Slower rates of prism adaptation but intact aftereffects in patients with early to mid-stage Parkinson's disease.

There is currently mixed evidence on the effect of Parkinson's disease on motor adaptation. Some studies report that patients display adaptation comparable to age-matched controls, while others report a complete inability to adapt to novel sensory perturbations. Here, early to mid-stage Parkinson's patients were recruited to perform a prism adaptation task. When compared to controls, patients showed slower rates of initial adaptation but intact aftereffects. These results support the suggestion that patients with early to mid-stage Parkinson's disease display intact adaptation driven by sensory prediction errors, as shown by the intact aftereffect. But impaired facilitation of performance through cognitive strategies informed by task error, as shown by the impaired initial adaptation. These results support recent studies that suggest that patients with Parkinson's disease retain the ability to perform visuomotor adaptation, but display altered use of cognitive strategies to aid performance and generalises these previous findings to the classical prism adaptation task.

Falls risk is predictive of dysphagia in Parkinson's disease.

OBJECTIVE: Evaluate the relationship between falls, freezing of gait, and swallowing disturbance in Parkinson's disease (PD). BACKGROUND: Dysphagia is a common symptom in PD, and is often thought of as an axial feature along with falls and gait disturbance. It is of interest to examine the relationship between these symptoms in PD, given the possibility of shared pathophysiology due to non-dopaminergic and extranigral dysfunction. METHODS: We recruited 29 consecutive non-demented patients with idiopathic PD and at least one clinically determined impairment in swallowing, falls, or freezing of gait. Swallow dysfunction was assessed using the Swallowing Disturbance Questionnaire (SDQ). The Falls Efficacy Scale and Freezing-of-gait questionnaire were recorded. Correlation analysis and multiple regression were used to determine the relationship between swallow and gait disturbance. RESULTS: Total SDQ score correlated strongly with the falls efficacy scale (Spearman's rho = 0.594; P = 0.001), but not with the freezing-of-gait score. Linear regression controlling for other factors associated with dysphagia identified falls efficacy score as a significant predictor of swallow dysfunction. CONCLUSIONS: The severity of dysphagia in PD is closely related to severity of falls, but not gait freezing. This may be helpful to more precisely determine the anatomical substrate of levodopa-resistant axial symptoms in PD and provide clues to further management.

Per-oral image guided gastrojejunostomy insertion for levodopa-carbidopa intestinal gel in Parkinson's disease is safe and may be advantageous.

BACKGROUND: Procedural aspects and complications of gastrojejunostomy insertion are important considerations in the use of levodopa-carbidopa intestinal gel therapy (LCIG) and may limit uptake. We describe our experience of using per-oral image guided gastrojejunostomy (PIG-J) which avoids the need for endoscopy and routine sedation in percutaneous endoscopic gastrojejunostomy (PEG-J) and allows more secure tube placement than radiologically inserted gastrojejunostomy techniques. METHODS: We describe a case series of 32 patients undergoing PIG-J insertion for LCIG therapy in a single centre. Under local anaesthetic, a fluoroscopy-guided gastric puncture allows access for the guidewire which is then used to pull through the gastrostomy tube allowing for secure fixation, followed by placement of the gastrojejunal extension. RESULTS: Between December 2015 to April 2020, 32/34 patients referred for PIG-J underwent this procedure successfully, 2 cases unsuccessful due to technical considerations. One patient developed delirium following successful implantation. Ten patients (31%) required a replacement tube due to blockage or displacement within the first 12 months of placement, including 2 patients who needed more than one replacement. Minor complications occurred in 10 other patients (31%), including infection (9 patients); a small haematoma not requiring intervention who later developed an infection (1 patient); and peri-stomal acid leakage (1 patient). CONCLUSION: In summary, PIG-J insertion is safe with a similar complication rate to traditional PEG-J, well tolerated and effective for use in LCIG administration. This may widen access to LCIG for PD patients who may not be suitable or unable to tolerate PEG-J.

Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson's Disease.

BACKGROUND: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson's disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [18F]DOPA uptake throughout the entire putamen. OBJECTIVE: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks. METHODS: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson's Disease Rating Scale (UPDRS) motor score. RESULTS: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7±20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6±23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI: -13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week 80 and placebo/GDNF at Week 40 showed significant differences for mean OFF state UPDRS motor (-9.6±6.7 vs. -3.8±4.2 points, p = 0.0108) and activities of daily living score (-6.9±5.5 vs. -1.0±3.7 points, p = 0.0003). No treatment-emergent safety concerns were identified. CONCLUSIONS: The aggregate study results, from the parent and open-label extension suggest that future testing with GDNF will likely require an 80- rather than a 40-week randomized treatment period and/or a higher dose.

Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease.

We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35-75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state [Hoehn and Yahr stage 2-3 and Unified Parkinson's Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45] and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 µg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 ± 17.6% in the active group and 11.8 ± 15.8% in the placebo group (least squares mean difference: -4.9%, 95% CI: -16.9, 7.1, P = 0.41). Secondary endpoints did not show significant differences between the groups either. A post hoc analysis found nine (43%) patients in the active group but no placebo patients with a large clinically important motor improvement (≥10 points) in the OFF state (P = 0.0008). 18F-DOPA PET imaging demonstrated a significantly increased uptake throughout the putamen only in the active group, ranging from 25% (left anterior putamen; P = 0.0009) to 100% (both posterior putamina; P < 0.0001). GDNF appeared to be well tolerated and safe, and no drug-related serious adverse events were reported. The study did not meet its primary endpoint. 18F-DOPA imaging, however, suggested that intermittent convection-enhanced delivery of GDNF produced a putamen-wide tissue engagement effect, overcoming prior delivery limitations. Potential reasons for not proving clinical benefit at 40 weeks are discussed.

Basal ganglia necrosis: a 'best-fit' approach.

A previously well 16-year-old boy developed a rapid-onset hypokinetic syndrome, coupled with a radiological appearance of extensive and highly symmetrical basal ganglia and white matter change. The diagnostic process was challenging and we systematically considered potential causes. After excluding common causes of this clinico-radiological picture, we considered common disorders with this unusual radiological picture and vice versa, before finally concluding that this was a rare presentation of a rare disease. We considered the broad categories of: metabolic; toxic; infective; inflammatory, postinfective and immune-mediated; neoplastic; paraneoplastic and heredodegenerative. Long-term follow-up gave insight into the nature of the insult, confirming the monophasic course. During recovery, and following presumed secondary aberrant reinnervation, his disorder evolved from predominantly hypokinetic to hyperkinetic. Here, we explore the process of finding a 'best-fit' diagnosis: in this case, acute necrotising encephalopathy.