Lambert—Eaton myasthenic syndrome and cerebellar ataxia: is Response to immunotherapy a clue to pathogenesis?

For some time, it has been recognized that the association between small-cell lung cancer (SCLC) and the presence of P/Q-type voltage-gated calcium channel (VGCC) antibodies may result in not only Lambert–Eaton myasthenic syndrome (LEMS), but also cerebellar ataxia. Over 40 years ago, Satoyoshi and colleagues described a patient with LEMS and SCLC with pathological evidence of paraneoplastic cerebellar degeneration (PCD), characterized by near-complete loss of the Purkinje cell layers and degeneration of subcortical areas. However, although the pathogenic effects of P/Qtype VGCCs resulting in disruption of neuromuscuIar transmission (and thus muscle weakness) and autonomic dysfunction are well established as cardinal features of LEMS, the processes by which these paraneoplastic antibodies cause cerebellar ataxia are less well understood. Cultured SCLC lines are known to express a wide range of neuronal antigens, including functional P/Q-type VGCCs on the cell surface, and it is thought that anti-tumor immunity results in the production of specific paraneoplastic antibodies. Antibodies specific to P/Q-type VGCCs are found in over 90% of patients with paraneoplastic LEMS and SCLC, regardless of whether there is coexistent cerebellar ataxia, but at lower frequencies (12%–54%) when the cerebellar ataxia and SCLC are not associated with LEMS. B€ urk and colleagues found raised P/Q-type VGCC antibodies in 8 of 67 (12%) patients with sporadic cerebellar degeneration without evidence of LEMS or associated cancer, although some antibody-positive patients did fulfill published criteria for other cerebellar ataxias, such as multiple system atrophy of the cerebellar type. In another large cohort, Graus and colleagues described the findings in 39 patients with PCD. A significant number of them (16 of 39, 41%) had P/Q-type VGCC antibodies, of whom 7 also had clinical evidence of LEMS. Of the 16 who were VGCC antibody positive, these antibodies were found in the cerebrospinal fluid (CSF) of 7, of whom 4 showed evidence of intrathecal synthesis of VGCC antibodies. One year later, in a postmortem study of 3 patients with PCD, SCLC, and LEMS, using specific binding of I-x-conotoxin MVIIC, the quantity of P/Q-type VGCCs was found to be reduced in cerebellar tissues (by up to 80%), particularly in the molecular layer, compared with control tissue, including from 1 patient with LEMS without PCD. Autologous immunoglobulin G (IgG) was bound to many of the remaining cerebellar P/Q-type VGCCs, almost exclusively in the 3 PCD LEMS patients, yet none of these patients had detectable P/Q-type VGCC antibodies in the CSF. More recently, McKasson et al. used a direct approach, demonstrating binding of VGCC antibodies to rat cerebellar tissue cultures, where the human VGCC antibodies were obtained from a patient with LEMS and autoimmune nonparaneoplastic cerebellar ataxia. Within 72 hours, Purkinje cells exhibited surface binding of specific VGCC antibody and, after 144 hours of exposure, there was evidence of Purkinje cell death, suggesting a rapid, deleterious effect of VGCC antibodies on cerebellar tissue. Antibodies to VGCCs have also been found to have a functional effect on cerebellar tissue. Pinto and colleagues demonstrated reduction in calcium currents in Purkinje cells from cultured rat cerebellar neurones when incubated with purified IgG from a patient with LEMS. In-vivo studies by Mart ın-Garc ıa et al. showed that mice injected intrathecally with purified IgG from a patient with both LEMS and PCD displayed significant reversible ataxia without neuromuscular weakness. Interestingly, when mice were injected with IgG from a patient with pure LEMS without ataxia there was no induced ataxia, nor weakness, in the animals. These findings have been interpreted as See editorial on pages 29–35, this issue.