Jennifer L. Lyons

Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection.

Background:Activated monocytes/macrophages play a role in severe forms of HIV-associated neurocognitive disorders (HAND), but little is known about the mechanisms driving milder forms that are prevalent despite combination antiretroviral therapy (cART). To examine relationships of monocyte activation markers to HAND of varying severity, we compared plasma and cerebrospinal fluid (CSF) biomarker levels with neurocognitive test scores in HIV+ subjects. Methods:Plasma and CSF soluble CD14 (sCD14), CCL2, and interleukin (IL) 6 were measured by enzyme-linked immunosorbent assay in 67 HIV+ subjects with nadir CD4 <300, and CSF inflammatory biomarkers were measured by multiplex assay in 14 subjects on suppressive cART. Results:Eighty-two percent were on cART, with 31% having undetectable plasma viral load (VL). CSF sCD14 was increased in subjects with impaired neurocognitive testing (P = 0.02), correlated inversely with global T scores in subjects with detectable but not undetectable plasma VL (P = 0.02), and yielded higher area under the receiver operating characteristic curve values for predicting impaired T scores (0.659) than plasma or CSF VL and current or nadir CD4 counts in single-marker and multivariate models. CSF sCD14, IL-6, IL-8, CCL2, CCL3, CXCL10, and interferon (IFN) gamma were increased in subjects on suppressive cART regardless of cognitive status and predicted patient class in unsupervised analyses, with IL-8, CCL2, and IFN&ggr; explaining most of the variance. Conclusions:CSF sCD14 is associated with impaired neurocognitive testing in patients with HIV on nonsuppressive cART, suggesting potential utility as a biomarker to monitor HAND progression. CSF sCD14, IL-6, IL-8, CCL2, CCL3, CXCL10, and IFN&ggr; remain elevated in patients on suppressive cART regardless of cognitive status, implying ongoing intrathecal inflammation even in the absence of clinical manifestations.

Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection

Objective:Mild forms of HIV-associated neurocognitive disorders (HAND) remain prevalent in the era of combination antiretroviral therapy (cART). Although elevated lipopolysaccharide (LPS) and immune activation are implicated in HAND pathogenesis, relationships of LPS and inflammatory markers to mild forms of HAND or impairment in specific cognitive domains are unknown. To examine these relationships, we compared plasma soluble CD14 (sCD14), CCL2, and LPS levels with neurocognitive test scores in a cART era cohort. Methods:We analyzed plasma from HIV+ subjects (n = 97) with nadir CD4 counts <300 and high frequency of hepatitis C virus coinfection and illicit drug use for relationships between sCD14, CCL2, and LPS levels and neurocognitive test scores. Results:Plasma sCD14 levels were higher in subjects with test scores indicating global impairment (P = 0.007), particularly in attention and learning domains (P = 0.015 and P = 0.03, respectively), regardless of HAND diagnosis. Plasma sCD14 levels correlated inversely with global, attention, and learning T scores (P = 0.036, 0.047, and 0.007, respectively) and yielded higher area under receiver operating characteristic values for predicting impaired scores than single-marker models based on plasma or cerebrospinal fluid viral load or CD4 count (area under receiver operating characteristic values = 0.71, 0.81, and 0.71, respectively) and in 4-marker models based on plasma sCD14 and 3 conventional markers compared with the 3-marker models. Conclusions:Plasma sCD14 is a biomarker associated with impaired neurocognitive testing in attention and learning domains in HIV-infected individuals with advanced disease, suggesting involvement of cortical and limbic pathways by inflammatory processes in the cART era. Plasma sCD14 is a potential biomarker to monitor HAND progression and therapeutic responses.

Utility of (1–3)-β-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)-β-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.

Cerebrospinal Fluid (1,3)-β-d-Glucan Detection as an Aid for Diagnosis of Iatrogenic Fungal Meningitis

ABSTRACT This case series highlights our experience with use of the Fungitell assay for quantifying (1,3)-β-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.

Infectious causes of stroke.

Most infectious pathogens have anecdotal evidence to support a link with stroke, but certain pathogens have more robust associations, in which causation is probable. Few dedicated prospective studies of stroke in the setting of infection have been done. The use of head imaging, a clinical standard of diagnostic care, to confirm stroke and stroke type is not universal. Data for stroke are scarce in locations where infections are probably most common, making it difficult to reach conclusions on how populations differ in terms of risk of infectious stroke. The treatment of infections and stroke, when concomitant, is based on almost no evidence and requires dedicated efforts to understand variations that might exist. We highlight the present knowledge and emphasise the need for stronger evidence to assist in the diagnosis, treatment, and secondary prevention of stroke in patients in whom an infectious cause for stroke is probable.

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.

Nonfatal PML in a patient with multiple sclerosis treated with dimethyl fumarate.

Dimethyl fumarate (DMF) is an oral medication for multiple sclerosis (MS) that is prescribed in part for its favorable safety profile. There have been 5 reported cases of progressive multifocal leukoencephalopathy (PML) with the use of fumaric acid esters in patients with psoriasis.1 Some have been on concomitant or prior immunosuppression and most had absolute lymphocyte counts (ALC) below 500. To date, 4 cases of PML (one published) have been reported in patients with MS on DMF (personal communication, Biogen, 2016).2 Herein, we report the details of one of these 4 cases: nonfatal PML in a patient with MS on DMF.

Utility of Measuring (1,3)-β-d-Glucan in Cerebrospinal Fluid for Diagnosis of Fungal Central Nervous System Infection

ABSTRACT (1-3)-β-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.

Worldwide reported use of IV tissue plasminogen activator for acute ischemic stroke

Background and Purpose Intravenous tissue plasminogen activator is the most effective treatment for acute ischemic stroke, and its use may therefore serve as an indicator of the available level of acute stroke care. The greatest burden of stroke is in low- and middle-income countries, but the extent to which intravenous tissue plasminogen activator is used in these countries is unreported. Summary of Review A systematic review was performed searching each country name AND ‘stroke’ OR ‘tissue plasminogen activator’ OR ‘thrombolysis’ using PubMed, Embase, Global Health, African Index Medicus, and abstracts published in the International Journal of Stroke (Jan. 1, 1996–Oct. 1, 2012). The reported use of intravenous tissue plasminogen activator was then analyzed according to country-level income status, total expenditure on health per capita, and mortality and disability-adjusted life years due to stroke. There were 118 780 citations reviewed. Of 214 countries and independent territories, 64 (30%) reported use of intravenous tissue plasminogen activator for acute ischemic stroke in the medical literature: 3% (1/36) low-income, 19% (10/54) lower-middle-income, 33% (18/54) upper-middle-income, and 50% (35/70) high-income-countries (test for trend, P < 0·001). When considering country-level determinants of reported intravenous tissue plasminogen activator use for acute ischemic stroke, total healthcare expenditure per capita (odds ratio 3·3 per 1000 international dollar increase, 95% confidence interval 1·4–9·9, P = 0·02) and reported mortality rate from cerebrovascular disease (odds ratio 1·02, 95% confidence interval 0·99–1·06, P = 0·02) were significant, but reported disability-adjusted life years from cerebrovascular diseases and gross national income per capita were not (P > 0·05). Of the 10 countries with the highest disability-adjusted life years due to stroke, only one reported intravenous tissue plasminogen activator use. Conclusions By reported use, intravenous tissue plasminogen activator for acute ischemic stroke is available to some patients in approximately one-third of countries. Access to advanced acute stroke care is most limited where the greatest burden of cerebrovascular disease is reported.

International electives in neurology training: A survey of US and Canadian program directors

Objective: To ascertain the current status of global health training and humanitarian relief opportunities in US and Canadian postgraduate neurology programs. Background: There is a growing interest among North American trainees to pursue medical electives in low- and middle-income countries. Such training opportunities provide many educational and humanitarian benefits but also pose several challenges related to organization, human resources, funding, and trainee and patient safety. The current support and engagement of neurology postgraduate training programs for trainees to pursue international rotations is unknown. Methods: A survey was distributed to all program directors in the United States and Canada (December 2012–February 2013) through the American Academy of Neurology to assess the training opportunities, institutional partnerships, and support available for international neurology electives. Results: Approximately half of responding programs (53%) allow residents to pursue global health–related electives, and 11% reported that at least 1 trainee participated in humanitarian relief during training (survey response rate 61%, 143/234 program directors). Canadian programs were more likely to allow residents to pursue international electives than US programs (10/11, 91% vs 65/129, 50%, p = 0.023). The number of trainees participating in international electives was low: 0%–9% of residents (55% of programs) and 10%–19% of residents (21% of programs). Lack of funding was the most commonly cited reason for residents not participating in global health electives. If funding was available, 93% of program directors stated there would be time for residents to participate. Most program directors (75%) were interested in further information on global health electives. Conclusions: In spite of high perceived interest, only half of US neurology training programs include international electives, mostly due to a reported lack of funding. By contrast, the majority of Canadian programs that responded allow international electives, likely due to clearer guidelines from the Royal College of Physicians and Surgeons of Canada compared to the Accreditation Council of Graduate Medical Education. However, the number of both Canadian and US neurology trainees venturing abroad remains a minority. Most program directors are interested in learning more information related to global health electives for neurology residents.