Donepezil-Induced Cervical Dystonia in Alzheimer's Disease: a Case

□ CASE REPORT □

Donepezil-induced Cervical Dystonia in Alzheimer’s Disease: A Case Report and Literature Review of Dystonia due to Cholinesterase Inhibitors

Ken Ikeda, Masaru Yanagihashi, Masahiro Sawada, Sayori Hanashiro, Kiyokazu Kawabe and Yasuo Iwasaki

Abstract

We herein report an 81-year-old woman with Alzheimer’s disease (AD) in who donepezil, a cholinesterase inhibitor (ChEI), caused cervical dystonia. The patient had a two-year history of progressive memory distur- bance fulfilling the NINCDS-ADRDA criteria for probable AD. Mini-Mental State Examination score was 19/30. The remaining examination was normal. After a single administration of donepezil (5 mg/day) for 10 months, she complained of dropped head. Neurological examination and electrophysiological studies supported a diagnosis of cervical dystonia. Antecollis disappeared completely at 6 weeks after cessation of donepezil. Dystonic posture can occur at various timings of ChEI use. Physicians should pay more attention to rapidly progressive cervical dystonia in ChEI-treated AD patients.

Key words: Alzheimer’s disease, cholinesterase inhibitor, donepezil, cervical dystonia, dropped head, Pisa syndrome

(Intern Med 53: 1007-1010, 2014) (DOI: 10.2169/internalmedicine.53.1857)

Introduction Case Report

Tardive dystonia syndrome is known as the complication An 81-year-old woman developed a progressive global in- of prolonged treatment with antipsychotic medications, par- tellectual deterioration for two years and visited our depart- ticularly classic antipsychotics. Pisa syndrome or pleurotho- ment. The first score of Mini-Mental State Examination tonus is a distinct form of tardive dystonia characterized by (MMSE) was 19/30. The remaining neurological examina- abnormal, sustained posturing with flexion of the neck and tion was normal, showing no parkinsonism. The patient was head to one side (1). This syndrome has been described pri- diagnosed with probable AD according to the NINCDS- marily as an adverse effect of neuroleptic drugs (1-3). ADRDA criteria (8). There was no prior history of halluci- Cholinesterase inhibitors (ChEIs) are widely used in patients nation, depression, extrapyramidal disorders or medication with Alzheimer’s disease (AD). This medication rarely with neuroleptics, antiepilepics or antiemetics. Treatment causes Pisa syndrome in patients with dementia with Lewy with donepezil (5 mg daily) was started, and the dementia bodies (4), multiple system atrophy (5) and AD (6, 7). We remained stable for nine months. At that time, MMSE score herein report a patient with AD who developed cervical was 18. Ten months after donepezil administration, the pa- dystonia after a single administration of donepezil and re- tient suddenly noticed dropped head. Antecollis worsened view the literature regarding ChEI-associated dystonia in AD for two weeks. Neurological examination revealed a severe patients. degree of anterior flexion and dystonic spasm in the neck (Fig. 1A). Other cranial nerves were normal. A slight degree of anterior flexion of the upper trunk was present at walk-

Department of Neurology, Toho University Omori Medical Center, Japan Received for publication October 4, 2013; Accepted for publication November 12, 2013 Correspondence to Dr. Ken Ikeda, [email protected]

1007 Intern Med 53: 1007-1010, 2014 DOI: 10.2169/internalmedicine.53.1857

dementia. Treatment with memantine hydrochloride (5 mg/ day) was initiated, and the dose was gradually increased to 20 mg/day without adverse effects. The patient has been fol- lowed carefully at our outpatient department.

Discussion

We herein reported the case of an AD patient who developed cervical dystonia during a single administration of donepezil (5 mg/day) for 10 months. Dystonia was im- proved at 6 weeks after donepezil discontinuation. Pisa syndrome (pleurothotonus) is an acquired, persistent truncal dystonia from the cervical to lumbar musculature that appears to be reversible. The distinct posture is characterized by an involuntary side flexion on either side of the body and head with a backward axial rotation. The patient looks like the leaning tower of Pisa. Ekbom et al. (1) first Figure 1. Photograph of cervical dystonia in the present pa- described this syndrome as a rare adverse effect of long- tient. A) Marked anterior flexion of the neck during donepezil term classic neuroleptic medication. Pisa syndrome can be treatment. B) Normal neck position at 6 weeks after donepezil triggered by other medications, including antiemetics, val- withdrawal. proic acid, lithium and atypical antipsychotics (9-11). The single or additional administration of ChEIs also causes this ing. The patient’s muscle strength and muscle stretch re- syndrome (6, 7, 12-22). Previous cases of ChEI-induced flexes were normal. Plantar responses were flexor. There dystonia who had no other central nervous system (CNS)- were no extrapyramidal signs in the trunk and the four ex- acting medications are summarized in Table. Truncal dysto- tremities. The sensory, cerebellar and autonomic systems nia, so-called Pisa syndrome, was present in 11 of 13 pa- were normal. Routine laboratory studies were unremarkable tients (6, 7, 13, 15-17, 20). Two patients developed cervical and serum levels of creatine kinase were within the normal dystonia, resulting in antecollis (19) or torticollis (22). The range. Chest X-ray, electrocardiography and carotid ultra- underlying pathophysiology of drug-induced dystonia is sonography were normal. Brain magnetic resonance imaging complex. The functional imbalance between the dopaminer- (MRI) disclosed a mild to moderate degree of cortical atro- gic and the cholinergic system could play a major role in phy predominantly in the temporal lobe. Electroencephalo- the pathogenesis of Pisa syndrome. Acetylcholine and gram and cervical cord MRI were unremarkable. MRI dopamine might contribute to axial muscle tone. Decreased showed no signal changes in the extensor and the flexor dopaminergic neurotransmission and/or excessive cholinergic muscles of the neck. Gallium scintigraphy of whole body neurotransmission whave been speculated to be present in revealed no abnormal accumulation. 123 I- ( 3 meta ) - patients with Pisa syndrome. Serotonergic or noradrenergic iodobenzylguanidine myocardial scintigraphy showed an dysfunction has also been implicated in the dystonic mecha- early and delayed heart/mediastinum ratio of 1.89 and 1.96, nism. The frequency of ChEI-induced Pisa syndrome re- respectively. Motor and sensory nerve conduction studies mains unclear because randomized clinical trials have not were within the normal ranges. F-wave was elicited well in investigated the long-term adverse reactions of ChEIs. the median, the ulnar and the tibial nerve. Needle electro- Highly selected patients who had younger age, better cogni- myography (EMG) was normal in the neck extensor, the tive status and no other CNS-acting drugs are typically in- sternocleidomastoid, the anterior scalenus and the trapezius cluded in randomized trials of ChEIs. In general, the risk muscle. Surface EMG revealed persistent muscle contraction factors for developing Pisa syndrome include a female gen- discharges in the right and the left sternocleidomastoid, an- der, old age, organic brain disease, combined pharmacologic terior scalenus and trapezius muscles at rest (Fig. 2A). treatment and previous treatment with classic neurolep- These electrophysiological findings supported the diagnosis tics (9, 23, 24). These clinical features are also comparable of cervical dystonia. Donepezil-triggered cervical dystonia in patients with ChEI-associated dystonia (6, 7, 12-22). In was suspected, and this medication was discontinued. At 2 contrast, the patient backgrounds in randomized ChEI trials weeks after cessation of donepezil, antecollis was attenuated. seem to differ from the predisposing factors of Pisa syn- Dystonia recovered completely at 6 weeks after the with- drome. Only a few previous studies estimated the incidence drawal of donepezil (Fig. 1B). Surface EMG revealed no or the prevalence of Pisa syndrome (16, 23, 24). A Canadian persistent muscle contraction discharges in the sternocleido- study surveyed all newly admitted psychogeriatric patients mastoid, the anterior scalenus and the trapezius muscle over a 5-year period and reported a prevalence of 8.3%, (Fig. 2B). The patient’s family strongly requested a substi- 6.4% in men and 9.3% in women (23). A German tute medication for ChEI in order to slow the progression of study (22) showed 17 patients among a population of

1008 Intern Med 53: 1007-1010, 2014 DOI: 10.2169/internalmedicine.53.1857

Figure 2. Surface EMG of the neck muscles. A) Persistent muscle contraction discharges were ob- served on both sides of the sternocleidomastoid, anterior scalenus and trapezius muscles at rest. B) The persistent muscle contraction discharges disappeared following the recovery from antecollis.

Table. Clinical Features of ChEI-associated Dystonia in AD Patients Treated without Other CNS-acting Drugs

Age/gender Country ChEI Duration of ChEI Prognosis of dystonia after ChEI withdrawal Recurrence of dystonia after Reference treatment ChEI re-administration 57 years/male Japan Donepezil 1 month Improvement at 1 week Donepezil 13 72 years/female Spain Donepezil 2 months Improvement at 16 days 72 years/female Sardinia Galantamine 1 month Improvement after injections of botulinum toxin 15 83 years/female Italy Rivastigmine 5 months Improvement at 16 days Donepezil 16 84 years/female Italy Donepezil 4 months Improvement at 1 week Rivastigmine 75 years/female Italy Donepezil 2.5 years Improvement 79 years/male France Rivastigmine 2 years ChEI was continued and death 6 82 years/male Brazil Donepezil 3 years Not described 17 98 years/male France Donepezil 3 months Improvement 7 80 years/male France Donepezil 18 months Improvement 79 years/female† Japan Donepezil A few weeks Improvement at 2 weeks 19 74 years/female Greece Donepezil A few hours Improvement at 8 days 20 70s late/female† Japan Donepezil < 1 month Improvement at several weeks 22 81 years/female† Japan Donepezil 10 months Improvement at 6 weeks Present case AD: Alzheimer’s disease, ChEI: cholinesterase inhibitor, CNS: central nervous system *Reference number † Cervical dystonia

45,000 psychiatric patients and the prevalence was 0.037%. electrophysiological and MRI findings did not suggest in- With respect to the incidence of ChEI-induced Pisa syn- flammatory and myopathic changes in the cervical muscula- drome, three patients developed this syndrome in an Italian tures. Together with the recovery from antecollis, the persis- cohort study of 7,395 ChEI-treated patients with mild to tent muscle contraction discharges vanished in the ster- moderate AD. The incidence was estimated to be two per nocleidomastoid, anterior scalenus and trapezius muscle. The 10,000 patients per year (16). Otherwise, the frequency of clinicoradiological and electrophysiological course supported cervical dystonia has not been studied in ChEI-treated AD the diagnosis of cervical dystonia in the present patient. patients. Only two Japanese patients were reported to de- Drug-induced Pisa syndrome is classified into acute and velop cervical dystonia after a single administration of done- tardive dystonia according to the onset and prognosis. The pezil (19, 22). The present patient exhibited antecollis at 10 duration of ChEI use is very variable from one day to 4 months after donepezil administration without other CNS- years (6, 7, 12-22). In the earliest onset of Pisa syndrome, acting drugs. The distinct head falling appearance required dystonia was present at a few hours after the administration differentiation from dropped head syndrome (DHS). DHS is of donepezil (20). In most patients, ChEI-associated dysto- characterized by severe neck extensor muscle weakness, re- nia occurred within six months after ChEI administration (6, sulting in a chin-on-chest deformity in the standing or sit- 7, 12-16, 18-20, 22). Four patients developed dystonia more ting position. Dropped head is correctable with passive neck than 1.5 years after ChEI treatment. Interestingly, other extension. This syndrome is caused by various etiological CNS-acting drugs were not administered in these pa- diseases, including motor neuron disease, peripheral neuro- tients (6, 7, 16, 17). The present patient developed cervical pathy, myasthenia gravis, polymyositis, muscular dystrophy, dystonia at 10 months after a single administration of done- neck extensor myopathy and Parkinson’s disease (25). Focal pezil. Therefore, slowly progressive cholinergic overfunction myositis in the neck was the most important differential di- could results in the delayed onset of dystonia when patients agnosis in the present patient. Gallium scintigraphy, the received single treatment with ChEI.

1009 Intern Med 53: 1007-1010, 2014 DOI: 10.2169/internalmedicine.53.1857

As a therapeutic strategy for drug-induced Pisa syndrome, Relation between cholinesterase inhibitors and Pisa syndrome in a withdrawing or reducing the dose of the causative drug is cohort of five French patients with Alzheimer’s disease. J Am Geriatr Soc 55: 1472-1487, 2007. recommended. Anticholinergic drugs are effective in some 7. Huvent-Grelle D, Roche J, Gaxatte C, Puisieux F. Relation be- patients treated with neuroleptics (9). However, anticholiner- tween Pisa syndrome and cholineesterase inhibitors in a cohort of gic medication is unfavorable in AD patients. A previous Alzheimer’s disease patients. Presse Med 38: 150-153, 2009. study mentioned that amantadine, a dopamine agonist, im- 8. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of proved Pisa syndrome slightly in AD patients (26) whereas Alzheimer’s disease: report of the NINCDS-ADRDA Work Group. other studies reported no benefits of this drug (27). ChEI Neurology 34: 939-944, 1984. 9. Suzuki T, Matsuzaka H. Drug-induced Pisa syndrome (pleurotho- withdrawal markedly ameliorated dystonia in most patients tonus): epidemiology and management. CNS Drugs 16: 165-174, (6, 7, 12-16, 18-22). One patient died to continue admini- 2002. stration of rivastigmine (6). Compared to the first episode, 10. Yohanan M, Aulakh JS, Weith J, Hawkins JW. Pisa syndrome in a dystonia reappeared at shorter periods after the same or a patient in a wheelchair taking valproic acid. Am J Psychiatry 163: different ChEI was administered again (12, 13, 16, 21). In- 325-326, 2006. 11. Duggal HS, Sivamony S, Umapathy C. Pisa syndrome and atypi- stead of ChEIs, memantine hydrochloride, a N-methyl-D- cal antipsychotics. Am J Psychiatry 161: 373-374, 2004. aspartate receptor antagonist, was administered in two pa- 12. Kwak YT, Han IW, Baik J, Koo MS. Relation between tients with AD. One patient exhibited galantamine-induced cholinesterase inhibitor and Pisa syndrome. 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