Fungal Meningoencephalitis

Slide 1 · Fungal Meningoencephalitis

Organisms • routes of entry • patterns of tissue injury • morphology

Pathology teaching lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Recognize routes of fungal invasion and the three characteristic patterns of CNS injury.

Differentiate Candida, Cryptococcus, Aspergillus, and mucormycetes by disease pattern and morphology.

Integrate host immune status, organism morphology, vascular effects, and diagnostic evidence.

Slide 3 · CNS fungal infection: Clinical setting

CNS fungal infections occur predominantly in immunocompromised individuals.

The brain is usually involved after disseminated hematogenous fungal infection.

The immune state profoundly affects both tissue response and pattern of involvement.

Slide 4 · Two principal routes to the CNS

01

Primary infection outside CNS

02

Bloodstream dissemination

03

CNS vascular access

04

Meningeal or brain invasion

A distinct route is local extension, notably from the sinuses into the orbit and brain in rhinocerebral mucormycosis.

Slide 5 · Frequent agents in CNS mycoses

Candida albicans: Commonly linked to disseminated candidiasis and brain microabscesses.

Cryptococcus neoformans: Encapsulated yeast with meningitis and perivascular accumulation.

Aspergillus fumigatus and mucormycetes: Strongly associated with angioinvasive injury.

Slide 6 · Major fungi and characteristic CNS patterns

Agent

Predominant clue

Typical CNS pathology

Candida

Disseminated invasive candidiasis

Multiple microabscesses ± granulomas

Cryptococcus

Encapsulated budding yeast

Chronic meningitis; perivascular aggregates

Aspergillus

Septate acute-angle hyphae

Angioinvasive necrosis; infarction

Mucormycetes

Broad, sparsely septate hyphae

Rhinocerebral spread; arterial invasion

Agent

Predominant clue

Typical CNS pathology

Slide 7 · Geographically endemic fungi can involve the CNS

Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis are recognized causes.

CNS involvement may follow a primary pulmonary or cutaneous infection.

Immunosuppression increases the probability of dissemination.

Slide 8 · Direct spread: Sinonasal origin

01

Airborne spores

02

Nasal / paranasal infection

03

Orbital / cranial extension

04

Cerebral involvement

Diabetes mellitus, especially with ketoacidosis, is an important host context for rhinocerebral mucormycosis.

Slide 9 · The three CNS injury compartments

MENINGES: Chronic meningitis

VESSELS: Necrotizing vasculitis, thrombosis, hemorrhagic infarction

PARENCHYMA: Microabscesses, granulomas, or yeast aggregates

An infection may involve more than one compartment simultaneously.

Slide 10 · Three principal patterns of fungal injury

Chronic meningitis

Persistent fungal involvement of meninges; Especially characteristic of cryptococcal disease.

Vasculitis

Angioinvasion damages vessels; Thrombosis and infarction may follow.

Parenchymal invasion

Organisms form abscesses, granulomas, or perivascular collections in the brain.

More than one pattern may be present in the same patient.

Slide 11 · Chronic fungal meningitis

The leptomeninges are a major target in cryptococcal disease.

Inflammation can be surprisingly sparse in severely immunosuppressed hosts.

Chronic granulomatous reactions are more likely when host cell-mediated defenses are relatively preserved.

Slide 12 · Angioinvasion → thrombosis → infarction

Fungal penetration of vessel wall

Intraluminal thrombosis

Downstream hemorrhagic infarction

Schematic: Vascular invasion

Slide 13 · Why vascular invasion is especially destructive

Aspergillus and mucormycetes penetrate vessel walls.

Necrotizing vasculitis promotes intravascular thrombosis.

Loss of perfusion causes infarction that may be strikingly hemorrhagic.

Slide 14 · Parenchymal infection: Two broad responses

Suppuration

Granulomatous reaction

Fungal microabscesses

Prominent neutrophil-rich injury can occur

Candida often produces multiple brain microabscesses

Macrophage-rich chronic response

Can accompany Candida or Cryptococcus

Magnitude depends on the host immune response

Slide 15 · Host–organism–tissue interaction

Organism

Morphologic phenotype

Host defenses

Level and type of inflammation

Tissue

Meningitis / vasculitis / invasion

The same fungus may produce markedly different tissue reactions in different hosts.

Slide 16 · Immune status changes morphology

Severe immunosuppression may permit extensive organisms with little inflammation.

More effective cell-mediated immunity may support macrophage-rich granulomas.

Interpret the inflammatory response together with fungal burden and clinical context.

Slide 17 · Tissue patterns: A diagnostic orientation

Pattern

Key process

Fungi prominently associated

Meningitis

Meningeal fungal persistence

Cryptococcus; endemic fungi

Microabscess

Parenchymal suppurative foci

Candida

Angioinvasion

Vessel injury and thrombosis

Aspergillus; mucormycetes

Perivascular yeast

Expanded Virchow–Robin spaces

Cryptococcus

Pattern

Key process

Fungi prominently associated

Slide 18 · Cryptococcal meningoencephalitis

Cryptococcus neoformans and C. Gattii grow as encapsulated yeasts in human tissue.

The CNS is a major site of disease following an often subtle pulmonary infection.

Disease may affect meninges, cortical gray matter, and basal nuclei.

Slide 19 · Two clinically important Cryptococcus species

C. Neoformans

C. Gattii

Frequent opportunist in AIDS or other immunosuppression

Often causes meningeal disease

Can occasionally infect otherwise healthy people

May cause disease in apparently immunocompetent hosts

Associated with localized mass lesions

Potential immune predisposition still warrants evaluation

Slide 20 · Cryptococcus: Exposure and entry

Environmental yeasts are acquired principally by inhalation.

C. Neoformans occurs in soil, notably soil containing pigeon guano.

C. Gattii occurs in soils and trees, including eucalypts.

Pulmonary infection can precede CNS dissemination without prominent pulmonary symptoms.

Slide 21 · Risk contexts for C. Neoformans

HIV-associated immunosuppression / AIDS.

Leukemia, lymphoma, or immunosuppressive treatment after transplantation.

Systemic lupus erythematosus and other disorders affecting host defense.

High-dose corticosteroid exposure is a major recognized risk factor.

Slide 22 · Cryptococcus: Capsule and budding yeast

Polysaccharide capsule

Impedes phagocytosis and recruitment of inflammatory cells

Budding yeast

Capsule stains with mucicarmine and PAS

Schematic — not a photomicrograph

Slide 23 · The cryptococcal capsule subverts host defense

The polysaccharide capsule impedes alveolar macrophage phagocytosis.

It limits leukocyte migration and recruitment of inflammatory cells.

It can reduce dendritic-cell antigen presentation and cytokine production.

Slide 24 · Cryptococcal melanin and virulence

Laccase catalyzes melanin synthesis.

Melanin supplies antioxidant protection and interferes with antibody-mediated phagocytosis.

The source also describes effects on antifungal susceptibility, iron binding, and cell-wall integrity.

Slide 25 · Other cryptococcal virulence attributes

Phospholipases may facilitate invasion.

Urease helps counter conditions inside phagocytic cells.

Chitin is necessary for structural stability of the yeast cell wall.

Titan cells and small microcells illustrate variable fungal cell size.

Slide 26 · Cryptococcus: Tissue morphology

Round budding yeast without hyphae or pseudohyphae in human tissue.

An abundant gelatinous polysaccharide capsule surrounds the yeast.

The capsule is highlighted by mucicarmine and periodic acid–Schiff stains.

Slide 27 · Perivascular cryptococcal “soap-bubble” spaces

Expanded perivascular space

Collections of encapsulated cryptococcal yeasts can accumulate with minimal inflammatory response.

“Soap-bubble” appearance

Schematic — not histology

Slide 28 · Why cryptococcal lesions may appear minimally inflamed

Encapsulated organisms can expand perivascular spaces with little reaction.

Severe cellular immune impairment limits effective inflammatory recruitment.

Marked organism burden does not necessarily imply marked tissue inflammation.

Slide 29 · Cryptococcal host response: Contrasting extremes

Severe immunosuppression

More preserved immunity

Abundant yeasts

Scant inflammation or gliosis

Gelatinous meningeal and perivascular collections

Chronic macrophage-rich granulomas

Lymphocytes and giant cells

Suppuration or granulomatous arteritis may occur

Slide 30 · Cryptococcal meningitis: Time course

Clinical evolution can be very rapid, including fulminant fatal disease.

Other cases evolve indolently over months or years.

Course should be interpreted alongside host immune status and fungal burden.

Slide 31 · Cryptococcal CSF and antigen evidence

CSF may contain relatively few inflammatory cells.

Protein concentration is usually elevated.

Yeast may be demonstrated with appropriate stains; Cryptococcal antigen assays provide indirect organism evidence.

Slide 32 · Cryptococcoma: A space-occupying pattern

C. Gattii may form relatively large localized CNS fungal masses.

Mass effect can produce symptoms of increased CNS pressure.

Imaging may mimic a neoplasm; Morphology and organism-directed studies remain necessary.

Slide 33 · Cryptococcus: Organism, host, lesion

Dimension

Dominant clue

Pathology significance

Organism

Encapsulated budding yeast

Mucicarmine / PAS-positive capsule

Host

Impaired cell-mediated immunity

Fungi with scant reaction

Location

Meninges and perivascular spaces

Chronic meningitis; soap bubbles

Variant pattern

C. gattii mass lesion

Cryptococcoma / mass effect

Dimension

Dominant clue

Pathology significance

Slide 34 · Cerebral candidiasis

Candida reaches the CNS during invasive disseminated disease.

Brain involvement commonly produces multiple microabscesses.

Granulomatous reactions can coexist with suppurative lesions.

Slide 35 · Candida: Disseminated infection to microabscess

01

Invasive Candida infection

02

Hematogenous spread

03

CNS seeding

04

Multiple brain microabscesses

Inflammation may be sparse, suppurative, or granulomatous depending on the degree of host immune competence.

Slide 36 · Candida: Morphology and staining

Candida may show budding yeast and pseudohyphal forms in tissue.

Gömöri methenamine silver and PAS stains help demonstrate fungal elements.

Morphologic recognition must be integrated with invasive disease and host status.

Slide 37 · Candida: The immune-response spectrum

Profound neutropenia predisposes to invasive systemic candidiasis.

Infected tissue can contain little inflammation, an acute suppurative response, or granulomas.

Lesion morphology is shaped by both fungus and host defenses.

Slide 38 · Mucormycosis: Organisms and disease

Opportunistic infection caused by molds such as Mucor and Rhizopus.

Additional genera named include Rhizomucor and Cunninghamella.

CNS involvement may follow direct spread or disseminated disease.

Slide 39 · Major host factors in mucormycosis

Diabetes mellitus, including diabetic ketoacidosis.

Neutropenia and systemic corticosteroid treatment.

Iron overload and disruption of protective tissue barriers.

Slide 40 · Mucormycetes: Iron and susceptibility

Fungal growth is enhanced by accessible free iron.

Diabetic ketoacidosis can increase available free iron.

Deferoxamine can act as a siderophore for the organism.

Slide 41 · Mucor defense: Spores to tissue invasion

01

Inhaled sporangiospores

02

Macrophage ingestion

03

Germinating hyphae

04

Neutrophil hyphal killing

Macrophage or neutrophil dysfunction permits the fungus to establish invasive infection.

Slide 42 · Rhinocerebral mucormycosis sequence

01

Paranasal sinuses

02

Orbit / periorbital tissues

03

Cranial vault

04

Meninges and brain

Local necrosis and arterial invasion can culminate in meningoencephalitis and cerebral infarction.

Slide 43 · Rhinocerebral mucormycosis: Tissue damage

Fungi invade nasal or sinus tissues and spread into neighboring compartments.

Invasion of arteries produces thrombosis and ischemic injury.

Infarction may complicate fungal meningoencephalitis.

Slide 44 · Angioinvasive molds: Basic tissue morphology

Mucormycetes

Aspergillus

Broad, irregular; Few or absent septa; Near right-angle branching

Narrower, septate; Acute-angle branching

Illustrative morphology — not a tissue section

Slide 45 · Mucormycetes: Microscopic recognition

Hyphae tend to be broad, irregular in width, and nonseptate or sparsely septate.

Branching frequently approaches a right angle.

H&E and special fungal stains may reveal organisms invading arterial walls.

Slide 46 · Aspergillus: Setting and entry

A. Fumigatus is the most common pathogenic Aspergillus species named.

Airborne conidia primarily enter via the respiratory tract.

Neutropenia and corticosteroid exposure favor invasive infection.

Slide 47 · Aspergillus: Initial defense versus invasion

01

Inhaled conidia

02

Macrophage recognition

03

Conidial germination

04

Tissue-invasive hyphae

Dectin-1 and TLR2 are involved in recognition; Neutrophils are essential in killing hyphae.

Slide 48 · Aspergillus: Why neutropenia matters

Alveolar macrophages ingest and kill inhaled conidia.

Neutrophils produce reactive oxygen intermediates that damage fungal hyphae.

Impaired neutrophil defenses strongly favor invasive aspergillosis.

Slide 49 · Aspergillus: Microscopic morphology

Tissue hyphae are typically septate.

Acute-angle branching is characteristic.

Similar-appearing hyphae may be caused by other filamentous fungi; Morphologic appearance alone is not always species-specific.

Slide 50 · Aspergillus: Vascular invasion and CNS injury

Pulmonary invasive disease may disseminate hematogenously to brain.

Angioinvasion is a prominent pathologic feature.

Hemorrhage and infarction accompany necrotizing inflammation.

Slide 51 · Aspergillus versus mucormycetes

Feature

Aspergillus

Mucormycetes

Hyphae

Narrower, septate

Broad, irregular; often aseptate

Branching

Acute angle

Frequent near right angles

Risk context

Neutropenia; corticosteroids

Diabetes; neutropenia; steroids; iron

Major CNS clue

Disseminated angioinvasion

Rhinocerebral extension; angioinvasion

Feature

Aspergillus

Mucormycetes

Slide 52 · Important pitfall: Hyphal morphology is not unique

Aspergillus-like septate acute-angle hyphae may occur with other molds.

Overlap with Pseudallescheria boydii and Fusarium.

Species assignment should not be made solely from an undifferentiated tissue fragment.

Slide 53 · Histoplasma: CNS risk arises from dissemination

Primary infection typically begins after inhalation of environmental microconidia.

Intracellular yeast survives in macrophages until effective T-cell immunity develops.

Dissemination may include meninges, especially with impaired cell-mediated immunity.

Slide 54 · Histoplasma and macrophage activation

01

Inhaled microconidia

02

Intracellular yeast in macrophages

03

Th1 lymphocyte response

04

IFN-γ–activated fungal killing

Disseminated infection is more likely when this cell-mediated pathway is impaired.

Slide 55 · Coccidioides: Meningeal dissemination

Coccidioides immitis and C. Posadasii are endemic dimorphic fungi.

Most primary infections are clinically limited; A minority disseminate.

Disseminated infection may involve the meninges; Depressed T-cell immunity is a risk factor.

Slide 56 · Coccidioides: Distinctive tissue form

Tissue form is a thick-walled spherule with many internal endospores.

Rupture releases endospores and may provoke a pyogenic reaction.

Inflammation may be granulomatous, suppurative, or mixed at involved sites.

Slide 57 · Blastomyces: Disseminated disease

Blastomyces dermatitidis commonly enters as a pulmonary infection.

Disseminated disease is a recognized clinical pattern.

The brain may be involved after dissemination, as noted in the CNS fungal overview.

Slide 58 · Blastomyces: Recognizable tissue yeast

Round yeast with a thick, double-contoured cell wall.

Broad-based budding is a characteristic morphologic clue.

Inflammatory lesions may be suppurative granulomas.

Slide 59 · Endemic fungi: Microscopy and CNS relevance

Organism

Tissue form

Relevant route or disease

Histoplasma

Small yeasts in macrophages

Hematogenous spread; meninges

Coccidioides

Spherules with endospores

Dissemination to meninges

Blastomyces

Thick-walled, broad-budding yeast

Disseminated disease can affect CNS

Organism

Tissue form

Relevant route or disease

Slide 60 · Morphology-focused differentiation of fungi

Tissue observation

Prioritize

Important caution

Encapsulated budding yeasts

Cryptococcus

Host reaction may be nearly absent

Multiple suppurative microabscesses

Candida

Use special stains for organism demonstration

Septate acute-angle hyphae

Aspergillus-like molds

Other hyaline molds can look similar

Broad nonseptate hyphae

Mucormycetes

Look for vessel wall invasion

Tissue observation

Prioritize

Important caution

Slide 61 · Pathology interpretation: Start with pattern

01

Define compartment

02

Assess inflammation

03

Inspect organism form

04

Check vascular invasion

Integrate the observed pattern with exposure and immunosuppression; Do not equate morphology with definitive species identification.

Slide 62 · Low inflammation does not exclude severe CNS mycosis

Potential false reassurance

More informative evidence

Relatively few CSF inflammatory cells

Minimal meningeal gliosis or infiltrate

Organism-rich perivascular spaces

Recognize host immune suppression

Identify fungal structures with appropriate stains

Use cryptococcal antigen assays when indicated

Slide 63 · Case: Progressive meningitis in advanced HIV

CLINICOPATHOLOGIC VIGNETTE

A person with advanced HIV has subacute neurologic illness. CSF contains few inflammatory cells but raised protein. An encapsulated budding yeast is suspected.

Which fungus and lesion pattern best fit the findings?

Slide 64 · Case interpretation: Cryptococcal meningitis

Cryptococcus neoformans — opportunistic meningeal infection

Limited CSF pleocytosis is compatible with cryptococcal meningitis.

Mucicarmine/PAS can highlight the capsule; Cryptococcal antigen assays support detection.

Perivascular yeast aggregates may show minimal inflammatory reaction.

Slide 65 · Case: Diabetic patient with sinus-to-brain extension

CLINICOPATHOLOGIC VIGNETTE

A patient with diabetic ketoacidosis develops an invasive paranasal sinus infection extending toward the orbit and cranial vault. Necrotic tissue contains broad, irregular fungal hyphae.

Identify the most likely category and main mechanism of brain injury.

Slide 66 · Case interpretation: Rhinocerebral mucormycosis

Mucormycetes — direct extension and arterial invasion

Fungi can spread from sinuses into the orbit and brain.

Arterial wall invasion causes thrombosis and cerebral infarction.

Broad often nonseptate hyphae with near right-angle branching favor this group.

Slide 67 · Case: Neutropenia with hemorrhagic cerebral injury

CLINICOPATHOLOGIC VIGNETTE

A profoundly neutropenic person with invasive pulmonary fungal disease develops cerebral lesions with hemorrhagic infarction. Tissue shows septate hyphae branching at acute angles.

What process explains the hemorrhage, and which mold is suggested?

Slide 68 · Case interpretation: Invasive aspergillosis

Angioinvasion with thrombosis — Aspergillus-like mold

Tissue-invasive hyphae damage vessel walls.

Vascular thrombosis and subsequent hemorrhagic infarction explain CNS injury.

Septate acute-angle hyphae suggest Aspergillus but are not species-specific.

Slide 69 · Final synthesis: Three lesions to recognize

Meningitis

Often cryptococcal; Chronic or fulminant disease may occur even with sparse CSF cells.

Vasculitis

Angioinvasive molds can cause thrombosis and hemorrhagic infarction.

Brain invasion

Candida microabscesses; Cryptococcal perivascular yeast; Fungal granulomas.

Match lesion pattern and fungus to the host context.

Slide 70 · Selected source references

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition (2026).

Primary CNS section: fungal meningoencephalitis and adjacent infectious diseases of the nervous system.

Supporting infectious disease sections: candidiasis, cryptococcosis, invasive aspergillosis, mucormycosis, and dimorphic fungi.

All illustrations in this deck are editable educational schematics, not real specimens.