Long-term antithrombotic therapy and risk of intracranial haemorrhage from cerebral cavernous malformations: a population-based cohort study, systematic review, and meta-analysis.

BACKGROUND: Antithrombotic (anticoagulant or antiplatelet) therapy is withheld from some patients with cerebral cavernous malformations, because of uncertainty around the safety of these drugs in such patients. We aimed to establish whether antithrombotic therapy is associated with an increased risk of intracranial haemorrhage in adults with cerebral cavernous malformations. METHODS: In this population-based, cohort study, we used data from the Scottish Audit of Intracranial Vascular Malformations, which prospectively identified individuals aged 16 years and older living in Scotland who were first diagnosed with a cerebral cavernous malformation during 1999-2003 or 2006-10. We compared the association between use of antithrombotic therapy after first presentation and the occurrence of intracranial haemorrhage or persistent or progressive focal neurological deficit due to the cerebral cavernous malformations during up to 15 years of prospective follow-up with multivariable Cox proportional hazards regression assessed in all individuals identified in the database. We also did a systematic review and meta-analysis, in which we searched Ovid MEDLINE and Embase from database inception to Feb 1, 2019, to identify comparative studies to calculate the intracranial haemorrhage incidence rate ratio according to antithrombotic therapy use. We then generated a pooled estimate using the inverse variance method and a random effects model. FINDINGS: We assessed 300 of 306 individuals with a cerebral cavernous malformation who were eligible for study. 61 used antithrombotic therapy (ten [16%] of 61 used anticoagulation) for a mean duration of 7·4 years (SD 5·4) during follow-up. Antithrombotic therapy use was associated with a lower risk of subsequent intracranial haemorrhage or focal neurological deficit (one [2%] of 61 vs 29 [12%] of 239, adjusted hazard ratio [HR] 0·12, 95% CI 0·02-0·88; p=0·037). In a meta-analysis of six cohort studies including 1342 patients, antithrombotic therapy use was associated with a lower risk of intracranial haemorrhage (eight [3%] of 253 vs 152 [14%] of 1089; incidence rate ratio 0·25, 95% CI 0·13-0·51; p<0·0001; I2=0%). INTERPRETATION: Antithrombotic therapy use is associated with a lower risk of intracranial haemorrhage or focal neurological deficit from cerebral cavernous malformations than avoidance of antithrombotic therapy. These findings provide reassurance about safety for clinical practice and require further investigation in a randomised controlled trial. FUNDING: UK Medical Research Council, Chief Scientist Office of the Scottish Government, The Stroke Association, Cavernoma Alliance UK, and the Remmert Adriaan Laan Foundation.

Neglect is more common and severe at extreme hemoglobin levels in right hemispheric stroke.

BACKGROUND AND PURPOSE: Anemia is 1 potential mechanism by which the brain receives inadequate oxygenation. The purpose of this study was to determine in acute stroke patients whether lower hemoglobin values were associated with worse hemispatial neglect. METHODS: In 203 subjects, neglect testing batteries were administered within 24 hours of admission for acute right hemispheric stroke. We analyzed the error rate on each test as well as "any neglect" (z score >or=2 on any of 3 selected tests compared with normal controls), as predicted by hemoglobin level, with adjustment for infarct size, National Institutes of Health Stroke Scale score, age, and sex. RESULTS: The association between hemoglobin and neglect varied on the basis of hemoglobin level. At lower hemoglobin levels (<12 g/dL), each 1-point higher hemoglobin value was protective (adjusted odds ratio=0.56; 95% CI, 0.35 to 0.89) from having "any neglect." However, for a hemoglobin value >14 g/dL, each 1-point higher hemoglobin value was associated with higher odds of having neglect (adjusted odds ratio=1.67; 95% CI, 1.09 to 2.57). Similar relations were found for predicted error rate on the horizontal line bisection, line cancellation, and copy Ogden scene neglect tests. These relations seemed to be more pronounced in individuals who had a diffusion/perfusion mismatch. CONCLUSIONS: Lower and higher hemoglobin levels were each associated with increased odds of neglect and with worse severity of neglect, independent of stroke size and severity. Higher hemoglobin values may represent dehydration or hyperviscosity. The importance of the extremes of hemoglobin in identifying individuals at risk for worse functional consequences of stroke warrants further study.

Blood pressure management in acute stroke.

The optimal management of arterial blood pressure in the setting of an acute stroke has not been defined. Many articles have been published on this topic in the past few years, but definitive evidence from clinical trials continues to be lacking. This situation is complicated further because stroke is a heterogeneous disease. The best management of arterial blood pressure may differ, depending on the type of stroke (ischemic or hemorrhagic) and the subtype of ischemic or hemorrhagic stroke. This article reviews the relationship between arterial blood pressure and the pathophysiology specific to ischemic stroke, primary intracerebral hemorrhage, and aneurysmal subarachnoid hemorrhage, elaborating on the concept of ischemic penumbra and the role of cerebral autoregulation. The article also examines the impact of blood pressure and its management on outcome. Finally, an agenda for research in this field is outlined.

Transcranial Doppler ultrasound in children with Sturge-Weber syndrome.

Transcranial Doppler ultrasound is a noninvasive vascular assessment technique proved useful in the management of pediatric disorders predisposed to stroke and may have similar utility for Sturge-Weber syndrome. Eight children with Sturge-Weber syndrome had velocities measured in the major cerebral arteries via the Stroke Prevention Trial in Sickle Cell Anemia methodology. Velocities and pulsatility indexes were compared between the unaffected and affected sides. All subjects had reduced velocity on the affected side; the mean middle cerebral artery percentage difference was 20% (95% CI, 15%-25%). Pulsatility index was increased on the affected side; mean middle cerebral artery pulsatility index percentage difference, 34% (95% CI, 15%-53%). Six subjects also had reduced posterior cerebral artery velocity on the affected side. Side-to-side differences in middle cerebral artery and posterior cerebral artery velocities correlated with severity of MRI asymmetry (Spearman rho = 0.88, P = .02). Decreased arterial flow velocity and increased pulsatility index in the middle cerebral artery and posterior cerebral artery suggests a high resistance pattern that may reflect venous stasis and may contribute to chronic hypoperfusion of brain tissue. Further study of Transcranial Doppler in children with Sturge-Weber syndrome is indicated.

The management of blood pressure after stroke.

BACKGROUND: Control of hypertension is a well-established goal of primary prevention of stroke, but management of blood pressure in patients with a previous stroke or in the setting of acute stroke is complicated by the effect blood pressure changes may have on cerebral perfusion. REVIEW SUMMARY: For patients with previous transient ischemic attack or chronic stroke, blood pressure reduction appears to be a safe and important facet of the secondary prevention of recurrent stroke. Less information is available concerning blood pressure management in acute stroke. Current protocols require strict blood pressure control in patients who are treated with thrombolytic therapy, to reduce the risk of hemorrhagic complications. In patients presenting with acute intracerebral hemorrhage, blood pressure reduction does not appear to cause significant reduction of cerebral blood flow, but at this time there are no studies to determine if there is a clinical benefit of acute blood pressure reduction in these patients. Finally, blood pressure reduction is not routinely recommended in patients with acute ischemic stroke, as it may precipitate further cerebral ischemia. Preliminary studies suggest, in fact, that there may be a role in the future for blood pressure elevation in the treatment of patients with acute ischemic stroke. CONCLUSIONS: Current data support the use of blood pressure reduction in the secondary prevention of stroke in patients with cerebrovascular disease. In the setting of acute stroke, however, data are limited and blood pressure management must be tailored to the specific clinical situation.

Blood pressure augmentation in acute ischemic stroke.

Although control of hypertension is established as an important factor in the primary and secondary prevention of stroke, management of blood pressure in the setting of acute ischemic stroke remains controversial. Given limited data, the general consensus is that there is no proven benefit to lowering blood pressure in the first hours to days after acute ischemic stroke. Instead, there is concern that relative hypotension may lead to worsening of cerebral ischemia. For many years, the use of blood pressure augmentation ("induced hypertension") has been studied in animal models and in humans as a means of maintaining or improving perfusion to ischemic brain tissue. This approach is now widely used in neurocritical care units to treat delayed neurological deficits after subarachnoid hemorrhage, but its use in ischemic stroke patients remains anecdotal. This article reviews the cerebral physiology, animal models and human studies of induced hypertension as a treatment for acute ischemic stroke. Although there has not been a large, randomized clinical trial of this treatment, the available clinical data suggests that induced hypertension can result in at least short-term neurological improvement, with an acceptable degree of safety.

Predicting abnormal coagulation in ischemic stroke: reducing delay in rt-PA use.

Normal prothrombin time (PT) and partial thromboplastin time (PTT) are recommended for administration of recombinant tissue-plasminogen activator (rt-PA) in stroke, but waiting for results can delay use. We examined the charts of 365 stroke patients to assess predetermined risk factors associated with elevated PT/PTT. Elevated PT/PTT can be predicted in patients taking warfarin or heparin/heparinoid or on hemodialysis, according to emergency department triage, with 100% sensitivity and 94.7% specificity. These results could be applied to rt-PA candidates and reduce potential delays.

Patients with diffusion-perfusion mismatch on magnetic resonance imaging 48 hours or more after stroke symptom onset: clinical and imaging features.

BACKGROUND: Abnormalities in diffusion-weighted (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) are thought to reflect the presence of brain tissue at risk for ischemic stroke. Many patients with acute ischemic stroke have a mismatch pattern in which the PWI volume is larger than the DWI lesion. This mismatch typically resolves over 24-48 hours. Little is known about the presence of DWI-PWI mismatch in later stages of stroke. METHODS: This is a retrospective study of 122 patients admitted with a diagnosis of acute ischemic stroke who had DWI and PWI abnormalities on studies performed within 7 days of onset of symptoms. Patients were divided into two groups: those with MRI performed <48 hours and those with MRI performed >or=48 hours from onset of symptoms. RESULTS: Among 42 patients with MRI performed >or=48 hours after onset of stroke symptoms, 15 of 42 (36%) showed a mismatch pattern, compared to 45 of 80 (56%) in the <48 hours group (P < 0.05). Most of the patients in the >or=48 hours group with mismatch had large artery occlusive disease and many had neurological fluctuations. A subset of these patients were treated with induced hypertension and showed clinical improvement. CONCLUSIONS: Some patients have persistent DWI-PWI mismatch up to several days after stroke onset. Further studies are needed to determine if these patients should be candidates for reperfusion therapy.

Brain injury from cardiac bypass procedures.

Patients who undergo coronary artery bypass grafting (CABG) are at increased risk for brain injury. Surgical techniques have advanced so that the risk of neurological sequelae is decreased, but there remains significant morbidity and mortality related to the postoperative period as well as to the surgery itself. In addition, patients who undergo CABG have comorbidities or demographic factors that may increase their likelihood of developing neurological complications. Pathophysiological mechanisms of cerebral injury after CABG range from hemodynamic compromise to embolization, either intraoperatively or postoperatively. Biochemical markers such as S100 and neuron-specific enolase may play a role in the prediction of outcome after CABG, and because of this may help elucidate other potential risk factors. Specific neurological sequelae are discussed, such as stroke, with summaries of the apparent risk factors, as well as encephalopathy, seizure, and both short- and long-term cognitive deficits. Changes in surgical technique have led to some improvements, but there is no definitive information yet as to the role of some of these, such as the use of off-pump CABG. Other techniques such as the use of an arterial filter are discussed, as are their potential benefits in the prevention of neurological complications.

Blood pressure management during acute ischaemic stroke.

Control of hypertension is a well-established goal of primary stroke prevention. Management of blood pressure in patients during acute ischaemic stroke, however, is complicated by the need to maintain brain perfusion. Lowering blood pressure in the acute setting may avoid the deleterious effects of high blood pressure but may also lead to cerebral hypoperfusion and worsening of the ischaemic stroke. Little information is available from clinical trials concerning optimal blood pressure management in acute stroke. Current protocols of thrombolytic therapy require strict blood pressure control below certain prescribed limits; however, in most acute stroke patients not treated with thrombolysis, blood pressure reduction is not routinely recommended and guidelines for target blood pressures are difficult to justify. Preliminary studies, in fact, suggest that there may be a role for blood pressure elevation in the treatment of some patients with acute ischaemic stroke.

Safety of induced hypertension therapy in patients with acute ischemic stroke.

INTRODUCTION: The management of blood pressure in acute stroke is controversial. Small pilot studies have suggested that blood pressure augmentation improves short-term neurological function, but the rate of adverse events with induced hypertension (IH) therapy is unknown. METHODS AND RESULTS: We reviewed 100 consecutive patients who underwent perfusion magnetic resonance imaging for acute ischemic stroke. IH therapy was employed in 46 patients and standard therapy (ST) in 54. The two groups had similar baseline characteristics, but more patients in the IH group had significant large-artery stenoses. The IH group achieved significantly higher mean arterial pressure (MAP) than the ST group within 3 days of initiation of therapy with a variety of vasopressor agents. Only 35% of patients in the IH group actually achieved the target MAP augmentation of 10-20% above baseline, however. All patients survived to discharge. Four patients experienced major adverse events in each group. Two patients in the IH group experienced intra cerebral hemorrhage compared to none in the ST group. Two patients in the ST group experienced myocardial ischemia, compared to none in the IH group. The National Institutes of Health Stroke Scale during the hospitalization and place of discharge were similar in both groups. Patients in the IH group were more likely to be admitted to the intensive care unit and had a longer hospital stay by nearly 4 days compared to the ST group. CONCLUSION: These data demonstrate the relative safety of IH therapy in acute stroke patients. Given the greater use of resources, however, the role of IH in improving clinical outcomes requires a prospective, randomized trial.

Blood pressure management in acute stroke.

The optimal management of arterial blood pressure in the setting of acute stroke has not been firmly defined. The different types of stroke--ischemic, intracerebral hemorrhage, and subarachnoid hemorrhage--have different pathophysiologies and require different approaches in terms of blood pressure management in the acute setting. This article reviews the current literature and experience at the authors' institution.

Low-grade carotid stenosis: looking beyond the lumen with MRI.

BACKGROUND AND PURPOSE: The management of carotid atherosclerosis is well-established for symptomatic stenosis above 69%, but the optimal approach for managing lower degrees of narrowing remains uncertain. Because the risk of stroke increases with higher grades of stenosis, we are inclined to consider low-grade disease to be low risk. This approach, however, does not take into account other factors such as plaque size or composition. Plaque may progress to a substantial size before it demonstrates significant stenosis by angiography. We know that low-grade disease can result in cerebrovascular ischemic events, but predicting vulnerable lesions has not been possible by relying on stenosis alone. SUMMARY OF REVIEW: An understanding of the clinical behavior of plaque causing little to no narrowing is now possible with the advent of high-resolution black blood MRI, a modality that does not rely on luminal narrowing for detection. CONCLUSIONS: We present the current understanding of the clinical implications of low-grade carotid stenosis with an example of the MRI assessment of high-risk carotid plaque causing minimal narrowing that highlights the importance of looking beyond the lumen.

Quantitation of contrast TCD in patients with and without atrial septal aneurysm.

BACKGROUND AND PURPOSE: Patients with a combination of atrial septal aneurysm (ASA) and patent foramen ovale (PFO) have a substantially higher rate of recurrent ischemic events as compared to PFO alone. One possible explanation is a greater degree of right-to-left shunting with the combination. METHODS: Retrospective study using contrast transcranial Doppler ultrasonography (c-TCD) to study the degree of shunting in 46 patients with PFO with either transient ischemic attack or cryptogenic ischemic stroke. Eight patients with PFO+ASA identified on transesophageal echocardiogram were compared to 38 patients with PFO but without ASA. RESULTS: The number of embolic counts was no different with or without an ASA. Valsalva maneuver increased number of emboli, especially in patients with large PFOs. CONCLUSIONS: Patients with ASA in addition to PFO do not appear to have an increased risk of right-to-left shunting as measured by c-TCD as compared to PFO alone.

Etiology of perfusion-diffusion magnetic resonance imaging mismatch patterns.

BACKGROUND AND PURPOSE: Diffusion-and perfusion-weighted magnetic resonance imaging (DWI and PWI) are useful tools for the assessment of brain ischemia. Discrepancies between the extent of DWI and PWI abnormalities are thought to depend pre dominantly on time from symptom onset to magnetic resonance imaging (MRI) examination. However, underlying ischemic stroke etiology can also be important. A mismatch may indicate the presence of tissue at risk for infarction, whereas the relevance of other DWI/PWI patterns is uncertain. The authors therefore investigated the etiology of brain ischemia in patients with different DWI/PWI patterns. METHODS: Retrospective study of 130 patients with acute brain ischemia and detailed stroke workup, including MRI within a week after symptom onset (40 +/- 39 hours). Patients were divided into the following groups: mis-match (PWI > DWI), reverse mismatch (DWI > PWI), and match (<25% difference between PWI and DWI). RESULTS: Mismatch occurred in 49% of patients, whereas 22% had reverse mis-match and 29% matched lesions. Time from symptom onset to MRI examination was similar between the 3 groups. Largeartery atherosclerosis increased by almost 4-fold the odds of mismatch (odds ratio: 3.89, 95% confidence interval: 1.72-8.78; P < .001), whereas patients with reverse mismatch were likely to have cryptogenic stroke. Patients with matched lesions were similarly distributed among different stroke subtypes. CONCLUSIONS: Ischemic stroke etiology appears to influence the development of specific DWI/PWI patterns. Prospective studies are needed to confirm these observations.

Assessment of transient ischemic attack with diffusion- and perfusion-weighted imaging.

BACKGROUND: Diagnosing TIA can be difficult, since evidence of brain ischemia is habitually lacking on CT and conventional MR imaging. It has been suggested that patients with acute brain infarction on neuroimaging should be considered stroke cases instead of TIA, regardless of duration of symptoms, implying that optimal diagnostic methods need to be utilized. We therefore postulated that perfusion-weighted MR imaging (PW imaging) would be useful in the diagnosis of TIA. METHODS: Retrospective analysis of 22 patients with reversible neurologic symptoms lasting less than 24 hours, assessed with DW and PW imaging. RESULTS: MR imaging was abnormal in 15 patients (68%): 12 had abnormal DW imaging, four had both DW and PW imaging defects (all with a mismatch) and three had an isolated PW imaging abnormality. There were no differences in symptom duration, stroke etiology or cardiovascular risk factors between patients with abnormal MR imaging and those with unremarkable scan. Patients with mismatch were more likely to need conventional angiography or other cerebrovascular procedures. CONCLUSION: The combined use of DW imaging and PW imaging provided evidence of brain ischemia in most patients with clinical diagnosis of TIA. Prospective studies using follow-up MR imaging are required to determine the outcome of affected tissue, as well as the clinical implications of DW-PW imaging abnormalities.