fasciculations - Axonal ionic pathophysiology in human peripheral neuropathy

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Curr Neurovasc Res. 2004 Oct;1(4):373-9.

Axonal ionic pathophysiology in human peripheral neuropathy and motor

neuron disease.

Kuwabara S, Misawa S.

Department of Neurology, Graduate School of Medicine, Chiba

University, Chiba, Japan. kuwabara-s@...

Testing the excitability of axons can provide insights into the ionic

mechanisms underlying the pathophysiology of axonal dysfunction in

human neuropathies and motor neuron diseases. Threshold tracking,

which was developed in the 1990's, non-invasively measures a number

of axonal excitability indices, which depend on membrane potential

and on the Na+ and K+ conductances. This paper reviews recent

advances in ionic-pathophysiological studies in human subjects in

vivo. Membrane potential of human axons can be estimated, because

most of the ion channels expressed on the axolemma are voltage-

dependent, and patterns of changes in multiple excitability indices

can suggest whether axons are depolarized or hyperpolarized. This has

been clearly demonstrated in a single patient with acute hypokalemia

(hyperpolarization) and patients with chronic renal failure

(depolarization due to hyperkalemia). Muscle cramps/fasciculations

arise from hyperexcitability of the motor axons. The enhanced

excitability can result from altered ion channel function; an

increase in persistent Na+ conductance, a decrease in accommodative

K+ conductance, and focal membrane depolarization, all of which

increase excitability, have been demonstrated in amyotrophic lateral

sclerosis or other disorders affecting lower motor neurons. Patients

with demyelinating neuropathy often complain of muscle fatigue.

During voluntary contraction, the activation of the electrogenic Na+-

K+ pump and resulting membrane hyperpolarization can cause activity-

dependent conduction block when the safety factor for impulse

transmission is critically reduced. Studies of ion-channel

pathophysiology in human subjects have recently begun. Investigating

ionic mechanisms is of clinical relevance, because once a specific

ionic conductance is identified, blocking or activating it may

provide a new therapeutic option for a variety of neuromuscular

diseases.