Search

Voltage-gated [Ca.sup.2+] channels are categorized as either high-voltage activated (HVA) or low-voltage activated (LVA), and a subtype (or subtypes) of HVA [Ca.sup.2+] channels link the presynaptic depolarization to rapid neuro-transmitter release. Reductions in transmitter release are characteristic of the autoimmune disorder, Lambert-Eaton syndrome (LES). Because antibodies from LES patients reduce [Ca.sup.2+] influx in a variety of cell types and disrupt the intramembrane organization of active zones at neuromuscular synapses, specificity of LES antibodies for the [Ca.sup.2+] channels that control transmitter release has been suggested as the mechanism for disease. We tested sera from four patients with LES. Serum samples from three of the four patients reduced both the maximal LVA and HVA [Ca.sup.2+] conductances in murine dorsal root ganglion neurons. Thus, even though LES is expressed as a neuromuscular and autonomic disorder, our studies suggest that [Ca.sup.2+] channels may be broadly affected in LES patients. To account for the specificity of disease expression, we suggest that incapacitation of only a fraction of the [Ca.sup.2+] channels clustered at active zones would severely depress transmitter-release. In particular, if several [Ca.sup.2+] channels in a cluster are normally required to open simultaneously before transmitter release becomes likely, the loss of a few active zone [Ca.sup.2+] channels would exponentially reduce the probability of transmitter release. This model may explain why LES is expressed as a neuromuscular disorder and can account for a clinical hallmark of LES, facilitation of neuromuscular transmission produced by vigorous voluntary effort.

Many studies have been conducted to observe the sequence of events in recovery from nerve damage. The majority of such studies have been performed in laboratory rats, and only rarely are detailed observations made in human patients recovering from nerve damage. With only minor exceptions, a dead nerve cell cannot be replaced. However, it is possible for new sprouts to arise from neighboring nerve fibers and make new contact with muscle cells deprived of their original nervous input. The sequence of events has been well studied in animals; a computerized method of recording electrical activity in the muscle has now provided an opportunity to observe these events in a human patient undergoing complete recovery from nerve damage. The patient developed paralysis of a facial muscle following surgery on a blood vessel abnormality. No voluntary movement occurred in the muscle for 15 days following the injury. At that time, rapid contractions were detected in some muscle fibers. By 29 days these fibrillations became numerous. These observations indicate that the sprouting of nerve fibers had occurred, and these new fibers were beginning to make contact with the muscle fibers. Computerized calculations based on the electrical activity suggested that these nerve fibers were most dense 37 days after the injury; at this time the fibrillations had already decreased in number. The first indications that normal use of the muscle were returning appeared at this time. By 67 days, the normal function of the muscle was complete. Nevertheless, measurements revealed abnormalities for more than 34 months after the initial injury. This indicates that even after the muscle fibers have been re-innervated, slow processes of reorganization continue to occur in the relation between the muscle and the recovering nerve. (Consumer Summary produced by Reliance Medical Information, Inc.)