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.

Misdiagnosis of cerebellar hemorrhage - features of 'pseudo-gastroenteritis' clinical presentations to the ED and primary care.

BACKGROUND: Early-stage cerebellar hemorrhage can present with nausea or vomiting absent other neurological symptoms or signs, potentially leading to an incorrect diagnosis of gastroenteritis. We sought to determine the frequency of gastroenteritis-like presentations and delayed or missed diagnoses among patients with spontaneous cerebellar hemorrhage. METHODS: This is a retrospective, case-control analysis of atraumatic, primary cerebellar hemorrhages derived from a systematic search of surgical pathology and autopsy databases at two large urban, academic medical centers from 1984 to 2006. Hospital visit and clinical symptom data were abstracted from electronic and paper medical records for included patients. Delayed or missed diagnoses were defined as those at least one previous visit for relevant clinical symptoms in the 7 days prior to the correct diagnosis being confirmed. RESULTS: Among 254 records captured by our search filter, we identified 35 cases of pathologically proven primary cerebellar hemorrhage. Four patients (11%) were misdiagnosed initially - three with "gastroenteritis" and one with "hypertension". In this small sample, misdiagnosed patients presented more often with normal mental state (100% vs. 35%, p=0.07) and nausea/vomiting (100% vs. 58%, p=0.22). Although patients deteriorated clinically after the initial misdiagnosis, and potentially dangerous diagnostic tests and treatment strategies were instituted as a result of misdiagnosis, none of the misdiagnosed patients died or suffered major permanent harms due to diagnostic delay. CONCLUSIONS: Our study is limited by the small number of identified cases. Nevertheless, it appears that patients with cerebellar hemorrhages can present with relatively unimpressive clinical findings without obvious neurological manifestations. Such individuals are sometimes misdiagnosed with gastroenteritis or other benign disorders initially, possibly when neurologic examination, particularly gait testing, is omitted or abridged. A careful search for subtle cerebellar signs, including dysarthria, limb ataxia, nystagmus or tandem gait instability, absent in true gastroenteritis cases, could potentially reduce misdiagnosis.

Intracranial plaque enhancement in patients with cerebrovascular events on high-spatial-resolution MR images.

PURPOSE: To characterize intracranial plaque inflammation in vivo by using three-dimensional (3D) high-spatial-resolution contrast material-enhanced black-blood (BB) magnetic resonance (MR) imaging and to investigate the relationship between intracranial plaque inflammation and cerebrovascular ischemic events. MATERIALS AND METHODS: The study was approved by the institutional review board and was HIPAA compliant. Twenty-seven patients (19 men; mean age, 56.8 years ± 12.4 [standard deviation]) with cerebrovascular ischemic events (acute stroke, n = 20; subacute stroke, n = 2; chronic stroke, n = 3; transient ischemic attack, n = 2) underwent 3D time-of-flight MR angiography and contrast-enhanced BB 3-T MR imaging for intracranial atherosclerotic disease. Each identified plaque was classified as either culprit (the only or most stenotic lesion upstream from a stroke), probably culprit (not the most stenotic lesion upstream from a stroke), or nonculprit (not within the vascular territory of a stroke). Plaque contrast enhancement was categorized on BB MR images (grade 0, enhancement less than or equal to that of normal arterial walls seen elsewhere; grade 1, enhancement greater than grade 0 but less than that of the pituitary infundibulum; grade 2, enhancement greater than or equal to that of the pituitary infundibulum), and degree of contrast enhancement was calculated. Associations of the likelihood of being a culprit lesion with both plaque contrast enhancement and plaque thickness were estimated with ordinal logistic regression. RESULTS: Seventy-eight plaques were identified in 20 patients with acute stroke (21 [27%] culprit, 12 [15%] probably culprit, and 45 [58%] nonculprit plaques). In these patients, grade 2 contrast enhancement was associated with culprit plaques (odds ratio 34.6; 95% confidence interval: 4.5, 266.5 compared with grade 0) when adjusted for plaque thickness. Grade 0 was observed in only nonculprit plaques. Culprit plaques had a higher degree of contrast enhancement than did nonculprit plaques (25.9% ± 13.4 vs 13.6% ± 12.3, P = .003). CONCLUSION: Contrast enhancement of intracranial atherosclerotic plaque is associated with its likelihood to have caused a recent ischemic event and may serve as a marker of its stability, thereby providing important insight into stroke risk.

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.

Split-belt treadmill adaptation transfers to overground walking in persons poststroke.

BACKGROUND AND OBJECTIVE: Following stroke, subjects retain the ability to adapt interlimb symmetry on the split-belt treadmill. Critical to advancing our understanding of locomotor adaptation and its usefulness in rehabilitation is discerning whether adaptive effects observed on a treadmill transfer to walking over ground. We examined whether aftereffects following split-belt treadmill adaptation transfer to overground walking in healthy persons and those poststroke. METHODS: Eleven poststroke and 11 age-matched and gender-matched healthy subjects walked over ground before and after walking on a split-belt treadmill. Adaptation and aftereffects in step length and double support time were calculated. RESULTS: Both groups demonstrated partial transfer of the aftereffects observed on the treadmill (P<.001) to overground walking (P<.05), but the transfer was more robust in the subjects poststroke (P<.05). The subjects with baseline asymmetry after stroke improved in asymmetry of step length and double limb support (P=.06). CONCLUSIONS: The partial transfer of aftereffects to overground walking suggests that some shared neural circuits that control locomotion for different environmental contexts are adapted during split-belt treadmill walking. The larger adaptation transfer from the treadmill to overground walking in the stroke survivors may be due to difficulty adjusting their walking pattern to changing environmental demands. Such difficulties with context switching have been considered detrimental to function poststroke. However, we propose that the persistence of improved symmetry when changing context to overground walking could be used to advantage in poststroke rehabilitation.

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.

Local intraarterial fibrinolysis administered in aliquots for the treatment of central retinal artery occlusion: the Johns Hopkins Hospital experience.

BACKGROUND AND PURPOSE: Central retinal artery occlusion results in acute visual loss with poor spontaneous recovery. Current standard therapies do not alter the natural history of disease. Several open-label clinical studies using continuous infusion of thrombolytic agents have suggested that local intraarterial fibrinolysis (LIF) is efficacious in the treatment of central retinal artery occlusion. The aim is to compare the visual outcome in patients with acute central retinal artery occlusion of presumed thromboembolic etiology treated with LIF administered in aliquots with that of patients treated with standard therapy. METHODS: We conducted a single-center, nonrandomized interventional study of consecutive patients with acute central retinal artery occlusion from July 1999 to July 2006. RESULTS: Twenty-one patients received LIF and 21 received standard therapy. Seventy-six percent of subjects in the LIF group had a visual acuity improvement of one line or more compared with 33% in the standard therapy group (P=0.012, Fisher exact). Multivariate logistic regression controlling for gender, history of prior stroke/transient ischemic attack, and history of hypercholesterolemia showed that patients who received tissue plasminogen activator were 36 times more likely to have improvement in visual acuity (P=0.0001) after adjusting for these covariates. Post hoc analysis showed that patients who received tissue plasminogen activator were 13 times more likely to have improvement in visual acuity of 3 lines or more (P=0.03) and 4.9 times more likely to have a final visual acuity of 20/200 or better (P=0.04). Two groin hematomas were documented in the LIF group. No ischemic strokes, retinal or intracerebral hemorrhages were documented. CONCLUSIONS: LIF administered in aliquots is associated with an improvement in visual acuity compared with standard therapy and has few side effects.

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.

Locomotor adaptation on a split-belt treadmill can improve walking symmetry post-stroke.

Human locomotion must be flexible in order to meet varied environmental demands. Alterations to the gait pattern occur on different time scales, ranging from fast, reactive adjustments to slower, more persistent adaptations. A recent study in humans demonstrated that the cerebellum plays a key role in slower walking adaptations in interlimb coordination during split-belt treadmill walking, but not fast reactive changes. It is not known whether cerebral structures are also important in these processes, though some studies of cats have suggested that they are not. We used a split-belt treadmill walking task to test whether cerebral damage from stroke impairs either type of flexibility. Thirteen individuals who had sustained a single stroke more than 6 months prior to the study (four females) and 13 age- and gender-matched healthy control subjects were recruited to participate in the study. Results showed that stroke involving cerebral structures did not impair either reactive or adaptive abilities and did not disrupt storage of new interlimb relationships (i.e. after-effects). This suggests that cerebellar interactions with brainstem, rather than cerebral structures, comprise the critical circuit for this type of interlimb control. Furthermore, the after-effects from a 15-min adaptation session could temporarily induce symmetry in subjects who demonstrated baseline asymmetry of spatiotemporal gait parameters. In order to re-establish symmetric walking, the choice of which leg is on the fast belt during split-belt walking must be based on the subject's initial asymmetry. These findings demonstrate that cerebral stroke survivors are indeed able to adapt interlimb coordination. This raises the possibility that asymmetric walking patterns post-stroke could be remediated utilizing the split-belt treadmill as a long-term rehabilitation strategy.

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.