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ObjectiveTo delineate a comprehensive curriculum for fellowship training in neuroinfectious diseases, we conducted a modified Delphi approach to reach consensus among 11 experts in the field.MethodsThe authors invited a diverse range of experts from the American Academy of Neurology Neuro-Infectious Diseases (AAN Neuro-ID) Section to participate in a consensus process using a modified Delphi technique.ResultsA comprehensive list of topics was generated with 101 initial items. Through 3 rounds of voting and discussion, a curriculum with 83 items reached consensus.ConclusionsThe modified Delphi technique provides an efficient and rigorous means to reach consensus on topics requiring expert opinion. The AAN Neuro-ID section provided the pool of diverse experts, the infrastructure, and the community through which to accomplish the consensus project successfully. This process could be applied to other subspecialties and sections at the AAN.

Importance Identifying infectious causes of subacute or chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. Objective To present a case series of patients with diagnostically challenging subacute or chronic meningitis using metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) supported by a statistical framework generated from mNGS of control samples from the environment and from patients who were noninfectious. Design, Setting, and Participants In this case series, mNGS data obtained from the CSF of 94 patients with noninfectious neuroinflammatory disorders and from 24 water and reagent control samples were used to develop and implement a weighted scoring metric based onzscores at the species and genus levels for both nucleotide and protein alignments to prioritize and rank the mNGS results. Total RNA was extracted for mNGS from the CSF of 7 participants with subacute or chronic meningitis who were recruited between September 2013 and March 2017 as part of a multicenter study of mNGS pathogen discovery among patients with suspected neuroinflammatory conditions. The neurologic infections identified by mNGS in these 7 participants represented a diverse array of pathogens. The patients were referred from the University of California, San Francisco Medical Center (n = 2), Zuckerberg San Francisco General Hospital and Trauma Center (n = 2), Cleveland Clinic (n = 1), University of Washington (n = 1), and Kaiser Permanente (n = 1). A weightedzscore was used to filter out environmental contaminants and facilitate efficient data triage and analysis. Main Outcomes and Measures Pathogens identified by mNGS and the ability of a statistical model to prioritize, rank, and simplify mNGS results. Results The 7 participants ranged in age from 10 to 55 years, and 3 (43%) were female. A parasitic worm (Taenia solium, in 2 participants), a virus (HIV-1), and 4 fungi (Cryptococcus neoformans,Aspergillus oryzae,Histoplasma capsulatum, andCandida dubliniensis) were identified among the 7 participants by using mNGS. Evaluating mNGS data with a weightedzscore–based scoring algorithm reduced the reported microbial taxa by a mean of 87% (range, 41%-99%) when taxa with a combined score of 0 or less were removed, effectively separating bona fide pathogen sequences from spurious environmental sequences so that, in each case, the causative pathogen was found within the top 2 scoring microbes identified using the algorithm. Conclusions and Relevance Diverse microbial pathogens were identified by mNGS in the CSF of patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for 1 year, the first reported case of CNS vasculitis caused byAspergillus oryzae, and the fourth reported case ofC dubliniensismeningitis. Prioritizing metagenomic data with a scoring algorithm greatly clarified data interpretation and highlighted the problem of attributing biological significance to organisms present in control samples used for metagenomic sequencing studies.

Diagnosis of CNS viral infections is challenging; yet, significant progress in laboratory diagnosis of CNS infections has come through applications of serology and polymerase chain reaction (PCR) to CSF and tissues. Advances in molecular and laboratory techniques, together with neuroimaging, epidemiologic, and surveillance efforts, are yielding greater success in CNS viral diagnosis and treatment.

In 2001, the incidence of primary and secondary syphilis increased in the United States for the first time in a decade. Increasing rates of early syphilis among men who have sex with men have been reported in many American cities, with similar outbreaks noted in Canada and Europe. In San Francisco, the increase has been particularly sharp and accompanied by an increase in the incidence of neurosyphilis. Early neurosyphilis develops within weeks to years of primary infection and primarily involves the meninges. Syndromes include syphilitic meningitis (often accompanied by cranial neuropathies), meningovascular syphilis (with associated ischemic stroke), or asymptomatic neurosyphilis. Late neurosyphilis occurs years to decades after exposure as cerebral or spinal gummatous disease or the classic parenchymal forms affecting the brain (general paresis or syphilitic encephalitis) or spinal cord and nerve roots (tabes dorsalis). Treponema pallidum, the causative agent, cannot be cultured in vitro, and microscopic techniques are laborious. Thus, diagnosis depends on serologic tests and cerebrospinal fluid (CSF) examination. The suboptimal sensitivity and specificity of these tests complicate diagnosis, particularly among patients coinfected with HIV. CSF examination should be performed to evaluate for neurosyphilis in all patients with positive serum syphilis serology and neurologic, ophthalmic, or tertiary disease, or in those who have failed therapy, and in HIV-infected patients with late latent syphilis or syphilis of unknown duration. Intravenous penicillin G is the recommended treatment for all forms of neurosyphilis and for syphilitic eye disease. An outpatient alternative, if adherence can be assured, is intramuscular benzathine penicillin with oral probenecid. Newer drugs that penetrate CSF, such as ceftriaxone or azithromycin, have not yet been adequately tested for neurosyphilis. Syphilis facilitates transmission of HIV (and vice versa), and thus all patients diagnosed with syphilis should be offered HIV testing.

A 61-year-old man presented with orthostatic headaches and asymmetric sensorineural hearing loss (ASNHL) 8 years after cervical laminoplasty. Percussion of his cervical spine elicited Lhermitte sign. Brain MRI demonstrated trace intraventricular blood and mild superficial siderosis (figure 1); digital subtraction angiogram had normal results. CT myelogram revealed fractured hardware puncturing adjacent dura with resultant CSF leak (figure 2).

Even at a time when HIV/AIDS and immunosuppressive therapy have increased the number of individuals living with significant immunocompromise, diabetes mellitus (DM) remains a major comorbid disorder for several rare but potentially lethal infections, including rhino-orbital-cerebral mucormycosis and malignant external otitis. DM is also a commonly associated condition in patients with nontropical pyomyositis, pyogenic spinal infections, Listeria meningitis, and blastomycosis. As West Nile virus spread to and across North America over a decade ago, DM appeared in many series as a risk factor for death or neuroinvasive disease. More recently, in several large international population-based studies, DM was identified as a risk factor for herpes zoster. The relationships among infection, DM, and the nervous system are multidirectional. Viral infections have been implicated in the pathogenesis of type 1 and type 2 DM, while parasitic infections have been hypothesized to protect against autoimmune disorders, including type 1 DM. DM-related neurologic disease can predispose to systemic infection - polyneuropathy is the predominant risk factor for diabetic foot infection. Because prognosis for many neurologic infections depends on timely institution of antimicrobial and sometimes surgical therapy, neurologists caring for diabetic patients should be familiar with the clinical features of the neuroinfectious syndromes associated with DM.

Migraine, stroke, epilepsy, certain movement disorders, and some primary brain tumors are among common neurologic disorders influenced by sex hormones. Central or peripheral nervous system dysfunction may herald disorders of the pituitary, parathyroid, or adrenal gland or complicate established endocrinopathies. Anterior pituitary excess states may occur with pituitary adenomas; macroadenomas may result in deficiency of one or more hormones or disrupt vision by compromise of upper cranial nerves. Excess or deficiency of antidiuretic hormone, synthesized in the posterior pituitary, causes the syndrome of inappropriate antidiuretic hormone or diabetes insipidus, respectively, and may result from disorders of the nervous system. Parathyroid dysfunction can lead to calcium abnormalities with resultant neurologic symptoms. Adrenal excess and deficiency states may impair neuropsychiatric or neuromuscular function.

Even at a time when HIV/AIDS and immunosuppressive therapy have increased the number of individuals living with significant immunocompromise, diabetes mellitus (DM) remains a major comorbid disorder for several rare but potentially lethal infections, including rhino-orbital-cerebral mucormycosis and malignant external otitis. DM is also a commonly associated condition in patients with nontropical pyomyositis, pyogenic spinal infections, Listeria meningitis, and blastomycosis. As West Nile virus spread to and across North America over a decade ago, DM appeared in many series as a risk factor for death or neuroinvasive disease. More recently, in several large international population-based studies, DM was identified as a risk factor for herpes zoster. The relationships among infection, DM, and the nervous system are multidirectional. Viral infections have been implicated in the pathogenesis of type 1 and type 2 DM, while parasitic infections have been hypothesized to protect against autoimmune disorders, including type 1 DM. DM-related neurologic disease can predispose to systemic infection - polyneuropathy is the predominant risk factor for diabetic foot infection. Because prognosis for many neurologic infections depends on timely institution of antimicrobial and sometimes surgical therapy, neurologists caring for diabetic patients should be familiar with the clinical features of the neuroinfectious syndromes associated with DM.

MAJOR ARTICLE HIV/AIDS Randomized Trial of Central Nervous System–Targeted Antiretrovirals for HIV-Associated Neurocognitive Disorder Ronald J. Ellis, 1 Scott Letendre, 2 Florin Vaida, 3 Richard Haubrich, 2 Robert K. Heaton, 4 Ned Sacktor, 7 David B. Clifford, 8 Brookie M. Best, 5 Susanne May, 9 Anya Umlauf, 4 Mariana Cherner, 4 Chelsea Sanders, 4 Craig Ballard, 6 David M. Simpson, 10 Cheryl Jay, 11 and J. Allen McCutchan 2 Departments of 1 Neurosciences, 2 Medicine, 3 Family & Preventive Medicine, and 4 Psychiatry, HIV Neurobehavioral Research Center, and Departments of Clinical Pharmacy and Pediatrics and 6 Pharmacy, University of California, San Diego; 7 Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; 8 Department of Neurology, Washington University, St. Louis, Missouri; 9 Department of Biostatistics, University of Washington, Seattle; 10 Department of Neurology, Mount Sinai Medical Center, New York, New York; and 11 Department of Neurology, University of California, San Francisco Background. Antiretroviral (ARV) medications differentially penetrate across the blood-brain barrier into central nervous system (CNS) tissues, potentially influencing their effectiveness in treating brain infection. Methods. This randomized controlled clinical trial (RCT) called for 120 participants at 5 study sites to be ran- domized 1:1 to CNS-targeted (CNS-T) or non–CNS-T ART. Entry clinical factors such as ARV experience were balanced across arms using an adaptive randomization approach. The primary outcome, change in neurocognitive performance, was measured as the difference in global deficit score (GDS) from baseline to week 16. Results. The study was terminated early on the recommendation of its data safety monitoring board on the basis of slow accrual and a low likelihood of detecting a difference in the primary outcome. No safety concerns were identified. Of 326 participants screened, 59 met entry criteria and were randomized. The primary intent- to-treat analysis included 49 participants who completed week 16. These comprised 39 men and 10 women with a mean age of 44 years (SD, 10 years), and median nadir and current CD4 + T-cell counts of 175 cells/µL and 242 cells/µL, respectively. The proportional improvement in GDS from baseline was nonsignificantly larger (7%; 95% confidence interval [CI], −31% to 62%) in the CNS-T arm than in the non-CNS-T arm, representing a treatment effect size of 0.09 (95% CI, −.48 to .65). Prespecified secondary analysis showed a trend interaction (P = .087), indicating that participants who had baseline plasma virologic suppression may have benefited from CNS-T. Conclusions. This study found no evidence of neurocognitive benefit for a CNS-T strategy in HIV-associat- ed neurocognitive disorders. A benefit for a subgroup or small overall benefits could not be excluded. Clinical Trials Registration. NCT00624195. Keywords. HIV; AIDS; cognitive disorders/dementia; antiretroviral therapy. Antiretroviral therapy (ART) benefits cognition in most people living with human immunodeficiency virus (HIV) [1], but not all benefit equally, and Received 19 August 2013; accepted 3 December 2013; electronically published 18 December 2013. Correspondence: Ronald J. Ellis, MD, PhD, University of California, San Diego, 220 Dickinson St, Suite B, Mailcode 8231, San Diego, CA 92103 (roellis@ucsd. edu). Clinical Infectious Diseases 2014;58(7):1015–22 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. DOI: 10.1093/cid/cit921 impairment persists in up to 50% [2]. Cognitively im- paired individuals are less likely to achieve virologic suppression [3]. In 2007, these and other changes prompted revisions in diagnostic criteria for HIV- associated neurocognitive disorder (HAND [4]), which includes HIV-associated dementia, mild neuro- cognitive disorder, and asymptomatic neurocognitive impairment. The present study hypothesized that achieving better distribution of antiretrovirals (ARVs) into the central nervous system (CNS) would reduce viral repli- cation, normalize downstream mediators of neuronal HIV/AIDS CID 2014:58 (1 April)

HIV-infected patients are vulnerable to developing altered mental status (AMS) for myriad reasons, including the effects of HIV itself, the accompanying immune dysfunction, associated systemic illness, comorbid psychiatric disorders, and complicated medication regimens. Combination antiretroviral therapy (ART) has decreased the incidence of central nervous system (CNS) opportunistic infections (OIs) and HIV-associated dementia, but the benefits are not absolute. In addition to CNS OIs and complications of complex multisystem disease, immune reconstitution events developing in the early weeks and months after initiating ART may affect the brain and cause AMS. This article examines the epidemiology, diagnosis, and currently available treatment for patients with HIV-related AMS.

Highly active antiretroviral therapy (HAART) has decreased opportunistic infections (OI) and AIDS deaths. Institution of HAART in advanced AIDS, however, may be complicated by the immune reconstitution syndrome (IRS)—inflammatory reactions leading to autoimmune diseases or atypical manifestations of OI.1 A 31-year-old man had progressive gait difficulty over 4 weeks. Examination revealed left leg weakness with impaired vibratory and position sense and pin and temperature loss to T5 on the right. HIV serology was positive with CD4 count 35/mm3 and viral load 26,000 copies/mL. Spine MRI showed a 1-cm enhancing, intradural, extramedullary mass at left T4 (figure, A). Results of cranial MRI were normal. Lumbar puncture revealed protein 153 mg/dL, glucose 37 mg/dL, and 73 white blood cells/mm3 (81% lymphocytes). Chest film was normal; purified protein derivative and controls were unreactive. The mass was resected. Pathology revealed abundant acid-fast organisms. Specific mycobacterial organism was not identified. Four agents against Mycobacterium tuberculosis (MTB) were begun; clarithromycin was added to cover Mycobacterium avium complex (MAC). Postoperatively, motor examination normalized. Mild sensory deficits …

The use of zidovudine (AZT) for the treatment of acquired immunodeficiency syndrome (AIDS) induces a DNA-depleting mitochondrial myopathy, which is histologically characterized by the presence of muscle fibers with "ragged-red"-like features, red-rimmed or empty cracks, granular degeneration, and rods (AZT fibers). Because dysfunctioning muscle mitochondria may lead to defects of beta-oxidation of fatty acids, we examined the degree of neutral fat accumulation and muscle carnitine levels in the muscle biopsy specimens from 21 patients with AZT-induced myopathic symptoms of varying severity. Six patients with no AZT fibers had normal endomyofibrillar lipid deposits and muscle carnitine levels; 7 patients with fewer than 5 AZT fibers per field had a mild (+) to moderate (++) increase in lipid droplets, and reduced muscle carnitine levels (3 patients); and 8 patients with more than 5 AZT fibers had severe muscle changes, a ++ to marked ( ) increase in lipid droplets, and reduced muscle carnitine levels (6 patients). Serial sections showed lipid globules often within "cracks" or vacuoles of the abnormal muscle fibers. We conclude that the muscle mitochondrial impairment caused by AZT results in (1) accumulation of lipid within the muscle fibers owing to poor utilization of long-chain fatty acids, (2) reduction of muscle carnitine levels probably due to decreased carnitine uptake by the muscle, and (3) depletion of energy stores within the muscle fibers. The findings may have potential therapeutic implications in the treatment of AZT-induced myopathic symptoms using oral carnitine supplementation.