Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures1,2. Its molecular pathophysiology is poorly understood, in part due to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1)3, THAP1 (DYT6)4, and CIZ15 have been identified. Using exome sequencing in two PTD families we identified a novel causative gene, GNAL, with a nonsense p.S293X mutation resulting in premature stop codon in one family and a missense p.V137M mutation in the other. Screening of GNAL in 39 PTD families, revealed six additional novel mutations in this gene. Impaired function of several of the mutations was shown by bioluminescence resonance energy transfer (BRET) assays.
Botulinum toxin type B (NeuroBloc) is safe and efficacious at 5,000 U and 10,000 U for the management of patients with cervical dystonia.
We conducted an open-label study to determine the utility of treating severe hand tremors with intramuscular injections of botulinum toxin (BTX) in forearm and arm muscles in 26 patients, 12 with Parkinson's disease (PD) and 14 with essential tremor (ET). The effect after 6 weeks for each patient was evaluated using two clinical rating scales, subjective evaluations of functional improvement and global disability, measures of weakness, and computer-assisted quantitative assessments of tremor. Although none of the clinical scores averaged > 3/4 point change, statistical significance was found on comparison of pre- and postinjection scores in the Webster Tremor and Global Disability Scales in the ET patients. Similarly, although average tremor amplitudes decreased by no more than 25% by quantitative analysis, amplitude decrease significantly correlated with patient subjective assessment in ET. In only two of 12 PD (17%) and three of 14 ET patients (21%) were major quantitative changes in tremor amplitude (> 50% reduction) found after BTX injections. Nevertheless, 10 patients (38%; five PD and five ET) reported moderate to marked subjective improvement in functional benefit after BTX. These findings suggest that although there were no major changes in clinical ratings or objective measurements, BTX injections may subjectively improve tremor in some patients, particularly those with ET.
We conducted a multicentered, retrospective review of clozapine's (CZP) effects on a range of psychiatric, sleep, cognitive, motor, and sensory disorders in Parkinson's disease (PD). Therapeutic outcomes and adverse events were compared with varying prescribing practices at participating sites. The medical records of 172 consecutive PD patients treated with CZP at four movement disorder clinics were reviewed. Low-dose CZP improved psychiatric symptoms of psychosis, anxiety, depression, hypersexuality, sleep disturbance, and akathisia. Tremor, torticollis, limb dystonia, and pain showed modest rates of improvement. Twenty-three percent of patients withdrew as a result of adverse events or treatment failure. Inpatient CZP initiation did not improve therapeutic efficacy, or reduce adverse events or the withdrawal rate. Low-dose CZP in the outpatient setting is generally an effective and well-tolerated treatment for many of the psychiatric, sleep, motor, and sensory disturbances common to late-stage PD.
; for the MYSTICOL Study Group IMPORTANCE RimabotulinumtoxinB (RIMA) may be preferable as an anti-sialorrhea treatment compared with current oral anticholinergic drugs in people with neurological disorders. OBJECTIVE To assess the safety, efficacy, and tolerability of RIMA injections for the treatment of sialorrhea in adults. DESIGN, SETTING, AND PARTICIPANTS This randomized, parallel, double-blind, placebo-controlled clinical trial of RIMA 2500 U and 3500 U was conducted from November 14, 2013, to January 23, 2017. A total of 249 adult patients with troublesome sialorrhea secondary to any disorder or cause were screened. Of them, 13 refused further participation in the study or were lost to follow-up and 49 did not fulfill the criteria for participation; 187 were ultimately enrolled. Patients had to have a minimum unstimulated salivary flow rate (USFR) of 0.2 g/min and a minimum Drooling Frequency and Severity Scale score of 4. EXPOSURES Patients were randomized 1:1:1 to RIMA, 2500 U (n = 63); RIMA, 3500 U (n = 64); or placebo (n = 60). MAIN OUTCOMES AND MEASURES Primary outcomes were the change in USFR from baseline to week 4 and the Clinical Global Impression of Change (CGI-C) at week 4. The CGI-C scores were recorded on a 7-point scale ranging from very much improved to very much worse. Adverse events were recorded throughout the trial period. RESULTS Of 187 patients enrolled (147 men [78.6%]; mean [SD] age, 63.9 [13.3] years), 122 patients had Parkinson disease (65.2%), 13 (7.0%) were stroke survivors, 12 had amyotrophic lateral sclerosis (6.4%), 6 had medication-induced sialorrhea (3.2%), 4 had adult cerebral palsy (2.1%), and 30 had sialorrhea owing to other causes (16.0%). A total of 176 completed the study. Treatment with both doses of RIMA significantly reduced USFR at week 4 vs placebo (mean treatment difference, −0.30 g/min [95% CI, −0.39 to −0.21] for both doses vs placebo, P < .001). The CGI-C scores were statistically significantly improved at week 4 for both treatment groups vs placebo (−1.21 [95% CI, −1.56 to −0.87] for 2500 U, −1.14 [95% CI, −1.49 to −0.80] for 3500 U, both P < .001). Treatment benefits were seen as early as 1 week after injection and were maintained over the treatment cycle of approximately 13 weeks. The RIMA injections were well tolerated compared with placebo. The most common adverse events were self-limited mild to moderate dry mouth, dysphagia, and dental caries. CONCLUSIONS AND RELEVANCE Treatment with RIMA (2500 U and 3500 U) in adults was well tolerated and reduced sialorrhea, with the onset of the effect at 1 week after the injection. These data support the clinical use of RIMA in the management of sialorrhea in adults.
Although dysphagia is a common problem for many Parkinson's disease (PD) patients, the effect of deep brain stimulation (DBS) on swallowing is unclear. Fourteen subjects with advanced PD underwent videofluorographic swallowing studies prior to bilateral DBS of the subthalamic nucleus (STN) and at 3 and 12 months postprocedure. They were tested under several stimulation and medication conditions. Subjects completed the Dysphagia Handicap Index at each time. There was a strong trend toward improved swallowing response for solid intake in the medication-free condition with the stimulator on compared with the stimulator off (P = .0107). Also, there was a trend toward improved oral preparation of thin liquids (P = .0368) in the medication-free condition when the stimulator was on versus off 12 months later. The remaining swallowing parameters showed no change or worsening of swallowing function regardless of stimulator or medication status. Results of the Dysphagia Handicap Index revealed significant improvement in subject self-perception of swallowing 3 and 12 months following the procedure compared with baseline on the functional subscale (P = .020 and P = .010, respectively), the emotional subscale (P = .013 and P = .003, respectively), and the total score (P = .025 and P = .003, respectively). These data suggest that bilateral STN-DBS does not substantively impair swallowing in PD. In addition, it may improve motor sequencing of the oropharyngeal swallow for solid consistencies (which are known to provide increased sensory feedback to assist motor planning of the oropharyngeal swallow). Subjects with advanced PD who are undergoing DBS may perceive significant improvement in swallowing ability despite the lack of objective improvements in swallowing function.
This study confirmed the beneficial effect of abobotulinumtoxinA on CD in routine clinical practice as measured by improvements in TWSTRS and PGIC. No new safety concerns were identified.
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