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Study on drug-induced parkinsonism and its clinical patterns in Eastern Indian population


 Consultant Neurologist and Director, Aarogyam Neuroclinic, Assistant Professor, SRIMS, Durgapur, West Bengal, India

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Date of Submission27-Jan-2022
Date of Decision08-Mar-2022
Date of Acceptance10-Mar-2022
Date of Web Publication25-Jun-2022
 

  Abstract 


Background: Drug-induced parkinsonism (DIP) is important as it is reversible if identified and treated early. We present herewith various clinical patterns and drugs commonly causing DIP. Materials and Methods: This is a retrospective study with done at the outpatient neurology services of Aarogyam Neuroclinic, from Durgapur, West Bengal, during January 1, 2021–July 31, 2021. In this study, consecutive patients satisfying the inclusion criteria for DIP were included in the study. The inclusion criteria were: 1. All patients with two of the four cardinal features of parkinsonism – bradykinesia, tremor, rigidity, and postural imbalance. 2. There should be a temporal relationship of intake of medications before the onset of symptoms. 3. Exclusion of other causes of parkinsonism. The age, sex, and other demographic characteristics of study population were studied. The pattern of parkinsonism – symmetric, asymmetric, tremor-dominant, or rigidity-dominant was noted. Results: Out of 52 patients studied, 34 (65.38%) were male and 18 (34.61%) were female. The most common age group involved was 60–70 years (30.76%), followed by 70–80 years (26.92%) and 50–60 years (19.23%). The mean age was 60.61 years with a standard deviation of 13.44 years. On analysis of the clinical patterns of parkinsonism, the most common type was tremor-dominant symmetric parkinsonism (53.84%), followed by asymmetric parkinsonism (25%) and akinetic-rigid parkinsonism (21.12%). Orofacial dyskinesias were seen in 17.3% along with parkinsonism. Common drugs associated with DIP were gastrointestinal motility agent levosulpiride (25%), calcium channel blockers such as flunarizine (19.23%), aripiprazole (11.53%), amisulpiride (7.69%), sodium valproate (7.69%), olanzapine (3.8%), and itopride, flupenthixol, and risperidone (1.72%). Forty patients were followed up for 6 months, of which, majority (50%) showed complete recovery, whereas 25% each showed partial or persistent symptoms. Conclusion: DIP is a common disorder with varied presentations. Early diagnosis is crucial for complete recovery.

Keywords: Drug, induced, parkinsonism, tremor


How to cite this URL:
Yadav PK. Study on drug-induced parkinsonism and its clinical patterns in Eastern Indian population. APIK J Int Med [Epub ahead of print] [cited 2022 Sep 25]. Available from: https://www.ajim.in/preprintarticle.asp?id=348294





  Introduction Top


Parkinsonism is a syndrome of neurodegenerative disorders with characteristic clinical features and pathologically correlated with the degeneration of multiple anatomical structures within the brain.

The most common mechanisms are progressive protein deposition of alpha-synuclein or tau in the central nervous system giving rise to a variety of different parkinsonism syndromes.[1],[2]

Idiopathic Parkinson's disease (IPD) is the most frequently seen subtype of parkinsonism with a incidence of about 14.2/100,000 person-years.[3] Drug-induced parkinsonism (DIP) is the second most common cause of parkinsonism after IPD.[4] Drug-induced movement disorders are a group of conditions, the most common being DIP followed by tremors, tardive dyskinesias, tardive dystonia, akathisia, and myoclonus. The manifestations of DIP can be very similar to IPD, and many a time, patients with DIP are misdiagnosed as IPD.[5],[6] DIP was first described in the early 1950s after the introduction of reserpine and chlorpromazine.

Postsynaptic D2 receptor blockade remains the usual mechanism leading to DIP. Presynaptic dopamine synthesis inhibition may be the cause for a few drugs such as tetrabenazine. Common agents causing DIP are typical antipsychotics such as chlorpromazine and prochlorperazine. Atypical antipsychotics such as olanzapine, risperidone, and aripiprazole are being increasingly recognized as a cause for DIP though to a much lesser extent than the former group of medications. Other drugs commonly involved are gastrointestinal motility agents such as (metoclopramide, levosulpiride, itopride, and clebopride), calcium channel blockers (flunarizine and cinnarizine), mood stabilizers such as lithium, valproate, and antidepressants such as selective serotonin reuptake inhibitors.[7],[8],[9]

Objectives

The objective of this study was to study the clinical patterns and medications leading to DIP in the study population.


  Materials and Methods Top


This is a retrospective study at the outpatient neurology services of Aarogyam Neuroclinic, Durgapur, West Bengal, during January 1, 2021–July 31, 2021. Consecutive patients satisfying the inclusion criteria for DIP were studied. All the patients were examined by the same neurologist during the initial visit as well as during the follow-up. The diagnosis of DIP was made after detailed history and examination using the inclusion criteria. All the patients enrolled in the study had given signed consent to participate in the clinical study.

The inclusion criteria were

  1. All patients with any two of the four cardinal features of parkinsonism – bradykinesia, tremor, rigidity, and postural imbalance
  2. There should be a temporal relationship of intake of medications before the onset of symptoms
  3. No features of parkinsonism before the intake of medications
  4. Exclusion of parkinson plus syndromes, multi-infarct state, normal pressure hydrocephalus, and other causes of secondary parkinsonism by appropriate investigations such as magnetic resonance imaging brain
  5. All other drug-induced movement disorders without parkinsonism were excluded from the study.


The age, sex, and other demographic characteristics of study population were studied. The pattern of parkinsonism – symmetric, asymmetric, tremor-dominant, or rigidity-dominant was noted. Detailed evaluation of the medication list was done. All the patients enrolled in the study were made to stop the offending medication and followed up every 2 months for 6 months. The change in the medication implicated in causing DIP was done after consulting the specialist who had prescribed the medication, to prevent worsening of the primary disease.


  Results Top


In the study period, a total of 52 patients were found to satisfy the inclusion criteria. Out of 52 patients studied, 34 (65.38%) were male and 18 (34.61%) were female. The most common age group involved was 60–70 years (30.76%), followed by 70–80 years (26.92%) and 50–60 years (19.23%). The least common age groups were <30 years, followed by more than 80 years. The mean age was 60.61 years with standard deviation of 13.44 years. On analysis of the clinical patterns of parkinsonism, the most common type of parkinsonism seen was tremor-dominant symmetric parkinsonism (53.84%), followed by asymmetric parkinsonism (asymmetry in either tremor/rigidity or bradykinesia) (25%) and akinetic-rigid parkinsonism (21.12%). Orofacial dyskinesias were seen along with parkinsonism in 17.3% of patients. One patient each had voice tremor and oculogyric crisis along with other manifestations of parkinsonism.

The patterns of parkinsonism are shown in [Figure 1].
Figure 1: Clinical patterns of parkinsonism

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The common drugs associated with DIP were gastrointestinal motility agent levosulpiride (25%), calcium channel blockers such as flunarizine (19.23%), aripiprazole (11.53%), amisulpride (7.69%), sodium valproate (7.69%), olanzapine (3.8%), and itopride, flupenthixol, and risperidone (1.72%). Combination of two or more drugs was associated in causing DIP in 19.23%. The details of the medications associated with DIP are shown in [Table 1].
Table 1: Medications causing drug-induced parkinsonism

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The patients were followed up every 2 monthly for 6 months duration. During the follow-up, patients were examined in detail by the same neurologist. Tremors, bradykinesia, rigidity, and postural imbalance were assessed, and any worsening or improvement in symptoms was noted. Twelve patients were lost during the follow-up. Forty patients underwent regular follow-up. In all the patients, the offending agent was discontinued and trihexyphenidyl was started in all patients. Minimum dosage of the trihexyphenidyl was between 2 mg and 10 mg depending on the severity of symptoms and tolerability of the medication. Trihexyphenidyl was continued minimum of 6 months during the follow-up period. During evaluation in the follow-up period of 6 months, 50% of the patients totally recovered from the DIP, 25% there was partial improvement, and 25% showed persistent symptoms.


  Discussion Top


The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V),[10] defines DIP as the presence of resting tremor, muscular rigidity, akinesia, or bradykinesia, developing within a few weeks of initiating or increasing the dosage of a drug (typically a neuroleptic) or after decreasing the dosage of an levodopa–carbidopa or dopamine agonists.

DIP can present with varied manifestations which can make it difficult to differentiate from IPD as well as other atypical parkinsonism syndromes. Thus, it becomes very important to check the medication list of any patient presenting with features of parkinsonism.

Age, gender, and genetic risk factors are the most common predisposing causes for developing DIP,[1],[11] of which age is the most common and most important risk factor. Age-related decrease in dopamine concentration and nigral degeneration leads to this predisposition.[12] Female gender is more susceptible to develop DIP. The cause is not very clear; however, estrogen-related suppression of dopamine receptors may be the probable underlying cause.[13],[14] Not all patients exposed to dopamine blocking agents develop DIP suggesting a underlying genetic predisposition. Genome-wide screening has shown that genes such as R (gamma-aminobutyric acid) are involved in this susceptibility.[15]

In our study, 57.68% of patients with DIP were above 60 years correlating with the fact that it was more common in elderly population. Thus, in the elderly population, we should avoid medications which have extrapyramidal side effects and also keep them under close follow-up to detect DIP. In our study, DIP was found to be more common in male gender (65.38%) compared to females (34.61%). This was contrary to previous studies which showed a female preponderance.[13],[14] (R?) The most common form of DIP in our study was tremor-dominant symmetric disease in more than half of the patients and asymmetric parkinsonism in a quarter. Akinetic-rigid state was seen in 21% of the patients. Few previous studies have quoted symmetric akinetic-rigid syndrome as the most frequent phenotype.[7],[16] Our study showed asymmetric presentation in 25% of patients which mimicked IPD. Resting tremor and asymmetric rigidity and bradykinesia have been mentioned in previous studies.[7] We found in our study that DIP could occur as early as 2 weeks after the use of offending medications or may occur after many years of use of offending drugs.

Many of the patients were on antihypertensives, oral hypoglycemic medications, statins, and other similar medications for medical comorbidities. We could not find out any correlation between the medications for comorbidities and the DIP.

Our study found associated orofacial dyskinesias along with parkinsonism in 17.3%, thereby making it an important marker suggesting an underlying DIP rather than IPD as mentioned previously.[17] Some of the previous studies have mentioned nonmotor symptoms such as hyposmia, constipation, urinary symptoms, and sexual dysfunctions as accompaniments which are seen in IPD rather than PD.[18] However, in our study, we did not evaluate this aspect.

Dopamine transporter imaging may be quite useful in differentiating presynaptic dopamine deficiency disorders such as IPD from DIP.[19]

Drugs such as typical antipsychotics, gastrointestinal motility drugs such as metoclopramide, levosulpiride, itopride, cisapride, antiepileptics such as sodium valproate and calcium channel blockers (flunarizine and cinnarizine), and atypical antipsychotics (risperidone, olanzapine, and aripiprazole) are commonly related to DIP.

The use of typical antipsychotics has become less and is not seen much commonly as a cause of DIP. In the newer antipsychotics, clozapine and quetiapine are the ones associated least with DIP and other extrapyramidal side effects.[20],[21] In our study, aripiprazole and amisulpride were the common agents related to DIP. Risperidone, flupenthixol, olanzapine, and haloperidol were the other agents noted to cause DIP. Use of more than one antipsychotic agent is another risk factor predisposing to develop DIP.

Metoclopramide used to be the most common prokinetic agent associated with extrapyramidal symptoms and DIP. However, nowadays, levosulpiride is emerging as a very common cause of DIP. It is less associated with other extrapyramidal syndromes unlike metoclopramide and causes mainly DIP.[22],[23]

Our study showed that levosulpiride is the most common drug-associated with DIP in 25% of cases. There was one case of DIP associated with itopride. Nowadays, with the rampant use of levosulpiride with proton-pump inhibitors, there is a tremendous upsurge in DIP due to this medication.

In our study, flunarizine was the second most common agent (19.3%) related to DIP. All the patients were on long-term flunarizine of 6 months or more before developing DIP. The mechanism of causing DIP is not very clear; however, reducing dopamine transmission or direct action on the dopamine receptors may be one of the causes of it.[24] Sodium valproate was related to DIP in 7.69% of the cases. This was similar to 5% DIP related to valproate long-term use in literature. The mechanism postulated is oxidative stress and mitochondrial dysfunction.[25]

Combination of valproate and flunarizine for migraine may lead to DIP commonly. Almost 20% of DIP cases were related to combination of two or more drugs with action on the D2 receptors. Hence, it becomes very important to look out for manifestations of parkinsonism during each follow-up when patients are being treated with such drugs.

One of our patients had voice tremors and one had oculogyric crisis along with features of parkinsonism. Both of the patients were on levosulpiride.

DIP usually resolves after stopping offending medication. Unfourtunately, in 10%–50%, it may persist or even progress.[26] There can be various patterns which may be seen during follow-up. Most common pattern is full and lasting recovery from DIP. Some patients may show persistence but no progression of symptoms, few may show progressive worsening of parkinsonism, and lastly and least commonly, some may show resolution in parkinsonism initially on stopping the offending medication followed by reappearance of symptoms later on. The last two patterns may, however, be cases of preclinical parkinsonism which may have manifested due to the offending drug. The time to recovery may be quite variable.[27]

Our study had a brief follow-up period of 6 months for these patients. In all the patients, the offending medications were discontinued or changed, and patients were started on trihexyphenidyl, amantadine, and rarely levodopa–carbidopa in refractory cases. Out of forty patients who were on regular checkups for 6 months (follow-up was possible only in forty patients), 50% of the patients totally recovered from the DIP, 25% there was partial improvement, and 25% showed persistent symptoms. Tremor was the earliest symptom to respond completely while orofacial dykinsesias was the most resistant symptom to treat. Whether some of the patients with persistent symptoms of parkinsonism had IPD or some other form of secondary or atypical parkinsonism was not clear and longer follow-up is required to assess the natural history of the disease.

The treatment of DIP is mainly removing the offending agent and changing to other medications which is efficacious for the medical condition as well which has less dopaminergic blocking ability. Anticholinergic agents are the drug of choice; however, the side effect profile should be considered before starting it in elderly population. Amantadine may be an alternative with less side effects. Levodopa may not be useful in dopamine receptor blockade-related DIP. It may be useful in DIP caused by tetrabenazine where dopamine depletion leads to parkinsonism.[28]

Limitations of our study were a short follow-up period because of which the course of persistent or worsening DIP could not be assessed.

Conclusion DIP is a common disorder which can have varied manifestations. Early diagnosis and stopping the offending medication is crucial for complete recovery.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Praveen Kumar Yadav,
Aarogyam Neuroclinic, B1More, J.L. Avenue, Paschim Burdwan, Durgapur, West Bengal
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajim.ajim_24_22



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