1

FUNGAL INFECTIONS OF CNS

DR PRAVEEN K TRIPATHI

11 July 2016

2

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.

3

GENERAL CONSIDERATIONS

11 July 2016

Yeast

• candida,• cryptococcus• trichosporon

Filamentous

• rhizopus,• rhizomucor,• mucor

Dimorphic Fungi

• blastomyces• histoplasma,• coccidoides• paracoccidoides

4

GENERAL CONSIDERATIONS

11 July 2016

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

11 July 2016

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

11 July 2016

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

11 July 2016

•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

11 July 2016

Small size --‐ yeast enter microcirculation micro--‐abscess,

meningitis

Larger hyphal forms--‐invade vasculature cause

infarcts

Host immune response

9

CNS MANIFESTATIONS

11 July 2016

Meningitis

Meningoencephalitis

Space occupying lesion

Hemorrhage,

infarction,

10

CLINICAL FEATURES

11 July 2016

CLINICAL FEATURES Meningeal syndromes--‐

headache, nausea, vomiting, neck stiffness fever, Cranial nerve paresis, Focal signs due to arteritis

Meningitis is subacute/ chronic Meningoencephalitis Hydrocephalus

11

11 July 2016

12

CLINICAL FEATURES

11 July 2016

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

11 July 2016

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

14

INVESTIGATIONS

11 July 2016

Blood cultures Imaging in CNS

MRI CT SCAN

Biopsies Evidence of infection elsewhere

15

DIAGNOSIS

11 July 2016

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

11 July 2016

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

11 July 2016

(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

11 July 2016

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.

19

11 July 2016

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)

20

11 July 2016

MRI of the brain showing pansinusitis with erosion ofthe bone and without dural breach or parenchymal spread(Stage II)

21

11 July 2016

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)

22

11 July 2016

CT of the brain showing infection in the maxillary and ethmoidal sinuses with extension into the orbit. (Stage IIIB)

23

TREATMENT

11 July 2016

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

24

TREATMENT

11 July 2016

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

11 July 2016

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

11 July 2016

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

27

Fungal Abscess

11 July 2016

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

11 July 2016

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

11 July 2016

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

11 July 2016

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)

11 July 2016

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)

11 July 2016

33

Cryptococcosis (European Blastomycosis)

11 July 2016

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

11 July 2016

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

35

Aspergillosis

11 July 2016

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

11 July 2016

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

11 July 2016

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

11 July 2016

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

11 July 2016

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

11 July 2016

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

11 July 2016

42

CNS Mucormycosis

11 July 2016

43

CNS Mucormycosis

11 July 2016

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

44

Candidiaisis

11 July 2016

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

11 July 2016

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

46

11 July 2016

47

Candidiasis

11 July 2016

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 ofCNS Fungal infections

11 July 2016

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

49

Antifungal Therapies

11 July 2016

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

50

11 July 2016

51

Antifungal Therapies

11 July 2016

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

52

11 July 2016

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

11 July 2016

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

11 July 2016

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

11 July 2016

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

11 July 2016

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.

57

PROGNOSIS

11 July 2016

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.

58

KEY POINTS

11 July 2016

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.

59

11 July 2016

THANK YOU