Tom Robinson

Levodopa-induced dyskinesia in Parkinson’s disease: clinical features, pathogenesis, prevention and treatment

Levodopa is the most effective drug for treating Parkinson’s disease. However, long-term use of levodopa is often complicated by significantly disabling fluctuations and dyskinesias negating its beneficial effects. Younger age of Parkinson’s disease onset, disease severity, and high levodopa dose increase the risk of development of levodopa-induced dyskinesias (LID). The underlying mechanisms for LID are unclear though recent studies indicate the importance of pulsatile stimulation of striatal postsynaptic receptors in their pathogenesis. The non-human primates with MPTP-induced parkinsonism serve as a useful model to study dyskinesia. Once established, LID are difficult to treat and therefore efforts should be made to prevent them. The therapeutic and preventative strategies for LID include using a lower dosage of levodopa, employing dopamine agonists as initial therapy in Parkinson’s disease, amantadine, atypical neuroleptics, and neurosurgery. LID can adversely affect the quality of life and increase the cost of healthcare.

Cocaine use and stroke.

Stroke is the third most common cause of death in developed countries. In England and Wales, 1000 people under the age of 30 have a stroke each year. Cocaine is the most commonly used class A drug, and the first report of cocaine-induced stroke was in 1977. Since the development of alkaloidal “crack” cocaine in the 1980s, there has been a significant rise in the number of case reports describing both ischaemic and haemorrhagic stroke associated with cocaine use. Cocaine is a potent central nervous system stimulant, and acts by binding to specific receptors at pre-synaptic sites preventing the reuptake of neurotransmitters. The exact mechanism of cocaine-induced stroke remains unclear and there are likely to be a number of factors involved including vasospasm, cerebral vasculitis, enhanced platelet aggregation, cardioembolism, and hypertensive surges associated with altered cerebral autoregulation. The evidence surrounding each of these factors will be considered here.

Intravenous tranexamic acid for hyperacute primary intracerebral hemorrhage: Protocol for a randomized, placebo-controlled trial:

Rationale Outcome after intracerebral hemorrhage remains poor. Tranexamic acid is easy to administer, readily available, inexpensive, and effective in other hemorrhagic conditions. Aim This randomized trial aims to test the hypothesis that intravenous tranexamic acid given within 8 h of spontaneous intracerebral hemorrhage reduces death or dependency. Design Phase III prospective double-blind randomized placebo-controlled trial. Participants within 8 h of spontaneous intracerebral hemorrhage are randomized to receive either intravenous tranexamic acid 1 g 10 min bolus followed by 1 g 8 h infusion, or placebo. Sample size estimates A trial of 2000 participants (300 from start-up phase and 1700 from main phase) will have 90% power to detect an ordinal shift of the modified Rankin Scale with odds ratio 0.79. Study outcomes The primary outcome is death or dependency measured by ordinal shift analysis of the 7 level mRS at day 90. Secondary outcomes are neurological impairment at day 7 and disability, quality of life, cognition, and mood at day 90. Safety outcomes are death, serious adverse events, thromboembolic events, and seizures. Cost outcomes are length of stay in hospital, readmission, and institutionalization. Discussion This pragmatic trial is assessing efficacy of tranexamic acid after spontaneous intracerebral hemorrhage. Recruitment started in 2013; as of 15th January 2016 1355 participants have been enrolled, from 95 centers in seven countries. Recruitment is due to end in 2017. TICH-2 Trial is registered as ISRCTN93732214.

Measurement of cerebral blood flow responses to the thigh cuff maneuver: a comparison of TCD with a novel MRI method

Cerebral autoregulation (CA) describes the mechanism responsible for maintaining cerebral blood flow (CBF) relatively constant, despite changes in mean arterial blood pressure (ABP). This paper introduces a novel method for assessing CA using magnetic resonance imaging (MRI). Images are rapidly and repeatedly acquired using a gradient-echo echo-planar imaging pulse sequence for a period of 4minutes, during which a transient decrease in ABP is induced by rapid release of bilateral thigh cuffs. The method was validated by comparing the observed MRI signal intensity change with the CBF velocity change in the middle cerebral arteries, as measured by transcranial Doppler (TCD) ultrasound, using a standardized thigh cuff maneuver in both cases. Cross-correlation analysis of the response profiles from the left and right hemispheres showed a greater consistency for MRI measures than for TCD, both for interhemisphere comparisons and for repeated measures. The new MRI method may provide opportunities for assessing regional autoregulatory changes following acute stroke, and in other conditions in which poor autoregulation is implicated.

Service factors causing delay in specialist assessment for TIA and minor stroke: a qualitative study of GP and patient perspectives.

Objective To understand how service factors contribute to delays to specialist assessment following transient ischaemic attack (TIA) or minor stroke. Design Qualitative study using semistructured interviews, analysis by constant comparison. Setting Leicester, UK. Participants Patients diagnosed with TIA or minor stroke, at hospital admission or in a rapid-access TIA clinic (n=42), general practitioners (GPs) of participating patients if they had been involved in the patients’ care (n=18). Data Accounts from patients and GPs of factors contributing to delay following action to seek help from a healthcare professional (HCP). Results The following categories of delay were identified. First, delay in assessment in general practice following contact with the service; this related to availability of same day appointments, and the role of the receptionist in identifying urgent cases. Second, delays in diagnosis by the HCP first consulted, including GPs, optometrists, out-of-hours services, walk-in centres and the emergency department. Third, delays in referral after a suspected diagnosis; these included variable use of the ABCD2 (Age, Blood pressure, Clinical features, Duration, Diabetes) risk stratification score and referral templates in general practice, and referral back to the patients’ GP in cases where he/she was not the first HCP consulted. Conclusions Primary and emergency care providers need to review how they can best handle patients presenting with symptoms that could be due to stroke or TIA. In general practice, this may include receptionist training and/or triage by a nurse or doctor. Mechanisms need to be established to enable direct referral to the TIA clinic when patients whose symptoms have resolved present to other agencies. Further work is needed to improve diagnostic accuracy by non-specialists.

Penumbra and re-canalization acute computed tomography in ischemic stroke evaluation: PRACTISE study protocol

Rationale Multimodal imaging, including computed tomography angiography and computed tomography perfusion imaging, yields additional information on intracranial vessels and brain perfusion and can differentiate between ischemic core and penumbra which may affect patient selection for intravenous thrombolysis. Hypothesis The use of multimodal imaging will increase the number of patients receiving intravenous thrombolysis and lead to better treatment outcomes. Sample size 400 patients. Methods and design PRACTISE is a prospective, multicenter, randomized, controlled trial in which patients presenting within 4.5 h of symptom onset are randomized to either the current evidence-based imaging (NCCT alone) or additional multimodal computed tomography imaging (NCCT + computed tomography angiography + computed tomography perfusion). Clinical decisions on intravenous recombinant tissue plasminogen activator are documented. Total imaging time in both arms and time to initiation of treatment delivery in those treated with intravenous recombinant tissue plasminogen activator, is recorded. Follow-up will include brain imaging at 24 h to document infarct size, the presence of edema and the presence of intra-cerebral hemorrhage. Clinical evaluations include NIHSS score at baseline, 24 h and day 7 ± 2, and mRS at day 90 to define functional outcomes. Study outcomes The primary outcome is the proportion of patients receiving intravenous recombinant tissue plasminogen activator. Secondary end-points evaluate times to decision-making, comparison of different image processing software and clinical outcomes at three months. Discussion Multimodal computed tomography is a widely available tool for patient selection for revascularization therapy, but it is currently unknown whether the use of additional imaging in all stroke patients is beneficial. The study opened for recruitment in March 2015 and will provide data on the value of multimodal imaging in treatment decisions for acute stroke.

How did patients diagnosed with minor stroke and TIA respond to the Act F.A.S.T campaign

Introduction: Intra-arterial thrombolysis (IAT) and mechanical thrombectomy (MT) have potential to improve revascularisation for acute ischaemic stroke with large vessel occlusions. Data from patients undergoing intra-arterial procedures for stroke at UHNS was used to review outcomes and procedural complications. Method: Data collected from case notes and telephone contact with the patient included demographics, baseline clinical data, mortality and NIHSS score after 1 week, and mortality and mRankin score at 3 months where available. Radiological outcomes and procedural complications were recorded. Results: From December 2009 to June 2011, 37 patients with an average baseline NIHSS score of 20 were treated. Complications included distal thrombus propagation (27%), asymptomatic subarachnoid extravasation (11%) and transient vasospasm (8%). Mortality at one week was 5% (2 deaths from malignant MCA syndrome) and 8% by 3 months (1 further malignant MCA syndrome). No deaths occurred during the procedure or from haemorrhage. Of survivors at 1 week, average NIHSS had decreased by 8 points (44% decrease). At 3 months average mRankin score was 2.9, 45% having a score of 2 or less. Conclusion: The figures compare favourably with the SITS monitoring data for therapeutic thrombolysis. Intra arterial interventions can be performed with acceptable outcomes and should be considered for proximal large vessel occlusions.

Controlling hypertension immediately post stroke: a cost utility analysis of a pilot randomised controlled trial

BackgroundElevated blood pressure (BP) levels are common following acute stroke. However, there is considerable uncertainty if and when antihypertensive therapy should be initiated.MethodEconomic evaluation alongside a double-blind randomised placebo-controlled trial (National Research Register Trial Number N0484128008) of 112 hypertensive patients receiving an antihypertensive regimen (labetalol or lisinopril) within 36 hours post stroke versus 59 receiving placebo. Outcomes were incremental cost per incremental: QALY, survivor, and patient free from death or severe disability (modified Rankin scale score < 4) at three months and 14 days post stroke.ResultsActively treated patients on average had superior outcomes and lower costs than controls at three months. From the perspective of the acute hospital setting, there was a 96.5% probability that the incremental cost per QALY gained at three months is below £30,000, although the probability may be overstated due to data limitations.ConclusionAntihypertensive therapy when indicated immediately post stroke may be cost-effective compared with placebo from the acute hospital perspective. Further research is required to confirm both efficacy and cost-effectiveness and establish whether benefits are maintained over a longer time horizon.