A single centre prospective study of three device-assisted therapies for Parkinson's disease.

Comparative studies assessing outcomes with the three device-assisted therapies could help to individualise treatment for patients living with Parkinson's disease. We designed a single-centre non-randomised prospective observational study assessing the quality of life (QoL), motor and non-motor outcomes at 6 and 12-months in patients treated with subcutaneous apomorphine continuous 16-hours infusion (APO), levodopa-carbidopa intestinal gel (LCIG) or subthalamic nucleus deep brain stimulation (STN-DBS). In this study, 66 patients were included (13 APO; 19 LCIG; 34 STN-DBS). At baseline, cognitive, non-motor and motor scores were significantly less severe in the STN-DBS group, whereas the LCIG group had a longer disease duration and higher non-motor scores. In the APO group, there were no statistically significant changes in non-motor, motor and QoL scales. The LCIG group had significant changes in QoL and motor scales that were significant after multiple comparison analysis at 6 and 12-months. The STN-DBS group showed improvement in QoL scores and non-motor and motor scores at 6 and 12-months after multiple comparison analysis. In this real-life prospective study, device-assisted therapies showed differences in their effects on QoL and motor and non-motor function at 12-months. However, there were also differences in baseline characteristics of the patient groups that were not based on pre-determined selection criteria. Differences in characteristics of patients offered and/or treatment with different device-assisted therapies may reflect within-centre biases that may, in turn, influence perceptions of treatment efficacy or outcomes. Treatment centres should be aware of this potential confounder when assessing and offering device-assisted treatment options to their patients and potential baseline differences need to be taken into consideration when comparing the results of non-randomised studies.

Parkinson disease.

Parkinson disease (PD) is a complex, multisystem disorder with both neurologic and systemic nonmotor manifestations. It is neurodegenerative in nature in which disordered balance, gait, and falls are universal problems that can be present at initial diagnosis, and which progress over time. Freezing of gait is a particularly debilitating feature of PD that becomes more prevalent over time with disease progression, being present in approximately 7% after 2 years of disease and 28% after 5 years. Approximately 60% of people with PD fall each year, with around 70% of fallers falling recurrently, and some recurrent fallers falling multiple times per week. Many risk factors for falls in people with PD have been identified; these include a history of falls, freezing of gait, and abnormalities in measures of balance, leg muscle strength, mobility, cognition, and fear of falling. Therapies for improving physical function and mobility include levodopa, cholinesterase inhibitors, methylphenidate, deep-brain stimulation, cuing for freezing of gait, and exercise. This chapter reviews the clinical, pathologic, and physiologic correlates of gait disturbance and falls in PD, as well as the evidence for medical and nonmedical interventions.

24-hour levodopa-carbidopa intestinal gel may reduce troublesome dyskinesia in advanced Parkinson's disease.

Levodopa-carbidopa intestinal gel (LCIG) is effective for the control of motor fluctuations in Parkinson's disease (PD). The objective of this study is to report the reduction of dyskinesias after transitioning from 16 to 24-h/day LCIG infusion. From a cohort of 74 PD patients treated with LCIG for motor fluctuations, we identified 12 patients that were treated with 24-h per day infusion with the aim to control troublesome daytime dyskinesia. Clinical, demographic, dyskinesia rating scales were evaluated. Daytime dyskinesia was reduced in 75% (9/12) patients following treatment with 24-h therapy, including 7 who were compared with 16-h therapy and 2 that were transitioned from oral dopaminergic therapy to 24-h LCIG. Combining the data from all 12 subjects, troublesome dyskinesias were reduced during 24-h LCIG; UPDRS 4.1 (time spent with dyskinesias) mean change was -1.5 ± 0.75, p = 0.010 (Wilcoxon signed-rank test) and UPDRS 4.2 (functional impact of dyskinesias) mean change was -1.7 ± 0.90, p = 0.016, without changing their UPDRS part 3 "ON" scores (p = 0.138) or H&Y (p = 0.157). In 5 patients, improvement in dyskinesia occurred despite an overall increase in the total daily levodopa dose. None of the patients had worsening of dyskinesia after a median follow-up of 28 months. 24-h per day infusion of LCIG may be a useful strategy in the management of troublesome dyskinesias in PD patients with disabling dyskinesias resistant to attempts to optimise 16-hours per day therapy. We postulate that this may be due to a pharmacodynamic as opposed to pharmacokinetic mechanism.

Intraduodenal levodopa-carbidopa intestinal gel infusion improves both motor performance and quality of life in advanced Parkinson's disease.

We report the efficacy and adverse effect profile of intraduodenal levodopa-carbidopa intestinal gel (LCIG) infusion from patients treated in a single Australian movement disorder centre. We conducted an open-label, 12 month prospective study of treatment with LCIG in patients with advanced Parkinson's disease in a single tertiary referral hospital unit specialising in movement disorders. Patients with levodopa-responsive, advanced Parkinson's disease with motor fluctuations despite optimal pharmacological treatment were enrolled and underwent a 16 hour daily infusion of LCIG for 12 months. Fifteen participants completed the trial. The mean (± standard deviation) improvement in Unified Parkinson's Disease Rating Scale part III was 37 ± 11%, mean daily "off" period reduced from 6.3 ± 2 to 1.9 ± 2 hours, total daily "on" time increased from 10.2 ± 3 to 13.7 ± 2 hours, "on" period without dyskinesia increased from 4.5 ± 3 to 7.5 ± 5 hours, and 39-item Parkinson's Disease Questionnaire Summary Index score improved by 32.5 ± 35%. The most common adverse event was reversible peripheral neuropathy secondary to vitamin B12 ± B6 deficiency (40%), local tube problems (40%), and impulse control disorder (ICD) (27%). No patient had stoma bleeding or peritonitis. All patients with ICD had a past psychiatric diagnosis of depression with or without anxiety and a higher daily levodopa intake at 6 and 12 months of LCIG infusion. Intraduodenal LCIG improves motor performance, quality of life and daily "on" period. Prior to and during duodenal LCIG infusion, clinicians should monitor for peripheral neuropathy and vitamin B12 and B6 deficiency, as supplementation can reverse peripheral neuropathy. This trial is registered at Clinicaltrials.gov as CT00335153.

24 h Levodopa-carbidopa intestinal gel may reduce falls and "unresponsive" freezing of gait in Parkinson's disease.

OBJECTIVE: We report a prospective, open label study of 24 h levodopa-carbidopa intestinal gel (LCIG) as treatment for levodopa "unresponsive" freezing of gait (FOG) associated with Parkinson's disease. METHOD: 5 patients with disabling FOG, documented as being levodopa "unresponsive", were commenced on continuous 24 h infusion LCIG therapy with the night-time rate at 50-80% of the daytime infusion rate. Patients underwent baseline, 3 and 6 month gait assessments, documentation of their falls frequency and completed FOG questionnaires. RESULT: Median 360° turn time improved by 54%, fall frequency score reduced from 3 to 0 at 6 months, FOG questionnaire score improved by 14% and Timed Up- and -Go 8 m walk was unchanged. CONCLUSION: 24 h LCIG therapy may reduce levodopa "unresponsive" FOG and associated falls. A larger prospective study is needed for confirmation.

An update on Huntington's disease: from the gene to the clinic.

PURPOSE OF REVIEW: This review highlights the recent advances in Huntington's disease, with a particular focus on development of disease biomarkers for use in therapeutic trials in the premotor phase of the disease, as well as the growing literature regarding pathophysiological mechanisms and their relevance to potential therapeutic targets. RECENT FINDINGS: There have been continued advances in the development of disease biomarkers, and promising neuroprotection trials are beginning to emerge in the premotor stage of Huntington's disease. Deeper understanding of the pathophysiological mechanisms is being translated into potential therapeutic strategies. SUMMARY: The premotor stage of Huntington's disease provides an ideal time to trial disease-modifying therapy, but reliable biomarkers are required for monitoring disease progression, and this remains an area of intense research. Our understanding of the underlying pathophysiological mechanisms continues to expand, and a number of promising therapeutic strategies are emerging, including strategies to silence mutant huntingtin expression.

Treatment of proximal upper limb tremor with botulinum toxin therapy.

BACKGROUND: Proximal-dominant upper limb tremor is highly disabling, and there is no effective medical therapy. In this study, we evaluated the efficacy of botulinum toxin (BTX) injections for the treatment of proximal tremor. METHODS: We conducted a retrospective analysis of open-label treatment with BTX in 19 patients with proximal tremor. The response to therapy was graded into four categories according to self-reported improvements in tremor and function. RESULTS: In total, 63% of patients reported moderate or marked benefit, defined as functional improvements sufficient enough to allow feeding or drinking from a cup; whereas 21% of patients reported mild benefit; and 15% of patients reported no benefit. One patient developed severe weakness of shoulder abduction and withdrew from the treatment; otherwise, the therapy was free of side effects. CONCLUSIONS: The current findings support the efficacy of BTX therapy in the treatment of proximal upper limb tremor with minimal side effects.

Dramatic improvement of truncal tardive dystonia following globus pallidus pars interna deep brain stimulation.

Truncal predominant tardive dystonia is an uncommon presentation of dystonia, and may be associated with significant disability. We report a patient with near-complete resolution of severe, disabling truncal tardive dystonia following globus pallidus pars interna deep brain stimulation. Her unusual clinical presentation highlights the difficulties in diagnosing unusual forms of dystonia, and the therapeutic gains that can be achieved once the diagnosis is recognised.

Postural instability in patients with Parkinson's disease. Epidemiology, pathophysiology and management.

Postural instability is one of the cardinal signs in Parkinson's disease (PD). It can be present even at diagnosis, but becomes more prevalent and worsens with disease progression. It represents one of the most disabling symptoms in the advanced stages of the disease, as it is associated with increased falls and loss of independence. Clinical and posturographic studies have contributed to significant advances in unravelling the complex pathophysiology of postural instability in patients with PD, but it still remains yet to be fully clarified, partly due to the difficulty in distinguishing between the disease process and the compensatory mechanisms, but also due to the fact that non-standardized techniques are used to measure balance and postural instability. There is increasing evidence that physical therapy, especially highly challenging balance exercises, can improve postural stability and reduce the risk of falls, although the long-term effects of physical therapy interventions on postural stability need to be explored given the progressive nature of PD. Pharmacotherapy with dopaminergic medications can provide significant improvements in postural instability in early- to mid-stage PD but the effects tend to wane with time consistent with spread of the disease process to non-dopaminergic pathways in advanced PD. Donepezil has been associated with a reduced risk of falls and methylphenidate has shown potential benefit against freezing of gait, but the results are yet to be replicated in large randomized studies. Surgical treatments, including lesioning and deep brain stimulation surgery targeting the subthalamic nucleus and the globus pallidus internus, tend to only provide modest benefit for postural instability. New surgical targets such as the pedunculopontine nucleus have emerged as a potential specific therapy for postural instability and gait disorder but remain experimental.