Neuroleptic Malignant Syndrome Due to Donepezil

Manuel Monti^1*, Francesco Paciullo¹, Paolo Diego L’Angiocola², Silvia Cenciarelli³ and David Giannadrea^3
*Correspondence: Manuel Monti, Department of Emergency, Assisi Hospital, USL Umbria 1, Italy, Email:

Keywords

Neuroleptic malignant syndrome • Donepezil • Fever of unknown origin

Introduction

Neuroleptic Malignant Syndrome (NMS) is a rare and potentially fatal syndrome of hyperthermia, stiffness, autonomic instability and altered mental status. Although early symptoms of NMS may involve changes in mental state, the syndrome can progress gradually and culminate in fever and elevated CPK [1]. Although antipsychotics, such as chlorpromazine and haloperidol, are the main drugs responsible, there are other drugs that can be considered to be the cause of NMS [2].

Case Report

A 80-year-old man with a past medical history of Addison disease, arterial hypertension and mild cognitive impairment, initially presented intermittent fever with onset from three days. His medications included amlodipine, oral steroid, and donepezil, which was administered at the dose of 10 mg/ day, started 15 days ago. All medications were autonomously administered. No other symptoms were reported and empiric therapy with piperacillin/ tazobactam was started. The patient was sent to the Emergency Department (ED) for further evaluation. At the time of admission the patient showed stupor (Glasgow coma scale-GCS-14; Eye 3, verbal 5, motor 6), without other relevant signs at the neurological, thoracic, cardiac and abdominal physical exam. He had tachycardia, 130 beat per minute, with a rhythmic pulse. His temperature was 38°, while other vital signs were normal. Electrocardiogram and chest radiography were normal. A trans-thoracic echocardiography only revealed hypertensive cardiopathy. Also a brain CT scan was performed without significant findings. Blood, urine, and sputum cultures were sent and then levofloxacin and parenteral fluids were started. Steroid daily dose was increased to avoid acute Addison disease decompensation. No particular data emerged from the hemato biochemical and cultural examinations; in particular, the blood count, with formula, the C-reactive protein, renal and hepatic function, thyroid function, and the electrolytes were normal. Adreno Cortico- Tropic Hormone (ACTH) and cortisol levels were not reduced. Culture tests from blood and urine were negative. Patient experienced during the following ten hours after the admission a further worsening of the fever to a stable level of 42°. At the neurological exam appeared diffuse severe muscular stiffness and bilateral fixed miose. Paracetamol, high dose aspirin, hydrocortisone, benzodiazepines, dantrolene and cold fluids were administered without benefits. A comprehensive blood panel was repeated without sensitive changes, the Creatinphosphokinase (CPK) was that was moderately increased (422 U/L-normal value 0-190 U/L). A total body CT scan was performed excluded infective localizations. The patient was then transferred to the Infectious Disease ward where a lumbar puncture was performed, which was negative. He died few hours later. An autopsy was performed but it did not show significant findings.

Discussion

We report the case of an immune compromised patient with resistant fever. Fever is a common cause of hospitalization in elderly. The prompt recognition of its causes is mandatory, especially if chronic immune depression concurs, to start an immediate antimicrobical therapy and prevent sepsis. Consequently, a complete imaging and microbiological panel of exams has to be started. In this case no diagnostic evidence of infections or other possible organic causes of fever was found. Also temperature was not modified by antipyretic therapy. They were therefore excluded other possible diagnoses that could explain the symptoms of our patient (Table 1). A donepezil induced acute neurological syndrome was hypothesized. The association of hyperthermia, muscle stiffness, autonomic instability, alteration of consciousness and high levels of CPK (albeit mild) allowed a diagnosis of malignant-like neuroleptic syndrome, despite the patient did not take antipsychotic treatment [2] Donepezil is useful for the treatment of dementia disorders, but the drug can cause an imbalance between the dopaminergic and cholinergic systems and these alterations may result in a dysregulation of dopaminergic, causing the onset of NMS [3]. The first and only case of NMS in donepezil mono therapy was described in 2003 [3-5].

Conclusion

Donepezil should be considered as possible cause of not responding fever in absence of other apparent conditions especially if cholinergic symptoms concur. The NMS is considered a very rare condition in patients taking donezepil, observed only in post-marketing experience. To our knowledge our case represents the second described in literature. Although the NMS is a very rare condition, but potentially serious, it would be advisable to discontinue donepezil therapy for every patient who is admitted for fever of unknown origin.

Learning Points

• Neuroleptic Malignant Syndrome (NMS) is an uncommon and potentially fatal complication of neuroleptic treatment.

• Donepezil may cause an imbalance between the dopaminergic and cholinergic systems resulting in adverse neurological reactions because of its pharmacological properties.

• Donepezil should be considered as possible cause of NMS.

References

1. Dominic J. Pileggi and Aaron M. Cook. “Neuroleptic Malignant Syndrome: Focus on Treatment and Re-challenge.” Ann Pharmacother 50 (2016): 973-981.
2. Ohkoshi, Nishi. “Neuroleptic Malignant-like Syndrome due to Donepezil and Maprotiline.” Neurol 60 (2003): 10501051.
3. Matsumoto, Kawanishi. “Neuroleptic Malignant Syndrome Induced by Donepezil.” Int J Neuropsychopharmacol 7 (2004): 101-103.
4. Ueki, Aako. “Malignant Syndrome Caused by a Combination of Bromperidol and Donepezil Hydrochloride in a Patient with Probable Dementia with Lewy Bodies.” Nihon Ronen Igakkai Zasshi 38 (2001): 822-824.
5. Tanya C Warwick, Venkata Moningi, Prasuna Jami and Kristy Lucas, et al. “Neuroleptic Malignant Syndrome Variant in a Patient Receiving Donepezil and Olanzapine.” Nat Clin Pract Neurol 4 (2008): 170-174.