Protocol: Using N-of-1 tests to identify responders to melatonin for sleep disturbance in Parkinson's disease.

BACKGROUND: 40% of Parkinson's Disease (PD) sufferers experience insomnia, impacting health and quality of life for patients and family members, especially carers. There is little evidence that current treatments are effective. OBJECTIVES: To determine the effectiveness of melatonin in reducing insomnia in 44 individuals with PD using N-of-1 trials. To aggregate group data to arrive at population estimates of effectiveness (measured by improvements in PDSS-2) and safety (measured by adverse events) of melatonin in improving insomnia in PD. To assess the feasibility of offering N-of-1 trials for insomnia in PD. METHODOLOGY: Participants will receive either immediate-release melatonin or placebo in random order in 3 paired two-week treatment periods (12 weeks total). Based on their response in a two-week run-in period on 3 mg daily, they will trial either 3 mg or 6 mg. Patients will keep daily sleep diaries and wear a MotionWatch throughout. After the trial patients will discuss their individual report with their doctor, which provides direct feedback about effectiveness and safety of melatonin for them. STATISTICAL METHODS: We will analyse N-of-1 tests 1) individually: effects of melatonin on PDSS-2 and safety will be reported; and 2) aggregated across individual N-of-1 studies, combined using a Bayesian multilevel random effects model, which will account for repeated measures on individuals over time, and will return posterior estimates of overall treatment effect, and effect in each individual. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12617001103358.

Altered expression of metabolic proteins and adipokines in patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the loss of upper cortical and lower motor neurons. ALS causes death within 2-5years of diagnosis. Diet and body mass index influence the clinical course of disease, however there is limited information about the expression of metabolic proteins and fat-derived cytokines (adipokines) in ALS. In healthy controls and subjects with ALS, we have measured levels of proteins and adipokines that influence metabolism. We find altered levels of active ghrelin, gastric inhibitory peptide (GIP), pancreatic polypeptide (PP), lipocalin-2, plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6) and 8 (IL-8), and tumor necrosis factor alpha (TNFα) in the plasma of ALS patients relative to controls. We also observe a positive correlation between the expression of plasma nerve growth factor (NGF) relative to disease duration, and an inverse correlation between plasma glucagon and the ALS functional rating scale-revised (ALSFRS-R). Further studies are required to determine whether altered expression of metabolic proteins and adipokines contribute to motor neuron vulnerability and how these factors act to modify the course of disease.

Improved language performance subsequent to low-frequency rTMS in patients with chronic non-fluent aphasia post-stroke.

BACKGROUND: Low-frequency repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential tool for neurorehabilitation and remediation of language in chronic non-fluent aphasia post-stroke. Inhibitory (1 Hz) rTMS has been applied to homologous language sites to facilitate behavioural language changes. Improvements in picture-naming performance and speech output over time have been reported. METHODS: Low-frequency (1 Hz) rTMS was applied to six real stimulation and six sham placebo patients for 20 min per day, for 10 days, and behavioural language outcome measures were taken at baseline (pre-stimulation) and 2 months post-stimulation. RESULTS: The findings demonstrate treatment-related changes observed in the stimulation group when compared to the placebo control group at 2 months post-stimulation on naming performance as well as other aspects of expressive language and auditory comprehension. CONCLUSIONS: These findings provide considerable evidence to support the theory of rTMS modulating mechanisms of transcallosal disinhibition in the aphasic brain and highlight the potential clinical applications for language rehabilitation post-stroke.

Natural history of blood glucose within the first 48 hours after ischemic stroke.

BACKGROUND: Despite suggestions that glucose levels rise after stroke before falling within a few hours, the natural history and determinants of this phenomenon remain unclear. We aimed to better characterize the time course of changes in glucose levels after ischemic stroke and to identify factors that affect poststroke glycemia. METHODS: Patients with ischemic stroke without previously diagnosed diabetes had blood glucose measured at least 4-hourly until 48 hours poststroke. The relationship between baseline factors, such as the NIH Stroke Scale, and blood glucose was assessed with mixed-effects models. The behavior of glucose over time was modeled in the whole cohort, and for the cohort partitioned into two around an admission glucose of 6.0 mmol/L. RESULTS: In the cohort of 124 patients the mean glucose was 6.6 mmol/L throughout the period of monitoring, with no change over time. Mixed-effects models identified more severe stroke and glucose-lowering therapy to be associated with higher poststroke glucose levels. When the cohort was partitioned, the mean glucose of those below 6.0 mmol/L at admission increased and the mean glucose of those above 6.0 mmol/L at admission decreased to the overall mean. CONCLUSIONS: Mean glucose levels remain static in patients with ischemic stroke without diabetes until at least 48 hours poststroke. Serial glucose levels are higher in patients with more severe stroke. Initially high or low mean glucose recordings exhibit regression to the mean over time, a change which may merely be a statistical phenomenon without necessarily indicating resolution of abnormal glycemia.

Motor imagery in Parkinson's disease: a PET study.

We used positron emission tomography (PET) with 15O-labelled water to record patterns of cerebral activation in six patients with Parkinson's disease (PD), studied when clinically "off" and after turning "on" as a result of dopaminergic stimulation. They were asked to imagine a finger opposition movement performed with their right hand, externally paced at a rate of 1 Hz. Trials alternating between motor imagery and rest were measured. A pilot study of three age-matched controls was also performed. We chose the task as a robust method of activating the supplementary motor area (SMA), defects of which have been reported in PD. The PD patients showed normal degrees of activation of the SMA (proper) when both "off" and "on." Significant activation with imagining movement also occurred in the ipsilateral inferior parietal cortex (both "off" and when "on") and ipsilateral premotor cortex (when "off" only). The patients showed significantly greater activation of the rostral anterior cingulate and significantly less activation of the left lingual gyrus and precuneus when performing the task "on" compared with their performance when "off." PD patients when imagining movement and "off" showed less activation of several sites including the right dorsolateral prefrontal cortex (DLPFC) when compared to the controls performing the same task. No significant differences from controls were present when the patients imagined when "on." Our results are consistent with other studies showing deficits of pre-SMA function in PD with preserved function of the SMA proper. In addition to the areas of reduced activation (anterior cingulate, DLPFC), there were also sites of activation (ipsilateral premotor and inferior parietal cortex) previously reported as locations of compensatory overactivity for PD patients performing similar tasks. Both failure of activation and compensatory changes are likely to contribute to the motor deficit in PD.

Prospective study of selective peripheral denervation for botulinum-toxin resistant patients with cervical dystonia.

We have carried out a prospective study of selective peripheral denervation (SPD) in cervical dystonia (CD) patients with primary or secondary botulinum toxin (BT) treatment failure using independent standardized assessment. Patients referred for surgery had a standardized clinical examination, neck muscle EMG, videofluoroscopic swallow and CT of the cervical spine, and were selected for surgery on the basis of the results of these investigations. CD severity, disability and pain were assessed preoperatively and at 3, 6, 9, 12 and 18 months postoperatively using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Severity of head tremor and dysphagia were scored using established rating scales. Additionally, psychosocial function was assessed in a representative subsample of patients (n = 12) using several established questionnaires. Of the 62 patients who were assessed, 22 (35.5%) were not offered surgery, most commonly because of widespread dystonia. Of the remaining 40 patients, 37 have so far had surgery, 31 of whom have been followed up for at least 1 year, and 15 for 18 months after surgery (mean follow-up duration 16.7 months). Using the TWSTRS global outcome score, 68% of patients derived functionally relevant improvement at 12 months after surgery. In the entire operated group, total TWSTRS scores were reduced by 30% at 6 and 12 months after surgery (P < 0.0001). The subscores for severity, disability and pain were reduced by 20, 30 and 40%, respectively, at 6 months (P < or = 0.01) and 20, 40 and 30%, respectively, at 12 months (P < 0.01). Pain increased over time, which appeared to result from muscle reinnervation. TWSTRS scores were not significantly improved in the six patients with primary BT treatment failure. Head tremor did not change. There was a significant improvement of body concept, perceived disfigurement, stigma, and quality of life in the 12 patients whose psychosocial function was assessed. Preoperative disability and restriction of head movement were negatively correlated and the initial response to BT treatment positively correlated with global outcome score. Spread or deterioration of dystonia elsewhere in the body occurred in three patients, with unpleasant sensory symptoms in denervated posterior cervical segments occurring in 14. Ten patients developed mild to moderate dysphagia, and two developed severe dysphagia. We conclude that SPD is an effective treatment for patients with secondary, but probably not for those with primary, BT treatment failure. Reinnervation is not infrequent and can compromise outcome. Postoperative morbidity is low, but there is a risk of dysphagia.

SPECT imaging of the dopamine transporter in juvenile-onset dystonia.

Juvenile-onset dystonia that improves after levodopa may occur in both dopa-responsive dystonia (DRD) and juvenile parkinsonism (JP), clinically similar conditions with different prognoses and management goals. The authors show normal striatal uptake of the dopamine transporter ligand FP-CIT with SPECT in a clinically atypical case of DRD, in contrast to the reduced uptake observed in JP.

Neuronal intranuclear inclusion disease and juvenile parkinsonism.

Juvenile parkinsonism (onset age <20 yrs) is uncommon and few cases with neuropathologic confirmation have been reported. We present the case of a 17-year-old boy who presented with asymmetric arm tremor and bulbar symptoms. His paternal great aunt had parkinsonism with onset at age 22 years. Examination revealed parkinsonism in the absence of additional neurologic signs except for delayed pupillary responses to light. He responded well to levodopa but developed motor fluctuations and disabling dyskinesias after 3 years of treatment. Following attempted withdrawal of levodopa at age 24 years, he developed severe aspiration pneumonia complicated by cardiorepiratory arrests and he died 6 months later. At autopsy, the dominant histologic feature was wide-spread neuronal hyaline intranuclear inclusions. Neuronal depletion was observed in the substantia nigra, locus ceruleus, and, to a lesser extent, in the frontal cortex, and inclusions were particularly prominent in these areas. Inclusions were immunoreactive for ubiquitin and were typical of those seen in neuronal intranuclear inclusion disease (NIID), a rare, multisytem neurodegenerative disease. NIID should be considered in the differential diagnosis of juvenile parkinsonism. A link between NIID and hereditary neurodegenerative disorders characterized by expanded polyglutamine tracts is supported by the similar appearance of intranuclear inclusions in both conditions and by a family history in some cases of NIID.

Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies.

Hedonistic homeostatic dysregulation is a neuropsychological behavioural disorder associated with substance misuse and addiction. The disorder has been recognised as a consequence of dopamine replacement therapy (DRT) in 15 patients with Parkinson's disease. The syndrome typically develops in male patients with early onset Parkinson's disease, and can occur with orally and subcutaneously administered DRT. These patients take increasing quantities of their DRT, despite increasingly severe drug induced dyskinesias, and may develop a cyclical mood disorder with hypomania or manic psychosis. There is impairment of social and occupational functioning. Tolerance develops to mood elevating effects of DRT and a negative affective withdrawal state occurs if the drugs are withdrawn or doses decreased. The clinical features and guidelines for managing this syndrome are discussed. A set of diagnostic criteria for further investigating this condition is proposed.

An ambulatory dyskinesia monitor.

OBJECTIVES: New treatments are now becoming available for the management of levodopa induced dyskinesias in Parkinsons's disease. However, assessment of their efficacy is limited by the inadequacies of current methods of dyskinesia measurement. The objective was to develop and validate a portable device capable of objectively measuring dyskinesias during normal daily activities. METHODS: A portable device was developed based on a triaxial accelerometer, worn on the shoulder, and a data recorder that can record levodopa induced dyskinesias. A computer program plots raw acceleration and acceleration over 0.5 Hz frequency bands against time. The acceleration in the different bands can then be compared with the raw acceleration trace, enabling identification and exclusion of confounding activities such as tremor and walking, which have a characteristic appearance on the trace. The validity of this device was assessed on 12 patients and eight age matched controls by comparing accelerations in the 1-3 Hz frequency band with established clinical dyskinesia rating scales. While wearing the monitor, subjects were videorecorded sitting and during dyskinesia provocation tasks, including mental activation tasks, eating, drinking, writing, putting on a coat, and walking. The dyskinesias were graded with both modified abnormal involuntary movement (AIM) and Goetz scales. The clinical ratings were then compared with the mean acceleration scores. RESULTS: Acceleration in the 1-3 Hz frequency band correlated well against both scales, during all individual tasks. Acceleration produced by normal voluntary activity (with the exception of walking, which produced large accelerations, even in controls) was small compared with dyskinetic activity. With walking excluded, the mean acceleration over the rest of the recording time correlated strongly with both the modified AIM (Spearman's rank (r=0.972, p<0.001) and Goetz (r=0.951, p<0.001) scales. CONCLUSIONS: This method provides an accurate, objective means for dyskinesia assessment, and compares favourably with established methods currently used.

Nonparkinsonian tremors.

Tremors other than those associated with Parkinson's disease are commonly encountered in clinical practice. The differentiation of tremor subtypes depends primarily on the presence of distinct clinical characteristics and is facilitated by the use of consistent nomenclature. Such differentiation can be helpful in determining the etiology of the tremor and assist in its management. In this review, the authors outline recently proposed changes to classification and review the clinical features, differential diagnosis, and current therapy for nonparkinsonian tremors.

Pleomorphic large cell sarcoma of the spleen with rhabdomyosarcomatous differentiation.

An unusual case is reported of pleomorphic large cell sarcoma of the spleen with rhabdomyosarcomatous differentiation in a 34-year old male. According to our knowledge, such a neoplasm has never been reported in the literature.