Background: Stiff-person syndrome (SPS) with antibodies to amphiphysin is a paraneoplastic disorder of the central nervous system with a putative autoimmune pathogenesis. Proof of a causal role of the antibodies is still lacking for this and all other antibody-associated paraneoplastic syndromes of the central nervous system.
Methods: We obtained the plasma filtrate of a patient with breast cancer and SPS that responded to therapeutic plasmapheresis. The purified IgG fraction included high-titre antibodies to the synaptic protein amphiphysin. In a cotransfer design, this IgG fraction was injected intraperitoneally into female Lewis rats that had received encephalitogenic T-helper (Th) lymphocytes specific for myelin basic protein, to induce an immune-mediated leaky blood-brain barrier. The rats were followed up with behavioural tests, video photography, and electromyography.
Findings: The injection of the IgG fraction including antibodies to amphiphysin resulted in a dose-dependent stiffness with spasms resembling human SPS. Control IgG injected into rats that had received the same encephalitogenic Th cells had no effect. IgG binding was demonstrated in the central nervous system of rats that showed signs of the disorder.
Interpretation: These experiments support the hypothesis of a pathogenetic role of antibodies to amphiphysin, thus adding paraneoplastic SPS to the group of antibody-mediated autoimmune disorders.
Relevance to practice: These findings provide a strong argument for a direct pathogenetic role of anti-amphiphysin in this type of SPS and support therapeutic attempts to eliminate these autoantibodies by plasmapheresis. The experimental approach used could help to elucidate the role of autoantibodies in other paraneoplastic syndromes, such as SPS with antibodies to glutamic acid decarboxylase, and others including anti-Hu-associated subacute cerebellar degeneration and limbic encephalitis.