Stroke is a leading cause of permanent disability. Therefore, primary prevention of first stroke and secondary prevention of recurrent stroke are a high priority. Primary prevention of ischemic ...stroke includes lifestyle modification and diet, treatment of risk factors including hypertension, diabetes mellitus and lipid disorders, antiplatelet therapy for high vascular risk patients, and anticoagulation in atrial fibrillation. Secondary prevention of ischemic stroke includes additional carotid surgery or stenting in selected symptomatic patients, closure of patent foramen ovale after cryptogenic stroke, treatment of insulin resistance, and best medical treatment of intracranial stenosis. The most important preventive strategies in the primary and secondary prevention of cerebral hemorrhage include the treatment of hypertension, reduction in alcohol intake, and occlusion of the left atrial appendage in patients with atrial fibrillation and permanent contraindications for oral anticoagulation.
Stroke is a leading cause of permanent disability. Therefore, primary prevention of first stroke and secondary prevention of recurrent stroke are a high priority. Primary prevention of ischemic ...stroke includes lifestyle modification and diet, treatment of risk factors including hypertension, diabetes mellitus and lipid disorders, antiplatelet therapy for high vascular risk patients, and anticoagulation in atrial fibrillation. Secondary prevention of ischemic stroke includes additional carotid surgery or stenting in selected symptomatic patients, closure of patent foramen ovale after cryptogenic stroke, treatment of insulin resistance, and best medical treatment of intracranial stenosis. The most important preventive strategies in the primary and secondary prevention of cerebral hemorrhage include the treatment of hypertension, reduction in alcohol intake, and occlusion of the left atrial appendage in patients with atrial fibrillation and permanent contraindications for oral anticoagulation.
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•Up to 90% of all strokes are preventable, and attributable to 10 modifiable risk factors.•Hypertension is ubiquitously the major modifiable risk factor for stroke, accounting for one-third of stroke in developed countries and two-thirds in developing countries.•Optimal stroke prevention requires a harmonious, integrated approach to educating about stroke risk and healthy lifestyle behaviors, simple screening and management of individuals for a history and presence of modifiable and treatable causal risk factors, and improving social and environmental factors.
Current guidelines recommend at least 24 hours of electrocardiographic (ECG) monitoring after an ischemic stroke to rule out atrial fibrillation. However, the most effective duration and type of ...monitoring have not been established, and the cause of ischemic stroke remains uncertain despite a complete diagnostic evaluation in 20 to 40% of cases (cryptogenic stroke). Detection of atrial fibrillation after cryptogenic stroke has therapeutic implications.
We conducted a randomized, controlled study of 441 patients to assess whether long-term monitoring with an insertable cardiac monitor (ICM) is more effective than conventional follow-up (control) for detecting atrial fibrillation in patients with cryptogenic stroke. Patients 40 years of age or older with no evidence of atrial fibrillation during at least 24 hours of ECG monitoring underwent randomization within 90 days after the index event. The primary end point was the time to first detection of atrial fibrillation (lasting >30 seconds) within 6 months. Among the secondary end points was the time to first detection of atrial fibrillation within 12 months. Data were analyzed according to the intention-to-treat principle.
By 6 months, atrial fibrillation had been detected in 8.9% of patients in the ICM group (19 patients) versus 1.4% of patients in the control group (3 patients) (hazard ratio, 6.4; 95% confidence interval CI, 1.9 to 21.7; P<0.001). By 12 months, atrial fibrillation had been detected in 12.4% of patients in the ICM group (29 patients) versus 2.0% of patients in the control group (4 patients) (hazard ratio, 7.3; 95% CI, 2.6 to 20.8; P<0.001).
ECG monitoring with an ICM was superior to conventional follow-up for detecting atrial fibrillation after cryptogenic stroke. (Funded by Medtronic; CRYSTAL AF ClinicalTrials.gov number, NCT00924638.).
Summary Background Aspirin is recommended for secondary prevention after transient ischaemic attack (TIA) or ischaemic stroke on the basis of trials showing a 13% reduction in long-term risk of ...recurrent stroke. However, the risk of major stroke is very high for only the first few days after TIA and minor ischaemic stroke, and observational studies show substantially greater benefits of early medical treatment in the acute phase than do longer-term trials. We hypothesised that the short-term benefits of early aspirin have been underestimated. Methods Pooling the individual patient data from all randomised trials of aspirin versus control in secondary prevention after TIA or ischaemic stroke, we studied the effects of aspirin on the risk and severity of recurrent stroke, stratified by the following time periods: less than 6 weeks, 6–12 weeks, and more than 12 weeks after randomisation. We compared the severity of early recurrent strokes between treatment groups with shift analysis of modified Rankin Scale (mRS) score. To understand possible mechanisms of action, we also studied the time course of the interaction between effects of aspirin and dipyridamole in secondary prevention of stroke. In a further analysis we pooled data from trials of aspirin versus control in which patients were randomised less than 48 h after major acute stroke, stratified by severity of baseline neurological deficit, to establish the very early time course of the effect of aspirin on risk of recurrent ischaemic stroke and how this differs by severity at baseline. Findings We pooled data for 15 778 participants from 12 trials of aspirin versus control in secondary prevention. Aspirin reduced the 6 week risk of recurrent ischaemic stroke by about 60% (84 of 8452 participants in the aspirin group had an ischaemic stroke vs 175 of 7326; hazard ratio HR 0·42, 95% CI 0·32–0·55, p<0·0001) and disabling or fatal ischaemic stroke by about 70% (36 of 8452 vs 110 of 7326; 0·29, 0·20–0·42, p<0·0001), with greatest benefit noted in patients presenting with TIA or minor stroke (at 0–2 weeks, two of 6691 participants in the aspirin group with TIA or minor stroke had a disabling or fatal ischaemic stroke vs 23 of 5726 in the control group, HR 0·07, 95% CI 0·02–0·31, p=0·0004; at 0–6 weeks, 14 vs 60 participants, 0·19, 0·11–0·34, p<0·0001). The effect of aspirin on early recurrent ischaemic stroke was due partly to a substantial reduction in severity (mRS shift analysis odds ratio OR 0·42, 0·26–0·70, p=0·0007). These effects were independent of dose, patient characteristics, or aetiology of TIA or stroke. Some further reduction in risk of ischaemic stroke accrued for aspirin only versus control from 6–12 weeks, but there was no benefit after 12 weeks (stroke risk OR 0·97, 0·84–1·12, p=0·67; severity mRS shift OR 1·00, 0·77–1·29, p=0·97). By contrast, dipyridamole plus aspirin versus aspirin alone had no effect on risk or severity of recurrent ischaemic stroke within 12 weeks (OR 0·90, 95% CI 0·65–1·25, p=0·53; mRS shift OR 0·90, 0·37–1·72, p=0·99), but dipyridamole did reduce risk thereafter (0·76, 0·63–0·92, p=0·005), particularly of disabling or fatal ischaemic stroke (0·64, 0·49–0·84, p=0·0010). We pooled data for 40 531 participants from three trials of aspirin versus control in major acute stroke. The reduction in risk of recurrent ischaemic stroke at 14 days was most evident in patients with less severe baseline deficits, and was substantial by the second day after starting treatment (2–3 day HR 0·37, 95% CI 0·25–0·57, p<0·0001). Interpretation Our findings confirm that medical treatment substantially reduces the risk of early recurrent stroke after TIA and minor stroke and identify aspirin as the key intervention. The considerable early benefit from aspirin warrants public education about self-administration after possible TIA. The previously unrecognised effect of aspirin on severity of early recurrent stroke, the diminishing benefit with longer-term use, and the contrasting time course of effects of dipyridamole have implications for understanding mechanisms of action. Funding Wellcome Trust, the National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford.
Objective
We aimed to estimate the incidence of cerebral sinus and venous thrombosis (CVT) within 1 month from first dose administration and the frequency of vaccine‐induced immune thrombotic ...thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA‐1273, in Germany.
Methods
A web‐based questionnaire was e‐mailed to all departments of neurology. We requested a report of cases of CVT occurring within 1 month of a COVID‐19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of 9 German states.
Results
A total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were younger than 60 years. Fifty‐three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%) vaccination, and none after mRNA‐1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within 1 month from first dose administration was 0.55 (95% confidence interval CI = 0.38–0.78) per 100,000 person‐months (which corresponds to a risk of CVT within the first 31 days of 0.55 per 100,000 individuals) for all vaccines and 1.52 (95% CI = 1.00–2.21) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (95% CI = 3.46–34.98) for ChAdOx1 compared to mRNA‐based vaccines and 3.14 (95% CI = 1.22–10.65) for females compared to non‐females. In 26 of 45 patients with CVT (57.8%), VITT was graded highly probable.
Interpretation
Given an incidence of 0.02 to 0.15 per 100,000 person‐months for CVT in the general population, these findings point toward a higher risk for CVT after ChAdOx1 vaccination, especially for women. ANN NEUROL 2021;90:627–639
Objective
To evaluate the efficacy, tolerability, and safety of eptinezumab 100 and 300 mg compared with placebo in patients with the dual diagnosis of chronic migraine (CM) and medication‐overuse ...headache (MOH).
Background
Eptinezumab, a humanized monoclonal antibody targeting calcitonin gene‐related peptide, may be effective for treating patients with a dual diagnosis of CM and MOH.
Methods
PROMISE‐2 (NCT02974153) was a double‐blind, randomized, placebo‐controlled, phase 3 study that comprised a screening visit, a 28‐day pretreatment period, and a 32‐week study duration. Patients in this exploratory analysis of a prespecified subgroup had confirmed diagnoses of both CM and MOH at screening. Patients were randomly assigned to receive intravenous eptinezumab 100, 300 mg, or placebo every 12 weeks. Efficacy outcomes included mean changes from baseline in monthly migraine days (MMDs) during weeks 1–12, migraine responder rates at week 12, and percentages of patients below International Classification of Headache Disorders thresholds for CM and MOH over weeks 1–24.
Results
There were 431 patients who were diagnosed with CM and MOH as specified in the protocol and received eptinezumab 100 mg (n = 139), 300 mg (n = 147), or placebo (n = 145). During the baseline period, these patients experienced an average of 16.7 migraine days across treatment arms. Over weeks 1–12, eptinezumab‐treated patients experienced greater reductions from baseline in MMDs than placebo patients (100 mg, change from baseline = −8.4, difference from placebo 95% confidence interval (CI) = −3.0 −4.56, −1.52, p < 0.0001 vs. placebo; 300 mg, change from baseline = −8.6, difference from placebo 95% CI = −3.2 −4.66, −1.78, p < 0.0001 vs. placebo; placebo, −5.4). Compared with placebo, more eptinezumab‐treated patients were ≥50% migraine responders (100 mg, 84/139 60.4%; 300 mg, 91/147 61.9%; placebo, 50/145 34.5%) or ≥75% responders (100 mg, 38/139 27.3%; 300 mg, 44/147 29.9%; placebo, 21/145 14.5%) over weeks 1–12. Therapeutic benefits with eptinezumab were observed from day 1 after dosing, and improvements were sustained with an additional dose. For the full 24‐week treatment period, 71/139 (51.1%), 80/147 (54.4%), and 47/145 (32.4%) of 100, 300 mg, and placebo‐treated patients, respectively, were below CM thresholds, and of the patients who provided sufficient acute medication data, 47/93 (50.5%), 53/107 (49.5%), and 26/96 (27.1%), respectively, were below medication‐overuse thresholds.
Conclusions
In patients diagnosed with both CM and MOH, eptinezumab treatment resulted in greater reductions in MMDs, higher responder rates, and fewer patients meeting CM and MOH criteria, thus demonstrating the efficacy and clinical utility of eptinezumab in this patient population.
Summary The management of patients with migraine is often unsatisfactory because available acute and preventive therapies are either ineffective or poorly tolerated. The acute treatment of migraine ...attacks has been limited to the use of analgesics, combinations of analgesics with caffeine, ergotamines, and the triptans. Successful new approaches for the treatment of acute migraine target calcitonin gene-related peptide (CGRP) and serotonin (5-hydroxytryptamine, 5-HT1F ) receptors. Other approaches targeting the transient receptor potential vanilloid (TRPV1) receptor, glutamate, GABAA receptors, or a combination of 5-HT1B/1D receptors and neuronal nitric oxide synthesis have been investigated but have not been successful in clinical trials thus far. In migraine prevention, the most promising new approaches are humanised antibodies against CGRP or the CGRP receptor. Non-invasive and invasive neuromodulation approaches also show promise as both acute and preventive therapies, although further studies are needed to define appropriate candidates for these therapies and optimum protocols for their use.
Regular or frequent use of analgesics and acute antimigraine drugs can increase the frequency of headache, and induce the transition from episodic to chronic headache or medication overuse headache. ...The 1-year prevalence of this condition in the general population is between 1% and 2%. Medication overuse headache is more common in women and in people with comorbid depression, anxiety, and other chronic pain conditions. Treatment of medication overuse headache has three components. First, patients need education and counselling to reduce the intake of medication for acute headache attacks. Second, some patients benefit from drug withdrawal (discontinuation of the overused medication). Finally, preventive drug therapy and non-medical prevention might be necessary in patients at onset of treatment or in patients who do not respond to the first two steps. The optimal therapeutic approach requires validation in controlled trials.
(Headache 2010;50:921‐936)
Objective.— To assess the efficacy, safety, and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine.
Background.— Chronic ...migraine is a prevalent, disabling, and undertreated neurological disorder. Few preventive treatments have been investigated and none is specifically indicated for chronic migraine.
Methods.— The 2 multicenter, pivotal trials in the PREEMPT: Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy clinical program each included a 24‐week randomized, double‐blind phase followed by a 32‐week open‐label phase (ClinicalTrials.gov identifiers NCT00156910, NCT00168428). Qualified patients were randomized (1:1) to onabotulinumtoxinA (155‐195 U) or placebo injections every 12 weeks. Study visits occurred every 4 weeks. These studies were identical in design (eg, inclusion/exclusion criteria, randomization, visits, double‐blind phase, open‐label phase, safety assessments, treatment), with the only exception being the designation of the primary and secondary endpoints. Therefore, the predefined pooling of the results was justified and performed to provide a complete overview of between‐group differences in efficacy, safety, and tolerability that may not have been evident in individual studies. The primary endpoint for the pooled analysis was mean change from baseline in frequency of headache days at 24 weeks. Secondary endpoints were mean change from baseline to week 24 in frequency of migraine/probable migraine days, frequency of moderate/severe headache days, total cumulative hours of headache on headache days, frequency of headache episodes, frequency of migraine/probable migraine episodes, frequency of acute headache pain medication intakes, and the proportion of patients with severe (≥60) Headache Impact Test‐6 score at week 24. Results of the pooled analyses of the 2 PREEMPT double‐blind phases are presented.
Results.— A total of 1384 adults were randomized to onabotulinumtoxinA (n = 688) or placebo (n = 696). Pooled analyses demonstrated a large mean decrease from baseline in frequency of headache days, with statistically significant between‐group differences favoring onabotulinumtoxinA over placebo at week 24 (−8.4 vs −6.6; P < .001) and at all other time points. Significant differences favoring onabotulinumtoxinA were also observed for all secondary efficacy variables at all time points, with the exception of frequency of acute headache pain medication intakes. Adverse events occurred in 62.4% of onabotulinumtoxinA patients and 51.7% of placebo patients. Most patients reported adverse events that were mild to moderate in severity and few discontinued (onabotulinumtoxinA, 3.8%; placebo, 1.2%) due to adverse events. No unexpected treatment‐related adverse events were identified.
Conclusions.— The pooled PREEMPT results demonstrate that onabotulinumtoxinA is an effective prophylactic treatment for chronic migraine. OnabotulinumtoxinA resulted in significant improvements compared with placebo in multiple headache symptom measures, and significantly reduced headache‐related disability and improved functioning, vitality, and overall health‐related quality of life. Repeat treatments with onabotulinumtoxinA were safe and well tolerated.
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