Prolonged and excessive phenytoin therapy leading to a severe and partially reversible polyneuropathy

Dear Editor, Phenytoin therapy and its ability to induce a mild or subclinical peripheral neuropathy has been previously studied (Mochizuki et al., 1981; Larsen and Larsen, 1989). We present the case of a female patient inexplicably treated with long-term and excessively dosed phenytoin for two decades leading to a severe sensorydominant painful polyneuropathy presenting with both limb and chest neuropathic pain. A 56-year-old female presented to our tertiary care neuromuscular clinic with complaints of paresthesias affecting her arms, legs, and sternal region. Twentythree years earlier, she experienced a single syncopal episode which was misdiagnosed as a seizure. She was started on phenytoin 300 mg daily, with the dose gradually increased until she was taking 800 mg/day, despite absence of any clinical episodes and without known cause for dose escalation. One year after starting phenytoin, she began to experience numbness and tingling, starting in her feet with progression up her legs. After several additional months, she noted similar symptoms in her fingers. She also developed a staggering gait, dyscoordination of limbs, and blurred and double vision and was chronically noted to be drowsy. These neurological symptoms persisted and progressed over 19 years, with numbness and tingling sensations extending to her mid-thigh and upper-mid arm regions, accompanied by burning sensations over her feet, legs, and arms and allodynia over her sternal region. A neurological assessment 19 years after phenytoin initiation led to the discontinuation of phenytoin, and 2 years later, she began to notice amelioration of her neurological symptoms. She had no history of other illnesses or medication use and medical history was otherwise unremarkable. Her general examination was unremarkable for normal cranial nerve assessment, strength testing, tone, muscle bulk, and coordination. Hyporeflexia was demonstrated at both patellar tendons, with areflexia at both Achilles tendons. Sensory examination revealed both diminished and hyperpathic sensation to pinprick sensation over both legs to the mid-thigh region bilaterally, both arms to the mid-forearm bilaterally, and over the mid-sternal region to approximately 8 cm lateral to the mid-position to both right and left parasternal regions. Light touch and temperature sensation was impaired to similar levels of the legs, arms, and mid-sternal region, with allodynia noted over the sternal region when light touch with a tissue paper was applied. Vibration sense was absent at the great toe bilaterally and demonstrated abnormal heightened threshold at the ankles bilaterally, while proprioception was mildly impaired at the great toe. Gait was somewhat cautious, and tandem gait was slightly impaired. Romberg sign was minimally positive, and no drift was noted. Palpation of the nerves did not reveal enlargement. Nerve-conduction studies in median, ulnar, radial, and sural nerves at the time of last assessment demonstrated improvement in both latencies and amplitude (sural amplitude not measured) relative to testing 4 years prior. No nerve biopsy was performed because of interval improvement. Findings in all other relevant investigations were normal. Phenytoin has been associated with a predominantly sensory peripheral polyneuropathy, particularly in patients receiving long-term phenytoin therapy. The most common symptoms of phenytoin-induced neuropathy are numbness, dysesthesias, paresthesias, and motor weakness in a stocking pattern affecting the legs (Larsen and Larsen, 1989). In most cases, ingestion of phenytoin for at least 1 week is required for development of neuropathic symptoms, but there has been one case report of neuropathy developing within hours after therapy commencement, with electrophysiological supporting data (Yoshikawa et al., 1999). Even in epileptic children on chronic phenytoin therapy without clinical features of peripheral neuropathy, Address correspondence to: Cory Toth, MD, FRCPC, Department of Neurological Sciences, Room 165, Heritage Medical Research Building, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. Tel: þ1-403-220-8831; Fax: þ1-306-2838731; E-mail: corytoth@shaw.ca Journal of the Peripheral Nervous System 9:198–199 (2004)