Abstract and Commentary
Commentary by Claire Henchcliffe, MD, Assistant Professor, Department of Neurology, Weill Medical College of Cornell University.
Synopsis: Immunohistochemistry revealed perivascular staining in spinal cords for human IgG in rats that received high-titer antibodies, high doses of low-titer antibodies or high doses of control IgG.
Source: Sommer C, et al. Paraneoplastic Stiff-Person Syndrome: Passive Transfer to Rats By Means of IgG Antibodies to Amphiphysin. Lancet. 2005;365:1406-1411.
Sommer and colleagues previously reported a woman with metastatic invasive ductal breast cancer who developed Stiff-Person Syndrome (SPS) with progressive stiffness and spasms in legs, arms, and trunk, leading to inability to stand or walk. Additional atypical features were encephalopathy and opsoclonus.1 High titers of anti-amphiphysin antibodies were present in serum and cerebrospinal fluid, and symptoms responded dramatically to plasmapheresis as titers fell. Symptoms recurred, and a second plasmapheresis trial was ineffective. Sommer et al purified immunoglobulin G (IgG) fractions from plasma filtrates obtained during the first and second plasmapheresis treatments. The first plasmapheresis filtrate yielded high anti-amphiphysin antibody titers (high titer SPS IgG) of 1 to 2 × 108, while the second plasmapheresis treatment yielded low anti-amphiphysin antibody titers (low titer SPS IgG) of 1 to 8 ×106.
At day 0, rats were pretreated with injection of encephalitogenic T-helper cells specific for myelin basic protein, inducing a mild form of adoptive transfer experimental allergic encephalomyelitis. Then, on days 3-7, daily intraperitoneal injections were administered, comprising either 10mg high titer SPS IgG, IgG from a control patient (undergoing plasmapheresis for dysproteinemic hyperviscosity syndrome), commercially available IgG (pooled human polyclonal immunoglobulins), or no treatment. Procedures were repeated at day 10, and animals were sacrificed at day 17. In a second series of experiments, 10mg or 100mg of low titer SPS IgG were administered in a similar protocol, and results were compared to high dose commercial IgG or no IgG. All rats treated with high titer SPS IgG-developed spasms in axial and hind limb muscles 15 to 30 minutes after injection. Spasms lasted up to 3 hours and were paralleled by bursts of electromyographic activity. These animals, as well as those receiving high doses of low titer SPS IgG, also demonstrated an abnormal dragging gait and increased lordosis. None of the controls had similar findings. Immunohistochemistry revealed perivascular staining in spinal cords for human IgG in rats that received high-titer antibodies, high doses of low titer antibodies, or high doses of control IgG.
Commentary
Stiff-person syndrome (SPS) is a rare disorder of the central nervous system, characterized by muscle rigidity with paroxysms of painful muscle spasms. Circumstantial evidence supports an immune-mediated mechanism affecting GABA-ergic neurotransmission in the spinal cord, and it is highly associated with auto-antibodies to glutamic acid decarboxylase 65kD isoform (GAD65). In a minority, SPS presents as a paraneoplastic syndrome associated with anti-amphiphysin antibodies. Whether these autoantibodies are instrumental in SPS pathophysiology or are merely an epiphenomenon, has been the subject of intense debate. A particular sticking point is that these epitopes are intracellular; amphiphysin, for example, is a cytosolic protein involved in synaptic vesicle endocytosis. This elegant study now provides evidence that, at least in this one patient, the neurological disorder is indeed immune-mediated. Many questions remain, however. We do not know whether anti-amphiphysin antibodies are responsible for the syndrome; although the causative agent was within a purified IgG fraction, there remains the possibility of co-existing, unidentified, antibodies. How extensively these findings generalize to other cases remains to be seen, and the patient reported here had a highly atypical array of symptoms. Furthermore, not all patients with SPS (or other paraneoplastic syndromes) improve with plasmapheresis or intravenous immunoglobulin infusions, despite the presence of autoantibodies. Despite gaps in our understanding, this article strongly supports attempts to treat such disorders by manipulating the immune system to remove autoantibodies. — Claire Henchcliffe
References
1. Wessig C, et al. Neuropathology and Binding Studies in Anti-Amphiphysin-Associated Stiff-Person Syndrome. Neurology. 2003;61:195-198.
Immunohistochemistry revealed perivascular staining in spinal cords for human IgG in rats that received high-titer antibodies, high doses of low-titer antibodies or high doses of control IgG.
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