Associations Between Transcranial Doppler Vasospasm and Clinical Outcomes After Aneurysmal Subarachnoid Hemorrhage: A Retrospective Observational Study.

OBJECTIVE: The objective is to examine the relationship between transcranial Doppler cerebral vasospasm (TCD-vasospasm), and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH). METHODS: In a retrospective cohort study, using univariate and multivariate analysis, we examined the association between TCD-vasospasm (defined as Lindegaard ratio >3) and patient's ability to ambulate without assistance, the need for tracheostomy and gastrostomy tube placement, and the likelihood of being discharged home from the hospital. RESULTS: We studied 346 patients with aSAH; median age 55 years (Interquartile range IQR 46,64), median Hunt and Hess 3 [IQR 1-5]. Overall, 68.6% (n=238) had TCD-vasospasm, and 28% (n=97) had delayed cerebral ischemia. At hospital discharge, 54.3% (n=188) were able to walk without assistance, 5.8% (n=20) had received a tracheostomy, and 12% (n=42) had received a gastrostomy tube. Fifty-three percent (n=183) were discharged directly from the hospital to their home. TCD-vasospasm was not associated with ambulation without assistance at discharge (adjusted odds ratio, aOR 0.54, 95% 0.19,1.45), tracheostomy placement (aOR 2.04, 95% 0.23,18.43), gastrostomy tube placement (aOR 0.95, 95% CI 0.28,3.26), discharge to home (aOR 0.36, 95% CI 0.11,1.23). CONCLUSION: This single-center retrospective study finds that TCD-vasospasm is not associated with clinical outcomes such as ambulation without assistance, discharge to home from the hospital, tracheostomy, and gastrostomy feeding tube placement. Routine screening for cerebral vasospasm and its impact on vasospasm diagnostic and therapeutic interventions and their associations with improved clinical outcomes warrant an evaluation in large, prospective, case-controlled, multi-center studies.

Taking a Chance to Recover: Families Look Back on the Decision to Pursue Tracheostomy After Severe Acute Brain Injury.

BACKGROUND: Tracheostomy represents one important and value-laden treatment decision after severe acute brain injury (SABI). Whether to pursue this life-sustaining treatment typically hinges on intense conversations between family and clinicians. The aim of this study was, among a cohort of patient who had undergone tracheostomy after SABI, to explore the long-term reflections of patients and their families as they look back on this decision. METHODS: For this qualitative study, we reviewed the electronic medical records of patients with SABI who underwent tracheostomy. We included all patients who were admitted to our 30-bed neuro-intensive care unit with SABI and underwent tracheostomy between November 2017 and October 2019. Using purposive sampling, we invited survivors and family members to participate in telephone interviews greater than 3 months after SABI until thematic saturation was reached. Interviews were audiotaped, transcribed, and analyzed by using thematic analysis. RESULTS: Overall, 38 patients with SABI in the neuro-intensive care unit underwent tracheostomy. The mean age of patients was 49 (range 18-81), with 19 of 38 patients diagnosed with traumatic brain injury and 19 of 38 with stroke. We interviewed 20 family members of 18 of 38 patients at a mean of 16 (SD 9) months after hospitalization. The mean patient age among those with an interview was 50 (range 18-76); the mean modified Rankin Scale score (mRS) was 4.7 (SD 0.8) at hospital discharge. At the time of the interview, ten patients lived at home and two in a skilled nursing facility and had a mean mRS of 2.6 (SD 0.9), and six had died. As families reflected on the decision to proceed with a tracheostomy, two themes emerged. First, families did not remember tracheostomy as a choice because the uncertain chance of recovery rendered the certain alternative of death unacceptable or because they valued survival above all and therefore could not perceive an alternative to life-sustaining treatment. Second, families identified a fundamental need to receive supportive, consistent communication centering around compassion, clarity, and hope. When this need was met, families were able to reflect on the tracheostomy decision with peace, regardless of their loved one's eventual outcome. CONCLUSIONS: After SABI, prognostic uncertainty almost transcends the concept of choice. Families who proceeded with a tracheostomy saw it as the only option at the time. High-quality communication may mitigate the stress surrounding this high-stakes decision.

Efficacy of Home Anticonvulsant Administration for Second-Line Status Epilepticus Treatment.

OBJECTIVE: To investigate whether receiving a second-line anticonvulsant medication that is part of a patient's home regimen influences outcomes in benzodiazepine-refractory convulsive status epilepticus. METHODS: Using the Established Status Epilepticus Treatment Trial data, allocation to a study drug included in the patient's home anticonvulsant medication regimen was compared to receipt of an alternative second-line study medication. The primary outcome was cessation of clinical seizures with improved consciousness by 60 minutes after study drug initiation. Secondary outcomes were seizure cessation adjudicated from medical records and adverse events. We performed inverse probability of treatment-weighted (IPTW) logistic regressions. RESULTS: Of 462 patients, 232 (50%) were taking 1-2 of the 3 study medications at home. The primary outcome was observed in 39/89 (44%) patients allocated to their home medication vs 76/143 (53%) allocated to a nonhome medication (IPTW odds ratio [OR] 0.66, 95% confidence interval [CI] 0.39-1.14). The adjudicated outcome occurred in 37/89 (42%) patients vs 82/143 (57%), respectively (IPTW OR 0.52, 95% CI 0.30-0.89). There was no interaction between study levetiracetam and home levetiracetam and there were no differences in adverse events. CONCLUSION: There was no difference in the primary outcome for patients who received a home medication vs nonhome medication. However, the retrospective evaluation suggested an association between receiving a nonhome medication and seizure cessation. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with refractory convulsive status epilepticus, use of a home second-line anticonvulsant compared to a nonhome anticonvulsant did not significantly affect the probability of stopping seizures.

Psychedelic-assisted therapy for functional neurological disorders: A theoretical framework and review of prior reports.

Functional neurological disorders (FNDs), which are sometimes also referred to as psychogenic neurological disorders or conversion disorder, are common disabling neuropsychiatric disorders with limited treatment options. FNDs can present with sensory and/or motor symptoms, and, though they may mimic other neurological conditions, they are thought to occur via mechanisms other than those related to identifiable structural neuropathology and, in many cases, appear to be triggered and sustained by recognizable psychological factors. There is intriguing preliminary evidence to support the use of psychedelic-assisted therapy in a growing number of psychiatric illnesses, including FNDs. We review the theoretical arguments for and against exploring psychedelic-assisted therapy as a treatment for FNDs. We also provide an in-depth discussion of prior published cases detailing the use of psychedelics for psychosomatic conditions, analyzing therapeutic outcomes from a contemporary neuroscientific vantage as informed by several recent neuroimaging studies on psychedelics and FNDs.

Case Series: Evidence of Borderzone Ischemia in Critically-Ill COVID-19 Patients Who "Do Not Wake Up".

This article describes the clinical course, radiological findings, and outcome of two patients with the novel 2019 coronavirus disease (COVID-19) who remained comatose for a prolonged duration following discontinuation of all sedation. These two male patients, one aged 59-years and another aged 53-years, both with a history of hypertension and neurologically intact on admission, developed worsening COVID-19 associated acute respiratory distress syndrome (ARDS). Both required benzodiazepine, opioid, neuromuscular blockade, therapeutic anticoagulation, and vasopressor infusions in addition to renal replacement therapy. Echocardiography demonstrated normal chamber size and systolic function in both cases. Each patient demonstrated only trace flexion to pain 7-10 days following discontinuation of all sedation. Magnetic Resonance Imaging on both patients demonstrated multifocal lesions on diffusion weighted imaging with apparent diffusion coefficient correlate in bilateral middle/anterior cerebral artery borderzones, and no large-vessel occlusion or severe stenosis. In both patients, continuous electroencephalography demonstrated no seizures. Neither patient had any documented period of sustained hypotension (mean arterial pressure <60 mmHg) or hypoxia (SpO2 <90%). Ninety days following initial presentation, the 59-years-old man was oriented, with fluent speech and able to ambulate with assistance, while the other 53-years-old man was at home and independent, undertaking the basic activities required by daily living. We conclude that critically-ill COVID-19 patients with prolonged coma following sedation discontinuation may demonstrate imaging features of ischemic injury in borderzone regions despite the absence of documented sustained hypotension or hypoxia. However, substantial neurological recovery is possible despite these findings.

Long-term and delayed functional recovery in patients with severe cerebrovascular and traumatic brain injury requiring tracheostomy.

OBJECTIVE: Data on long-term functional recovery (LFR) following severe brain injury are essential for counseling of surrogates and for appropriate timing of outcome assessment in clinical trials. Delayed functional recovery (DFR) beyond 3-6 months is well documented following severe traumatic brain injury (sTBI), but there are limited data on DFR following severe cerebrovascular brain injury. The objective of this study was to assess LFR and DFR in patients with sTBI and severe stroke dependent on tracheostomy and tube feeding at the time of discharge from the intensive care unit (ICU). METHODS: The authors identified patients entered into their tracheostomy database 2008-2013 with sTBI and severe stroke, encompassing SAH, intracerebral hemorrhage (ICH), and acute ischemic stroke (AIS). Eligibility criteria included disease-specific indicators of severity, Glasgow Coma Scale score < 9 at time of tracheostomy, and need for tracheostomy and tube feeding at ICU discharge. Assessment was at 1-3 months, 6-12 months, 12-24 months, and 24-36 months after initial injury for presence of tracheostomy, ability to walk, and ability to perform basic activities of daily living (B-ADLs). Long-term functional recovery (LFR) was defined as recovery of the ability to walk or perform B-ADLs by the 24- to 36-month follow-up. Delayed functional recovery (DFR) was defined as progression in functional milestones between any 2 time points beyond the 1- to 3-month follow-up. RESULTS: A total of 129 patients met the eligibility criteria. Functional outcomes were available for 129 (100%), 97 (75%), 83 (64%), and 80 (62%) patients, respectively, from assessments at 1-3, 6-12, 12-24 and 24-36 months; 33 (26%) died by 24-36 months. Fifty-nine (46%) regained the ability to walk and 48 (37%) performed B-ADLs at some point during their recovery. Among survivors who had not achieved the respective milestone at 1-3 months, 29/58 (50%) were able to walk and 28/74 (38%) performed B-ADLs at 6-12 months. Among survivors who had not achieved the respective milestone at 6-12 months, 5/16 (31%) were able to walk and 13/30 (43%) performed B-ADLs at 12-24 months. There was no significant difference in rates of LFR or DFR between patients with sTBI and those with severe stroke. CONCLUSIONS: Among patients with severe brain injury requiring tracheostomy and tube feeding at ICU discharge, 46% regained the ability to walk and 37% performed B-ADLs 2-3 years after injury. DFR beyond 1-3 and 6-12 months was seen in over 30% of survivors, with no significant difference between sTBI and severe stroke.

Pleocytosis is not fully responsible for low CSF glucose in meningitis.

OBJECTIVE: The mechanism of hypoglycorrhachia-low CSF glucose-in meningitis remains unknown. We sought to evaluate the relative contribution of CSF inflammation vs microorganisms (bacteria and fungi) in lowering CSF glucose levels. METHODS: We retrospectively categorized CSF profiles into microbial and aseptic meningitis and analyzed CSF leukocyte count, glucose, and protein concentrations. We assessed the relationship between these markers using multivariate and stratified linear regression analysis for initial and repeated CSF sampling. We also calculated the receiver operating characteristics of CSF glucose and CSF-to-serum glucose ratios to presumptively diagnose microbial meningitis. RESULTS: We found that increasing levels of CSF inflammation were associated with decreased CSF glucose levels in the microbial but not aseptic category. Moreover, elevated CSF protein levels correlated more strongly than the leukocyte count with low CSF glucose levels on initial (R2 = 36%, p < 0.001) and repeated CSF sampling (R2 = 46%, p < 0.001). Hypoglycorrhachia (<40 mg/dL) was observed in 50.1% of microbial cases, but only 9.6% of aseptic cases, most of which were neurosarcoidosis. Absolute CSF glucose and CSF-to-serum glucose ratios had similar low sensitivity and moderate-to-high specificity in diagnosing microbial meningitis at thresholds commonly used. CONCLUSIONS: The main driver of hypoglycorrhachia appears to be a combination of microbial meningitis with moderate to high degrees of CSF inflammation and proteins, suggesting that the presence of microorganisms capable of catabolizing glucose is a determinant of hypoglycorrhachia in meningitis. A major notable exception is neurosarcoidosis. Low CSF glucose and CSF-to-serum glucose ratios are useful markers for the diagnosis of microbial meningitis.

Infectivity and insertional mutagenesis of endogenous retrovirus in autoimmune NZB and B/W mice.

Murine leukaemia virus has been suggested to contribute to both autoimmune disease and leukaemia in the NZB mouse and in the (NZB × NZW) F1 (abbreviated B/W) mouse. However, with apparently only xenotropic but no ecotropic virus constitutively expressed in these mice, few mechanisms could explain the aetiology of either disease in either mouse strain. Because pseudotyped and/or inducible ecotropic virus may play a role, we surveyed the ability of murine leukaemia virus in NZB, NZW and B/W mice to infect and form a provirus. From the spleen of NZB mice, we isolated circular cDNA of xenotropic and polytropic virus, which indicates ongoing infection by these viruses. From a B/W lymphoma, we isolated and determined the complete sequence of a putative ecotropic NZW virus. From B/W mice, we recovered de novo endogenous retroviral integration sites (tags) from the hyperproliferating cells of the spleen and the peritoneum. The tagged genes seemed to be selected to aid cellular proliferation, as several of them are known cancer genes. The insertions are consistent with the idea that endogenous retrovirus contributes to B-cell hyperproliferation and progression to lymphoma in B/W mice.

ß2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis.

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify ß2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.

As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival.

Colony-stimulating factor 1 (CSF1) and interleukin-34 (IL-34) are functional ligands of the CSF1 receptor (CSF1R) and thus are key regulators of the monocyte/macrophage lineage. We discovered that systemic administration of human recombinant CSF1 ameliorates memory deficits in a transgenic mouse model of Alzheimer's disease. CSF1 and IL-34 strongly reduced excitotoxin-induced neuronal cell loss and gliosis in wild-type mice when administered systemically before or up to 6 h after injury. These effects were accompanied by maintenance of cAMP responsive element-binding protein (CREB) signaling in neurons rather than in microglia. Using lineage-tracing experiments, we discovered that a small number of neurons in the hippocampus and cortex express CSF1R under physiological conditions and that kainic acid-induced excitotoxic injury results in a profound increase in neuronal receptor expression. Selective deletion of CSF1R in forebrain neurons in mice exacerbated excitotoxin-induced death and neurodegeneration. We conclude that CSF1 and IL-34 provide powerful neuroprotective and survival signals in brain injury and neurodegeneration involving CSF1R expression on neurons.