Efficacy and Contextual (Placebo) Effects of CGRP Antibodies for Migraine: Systematic Review and Meta-analysis.

BACKGROUND: CGRP Antibodies are high-cost newly licensed migraine preventatives. OBJECTIVE: To calculate the overall reduction in monthly migraine days and the proportion contextual effect (PCE) using meta-analysis. The PCE is the ratio between the reduction in Monthly Migraine Days in the placebo group and the reduction in Monthly Migraine Days in the CGRP-Ab group after 3 months of treatment. METHODS: Meta-analysis of randomized double-blind placebo-controlled trials of anti-CGRP antibodies in people with episodic migraine (EM) or chronic migraine (CM) in persons aged 18 or over. Non-randomized trials and trials in persons under 18 years excluded. Search of National Clinical Trials Register 2000-2019, MEDLINE to September 2019, Hand search of major headache conference abstract books 2012-2019. Two investigators used standard proforma to reach consensus. Trial quality assessed using Cochrane Collaboration risk of bias tool. PRISMA guidelines followed. RESULTS: 21 completed trials with 13367 participants (8075 EM, 5292 CM). Compared to placebo, pooled reduction in MMD was 1.50 days in 15 EM trials (95%CI 1.16, 1.84; I2  = 69%, Phetereogeneity  < .001) and 2.24 days in 7 CM trials (95%CI 1.82, 2.65, I2  = 15%, Phetereogeneity  = .320). In EM trials, pooled PCE was 0.66 (95%CI 0.59,0.75; I2  = 64%, Phetereogeneity  = .001). In CM trials the PCE was .68 (95%CI 0.61, 0.75; I2  = 20%, Phetereogeneity  = .280). Industry funded every study, but risk of bias was low. CONCLUSIONS: CGRPAbs are effective but sixty-six percent of the benefit is from contextual effects, including placebo effect. Contextual effects merit further scrutiny as a means of improving migraine headache.

Malignant meningitis secondary to oesophageal adenocarcinoma presenting with sensorineural hearing loss: a series of three cases and discussion of the literature.

Malignant meningitis may rarely present to the otolaryngologist. We report our experience with 3 patients presenting with sudden, progressive bilateral sensorineural hearing loss secondary to malignant meningitis. The primary tumour in all 3 cases was oesophageal adenocarcinoma. All 3 cases were notable for the rapidity of the patients' clinical deterioration; the interval from presentation to death ranged from 21 to 28 days. We suggest that otolaryngologists should remain vigilant to the possibility of this devastating diagnosis and have a low threshold for further investigation in patients with suspicious features. It is important to note that initial MRI and lumbar puncture may be negative and repeat testing should be undertaken if there is clinical suspicion.

A systematic review of causes of sudden and severe headache (Thunderclap Headache): should lists be evidence based?

BACKGROUND: There are many potential causes of sudden and severe headache (thunderclap headache), the most important of which is aneurysmal subarachnoid haemorrhage. Published academic reviews report a wide range of causes. We sought to create a definitive list of causes, other than aneurysmal subarachnoid haemorrhage, using a systematic review. METHODS: Systematic Review of EMBASE and MEDLINE databases using pre-defined search criteria up to September 2009. We extracted data from any original research paper or case report describing a case of someone presenting with a sudden and severe headache, and summarized the published causes. RESULTS: Our search identified over 21,000 titles, of which 1224 articles were scrutinized in full. 213 articles described 2345 people with sudden and severe headache, and we identified 6 English language academic review articles. A total of 119 causes were identified, of which 46 (38%) were not mentioned in published academic review articles. Using capture-recapture analysis, we estimate that our search was 98% complete. There is only one population-based estimate of the incidence of sudden and severe headache at 43 cases per 100,000. In cohort studies, the most common causes identified were primary headaches or headaches of uncertain cause. Vasoconstriction syndromes are commonly mentioned in case reports or case series. The most common cause not mentioned in academic reviews was pneumocephalus. 70 non-English language articles were identified but these did not contain additional causes. CONCLUSIONS: There are over 100 different published causes of sudden and severe headache, other than aneurysmal subarachnoid haemorrhage. We have now made a definitive list of causes for future reference which we intend to maintain. There is a need for an up to date population based description of cause of sudden and severe headache as the modern epidemiology of thunderclap headache may require updating in the light of research on cerebral vasoconstriction syndromes.

A Neurodisparity Index of Nationwide Access to Neurological Health Care in Northern Ireland.

Nationwide disparities in managing neurological patients have rarely been reported. We compared neurological health care between the population who reside in a Health and Social Care Trust with a tertiary neuroscience center and those living in the four non-tertiary center Trusts in Northern Ireland. Using the tertiary center Trust population as reference, neurodisparity indices (NDIs) defined as the number of treated patients resident in each Trust per 100,000 residents compared to the same ratio in the tertiary center Trust for a fixed time period. NDIs were calculated for four neurological pathways-intravenous thrombolysis (iv-tPA) and mechanical thrombectomy (MT) for acute ischemic stroke (AIS), disease modifying treatment (DMT) in multiple sclerosis (MS) and admissions to a tertiary neurology ward. Neurological management was recorded in 3,026 patients. Patients resident in the tertiary center Trust were more likely to receive AIS treatments (iv-tPA and MT) and access to the neurology ward (p < 0.001) than patients residing in other Trusts. DMT use for patients with MS was higher in two non-tertiary center Trusts than in the tertiary center Trust. There was a geographical gradient for MT for AIS patients and ward admissions. Averaged NDIs for non-tertiary center Trusts were: 0.48 (95%CI 0.32-0.71) for patient admissions to the tertiary neurology ward, 0.50 (95%CI 0.38-0.66) for MT in AIS patients, 0.78 (95%CI 0.67-0.92) for iv-tPA in AIS patients, and 1.11 (95%CI 0.99-1.26) for DMT use in MS patients. There are important neurodisparities in Northern Ireland, particularly for MT and tertiary ward admissions. Neurologists and health service planners should be aware that geography and time-dependent management of neurological patients worsen neurodisparities.

The incidence of motor nueron disease in Scotland.

Between 1989 and 1998, 1226 cases of ALS/MND were identified in Scotland, with mean age of onset 65.2 (SD 11.9) years for men and 67.2 (SD 11.0) for women. Annual standardized incidence was 2.40 per 100,000 (95% CI 2.22-2.58). Using capture recapture methods we confirm a high level of case ascertainment for each year of study. Incidence and ascertainment of ALS has remained stable in a large population over a prolonged period of time. Large population-based databases can be used to test aetiological hypotheses.

Frequency, timing and outcome of gastrostomy tubes for amyotrophic lateral sclerosis/motor neurone disease--a record linkage study from the Scottish Motor Neurone Disease Register.

AIMS: To describe the frequency, timing and outcome from gastrostomy in amyotrophic lateral sclerosis/motor neurone disease (ALS/MND). METHODS: The Scottish MND Register, a population based disease register (1989-1998), with record linkage to the Scottish Morbidity 1 dataset of hospital discharges coded for gastrostomy procedure was used. Descriptive statistics of patients undergoing gastrostomy were extracted. Survival analysis used Kaplan Meier and Cox proportional hazards methods. RESULTS: For patients diagnosed between 1989-98, 142 percutaneous endoscopic gastrostomy (PEG) insertion episodes were identified in 1226 patients, 130 of which occurred before the censoring date of 31 December 1999.Annually, on average, 5% of all revalent patients underwent gastrostomy, and this rate appeared to double between 1989-98. The cumulative incidence of gastrostomy was 11%. Mean age at PEG tube insertion was 66.8 years, with a mean disease duration of 24 months. Median survival from PEG tube insertion was 146 days. The 1 month mortality after gastrostomy was 25%. Gastrostomy did not confer a survival advantage compared with no gastrostomy. CONCLUSIONS: We found that gastrostomy feeding tubes are being inserted more frequently in people with ALS/MND. An unexpectedly high early mortality was detected which probably reflects a lack of selection bias compared with previously published data. It is possible that changes in the practice of gastrostomy placement since 1998 result in better outcomes for patients with ALS/MND. Prospective studies are required to assess the risks and benefits of enteral nutrition in ALS/MND.

Cost-utility analysis of vagus nerve stimulators for adults with medically refractory epilepsy.

INTRODUCTION: The cost-utility of vagus nerve stimulator (VNS) devices for medically refractory epilepsy has yet to be estimated. METHODS: Using a meta-analysis of randomised controlled trials of VNS, we estimate that six people require implantation in order for one person to experience a 50% reduction in seizure frequency. Costs averted from improved epilepsy control were ascertained from published literature. Values for health states were obtained from a series of 42 seizure clinic attenders using time trade-off techniques and the EQ-5D health status instrument. The cost per quality adjusted life year gained was estimated and the values obtained were tested in a sensitivity analysis. RESULTS: Improved epilepsy control averted, on average, 745 pounds sterling health care costs per annum. People with epilepsy had great difficulty performing the time trade-off experiment, but those who managed to complete the task valued a 50% reduction in their own seizure frequency at 0.285 units. For a programme of six implants, the baseline model estimated the cost per quality adjusted life year gained at 28,849 pounds sterling. The most favourable estimate was equal to 4785 pounds sterling per quality adjusted life year gained, assuming that the number needed to treat was similar to published series in which one response was obtained for every three implants. The least favourable estimate was equal to 63,000 pounds sterling per quality adjusted life year gained, when EQ-5D utility values were used. The cost per quality adjusted life year gained was not sensitive to changes in length of stay, nor complication rates, but was significantly influenced by cost of device and device battery life expectancy. CONCLUSION: There is not a strong economic argument against a programme of VNS implantation, although care should be taken to try and identify and treat those most likely to benefit.

Diagnostic Lumbar Puncture.

Diagnostic Lumbar Puncture is one of the most commonly performed invasive tests in clinical medicine. Evaluation of an acute headache and investigation of inflammatory or infectious disease of the nervous system are the most common indications. Serious complications are rare, and correct technique will minimise diagnostic error and maximise patient comfort. We review the technique of diagnostic Lumbar Puncture including anatomy, needle selection, needle insertion, measurement of opening pressure, Cerebrospinal Fluid (CSF) specimen handling and after care. We also make some quality improvement suggestions for those designing services incorporating diagnostic Lumbar Puncture.

Multiple sclerosis in Tayside, Scotland: detection of clusters using a spatial scan statistic.

Debate continues over the relative importance of genetic factors over infectious agents in the aetiology of multiple sclerosis (MS). Detection of clusters of MS in space and time in the Tayside region of Scotland, UK would provide valuable evidence for the movement of infectious agents into a genetically susceptible population. A spatial scan statistic was used to detect, locate and provide a robust statistical test of any clusters found, without prior knowledge of their location or size. This was applied to a population-based MS register for the Tayside region of Scotland from 1970 to 1997, allowing for age at symptom onset, gender, population density and social deprivation. There were a total of 772 cases during the study period; an annual incidence of 72 per 100000. The mean age of symptom onset was 35.7 (SD = 10.5) and 73.8% of cases were women. There was a general increase in cases over time probably reflecting gradually better detection and diagnosis. There was a peak around the mid-1990s and some evidence of periodicity. There was a highly significant temporal cluster between 1982 and 1995 (P = 0.002) for the whole region. Additionally, a significant spatial cluster for the time period 1993-1995 was found centred in the rural area south-west of Perth (P=0.016). Significant temporal and spatial-temporal clusters are consistent with exogenous factors contributing to the distribution of MS in Tayside, Scotland.

The epidemiology of amyotrophic lateral sclerosis (ALS/MND) in people aged 80 or over.

OBJECTIVE: To describe the clinical features, incidence, survival and process of care of people with Amyotrophic Lateral Sclerosis/Motor Neurone Disease aged 80 years or more at diagnosis. DESIGN: Prospective, population-based descriptive epidemiological study. SETTING: Scotland (population 5.1 million), The Scottish Motor Neurone Disease Register 1989-1998. PARTICIPANTS: 135 people aged 80 years or over at diagnosis. METHODS: Descriptive Epidemiology of Amyotrophic Lateral Sclerosis/Motor Neurone Disease in the over 80s. Survival described using Kaplan-Meier curves. RESULTS: 135 of 1226 cases (11%) were aged 80 years or more. Sixty-seven (50%) had bulbar onset, and 58 (43%) were men. The standardised incidence was 10.2/100000 (95% CI 7.4-13.1) in men and 6.1/100000 (95% CI = 4.3-7.6) in women. Median survival from first symptoms was 1.7 years (IQR 1.0-2.8), less than younger patients (P = 0.0003; log Rank test). We found evidence of differences in the process of care, as older people were less likely to be prescribed Riluzole (OR 0.12, 95% CI = 0.02-0.89) or be assessed by a neurologist (OR 0.76, 95% CI = 0.67-0.86). CONCLUSION: This is the first comprehensive report of the epidemiology of Amyotrophic Lateral Sclerosis/Motor Neurone Disease in older people. Clinical presentation and survival differ from the population as a whole. There is evidence of a different process of care. While this may be to the detriment of their survival, this finding would need to be confirmed by further prospective studies.