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).

Quantitative analysis of MR T2 relaxation times in neck muscles.

T2 relaxation times (T2 times) are different between resting and exercised muscles and between muscles of healthy subjects and subjects with muscle pathology. However, studies specifically focusing on neck muscles are lacking. Furthermore, normative neck muscle T2 times are not well defined and methodology used to analyse T2 times in neck muscles is not robust. We analysed T2 times in key neck muscles and explored factors affecting variability between muscles. 20 healthy subjects were recruited. Two circular regions of interest (ROIs) were drawn in two mutually exclusive regions within neck muscles on T2 weighted images and values averaged. ROI measurements were performed by a co-investigator, supervised by a neuro-radiologist. For the first ten subjects, measurements were done from C1-T1. For the remaining subjects, ROIs were drawn at two pre-determined levels. Two MRIs were repeated at 31 degrees acquisition to evaluate the effect of muscle fibre orientation. ROI values were translated into T2 times. Results showed semispinalis capitis had the longest T2 times (range 46.88-51.42 ms), followed by splenius capitis (range 47.37-48.33 ms), trapezius (range 45.27-47.46 ms), levator scapulae (range 43.17-45.63 ms) and sternocleidomastoid (range 38.45-42.91 ms). T2 times did not vary along length of muscles and were unaffected by muscle fibre orientation (P > 0.05). T2 times of splenius capitis correlated significantly with age at C2/C3 and C5/C6 levels and trapezius at C7/T1 level. Gender did not influence relaxation times (P > 0.05). In conclusion, results of normative neck muscle T2 time values and factors influencing the T2 times could serve as a reference for future MR analysis of neck muscles. The methodology used may also be useful for related studies of neck muscles.

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.

Reversal of long term potentiation-like plasticity in primary motor cortex in patients with progressive supranuclear palsy.

OBJECTIVE: Abnormal primary motor cortex plasticity might be involved in the pathophysiology of progressive supranuclear palsy. In the present study we aimed to investigate possible abnormalities of depotentiation, a mechanism involved in plasticity regulation, in this condition. METHODS: Primary motor cortex excitability, investigated with single and paired-pulse transcranial magnetic stimulation, as well as long-term potentiation-like plasticity and its reversibility, were studied using theta burst stimulation in 15 patients with progressive supranuclear palsy and 11 healthy controls. Participants underwent two sessions using (1) the intermittent theta-burst stimulation (potentiation protocol) and (2) intermittent theta-burst stimulation combined with a depotentiation protocol (a short continuous theta-burst stimulation). RESULTS: Patients with PSP had higher corticospinal excitability and lower intracortical inhibition than healthy controls. Intermittent theta-burst stimulation elicited an abnormally increased long term potentiation-like effect in patients in comparison to healthy subjects. However, the depotentiation protocol was able to reverse the effects intermittent theta-burst stimulation on motor cortex excitability both in patients and in healthy controls. CONCLUSIONS: Altered primary motor cortex plasticity in patients with PSP does not reflect an abnormality of depotentiation. SIGNIFICANCE: This study provides information for a deeper understanding of the possible pathophysiological mechanisms underlying the altered M1 plasticity in PSP.

Plasma Screening for Progranulin Mutations in Patients with Progressive Supranuclear Palsy and Corticobasal Syndromes.

Progranulin gene (GRN) mutations are characterized by heterogeneous presentations. Corticobasal syndrome (CBS) is often associated with GRN mutations, whereas association with progressive supranuclear palsy syndrome (PSPS) is rare. Plasma progranulin levels were evaluated in 34 patients, including 19 with PSPS, 12 with CBS, and 3 with mixed signs, with the purpose to screen for the presence of causal mutations, associated with low levels. We found undetectable levels in a patient with CBS. Sequencing confirmed the presence of the Thr272fs deletion. Progranulin mutation screening is suggested in cases of CBS, even in the absence of positive family history for dementia and/or movement disorders.

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.

Influence of single nucleotide polymorphisms in COMT, MAO-A and BDNF genes on dyskinesias and levodopa use in Parkinson's disease.

BACKGROUND: Clinical heterogeneity in the development of levodopa-induced dyskinesias (LID) suggests endogenous factors play a significant role in determining their overall prevalence. OBJECTIVE: We hypothesised that single nucleotide polymorphisms (SNPs) in specific genes may result in a clinical phenotype conducive to an increased risk of LID. METHODS: We examined the influence of SNPs in the catechol-O-methyltransferase (COMT), monoamine oxidase A (MAO-A) and brain-derived neurotrophic factor (BDNF) genes on LID in a cohort of 285 pathologically confirmed Parkinson's disease patients, using data from their complete disease course. RESULTS: Dyskinetic patients demonstrated younger age at disease onset (60.3 vs. 66.4 years, p < 0.0001), a longer disease duration (17.0 vs. 12.0 years, p < 0.0001) and a higher maximum daily levodopa equivalent dose (LED; 926.7 vs. 617.1 mg/day, p < 0.0001) than patients without dyskinesias. No individual SNP was found to influence prevalence or time to onset of dyskinesias, including after adjustment for known risk factors. We observed that patients carrying alleles conferring both high COMT activity and increased MAO-A mRNA expression received significantly higher maximum and mean daily LEDs than those with low enzyme activity/mRNA expression (max LED: 835 ± 445 vs. 508 ± 316 mg; p = 0.0056, mean LED: 601 ± 335 vs. 398 ± 260 mg; p = 0.025). CONCLUSIONS: Individual SNPs in BDNF, COMT and MAO-A genes did not influence prevalence or time to onset of dyskinesias in this cohort. The possibility that combined COMT and MAO-A genotype is a significant factor in determining an individual's lifetime levodopa exposure warrants further investigation.

Short and long term outcome of bilateral pallidal stimulation in chorea-acanthocytosis.

BACKGROUND: Chorea-acanthocytosis (ChAc) is a neuroacanthocytosis syndrome presenting with severe movement disorders poorly responsive to drug therapy. Case reports suggest that bilateral deep brain stimulation (DBS) of the ventro-postero-lateral internal globus pallidus (GPi) may benefit these patients. To explore this issue, the present multicentre (n=12) retrospective study collected the short and long term outcome of 15 patients who underwent DBS. METHODS: Data were collected in a standardized way 2-6 months preoperatively, 1-5 months (early) and 6 months or more (late) after surgery at the last follow-up visit (mean follow-up: 29.5 months). RESULTS: Motor severity, assessed by the Unified Huntington's Disease Rating Scale-Motor Score, UHDRS-MS), was significantly reduced at both early and late post-surgery time points (mean improvement 54.3% and 44.1%, respectively). Functional capacity (UHDRS-Functional Capacity Score) was also significantly improved at both post-surgery time points (mean 75.5% and 73.3%, respectively), whereas incapacity (UHDRS-Independence Score) improvement reached significance at early post-surgery only (mean 37.3%). Long term significant improvement of motor symptom severity (≥ 20 % from baseline) was observed in 61.5 % of the patients. Chorea and dystonia improved, whereas effects on dysarthria and swallowing were variable. Parkinsonism did not improve. Linear regression analysis showed that preoperative motor severity predicted motor improvement at both post-surgery time points. The most serious adverse event was device infection and cerebral abscess, and one patient died suddenly of unclear cause, 4 years after surgery. CONCLUSION: This study shows that bilateral DBS of the GPi effectively reduces the severity of drug-resistant hyperkinetic movement disorders such as present in ChAc.