Rivastigmine is a commonly used drug of carbamate type in dementia of Alzheimer's type with mild to moderate severity. It is also indicated in Parkinson's disease with dementia (PDD). The drug is available orally and as a transcutaneous patch; the latter form reduces the gastrointestinal side effects associated with oral formulation. The drug acts by inhibiting acetylcholinesterase and butyrylcholinesterase in the brain and other tissues and thus increases cholinergic activity as a result of inhibition of acetylcholine metabolism.
Common side effects of oral rivastigmine are gastrointestinal in nature and include anorexia, nausea, vomiting, diarrhea, and abdominal discomfort. Psychiatric side effects include hallucinations, agitation, and confusion. Cardiac side effects may include bradycardia and ventricular extrasystole. Rivastigmine patch can cause local cutaneous allergic reactions. Dyskinesia has very rarely been associated with drug.
Case study
A 75-year-old female, retired medical doctor by profession, not a known case of diabetes or hypertension, presented with complaints of gradual deterioration of recent memory for the last one year. There was no past significant medical or family history. General physical examination was unremarkable. Her weight was 60 kg and height was 5 feet 6 inches. She was oriented to time, place, and person. She had moderately severe impairment of recent and remote memory, scoring 15/30 on Mini-Mental Status Examination. She had no behavioral and psychological symptoms of dementia and was not taking any antidepressants or antipsychotics. Routine blood investigations were normal, including liver function tests. Magnetic Resonance Imaging of the brain showed diffuse cortical and moderate degree of hippocampal atrophy. She was diagnosed as a case of probable Alzheimer's disease. She was commenced on a patch of 5 mg/cm2 rivastigmine, which she tolerated well. One month later, dose of rivastigmine patch was increased to 10 mg/cm2. There was no treatment gap between two dosages. She had removed old patch before applying the new one and also changed the site of patch. Within three hours of patch application, she developed acute dystonic reaction with neck twisting, involuntary movements of both upper limbs, and extreme restlessness. She also had recurrent vomiting, diarrhea, and abdominal distension necessitating hospitalization. Her vitals were stable.
She was treated with intravenous fluid and oxygen inhalation. She did not receive metoclopramide or any other dopamine antagonists. The dystonic movements dramatically remitted with intravenous injection of diazepam (5 mg). Rivastigmine patch was discontinued for a week. On reapplication of 10 mg/cm2 patch she experienced similar reaction. The temporal relationship between drug dose escalation and occurrence of acute dystonic reaction established a diagnosis of adverse drug reaction (ADR) resulting from rivastigmine patch. Naranjo's algorithm (Naranjo et al., Reference Naranjo, Busto, Sellers, Sandor, Ruiz, Roberts, Janecek, Domecq and Greenblatt1981) was applied to reaction and ADR was found to be probable.
Discussion
Dystonic reactions are adverse extrapyramidal side effects and can occur immediately after drug administration. Dystonic reactions (e.g., dyskinesias) are characterized by intermittent spasmodic or sustained voluntary muscle contractions in the region of face, trunk, extremities, pelvis, etc. Dystonic reactions are rarely life-threatening, yet often produce significant anxiety or discomfort (Pope et al., Reference Pope, Adams, Paton, Weaver and Barnes2010). Drug-induced dystonias are reported frequently with antipsychotics, antiemetics, methyldopa, fluoxetine, lithium, etc. (Suzuki et al., Reference Suzuki, Koizumi, Moroji, Sakuma, Hori and Hori1990). Treatment is very effective and symptomatic relief is there within minutes.
In rare case reports of anticholinesterases, e.g., galantamine- (Cossu et al., Reference Cossu, Melis, Melis, Maccioni, Putzu, Catte and Putzu2004) and donepezil-induced (Panagiotis et al., Reference Panagiotis, Pantelis, George and Dimitris2012) extrapyramidal side effects have been described. In case of galantamine-induced extrapyramidal symptoms, there was no previous exposure to antipsychotics and patient recovered several weeks of botulinum toxin injections. Likewise, such symptoms occurred in case of donepezil after administration of single dose. In the published literature, there is only one case report of rivastigmine-induced dystonia in a 61-year-old woman with Alzheimer's disease (Pavlis et al., Reference Pavlis, Kutscher, Carnahan, Kennedy, Gerpen and Schlenker2007). She was taking a number of concurrent medications. Authors of this report concluded that the concurrent drugs might have reduced the threshold for development of dyskinetic reactions in their case.
In our case, rivastigmine patch-induced dystonia occurred on two separate occasions and the patient was not on any other medication. Rivastigmine follows a nonlinear pharmacokinetics and inhibits both acetylcholinesterase and butyrylcholinesterase, thus can potentially increase muscle tone, leading to dystonic reactions. The possible mechanism of occurrence of dystonia with rivastigmine in the present case could be excessive increase in cholinergic activity due to anticholinesterase action of rivastigmine in the brain. This can disrupt usual balance between dopaminergic and cholinergic receptors in the basal ganglia (Panagiotis et al., Reference Panagiotis, Pantelis, George and Dimitris2012).
