Neuropathy and myopathy can cause weakness during critical illness. To determine whether reduced excitability of peripheral nerves, rather than degeneration, is the mechanism underlying acute neuropathy in critically ill patients, we prospectively followed patients during the acute phase of critical illness and early recovery and assessed nerve conduction. During the period of early recovery from critical illness, patients recovered from neuropathy within days. This rapidly reversible neuropathy has not to our knowledge been previously described in critically ill patients and may be a novel type of neuropathy. In vivo intracellular recordings from dorsal root axons in septic rats revealed reduced action potential amplitude, demonstrating that reduced excitability of nerve was the mechanism underlying neuropathy. When action potentials were triggered by hyperpolarizing pulses, their amplitudes largely recovered, indicating that inactivation of sodium channels was an important contributor to reduced excitability. There was no depolarization of axon resting potential in septic rats, which ruled out a contribution of resting potential to the increased inactivation of sodium channels. Our data suggest that a hyperpolarized shift in the voltage dependence of sodium channel inactivation causes increased sodium inactivation and reduced excitability. Acquired sodium channelopathy may be the mechanism underlying acute neuropathy in critically ill patients.
Kevin R. Novak, Paul Nardelli, Tim C. Cope, Gregory Filatov, Jonathan D. Glass, Jaffar Khan, Mark M. Rich
Submitter: Nicola Latronico | latronic@med.unibs.it
University of Brescia, Italy
Published April 27, 2009
Pluralitas non est ponenda sine necessitate. William of Occam, 14th century.
I read with interest the study by Novak et al. on inactivation of sodium channels as the cause of reversible neuropathy in critical illness(1), The authors found that patients recovered from electrophysiologic-proven neuropathy within days. In a septic model of cecal ligation and puncture in rats, they were able to demonstrate that a hyperpolarized shift in the voltage dependence of sodium channel inactivation caused increased sodium inactivation and reduced axonal excitability.
These results fit well with our demonstration that electrophysiological tests demonstrating axonal neuropathy may diverge from neuropathologic studies demonstrating normal nerves in the early stage of human sepsis(2). In a recent study in 92 critically ill adult patients(3), we found that the amplitude of the nerve action potential amplitude decreased abruptly within 24 hours in 18 patients (64.3%), and in 10 patients (35.7%) the amplitude dropped progressively over a median of 3.0 days (IQR 2 to 5 days). During the follow-up, the electrophysiological alterations resolved in 10 of 28 patients but persisted in 18. The 15 survivors – 6 with myopathy; 4 with neuropathy, 3 with combined myopathy an neuropathy, and 2 with undetermined diagnosis- all had severe muscle weakness and paralysis, which persisted in 4 patients with neuropathy until the end of the 1-year observation period(4).
These results are in accordance with the hypothesis that axonal degeneration may not be the only cause of muscle weakness and paralysis; instead, a nerve or muscle-nerve dysfunction may me the initial pathophysiological mechanism. The term “acute reversible paralysis” well emphasizes the two most relevant aspects of the syndrome: the sudden onset and potential reversibility(5). However, the hypothesis made by Novak that there are two different axonal neuropathies –one due to axonal degeneration and one due axonal inexcitability- is highly implausible. Instead, the rule of diagnostic parsimony, the so called Occam’ razor, is well applied here. As the authors acknowledge, the severity of the inflammatory process, both in terms of intensity and duration, is the likely explanation: in the sepsis-related low-energy state, the nerves try to maintain their structure and thus to survive by reducing or abolishing the function, a phenomenon easily documented by electrophysiological testing. With persisting sepsis, the energy supply and/or use is not restored and histologic alterations ensue (3, 6).
Future studies should try to identify the pathway(s) leading to sodium channel inactivation in states of energy failure such as sepsis and multiple organ failure in critically ill patients.