Approach to the patient with early Parkinson disease: diagnosis and management.

This article presents an evidence-based approach to the patient with newly diagnosed Parkinson disease (PD). It includes a discussion of the current understanding of the aetio-pathogenesis of PD and of clinical features, both motor and non-motor, that assist the clinician in making this diagnosis. An approach to the management of early stage PD is discussed, including emerging evidence of the benefits of physical exercise in this condition, and issues to consider in the selection of dopaminergic medication. The newly diagnosed patient with PD is often keen to know what the future holds for them, as they face this progressive neurodegenerative condition. While currently available medical therapies are symptomatic, rather than disease-modifying, in nature, it is hoped that improved understanding of the aetio-pathogenesis of PD will pave the way for future disease-modifying therapies.

Updates and advances in the treatment of Parkinson disease.

Parkinson disease (PD) is a complex neurodegenerative disorder that can present heterogeneously with a combination of motor and non-motor symptoms. α-synuclein, a neuronal protein, can undergo aberrant conformational change resulting in the intra-neuronal accumulation of toxic oligomers that form Lewy bodies, the pathological hallmark of PD. There is evidence that pathological α-synuclein exhibits prion-like behaviour in its mode of transmission through the nervous system. The choice of initial dopaminergic treatments should be individually tailored but long term outcomes appear to be equivalent. There is level A evidence supporting the benefit of three different device-assisted therapies in treating troublesome motor fluctuations and dyskinesias. Stem cell transplantation as currently being trialled is predominantly a symptomatic therapy targeting only limited regions of the brain affected by PD, and will need to be proven to be not only as effective but as safe as currently available device-assisted therapies. New modes of treatment including active immunisation against oligomeric α-synuclein and drugs that alter cellular metabolism show some promise. The inability to effectively treat a range of non-motor, non-dopaminergic symptoms remains a major therapeutic challenge.

Long-term adherence to apomorphine infusion in patients with Parkinson disease: a 10-year observational study.

BACKGROUND: Patients with Parkinson disease (PD) commonly experience motor fluctuations and dyskinesias in response to oral dopaminergic medications. Affected patients may benefit from device-assisted therapy, such as medication infusion or deep brain stimulation surgery. This is the first Australian study of the long-term adherence to apomorphine infusion (AI) in patients with PD. AIMS: To assess the adherence to AI in patients with PD in a single centre over a 10-year period and to find the reasons for discontinuation in patients who discontinued AI. METHODS: This is an observational study of patients with PD treated with AI between 2004 and 2014. Outcome measures included changes in motor function and quality of life following AI, change in dose of other dopaminergic medications following AI, duration of infusion, adverse effects, reasons for cessation of AI and subsequent treatment after cessation. RESULTS: Mean duration of AI was 21.65 months. No patient achieved apomorphine monotherapy, and the mean reduction in the levodopa-equivalent dose of other dopaminergic medications after AI was 22.7%. The benefit of AI on motor function and quality of life was rated as 'much improved' or 'better' in 83% of patients. The most common reasons for discontinuation of AI were adverse effects and inadequate motor benefit. Most patients who discontinued AI were subsequently treated with another device-assisted therapy. CONCLUSION: AI is an effective therapy for severe motor response complications in PD, especially in the short and medium term. However, many patients cannot be maintained on AI in the longer term.

Practical approaches to commencing device-assisted therapies for Parkinson disease in Australia.

In Australia 1% of individuals aged over 50 years have Parkinson disease (PD). Guidance for commencing device-assisted therapies (DAT) for PD in Australia was developed based on a review of European recommendations and their relevance to the local clinical setting. An online survey and teleconference discussions were held by a group of eight local movement disorder experts to develop consensus. Referral to a movement disorder specialist and consideration of DAT is appropriate when motor fluctuations cause disability or reduced quality of life, response to treatment is inconsistent or motor fluctuations and dyskinesias require frequent treatment adjustment without apparent benefit and levodopa is required four or more times daily. Three types of DAT are available in Australia for patients with PD: continuous subcutaneous apomorphine; continuous levodopa-carbidopa intestinal gel infusion; and deep brain stimulation. All improve consistency of motor response. The most important aspects when considering which DAT to use are the preferences of the patient and their carers, patient comorbidities, age, cognitive function and neuropsychiatric status. Patients and their families need to be provided with treatment options that are suitable to them, with adequate explanations regarding the recommendations and comparison of potential device-related complications. DAT are best managed, where possible, in a specialist centre with experience in all three types of therapy. Proactive and early management of symptoms during disease progression is essential to maintain optimally motor responses and quality of life in patients with PD.

Continuous Subcutaneous Foslevodopa/Foscarbidopa in Parkinson's Disease: Safety and Efficacy Results From a 12-Month, Single-Arm, Open-Label, Phase 3 Study.

INTRODUCTION: Foslevodopa/foscarbidopa, a soluble formulation of levodopa/carbidopa (LD/CD) prodrugs for the treatment of Parkinson's disease (PD), is administered as a 24-hour/day continuous subcutaneous infusion (CSCI) with a single infusion site. The efficacy and safety of foslevodopa/foscarbidopa versus oral immediate-release LD/CD was previously demonstrated in patients with PD in a 12-week, randomized, double-blind, phase 3 trial (NCT04380142). We report the results of a separate 52-week, open-label, phase 3 registrational trial (NCT03781167) that evaluated the safety/tolerability and efficacy of 24-hour/day foslevodopa/foscarbidopa CSCI in patients with advanced PD. METHODS: Male and female patients with levodopa-responsive PD and ≥ 2.5 hours of "Off" time/day received 24-hour/day foslevodopa/foscarbidopa CSCI at individually optimized therapeutic doses (approximately 700-4250 mg of LD per 24 hours) for 52 weeks. The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in normalized "Off" and "On" time, percentage of patients reporting morning akinesia, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Sleep Scale-2 (PDSS-2), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQol 5-dimension questionnaire (EQ-5D-5L). RESULTS: Of 244 enrolled patients, 107 discontinued, and 137 completed treatment. Infusion site events were the most common adverse events (AEs). AEs were mostly nonserious (25.8% of patients reported serious AEs) and mild/moderate in severity. At week 52, "On" time without troublesome dyskinesia and "Off" time were improved from baseline (mean [standard deviation (SD)] change in normalized "On" time without troublesome dyskinesia, 3.8 [3.3] hours; normalized "Off" time, -3.5 [3.1] hours). The percentage of patients experiencing morning akinesia dropped from 77.7% at baseline to 27.8% at week 52. Sleep quality (PDSS-2) and quality of life (PDQ-39 and EQ-5D-5L) also improved. CONCLUSION: Foslevodopa/foscarbidopa has the potential to provide a safe and efficacious, individualized, 24-hour/day, nonsurgical alternative for patients with PD. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03781167.

Upper limb tremor.

Tremor is a common clinical problem in middle-aged and older patients, and Parkinson disease (PD) is one of the commonest causes. Careful history-taking and physical examination is usually sufficient for diagnosis of PD; extensive investigation is generally not required. Treatment of PD should be individualised, taking into account the patient's age, lifestyle, severity of motor symptoms, level of disability, comorbidities, expectations of treatment and PD subtype (eg, akinetic rigid or tremor dominant). In PD, optimal medical therapy often involves a combination of dopaminergic medications, aiming for doses that provide adequate symptom relief without adverse effects such as dyskinesias and impulse-control disorders. Continuous dopaminergic stimulation and deep brain stimulation should be considered for patients with PD whose motor symptoms cannot be adequately controlled with oral medication, especially those aged less than 70 years.

Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson's disease: a randomised, double-blind, active-controlled, phase 3 trial.

BACKGROUND: Levodopa is the most effective symptomatic therapy for Parkinson's disease, but patients with advanced Parkinson's disease develop motor fluctuations with chronic oral levodopa therapy. Foslevodopa-foscarbidopa is a soluble formulation of levodopa and carbidopa prodrugs that is delivered as a 24-h/day continuous subcutaneous infusion, and we aimed to assess the safety and efficacy of this formulation in patients with advanced Parkinson's disease. METHODS: A 12-week randomised, double-blind, double-dummy, active-controlled study was done at 65 academic and community study centres in the USA and Australia. Patients with levodopa-responsive advanced Parkinson's disease inadequately controlled on current therapy, including at least 2·5 h of average daily off time, were randomly assigned (1:1) to continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. Randomisation was stratified by site by means of a permutated-block schedule with a block size of two. The participants, treating investigators, study site personnel, and sponsor were masked to treatment group allocation. The primary and first key secondary endpoint in the hierarchical testing strategy were change from baseline to week 12 in on time without troublesome dyskinesia and off time, respectively; both endpoints were evaluated by an intention-to-treat analysis applying a mixed model for repeated measures analysis. Safety and tolerability were assessed throughout the study. The study is completed and is listed on ClinicalTrials.gov, NCT04380142. FINDINGS: Between Oct 19, 2020, and Sept 29, 2021, of 270 participants screened and 174 enrolled, 141 were randomly assigned and received continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo capsules (n=74) or oral encapsulated immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution (n=67). Compared with levodopa-carbidopa, foslevodopa-foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (model-based mean [SE] 2·72 [0·52] vs 0·97 [0·50] h; difference 1·75 h, 95% CI 0·46 to 3·05; p=0·0083) and a significantly greater reduction in off time (-2·75 [0·50] vs -0·96 [0·49] h; difference -1·79 h, -3·03 to -0·54; p=0·0054). Hierarchical testing ended after the first secondary endpoint. Adverse events were reported in 63 (85%) of 74 patients in the foslevodopa-foscarbidopa group versus 42 (63%) of 67 in the levodopa-carbidopa group, and incidences of serious adverse events were similar between the groups (six [8%] of 74 vs four [6%] of 67, respectively). The most frequent adverse events in the foslevodopa-foscarbidopa group were infusion site adverse events (erythema 20 [27%]), pain 19 [26%]), cellulitis (14 [19%]), and oedema (nine [12%]), most of which were non-serious and mild-moderate in severity. The only system organ class that had more than one serious adverse event in the foslevodopa-foscarbidopa group was infections and infestations (catheter site cellulitis [one [1%]] and infusion site cellulitis [one [1%]). Adverse events led to premature discontinuation of study drug in 16 (22%) of 74 participants in the foslevodopa-foscarbidopa group versus one (1%) of 67 participants in the oral levodopa-carbidopa group. INTERPRETATION: Foslevodopa-foscarbidopa improved motor fluctuations, with benefits in both on time without troublesome dyskinesia and off time. Foslevodopa-foscarbidopa has a favourable benefit-risk profile and represents a potential non-surgical alternative for patients with advanced Parkinson's disease. FUNDING: AbbVie.

EPITHET: Positive Result After Reanalysis Using Baseline Diffusion-Weighted Imaging/Perfusion-Weighted Imaging Co-Registration.

BACKGROUND AND PURPOSE: the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) was a prospective, randomized, double-blinded, placebo-controlled, phase II trial of alteplase between 3 and 6 hours after stroke onset. The primary outcome of infarct growth attenuation on MRI with alteplase in mismatch patients was negative when mismatch volumes were assessed volumetrically, without coregistration, which underestimates mismatch volumes. We hypothesized that assessing the extent of mismatch by coregistration of perfusion and diffusion MRI maps may more accurately allow the effects of alteplase vs placebo to be evaluated. METHODS: patients were classified as having mismatch if perfusion-weighted imaging divided by coregistered diffusion-weighted imaging volume ratio was >1.2 and total coregistered mismatch volume was ≥ 10 mL. The primary outcome was a comparison of infarct growth in alteplase vs placebo patients with coregistered mismatch. RESULTS: of 99 patients with baseline diffusion-weighted imaging and perfusion-weighted imaging, coregistration of both images was possible in 95 patients. Coregistered mismatch was present in 93% (88/95) compared to 85% (81/95) with standard volumetric mismatch. In the coregistered mismatch patients, of whom 45 received alteplase and 43 received placebo, the primary outcome measure of geometric mean infarct growth was significantly attenuated by a ratio of 0.58 with alteplase compared to placebo (1.02 vs 1.77; 95% CI, 0.33-0.99; P=0.0459). CONCLUSIONS: when using coregistration techniques to determine the presence of mismatch at study entry, alteplase significantly attenuated infarct growth. This highlights the necessity for a randomized, placebo-controlled, phase III clinical trial of alteplase using penumbral selection beyond 3 hours.

Driving restrictions following deep brain stimulation surgery.

BACKGROUND: There are currently no Australian guidelines to assist clinicians performing deep brain stimulation (DBS) procedures in setting postoperative driving restrictions. PURPOSE: We aimed to provide recommendations for post-DBS driving restrictions to guide practice in Australia. METHODS: A review of current Australian and international driving guidelines, literature regarding the adverse effects of DBS and literature regarding the long-term effect of neurostimulation on driving was conducted using Elton B Stephens Company discovery service-linked databases. Australian neurologists and neurosurgeons who perform DBS were surveyed to gain insight into existing practice. RESULTS: No guidance on driving restrictions following DBS surgery was found, either in existing driving guidelines or in the literature. There was a wide difference seen in the rates of reported adverse effects from DBS surgery. The most serious adverse events (haemorrhage, seizure and neurological dysfunction) were uncommon. Longer term, there does not appear to be any adverse effect of DBS on driving ability. Survey of Australian practitioners revealed a universal acceptance of the need for and use of driving restrictions after DBS but significant heterogeneity in how return to driving is managed. CONCLUSION: We propose a 6-week driving restriction for private licences and 6-month driving restriction for commercial licences in uncomplicated DBS. We also highlight some of the potential pitfalls and pearls to assist clinicians to modify these recommendations where needed. Ultimately, we hope this will stimulate further examination of this issue in research and by regulatory bodies to provide more robust direction for practitioners performing DBS implantation.

Sodium selenate as a disease-modifying treatment for progressive supranuclear palsy: protocol for a phase 2, randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder for which there are currently no disease-modifying therapies. The neuropathology of PSP is associated with the accumulation of hyperphosphorylated tau in the brain. We have previously shown that protein phosphatase 2 activity in the brain is upregulated by sodium selenate, which enhances dephosphorylation. Therefore, the objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying therapy for PSP. METHODS AND ANALYSIS: This will be a multi-site, phase 2b, double-blind, placebo-controlled trial of sodium selenate. 70 patients will be recruited at six Australian academic hospitals and research institutes. Following the confirmation of eligibility at screening, participants will be randomised (1:1) to receive 52 weeks of active treatment (sodium selenate; 15 mg three times a day) or matching placebo. Regular safety and efficacy visits will be completed throughout the study period. The primary study outcome is change in an MRI volume composite (frontal lobe+midbrain-3rd ventricle) over the treatment period. Analysis will be with a general linear model (GLM) with the MRI composite at 52 weeks as the dependent variable, treatment group as an independent variable and baseline MRI composite as a covariate. Secondary outcomes are change in PSP rating scale, clinical global impression of change (clinician) and change in midbrain mean diffusivity. These outcomes will also be analysed with a GLM as above, with the corresponding baseline measure entered as a covariate. Secondary safety and tolerability outcomes are frequency of serious adverse events, frequency of down-titration occurrences and frequency of study discontinuation. Additional, as yet unplanned, exploratory outcomes will include analyses of other imaging, cognitive and biospecimen measures. ETHICS AND DISSEMINATION: The study was approved by the Alfred Health Ethics Committee (594/20). Each participant or their legally authorised representative and their study partner will provide written informed consent at trial commencement. The results of the study will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620001254987).

An update on Tourette syndrome.

Recent advances in our understanding of the phenomenology, etiology, pathophysiology, and treatment of Tourette syndrome are discussed. Tourette syndrome appears to involve dysfunction of limbic and somatosensory "traffic" through the basal ganglia, within corticostriatal-thalamocortical circuits. Dynamic alterations in the balance of these inputs may dictate the manifestations (sensory, motor, affective, and behavioral) of the disorder at any given time. Individualized assessment and treatment are the keys to optimal treatment of this condition.

Progressive cranial neuropathy and uterine involvement in myeloid sarcoma.

A rare extramedullary manifestation of haematological malignancy, myeloid sarcoma is most commonly seen in patients with acute myeloid leukaemia. We report on an adult patient who presented with an atypical phenotype of progressive cranial neuropathy without blood or bone marrow involvement, and in whom obtaining material for pathological diagnosis was made challenging by unusual findings of absent fluorodeoxyglucose-positron emission tomography avidity and involvement of sites not readily accessible to biopsy (orbital apex and cauda equina). The eventual diagnosis was obtained through biopsy of the uterine cervix before being verified on repeat lymph node and cerebrospinal fluid sampling prior to initiation of chemotherapy.

Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial.

BACKGROUND: Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3-6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). METHODS: We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3-6 h after onset of ischaemic stroke. PWI and DWI were done before and 3-5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537. FINDINGS: We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71.6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1.24 with alteplase and 1.78 with placebo (ratio 0.69, 95% CI 0.38-1.28; Student's t test p=0.239); the median relative infarct growth was 1.18 with alteplase and 1.79 with placebo (ratio 0.66, 0.36-0.92; Wilcoxon's test p=0.054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than was no reperfusion. INTERPRETATION: Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted.

The distinctive movement disorder of ovarian teratoma-associated encephalitis.

The movement disorder observed in four cases of ovarian teratoma associated encephalitis is described. The illness began with neuropsychiatric symptoms and was followed by prolonged unresponsiveness, respiratory failure, and autonomic instability. The movement disorder consisted of semirhythmic repetitive bulbar and limb movements and persisted during prolonged periods of unresponsiveness, diminishing as awareness returned. The characteristics of the movement disorder differed from recognized dyskinesias. It is suggested that interruption of forebrain corticostriatal inputs by anti-N-methyl-D-aspartate (NMDA) receptor antibodies removes tonic inhibition of brainstem pattern generators releasing primitive patterns of bulbar and limb movement. Recognition of the distinctive movements should prompt a search for an ovarian teratoma since the condition is responsive to tumor resection and immunomodulation.

Brainstem lesions and gait.

The brainstem contains virtually all of the important structures involved in experimental models of locomotion, encompassing control of upright posture, balance, and stepping. The physiologic basis for these functions is intricately related. Studies of the effects of lesions and disease on these functions in humans are limited to clinical observation and hampered by the anatomic complexity of closely spaced structures and lack of selectivity of lesions. Accordingly, any description of the clinical effects of brainstem lesions on gait and posture is imprecise because weakness and ataxia either predominate over or obscure any selective disturbance of the control of locomotion that may be correlated with the findings in experimental models. New and more sophisticated methods of brain imaging along with physiologic studies of balance and stepping may provide advances in human gait disorders, especially in relation to the brainstem control of locomotion.