Clinical Impact of 123I-Ioflupane SPECT (DaTscan) in a Movement Disorder Center.

BACKGROUND/AIMS: The clinical diagnosis of degenerative forms of parkinsonism is imperfect, with past studies reporting a high rate of misdiagnosis by neurologists and movement disorder specialists, particularly early in the disease course. 123I-ioflupane SPECT (DaTscan) is a diagnostic neuroimaging tool used to distinguish essential tremor from tremor due to degenerative parkinsonisms. The present study expands upon prior studies of the clinical impact of DaTscan imaging in movement disorder centers by assessing quantitative estimates of diagnostic certainty, the impact on subsequent clinical decisions, and the degree to which the asymmetry in the results corresponds to laterality by clinical history and examination. METHODS: In a prospective, observational study of the impact of DaTscan imaging in a movement disorder center over the course of 18 months, 4 specialists completed a questionnaire at the time they ordered imaging and again within 1 month after imaging. RESULTS: Twenty-seven patients underwent DaTscan imaging; the result was normal in 4 cases (14.8%), abnormal in 22 cases (81.4%), and equivocal in 1 case (3.7%). In all cases of a normal result, the post-scan-predicted chance of degenerative parkinsonism decreased compared to the pre-scan prediction (p < 0.05), and in all cases of abnormal scan, the post-scan chance of degenerative parkinsonism increased or remained high (p < 0.0001). Clinical impacts were observed following imaging in a total of 24 patients (88.9%), including changes in medications for 18 patients and psychological impacts for 11 patients. Asymmetric clinical symptoms were corroborated based on the expected asymmetry of dopamine uptake deficits in 57.1% of the cases, were not present in 23.8%, and were opposite of expectations in 19.0% of the scans. CONCLUSION: DaTscan imaging results have an impact on physician's confidence in the diagnosis of parkinsonism and may also have a psychological impact on patients. DaTscan imaging may be a useful adjunct to clinical history and examination in selected patients.

Reliability of a new scale for essential tremor.

BACKGROUND: The objective of this study was to determine the reliability of a new scale for the clinical assessment of essential tremor. The Essential Tremor Rating Assessment Scale contains 9 performance items that rate action tremor in the head, face, voice, limbs, and trunk from 0 to 4 in half-point intervals. Head and limb tremor ratings are defined by specific amplitude ranges in centimeters. METHODS: Videos of 44 patients and 6 controls were rated by 10 specialists on 2 occasions 1-2 months apart. Inter- and intrarater reliability was assessed with a 2-way random-effects intraclass correlation, using an absolute agreement definition. RESULTS: Inter- and intrarater intraclass correlations for head and upper-limb tremor ranged from 0.86 to 0.96, and intraclass correlations for total score were 0.94 and 0.96. The intraclass correlations for voice, face, trunk, and leg were less robust. CONCLUSIONS: This scale is an exceptionally reliable tool for the clinical assessment of essential tremor.

Psychogenic facial movement disorders: clinical features and associated conditions.

The facial phenotype of psychogenic movement disorders has not been fully characterized. Seven tertiary-referral movement disorders centers using a standardized data collection on a computerized database performed a retrospective chart review of psychogenic movement disorders involving the face. Patients with organic forms of facial dystonia or any medical or neurological disorder known to affect facial muscles were excluded. Sixty-one patients fulfilled the inclusion criteria for psychogenic facial movement disorders (91.8% females; age: 37.0 ± 11.3 years). Phasic or tonic muscular spasms resembling dystonia were documented in all patients most commonly involving the lips (60.7%), followed by eyelids (50.8%), perinasal region (16.4%), and forehead (9.8%). The most common pattern consisted of tonic, sustained, lateral, and/or downward protrusion of one side of the lower lip with ipsilateral jaw deviation (84.3%). Ipsi- or contralateral blepharospasm and excessive platysma contraction occurred in isolation or combined with fixed lip dystonia (60.7%). Spasms were reported as painful in 24.6% of cases. Symptom onset was abrupt in most cases (80.3%), with at least 1 precipitating psychological stress or trauma identified in 57.4%. Associated body regions involved included upper limbs (29.5%), neck (16.4%), lower limbs (16.4%), and trunk (4.9%). There were fluctuations in severity and spontaneous exacerbations and remissions (60%). Prevalent comorbidities included depression (38.0%) and tension headache (26.4%). Fixed jaw and/or lip deviation is a characteristic pattern of psychogenic facial movement disorders, occurring in isolation or in combination with other psychogenic movement disorders or other psychogenic features.

Treatment of Parkinson disease: a 64-year-old man with motor complications of advanced Parkinson disease.

In early stages, Parkinson disease typically begins with asymmetric or unilateral motor symptoms due to combinations of mild bradykinesia, rigidity, and tremor. In most cases, with progression, signs of more generalized bradykinesia appear, which include facial masking, reduced voice volume, and slowing of activities of daily living. In more advanced Parkinson disease, other disabling manifestations may follow, such as impaired balance, gait freezing, falls, speech disturbance, and cognitive impairment. Levodopa is the most effective medical treatment for Parkinson disease. However, motor complications uniquely related to levodopa treatment may emerge that may be difficult to manage. These include fluctuating levodopa responses and involuntary movements and postures known as dyskinesia and dystonia. Medication adjustments are usually effective, but in some cases surgical intervention with deep brain stimulation becomes necessary to alleviate motor complications. The case of Mr L, a man with an 11-year history of Parkinson disease, illustrates these emerging motor complications and the manner in which they may be managed both medically and surgically.

The c.-237_236GA>TT THAP1 sequence variant does not increase risk for primary dystonia.

BACKGROUND: Sequence variants in coding and noncoding regions of THAP1 have been associated with primary dystonia. METHODS: In this study, 1,446 Caucasian subjects with mainly adult-onset primary dystonia and 1,520 controls were genotyped for a variant located in the 5'-untranslated region of THAP1 (c.-237_236GA>TT). RESULTS: Minor allele frequencies were 62/2892 (2.14%) and 55/3040 (1.81%) in subjects with dystonia and controls, respectively (P=0.202). Subgroup analyses by gender and anatomical distribution also failed to attain statistical significance. In addition, there was no effect of the TT variant on expression levels of THAP1 transcript or protein. DISCUSSION: Our findings indicate that the c.-237_236GA>TT THAP1 sequence variant does not increase risk for adult-onset primary dystonia in Caucasians.

Survey of U.S. neurologists' attitudes towards deep brain stimulation for Parkinson's disease.

OBJECTIVES: Deep brain stimulation (DBS) for Parkinson's disease (PD) was approved by the Food and Drug Administration in 2002 and has demonstrated clinical benefit in advanced PD. Our aim was to assess attitudes of U.S. neurologists towards the role of DBS in management of advanced PD. MATERIALS AND METHODS: We sent a 40-item Internet-based survey assessing opinions regarding the role of medical and surgical therapies in managing PD to 7722 neurologists in the American Medical Association Physician MasterFile data base. RESULTS: The response rate was low (4.2%). In total, 78 of the 298 (26%) responders self-identified as movement disorders specialists. Specialists and non-specialists had differences on a number of medical strategies used to manage PD. There were no statistically significant differences in reasons for or against referring patients for DBS, except for the number of non-specialists who agreed with referring a patient who had a "poor or absent response to levodopa" (71% vs. 16%, p < 0.001). Both groups indicated a need for more information concerning appropriate indications for DBS, adverse effects of surgery, and postoperative programming. CONCLUSIONS: Movement disorders specialists and non-specialists were in general agreement towards the beneficial role of DBS in management of advanced PD except for whether to refer patients with poor or absent response to levodopa.

Sustained dyskinesias following elective cessation and reactivation of chronic subthalamic nucleus deep brain stimulation for a surgical procedure.

OBJECTIVES: Subthalamic nucleus deep brain stimulation (STN DBS) is effective for treatment of levodopa-induced dyskinesias in patients with Parkinson's disease (PD). Medical or surgical procedures requiring electrocautery may require inactivation of the pulse generators to avoid damage to the lead or extension wire or possible reprogramming of the stimulators. This generally causes only mild and temporary disability. We report a patient with previously well-controlled dyskinesias who had severe and prolonged dyskinesias following reactivation of deep brain stimulation (DBS) following an orthopedic procedure. MATERIALS AND METHODS: Retrospective chart review. RESULTS: The patient underwent two orthopedic procedures, each requiring inactivation of DBS. After reactivation of DBS, the patient experienced severe dyskinesias that ultimately required sedation and ventilation to control large-amplitude dyskinesias. CONCLUSIONS: Clinicians caring for PD patients treated with STN DBS should be aware of the possible reappearance of severe dyskinesias arising from routine inactivation and reactivation of pulse generators for medical or surgical procedures.

High-throughput mutational analysis of TOR1A in primary dystonia.

BACKGROUND: Although the c.904_906delGAG mutation in Exon 5 of TOR1A typically manifests as early-onset generalized dystonia, DYT1 dystonia is genetically and clinically heterogeneous. Recently, another Exon 5 mutation (c.863G>A) has been associated with early-onset generalized dystonia and some DeltaGAG mutation carriers present with late-onset focal dystonia. The aim of this study was to identify TOR1A Exon 5 mutations in a large cohort of subjects with mainly non-generalized primary dystonia. METHODS: High resolution melting (HRM) was used to examine the entire TOR1A Exon 5 coding sequence in 1014 subjects with primary dystonia (422 spasmodic dysphonia, 285 cervical dystonia, 67 blepharospasm, 41 writer's cramp, 16 oromandibular dystonia, 38 other primary focal dystonia, 112 segmental dystonia, 16 multifocal dystonia, and 17 generalized dystonia) and 250 controls (150 neurologically normal and 100 with other movement disorders). Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known DeltaGAG DYT1 dystonia and 88 subjects with DeltaGAG-negative dystonia. RESULTS: HRM of TOR1A Exon 5 showed high (100%) diagnostic sensitivity and specificity. HRM was rapid and economical. HRM reliably differentiated the TOR1A DeltaGAG and c.863G>A mutations. Melting curves were normal in 250/250 controls and 1012/1014 subjects with primary dystonia. The two subjects with shifted melting curves were found to harbor the classic DeltaGAG deletion: 1) a non-Jewish Caucasian female with childhood-onset multifocal dystonia and 2) an Ashkenazi Jewish female with adolescent-onset spasmodic dysphonia. CONCLUSION: First, HRM is an inexpensive, diagnostically sensitive and specific, high-throughput method for mutation discovery. Second, Exon 5 mutations in TOR1A are rarely associated with non-generalized primary dystonia.

Deep brain stimulation effects on gait variability in Parkinson's disease.

The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on fall risk in patients with Parkinson's disease (PD) currently remain unclear. Although several gait parameters, such as gait speed, have shown improvement with DBS, some studies have reported an increased fall risk following DBS. The purpose of this study was to examine the effect of bilateral DBS on gait variability, a marker of fall risk. The gait of 13 patients with idiopathic PD was analyzed to determine the influence of DBS, levodopa and both therapies together. Following treatment with both levodopa and STN DBS, subjects displayed improved gait speed, reduced gait variability (enhanced stability), and lower Unified Parkinson's Disease Rating Scale (UPDRS) scores. Although UPDRS scores improved with STN DBS alone, parallel improvements were not seen for gait variability. These findings suggest that different mechanisms may contribute to performance on UPDRS motor testing and gait stability in response to DBS.

Single-dose administration of MK-0657, an NR2B-selective NMDA antagonist, does not result in clinically meaningful improvement in motor function in patients with moderate Parkinson's disease.

The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selective NMDA receptor antagonist. Patients (n=16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P=.025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P=.110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.

Comparison of the Fahn-Tolosa-Marin Clinical Rating Scale and the Essential Tremor Rating Assessment Scale.

BACKGROUND: The Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM) has been used in large trials for essential tremor (ET), but its anchors for ratings from 0 to 4 of upper limb tremor are probably too low for patients with severe tremor (tremor amplitude >4 cm; grade 4). The Essential Tremor Rating Assessment Scale (TETRAS) is a validated clinical scale designed specifically for the assessment of ET severity. TETRAS has anchors that span a larger range of tremor amplitudes (>20 cm = grade 4), making it more suitable for assessing patients with severe ET. However, there is no direct comparison of these scales in any clinical trial. METHODS: Upper limb postural and kinetic tremor items from both scales were compared using blinded, video-recorded examinations of patients with moderate-to-severe ET who participated in a trial of focused ultrasound thalamotomy. RESULTS: FTM ratings of postural and kinetic tremor correlated strongly with those of TETRAS. However, FTM exhibited a ceiling effect for severe tremor. Rest tremor, exclusive to FTM, correlated poorly with postural and kinetic tremor and had very poor test-retest reliability. In contrast, wing-beating postural tremor, exclusive to TETRAS, exhibited excellent test-retest reliability and a strong correlation with kinetic and limbs-extended-forward postural tremor. Test-retest reliabilities of the other TETRAS and FTM ratings were excellent, and both scales had good sensitivity to treatment effect. CONCLUSIONS: TETRAS has 2 main advantages over FTM in the assessment of tremor severity: (1) the absence of a ceiling effect in patients with severe ET, and (2) the inclusion of wing-beating tremor.

Tai Chi for Reducing Dual-task Gait Variability, a Potential Mediator of Fall Risk in Parkinson's Disease: A Pilot Randomized Controlled Trial.

OBJECTIVES: To assess the feasibility and inform design features of a fully powered randomized controlled trial (RCT) evaluating the effects of Tai Chi (TC) in Parkinson's disease (PD) and to select outcomes most responsive to TC assessed during off-medication states. DESIGN: Two-arm, wait-list controlled RCT. SETTINGS: Tertiary care hospital. SUBJECTS: Thirty-two subjects aged 40-75 diagnosed with idiopathic PD within 10 years. INTERVENTIONS: Six-month TC intervention added to usual care (UC) versus UC alone. OUTCOME MEASURES: Primary outcomes were feasibility-related (recruitment rate, adherence, and compliance). Change in dual-task (DT) gait stride-time variability (STV) from baseline to 6 months was defined, a priori, as the clinical outcome measure of primary interest. Other outcomes included: PD motor symptom progression (Unified Parkinson's Disease Rating Scale [UPDRS]), PD-related quality of life (PDQ-39), executive function (Trail Making Test), balance confidence (Activity-Specific Balance Confidence Scale, ABC), and Timed Up and Go test (TUG). All clinical assessments were made in the off-state for PD medications. RESULTS: Thirty-two subjects were enrolled into 3 sequential cohorts over 417 days at an average rate of 0.08 subjects per day. Seventy-five percent (12/16) in the TC group vs 94% (15/16) in the UC group completed the primary 6-month follow-up assessment. Mean TC exposure hours overall: 52. No AEs occurred during or as a direct result of TC exercise. Statistically nonsignificant improvements were observed in the TC group at 6 months in DT gait STV (TC [20.1%] vs UC [-0.1%] group [effect size 0.49; P = .47]), ABC, TUG, and PDQ-39. UPDRS progression was modest and very similar in TC and UC groups. CONCLUSIONS: Conducting an RCT of TC for PD is feasible, though measures to improve recruitment and adherence rates are needed. DT gait STV is a sensitive and logical outcome for evaluating the combined cognitive-motor effects of TC in PD.

Long-term evaluation of deep brain stimulation of the thalamus.

OBJECT: The effects of thalamic deep brain stimulation (DBS) on essential tremor (ET) and Parkinson disease (PD) have been well documented, but there is a paucity of long-term data. The aim of this study was to evaluate the long-term safety and efficacy of DBS of the ventralis intermedius nucleus (VIM) of the thalamus for PD and ET. METHODS: Thirty-eight of 45 patients enrolled at five sites completed a 5-year follow-up study. There were 26 patients with ET and 19 with PD undergoing 29 unilateral (18 ET/11 PD) and 16 bilateral (eight ET/eight PD) procedures. Patients with ET were evaluated using the Tremor Rating Scale, and patients with PD were evaluated using the Unified Parkinson's Disease Rating Scale. The mean age of patients with ET was 70.2 years and 66.3 years in patients with PD. Unilaterally implanted patients with ET had a 75% improvement of the targeted hand tremor; those with bilateral implants had a 65% improvement in the left hand and 86% in the right compared with baseline. Parkinsonian patients with unilateral implants had an 85% improvement in the targeted hand tremor and those with bilateral implants had a 100% improvement in the left hand and 90% improvement in the right. Common DBS-related adverse events in patients receiving unilateral implants were paresthesia (45%) and pain (41%), and in patients receiving implants bilaterally dysarthria (75%) and balance difficulties (56%) occurred. Device-related surgical revisions other than IPG replacements occurred in 12 (27%) of the 45 patients. CONCLUSIONS: Thalamic stimulation is safe and effective for the long-term management of essential and Parkinsonian tremors. Bilateral stimulation can cause dysarthria and incoordination and should be used cautiously.

Drooling in Parkinson's disease: A randomized controlled trial of incobotulinum toxin A and meta-analysis of Botulinum toxins.

INTRODUCTION: Botulinum toxins are a therapeutic option for drooling in Parkinson's Disease (PD). The aims of this study were to: 1. evaluate the efficacy of incobotulinum toxin A for drooling in PD. 2. Perform a meta-analysis of studies of Botulinum toxins for drooling in PD. METHODS: 1. Primary study: Randomized, double blind, placebo controlled, cross over trial. Incobotulinum toxin (100 units) or saline was injected into the parotid (20 units) and submandibular (30 units) glands. Subjects returned monthly for three evaluations after each injection. Outcome measures were saliva weight and Drooling Frequency and Severity Scale. 2. Systematic review of literature, followed by inverse variance meta-analyses using random effects models. RESULTS: 1. Primary Study: Nine of 10 subjects completed both arms. There was no significant change in the primary outcome of saliva weight one month after injection in the treatment period compared to placebo period (mean difference, gm ± SD: -0.194 ± 0.61, range: -1.28 to 0.97, 95% CI -0.71 to 0.32). Secondary outcomes also did not change. 2. Meta-analysis of six studies demonstrated significant benefit of Botulinum toxin on functional outcomes (effect size, Cohen's d: -1.32, CI -1.86 to -0.78). The other studies used a higher dose of Botulinum toxin A into the parotid glands. CONCLUSIONS: This study did not demonstrate efficacy of incobotulinum toxin A for drooling in PD, but lacked precision to exclude moderate benefit. The parotid/submandibular dose-ratio may have influenced results. Studies evaluating higher doses of incobotulinum toxin A into the parotid glands may be useful.