Publications by authors named "Hubert H Fernandez"

221 Publications

Estimating the Risk of Deep Brain Stimulation in the Modern Era: 2008 to 2020.

Oper Neurosurg (Hagerstown) 2021 Oct;21(5):277-290

Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio, USA.

Background: Deep brain stimulation (DBS) was first approved by the United States Food and Drug Administration in 1997. Although the fundamentals of DBS remain the same, hardware, software, and imaging have evolved significantly.

Objective: To test our hypothesis that the aggregate complication rate in the medical literature in the past 12 years would be lower than what is often cited based on early experience with DBS surgery.

Methods: PubMed, PsycINFO, and EMBASE were queried for studies from 2008 to 2020 that included patients treated with DBS from 2007 to 2019. This yielded 34 articles that evaluated all complications of DBS surgery, totaling 2249 patients.

Results: The overall complication rate in this study was 16.7% per patient. There was found to be a systemic complication rate of 0.89%, intracranial complication rate of 2.7%, neurological complication rate of 4.6%, hardware complication rate of 2.2%, and surgical site complication rate of 3.4%. The infection and erosion rate was 3.0%.

Conclusion: This review suggests that surgical complication rates have decreased since the first decade after DBS was first FDA approved. Understanding how to minimize complications from the inception of a technique should receive more attention.
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http://dx.doi.org/10.1093/ons/opab261DOI Listing
October 2021

Impact of behavioral side effects on the management of Parkinson patients treated with dopamine agonists.

Clin Park Relat Disord 2021 2;4:100091. Epub 2021 Mar 2.

Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, USA.

Dopamine agonists are one of the main stay of treatment option for Parkinson disease (PD). Side effects that develop from their use are generally categorized into and . Behavioral side effects include: impulse control behavior disorder (ICD), psychosis and cognitive impairment. Non-behavioral side effects include: nausea/vomiting, "sleep attacks", leg swelling, weight gain and orthostasis. The aim of this study is to evaluate the clinicians' response to PD patients who developed behavioral side effects from dopamine agonists, in comparison to those patients who developed only non-behavioral side effects. We performed a retrospective chart review of all patients diagnosed with PD over a two year period. Among 313 patients who were on a dopamine agonist, 156 reported side effects. Sixty-five patients reported behavioral (with or without non-behavioral) side effects, while 91 experienced only non-behavioral side effects. Forty-nine out of the 65 patients (75.3%) who experienced behavioral side effects had their dopamine agonist dose decreased compared to 53 out of 91patients (58.2%) who experienced only non-behavioral side effects (Chi square = 4.92, p < 0.05). Patients with behavioral side effects were 3 times more likely have their dose decreased (OR = 3.3; 95%CI = 1.442-7.551; P = 0.005). However, neither taper speed nor the occurrence of dopamine agonist withdrawal syndrome (DAWS) differed between the two groups. Amongst PD patients treated with dopamine agonists, the presence of behavioral side effects independently increased the chance of dopamine agonist dose reduction. Prospective studies are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.prdoa.2021.100091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299972PMC
March 2021

An Open-Label Phase 2a Study to Evaluate the Safety and Tolerability of Perampanel in Cervical Dystonia.

Mov Disord Clin Pract 2021 Jul 13;8(5):743-749. Epub 2021 May 13.

Rush University Medical Centre Chicago Illinois USA.

Background: Cervical dystonia (CD) is the most common focal isolated dystonia. Preclinical studies report that AMPA-selective glutamate receptor antagonists improve dystonia. Perampanel is a clinically available, AMPA receptor antagonist that has shown efficacy and safety in epilepsy.

Objectives: To determine safety and tolerability of perampanel in CD.

Methods: We performed a phase 2a, open-label, multicenter study to evaluate tolerability and safety of perampanel in CD. Included subjects had primary CD; those on botulinum toxin were 8 weeks post last injection. All subjects received perampanel 2 mg/day, titrated 2 mg weekly over 6 weeks, to maximum 12 mg/day; maintenance phase was 4 weeks, ending at week 10. Primary endpoints included tolerability, defined as ability to remain on perampanel for the maintenance period, at any dose level and safety, determined from adverse events (AEs) collected at each visit. Secondary exploratory endpoints included Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), quality of life (cervical dystonia impact profile [CIDP]-58) and Clinical Global Impression of change (CGI).

Results: CD participants (n = 25) were recruited. Eight subjects withdrew; 4 because of AEs, 3 for other reasons and 1 lost to follow up. One subject tolerated 12 mg/day. Eight subjects (30.8%) tolerated 2 mg, whereas 19.2% tolerated 4 mg/day, and 15.4% tolerated 6 mg or 8 mg/day. All subjects experienced AEs. The most common AEs were dizziness, imbalance, and irritability. Exploratory endpoints of TWSTRS showed some improved pain scores and CIDP-58 improved sleep.

Conclusions: Tolerability to perampanel was variable in CD subjects. Lower doses would be considered for future studies in this population.
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http://dx.doi.org/10.1002/mdc3.13229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287187PMC
July 2021

Best Practices in the Clinical Management of Progressive Supranuclear Palsy and Corticobasal Syndrome: A Consensus Statement of the CurePSP Centers of Care.

Front Neurol 2021 1;12:694872. Epub 2021 Jul 1.

Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders.
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http://dx.doi.org/10.3389/fneur.2021.694872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284317PMC
July 2021

Long-Term Deutetrabenazine Treatment Is Associated With Continued Improvement in Tardive Dyskinesia in the Completed 3-Year Open-Label Extension Study.

CNS Spectr 2021 04;26(2):162

Georgetown University, Washington, DC, USA.

Background: The 12-week ARM-TD and AIM-TD studies in tardive dyskinesia (TD) patients showed statistically significant improvements in TD symptoms with deutetrabenazine. The completed open-label extension (OLE) study (SD-809-C-20) evaluated long-term efficacy and safety of deutetrabenazine in TD.

Methods: Patients who completed ARM-TD or AIM-TD enrolled in the OLE study, with deutetrabenazine dose titrated based on dyskinesia control and tolerability. Change from baseline in Abnormal Involuntary Movement Scale (AIMS) score was assessed by local site raters. Treatment success was evaluated locally as patients being "much improved" or "very much improved" on Clinical Global Impression of Change (CGIC).

Results: 343 patients enrolled in the OLE study; 6 patients were excluded from analyses. At Week 54 (n=249; dose [mean±SE]: 38.7±0.66mg/day), mean change from baseline in AIMS score was -4.8±0.28; 66% of patients experienced treatment success. At Week 106 (n=194; dose: 39.3±0.75mg/day), mean change from baseline in AIMS score was -5.4±0.33; 65% of patients experienced treatment success. At Week 145 (n=160; dose: 39.4±0.83mg/day), mean change from baseline in AIMS score was -6.6±0.37; 73% of patients experienced treatment success. Treatment was generally well tolerated across 723 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) for akathisia/restlessness were 0.01, somnolence/sedation were 0.07, and symptoms which may represent parkinsonism or depression were 0.08 each.

Conclusions: Patients who received long-term treatment with deutetrabenazine achieved sustained improvement in AIMS scores. Findings from this open-label trial with response-driven dosing suggest the possibility of increasing benefit over time.

Funding: Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.
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http://dx.doi.org/10.1017/S1092852920002606DOI Listing
April 2021

Effect of Deutetrabenazine on Metabolic Parameters in the Treatment of Tardive Dyskinesia.

CNS Spectr 2021 04;26(2):159-160

Teva Pharmaceuticals, Basel, Switzerland.

Background: Deutetrabenazine, a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved by the FDA for treatment of tardive dyskinesia (TD) in adults. Dopamine-receptor antagonists (DRAs) are associated with worsening of metabolic parameters, including weight gain, hyperlipidemia, and elevated blood glucose. This post hoc analysis assessed the short- and long-term effects of deutetrabenazine treatment on weight and metabolic parameters in individuals treated for TD.

Methods: Two 12-week, randomized placebo-controlled trials (RCTs) of deutetrabenazine for patients with TD evaluated either fixed dosing (AIM-TD; 12, 24, or 36 mg) or dose titration (ARM-TD; max dose, 48 mg/day). Patients completing ARM-TD or AIM-TD were included in an open-label extension (OLE) study, in which all patients underwent response-driven titration of deutetrabenazine from 12 mg/day up to a maximum total dose of 48 mg/day. Weight, body mass index (BMI), serum glucose, serum total cholesterol, and serum triglycerides were evaluated at baseline and during treatment in the RCTs and in the OLE.

Results: In the RCTs, 282 and 133 patients received deutetrabenazine or placebo. At baseline, 77% of patients used DRAs. At Week 12, no meaningful changes in weight were observed, with mean (standard error) weight changes of 0.9-1.2 (0.3-0.5) and 0.2 (0.3) kg in the deutetrabenazine and placebo groups, respectively, and mean BMI changes of 0.3-0.5 (0.1-0.2) and 0.1 (0.1) kg/m2. 337 patients were included in the analysis of the OLE study. No meaningful changes were observed in weight (mean change: 0.4 [0.4] kg at Week 54, -0.5 [0.6] kg at Week 106, and -1.1 [0.6] kg at Week 145) or BMI (mean change: 0.1 [0.2] kg/m2 at Week 54, -0.2 [0.2] kg/m2 at Week 106, and -0.3 [0.2] kg/m2 at Week 145). Across the studies, no meaningful changes were observed in triglyceride, cholesterol, or glucose levels.

Conclusion: Deutetrabenazine does not affect common metabolic parameters in patients with TD, even during long-term exposure.

Funding: Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.
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http://dx.doi.org/10.1017/S1092852920002564DOI Listing
April 2021

Should we start integrating genetic data in decision-making on device-aided therapies in Parkinson disease? A point of view.

Parkinsonism Relat Disord 2021 Jul 18;88:51-57. Epub 2021 May 18.

Center for Neurological Restoration, Cleveland Clinic Neurological Institute, OH, USA. Electronic address:

Parkinson disease (PD) is a complex heterogeneous neurodegenerative disorder. Association studies have revealed numerous genetic risk loci and variants, and about 5-10% suffer from a monogenic form. Because the presentation and course of PD is unique to each patient, personalized symptomatic treatment should ideally be offered to treat the most disabling motor and non-motor symptoms. Indeed, clinical milestones and treatment complications that appear during disease progression are influenced by the genetic imprint. With recent advances in PD, more patients live longer to become eligible for device-aided therapies, such as apomorphine continuous subcutaneous infusion, levodopa duodenal gel infusion, and deep brain stimulation surgery, each with its own inclusion and exclusion criteria, advantages and disadvantages. Because genetic variants influence the expression of particular clinical profiles, factors for better or worse outcomes for device-aided therapies may then be proactively identified. For example, mutations in PRKN, LRRK2 and GBA express phenotypes that favor suitability for different device therapies, although with marked differences in the therapeutic window; whereas multiplications of SNCA express phenotypes that make them less desirable for device therapies.
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http://dx.doi.org/10.1016/j.parkreldis.2021.05.013DOI Listing
July 2021

Correction to: Genetic updates on paroxysmal dyskinesias.

J Neural Transm (Vienna) 2021 Jun 12. Epub 2021 Jun 12.

Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.

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http://dx.doi.org/10.1007/s00702-021-02361-9DOI Listing
June 2021

Efficacy results of pimavanserin from a multi-center, open-label extension study in Parkinson's disease psychosis patients.

Parkinsonism Relat Disord 2021 06 28;87:25-31. Epub 2021 Apr 28.

ACADIA Pharmaceuticals Inc., San Diego, CA, USA.

Introduction: Pimavanserin, a selective 5-HT inverse agonist/antagonist, was approved for hallucinations and delusions associated with Parkinson's disease psychosis (PDP). We present durability of response with pimavanserin in patients with PDP for an additional 4 weeks of treatment.

Methods: This was an open-label extension (OLE) study in patients previously completing one of three double-blind, placebo-controlled (Core) studies. All patients received pimavanserin 34 mg once daily. Efficacy assessments included the Scale for the Assessment of Positive Symptoms (SAPS) PD and H + D scales, Clinical Global Impression (CGI) Improvement and Severity scales and Caregiver Burden Scale (CBS), through 4 weeks in the OLE. Safety assessments were conducted at each visit.

Results: Of 459 patients, 424 (92.4%) had a Week 4 efficacy assessment. At Week 4 (10 weeks total treatment), SAPS-PD mean (standard deviation) change from OLE baseline was -1.8 (5.5) and for SAPS-H + D was -2.1 (6.2) with pimavanserin 34 mg. Patients receiving placebo during the Core studies had greater improvements (SAPS-PD -2.9 [5.6]; SAPS-H + D -3.5 [6.3]) during the OLE. For participants treated with pimavanserin 8.5 or 17 mg during the Core studies, further improvement was observed during the OLE with pimavanserin 34 mg. The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (-7.1 vs. -7.0). The CGI-I response rate (score of 1 or 2) at Week 4 was 51.4%. Adverse events were reported by 215 (46.8%) patients during the first 4 weeks of OLE. The most common AEs were fall (5.9%), hallucination (3.7%), urinary tract infection (2.8%), insomnia (2.4%), and peripheral edema (2.2%) CONCLUSIONS: Patients previously on pimavanserin 34 mg during three blinded core studies had durability of efficacy during the subsequent 4 week OLE SAPS-PD assessment. Patients previously on blinded placebo improved after 4 weeks of OL pimavanserin treatment. These results in over 400 patients from 14 countries support the efficacy of pimavanserin for treating PDP.
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http://dx.doi.org/10.1016/j.parkreldis.2021.04.012DOI Listing
June 2021

Genetic updates on paroxysmal dyskinesias.

J Neural Transm (Vienna) 2021 04 30;128(4):447-471. Epub 2021 Apr 30.

Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.

The paroxysmal dyskinesias are a diverse group of genetic disorders that manifest as episodic movements, with specific triggers, attack frequency, and duration. With recent advances in genetic sequencing, the number of genetic variants associated with paroxysmal dyskinesia has dramatically increased, and it is now evident that there is significant genotype-phenotype overlap, reduced (or incomplete) penetrance, and phenotypic variability. In addition, a variety of genetic conditions can present with paroxysmal dyskinesia as the initial symptom. This review will cover the 34 genes implicated to date and propose a diagnostic workflow featuring judicious use of whole-exome or -genome sequencing. The goal of this review is to provide a common understanding of paroxysmal dyskinesias so basic scientists, geneticists, and clinicians can collaborate effectively to provide diagnoses and treatments for patients.
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http://dx.doi.org/10.1007/s00702-021-02335-xDOI Listing
April 2021

Comparison of Safety and Tolerability of Deutetrabenazine During Titration and Maintenance in Patients with Tardive Dyskinesia.

CNS Spectr 2021 04;26(2):164

Teva Pharmaceutical Industries Ltd., West Chester, PA, USA.

Background: Deutetrabenazine is approved to treat tardive dyskinesia (TD) in adults and is titrated weekly by 6 mg/day, from 12 to 48 mg/day, based on dyskinesia control and tolerability. This analysis compared the safety of deutetrabenazine during titration versus maintenance.

Methods: Safety was assessed during titration versus maintenance using integrated data from two 12-week placebo-controlled studies (ARM-TD and AIM-TD) and the open-label extension study. Rates were compared for overall and serious adverse events (AEs), AEs leading to discontinuation, treatment-related AEs, common AEs (≥4%), and specific AEs (parkinsonism, suicidal ideation, akathisia, restlessness).

Results: In titration versus maintenance, AE rates with placebo (n=130) were: overall, 43.1% vs 25.4%; serious, 4.6% vs 2.3%; leading to discontinuation, 3.1% vs 0; treatment-related, 26.9% vs 10.0%. For placebo, common AEs during titration were somnolence, headache, nausea, fatigue, and dry mouth; none occurred during maintenance. In titration versus maintenance, AE rates in fixed-dose deutetrabenazine 12-36 mg (n=216) were: overall, 33.3-38.9% vs 22.2-29.2%; serious, 2.8-6.9% vs 0-1.4%; leading to discontinuation, 2.8-5.6% vs 0; treatment-related, 8.3-16.7% vs 8.3-13.9%. For fixed-dose deutetrabenazine, common AEs during titration were headache, diarrhea, nasopharyngitis, depression, hypertension, and dry mouth; headache was the only common AE during maintenance. In titration versus maintenance, AE rates with flexible-dose deutetrabenazine (n=168) were: overall, 49.4% vs 32.7%; serious, 3.6% vs 2.4%; leading to discontinuation, 2.4% vs 0.6%. For flexible-dose deutetrabenazine, the only common AE during titration was somnolence; none occurred during maintenance. Rates of parkinsonism, suicidal ideation, akathisia, and restlessness were low and comparable in titration and maintenance.

Conclusions: Deutetrabenazine was well-tolerated, with AE rates similar to placebo during both phases; AE rates were higher during titration and decreased during maintenance.

Funding: Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.
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http://dx.doi.org/10.1017/S1092852920002643DOI Listing
April 2021

Dystonia and leveraging oral pharmacotherapy.

J Neural Transm (Vienna) 2021 04 20;128(4):521-529. Epub 2021 Apr 20.

Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

Dystonia is a clinically diverse disorder, characterized by sustained or intermittent muscle contractions causing abnormal and often repetitive movements and/or postures. Accurate clinical diagnosis is tantamount to effective dystonia management. Current guidelines in the treatments of dystonia, including oral therapy, are prescribed to improve symptoms and to restore functional capacity. Identifying treatable causes from co-existing phenomenologies is relevant to provide the most optimal and disease-specific medications. In other forms of dystonia, genetic factors may affect outcome. Moreover, proper selection of patients, early initiation of medications and customized drug titration are keys to increasing the chances of success when using oral therapies for dystonia. Treatment of dystonia primarily involves agents that target dopamine and acetylcholine receptors. Other drugs used include benzodiazepines, baclofen, antiepileptics, some antipsychotics drugs and antihistamine, with different levels of evidence of effectiveness. Unfortunately, most of the widely used drugs have low levels of evidence and are primarily based on anecdotal experiences. Finally, other adjunctive therapeutic strategies are often necessary to complement oral therapy.
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http://dx.doi.org/10.1007/s00702-021-02339-7DOI Listing
April 2021

Use of a Smartphone to Gather Parkinson's Disease Neurological Vital Signs during the COVID-19 Pandemic.

Parkinsons Dis 2021 8;2021:5534282. Epub 2021 Apr 8.

Cleveland Clinic, Lerner Research Institute, Department of Biomedical Engineering, Cleveland, OH, USA.

Introduction: To overcome travel restrictions during the COVID-19 pandemic, consumer-based technology was rapidly deployed to the smartphones of individuals with Parkinson's disease (PD) participating in a 12-month exercise trial. The aim of the project was to determine the feasibility of utilizing a combined synchronous and asynchronous self-administered smartphone application to characterize PD symptoms.

Methods: A synchronous video virtual visit was completed for the administration of virtual Movement Disorder Society-Unified Parkinson's Disease Rating Scale III (vMDS-UPDRS III). Participants asynchronously completed a mobile application consisting of a measure of upper extremity bradykinesia (Finger Tapping Test) and information processing.

Results: Twenty-three individuals completed the assessments. The mean vMDS-UPDRS III was 23.65 ± 8.56 points. On average, the number of taps was significantly greater for the less affected limb, 97.96 ± 17.77 taps, compared to the more affected, 89.33 ± 18.66 taps ( = 0.025) with a significantly greater number of freezing episodes for the more affected limb ( < 0.05). Correlation analyses indicated the number of errors and the number of freezing episodes were significantly related to clinical ratings of vMDS-UPDRS III bradykinesia (Rho = 0.44, < 0.01;  = 0.43, < 0.01, resp.) and finger tapping performance (Rho = 0.31, = 0.03; Rho = 0.32, = 0.03, resp.). . The objective characterization of bradykinesia, akinesia, and nonmotor function and their relationship with clinical disease metrics indicate smartphone technology provides a remote method of characterizing important aspects of PD performance. While theoretical and position papers have been published on the potential of telemedicine to aid in the management of PD, this report translates the theory into a viable reality.
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http://dx.doi.org/10.1155/2021/5534282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035908PMC
April 2021

ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum.

Front Neurol 2021 1;12:637890. Epub 2021 Apr 1.

Department of Neurology and Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States.

The Na+/K+ ATPases are Sodium-Potassium exchanging pumps, with a heteromeric α-β-γ protein complex. The α3 isoform is required as a rescue pump, after repeated action potentials, with a distribution predominantly in neurons of the central nervous system. This isoform is encoded by the ATP1A3 gene. Pathogenic variants in this gene have been implicated in several phenotypes in the last decades. Carriers of pathogenic variants in this gene manifest neurological and non-neurological features in many combinations, usually with an acute onset and paroxysmal episodes triggered by fever or other factors. The first three syndromes described were: (1) rapid-onset dystonia parkinsonism; (2) alternating hemiplegia of childhood; and, (3) cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS syndrome). Since their original description, an expanding number of cases presenting with atypical and overlapping features have been reported. Because of this, ATP1A3-disorders are now beginning to be viewed as a phenotypic continuum representing discrete expressions along a broadly heterogeneous clinical spectrum.
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http://dx.doi.org/10.3389/fneur.2021.637890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047318PMC
April 2021

Non-Motor Fluctuations in Parkinson's Disease: Validation of the Non-Motor Fluctuation Assessment Questionnaire.

Mov Disord 2021 06 15;36(6):1392-1400. Epub 2021 Feb 15.

James J. and Joan A. Gardner Center for Parkinson's Disease and Movement Disorders Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA.

Background: In patients with Parkinson's disease (PD), sleep, mood, cognitive, autonomic, and other non-motor symptoms may fluctuate in a manner similar to motor symptoms.

Objectives: To validate a final version of a patient-rated questionnaire that captures the presence and severity of non-motor fluctuations in levodopa-treated PD patients (NoMoFA).

Methods: We recruited PD subjects from five movement disorders centers across the US and Canada. We assessed the internal consistency, floor and ceiling effects, test-retest reliability, and concurrent validity of NoMoFA. Classical test theory and item response theory methods informed item reduction and Delphi process yielded a final questionnaire.

Results: Two hundred subjects and their care-partners participated in the study (age: 66.4 ± 9.6 years; disease duration: 9 ± 5.5 years; median Hoehn and Yahr [H&Y] OFF: 3 [range 1-5]; mean Unified Parkinson's Disease Rating Scale (UPDRS) III ON score: 27.4 ± 14.9). Acceptability of the scale was adequate. There were floor effects in 8/28 items. Cronbach's alpha was 0.894. While eight items had "item-to-total" correlations below the cutoff of 0.4, removing these items did not improve Cronbach's alpha. Test-retest reliability was acceptable (intraclass correlation coefficient [ICC] 0.73; 95% confidence interval, 0.64-0.80). Concurrent validity was adequate with all Spearman's rho values comparing NoMoFA score to other measures of parkinsonian severity showing significance and in the expected direction. A final Delphi panel eliminated one item to avoid redundancy.

Conclusions: The final 27-item self-administered NoMoFA is a valid and reliable questionnaire, capturing both static and fluctuating non-motor symptoms in PD. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28507DOI Listing
June 2021

When patients lead: An editorial to 'self-concocted, curious, and creative coping strategies in movement disorders' by Mulroy et al.

Parkinsonism Relat Disord 2021 02 9;83:130-131. Epub 2020 Dec 9.

Department of Neurology and Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

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http://dx.doi.org/10.1016/j.parkreldis.2020.12.003DOI Listing
February 2021

High intensity aerobic exercise improves information processing and motor performance in individuals with Parkinson's disease.

Exp Brain Res 2021 Mar 4;239(3):777-786. Epub 2021 Jan 4.

Department of Biomedical Engineering, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, USA.

Parkinson's disease (PD) adversely affects information processing and motor performance. The impact of aerobic exercise on modifying the deleterious effects of PD underlying information and motor control processes is not well established. The primary aim of this project was to determine the effects of an 8-week high intensity exercise intervention on information processing and movement execution in individuals with PD. A secondary aim sought to understand the effects of antiparkinsonian medication relative to exercise on motor control processes. Data were collected at baseline (on- and off-medication) and upon completion of the exercise intervention (off-medication). Information processing and motor execution were evaluated via simple and choice reaction time paradigms (SRT and CRT) performed on a mobile device. Neither exercise nor medication impacted information processing or movement execution under the SRT paradigm. However, under CRT, exercise improved movement execution and information processing: total time was significantly reduced from 814 to 747 ms (p < 0.001), reaction time improved from 543 to 502 ms (p < 0.001), movement time improved from 270 to 246 ms (p = 0.01), and movement velocity improved from 28 cm/sec to 30 cm/sec (p = 0.01). Improvements in total time and reaction time in the CRT paradigm persisted 4 and 8 weeks following exercise cessation. Antiparkinsonian medication improved motor execution, but not information processing. The improvement in information processing following aerobic exercise, but not levodopa administration, suggests high intensity exercise may be enhancing neural processing and non-motor pathways outside those impacted by medication. The persistence of symptom improvement despite exercise intervention cessation indicates exercise is a candidate for disease modification. Trial registration: The trial was first registered at ClinicalTrials.gov on 7/10/2012 under registration number NCT01636297.
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http://dx.doi.org/10.1007/s00221-020-06009-0DOI Listing
March 2021

Untangling the complicated web of ATP1A3 mutations.

Parkinsonism Relat Disord 2020 09 10;78:186-188. Epub 2020 Sep 10.

Department of Neurology, Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

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http://dx.doi.org/10.1016/j.parkreldis.2020.09.010DOI Listing
September 2020

Pharmacological Treatment of Early Motor Manifestations of Parkinson Disease (PD).

Neurotherapeutics 2020 10 15;17(4):1331-1338. Epub 2020 Sep 15.

Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

Parkinson disease (PD), as a slowly progressive neurodegenerative disorder, undergoes six neuropathological stages. The earliest clinical manifestation presents in the middle stage of the disorder pathologically, when 50% or more of the dopaminergic neurons have degenerated in the substantia nigra. This discrepancy between the early stage clinically and that pathologically has, in part, spurred the debate as to when it is best to initiate symptomatic therapy. The most well-studied monotherapeutic agents for PD in its early course include levodopa (the cornerstone of PD therapy), dopamine agonists, and monoamine oxidase inhibitors (MAOIs). With several options for initiating pharmacologic therapy, along with the heterogenous presentation of the disorder, an individualized approach is warranted. Careful deliberation must be done to optimize risk reduction while providing effective symptom control, taking the chronological age, comorbidities, social and financial disposition, work status, and both immediate- and long-term goals into consideration. Generally, treatment can be delayed in patients with mild symptoms and minimal functional impairment at any age. If treatment must be initiated, dopamine agonists and monoamine oxidase type B inhibitors can be used, especially in younger patients with milder disease. However, for older patients, those with moderate to severe PD symptoms, regardless of age, or for patients with greater comorbidities, levodopa generally remains the better choice. Eventually, regardless of initial therapy, studies have shown that most will eventually require levodopa therapy when symptoms become more disabling.
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http://dx.doi.org/10.1007/s13311-020-00924-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851218PMC
October 2020

Long-term evaluation of open-label pimavanserin safety and tolerability in Parkinson's disease psychosis.

Parkinsonism Relat Disord 2020 08 28;77:100-106. Epub 2020 Jun 28.

ACADIA Pharmaceuticals Inc., San Diego, CA, USA.

Introduction: Pimavanserin is a selective 5-HT inverse agonist/antagonist approved for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Results from short-term, placebo-controlled studies demonstrated a positive benefit/risk profile. This multi-year, open-label study assessed long-term safety and tolerability of pimavanserin.

Methods: This was an open-label extension (OLE) study in patients previously completing a double-blind, placebo-controlled study or a previous OLE study. Safety was evaluated from adverse events (AEs), clinical laboratory results, motor symptoms, electrocardiograms (ECG), and mortality. Durability of response was assessed from the Clinical Global Impression-Severity (CGI-S) scale and Caregiver Burden Scale (CBS).

Results: Of 459 participants treated in this OLE study (average age 71.2 years), the median duration of treatment was 454 days. Over the entire study period (approximately 11 years), ≥1 AE occurred in 392 (85.4%) patients; the majority were of mild to moderate intensity, with fall (32.0%), urinary tract infection (19.0%), and hallucination (13.7%) most common. Serious AEs occurred in 188 (41.0%) patients, and an AE leading to study termination or dose discontinuation occurred in 133 (29.0%) patients. Sixty-one patients died, 59 (12.9%) during treatment or within 30 days after the last dose of study drug; the observed mortality rate was 6.45 per 100 patient-years of exposure. Mean scores for the CGI-S scale and CBS generally remained stable for up to 192 weeks (>3.5 years).

Conclusions: Long-term treatment with pimavanserin 34 mg once daily demonstrated a favorable benefit/risk profile with no unexpected safety concerns. Mortality rates suggested no increased risk following long-term treatment.
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http://dx.doi.org/10.1016/j.parkreldis.2020.06.026DOI Listing
August 2020

Adaptive neurology in COVID-19 times.

Parkinsonism Relat Disord 2020 06 4;75:124-125. Epub 2020 Jun 4.

Department of Neurology, Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

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http://dx.doi.org/10.1016/j.parkreldis.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270818PMC
June 2020

Botulinum neurotoxin injections for muscle-based (dystonia and spasticity) and non-muscle-based (neuropathic pain) pain disorders: a meta-analytic study.

J Neural Transm (Vienna) 2020 06 7;127(6):935-951. Epub 2020 Mar 7.

Movement Disorders Section, Department of Neurology, Hannover Medical School, Hannover, Germany.

Apart from the known efficacy of Botulinum Neurotoxin Type A (BoNT/A) in hyperactive striated and smooth muscles, different pain states have become potential targets of toxin effects. This present study determined the comparative toxin effectiveness in pain reduction among those patients injected with BoNT/A in muscle-based and in non-muscle-based conditions. Randomized controlled trials (RCTs) on the effect of BoNT/A on selected pain conditions were included. The conditions were spasticity and dystonia for muscle-based pain. For non-muscle-based pain, conditions included were painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), trigeminal neuralgia (TN), complex regional pain syndrome (CRPS), and spinal cord injury (SCI). In view of possibly differing pathophysiology, myofascial pain, temporomandibular joint (TMJ), other joint or tendon pains, cervicogenic and lumbar pains, migraine and visceral pain syndromes were excluded. Standardized mean difference was used as the effect measure and computed with STATA. 25 RCTs were analyzed. Pooled estimates showed significantly lower pain score in the Treatment group (z = 5.23, p < 0.01, 95% CI = - 0.75, - 0.34). Subgroup analyses showed that BoNT/A significantly reduced both muscle-based (z = 3.78, p < 0.01, 95% CI = - 0.72, - 0.23) and non-muscle-based (z = 3.37, p = 0.001, 95% CI = - 1.00, - 0.27) pain. Meta-regression using four covariates namely dosage, route, frequency and duration was done which revealed that dosage significantly affects standardized mean differences, while the other three covariates were insignificant. The joint F-test was found to be insignificant (p value = 0.1182). The application of the model with these covariates does not significantly explain the derived heterogeneity of standardized mean differences. In conclusion, BoNT/A can be effectively used in muscle-based and non-muscle-based pain disorders. We detected no difference between the presence and magnitude of pain relief favoring muscle-based compared to non-muscle-based pain. Thus, we cannot say whether or not there might be independent mechanisms of toxin-induced pain relief for pain generated from either muscle or nerve hyperactivity.
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http://dx.doi.org/10.1007/s00702-020-02163-5DOI Listing
June 2020

Delivering patient-centered care in Parkinson's disease: Challenges and consensus from an international panel.

Parkinsonism Relat Disord 2020 03 27;72:82-87. Epub 2020 Feb 27.

Center for Neurorestoration, Cleveland Clinic, Cleveland, OH, USA.

An international panel of movement disorders specialists explored the views and perceptions of people with Parkinson's disease (PD) about their condition and its treatment, including the potential mismatch between the clinician's view of the patient's condition and their own view of what aspects of the disease most affect their daily lives. The initiative was focused on Asian countries, so participants comprised experts in the management of PD from key centers in Asia, with additional insight provided by European and the North American movement disorders experts. Analysis of peer-reviewed publications on patient perceptions of PD and the factors that they consider important to their wellbeing identified several contributing factors to the mismatch of views, including gaps in knowledge of PD and its treatment, an understanding of the clinical heterogeneity of PD, and the importance of a multidisciplinary approach to patient care. The faculty proposed options to bridge these gaps to ensure that PD patients receive the personalized treatment they need to achieve the best possible outcomes. It was considered essential to improve patient knowledge about PD and its treatment, as well as increasing the awareness of clinicians of PD heterogeneity in presentation and treatment response. A multidisciplinary and shared-care approach to PD was needed alongside the use of patient-centered outcome measures in clinical trials and clinical practice to better capture the patient experience and improve the delivery of individualized therapy.
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http://dx.doi.org/10.1016/j.parkreldis.2020.02.013DOI Listing
March 2020

Unique white matter structural connectivity in early-stage drug-naive Parkinson disease.

Neurology 2020 02 27;94(8):e774-e784. Epub 2019 Dec 27.

From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.

Objective: To investigate the topographic arrangement and strength of whole-brain white matter (WM) structural connectivity in patients with early-stage drug-naive Parkinson disease (PD).

Methods: We employed a model-free data-driven approach for computing whole-brain WM topologic arrangement and connectivity strength between brain regions by utilizing diffusion MRI of 70 participants with early-stage drug-naive PD and 41 healthy controls. Subsequently, we generated a novel group-specific WM anatomical network by minimizing variance in anatomical connectivity of each group. Global WM connectivity strength and network measures were computed on this group-specific WM anatomical network and were compared between the groups. We tested correlations of these network measures with clinical measures in PD to assess their pathophysiologic relevance.

Results: PD-relevant cortical and subcortical regions were identified in the novel PD-specific WM anatomical network. Impaired modular organization accompanied by a correlation of network measures with multiple clinical variables in early PD were revealed. Furthermore, disease duration was negatively correlated with global connectivity strength of the PD-specific WM anatomical network.

Conclusion: By minimizing variance in anatomical connectivity, this study found the presence of a novel WM structural connectome in early PD that correlated with clinical symptoms, despite the lack of a priori analytic assumptions. This included the novel finding of increased structural connectivity between known PD-relevant brain regions. The current study provides a framework for further investigation of WM structural changes underlying the clinical and pathologic heterogeneity of PD.
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http://dx.doi.org/10.1212/WNL.0000000000008867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136053PMC
February 2020

Factors Associated With Postoperative Confusion and Prolonged Hospital Stay Following Deep Brain Stimulation Surgery for Parkinson Disease.

Neurosurgery 2020 04;86(4):524-529

Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio.

Background: Several patient and disease characteristics are thought to influence DBS outcomes; however, most previous studies have focused on long-term outcomes with only a few addressing immediate postoperative course.

Objective: To evaluate predictors of immediate outcomes (postoperative confusion and length of postoperative hospitalization) following deep brain stimulation surgery (DBS) in Parkinson disease (PD) patients.

Methods: We conducted a retrospective study of PD patients who underwent DBS at our institution from 2006 to 2011. We computed the proportion of patients with postoperative confusion and those with postoperative hospitalization longer than 2 d. To look for associations, Fisher's exact tests were used for categorical predictors and logistic regression for continuous predictors.

Results: We identified 130 patients [71% male, mean age: 63 ± 9.1, mean PD duration: 10.7 ± 5.1]. There were 7 cases of postoperative confusion and 19 of prolonged postoperative hospitalization. Of the 48 patients with tremors, none had postoperative confusion, whereas 10.1% of patients without tremors had confusion (P = .0425). Also, 10.2% of patients with preoperative falls/balance-dysfunction had postoperative confusion, whereas only 1.6% of patients without falls/balance-dysfunction had postoperative confusion (P = .0575). For every one-unit increase in score on the preoperative on-UPDRS III/MDS-UPDRS III score, the odds of having postoperative confusion increased by 10% (P = .0420). The following factors were noninfluential: age, disease duration, dyskinesia, gait freezing, preoperative levodopa-equivalent dose, number of intraoperative microelectrode passes, and laterality/side of surgery.

Conclusion: Absence of tremors and higher preoperative UPDRS III predicted postoperative confusion after DBS in PD patients. Clinicians' awareness of these predictors can guide their decision making regarding patient selection and surgical planning.
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http://dx.doi.org/10.1093/neuros/nyz316DOI Listing
April 2020

Tardive Dyskinesia: Treatment Update.

Curr Neurol Neurosci Rep 2019 08 16;19(9):69. Epub 2019 Aug 16.

Center for Neurological Restoration, Cleveland Clinic, 9500 Euclid Avenue, S-3, Cleveland, OH, 44198, USA.

Purpose Of Review: Tardive dyskinesia (TD) is caused by exposure to medications with dopamine antagonism, mainly antipsychotics. It often distresses individuals, physically and emotionally and affects their quality of life. We evaluated peer-reviewed recently published articles with a goal of providing a critically appraised update on the latest advancements in this field.

Recent Findings: In 2017, FDA approved VMAT2 inhibitors, deutetrabenazine and valbenazine. They have demonstrated efficacy in several class 1 studies. Also there have been update in the evidence-based guidelines for treatment for tardive dyskinesia. Various medication classes are being used for treatment of TD with VMAT2 inhibitors to be first FDA-approved medications. Their use should be tailored to the individual patient. Long-term studies will further guide us in how to optimize treatment, especially in the real-world setting. As clinicians, we need to take into consideration all aspects of symptomatology, etiology, potential side effects of the medications, to find the best possible "match" for our patients.
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http://dx.doi.org/10.1007/s11910-019-0976-1DOI Listing
August 2019

Height and weight changes after deep brain stimulation in patients with Parkinson disease: role of clinical subtypes.

Heliyon 2019 Jun 25;5(6):e01862. Epub 2019 Jun 25.

Center for Neurological Restoration, Cleveland Clinic, 9500 Euclid Avenue, Desk U2, Cleveland, OH, 44195, USA.

Increased body mass index (BMI) after deep brain stimulation (DBS) in Parkinson's disease (PD) has been repeatedly reported in literature. However, little is known about the effect of PD clinical subtypes on weight and height changes after DBS. We aimed to study the differential effect of tremor-predominant versus hypokinetic-rigid disease on weight and height changes after DBS.

Methodology: we chart-reviewed PD patients who underwent DBS at our center from 2006 to 2011. Weight and height data were obtained at the pre-surgical period, at 1-year post-surgery, and at the latest available follow-up (LAF).

Results: There were 130 patients in the dataset (70% male, mean age 63+/-9.1). Eighty-eight patients had available data at 1-year post-DBS or longer. Mean LAF was 4.36+/-1.64 years. A BMI increment by 1 Kg/m2 or more was noticed in 35% after 1-year. Increased height (1cm-or-more) was seen in 24% of patients at 1-year. At 1-year post-DBS, 41.8% of patients with hypokinetic-rigid subtype increased in height compared to only 14.2% in the tremor-predominant group (OR 4.3, 95 % CI 1.3167-14.1246, P=0.015). There was no correlation between PD subtype and weight change after DBS.

Conclusion: This study confirms BMI increase after DBS in PD patients and reports a novel finding of increased height after DBS in patients with hypokinetic-rigid PD. This might be secondary to improved axial rigidity following DBS. Resolution of tremor is probably unrelated to the increase in body weight after surgery since weight gain did not differ between patients with tremor-predominant and those with hypokinetic-rigid subtype.
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http://dx.doi.org/10.1016/j.heliyon.2019.e01862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600002PMC
June 2019

Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia.

J Neurol Neurosurg Psychiatry 2019 12 10;90(12):1317-1323. Epub 2019 Jul 10.

Georgetown University, Washington, District of Columbia, USA.

Objective: To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD).

Method: Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106). Patients began deutetrabenazine at 12 mg/day, titrating up to a dose that was tolerable and provided adequate dyskinesia control, based on investigator judgement, with a maximum allowed dose of 48 mg/day (36 mg/day for patients taking strong cytochrome P450 2D6 (CYP2D6) inhibitors). Safety measures included incidence of adverse events (AEs) and scales used to monitor parkinsonism, akathisia/restlessness, anxiety, depression, suicidality and somnolence/sedation. Efficacy endpoints included the change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 to 7) from baseline and the proportion of patients rated as 'Much Improved' or 'Very Much Improved' on the Clinical Global Impression of Change.

Results: A total of 343 patients enrolled in the extension study, and there were 331 patient-years of exposure in this analysis. The exposure-adjusted incidence rates of AEs with long-term treatment were comparable to or lower than those observed in the phase 3 trials. The mean (SE) change in AIMS score was -4.9 (0.4) at Week 54 (n = 146), - 6.3 (0.7) at Week 80 (n = 66) and -5.1 (2.0) at Week 106 (n = 8).

Conclusions: Overall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD.

Trial Registration Number: NCT02198794.
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http://dx.doi.org/10.1136/jnnp-2018-319918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902058PMC
December 2019

Defining the spectrum of spasticity-associated involuntary movements.

Parkinsonism Relat Disord 2019 08 12;65:79-85. Epub 2019 May 12.

The Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA.

Background: Spasticity can be associated with several hyperkinetic involuntary movements generally referred to as "spasms" despite different phenomenology and clinical characteristics.

Objective: To better characterize the phenomenology and clinical characteristics of spasticity-associated involuntary movements.

Methods: We performed a cross-sectional study of a consecutive patient sample from the spasticity clinic. Each patient was interviewed by a movement-disorder neurologist who conducted a standardized movement-disorder survey and a focused exam. Patients with involuntary movements were video-recorded and videos were independently rated by a separate blinded movement-disorder neurologist.

Results: Sixty-one patients were included (54% female, mean age 49.7 ± 13.9 years). Of the entire cohort, 11.5% had spinal, 44.3% had cerebral, and 44.3% had mixed-origin spasticity. Fifty-eight patients (95%) reported one or more involuntary movements: 75% tonic spasms (63% extensor, 58% isometric, 41% flexor/adductor), 52% spontaneous clonus, 34% myoclonus, 33% focal dystonia, and 28% action tremor. One third of the involuntary movements were painful. Only 53% of patients reported that their involuntary movements were much or very-much improved with their current anti-spasticity management. Patients treated with intrathecal baclofen therapy were more likely to report much or very-much improvement compared to patients receiving oral and/or botulinum therapy (P = 0.0061 and 0.0069 respectively).

Conclusion: Most spastic patients experience spasticity-associated involuntary movements of variable phenomenology and impact. However, only half of these patients experience significant improvement with the current management strategies. More research is needed to explore better treatment options for spasticity-associated involuntary movements with focus on phenomenology-specific approaches.
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http://dx.doi.org/10.1016/j.parkreldis.2019.05.007DOI Listing
August 2019
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