Facts and fallacies on anti-GM1 antibodies: physiology of motor neuropathies.

Antibodies to ganglioside GM1 (anti-GM1 antibodies) have been implicated in the pathogenesis of Guillain–Barré syndrome (GBS), multifocal motor neuropathy (MMN) and motor neuron disease. Although the elevated titres of these antibodies have been amply documented in multifocal motor neuropathy and a motor axonal variant of GBS, or acute motor axonal neuropathy (AMAN), their exact role in the pathogenesis remains elusive. The GM1 epitope is present not only in motor neurons and their axons but also in the dorsal root ganglion cells and sensory axons. If anti-GM1 antibodies are pathogenic, what dictates the predilection for the motor system, and how do these antibodies affect the nervous system? In an in vitro study, Takigawa and colleagues (Takigawa et al., 1995) showed an acute increase in the potassium current and, in the presence of complement, irreversible loss of the sodium current after topical application of the antibody to a mixed nerve, providing a rationale for the hypothesis that anti-GM1 antibodies block sodium channels, causing conduction block (Waxman, 1995). This finding also led to the contention that sodium channels may play a role in the pathophysiology of motor neuron disease (Gutmann et al., 1996). In this issue of Brain, Paparounas and colleagues (Paparounas et al., 1999) report that anti-GM1 antibodies, bound to the nodes of Ranvier, activate the complement cascade without causing conduction block in vitro. This observation speaks against the role of anti-GM1 antibodies as a primary blocker of sodium channels. Using an in vivo model, we too failed to document sodium channel blocking even at rare sites of demyelinative conduction block (Hirota et al., 1997). Moreover, tetrodotoxin, a known sodium channel blocker, causes abnormalities quite unlike the findings seen in AMAN or MMN, namely marked slowing of conduction velocities and definite sensory involvement, as reported in a case of puffer fish poisoning (Oda et al., 1989). A recent study showed that sodium channels have no epitopes shared by GM1 (Sheikh et al., 1999). Activation of the complement cascade as shown by Paparounas and colleagues (Paparounas et al., 1999) probably leads to axonal damage in vivo. If so, the irreversible drop of sodium current (Takigawa et al., 1995) may represent non-specific leakage as a result of axonal membrane disruption. This would explain the close association between the antibody and GBS with predominant axonal involvement or AMAN.