Monash-Alfred protocol for assessment of atypical parkinsonian syndromes (MAP-APS).

Introduction: Atypical parkinsonian syndromes (APS) are rare neurodegenerative syndromes for which parkinsonism is one significant feature. APS includes progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS). The diagnosis of APS remains reliant on clinical features with no available diagnostic or prognostic biomarker. Clinical scales remain the gold standard assessment measures in clinical trials and research. The lack of standardised approach for research cohorts has contributed to shortcomings in disease understanding and limits collaboration between researchers. The primary objectives of this study are to (1) establish an assessment protocol for parkinsonian syndromes and (2) to implement it at a single site to establish the viability and utility of populating a clinical and biological databank of patients with APS. Methods: The Monash Alfred Protocol for Assessment of APS was devised by expert consensus within a broad multidisciplinary team. Eligible patients are diagnosed as possible or probable PSP, MSA or CBS by a consultant neurologist with expertise in movement disorders. Participants will be assessed at recruitment and then annually for up to 3 years; individuals within 5 years of index symptom onset will also undergo a once-off 6-month assessment. Ethics and dissemination: Each participant or their legally authorised representative will provide informed written consent prior to commencement of the study. Data will be stored on a locally hosted Research Electronic Data Capture database. Trial registration number: Australian New Zealand Clinical Trials Registry (ANZCTN 12622000923763).

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).

Impact of prefrontal intermittent theta-burst stimulation on working memory and executive function in Parkinson's disease: A double-blind sham-controlled pilot study.

Cognitive impairment is a prevalent non-motor feature of Parkinson's disease (PD) which can present even in early stages of the disease. Impairments in executive processing and working memory (WM) are common and have been attributed, in part, to abnormalities within the dorsolateral prefrontal cortex (DLPFC) and broader fronto-striatal circuitry. Previous studies in cognitively normal adults have suggested intermittent Theta Burst Stimulation (iTBS), an excitatory plasticity-inducing non-invasive brain stimulation technique, can enhance these cognitive functions. Fourteen participants with a diagnosis of idiopathic PD received either Active or Sham iTBS over the left DLPFC across two separate experimental sessions as part of a double-blind sham-controlled crossover experimental design. The Berg's Card Sorting Test (BCST) and N-Back tasks, which measure executive function and WM respectively, were administered prior to iTBS and again five- and 30-minutes following stimulation. Despite being well-tolerated, iTBS failed to modulate performance on any of the cognitive outcome measures. This finding was further supported by Bayes Factor analyses which indicated moderate levels of support for the null hypothesis overall. This initial pilot study therefore does not support single-session iTBS as an efficacious method for modulating either executive processes or WM in PD. We discuss potential reasons for this finding along with directions for future research.

Dystonic crises in dopa-responsive dystonia induced by energy drinks.

We present an interesting case of recurrent dystonic crises in dopa-responsive dystonia (DRD) likely induced by excessive consumption of aspartame-containing products, in particular sugar-free energy drinks. This has a strong practical value as acute presentations to the emergency department can be avoided in these susceptible individuals. Usual medical and dietary advice in the treatment of DRD would include the avoidance of high-dose phenylalanine-containing products, and to this we would advocate the avoidance of high-dose aspartame-containing products.

Measuring disease progression and disability in orthostatic tremor.

OBJECTIVE: To develop a questionnaire quantifying the impact of orthostatic tremor (OT) on patients' function and quality of life to enable longitudinal measurement of disease severity. METHODS: Patients with OT were interviewed in order to identify domains for a new disease-specific impact profile. The OT impact profile (OTIP) included forty-seven items across activities of daily living (9), mobility (9), social participation (2), assistance (8) and emotional effects (19) scored from 0 to 4 (total range 0-188). The same patients were invited to complete this at baseline and six-years later. An exploratory univariate linear regression analysis was performed to identify factors contributing to OTIP scores. RESULTS: Thirty-three patients were initially interviewed. Twenty-one completed the OTIP at baseline and 16 at follow-up. Over time there was an increase in falls and requirement for gait aids. The mean total OTIP score at baseline was 96(SD 52). There was no significant difference in the mean total (84, p = 0.4) or sub-domain scores at follow up. Regression analysis found the utility of gait aids and disease duration to predict a worse score. CONCLUSION: OT has a broad range of impacts on patients' quality of life and the OTIP appears to have some utility in measuring the functional impact. We found no change in overall disease impact on multiple domains over six years follow-up. This apparent lack of change may be due to the significant early impact that fear of falling has on patients.

Neck pain: What if it is not musculoskeletal?

BACKGROUND: Neck pain is a common presentation in general practice, with muscle strain or osteoarthritis the most common diagnoses. A systematic approach for identifying red flags for alternative causes is required to appropriately investigate or refer for specialist opinion. OBJECTIVE: The aim of this article is to highlight features of neurological and other causes of neck pain in adults that may present in general practice, and to outline a quick and practical diagnostic approach. DISCUSSION: Neck pain in adults may result from musculoskeletal or neurological disease, or as a component of a wide variety of metabolic, infective or malignant disorders. Focused attention to those components of history and examination that suggest alternative conditions can assist the diagnostic process.

Levodopa-carbidopa intestinal gel: is the naso-jejunal phase a redundant convention?

Levodopa-carbidopa intestinal gel (LCIG) is an effective treatment for Parkinson disease. Initiating therapy involves an initial naso-jejunal (NJ) titration phase. The NJ phase is prolonged with significant morbidity. The aim of this study is to assess the impact of proceeding without the NJ phase on resource utilisation and the outcomes of patients. Twenty-five patients were started on LCIG using the patients existing levodopa equivalent dose (LED). We recorded change in LED, length of hospital stay, readmission rates and use of outpatient services and clinical outcomes within 6 months. The median length of stay was 4.5 days. Patients had four outpatient clinic reviews and 2.5 community nurse contacts within 6 months. There was no significant change in daily LED on discharge (P = 0.56). There were significant improvements in all Unified Parkinson Disease Rating Scale subscores (P < 0.05), the Freezing of Gait scale (P < 0.01) and Parkinson Disease Quality Of Life 39 score (P < 0.01). Initiating LCIG without the NJ phase resulted in short admissions, a minimal outpatient burden and no significant requirement for dose titration while producing good clinical outcomes.

Isolated asymptomatic pulmonary arteriovenous malformation presenting with ischaemic stroke.

Young onset stroke is uncommon, and may be due to conditions other than traditional vascular risk factors. A 42-year-old woman with an ischaemic stroke was found to have left atrial bubble study positivity on transthoracic echocardiogram (TTE) suggestive of patent foramen ovale, however she also had low peripheral oxygen saturation. Investigation revealed an isolated pulmonary arteriovenous malformation (PAVM), visible on admission chest radiograph. This can cause embolic stroke and is an alternate cause of the TTE findings. The PAVM was able to be closed via endovascular intervention, removing the shunt and therefore removing her risk of recurrent stroke events. This is a rare cause of embolic stroke in young people which can be easily missed on investigation yet is amenable to treatment.

Delays to the diagnosis of cervical dystonia.

The diagnosis of cervical dystonia (CD) is based on physical examination and is therefore reliant on clinician experience. Due to variability of presenting symptoms it may be misdiagnosed, thus delaying the provision of effective treatment. We sought to determine the average time taken to make a diagnosis of CD in our clinical cohort and explore contributing factors to diagnostic delay. Forty-nine patients with a diagnosis of CD attending a movement disorder specialist for treatment completed a questionnaire regarding symptoms and clinical interactions at onset and diagnosis. The mean time from symptom onset to diagnosis was 6.8 years (range 0-53 years). More than 50% of patients sought physical therapies initially, prior to consulting their general practitioner. Only 40% of patients sought medical advice within the first 6 months of symptom onset and only 10% were given an initial diagnosis of CD. The first referral from the general practitioner was to a specialist other than a neurologist in 31% of patients. Patients were seen by a mean of three doctors (range one to nine) before being given the correct diagnosis of CD. Delay to diagnosis of CD may in part be due to lack of awareness of the condition amongst health care professionals. Improved diagnostic skill appears likely to have had a substantial impact on the delivery of appropriate treatment in this population.

Treatment of camptocormia with botulinum toxin.

Camptocormia is defined as an involuntary axial postural distortion of >45° flexion which occurs in the upright position, increases whilst walking and resolves when supine (Ashour and Jankovic, 2006). Unlike orthopaedic or age related kyphosis it is not a fixed structural deformity and produces kyphosis at predominantly lumbar and thoracic rather than cervical regions. Camptocormia has been reported due to a wide range of neurologic, psychiatric, muscular and orthopaedic conditions as well as rare reports of its emergence following the initiation of a number of medications (Finsterer and Strobl, 2010). Parkinson's disease (PD) includes prominent motor features of bradykinesia, rigidity and reduced postural balance responses in all those affected with this disease, but can also cause a range of other motor and non-motor features. Camptocormia is reported in a minority of patients with PD, and it is usually associated with longer disease duration and greater disease burden (Tiple et al., 2009). The aetiology of camptocormia in PD is debated, and responses to treatment have been generally poor and variable between studies. Recent studies have suggested the use of botulinum toxin may improve posture in some affected individuals.

Serotonergic markers in Parkinson's disease and levodopa-induced dyskinesias.

Preclinical animal models implicate serotonin neurons in the pathophysiology of levodopa (l-dopa)-induced dyskinesias in Parkinson's disease (PD), but effective treatment remains elusive. We examined the relationship between serotonin and l-dopa-induced dyskinesias in a pathologically confirmed cohort of PD patients. We obtained brain tissue from 44 PD cases and 17 age-matched controls and assessed monoamine levels and the serotonin and dopamine transporters in the striatum, and the extent of dopaminergic and serotonergic cell preservation in the substantia nigra (SN) and the dorsal raphe nuclei (DRN), respectively. As expected, PD patients demonstrated a severe loss of all dopaminergic markers, including dopamine (P < 0.0001) and the dopamine transporter (P < 0.0001) in the striatum, and dopaminergic neurons (P < 0.001) in the SN, compared with controls. Marked serotonin loss was observed in the caudate (but not putamen) in PD patients compared with controls (P < 0.001), but no difference was found in the levels of the serotonin transporter in the striatum or density of serotonergic neurons in the DRN between these groups, suggesting a functional but not structural change in the serotonergic system in PD. No difference was seen in levels of serotonergic and dopaminergic markers in the striatum between PD patients with and without dyskinesias, or between cases separated according to the clinical severity of their dyskinesias. The absence of a correlation between striatal serotonin markers and the incidence and severity of l-dopa-induced dyskinesias suggests that an intact and functioning serotonergic system is not a risk factor for developing dyskinesias in PD.

Sex differences in Parkinson's disease.

Sex-related differences in Parkinson's disease (PD) have been recognised, but remain poorly understood. We aimed to further clarify real-life differences in disease experience according to sex, by evaluating quality of life (QoL), demographic and clinical characteristics of PD patients. A cross-sectional survey was conducted on 210 PD patients (129 men, 81 women) attending specialist neurological clinics across three centres. Outcome measures included the motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS-III) and QoL as measured by the 39-item Parkinson's Disease Questionnaire (PDQ-39). A male to female ratio of 1.6:1 was observed. Men reported a greater disease burden than women as noted by higher UPDRS-III scores (27 ± 13 versus 23 ± 13, p=0.032), daily levodopa equivalent doses (898.1 ± 481.3mg versus 750.7 ± 427.2mg, p=0.037) and caregiver reliance (44% versus 29.5%, p=0.039). The UPDRS-III score was significantly associated with sex after controlling for age and disease duration, with men more severely affected (ß=-0.165, r(2)=0.101, p=0.028). The PDQ-39 showed men reported lower QoL in activities of daily living (ADL), cognition and communication sub-scales (p<0.05). An association was identified in men between PDQ-39 ADL and cognition sub-scales (r=0.660, p<0.001). Men with an appointed caregiver had a higher PDQ-39 Summary Index (t=3.222, degrees of freedom=122, p=0.002). PD was found to have greater overall impact on the health and well-being of male patients in sub-specialty clinical practice. Our study further supports the need for increased sex-delineated clinical assessment and consideration of potential differences required in the management of PD.

Diagnosis of dystonic syndromes--a new eight-question approach.

Dystonia is a syndrome of abnormal involuntary movements that are repetitive, twisting or patterned, and can result in abnormal postures. Dystonia may be generalized or focal, and can occur as a primary syndrome or secondary to another disease--over 50 clinical conditions are reported to cause dystonia. Classification of dystonia is based on genetic background, anatomical distribution, age at onset, and neurodegenerative processes. In many cases, manifestations of dystonia are identical regardless of the aetiology, which makes accurate diagnosis challenging, if not impossible, without additional investigations. Exhaustive lists of the causes of dystonia are not practical to aid clinicians when attempting to determine if a hyperkinetic movement can be diagnosed as dystonic. The existing diagnostic algorithms for dystonic syndromes rely on the clinician's experience, without a streamlined diagnostic pathway. Non-specialist clinicians and neurologists may, therefore, find diagnosis of dystonic syndromes difficult. In this Review, an eight-question approach is proposed, with a summary of the evidence for investigations that enable successful diagnosis of dystonic syndromes. The aim of this approach is to inform both specialists and general neurologists on the appropriate diagnostic test for each patient who presents with a possible dystonic syndrome.