fungal infection intracranial diagnosis and management

1. FUNGAL INFECTIONS
OF CNS
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2. GENERAL CONSIDERATIONS
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 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.

3. GENERAL CONSIDERATIONS
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Yeast
• candida,
• cryptococcus
• trichosporon
Filamentous
• rhizopus,
• rhizomucor,
• mucor
Dimorphic
Fungi
• blastomyces
• histoplasma,
• coccidoides
• paracoccidoides

4. 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.

5. 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”

6. 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.

7. 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

8. Pathology
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Small size --‐ yeast enter
microcirculation micro--‐abscess,
meningitis
Larger hyphal forms--
‐invade vasculature cause
infarcts
Host immune response

9. CNS MANIFESTATIONS
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Meningitis
Meningoencephalitis
Space occupying
lesion
Hemorrhage,
infarction,

10. 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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12. 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

13. INVESTIGATIONS
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 INVESTIGATIONS Routine CSF proteins, sugar
 Cell examination
 Biochemical count
 Cytological examination--‐India ink
 Cultures
 Immunoassay/
 PCR

14. INVESTIGATIONS
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 Blood cultures
 Imaging in CNS
 MRI
 CT SCAN
 Biopsies
 Evidence of infection elsewhere

15. 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%.

16. 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

17. CT SCAN
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(A) Noncontrast, (B) contrast CT, (C) MRI gadolinium images showing
cerebral aspergillosis close to the frontal sinus

18. 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 of
the 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)

23. TREATMENT
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Non-Specific Measures
 Control of predisposing factors
 Treatment of intracranial hypertension, e.g. mannitol and
furosemide.
Specific Measures
Antifungals can be classified as:
 Polyenes: Amphotericin, Nystatin
 Azoles: Miconazole, Ketoconazole, osaconazole, Ravucon-
azole, Voriconazole, Eberconazole, Itraconazole.
 Antimetabolic: Flucytosine
 Antiprotozoal: Atovaquone
 Echinocandins: Caspofungin, Misafungin, Aniducafungin

24. 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

25. 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

26. 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 infection
Histoplasma meningitis
 5‐10 % cases of disseminated disease
Rx:
 Cryptococcal: Amphotericin B (AMB) + flucytosine
 Candida: AMB
 Coccidiodal: IV + Intrathecal/intraventricular AMB
 Blasto‐ & Histoplasmosis: AMB + Fluconazone

27. 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

28. 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

29. 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

30. 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

31. 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

32. Cryptococcosis (European
Blastomycosis)
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33. 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

34. Cryptococcosis : Treatment
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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 OD

35. 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

36. 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.

37. 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

38. 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

39. 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

40. 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

41. CNS Mucormycosis
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42. CNS Mucormycosis
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43. 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 mortality
Diagnosis :
 biopsy of necrotic material or nasal mucosa
 Sabouraud’s agar: grows rapidly
Rx: 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

44. 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.

45. 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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47. 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

48. Principles of Management of
CNS Fungal infections
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Correction of underlying pathogenic risk factor:
 Immunosupression
 Neutropenia
 Diabetes
 Ketoacidosis
 Steroid use
Removal of source of infection:
 Drains, shunts, i.v. lines
 Radical sx of orbit and paranasal sinuses: irrigation with
antifungals
Antifungal drugs
NSx intervention

49. 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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51. 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.

53. 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.

54. 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.

55. 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.

56. PROGNOSIS
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Poor Prognostic Factors
1. 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 titre
greater than 1:32.
vii. Corticosteroid therapy for lymphoreticular malignancy.

57. 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 focal
neurological deficit.
3. Coccidioidal meningitis:
i. Presence of hydrocephalus.
ii. Presence of an underlying disease.
iii. Non-Caucasian races.

58. 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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