Publications by authors named "Peter Hedera"

111 Publications

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 Clinical Sciences, Florida State University, Tallahassee, FL 32306, 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

Prevalence of Comorbid Spasticity and Urinary Incontinence in Residents of a Long-Term Care Facility.

J Gerontol Nurs 2020 Oct 27;46(10):35-42. Epub 2020 Aug 27.

The current study evaluated the prevalence of comorbid spasticity and urinary incontinence (UI) in a long-term care facility. Medical history, presence of UI, and activities of daily living (ADL) dependency were obtained from medical records and Minimum Data Set 3.0. Quality of life was assessed with the EuroQoL-5D-5L (EQ-5D). Comorbid spasticity and UI presented in 29% of participants (14 of 49). Participants with spasticity and UI had higher ADL dependency and lower EQ-5D than participants without both conditions (4.9, 95% confidence interval [CI] [1.6, 80.], p = 0.003; -0.17, 95% CI [-0.33, 0.00], p = 0.044; respectively). More than one half of participants with lower limb spasticity had severe UI, compared to only 10% without lower limb spasticity (relative risk = 5.5; 95% CI [1.9, 15.9]; p = 0.006). Comorbid spasticity and UI may be common in the long-term care setting and negatively associated with ADL and quality of life. Further investigation is needed to confirm these findings. [Journal of Gerontological Nursing, 46(10), 35-42.].
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http://dx.doi.org/10.3928/00989134-20200820-01DOI Listing
October 2020

ing toward better understanding of CADASIL.

Authors:
Peter Hedera

Neurology 2020 09 3;95(13):565-566. Epub 2020 Aug 3.

From the Department of Neurology, University of Louisville, KY.

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http://dx.doi.org/10.1212/WNL.0000000000010507DOI Listing
September 2020

Deep brain stimulation in early-stage Parkinson disease: Five-year outcomes.

Neurology 2020 07 29;95(4):e393-e401. Epub 2020 Jun 29.

From the Departments of Neurology (M.L.H., M.T., L.E.H., A.D.C., S.H.M., A.L.M., T.L.D., F.T.P., P.H., D.C.), Neurosurgery (P.E.K.), and Biostatistics (L.W.), Vanderbilt University Medical Center, Nashville, TN; and Department of Neurology (K.R.C.), Walter Reed National Military Center, Bethesda, MD.

Objective: To report 5-year outcomes from the subthalamic nucleus (STN) deep brain stimulation (DBS) in early-stage Parkinson disease (PD) pilot clinical trial.

Methods: The pilot was a prospective, single-blind clinical trial that randomized patients with early-stage PD (Hoehn & Yahr II off medications) to receive bilateral STN DBS plus optimal drug therapy (ODT) vs ODT alone (IDEG050016, NCT0282152, IRB040797). Participants who completed the 2-year trial participated in this observational follow-up study, which included annual outpatient visits through 5 years. This analysis includes 28 patients who were taking PD medications for 6 months to 4 years at enrollment. Outcomes were analyzed using both proportional odds logistic regression and linear mixed effects models.

Results: Early STN DBS + ODT participants required lower levodopa equivalent daily doses ( = 0.04, β = -240 mg, 95% confidence interval [CI] -471 to -8) and had 0.06 times the odds of requiring polypharmacy at 5 years compared to early ODT participants ( = 0.01, odds ratio [OR] 0.06, 95% CI 0.00 to 0.65). The odds of having worse rest tremor for early STN DBS + ODT participants were 0.21 times those of early ODT participants ( < 0.001, OR 0.21, 95% CI 0.09 to 0.45). The safety profile was similar between groups.

Conclusions: These results suggest that early DBS reduces the need for and complexity of PD medications while providing long-term motor benefit over standard medical therapy. Further investigation is warranted, and the Food and Drug Administration has approved the conduct of a prospective, multicenter, pivotal clinical trial of DBS in early-stage PD (IDEG050016).

Classification Of Evidence: This study provides Class II evidence that DBS implanted in early-stage PD decreases the risk of disease progression and polypharmacy compared to optimal medical therapy alone.
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http://dx.doi.org/10.1212/WNL.0000000000009946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455319PMC
July 2020

A Simple Bedside Screening Tool for Spasticity Referral.

Clin Interv Aging 2020 13;15:655-662. Epub 2020 May 13.

Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.

Background And Objectives: Spasticity is common in long-term care facilities; however, this often-disabling condition is largely underdiagnosed in this setting and therefore left untreated. This study aimed to test the ability of a three-question flowchart used at the bedside by primary care providers in the long-term care setting to identify residents in need of referral to a specialist for spasticity consultation.

Methods: All residents of a single long-term care facility were approached for participation in this cross-sectional, observational study. Spasticity diagnostic evaluations by a movement disorders specialist neurologist (reference standard) were compared with referral determinations made by two primary care providers [a primary care physician (PCP) and a nurse practitioner (NP)] using the simple flowchart.

Results: The analysis included 49 residents (80% male, age 78.2±9.0 years) who were evaluated by the reference standard neurologist and at least one primary care provider. The bedside referral tool demonstrated high sensitivity and moderate specificity when used by the PCP (92% and 78%, respectively; AUC=0.84) and NP (80% and 53%, respectively; AUC=0.67).

Conclusion: This simple tool may be useful for primary care providers to identify residents to be referred to a specialist for evaluation and treatment of spasticity. These results warrant further investigation of the potential utility of this screening tool across multiple long-term care facilities and various types of care providers.
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http://dx.doi.org/10.2147/CIA.S248602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234972PMC
November 2020

Liver transplant for neurologic Wilson disease: Hope or fallacy?

Neurology 2020 05 12;94(21):907-908. Epub 2020 May 12.

From the Sheffield Institute for Translational Neuroscience (SITraN) (O.B.), University of Sheffield, United Kingdom; Internal Medicine IV (K.H.W.), University Hospital Heidelberg, Germany; and Division of Movement Disorders (P.H.), Department of Neurology, Vanderbilt University, Nashville TN.

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http://dx.doi.org/10.1212/WNL.0000000000009476DOI Listing
May 2020

Efficacy and Safety of AbobotulinumtoxinA for the Treatment of Hemiparesis in Adults with Lower Limb Spasticity Previously Treated With Other Botulinum Toxins: A Secondary Analysis of a Randomized Controlled Trial.

PM R 2020 09 27;12(9):853-860. Epub 2020 Mar 27.

Service de Rééducation Neurolocomotrice, EA 7377 BIOTN, Université Paris-Est, Hospital Albert Chenevier-Henri Mondor, Créteil, France.

Objective: To examine the safety and efficacy of abobotulinumtoxinA in patients previously treated with botulinum toxin type A (BoNT-A) products other than abobotulinumtoxinA.

Design: Secondary analysis from a phase 3, double-blind, single-cycle, randomized, placebo-controlled study.

Setting: Fifty-two centers (11 countries).

Patients: Adults with spastic hemiparesis were randomized (1:1:1) to receive abobotulinumtoxinA 1000 U, 1500 U, or placebo in their affected lower limb.

Main Outcome Measurements: Muscle tone (6-point Modified Ashworth Scale [MAS], 0-5) for the gastrocnemius-soleus complex (GSC); proportion of MAS responders (≥1-point improvement); angle of catch (X ) and spasticity grade (Y) for the GSC and soleus. Assessments were at weeks 1, 4, and 12 post-injection. Only descriptive statistics are presented.

Results: Of 388 patients, 84 received previous BoNT-A treatment (abobotulinumtoxinA 1000 U: N = 30; abobotulinumtoxinA 1500 U: N = 28; placebo: N = 26). At week 4, mean (SD) changes in MAS score in the GSC were - 0.8 (1.1), -0.9 (1.0), and - 0.4 (0.7) for abobotulinumtoxinA 1000 U, 1500 U, and placebo, respectively. Greater MAS responder rates were observed for abobotulinumtoxinA versus placebo at all time points. Mean (SD) changes (week 4) for abobotulinumtoxinA 1000 U, 1500 U, and placebo for X were: GSC, 8° (21), 6° (10) and 1° (7); soleus, 11° (21), 5° (9) and 0° (8), respectively; for Y: GSC, -0.4 (0.7), -0.6 (0.8) and - 0.0 (0.9); soleus, -0.5 (0.7), -0.5 (0.7) and - 0.1 (0.6), respectively. Safety data and adverse events were consistent with the overall known profile of abobotulinumtoxinA.

Conclusions: Patients previously treated with other BoNT-As showed improved muscle tone and spasticity at week 4 following abobotulinumtoxinA injection versus placebo. These findings suggest that abobotulinumtoxinA, at the recommended doses, has a good safety and efficacy profile in adults with lower limb spasticity who were previously treated with other BoNT-A products.
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http://dx.doi.org/10.1002/pmrj.12348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540573PMC
September 2020

Clinical management of Wilson disease.

Authors:
Peter Hedera

Ann Transl Med 2019 Apr;7(Suppl 2):S66

Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.

The availability of effective therapies distinguishes Wilson disease (WD) from other inherited neurometabolic diseases. The cause of hepatic, neurologic or psychiatric symptoms is copper overload and subsequent copper toxicity. Diagnosed WD patients require life-long pharmacologic therapy that is focused on reversal of copper overload with maintenance of a long-term negative copper balance. This is associated with the rapid control of free or non-ceruloplasmin bound copper that is mostly responsible for acute cytotoxic effects. Currently available therapies can be divided into chelators and zinc salts. They have different mechanisms of action and the onset of efficacy that influences their selection in acute and chronic stages of therapy. We review the use of D-penicillamine and trientine for chelation therapies, including the required monitoring of therapy for its efficacy and possible overtreatment with iatrogenic copper deficiency. Additionally, the use of zinc salts is also discussed, including a possibility of its use for the initial therapy in an acute stage of the disease. Supportive and symptomatic therapies for liver failure and neuropsychiatric symptoms are also reviewed.
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http://dx.doi.org/10.21037/atm.2019.03.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531662PMC
April 2019

Deep Brain Stimulation for Treatment of Tremor.

Neurosurg Clin N Am 2019 Apr;30(2):147-159

Vanderbilt University Medical Center, Room 4333, VAV, 1500 21st Avenue, Nashville, TN 37212, USA. Electronic address:

Deep brain stimulation is now the most common surgical treatment of tremor. Tremor can be classified as action or resting tremor and is one of the most common movement disorders. Initial treatment of tremor should focus on medical treatment but, if patients fail medical therapy, deep brain stimulation should be considered with likely success. The usual target is the ventral intermediate nucleus of the thalamus. Common side effects of treatment include paresthesias, dysarthria, and less often ataxia. Future directions of research and development, including directional leads and closed-loop stimulation, may eventually lead to additional improvement in patient outcomes.
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http://dx.doi.org/10.1016/j.nec.2019.01.002DOI Listing
April 2019

Wilson's disease: A master of disguise.

Authors:
Peter Hedera

Parkinsonism Relat Disord 2019 02 14;59:140-145. Epub 2019 Feb 14.

Department of Neurology, Vanderbilt University Medical Center, 465 21st Avenue South, 6140 MRB III, Nashville, 37232- 8552, TN, USA. Electronic address:

Wilson's disease (WD), in contrast to many neurogenetic metabolic diseases, can be very effectively treated in acute and chronic stages of the disease. However, early recognition is paramount because delays in treatments have much higher risk of unfavorable clinical outcomes. Identification of WD remains challenging because it is a great imitator and requires a high index of suspicion for correct and timely diagnosis. Initial neurologic problems can be seen in approximately 40%-50% of patients and the rest has either hepatic or primarily psychiatric manifestations. Neurologic and neuropsychiatric problems in WD are quite nonspecific and we discuss the most common clinical problems associated with early and late stages of the disease. Many patients with neurologic symptoms do not have any obvious hepatic symptoms. Most common neurologic abnormalities include dysarthria, dystonia, tremor and Parkinsonism. In spite of its phenotypic heterogeneity, laboratory abnormalities, reflecting abnormal copper homeostasis, are very specific and the diagnosis of WD remains laboratory based. We review most important challenges and pitfalls in laboratory evaluation of WD, including emerging role of genetic testing. Pharmacologic treatments need to be life-long and are focused on restoration of negative copper balance without inducing iatrogenic copper deficiency. The gold standard of therapy is chelation of excessive copper. Chelators may induce further clinical deterioration in some treated patients. We also review most promising novel therapeutic approaches that appear to better control non-ceruloplasmin or free copper because elevation of free copper may be responsible for paradoxical neurologic worsening.
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http://dx.doi.org/10.1016/j.parkreldis.2019.02.016DOI Listing
February 2019

White matter differences between essential tremor and Parkinson disease.

Neurology 2019 01 30;92(1):e30-e39. Epub 2018 Nov 30.

From the Departments of Radiology and Radiological Sciences (M.R.J., M.J.D.), Neurological Surgery (D.J.E., P.E.K.), Biostatistics (Y.-C.L., H.K.), Neurology (P.T., P.H., M.J.D.), and Psychiatry (M.J.D.), Vanderbilt University Medical Center, Nashville, TN; Department of Pathophysiology and Transplantation (G.F.) University of Milan, Italy; and Chemical and Physical Biology Program (K.J.P.) and Departments of Electrical Engineering (B.A.L., B.M.D.), Computer Engineering (B.A.L., B.M.D.), Computer Science and Biomedical Engineering (B.A.L., B.M.D.), and Neurology (D.O.C.), Vanderbilt University, Nashville, TN.

Objective: To assess white matter integrity in patients with essential tremor (ET) and Parkinson disease (PD) with moderate to severe motor impairment.

Methods: Sedated participants with ET (n = 57) or PD (n = 99) underwent diffusion tensor imaging (DTI) and fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity values were computed. White matter tracts were defined using 3 well-described atlases. To determine candidate white matter regions that differ between ET and PD groups, a bootstrapping analysis was applied using the least absolute shrinkage and selection operator. Linear regression was applied to assess magnitude and direction of differences in DTI metrics between ET and PD populations in the candidate regions.

Results: Fractional anisotropy values that differentiate ET from PD localize primarily to thalamic and visual-related pathways, while diffusivity differences localized to the cerebellar peduncles. Patients with ET exhibited lower fractional anisotropy values than patients with PD in the lateral geniculate body ( < 0.01), sagittal stratum ( = 0.01), forceps major ( = 0.02), pontine crossing tract ( = 0.03), and retrolenticular internal capsule ( = 0.04). Patients with ET exhibited greater radial diffusivity values than patients with PD in the superior cerebellar peduncle ( < 0.01), middle cerebellar peduncle ( = 0.05), and inferior cerebellar peduncle ( = 0.05).

Conclusions: Regionally, distinctive white matter microstructural values in patients with ET localize to the cerebellar peduncles and thalamo-cortical visual pathways. These findings complement recent functional imaging studies in ET but also extend our understanding of putative physiologic features that account for distinctions between ET and PD.
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http://dx.doi.org/10.1212/WNL.0000000000006694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336163PMC
January 2019

Confined Thalamic Deep Brain Stimulation in Refractory Essential Tremor.

Stereotact Funct Neurosurg 2018 19;96(5):296-304. Epub 2018 Nov 19.

Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA,

Background: Thalamic ventral intermediate nucleus (VIM) deep brain stimulation (DBS) is an effective therapy for medication-refractory essential tremor (ET). However, 13-40% of patients with an initially robust tremor efficacy lose this benefit over time despite reprogramming attempts. At our institution, a cohort of ET patients with VIM DBS underwent implantation of a second anterior (ventralis oralis anterior; VOA) DBS lead to permit "confined stimulation." We sought to assess whether confined stimulation conferred additional tremor capture compared to VIM or VOA stimulation alone.

Methods: Seven patients participated in a protocol-based programming session during which a video-recorded Fahn-Tolosa-Marin Part A (FTM-A) tremor rating scale was used in the following 4 DBS states: off stimulation, VIM stimulation alone, VOA stimulation alone, and dual lead (confined) stimulation.

Results: The average (SD) baseline FTM-A off score was 17.6 (4.0). VIM stimulation alone lowered the average FTM-A total score to 6.9 (4.0). Confined stimulation further attenuated the tremor, reducing the total score to 5.7 (2.8).

Conclusions: Confined thalamic DBS can provide additional symptomatic benefits in patients with unsatisfactory tremor control from VIM or VOA stimulation alone.
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http://dx.doi.org/10.1159/000493546DOI Listing
May 2019

Novel Type of Complicated Autosomal Dominant Hereditary Spastic Paraplegia Associated with Congenital Distal Arthrogryposis Type I.

Brain Sci 2018 Jul 19;8(7). Epub 2018 Jul 19.

Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurological disorders. HSP is classified as pure when only a spastic weakness of the lower extremities is present. Complex HSP comes with additional neurological or systemic abnormalities. Complex HSP with skeletal abnormalities is rare and mostly seen in autosomal recessive HSP. Autosomal dominant (AD) complex HSP with skeletal abnormalities are consistently seen only in SPG9 (spastic gait type 9). In this paper, we report a kindred condition with AD HSP among four living affected individuals who had progressive, adult onset spastic paraparesis that was associated with a distal arthrogryposis (DA) in every affected individual. They also had episodes of rhabdomyolysis without any clinical signs of myopathy. Exhaustive genetic analysis including targeted sequencing of known HSP and DA genes and whole exome sequencing did not identify the disease-causing gene. It excluded all known HSP and DA genes. We propose that this is a novel genetic type of complex AD HSP. Elucidation of a genetic cause of this type of HSP will further contribute to our understanding of axonal degeneration and skeletal abnormalities.
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http://dx.doi.org/10.3390/brainsci8070136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071261PMC
July 2018

Effects of deep brain stimulation on rest tremor progression in early stage Parkinson disease.

Neurology 2018 07 29;91(5):e463-e471. Epub 2018 Jun 29.

From the Departments of Neurology (M.L.H., M.T., L.E.H., A.L.M., A.D.C., T.L.D., F.T.P., P.H., D.C.) and Neurosurgery (P.E.K.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurology (M.R.D.), Emory University School of Medicine, Atlanta, GA; Laboratory of Molecular Immunology (L.E.H.), National Institute of Allergy and Infectious Diseases, Bethesda, MD; Movement Disorders and Neuromodulation Center (J.L.O.), Department of Neurology, University of California San Francisco; Department of Neurology (K.R.C.), Walter Reed National Military Center, Bethesda; and Department of Epidemiology (L.T.D., A.L.S., D.M.S., J.T.), Johns Hopkins University, Baltimore, MD.

Objective: To evaluate whether the progression of individual motor features was influenced by early deep brain stimulation (DBS), a post hoc analysis of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) score (after a 7-day washout) was conducted from the 2-year DBS in early Parkinson disease (PD) pilot trial dataset.

Methods: The prospective pilot trial enrolled patients with PD aged 50-75 years, treated with PD medications for 6 months-4 years, and no history of dyskinesia or other motor fluctuations, who were randomized to receive optimal drug therapy (ODT) or DBS plus ODT (DBS + ODT). At baseline and 6, 12, 18, and 24 months, all patients stopped all PD therapy for 1 week (medication and stimulation, if applicable). UPDRS-III "off" item scores were compared between the ODT and DBS + ODT groups (n = 28); items with significant between-group differences were analyzed further.

Results: UPDRS-III "off" rest tremor score change from baseline to 24 months was worse in patients receiving ODT vs DBS + ODT ( = 0.002). Rest tremor slopes from baseline to 24 months favored DBS + ODT both "off" and "on" therapy ( < 0.001, = 0.003, respectively). More ODT patients developed new rest tremor in previously unaffected limbs than those receiving DBS + ODT ( = 0.001).

Conclusions: These results suggest the possibility that DBS in early PD may slow rest tremor progression. Future investigation in a larger cohort is needed, and these findings will be tested in the Food and Drug Administration-approved, phase III, pivotal, multicenter clinical trial evaluating DBS in early PD.

Classification Of Evidence: This study provides Class II evidence that for patients with early PD, DBS may slow the progression of rest tremor.
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http://dx.doi.org/10.1212/WNL.0000000000005903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093763PMC
July 2018

WTX101 - an investigational drug for the treatment of Wilson disease.

Expert Opin Investig Drugs 2018 Jun 8;27(6):561-567. Epub 2018 Jun 8.

d Department of Gastroenterology and Hepatology , Medical University of Vienna , Vienna , Austria.

Introduction: Wilson disease (WD) is a genetic disorder in which excess toxic copper accumulates in the liver, brain, and other tissues leading to severe and life-threatening symptoms. Copper overload can be assessed as non-ceruloplasmin-bound copper non-ceruloplasmin-bound copper (NCC) in blood. Current therapies are limited by efficacy, safety concerns, and multiple-daily dosing. Areas covered: This article reviews the literature on WTX101 (bis-choline tetrathiomolybdate), an oral first-in-class copper-protein-binding agent in development for the treatment of WD. Expert opinion: In a proof-of-concept phase II trial, once-daily WTX101 over 24 weeks rapidly lowered NCC levels and this was accompanied by improved neurological status without apparent initial drug-induced paradoxical worsening, reduced disability, stable liver function, with a favorable safety profile. WTX101 directly removes excess copper from intracellular hepatic copper stores and also forms an inert tripartite complex with copper and albumin in the circulation and promotes biliary copper excretion. These mechanisms may explain the rapid biochemical and clinical improvements observed. A phase III trial of WTX101 is ongoing and results are eagerly awaited to confirm if WTX101 can improve the treatment of this devastating disease.
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http://dx.doi.org/10.1080/13543784.2018.1482274DOI Listing
June 2018

Whole-exome sequencing for variant discovery in blepharospasm.

Mol Genet Genomic Med 2018 May 16. Epub 2018 May 16.

Departments of Neurology and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee.

Background: Blepharospasm (BSP) is a type of focal dystonia characterized by involuntary orbicularis oculi spasms that are usually bilateral, synchronous, and symmetrical. Despite strong evidence for genetic contributions to BSP, progress in the field has been constrained by small cohorts, incomplete penetrance, and late age of onset. Although several genetic etiologies for dystonia have been identified through whole-exome sequencing (WES), none of these are characteristically associated with BSP as a singular or predominant manifestation.

Methods: We performed WES on 31 subjects from 21 independent pedigrees with BSP. The strongest candidate sequence variants derived from in silico analyses were confirmed with bidirectional Sanger sequencing and subjected to cosegregation analysis.

Results: Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, and MRPL15 were found in two or more independent pedigrees. To our knowledge, none of these genes have previously been associated with isolated BSP, although other CACNA1A mutations have been associated with both positive and negative motor disorders including ataxia, episodic ataxia, hemiplegic migraine, and dystonia.

Conclusions: Our WES datasets provide a platform for future studies of BSP genetics which will demand careful consideration of incomplete penetrance, pleiotropy, population stratification, and oligogenic inheritance patterns.
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http://dx.doi.org/10.1002/mgg3.411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081235PMC
May 2018

Hereditary Myelopathies.

Authors:
Peter Hedera

Continuum (Minneap Minn) 2018 04;24(2, Spinal Cord Disorders):523-550

Purpose Of Review: Hereditary myelopathies are very diverse genetic disorders, and many of them represent a widespread neurodegenerative process rather than isolated spinal cord dysfunction. This article reviews various types of inherited myelopathies, with emphasis on hereditary spastic paraplegias and spastic ataxias.

Recent Findings: The ever-growing number of myelopathy-causing genes and broadening of phenotype-genotype correlations makes the molecular diagnosis of inherited myelopathies a daunting task. This article emphasizes the main phenotypic clusters among inherited myelopathies that can facilitate the diagnostic process. This article focuses on newly identified genetic causes and the most important identifying clinical features that can aid the diagnosis, including the presence of a characteristic age of onset and additional neurologic signs such as leukodystrophy, thin corpus callosum, or amyotrophy.

Summary: The exclusion of potentially treatable causes of myelopathy remains the most important diagnostic step. Syndromic diagnosis can be supported by molecular diagnosis, but the genetic diagnosis at present does not change the management. Moreover, a negative genetic test does not exclude the diagnosis of a hereditary myelopathy because comprehensive molecular testing is not yet available, and many disease-causing genes remain unknown.
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http://dx.doi.org/10.1212/CON.0000000000000580DOI Listing
April 2018

Can lifestyle modification slow progression of Parkinson disease?

Neurology 2017 10 29;89(17):1760-1761. Epub 2017 Sep 29.

From the Department of Neurology, Vanderbilt University Medical Center, Nashville, TN.

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http://dx.doi.org/10.1212/WNL.0000000000004580DOI Listing
October 2017

Phenotypic Discordance in Siblings with Identical Compound Heterozygous PARK2 Mutations.

Brain Sci 2017 Jun 24;7(7). Epub 2017 Jun 24.

Department of Neurology, Vanderbilt University Medical Center, 1301 Medical Center Dr. Suite 3930, Nashville, TN 37232-5400, USA.

mutations are the most common cause of early-onset Parkinson's disease. No genotype-phenotype correlation exists, and phenotypic variability is quite common. We report two siblings with confirmed identical compound heterozygous mutations in the gene manifesting strikingly different phenotypes. The older brother demonstrated marked parkinsonism by his mid-20's, whereas the younger brother developed exercise-induced dystonia in his mid-30's with no subsequent clinical progression, highlighting the clinical heterogeneity of the disease and implying the role of other genetic and/or environmental factors in disease progression. The younger sibling, despite his mild symptoms, had a clearly abnormal dopamine transporter (DaT)-SPECT scan. To our knowledge, this is the first such reported case of an abnormal DaT-SPECT scan in a patient with biallelic mutations who does not meet the clinical criteria for Parkinson's disease.
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http://dx.doi.org/10.3390/brainsci7070071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532584PMC
June 2017

Effects of repeated abobotulinumtoxinA injections in upper limb spasticity.

Muscle Nerve 2018 02 13;57(2):245-254. Epub 2017 Aug 13.

Ipsen Innovation, Les Ulis, France.

Introduction: The efficacy of single injections of abobotulinumtoxinA (Dysport) is established in adults with upper limb spasticity. In this study we assessed the effects of repeated injections of abobotulinumtoxinA over 1 year.

Methods: Patients (n = 258, safety population) received 500 U, 1,000 U, or 1,500 U (1,500-U dose included 500-U shoulder injections) for up to 4 or 5 treatment cycles. Assessments included treatment-emergent adverse events (TEAEs), muscle tone, passive and active range of motion (X X ), angle of catch (X ), Disability Assessment Scale (DAS) score, Modified Frenchay Scale (MFS) score, and Physician Global Assessment (PGA) score.

Results: The incidence of TEAEs decreased across cycles. Muscle tone reduction and X remained stable across cycles, whereas X and X continued to improve at the finger, wrist, and elbow flexors. DAS and PGA improved across cycles. MFS improved best with 1,500 U.

Discussion: A favorable safety profile and continuous improvements in active movements and perceived and active function were associated with repeated abobotulinumtoxinA injections in upper limb muscles. Muscle Nerve 57: 245-254, 2018.
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http://dx.doi.org/10.1002/mus.25721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811783PMC
February 2018

Case report of novel gene mutation causing episodic ataxia type 2.

SAGE Open Med Case Rep 2017 8;5:2050313X17706044. Epub 2017 May 8.

Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Episodic ataxia type 2 (OMIM 108500) is an autosomal dominant channelopathy characterized by paroxysms of ataxia, vertigo, nausea, and other neurologic symptoms. More than 50 mutations of the CACNA1A gene have been discovered in families with episodic ataxia type 2, although 30%-50% of all patients with typical episodic ataxia type 2 phenotype have no detectable mutation of the CACNA1A gene.

Case: A 46-year-old Caucasian man, with a long history of bouts of imbalance, vertigo, and nausea, presented to our hospital with 2 weeks of ataxia and headache. Subsequent evaluation revealed a novel mutation in the CACNA1A gene: c.1364 G > A Arg455Gln. Acetazolamide was initiated with symptomatic improvement.

Conclusion: This case report expands the list of known CACNA1A mutations associated with episodic ataxia type 2.
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http://dx.doi.org/10.1177/2050313X17706044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431607PMC
May 2017

Emerging strategies in the management of essential tremor.

Authors:
Peter Hedera

Ther Adv Neurol Disord 2017 Feb 30;10(2):137-148. Epub 2016 Nov 30.

Department of Neurology, Vanderbilt University, 465 21st Avenue South, 6140 MRB III, Nashville, TN 37240, USA.

Currently available therapies for essential tremor (ET) provide sufficient control only for less than a half of patients and many unmet needs exist. This is in part due to the empiric nature of existing treatment options and persisting uncertainties about the pathogenesis of ET. The emerging concept of ET as a possible neurodegenerative disorder, better understanding of associated biochemical changes, including alterations in the γ-aminobutyric acid (GABA)-ergic system and gap junctions, and the identification of the role of the leucine-rich repeat and immunoglobulin-like domain-containing 1 (LINGO-1) gene in ET pathogenesis suggest new avenues for more targeted therapies. Here we review the most promising new approaches to treating ET, including allosteric modulation of GABA receptors and modifications of the LINGO-1 pathway. Medically refractory tremor can be successfully treated by high-frequency deep brain stimulation (DBS) of the ventral intermediate nucleus, but surgical therapies are also fraught with limitations due to adverse effects of stimulation and the loss of therapeutic response. The selection of additional thalamic and extrathalamic targets for electrode placements and the development of a closed-loop DBS system enabling automatic adjustment of stimulation parameters in response to changes in electrophysiologic brain activity are also reviewed. Tremor cancellation methods using exoskeleton and external hand-held devices are also briefly discussed.
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http://dx.doi.org/10.1177/1756285616679123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367648PMC
February 2017

Update on the clinical management of Wilson's disease.

Authors:
Peter Hedera

Appl Clin Genet 2017 13;10:9-19. Epub 2017 Jan 13.

Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.

Wilson's disease (WD), albeit relatively rare, is an important genetic metabolic disease because of highly effective therapies that can be lifesaving. It is a great imitator and requires a high index of suspicion for correct and timely diagnosis. Neurologic, psychiatric and hepatologic problems in WD are very nonspecific, and we discuss the most common clinical phenotypes. The diagnosis remains laboratory based, and here we review the most important challenges and pitfalls in laboratory evaluation of WD, including the emerging role of genetic testing in WD diagnosis. WD is a monogenic disorder but has very high allelic heterogeneity with >500 disease-causing mutations identified, and new insights into phenotype-genotype correlations are also reviewed. The gold standard of therapy is chelation of excessive copper, but many unmet needs exist because of possible clinical deterioration in treated patients and potential adverse effects associated with currently available chelating medications. We also review the most promising novel therapeutic approaches, including chelators targeting specific cell types, cell transplantation and gene therapy.
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http://dx.doi.org/10.2147/TACG.S79121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5245916PMC
January 2017

Cortical asymmetry in Parkinson's disease: early susceptibility of the left hemisphere.

Brain Behav 2016 12 6;6(12):e00573. Epub 2016 Oct 6.

Vanderbilt University Institute of Imaging Science Nashville TN USA.

Background And Purpose: Clinically, Parkinson's disease (PD) presents with asymmetric motor symptoms. The left nigrostriatal system appears more susceptible to early degeneration than the right, and a left-lateralized pattern of early neuropathological changes is also described in several neurodegenerative conditions, including Alzheimer's disease, frontotemporal dementia, and Huntington's disease. In this study, we evaluated hemispheric differences in estimated rates of atrophy in a large, well-characterized cohort of PD patients.

Methods: Our cohort included 205 PD patients who underwent clinical assessments and T1-weighted brain MRI's. Patients were classified into Early (= 109) and Late stage (= 96) based on disease duration, defined as greater than or less than 10 years of motor symptoms. Cortical thickness was determined using FreeSurfer, and a bootstrapped linear regression model was used to estimate differences in rates of atrophy between Early and Late patients.

Results: Our results show that patients classified as Early stage exhibit a greater estimated rate of cortical atrophy in left frontal regions, especially the left insula and olfactory sulcus. This pattern was replicated in left-handed patients, and was not influenced by the degree of motor symptom asymmetry (i.e., left-sided predominant motor symptoms). Patients classified as Late stage exhibited greater atrophy in the bilateral occipital, and right hemisphere-predominant cortical areas.

Conclusions: We show that cortical degeneration in PD differs between cerebral hemispheres, and findings suggest a pattern of early left, and late right hemisphere with posterior cortical atrophy. Further investigation is warranted to elucidate the underlying mechanisms of this asymmetry and pathologic implications.
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http://dx.doi.org/10.1002/brb3.573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167000PMC
December 2016

Hyperkinetic psychogenic movement disorders remain a diagnosis at first sight.

Neurology 2017 01 2;88(2):114-115. Epub 2016 Dec 2.

From the Department of Neurology (P.H.), Vanderbilt University Medical Center, Nashville, TN; and Department of Medical and Surgical Sciences (A.G.), Institute of Neurology, University Magna Græcia, Catanzaro, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000003494DOI Listing
January 2017

Poster 288 Efficacy and Safety of Repeated AbobotulinumtoxinA Injections in Adults with Lower Limb Spasticity.

PM R 2016 Sep 24;8(9S):S254. Epub 2016 Sep 24.

EA7377 BIOTN, Université Paris-Est Créteil, Service de Rééducation Neurolocomotrice, Hôpitaux Universitaires Henri Mondor, Créteil, France.

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http://dx.doi.org/10.1016/j.pmrj.2016.07.461DOI Listing
September 2016

Speech-activated Myoclonus Mimicking Stuttering in a Patient with Myoclonus-Dystonia Syndrome.

Tremor Other Hyperkinet Mov (N Y) 2016 1;6:405. Epub 2016 Jul 1.

Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Acquired neurogenic stuttering has been considered a fairly uncommon clinical occurrence; speech-activated myoclonus is a rare entity that can mimic stuttering and is caused by a wide array of etiologies.

Case Report: Here we report a patient with myoclonus-dystonia syndrome (MDS), due to an identified disease-causing mutation, who displayed speech-activated myoclonus mimicking stuttering.

Discussion: In MDS, myoclonus has only infrequently been reported to affect speech. This case further expands the spectrum of conditions causing the rare clinical phenomenon of speech-activated myoclonus.
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http://dx.doi.org/10.7916/D8J966FPDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930628PMC
July 2016

Hereditary and metabolic myelopathies.

Authors:
Peter Hedera

Handb Clin Neurol 2016 ;136:769-85

Department of Neurology, Vanderbilt University, Nashville, TN, USA. Electronic address:

Hereditary and metabolic myelopathies are a heterogeneous group of neurologic disorders characterized by clinical signs suggesting spinal cord dysfunction. Spastic weakness, limb ataxia without additional cerebellar signs, impaired vibration, and positional sensation are hallmark phenotypic features of these disorders. Hereditary, and to some extent, metabolic myelopathies are now recognized as more widespread systemic processes with axonal loss and demyelination. However, the concept of predominantly spinal cord disorders remains clinically helpful to differentiate these disorders from other neurodegenerative conditions. Furthermore, metabolic myelopathies are potentially treatable and an earlier diagnosis increases the likelihood of a good clinical recovery. This chapter reviews major types of degenerative myelopathies, hereditary spastic paraplegia, motor neuron disorders, spastic ataxias, and metabolic disorders, including leukodystrophies and nutritionally induced myelopathies, such as vitamin B12, E, and copper deficiencies. Neuroimaging studies usually detect a nonspecific spinal cord atrophy or demyelination of the corticospinal tracts and dorsal columns. Brain imaging can be also helpful in myelopathies caused by generalized neurodegeneration. Given the nonspecific nature of neuroimaging findings, we also review metabolic or genetic assays needed for the specific diagnosis of hereditary and metabolic myelopathies.
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http://dx.doi.org/10.1016/B978-0-444-53486-6.00038-7DOI Listing
February 2017