Article, Neurology

Amantadine-induced serotonin syndrome in a patient with renal failure

Case Report

Amantadine-induced Serotonin syndrome in a patient with renal failureB

Abstract

Amantadine, an anti-influenza Agent, is commonly used in the treatment of parkinsonism. It also has serotonergic activity. Amantadine can induce toxicity in patient with renal dysfunction because it is excreted mainly in the urine. We report a rare case of amantadine-induced serotonin syndrome in a 78-year-old man with Parkinson’s disease and renal failure who developed confusion, halluci- nation, agitation, myoclonus, fever, diarrhea, and hyperten- sion after amantadine use.

Amantadine, an antiviral agent against influenza virus type A, also plays a role in antiparkinsonism by its dopaminergic effect [1]. Amantadine-induced toxicities were reported in patients with renal dysfunction because their elimination is mainly by kidney [2,3]. Amantadine is considered a serotonergic drug but had been only reported to induce serotonin syndrome (SS) with the combination of sertraline (a Selective serotonin reuptake inhibitor) [4]. We present a rare case of amantadine-induced SS in a patient with chronic renal failure.

A 78-year-old man with chronic renal failure on hemodialysis presented to our ED with generalized myoclonus jerk for 3 days on March 31, 2007. He was diagnosed to have Parkinson’s disease 8 years ago and had been taking carbidopa 100 mg/levodopa 400 mg, ropinirole

4 mg, and clonazepam 1 mg/d. His medication was changed to amantadine 100 mg and levodopa 600 mg/ benserazide 150 mg/d at another hospital on March 16. He developed weakness, confusion, and visual hallucination 2 days later, and his family discontinued his medication on March 24. He was administered with levodopa 300 mg/ benserazide 75 mg/d in our hospital on March 27. Delirium progressed, and severe, symmetrical, and multifocal myoclonus jerk was seen in all extremities, involving his eyelid and jaw on the next day. In addition, fever and diarrhea were also found.

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Upon ED arrival, he was disoriented with following vital signs: body temperature, 38.4?C; heart beat, 84 per minute; respiratory rate, 20 per minute; and blood pressure, 160/78 mm Hg. Physical examination showed spontaneous myoclonus over eyelid, jaw, and all extremities, especially over the hand and feet. Rigidity was mild but more predominantly in truncal muscles. Nevertheless, there was no mydriasis, hyperreflexia, sialorrhea, or diaphoresis.

Laboratory data revealed blood urea nitrogen of 31 mg/dL, serum creatinine of 7.8 mg/dL, sodium 148 of mEq/L, and potassium of 4.5 mEq/L. There was no leukocytosis but with mild elevation of Creatine phosphokinase level (452 U/L; normal range, 39-308 U/L). Head computed tomography scan and cerebrospinal fluid study result were normal.

He was admitted for intensive care. Carbidopa 100 mg/ levodopa 400 mg, ropinirole 2 mg, and clonazepam 1 mg/d were readministered. Electroencephalogram was obtained and showed intermittent generalized diffuse slow waves. His myoclonus and delirium disappeared after amantadine was discontinued over 12 days. Fever, hypertension, and diarrhea also subsided. Finally, whole cultures of blood, urine, and cerebrospinal fluid were negative and the patient was discharged on April 15 without any sequelae.

The SS is often described as a clinical triad of altered mental status, autonomic hyperactivity, and neuromuscular abnormalities [5]. However, SS is often confused with neu- roleptic malignant syndrome (NMS), because both present with similar features [6]. Serotonin syndrome is a toxic reaction owing to overstimulation of 5HT2a receptors in the CNS, whereas NMS is an idiosyncratic reaction to neuro- leptics. Serotonin syndrome presents with hyperkinesia, hyperreflexia, clonus, and pyramidal rigidity, whereas NMS presents with bradykinesia and extrapyramidal rigidity [7].

Matsunaga et al [2] reported that 2 patients with renal dysfunction developed progressively generalized myoclonus and altered mental status after amantadine treatment was ascribed to serotonergic mechanisms [1]. Amantadine can accumulate to toxic levels in patients with renal dysfunction because approximately 90% of amantadine is excreted in the urine and little is removed by hemodialysis [8].

Amantadine and levodopa were discontinued for 3 days in our patient; dopaminergic withdrawal-induced NMS was still unreasonable owing to the preceded symptoms. The amantadine dosage of 100 mg/d that had been

112.e6 Case Report

prescribed for 8 days to our patient exceeded the re- commended dosage of 200 mg/wk in patients with renal dysfunction. Overaccumulation of amantadine followed by the initial presentation of altered mental status and later presentation of myoclonus, pyramidal rigidity, fever, hypertension, and diarrhea not only clinically indicates SS [6], but also meets the Hunter serotonin toxicity criteria [9]. Eelectroencephalogram showing diffuse slowing was also reported in SS [4]. However, SS has a more rapid onset (hours) than NMS (days). Our explanation is that combinations of serotonergic drugs result in more severe toxicity and Rapid progression than overdose of single drug alone [2,4,9].

Serotonin syndrome may become life threatening so that emergency physicians must avoid overlooking the early signs of increased serotonergic activity. It is also important for emergency physicians to differentiate SS from NMS. Bromocriptine, a dopamine agonist, will improve NMS, but it will exacerbate the SS by its serotonergic effect [7]. On the whole, History taking and physical examination remain the most important clues for accurate diagnosis.

Po-Liang Cheng MD Shih-Wen Hung MD Li-Wei Lin MD Emergency Department

Shin-Kong Wu Ho-Su Memorial Hospital

Taipei 111, Taiwan, ROC E-mail address: [email protected]

Chee-Fah Chong MS, MD

Emergency Department Shin-Kong Wu Ho-Su Memorial Hospital

Taipei 111, Taiwan, ROC

School of Medicine Fu Jen Catholic University Taipei 242, Taiwan, ROC

Chi-Ieong Lau MD

Neurology Department Shin-Kong Wu Ho-Su Memorial Hospital

Taipei 111, Taiwan, ROC

doi:10.1016/j.ajem.2007.07.015

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myoclonus. Neurology 2001;56:279-80.

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