Lambert Eaton Myasthenic Syndrome Clinical features

Lambert-Eaton myasthenic syndrome (LEMS) is a presynaptic disorder of neuromuscular transmission which is caused by the production of antibodies to voltage-gated Ca2+ channels at the motor nerve terminals. This results in a marked reduction in acetylcholine release, the failure of neuromuscular transmission and muscle weakness. Muscle weakness is most common in the limbs, so that patients complain that their legs feel stiff or weak and they find difficulty in walking: indeed, in some individuals the symptoms of the disease may be sufficiently severe to render them bedbound. Tendon reflexes are also weak or absent. Unlike myasthenia gravis, in LEMS muscle weakness does not increase with exercise; in fact, muscle strength and tendon reflexes are briefly enhanced during the first few seconds of maximal effort. LEMS is also associated with symptoms indicative of disturbance of the autonomic nervous system, including decreased salivation and sweating, constipation and impotence. In most, but not all, patients the onset of the disease is gradual.

In around 60% of patients, LEMS is associated with small cell carcinoma of the lung. It is believed that voltage-gated Ca2+ channels present in the tumour trigger the production of autoantibodies that cross-react with Ca2+ channels at the nerve terminal. Consistent with this idea, LEMS antibodies downregulate Ca2+ channels in cells isolated from small cell carcinomas (Johnston et al., 1994). In addition, removal of the carcinoma, or radiotherapy, leads to neurological recovery, as is expected if the tumour is driving autoantibody production. LEMS often presents before radiological evidence of small cell carcinoma, and provides a useful indicator of the underlying tumour, which enables its earlier treatment. It is therefore important to investigate all patients presenting with LEMS for small cell carcinoma of the lung.

In many LEMS patients, 4-aminopyridine therapy may be beneficial. This drug blocks K+ channels at the presynaptic terminal. It therefore lengthens the action potential duration, prolonging Ca2+ entry and thus augmenting transmitter release. The effects of 4-aminopyridine can be quite spectacu-lar—a patient unable to stand initially may be able to walk nearly normally within an hour of treatment with the drug (Murray and Newsom-Davis, 1981).

Autoantibodies

Evidence for the autoimmune nature of LEMS was first provided by studies showing that injection of mice with IgG derived from LEMS patients reproduced many of the features of the disease (Lang et al, 1983). In vitro studies of neuromuscular transmission in these mice showed that at low stimulation rates the amplitude of the epp was much lower than that of control animals because of a reduction in acetylcholine release (Fig. 21.6A). At high frequencies of nerve stimulation, there was some facilitation of the epps in LEMS animals, indicating that the final stimulus in a train caused more transmitter release than the first (Fig. 21.6B). This facilitation is probably the explanation for the short-term increase in strength observed in LEMS patients after vigorous muscle activation. It results from the fact that the reduced density of Ca2+ channels at LEMS nerve terminals means that at low stimulation rates Ca2+ entry is insufficient to stimulate the normal level of transmitter release, whereas at higher stimulation rates release is facilitated by the accumulation of intracellular Ca2+.

At the neuromuscular junction, transmitter release occurs at discrete sites called active zones. In freeze-fracture electron micrographs, the active zones are characterized by intramembranous particles, which are organised into linear arrays resembling tramlines (Fig. 21.7A). These particles are thought to constitute voltage-gated Ca2+ channels. LEMS antibodies disrupt the regular tramlines of active zone particles and reduce their number, both in patients and in mice injected with LEMS immunoglobulin (Fukunaga et al, 1982, 1983) (Fig. 21.7B). These morphological changes correlate with a reduction in the amplitude of the endplate potential, as is expected if LEMS antibodies cause the internalization and downregulation of Ca2+ channels at the motor nerve terminals (Engel, 1991). There is evidence that the antibodies crosslink adjacent Ca2+ channels, thus producing an aggregation of membrane

FIGURE 21.6 LEMS ANTIBODIES AFFECT NEUROMUSCULAR TRANSMISSION

Trains of endplate potentials recorded in response to nerve stimulation from the muscle of a mouse pretreated with IgG isolated from LEMS patients (A) or pretreated with control IgG (B). From Lang et al. (1983).

FIGURE 21.6 LEMS ANTIBODIES AFFECT NEUROMUSCULAR TRANSMISSION

Trains of endplate potentials recorded in response to nerve stimulation from the muscle of a mouse pretreated with IgG isolated from LEMS patients (A) or pretreated with control IgG (B). From Lang et al. (1983).

Active Zone Freeze Fracture Endplate

FIGURE 21.7 LEMS ANTIBODIES DISRUPT PRESYNAPTIC Ca2+ CHANNEL ORGANIZATION

Freeze-fracture electron micrographs of the presynaptic membrane of mouse diaphragm muscle, viewed face on. Mice were pretreated with control IgG (A) or IgG isolated from LEMS patients (B). Numerous active zone particles arranged in tramlines (arrows) are present in (A), while in (B) active zone particles are disorganized and fewer in number. The active zone particles are believed to correspond to P/Q-type Ca2+ channels. Photograph supplied by Andrew Engel.

FIGURE 21.7 LEMS ANTIBODIES DISRUPT PRESYNAPTIC Ca2+ CHANNEL ORGANIZATION

Freeze-fracture electron micrographs of the presynaptic membrane of mouse diaphragm muscle, viewed face on. Mice were pretreated with control IgG (A) or IgG isolated from LEMS patients (B). Numerous active zone particles arranged in tramlines (arrows) are present in (A), while in (B) active zone particles are disorganized and fewer in number. The active zone particles are believed to correspond to P/Q-type Ca2+ channels. Photograph supplied by Andrew Engel.

particles and disrupting the linear arrays, and that this is followed by internalization and degradation of the antibody-channel complex (Peers et al., 1993).

A number of studies have addressed the question of which type of Ca2+ channel constitutes the primary target for LEMS antibodies. As explained in Chapter 9, there are several different types of voltage-gated Ca2+ channels. Of these, N-, L- and P/Q-type Ca2+ channels are present in presynaptic nerve terminals. The P/Q-type of Ca2+ channel appears to be the most important for acetylcholine release at the mammalian neuromuscular junction, since specific inhibitors of P/Q-type, but not N- and L-type, Ca2+ channels block neuromuscular transmission (Protti et al., 1996). Approximately 90% of patients with LEMS have antibodies to P/Q-type Ca2+ channels, as demonstrated by their ability to immunoprecipitate radiolabeled P/Q-type Ca2+ channels extracted from human cerebellum (Motomura et al., 1995). By contrast, only about 30% of patients have antibodies to N-type Ca2+ channels and even fewer have antibodies to L-type Ca2+ channels. Some studies have also shown a linear relationship between the titre of P/Q-type Ca2+ channels and disease severity in individual patients (Motomura et al., 1997). Furthermore, LEMS

antibodies block Ca2+ uptake into mammalian cells transfected with P/Q-type, but not with N-, L- or R-type Ca2+ channels (Lang et al., 1998). Thus, P/Q-type Ca2+ channels appear to be the primary target for LEMS antibodies. The ability of LEMS sera to immunoprecipitate N- and L-type, as well as P/Q-type, Ca2+ channels (Motomura et al., 1997) is now believed to reflect immunologic cross-reactivity (i.e., different types of voltage-gated Ca2+ channels have a similar epitope) or the possibility that in some patients the underlying small cell carcinoma may express multiple types of Ca2+ channel.

The P/Q-type Ca2+ channel is composed of a1A-, a2-, and S-subunits (see Chapter 9 for full details). The a1-subunit is functionally the most important as it acts as the channel pore, the voltage sensor and the receptor for many drugs. The other subunits have auxiliary roles. The ^-subunit is entirely cytosolic and is therefore unlikely to be a target for circulating autoantibodies, but theoretically the extracellular domains of a1A-, a2-, or S-subunits could serve as potential epitopes for LEMS antibodies. The a1A-subunit has four homologous repeats (I-IV), each of which consists of six putative transmembrane segments and a loop between segments 5 and 6 which dips back down into the membrane and lines the channel pore (see Chapter 9). In one study, antibodies to the S5-S6 linker in repeats II and IV were identified in 30% and 20% of LEMS patients respectively, suggesting that these regions of the protein may serve as targets for autoantibodies (Takamori et al., 1997). Other studies have suggested that some LEMS antibodies may interact with the subunit of voltage-gated Ca2+ channels (Rosenfeld et al., 1993), but these antibodies would not be pathogenic since the ^-subunit is cytosolic.

In addition to suppressing neuromuscular transmission, LEMS antibodies also interfere with transmitter release from parasympathetic and sympathetic neurones, by downregulation of voltage-gated Ca2+ channels (Waterman et al., 1997). This effect accounts for the autonomic dysfunction observed in LEMS patients. P/Q-type channels also are found at high density in the cerebellum. Fortunately, however, antibodies do not generally cross the blood-brain barrier and therefore cannot access neurones of the central nervous system. Consequently, the effect of LEMS antibodies is usually confined to Ca2+ channels of the peripheral nervous system. However, a small proportion of patients with paraneoplastic cerebellar ataxia have antibodies to voltage-gated Ca2+ channels (Mason et al., 1997).

In a small number of patients with LEMS, antibodies to N- or P/Q-type Ca2+ channels cannot be detected (Motomura et al., 1997). However, as their clinical symptoms respond to plasma exchange and immunosuppressive drugs, their disease is likely to be antibody-mediated. In these patients, however, the offending antibodies appear to be directed at other proteins of the neuromuscular junction.

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