Clinical spectrum of high-titre GAD65 antibodies

Abstract

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.

Antibody-Mediated Autoimmune Diseases of the CNS: Challenges and Approaches to Diagnosis and Management

“…Progressive encephalopathy with rigidity and myoclonus (PERM) is a rare phenotype characterized by the occurrence of muscular rigidity, spasms, and myoclonus in association with encephalopathy and usually accompanied by a normal MRI head and spine ( 44 ). This syndrome is part of the stiff-person spectrum disorders and is mostly seen with GAD65 and GlyR autoantibodies; autoimmune cerebellar ataxia and epilepsy may also coexist with GAD65 antibodies ( 45 , 46 ). Tetanus and malignant hyperthermia are among the differential diagnosis.…”

“…However, the detection of high-titer GAD65 autoantibodies in the serum and/or CSF of neurologic patients is not sufficient for a diagnosis of GAD65 autoimmunity in the absence of one of the compatible clinical phenotypes of stiff-person spectrum, autoimmune ataxia or autoimmune epilepsy. In a recent study of 323 patients with high-titer GAD65 autoantibodies seen at Mayo Clinic, one third had an alternative diagnosis ( 45 ). Awareness of the typical clinical-MRI phenotypes associated with the different neural autoantibodies is important to avoid misdiagnosis and inappropriate treatment.…”

“…Autoantibodies targeting intracellular antigens rarely respond even to aggressive immunosuppression, so that stabilization of the neurologic deficit is frequently considered a good achievement. A recent study on 212 patients with GAD65 autoimmunity found complete immunotherapy response in only 1% of cases ( 45 ). In patients with paraneoplastic CNS syndromes, progression of the underlying cancer is a major cause of death ( 153 ).…”

Autoimmune Disorders of the Nervous System: Pathophysiology, Clinical Features, and Therapy

“…Thus, epitopes of GAD65 and also amphiphysin can be exposed to antibodies during synaptic fusion and reuptake. High titers of anti-GAD65 have been linked to stiff person spectrum disorders, cerebellar ataxia and limbic encephalitis (73).…”

Current Nosology of Neural Autoantibody-Associated Dementia

“…Several autoantibodies ( Table 1 ) are often now reported to be associated with cognitive dysfunction ( Dalmau et al, 1992 ; Pittock et al, 2005 ; Honnorat et al, 2009 ; White and Beringer, 2010 ; Maat et al, 2015 ; Do et al, 2017 ; Ortega Suero et al, 2018 ; Hansen et al, 2020a , b , 2021a ; Maudes et al, 2020 ; Wickel et al, 2020 ; Budhram et al, 2021 ; Helmstaedter et al, 2021 ). Prominent autoantibody candidates strongly associated with cognitive impairment within the spectrum of autoantibodies against intracellular antigens are those directed against GAD65, AK5, GFAP, and Ma2.…”