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

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.

Long-term Effectiveness of IVIg Maintenance Therapy in 36 Patients With GAD Antibody–Positive Stiff-Person Syndrome

“…Five GAD-positive patients also had cerebellar involvement, as part of GAD-SPS spectrum disorder. 4,5,17…”

Autoimmune Neurological Disorders with IgG4 Antibodies: a Distinct Disease Spectrum with Unique IgG4 Functions Responding to Anti-B Cell Therapies

“…The DPPX antibodies are both of the IgG4 and IgG1 subclass and reduce cell membrane protein levels of DPPX and Kv4.2 potassium channels in cultured neurons increasing neuronal excitability in myenteric neurons [29]. Because of the widespread distribution of Kv4.2 complexes, these patients present with a multifocal neurologic phenotype with severe prodromal weight loss or diarrhea, followed by cognitive dysfunction, memory deficits, CNS hyperexcitability, hyperekplexia, myoclonus, tremor, seizures, dysautonomic manifestations, and brainstem or cerebellar dysfunction, peaking at 8 months from onset [29][30][31]. The triad of weight loss due to gastrointestinal symptoms, cognitive-mental dysfunction, and CNS hyperexcitability is highly suspicious for DPPX autoimmunity.…”

“…Patients respond to immunotherapy with reversibility of the effects exerted by these antibodies in cultured neurons. The DPPX-associated neurologic syndrome resemble that of PERM [31] and, although the antibody effects are probably due to a combined effect of IgG1 and IgG4 immunoglobulins, it responds better to second-line immunotherapy most often with rituximab [29,30]; interestingly, relapses are more frequent when this therapy is discontinued pointing more to an IgG4 rather than IgG1connected immunopathogenesis.…”

Stiff-Person-Syndrom – Ein Update zu Symptomen, Diagnostik und Therapie

“…Bei ca. 60% der Patienten mit SPSE finden sich im Serum und Liquor Antikörper gegen das intraneurale Enzym Glutamat-Decarboxylase (GAD) [1]. GAD ist an der Synthese und Freisetzung des inhibitorisch wirkenden Neurotransmitters Gamma-Aminobuttersäure (GABA) in Gehirn und Rückenmark beteiligt.…”

“…GAD ist an der Synthese und Freisetzung des inhibitorisch wirkenden Neurotransmitters Gamma-Aminobuttersäure (GABA) in Gehirn und Rückenmark beteiligt. Daneben sind Autoantikörper gegen Glycinrezeptoren (GlyR), Amphiphysin und Gephyrin mit SPSE assoziiert, sehr selten gegen weitere Antigene [1] (s. ▶ Abb. 1).…”