Abnormal Movements with Donepezil in Alzheimer Disease

Donepezil’s adverse drug reactions (ADRs) are mainly related to its cholinomimetic action and most commonly include 2,3: nausea (11%), diarrhea (10%), insomnia (9%), vomiting (5%), and anorexia (4%); neuromuscular effects (cramps, spasms) are also described. Adverse effects related to donepezil are typically dose related and are often mild, transient, and reversible despite continued donepezil treatment. We report the development of restless legs, mumbling, and stuttering in a patient receiving donepezil. Case Report. A 72-year-old white man had been treated with donepezil 5 mg/d since April 1998 for Alzheimer disease diagnosed in January 1998. At this time, the patient was not receiving any other medications and did not have any other concurrent medical conditions. The Mini-Mental State score was 24. His medical history was significant for prostatic surgery, arteritis, and an iodine allergy. In July 1998, his Mini-Mental State score improvement led to an increase in donepezil dosage to 10 mg/d. Five days after the increase, the patient presented with abnormal movements of the lower limbs consistent with restless leg syndrome (RLS). These movements appeared several times a day for a few minutes and then resolved spontaneously each time. Four months later (November 1998), the patient exhibited mumbling and stuttering several times a day in addition to RLS. In December 1998, tiapride 500 mg/d, a sedative neuroleptic, and zopiclone 10 mg/d, a nonbenzodiazepine-type hypnotic, were added for three weeks because of delirium. RLS, mumbling, and stuttering continued until the next hospitalization in May 1999. Donepezil was discontinued and risperidone 0.5 mg twice a day introduced for mumbling. One month later, in June 1999, all ADRs disappeared. Because of his Alzheimer disease, donepezil was reintroduced four weeks later at a dosage of 5 mg during the first 15 days and then 10 mg/d thereafter. The rechallenge was positive, and the same abnormal movements (abnormal leg movements, mumbling, stuttering) reappeared. Donepezil was immediately discontinued, which again led to the resolution of the ADRs. Discussion. According to the Naranjo probability scale, 4 the causality was evaluated as probable, since a positive rechallenge occurred. Various neuromuscular ADRs have been reported with donepezil: muscle cramps occur with an incidence of 5%; muscle fasciculations or spasms, or dysarthria 2 occur less frequently. To our knowledge, no case of mumbling or stuttering has been reported with donepezil or other cholinomimetics. Our patient’s ADRs could be secondary to spasm of facial, neck, or phonation muscles. However, the pathophysiologic mechanism of stuttering is distinct from dysarthria. In a review of the literature of drug-induced stuttering, Brady 5 suggests the involvement of different neurotransmitter systems such as the cholinergic, dopaminergic, noradrenergic, and serotoninergic pathways. The occurrence of stuttering with neuroleptics or imipraminic drugs may explain the involvement of dopaminergic or cholinergic mechanisms, respectively. In conclusion, the ADRs occurring in our patient persisted for 10 months during donepezil treatment and resolved after discontinuation. They were clearly dose related, and there was a positive rechallenge.