Psychosomatics 45:537-538, December 2004
© 2004 The Academy of Psychosomatic Medicine
Confusion Associated With Isoniazid-Induced Pyridoxine Deficiency
Roy R. Reeves, D.O., Ph.D., and
Vincent Liberto, M.D., Jackson, Miss.
Key Words: other somatic therapy • neurophysiology
TO THE EDITOR: As the incidence of tuberculosis rises, toxicity caused by isoniazid can be expected to increase in frequency. Manifestations of isoniazid toxicity include nausea, vomiting, ataxia, dizziness, stupor, metabolic acidosis, seizures, and coma.1,2 We describe a patient with isoniazid toxicity who had what initially appeared to be psychiatric symptoms.
Case Report
Mr. A, a 54-year-old Caucasian man employed as an office manager, was found to have a positive skin test for purified protein derivative of tuberculin and was given prophylactic isoniazid, 300 mg/day. A chest X-ray was normal. Mr. A was not given a prescription for pyridoxine. His medical history included hypertension, mild chronic obstructive pulmonary disease, prostatic hypertrophy, recurrent headache and back pain, and posttraumatic stress disorder. He reported no drug or alcohol abuse. He smoked a pack of cigarettes a day. His medications included 0.4 mg of tamulosin at bedtime, two puffs t.i.d. of an albuterol inhaler, 20 mg b.i.d. of isosorbide dinitrate, 40 mg/day of nadolol, 20 mg b.i.d. of paroxetine, 20 mg b.i.d. of rabeprazole, one tablet of propoxyphene every 6 hours as needed for pain, and 1 mg of clonazepam at bedtime.
Two weeks after beginning isoniazid treatment, Mr. A drove himself to a morning business appointment. There he appeared to have difficulty thinking and was thought to have a mental problem. He was taken to his psychiatrist and then to the emergency department. His wife later confirmed that his thinking was clear before he left home, although she had noticed episodes of slight confusion lasting a few minutes each the previous day.
A physical examination revealed no acute abnormalities. Deep tendon reflexes were brisk and slightly more on the right side. Mr. A moved his extremities symmetrically. His gait and coordination were normal except for a slight clumsiness. A chest X-ray, a CBC, a metabolic profile, a urinalysis, a drug screen, a computerized tomographic scan of his head, and measures of thyroid-stimulating hormone, rapid plasma reagent, and arterial blood gases were unremarkable.
Mr. A was oriented to person but not to place or date. He could follow only one-stage instructions and was unable to perform simple calculations. He could not spell words longer than three letters. He did not recognize a doctor he had known for years.
Mr. A was given pyridoxine, 100 mg intravenously. Within 20 minutes, he was fully oriented and able to perform cognitive tasks appropriately. He could remember leaving home and going to his meeting but had only nebulous recall of events after that. Subsequently, he has continued treatment with isoniazid supplemented with pyridoxine, 25 mg/day, and has had no further problems.
Discussion
The patient's onset of symptoms within 2 weeks of treatment with isoniazid and his rapid response to pyridoxine suggest that isoniazid-induced pyridoxine deficiency was the cause of his altered mental status. Isoniazid may induce a state of pyridoxine deficiency by combining with pyridoxine and generating inactive isoniazid-pyridoxal hydrozones, thus depleting the supply of pyridoxine.3,4 This pyridoxine deficiency in turn inhibits the enzymes that modulate brain  -aminobutyric acid (GABA) synthesis because both major enzymes in the GABA pathway (GABA transaminase and glutamic acid decarboxylase) require pyridoxal phosphate as a cofactor. The net effect is a decrease in the amount of GABA in the brain. Because GABA is an inhibitory neurotransmitter that functions to prevent seizures, convulsions may occur.3,5
It is not clear what isoniazid effects besides seizures may be related to pyridoxine deficiency.6 This case suggests that mental status alteration without other manifestations may occur secondary to decreases in pyridoxine. Besides its role in the synthesis of GABA, pyridoxine is also an essential cofactor in the metabolic pathways of other major neurotransmitters, dopamine, serotonin, and tryptamine.3–5 Thus, decreased pyridoxine could theoretically result in an alteration of mental status by a variety of mechanisms.
Why this patient was vulnerable to this complication is unclear. He may have been more susceptible to the effects of decreased pyridoxine because he had multiple medical problems and was taking multiple medications. Of interest, he responded dramatically to what could be considered a low dose of pyridoxine. In cases of isoniazid overdose, pyridoxine is administered in a dose equivalent to the suspected maximum amount of isoniazid ingested.1,4 One would think that our patient would have required at least 300 mg/day of pyridoxine because he was taking 300 mg/day of isoniazid. However, his symptoms were dramatically reversed with only 100 mg/day.
Rising use of isoniazid increases the likelihood of encountering patients with pyridoxine deficiency. Because the lack of pyridoxine may alter different neurotransmitters, pyridoxine deficiency may be an important consideration in patients with an altered mental status. Clinicians should be aware of this potential etiology of cerebral dysfunction because pyridoxine deficiency is easily treated when suspected; if unrecognized, serious consequences may result.
REFERENCES
- Romero JA, Kuczler FJ: Isoniazid overdose: recognition and management. Am Fam Physician 1998; 57:749–752[Medline]
- Wason S, Lacouture PG, Lovejoy FH: Single high-dose pyridoxine treatment for isoniazid overdose. JAMA 1981; 246:1102–1104[Abstract/Free Full Text]
- Orlowski JP, Paganini EP, Pippenger CE: Treatment of a potentially lethal dose isoniazid ingestion. Ann Emerg Med 1988; 17:73–76[CrossRef][Medline]
- Yarbrough BE, Wood JP: Isoniazid overdose treated with high dose pyridoxine. Ann Emerg Med 1983; 12:303–305[Medline]
- Boehnert MT, Lewande WJ, Gaudreault P, Lovejoy FH Jr: Advances in clinical toxicology. Pediatr Clin North Am 1985; 32:193–211[Medline]
- Brent J, Nyugen V, Kulig K, Rumack BH: Reversal of prolonged isoniazid-induced coma by isoniazid. Arch Intern Med 1990; 150:1751–1753[Abstract/Free Full Text]
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