Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium.

BACKGROUND: Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research. METHODS: In March 2012, the International Encephalitis Consortium, a committee begun in 2010 with members worldwide, held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study. RESULTS: We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed. CONCLUSIONS: We anticipate that this document, representing a synthesis of our discussions and supported by literature, will serve as a practical aid to clinicians evaluating patients with suspected encephalitis and will identify key areas and approaches to advance our knowledge of encephalitis.

Antibacterial agents in infections of the central nervous system.

Experimental animal models have provided information applicable to antimicrobial therapy of infections of the central nervous system. The efficacy of an antimicrobial agent in the therapy of bacterial meningitis depends on its ability to penetrate the blood-brain barrier, its activity in purulent cerebrospinal fluid, and a demonstration of rapid bactericidal activity against the offending pathogen. The recent emergence of resistant pathogens is challenging the therapy for bacterial meningitis. Various strategies for treating resistant pathogens have been evaluated in experimental animal models. Encouraging results have led to clinical trials to evaluate the efficacy of newer agents, alone or in combination with standard regimens.

Issues in the management of bacterial meningitis.

Acute bacterial meningitis is associated with significant morbidity and mortality despite the availability of effective antimicrobial therapy. The emergence of antibiotic-resistant bacterial strains in recent years has necessitated the development of new strategies for empiric antimicrobial therapy for bacterial meningitis. Specifically, the emergence of strains of Streptococcus pneumoniae that are resistant to penicillin and the cephalosporins have led to empiric therapy for patients with pneumococcal meningitis consisting of vancomycin plus a third-generation cephalosporin pending susceptibility testing. Third-generation cephalosporins are also effective as empiric therapy against other pathogens that cause community-acquired bacterial meningitis, with the exception of Listeria monocytogenes, for which ampicillin or penicillin G is the antimicrobial agent of choice. Adjunctive dexamethasone should be administered to infants and children with suspected or proven Haemophilus influenzae type b meningitis to reduce audiologic and neurologic sequelae; administration concomitant with or just before the first dose of the antimicrobial agent is optimal for best results.

Bacterial meningitis. Practical guidelines for management.

The therapy of bacterial meningitis has evolved over the past century. Initially, antimeningococcal antiserum was used to treat patients with meningococcal meningitis. During the 1930s, sulphonamides were the first antibiotics used in the treatment of bacterial meningitis. The use of other antibiotics followed in later decades. Insights into the pathophysiology of meningitis have led to the use of prophylaxis against infection, as well as adjunctive therapy aimed at attenuating the harmful sequelae, should infection occur. This article outlines the basic principles important in the selection of appropriate antimicrobials. the emergence of resistant organisms, specifically Streptococcus pneumoniae and Haemophilus influenzae, has necessitated changes in previously effective antimicrobial regimens. The availability of third generation cephalosporins has increased the survival rate for meningitis caused by Gram-negative bacilli. Research into the use of adjunctive steroids has led to the recommendation that these agents be used in the paediatric population, which traditionally has had a high prevalence of H. influenzae meningitis. The high efficacy of H. influenzae type b conjugate vaccine and the observation that steroids, by decreasing inflammation, also decrease CNS penetration of some drugs, has led to reconsideration of routine steroid use. Effective chemoprophylactic regimens for contacts of patients with either H. influenzae or Neisseria meningitidis can diminish the spread of infection. Vaccination for both immunocompetent and immunodeficient patients protects against disease caused by some of the more common meningeal pathogens.

Antibacterial agents in infections of the central nervous system and eye.

Experimental animal models have provided much information that can be applied to antimicrobial therapy of infections of the central nervous system and eye. The efficacy of an antimicrobial agent in the therapy of meningitis depends upon its ability to penetrate the blood-brain barrier, be active in purulent cerebrospinal fluid, and demonstrate rapid bacterial activity against the offending pathogen. In ocular infections, topically administered drugs must overcome various barriers to penetrate into the eye, or these barriers must be bypassed (i.e., by periocular or intravitreal injection) for optimal therapy. This article reviews the basic therapeutic principles for the treatment of infections of the central nervous system and eye, and gives recommendations for the treatment of specific infections.

Therapy of fungal meningitis.

There has been an increase in recent years in the number of reported cases of meningitis and brain abscesses caused by fungi. This increase is due to the availability of better diagnostic techniques for fungal infections and the ever-increasing population of immunocompromised hosts (1,2). The patients most susceptible to invasive fungal infections include those with hematologic malignancies; those receiving hyperalimentation, corticosteroids, or cytotoxic drugs; transplant recipients; injection drug abusers; and those with the acquired immunodeficiency syndrome (AIDS). Although many fungi infect only immunologically impaired patients, some will infect normal hosts as well. The successful treatment of central nervous system (CNS) fungal infections is highly dependent on the underlying immune status of the host, as well as on the prompt initiation of appropriate antifungal therapy. However, the diagnosis of these infections may be difficult, and proper therapy often delayed. Furthermore, information on treatment regimens ranges from extensive, as in the case of cryptococcal meningitis, to scanty or nonexistent in the case of rare, opportunistic fungi. For > 3 decades, the standard antifungal agent for the treatment of CNS fungal infections has been amphotericin B. However, the effectiveness of amphotericin B is often eliminated by poor CNS penetration, fungal resistance, and toxicity (3). Because of the problems associated with use of amphotericin B, newer azole antifungal agents have been developed, some of which are efficacious in the therapy of fungal meningitis. We give an overview of the antifungal agents currently available for clinical use and their utility in the treatment of fungal meningitis.

Therapy of penicillin-resistant pneumococcal meningitis.

Antimicrobial therapy of pneumococcal meningitis has been altered in recent years based on changes in pneumococcal susceptibility patterns, with emergence of strains that are either relatively or highly resistant to penicillin G (minimal inhibitory concentrations of 0.1-1.0 micrograms/ml and > or = 2 micrograms/ml, respectively. In areas of the world where relatively penicillin-resistant strains of Streptococcus pneumoniae are present, the third generation cephalosporins (either cefotaxime or ceftriaxone) should be used as empiric therapy, and for highly penicillin-resistant pneumococcal strains, vancomycin (with or without rifampin) is recommended. It is imperative that susceptibility testing be performed on all cerebrospinal fluid pneumococcal isolates to guide the choice of antimicrobial therapy. Vaccination recommendations with the 23-valent pneumococcal vaccine should also be strictly enforced for use in appropriate populations that are at increased risk of pneumococcal infections.

Itraconazole: a new triazole antifungal agent.

The azole antifungal agents represent a major advance in the management of superficial and systemic fungal infections. Itraconazole appears to have a broad spectrum of in vitro activity and is the first azole antifungal agent to have activity against Aspergillus species. Itraconazole acts primarily by impairing the synthesis of ergosterol, resulting in a defective fungal cell membrane with altered permeability and function. It is effective for a wide variety of mycotic infections and some fungal meningeal infections. Most adverse effects have been relatively minor and do not lead to discontinuation of therapy.

Oral LY217896 for prevention of experimental influenza A virus infection and illness in humans.

The efficacy and safety of oral LY217896 for prevention of experimental influenza A/Kawasaki/86 (H1N1) virus infection were assessed in susceptible males randomly assigned to receive LY217896 (75 mg) or placebo once daily for 7 days beginning 24 h prior to viral challenge. The rates of virus shedding (100% in both groups), days of viral shedding (3.1 +/- 1.3 for the LY217896 group; 2.8 +/- 1.3 for the placebo group), and titers of virus in nasal washings did not differ between the groups. Mild upper respiratory tract illness (72% in the LY217896 group; 69% in the placebo group) developed in similar proportions of each group. LY217896 was associated with asymptomatic rises in serum uric acid levels and was ineffective in modifying the virologic or clinical course of experimental influenza A (H1N1) virus infection.

Case report: increase in CD4 lymphocyte counts after splenectomy in HIV-infected patients.

The records were reviewed of five human immunodeficiency virus (HIV) type 1-infected patients who underwent splenectomy, four for HIV-associated thrombocytopenia and one for gastric compression secondary to splenomegaly. After splenectomy, the four adult patients all had marked, sustained increases in their absolute CD4 lymphocyte counts; greater increases were observed in CD8 lymphocyte counts, accounting for decreases in the CD4:CD8 ratios. In patients 5 (one of triplets, all of whom were infected with HIV after a blood transfusion), absolute CD4 lymphocyte counts were stabilized after splenectomy; the other siblings manifested a decline in CD4 counts, which was associated with a delay in physical development and recurrent episodes of varicella. Immunohistochemical staining of spleen sections demonstrated significantly higher numbers of CD4 cells in splenic tissue from HIV-infected patients than from patients splenectomized secondary to trauma (2,070 +/- 284 vs. 962 +/- 296; p = 0.025). In addition, the HIV-infected patients had significantly higher percentages of CD4 lymphocytes in splenic tissue than in peripheral blood (49.3 +/- 11.0 vs. 20.3 +/- 7.9; p = 0.005), suggesting that CD4 cells were sequestered in the spleens of these patients. These findings have implications for the management of splenectomized HIV-infected patients with regard to optimal timing of initiation of zidovudine therapy and for prophylaxis of Pneumocystis carinii pneumonia.

Neurologic complications of infective endocarditis.

The average overall incidence of neurologic complications in patients with infective endocarditis is 30%, with the vast majority of these complications in patients with left-sided valvular disease. The incidence of central nervous system manifestations, particularly of embolic events, tends to be higher in cases of endocarditis caused by more virulent organisms, such as S. aureus and the Enterobacteriaceae. The clinical presentation is dependent on the area of the central nervous system involved. CT and MRI scanning are useful radiologic imaging techniques for the diagnosis of central nervous system complications in patients with infective endocarditis; cerebral angiography should be used in patients with suspected intracranial mycotic aneurysm. The cornerstone of management is appropriate antimicrobial therapy. Neurosurgical intervention may be required for certain patients with intracranial mycotic aneurysms that do not disappear after antimicrobial therapy or for aneurysms that enlarge or bleed. Anticoagulants should be continued in patients with prosthetic valve endocarditis who do not have evidence of intracranial hemorrhage. Anticoagulants should be avoided (unless thromboembolic events are from a site other than the vegetation) in patients with native valve endocarditis owing to the risk of hemorrhagic central nervous system complications. Case fatality rates tend to be higher in patients with neurologic complications of infective endocarditis. Earlier diagnostic and therapeutic interventions for patients with central nervous system complications of infective endocarditis will, it is hoped, improve the outcome in patients with this disorder.

Pathogenesis and pathophysiology of bacterial meningitis.

Bacterial meningitis remains a disease with associated unacceptable morbidity and mortality rates despite the availability of effective bactericidal antimicrobial therapy. Through the use of experimental animal models of infection, a great deal of information has been gleaned concerning the pathogenic and pathophysiologic mechanisms operable in bacterial meningitis. Most cases of bacterial meningitis begin with host acquisition of a new organism by nasopharyngeal colonization followed by systemic invasion and development of a high-grade bacteremia. Bacterial encapsulation contributes to this bacteremia by inhibiting neutrophil phagocytosis and resisting classic complement-mediated bactericidal activity. Central nervous system invasion then occurs, although the exact site of bacterial traversal into the central nervous system is unknown. By production and/or release of virulence factors into and stimulation of formation of inflammatory cytokines within the central nervous system, meningeal pathogens increase permeability of the blood-brain barrier, thus allowing protein and neutrophils to move into the subarachnoid space. There is then an intense subarachnoid space inflammatory response, which leads to many of the pathophysiologic consequences of bacterial meningitis, including cerebral edema and increased intracranial pressure. Attenuation of this inflammatory response with adjunctive dexamethasone therapy is associated with reduced concentrations of tumor necrosis factor in the cerebrospinal fluid, with diminished cerebrospinal fluid leukocytosis, and perhaps with improvement of morbidity, as demonstrated in recent clinical trials. Further information on the pathogenesis and pathophysiology of bacterial meningitis should lead to the development of more innovative treatment and/or preventive strategies for this disorder.

Candida prosthetic arthritis: report of a case treated with fluconazole and review of the literature.

Prosthetic arthritis due to Candida species is uncommon, with only 15 cases reported in the literature. We recently cared for a human immunodeficiency virus-infected patient who developed Candida parapsilosis prosthetic arthritis unresponsive to resection arthroplasty, intravenous amphotericin B, and suppressive ketoconazole therapy. Treatment with fluconazole led to mycologic cure and symptom improvement, although he subsequently underwent above-the-knee amputation due to continued joint instability. Fluconazole may be useful follow-up therapy after a course of amphotericin B combined with resection arthroplasty or when removal of the prosthesis cannot be accomplished.

Pathogenesis and pathophysiology of bacterial meningitis.

Despite the availability of bactericidal antibiotics with potent in vitro activity against the major meningeal pathogens, the morbidity and mortality from bacterial meningitis remains unacceptably high. Animal models have proven to be extremely valuable in the study of the pathogenesis and pathophysiology of bacterial meningitis, with the hopes of providing new information that may lead to an improved outcome from this disorder. Bacterial meningitis usually begins with nasopharyngeal colonization by a new organism, followed by invasion and bacteremia. Subsequently there is central nervous system invasion, although the exact site and mechanism of meningeal invasion are unknown. The generation of an intense subarachnoid space inflammatory response, induced by release of bacterial virulence factors and/or inflammatory cytokines, contributes to many of the pathophysiologic consequences of bacterial meningitis, including cerebral edema, increased intracranial pressure, and alterations of cerebral blood flow. Attenuation of this inflammatory response (e.g. by co-administration of antiinflammatory agents) may diminish many of these pathophysiologic consequences of meningitis, and perhaps improve morbidity and mortality from this disorder.

Candidal endophthalmitis after lithotripsy of renal calculi.

Candidal endophthalmitis is most commonly due to hematogenous seeding of the eye by Candida albicans. Although it is most often seen as a manifestation of disseminated candidiasis in patients who are seriously ill, other patients may have candidal endophthalmitis as the only evidence of fungal infection. We have presented a case of endophthalmitis due to C albicans in a patient who had bilateral renal calculi and who had received multiple antibiotics and extracorporeal shock wave lithotripsy.

Azithromycin and clarithromycin: overview and comparison with erythromycin.

Azithromycin and clarithromycin are erythromycin analogues that have recently been approved by the FDA. These drugs inhibit protein synthesis in susceptible organisms by binding to the 50S ribosomal subunit. Alteration in this binding site confers simultaneous resistance to all macrolide antibiotics. Clarithromycin is several-fold more active in vitro than erythromycin against gram-positive organisms, while azithromycin is 2- to 4-fold less potent. Azithromycin has excellent in vitro activity against H influenzae (MIC90 0.5 microgram/ml), whereas clarithromycin, although less active against H influenzae (MIC90 4.0 micrograms/ml) by standard in vitro testing, is metabolized into an active compound with twice the in vitro activity of the parent drug. Both azithromycin and clarithromycin are equivalent to standard oral therapies against respiratory tract and soft tissue infections caused by susceptible organisms, including S aureus, S pneumoniae, S pyogenes, H influenzae, and M catarrhalis. Clarithromycin is more active in vitro against the atypical respiratory pathogens (e.g., Legionella), although insufficient in vivo data are available to demonstrate a clinical difference between azithromycin and clarithromycin. Superior pharmacodynamic properties separate the new macrolides from the prototype, erythromycin. Azithromycin has a large volume of distribution, and, although serum concentrations remain low, it concentrates readily within tissues, demonstrating a tissue half-life of approximately three days. These properties allow novel dosing schemes for azithromycin, because a five-day course will provide therapeutic tissue concentrations for at least ten days. Clarithromycin has a longer serum half-life and better tissue penetration than erythromycin, allowing twice-a-day dosing for most common infections. Azithromycin pharmacokinetics permit a five-day, single daily dose regimen for respiratory tract and soft tissue infections, and a single 1 g dose of azithromycin effectively treats C trachomatis genital infections; these more convenient dosing schedules improve patient compliance. Azithromycin and clarithromycin also are active against some unexpected pathogens (e.g., B burgdorferi, T gondii, M avium complex, and M leprae). Clarithromycin, thus far, appears the most active against atypical mycobacteria, giving new hope to what has become a difficult group of infections to treat. Gastrointestinal distress, a well known and major obstacle to patient compliance with erythromycin, is relatively uncommon with the new macrolides. Further clinical data and experiences may better define and expand the role of these new macrolides in the treatment of infectious diseases.