Sleep disturbances and excessive daytime sleepiness in Parkinson disease: an overview.

Sleep disturbances are frequent in Parkinson disease. These disorders can be broadly categorized into those that involve nocturnal sleep and excessive daytime sleepiness. The disorders that are often observed during the night in PD include sleep fragmentation that may be due to recurrent PD symptoms, sleep apnea, Restless Leg Syndrome/ periodic limb movements and REM sleep behavior disorder. Excessive daytime sleepiness is also a common occurrence in PD. EDS can arise from several etiologies, and patients may have more than one etiology responsible. The causes of EDS include nocturnal sleep disorder with sleep deprivation and resulting daytime somnolence, the effect of drugs used to treat PD, and possibly neurodegeneration of central sleep/wake areas. Appropriate diagnosis of the sleep disturbance affecting a PD patient can lead to specific treatments that can consolidate nocturnal sleep and enhance daytime alertness.

Use of botulinum toxin type A in the treatment of cervical dystonia.

Botulinum toxin is the most neurotoxic substance known, with a specific action at cholinergic synapses. Acting as a zinc endopeptidase, botulinum toxin cleaves specific proteins involved in vesicle fusion, thereby preventing release of acetylcholine. The therapeutic effect of the toxin taken up presynaptically at the neuromuscular junction is to weaken muscle. Botulinum toxin type A (BTX-A) has been shown to be safe and effective in the treatment of cervical dystonia (CD; also known as spasmodic torticollis). In patients with CD, injections of botulinum toxin dampen or eliminate involuntary muscle activity and improve control of neck movement, pain, and range of motion. To successfully use botulinum toxin as a therapeutic modality, targeting the dystonic muscles, injecting a sufficient quantity of toxin and minimizing diffusion into uninvolved muscle collectively provide the best outcome with the fewest adverse reactions. EMG guidance may allow more precise injections. To maintain responsiveness to the toxin over repeated injections, using the lowest dose at the longest dosing interval has been suggested.

Dysphagia after botulinum toxin injections for spasmodic torticollis: clinical and radiologic findings.

We prospectively evaluated the frequency, severity, and radiologic features of swallowing abnormalities following Botox treatment of spasmodic torticollis. We performed both clinical and radiologic evaluations of swallowing before and following Botox in 18 consecutive cervical dystonia patients receiving their first Botox treatment. Before Botox, 11% of the patients had clinical symptoms of dysphagia and 22% had radiologic signs of a peristaltic abnormality. After Botox, the signs and symptoms of dysphagia in these patients did not change, but an additional 33% developed new dysphagic symptoms and 50% of the patients developed new peristaltic abnormalities by radiologic studies. Complaints of swallowing difficulty were always associated with abnormal radiologic findings. Neither the total Botox dose nor Botox into particular muscles differed between those with dysphagia and those without.

Botulinum toxin injection for spasmodic torticollis: increased magnitude of benefit with electromyographic assistance.

To determine the usefulness of EMG-assisted botulinum toxin (BOTOX) injections for the treatment of spasmodic torticollis (ST), we randomized 52 ST patients into two groups and studied them prospectively. In one group [(E+C)RX, N = 28], the muscles were selected for BOTOX injection using both clinical and EMG examination and then injected with EMG assistance. In the second group [(C)RX, N = 24] the muscles were selected for BOTOX injection based solely on clinical examination and injected without EMG assistance. The percentage of patients showing any improvement after BOTOX as similar in both the (E+C)RX and (C)RX groups. A significantly greater magnitude of improvement was present in the (E+C)RX group, as well as a significantly greater number of patients with marked improvement. In particular, patients with retrocollis, head tilt, and shoulder elevation demonstrated additional benefit with EMG-assisted BOTOX injection. EMG assistance may be effective because the technique increases the ability to effectively identify and treat the deep cervical muscles.

Physical therapy and Parkinson's disease: a controlled clinical trial.

In a randomized, single-blind, crossover study, we evaluated physical disability in moderately advanced Parkinson's disease (PD) patients after 4 weeks of normal physical activity and 4 weeks of an intensive physical rehabilitation program. We used a timed motor task and a standard assessment of PD severity (the Unified Parkinson's Disease Rating Scale [UPDRS] with subscales for mentation, activities of daily living [ADL], and motor function) completed by an investigator blinded to the physical rehabilitation status of the patient. Following physical rehabilitation, there was significant improvement in the UPDRS ADL and motor scores, but no change in mentation score. During the 6 months following physical rehabilitation, patients did not regularly exercise, and the UPDRS scores returned to baseline. We conclude that physical disability in moderately advanced PD objectively improves with a regular physical rehabilitation program, but this improvement is not sustained when normal activity is resumed.

Sleep-related violence, injury, and REM sleep behavior disorder in Parkinson's disease.

OBJECTIVE: To determine the occurrence of REM sleep behavior disorder (RBD) and sleep-related injury (SRI) in an outpatient PD practice. BACKGROUND: RBD is a frequent cause of SRI in older individuals. Although RBD is seen in PD, the association of SRI and RBD in PD has not been previously assessed. DESIGN/METHODS: Consecutive patients with PD and their caregivers were interviewed using a structured questionnaire assessing the presence of RBD and SRI. Patients fulfilling the International Classification of Sleep Disorders (ICSD) criteria for RBD were compared with non-RBD patients. In a separate analysis, patients with a prior SRI were compared to those without. RESULTS: Of the 61 patient/caregiver pairs, 15% (7 men and 2 women) met the clinical criteria for RBD. There were more episodes of SRI in the RBD group, with 33% causing injury to themselves or to their caregivers compared with 6% of the non-RBD group (chi(2) = 13, p = 0.005). In the second analysis, 15% (all men) patient/caregiver pairs reported SRI. Of these, 66% of the patients had behaviors resembling those seen in RBD, and 33% had recalled dream content. There is a significant association between SRI and RBD for dream-enacting sleep behaviors (Fisher's exact test, p = 0.0001). CONCLUSION: PD patients with SRI frequently have behavioral features of RBD. If RBD underlies most SRI, treatment with appropriate pharmacologic agents, such as clonazepam, may prevent future occurrences of SRI.

Menstrual-related changes in motoric function in women with Parkinson's disease.

Questionnaire studies have found that parkinsonism worsens in women during the premenstrual period, when estrogen and progesterone levels are presumably at their nadir. To assess this patient-based observation and correlate motor signs with hormonal levels, the authors prospectively studied 10 menstruating women with PD in their "off" state, on 5 successive weeks. Although PD severity fluctuated during the study period, there was no significant correlation between the objective or subjective measures of parkinsonism and estrogen and progesterone levels.

Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia.

OBJECTIVE: To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with type A-resistant cervical dystonia (CD). BACKGROUND: Local intramuscular injections of BoNT are an effective therapy for CD. After repeated use, some patients become resistant to therapy. BoNT/B, effective in type A toxin-responsive patients, is proposed as an alternative therapy for type A-resistant patients. METHODS: The authors performed a 16-week, double-blind, placebo-controlled trial of BoNT/B in type A-resistant patients with CD. After resistance to therapy was confirmed with the frontalis-type A test, placebo or 10,000 U BoNT/B was administered in a single session into two to four clinically involved muscles. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was the primary efficacy measurement. TWSTRS-Total, three visual analog scales (Patient Global Assessment of Change, Principal Investigator Global Assessment of Change, Patient Analog Pain Assessment), and adverse events were assessed at baseline and weeks 2, 4, 8, 12, and 16. RESULTS: A total of 77 patients participated (38 placebo, 39 active). Improvements in severity, disability, and pain were documented in the BoNT/B-treated group. TWSTRS-Total scores were improved in the BoNT/B-treated group at weeks 4 (p = 0.0001), 8 (p = 0.0002), and 12 (p = 0.0129). All three visual analog scales demonstrated improvements at week 4 (p < 0.0001, 0.0001, and 0.001). A Kaplan-Meier analysis supported a duration of effect of 12 to 16 weeks in the active group. Dry mouth and dysphagia were self-limited adverse effects, reported more commonly in the BoNT/B group. CONCLUSIONS: Botulinum toxin type B (BoNT/B) (NeuroBloc) is safe and efficacious for the management of patients with type A-resistant cervical dystonia with an estimated duration of treatment effect of 12 to 16 weeks.

Adrenal medullary transplant to the striatum of patients with advanced Parkinson's disease: 1-year motor and psychomotor data.

We studied motor and psychomotor changes over 1 year after surgery in 7 patients with severe idiopathic Parkinson's disease (PD) who underwent intrastriatal autologous adrenal medulla transplant. Significant clinical improvements were present 1 year after surgery and primarily involved increased quantity of "on" time and increased quality of "off" time: "on" time increased from a mean 60.7% of the waking day to 82.7%, and "off" function improved. In contrast, although "on" function also improved, statistically significant improvement occurred in only 1 measure, the Unified Parkinson's Disease Rating Scale activities of daily living subscale. Medications did not change, and motor fluctuations persisted. Improvement began several weeks after surgery, was maximal at 4 to 6 months, and was sustained thereafter. There was significant group improvement in quality of life measures of sleep and rest, social isolation, and ambulation. One patient had severe, recurrent depression postoperatively. The efficacy of adrenal transplant surgery is not transient, and specific functional improvements can be prolonged.

A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor.

OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand. BACKGROUND: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor. METHODS: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer. RESULTS: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness. CONCLUSION: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.

Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-responsive cervical dystonia.

OBJECTIVE: To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with cervical dystonia (CD). BACKGROUND: BoNT/B is a form of chemodenervation therapy for the treatment of patients with CD. METHODS: The authors performed a 16-week, randomized, multicenter, double-blind, placebo-controlled trial of BoNT/B in patients with CD who continue to respond to botulinum toxin type A. Placebo, or 5,000 U or 10,000 U of BoNT/B was administered in two to four muscles involved clinically in CD. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 was the primary efficacy measure. Clinical assessments and adverse events were recorded for treatment day 1 and at weeks 2, 4, 8, 12, and 16. RESULTS: A total of 109 patients were enrolled randomly across all three treatment groups. The mean improvement in the TWSTRS-Total scores in each group at week 4 was 4.3 (placebo), 9.3 (5,000 U), and 11.7 (10,000 U). For the prospectively defined primary contrast (10,000 U versus placebo), highly significant differences were noted for the primary (TWSTRS-Total, baseline to week 4, p = 0.0004) and supportive secondary (Patient Global Assessment, baseline to week 4, p = 0.0001) outcome measures. Improvement in pain, disability, and severity of CD occurred for patients who were treated with BoNT/B when compared with placebo-treated patients. Overall, improvements associated with BoNT/B treatment were greatest for patients who received the 10,000-U dose. The duration of treatment effect for BoNT/B was 12 to 16 weeks for both doses. CONCLUSION: 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.

The adrenal medullary transplant operation for Parkinson's disease: clinical observations in five patients.

The recent report by Madrazo and coworkers on the successful treatment of Parkinson's disease using adrenal medullary tissue transplanted to the caudate nucleus has aroused international interest in the procedure. The present article reports our initial experiences with the operation in five patients and discusses the postoperative effects of the procedure, the protocol used to monitor motor performance, and the need for cooperation with the two registries that have been created to follow morbidity, mortality, and efficacy. We intend to alert the neurosurgeon to important side effects, but not to assess the long term efficacy of the procedure. Postoperatively, a number of transient effects were seen in our patients, the most striking being somnolence, delusions, and lack of significant pain in spite of a large abdominal incision. The only complications have been respiratory. After the early postoperative period, gradual improvement of on-off times and Schwab-England disability scores was seen over 20 weeks. Long term cooperative studies are needed to demonstrate the efficacy of this procedure. neurosurgeons doing transplant operations are urged to join the registries so that uniform information can be collected.

Quantitative electromyographic analysis of changes in muscle activity following botulinum toxin therapy for cervical dystonia.

Reports of efficacy of botulinum toxin for cervical dystonia have relied on subjective reports of improvement or various clinical rating scales. We studied 19 patients with cervical dystonia using Turns analysis to determine if quantitative EMG measures of muscle activity changed following botulinum toxin injections. Before and after botulinum toxin injections, six muscles were evaluated bilaterally. Quantitative EMG analysis of active muscles injected with botulinum toxin showed a significant decline in muscle activity after botulinum toxin (F = [1,41] 55.0; p < 0.001). Significant reductions in quantitative EMG parameters were also noted in noninjected active muscles after botulinum toxin treatment (F = [1,51] 59.15; p < 0.001). The sum of EMG activity for all active muscles was calculated for each subject and showed a significant reduction after botulinum toxin injection [MANOVA: (F = [1,5] 5.69; p < 0.05]. Quantitative EMG assessment provides an objective measure of response to botulinum toxin. Decreased muscle activity in noninjected muscles may result from toxin diffusion or reflect relaxation of muscles only secondarily involved in cervical dystonia.

High-resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease.

BACKGROUND: In the midbrain of patients with Parkinson disease (PD), there is a selective loss of dopaminergic neurons in the ventrolateral and caudal substantia nigra (SN). In a mouse model of PD, investigators have administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and found that measures derived using diffusion tensor imaging (DTI) were correlated with the number of dopamine neurons lost following intoxication. METHODS: Twenty-eight subjects (14 with early stage, untreated PD and 14 age- and gender-matched controls) were studied with a high-resolution DTI protocol at 3 Tesla using an eight-channel phase array coil and parallel imaging to study specific segments of degeneration in the SN. Regions of interest were drawn in the rostral, middle, and caudal SN by two blinded and independent raters. RESULTS: Fractional anisotropy (FA) was reduced in the SN of subjects with PD compared with controls (p < 0.001). Post hoc analysis identified that reduced FA for patients with PD was greater in the caudal compared with the rostral region of interest (p < 0.00001). A receiver operator characteristic analysis in the caudal SN revealed that sensitivity and specificity were 100% for distinguishing patients with PD from healthy subjects. Findings were consistent across both raters. CONCLUSIONS: These findings provide evidence that high resolution diffusion tensor imaging in the substantia nigra distinguishes early stage, de novo patients with Parkinson disease (PD) from healthy individuals on a patient by patient basis and has the potential to serve as a noninvasive early biomarker for PD.

The treatment of cervical dystonia with botulinum toxins.

Botulinum neurotoxin (BoNT) treatment has been used extensively for the treatment of cervical dystonia. There are three established brands and two serotypes of BoNT commercially available in most of the world, and several additional brands are available in selected geographic regions. In most controlled studies, there is significant improvement following treatment for head posture, pain and disability. The common side effects of treatment include dysphagia, dry mouth, and neck weakness. Each brand and serotype is pharmacologically distinct. The dosing of each type differs, and no simple dose equivalency has been established. With repeated treatment, the development of immunoresistance is observed in a percentage of patients. However, it is likely that each brand and serotype may differ in immunogenic potential and occurrence of secondary unresponsiveness, an issue that is currently under active investigation.

Fatigue in levodopa-naive subjects with Parkinson disease.

BACKGROUND: Fatigue is a common complaint in Parkinson disease (PD). We investigated fatigue in a cohort of previously untreated patients with early PD enrolled in the Earlier vs Later Levodopa (ELLDOPA) clinical trial. METHODS: A total of 361 patients were enrolled in the randomized, double-blind, placebo-controlled ELLDOPA trial and assigned to receive placebo or carbidopa-levodopa 37.5/150 mg, 75/300 mg, or 150/600 mg daily for 40 weeks, followed by a 2-week medication washout period. Subjects who scored >4 on the Fatigue Severity Scale were classified as fatigued. PD severity was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn-Yahr scale, and Schwab-England Activities of Daily Living Scale. A subgroup of subjects underwent [(123)I]-beta-CIT SPECT to measure striatal dopamine transporter density. RESULTS: Of the 349 ELLDOPA subjects who completed fatigue measures, 128 were classified as fatigued at baseline. The fatigued group was significantly more impaired neurologically (UPDRS, all subscales and Hoehn and Yahr staging) and functionally (Schwab-England Scale) but no significant differences were observed in beta-CIT measurements between the two groups. Analysis of covariance showed a greater increase in fatigue score from baseline to the end of the 2-week washout in the placebo group (0.75 points) than in the three groups receiving levodopa (increases of 0.30 [150 mg/day], 0.36 [300 mg/day], and 0.33 [600 mg/day]; p = 0.03 for heterogeneity). CONCLUSIONS: Fatigue is a frequent symptom in early, untreated, non-depressed patients with Parkinson disease (PD), affecting over 1/3 of the patients in this cohort at baseline and 50% by week 42. Fatigue was associated with the severity of PD, and progressed less in patients treated with levodopa.

Treatment of cervical dystonia with botulinum toxins.

Botulinum toxin (BoNT) treatment has been used extensively for the treatment of cervical dystonia. In most studies, there is significant improvement following treatment for head posture and pain. The common side effects following treatment include dysphagia, dry mouth, and neck weakness. There are five brands and two serotypes of BoNT available. The dosing of each serotype and brand differs. Perhaps more importantly, each brand and serotype may differ in immunogenic potential and occurrence of secondary unresponsiveness, an issue that is currently under active investigation. Although many aspects of the technique of injection have not been adequately studied, general guidelines are available.

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.