Marie-Germaine Bousser

Effects of Blood Pressure Lowering on Cerebral White Matter Hyperintensities in Patients With Stroke The PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy

Background—The prevalence of white matter hyperintensities (WMHs) detected on cerebral MRI is associated with hypertension, but it is not known whether blood pressure lowering can arrest their progression. We report here the results of an MRI substudy of PROGRESS (Perindopril Protection Against Recurrent Stroke Study), a randomized trial of blood pressure lowering in subjects with cerebrovascular disease. Methods and Results—The substudy comprised 192 participants who had a cerebral MRI both at baseline and after a mean follow-up time of 36 months (SD=6.0 months). At the first MRI, WMHs were graded with a visual rating scale from A (no WMH) to D (severe WMH). Participants were assigned to a combination of perindopril plus indapamide (or their placebos; 58%) or to single therapy with perindopril (or placebo). At the time of the second MRI, the blood pressure reduction in the active arm compared with the placebo arm was 11.2 mm Hg for systolic blood pressure and 4.3 mm Hg for diastolic blood pressure. Twenty-four subjects (12.5%) developed new WMHs at follow-up. The risk of new WMH was reduced by 43% (95% CI −7% to 89%) in the active treatment group compared with the placebo group (P=0.17). The mean total volume of new WMHs was significantly reduced in the active treatment group (0.4 mm3 [SE=0.8]) compared with the placebo group (2.0 mm3 [SE=0.7]; P=0.012). This difference was greatest for patients with severe WMH at entry, 0.0 mm3 (SE=0) in the active treatment group versus 7.6 mm3 (SE=1.0) in the placebo group (P<0.0001). Conclusions—These results indicate that an active blood pressure–lowering regimen stopped or delayed the progression of WMHs in patients with cerebrovascular disease.

Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study

Objective To evaluate the association of overall and specific headaches with volume of white matter hyperintensities, brain infarcts, and cognition. Design Population based, cross sectional study. Setting Epidemiology of Vascular Ageing study, Nantes, France. Participants 780 participants (mean age 69, 58.5% women) with detailed headache assessment. Main outcome measures Brain scans were evaluated for volume of white matter hyperintensities (by fully automated imaging processing) and for classification of infarcts (by visual reading with a standardised assessment grid). Cognitive function was assessed by a battery of tests including the mini-mental state examination. Results 163 (20.9%) participants reported a history of severe headache and 116 had migraine, of whom 17 (14.7%) reported aura symptoms. An association was found between any history of severe headache and increasing volume of white matter hyperintensities. The adjusted odds ratio of being in the highest third for total volume of white matter hyperintensities was 2.0 (95% confidence interval 1.3 to 3.1, P for trend 0.002) for participants with any history of severe headache when compared with participants without severe headache being in the lowest third. The association pattern was similar for all headache types. Migraine with aura was the only headache type strongly associated with volume of deep white matter hyperintensities (highest third odds ratio 12.4, 1.6 to 99.4, P for trend 0.005) and with brain infarcts (3.4, 1.2 to 9.3). The location of infarcts was predominantly outside the cerebellum and brain stem. Evidence was lacking for cognitive impairment for any headache type with or without brain lesions. Conclusions In this population based study, any history of severe headache was associated with an increased volume of white matter hyperintensities. Migraine with aura was the only headache type associated with brain infarcts. Evidence that headache of any type by itself or in combination with brain lesions was associated with cognitive impairment was lacking.

Migraine and stroke: a complex association with clinical implications

Migraine and stroke are two common and heterogeneous neurovascular disorders with complex relations. Data show no firm association between stroke and migraine without aura--by far the most common type of migraine--but a doubling of the risk of ischaemic stroke in people who have migraine with aura. Migraine with aura is characterised by a low brain threshold for cortical spreading depression, the biological substrate of the aura, which can be triggered by many factors, including specific diseases that can by themselves increase the risk of ischaemic stroke. Whether the increased risk of ischaemic stroke applies to migraine with aura as a primary headache disorder or is partly due to migraine with aura secondary to other disorders remains to be elucidated.

Effects of perindopril-based lowering of blood pressure on intracerebral hemorrhage related to amyloid angiopathy: the PROGRESS trial

Background and Purpose— Patients with cerebral amyloid angiopathy (CAA) are at high risk for intracerebral hemorrhage (ICH), but no effective prevention strategies have been established. The objective is to determine whether lowering of blood pressure (BP) provides protection for this high-risk patient group. Methods— This study is a subsidiary analysis of the PROGRESS trial—a randomized, placebo-controlled trial that established the beneficial effects of BP lowering in patients with cerebrovascular disease; 6105 patients were randomly assigned to either active treatment (perindopril for all participants plus indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo. Outcomes were probable CAA-related ICH as defined by the Boston criteria, probable hypertension-related ICH, and unclassified ICH. Results— Over a mean follow-up of 3.9 years, 16 probable CAA-related ICH, 51 probable hypertension-related ICH, and 44 unclassified ICH occurred. Active treatment reduced the risk of CAA-related ICH by 77% (95% CI, 19%–93%), that of hypertension-related ICH by 46% (95% CI, 4%–69%), and that of unclassified ICH by 43% (95% CI, −5%–69%). There was no evidence of differences in the magnitude of the effects of treatment among different types of ICH (P homogeneity=0.4). Conclusions— BP-lowering treatment is likely to provide protection against all types of ICH.

Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection

Spontaneous intracranial artery dissection is an uncommon and probably underdiagnosed cause of stroke that is defined by the occurrence of a haematoma in the wall of an intracranial artery. Patients can present with headache, ischaemic stroke, subarachnoid haemorrhage, or symptoms associated with mass effect, mostly on the brainstem. Although intracranial artery dissection is less common than cervical artery dissection in adults of European ethnic origin, intracranial artery dissection is reportedly more common in children and in Asian populations. Risk factors and mechanisms are poorly understood, and diagnosis is challenging because characteristic imaging features can be difficult to detect in view of the small size of intracranial arteries. Therefore, multimodal follow-up imaging is often needed to confirm the diagnosis. Treatment of intracranial artery dissections is empirical in the absence of data from randomised controlled trials. Most patients with subarachnoid haemorrhage undergo surgical or endovascular treatment to prevent rebleeding, whereas patients with intracranial artery dissection and cerebral ischaemia are treated with antithrombotics. Prognosis seems worse in patients with subarachnoid haemorrhage than in those without.

APOE genotype, ethnicity, and the risk of cerebral hemorrhage

Objective: The apolipoprotein E (APOE) polymorphism is an established risk factor for intracerebral hemorrhage (ICH) that is related to cerebral amyloid angiopathy in the white population. Among Asian populations, although ICH represents up to one third of all strokes and has high rates of mortality and morbidity, the role of the APOE polymorphism has not been well studied. Methods: The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a randomized, double-blind, placebo-controlled trial of a blood pressure lowering regimen in subjects with prior cerebrovascular disease. APOE status was determined for 5,671 patients, including 2,148 Asians (38%). Results: During the 3.9 years of follow-up, ICH occurred in 99 patients. Overall, carrying an ε2 or ε4 allele of the APOE polymorphism was associated with an adjusted hazard ratio (HRa) of 1.85 (95% CI = 1.24 to 2.76). In Asian patients the risk of ICH for ε2 or ε4 carriers was 2.11 (95% CI = 1.28 to 3.47) and 1.48 (95% CI = 0.76 to 2.87) in Europeans. Carriers of the ε2 or ε4 allele had an increased risk of both incident and recurrent ICH, and both cortical and deep ICH, and most risk estimates were higher in Asians than in Europeans. For both ethnic groups and for subtypes of ICH active treatment more than halved the risk of ICH and the treatment effects were not different in carriers of the ε2 or ε4 allele and in those with the ε3ε3 genotype. Conclusions: There is a strong association between APOE genotype and the risk of intracerebral hemorrhage (ICH). In Asian patients the role of APOE polymorphisms in ICH is much broader than was previously supposed.

Reductions in the Risks of Recurrent Stroke in Patients With and Without Diabetes: The PROGRESS Trial

Background: Analyses of the risks of stroke were conducted for subjects with and without diabetes, participating in a randomized, double‐blind, placebo‐controlled trial of a perindopril‐based blood pressure lowering regimen in 6105 people with prior stroke or transient ischaemic attack (TIA), followed for a median of 3.9 years. Findings: Seven hundred and sixty‐one patients had diabetes at baseline. Diabetes increased the risk of recurrent stroke by 35% (95% CI 10–65%) principally through an effect on ischaemic stroke (1.53, 95% CI 1.23–1.90). Active treatment reduced blood pressure by 9.5/4.6 mmHg in patients with diabetes and by 8.9/3.9 mmHg in patients without diabetes. The proportional risk reductions achieved for stroke in patients with diabetes, 38% (95% CI 8–58%), and patients without diabetes, 28% (95% CI 16–39%), were not significantly different (p homogeneity = 0.5). The absolute reduction in the risk of recurrent stroke in the patients with diabetes was equivalent to one stroke avoided among every 16 (95% CI 9–111) patients treated for 5 years. Conclusions: Diabetes is an important risk factor for stroke in patients with established cerebrovascular disease. Treatment with the ACE inhibitor perindopril with discretionary use of the diuretic indapamide produced reductions in the risk of recurrent stroke in patients with diabetes that were at least as great as those achieved in patients without diabetes.

Longitudinal diffusion changes in cerebral hemispheres after MCA infarcts

Diffusion tensor imaging can be used in vivo to assess the longitudinal and regional microstructural changes occurring after middle cerebral artery (MCA) infarcts in humans. Nine patients were investigated 1 week (D7), 1 (M1), 3 (M3), and 6 months (M6) after the occurrence of an isolated MCA infarction. First, an overall analysis was performed using histograms of mean diffusivity (MD) and fractional anisotropy (FA) in each hemisphere. Thereafter, the regional pattern of diffusion changes was investigated voxel by voxel with statistical parametric mapping 99. In the hemisphere ipsilateral to the infarction, histogram analysis revealed a significant decrease in FA between D7 and M6 associated with a progressive increase in MD from D7 to M3. Remote from the MCA territory, the voxel by voxel analyses detected a significant increase in MD within the thalamus at M3 and M6 and a reduction in FA along the pyramidal tract at M6. In the contralateral hemisphere, between D7 and M6, a significant hemispheric atrophy was observed in association with a global reduction in anisotropy, in the absence of distinctive regional diffusion changes. These results suggest that micro- and macrostructural tissue modifications can be detected with diffusion tensor imaging in regions remote from the ischemic area in both hemispheres.

Cortical changes in cerebral small vessel diseases: a 3D MRI study of cortical morphology in CADASIL

Brain atrophy represents a key marker of disease progression in cerebrovascular disorders. The 3D changes of cortex morphology occurring during the course of small vessel diseases of the brain (SVDB) remain poorly understood. The objective of this study was to assess the changes affecting depth and surface area of cortical sulci and their clinical and radiological correlates in a cohort of patients with cerebral autosomal dominant arteriolopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic SVDB. Data were obtained from a series of 69 CADASIL patients. Validated methods were used to determine depth and surface area of four cortical sulci. The ratio of brain to intracranial cavity volumes (brain parenchymal fraction--BPF), volume of lacunar lesions (LL) and of white matter hyperintensities, number of cerebral microhaemorrhages, and mean apparent diffusion coefficient were also measured. Association between depth and surface area of the cortical sulci and BPF, clinical status and subcortical MRI lesions were tested. Depth and surface area of cortical sulci obtained in 54 patients were strongly correlated with both cognitive score and disability scales. Depth was related to the extent of subcortical lesions, surface area was related only to age. In additional analyses, the depth of the cingular sulcus was independently associated with the volume of LL (P = 0.001), and that of the superior frontal sulcus with the mean apparent diffusion coefficient (P = 0.003). In CADASIL, important morphological changes of cortical sulci occur in association with clinical worsening, extension of subcortical tissue damage and progression of global cerebral atrophy. These results suggest that the examination of cortical morphology may be of high clinical relevance in SVDB.

Prior Events Predict Cerebrovascular and Coronary Outcomes in the PROGRESS Trial

Background and Purpose— The relationship between baseline and recurrent vascular events may be important in the targeting of secondary prevention strategies. We examined the relationship between initial event and various types of further vascular outcomes and associated effects of blood pressure (BP)–lowering. Methods— Subsidiary analyses of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial that established the benefits of BP–lowering in 6105 patients (mean age 64 years, 30% female) with cerebrovascular disease, randomly assigned to either active treatment (perindopril for all, plus indapamide in those with neither an indication for, nor a contraindication to, a diuretic) or placebo(s). Results— Stroke subtypes and coronary events were associated with 1.5- to 6.6-fold greater risk of recurrence of the same event (hazard ratios, 1.51 to 6.64; P=0.1 for large artery infarction, P<0.0001 for other events). However, 46% to 92% of further vascular outcomes were not of the same type. Active treatment produced comparable reductions in the risk of vascular outcomes among patients with a broad range of vascular events at entry (relative risk reduction, 25%; P<0.0001 for ischemic stroke; 42%, P=0.0006 for hemorrhagic stroke; 17%, P=0.3 for coronary events; P homogeneity=0.4). Conclusions— Patients with previous vascular events are at high risk of recurrences of the same event. However, because they are also at risk of other vascular outcomes, a broad range of secondary prevention strategies is necessary for their treatment. BP–lowering is likely to be one of the most effective and generalizable strategies across a variety of major vascular events including stroke and myocardial infarction.