Drug-Induced Parkinsonism as a Risk Factor for Parkinson's Disease: A Historical Cohort Study in Olmsted County, Minnesota

doi:10.4065/73.8.724

Mayo Clinic Proceedings

Volume 73, Issue 8, August 1998, Pages 724-727

https://doi.org/10.4065/73.8.724 Get rights and content

Objective

To investigate whether subjects who experienced a reversible episode of drug-induced parkinsonism have an increased risk of subsequent Parkinson's disease.

Design

We undertook a historical cohort study based on the medical records-linkage system of the Rochester Epidemiology Project in Olmsted County, Minnesota.

Material and Methods

All subjects in whom drug-induced parkinsonism developed between 1955 and 1990 and was indexed in the medical records-linkage system were identified. In the 24 eligible subjects, follow-up for the subsequent development of Parkinson's disease consisted of a total of 192.7 person-years. The observed number of cases of Parkinson's disease was compared with the expected number of cases in an age- and sex-matched cohort from the general population,

Results

In 2 of 24 subjects with drug-induced parkinsonism, Parkinson's disease later developed. A comparison with the expected number of cases in the general population (0.08) yielded a relative risk of 24.3 (95% confidence interval, 2.9 to 87.5; P= 0.006).

Conclusion

Our findings suggest that drug-induced parkinsonism is associated with an increased risk of Parkinson's disease. Clarification of the mechanisms of this association may have preventive implications.

Section snippets

Patients And Methods

Subjects affected by drug-induced parkinsonism were identified from two sources. The medical records-linkage system of the Rochester Epidemiology Project was used to identify patients with drug-induced parkinsonism who resided in Olmsted County, Minnesota, at the time of onset of the disorder.⁴ Using the computerized indexes of the system, we identified subjects who received a diagnosis of drug-induced parkinsonism between Jan. 1, 1970, and Dec. 31, 1990. Because drug-induced parkinsonism was

Results

Of the 120 potential cases of drug-induced parkinsonism initially identified through the medical records-linkage system, 70 cases (58%) were excluded (another cause of parkinsonism in 29, indeterminate temporal relationship between use of dopamine antagonist and onset of parkinsonism in 15, nonresident in 11, insufficient data to confirm the diagnosis of parkinsonism in 9, and more than one reason in 6).

Of the remaining 50 patients with drug-induced parkin sonism, use of dopamine antagonists

Discussion

Our findings suggest that subjects who experience an episode of drug-induced parkinsonism are at increased risk for the subsequent development of Parkinson's disease. These findings are consistent with the limited prior results of investigations in this area. The one previous study thai addressed the frequency of Parkinson's disease in patients with drug-induced parkinsonism was based on patients referred to a geriatrics unit. Stephen and Williamson⁶ prospectively identified 5 cases of

Conclusion

We suggest that drug-induced parkinsonism is associated with an increased risk of Parkinson's disease; however, the mechanism of this increased risk remains to be determined. Because of the relatively high frequency of drug-induced parkinsonism in the population,¹ this association deserves further investigation. Better understanding of the relationship between drug-induced parkinsonism and Parkinson's disease may have preventive implications.

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There are more references available in the full text version of this article.

Cited by (30)

Permanent non-progressive cinnarizine and flunarizine-induced parkinsonism: An under-recognized tardive syndrome in the elderly?
2023, Journal of the Neurological Sciences
Citation Excerpt :
In a case series of 74 patients with DIP induced by cinnarizine, a cumulative percentage of 15% evolved toward a progressive parkinsonism uncovered by the offending drug both after a complete or incomplete recovery from DIP [24]. A hypothesis for both clinical courses is that the occurrence of DIP may represent a risk factor for the subsequent development of PD [25,26] and the definition of “DIP antedating PD” has been employed to describe this clinical scenario [27]. Furthermore, it has been reported that a previous prolonged exposure to DA receptor antagonists, mainly benzamides and CNZ and FNZ, may increase the long-term risk of “incident parkinsonism and probable PD”, following their discontinuation, in absence of development of DIP in 70% of the patients during the exposure to these drugs [28].
Secondary parkinsonism induced by exposure to dopamine (DA) receptor antagonists as first and second generation antipsychotics, DA storage depleters, calcium channel blockers, benzamides substituted and other classes of drugs is traditionally believed to be completely reversible in most of patients following withdrawal of the offending drug even though after a variable time delay. The lack of recovery or initial full recovery with subsequent development of progressive parkinsonism has been regarded to result from an underlying subclinical degenerative process like PD unmasked by the inducing drug. These well-recognized clinical outcomes of drug-induced parkinsonism (DIP) have disregarded the existence of another outcome, characterized by permanent non-progressive parkinsonism. This syndrome may fullfil the criteria of tardive parkinsonism, a controversial entity currently referred to as a persistent condition without indication of its long-term course and clinical features. On reviewing the published literature on DIP, we have identified two prospective long-term follow-up of elderly patients in which parkinsonism induced by the calcium channel antagonists cinnarizine and flunarizine became permanent and non-progressive following drug discontinuation in a non-negligible proportion of patients, consistent with the clinical concept of a true tardive syndrome, according to currently accepted criteria.
The authors hypothesize that the development of tardive parkinsonism might be due to a neurotoxic effect of the pharmacodynamic proprieties of the calcium channel blockers and their metabolites, exerted on post-synaptic striatal neurons and/or a neurotoxic damage on presynaptic DA neurons in patients without an underlying subclinical degenerative parkinsonism, so accounting for the stable and non-progressive course over time.
Diabetes mellitus and drug-induced parkinsonism: A case-control study
2009, Journal of the Neurological Sciences
To investigate if diabetes is more common in drug-induced parkinsonism patients. We performed a hospital-based retrospective case–control study on 44 drug-induced parkinsonism (DIP) patients, 177 Parkinson disease patients, and 176 acute stroke patients matched for age and sex who were seen over the same period at the same hospital. The frequency of diabetes, age-at onset and sex were compared between DIP and IPD or acute stroke. Multivariate analysis showed that patients with diabetes are more frequent in DIP compared with IPD (p < 0.001, adjusted OR 5.48; 95% CI, 2.52–11.94). The frequency of diabetes in DIP was comparable to that in acute stroke patients (p = 0.16, adjusted OR 0.62; 95% CI, 0.32–1.21). These data suggest that diabetes may be a risk factor for DIP. Drugs with dopamine receptor blocking potency should be avoided in elderly with diabetes.
Comparative features of the epidemiology of multiple sclerosis and Parkinson's disease: Environmental factors of potential etiological importance
2007, Journal of the Neurological Sciences
Multiple sclerosis (MS) and Parkinson's disease (PD) are diseases of unknown cause. The etiology of MS is usually considered to be due to a number of potential biological agents while the etiology of PD is usually associated with toxic agents. Despite these differences, both pathologies have strong epidemiological similarities. A comparative analysis is performed of the epidemiology of MS and PD. Potential causal factors for PD may include dopamine-like pharmacological agents. It is proposed that potential causal agents such as certain drugs plus certain vaccines could explain rationally the epidemiology of MS. Ecology and genetics could not be the appropriate lines of research in the etiology of MS/PD because they are supported only in part by the epidemiology.
Drug-induced parkinsonism
2007, Handbook of Clinical Neurology
Citation Excerpt :
A number of studies have shown that in a variable number of cases DIP is only the expression of subclinical PD unmasked by the action of neuroleptics, calcium channel blockers or other drugs known to cause DIP. Several authors have shown that findings suggest that DIP is associated with an increased risk for PD (Chabolla et al., 1998). Several studies have shown that cigarette smoking may have a protective effect as regards the risk for PD (Allam et al., 2004).
Parkinsonism encompasses a heterogeneous group of movement disorders, including resting tremor, rigidity, bradykinesia, and postural instability, all of which have a significant impact on an individual's quality of life. The most frequent causes of secondary movement disorders include drug-induced movement disorders (DIMD), most of which are induced by antidopaminergic drugs, often causing severe psychosocial disturbance in both non-psychotic patients and patients with schizophrenia. DIMD encompasses a broad spectrum of syndromes, diverse in time of onset and in their clinical manifestations. Among various types of DIMD, drug-induced Parkinsonism (DIP) is one of the most frequent but poorly recognized disorder. It is frequently indistinguishable from idiopathic PD which results from the blockade of striatal dopamine receptors. DIP also represents one of the most frequent causes of secondary Parkinsonism in clinical practice. The clinical features of DIP mimic those of PD. Bradykinesia, rigidity, impaired postural reflexes, and tremor also occurs. Some of the risk factors associated with DIP include (1) age, (2) pre-existing movement disorders, (3) cigarette smoking, (4) genetics, and (5) gender.
Microeletrode guided stereotactic pallidotomy and pallido-thalamotomy for treatment of Parkinson's disease
2006, Neurocirugia
Los autores valoraron el efecto terapéutico de palidotomía y palido-talamotomía combinada guiada por MR y microelectrodos en 33 pacientes con enfermedad de Parkinson, cuyos síntomas fueron resistentes al tratamiento farmacológico.
Los pacientes fueron evaluados en base a los test estandarizados a nivel internacional que se efectuaron antes y después de la operación: al 2° día, así como a lo largo de 12 meses, con un intervalo de 3 meses entre ellos. Los pacientes fueron divididos en dos grupos; en los del grupo “A”, los síntomas parkinsonianos, incluso el temblor, disminuyeron después de una palidotomía. En los pacientes del grupo “B”, el temblor no disminuyó tras la palidotomía, razón por la cual ésta se complementó con una talamotomía.
Con la ayuda de la escala UPDRS III se obtuvieron los siguientes resultados: después de la palidotomía en “fase on” el promedio preoperatorio de 51,2 disminuyó a 29,5 al 2° día, a 26 a los 3, 6 y 9 meses, y a 28,7 a los 12 meses después de la operación; en “fase off” el promedio preoperatorio de 64,3 declinó a 31,6 al 2° día, a 26 a los 3, 6 y 9 meses, y a 30,5 a los 12 meses después de la operación. Después de la palidotalamotomía en “fase on” el promedio preoperatorio de 43,5 disminuyó a 27,9 al 2° día, a 22,9 a los 3 meses, a 22,8 a los 6 meses, y a 24,5 a los 9 y 12 meses después de la operación. De igual manera, en “fase off” el promedio preoperatorio de 62,6 declinó a 38 al 2° día, a 30 a los 3 meses, a 31,8 a los 6 meses, y a 33,8 a los 9 y 12 meses después de la operación.
Para aquellos pacientes, en quienes la palidotomía no fue suficiente en el control del temblor, la palido-talamotomía fue efectiva. Los síntomas clínicos, de acuerdo con las escalas utilizadas, mejoraron significativamente en los dos grupos (student t: P < 0,0001); sin embargo, las lesiones bilaterales conllevan un alto riesgo de morbilidad.
Authors evaluated the therapeutic effect of the MRI and microelectrodeguided stereotactic pallido- and pallido-thalamotomy in 33 patients with Parkinson's disease (PD), whose symptoms were refractory to pharmacological therapy.
The patients were evaluated according to the internationally standardized rating scales (UPDRS part II, III, Schawb & England, Hoehn & Yahr, and Fahn) at six timepoints: before the operation, and 2 days, 3, 6, 9 and 12 months postoperatively. The patients were divided into 2 groups. Those in group A had relief of all main parkinsonian symptoms after pallidotomy including tremor. The patients in group B had no relief of tremor after pallidotomy. For them the pallidotomy was completed by thalamotomy in the same sitting, which had resulted in cessation of tremor.
The following results were obtained by using the UPDRS part III: after pallidotomy “On state” mean: preoperative 51,2, postoperative at 2^nd day 29,5 at 3, 6 and 9^th month 26, and at 12^th month 28,7. “Off state” mean: preoperative 64,3, postoperative at 2^nd day 31,6, at 3, 6 and 9^th month 26, and at 12^th months 30,5. After pallidothalamotomy “On state” mean: preoperative 43,5, postoperative at 2^nd day 27,9, at 3^rd month 22,9, at 6^th month 22,8, and at 9 and 12^th month 24,5. “Off state” mean: preoperative 62,6, postoperative at 2^nd day 38, at 3^rd month 30, at 6^th month 31,8 and at 9 and 12^th month 33,8.
For those patients, whose tremor was not successfully controlled by pallidotomy, the combined pallido-thalamotomy was effective. The clinical symptomps, according to the rating scales, improved significantly in both groups (student t: P < 0,0001), but bilateral lesioning carried higher surgical morbidity.
Other Parkinson syndromes
2001, Neurologic Clinics
Citation Excerpt :
Rare cases of persistent parkinsonism despite withdrawal of NL have been reported.73 Such cases should raise the suspicion of underlying PD that was clinically unmasked by NL exposure.15 The presence of mild DIP is not necessarily an indication for NL withdrawal.

View all citing articles on Scopus

: This study was supported in part by Grant NS 33978 from the National Institute of Neurological Disorders and Stroke, Grant AR 30582 from the National Institutes of Health, Public Health Service, and the Mayo Foundation.

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Original ArticleDrug-Induced Parkinsonism as a Risk Factor for Parkinson's Disease: A Historical Cohort Study in Olmsted County, Minnesota

Objective

Design

Material and Methods

Results

Conclusion

Section snippets

Patients And Methods

Results

Discussion

Conclusion

Lancet

Epidemiology of parkinsonism; incidence, classification, and mortality

Ann Neural

A survey of drug-induced extrapyramidal reactions

JAMA

Extrapyramidal effects of neuroleptics

J Neural Neumsurg Psychiatry

History of the Rochester Epidemiology Project

Mayo Clm Proc

Original Article
Drug-Induced Parkinsonism as a Risk Factor for Parkinson's Disease: A Historical Cohort Study in Olmsted County, Minnesota