Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

Antibiotics for the neurological complications of Lyme disease.

BACKGROUND: Various central nervous system-penetrant antibiotics are bactericidal in vitro and in vivo against the causative agent of Lyme neuroborreliosis (LNB), Borrelia burgdorferi. These antibiotics are routinely used clinically to treat LNB, but their relative efficacy is not clear. OBJECTIVES: To assess the effects of antibiotics for the treatment of LNB. SEARCH METHODS: On 25 October 2016 we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We searched clinical trial registers on 26 October 2016. We reviewed the bibliographies of the randomized trials identified and contacted the authors and known experts in the field to identify additional published or unpublished data. There were no language restrictions when searching for studies. SELECTION CRITERIA: Randomized clinical trials of antibiotic treatment of LNB in adults and children that compared any antibiotic treatment, including combinations of treatments, versus any other treatment, placebo, or no treatment. We excluded studies of entities considered as post-Lyme syndrome. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified seven randomized studies involving 450 European participants with LNB for inclusion in this systematic review. We found no trials conducted in the United States. Marked heterogeneity among these studies prevented meta-analysis. None of the studies included a placebo control on the initial antibiotic treatment, and only one was blinded. None were delayed-start studies. All were active comparator studies, and most were not adequately powered for non-inferiority comparison. The trials investigated four antibiotics: penicillin G and ceftriaxone in four studies, doxycycline in three studies, and cefotaxime in two studies. One study tested a three-month course of oral amoxicillin versus placebo following initial treatment with intravenous ceftriaxone. One study was limited to children. The trials measured efficacy using heterogeneous physician- or patient-reported outcomes, or both. In some cases cerebrospinal fluid analysis was included as an indirect biomarker of disease and outcome. None of the studies reported on our proposed primary outcome, 'Improvement in a measure of overall disability in the long term (three or more months).' None of the trials revealed any between-group differences in symptom resolution in response to active treatment. In general, treatment was tolerated well. The quality of adverse event reporting, however, was low. AUTHORS' CONCLUSIONS: There is mostly low- to very low-quality clinical evidence from a limited number of mostly small, heterogeneous trials with diverse outcome measures, comparing the relative efficacy of central nervous system-penetrant antibiotics for the treatment of LNB. The few existing randomized studies have limited power and lack consistent and well-defined entry criteria and efficacy endpoints. It is not possible to draw firm conclusions on the relative efficacy of accepted antibiotic drug regimens for the treatment of LNB. The majority of people are reported to have good outcomes, and symptoms resolve by 12 months regardless of the antibiotic used. A minority of participants did not improve sufficiently, and some were retreated. These randomized studies provide some evidence that doxycycline, penicillin G, ceftriaxone, and cefotaxime are efficacious in the treatment of European LNB. No evidence of additional efficacy was observed when, in one study, an initial antibiotic treatment with intravenous ceftriaxone was followed by additional longer treatment with oral amoxicillin. There is a lack of evidence identified through our high-quality search strategy on the efficacy of antibiotics for treatment of LNB in the United States.

HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors.

PURPOSE: Human immunodeficiency virus-1 (HIV)-associated neurocognitive disorder (HAND) is a neurodegenerative disease for which there is no available neuroprotective therapy. Viral proteins, such as Tat, have been implicated as agents of neurotoxicity via multiple mechanisms, including effects by directly binding to the NMDA receptor. We evaluated the ability of the immune response against Tat to modulate neurotoxicity at glutamate receptors. METHODS: Neurotoxicity was measured in primary neuronal-glial cultures and in hippocampal slice cultures. We used immunoprecipitation experiments to demonstrate interaction between Tat, NMDA receptor, and anti-Tat antibody. Using known structures of Tat and NMDA receptors, we developed a model of their interactions. RESULTS: Antibodies to Tat attenuated Tat-mediated neurotoxicity. Interestingly, Tat immune complexes also blocked neurotoxicity caused by NMDA receptor agonists but not kainate/AMPA receptor agonists. Neither Tat nor antibody alone blocked the excitotoxic effect, nor did an unrelated antigen-antibody complex. The protective effect of the Tat immune complexes was also lost when Tat was modified by nitrosylation or by using a deletion mutant of Tat. CONCLUSIONS: The ability of viral immune complexes to interact with NMDA receptors and prevent excitotoxicity represents a novel host defense mechanism. Host immune responses may influence host susceptibility to various effects of viral proteins, modulating HIV complications, such as onset of HAND. These observations provide rationale for development of vaccine therapies targeting Tat for prevention of HAND.

Clinical Practice Guidelines by the Infectious Diseases Society of America, American Academy of Neurology, and American College of Rheumatology: 2020 Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

Building a neuroinfectious disease consensus curriculum.

OBJECTIVE: To 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. METHODS: The 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. RESULTS: A comprehensive list of topics was generated with 101 initial items. Through 3 rounds of voting and discussion, a curriculum with 83 items reached consensus. CONCLUSIONS: The 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.

Evolution of HIV dementia with HIV infection.

Dementia remains one of the most fearsome complications of HIV infection. It also poses a significant challenge for the clinician both in terms of diagnosis and treatment. The use of antiretroviral agents has led to a decrease in the incidence of HIV dementia but the prevalence of milder forms of neurocognitive impairment has increased. Occasionally, the immune reconstitution caused by these agents may target the brain leading to a syndrome characterized by a severe, progressive and often fatal dementia. The progression of HIV dementia may also be determined by host and viral genetic factors, and the existence of co-morbid factors such as drug abuse, hepatitis C infection and aging. Oxidative stress markers appear to be predictive of active dementia. However, currently there is no specific treatment available for HIV dementia.

Developments in HIV neuropathogenesis.

Despite the fact that neurons are rarely infected by the human immunodeficiency virus (HIV), neuronal loss is common in patients with HIV infection, likely due to the effects of viral proteins and inflammatory mediators on these cells. Despite the widespread use of highly active antiretroviral therapy (HAART), at least in developed nations, cognitive impairment and other neurological complications of HIV infection persist with devastating personal and socioeconomic consequences. Fortunately, we have made important advances in recent years in defining the molecular mechanisms by which HIV infection targets the nervous system for damage. Such understanding has opened numerous therapeutic options, which are only now beginning to be exploited. This review will highlight the current state of thought regarding the neuropathogenesis of HIV infection. It will summarize the most recent research looking at the roles of both viral and host factors in mediating HIV-induced neurological disease. Utilizing this knowledge base, a framework will be outlined for current and future therapeutic trials to prevent or improve neurological complications of HIV infection.

HIV-associated neurocognitive disorders: Five new things.

HIV-associated neurocognitive disorders (HAND) remain an important cause of cognitive dysfunction. Current nomenclature for HAND includes HIV-associated dementia and milder forms known as asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND). ANI and MND remain highly prevalent despite combined antiretroviral therapy (cART). These mild forms of HAND must be diagnosed through neuropsychological testing. If a patient has HAND, it remains unclear whether using a cART regimen with theoretically superior CNS penetration improves the prognosis. Nevertheless, a CNS penetration effectiveness score for antiretrovirals is available. Other factors to consider when diagnosing and treating HIV infection and HAND include the HIV clade or subtype. Data suggest that HAND occurs more often in association with certain clades, and higher vigilance for cognitive dysfunction may be recommended. Finally, comorbidities, such as diseases associated with advanced age, other infections, and drug abuse, need to be considered as cofactors for cognitive dysfunction and treated accordingly.

Developing neuroprotective strategies for treatment of HIV-associated neurocognitive dysfunction.

Important advances have been made in recent years in identifying the molecular mechanisms of HIV neuropathogenesis. Defining the pathways leading to HIV dementia has created an opportunity to therapeutically target many steps in the pathogenic process. HIV itself rarely infects neurons, but significant neuronal damage is caused both by viral proteins and by inflammatory mediators produced by the host in response to infection. Highly active antiretroviral therapy (HAART) does not target these mediators of neuronal damage, and the prevalence of HIV-associated neurocognitive dysfunction has actually been rising in the post-HAART era. This review will briefly summarize our current understanding of the mechanisms of HIV-induced neurological disease, and emphasize translation of this basic research into potential clinical applications.

Ceftriaxone protects against the neurotoxicity of human immunodeficiency virus proteins.

Human immunodeficiency virus (HIV) proteins Tat and gp120 have been implicated in the pathogenesis of HIV dementia by various mechanisms, including down-regulation of excitatory amino acid transporter-2 (EAAT2), which is responsible for inactivation of synaptic glutamate. Recent work indicates that beta-lactam antibiotics are potent stimulators of EAAT2 expression. The authors treated mixed human fetal neuronal cultures with recombinant gp120 or Tat, in the presence or absence of ceftriaxone, and determined neurotoxicity by measuring mitochondrial membrane potential and neuronal cell death. Ceftriaxone produced dose-dependent attenuation of the neurotoxicity and neuronal cell death caused by both viral proteins. This study demonstrates that this class of drugs may have therapeutic efficacy in HIV dementia.

Viruses and the brain: from inflammation to dementia.

Many viruses cause encephalitis, but understanding the mechanisms by which viral infection leads to encephalopathy or dementia remain elusive. In many cases, inflammation generated by the host's attempt to combat the infection is itself implicated as a primary factor in causing neuronal dysfunction or degeneration. In this review, we outline the current state of knowledge regarding the pathophysiology of CNS (central nervous system) injury in viral infection. We focus our review on the neuropathogenesis of HIV type 1 (HIV-1)-associated dementia, because, within this class of infection, it is the best studied. We will also discuss the key similarities and differences in the pathological mechanisms of other important viral encephalitides. Understanding these mechanisms should ultimately enable development of immunomodulatory therapies for treating these infections, as well as other neuro-inflammatory conditions.

Pseudomonas aeruginosa infective endocarditis presenting as bacterial meningitis.

Pseudomonas aeruginosa is a rare cause of infective endocarditis. The case of community-acquired P. aeruginosa infective endocarditis reported here is the first described in the literature to present as bacterial meningitis. Furthermore, new risk factors for P. aeruginosa infective endocarditis, including mitral annular calcification and re-use of insulin syringes, are proposed. Treatment of P. aeruginosa infective endocarditis complicated by bacterial meningitis is discussed.