This study aims to find the presence of islets cell auto-antibodies (ICA) and autoantibody to glutamic acid decarboxylase-65 (GAD-65) in non-insulin requiring young diabetic patients of Bangladesh. Objective: To evaluate the presence of ICA and GAD-65 between the non-insulin requiring young type-2 diabetic patients and compare with the non-diabetic control group. Method: This case control study was carried out at the Department of Immunology, BIRDEM General Hospital, Dhaka for a period of one year from July 2013, A total of 120 non-insulin requiring (≥12 months) young type-2 diabetic patients and 60 age, sex matched non-diabetic were enrolled as control subjects following inclusion and exclusion criteria. ICA and GAD-65 tests were performed by enzyme linked immune-sorbent assay (ELISA) method by using kits from DRG Inc. International, USA. Results: In this study statistically significant difference found between non insulin requiring young diabetic patients and non diabetic control in respect of positive ICA result (p=0.015). The moderately strong negative association was found between different age of onset of diabetes mellitus and value of ICA level (r=-0.45). Only 20-24 years age group showed statistically significant difference between patient and control (p=0.013). Statistically significant difference was not found in GAD-65 values of non insulin requiring young diabetic patients and non diabetic controls (p=0.441). Conclusion: This study revealed that there is significant difference present in respect of ICA among non-insulin requiring young diabetic patients and non-diabetic controls. Therefore, autoimmune pathogenesis of beta cell killing by producing ICA against islets cell take place in young type-2 diabetic patients. Bangladesh Med Res Counc Bull 2020; 46(2): 104-108