Publications by authors named "Carlos Singer"

126 Publications

Amantadine Revisited: A Contender for Initial Treatment in Parkinson's Disease?

CNS Drugs 2021 Oct 14. Epub 2021 Oct 14.

Department of Neurology, University of Miami Miller School of Medicine, 1150 NW 14th Street, Suite 609, Miami, FL, 33136, USA.

The best practice for the initiation of symptomatic motor treatment for Parkinson's disease is an ongoing topic of debate. Fueled by interpretation of the results of the LEAP and MED Parkinson's disease studies, many practitioners opt for early initiation of levodopa formulations, avoiding dopamine agonists to circumvent potential deleterious side effects, namely impulse control disorder. Compared with levodopa, monoamine oxidase inhibitors may lack necessary potency. Ignored in this academic debate is another therapeutic option for patients with Parkinson's disease requiring treatment initiation: amantadine. Amantadine was first reported effective in the treatment of Parkinson's disease in 1969 and several studies were published in the 1970s supporting its efficacy. Currently, amantadine is mainly utilized as an add-on therapy to mitigate levodopa-related dyskinesia and, more recently, new long-acting amantadine formulations have been developed, with new indications to treat motor fluctuations. Amantadine has not been reported to cause dyskinesia and is rarely implicated in impulse control disorder.
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http://dx.doi.org/10.1007/s40263-021-00862-5DOI Listing
October 2021

Do Benzodiazepines Impair Motor and Nonmotor Symptoms in a Sample of Parkinson's Disease Patients?

Cureus 2021 Feb 8;13(2):e13220. Epub 2021 Feb 8.

Neurology, University of Miami, Miami, USA.

Background Anxiety and sleep disturbances are prevalent in Parkinson's disease (PD). Benzodiazepines (BZDs) are commonly used to treat these symptoms; however, they are associated with unfavorable side effects such as falls and cognitive slowing in the general non-PD population. Examining the effects of BZDs in PD is imperative as these medications could pose an increased risk to PD patients who are already vulnerable to falls and cognitive deficits. Methods Eighty-four patients diagnosed with idiopathic PD, of which 60% were Hispanic, underwent clinical evaluations including the Unified Parkinson's Disease Rating Scale (UPDRS) and comprehensive neuropsychological testing examining global cognition, language, visuospatial skills, memory, executive function, mood, and sleep quality. Thirty-six patients taking BZDs (BZD+) were compared to forty-eight patients not using any BZDs (BZD-) employing appropriate statistical tests depending on the measures' characteristics. Results BZD+ PD patients performed below the BZD- group on short-term memory but not on delayed recall, and performed better on a measure of visuospatial judgment. The BZD+ group endorsed more symptoms of anxiety and depression as well as poorer sleep quality. No significant differences were noted on other measures of cognition or motor function. Conclusion PD patients taking BZDs may experience select changes in cognition and mood. These changes are isolated and mild, and suggest that for some patients, BZDs may be a viable pharmacologic intervention that does not alter cognitive and motor function compared to those not taking these medications.
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http://dx.doi.org/10.7759/cureus.13220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945787PMC
February 2021

Novel Variants in and Identified in Latino Parkinson Disease Cohort Enriched for Caribbean Origin.

Front Neurol 2020 12;11:573733. Epub 2020 Nov 12.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States.

The Latino population is greatly understudied in biomedical research, including genetics. Very little information is available on presence of known variants originally identified in non-Hispanic white patients or novel variants in the Latino population. The Latino population is admixed, with contributions of European, African, and Amerindian ancestries. Therefore, the ancestry surrounding a gene (local ancestry, LA) can be any of the three contributing ancestries and thus can determine the presence or risk effect of variants detected. We sequenced the major exons and exons of reported Latino-specific variants in and and performed genome-wide genotyping for LA assessments in 79 Latino Parkinson disease (PD) patients, of which ~80% identified as Caribbean Latino. We observed five carriers of LRRK2 p.G2019S, one GBA p.T408M, and three GBA p.N409S on European as well as three GBA p.L13R on African LA backgrounds. Previous Latino variant GBA p.K237E was not observed in this dataset. A novel highly conserved and predicted damaging variant LRRK2 p.D734N was identified in two unrelated individuals with African LA. Additionally, we identified rare, functional variants LRRK2 p.P1480L and GBA p.S310G in one individual each heterozygous for European/Amerindian LA. Additional functional analysis will be needed to determine the pathogenicity of the novel variants in PD. However, the identification of novel disease variants in the Latino cohort potentially contributing to PD supports to importance of inclusion of Latinos in genetics research to provide insight in PD genetics in Latinos specifically as well as other populations with the same ancestral contributions.
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http://dx.doi.org/10.3389/fneur.2020.573733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689018PMC
November 2020

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.

J Clin Med 2020 Nov 16;9(11). Epub 2020 Nov 16.

Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington's disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington's Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.
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http://dx.doi.org/10.3390/jcm9113682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696926PMC
November 2020

The retina as a window to the basal ganglia: Systematic review of the potential link between retinopathy and hyperkinetic disorders in diabetes.

Parkinsonism Relat Disord 2020 11 13;80:194-198. Epub 2020 Oct 13.

The Edmond J. Safra Program in Parkinson Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Division of Neurology, Department of Medicine, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.

There is evidence that glycemic fluctuations trigger vascular-mediated dysfunction in both the retina and the striatopallidal regions in patients with diabetes. The latter is associated with a variety of hyperkinetic disorders that are rare but disabling and potentially preventable. We conducted a systematic review of the potential association between diabetic retinopathy and the risk and prognosis of hyperkinetic disorders in patients with diabetes. We identified a total of 461 articles and 147 were eligible for review. Nine out of 147 articles (6.12%) reported 13 patients with information on diabetic retinopathy. Glycemic fluctuations were present at onset in 10 patients (77%) and retinopathy was present in nine of them (69.23%). The degree of retinopathy was reported in four patients. Two had severe, bilateral proliferative retinopathy, one had moderate-to-severe non-proliferative retinopathy and one had non-proliferative retinopathy. In the nine patients with retinopathy, hyperkinesia persisted, required higher doses of dopamine receptor antagonists or deep brain stimulation. Retinopathy was absent in four cases (30.77%). In these patients, hyperkinesia resolved spontaneously or with lower doses of dopamine receptor antagonists. Diabetic retinopathy could be an indirect marker of striatopallidal microangiopathy in patients with diabetes. The severity of retinopathy may be associated with increased risk or worse prognosis for patients who develop hyperkinetic disorders of the diabetic striatopathy spectrum. Early detection of retinopathy could identify patients in which avoiding glycemic fluctuations may prevent the development of striatopathy and hyperkinetic disorders.
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http://dx.doi.org/10.1016/j.parkreldis.2020.10.025DOI Listing
November 2020

Transtentorial Fluctuations and Atypical Parkinsonism After Ventriculo-Peritoneal Shunting.

Can J Neurol Sci 2021 07 16;48(4):582-584. Epub 2020 Oct 16.

Division of Movement Disorders, Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA.

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http://dx.doi.org/10.1017/cjn.2020.228DOI Listing
July 2021

Palliative Care in Parkinson Disease-Is It Beneficial for All?

JAMA Neurol 2020 11;77(11):1450

Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida.

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http://dx.doi.org/10.1001/jamaneurol.2020.3212DOI Listing
November 2020

Minority Enrollment in Parkinson's Disease Clinical Trials: Meta-Analysis and Systematic Review of Studies Evaluating Treatment of Neuropsychiatric Symptoms.

J Parkinsons Dis 2020 ;10(4):1709-1716

Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.

Background: Randomized clinical trials (RCTs) in Parkinson's disease (PD) have historically enrolled a low number of underrepresented minorities, lessening the generalizability of therapeutic developments. Although there are racial disparities in PD, little is known regarding neuropsychiatric symptoms and other nonmotor manifestations across all races/ethnicities.

Objective: To assess minority participation in PD trials evaluating the treatment of neuropsychiatric symptoms and explore underlying reasons.

Methods: We systematically searched PubMed and Embase for RCTs with a primary goal of treating neuropsychiatric symptoms in PD patients from 2000-2019. The pooled prevalence and 95% confidence interval (CI) of being white and enrolled in a clinical trial was calculated using the inverse variance method. I-square was calculated as a measure of heterogeneity and meta-regression was used to evaluate temporal trends.

Results: We included 63 RCTs with a total of 7,973 patients. In pooled analysis, 11 (17.5%) RCTs reported race/ethnicity. Of studies reporting this data, 5 African American (0.2%), 16 Hispanics (0.64%), and 539 Asians (21.44%) were enrolled. The pooled prevalence of being white in clinical trials was 98% (CI 0.97-0.98, p < 0.001), with 1,908 patients (75.8%). NIH-funded studies were most likely to report racial data when compared to non-NIH trials (p = 0.032).

Conclusion: This large pooled analysis found a small percentage of RCTs reporting race/ethnicity when evaluating treatment of neuropsychiatric symptoms in PD. There was a disproportionally high number of white patients when compared to African Americans and Hispanics. More studies are needed to investigate this discrepancy and improve rates of & minority enrollment in PD trials.
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http://dx.doi.org/10.3233/JPD-202045DOI Listing
September 2021

From Mucuna Pruriens to deep brain stimulation: A two-decade case history.

Parkinsonism Relat Disord 2020 08 21;77:26-27. Epub 2020 Jun 21.

University of Miami Miller School of Medicine, Department of Neurology, United States.

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http://dx.doi.org/10.1016/j.parkreldis.2020.06.014DOI Listing
August 2020

Trends of inpatient palliative care use among hospitalized patients with Parkinson's disease.

Parkinsonism Relat Disord 2020 08 13;77:13-17. Epub 2020 Jun 13.

Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.

Introduction: Palliative care in Parkinson's Disease (PD) is an effective intervention to improve quality of life, although historically, access and availability have been very restricted.

Methods: We performed a retrospective cohort study using the National Inpatient Sample (NIS) data from 2007 to 2014. Diagnostic codes were used to identify patients with PD and palliative care referral. Trends were calculated and logistic analysis performed to identify predictors of palliative care use.

Results: We identified 397,963 hospitalizations from 2007 to 2014 for patients with PD. Of these, 10,639 (2.67%) were referred to palliative care. The rate of consultation increased from 0.85% in 2007 to 4.49% in 2014. For 1 unit in year increase, there was 1.23 time the odds of receiving palliative consultation (OR 1.23, CI 1.21-1.25, p < 0.0001). Hispanics (OR 0.90, CI 0.81-1.01, p = 0.0550), Black (OR 0.90, CI 0.81-1.01, p = 0.0747) and White patients had similar rates of referral after adjustment. Women were less likely to be referred to palliative care (OR 0.90, CI 0.87-0.94, p < 0.0001). Other factors strongly associated with a higher rate of referrals included private insurance when compared to Medicare (OR 2.14, CI 1.89-2.41, p < 0.0001) and higher income (OR 1.41, CI 1.30-1.53, p < 0.0001).

Conclusion: There has been a significant increase in palliative care referrals among hospitalized patients with PD in the US, although the overall rate remains low. After controlling for confounders, racial and ethnic disparities were not found. Women, patients with Medicare/Medicaid, and those with lower income were less likely to be referred to palliative care.
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http://dx.doi.org/10.1016/j.parkreldis.2020.06.011DOI Listing
August 2020

Parkinson Disease.

Clin Geriatr Med 2020 02 5;36(1):xiii-xiv. Epub 2019 Oct 5.

Department of Neurology, University of Maryland School of Medicine, 110 South Paca Street, 3rd Floor, Baltimore, MD 21201, USA. Electronic address:

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http://dx.doi.org/10.1016/j.cger.2019.10.001DOI Listing
February 2020

Management of Urologic and Sexual Dysfunction in Parkinson Disease.

Clin Geriatr Med 2020 02 10;36(1):69-80. Epub 2019 Sep 10.

Department of Neurology, University of Miami Miller School of Medicine, 1150 Northwest 14th Street, Suite 609, Miami, FL 33136, USA.

Parkinson disease (PD) is a complex of motor and nonmotor symptoms. Among the nonmotor symptoms, urinary and sexual dysfunctions are common and negatively affect the quality of life. More than 50% of patients with PD complain of urinary dysfunction and 20% have sexual dysfunction. Understanding the anatomy and physiology of the urogenital system informs the rationale for the mechanism of action of drug therapies. The management of urinary and sexual dysfunction in PD, including behavioral, medical, and procedural interventions, is reviewed in this article.
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http://dx.doi.org/10.1016/j.cger.2019.09.011DOI Listing
February 2020

A Phase 3, 1-Year, Open-Label Trial of Valbenazine in Adults With Tardive Dyskinesia.

J Clin Psychopharmacol 2019 Nov/Dec;39(6):620-627

Neurocrine Biosciences, Inc., San Diego, CA.

Purpose/background: Valbenazine is approved to treat tardive dyskinesia (TD) in adults. KINECT 4 (NCT02405091) was conducted to explore the long-term effects of once-daily valbenazine in patients with TD.

Methods/procedures: The study included a 48-week, open-label treatment period and 4-week washout. Dosing was initiated at 40 mg/d, with escalation to 80 mg/d at week 4 based on efficacy and tolerability. Standard safety methods were applied, including treatment-emergent adverse event (TEAE) reporting. Valbenazine effects on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD, and Patient Global Impression of Change.

Findings/results: After week 4, <15% of all participants had a serious TEAE (13.7%) or TEAE leading to discontinuation (11.8%). Participants experienced TD improvements during long-term treatment as indicated by mean change from baseline to week 48 in AIMS total score (sum of items 1-7, evaluated by site raters) with valbenazine 40 mg/d (-10.2 [n = 45]) or 80 mg/d (-11.0 [n = 107]). At week 48, most participants had ≥50% improvement from baseline in AIMS total score (40 mg/d, 90.0%; 80 mg/d, 89.2%), Clinical Global Impression of Change-TD rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 95.9%), and Patient Global Impression of Change rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 89.2%). No dose effects were apparent by week 36. Week 52 results indicated some loss of effect after washout.

Implications/conclusions: Valbenazine was generally well tolerated, and no new safety concerns were detected. Substantial clinician- and patient-reported improvements were observed in adults with TD who received once-daily valbenazine for up to 48 weeks.
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http://dx.doi.org/10.1097/JCP.0000000000001111DOI Listing
April 2020

Motivations for Participation in Parkinson Disease Genetic Research Among Hispanics versus Non-Hispanics.

Front Genet 2019 16;10:658. Epub 2019 Jul 16.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States.

Involvement of participants from different racial and ethnic groups in genomic research is vital to reducing health disparities in the precision medicine era. Racial and ethnically diverse populations are underrepresented in current genomic research, creating bias in result interpretation. Limited information is available to support motivations or barriers of these groups to participate in genomic research for late-onset, neurodegenerative disorders. To evaluate willingness for research participation, we compared motivations for participation in genetic studies among 113 Parkinson disease (PD) patients and 49 caregivers visiting the Movement Disorders clinic at the University of Miami. Hispanics and non-Hispanics were equally motivated to participate in genetic research for PD. However, Hispanic patients were less likely to be influenced by the promise of scientific advancements ( = 0.01). This lack of scientific interest, but not other motivations, was found to be likely confounded by lower levels of obtained education ( = 0.001). Overall, these results suggest that underrepresentation of Hispanics in genetic research may be partly due to reduced invitations to these studies.
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http://dx.doi.org/10.3389/fgene.2019.00658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646686PMC
July 2019

Gender Disparities in Deep Brain Stimulation for Parkinson's Disease.

Neuromodulation 2019 Jun 23;22(4):484-488. Epub 2019 May 23.

University of Miami Miller School of Medicine, Department of Neurology, Miami, FL, USA.

Objectives: This study sought to determine whether there is a gender disparity in patients undergoing deep brain stimulation (DBS) surgery for Parkinson's disease (PD) at a single health system, and better understand the reasons for this discrepancy.

Materials And Methods: We analyzed data from the University of Miami DBS Database, which included 3251 PD patients, using chi-square, repeated measures ANOVA, and t tests to examine gender differences in the number of patients referred for surgery, reasons for referral, number receiving/not receiving surgery, reasons for not receiving surgery, and postsurgical outcomes.

Results: During the study period, 207 PD patients were referred for DBS (75.8% male), and 100 underwent surgery (77.0% male). Of those who did not receive surgery, the most common reasons were need for further medical optimization (26.2%), suboptimal performance on neuropsychological evaluation (22.4%), other reason (20.6%), lost to follow-up (18.7%), or patient preference (12.2%). However, in women one of the most common reasons was patient preference (28.0%), and this was significant compared to men (p < 0.001). Men were more likely to be lost to follow-up (p = 0.046). There was no statistically significant difference in postsurgical outcomes.

Conclusions: Despite similar postsurgical improvements, women were less likely to undergo DBS surgery due to their own preference, while men were more likely to be lost to follow-up. These data underscore the need for increased education and awareness of DBS so that all patients with PD who qualify for surgery can benefit from this procedure.
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http://dx.doi.org/10.1111/ner.12973DOI Listing
June 2019

The Parkinson's Disease Sleep Scale-2 (PDSS-2): Validation of the Spanish Version and Its Relationship With a Roommate-Based Version.

Mov Disord Clin Pract 2019 Apr 18;6(4):294-301. Epub 2019 Mar 18.

Movement Disorders Unit, Neurology department La Paz University Hospital Madrid Spain.

Background: Because of the prevalence and impact of sleep disorders in Parkinson's disease (PD), valid instruments for their evaluation and monitoring are necessary. However, some nocturnal sleep disorders may go unnoticed by patients themselves.

Objectives: To validate a pan-Spanish version of the Parkinson's Disease Sleep Scale Version 2 (PDSS-2) and to test the relationships between the PDSS-2 and a PDSS-2 roommate version.

Methods: PD patients (n = 399) from seven Spanish-speaking countries were included. In addition to the tested PDSS-2 scales, valid measures for sleep disorders and both motor and nonmotor manifestations were applied. Acceptability, dimensionality, reliability, precision, and construct validity were explored, as well as discrepancies and agreement between the PDSS-2 and the roommate version.

Results: PDSS-2 showed negligible floor and ceiling effects. Four factors (57% of the variance) were identified. Reliability parameters were satisfactory: alpha = 0.84; item homogeneity coefficient = 0.27; corrected item total correlation = 0.28 to 0.61; and test-retest reliability (average kappa = 0.70; intraclass correlation coefficient [ICC] = 0.83). The standard error of measurement was 5.84, and correlations with other scales assessing nocturnal sleep were high (r = 0.62-0.56). In comparison to the patient-based total score, the by proxy total score showed no significant difference, high correlation (r = 0.70), and acceptable agreement (ICC = 0.69), but there were discrepancies in two or more points in 18% of item scores.

Conclusions: The Spanish version of the PDSS-2 has shown satisfactory clinimetric attributes. Acceptability and precision data are presented for the first time. The PDSS-2 roommate version could be useful to complement the patient-based evaluation, but additional studies are needed.
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http://dx.doi.org/10.1002/mdc3.12749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476589PMC
April 2019

Tandem gait abnormality in Parkinson disease: Prevalence and implication as a predictor of fall risk.

Parkinsonism Relat Disord 2019 06 23;63:83-87. Epub 2019 Feb 23.

University of Miami Miller School of Medicine, Miami, FL, USA.

Introduction: We report the prevalence of abnormal tandem gait (TG) in patients with idiopathic Parkinson disease (PD) and its association with symptoms of subjective unsteadiness, falls, freezing of gait, and cognitive impairment.

Methods: We assessed subjective balance impairment, fall history, antero-posterior postural instability, and TG in PD patients (Hoehn and Yahr (HY) stage 0-4). We recorded the age, sex, current medications, HY stage, Schwab and England (S&E) scale score, and MOCA score for each patient. Logistic regression was used to evaluate age-adjusted associations between TG and other demographic and clinical factors.

Results: A total of 102 patients with PD were assessed. Of those, 63.5% of HY 2 patients and 100% of HY 2.5 and 3 patients had a TG abnormality. The presence of TG abnormality was associated with subjective imbalance, falls, freezing of gait, S&E < 80, and MOCA score <24 after adjustment for age.

Conclusions: TG abnormality is common in PD, precedes the development of antero-posterior postural instability, is associated with cognitive impairment, and may predict fall risk. A longitudinal study will help determine if TG is a predictor of impending progression from HY 2 to HY 3.
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http://dx.doi.org/10.1016/j.parkreldis.2019.02.034DOI Listing
June 2019

Revisiting eligibility for deep brain stimulation: Do preoperative mood symptoms predict outcomes in Parkinson's disease patients?

Parkinsonism Relat Disord 2019 06 16;63:131-136. Epub 2019 Feb 16.

University of Miami, Department of Neurology, 1150 NW 14th Street Miami, 33136, Florida, USA.

Introduction: Anxiety and depression are common in PD, occurring in an estimated 30%-40% of PD patients. However, the extent to which these emotional symptoms interfere with Deep Brain Stimulation (DBS) outcomes is not well established. This study examined the association between pre-operative emotional well-being and postsurgical cognitive, emotional, and motor performance in PD.

Methods: Forty-nine PD patients underwent neurological, neuropsychological (global cognition, processing speed, language, visuospatial, memory), and emotional assessments pre- and post-DBS. Fifteen patients were administered the UPDRS. Patients were divided into Anxious (Anx; n = 21), Comorbid Anxious and Depressed (Anx + Dep; n = 15), and Emotionally Asymptomatic (EA; n = 13) based on BAI and BDI-II cutoffs, and compared on pre-post changes in neurocognitive, mood, and motor scores using analyses of covariance (ANCOVA), controlling for education, ethnicity, and disease duration.

Results: Pre-DBS, there were no significant differences between the three groups on any neuropsychological measure. Overall change from pre-to post-DBS revealed declines on multiple cognitive measures and lower symptom endorsement on the BAI among all participants. No group differences were observed on neurocognitive measures, mood, or UPDRS.

Conclusions: PD patients with mild-moderate anxiety or comorbid anxiety/depression pre-DBS do not show greater cognitive, emotional, and motor changes post-DBS compared to emotionally asymptomatic patients. These data emphasize the importance of discussing potential DBS outcomes, while keeping in mind that psychiatric comorbidity should not necessarily exclude patients from DBS. The notion that premorbid mood symptoms could disqualify a candidate for surgery would be a disservice, as this group performs comparably to asymptomatic peers.
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http://dx.doi.org/10.1016/j.parkreldis.2019.02.019DOI Listing
June 2019

Teaching NeuroImages: Severe spasms resembling status dystonicus as an unusual presentation of stiff-person syndrome.

Neurology 2019 02;92(7):e748

From the Department of Neurology, University of Miami Miller School of Medicine, FL.

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http://dx.doi.org/10.1212/WNL.0000000000006925DOI Listing
February 2019

A Co-occurrence of Trinucleotide Repeat Disorders.

Mov Disord Clin Pract 2018 Nov-Dec;5(6):643-644. Epub 2018 Sep 30.

University of Miami Miller School of Medicine Miami Florida USA.

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http://dx.doi.org/10.1002/mdc3.12664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277356PMC
September 2018

Dancing Dorsal Quadrilaterals: A Novel Peripherally Induced Movement Disorder.

JAMA Neurol 2019 03;76(3):351-354

The Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Division of Neurology, University of Toronto, Toronto, Ontario, Canada.

Importance: Recognized peripherally induced movement disorders include the painful legs moving toes syndrome, postamputation dyskinesias, and belly dancer dyskinesias.

Objective: To introduce and characterize the dancing dorsal quadrilaterals, a novel peripherally induced movement disorder that predominantly affects dorsal quadrilateral muscles (trapezius and rhomboids) after upper spine instrumentation.

Design, Setting, And Participants: Between 1990 and 2015, a total of 4 patients who developed abnormal movements of the dorsal quadrilateral muscles after upper spine instrumentation were referred to movement disorders clinics at 3 academic medical centers in the United States, Canada, and Argentina. A prospective and retrospective analysis of the clinical and electrophysiologic characteristics of their abnormal movements is presented in this brief report. Data were analyzed between July 2015 and January 2018.

Exposures: Extensive upper spine instrumentation complicated with misalignment and prolonged postsurgical neuropathic pain.

Main Outcomes And Measures: Video documentation of clinical and electrophysiologic characteristics of dancing dorsal quadrilaterals.

Results: Four patients with upper spine disease (2 women and 2 men, ranging in age from early 30s to early 70s) required extensive surgical manipulation and instrumentation that was complicated by misalignment, prolonged dorsal neuropathic pain, and unusual abnormal movements. These movements consisted of semirhythmic, repetitive writhing, and jerky movements of the scapular region with distinctive rotatory motions. They are referred to as the dancing dorsal quadrilaterals because they predominantly affected the bilateral trapezius and rhomboids (dorsal quadrilateral muscles) but could spread to adjacent muscles, and they are similar in appearance and possibly pathogenesis to "belly dancer" dyskinetic movements. The movements of the dancing dorsal quadrilaterals occur when upright but not when lying down or during voluntary muscle activation. Sensory stimulation also diminishes the movements. Long-duration bursts of normal motor unit potentials with normal recruitment pattern were evidenced.

Conclusions And Relevance: The dancing dorsal quadrilaterals syndrome represents a further example of a peripherally induced movement disorder characterized by neuropathic pain preceding a regional movement disorder following soft-tissue or nerve injury.
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http://dx.doi.org/10.1001/jamaneurol.2018.3948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439723PMC
March 2019

Hemodynamic responses to an exercise stress test in Parkinson's disease patients without orthostatic hypotension.

Appl Physiol Nutr Metab 2019 Jul 6;44(7):751-758. Epub 2018 Dec 6.

a Laboratory of Neuromuscular Research & Active Aging, Department of Kinesiology and Sport Sciences, University of Miami, Coral Gables, FL 33146, USA.

The presence of postganglionic sympathetic denervation is well established in Parkinson's disease (PD). Denervation at cardiac and blood vessel sites may lead to abnormal cardiovascular and hemodynamic responses to exercise. The aim of the present investigation was to examine how heart rate (HR) and hemodynamics are affected by an exercise test in PD patients without orthostatic hypotension. Thirty individuals without orthostatic hypotension, 14 individuals with PD, and 16 age-matched healthy controls performed an exercise test on a cycle ergometer. Heart rate, blood pressure, and other hemodynamic variables were measured in a fasted state during supine rest, active standing, exercise, and supine recovery. Peak HR and percent of age-predicted maximum HR (HR) achieved were significantly blunted in PD ( < 0.05, < 0.01). HR remained significantly elevated in PD during recovery compared with controls ( = 0.03, < 0.05). Systolic, diastolic, and mean arterial pressures were significantly lower at multiple time-points during active standing in PD compared with controls. Systemic vascular resistance index (SVRI) decreased significantly at the onset of exercise in PD, and remained significantly lower during exercise and the first minute of supine recovery. End diastolic volume index (EDVI) was significantly lower in PD during supine rest and recovery. Our results indicate for the first time that normal hemodynamics are disrupted during orthostatic stress and exercise in PD. Despite significant differences in EDVI at rest and during recovery, and SVRI during exercise, cardiac index was unaffected. Our finding of significantly blunted HR and HR recovery in PD patients has substantial implications for exercise prescription and recovery guidelines.
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http://dx.doi.org/10.1139/apnm-2018-0638DOI Listing
July 2019

Safinamide in the management of patients with Parkinson's disease not stabilized on levodopa: a review of the current clinical evidence.

Ther Clin Risk Manag 2018 18;14:1737-1745. Epub 2018 Sep 18.

Department of Neurology, Division of Parkinson's Disease and Movement Disorders, University of Miami - Miller School of Medicine, Miami, FL, USA,

Safinamide (Xadago) is a novel medication with both dopaminergic and non-dopaminergic effects, approved first by the European Commission and more recently by the US Food and Drug Administration (FDA) as an adjunctive treatment to carbidopa/levodopa in patients with mid- to late-stage Parkinson's disease (PD) and motor fluctuations. It works through multiple mechanisms, namely as a reversible selective monoamine oxidase-B inhibitor and through modulation of glutamate release. Safinamide is extensively metabolized via oxidation to several inactive metabolites that are excreted primarily through the urine. Several large Phase III clinical trials of patients with advanced PD with motor fluctuations have shown that safinamide, administered orally at doses of 50-100 mg daily, increased ON time with no or non-troublesome dyskinesia, decreased daily OFF time, improved overall motor function (as measured by Unified Parkinson's Disease Rating Scale [UPDRS] part III total score), and quality of life (as measured by Clinical Global Impression-Change and 39-item Parkinson's Disease Questionnaire). In large clinical trials of patients with early PD on a single dopamine agonist, safinamide administered orally at a dose of 100 mg daily improved overall motor function as measured by UPDRS part III total score; however, some of the results reported were exploratory. Safinamide is generally well-tolerated and safe, with few to no treatment-related adverse events. Safinamide does not cause new or worsening dyskinesia and may be able to reduce this symptom in patients reporting it at baseline. Evidence suggests that safinamide is a good option for add-on therapy to carbidopa/levodopa in patients with advanced PD with motor complications, but there is still insufficient evidence to recommend it as monotherapy or add-on therapy in patients with early PD.
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http://dx.doi.org/10.2147/TCRM.S139545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152599PMC
September 2018

Author Correction to: Pooled Analyses of Phase III Studies of ADS-5102 (Amantadine) Extended-Release Capsules for Dyskinesia in Parkinson's Disease.

CNS Drugs 2018 04;32(4):399-400

Adamas Pharmaceuticals, Inc., Emeryville, CA, USA.

An Online First version of this article was made available online at http://link.springer.com/journal/40263/onlineFirst/page/1 on 12 March 2018. An error was subsequently identified in the article, and the following correction should be noted.
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http://dx.doi.org/10.1007/s40263-018-0510-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828147PMC
April 2018

Relationship between the MDS-UPDRS and Quality of Life: A large multicenter study of 3206 patients.

Parkinsonism Relat Disord 2018 07 28;52:83-89. Epub 2018 Mar 28.

Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS_1127, CIC_1422, CNRS UMR_7225, AP-HP, ICM, Hôpital Pitié-Salpêtrière, Département des maladies du système nerveux, F-75013, Paris, France.

Background: The relationship between Health-Related Quality of Life (HRQoL) and MDS-UPDRS has not been fully studied so far. The aim of this study was to evaluate the relationship between all MDS-UPDRS components and HRQoL in a representative international cohort of PD patients.

Methods: We collected demographic and disease-related data as well as MDS-UPDRS and PDQ8 scales. Data were analyzed using correlations between PDQ8 and all MDS-UPDRS items, subsequently two hierarchical multiple regressions were performed, first between the scores of the MDS-UPDRS Parts and PDQ8 and second between individual items from those Parts demonstrating significant relationship to PDQ8 scores in the first regression. LASSO regression analyses were performed to evaluate the relationship between PDQ8 and all individual MDS-UPDRS items.

Results: A total of 3206 PD patients were included in the study. In the first regression analysis, PDQ8 was significantly related to MDS-UPDRS parts I and II, but not to III and IV. In the second regression model, significant contributions to PDQ8 were found for Part I items Fatigue, Pain, Depressed mood, Apathy; and Part II items Dressing, Doing hobbies, Freezing, Speech and Tremor. In the LASSO analysis, six Part I, seven Part II, three Part III and one Part IV items contributed to PDQ8 scores. The five items most significantly related to the model were Depressed mood, Dressing, Apathy, Pain and Fatigue.

Conclusions: This is so far the largest study related to HRQoL issues in PD. Restrictions in activities of daily living and non-motor symptoms significantly contribute to HRQoL in PD.
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http://dx.doi.org/10.1016/j.parkreldis.2018.03.027DOI Listing
July 2018

Pooled Analyses of Phase III Studies of ADS-5102 (Amantadine) Extended-Release Capsules for Dyskinesia in Parkinson's Disease.

CNS Drugs 2018 04;32(4):387-398

Adamas Pharmaceuticals, Inc., Emeryville, CA, USA.

Background: Although levodopa is considered the most effective pharmacotherapy for motor symptoms of Parkinson's disease (PD), chronic use is associated with motor complications, including fluctuating response and unpredictable, involuntary movements called dyskinesia. ADS-5102 (amantadine) extended-release (ER) capsules (GOCOVRI) is a recent US FDA-approved treatment for dyskinesia in PD patients. ADS-5102 is a high-dose, ER formulation of amantadine, administered orally once daily at bedtime, that achieves high plasma drug concentrations throughout the day.

Objective: In this study, we present pooled results from two randomized, double-blind, placebo-controlled, phase III ADS-5102 trials.

Patients And Methods: The two studies in PD patients with dyskinesia shared design and eligibility criteria, differing only in treatment duration. Results from common assessment time points were pooled.

Results: At 12 weeks, the least squares (LS) mean change in total score on the Unified Dyskinesia Rating Scale among 100 patients randomized to ADS-5102 and 96 patients randomized to placebo was - 17.7 (standard error [SE] 1.3) vs. - 7.6 (1.3) points, respectively (- 10.1 points, 95% confidence interval [CI] - 13.8, - 6.5; p < 0.0001). The relative treatment difference between groups was 27.3% (p < 0.0001). At 12 weeks, the LS mean change in OFF time was - 0.59 (0.21) vs. +0.41 (0.20) h/day, a difference of - 1.00 h/day (95% CI - 1.57, - 0.44; p = 0.0006). For both efficacy measures, a significant difference from placebo was attained by two weeks, the first post-baseline assessment, and was maintained throughout 12 weeks. In the pooled ADS-5102 group, the most common adverse events were hallucination, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension.

Conclusions: These analyses provide further evidence supporting ADS-5102 as an adjunct to levodopa for treating both dyskinesia and OFF time in PD patients with dyskinesia. Clinicaltrials.gov identifier: NCT02136914 and NCT02274766.
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http://dx.doi.org/10.1007/s40263-018-0498-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934466PMC
April 2018

Extended-release oral capsule of carbidopa-levodopa in Parkinson disease.

Ther Adv Neurol Disord 2018 30;11:1756285617737728. Epub 2017 Oct 30.

University of Miami School of Medicine, 1150 NW 14th St, Suite 609, Miami, FL 33136-1015, USA.

Motor fluctuations complicate the treatment of patients with Parkinson's disease receiving levodopa. Extended-release carbidopa-levodopa has a pharmacokinetic profile that provides a more continuous levodopa serum concentration. Patients taking this formulation can expect longer duration of action and fewer doses per day, similar clinical improvement when compared to other levodopa formulations, and with a theoretically lower risk of developing motor fluctuations. Several studies, including three randomized control trials provide evidence for the efficacy, safety and tolerability of extended release carbidopa-levodopa in patients with both early and advanced Parkinson's disease are reviewed here. Also provided is guidance for dosing of and conversion to extended release carbidopa-levodopa as well as a discussion of its place in the clinical practice.
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http://dx.doi.org/10.1177/1756285617737728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784558PMC
October 2017

It is dopey to stop giving dopamine to hospitalized patients with Parkinson's disease.

Expert Rev Neurother 2018 01 20;18(1):1-3. Epub 2017 Oct 20.

a Department of Neurology , University of Miami Miller School of Medicine , Miami , FL , USA.

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http://dx.doi.org/10.1080/14737175.2017.1392857DOI Listing
January 2018

Association of metabolic syndrome and change in Unified Parkinson's Disease Rating Scale scores.

Neurology 2017 Oct 29;89(17):1789-1794. Epub 2017 Sep 29.

From the Department of Neurology (M.L.) and Department of Clinical Pharmacy (J.L.B.), Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Neurology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora; Department of Biostatistics (S.L., Y.Z.), University of Texas Health Science Center at Houston; Center for Human Experimental Therapeutics (S.S.), University of Rochester, NY; Department of Neurology (A.-M.A.W.), Massachusetts General Hospital and Harvard Medical School, Boston; Department of Pharmacy (P.S.W.), Singapore General Hospital; Department of Neurology (D.K.S.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; Department of Pathology, Anatomy, & Cell Biology (J.S.), Thomas Jefferson University, Philadelphia, PA; Department of Biostatistics (Y.Z.), School of Public Health, University of Texas Health Science Center, Houston; Department of Biostatistics (A.P.), School of Public Health, University of Texas Health Science Center at Houston-UTHealth, Austin; Department of Neurology (R.D.), University of Arkansas for Medical Sciences, Little Rock; Department of Neurology (C.W.C.), University of California San Francisco; Department of Neurology (C.S.), Leonard M. Miller School of Medicine, University of Miami, FL; Department of Neurology (F.C.), University of Pittsburgh, PA; and Department of Neurological Sciences (J.T.B.), Larner College of Medicine, University of Vermont, Burlington. Dr. Luo is currently with the Department of Biostatistics and Bioinformatics, Duke University, Durham, NC.

Objective: To explore the association between metabolic syndrome and the Unified Parkinson's Disease Rating Scale (UPDRS) scores and, secondarily, the Symbol Digit Modalities Test (SDMT).

Methods: This is a secondary analysis of data from 1,022 of 1,741 participants of the National Institute of Neurological Disorders and Stroke Exploratory Clinical Trials in Parkinson Disease Long-Term Study 1, a randomized, placebo-controlled trial of creatine. Participants were categorized as having or not having metabolic syndrome on the basis of modified criteria from the National Cholesterol Education Program Adult Treatment Panel III. Those who had the same metabolic syndrome status at consecutive annual visits were included. The change in UPDRS and SDMT scores from randomization to 3 years was compared in participants with and without metabolic syndrome.

Results: Participants with metabolic syndrome (n = 396) compared to those without (n = 626) were older (mean [SD] 63.9 [8.1] vs 59.9 [9.4] years; < 0.0001), were more likely to be male (75.3% vs 57.0%; < 0.0001), and had a higher mean uric acid level (men 5.7 [1.3] vs 5.3 [1.1] mg/dL, women 4.9 [1.3] vs 3.9 [0.9] mg/dL, < 0.0001). Participants with metabolic syndrome experienced an additional 0.6- (0.2) unit annual increase in total UPDRS ( = 0.02) and 0.5- (0.2) unit increase in motor UPDRS ( = 0.01) scores compared with participants without metabolic syndrome. There was no difference in the change in SDMT scores.

Conclusions: Persons with Parkinson disease meeting modified criteria for metabolic syndrome experienced a greater increase in total UPDRS scores over time, mainly as a result of increases in motor scores, compared to those who did not. Further studies are needed to confirm this finding.

Clinicaltrialsgov Identifier: NCT00449865.
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http://dx.doi.org/10.1212/WNL.0000000000004572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664310PMC
October 2017

How tandem gait stumbled into the neurological exam: a review.

Neurol Sci 2018 Jan 11;39(1):23-29. Epub 2017 Sep 11.

University of Miami School of Medicine, Professional Arts Center, 1150 NW 14th Street, Suite 609, Miami, FL, 33136, USA.

Tandem gait testing is an integral part of the neurological exam. It is informative in a wide variety of disorders ranging from cerebellar disease to vestibular and peripheral neuropathies, parkinsonism, and other neurodegenerative conditions. We discuss the history and development of tandem gait testing as well as its technique, utility, and limitations in the assessment of neurological conditions. Tandem gait has emerged as a tool in the assessment of cerebellar disease, Huntington disease, idiopathic Parkinson's disease, atypical parkinsonism, peripheral neuropathies, and vestibulopathies. Its origin can be deduced from experimental observation and clinical experience as far back as the early nineteenth century. Despite the long history and ubiquitous performance of tandem gait testing, there is no standardized, guideline-based protocol to model for more homogenous research and clinical practices. Such a protocol should be developed using historical texts and manuscripts as well as the consensus of the medical research community. With standard protocols, further studies could define the sensitivity of abnormal tandem gait testing in cerebellar disorders, more diffuse neurodegeneration, and peripheral pathologies. Tandem gait can be a useful marker of dysfunction in neurologic conditions whose pathologies extend beyond the vermis or vestibulocerebellar module to include interconnected networks throughout the nervous system.
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http://dx.doi.org/10.1007/s10072-017-3108-1DOI Listing
January 2018
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