Case files of the Program in Medical Toxicology at Brown University: Amantadine withdrawal and the neuroleptic malignant syndrome

Abstract

A sixty-one-year old woman with a history of depression and idiopathic dystonia presented to the emergency department (ED) with fever, nausea, muscle rigidity, and redness in her extremities. The patient had seen various specialists for her dystonia during the preceding year and had tried multiple medication regimens, including benztropine and tizanidine. The patient described her home medications as tizanidine 2 mg three times daily, diazepam 2.5 mg daily, escitalopram 100 mg daily, rosuvastatin 10 mg daily and bupropion 300 mg nightly.At ED presentation her vital signs were: temperature 37.5°C (99.5F), blood pressure 157/76 mmHg, heart rate 105 beats per minute, respirations 24 per minute, and oxygen saturation of 100% on room air. Her physical examination was significant for diaphoresis, tachycardia, diffuse flushing, tremors in her upper and lower extremities, muscle rigidity, and hyperreflexia in the upper and lower extremities. The tremors were low amplitude and worse with intention, while the rigidity had cogwheeling features and was more notable in her lower extremities. Initial laboratory evaluation was significant for a creatine phosphokinase (CPK) of 1146 IU/L. Her electrocardiogram showed sinus tachycardia with normal QRS and QT intervals, and no evidence of acute ischemia.Two months earlier, the patient's neurologist had started her on amantadine 100 mg twice daily for dystonia. Three days prior to ED presentation, the patient abruptly stopped taking her amantadine on the advice of a pharmacist, secondary to bilateral lowerextremity edema. The following day, the patient presented to her primary care physician complaining of nausea, tremors, and diffuse flushing. The physician treated her for an allergic reaction with oral steroids and diphenhydramine. The patient's symptoms worsened over the next day with increasing tremors and rigidity, low-grade fever, nausea, and flushing, which prompted her presentation to the ED.

Dependence, withdrawal and rebound of CNS drugs: an update and regulatory considerations for new drugs development

“…This is an uncommon, but potentially fatal complication ( Sechi et al , 1984 ) which follows reduction or cessation of anti-parkinsonian medications, including levodopa, dopamine agonists, and even amantadine ( Friedman et al , 1985 ; Rosse and Ciolino, 1985 ; Rainer et al , 1991 ; Mizuno et al , 2003 ; Serrano-Duenas, 2003 ; Brantley et al , 2009 ; Newman et al , 2009 ) and labels e.g. Apokyn 2004, Parlodel 2012, Sinemet 2017, Requip 2017.…”

Neuroleptic Malignant Syndrome – A medical emergency in a psychiatric patient

“…Other suspected risk factors are dehydration, iron deficiency, hyperthyroidism, malnutrition, alcoholism, male gender, younger age, increased ambient temperature, previous episode of NMS, concomitant use of other psychoactive substances (especially lithium), and presence of structural or functional brain disorders such as encephalitis, tumor, delirium, or dementia [10][11][12][13] . Sudden withdrawal of dopaminergic drugs in a Parkinson disease patient may also provoke NMS 5,14 . In our patient, risperidone, a potent antipsychotic drug was started and the dose was also increased rapidly in a view to controlling her schizophrenic symptoms, all these seem to trigger her to develop NMS.…”

Neuroleptic Malignant Syndrome

“…2,9,19 Moreover, removal of dopamine agonists can induce NMS symptoms. 20,21 Genetic polymorphisms with the D 2 receptor may also factor into the risk for individual patients. For example, patients with a taqI A, A1 allele may be up to 10 times more likely to experience NMS than noncarriers.…”

“…Reports of discontinuation of medications for Parkinson's disease (PD) or inadequate dose resulting from malabsorption that have led to NMS have been published. 20,26,27 Similarly, sudden discontinuation of antipsychotics may produce a withdrawal NMS, attributed not to dopamine blockade but a general dysregulation of the central dopamine signal pathways. 28 Environmental risk factors that may predispose the patient to development of NMS include an elevated ambient room temperature or prolonged heat exposure, the use of patient restraints, and dehydration.…”

“…28 Its mechanism of action, though not clearly understood, is likely a result of both direct increase in dopamine release and reduction in reuptake. 20,42 It also has anticholinergic-like activity that could shift D 2 -receptors to high-affinity states; this would also explain its anticholinergic adverse effect profile (ie, dry mouth, urinary retention, and constipation). 20,43 It also functions as a weak NMDA (N-methyl-d-aspartic acid) receptor antagonist and has shown to improve dyskinesias associated with levodopa.…”