Long Lag Between Drug‐induced Parkinsonism and Idiopathic Parkinson's Disease in Idiopathic REM Sleep Behavior Disorder

Atypical antipsychotics often cause parkinsonian symptoms. In some cases,1 the drug-induced parkinsonism (DIP) may resolve, only to have Parkinson's disease (PD) develop some time later, suggesting that the medication unmasked compensated subclinical dysfunction.2 This is consistent with dopaminergic neuroimaging studies in early PD, that suggest the existence of compensatory mechanisms for subtle substantia nigra denervation; however, the duration of the prodromal compensatory period is unclear. We identified an individual with defined prodromal PD, who developed transient DIP on atypical antipsychotics, finally developing idiopathic Parkinson's disease (iPD) after a 12-year lag. A 61-year-old man presented with dream-enacting behaviors for 11 years. Polysomnography diagnosed REM sleep behavior disorder (RBD). At baseline visit, he also had orthostatic hypotension (40 mm Hg drop), depressed mood, and hyposmia; however, motor testing was normal (Unified Parkinson Disease Rating Scale Part III = 2). At baseline, he met MDS criteria for prodromal PD, with total LR = 1146, and probability = 93.6%.3 Of note, the MDS prodromal research criteria has been developed recently in 2015 and was retrospectively applied on his baseline clinical data. After baseline visit, an outside physician prescribed him olanzapine 5 mg at bedtime for his depressive symptoms. The following year, we observed clear DIP with a total UPDRS-III of 20, sufficient to meet MDS parkinsonism criteria. Parkinsonism was clearly symmetric, both on UPDRS and quantitative motor testing, with no rest tremor. We suggested stopping olanzapine immediately; however, it was only reduced to 2.5 mg. The following year, UPDRS-III was 11, and we again suggested stopping olanzapine completely. After drug discontinuation, DIP completely resolved, and UPDRS-III score ranged from 1 to 6 in each yearly follow-up, for 10 years (Fig. 1). Over the following 10 years, additional erectile dysfunction, constipation, and urinary dysfunction developed and olfaction and orthostatic hypotension worsened. On the 13th annual follow-up examination, his motor state deteriorated with a UPDRS-III score of 18 (Fig. 1). This time, his motor symptoms were asymmetrical (asymmetry index = 0.58 > 0.3)4 with right-side dominance. This case is noteworthy as most published estimates of the time interval between DIP and iPD average 2 to 3 years,5 however, we found a lag time of 12 years, even with a relatively low dose of a low-potency dopamine-blocker. Although it is possible that this could have been a coincidental association of unrelated events, we feel it unlikely. First, despite normal motor state he already met criteria for prodromal PD, because of documented RBD, hyposmia, and orthostatic hypotension (a diagnosis proved correct by his eventual conversion). Second, he was relatively young at the time of prescription (i.e., 62 years) and had persistent parkinsonism even on the lowest available dose (2.5 mg per day) of a relatively atypical neuroleptic. Even in a patient for whom there was no prior documentation of idiopathic RBD, it can be argued that development of parkinsonism on such a low-dose atypical neuroleptic deserves evaluation for potential prodromal PD. This case suggests that the prodromal motor state in some cases of PD can be very long and progression very slow. To our knowledge, there is only one previously-published case of a similarly long prodromal motor interval, based upon video analysis of English soccer player Ray Kennedy, which found a 10 to 14 year interval.6 Early subtle motor disturbances, autonomic dysfunction that presented as excessive perspiration and accompanying feelings of heat, and fatigue were the prodromal features found that case.6 Therefore, it appears that the motor prodromal interval of PD can be longer than average estimates from previous work.7 We acknowledge the limitation of having no access to DaT-scan at the time when DIP was developed in our patient, as DaT-scan can differentiate DIP from iPD. In patients with suspicious DIP, an abnormal DaT-scan may reflect prodromal PD unmasked by the anti-dopaminergic drugs rather than true DIP.8 In patients with prodromal disease and early asymptomatic dopaminergic loss, even low-dose antipsychotics can impair compensatory mechanisms and allow sufficient denervation for motor signs to appear.9 Dopamine antagonists should be used with extreme caution in individuals with high likelihood of prodromal PD, such as patients with idiopathic RBD. 1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique. S.M.F: 1A, 1B, 1C, 3A, 3B B.K.D.: 1A, 1B, 1C, 3A, 3B A.P.: 1B, 1C, 3B J.Y.M.: 1B, 1C, 3B R.B.P.: 1A, 1B, 1C, 3A, 3B We would like to thank the patient and his family for their patience, cooperation, and permission. Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Furthermore, the case has provided a written informed consent. Funding Sources and Conflicts of Interest: The authors report no funding sources for this study and have no conflicts of interest. Financial disclosure for the previous 12 months: S.M. Fereshtehnejad reports the following disclosures: employment with McGill University (Montreal, QC, Canada); grants from Canada First Research Excellence Fund for the Healthy Brains for Healthy Lives (HBHL) Initiative postdoctoral fellowship, Richard and Edith Strauss postdoctoral fellowship (McGill University), Preston Robb fellowship (Montreal Neurological Institute). B.K. Dawson has no disclosures to report. A. Pelletier reports the following disclosures: employment with Research Institute of the McGill University Health Centre (Montreal, QC, Canada). J.Y. Montplaisir reports the following disclosures: employment with Centre for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal and Department of Psychiatry, Université de Montréal (Montreal, QC, Canada); grants from GSK, Merck; honoraria from Valeant, Otsuka Pharmaceutical; advisory board of Sanofi-Aventis, Servier, Merck, Jazz Pharmaceutical, Valeant Pharmaceutical, Impax Laboratory. R.B. Postuma reports the following disclosures: employment with Department of Neurology, Montreal General Hospital (Montreal, QC, Canada); grants from Fonds de la Recherche en Sante Quebec, the Canadian Institute of Health Research, the Parkinson Society of Canada, the Weston-Garfield Foundation, the Michael J. Fox Foundation, and the Webster Foundation; honoraria from Novartis Canada, Teva Neurosciences; and consultancies for Biotie, Roche.

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