Neurologic Syndromes Related to Anti-GAD65

Antibodies against glutamic acid decarboxylase (GAD), the enzyme catalyzing the conversion of the excitatory neurotransmitter glutamate to inhibitory gamma-aminobutyric acid (GABA), can impair GABAergic neurotransmission, resulting in neuronal excitability disorders, with most characteristic the stiff person syndrome (SPS). However, GAD antibodies also are associated with other neurological diseases comprising the “GAD antibody–spectrum disorders (GAD-SD)” that include refractory autoimmune epilepsy (AE), limbic encephalitis (LE), cerebellar ataxia CA), and nystagmus. Because GAD is expressed on β-pancreatic cells, low-titer GAD-Abs are also detected in DM1 diabetes. Although the pathogenicity of GAD-Abs is unclear, it is known that only highly elevated serum GAD-titers, detected also in the CSF, are autoimmune markers of GAD-SD.¹ Determining the high-cutoff GAD-Ab titers connected with distinct neurologic phenotypes is clinically fundamental for diagnosis and response to therapy. The study by Muñoz-Lopetegi et al sheds light on these issues based on a retrospective chart review of 56 GAD-Ab–positive patients.

After establishing the specificity, reliability, and clinical relevance of high-cutoff ELISA titers using immunohistochemistry and cell-based assays, the authors examined the clinical phenotypes in: 36 patients with high >10,000-IU/m (median 74,700) GAD-Ab titers; 20 with low <10,000-IU/mL titers; and 61 with DM1. Overall, 34 of 36 patients with high-GAD-Ab titers had typical neurologic disorders: 7 SPS; 9 AE; 9 LE; 3 CA; and 6 overlap syndromes. In contrast, 12 of20 low–GAD-Ab titer patients had various neurological diagnoses, some autoimmune (like other encephalitides) and others non-immune (like multiple system atrophy, nonspecific ataxia, or even functional disorders). In DM1, the median GAD-Ab titer was 86 IU/mL, verifying previous studies.¹ As previously reported, there was no association between GAD-Ab titer and disease severity. In 15 of 17 retrospectively reviewed patients who responded to immunotherapies (mostly IVIg), the titers decreased by >25%; in controlled studies with IVIg and rituximab, however, such a reduction was not statistically significant.

The study has several important new or verified messages for the practicing neurologists. First and most importantly, it confirms that anti–GAD65-Ab titers do matter: if high (>10,000), titers are diagnostic for a true GAD-SD, necessitating prolonged immunotherapy; in contrast, lower (<10,000) titers are associated with atypical or nonspecific neurological disorders requiring more extensive investigations, whereas very low titers are seen in DM1 or normals. Importantly, a recent study has shown that GAD-Abs are also seen within the various IVIg preparations and GAD-Abs are detected in patients receiving IVIg.² Second, high (>10,000) titers are not arbitrary but based on cell-based assays indicating specificity, diagnostic significance, and association with measurable GAD-Ab titers in the CSF. Third, screening for GAD-Ab should be considered in clinical practice as high titers denote an immunotherapy-responsive GAD-spectrum disorder.

References

1. Alexopoulos H, Dalakas MC. Immunology of stiff person syndrome and other GAD-associated neurological disorders. Expert Rev Clin Immunol, 2013;9(11):1043-1053. https://www.tandfonline.com/doi/abs/10.1586/1744666X.2013.845527?journalCode=ierm20
2. Dimitriadou M, Alexopoulos H, Akrivou S, et al. Anti-neuronal antibodies within the IVIg preparations: Importance in clinical practice. Neurotherapeutics. 2020;17(1):235-242. https://link.springer.com/article/10.1007%2Fs13311-019-00796-3