Mobility, mood and site of care impact health related quality of life in Parkinson's disease.

OBJECTIVE: Examine the correlates of Health Related Quality of Life (HRQL) in a large cohort of Parkinson's disease (PD) patients from National Parkinson Foundation (NPF) Centers of Excellence (COEs). BACKGROUND: Improving outcomes for PD will depend upon uncovering disease features impacting HRQL to identify targets for intervention and variables for risk-adjustment models. Differences in HRQL outcomes between COEs could uncover modifiable aspects of care delivery. METHODS: This cross-sectional study examined the relative contribution of demographic, social, clinical and treatment features potentially related to HRQL, as measured by the PDQ-39, in 4601 consecutive subjects from 18 COEs. Stepwise linear regression was utilized to identify correlates of HRQL. RESULTS: The variability in the PDQ-39 summary index score correlated with H&Y stage (R(2) = 22%), Timed up and Go (TUG) (17%), disease duration (11%), comorbidities (8%), cognitive status (8%), antidepressant use (6%) and center at which a patient received care (5%). Stepwise regression reordered the importance of the variables, with the H&Y first and TUG and the center becoming equal and the second most important variables determining the PDQ-39 total score. All independent variables together accounted for 44% of the variability in HRQL. CONCLUSIONS: We confirmed many but not all HRQL associations found in smaller studies. A novel observation was that the site of care was an important contributor to HRQL, suggesting that comparison of outcomes and processes among centers may identify best practices.

The "floating door sign" in Parkinson's disease.

Individuals with Parkinson's disease (PD) display micrographia. We report a new method to elicit micrographic drawing in individuals with PD and compare this to drawing in individuals with essential tremor (ET). We asked 81 individuals with PD and 19 individuals with ET to draw a house and write a sentence. We examined house height and whether vertical lines of the door connected to the house floor. If both vertical door lines failed to reach the floor by more than 1mm we designated this a "floating door sign". House height of <5 cm and letter height of <5 mm were considered micrographic drawing and writing. 45 of 81 PD patients displayed a "floating door sign" compared with only 4 of 19 ET patients (p = 0.0103). 24 of 81 PD patients compared with 1 of 19 ET patients had micrographic writing (p = 0.0224). 60 of 81 PD patients compared with 9 of 19 ET patients had micrographic drawing (p = 0.00526). The "floating door sign" correlated with micrographic writing (p = 0.0275) but not micrographic drawing. The "floating door sign" had a positive predictive value for PD but not ET. We believe it correlates with hypometeric hand movements which cause inadequate stroke size, a phenomenon described in PD.

Laserlight cues for gait freezing in Parkinson's disease: an open-label study.

Freezing of gait (FOG) and falls are major sources of disability for Parkinson's disease (PD) patients, and show limited responsiveness to medications. We assessed the efficacy of visual cues for overcoming FOG in an open-label study of 26 patients with PD. The change in the frequency of falls was a secondary outcome measure. Subjects underwent a 1-2 month baseline period of use of a cane or walker without visual cues, followed by 1 month using the same device with the laserlight visual cue. The laserlight visual cue was associated with a modest but significant mean reduction in FOG Questionnaire (FOGQ) scores of 1.25 ± 0.48 (p = 0.0152, two-tailed paired t-test), representing a 6.6% improvement compared to the mean baseline FOGQ scores of 18.8. The mean reduction in fall frequency was 39.5 ± 9.3% with the laserlight visual cue among subjects experiencing at least one fall during the baseline and subsequent study periods (p = 0.002; two-tailed one-sample t-test with hypothesized mean of 0). Though some individual subjects may have benefited, the overall mean performance on the timed gait test (TGT) across all subjects did not significantly change. However, among the 4 subjects who underwent repeated testing of the TGT, one showed a 50% mean improvement in TGT performance with the laserlight visual cue (p = 0.005; two-tailed paired t-test). This open-label study provides evidence for modest efficacy of a laserlight visual cue in overcoming FOG and reducing falls in PD patients.

Novel THAP1 sequence variants in primary dystonia.

BACKGROUND: THAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and regulates cell proliferation. An exon 2 insertion/deletion frameshift mutation in THAP1 is responsible for DYT6 dystonia in Amish-Mennonites. Subsequent screening efforts in familial, mainly early-onset, primary dystonia identified additional THAP1 sequence variants in non-Amish subjects. OBJECTIVE: To examine a large cohort of subjects with mainly adult-onset primary dystonia for sequence variants in THAP1. METHODS: With high-resolution melting, all 3 THAP1 exons were screened for sequence variants in 1,114 subjects with mainly adult-onset primary dystonia, 96 with unclassified dystonia, and 600 controls (400 neurologically normal and 200 with Parkinson disease). In addition, all 3 THAP1 exons were sequenced in 200 subjects with dystonia and 200 neurologically normal controls. RESULTS: Nine unique melting curves were found in 19 subjects from 16 families with primary dystonia and 1 control. Age at dystonia onset ranged from 8 to 69 years (mean 48 years). Sequencing identified 6 novel missense mutations in conserved regions of THAP1 (G9C [cervical, masticatory, arm], D17G [cervical], F132S [laryngeal], I149T [cervical and generalized], A166T [laryngeal], and Q187K [cervical]). One subject with blepharospasm and another with laryngeal dystonia harbored a c.-42C>T variant. A c.57C>T silent variant was found in 1 subject with segmental craniocervical dystonia. An intron 1 variant (c.71+9C>A) was present in 7 subjects with dystonia (7/1,210) but only 1 control (1/600). CONCLUSIONS: A heterogeneous collection of THAP1 sequence variants is associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia.

Clinico-immunologic aspects of botulinum toxin type B treatment of cervical dystonia.

In this multicenter study of 100 patients with cervical dystonia, we examined the immunogenicity of botulinum toxin type B (BTX-B) and correlated the clinical response with the presence of blocking antibodies (Abs) using a novel mouse protection assay. One-third of the patients who were negative for BTX-B Abs at baseline became positive for BTX-B Abs at last visit. Thus, the high antigenicity of BTX-B limits its long-term efficacy.

Development and initial validation of a screening tool for Parkinson disease surgical candidates.

As there is currently no standardized assessment tool for evaluating Parkinson disease (PD) patients for deep brain stimulation (DBS), the authors developed the Florida Surgical Questionnaire for Parkinson Disease (FLASQ-PD). Part I of the study was a retrospective analysis of 174 patients presenting for a surgical screening. Part II was a multicenter study to assess the correlation of FLASQ-PD scores. The results of this study suggest that the FLASQ-PD may be a useful triage tool for screening PD patients for DBS surgery.

Cognitive slowing in Parkinson's disease resolves after practice.

OBJECTIVE: To assess the effect of dopaminergic repletion on working memory in Parkinson's disease. METHODS: The role of dopaminergic state on working memory in patients with Parkinson's disease was determined using the Sternberg item recognition paradigm, a continuous performance task that dissociates the motor and cognitive components of response time. Ten patients with Parkinson's disease were tested in an "on" state (on dopaminergic drug treatment) and a practical "off" state in two sessions held one week apart in counterbalanced order; 10 controls matched for age and education were studied at the same time points. RESULTS: Patients with Parkinson's disease showed impaired working memory, independent of motor slowing. During session 1, the performance of the patients was worse than the controls, regardless of dopaminergic state. The patients showed a significant improvement in the cognitive component of task performance during the second session, such that they no longer differed from the controls. The performance of the control subjects remained stable over the two sessions. CONCLUSIONS: Working memory performance of patients with Parkinson's disease did not change in association with dopaminergic state; rather, the performance improved over time. The pattern of improvement over time suggests a delay in proceduralising the task, similar to the deficits shown by such patients in procedural learning of other tasks.

Impact on quality of life of botulinum toxin treatments for spasmodic dysphonia and oromandibular dystonia.

OBJECTIVE: To determine the impact on quality of life of botulinum toxin treatments for common dystonias of the head and neck. DESIGN: Cross-sectional survey study of a patient cohort treated with botulinum toxin injections for spasmodic dysphonia (SD) or oromandibular dystonia (OMD). INTERVENTIONS AND OUTCOME MEASURES: The Glasgow Benefit Inventory was used to quantify the health benefit of treatment. Data were collected for demographics, time intervals relative to diagnosis, treatment duration, and frequency of injections. The groups were compared to determine whether differences existed in benefit from treatment. Correlation analysis was conducted for inventory scores and time intervals. RESULTS: A total of 23 patients (5 with OMD and 18 with SD) completed the questionnaire. The mean total benefit score was +38.04 (possible range, -100 to +100) for the whole group (P<.001). The OMD group derived a nonsignificantly smaller benefit (+21.67 vs +42.59) (P =.07). The mean subscores for the combined group were +39.67, +26.81, and +42.75 for the general, social support, and physical health subscores, respectively (P< or =.001). The difference in mean subscores between the 2 groups was not statistically significant, although patients with OMD had a lower social support subscore (+6.67 vs. +32.41). No correlation was found between duration of therapy or frequency of injections and the Glasgow Benefit Inventory score. CONCLUSIONS: Patients with OMD or SD derive considerable benefit when treated with botulinum toxin. The magnitude of benefit is largely independent of the time course of therapy. Treatment with botulinum toxin for these conditions is effective on the basis of quality-of-life criteria.

Spasmodic torticollis and reproductive function in women.

This investigation assessed a possible relationship between idiopathic spasmodic torticollis (ST) and reproductive function in women. Fifth decade ST onset, the peak decade for menopause, was over represented. Menstrual exacerbation of symptoms was significantly more common than in controls. Oral contraceptive use and pregnancy did not have adverse effects. Reproductive disorders and hysterectomy were significantly more common than in neurological and normal controls. The possibility that ST onset and severity may relate to reproductive state and hormonal factors warrants further investigation.

Abnormalities of spatial and temporal sensory discrimination in writer's cramp.

Clinical observations of patients with writer's cramp suggest that abnormalities of the sensory system may be a frequent finding in this disorder. Neurophysiological data from an animal model of focal dystonia have revealed cells in somatosensory cortex with enlarged and overlapping tactile receptive fields. However, psychophysical studies so far have been unable to document a clinical correlate supporting a similar enlargement of receptive fields in humans. We compared the fingertip discrimination of the orientation of fine spatial gratings between writer's cramp and control subjects and found a significant decrease in grating sensitivity in the patients, consistent with the possibility of enlarged tactile receptive fields. In addition, we duplicated previous experiments showing an abnormality of tactile temporal discrimination. The results provide psychophysical measures which may relate to the development of sensory cortical reorganization in patients with writer's cramp.

Tardive Dyskinesia.

Although there are many published studies on the treatment of tardive dyskinesia (TD), relatively few treatments have proven to be consistently useful in clinical practice. Reviewed critically, most treatments have produced only slight to moderate benefit in less than half the patients treated. Emphasis instead is on prevention, prompt detection, and management of early and potentially reversible cases. If a patient develops dyskinesia while taking an antipsychotic drug (APD), ideal management is immediate discontinuation of the APD, if this is psychiatrically feasible. The manifestations of TD should be documented and the patient examined to exclude other possible causes of dyskinesia. APDs should then be withheld in the hope that the dyskinesia will disappear. Although the dyskinesia may fade within several weeks, it has the potential to recur if APD treatment is reintroduced. Psychiatric reevaluation to consider alternative psychiatric diagnoses or treatments is strongly advised. If there is no alternative to reintroducing an APD for psychiatric treatment, then an atypical neuroleptic should be considered. Because dyskinesia is very often not disturbing enough to require treatment, the need for treatment of TD should be carefully assessed. For mild dyskinesia, low doses of a benzodiazepine (eg, clonazepam) may reduce the amount of both dyskinesia and associated anxiety. Anticholinergic drugs are unhelpful and may aggravate TD but, similar to their effect in idiopathic dystonia, may be effective in tardive dystonia. Botulinum toxin injections are of considerable value in managing localized forms of tardive dystonia, such as retrocollis or blepharospasm. Tetrabenazine and reserpine are presynaptic dopamine depletors that may have considerable efficacy in TD, especially tardive dystonia; however, their use is often limited by side effects. Based on the rationale that TD may be due to formation of free radicals, vitamin E has been used for treatment of TD, with mixed results. In some patients with persistent and disabling TD that fails to remit even after the patient is no longer taking an APD, it may be necessary to resume treatment eventually with a typical APD. This approach should be considered only as a last resort to suppress TD, however, because it carries the risk of preventing remission and possibly aggravating TD. In this case, further attempts to taper and discontinue the APD are recommended. At present, there is no evidence that established TD continues to progress in severity with continued APD exposure. This nonprogressive character of TD may provide to be a consolation to the patient and family and is also of potential medical-legal importance.

Remacemide: current status and clinical applications.

Remacemide (RMC) is a non-competitive, low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist that does not cause the behavioural and neuropathological side effects seen with other NMDA receptor antagonists. RMC and its active metabolite, AR-R 12495 AR, which has moderate affinity for the NMDA receptor, also interact with voltage-dependent neuronal sodium channels. Both agents show efficacy in a variety of animal models of epilepsy, parkinsonism and cerebral ischaemia. There is no evidence for teratogenicity or genotoxicity. RMC delays the absorption of L-dopa and elevates the concentrations of drugs metabolised by the hepatic cytochrome P450 3A4 isoform. RMC and AR-R 12495 AR have moderate protein binding and linear pharmacokinetics. Controlled studies show evidence of efficacy in treating epilepsy and Parkinson's disease. Post-surgical outcomes in RMC-treated patients at risk for intra-operative cerebral ischaemia are also encouraging. Adverse effects are related to the gastrointestinal and central nervous systems. RMC is a promising drug with numerous potential applications for both acute or chronic conditions associated with glutamate-mediated neurotoxicity.

Comparison of acute- and delayed-onset posttraumatic cervical dystonia.

Head, neck, or shoulder trauma is an occasional antecedent event before the appearance of cervical dystonia. A clinically distinctive syndrome of acute-onset posttraumatic cervical dystonia characterized by markedly restricted range of neck motion, absence of phasic involuntary movements, and poor response to treatment has previously been described. Patients with cervical dystonia attending a movement disorder clinic were reviewed for history of trauma before onset of symptoms. Patients with symptom onset within 4 weeks of trauma were compared with patients who developed symptoms between 3 months and 1 year after trauma. Acute-onset cervical dystonia was characterized by markedly reduced cervical mobility; prominent shoulder elevation with trapezius hypertrophy in most patients, absence of involuntary movements, sensory tricks, or activation maneuvers; and poor response to botulinum toxin injection. By contrast, delayed-onset cervical dystonia was clinically indistinguishable from nontraumatic idiopathic cervical dystonia. Acute-onset posttraumatic cervical dystonia is similar to limb dystonia after peripheral trauma and may represent a form of nondystonic muscle spasm similar to torticollis associated with musculoskeletal injuries of the cervical spine and craniocervical junction.

High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor.

Pharmacologic treatment for essential tremor and the tremor of Parkinson's disease is often inadequate. Stereotaxic surgery, such as thalamotomy, can effectively reduce tremors. We performed a multicenter trial of unilateral high-frequency stimulation of the ventral intermedius nucleus of the thalamus in 29 patients with essential tremor and 24 patients with Parkinson's disease, using a blinded assessment at 3 months after surgery to compare clinical rating of tremor with stimulation ON with stimulation OFF and baseline and a 1-year follow-up. Six patients were not implanted because of lack of intraoperative tremor suppression (2 patients), hemorrhage (2 patients), withdrawal of consent (1 patient), and persistent microthalamotomy effect (1 patient). A significant reduction in both essential and parkinsonian tremor occurred contralaterally with stimulation. Patients reported a significant reduction in disability. Measures of function were significantly improved in patients with essential tremor. Complications related to surgery in implanted patients were few. Stimulation was commonly associated with transient paresthesias. Other adverse effects were mild and well tolerated. Efficacy was not reduced at 1 year. Chronic high-frequency stimulation is safe and highly effective in ameliorating essential and parkinsonian tremor.

Botulinum toxin type B: a double-blind, placebo-controlled, safety and efficacy study in cervical dystonia.

We enrolled and treated 122 patients with idiopathic cervical dystonia in a double-blind, placebo-controlled safety and efficacy study of botulinum toxin type B (BotB). Both A-responsive and A-resistant patients were enrolled. Patients received intramuscular injections of either BotB (2,500 U, 5,000 U, or 10,000 U) or placebo. The primary outcome measure of efficacy was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at 4 weeks following study drug administration. Secondary measures of efficacy were TWSTRS-Severity, -Disability, and -Pain subscale scores, and Analog Pain Assessment, Investigator Global Assessment, Patient Global Assessment, and Sickness Impact Profile scores. Duration of effect was estimated with an intent-to-treat analysis of responders. Safety measures included clinical parameters, laboratory tests, and adverse events. The primary and most of the secondary analyses indicated a statistically significant treatment effect and a dose response. BotB is safe, well tolerated, and efficacious in the treatment of cervical dystonia at the doses tested.