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.

Minoxidil-induced systemic lupus erythematosus.

A patient treated for two months with the antihypertensive agent minoxidil developed pleural and pericardial effusions in association with a positive antinuclear antibody titer. No evidence of central nervous system or renal involvement was present, and results of specific tests for idiopathic systemic lupus erythematosus, including anti-double-stranded DNA and anti-Smith antibodies, were negative. Complement levels were normal. The patient's clinical picture improved and titers of antinuclear antibody decreased after discontinuation of minoxidil therapy, suggesting that minoxidil induced a lupus-like syndrome in this patient.

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.

Adenosine analogue induced ultrastructural changes in the nucleolus that correlate with inhibition of ribosomal RNA processing.

The aminonucleotide of puromycin (AMS) is known to have a differential effect on ribosomal RNA (rRNA) synthesis and the cell-cycle traverse in normal as compared to neoplastic or virally transformed cells. In this study, AMS and its demethylated derivative, 3'-amino-3'-deoxyadenosine (3'-AmA) have been used to compare their effects on normal (IMR 90) versus transformed (AG 2804) human fibroblasts with regard to preribosomal RNA (pre-rRNA) transcription, the processing of this RNA, and structural changes in the nucleolus. The processing of pre-rRNA in normal and transformed fibroblasts treated with 3'-AmA for 4 hr was markedly depressed. However, this process did not appear to be affected by the AMS treatment of normal cells, while in transformed cells it was maximally inhibited within 4 hr of exposure to this drug. Ultrastructural changes were observed in the nucleoli of normal and transformed cells treated with 3'-AmA, whereas treatment of these cells with AMS produced alterations of nucleolar structure only in the transformed cells. These changes correlated with the onset of inhibition of pre-rRNA processing. Our findings suggest that the impairment of pre-rRNA processing produced by AMS and 3'-AmA in transformed cells and by 3'-AmA in normal cells may be due to structural disorganization of the nucleolus produced by these antimetabolites.

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.

Ofloxacin.

Ofloxacin is a newly licensed fluoroquinolone with an antimicrobial spectrum similar to ciprofloxacin. Compared with ciprofloxacin, the MIC90 values for ofloxacin are lower for S aureus, C trachomatis, and Ureaplasma urealyticum, but somewhat higher against gram-negative bacteria (especially P aeruginosa). Ofloxacin has favorable pharmacokinetics with almost 100% bioavailability; peak serum concentrations obtained one to two hours following oral dosing are higher than those achieved with ciprofloxacin. The oral bioavailability is decreased by the coadministration of antacids, but ofloxacin does not alter serum theophylline concentrations. Ofloxacin has demonstrated bacteriologic and clinical efficacy in the treatment of urinary tract infections, respiratory tract infections, prostatitis, and skin and soft tissue infections caused by susceptible organisms, although there are little data to recommend ofloxacin over ciprofloxacin for these indications. Ofloxacin should not be used alone to treat anaerobic or mixed aerobic/anaerobic infections, and a penicillin or cephalosporin is preferred for known or suspected streptococcal or pneumococcal infection. Ofloxacin is the only quinolone currently approved for the treatment of uncomplicated gonorrhea. It also is effective therapy for nongonococcal urethritis, although the tetracyclines are much less expensive. Ofloxacin has a good safety profile, but, as with other fluoroquinolones, it should not be used in children or in pregnant or nursing women. Further comparative trials may broaden the range of infections that can be treated with ofloxacin.

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.

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.

Aztreonam.

Aztreonam, the first commercially available monobactam, has a wide range of activity against aerobic gram-negative bacilli. It can be administered two to three hours daily because its half-life is 1.6 to 2 hours. Excellent blood and tissue concentrations are attained. The MIC of aztreonam against most Enterobacteriaceae is less than or equal to 2 micrograms/ml and against P aeruginosa less than or equal to 16 micrograms g/ml. Aztreonam has been used in a wide array of infections of the urinary tract and respiratory tract, blood, intra-abdominal and gynecologic infections and infections of the skin, bones and joints. As empiric therapy, aztreonam is usually combined with another antimicrobial agent active against anaerobes and/or aerobic gram-positive cocci until culture results are available. One exception is empiric therapy for gram-negative urinary tract infections in which aztreonam can be used initially as monotherapy against susceptible gram-negative pathogens. In general, the efficacy of aztreonam is equal or superior to that of the aminoglycosides. Adverse reactions to aztreonam are unusual, and it as been shown to be a poor hapten, permitting its administration to patients with proven allergy to the penicillins and cephalosporins. Aztreonam is a useful addition to the available antibiotics for treatment of gram-negative infections.

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.

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.

Applications of therapy in animal models to bacterial infection in human disease.

Animal models have proven to be invaluable in bridging the gap between in vitro susceptibility testing of an antibiotic and anticipating results obtained in clinical studies. Variables such as antibiotic concentration, inoculum of organism, and pharmacokinetic parameters of the drug can be carefully controlled to provide information about the principles of treating infectious diseases as well as an evaluation of specific antimicrobial agents. End points of treatment can be precisely defined (that is, CSF sterility in meningitis, vegetation counts of bacteria in endocarditis) to allow a quantitative evaluation of a new antibiotic. However, it is important to realize that there may be differences in disease pathogenesis and antibiotic pharmacokinetics between experimental infections in animal models and infections in humans. Therefore, results in animal models should be interpreted with caution and compared with results obtained with antimicrobial regimens in clinical studies. Perhaps one of the most useful features of animal models is suggesting which antimicrobials would not be expected to be of therapeutic benefit in man.

Pathogenesis and pathophysiology of meningitis.

Advances in the understanding of the pathogenesis and pathophysiology of meningitis have occurred primarily through the use of experimental animal models. These models have proven to be particularly valuable in experimental bacterial meningitis, focusing on the bacterial virulence factors responsible for the initiation of infections, CNS invasion, and induction of SAS inflammation. Recent studies have examined the formation of host inflammatory cytokines in response to these virulence factors. These cytokines may be responsible for many of the pathophysiologic consequences of bacterial meningitis (eg. increased BBB permeability, cerebral edema, and increased intracranial pressure). Meningitis due to C. neoformans occurs most commonly in patients with defects in cell-mediated immunity (eg, AIDS), and the depletion of T helper cells in AIDS patients may allow unrestricted cryptococcal growth. Viral meningitis is an illness of low prevalence when compared with the overall occurrence of viral infections at other sites. CNS infection usually occurs by means of traversal across barriers that normally exclude viral invasion of the CNS, primarily through hematogenous dissemination from initial sites of infection. These advances in the pathogenesis and pathophysiology of bacterial, fungal, and viral meningitis may lead to the development of innovative treatment strategies for these disorders.

Bacterial meningitis in adults.

Bacterial meningitis continues to be an important cause of morbidity and mortality despite the availability of effective bactericidal antibiotics. Penicillin or ampicillin remains the drug of choice for meningitis caused by Streptococcus pneumoniae and Neisseria meningitidis. The third generation cephalosporins have revolutionized the treatment of gram-negative meningitis. Future therapy for bacterial meningitis will use recent developments in the understanding of pathogenic and pathophysiologic mechanisms underlying this disease.

Meningitis in the neurosurgical patient.

In the patient with a basilar skull fracture and CSF leak, the risk of meningitis is greatly increased. The diagnosis of both leak and infection can be obscured by the patient's other injuries, and requires aggressive investigation of symptoms that suggest infection. Although the diagnosis is made with CSF cultures, when clinically suspected, treatment should begin after appropriate cultures have been obtained. Treatment should be directed against the most likely organisms, Streptococcus pneumoniae, Haemophilus influenzae, and the other organisms common to the upper respiratory tract. There are no good indications for prophylactic antibiotic usage in patients with known CSF leaks. The patient with a shunt or other CNS prosthetic device may have various manifestations of infection, depending on the type of device and its termination. Frank meningitis or ventriculitis is not always present. Diagnosis requires direct culturing of the shunt milieu, with the most frequent isolates being staphylococcal species and gram-negative enteric bacilli. The most effective therapy, for both eradication of the infection and minimization of the duration and morbidity of therapy, involves removal of the infected shunt, external drainage during parenteral antibiotic therapy, and complete replacement of hardware at the time of internalization. The postsurgical patient will not develop meningitis very frequently, but like the posttrauma patient, concurrent factors can make the diagnosis difficult. Differentiating infectious from chemical meningitis must often be initially based on CSF cell counts and chemistries alone. Treatment to cover the most likely organism, staphylococcal species and respiratory flora, should be started before the culture results are finalized.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.