The COVID-19 pandemic continues to affect millions of people globally, with increasing burdens of morbidity and mortality. More reports describe concomitant COVID-19 neurological manifestations,^1-5 including symptoms such as headache, myalgia, anosmia, and ageusia as well as neurological syndromes such as encephalopathy, stroke, and coma, among others.^1,6-17 Reports comprise case series^8-10,18 and single and/or regional cohorts^4,19-23 with varying data definitions, limiting the ability to accurately estimate the incidence of COVID-19 neurological manifestations and precluding data pooling and generalization across populations.^24-26

Background and objectives One year after the onset of the coronavirus disease 2019 (COVID-19) pandemic, we aimed to summarize the frequency of neurologic manifestations reported in patients with COVID-19 and to investigate the association of these manifestations with disease severity and mortality. Methods We searched PubMed, Medline, Cochrane library, ClinicalTrials.gov, and EMBASE for studies from December 31, 2019, to December 15, 2020, enrolling consecutive patients with COVID-19 presenting with neurologic manifestations. Risk of bias was examined with the Joanna Briggs Institute scale. A random-effects meta-analysis was performed, and pooled prevalence and 95% confidence intervals (CIs) were calculated for neurologic manifestations. Odds ratio (ORs) and 95% CIs were calculated to determine the association of neurologic manifestations with disease severity and mortality. Presence of heterogeneity was assessed with I², meta-regression, and subgroup analyses. Statistical analyses were conducted in R version 3.6.2. Results Of 2,455 citations, 350 studies were included in this review, providing data on 145,721 patients with COVID-19, 89% of whom were hospitalized. Forty-one neurologic manifestations (24 symptoms and 17 diagnoses) were identified. Pooled prevalence of the most common neurologic symptoms included fatigue (32%), myalgia (20%), taste impairment (21%), smell impairment (19%), and headache (13%). A low risk of bias was observed in 85% of studies; studies with higher risk of bias yielded higher prevalence estimates. Stroke was the most common neurologic diagnosis (pooled prevalence 2%). In patients with COVID-19 ≥60 years of age, the pooled prevalence of acute confusion/delirium was 34%, and the presence of any neurologic manifestations in this age group was associated with mortality (OR 1.80, 95% CI 1.11–2.91). Discussion Up to one-third of patients with COVID-19 analyzed in this review experienced at least 1 neurologic manifestation. One in 50 patients experienced stroke. In those >60 years of age, more than one-third had acute confusion/delirium; the presence of neurologic manifestations in this group was associated with nearly a doubling of mortality. Results must be interpreted with the limitations of observational studies and associated bias in mind. Systematic Review Registration PROSPERO CRD42020181867.

Intracerebral hemorrhage (ICH) is a devastating form of stroke affecting millions of people worldwide. Parenchymal hematoma triggers a series of reactions leading to primary and secondary brain injuries and permanent neurological deficits. Microglia and macrophages carry out hematoma clearance, thereby facilitating functional recovery after ICH. Here, we elucidate a pivotal role for the interleukin (IL)-4)/signal transducer and activator of transcription 6 (STAT6) axis in promoting long-term recovery in both blood- and collagenase-injection mouse models of ICH, through modulation of microglia/macrophage functions. In both ICH models, STAT6 was activated in microglia/macrophages (i.e., enhanced expression of phospho-STAT6 in Iba1⁺ cells). Intranasal delivery of IL-4 nanoparticles after ICH hastened STAT6 activation and facilitated hematoma resolution. IL-4 treatment improved long-term functional recovery in young and aged male and young female mice. In contrast, STAT6 knockout (KO) mice exhibited worse outcomes than WT mice in both ICH models and were less responsive to IL-4 treatment. The construction of bone marrow chimera mice demonstrated that STAT6 KO in either the CNS or periphery exacerbated ICH outcomes. STAT6 KO impaired the capacity of phagocytes to engulf red blood cells in the ICH brain and in primary cultures. Transcriptional analyses identified lower level of IL-1 receptor-like 1 (ST2) expression in microglia/macrophages of STAT6 KO mice after ICH. ST2 KO diminished the beneficial effects of IL-4 after ICH. Collectively, these data confirm the importance of IL-4/STAT6/ST2 signaling in hematoma resolution and functional recovery after ICH. Intranasal IL-4 treatment warrants further investigation as a clinically feasible therapy for ICH. Significance Hemorrhagic stroke, resulting from intracerebral hemorrhage, is a devastating medical condition currently without effective cure. Here we report that intranasal delivery of IL-4, a well-known antiinflammatory cytokine, facilitates microglia- and macrophage-mediated hematoma resolution and improves long-term functional recovery in two different mouse models of intracerebral hemorrhage. Mechanistically, IL-4 activates a signaling cascade involving signal transducer and activator of transcription 6 and IL-1 receptor-like 1, thereby enhancing the phagocytotic capability of microglia and macrophages to remove red blood cells from intracerebral hematomata. Our in vitro and in vivo preclinical studies support the view that IL-4 treatment has the therapeutic potential to promote hematoma resolution and functional restoration in hemorrhagic stroke victims.

Growing evidences suggest that stroke is a systemic disease affecting many organ systems beyond the brain. Stroke-related systemic inflammatory response and immune dysregulations may play an important role in brain injury, recovery, and stroke outcome. The two main phenomena in stroke-related peripheral immune dysregulations are systemic inflammation and post-stroke immunosuppression. There is emerging evidence suggesting that the spleen contracts following ischemic stroke, activates peripheral immune response and this may further potentiate brain injury. Whether similar brain–immune crosstalk occurs in hemorrhagic strokes such as intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) is not established. In this review, we systematically examined animal and human evidence to date on peripheral immune responses associated with hemorrhagic strokes. Specifically, we reviewed the impact of clinical systemic inflammatory response syndrome (SIRS), inflammation- and immune-associated biomarkers, the brain–spleen interaction, and cellular mediators of peripheral immune responses to ICH and SAH including regulatory T cells (Tregs). While there is growing data suggesting that peripheral immune dysregulation following hemorrhagic strokes may be important in brain injury pathogenesis and outcome, details of this brain-immune system cross-talk remain insufficiently understood. This is an important unmet scientific need that may lead to novel therapeutic strategies in this highly morbid condition.

Cal trials and evidence to date, prognostic considerations, controversies, recent developments, and future directions in SAH. RECENT FINDINGS Historically, management of SAH focused on prevention and treatment of subsequent cerebral vasospasm, which was thought to be the primary cause of delayed cerebral ischemia. Clinical and translational studies over the past decade, including several therapeutic phase 3 randomized clinical trials, suggest that the pathophysiology of SAH-associated brain injury is multiphasic and multifactorial beyond large vessel cerebral vasospasm. The quest to reduce SAH-associated brain injury and improve outcomes is shifting away from large vessel cerebral vasospasm to a new paradigm targeting multiple brain injury mechanisms, including early brain injury, delayed cerebral ischemia, microcirculatory dysfunction, spreading cortical depolarization, inflammation, and the brain-body interaction in vascular brain injury with critical illness. Despite multiple negative randomized clinical trials in search of potential therapeutic agents ameliorating the downstream effects after SAH, the overall outcome of SAH has improved over recent decades, likely related to improvements in interventional options for ruptured cerebral aneurysms and in critical care management. Emerging clinical evidence also suggests potential harmful impact of historic empiric treatments for SAH-associated vasospasm, such as prophylactic induction of hypertension, hypervolemia, and hemodilution (triple H therapy). With decreasing mortality, long-term SAH survivorship and efforts to reduce chronic morbidity and to improve quality of life and patient-centered outcome are growing areas of unmet need. Despite existing guidelines, significant variabilities in local and regional practices and in scientific terminologies have historically limited advancement in SAH care and therapeutic development. Large global collaborative efforts developed harmonized SAH common data elements in 2019, and studies are under way to examine how existing variabilities in SAH care impact long-term SAH outcomes. SUMMARY Although the overall incidence and mortality of SAH is decreasing with advances in preventive and acute care, SAH remains a major cause of long-term morbidity in survivors. Significant variabilities in care settings and empiric treatment protocols and inconsistent scientific terminologies have limited advancement in patient care and therapeutic clinical studies. Large consensus efforts are under way to introduce clinical guidelines and common data elements to advance therapeutic approaches and improve patient outcome....