Neurotoxicity Related to the Use of Topical Tretinoin (Retin-A)

Case Report

A 39-year-old woman was healthy except for mild, untreated depression and chronic hepatitis C. She had used topical tretinoin (Retin-A cream, 0.025% tretinoin) for treatment of acne 6 to 8 weeks before visiting the neurology department. The medication was not prescribed by a physician but rather was “borrowed” from a friend. Although the medication caused itching, she continued using it, often excoriating her skin by scratching. The patient reported headache, memory loss, and unsteadiness that interfered with walking, driving, and working. Medical evaluation 4 weeks after she began using topical tretinoin showed truncal ataxia and dysarthria. The only medication she admitted using was cyclobenzaprine hydrochloride (10 mg, 1 tablet 2 to 4 times weekly), which she stated she took only occasionally. Symptoms increased during the next 2 weeks. Neurologic examination showed mild dysarthria, finger-to-nose ataxia, truncal ataxia requiring the use of a walker, normal deep-tendon reflexes, and normal cranial nerves. Motor and sensory test results were normal. Mental status examination showed anxiety and depression that had worsened during the previous 6 weeks. Brain magnetic resonance imaging yielded normal results.

Alanine and aspartate aminotransferase levels were 25% to 30% above normal, consistent with hepatic disease, but had been at similar levels for the previous 5 years. Electroencephalographic results were normal.

The patient initially received doxepin hydrochloride, 30 mg daily for 2 weeks. Despite temporary improvement, symptoms recurred 6 weeks later, including worsening dysarthria. After toxic encephalopathy and depression were diagnosed at psychiatric evaluation, we attempted to identify any exposure to a potentially neurotoxic chemical.

The patient then mentioned that she had been using large amounts of topical tretinoin during the 6 to 8 weeks before her first visit to the neurology department. Topical tretinoin use was discontinued for 4 weeks but was restarted when acne worsened. The transient improvement in ataxia, dysarthria, and headache that occurred 2 weeks after the patient's first visit to the neurology department corresponded with discontinuation of this medication. However, resumed use of topical tretinoin was associated with a recurrence of the patient's symptoms.

Topical tretinoin use was again discontinued, and symptoms resolved within 4 weeks. After 8 months, symptoms had not recurred. Liver function test results have not changed.

Discussion

Topical tretinoin, or all-trans retinoic acid, is a synthetic retinoid that also occurs naturally and may be a normal metabolite of vitamin A. The degree of topical tretinoin absorption through intact skin is reported to be less than 5% [3]. Extensive clinical experience has not identified a specific neurologic toxicity resulting from the use of this form of retinoic acid. Neurotoxicity of vitamin A and synthetic retinoids resulting from use of oral forms of these medications has been described; symptoms include headache, pseudotumor cerebri, irritability, ataxia, fatigue, depression, and psychosis [5-9].

Vitamin A is readily available in Western diets. It is found as retinyl esters or provitamin A (carotenoids) [5]. The compounds pass through the lumen of the gut after being converted to retinol by pancreatic lipases and re-esterified in the mucosal cells and are transported by chylomicrons in the lymphatic system to the systemic circulation. The retinol is then taken up by the liver for storage and later release. Retinol is bound to retinol-binding protein for release in the circulation [10]. Preexisting liver injury may impair the ability of the liver to produce retinol-binding protein and may limit the effectiveness of transport mechanisms [11]. In addition, high concentrations of vitamin A may be toxic to the liver, eventually producing cirrhosis [12, 13]. Therefore, long-term exposure to high doses of vitamin A or preexisting injury to the liver or both may result in high concentrations of unbound retinol, which may be physiologically unavailable to vitamin A-dependent target tissues and which may also produce additional hepatotoxicity [14] as well as neurotoxicity [15].

Retinoic acid may produce the neurotoxic symptoms of hypervitaminosis A in patients with preexisting hepatic dysfunction [14]. Inability to conjugate retinoic acid to an excretable form or to produce retinol-binding proteins may contribute to toxicity [14]. Because our patient did not consider her topical medication to be a drug and because it was supplied by a friend, review of her medical records failed to identify topical tretinoin as a potential cause of her symptoms.

Physicians should use caution in prescribing topical retinoids for patients who have known or potential hepatic dysfunction.