Fungal brain infections Eileen P. Scully, Lindsey R. …

1 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is brain infectionsEileen P. scully , Lindsey R. Baden and Joel T. KatzIntroduction to pathogenic fungiClinically relevant fungi include yeasts, filamentousfungi and dimorphic fungi. Yeasts are unicellular organ-isms and include the relatively commonCandidaspp. andCryptococcusspp., and less common pathogens such asTrichosporonspp. The filamentous fungi (molds) arecharacterized by branching hyphae, which are eitherseptate or aseptate and are further subdivided into thehyalinized and the dematiaceous (darkly pigmented)groups. These classes include the more commonAsper-gillusspp. and the zygomycetes, includingRhizopus,RhizomucorandMucor. Less common pigmented moldsthat infect the central nervous system (CNS) includePseudallescheriaandFusariumspecie s.

2 Finally, thedimorphic, or so-called endemic , fungi are filamentousat 258C and yeasts or spherules in host tissue or whenincubated at 358C, and includeBlastomyces(south-easternand south-central North America),Histoplasma(UnitedStates and Africa),Coccidioides(American southwest),Paracoccidioides(Brazil, Venezuela, Colombia) andPeni-cillium marneffei(south-east Asia) [1 ,2 ,3].Host populations at riskWith the exception of the endemic fungi and trauma-induced inoculation, invasive Fungal infections are largelyconfined to immunocompromised patients, with vari-ations in patterns of susceptibility based on the degreeand category of immune dysfunction. Frequently citedrisk factors for Fungal brain infections are HIV/AIDS,hematopoietic stem cell transplant (HSCT), lymphoidmalignancies, neutropenia, hereditary immune defects,immunosuppressive medications, diabetes mellitus, intra-venousdrugabuseandmechanicalbreakd ownofthebloodbrain barrier via surgery or trauma (Table 1).

3 Indwellingcatheters are a risk factor for developing candidemia [4],which in turn increases the risk of CNS seeding [5].Classically, neutropenia is associated with infection withAspergillusand other molds, highlighting the importanceof circulating phagocytes in controlling these duration and depth of the neutropenia are directlyrelated to the risk, and patients with prolonged neutro-penia, such as those with aplastic anemia or other causesof bone marrow failure, are at the highest risk. Althoughless common,Candidaspp. brain infections are alsoassociated with profound neutropenia. In a series ofinvasive filamentous Fungal infections among patientswith hematologic malignancies, CNS disease of cases [6]. HSCT patients exhibit a bimodalsusceptibility to invasive mold infections , particularlyAspergillus first in the early posttransplant neutropenicphase, and later during the postengraftment period whenhigh levels of immunosuppression are given for graftversus host disease (GvHD) [7].

4 Infectious complications of nonmyeloablative allogeneictransplantation are beginning to be defined. This popu-lation frequently has high-risk characteristics includingBrigham and Women s Hospital, Harvard MedicalSchool, Boston, Massachusetts, USAC orrespondence to Joel T. Katz, MD, Division ofInfectious Diseases, Brigham and Women s Hospital,Harvard Medical School, 75 Francis Street, Boston,MA 02115, USATel: +1 617 732 5540; e-mail: Opinion in Neurology2008, 21:347 352 Purpose of reviewFungal infections of the central nervous system, once a relatively rare occurrence, areincreasingly common due to the expansion of immunocompromised populations at risk,and therefore are important to recognize early and manage findingsThe specific infectious risk posed by novel immune-modifying therapies can, in mostcases, be predicted on the basis of the immune target and medication timing.

5 Inaddition, major advances in noninvasive diagnostic tests ( serum beta glucan andgalactomannan assays), and the recent introduction of more effective antifungaltherapies, have led to a dramatic improvement in clinical current review provides approaches to patients with suspected central nervoussystem Fungal infections based on host-risk factors, clinical syndromes and , candida, central nervous system, fungi, mycosesCurr Opin Neurol 21:347 352 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins1350-75401350-7540 2008 Wolters Kluwer Health | Lippincott Williams & WilkinsCopyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is age, previously treated and refractory diseaseand comorbid conditions that direct them toward thenonmyeloablative approach.

6 Although initial case seriesfound lower rates of invasive Fungal infection comparedwith HSCT, a recent series including 30 patients docu-mented 33% prevalence of invasive Fungal infection thatdirectly contributed to mortality, including at least threecases with CNS involvement. Risk factors for CNSinfection included high-grade GvHD, corticosteroiduse, recurrent neutropenia, and refractory or relapseddisease prior to transplant [8].Solid-organ transplant recipients treated with immuno-suppressive agents, including corticosteroids and calci-neurin inhibitors, are also at significant risk for CNSfungal infections , includingCandida(liver, pancreasand small bowel) andAspergillus(lung and liver). Cryp-tococcal disease, frequently involving the CNS, has areported incidence of approximately in this popu-lation [9].

7 Invasive Fungal infections tend to occur later insolid-organ transplant recipients (mean years aftertransplant), with later presentations in renal graft recipi-ents who require lower levels of prolonged immunosup-pression. Renal transplant recipients from endemic areasalso have high rates ofCoccidioidesspp. ( ), andpresent with disseminated and CNS disease that canbe prevented by targeted prophylaxis [10].Although the most well known infectious complication ofanti-tumor necrosis factor (TNF)-atherapy may betuberculosis, there is a growing evidence of an increasedincidence of invasive Fungal infections , including cryp-tococcosis, histoplasmosis, candidiasis and aspergillosis[11 14]. However, to date there are relatively few casesreported of CNS patients have a clearly enhanced risk forCNS cryptococcal disease, supporting the role of T-cellmediated immunity in the control of this infection [15].

8 Apopulation-based surveillance program documented adeclining rate of infection and emphasized the strongassociation with effective HIV treatment, with 89% ofinfections occurring in patients known to be HIV-infected. In contrast to HIV patients who primarilydevelop cryptococcal meningitis, patients on TNFinhibitors are more likely to present with pulmonarydisease or isolated fungemia [14,16]. CNSA spergillusinfections in HIV patients occur at a rate higher thanthe general population, and the clinical presentation canvary from abscess to meningitis/meningoencephalitis/ara-chnoi ditis. There is evidence to suggest that defects inT-cell immunity, as is seen with HIV infection, predis-pose to progressive or more widespread CNS diseasewhen patients are infected with endemic fungi such asblastomycosis, histoplasmosis andP.

9 Marneffei[17 19].Clinical syndromesClinical syndromes of CNS infection have been reviewedelsewhere [1 ,2 ,3,20]. The most important CNS fungalsyndromes that bring patients to medical attention aremeningitis and brain abscess with or without vascularinvasion (Table 2).Meningitis generally presents with headache, meningis-mus, photophobia, papilledema, diminished conscious-ness, and, in advanced cases, seizure or complicationsfrom increased intracranial pressure ( 6th nerve palsy).The cardinal features may be variably present in immu-nocompromised patients; thus high clinical suspicion isrequired. Fungal meningitis can have a variable pace andseverity and may be clinically indistinguishable frombacterial causes of a chronic brain abscesses typically present with a focalneurological abnormality, headache and/or seizure, whichis the consequence of local destruction or compression ofadjacent brain tissue.

10 Certain Fungal pathogens, in particu-larAspergillus, will often have a degree of angioinvasionthat can produce simultaneous infarction and/or meningi-tis. Clinical evidence for angioinvasive disease includesthe presence of a new stroke-like syndrome and/or menin-geal signs. Other presentations of brain abscesses includedirect extension to the CNS from preexisting sinusitis orosteomyelitis and infections associated with foreign bodiesincluding shunts or prior head trauma. As Fungal and348 Inflammatory diseases and infectionTable 1 Major risk factors for Fungal central nervous systeminfectionsRisk factorImmune defectPrincipalsusceptibilityHIV/AIDST-c ellCryptococcus neoformansCoccidioides immitisHistoplasma capsulatumPenicillium T, B andgranulocyte; cathetersImmune suppressivemedicationsCorticosteroids Monocyte andmacrophageCryptococcus neoformansComplement andimmunoglobulinreceptorsCandidasppTNF inhibitors CytokineCryptococcus neoformansT-cell and B-cellsignalingHistoplasma boydiiPigmented moldsHSCT, hematopoietic stem cell transplant; TNF, tumor necrosis Lippincott Williams & Wilkins.