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Case Report: Visual Toxicity in Acute Isoniazid Overdose
Paul R Lockman RN, CSPI [1,2]; Shu Shum, MD ; David D. Allen, R.Ph, Ph.D. 
 Texas Panhandle Poison Center, Northwest Texas Healthcare System, Amarillo, Texas;
 Texas Tech University Health Sciences Center School of Pharm
Int J Med Toxicol 2001; 4(3): 21
This case report is supported by an unrestricted educational grant from
Orphan Medical, Inc. For more information, please call 1-888-8ORPHAN.
Address for Correspondence
Address for Correspondence
Paul Lockman RN, CSPI
1501 South Coulter, Amarillo Texas 79106
Case Report: Isoniazid neurotoxicity has been well studied. Acute and chronic effects have been characterized with isoniazid use. The classic clinical triad of acute isoniazid neurotoxicity includes seizures, metabolic acidosis and coma is well recognized. However, more subtle signs of this neurotoxicity do exist. We report a case of attempted suicide by acute isoniazid ingestion that resulted in visual toxicity lasting 20 hours. The neuritis resolved after pyridoxine administration. Clinicians should be aware that acute isoniazid neurotoxicity may potentially present with less classical neurological signs and symptoms. In addition, certain symptoms, such as visual toxicity, may respond to pyridoxine administration.
Since its introduction in 1952, isoniazid has been the cornerstone treatment for active tuberculosis and prophylactic treatment of a positive tuberculin skin test (1). In the last decade, isoniazid use has dramatically increased due to an increased incidence of tuberculosis. A significantly increased incidence of tuberculosis has been reported in minorities, young adults, children and the acquired immunodeficiency syndrome patients(2). A corresponding increase in isoniazid-induced neurotoxicity has been reported(3).
Symptoms of isoniazid neurotoxicity may present as acute or chronic toxicity. Acute overdoses of isoniazid have been identified with a classical triad of symptoms including seizures refractory to standard anticonvulsants, metabolic acidosis and coma. Chronic therapy leads to peripheral neuropathies, toxic encephalopathy, ataxia, stupor, memory impairment, toxic psychosis, optic neuritis and optic atrophy (4). However, case reports of ocular neurotoxicity secondary to acute isoniazid therapy or overdose have not appeared recently in the literature. The following report documents a patient developing visual toxicity secondary to acute isoniazid poisoning.
A 17 year old, Hispanic, 61.4 kg female ingested isoniazid in a suicide attempt with no previous exposure to isoniazid. Two hours after ingestion, she developed headache and decreased visual acuity. The patient induced vomiting twice, after which she drank milk. The headache remained and visual difficulty worsened.
On arrival at the hospital, three hours post-ingestion, she was alert and oriented to person, place and time, and admitted ingesting isoniazid, six grams. Activated charcoal/sorbitol, fifty grams and intravenous pyridoxine, three grams were administered. Vital signs were blood pressure-137/78 mmHg, temperature 97.5°F, heart rate 100/minute, and respiratory rate 22/min. No evidence of seizures or altered mental status was noted. Arterial blood gas results were pH 7.411, p02 71.2 mmHg, pC02 37.3 mmHg, and oxygen saturation 93.8% on room air. Urine immunoassay screening for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates and phencyclidine were negative. Further history indicated that she ingested approximately nine grams isoniazid (146mg/kg). Upon determination of this dose, two more grams of pyridoxine were administered.
Cranial nerve examination revealed I, III-XII to be intact and normal. Pupils were equally round and reactive to light and accommodation. Extraocular movements remained intact. Visual acuity exam revealed light perception visual acuity but difficulty identifying specific objects was noted. An ophthalmoscopic examination eight hours post ingestion revealed bilateral hyperemic fundi. No blurred disk margins were noted. The patient was then given an additional five grams of pyridoxine for a total dose of ten grams.
Visual acuity improved over the next few hours. An ophthalmoscopic exam at 12 hours post-ingestion revealed normal fundi bilaterally. The patient reported normal vision by 20 hours post-ingestion.
Isoniazid, the hydrazide of isonicotinic acid, is rapidly absorbed from the gastrointestinal tract with peak serum levels occurring within one to two hours. Its apparent volume of distribution is 0.6 L/kg with wide distribution throughout the body and protein binding is about 10 to 15%. Approximately 75-95% of the drug is metabolized and excreted in the urine within 24 hours (5).
The significant metabolic pathway of isoniazid, the acetylation reaction, is under genetic regulation. In individuals who are slow acetylators, standard therapy of isoniazid may lead to greater exposure to the hepatotoxic reactive intermediate acetylhydrazine (6). Approximately 50% of Caucasians and African Americans are fast acetylators, whereas 95% of Eskimos and 88% of Japanese are fast acetylators. In contrast, only 18% of Egyptians are fast acetylators (7).
A central portion of isoniazid toxicity revolves around its effect on pyridoxine metabolism. Isoniazid decreases pyridoxine activity and ultimately depletes systemic pyridoxine levels (8). Urinary excretion of pyridoxine doubles with therapeutic isoniazid dosing and can quadruple with doses of 20 mg/kg (9). Three mechanisms are responsible for interfering with the function and supply of pyridoxine (10,11).
1) Isoniazid binds directly with pyridoxine to form isonicotinylhydrazide, which is excreted in the urine.
2) Isoniazid is dehydrized to its hydrazones; and they block pyridoxine phosphokinase. Pyridoxine phosphokinase is required for the conversion of pyridoxine to its biologic active form, pyridoxal 5' phosphate.
3) Isoniazid hydrazides inactivate pyridoxal 5' phosphate, which is essential for the formation of gamma amino-butyric acid from glutamic acid.
Lack of GABA formation, the primary inhibitory neurotransmitter, and the accumulation of glutamic acid are the presumed etiology for CNS excitation and seizures, which are common neurotoxic symptoms in acute isoniazid overdoses.
The three mechanisms described above demonstrate how isoniazid can deplete the body of pyridoxine. Pyridoxine is considered an antidote for isoniazid toxicity. In acute toxicity, pyridoxine has been shown to halt seizures, correct metabolic acidosis and shorten coma duration (12). Pyridoxine should be administered to all symptomatic patients with the gram dose equaling the gram dose of ingested isoniazid. If the quantity of ingested isoniazid is unknown, a five gram dose of pyridoxine should be administered. Repeated doses may be given on the basis of resolution of the signs and symptoms.
While acute depletion of pyridoxine is the etiology of seizures, chronic depletion is thought to produce peripheral neuropathies through nerve demyelination and a softening of the grey matter in the spinal cord. This chronic nerve demyelination may also occur along the optic tracts resulting in optic neuritis, and ultimately optic atrophy, presenting mainly as a decrease in visual acuity (13).
While optic neuritis has been shown to be an untoward effect of chronic isoniazid therapy (14), documentation of recent such case reports are lacking. In 1957, Kass et al, reported two patients developing bilateral optic neuritis while on chronic isoniazid therapy; one of which responded to pyridoxine and isoniazid discontinuation (15). The other died from unrelated causes. In 1959, Money documented a patient who was on isoniazid therapy and developed acute retrobulbar neuropathy with visual blurring which responded to pyridoxine (16). Other cases of optic neuritis have been documented often in association with peripheral neuropathies (17). These case reports document optic neuritis development while the patient was on standard isoniazid therapy. Case reports of isolated visual findings in acute isoniazid poisoning were not found in a search of Medline and Pubmed.
While acute isoniazid neurotoxicity is usually associated with seizures, metabolic acidosis and coma, the patient described in this case report developed only blurred vision. The resolution of the visual toxicity coincided with the adequate administration of pyridoxine. There is no proposed toxicologic mechanism for acute isoniazid-induced visual toxicity. Therefore, we report such a case for the first time to our knowledge. Due to the nature of the patient’s prompt response to pyridoxine, the toxicologic pathophysiology may be mediated through pyridoxine depletion. With increasing tuberculosis incidence and, consequently, increased isoniazid use, there needs to be an increased awareness of isoniazid side effects, neurotoxicity and potential ocular toxicity. Isoniazid poisoning may occasionally present with isolated neurotoxic findings; the visual findings in our case being such an example.
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