Outcome of Drug-Induced Parkinsonism in the Elderly: A Permanent Nonprogressive Parkinsonian Syndrome May Occur Following Discontinuation of Cinnarizine and Flunarizine.

Parkinsonism induced by dopamine receptor antagonists, traditionally considered completely reversible following offending drug withdrawal, may unmask a degenerative parkinsonism in the patients with an underlying subclinical disease. In elderly patients, parkinsonism induced by the calcium channel blockers such as piperazine derivates cinnarizine and flunarizine may persist following drug discontinuation resulting in a permanent nonprogressive syndrome fulfilling the criteria for tardive parkinsonism. Whether this outcome occurs also following exposure to dopamine receptor antagonists such as neuroleptics and benzamide derivates or represents a class effect of the voltage-gated L-type calcium channel blockers, such as cinnarizine and flunarizine, due to their complex pharmacodynamic properties remains to be established.

Phenomenology, quality of life, and predictors of reversibility in patients with drug-induced movement disorders: a prospective study.

BACKGROUND: Drug-induced movement disorders (DIMDs) form an important subgroup of secondary movement disorders, which despite conferring a significant iatrogenic burden, tend to be under-recognized and inappropriately managed. OBJECTIVE: We aimed to look into phenomenology, predictors of reversibility, and its impact on the quality of life of DIMD patients. METHODS: We conducted the study in the Department of Neurology at a tertiary-care centre in India. The institutional ethics-committee approved the study. We assessed 55-consecutive DIMD patients at presentation to our movement disorder clinic. Subsequently, they followed up to evaluate improvement in severity-scales (UPDRS, UDRS, BARS, AIMS) and quality of life (EuroQol-5D-5L). Wilcoxan-signed-rank test compared the scales at presentation and follow-up. Binary-logistic-regrerssion revealed the independent predictors of reversibility. RESULTS: Fourteen patients (25.45%) had acute-subacute DIMD and 41 (74.55%) had tardive DIMD. Tardive-DIMD occurred more commonly in the elderly (age 50.73±16.92 years, p<0.001). Drug-induced-Parkinsonism (DIP) was the most common MD, followed by tardivedyskinesia. Risperidone and levosulpiride were the commonest culprit drugs. Patients in both the groups showed a statistically significant response to drug-dose reduction /withdrawal based on follow-up assessment on clinical-rating-scales and quality of life scores (EQ-5D-5L). DIMD was reversible in 71.42% of acute-subacute DIMD and 24.40% of patients with chronic DIMD (p=0.001). Binary-logistic-regression analysis showed acute-subacute DIMDs and DIP as independent predictors of reversibility. CONCLUSION: DIP is the commonest and often reversible drug-induced movement disorder. Levosulpiride is notorious for causing DIMD in the elderly, requiring strict pharmacovigilance.

Effects of defoliant exposure and medication use on the development of Parkinson's disease in veterans.

BACKGROUND: Vietnam-era veterans were exposed to Agent Orange (AO), which is associated with a high prevalence of Parkinson's disease (PD). However, little is known about the development of PD-like symptoms caused by drug-induced parkinsonism (DIP) in such populations. This study aimed to investigate PD incidence and PD risk following exposure to AO or DIP-risk drugs in veterans. METHODS: A retrospective cohort study was conducted using 12 years (2009-2020) of electronic medical records of the Veterans Health Service Medical Center, the largest Veterans Affairs hospital in South Korea (n = 37,246; 100% male; age, 65.57 ± 8.12 years). Exposure to AO or DIP-risk drugs, including antipsychotic, prokinetic, anti-epileptic, dopamine-depleting and anti-anginal agents, was assessed in veterans with PD, operationally defined as having a PD diagnosis and one or more prescriptions for PD treatment. The PD risk was calculated using multiple logistic regression analysis adjusted for age and comorbidities. RESULTS: The rates of DIP-risk drug use and AO exposure were 37.92% and 62.62%, respectively. The PD incidence from 2010 to 2020 was 3.08%; 1.30% with neither exposure, 1.63% with AO exposure, 4.38% with DIP-risk drug use, and 6.33% with both. Combined exposure to AO and DIP-risk drugs increased the PD risk (adjusted odds ratio = 1.68, 95% confidence interval, 1.36-2.08, P < 0.001). CONCLUSIONS: The PD incidence was 1.31 times higher with AO exposure alone and 1.68 times higher with AO exposure and DIP-risk drug use. The results suggest the necessity for careful monitoring and DIP-risk drug prescription in patients with AO exposure.

Retinal Thickness and Its Interocular Asymmetry Between Parkinson's Disease and Drug-Induced Parkinsonism.

BACKGROUND: Drug-induced parkinsonism (DIP) is common, but diagnosis is challenging. Although dopamine transporter imaging is useful, the cost and inconvenience are problematic, and an easily accessible screening technique is needed. We aimed to determine whether optical coherence tomography (OCT) findings could differentiate DIP from Parkinson's disease (PD). METHODS: We investigated 97 de novo PD patients and 27 DIP patients using OCT and [18F] N-(3-fluoropropyl)-2b-carbon ethoxy-3b-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography. We compared peripapillary retinal nerve fiber layer thickness (pRNFLT) and macular retinal thickness (mRT) between PD and DIP patients as well as interocular differences in the pRNFLT and the mRT. Asymmetric index (%) for retinal thickness (AIRT) was calculated to measure the interocular differences between pRNFLT and mRT. The correlation between AIRT and total striatal specific/non-specific binding ratio asymmetry index (SNBRAI) was investigated in PD and DIP patients. RESULTS: No significant differences in pRNFLT and mRT values were observed between PD and DIP patients (all P values > 0.090). The mean SNBRAI was significantly higher in PD than in DIP (P = 0.008) patients; however, AIRT did not differ between PD and DIP patients in pRNFLT and mRT (all P values > 0.100). SNBRAI did not correlate with AIRT of pRNFL or mRT in PD and DIP patients (all P values > 0.060). CONCLUSION: Our study showed no benefit of retinal thickness and interocular asymmetry measurements using OCT for distinguishing PD from DIP in the early stages. Additional investigations are needed for confirmation.

Use of antipsychotics and long-term risk of parkinsonism.

INTRODUCTION: Few epidemiological studies have assessed the risk of parkinsonisms after prolonged use of neuroleptics. We aimed to examine the long-term risk of degenerative parkinsonisms (DP) associated with previous use of neuroleptics. METHODS: All residents in Piedmont, Northern-west Italy, older than 39 years (2,526,319 subjects), were retrospectively followed up from 2013 to 2017. Exposure to neuroleptics was assessed through the regional archive of drug prescriptions. The development of DP was assessed using the regional archives of both drug prescriptions and hospital admissions. We excluded prevalent DP cases at baseline as well as those occurred in the first 18 months (short-term risk). The risk of DP associated with previous use of neuroleptics was examined through Cox regression, using a matched cohort design. RESULTS: The risk of DP was compared between 63,356 exposed and 316,779 unexposed subjects. A more than threefold higher risk of DP was observed among subjects exposed to antipsychotics, compared to those unexposed (HR = 3.27, 95% CI 3.00-3.57), and was higher for exposure to atypical than typical antipsychotics. The risk decreased after 2 years from therapy cessation but remained significantly elevated (HR = 2.38, 95% CI 1.76-3.21). CONCLUSIONS: These results indicate a high risk of developing DP long time from the start of use and from the cessation for both typical and atypical neuroleptics, suggesting the need of monitoring treated patients even after long-term use and cessation.

Differences in cause and 12-month follow-up outcome of parkinsonian symptoms in depressed older adults treated with antipsychotics: a case series.

BACKGROUND: Parkinsonian symptoms are common adverse effects of antipsychotics. Older adults are particularly vulnerable to drug-induced parkinsonism. Nonetheless, parkinsonian symptoms in seniors treated with antipsychotics cannot be straightforwardly attributed to antipsychotic medication. A comprehensive diagnostic workup is necessary in many cases in order to shed light on the cause of such symptoms in this patient population. CASE SERIES: Eight cases of hospitalized depressed older adults with parkinsonian symptoms, who were treated for at least one year with antipsychotics, are reported. Based on neurological consultation, structural brain imaging and Ioflupane (I-123) dopamine transporter (DAT) single photon emission computerized tomography (SPECT), Parkinson's disease was diagnosed in one case, idiopathic tremor in another, vascular parkinsonism in another one, while in another individual parkinsonian symptoms persisted at 12-month post-discharge follow-up even though his/her symptoms were classified as drug-induced on discharge. In four patients, parkinsonian symptoms were definitely drug-induced and no movement disturbances were reported at follow-up. CONCLUSIONS: Differences in the cause and outcome of parkinsonian symptoms in seniors treated with antipsychotics merit systematic and in-depth study considering the therapeutic and prognostic implications of an accurate detection of the cause of such symptoms. Familiarizing clinical psychiatrists with these differences could pave the way towards approaching seniors with severe, atypical and/or persistent parkinsonian symptoms in a more individualized diagnostic and therapeutic manner, and towards more cautious prescribing of antipsychotics in this age group.

Altered Functional Connectivity of the Orbital Cortex and Striatum Associated with Catalepsy Induced by Dopamine D1 and D2 Antagonists.

The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious motor dysfunction, such as catalepsy and Parkinsonism. However, the neuronal mechanism underlying the drug-induced motor dysfunction is not well understood. Here, we examine brain-wide activation patterns in Fos-enhanced green fluorescent protein reporter mice that exhibit cataleptic behavior induced by SCH39166, a dopamine D1-like receptor antagonist, and raclopride, a dopamine D2-like receptor antagonist. Support vector classifications showed that the orbital cortex (ORB) and striatum including the caudoputamen (CP) and nucleus accumbens (ACB), prominently contribute to the discrimination between brains of the vehicle-treated and both SCH39166- and raclopride-treated mice. Interregional correlations indicated that the increased functional connectivity of functional networks, including the ORB, CP, and ACB, is the common mechanism underlying SCH39166- and raclopride-induced cataleptic behavior. Moreover, the distinct mechanisms in the SCH39166- and raclopride-induced cataleptic behaviors are the decreased functional connectivity between three areas above and the cortical amygdala, and between three areas above and the anterior cingulate cortex, respectively. Thus, the alterations of functional connectivity in diverse brain regions, including the ORB, provide new insights on the mechanism underlying drug-induced movement disorders.

Using accelerometer as a diagnostic tool to detect drug-induced parkinsonism (DIP) secondary to first-generation anti-psychotic medications.

OBJECTIVE: The objective of this study is to examine the effectiveness of an accelerometer-based compact system in detecting and quantifying drug-induced parkinsonism (DIP) in patients with schizophrenia. METHOD: A pilot study controlled clinical trial comprising 6 people with schizophrenia and 11 control subjects was conducted at Alfred Health, Melbourne. Participants had their movements assessed using Barnes Akathisia Rating Scale (BARS), Simpson Angus Scale (SAS) and Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) followed by an assessment of gait using three triaxial accelerometers. RESULTS: Median BARS, SAS, MDS-UPDRS III and accelerometer scores were significantly higher for patients with schizophrenia than controls. Accelerometers detected three times more rest tremor than clinical rating scales. Patients with schizophrenia had 70% of their dynamic acceleration at frequencies between 4 and 10 Hz, which is almost twice that observed in the control population (38%). Accelerometer scores were significantly correlated with BARS scores. CONCLUSION: Accelerometers were able to accurately detect patients with DIP better than some clinical rating scale including the SAS. Further larger-scale studies must be conducted to further demonstrate the accuracy of accelerometers in detecting DIP.

Association between Trimetazidine and Parkinsonism: A Population-Based Study.

BACKGROUND: The prevalence of drug-induced parkinsonism (DIP) has been reported with the use of trimetazidine (TMZ), an antianginal medication available in Asian and European countries. Very few studies have evaluated the association between DIP and TMZ use, and studies using population-based data from national databases are lacking. OBJECTIVES: To investigate the association between DIP and use of TMZ in patients with angina using data from a national healthcare claims database and to determine the predictive factors of DIP in TMZ use. METHODS: A cross-sectional study was conducted on patients aged 40 years or more diagnosed with angina, using the Korean National Healthcare claims 2014 database. The association between TMZ use and DIP was evaluated using multivariate logistic regression analysis, adjusting for confounders, including age; sex; insurance type; comorbidities; and concurrent medications known to be commonly associated with DIP, such as typical and atypical antipsychotics. RESULTS: Of the patients included in the study, 19% were prescribed TMZ. In addition, 2.5% of TMZ users had preexisting extrapyramidal and movement disorders. TMZ use was found to be a significant predictor of a new diagnosis of parkinsonism (adjusted OR [aOR] 1.39; 95% CI 1.06-1.81; p = 0.016). Age ≥65 years (aOR 2.07; 95% CI 1.13- 3.74; p = 0.017) and stroke as comorbid disease (aOR 3.23; 95% CI 1.87-5.61; p < 0.001) were also significantly associated with a new diagnosis of parkinsonism in TMZ users. CONCLUSIONS: Treatment with TMZ was a statistically significant predictor of a new diagnosis of parkinsonism. Efforts should focus on close monitoring of, and education on, TMZ use in relation to DIP in all patients who are prescribed TMZ, including those with preexisting extrapyramidal and movement disorders.

Prevalence and incidence of Parkinson's disease and drug-induced parkinsonism in Korea.

BACKGROUND: Parkinson's disease (PD) and drug-induced parkinsonism (DIP) are the major diseases of parkinsonism. To better understand parkinsonism, we aimed to assess the prevalence and incidence of PD and DIP in Korea from 2012 to 2015. METHODS: We used the Health Insurance Review and Assessment Service database, which covers the entire population in Korea. We used claims during 2011-2015 to assess epidemiology of PD and DIP during 2012-2015. Retrospective cross-sectional study design was employed to assess prevalence, whereas retrospective cohort study design was used to determine incidence. Patients with at least one claim with ICD-10 G20 and who received antiparkinsonian drugs for at least 60 days were classified as having PD. We excluded patients with antiparkinsonian drugs that can be used for indications other than PD. Patients with at least one claim with ICD-10 G211 or G251 during the prescription period of drugs that are frequently related with DIP were classified as having DIP. Incident cases had a disease-free period of 1 year before diagnosis. To evaluate the significance of changes in the prevalence or incidence over time, Poisson regression was used to determine p for trend. RESULTS: The prevalence of PD increased from 156.9 per 100,000 persons in 2012 to 181.3 per 100,000 persons in 2015 (p for trend< 0.0001). The incidence of PD decreased steadily from 35.4 per 100,000 person-years in 2012 to 33.3 per 100,000 person-years in 2015 (p for trend< 0.0001). The prevalence of DIP increased from 7.3 per 100,000 persons in 2012 to 15.4 per 100,000 persons in 2015 (p for trend< 0.0001) and the incidence of DIP increased from 7.1 per 100,000 person-years in 2012 to 13.9 per 100,000 person-years in 2015 (p for trend< 0.0001). CONCLUSIONS: Our study suggests that the incidence of PD has gradually decreased whereas, the incidence of DIP increased from 2012 to 2015. Further studies are warranted to examine possible causes of increased DIP incidence in order to develop management strategy for parkinsonism.

The symptoms asymmetry of drug-induced parkinsonism is not related to nigrostriatal cell degeneration: a SPECT-DaTSCAN study.

AIM: Drug-induced parkinsonism (DIP) is the most common form of parkinsonism after Parkinson's disease (PD) itself. It has been widely believed that DIP is characterised by symmetry of symptoms. Studies of patients with DIP in whom PD had been ruled out by SPECT-DaTSCAN have shown that symptom asymmetry is a common element of DIP clinical presentation. The aim of our study was to determine whether the asymmetry of symptoms in DIP is related to any abnormality within the presynaptic part of the nigrostriatal dopaminergic system. MATERIALS AND METHODS: Eleven patients with the diagnosis of DIP and asymmetric symptoms were studied. Their individual SPECT-DaTSCANs were normal. Indices calculated for the whole group of radiotracer uptake in the whole striatum, putamen and caudate contralateral to more severe DIP symptoms were compared to values obtained in the opposite hemisphere. RESULTS: We did not find significant differences in radiotracer uptake in structures contralateral to more severe clinical symptoms when compared to the homolateral hemisphere. CONCLUSIONS: Our results have not confirmed the presence of a presynaptic nigrostriatal deficit which could be related to asymmetry of DIP. The factors responsible for the asymmetry of DIP symptoms should be sought in the postsynaptic part of the nigrostriatal dopaminergic system.

Acute dopamine receptor blockade in substantia nigra pars reticulata: a possible model for drug-induced Parkinsonism.

Dopamine (DA) depletion modifies the firing pattern of neurons in the substantia nigra pars reticulata (SNr), shifting their mostly tonic firing toward irregularity and bursting, traits of pathological firing underlying rigidity and postural instability in Parkinson's disease (PD) patients and animal models of Parkinsonism (PS). Drug-induced Parkinsonism (DIP) represents 20-40% of clinical cases of PS, becoming a problem for differential diagnosis, and is still not well studied with physiological tools. It may co-occur with tardive dyskinesia. Here we use in vitro slice preparations including the SNr to observe drug-induced pathological firing by using drugs that most likely produce it, DA-receptor antagonists (SCH23390 plus sulpiride), to compare with firing patterns found in DA-depleted tissue. The hypothesis is that SNr firing would be similar under both conditions, a prerequisite to the proposal of a similar preparation to test other DIP-producing drugs. Firing was analyzed with three complementary metrics, showing similarities between DA depletion and acute DA-receptor blockade. Moreover, blockade of either nonselective cationic channels or Cav3 T-type calcium channels hyperpolarized the membrane and abolished bursting and irregular firing, silencing SNr neurons in both conditions. Therefore, currents generating firing in control conditions are in part responsible for pathological firing. Haloperidol, a DIP-producing drug, reproduced DA-receptor antagonist firing modifications. Since acute DA-receptor blockade induces SNr neuron firing similar to that found in the 6-hydroxydopamine model of PS, output basal ganglia neurons may play a role in generating DIP. Therefore, this study opens the way to test other DIP-producing drugs. NEW & NOTEWORTHY Dopamine (DA) depletion enhances substantia nigra pars reticulata (SNr) neuron bursting and irregular firing, hallmarks of Parkinsonism. Several drugs, including antipsychotics, antidepressants, and calcium channel antagonists, among others, produce drug-induced Parkinsonism. Here we show the first comparison between SNr neuron firing after DA depletion vs. firing found after acute blockade of DA receptors. It was found that firing in both conditions is similar, implying that pathological SNr neuron firing is also a physiological correlate of drug-induced Parkinsonism.

Early-onset drug-induced parkinsonism after exposure to offenders implies nigrostriatal dopaminergic dysfunction.

OBJECTIVES: The onset of parkinsonism in patients with drug-induced parkinsonism (DIP) exhibits extensive individual variability following exposure to offending drugs. We investigated whether the individual variations in the onset time of parkinsonism reflected the underlying subtle dopaminergic dysfunction in DIP. METHODS: We enrolled 71 patients with DIP who had visually normal striatal dopamine transporter (DAT) availability in 18F-FP-CIT positron emission tomography scans. According to their exposure durations to the offending drugs prior to onset of the parkinsonism, the patients were divided into the early-onset group (duration ≤6 months; n=35) and delayed-onset group (duration >6 months; n=36). We performed the quantitative analysis of the DAT availability in each striatal subregion between the groups. RESULTS: No patients with DIP had DAT availability that was more than 2 SD below the normal mean of DAT availability. Compared with the delayed-onset group, the early-onset DIP group had decreased DAT availability in the striatal subregions including the posterior putamen (p=0.018), anterior putamen (p=0.011), caudate (p=0.035) and ventral striatum (p=0.027). After adjusting for age, sex and cross-cultural smell identification test scores, a multivariate analysis revealed that the DAT availability in the striatal subregions of the patients with DIP was significantly and positively associated with the natural logarithm of the duration of drug exposure. CONCLUSIONS: These results suggest that a short exposure to the offending drugs before the development of parkinsonism would be associated with subtle nigrostriatal dopaminergic dysfunction in patients with DIP.

High exposure compared with standard exposure to metoclopramide associated with a higher risk of parkinsonism: a nationwide population-based cohort study.

AIMS: We conducted a cohort study utilizing a nationwide health insurance database to assess the European Medicines Agency's restrictions on using metoclopramide and its association with the risk of parkinsonism. METHODS: New oral metoclopramide users aged ≥20 years, and age- and gender-matched non-users were recruited between 2001 and 2011. Users were divided into high-exposure (dose >30 mg day-1 and/or duration >5 days) and standard-exposure (dose ≤30 mg day-1 and duration ≤5 days) groups. The adjusted hazard ratio (aHR) with 95% confidence interval (CI) estimated the risk of parkinsonism. RESULTS: During a 1-year period, 122 of 218 931 (0.06%) users of metoclopramide vs. 56 of 218 931 (0.03%) non-users developed parkinsonism (P < 0.001). Among the 122 cases of parkinsonism in users, 64 (0.04%) were from 168 566 standard-exposure users and 58 (0.12%) from 50 365 high-exposure users. Compared with non-users, the risk of parkinsonism was higher in users (aHR 2.16; 95% CI 1.54, 3.02), including standard-exposure (aHR 1.73; 95% CI 1.11, 2.70), and high-exposure (aHR 3.15; 95% CI 1.78, 5.57) users. High-exposure users had a higher risk of parkinsonism than standard-exposure users (aHR 1.83; 95% CI 1.28, 2.63). Within the high-exposure group, 45 233 of 50 365 (89.81%) users and 55 of 58 (94.83%) parkinsonism were from long-duration exposure; 5 132 of 50 365 (10.19%) users and 3 of 58 (5.17%) parkinsonism were from high-dose exposure and long-duration + high-dose exposure. CONCLUSIONS: The risk of parkinsonism in metoclopramide users, although extremely low (0.06%), is 2.16-fold greater than in non-users. High-exposure users have a 1.83-fold higher risk than standard-exposure users. As users in high-exposure group had a higher risk of parkinsonism than in standard-exposure group, and the majority of users and parkinsonism in high-exposure group were from long-duration exposure; thus, physician are advised to avoid prescribing metoclopramide for >5 days, even if the daily dose is ≤30 mg.

Vascular Parkinsonism in a Tertiary Care Stroke Prevention Clinic and the Development of a New Screening Strategy.

OBJECTIVES: To determine the prevalence of vascular parkinsonism (VasP) in a stroke prevention clinic (SPC). BACKGROUND: VasP can be defined by an onset of parkinsonism with prominent gait problems occurring within 1 year of stroke. METHODS: We created a screening strategy based on the Tanner Questionnaire (TQ), a validated scale for parkinsonism, and the creation of a 4-point Five-Minute Assessment Scale (FMAS) operationalizing Zijlmans' criteria for the diagnosis of VasP. Consecutive stroke patients were screened over a 12-month period using the TQ and the FMAS. SAS statistical software was used. RESULTS: Two hundred forty patients (52.5% females) were screened (mean age of 65 years, standard deviation, 14.5). Twenty-five percent of patients had a TQ score ≥ 4 with a median FMAS of 2. In this group, 32.6% (15/46) were found to have parkinsonism. Seventeen percent (8/46) were diagnosed with VasP having an FMAS of 4. Seventy-five of the participants obtained a TQ ≤ 3, with a median FMAS of 1. Only 1 patient in this group had parkinsonism (1.9%; 1/194). Using a cutoff of 4 points in the TQ resulted in a sensitivity of 93.8%, a specificity of 86.2% for parkinsonism, and a sensitivity of 100% with a specificity of 83% for VasP. Patients with FMAS = 4 (VasP) attained higher scores in the TQ with a median of 5 (Spearman rank correlation coefficient for the TQ and the FMAS (rs) = .447, P < .0005). CONCLUSIONS: We documented a prevalence of 3% (8/240) for VasP in an SPC. We propose a new, easier, and unified 2-step TQ-FMAS screening strategy for this condition.

Assessment of Incidence and Character of Neurologic/ Neuropsychiatric Complications in a Group of Patients with Malignant Melanoma Treated with Adjuvant High Dose Interferon.

BACKGROUND: Authors describe the incidence and character of neurologic and neuropsychiatric complications - particularly depression and parkinsonism - during adjuvant treatment of malignant melanoma (MM) with high dose interferon (HDI). Among the most frequently observed side effects are fatigue, hematotoxicity, and hepatotoxicity. Most research has been directed at depression and parkinsonism because of the lack of literature concerning these complications. Interferon induced parkinsonism has only been described rarely and only in case reports. PATIENTS AND METHODS: Twenty-nine patients with MM, treated from January 2010 to January 2014 with adjuvant high dose interferon alfa-2b intravenous (HDI 20MIU/sqm for 5 days per week during the first 4 weeks, and then maintenance subcutaneous 10MIU/sqm up to a total time of 1 year) were retrospectively evaluated and the incidence and character of neurologic and neuropsychiatric complications were determined. RESULTS: Significant neurologic and neuropsychiatric complications were observed in 3 of the 29 patients. Dose modifications were required in 2 cases. One case developed parkinsonism and treatment had to be stopped after 10 applications of intravenous interferon. CONCLUSION: High dose interferon can cause depression and parkinsonism. Prophylaxis with antidepressant medication can keep the incidence of depression as low as 10% or lower. Development of parkinsonism during HDI is rare. According to available reports, this is the first description of parkinsonism development related to HDI in MM. Key words malignant melanoma - high dose interferon - neurologic and neuropsychiatric complication - drug-induced depression - drug-induced  parkinsonism The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 7. 4. 2018 Accepted: 16. 8. 2018.

Microstructural white matter alterations in patients with drug induced parkinsonism.

Drug-induced parkinsonism (DIP) is the second most common etiology of parkinsonism. And yet, there is little information on structural imaging in DIP to elucidate the accurate underlying pathomechanisms. To investigate microstructural white matter (WM) in patients with DIP using diffusion tensor image and to determine its relationship to severity of parkinsonian motor symptoms and cognitive function. A total of 42 patients with DIP, 65 with Parkinson's disease, and 33 control subjects were recruited from a movement disorders outpatient clinic. We performed comparative analysis of fractional anisotropy (FA) and mean diffusivity (MD) values among groups using tract-based spatial statistics. Correlation analysis between WM integrity and parkinsonian motor symptoms and cognitive performance was also performed in DIP patients using voxel-wise statistical analysis. DIP patients had significantly lower FA and higher MD values over widespread WM areas than control subjects. The patients with DIP had poor cognitive performance relative to control subjects, which correlated well with WM properties. Additionally, the parkinsonian motor symptoms were negatively correlated with FA values. In contrast, exposure time to the offending drugs prior to the development of parkinsonism or duration of parkinsonism showed no significant association with FA or MD values. The present study demonstrates that disruption of the WM microstructure is extensive in patients with DIP, and it is correlated with clinical parameters of parkinsonism and cognitive performance. This suggests that DIP may be reflective of underlying abnormality of microstructural WM. Hum Brain Mapp 38:6043-6052, 2017. © 2017 Wiley Periodicals, Inc.

Incidence and time trends of drug-induced parkinsonism: A 30-year population-based study.

BACKGROUND: Epidemiological studies of drug-induced parkinsonism remain limited. OBJECTIVES: To investigate the incidence and time trends of drug-induced parkinsonism over 30 years in a geographically defined American population. METHODS: We used the medical records-linkage system of the Rochester Epidemiology Project to identify all persons in Olmsted County, Minnesota, who received a screening diagnostic code for parkinsonism from 1976 through 2005. A movement disorders specialist reviewed the complete medical records of each person to confirm the presence of drug-induced parkinsonism associated with dopamine-blocking or dopamine-depleting medications. RESULTS: Among 906 incident cases of parkinsonism from 1976 to 2005, 108 persons had drug-induced parkinsonism (11.9%). The average annual incidence rate of drug-induced parkinsonism was 3.3 per 100,000 person-years, was higher in women, and increased with older age. Drug-induced parkinsonism was the fifth-most common type of parkinsonism overall; however, it was the most common type among persons younger than age 40 years. Typical antipsychotic drugs were the most common class of drugs associated with parkinsonism, whereas atypical antipsychotic drugs were rarely involved. The incidence rate of drug-induced parkinsonism decreased 32.0% per decade (relative risk = 0.68; 95% confidence interval: 0.49-0.94) and 68.6% over the 30 years of the study. The decrease was similar in men (65.2%) and women (69.4%); however, the trend was significant only in women. CONCLUSIONS: The incidence of drug-induced parkinsonism increased with older age and was higher in women at all ages. Typical antipsychotic drugs were the most common cause. The incidence of drug-induced parkinsonism decreased over the 30 years of the study because of changes in drug use. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Risk of parkinsonism induced by flunarizine or cinnarizine: a population-based study.

PURPOSE: This retrospective cohort study used a population-based dataset to test the risk for parkinsonism in patients receiving flunarizine and cinnarizine, compared with matched controls. METHODS: Data were obtained from the National Health Insurance Research Dataset of Taiwan. Patients receiving flunarizine or cinnarizine for more than 1 month between 2000 and 2005 were enrolled. Exclusion criteria included receiving flunarizine, cinnarizine, or antipsychotics for more than 1 month during 1997-1999, a history of neurodegenerative diseases, and an age of less than 30 years. One matched control for each patient was selected. Each participant was followed for diagnosis of parkinsonism within a 3-year observation period. Stroke, diabetes mellitus, total prescription days, and doses of flunarizine or cinnarizine were recorded. RESULTS: The study and control groups consisted of 9830 subjects. In the study group, 280 patients (2.9 %) were diagnosed with parkinsonism with a median observation period of 1.2 years, and 49 participants (0.5 %) were diagnosed in the control group with a median observation period of 1.9 years. The adjusted hazard ratio for parkinsonism among patients receiving flunarizine and cinnarizine was 5.117 (95 % CI = 3.758-6.967). Age, stroke, and diabetes mellitus were significant risk factors, but female sex and total doses of the study drugs were not. CONCLUSIONS: This study demonstrates that flunarizine and cinnarizine significantly increase the risk for parkinsonism. The treatment benefits of these two agents should be balanced with this adverse effect. Physicians must look carefully for early signs of parkinsonism in patients treated with flunarizine and cinnarizine.