Fungal & Tuberculous CNS Infections

Fungal and mycobacterial infections of the CNS produce distinctive pathology characterized by chronic granulomatous inflammation, characteristic organisms identifiable with special stains, and a propensity for basal cistern involvement with vasculitis and hydrocephalus. Both fungal and tuberculous CNS disease are most often seen in immunocompromised hosts or in patients with widespread systemic disease. Recognition is critical because effective treatment exists for most but requires identification of the specific pathogen. This page covers the major CNS fungal infections and tuberculous CNS disease.

Tuberculous Meningitis (TBM)

Pathology

  • Basal cistern predominance: thick, gelatinous exudate at base of brain.
  • Granulomatous inflammation: caseating granulomas with epithelioid cells, Langhans giant cells, lymphocytes.
  • Vasculitis: of vessels traversing the basal exudate (lenticulostriate, perforators, brainstem perforators) → deep infarcts, often basal ganglia and internal capsule.
  • Hydrocephalus: communicating (basal exudate obstructing CSF flow at outlets) or obstructive.
  • Tuberculoma: focal granulomatous mass, can be solitary or multiple.
  • Acid-fast bacilli: in caseating necrosis (Ziehl-Neelsen, Fite stains).
  • Cranial nerve involvement: especially CN II (from base), CN III, IV, VI, VII.

Clinical

  • Subacute meningitis with fever, headache, neck stiffness.
  • Cranial neuropathies.
  • Cognitive decline, behavioral change.
  • Strokes (basal ganglia, capsular).
  • Hydrocephalus → progressive deterioration.
  • Often coexistent pulmonary TB or other extrapulmonary sites.

Diagnosis

  • CSF: lymphocytic pleocytosis (sometimes neutrophilic early), markedly elevated protein (often 200-500 mg/dL), low glucose, sometimes mononuclear with pellicle on standing.
  • CSF AFB stain (sensitivity 10-40%).
  • CSF culture (slow, weeks).
  • CSF PCR (Xpert MTB/RIF) — rapid, more sensitive.
  • Imaging: basal meningeal enhancement, hydrocephalus, tuberculomas, infarcts.

Treatment

RIPE for 12 months (isoniazid, rifampin, pyrazinamide, ethambutol). Steroids for first 6-8 weeks (proven mortality benefit). EVD if hydrocephalus.

Tuberculoma

Focal granulomatous mass, central caseating necrosis, surrounded by epithelioid cells, Langhans giant cells, lymphocytes, peripheral fibrotic capsule. Can be solitary or multiple. Imaging: ring or homogeneous enhancement; “target sign” with central calcification + ring enhancement is characteristic. Differential: tumor, abscess, neurocysticercosis.

Spinal Tuberculosis

  • Pott disease: vertebral osteomyelitis with collapse and cord compression.
  • Spinal tuberculoma: intramedullary or intradural extramedullary.
  • Tuberculous arachnoiditis: chronic inflammatory cord encasement.

Cryptococcal Meningitis

Pathology

  • Cryptococcus neoformans: encapsulated yeast; thick polysaccharide capsule visible with mucicarmine (red) or India ink (clear halo around yeast).
  • Predilection for basal cisterns and perivascular spaces.
  • “Soap bubble” appearance: cystic dilated perivascular spaces filled with yeasts and capsular material.
  • Minimal inflammatory response in severely immunocompromised; more inflammation in immunocompetent.
  • Increased ICP: from CSF outflow obstruction by capsular polysaccharide.

Clinical

  • Subacute meningitis with headache, fever, behavior change.
  • Cranial neuropathies.
  • Visual loss from raised ICP.
  • Mostly in HIV/AIDS with CD4 < 100, transplant recipients, immunosuppressed.
  • Cryptococcus gattii: in immunocompetent patients (some geographic areas).

Diagnosis

  • CSF: lymphocytic pleocytosis (mild), elevated opening pressure, elevated protein, low glucose.
  • CSF cryptococcal antigen (CrAg lateral flow assay): highly sensitive.
  • India ink stain: rapid bedside diagnosis.
  • Cryptococcal culture.
  • Serum CrAg.

Treatment

  • Amphotericin B + flucytosine (induction).
  • Fluconazole (consolidation, maintenance).
  • Aggressive ICP management: serial LPs, EVD if needed.
  • ART initiation timing: delay 4-6 weeks after starting antifungals to reduce IRIS risk.

Mucormycosis (Mucor, Rhizopus)

Pathology

  • Angioinvasive: hyphae invade vessel walls.
  • Hemorrhagic necrosis: from vessel thrombosis.
  • Broad, ribbon-like, non-septate hyphae on H&E and GMS.
  • Predilection for orbital, sinonasal, and cerebral invasion.

Clinical (Rhino-orbital-cerebral Mucormycosis)

  • Patients in diabetic ketoacidosis, with hematologic malignancy, transplant recipients, on iron chelation, on chronic corticosteroids.
  • Facial pain, sinus symptoms, orbital pain, proptosis, ophthalmoplegia, cranial neuropathies.
  • Rapid progression to cerebritis with infarction.
  • High mortality despite treatment.

Treatment

Surgical debridement (often radical) + IV liposomal amphotericin B + treatment of underlying condition. Treatment must be aggressive and prompt.

Aspergillosis

Pathology

  • Angioinvasive: hyphae invade vessel walls → infarction and hemorrhage.
  • Septate hyphae with acute (45°) branching on GMS.
  • Predilection for cerebral, paranasal sinus, lung.

Clinical

  • Immunocompromised patients (neutropenia, transplant, corticosteroids).
  • Brain abscesses (often multiple), cerebritis, mycotic aneurysms with hemorrhage.
  • Sinusitis can extend through bone into brain.

Treatment

Voriconazole (first-line), liposomal amphotericin B (alternative). Sometimes surgical drainage.

Candidiasis

CNS candidiasis: in immunocompromised, neonatal (premature infants); microabscesses, sometimes vasculitis with infarcts.

Coccidioidomycosis

Endemic in southwestern US. Chronic meningitis; basal preference; CSF eosinophilia possible. Treatment: fluconazole, sometimes for life.

Histoplasmosis

Granulomatous meningoencephalitis; in immunocompromised; soldering iron-like inclusions in macrophages (small yeast forms).

Blastomycosis

Broad-based budding yeast; granulomatous CNS infection.

Neurocysticercosis

Pathology

  • Cystic larvae of Taenia solium in brain parenchyma, ventricles, subarachnoid space, eye.
  • Stages: viable (no inflammation), degenerating (inflammation), calcified (resolved).
  • Each cyst has a scolex (head of worm) visible inside.

Clinical

  • Most common parasitic CNS infection worldwide.
  • Seizures: most common presentation.
  • Hydrocephalus (ventricular cysts, racemose intraventricular form).
  • Stroke (subarachnoid form with vasculitis).

Treatment

Albendazole or praziquantel + steroids (to mitigate inflammation from dying parasites). Surgery for hydrocephalus, intraventricular cysts.

Cerebral Malaria

Plasmodium falciparum sequestration in cerebral capillaries; “ring hemorrhages” microscopically. High mortality in children in endemic areas. Coma + fever + seizures. Treat with IV artesunate.

🔍 Did You Know?

The classical “soap bubble” appearance of cryptococcal infection in the brain reflects an unusual mechanism: the polysaccharide capsule of Cryptococcus neoformans is so thick that the yeasts displace surrounding tissue rather than being phagocytosed and destroyed. In a perivascular space, expanding cryptococci dilate the space into a cystic structure that can reach centimeters in size, filled with capsule material and yeasts but with very little inflammatory response. The pattern is most visible on autopsy of severely immunocompromised patients — particularly those with HIV/AIDS and very low CD4 counts — where the muted immune response allows the cryptococci to fill the perivascular spaces with little surrounding cellular reaction. The “soap bubble” can be visible on MRI as well, with small cystic lesions clustered around perforating vessels, particularly in the basal ganglia. The mechanism explains a clinical observation that puzzled early clinicians: cryptococcal meningitis often produces dramatically elevated CSF pressure not from inflammation but from the polysaccharide capsule itself, which physically obstructs CSF outflow. Aggressive ICP management — serial LPs to drain CSF, sometimes EVD — is as important as antifungal therapy in cryptococcal meningitis. The lesson: in HIV/AIDS with subacute meningitis, send the cryptococcal antigen, measure the opening pressure, and be prepared to manage ICP from the capsule physics, not just the infection.

Pitfalls and Pearls

  • TBM: basal exudate + vasculitis + hydrocephalus + tuberculomas; treat with RIPE + steroids 6-8 weeks.
  • Cryptococcus: HIV + low CD4; soap-bubble perivascular spaces; CrAg + India ink; raised ICP from capsule.
  • Mucor: DKA / immunocompromised + sinus / orbital / brain; broad ribbon-like non-septate hyphae; angioinvasive; surgical debridement + ampho B.
  • Aspergillus: septate hyphae 45° branching; angioinvasive; voriconazole.
  • Cysticercosis: seizures + cystic lesions with scolex; albendazole + steroids.
  • Cerebral malaria: P. falciparum + capillary sequestration; ring hemorrhages.
  • Coccidioidomycosis meningitis: lifelong fluconazole sometimes required.
  • TB tuberculoma “target sign”: central calcification + ring enhancement.
  • TBM hydrocephalus: communicating; basal exudate.
  • Cryptococcal IRIS: delay ART 4-6 weeks after antifungal start.
  • Spinal Pott disease: vertebral collapse + cord compression.

References

  1. Love S, Budka H, Ironside JW, Perry A, eds. Greenfield’s Neuropathology. 9th ed. CRC Press; 2015.
  2. Thwaites G, Fisher M, Hemingway C, et al; British Infection Society. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect. 2009;59(3):167-187.
  3. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease. Clin Infect Dis. 2010;50(3):291-322.
  4. Spellberg B, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev. 2005;18(3):556-569.
  5. Garcia HH, Nash TE, Del Brutto OH. Clinical symptoms, diagnosis, and treatment of neurocysticercosis. Lancet Neurol. 2014;13(12):1202-1215.