Correspondence

Nitric Oxide–Induced Motor Neuron Disease in a Patient with Alcoholism

N Engl J Med 1995; 332:1036April 13, 1995

Article

To the Editor:

Nitric oxide is a gas neurotransmitter involved in multiple physiologic and pathologic processes.1 We report a case in which the use of nitric oxide for the treatment of pulmonary hypertension after lung transplantation may have caused extensive lower motor neuron disorder.

Nitric oxide activates guanylate cyclase, which is a transduction mechanism for the glutamatergic N-methyl-d-aspartate (NMDA) receptor. Glutamate and other excitatory amino acids can damage neurons if they persistently or excessively stimulate their receptors. They have been implicated in degenerative motor neuron diseases such as amyotrophic lateral sclerosis and Guam motor neuron disease.2 In ethanol dependence and withdrawal, glutamatergic transmission is up-regulated as a result of the increased density of NMDA receptors.3 This up-regulation may render motor neurons more susceptible to “excitotoxic” insults such as anoxia, trauma, exposure to environmental excitotoxins, or — in the case of our patient — overexposure to nitric oxide.

A 58-year-old woman who drank alcohol daily for two decades met the criteria for alcohol dependence listed in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders 4 and was taking oxazepam (Serax) at a daily dose of 20 to 30 mg for anxiety. Her blood alcohol level was 0.42 percent on admission. No evidence of alcoholic myopathy or polyneuropathy was found. The patient's primary pulmonary hypertension required bilateral sequential lung transplantation. After receiving nitric oxide as a pulmonary dilator5 post-operatively for 15 days, she was found to be paralyzed and areflexic in all four extremities. Cranial-nerve motor function was normal. Electromyography revealed extensive denervation. Metabolic, endocrinologic, toxic, and infectious causes were ruled out. The patient's creatine kinase concentration was normal, and she did not have myoglobulinemia. The neurologic consultant diagnosed a neuropathy of indeterminate cause. The patient required tracheostomy and mechanical ventilation. Her muscle power improved gradually over a period of three months.

We hypothesize that long-term up-regulation of NMDA receptors by ethanol3 renders the central nervous system susceptible to neurotoxic insult during untreated alcohol withdrawal. Nitric oxide is known to induce glutamate-receptor–mediated neurotoxicity. Although conventional wisdom holds that nitric oxide is quickly scavenged by hemoglobin, there is evidence that it can be stored and become functionally active away from the site of production.6 Thus, the introduction of nitric oxide in the context of ethanol-mediated up-regulation of NMDA receptors may have damaged the lower motor neurons. This hypothesized mechanism warrants further investigation and cautious use of nitric oxide in patients with enhanced glutamatergic transmission states, such as ischemia, stroke, epilepsy, or, as in this case, chronic alcohol consumption.

Guochuan E. Tsai, M.D., Ph.D.
David R. Gastfriend, M.D.
Massachusetts General Hospital, Boston, MA 02114

6 References

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   Mulsch A, Mordvintcev P, Vanin AF, Busse R. The potent vasodilating and guanylyl cyclase activating dinitrosyl-iron(II) complex is stored in a protein-bound form in vascular tissue and is released by thiols. FEBS Lett 1991;294:252-256
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Citing Articles (6)

Citing Articles

1. 1

   W Kuebler. (2003) Inhaled nitric oxide induces cerebrovascular effects in anesthetized pigs. Neuroscience Letters 348:2, 85-88
   CrossRef

2. 2

   Patrick M. Kochanek, Shekhar Venkataraman, Michael J. Whalen, Heidi Dalton. (1998) Is the administration of inhaled nitric oxide (NO) associated with electroencephalogram abnormalities? There is NO harm in looking. Critical Care Medicine 26:11, 1788-1789
   CrossRef

3. 3

   Marion Moenkhoff, Bernhard Schmitt, Gabriele Wohlrab, Katharina Waldvogel, Sergio Fanconi, Oskar Baenziger. (1998) Electroencephalogram changes during inhalation with nitric oxide in the pediatric intensive care patient-A preliminary report. Critical Care Medicine 26:11, 1887-1892
   CrossRef

4. 4

   Jean-Charles Preiser, Daniel De Backer, Frédéric Debelle, Bernard Vray, Jean-Louis Vincent. (1998) The metabolic fate of long-term inhaled nitric oxide. Journal of Critical Care 13:3, 97-103
   CrossRef

5. 5

   Greenfield, L. John Jr., Albers, James W., . (1995) Nitric Oxide and Motor Neuron Disease. New England Journal of Medicine 333:8, 522-523
   Full Text

6. 6

   &NA;. (1995) Nitric oxide. Reactions Weekly &NA;:547, 8
   CrossRef

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