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Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (~25%) and the identification of several disease-linked genes, the etiology in most patients remains elusive. Moreover, understanding the correlations between clinical manifestation and genetic variants has become increasingly complex. To comprehensively unravel dystonia's genetic spectrum, we performed exome sequencing on 1,924 dystonia patients [40.3% male, 92.9% White, 93.2% isolated dystonia, median age at onset (AAO) 33 years], including 1,895 index patients, who were previously genetically unsolved. The sample was mainly based on two dystonia registries (DysTract and the Dystonia Coalition). Further, 72 additional patients of Asian ethnicity, mainly from Malaysia, were also included. We prioritized patients with negative genetic prescreening, early AAO, positive family history, and multisite involvement of dystonia. Rare variants in genes previously linked to dystonia ( n =405) were examined. Variants were confirmed via Sanger sequencing, and segregation analysis was performed when possible. We identified 137 distinct likely pathogenic or pathogenic variants (according to ACMG criteria) across 51 genes in 163/1,924 patients [42.9% male, 85.9% White, 68.7% isolated dystonia, median AAO 19 years]. This included 153/1,895 index patients, resulting in a diagnostic yield of 8.1%. Notably, 77/137 (56.2%) of these variants were novel, with recurrent variants in EIF2AK2 , VPS16 , KCNMA1 , and SLC2A1 , and novel variant types such as two splice site variants in KMT2B , supported by functional evidence. Additionally, 321 index patients (16.9%) harbored variants of uncertain significance in 102 genes. The most frequently implicated genes included VPS16 , THAP1 , GCH1 , SGCE , GNAL , and KMT2B. Presumably pathogenic variants in less well-established dystonia genes were also found, including KCNMA1 , KIF1A , and ZMYND11. At least six variants (in ADCY5 , GNB1 , IR2BPL, KCNN2 , KMT2B , and VPS16 ) occurred de novo, supporting pathogenicity. ROC curve analysis indicated that AAO and the presence of generalized dystonia were the strongest predictors of a genetic diagnosis, with diagnostic yields of 28.6% in patients with generalized dystonia and 20.4% in those with AAO < 30 years. This study provides a comprehensive examination of the genetic landscape of dystonia, revealing valuable insights into the frequency of dystonia-linked genes and their associated phenotypes. It underscores the utility of exome sequencing in establishing diagnoses within this heterogeneous condition. Despite prescreening, presumably pathogenic variants were identified in almost 10% of patients. Our findings reaffirm several dystonia candidate genes and expand the phenotypic spectrum of some of these genes to include prominent, sometimes isolated dystonia., Competing Interests: K.E.Z. has received research support from Strathmann and the German Research Council. She reports speaker’s honoraria from Bayer Vital GmbH, BIAL, AbbVie, Alexion, Allergan and Merz outside the submitted work. She has served as a consultant and received fees from Merz, Ipsen, Alexion, Bial and the German Federal Institute for Drugs and Medical Devices (BfArM). J.S.P. has research support RF1NS075321, RO1NS134586, RO1NS103957, NS107281, NS097437, U54NS116025, U19 NS110456, NS097799, R33 AT010753, RO1NS118146, NS124738, R01AG065214, NS124789, R21 NS133875, R21TR004422, R21TR005231. Foundation support: Michael J Fox Foundation, Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson disease research fund), American Parkinson Disease Association (APDA) Advanced Research Center at Washington University, Missouri Chapter of the APDA, Paula and Rodger Riney Fund, Jo Oertli Fund, Huntington Disease Society of America, Murphy Fund, Fixel Foundation, N. Grant Williams Fund, Pohlman Fund, CHDI and Prilenia. He is also co-director for the Dystonia Coalition, which has received the majority of its support through the NIH (grants NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke TR 001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). R.L.B. performs botulinum toxin injections at the University of Rochester (50% effort); serves/has served on scientific advisory board for Allergan, Ipsen, Merz and Revance; receives research support Fox Foundation; NIH (NINDS, ORDR): Dystonia Coalition Projects, Site PI; Consultant and research study rater for Abbvie/Allergan; holds stock options in VisualDx; and serves/has served as an expert witness in legal proceedings including malpractice, not involving commercial entities. J.V. has received consultancies from Medtronic, Boston Scientific, Ceregate, and Newronika. He has served on advisory boards for Medtronic and Boston Scientific. He reports speaker’s honoraria from Medtronic, Boston Scientific, Abbott, AbbVie, Bial, and Zambon outside the submitted work. H.A.J. has active or recent grant support (recent, active, or pending) from the US government (NIH), private philanthropic organizations (Cure Dystonia Now, Lesch-Nyhan Syndrome Children’s Research Foundation), and industry (Abbvie, Addex, Aeon, Sage, Ipsen, Jazz). H.A.J. has also served on advisory boards or as a consultant for the NIH (CREATE Bio DSMB) and industry (Abbvie, Addex, Ipsen, Merz, and Vima). He has received stipends for administrative work from the International Parkinson’s Disease and Movement Disorders Society. H.A.J. has also served on the Scientific Advisory Boards for several private foundations (Benign Essential Blepharospasm Research Foundation, Dystonia Medical Research Foundation). He also is principle investigator for the Dystonia Coalition, which has received the majority of its support through the NIH (NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke TR001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). C.Kl. has served as medical advisor to Centogene, Retromer Therapeutics, Takeda, and Lundbeck and has received speakers’ honoraria from Bial and Desitin. C.Ka. reports serving on advisory boards for Biogen and Roche outside of the submitted work. The other authors report no competing interests.

Optokinetic nystagmus (OKN) is a reflexive eye movement in response to movement of the viewer's visual environment that consists of a slow phase eye movement in the direction of the stimulus followed by a quick phase in the opposite direction. When tested at the bedside, the slow phases represent smooth pursuit, while the quick phases represent saccades. Normally, OKN is conjugate and symmetric (horizontally and vertically). Abnormalities in the optokinetic response can provide diagnostic and localising value. We describe six clinical scenarios where OKN testing is most useful for the practising neurologist., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility., Objective: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach., Methods: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal., Results: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10 -8 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10 -6 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10 -8 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823)., Conclusion: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data., Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression., Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019., Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years., Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity., Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years)., Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD., Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Several genetic and environmental factors have been reported in progressive supranuclear palsy (PSP), although none were identified as a definitive cause. We aimed to explore potential gene-environment interactions in PSP. Two hundred and ninety two PSP cases and 292 controls matched for age, sex, and race from the ENGENE-PSP were analyzed to determine the association between PSP and minor alleles of 5 single nucleotide polymorphisms (SNPs) in 4 genes (MAPT, MOBP, EIF2AK3, and STX6), which were previously associated with PSP risk. Interactions between these SNPs and environmental factors, including previously reported occupational and agricultural risk factors for PSP, were assessed for PSP odds and age of symptom onset. Minor alleles of MAPTrs242557 and EIF2AK3rs7571971 were individually associated with increased odds; MAPTrs8070723 minor alleles were associated with lower PSP odds. There were several gene-environment interactions for PSP odds and age of symptom onset, however, they did not remain significant after FDR-correction. Larger scale studies are required to determine potential interactions., Competing Interests: IL supported by the National Institutes of Health grants: 2R01AG038791-06A, U01NS090259, U01NS100610, U01NS80818, R25NS098999, P20GM109025; U19 AG063911-1; 1R21NS114764-01A1; Michael J Fox Foundation, Lewy Body Association, Abbvie, Biogen, Centogene, Roche, EIP-Pharma and Biohaven Pharmaceuticals. She was member of a Lundbeck Advisory Board. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. DSt supported by the Abbvie, Inc., the American Parkinson Disease Association, the Michael J. Fox Foundation for Parkinson Research, Alabama Department of Commerce, the Department of Defense, and NIH grants P50NS108675, R25NS079188, and T32NS095775. He has a clinical practice and is compensated for these activities through the University of Alabama Health Services Foundation. He has served as a consultant for or received honoraria from Abbvie Inc., Sutter Health, the International Parkinson Disease and Movement Disorder Society, Theravance, McGraw Hill, and Sanofi-Aventis. He is a member of the faculty of the University of Alabama at Birmingham and is supported by endowment and University funds. CM received research funding from The Michael J Fox Foundation, Canadian Institutes of Health Research, Parkinson's Foundation (US), International Parkinson and Movement Disorders Society. She is employed by University Health Network, contracted by Grey Matter Technologies, and receives financial compensation as a steering committee member from the Michael J Fox Foundation. DSh employed by Banner Health, received research support from the Arizona Alzheimer's Consortium, Abbvie, Acadia, Aptinyx, Axovant, Biogen, Eisai, Eli Lilly, Enterin, Neurocrine, Michael J Fox Foundation, NIH, Nuvelution, Theravance and Teva; consultant fees from Amneal, Forensis and Neurocrine; speaker honoraria from Acorda, Neurocrine, Sunovion, Teva and US World Meds. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Litvan, Proudfoot, Martin, Standaert, Riley, Hall, Marras, Bayram, Dubinsky, Bordelon, Reich, Shprecher, Kluger, Cunningham, Schellenberg and Jankovic.)

Background: The cause of progressive supranuclear palsy (PSP) is largely unknown. Based on evidence for impaired mitochondrial activity in PSP, we hypothesized that the disease may be related to exposure to environmental toxins, some of which are mitochondrial inhibitors., Methods: This multicenter case-control study included 284 incident PSP cases of 350 cases and 284 age-, sex-, and race-matched controls primarily from the same geographical areas. All subjects were administered standardized interviews to obtain data on demographics, residential history, and lifetime occupational history. An industrial hygienist and a toxicologist unaware of case status assessed occupational histories to estimate past exposure to metals, pesticides, organic solvents, and other chemicals., Results: Cases and controls were similar on demographic factors. In unadjusted analyses, PSP was associated with lower education, lower income, more smoking pack-years, more years of drinking well water, more years living on a farm, more years living 1 mile from an agricultural region, more transportation jobs, and more jobs with exposure to metals in general. However, in adjusted models, only more years of drinking well water was significantly associated with PSP. There was an inverse association with having a college degree., Conclusions: We did not find evidence for a specific causative chemical exposure; higher number of years of drinking well water is a risk factor for PSP. This result remained significant after adjusting for income, smoking, education and occupational exposures. This is the first case-control study to demonstrate PSP is associated with environmental factors. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Background: A 60 year-old woman with multiple sclerosis (MS) and chronic hearing loss presented with head tremor and vestibular hypofunction, the combination of which can produce oscillopsia--a visual sensation that steady objects in the visual field are oscillating. This case highlights the fact that in patients with pseudonystagmus, oscillopsia is attributable to the association of head tremor and vestibular hypofunction., Investigations: Eye and head movements were measured simultaneously with the search coil technique., Diagnosis: Patients with MS can present with oscillopsia, and spontaneous pendular nystagmus is often observed in these individuals. In our patient, the oscillopsia was not due to pendular nystagmus, but rather to pseudonystagmus (of gaze) resulting from diminished compensatory vestibulo-ocular reflex responses to head tremor., Management: A two-step strategy can be used in patients with pseudonystagmus: pharmacological treatment of head tremor, and vestibular rehabilitation to improve balance and diminish oscillopsia associated with head movement. Various health-care providers at other institutes attempted to address our patient's dystonic head tremor with botulinium toxin injections in the neck muscles; the response was unsatisfactory. We offered treatment with baclofen, which the patient did not tolerate. We also discussed the option of vestibular rehabilitation, which the patient did not pursue.

Background: Pace mapping has been used to identify the site of origin of focal ventricular arrhythmias. The spatial resolution of pace mapping has not been adequately quantified using currently available three-dimensional mapping systems., Objective: The purpose of this study was to determine the spatial resolution of pace mapping in patients with idiopathic ventricular tachycardia or premature ventricular contractions originating in the right ventricular outflow tract., Methods: In 16 patients with idiopathic ventricular tachycardia/ectopy from the right ventricular outflow tract, comparisons and classifications of pace maps were performed by two observers (good pace map: match >10/12 leads; inadequate pace map: match < or =10/12 leads) and a customized MATLAB 6.0 program (assessing correlation coefficient and normalized root mean square of the difference (nRMSd) between test and template signals). With an electroanatomic mapping system, the correlation coefficient of each pace map was correlated with the distance between the pacing site and the effective ablation site. The endocardial area within the 10-ms activation isochrone was measured., Results: The ablation procedure was effective in all patients. Sites with good pace maps had a higher correlation coefficient and lower nRMSd than sites with inadequate pace maps (correlation coefficient: 0.96 +/- 0.03 vs 0.76 +/- 0.18, P <.0001; nRMSd: 0.41 +/- 0.16 vs 0.89 +/- 0.39, P <.0001). Using receiver operating characteristic curves, appropriate cutoff values were >0.94 for correlation coefficient (sensitivity 81%, specificity 89%) and < or =0.54 for nRMSd (sensitivity 76%, specificity 80%). Good pace maps were located a mean of 7.3 +/- 5.0 mm from the effective ablation site and had a mean activation time of -24 +/- 7 ms. However, in 3 (18%) of 16 patients, the best pace map was inadequate at the effective ablation site, with an endocardial activation time at these sites of -25 +/- 12 ms. Pace maps with correlation coefficient > or =0.94 were confined to an area of 1.8 +/- 0.6 cm2. The 10-ms isochrone measured 1.2 +/- 0.7 cm2., Conclusion: The spatial resolution of a good pace map for targeting ventricular tachycardia/ectopy is 1.8 cm2 in the right ventricular outflow tract and therefore is inferior to the spatial resolution of activation mapping as assessed by isochronal activation. In approximately 20% of patients, pace mapping is unreliable in identifying the site of origin, possibly due a deeper site of origin and preferential conduction via fibers connecting the focus to the endocardial surface.

Background: Idiopathic premature ventricular complexes (PVCs) usually are considered benign, even when frequent. However, case reports have demonstrated a possible link between frequent PVCs and left ventricular (LV) dysfunction. In addition, frequent PVCs recently were demonstrated to be associated with increased LV dimensions and cardiomyopathy., Methods: Among 60 consecutive patients with idiopathic, frequent PVCs (>10/hour), a reduced LV ejection fraction (EF; mean 34% +/- 13%) was present in 22 (37%) patients. Patients with decreased LV function had a greater PVC burden on a 24-hour Holter monitor than patients with normal EF (37% +/- 13% vs. 11% +/- 10% of all QRS complexes; P <.0001). There was a significant inverse correlation between the PVC burden and the EF before ablation (r = 0.73, P <.0001)., Results: The PVCs originated in the right ventricular outflow tract in 31 (52%) of 60 patients, the LV outflow tract in 9 (15%) of 60 patients, and in other sites in 13 (22%) of 60 patients. The site of PVC origin could not be determined in seven patients. Ablation was completely successful in 48 (80%) patients. In patients with an abnormal EF before ablation, LV function normalized in 18 (82%) of 22 patients from a baseline of 34% to 59% +/- 7% (P <.0001) within 6 months. In the four patients in whom ablation was ineffective, the EF further declined from 34% +/- 10% to 25% +/- 7% (P = .06) during follow-up. In a control group of 11 patients with a similar PVC burden (30% +/- 8%) and a reduced EF (28% +/- 13%) who did not undergo ablation, the EF remained unchanged in 10/11 patients over 19 +/- 17 months of follow-up and one patient underwent heart transplantation., Conclusion: LV dysfunction in the setting of frequent, idiopathic PVCs may represent a form of cardiomyopathy that can be reversed by catheter ablation of the PVCs.

Multiple system atrophy (MSA) is characterized clinically by Parkinsonism, cerebellar dysfunction, and autonomic impairment. Multiple mutations in the LRRK2 gene are associated with parkinsonian disorders, and the most common one, the G2019S mutation, has been found in approximately 1% of sporadic cases of Parkinsonism. In a well-characterized cohort of 136 subjects with probable MSA and 110 neurologically evaluated control subjects, none carried the G2019S mutation. We conclude that the G2019S mutation in the LRRK2 gene is unlikely to be associated with MSA., ((c) 2006 Movement Disorder Society.)

Objectives: The objective of this study was to assess the role of Purkinje fibers in monomorphic, post-infarction ventricular tachycardia (VT)., Background: Ventricular fibrillation and polymorphic VT in the setting of acute myocardial infarction (MI) may be triggered by ectopy arising from Purkinje fibers., Methods: From among a group of 81 consecutive patients with post-infarction monomorphic VT referred for catheter ablation, 9 patients were identified in whom the clinical VT had a QRS duration < or =145 ms. Mapping was performed focusing on areas with Purkinje potentials., Results: A total of 11 VTs with a QRS duration < or =145 ms were induced and mapped in the 9 patients; 9 of the 11 VTs had a right bundle branch block/left-axis morphology that mimicked left posterior fascicular VT. The mean VT cycle length was 402 +/- 82 ms. Eight of 9 patients had a history of inferior MI involving the left ventricular septum. One patient had an anterior wall MI with septal involvement. Mapping during VT demonstrated re-entry involving the inferior left ventricular wall. In each of the VTs, a Purkinje potential was present at the exit site of the VT re-entry circuit. Single radiofrequency catheter ablation lesions were successful in eliminating these VTs in all patients., Conclusions: The Purkinje system may be part of the re-entry circuit in patients with post-infarction monomorphic VT, resulting in a type of VT with a relatively narrow QRS complex that mimics fascicular VT.

Objectives: The purpose of this study was to identify ventricular tachycardia (VT) isthmus sites by pace-mapping within scar tissue and to identify electrogram characteristics that are helpful in identifying VT isthmus sites during sinus rhythm (SR)., Background: Pace-mapping has been used in the scar border zone to identify the exit site of post-infarction VT., Methods: In 19 consecutive patients (18 men, mean age 66 +/- 9 years, mean ejection fraction 0.24 +/- 0.12) with post-infarction VT, a left ventricular voltage map was generated during SR. Pace-mapping was performed at sites with abnormal electrograms or isolated potentials. Radiofrequency ablation was performed at isthmus sites as defined by pace-mapping (perfect pace-map = 12/12 matching electrocardiogram leads; good pace-map = 10/12 to 11/12 matching electrocardiogram leads) and/or entrainment mapping., Results: A total of 81 VTs (mean cycle length 396 +/- 124 ms) were inducible. In 16 of the 19 patients, a total of 41 distinct isthmus areas of 41 distinct VTs were identified and successfully ablated. All but one displayed isolated potentials during SR. Furthermore, 22 of the 81 VTs (27%) for which no isthmus was identified became noninducible after ablation of a targeted VT. The 16 patients in whom > or =1 isthmus was identified and ablated were free of arrhythmic events during a mean follow-up of 10 months., Conclusions: During SR, excellent or good pace-maps at sites of isolated potentials within areas of scar identify areas of fixed block that are protected and part of the critical isthmus of post-infarction VT. Shared common pathways might explain why non-targeted VTs might become noninducible after ablation of other VTs.

Background: Mapping criteria for hemodynamically tolerated, postinfarction ventricular tachycardia (VT) have been evaluated in only small series of patients., Objectives: The purpose of this study was to evaluate the utility of various mapping criteria for identifying a critical VT circuit isthmus in a post hoc analysis., Methods: Ninety VTs (cycle length 491 +/- 84 ms) were mapped in 48 patients with a prior myocardial infarction. The mapping catheter was positioned within a protected area of the reentrant circuit of the targeted VTs at 176 sites. All sites showed concealed entrainment. The predictive values of the following mapping criteria for a successful ablation site were compared: discrete isolated potential during VT, inability to dissociate the isolated potential from the VT, endocardial activation time >70 ms, matching electrogram-QRS and stimulus-QRS intervals, VT termination without global capture during pacing, stimulus-QRS/VT cycle length ratio

Background: Mechanical trauma has been described as a helpful guide for ablation of atrial tachycardias and accessory pathways. In postinfarction ventricular tachycardia (VT), the reentrant circuit is partly endocardial and therefore may be susceptible to catheter trauma., Objectives: The purpose of this study was to determine the prevalence and significance of VT termination resulting from catheter trauma., Methods: A consecutive series of 39 patients (mean age 68 +/- 7 years, ejection fraction 0.25 +/- 0.02) underwent left ventricular mapping for postinfarction VT. Mapping was performed during 62 hemodynamically tolerated VTs (mean cycle length 451 +/- 88 ms). Only hemodynamically tolerated VTs that did not terminate spontaneously and VTs that were reproducibly inducible were included in the study. VT termination was considered mechanical only if it was not caused by a premature depolarization., Results: In 13 of 62 VTs (21%) in 8 of 39 patients (21%), either VT terminated during catheter placement at a particular site (n = 7) or a previously reproducibly inducible VT became no longer inducible with the mapping catheter located at a particular site (n = 6). The stimulus-QRS interval was significantly shorter at sites where mechanical trauma affected the reentrant circuit compared with sites having concealed entrainment (102 +/- 56 ms vs 253 +/- 134 ms, P = .003). At the site that was susceptible to mechanical trauma, the pace map was identical or highly similar in 13 of 13 VTs. After radiofrequency ablation at these sites, the targeted VTs were no longer inducible. No patient had recurrence of the targeted VT during a mean follow-up of 15 +/- 11 months., Conclusions: Catheter contact at a critical endocardial site can interrupt postinfarction VT or prevent its induction. Radiofrequency ablation at sites of mechanical termination of VT has a high probability of success.

Background: Parkinson disease (PD) is a degenerative neurological disorder for which no treatment has been shown to slow the progression., Objective: To determine whether a range of dosages of coenzyme Q10 is safe and well tolerated and could slow the functional decline in PD., Design: Multicenter, randomized, parallel-group, placebo-controlled, double-blind, dosage-ranging trial., Setting: Academic movement disorders clinics., Patients: Eighty subjects with early PD who did not require treatment for their disability., Interventions: Random assignment to placebo or coenzyme Q10 at dosages of 300, 600, or 1200 mg/d., Main Outcome Measure: The subjects underwent evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12-, and 16-month visits. They were followed up for 16 months or until disability requiring treatment with levodopa had developed. The primary response variable was the change in the total score on the UPDRS from baseline to the last visit., Results: The adjusted mean total UPDRS changes were +11.99 for the placebo group, +8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group, and +6.69 for the 1200-mg/d group. The P value for the primary analysis, a test for a linear trend between the dosage and the mean change in the total UPDRS score, was.09, which met our prespecified criteria for a positive trend for the trial. A prespecified, secondary analysis was the comparison of each treatment group with the placebo group, and the difference between the 1200-mg/d and placebo groups was significant (P =.04)., Conclusions: Coenzyme Q10 was safe and well tolerated at dosages of up to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10 than in those assigned to placebo, and the benefit was greatest in subjects receiving the highest dosage. Coenzyme Q10 appears to slow the progressive deterioration of function in PD, but these results need to be confirmed in a larger study.