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Neurotherapeutics
Published in: Neurotherapeutics 3/2022

Open Access 01-04-2022 | Epilepsy | Review

Stiff-person Syndrome and GAD Antibody-spectrum Disorders: GABAergic Neuronal Excitability, Immunopathogenesis and Update on Antibody Therapies

Author: Marinos C. Dalakas

Published in: Neurotherapeutics | Issue 3/2022

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Abstract

Although antibodies against Glutamic Acid Decarboxylase (GAD) were originally associated with Stiff Person Syndrome (SPS), they now denote the “GAD antibody-spectrum disorders (GAD-SD)” that include Cerebellar Ataxia, Autoimmune Epilepsy, Limbic Encephalitis, PERM and eye movement disorder. In spite of the unique clinical phenotype that each of these disorders has, there is significant overlapping symptomatology characterized by autoimmune neuronal excitability. In addition to GAD, three other autoantibodies, against glycine receptors, amphiphysin and gephyrin, are less frequently or rarely associated with SPS-SD. Very high serum anti-GAD antibody titers are a key diagnostic feature for all GAD-SD, commonly associated with the presence of GAD antibodies in the CSF, a reduced CSF GABA level and increased anti-GAD-specific IgG intrathecal synthesis denoting stimulation of B-cell clones in the CNS. Because anti-GAD antibodies from the various hyperexcitability syndromes recognize the same dominant GAD epitope, the clinical heterogeneity among GAD-SD patients remains unexplained. The paper highlights the biologic basis of autoimmune hyperexcitability connected with the phenomenon of reciprocal inhibition as the fundamental mechanism of the patients’ muscle stiffness and spasms; addresses the importance of high-GAD antibody titers in diagnosis, pinpointing the diagnostic challenges in patients with low-GAD titers or their distinction from functional disorders; and discusses whether high GAD-antibodies are disease markers or pathogenic in the context of their association with reduced GABA level in the brain and CSF. Finally, it focuses on therapies providing details on symptomatic GABA-enhancing drugs and the currently available immunotherapies in a step-by-step approach. The prospects of future immunotherapeutic options with antibody therapies are also summarized.
Appendix
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Metadata
Title
Stiff-person Syndrome and GAD Antibody-spectrum Disorders: GABAergic Neuronal Excitability, Immunopathogenesis and Update on Antibody Therapies
Author
Marinos C. Dalakas
Publication date
01-04-2022
Publisher
Springer International Publishing
Keyword
Epilepsy
Published in
Neurotherapeutics / Issue 3/2022
Print ISSN: 1933-7213
Electronic ISSN: 1878-7479
DOI
https://doi.org/10.1007/s13311-022-01188-w

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