Intravenous Thrombolysis for Stroke and Presumed Stroke in Human Immunodeficiency Virus-Infected Adults: A Retrospective, Multicenter US Study.

BACKGROUND AND PURPOSE: Human immunodeficiency virus (HIV) infection has been shown to increase both ischemic and hemorrhagic stroke risks, but there are limited data on the safety and outcomes of intravenous thrombolysis with tPA (tissue-type plasminogen activator) for acute ischemic stroke in HIV-infected patients. METHODS: A retrospective chart review of intravenous tPA-treated HIV patients who presented with acute stroke symptoms was performed in 7 large inner-city US academic centers (various search years between 2000 and 2017). We collected data on HIV, National Institutes of Health Stroke Scale score, ischemic stroke risk factors, opportunistic infections, intravenous drug abuse, neuroimaging findings, and modified Rankin Scale score at last follow-up. RESULTS: We identified 33 HIV-infected patients treated with intravenous tPA (mean age, 51 years; 24 men), 10 of whom were stroke mimics. Sixteen of 33 (48%) patients had an HIV viral load less than the limit of detection while 10 of 33 (30%) had a CD4 count <200/mm3. The median National Institutes of Health Stroke Scale score at presentation was 9, and mean time from symptom onset to tPA was 144 minutes (median, 159). The median modified Rankin Scale score for the 33-patient cohort was 1 and for the 23-patient actual stroke cohort was 2, measured at a median of 90 days poststroke symptom onset. Two patients had nonfatal hemorrhagic transformation (6%; 95% confidence interval, 1%-20%), both in the actual stroke group. Two patients had varicella zoster virus vasculitis of the central nervous system, 1 had meningovascular syphilis, and 7 other patients were actively using intravenous drugs (3 cocaine, 1 heroin, and 3 unspecified), none of whom had hemorrhagic transformation. CONCLUSIONS: Most HIV-infected patients treated with intravenous tPA for presumed and actual acute ischemic stroke had no complications, and we observed no fatalities. Stroke mimics were common, and thrombolysis seems safe in this group. We found no data to suggest an increased risk of intravenous tPA-related complications because of concomitant opportunistic infections or intravenous drug abuse.

Emerging Cases of Powassan Virus Encephalitis in New England: Clinical Presentation, Imaging, and Review of the Literature.

BACKGROUND: Powassan virus (POWV) is a rarely diagnosed cause of encephalitis in the United States. In the Northeast, it is transmitted by Ixodes scapularis, the same vector that transmits Lyme disease. The prevalence of POWV among animal hosts and vectors has been increasing. We present 8 cases of POWV encephalitis from Massachusetts and New Hampshire in 2013-2015. METHODS: We abstracted clinical and epidemiological information for patients with POWV encephalitis diagnosed at 2 hospitals in Massachusetts from 2013 to 2015. We compared their brain imaging with those in published findings from Powassan and other viral encephalitides. RESULTS: The patients ranged in age from 21 to 82 years, were, for the most part, previously healthy, and presented with syndromes of fever, headache, and altered consciousness. Infections occurred from May to September and were often associated with known tick exposures. In all patients, cerebrospinal fluid analyses showed pleocytosis with elevated protein. In 7 of 8 patients, brain magnetic resonance imaging demonstrated deep foci of increased T2/fluid-attenuation inversion recovery signal intensity. CONCLUSIONS: We describe 8 cases of POWV encephalitis in Massachusetts and New Hampshire in 2013-2015. Prior to this, there had been only 2 cases of POWV encephalitis identified in Massachusetts. These cases may represent emergence of this virus in a region where its vector, I. scapularis, is known to be prevalent or may represent the emerging diagnosis of an underappreciated pathogen. We recommend testing for POWV in patients who present with encephalitis in the spring to fall in New England.

Myeloradiculopathy associated with chikungunya virus infection.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that is endemic to parts of Africa, South and Southeast Asia, and more recently the Caribbean. Patients typically present with fever, rash, and arthralgias, though neurologic symptoms, primarily encephalitis, have been described. We report the case of a 47-year-old woman who was clinically diagnosed with CHIKV while traveling in the Dominican Republic and presented 10 days later with left lower extremity weakness, a corresponding enhancing thoracic spinal cord lesion, and positive CHIKV serologies. She initially responded to corticosteroids, followed by relapsing symptoms and gradual clinical improvement. The time lapse between acute CHIKV infection and the onset of myelopathic sequelae suggests an immune-mediated phenomenon rather than direct activity of the virus itself. Chikungunya virus should be considered in the differential diagnosis of myelopathy in endemic areas. The progression of symptoms despite corticosteroid administration suggests more aggressive immunomodulatory therapies may be warranted at disease onset.

Stroke in HIV-infected African Americans: a retrospective cohort study.

The risk of having a first stroke is nearly twice as high among African Americans compared to Caucasians. HIV/AIDS is an independent risk factor for stroke. Our study aimed to report the risk factors and short-term clinical outcomes of African Americans with HIV infection and new-onset stroke admitted at the Johns Hopkins Hospitals (2000-2012). Multivariate linear regression was used to examine the association between potential predictors and odds of an unfavorable outcome, defined as a higher modified Rankin Scale (mRS) score on hospital discharge. African Americans comprised 105/125 (84%) of HIV-infected new-onset stroke inpatients (median age 50 years; 69% men; median CD4 140/mL; ischemic 77%; 39% taking highly active antiretroviral therapy). Vascular risk factors were common: hypertension (67%), cigarette smoking (66%), dyslipidemia (42%), hepatitis C (48%), intravenous drug abuse (32%), and prior myocardial infarction (29%). Prior aspirin and statin use were uncommon (18%, 9%). Unfavorable outcome (mRS score 4-6, n = 22 of 90 available records) was noted in 24% of patients, including seven in-hospital deaths. On multivariate analyses, higher CD4 count on hospital admission was associated with a lower mRS (-0.2 mRS points per 1 unit increase in CD4, 95% CI (-0.3, 0), p = 0.03). Intracerebral hemorrhage was also associated with a lower mRS (1.0 points lower, 95% CI (0.2, 1.8) compared to ischemic stroke, p = 0.01) after adjustment for other potential predictors. This underscores the importance of HIV infection on functional stroke outcomes beyond its recognized influence on stroke risk.

Infectious Meningitis and Encephalitis.

The clinician who is evaluating a patient with a suspected central nervous system infection often faces a large differential diagnosis. There are several signs, symptoms, geographical clues, and diagnostic testing, such as cerebrospinal fluid abnormalities and magnetic resonance imaging abnormalities, which can be helpful in identifying the etiological agent. By taking a systematic approach, one can often identify life-threatening, common, and/or treatable etiologies. Here the authors describe some of the pearls and pitfalls in diagnosing and treating acute infectious meningitis and encephalitis.

Utility of measuring (1,3)-ß-d-glucan in cerebrospinal fluid for diagnosis of fungal central nervous system infection.

(1-3)-ß-d-Glucan (BDG) from cerebrospinal fluid (CSF) is a promising marker for diagnostic and prognostic aid of central nervous system (CNS) fungal infection, but its relationship to serum values has not been studied. Herein, we detected BDG from CSF at levels 2-fold lower than those in serum in patients without evidence of fungal disease but 25-fold higher than those in in serum in noncryptococcal CNS fungal infections. CSF BDG may be a useful biomarker in the evaluation of fungal CNS disease.

Utility of (1-3)-ß-D-glucan testing for diagnostics and monitoring response to treatment during the multistate outbreak of fungal meningitis and other infections.

BACKGROUND: The 2012 outbreak of fungal meningitis associated with contaminated methylprednisolone produced by a compounding pharmacy has resulted in >750 infections. An important question facing patients and clinicians is the duration of antifungal therapy. We evaluated (1-3)-ß-d-glucan (BDG) as a marker for monitoring response to treatment. METHODS: We determined sensitivity and specificity of BDG testing using the Fungitell assay, by testing 41 cerebrospinal fluid (CSF) specimens from confirmed cases of fungal meningitis and 66 negative control CSF specimens. We also assessed whether BDG levels correlate with clinical status by using incident samples from 108 case patients with meningitis and 20 patients with serially collected CSF. RESULTS: A cutoff value of 138 pg/mL provided 100% sensitivity and 98% specificity for diagnosis of fungal meningitis in this outbreak. Patients with serially collected CSF were divided into 2 groups: those in whom BDG levels declined with treatment and those in whom BDG remained elevated. Whereas most patients with a decline in CSF BDG had clinical improvement, all 3 patients with continually elevated BDG had poor clinical outcomes (stroke, meningitis relapse, or development of new disease). CONCLUSIONS: Our data suggest that measuring BDG in CSF is a highly sensitive test for diagnosis of fungal meningitis in this outbreak. Analysis of BDG levels in serially collected CSF demonstrated that BDG may correlate with clinical response. Routine measurement of BDG in CSF may provide useful adjunctive data for the clinical management of patients with outbreak-associated meningitis.

Hemorrhagic and ischemic stroke secondary to herpes simplex virus type 2 meningitis and vasculopathy.

Herpes simplex virus type 2 (HSV-2) meningitis dogmatically is benign and self-limited in the immune competent patient. However, we describe how left untreated HSV-2 meningitis can be complicated by vasculitis and both ischemic and hemorrhagic stroke. We report a 57-year-old woman with lymphocytic meningitis complicated by ischemic stroke and intracerebral hemorrhage in the setting of vasculopathy and HSV-2 DNA detected in CSF successfully treated with acyclovir and corticosteroids. Subsequent angiographic magnetic resonance imaging revealed improvement in the vasculopathy after treatment. This case demonstrates that HSV-2 meningitis may take a less benign course and further provides the first evidence of angiographic improvement in addition to clinical improvement after definitive treatment.

Cerebrospinal fluid (1,3)-ß-D-glucan detection as an aid for diagnosis of iatrogenic fungal meningitis.

This case series highlights our experience with use of the Fungitell assay for quantifying (1,3)-ß-d-glucan in cerebrospinal fluid during the current U.S. outbreak of fungal meningitis related to contaminated methylprednisolone acetate. This test may prove a useful adjunct in diagnosis and management of exposed patients.

Iatrogenic Exserohilum infection of the central nervous system: mycological identification and histopathological findings.

An outbreak of fungal infections has been identified in patients who received epidural injections of methylprednisolone acetate that was contaminated with environmental molds. In this report, we present the mycological and histopathological findings in an index case of Exserohilum meningitis and vasculitis in an immunocompetent patient, who received a cervical spine epidural steroid injection for chronic neck pain 1 week before the onset of fulminant meningitis with subsequent multiple brain and spinal cord infarcts. The fungus was recovered from two separate cerebrospinal fluid specimens collected before initiation of antifungal therapy and at autopsy on standard bacterial and fungal culture media. The mold was identified phenotypically as Exserohilum species. DNA sequencing targeting the internal transcribed spacer region and D1/D2 region of 28S ribosomal DNA enabled further speciation as E. rostratum. Gross examination at autopsy revealed moderate brain edema with bilateral uncal herniation and a ventriculostomy tract to the third ventricle. The brainstem, cerebellum, and right orbitofrontal cortex were soft and friable, along with hemorrhages in the cerebellar vermis and thalamus. Microscopic examination demonstrated numerous fungi with septate hyphae invading blood vessel walls and inducing acute necrotizing inflammation. The leptomeninges were diffusely infiltrated by mixed inflammatory cells along with scattered foci of fungal elements. This is the first report of iatrogenic E. rostratum meningitis in humans. This report describes the microbiological procedures and histopathological features for the identification of E. rostratum (a pigmented vascularly invasive fungi), the cause of a current nationwide outbreak of fatal fungal meningitis.

Viral Meningitis and Encephalitis.

PURPOSE OF REVIEW: This article discusses meningitis and encephalitis infections caused by viruses, excluding herpes family and human immunodeficiency virus (HIV). RECENT FINDINGS: The viral infections of the nervous system detailed in this article have no specific treatment other than supportive care. However, many of the viruses discussed are highly preventable by vaccination, proper skin protection against transmitting vectors, and postexposure prophylaxis. SUMMARY: While meningitis and encephalitis caused by viruses may have some clinical overlap, the management and outcomes can be highly disparate, making distinction between the two imperative. Furthermore, despite their relative rarity in terms of clinical disease, many of the viral infections discussed herein are highly preventable. Given the morbidity and mortality attached to such infections, provider and patient education are the best approach available to prevent these potentially devastating illnesses.

HIV and spinal cord disease.

The epidemiology of spinal cord disease in human immunodeficiency virus (HIV) infection is largely unknown due to a paucity of data since combination antiretroviral therapy (cART). HIV mediates spinal cord injury indirectly, by immune modulation, degeneration, or associated infections and neoplasms. The pathologies vary and range from cytotoxic necrosis to demyelination and vasculitis. Control of HIV determines the differential for all neurologic presentations in infected individuals. Primary HIV-associated acute transverse myelitis, an acute inflammatory condition with pathologic similarities to HIV encephalitis, arises in early infection and at seroconversion. In contrast, HIV vacuolar myelopathy and opportunistic infections predominate in uncontrolled disease. There is systemic immune dysregulation as early as primary infection due to initial depletion of gut-associated lymphoid tissue CD4 cells and allowance of microbial translocation across the gut that never fully recovers throughout the course of HIV infection, regardless of how well controlled. The subsequent proinflammatory state may contribute to spinal cord diseases observed even after cART initiation. This chapter will highlight an array of spinal cord pathologies classified by stage of HIV infection and immune status.

Infections of the Nervous System.

Microorganisms can affect the entire neuraxis, producing a variety of neurologic complications that frequently entail prolonged hospitalizations and complicated treatment regimens. The spread of pathogens to new regions and the reemergence of opportunistic organisms in immunocompromised patients pose increasing challenges to health care professionals. Because rapid diagnosis and treatment may prevent long-term neurologic sequelae, providers should approach these diseases with a structured, neuroanatomic framework, incorporating a thorough history, examination, laboratory analysis, and neuroimaging in their clinical reasoning and decision-making.

Clinical pathologic case report: A 70-year-old man with inflammatory cerebral amyloid angiopathy causing headache, cognitive impairment, and aphasia.

A 70-year-old man presented with two months of worsening cognitive impairment, hallucinations, and difficulty speaking, with superimposed headaches. Cerebrospinal fluid analysis was notable for lymphocytic pleocytosis and elevated protein. Imaging studies revealed multiple acute and subacute infarcts with cortical microhemorrhages. The patient underwent a stereotactic brain biopsy. In this article, we discuss the patient's differential diagnosis, pathologic findings, ultimate diagnosis, and clinical outcome.

DNannotator: Annotation software tool kit for regional genomic sequences.

Sequence annotation is essential for genomics-based research. Investigators of a specific genomic region who have developed abundant local discoveries such as genes and genetic markers, or have collected annotations from multiple resources, can be overwhelmed by the difficulty in creating local annotation and the complexity of integrating all the annotations. Presenting such integrated data in a form suitable for data mining and high-throughput experimental design is even more daunting. DNannotator, a web application, was designed to perform batch annotation on a sizeable genomic region. It takes annotation source data, such as SNPs, genes, primers, and so on, prepared by the end-user and/or a specified target of genomic DNA, and performs de novo annotation. DNannotator can also robustly migrate existing annotations in GenBank format from one sequence to another. Annotation results are provided in GenBank format and in tab-delimited text, which can be imported and managed in a database or spreadsheet and combined with existing annotation as desired. Graphic viewers, such as Genome Browser or Artemis, can display the annotation results. Reference data (reports on the process) facilitating the user's evaluation of annotation quality are optionally provided. DNannotator can be accessed at http://sky.bsd.uchicago.edu/DNannotator.htm.