Developing Systems of Emergency and Inpatient Neurologic Care in Resource-Limited Settings.

Neurologic diseases represent a significant global health challenge, leading to disability and mortality worldwide. Healthcare systems in low- and middle-income countries are disproportionally affected. In these resource-limited settings, numerous barriers hinder the effective delivery of emergency and inpatient neurologic care, including shortages of trained personnel, limited access to diagnostics and essential medications, inadequate facilities, and absence of rehabilitation services. Disparities in the neurology workforce, limited access to neuroimaging, and availability of acute interventions further exacerbate the problem. This article explores strategies to enhance global capacity for inpatient neurologic care, emphasizing the importance of workforce development, context-specific protocols, telehealth solutions, advocacy efforts, and collaborations.

Addressing disparities in the global epidemiology of stroke.

Stroke is the second leading cause of death and the third leading cause of disability worldwide. Though the burden of stroke worldwide seems to have declined in the past three decades, much of this effect reflects decreases in high-income countries (HICs). By contrast, the burden of stroke has grown rapidly in low-income and middle-income countries (LMICs), where epidemiological, socioeconomic and demographic shifts have increased the incidence of stroke and other non-communicable diseases. Furthermore, even in HICs, disparities in stroke epidemiology exist along racial, ethnic, socioeconomic and geographical lines. In this Review, we highlight the under-acknowledged disparities in the burden of stroke. We emphasize the shifting global landscape of stroke risk factors, critical gaps in stroke service delivery, and the need for a more granular analysis of the burden of stroke within and between LMICs and HICs to guide context-appropriate capacity-building. Finally, we review strategies for addressing key inequalities in stroke epidemiology, including improvements in epidemiological surveillance and context-specific research efforts in under-resourced regions, development of the global workforce of stroke care providers, expansion of access to preventive and treatment services through mobile and telehealth platforms, and scaling up of evidence-based strategies and policies that target local, national, regional and global stroke disparities.

Sporadic Creutzfeldt-Jakob Disease Initially Presenting With Posterior Reversible Encephalopathy Syndrome: A Case Report.

INTRODUCTION: Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal neurodegenerative condition caused by prion proteins. Cortical and subcortical diffusion-weighted imaging restriction on magnetic resonance imaging (MRI) is associated with sCJD. Posterior reversible encephalopathy syndrome (PRES) results from impaired vessel autoregulation due to an identifiable trigger, which is associated with subcortical fluid-attenuated inversion recovery changes on MRI. We report a case of sCJD initially presenting with PRES. CASE REPORT: A 70-year-old woman presented to an outside hospital with progressive confusion and difficulty in managing activities of daily living. Initial examination revealed stuporous mental state and stimulus-induced myoclonus. MRI revealed bilateral subcortical occipital lobe T2-fluid-attenuated inversion recovery hyperintensities without contrast enhancement suggestive of PRES. Electroencephalogram (EEG) revealed frequent generalized periodic discharges meeting criteria for nonconvulsive status epilepticus. Clinical examination and EEG did not improve despite escalating antiseizure medications. Initial lumbar puncture was unremarkable. She was transferred to our hospital with a presumptive diagnosis of PRES, although there was no clear trigger. Continuous EEG revealed ongoing generalized periodic discharges with myoclonic activity meeting criteria for myoclonic seizures that were refractory to multiple antiseizure medications. Repeat MRI showed resolution of PRES but revealed subtle diffuse cortical diffusion-weighted imaging restriction. Repeat lumbar puncture was performed and 14-3-3 and real-time quaking-induced conversion returned positive, confirming sCJD. CONCLUSIONS: This case reports highlights that sCJD can present with neuroimaging consistent with PRES. The diagnosis of sCJD should be considered in patients with PRES who continue to show neurological decline despite optimal management and radiographic improvement of PRES on MRI. Further research is needed to identify a pathophysiological relationship between these clinical phenotypes.

Emergent external ventricular drain placement in patients with factor Xa inhibitor-associated intracerebral hemorrhage after reversal with andexanet alfa.

BACKGROUND: Andexanet alfa (AA), a factor Xa-inhibitor (FXi) reversal agent, is given as a bolus followed by a 2-hour infusion. This long administration time can delay EVD placement in intracerebral hemorrhage (ICH) patients. We sought to evaluate the safety of EVD placement immediately post-AA bolus compared to post-AA infusion. METHODS: We conducted a retrospective study that included adult patients admitted with FXi-associated ICH who received AA and underwent EVD placement The primary outcome was the occurrence of a new hemorrhage (tract, extra-axial, or intraventricular hemorrhage). Secondary outcomes included mortality, intensive care unit and hospital length of stay, and discharge modified Rankin Score. The primary safety outcome was documented thrombotic events. RESULTS: Twelve patients with FXi related ICH were included (EVD placement post-AA bolus, N = 8; EVD placement post-AA infusion, N = 4). Each arm included one patient with bilateral EVD placed. There was no difference in the incidence of new hemorrhages, with one post-AA bolus patient had small, focal, nonoperative extra-axial hemorrhage. Morbidity and mortality were higher in post-AA infusion patients (mRS, post-AA bolus, 4 [4-6] vs. post-AA infusion 6 [5,6], p = 0.24 and post-AA bolus, 3 (37.5 %) vs. post-AA infusion, 3 (75 %), p = 0.54, respectively). One patient in the post-AA bolus group had thrombotic event. There was no difference in hospital LOS (post-AA bolus, 19 days [12-26] vs. post-AA infusion, 14 days [9-22], p = 0.55) and ICU LOS (post-AA bolus, 10 days [6-13] vs. post-AA infusion, 11 days [5-21], p = 0.86). CONCLUSION: We report no differences in the incidence of tract hemorrhage, extra-axial hemorrhage, or intraventricular hemorrhage post-AA bolus versus post-AA infusion. Larger prospective studies to validate these results are warranted.

Subdural empyema secondary to pansinusitis after coronavirus disease 2019 infection in an immunocompetent patient: illustrative case.

BACKGROUND: Superimposed intracranial infection is an uncommon but clinically significant complication in patients with active coronavirus disease 2019 (COVID-19), particularly in those with predisposing immunocompromising conditions. OBSERVATIONS: The authors describe a case of subdural empyema, secondary to extension from pansinusitis, in a 20-year-old otherwise healthy immunocompetent male who was recently diagnosed with COVID-19. Despite his critical condition at time of presentation, he made a full clinical recovery with aggressive multidisciplinary surgical management between neurosurgery and otolaryngology, despite negative cultures to guide directed antimicrobial therapy. Ultimately, use of molecular-based polymerase chain reaction testing diagnosed Aspergillus fumigatus as the offending pathogen after the patient had already recovered and was discharged from the hospital. LESSONS: This case demonstrates the potential for significant superimposed intracranial infection even in young, healthy individuals, infected by COVID-19 and suggests an aggressive surgical approach to achieve source control, particularly in the absence of positive cultures to guide antimicrobial therapies, may lead to rapid clinical improvement.

Providing Neurocritical Care in Resource-Limited Settings: Challenges and Opportunities.

Acute neurologic illnesses (ANI) contribute significantly to the global burden of disease and cause disproportionate death and disability in low-income and middle-income countries (LMICs) where neurocritical care resources and expertise are limited. Shifting epidemiologic trends in recent decades have increased the worldwide burden of noncommunicable diseases, including cerebrovascular disease and traumatic brain injury, which coexist in many LMICs with a persistently high burden of central nervous system infections such as tuberculosis, neurocysticercosis, and HIV-related opportunistic infections and complications. In the face of this heavy disease burden, many resource-limited countries lack the infrastructure to provide adequate care for patients with ANI. Major gaps exist between wealthy and poor countries in access to essential resources such as intensive care unit beds, neuroimaging, clinical laboratories, neurosurgical capacity, and medications for managing complex neurologic emergencies. Moreover, many resource-limited countries face critical shortages in health care workers trained to manage neurologic emergencies, with subspecialized neurocritical care expertise largely absent outside of high-income countries. Numerous opportunities exist to overcome these challenges through capacity-building efforts that improve outcomes for patients with ANI in resource-limited countries. These include research on needs and best practices for ANI management in LMICs, developing systems for effective triage, education and training to expand the neurology workforce, and supporting increased collaboration and data sharing among LMIC health care workers and systems. The success of these efforts in curbing the disproportionate and rising impact of ANI in LMICs will depend on the coordinated engagement of the global neurocritical care community.

Inpatient Management of Acute Stroke of Unknown Type in Resource-Limited Settings.

Stroke is the second leading cause of death and disability worldwide, with a disproportionate burden on low- and middle-income countries. Critical elements of guideline-based stroke care developed in high-income countries are not applicable to resource-limited settings, where lack of access to neuroimaging prevents clinicians from distinguishing between ischemic stroke and intracranial hemorrhage, requiring challenging clinical decision-making, particularly in the acute setting. We discuss strategies for acute inpatient management of stroke of unknown type with a focus on blood pressure management and antiplatelet therapy when neuroimaging is unavailable, and review some of the challenges and strategies for successfully implementing stroke unit care in resource-limited health care settings.

The Safety and Efficacy of Desmopressin in Patients With Intracranial Hemorrhage and a History of Alcohol Use.

BACKGROUND: Patients with a history of alcohol use disorder are at an increased risk of hematoma expansion following intracranial hemorrhage (ICH) due to the effects of alcohol on platelet aggregation. Desmopressin (DDAVP) improves platelet aggregation and may decrease hematoma expansion in patients with ICH. However, DDAVP may also increase the risk of hyponatremia and thrombotic events. Evidence is limited regarding the safety and efficacy of DDAVP in alcohol use (AU)-associated ICH. METHODS: This was a retrospective chart review of adult patients with radiographic evidence of ICH and a confirmed or suspected history of alcohol use upon admission. Patients were categorized into groups based on DDAVP administration. Safety outcomes included hyponatremia (serum sodium <135 mEq/L or decrease in serum sodium of ≥ 5 mEq/L for patients with baseline sodium <135 mEq/L) within 24 hours of ICH and thrombotic events within 7 days of ICH. The primary efficacy outcome was the incidence of hematoma expansion, defined as any expansion of the hemorrhage noted on repeat imaging within 32 hours. RESULTS: In total, 52 patients were included in the safety analysis (27 DDAVP and 25 non-DDAVP). Although hyponatremia was numerically higher in the DDAVP group, there was no significant difference between groups (19.2% vs 4.2%, P = 0.192). Thrombotic complications were similar between the DDAVP and non-DDAVP groups (11.1% vs. 8%, P = 1.0). Thirty-nine patients met criteria for hemostatic efficacy analysis. There was no difference in hematoma expansion between the DDAVP and non-DDAVP groups (23.1% vs 34.6%, P = 0.71) and these findings were consistent after adjusting for differences in baseline characteristics (OR 0.63, 95% CI 0.1-3.3). CONCLUSION: The administration of DDAVP was not associated with adverse safety events, but did not significantly reduce the incidence of hematoma expansion in patients with AU-associated ICH.

Disorders of Consciousness in Hospitalized Patients with COVID-19: The Role of the Systemic Inflammatory Response Syndrome.

BACKGROUND: Prevalence and etiology of unconsciousness are uncertain in hospitalized patients with coronavirus disease 2019 (COVID-19). We tested the hypothesis that increased inflammation in COVID-19 precedes coma, independent of medications, hypotension, and hypoxia. METHODS: We retrospectively assessed 3203 hospitalized patients with COVID-19 from March 2 through July 30, 2020, in New York City with the Glasgow Coma Scale and systemic inflammatory response syndrome (SIRS) scores. We applied hazard ratio (HR) modeling and mediation analysis to determine the risk of SIRS score elevation to precede coma, accounting for confounders. RESULTS: We obtained behavioral assessments in 3203 of 10,797 patients admitted to the hospital who tested positive for SARS-CoV-2. Of those patients, 1054 (32.9%) were comatose, which first developed on median hospital day 2 (interquartile range [IQR] 1-9). During their hospital stay, 1538 (48%) had a SIRS score of 2 or above at least once, and the median maximum SIRS score was 2 (IQR 1-2). A fivefold increased risk of coma (HR 5.05, 95% confidence interval 4.27-5.98) was seen for each day that patients with COVID-19 had elevated SIRS scores, independent of medication effects, hypotension, and hypoxia. The overall mortality in this population was 13.8% (n = 441). Coma was associated with death (odds ratio 7.77, 95% confidence interval 6.29-9.65) and increased length of stay (13 days [IQR 11.9-14.1] vs. 11 [IQR 9.6-12.4]), accounting for demographics. CONCLUSIONS: Disorders of consciousness are common in hospitalized patients with severe COVID-19 and are associated with increased mortality and length of hospitalization. The underlying etiology of disorders of consciousness in this population is uncertain but, in addition to medication effects, may in part be linked to systemic inflammation.

Head-to-Head Comparison of Social Network Assessments in Stroke Survivors.

BACKGROUND AND PURPOSE: Social networks influence human health and disease through direct biological and indirect psychosocial mechanisms. They have particular importance in neurologic disease because of support, information, and healthy behavior adoption that circulate in networks. Investigations into social networks as determinants of disease risk and health outcomes have historically relied on summary indices of social support, such as the Lubben Social Network Scale-Revised (LSNS-R) or the Stroke Social Network Scale (SSNS). We compared these 2 survey tools to personal network (PERSNET) mapping tool, a novel social network survey that facilitates detailed mapping of social network structure, extraction of quantitative network structural parameters, and characterization of the demographic and health parameters of each network member. METHODS: In a cohort of inpatient and outpatient stroke survivors, we administered LSNS-R, SSNS, and PERSNET in a randomized order to each patient. We used logistic regression to generate correlation matrices between LSNS-R scores, SSNS scores, and PERSNET's network structure (eg, size and density) and composition metrics (eg, percent kin in network). We also examined the relationship between LSNS-R-derived risk of social isolation with PERSNET-derived network size. RESULTS: We analyzed survey responses for 67 participants and found a significant correlation between LSNS-R, SSNS, and PERSNET-derived indices of network structure. We found no correlation between LSNS-R, SSNS, and PERSNET-derived metrics of network composition. Personal network mapping tool structural and compositional variables were also internally correlated. Social isolation defined by LSNS-R corresponded to a network size of <5. CONCLUSIONS: Personal network mapping tool is a valid index of social network structure, with a significant correlation to validated indices of perceived social support. Personal network mapping tool also captures a novel range of health behavioral data that have not been well characterized by previous network surveys. Therefore, PERSNET offers a comprehensive social network assessment with visualization capabilities that quantifies the social environment in a valid and unique manner.

COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital.

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.

Aspiration Pneumonia in Adults Hospitalized With Stroke at a Large Academic Hospital in Zambia.

BACKGROUND AND OBJECTIVES: Preventing complications of stroke such as poststroke aspiration pneumonia (PSAP) may improve stroke outcomes in resource-limited settings. We investigated the incidence and associated mortality of PSAP in Zambia. METHODS: We conducted a prospective cohort study of adults with stroke at University Teaching Hospital (Lusaka, Zambia) between December 2019 and March 2020. NIH Stroke Scale, Glasgow Coma Scale, and Modified Rankin Scale scores and 9 indicators of possible PSAP were collected serially over each participant's admission. PSAP was defined as ≥4 indicators present, and possible PSAP as 2%-3% present. T tests and χ2 tests were used to compare clinical parameters across PSAP groups. Logistic regression was used to assess the relative effects of age, sex, PSAP status, and initial stroke severity on inpatient mortality. RESULTS: We enrolled 125 participants. Mean age was 60 ± 16 years, 61% were female, 55% of strokes were ischemic, and the baseline NIH Stroke Scale score was 19.7 ± 8.7. Thirty-eight (30%) had PSAP, and 32 (26%) had possible PSAP. PSAP was associated with older age and more adverse stroke severity scores. Fifty-nine percent of participants with PSAP died compared with 39% with possible PSAP and 8% with no PSAP. PSAP status independently predicted inpatient mortality after controlling for age, sex, and initial stroke severity. Swallow screening was not performed for any participant. DISCUSSION: PSAP is common and life threatening in Zambia, especially among older participants with severe stroke presentations. PSAP was associated with significantly increased mortality independent of initial stroke severity, suggesting that interventions to mitigate PSAP may improve stroke outcomes in Zambia and other resource-limited settings.

Neuronophagia and microglial nodules in a SARS-CoV-2 patient with cerebellar hemorrhage.

We document the neuropathologic findings of a 73-year old man who died from acute cerebellar hemorrhage in the context of relatively mild SARS-CoV2 infection. The patient developed sudden onset of headache, nausea, and vomiting, immediately followed by loss of consciousness on the day of admission. Emergency medical services found him severely hypoxemic at home, and the patient suffered a cardiac arrest during transport to the emergency department. The emergency team achieved return of spontaneous circulation after over 17 min of resuscitation. A chest radiograph revealed hazy bilateral opacities; and real-time-PCR for SARS-CoV-2 on the nasopharyngeal swab was positive. Computed tomography of the head showed a large right cerebellar hemorrhage, with tonsillar herniation and intraventricular hemorrhage. One day after presentation, he was transitioned to comfort care and died shortly after palliative extubation. Autopsy performed 3 h after death showed cerebellar hemorrhage and acute infarcts in the dorsal pons and medulla. Remarkably, there were microglial nodules and neuronophagia bilaterally in the inferior olives and multifocally in the cerebellar dentate nuclei. This constellation of findings has not been reported thus far in the context of SARS-CoV-2 infection.

The utility of EEG monitoring in neonates with hyperammonemia due to inborn errors of metabolism.

BACKGROUND: Continuous EEG studies demonstrate that neonates with seizures due to cerebral pathology, such as hypoxia ischemia, exhibit predominantly electrographic seizures (i.e. those only detected with EEG because they lack clinical features). Previous small case series demonstrate EEG changes and seizures during hyperammonemia associated with inborn errors of metabolism (IEM) but there are no reports utilizing continuous EEG in these conditions. OBJECTIVE: To characterize seizures and evaluate the utility of continuous EEG recording during hyperammonemia due to inborn errors of metabolism. METHODS: We retrospectively reviewed medical records and EEG tracings of neonates who presented with hyperammonemia due to inborn errors of metabolism who had continuous EEG and full medical records available for review, including follow up. RESULTS: Eight neonates with hyperammonemia were studied, 7 had urea cycle defects: Argininosuccinate lyase deficiency [3], (ornithine transcarbamylase deficiency [3], carbomyl phosphate synthase deficiency [1] and one had an organic acidemia: Methylmalonic acidemia [1]. Most common presentations were lethargy and poor feeding at 12-72 h of life. The highest blood ammonia level was 874 µmol/L (median); range 823-1647 µmol/L (normal value <50 µmol/L in term neonates). Seven were treated with hemodialysis in addition to nitrogen scavengers. Seven neonates had seizures; six had only electrographic seizures. Seizures initially occurred within 24-36 h of clinical presentation, sometimes with normal ammonia and glutamine levels. Neonates with seizures all lacked state changes on EEG. Inter burst interval duration correlated with degree of hyperammonemia. Two cases with normal plasma ammonia but increasing interburst interval duration were proven to have stroke by MRI. CONCLUSIONS: Seizures occur frequently in neonates with hyperammonemia; most can be detected only with continuous EEG. Seizures may occur when ammonia and glutamine levels are normal. Interburst interval duration is associated with ammonia levels or cerebral dysfunction from other brain pathology. Continuous EEG can be a useful tool for managing infants with hyperammonemia and may be essential for seizure management especially for infants in deep metabolic coma.