Angiographic Treatment of Asymptomatic Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage for the Prevention of Delayed Cerebral Ischemia.

OBJECTIVE: Angiographic treatment of asymptomatic cerebral vasospasm (CVS) in aneurysmal subarachnoid hemorrhage remains controversial. We sought to investigate its relationship with the development of delayed cerebral ischemia. METHODS: Consecutive patients admitted between July 2017 and June 2019, with a diagnosis of aneurysmal subarachnoid hemorrhage, were retrospectively analyzed. The rate of development of delayed cerebral ischemia was compared between a group of patients who underwent cerebral angiography for asymptomatic CVS and those who did not. The Mann-Whitney U test or χ2 test was used to compare the 2 groups. RESULTS: Thirty-seven of the 94 patients with aneurysmal subarachnoid hemorrhage were screened for CVS, of whom 16 (43%) had moderate-severe vasospasm. When patients who underwent therapeutic cerebral angiography were compared with those who did not and after adjusting for sex, age, and grade of subarachnoid hemorrhage, treatment was not found to be significantly associated with delayed cerebral ischemia (hazard ratio = 0.82, 95% confidence interval: 0.19-3.52, P = 0.79). We found that the median length of stay in the intensive care unit and hospital increased significantly with the severity of CVS (P < 0.001). CONCLUSIONS: Cerebral angiography has a low rate of detecting moderate-severe CVS in asymptomatic patients. Moreover, there was no statistically significant difference in the rate of delayed cerebral ischemia between asymptomatic patients treated versus those not treated for CVS. There was significant association between the severity of CVS and the intensive care unit and hospital length of stay. More studies are needed to evaluate the utility of treating asymptomatic CVS in high-grade aneurysmal subarachnoid hemorrhage.

The Potential Role of Neuromodulation in Subarachnoid Hemorrhage.

OBJECTIVES: Aneurysmal subarachnoid hemorrhage (SAH) continues to be a difficult cerebrovascular disease with limited pharmacologic treatment options. Cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) are leading causes of morbidity and mortality after SAH. Despite the advances in the understanding of its pathophysiology and tremendous efforts to date, nimodipine is currently the sole Food and Drug Administration-approved treatment for patients with SAH, with benefits that are marginal at best. The neuromodulation therapies are promising, especially those that target CV and DCI to improve functional outcomes. The aim of this review is therefore to summarize the available evidence for each type of neuromodulation for CV and DCI, with a special focus on its pathophysiological mechanisms, in addition to their clinical utility and drawbacks, which we hope will lead to future translational therapy options after SAH. MATERIALS AND METHODS: We conducted a comprehensive review of preclinical and clinical studies demonstrating the use of neuromodulation for SAH. The literature search was performed using PubMed, Embase, and ClinicalTrials.gov. A total of 21 articles published from 1992 to 2021 and eight clinical trials were chosen. RESULTS: The studies reviewed provide a compelling demonstration that neuromodulation is a potentially useful strategy to target multiple mechanisms of DCI and thus to potentially improve functional outcomes from SAH. There are several types of neuromodulation that have been tested to treat CV and DCI, including the trigeminal/vagus/facial nerve stimulation, sphenopalatine ganglion and spinal cord stimulation, transcranial direct electrical stimulation, transcutaneous electrical neurostimulation, and electroacupuncture. Most of them are in the preclinical or early phases of clinical application; however, they show promising results. CONCLUSIONS: DCI has a complex pathogenesis, making the unique anatomical distribution and pleiotropic capabilities of various types of neuromodulation a promising field of study. We may be at the cusp of a breakthrough in the use of these techniques for the treatment of this stubbornly difficult disease.

Predictors of Opiate Utilization in the Treatment of Headache and Impact on Three-Month Outcomes Following Subarachnoid Hemorrhage.

Despite multiple investigational drugs, headache due to subarachnoid hemorrhage (SAH) remains inadequately controlled and requires high opiate utilization. This study investigates the factors associated with increased opiate usage for the management of headache in SAH in the first 14 days of admission, the association between opiate usage and hospital length of stay, and the incidence of opiate consumption during the outpatient follow up. This is a single-center cross-sectional study. A total of 138 patients admitted between January 1, 2017, and May 31, 2019, with a diagnosis of SAH, were identified through a neurocritical care dashboard. Outpatient electronic medical records were evaluated at three months. Statistical analysis included descriptive statistics, Mann-Whitney U test, stepwise regression, and multiple regression analysis. We found that of 138 patients, the majority (90%) were prescribed opiates during their hospitalization, and the mean daily morphine equivalent dosage was 18.74 mg. Steroid usage was associated with an increase in 14-day opiate usage (r = 0.4, p = 0.0001); however, the cerebral spinal fluid profile did not show a statistically significant correlation. Over 14 days, smokers significantly used more opiates compared to nonsmokers (353 mg vs. 184 mg, p = 0.01). In addition, peri-mesencephalic SAH required less morphine compared to aneurysmal SAH (195 mg vs. 283 mg, p = 0.004). Aneurysm clipping was associated with less opiate usage compared to aneurysm coiling (186 vs. 320, p = 0.08). Only the high Hunt and Hess scale score predicted opiate usage, and the high modified Fisher scale score, aneurysmal SAH, and more opiate usage predicted hospital length of stay. A total of 48 patients (42%) suffered from headaches during their outpatient follow-up within three months of discharge; however, only six (5%) were still on opiates. There was a significant association between the amount of opiate used in the first 14 days of admission and the rate of post-discharge headache. In summary, even though patients admitted with SAH require a large amount of opiate for headache management, this did not lead to more opiate consumption in the outpatient setting. However, patients continued to suffer from headaches at three months follow-up. This high opiate consumption is associated with increased hospital length of stay. Studies are needed to identify opiate sparing analgesics that target the pathogenesis of headaches in this patient population.

Ketamine for empiric treatment of cortical spreading depolarization after subdural hematoma evacuation.

BACKGROUND: It is widely known that some patients surgically treated for subdural hematoma (SDH) experience neurologic deficits not clearly explained by the acute brain injury or known sequelae like seizures. There is increasing evidence that cortical spreading depolarization (CSD) may be the cause. A recent article demonstrated that CSD occurred at a rate of 15 % and was associated with neurological deterioration in a subset of patients following chronic subdural hematoma evacuation. Furthermore, CSD can lead to ischemia leading to worsening neurologic deficits. CSD is usually detected on electrocorticography (ECoG) and needs cortical strip electrode placement with equipment and expertise that may not be readily available. CASE DESCRIPTION: We report three cases of patients with subdural hematoma (SDH) not undergoing ECoG in whom CSD was suspected to be the cause of their neurologic deficits post evacuation. Extensive workup including neuroimaging and electroencephalography (EEG) were inconclusive. Patients were subsequently treated with ketamine infusion and had resultant neurological recovery. CONCLUSIONS: Ketamine infusion can help reverse neurologic deficits in patients with SDH in whom the deficits are not explained by neuroimaging or electrographic seizure. CSD is a known phenomenon that can result in neurological injury and must remain in the differential diagnosis of such patients. Though only limited cases are discussed (n = 3), this small case series provides the basis for conducting clinical trials evaluating the efficacy of ketamine in improving functional outcome in brain-injured patients demonstrating evidence of CSD.

Behavioral Changes Without Respiratory Symptoms as a Presenting Sign of COVID-19 Encephalitis.

The clinical presentation, diagnosis, and treatment of coronavirus disease 2019 (COVID-19) encephalitis are still being characterized. Few case reports describing COVID-19 encephalitis are available in the literature. We present a case of COVID-19 encephalitis who presented with behavioral disturbances without respiratory symptoms.

WITHDRAWN: Neurological examination, rather than vascular risk factor assessment, serves to distinguish strokes from stroke mimics in a population with high prevalence of vascular risk factors.

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Transgenic expression of HuR increases vasogenic edema and impedes functional recovery in rodent ischemic stroke.

BACKGROUND AND PURPOSE: Ischemic stroke produces significant morbidity and mortality, and acute interventions are limited by short therapeutic windows. Novel approaches to neuroprotection and neurorepair are necessary. HuR is an RNA-binding protein (RBP) which modulates RNA stability and translational efficiency of genes linked to ischemic stroke injury. METHODS: Using a transgenic (Tg) mouse model, we examined the impact of ectopic HuR expression in astrocytes on acute injury evolution after transient middle cerebral artery occlusion (tMCAO). RESULTS: HuR transgene expression was detected in astrocytes in perilesional regions and contralaterally. HuR Tg mice did not improve neurologically 72h after injury, whereas littermate controls did. In Tg mice, increased cerebral vascular permeability and edema were observed. Infarct volume was not affected by the presence of the transgene. CONCLUSIONS: Ectopic expression of HuR in astrocytes worsens outcome after transient ischemic stroke in mice in part by increasing vasogenic cerebral edema. These findings suggest that HuR could be a therapeutic target in cerebral ischemia/reperfusion.

Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel.

BACKGROUND: Despite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies. OBJECTIVE: To develop guidelines for CCM management. METHODS: The Angioma Alliance ( www.angioma.org ), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol. RESULTS: Of 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was level A (because of the absence of randomized controlled trials), 11 (48%) were level B, and 12 (52%) were level C. Recommendations were class I in 8 (35%), class II in 10 (43%), and class III in 5 (22%). CONCLUSION: Current evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines .

Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.

PURPOSE: The phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established. METHODS: We analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations. RESULTS: We determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding. CONCLUSION: These findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196.

Unusual case of bilateral caudate infarcts following pituitary apoplexy.

IMPORTANCE: Cerebral ischemia due to pituitary apoplexy is very rare. It may be caused by vasospasm or direct compression of cerebral vessels by the expanding mass. Bilateral caudate infarcts also are very rare. To our knowledge, this is the first case report that presents pituitary apoplexy causing compression of bilateral anterior cerebral artery branches and leading to bilateral caudate infarcts. OBSERVATIONS: An 81-year-old woman with a pituitary macroadenoma presented with circulatory shock due to pituitary apoplexy. Neurological examination revealed new asymmetric quadriparesis with chronic bilateral visual disturbance. On brain magnetic resonance imaging, she was found to have watershed infarcts in the anterior cerebral artery-middle cerebral artery and middle cerebral artery-posterior cerebral artery watershed zones in addition to bilateral caudate infarcts. CONCLUSIONS AND RELEVANCE: Pituitary apoplexy can cause compression of bilateral anterior cerebral arteries from the expanding mass and lead to bilateral caudate infarcts. It is important to understand the pathophysiology of cerebral ischemia in pituitary apoplexy to improve management.

Relationship of growth to aneurysm rupture in asymptomatic aneurysms ≤ 7 mm: a systematic analysis of the literature.

BACKGROUND: The apparent paradox of natural history data suggesting low rupture risk of small asymptomatic aneurysms and the median size of aneurysm rupture remains unexplained. Aneurysm growth rates and their potential relationship with rupture risk have not been well examined in natural history studies. OBJECTIVE: To examine the question of whether small asymptomatic aneurysms ≤ 7 mm that are followed up over time rupture and to determine the relationship between aneurysm growth and rupture. METHODS: We reviewed all publications on unruptured aneurysms published from 1966 to 2009. We then selected all aneurysms ≤ 7 mm for which measurements were reported for at least 2 time points and for which initial asymptomatic status and ultimate outcome (rupture vs unruptured) were reported. Using the Mann-Whitney U test, we compared absolute diameter annual growth rate. RESULTS: Our search retrieved 64 aneurysms. Thirty aneurysms ruptured during follow-up, of which 27 were enlarged before rupture (90%). Thirty-four aneurysms did not rupture, of which 24 enlarged during follow-up (71%). There was a statistically significant trend toward larger absolute diameter growth for ruptured aneurysms vs unruptured aneurysms (3.89 ± 2.34 vs 1.79 ± 1.02 mm; P < .001), respectively. Annual growth rates for aneurysms for the 2 groups, however, were not statistically different (27.46 ± 18.76 vs 32.00 ± 29.30; P = .92). CONCLUSION: Small aneurysms are prone to growth and rupture. Aneurysm rupture is more likely to occur in aneurysms with larger absolute diameter growth, but rupture can also occur in the absence of growth. The annual growth rate in both groups suggests that rate of growth of aneurysms is highly variable and unpredictable, justifying treatment or close diagnostic follow-up.