Stiff person syndrome

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Abstract
Objective: To characterize the specificity of anti-GAD65 antibodies in patients with stiff person syndrome (SPS), quantify antibody titers, and examine antibody production within the CNS. Methods: The authors studied 18 patients with SPS and positive serum immunoreactivity to gamma-aminobutyric acid (GABA)-ergic neurons. The reactivity of serum and CSF to purified GAD antigen was examined by Western blots, and the anti-GAD65 antibody titers in serum and CSF were quantified by ELISA and compared with 70 disease controls (49 with other autoimmune disorders and 11 with insulin-dependent diabetes mellitus). The intrathecal synthesis of anti-GAD65 IgG was calculated, and the functional significance of the antibodies was examined by measuring the GABA levels in the CSF. Results: The serum and CSF of all selected patients with SPS had high anti-GAD65 titers (from 7.0 to 215 μg/mL in serum and from 92 to 2500 ng/mL in CSF) and immunoreacted strongly with recombinant GAD65 on Western blots and with GABA-ergic neurons on rat cerebellum. Among controls, only the serum of eight patients with insulin-dependent diabetes mellitus had low anti-GAD65 antibody titers (from 200 to 1760 ng/mL) but no reactivity to recombinant GAD65. The CSF showed oligoclonal IgG bands in 10 (67%) of 15 patients and an increased anti-GAD65-specific IgG index in 11 (85%) of 13. The mean level of GABA in the CSF was lower in patients with SPS than in controls. Conclusions: In patients with SPS, there is marked intrathecal antibody response against neuronal GAD65 epitopes, indicating a clonal B cell activation in the CNS. Anti-GAD65 antibodies at high titers, when confirmed with immunoblots, are highly specific for SPS and appear to impair GABA synthesis.