Dopamine Gene Profiling to Predict Impulse Control and Effects of Dopamine Agonist Ropinirole.

Dopamine agonists can impair inhibitory control and cause impulse control disorders for those with Parkinson disease (PD), although mechanistically this is not well understood. In this study, we hypothesized that the extent of such drug effects on impulse control is related to specific dopamine gene polymorphisms. This double-blind, placebo-controlled study aimed to examine the effect of single doses of 0.5 and 1.0 mg of the dopamine agonist ropinirole on impulse control in healthy adults of typical age for PD onset. Impulse control was measured by stop signal RT on a response inhibition task and by an index of impulsive decision-making on the Balloon Analogue Risk Task. A dopamine genetic risk score quantified basal dopamine neurotransmission from the influence of five genes: catechol-O-methyltransferase, dopamine transporter, and those encoding receptors D1, D2, and D3. With placebo, impulse control was better for the high versus low genetic risk score groups. Ropinirole modulated impulse control in a manner dependent on genetic risk score. For the lower score group, both doses improved response inhibition (decreased stop signal RT) whereas the lower dose reduced impulsiveness in decision-making. Conversely, the higher score group showed a trend for worsened response inhibition on the lower dose whereas both doses increased impulsiveness in decision-making. The implications of the present findings are that genotyping can be used to predict impulse control and whether it will improve or worsen with the administration of dopamine agonists.

Autonomic dysfunction is a major feature of cerebellar ataxia, neuropathy, vestibular areflexia 'CANVAS' syndrome.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative ganglionopathy. Prompted by the presence of symptomatic postural hypotension in two patients with CANVAS, we hypothesized that autonomic dysfunction may be an associated feature of the syndrome. We assessed symptoms of autonomic dysfunction and performed autonomic nervous system testing among 26 patients from New Zealand. After excluding three patients with diabetes mellitus, 83% had evidence of autonomic dysfunction; all patients had at least one autonomic symptom and 91% had more than two symptoms. We also found a higher rate of downbeat nystagmus (65%) than previously described in CANVAS. We confirmed that sensory findings on nerve conduction tests were consistent with a sensory ganglionopathy and describe two patients with loss of trigeminal sensation consistent with previous pathological descriptions of trigeminal sensory ganglionopathy. Our results suggest that autonomic dysfunction is a major feature of CANVAS. This has implications for the management of patients with CANVAS as the autonomic symptoms may be amenable to treatment. The findings also provide an important differential diagnosis from multiple system atrophy for patients who present with ataxia and autonomic failure.

The nature of, and reasons for, 'inappropriate' hospitalisations among patients with palliative care needs: a qualitative exploration of the views of generalist palliative care providers.

BACKGROUND: Recent studies have concluded that there is significant potential to reduce the extent of 'inappropriate' hospitalisations among patients with palliative care needs. However, the nature of, and reasons for, inappropriate hospitalisations within a palliative care context is under-explored. AIM: To explore the opinions of 'generalist' palliative care providers regarding the nature of, and reasons for, inappropriate admissions among hospital inpatients with palliative care needs. DESIGN: Qualitative study with data collected via individual interviews and focus groups. SETTING/PARTICIPANTS: Participants (n = 41) comprised 'generalist' palliative care providers working in acute hospital and community settings. SETTING: One District Health Board in an urban area of New Zealand. RESULTS: The majority of participants discussed 'appropriateness' in relation to their own understanding of a good death, which typically involved care being delivered in a 'homely' environment, from known people. Differing attitudes among cultural groups were also evident. The following reasons for inappropriate admissions were identified: family carers being unable to cope, the 'rescue culture' of modern medicine, the financing and availability of community services and practice within aged residential care. CONCLUSIONS: On the basis of our findings, we recommend a shift to the term 'potentially avoidable' admission rather than 'inappropriate admission'. We also identify an urgent need for debate regarding the role of the acute hospital within a palliative care context. Interventions to reduce hospital admissions within this population must target societal understandings of death and dying within the context of medicalisation, as well as take into account cultural and ethnic diversity in attitudes, if they are to be successful.

A long-term follow-up of safety and clinical efficacy of NTCELL® [Immunoprotected (Alginate-encapsulated) porcine choroid plexus cells for xenotransplantation] in patients with Parkinson's disease.

INTRODUCTION: In 2019, we published the results of a Phase IIb randomized controlled trial of putaminal encapsulated porcine choroid plexus cell (termed NTCELL®) administration in patients with Parkinson's disease. This study failed to meet its primary efficacy end-point of a change in UPDRS part III score in the 'off' state at 26-weeks post-implant. However, a number of secondary end-points reached statistical significance. We questioned whether with longer follow-up, clinically significant improvements would be observed. For this reason, we decided to follow-up all patients periodically to week 104. Herein, we report the results of this long-term follow-up. METHODS: All 18 patients included in the original study were periodically re-assessed at weeks 52, 78 and 104 post-implant. At each time-point, motor and non-motor function, quality of life and levodopa equivalent daily dose was assessed using a standardized testing battery. RESULTS: At week 104, no significant differences in UPDRS part III scores in the 'off' state were observed in any of the treatment groups compared to baseline. Only a single serious adverse event - hospitalisation due to Parkinson's disease rigidity not responding to changes in medications - was considered potentially related to the implant procedure. There was no evidence of xenogeneic viral transmission. CONCLUSION: Un-blinded, long-duration follow-up to week 104 post-implantation showed no evidence that putaminal NTCELL® administration produces significant clinical benefit in patients with moderately advanced Parkinson's disease.

A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease.

Multiple lines of evidence point to mitochondrial oxidative stress as a potential pathogenic cause for Parkinson's disease (PD). MitoQ is a powerful mitochondrial antioxidant. It is absorbed orally and concentrates within mitochondria where it has been shown to protect against oxidative damage. We enrolled 128 newly diagnosed untreated patients with PD in a double-blind study of two doses of MitoQ compared with placebo to explore the hypothesis that, over 12 months, MitoQ would slow the progression of PD as measured by clinical scores, particularly the Unified Parkinson Disease Rating Scale. We showed no difference between MitoQ and placebo on any measure of PD progression. MitoQ does not slow the progression of PD, and this finding should be taken into account when considering the oxidative stress hypothesis for the pathogenesis of PD.

A phase IIb, randomised, double-blind, placebo-controlled, dose-ranging investigation of the safety and efficacy of NTCELL® [immunoprotected (alginate-encapsulated) porcine choroid plexus cells for xenotransplantation] in patients with Parkinson's disease.

INTRODUCTION: Regenerative therapies in Parkinson's disease aim to slow neurodegeneration and re-establish damaged neuronal circuitry. Neurotrophins are potent endogenous regulators of neuronal survival, development and regeneration. They represent an attractive regenerative treatment option in Parkinson's disease. Porcine choroid plexus produces a number of neurotrophins, and can be safely delivered to the striatum in an encapsulated formulation (termed NTCELL®) to protect them from immune attack. NTCELL® has shown regenerative potential in animal models of stroke, Huntington's disease and Parkinson's disease. Following promising results from an initial open label safety study of intra-striatal delivery of NTCELL® in human subjects, we sought to specifically investigate the safety and efficacy of NTCELL® for the treatment of Parkinson's disease. METHODS: 18 patients aged 56-65 years with idiopathic Parkinson's disease of at least 5 years duration were randomised to receive either sham surgery (general anaesthesia and partial thickness burr holes) or intra-striatal delivery of NTCELL® (the 3 groups in the treatment arm receiving incremental NTCELL® doses). RESULTS: At 26 weeks, we found no significant difference in total UPDRS scores ('on' and 'off'), UPDRS motor scores ('on' and 'off'), PDQ-39, UDysRS, timed walk or modified Hoehn and Yahr stage between patients implanted with NTCELL® and patients undergoing sham procedure. There were no serious adverse events or xenogeneic viral transmission during the study. CONCLUSION: The study did not meet its primary efficacy end-point of a change in UPDRS at 26 weeks post-intervention compared with baseline. Stereotactic NTCELL® implantation was safe and well tolerated.

Replication of association between ELAVL4 and Parkinson disease: the GenePD study.

Genetic variants in embryonic lethal, abnormal vision, Drosophila-like 4 (ELAVL4) have been reported to be associated with onset age of Parkinson disease (PD) or risk for PD affection in Caucasian populations. In the current study we genotyped three single nucleotide polymorphisms in ELAVL4 in a Caucasian study sample consisting of 712 PD patients and 312 unrelated controls from the GenePD study. The minor allele of rs967582 was associated with increased risk of PD (odds ratio = 1.46, nominal P value = 0.011) in the GenePD population. The minor allele of rs967582 was also the risk allele for PD affection or earlier onset age in the previously studied populations. This replication of association with rs967582 in a third cohort further implicates ELAVL4 as a PD susceptibility gene.

The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study.

BACKGROUND: We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD. METHODS: A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample. RESULTS: Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families. CONCLUSION: Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Huntington CAG repeat size does not modify onset age in familial Parkinson's disease: the GenePD study.

The ATP/ADP ratio reflects mitochondrial function and has been reported to be influenced by the size of the Huntington disease gene (HD) repeat. Impaired mitochondrial function has long been implicated in the pathogenesis of Parkinson's disease (PD), and therefore, we evaluated the relationship of the HD CAG repeat size to PD onset age in a large sample of familial PD cases. PD affected siblings (n = 495), with known onset ages from 248 families, were genotyped for the HD CAG repeat. Genotyping failed in 11 cases leaving 484 for analysis, including 35 LRRK2 carriers. All cases had HD CAG repeats (range, 15-34) below the clinical range for HD, although 5.2% of the sample (n = 25) had repeats in the intermediate range (the intermediate range lower limit = 27; upper limit = 35 repeats), suggesting that the prevalence of intermediate allele carriers in the general population is significant. No relation between the HD CAG repeat size and the age at onset for PD was found in this sample of familial PD.

Down the Stairs Dystonia-A Novel Task-Specific Focal Isolated Syndrome.

Adult-onset, task-specific dystonia of the lower limb is a rare occurrence. In this report, the authors present 6 cases of task-specific dystonia manifested only when going down the stairs. These patients were seen by 6 different neurologists from across Canada, Australia, and New Zealand, and all videos were reviewed by 1 movement disorders specialist who made the final diagnosis. Video description of each case is also presented. All 6 patients demonstrated dystonia of 1 of their lower limbs specifically only when going down the stairs. The remainder of the neurological examination was normal, and distractibility, inconsistency, fixed dystonia, or a premonitory urge were absent, making functional movement disorder and tic disorder unlikely. These 6 patients display a distinct, adult-onset, focal isolated dystonia manifested only on going down the stairs that is recognizable as a new task-specific dystonia of the lower extremity.

The extent and cost of potentially avoidable admissions in hospital inpatients with palliative care needs: a cross-sectional study.

OBJECTIVE: More than 90% of people spend time in hospital in the last year of life and, in many developed countries, hospitals are the setting in which most people will die. Previous research indicates that a proportion of these hospital admissions could have been avoided. The objective of this study was to establish the extent and cost of potentially avoidable hospital admissions among patients with palliative care needs. METHODS: A prospective survey of hospital inpatients was undertaken to identify patients who met clinical criteria indicating palliative care need. Case notes were reviewed by two expert palliative care clinicians to determine if the hospital admission was potentially avoidable. An analysis of the cost of potentially avoidable admissions compared to all other admissions for those patients identified as being in the last year of life was carried out using the statistical analysis software R V.2.15.1. Logistic regression was performed using the logit (log of OR) link. The binary outcome of the logistic regression model was a potentially avoidable admission. RESULTS: Of the 99 patients who met the criteria for palliative care need, 22 were deemed to have experienced a potentially avoidable admission. Those living in a residential aged care facility were more at risk of experiencing such admissions. The mean total cost of hospital care for those with palliative care needs was lower for those whose admission was deemed potentially avoidable. CONCLUSIONS: A significant proportion of patients with palliative care needs experience a potentially avoidable admission. Although these admissions are relatively short compared to those whose admissions are unavoidable, any hospital admission impacts on the experiences of patients and families and may contribute to unnecessary hospital expenditure.

Factors for predicting premature termination from a multidisciplinary inpatient chronic pain program.

Forty-eight chronic pain patients who were discharged from or left the 21-day inpatient component of a multidisciplinary pain program prior to completion were compared with a randomly selected matched group of program patients who stayed the entire 21 days. The purpose of the study was to determine if pre-admission factors are useful in predicting whether a chronic pain patient will complete an inpatient pain program. The results of pre-admission MMPI, POMS, MPQ, and information obtained from a questionnaire specially created for the program were studied. On the tests, the non-completers admitted to less psychopathology than those who did complete the program. The non-completers also had a higher number of pain-related surgeries and were more likely to be college graduates; limited social support from their families and lower MMPI premature termination scale scores were also found. Implications of these findings for the management of chronic pain patients are discussed.

Multiple cranial nerve palsies as the first presentation of sarcoidosis.

Sarcoidosis is a disease process which predominantly affects the lungs but can involve virtually any organ in the human body. Neurosarcoidosis is a rare manifestation which can present in a variety of ways. There is no single diagnostic test for sarcoidosis; hence, the diagnosis is based on combined clinical, laboratorial, and radiological grounds. We describe a rare case where a patient presented with dysphagia, hoarseness, hearing loss, and unsteadiness.

Upper limb compartment syndrome: an unusual complication of stroke thrombolysis.

Bleeding is the most important complication of treatment with intravenous tissue plasminogen activator for acute ischemic stroke. Neurologists are familiar with intracranial hemorrhage, the most feared site for bleeding following thrombolysis, but extracranial bleeding can also occur resulting in substantial morbidity and mortality. We describe an 88-year-old woman with an acute stroke who developed bleeding into the left arm complicated by hemodynamic instability and compartment syndrome following intravenous thrombolysis. The patient was treated conservatively in view of the risks associated with fasciotomy and her other medical comorbidities.

Clinical staff perceptions of palliative care-related quality of care, service access, education and training needs and delivery confidence in an acute hospital setting.

CONTEXT: Central to appropriate palliative care management in hospital settings is ensuring an adequately trained workforce. In order to achieve optimum palliative care delivery, it is first necessary to create a baseline understanding of the level of palliative care education and support needs among all clinical staff (not just palliative care specialists) within the acute hospital setting. OBJECTIVES: The objectives of the study were to explore clinical staff: perceptions concerning the quality of palliative care delivery and support service accessibility, previous experience and education in palliative care delivery, perceptions of their own need for formal palliative care education, confidence in palliative care delivery and the impact of formal palliative care training on perceived confidence. METHODS: A purposive sample of clinical staff members (598) in a 710-bed hospital were surveyed regarding their experiences of palliative care delivery and their education needs. RESULTS: On average, the clinical staff rated the quality of care provided to people who die in the hospital as 'good' (x̄=4.17, SD=0.91). Respondents also reported that 19.3% of their time was spent caring for end-of-life patients. However, only 19% of the 598 respondents reported having received formal palliative care training. In contrast, 73.7% answered that they would like formal training. Perceived confidence in palliative care delivery was significantly greater for those clinical staff with formal palliative care training. CONCLUSIONS: Formal training in palliative care increases clinical staff perceptions of confidence, which evidence suggests impacts on the quality of palliative care provided to patients. The results of the study should be used to shape the design and delivery of palliative care education programmes within the acute hospital setting to successfully meet the needs of all clinical staff.

Clinically significant placebo analgesic response in a pilot trial of botulinum B in patients with hand pain and carpal tunnel syndrome.

OBJECTIVE: We conducted a pilot trial to assess the effect of botulinum toxin B on palmar pain and discomfort in carpal tunnel syndrome (CTS) patients. Design. Randomized, double-blind, placebo-controlled. PATIENTS: Twenty ambulatory CTS patients. Intervention. Botulinum toxin B or placebo injections into three hypothenar muscles anatomically linked or attached to the carpal tunnel and its tentorium, that is, the Opponens Digiti Minimi and Flexor Digiti Minimi, located with electromyography (EMG), and the Palmaris Brevis Muscle, anatomically located without EMG. SETTING: New York City hospital. OUTCOME MEASURES: Outcomes were measured with numeric ratings, with higher scores indicating worse outcomes. Daily, subjects recorded their 0-10 numeric ratings of overall pain levels and pain-related sleep disturbances. During weekly telephone calls, they reported their 0-10 ratings for overall pain, pain-related sleep disturbance, and CTS-related tingling during the night and day as experienced over the preceding 24 hours. For each of four clinic visits, we averaged each subject's ratings of nine quality of life indicators from the West Haven-Yale Multidimensional Pain Inventory (WHYMPI), each measured on a 0-6 numeric scale. RESULTS: Over the 13-week trial, compared to baseline scores, the following outcomes predominantly showed decreases of statistical significance (P < or = 0.050) or borderline significance (0.050 < P < or = 0.10) for weeks 2 through 8: overall pain per daily diary entries and per weekly telephone reports, and pain-related sleep disturbance in the placebo group per phone report and in the botulinum toxin B group per diary report. CTS painful night tingling and day tingling, as well as the average scores of the WHYMPI quality of life indicators, showed improvements with statistical or borderline significance for almost each follow-up week. Between-group analyses, however, demonstrated that at each follow-up week, there was no statistically significant difference between the two study groups regarding changes from baseline in any study outcome. CONCLUSION: Botulinum toxin B is not dramatically superior to placebo for the relief of CTS symptoms. Possible explanations of the improvements in each study group are explored.