Intracranial fungal INFECTIONS
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This document summarizes information about intracranial fungal infections, including their diagnosis and management. It discusses the various fungi that can cause intracranial infections such as yeasts, filamentous fungi, and dimorphic fungi. It describes the different clinical manifestations in the CNS including meningitis, abscesses, and vasculitis. Investigations like CSF analysis, cultures, imaging and biopsies are outlined. Treatment involves controlling predisposing factors, antifungal drugs like amphotericin B and azoles, and managing complications. Specific fungi like cryptococcosis, aspergillosis, mucormycosis and their treatments are explained. New antifungal agents and experimental
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Intracranial fungal INFECTIONS
- 1. INTRACRANIAL FUNGAL INFECTIONS : DIAGNOSIS AND MANGEMENT MODERATORS Prof S.S. Kale Dr Manoj Phalak PRESENTED BY Dr Ankit Jain
- 2. Introduction Fungiaresaphrophytes • Yeast-‐ candida,cryptococcus, trichosporon • Filamentous– rhizopus,rhizomucor,mucor • DimorphicFungi-‐blastomyces, histoplasma, coccidoides,paracoccidoides
- 3. • Commonlyseenin tropicalcountriesbecauseof favorable environmentandthermaldimorphism • Incidenceisincreasingworldwide • -‐Immunosuppression • -‐Broadspectrumantibiotic • -‐Steroids • -‐Drugabuse • -‐AIDS,malignancy • -‐Internationaltravel
- 5. MODES OF INFECTION -‐Hematogenousspread ‐Direct Inoculation -Adjacentcontiguous spread
- 7. CNSMANIFESTATIONS • Meningitis • Meningoencephalitis • Hydrocephalus • SOL: Granuloma formation, Abscesses • Vasculitis • Infarction • Hemorrhage • Myelopathy
- 12. • -‐Cultures • -‐Immunoassay/PCR • Aspergillus–Galactomannanassay -Fungus (1, 3)-β-D-Glucan Assay –IgGAssay • Candida-Mannanassay -Fungus (1, 3)-β-D-Glucan Assay • Bloodcultures • ImaginginCNS • MRI • CTSCAN • Biopsies • Evidenceofinfectionelsewhere
- 13. COCCIDIOMYCOSIS
- 17. ASPERGILLOSIS
- 18. CRYPTOCOCCOSIS
- 19. RHIZOPUS
- 21. BLASTOMYCOSIS
- 23. DIFFERENT BRAIN ABSCESSES G. Luthra, A. Parihar, K. Nath, S. Jaiswal, K.N. Prasad, N. Husain, M. Husain, S. Singh, S. Behari and R.K. Gupta American Journal of Neuroradiology August 2007, 28 (7) 1332-1338; DOI: https://doi.org/10.3174/ajnr.A0548
- 24. TREATMENT • Non-Specific Measures Control of predisposing factors like Diabetes • Anti fungals • Reatment of secondary complications like raised icp,hydrocephalus,meningitis
- 25. Management of intracranialfungal masses • Mostcommonly-‐Aspergillusspecies dividedinto: a.Rhinocerebral/sinocranial b.primary intracranial- 1.extraaxial 2.intraaxial • frontallobesmostcommonlyinvolved • fungalaneurysms– veryrare, • angioinvasive nature of aspergillus is directly related to its ability to digest elastic tissue, by production of the enzyme elastase
- 26. Differentialdiagnosis • —Tuberculoma • Lymphoma • Gliomas • Softtissue malignancy • Intracerebral– soft, suckablewith pocketsof pus • Rhinocerebral-‐firm fibrous
- 27. Surgicalmanagement •Stereotactic biopsy/aspiration-‐deepseated lesions/ eloquentarea,multiple lesions, frail patient • Craniotomy– for easily accessibleareas • PNSlesion-‐otolaryngorhinological surgery(FESS) • Shunt surgery • Endovascularcoiling for fungal aneurysms • Antifungal therapy
- 28. Cryptococcus • Soilenrichedpigeondroppings • Routeofentry-‐respiratorysystem • affectsREsystem • Basalmeningitis,Meningoencephalitis, • Granulomasandcysts-‐subependymalregionsofthalamus andbasalganglia-‐singleorgroupedin jellylikemass • Spinalcryptococcosis-‐masslesions,spinal arachanoiditis
- 29. Treatment • Untreated : fatal • Immunocompetent AMB ‐0.7‐1mg/kg/d + 5‐flucytosine 100mg/kg/d for 6‐10 weeks or AMB ‐0.7‐1mg/kg/d x 6 weeks + Fluconazole ‐ 400mg/d for 10 weeks can be continued for 6‐12 months • Immunocompromised Induction (≥2 weeks): AMB 0.7 mg/kg IV + flucytosine 25 mg/kg PO QID Lipid formulation AMB 4‐6 mg/kg IV + flucytosine 25 mg/kg PO QID Consolidation (8 weeks): Fluconazole 400 mg PO Chronic maintenance: Fluconazole 200 mg PO 0D
- 30. • FlucytosineincreasesrateofCSFsterilizationduring inductiontherapy • Consolidationtherapyshouldnotbestarteduntil >2 weeksofsuccessfulinduction therapy: • Significantclinicalimprovement • NegativeCSFcultureonrepeatlumbarpuncture • Fluconazolemoreeffectivethanitraconazolefor consolidationtherapy
- 31. Role of —Secondary prophylaxis: • Lifelongsuppressivetreatment(aftercompletionof initialtherapy),unlessimmunereconstitutionon ART • Preferred:fluconazole200mg/d • Considerdiscontinuingmaintenancetherapyin asymptomaticpatientsonARTwithsustainedincreasein CD4countto>200cells/µLfor≥6months • RestartmaintenancetherapyifCD4countdecreasesto <200cells/µL
- 32. Prognosticfactors Cryptococcus • Positiveindiainktest • Highopeningpressure • LowCSFleucocyte • Extraneuralcryptococcosis • Absentantibody • InitialCSF/serumcryptococcaltitre1:32
- 33. Aspergillosis • Saprophyteinsoil • HematogenousspreadfromGItract/Pulmonary region • Highaffinitytobloodvessels • AbscessesorGranulomasinCNS • Treatmentconsistsofsurgery+antifungals
- 34. Treatment • Preferred:Voriconazole -6mg/kgIVQ12Hfor1day,then4mg/kg IV Q12Huntilclinicalresponse,then200mgPOQ12H • —NotwellstudiedinHIV-‐infectedpatients;significant interactionswithproteaseinhibitorsandefavirenz • Alternative: • AmphotericinB1mg/kgIV/d orAmphotericinB lipid formulation5mg/kgIV/d • Caspofungin70mgIVfor1,then50mgIV/d • Posaconazole400mgPO BID
- 35. Mucormycosis • Rhizopus,rhizomucorandabsidia • CNS-‐entryisbydirectextensionthroughparanasal sinusesalongnerves,bloodvessels andcartilage • Clinical features- • Periorbitalpain • Nasaldischarge • Poorlycontrolleddiabetic– Blacknecroticmass • Externalopthalmoplegia andvision
- 37. Candidiasis • Gutcommensal;through bloodtoCNS • Immunosuppressed, • ivaccess, • neutropenicpatients, • parenteralnutrition, • neurosurgicalprocedures • Smallintraparenchymalmicroabscessesin anterior andmiddlecerebralterritory
- 39. Blastomycosis • Inhalationofairbornespores SpreadtoCNSviahematogenousroute orbonyinvolvement,vertebraearecommonly involved • Mimicstuberculosisofspine • Treatment • surgery +antifungal treatment
- 40. Coccidiodomycosis • Soilsaprophyte • —Routeofentryofspore-‐lung •chronicmeningitis,granulomasinbasalmeninges mimickingtuberculousmeningitis • infectsvertebralbodies • —Diagnosisby-‐subcutaneousnodules,csfantibodies, biopsy • Treatment-‐amphotericinbor azoles
- 41. Nocardiosis • Notatruefungi • AFB+ • Soilsaprophyte • Routeofentry-‐lung/skin • CNS-‐abscesses,granulomas,meningitis • Treatment-‐sulphonamides
- 43. Amphotericin -B • Mainstay of treatment of all intracranial fungal infections • Effective against all the fungi except dermatiaceous . • MOA: – binds to ergosterol the principal steroid of fungal cell membrane, and disrupts the cell membrane. – Immunoadjuvant: ↑ both the humoral and CMI. • Dosage: – 1 mg test dose in 25‐50 ml of 5% D infused over 1‐2 hours.Preloading with 500ml saline – AmphotericinBdissolvedin500ml5%dextroseandstartedatasmalldosetranfusedover4-‐6hrs – Started at 0.25 mg/kg on Day‐1 – Daily increments of 5 mg or 0.1 mg/kg: until max dose of 0.5‐ 0.75 mg/kg/day is achieved. – In severe infections & in immunocompromised patients: the total daily dosages of 1mg/kg may be administered. – Total cumulative dose upto 3 gm can be given • Doseconcentrationforinfusion<0.1mg/ml
- 44. • Poorly crosses BBB: intraventricular/ intrathecal or intracavitary administration is also recommended. • – Intrathecal therapy is started at 0.025 mg and gradually increased to 0.25‐0.5 mg. • Duration of therapy: continued for 6‐12 weeks. • Side‐effects: • a) Acute‐ Chills, Fever, headache, thrombophlebitis, myalgia, arthalgia in >50% of the patients. • b) Chronic‐ Renal toxicity (most significant), hypokalemia, hypomagnesemia, normochromic normocytic anemia and rarely thrombocytopenia. • The combination therapy with flucytosine may results in enhanced bone marrow suppression. • Use in pregnancy is to be deferred because of possible teratogenicity.
- 45. Lipid formulation of polyenes – Improve the therapeutic index for polyene macrolides – AMB lipid complex or AMB colloidal dispersion – Liposomal AMB • invasive fungal infections in patients refractory or intolerant to standard AmB • AMB incorporated into the phospholipid bilayer membrane, rather than in closed aqueous phase. • In vivo testing of liposomal AmB (1 or 3 mg/kg/d) –Significantly higher success rate –Twofold to sixfold decrease in adverse events –Lower incidence of severe drug‐related side effects –Fewer nephrotoxicity – Liposomal nystatin • phase III clinical trials
- 46. Flucytosine (5‐FC) • Pyrimidine analogue, converted inside the cell into 5 fluoro‐uracil, which inhibits DNA synthesis. • Crosses BBB: esp useful for Cryptococcus, Candida, Aspergillus and Chromoblastomycosis infections. • Works synergistically with AMB and reduces it’s toxicity. • Dosage: 100‐150 mg/kg/day in four divided doses. Side‐effects: Rash, GI discomfort, diarrhea, reversible elevations in hepatic enzymes and pancytopenia
- 47. Azoles • interferewithergosterolsynthesisby bindingto lanosterol14‐demethylase • e.g.-‐voriconazole,fluconazole,itraconazole • Dose200mg-‐1200mg/day • Adverseeffect-‐nausea,lossofhair, gynecomastia, hepatotoxic
- 49. • New antifungal agents – Pradimicins-benanomicins • bind to cell wall mannoproteins causing osmotic sensitive lysis and cell death – Nikkonycins • competitive inhibitors of fungal chitin-‐synthase enzymes – Allylamines/thiocarbamates • non-competitive inhibitors of squalene epoxidase – Sordarins • inhibit protein synthesis, i.e. elongation factor 2 – Cationic peptides • bind to ergosterol and cholesterol and lead to cell lysis Journal of Antimicrobial Chemotherapy, Volume 44, Issue 2, January 1999, Pages 151–162
- 50. Experimentalimmunotherapy • —Increaseneutrophil,stimulateneutrophilsandmacrophages-‐ G-‐CSFsandGM-‐CSFs • Increasecellularimmunity-‐IFN-‐gamma • —Increasehumoralimmunity-‐vaccines Scorzoni L, de Paula E Silva AC, Marcos CM, et al. Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis. Front Microbiol. 2017;8:36. Published 2017 Jan 23. doi:10.3389/fmicb.2017.00036
- 51. Intracranial Fungal Granuloma In Immunocompetent Children: A Ten Year Clinicopathological Study F U Ahmad, V Naik, A Gupta, A Suri, C Sarkar, A K Mahapatra, B S Sharma AANS Nov 2007 • 8 Patients : Age ranged from 7 years to 17 years. • 5 males and 3 females. • Headache, proptosis and seizures were common presenting complaints • Five had anterior cranial fossa lesions, 3 had middle fossa lesions and 1 in CP angle • Two patients expired due to meningoencephelitis and infarcts. • Rest all had good clinical outcome. • Conclusions: ICFG is rare in children, is often misdiagnosed beforesurgery • high morality rate unless managed properly. • Poor neurological status at presentation and opening of ventricles during surgery are poor prognosticators. • Prompt therapy with antifungal drugs and radical surgery can lead to good outcome.
- 52. Bilateral ACA aneurysm due to mucormycosis. M K Kasliwal, V Reddy, S Sinha, B S Sharma, P Das, V Suri Journal of clinical neuroscience (2009) Vol16, Issue: 1, Pages: 156‐159 • True mycotic aneurysms are extremely rare • dismal prognosis. • mostly follow fungal meningitis or septicemia • highlights an atypical presentation of fungal infection that can perplex the best of clinicians and thus delay diagnosis. • high index of suspicion should be maintained when a neurosurgical patient is predisposed to fungal infection.
- 53. THANK YOU