Axonal excitability in disorders of the peripheral and central nervous system

Peripheral axonal excitability techniques have given pathophysiological insights into many peripheral nerve disorders, with clinical application still in its infancy. Small excitability changes are usually seen compared to controls, raising questions of sensitivity. The remote effects of central lesions on peripheral excitability are not well defined. The purpose of this thesis was to correlate the changes of excitability in peripheral neuropathic disorders with their clinical signs and nerve conduction findings, and to examine for changes in peripheral nerves in a predominantly central nervous disease model. Three peripheral disorders were studied in this way for the first time. To look for a central effect on peripheral nerves, multiple sclerosis (MS) was studied, and compared with other lesional central nervous disorders. Ischaemic depolarisation was suggested in end-stage liver disease and this was not reversible one year after liver transplantation. Similar findings were noted in HIV-positive subjects but only in nucleoside drug-related neuropathy, distinguishing it from distal sensory polyneuropathy. In mitochondrial disease, motor studies showed no changes at rest or with experimental ischaemia. Sensitivity and subset comparisons indicate that in liver disease, some excitability changes correlated with peripheral clinical signs but not standard nerve conduction abnormalities. The reverse was true in mitochondrial disease. Roughly 20-25% of patients with end-stage liver neuropathy and nucleoside neuropathy were identified to fall outside control 95% confidence interval limits. Upregulated slow K+ channels seen in peripheral motor axons of MS are possibly a response to enhanced persistent inward currents (PICs) at the motoneuron following suprasegmental input interruption. In contrast, peripheral sensory studies show increased fast K+ conductance through altered gating kinetics, possibly because of humoral factors acting locally to loosen the paranodal seal