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Phenytoin toxicity masquerading as motor neurone disease

We report a case of phenytoin toxicity masquerading as motor neurone disease. A middle aged lady presented with progressive difficulty walking, weakness, dysarthria, dysphagia and weight loss. She had had a subarachanoid haemorrhage 23 years earlier, and aneurysm clipping. She developed tonic-clonic seizures treated with phenytoin 600 mg daily, sodium valproate 1 g daily and clonazepam 1 mg daily. Clinical examination identified bulbar weakness, diplopia, motor weakness greater on the right (Medical Research Council Grade 3 ⁄ 4), with hyperreflexia and fasciculations. The patient was admitted for further investigation. According to the revised el Escorial criteria [1] she fulfilled the criteria for clinically possible amyotrophic lateral sclerosis (lower motor neurone weakness in more than three regions, upper motor neurone weakness in only one region). Electromyography and nerve conduction studies showed chronic denervation with signs of re-innervation. Magnetic resonance imaging of the brain and spinal cord showed brain damage in the right parieto-occipital region (consistent with previous craniotomy) and minor degenerative changes at L5 ⁄ S1. A chest, abdomen and pelvis computed tomography scan was unremarkable. Further investigations, including cerebrospinal fluid microscopy and biochemistry, creatine kinase, tumour markers, antibodies, complement, vitamin D, vitamin B12, folate, treponema serology, Bence Jones protein and viral hepatitis screen were unremarkable. Liver function tests were mildly deranged and an abdominal ultrasound showed changes consistent with fatty liver. On admission the patient was hypoalbuminaemic, probably secondary to poor mobility and malnutrition. The working diagnosis was motor neurone disease. The patient developed increasing bulbar weakness, and chest sepsis, probably from aspiration. She received ventilatory and inotropic support on the Neurosciences Critical Care Unit. Corrected phenytoin levels were 237 lmol.l, so phenytoin was stopped. Serum albumin continued to fall and the serum phenytion level peaked to a corrected value of 270 lmol.l. After normalisation of the corrected phenytoin level, within 2 weeks, motor power, respiratory function and bulbar weakness improved. At discharge mobilisation, bulbar function and nerve conduction studies were normal. Two months after discharge the patient remains well and seizure-free. The mean plasma elimination half-life of phenytoin is slightly prolonged following chronic oral administration and its bioavailability varies between individuals [2]. A fixed percentage of the drug is metabolised per unit time, but at higher doses enzymes become saturated, causing a disproportionate change in plasma level [3]. Phenytoin is metabolised mainly in the liver by parahydroxylation with the cytochrome P450 system [2, 3]. This could lead to drug interactions. Coadministration of valproate probably increased phenytoin levels further [4]. Phenytoin toxicity causes nystagmus, diplopia, slurred speech and ataxia, followed by confusion, drowsiness, coma and seizures as levels increase. Life threatening arrhythmias, ECG changes and hypotension may occur. Hypoalbuminemia (common in the critically ill) decreases the level of phenytoin protein binding and increases its free fraction. Corrected phenytoin level can be obtained by the following formula in presence of hypoalbuminemia: Corrected phenytoin level = measured phenytoin ⁄ [(albumin · 0.2) + 0.1] [5]. We highlight the possibility of toxicity in patients on long term phenytoin with atypical symptoms, and recommend calculation of the corrected levels. In addition, when prescribing phenytoin, one should always consider the altered pharmacokinetics and dynamics that may occur in critical illness. If there is any suspicion of toxicity phenytoin levels should always be corrected for serum albumin.