What are the common causative agents, classical presentations, and histological findings of central nervous system (CNS) infections, including bacterial, viral, fungal, and parasitic infections?

CNS Infection Causative Agents: Classical Presentations and Histological Findings

Viral Infections

Herpes Simplex Virus (HSV)

HSV is the most commonly diagnosed viral encephalitis in industrialized nations, with HSV-1 accounting for 90% of cases and HSV-2 for 10%. 1

• Presentation: Acute onset of altered mental status, fever, behavioral changes, speech disturbances, focal neurological deficits, and seizures with temporal lobe predilection 1
• CSF findings: Lymphocytic pleocytosis, elevated protein, normal to slightly decreased glucose, red blood cells may be present 1
• Histology: Hemorrhagic necrosis of temporal lobes, intranuclear eosinophilic inclusions (Cowdry type A bodies) in neurons and glial cells 1
• Imaging: MRI shows temporal lobe involvement with hemorrhagic changes 1
• Special note: HSV-2 typically occurs in immunocompromised individuals and neonates, causing disseminated infection 1

Varicella Zoster Virus (VZV)

• Presentation: Encephalitis especially in immunocompromised patients, may present with multifocal leukoencephalopathy, often with concurrent or recent rash 1
• CSF findings: Lymphocytic pleocytosis, elevated protein 1
• Histology: Multinucleated giant cells with intranuclear inclusions, vasculitis with vessel wall inflammation 1

Enteroviruses

• Presentation: More commonly cause aseptic meningitis but can cause encephalitis, particularly in young children and immunocompromised patients 1
• CSF findings: Lymphocytic pleocytosis, normal glucose, mildly elevated protein 1
• Histology: Perivascular lymphocytic infiltrates, minimal parenchymal necrosis 1

Cytomegalovirus (CMV)

• Presentation: Almost exclusively in immunocompromised patients (CD4 <50), subacute presentation with encephalitis or ventriculoencephalitis 1
• CSF findings: May be acellular in immunocompromised patients, elevated protein 1
• Histology: Microglial nodules, characteristic "owl's eye" intranuclear and cytoplasmic inclusions in neurons and glial cells 1

Epstein-Barr Virus (EBV)

• Presentation: Encephalitis in immunocompromised patients, associated with primary CNS lymphoma in advanced HIV 1
• CSF findings: Variable pleocytosis, elevated protein 1

JC/BK Virus

• Presentation: Progressive multifocal leukoencephalopathy (PML) in severely immunocompromised patients, presents with dementia rather than acute encephalitis 1
• CSF findings: Often normal or minimal pleocytosis 1
• Histology: Demyelination, enlarged oligodendrocytes with intranuclear inclusions, bizarre astrocytes 1

Measles Virus

• Presentation: Subacute sclerosing panencephalitis (SSPE) in immunocompetent patients years after initial infection; inclusion body encephalitis in immunocompromised 1
• Histology: Intranuclear and cytoplasmic inclusions in neurons and glial cells, gliosis 1

Bacterial Infections

Mycobacterium tuberculosis

Tuberculous meningitis is one of the most common CNS infections globally and presents with chronic meningitis. 1, 2

• Presentation: Subacute to chronic course (≥4 weeks), fever, headache, altered mental status, cranial nerve palsies (especially VI), stroke-like symptoms from vasculitis 1, 2
• CSF findings: Lymphocytic pleocytosis (though may be neutrophilic early), markedly elevated protein (often >100 mg/dL), low glucose (<45 mg/dL or CSF:blood ratio <0.5), elevated opening pressure 1, 2
• Histology: Granulomas with caseous necrosis, acid-fast bacilli on Ziehl-Neelsen stain, thick gelatinous basal exudate, vasculitis 1
• Imaging: Basal meningeal enhancement, tuberculomas (ring-enhancing lesions), hydrocephalus, infarcts 2
• Diagnostic note: Culture sensitivity is only 25-70%; large CSF volumes (≥5 mL) improve yield 1

Treponema pallidum (Neurosyphilis)

• Presentation: Variable presentations including meningitis, meningovascular syphilis with stroke, general paresis, tabes dorsalis 1
• CSF findings: Lymphocytic pleocytosis, elevated protein, positive VDRL (specific but not sensitive), positive treponemal antibodies 1
• Histology: Perivascular lymphoplasmacytic infiltrates, obliterative endarteritis, gummas (granulomatous lesions) 1

Borrelia burgdorferi (Lyme Neuroborreliosis)

• Presentation: Facial nerve palsy, lymphocytic meningitis, radiculoneuritis, often with history of erythema migrans 1
• CSF findings: Lymphocytic pleocytosis, elevated protein, intrathecal antibody production 1

Listeria monocytogenes

• Presentation: Meningitis or rhombencephalitis in immunocompromised, elderly, pregnant women, and neonates 1
• CSF findings: Neutrophilic or lymphocytic pleocytosis, elevated protein, low glucose 1
• Histology: Microabscesses, gram-positive rods on Gram stain 1

Mycoplasma pneumoniae

• Presentation: Para-infectious or post-infectious encephalitis, often with respiratory symptoms 1
• CSF findings: Lymphocytic pleocytosis, normal glucose 1

Tropheryma whipplei (Whipple's Disease)

• Presentation: Cognitive decline, supranuclear ophthalmoplegia, myoclonus, often with systemic symptoms (diarrhea, weight loss, arthralgia) 1
• Histology: PAS-positive macrophages containing bacilli 1

Pyogenic Bacterial Meningitis

Acute bacterial meningitis requires immediate empirical antibiotics after blood cultures, even if LP is delayed. 3

• Common organisms: Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae (age-dependent) 1
• Presentation: Acute onset (<24 hours) of fever, severe headache, neck stiffness, altered mental status, photophobia 1, 2
• CSF findings: Neutrophilic pleocytosis (>1000 cells/μL), markedly elevated protein, low glucose (CSF:blood ratio <0.4), elevated lactate 1, 3, 2
• Histology: Purulent exudate in subarachnoid space, neutrophilic infiltration, organisms visible on Gram stain 1
• Diagnostic note: Gram stain sensitivity is 60-80% without prior antibiotics, 40-60% with prior treatment 1

Brain Abscess

Neurosurgical aspiration or excision should be performed as early as possible for microbiological diagnosis and treatment. 3, 4

• Common organisms: Polymicrobial (streptococci, staphylococci, anaerobes), E. coli post-neurosurgery or in immunocompromised 4, 5
• Presentation: Headache, focal neurological deficits, seizures, fever (may be absent), signs of increased intracranial pressure 4, 6
• Imaging: Ring-enhancing lesion with restricted diffusion on MRI DWI/ADC, surrounding vasogenic edema 3, 4
• Histology: Central necrosis with neutrophils, fibrous capsule, surrounding gliosis and edema 4
• Treatment duration: 6-8 weeks IV antibiotics for aspirated abscesses, 4 weeks after complete excision 4

Fungal Infections

Cryptococcus neoformans/gattii

Cryptococcal antigen testing on CSF has >90% sensitivity and specificity and has replaced India ink staining. 1

• Presentation: Subacute to chronic meningitis in immunocompromised (especially HIV with CD4 <100), headache, fever, altered mental status, minimal meningismus 1
• CSF findings: Lymphocytic or minimal pleocytosis (may be acellular in AIDS), elevated protein, low glucose, markedly elevated opening pressure (often >25 cm H2O) 1
• Histology: Encapsulated yeast with narrow-based budding, mucicarmine stain highlights thick polysaccharide capsule, gelatinous pseudocysts in brain parenchyma 1, 7
• Imaging: Gelatinous pseudocysts in basal ganglia, dilated Virchow-Robin spaces, meningeal enhancement 7

Coccidioides species

• Presentation: Chronic meningitis in endemic areas (southwestern US), immunocompromised at higher risk 1
• CSF findings: Lymphocytic pleocytosis, low glucose, elevated protein, eosinophils may be present 1
• Histology: Spherules with endospores, granulomatous inflammation 7
• Diagnostic note: Complement fixation on CSF is more sensitive than culture or direct smear 1

Histoplasma capsulatum

• Presentation: Chronic meningitis in endemic areas (Ohio/Mississippi River valleys), primarily in immunocompromised 1
• Histology: Small intracellular yeasts within macrophages, granulomas 7

Mucormycosis

• Presentation: Rapidly progressive rhinocerebral infection in diabetics (especially DKA) and immunocompromised, facial pain, proptosis, black necrotic eschars 2, 7
• Histology: Broad, non-septate hyphae with right-angle branching, angioinvasion with vessel thrombosis and tissue necrosis 2, 7

Aspergillus species

• Presentation: Brain abscesses or hemorrhagic infarcts in severely immunocompromised, often with pulmonary involvement 7
• Histology: Septate hyphae with acute-angle (45°) branching, angioinvasion 7

Parasitic Infections

Toxoplasma gondii

Toxoplasmosis causes ring-enhancing lesions in immunocompromised patients, especially with HIV and CD4 <100. 1

• Presentation: Multiple brain abscesses in AIDS patients, headache, focal deficits, seizures, altered mental status 1, 7
• CSF findings: Often normal or mild lymphocytic pleocytosis; serum antibody testing more useful than CSF 1
• Histology: Tachyzoites (crescent-shaped), tissue cysts with bradyzoites, necrotizing encephalitis with perivascular inflammation 7
• Imaging: Multiple ring-enhancing lesions with predilection for basal ganglia and corticomedullary junction 7

Plasmodium falciparum (Cerebral Malaria)

• Presentation: Altered consciousness, seizures, coma in travelers from endemic areas, often with fever and thrombocytopenia 1, 7
• Diagnosis: Thick and thin blood films showing parasites, malaria pigment in neutrophils/monocytes 1, 7
• Histology: Sequestration of parasitized red blood cells in cerebral capillaries, ring hemorrhages, petechial hemorrhages 7

Taenia solium (Neurocysticercosis)

• Presentation: Seizures (most common), headaches, hydrocephalus, focal deficits depending on cyst location and stage 1, 2
• CSF findings: Eosinophilic pleocytosis (when cysts degenerate), elevated protein 2
• Histology: Cystic lesions containing scolex with hooklets and suckers, surrounding granulomatous inflammation in degenerating cysts, calcifications in dead cysts 2, 7
• Imaging: Multiple cystic lesions in various stages (vesicular, colloidal, granular-nodular, calcified) 2

Trypanosoma species (African Trypanosomiasis)

• Presentation: Sleeping sickness with progressive neuropsychiatric symptoms, sleep disturbances, movement disorders 1
• CSF findings: Lymphocytic pleocytosis, elevated protein, trypanosomes visible on microscopy 1

Prion Disease

Creutzfeldt-Jakob Disease (CJD)

• Presentation: Rapidly progressive dementia, myoclonus, ataxia, visual disturbances 1
• CSF findings: Elevated 14-3-3 protein, elevated tau protein, normal cell count and glucose 1
• Histology: Spongiform changes (vacuolation of neuropil), neuronal loss, gliosis, no inflammation, PrP immunostaining positive 1
• Imaging: Cortical ribboning and basal ganglia hyperintensity on DWI/FLAIR MRI 1

Special Populations

Immunocompromised Patients

Immunocompromised patients require broader microbiological workup including CMV, EBV, HHV-6, Toxoplasma, Cryptococcus, Listeria, and mycobacteria. 1

• Presentation: More subtle and subacute presentations, may lack fever or meningismus 1
• CSF findings: May be acellular despite active infection due to impaired inflammatory response 1
• Imaging: MRI is superior to CT; should be performed before LP due to higher risk of mass lesions without focal signs 1

Returning Travelers

Malaria and tuberculous meningitis are the most common causes of encephalopathy in returning travelers. 1

• Additional considerations: Dengue, rabies, Japanese encephalitis, West Nile virus, tick-borne encephalitis depending on geographic exposure 1
• Diagnostic approach: Blood films for malaria even with prophylaxis or presumed immunity, TB testing with travel history from endemic areas 1