Oana M. Dumitrascu

Still cooling after all these years: Meta-analysis of pre-clinical trials of therapeutic hypothermia for acute ischemic stroke:

Therapeutic hypothermia is the most potent neuroprotectant for experimental cerebral ischemia, illustrated in a 2007 meta-analysis published in this journal. To address recent therapeutic nihilism, we systematically reviewed recent experimental literature. Quality scoring showed considerable improvement in study design. Using several outcome measures in a variety of models and species, therapeutic hypothermia was protective compared with normothermia, with powerful and statistically significant normalized treatment effect sizes, in 60 papers comprising 216 comparisons. In the past 5 years, preclinical studies of ischemic stroke re-emphasize that therapeutic hypothermia is potently effective, justifying further development in larger human clinical trials.

Is Intravenous Thrombolysis Safe and Effective in Central Retinal Artery Occlusion? A Critically Appraised Topic

Background: Central retinal artery occlusion (CRAO) is a neurological and ophthalmologic emergency associated with poor visual recovery. There is a dilemma regarding the appropriate treatment, as formal guidelines are lacking. Despite being considered an ocular equivalent of cerebral infarction, the time window of intravenous (IV) thrombolysis administration for maximum efficacy and safety in CRAO remains uncertain. Objective: To critically assess the current evidence regarding the safety and effectiveness of IV thrombolysis in the treatment of patients with CRAO. Methods: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, and content experts in the fields of vascular neurology and ophthalmology. Results: A recent patient-level meta-analysis was selected for critical appraisal. The study compared the visual recovery rates after IV thrombolysis in CRAO against the natural history of this illness and conservative therapies (ocular massage, anterior chamber paracentesis, and/or hemodilution). Time to thrombolytic therapy administration had a significant impact on visual recovery in CRAO (P<0.001). IV thrombolysis within the first 4.5 hours after symptom onset resulted in recovery of vision in 50.0% of the patients [95% confidence interval (CI), 32.4%-67.6%]. The rate of visual recovery was nearly 3 times higher than in the natural history cohort [odds ratio, 4.7 (95% CI, 2.3-9.6); P<0.001], with a 32.3% absolute risk reduction and a number needed to treat of 4.0 (95% CI, 2.6-6.6). There was no significant difference in the recovery rate after thrombolysis compared with the natural history cohort for those patients treated after 4.5 hours. No major hemorrhages occurred after alteplase administration in this meta-analysis. Conclusions: IV thrombolysis in CRAO seems to be safe and effective within the first 4.5 hours of symptom onset. A clinical decision based on this meta-analysis alone cannot be made due to several limitations. A randomized controlled clinical trial of early IV alteplase administration in CRAO is necessary to provide evidence-based therapeutic guidance.

Acute Basilar Artery Occlusion: Does Recanalization Improve Clinical Outcome? A Critically Appraised Topic.

Background: Acute basilar artery occlusion (BAO) is a devastating, life-threatening condition that accounts for approximately 1% of all strokes. Currently, there is no consensus on the best treatment strategy for patients with BAO. Whereas endovascular reperfusion therapy is proven to improve outcomes in anterior circulation stroke, its benefit in acute BAO has not been confirmed in randomized controlled trials. Objective: To critically assess the current evidence regarding recanalization in acute BAO, and to discuss the outcomes of different treatment strategies in the management of acute BAO. Materials and Methods: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, and content experts in the field of vascular and hospital neurology. Results: A recent meta-analysis was selected for critical appraisal to assess the recanalization hypothesis in acute BAO. The authors performed a systematic literature search through August 2013 and pooled in the analysis of 45 studies and 2056 patients. The overall recanalization rate was 75% in this meta-analysis. The authors concluded that recanalization was associated with a 1.5-fold reduction in the risk of death or dependency, and a 2-fold reduction in the risk of mortality. Subgroup analysis comparing different modes of intervention revealed data that favor endovascular intervention over intravenous thrombolysis (IVT). However, the authors were not able to obtain a statistically valid direct comparison of the 2 therapies as their meta-analysis included observational studies. Subgroup analysis on the treatment window revealed that onset-to-treatment time of <12 hours was associated with a higher recanalization rate (81%) and a lower intracranial hemorrhage rate (10%) compared with onset-to-treatment time >12 hours. Conclusions: IVT is the standard of care for BAO patients presenting within 4.5 hours of symptom onset, whereas recanalization is associated with better outcomes regardless of how recanalization is achieved. Randomized controlled trials comparing IVT plus endovascular treatment versus IVT in the treatment of acute BAO are needed to provide evidence-based management guidance.

Prediction of Delayed Cerebral Ischemia with Cerebral Angiography: A Meta-Analysis

ObjectCerebral catheter angiography is the gold standard for diagnosing cerebral artery vasospasm (vasospasm) in aneurysmal subarachnoid hemorrhage (SAH). We have previously published a meta-analysis of prediction of delayed cerebral ischemia (DCI) from transcranial Doppler (TCD) evidence of vasospasm. Analogous data relating to prediction of DCI have not been previously collated for cerebral angiography nor reconciled against TCD.MethodsWe searched PUBMED, the Cochrane database, and clinicaltrials.gov for studies that used cerebral angiography for diagnosis of vasospasm and evaluated DCI in patients with SAH. We performed a random-effects meta-analysis of prediction of DCI with cerebral angiography, reconciling its accuracy against that of TCD. We also report quality of evidence for the value of cerebral angiography and TCD in SAH based on pooled data from our meta-analyses.ResultsA total of 15 studies (n = 5463) were included in the meta-analysis. Sensitivity (SN), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) of cerebral angiography for prediction of DCI are 57, 68, 32, and 90%. These metrics for TCD, based on our previous meta-analysis, are 90, 71, 57, and 92%. We report that test accuracy estimates are “moderate” for TCD and “low” for angiography based on pooled data from our meta-analyses.ConclusionTCD evidence of vasospasm is a better predictor of DCI than angiographic vasospasm. Future comparative effectiveness studies can better define the value of these diagnostic tools in patients with SAH.

Amyloid-Beta-Related Angiitis with Distinctive Neuro-Ophthalmologic Features

ABSTRACT Amyloid beta-related angiitis (ABRA) is a subtype of cerebral amyloid angiopathy-related inflammation, with distinctive pathology and prognosis compared with cerebral amyloid angiopathy (CAA). On a spectrum of increasing severity, ABRA is considered to be in-between the less aggressive inflammatory-CAA and the more severe primary central nervous system (CNS) angiitis. Whereas retinal pathological changes were described in subjects with primary or secondary CNS angiitis, and non-inflammatory CAA, bilateral posterior pole superficial and peripapillary retinal hemorrhages have not been reported as initial signs in patients with pathology-confirmed ABRA, accompanying neurological spells and characteristic neuroimaging findings.

Retinal Microvascular Abnormalities as Surrogate Markers of Cerebrovascular Ischemic Disease: A Meta-Analysis

BACKGROUND To determine the predictive value of retinal microvascular abnormalities for cerebrovascular ischemic diseases (CVDs), we aimed to investigate the quantitative association between retinal microvascular changes and CVD subcategories: white matter hyperintensities (WMHIs), lacunar infarcts (LIs), and cerebral infarctions (CIs). METHODS Using Meta-analyses Of Observational Studies in Epidemiology guidelines, we searched 6 databases through September 2016 for studies evaluating the linkage between retinal microvascular abnormalities and WMHI, and LI and CI. Studies were included if they reported odds ratios (ORs) and 95% confidence intervals or raw patient level data (that were computed into ORs). Unadjusted and vascular risk-factor adjusted ORs were pooled into meta-analysis using DerSimonian Laird random effects model. Study quality and dissemination biases were assessed and integrated. RESULTS From 24,444 search-identified records, 28 prospective studies encompassing 56,379 patients were eligible for the meta-analysis. After vascular risk-factor adjustment, focal arteriolar narrowing was associated with WMHI (OR, 1.24 [1.01-1.79]), LI (OR, 1.77 [1.14-2.74]), and CI (OR, 1.75 [1.14-2.69]). Venular dilation was associated with LI (OR, 1.46 [1.10-1.93]), and retinal hemorrhages with WMHI (OR, 2.23 [1.34-3.70]). Any retinopathy exhibited significant association with CI (OR, 1.96 [1.65-2.50]). Heterogeneity was significant (I2>50%) for all syntheses except retinal hemorrhages and WMHI, and retinopathy and CI (I2=0 ⋅ 0%). Associations remained significant after adjustments for quality and publication bias. CONCLUSIONS We found the most significant association between retinal hemorrhages and WMHI. Focal arteriolar narrowing and retinopathy predicted CVD subtypes after risk-factor adjustment, suggesting that features different than traditional vascular risk factors, are involved in CVD pathophysiology.

Retinal Vascular Imaging in Vascular Cognitive Impairment: Current and Future Perspectives

Vascular cognitive disorders are heterogeneous and increasingly recognized entities with intricate correlation to neurodegenerative conditions. Retinal vascular analysis is a noninvasive approach to study cerebrovascular pathology, with promise to assist particularly during early disease phases. In this article, we have systematically summarized the current understanding, potential applications, and inevitable limitations of retinal vascular imaging in patients with vascular cognitive impairment. In addition, future directions in the field with support from automated technology using deep learning methods and their existing challenges are emphasized.

Pitfalls and Rewards for Implementing Ocular Motor Testing in Acute Vestibular Syndrome: A Pilot Project

Objectives: Isolated acute vestibular syndrome (iAVS) presentations to the emergency department (ED) pose management challenges, given the concerns for posterior circulation strokes. False-negative brain imaging may erroneously reassure clinicians, whereas HINTS-plus examination outperforms imaging to screen for strokes in iAVS. We studied the feasibility of implementing HINTS-plus testing in the ED, aiming to reduce neuroimaging in patients with iAVS. Methods: We launched an institutional Quality Improvement initiative, using DMAIC methodology. The outcome measures [proportion of iAVS subjects who had HINTS-plus examinations and underwent neuroimaging by computed tomography/magnetic resonance imaging (CT/MRI)] were compared before and after the established intervention. The intervention consisted of formal training for neurologists and emergency physicians on how to perform, document, and interpret HINTS-plus and implementation of novel iAVS management algorithm. Neuroimaging was not recommended if HINTS-plus suggested peripheral vestibular etiology. If a central process was suspected, brain MRI/MR angiogram was performed. Head CT was reserved only for thrombolytic time-window cases. Results: In the first 2 months postimplementation, HINTS-plus testing performance by neurologists increased from 0% to 80% (P=0.007), and by ED providers from 0% to 9.09% (P=0.367). Head CT scans were reduced from 18.5% to 6.25%. Brain MRI use was reduced from 51.8% to 31.2%. About 60% of the iAVS subjects were discharged from the ED; none were readmitted or had another ED presentation in the ensuing 30 days. Conclusions: Implementation of HINTS-plus evaluation in the ED is valuable and feasible for neurologists, but challenging for emergency physicians. Future studies should determine the “dose-response” curve of educational interventions.

Opsoclonus-myoclonus syndrome during rituximab treatment for autoimmune autonomic ganglionopathy

Adult-onset opsoclonus-myoclonus syndrome (OMS) is an autoimmune disorder with paraneoplastic, parainfectious, or idiopathic etiologies.1 Nonparaneoplastic cases are generally immunotherapy responsive.1 Although previously described accompanying encephalopathy in NMDA receptor (NMDA-R) encephalitis,2 OMS occurring as an isolated CNS finding in an NMDA-R antibody–positive patient appears to be unusual, particularly among patients with preexisting α3AChR antibody–associated dysautonomia. We describe a patient in whom an autoimmune CNS disorder isolated to OMS arose in the context of rituximab treatment administered for refractory autoimmune dysautonomia.

Gastrointestinal and Urologic Sphincter Dysfunction in Stiff Person Syndrome.

Objectives: Stiff person syndrome is a neurologic disorder characterized by axial rigidity leading to progressive disability, with broad clinical spectrum. Methods: We report 2 cases with unique clinical presentation. Results: Two young men suffered progressive urinary retention requiring bladder catheterization, anorectal spasms and constipation, complicated subsequently with lower extremity trigger-induced spasms, and gait instability. Associated symptoms revealed brainstem involvement (vertigo, diplopia, and cranial neuropathies) and dysautonomia (abnormal sweating and orthostatic hypotension). Anal manometry demonstrated incomplete relaxation of the anal sphincter. The first case was associated with diabetes mellitus type I, did not respond to classical therapies, but was responsive to rituximab. The second case responded to intravenous immunoglobulin infusions. Paraneoplastic profiles were negative, and anti-GAD65 antibody titers remained elevated despite successful therapeutic responses. Conclusions: We want to raise awareness that stiff person syndrome can present with esophageal, anorectal, and urethral sphincter disturbance. Rituximab is a good therapeutic option in intractable cases.