fungal infection of cns
TRANSCRIPT
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FUNGAL INFECTIONS OF CNS
DR PRAVEEN K TRIPATHI
11 July 2016
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GENERAL CONSIDERATIONS
11 July 2016
Phylum thallophyta, but lack chlorophyll. Unicellular or multicellular OR dimorphic The human immune system, normal colonising
bacteria and fungus and low pathogenicity are all responsible for the rare occurrence of these infections.
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GENERAL CONSIDERATIONS
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Yeast
• candida,• cryptococcus• trichosporon
Filamentous
• rhizopus,• rhizomucor,• mucor
Dimorphic Fungi
• blastomyces• histoplasma,• coccidoides• paracoccidoides
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GENERAL CONSIDERATIONS
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The factors contributing to the increasing incidence of fungal infections are:
Prolonged use of broad-spectrum antibiotics and the use of antimetabolites and steroids.
Social evils such as drug addiction and substance abuse. Diseases like diabetes mellitus, renal failure, malnutrition, AIDS and systemic lupus erythematosus. Increase in international travel with the risk of environmental
exposure. Longer survival of patients with lymphoproliferative malignancies. Larger ageing population.
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HISTORY
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Fungal infections of the CNS have been recognised since the end of the 19th century.
Paltauf, in 1885, reported a case of cerebral mucormycosis. Von Hanseman in 1905 - a yeast isolated from the CSF. 1933: Smith & Sano – 1st case of candida meningitis 1943 : Gregory – described Rhinocerebral zygomycosis. 1953: 1st useful polyene drug Nystatin Ramamurthi et al. in 1954 the published a case of
intramedullary cryptococcal granuloma . 1956: 2nd polyene drug Amphotericin B (AMB) “Standard”
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EPIDEMIOLOGY
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Intracranial fungal masses have been predominantly reported from India, Pakistan, Saudi Arabia, Africa and California in the United States.
Diabetes mellitus is a frequent predisposing illness in India especially when associated with paranasal sinus involvement.
Worldwide travel has increased the exposure of many communities to formally geographically limited fungal infections.
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PATHOPHYSIOLOGY
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•neurotropism,•altered defence mechanisms
in the host.The pathogenicity
of fungi is attributed to
•Hematogenous spread•Direct inoculation•Adjacent contiguous spread
Mode of infection
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Pathology
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Small size --‐ yeast enter microcirculation micro--‐abscess,
meningitis
Larger hyphal forms--‐invade vasculature cause
infarcts
Host immune response
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CNS MANIFESTATIONS
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Meningitis
Meningoencephalitis
Space occupying lesion
Hemorrhage,
infarction,
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CLINICAL FEATURES
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CLINICAL FEATURES Meningeal syndromes--‐
headache, nausea, vomiting, neck stiffness fever, Cranial nerve paresis, Focal signs due to arteritis
Meningitis is subacute/ chronic Meningoencephalitis Hydrocephalus
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CLINICAL FEATURES
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Rhino cerebral syndrome Most often in the anterior skull base or the sellar and parasellar regions, orbital pain, nasal
discharge and facial edema. Proptosis and visual loss may be present.
Skull-base syndromes- often the presenting clinical syndromes in patients with sinocranial aspergillosis
Intracranial granulomas – occur mostly in the third, fourth and fifth decades of life They present with focal neurological deficits depends on the site and mimic any intracranial
mass with features of raised intracranial pressure, seizures and altered sensorium. Cerebrovascular accident –
Aspergillosis or mucormycosis may produce sudden onset of deficit due to vasculitis. Vascular involvement is usually associated with large vessel vasculitis by invasion or
embolization. Spinal myelopathy and myeloradiculopathy
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INVESTIGATIONS
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INVESTIGATIONS Routine CSF proteins, sugar Cell examination Biochemical count Cytological examination--‐India ink Cultures Immunoassay/ PCR
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INVESTIGATIONS
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Blood cultures Imaging in CNS
MRI CT SCAN
Biopsies Evidence of infection elsewhere
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DIAGNOSIS
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Suspicion of CNS mycosis is the most important initial step in the diagnosis. Cerebrospinal Fluid Examination
CSF protein is elevated and glucose diminished. In aspergillosis with deep-seated granulomas, the CSF is normal.
A mononuclear pleocytosis is seen ranging between 20 cells/cubic mm and 500 cells/cubic mm except candidiasis and zygomycosis, there may be a polymorphonuclear increase.
Cytological examination of the CSF may occasionally reveal the fungus. For cryptococcal meningitis, India ink preparation is a simple and effective test.
Positive cultures confirm the diagnosis of fungal meningitis, but may be difficult to obtain or may take a long time.
In cryptococcal meningitis, the latex agglutination test for capsular polysaccharides in CSF is positive in 90%.
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DIAGNOSIS
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CT or MR scan may reveal features of meningitis, granulomas, hydrocephalus, infarction or spinal cord compression.
In rhino-orbital syndromes, CT or MR is especially helpful. The granulomas appear as irregular hypodense lesions with irregular and
minimal contrast enhancement and disproportionate perilesional oedema. The MRI is very useful to visualise ocular muscle or nerve involvement
and will show involvement of the paranasal sinuses Granulomas have a low T2 intensity compared with surrounding
hyperintense cerebral oedema. Ring enhancing T2 heterointense lesions with irregular walls and non-
enhancing intracavitary projections having a low ADC are indicative of a fungal abscess.
Spinal involvement shows disc involvement or sparing, heterogeneous marrow signal alteration and extensive extraosseous involvemen
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CT SCAN
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(A) Noncontrast, (B) contrast CT, (C) MRI gadolinium images showing cerebral aspergillosis close to the frontal sinus
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classification of Rhinocerebral fungal infections depending on the extent of the lesion
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Stage I: Purely rhino-sino-orbital. Stage II: Involvement of the bone without dural breach
in addition to sinus involvement. Stage IIIA: Spread of infection from the sinus to the
skull base, involvement of the bone and breach of the dura.
Stage IIIB: Infection involving the brain parenchyma. Stage IV: Fulminant meningoencephalitis and large
infarcts.
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MRI of the brain showing evidence of fungal infection in the ethmoidal and maxillary sinuses (arrows).Infection is limited to the sinuses and not involving the dura or extending intracranially (Stage I)
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MRI of the brain showing pansinusitis with erosion ofthe bone and without dural breach or parenchymal spread(Stage II)
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MRI of the brain showing evidence of infection in the ethmoidal sinuses with skull base erosion and spread to the dura seen as dural thickening (arrow) (Stage IIIA)
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CT of the brain showing infection in the maxillary and ethmoidal sinuses with extension into the orbit. (Stage IIIB)
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TREATMENT
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Non-Specific Measures Control of predisposing factors Treatment of intracranial hypertension, e.g. mannitol and furosemide. Specific MeasuresAntifungals can be classified as: Polyenes: Amphotericin, Nystatin Azoles: Miconazole, Ketoconazole, osaconazole, Ravucon-azole,
Voriconazole, Eberconazole, Itraconazole. Antimetabolic: Flucytosine Antiprotozoal: Atovaquone Echinocandins: Caspofungin, Misafungin, Aniducafungin
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TREATMENT
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Surgical management Stereotactic biopsy/aspiration‐ deep seated lesions/
eloquent area, multiple lesions, frail patient Craniotomy – for easily accesible areas Combined Approaches with ENT surgeon PNS lesion‐ otolaryngorhinological surgery (FESS) Shunt surgery‐ if associated HCP Endovascular coiling for fungal aneurysms Antifungal therapy
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Meningitis and meningoencephalitis
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Subacute / chronic But as lethal as bacterial if untreated Most yeasts: Crytococcus, Blastomyces,
Coccidiomyces, Paracoccidoides, Sporotrichium, Histoplasma and Candida
Access to microcirculation: seed subarachnoid space
Meningitis most significant complication of Coccidiodes infection
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Meningitis and meningoencephalitis
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Cryptococcal meningitis: 5‐10% of HIV pts have it as AIDS defining ilness 40% initial manifestation of HIV infectionHistoplasma meningitis 5‐10 % cases of disseminated diseaseRx: Cryptococcal: Amphotericin B (AMB) + flucytosine Candida: AMB Coccidiodal: IV + Intrathecal/intraventricular AMB Blasto‐ & Histoplasmosis: AMB + Fluconazone
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Fungal Abscess
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Common : Candida, aspergillus, cladosporium, mucormycosis, fungus like bacteria (nocardiosis and actinomycosis)
Multiple areas of infection within the brain Meningoencephalitis with vasculitis thromboisis
→hemorrhagic infarct → abscess forms 70 % neonates with systemic fungal infections. Candidal: small, multiple, round, hypoechoic lesions with
echogenic areas in periventricular region. Aspergillosis: few large echogenic in periventricular areas. Stereotactic /USG guided aspiration with antifungal drugs with
excision whenever possible/ needed
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Fungal granulomas
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Common: Aspergillus, Histoplasma, Blasto‐, Paracoccidiomycoses,Cryptococcus,Actinomycosis.
Resemble tuberculomas, but are More fibrous – often cut with knife or scissors as they
resist curretting. Clear plane of cleavage as in tuberculomas and
meningiomas is not present. Adherence to dura is firmer.
Should be completely excised f/b antifungal Rx
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Management of fungal intracranial fungal masses
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Most commonly‐ Aspergillus, Mucor sp Divided into
Rhinocerbral /sinocranial Primary intracranial‐
1. extra axial 2.intra axial
frontal lobes most commonly involved Differential diagnosis‐
– Tuberculoma– Lymphoma– Gliomas– Soft tissue malignancy
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Management of fungal intracranial fungal masses
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Surgical management Stereotactic biopsy/aspiration‐ deep seated lesions/
eloquent area, multiple lesions, frail patient Craniotomy – for easily accesible areas Combined Approaches with ENT surgeon PNS lesion‐ otolaryngorhinological surgery (FESS) Shunt surgery‐ if associated HCP Endovascular coiling for fungal aneurysms Antifungal therapy
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Cryptococcosis (European Blastomycosis)
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Ubiquitous – soil and bird excreta (PIGEON) Spherical budding capsulated yeast (5‐20 μ) Route of entry‐ respiratory system: affects RE system- LUNGS Secondary dissemination: hematogenous Basal meningitis, Meningoencephalitis, Granulomas and cysts‐ subependymal regions of thalamus
and basal ganglia‐ single or grouped in jelly like mass Spinal cryptococcosis‐ mass lesions, spinal arachanoiditis One of the mc CNS infections in immunocompromised,
children, elderly
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Cryptococcosis (European Blastomycosis)
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Cryptococcosis (European Blastomycosis)
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Leptomeninges: infiltrated, thickened & opaque Virchow‐Robin spaces: distended with organisms Granulomatous lesions in parenchyma Spinal arachnoididtis Chronic fibrosing leptomeningitis may l/t HCP Basal ganglionic pseudocysts (less common): exuberant capsular
material produced by prolifertaing crytococci Rarely aggregate: Cryptococcoma, Toruloma Meningitis:
– minimal inflammation: capsule masks surface ag– Glial reaction & cerebral edema –minimal– Slimy exudate over surface and base of brain
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Cryptococcosis : Treatment
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Untreated : fatalImmunocompetent 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 OD
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Aspergillosis
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Temperate climate, constant exposure to high spore content Moldy work environment Species causing CNS infection: A. fumigatus, A. niger,
A.flavus, A. oxyzae Saprophytic, ubiquitous, opportunistic: soil, plants and
decaying matter Primary portal of entry: respiratory tract Infection of brain:
– Directly : nasal sinuses via vas channels– Blood born : lungs , GIT– Airborne: contaminating neurosurgical operative field
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Aspergillosis : Neuropathology
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Sinocranial in origin is MC 1° focus‐ paranasal sinuses Chronic mycoses of paranasal sinuses:– Orbital, cranial, intracranial
(extradural, dural, intradural) Angiotropic – marked tendency to invade vs: most striking
featurevascular invasion with thrombosis. Necrotizing angitis, 2° thrombosis & hemorrhage Acute manifestations of FND in ACA & MCA distribution
Hemorrhagic infarcts may convert to septic infarcts with associated cerebritis and abscesses
Hyphae in blood vs of all sizes with invasion through walls into adjacent tissues; reverse invasion can occur.
Purulent lesions: chronic , tendency for fibrosis and granuloma formation.
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Aspergillosis : Presentation
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Suspected : acute onset FND due to suspected vascular or SOL, esp in immunocompromised.
Paranasal sinus disease patients: orbital extension with proptosis, ocular palsies, visual deterioration and chemosis (Orbitorhinocerebral syndrome)
Intracranial SOL with ↑ ICP Acute stroke Aneurysms Meningitis: very few cases
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Aspergillosis : Diagnosis
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Direct exam & culture CSF: pleocytosis – 600 cells/mm³, mod ↑
proteins but sugar is normal. Rarely found in CSF: Methenamine Ag Branched hyphae at 45° C In 15 % KOH stain Serologic test Double diffusion CIE, IF, ELISA Spinal disease: image‐guided aspiration biopsy Colonies on Sabraud’s agar aspiration, vertebral biopsy, histological examination and culture
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Aspergillosis : Treatment
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Aggressive NSx intervention: abscess, granuloma, focally infarcted brain. Correction of underlying risk factors and source of infection AMB + Flucytosine combinaion used Preferred:
Voriconazole ‐6 mg/kg IV Q12H for 1 day, then 4 mg/kg IV Q12H until clinical response, then 200 mg PO Q12H
Not well studied in HIV‐infected patients; significant interactions with protease inhibitors and efavirenz
Alternative:– Amphotericin B 1 mg/kg IV/d or amphotericin B lipid formulation 5mg/kg
IV /d– Itraconazole high dose 880 mg/d x 4 months f/b 400 mg/d x 5 months– Caspofungin 70 mg IV for 1, then 50 mg IV /d– Posaconazole 400 mg PO BID
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CNS Mucormycosis
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Rhizopus, mucor and absidia genera R. arrhizus, R. oryzae ‐ 95 % cases Ubiquitous in soil, manure, decaying vegetation Airborne infection in rhinosino‐orbital region, resp system,
GIT CNS infection by direct invasion through paranasal sinuses
along nerves, blood vessels, cartilage or hematogenous Associated with diabetic ketoacidosis, iv drug abuse, renal
transplant, malignancy, steroids Rhinocerebral syndrome
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CNS Mucormycosis
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CNS Mucormycosis
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CNS Mucormycosis
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Angiotropic : Occlude vessels‐ thrombosis and associated infarction Hemorrhage into infarcted brain or from mycotic aneurysm Fronatal lobe abscess and infarct Predominatly neutrophilic response – granulomas not seen Orbitorhinocerebral ds is potentially lethal with rapid progression and
high mortalityDiagnosis : biopsy of necrotic material or nasal mucosa Sabouraud’s agar: grows rapidlyRx: control diabetes and predisposing conditions AMB+ TMP-SMX 10‐12 wks with radical debridement to reduce
mass with irrigation of paranasal sinuses with antifungal agents
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Candidiaisis
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Most common cerebral mycoses in autopsy studies Ubiquitous present as epithelial infections when balance with host is
altered in favor of yeast Primary focus: infects GIT – oral cavity, esophagus Spread to CNS‐ hematogenous: also from colonized ventricular
drains, shunt tubings & central venous lines Direct inoculation via infected wound Neutropenic patients esp susceptible Invasion of small blood vs: thrombosis & infarct Disseminated meningitis or focal encephalitis Multiple micro abscesses & microgranuloma in ACA & MCA
territory.
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Candidiaisis : Symptomatology
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Cranial: Low grade meningitis Marked basal infiltrates Multiple cranial nerve palsies, ↓ consciousness, HCP
Spinal : rare – vertebral body or disc Hematogenous Local invasion: post‐op complication of spine surg Persistent low back ache , neurological deficits Imaging: nonspecific spondylitis and discitis
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Candidiasis
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Diagnosis Suspected : EVD or blocked shunts CSF exam and culture Serology: double diffusion CIE, IF, Latex agg test Fundus exam: endopthalmitis before permanent visual loss
Treatment Removal of infected foci Correction of predisposing factors NSx for abscess AMB ± Flucytosine
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Principles of Management ofCNS Fungal infections
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Correction of underlying pathogenic risk factor: Immunosupression Neutropenia Diabetes Ketoacidosis Steroid useRemoval of source of infection: Drains, shunts, i.v. lines Radical sx of orbit and paranasal sinuses: irrigation with antifungalsAntifungal drugsNSx intervention
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Antifungal Therapies
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Mycoses: among the most difficult diseases to heal Resist the oxidative damage of T cells during CMI
responses Fungi are biochemically similar to human cells and
antifungal drugs can harm human tissues Fungi have ergosterol in their membranes rather than
cholesterol and it is often a target for antifungal treatment
Side effects can still result, especially with long‐term use
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Antifungal Therapies
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Amphotericin B (AMB): 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. 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 of 1mg/kg
may be administered. Total cumulative dose upto 3 gm can be given
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Poorly crosses BBB: intraventricular/ intrathecal or intracavitary administration is also recommended.
Intrathecal is – therapy 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.
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Surgical Treatment
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Stereotactic biopsy‐ To establish the diagnosis and identification of the
organism Mass is deep seated, is in eloquent location In case of multiple lesions when the diagnosis is in
question possibility of being performed even under local anesthesia Attractive option especially in patients who do not have
much mass effect mandating significant decompression of the lesion.
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Surgical Treatment
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Surgical excision‐ Helps in establishing the diagnosis as well as reducing the mass
effect Improving the efficacy of the antifungal therapy. Radical excision of the granuloma with minimal contamination of
the CSF spaces is the preferred treatment modality. Basa arteritis or cavernous sinus thrombosis is a major
determinant in the good outcome of the skull base granulomas in the Rhinocerebral group.
Procedure should only be undertaken when it can be performed without causing much morbidity or incurring fresh neurological deficits.
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Surgical Treatment
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Ventriculo‐peritoneal shunt For hydrocephalus which is often communicating, the
block being present at the basal cisterns due to basal archnoiditis.
Intracavitary administration of AMB In fungal abscesses: reported to have good outcomes. Can also be done via ommaya reservoirs, which can be
used to instill the antifungals drug.
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PROGNOSIS
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Poor Prognostic Factors1. Cryptococcal meningitis:i. Initial positive India ink test.ii. High CSF opening pressure.iii. Low lumbar CSF leucocytes (less than 20/cu mm)iv. Cryptococci isolated from extraneural tissue.v. Absent anticryptococcal antibody.vi. Initial CSF or serum cryptococcal antigen titregreater than 1:32.vii. Corticosteroid therapy for lymphoreticular malignancy.
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PROGNOSIS
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2. Candidal meningitis:i. An interval from the onset to diagnosis of more than 2
weeks.ii. CSF glucose level below 35 mg/dl.iii. Development of intracranial hypertension or focalneurological deficit.3. Coccidioidal meningitis:i. Presence of hydrocephalus.ii. Presence of an underlying disease.iii. Non-Caucasian races.
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KEY POINTS
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CNS mycoses are increasing in the last few decades with increasing immunocompromized population worldwide.
The most common source of CNS infection is the paranasal and the mastoid sinuses.
CNS manifestations include subacute or chronic meningitis, encephalitis, intracranial abscesses or granulomas, stroke and rarely myelopathy.
Suspicion is the key to diagnosis; laboratory studies often do not help. Histology can give a specific diagnosis.
Amphotericin B remains the mainstay of therapy; Fluconazole and flucytosine, used in the long-term maintenance therapy, are known to achieve high levels in the CNS.
The newer candins are effective but are expensive. Surgical therapy for diagnosis, drainage of abscess or hydrocephalus, may be
indicated. Surgical total excision followed by aggressive systemic antifungal therapy offers the best outcomes in patients with intracranial mass lesions.
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