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INFECTIONS OF THE NERVOUS SYSTEM
Hematogenous spread via arteries: most common
Retrograde venous spread through anastomoses between veins of face and venous sinuses of skull
Direct implantation • Post-traumatic• Iatrogenic (lumbar puncture needle)
Local extension from infection in the skull or spine
Peripheral nerves - rabies and herpes zoster
Epidural and Subdural Infections
Bacterial/fungal infections, usually direct local spread
Epidural abscess, Subdural empyema
Fever, headache, neck stiffness
Treatment - complete recovery, if untreated - focal neurologic signs, lethargy, and coma
Meningitis Inflammation of lepto-meninges and CSF in subarachnoid space
Chemical meningitis: in response to a nonbacterial irritant
Infectious meningitis: • acute pyogenic (bacterial)• aseptic (viral)• chronic (tuberculous, spirochetal, or cryptococcal)
Acute Pyogenic Meningitis (Bacterial Meningitis)
In neonates: E.coli, group B streptococciIn elderly: Strep.pneumoniae, Listeria monocytogenes In adolescents/young adults: Neisseria meningitides
Signs of meningeal irritation - headache, photophobia, irritability, clouding of consciousness, and neck stiffness
Lumbar puncture: increased pressure, abundant neutrophils, elevated protein, and reduced glucose
Gram smear/ Bacterial culture
Morphology
Exudate on the surface
Engorged and prominent vessels
Meningoencephalitis: spread into brain
Microscopic examination:
Neutrophils in subarachnoid space (in severely affected cases)
around leptomeningeal blood vessels (in less severe cases)
Brain Abscesses Brain abscesses following neonatal group B streptococcus meningitis
Pus in the subarachnoid space
Aseptic Meningitis (Viral Meningitis)
Meningeal irritation, fever, and alterations of consciousness of relatively acute onset without recognizable organisms
Self-limiting, treated symptomatically
Lumbar puncture: increased lymphocytes (pleiocytosis), moderate protein elevation, normal glucose content
70% cases - enterovirus
No distinctive macroscopic / microscopic characteristics
Tuberculous Meningitis
Headache, malaise, mental confusion, and vomiting
Lumbar puncture: moderate cellularity - mononuclear cells, or a mixture of polymorphonuclear and mononuclear cells
markedly elevated protein level glucose content moderately reduced to normal
Well-circumscribed intraparenchymal mass (tuberculoma)
Chronicity causes arachnoid fibrosis - hydrocephalus
Morphology
Gelatinous /fibrinous exudate in subarachnoid space at base of brain, discrete white granules scattered over leptomeninges
Microscopic examination: Lymphocytes, plasma cells, and macrophagesGranulomas with caseous necrosis and giant cellsAcid fast bacilli
Neurosyphilis Tertiary stage in 10% of untreated cases
Paretic neurosyphilis progressive loss of mental/physical functions, mood alterations (delusions of grandeur), severe dementia
Tabes dorsalis • damage to sensory nerves in dorsal roots - locomotor ataxia• loss of pain causing skin and joint damage (Charcot joints)• lightning pains, absent deep tendon reflexes
Individuals with HIV infection are at increased risk
Morphology
Meningovascular neurosyphilisObliterative endarteritis with perivascular plasma cells and lymphocytesCerebral gummas in meninges extending into brain
Paretic neurosyphilis - loss of neurons with proliferation of microglia (rod cells) and gliosis
Tabes dorsalis - loss of axons and myelin in dorsal roots, with pallor and atrophy in dorsal columns of spinal cord
Neuroborreliosis
Borrelia burgdorferi - pathogen of Lyme disease
Neurologic symptoms are highly variable and include aseptic meningitis, facial nerve palsies, mild encephalopathy, and polyneuropathies
Brain Abscesses
Mostly bacterial infectionsDirect implantation, local extension (mastoiditis, paranasal sinusitis) or hematogenous spread (from heart, lungs, bones or after tooth extraction)
Predisposing conditions Acute bacterial endocarditis: multiple abscessesCyanotic congenital heart disease: right-to-left shunt with loss of pulmonary filtration of organismsChronic pulmonary sepsis: bronchiectasis
Clinically: progressive focal deficits, signs of raised intracranial pressure
CSF findings & Morphology
Lumbar puncture: WBC & Proteins raised Glucose content normal
Gross: lesions with central liquefactive necrosis and a surrounding FIBROUS CAPSULE
Microscopic examination: Exuberant neovascularization around necrosis Zone of reactive gliosis outside the fibrous capsule
Viral Encephalitis
Associated with meningeal inflammation – MENINGOENCEPHALITIS
Microscopy: perivascular and parenchymal mononuclear cell infiltrates, microglial nodules, and neuronophagia
Certain viruses may form inclusion bodies
Inclusion bodies : eosinophilic masses consisting of packed viral particles and products of their replication
Arboviruses Important cause of epidemic encephalitis, especially in tropical regions, high morbidity and mortality
Eastern/Western equine encephalitis and West Nile virus
Animal hosts act as reservoirs, transmitted by mosquitoes
Lumbar puncture: • Colorless, slightly elevated pressure • Neutrophilic pleiocytosis that changes to lymphocytes• Protein level is elevated, but sugar content is normal
Microscopic: Lymphocytic meningoencephalitis, multifocal gray and white matter necrosis, neuronophagia, microglial nodules
Herpes Simplex Virus Type 1
Mostly children and young adults
Symptoms: alterations in mood, memory, behavior reflect frontal/temporal involvement
Morphology :Mostly involves inferior and medial regions of temporal and orbital gyri of frontal lobes
Perivascular inflammation, Cowdry type A inclusion
Herpes Simplex Virus Type 2 Usually meningitis in adults
Disseminated severe encephalitis in neonates born by vaginal delivery to women with active primary HSV genital infections
Neonatal HSV encephalitis – the patient died four weeks after the onset of symptoms, despite treatment with Acyclovir. Necrotizing encephalitis that caused a diffuse meltdown of the brain without predilection for the frontal and temporal lobes
Varicella-Zoster Virus (Herpes Zoster)
Primary - chickenpox, then latent in dorsal root ganglia
Reactivation in adults: ShinglesPost-herpetic neuralgia
Granulomatous arteritis leads to infarcts In immunosuppressed patients causes acute encephalitis
Cytomegalovirus
Fetuses / immunosuppressed
In utero: periventricular necrosis and calcification, microcephaly
Morphology :In immunosuppressed patient - subacute encephalitis, with CMV inclusion-bearing cells
Poliovirus
Enterovirus
Infection causes subclinical/mild gastroenteritis, but in few cases flaccid paralysis with muscle wasting and hyporeflexia
Post-polio syndrome : progressive weakness with decreased muscle bulk and pain, 25-35 years after resolution of initial illness
Rabies
Severe encephalitis transmitted to humans by the bite of rabid animal
Virus ascends along peripheral nerves from wound site
Negri body
• Extraordinary CNS excitability• Violent motor responses progressing to convulsions • Hydrophobia• Alternating mania and stupor progress to coma/death
Human Immunodeficiency Virus
• Direct effects• Opportunistic infections• Tumors
Patterns of direct injury: • Aseptic HIV-1 meningitis
• HIV-1 meningoencephalitis - microglial nodules containing macrophage-derived multinucleated giant cells
• Vacuolar myelopathy resembling subacute combined degeneration (serum B12 is normal)
Progressive Multifocal Leukoencephalopathy (PML)
JC virus, a polyomavirus
Infects oligodendrocytes causes demyelination
In immunosuppressed
Patches of irregular, white matter destruction
Enlarged oligodendrocyte nuclei with ground glass appearance (chromatin replaced by viral inclusion)
Fungal Encephalitis
Candida, Mucor, Aspergillus, Cryptococcus - common
Histoplasma, Coccidioides, Blastomyces - in immunosuppressed
Candida - multiple microabscesses, with/without granuloma
Mucor - most commonly in diabetics with ketoacidosis
Aspergillus - predilection for blood vessel invasion and thrombosis (widespread septic hemorrhagic infarctions)
India Ink stain of CSF showing encapsulated yeast Mucicarmine stain of brain infected with C. neoformans
associated with AIDS
CSF - few cells, high level of protein
Mucoid encapsulated yeasts in CSF seen by INDIA INK(In tissue sections: PAS, mucicarmine, silver stains)
Fungal capsule is characteristic for Cryptococcus and forms "Soap bubble abcesses”
Cerebral Toxoplasmosis
Toxoplasma gondii
CT/MRI: multiple ring-enhancing lesions
Morphology:• Multiple abscesses • Acute lesions - necrosis
surrounded by acute/chronic inflammation and vascular proliferation
• Free tachyzoites and encysted bradyzoites
Cysticercosis
End-stage infection by Taenia solium
Cysts can be found in brain and subarachnoid space - present as mass lesion and can cause seizures
Morphology • Marked gliosis around cyst• Body wall and hooklets from mouth
parts are seen• If organism within cyst dies, intense
inflammatory infiltrate with eosinophils
Amebic meningoencephalitis - different patterns with different species
Naegleria: swimming in non-flowing warm fresh water rapidly fatal necrotizing encephalitis
Acanthamoeba: chronic granulomatous meningoencephalitis
Other protozoal infections
PRION DISEASES
Sporadic, familial, iatrogenic / variant forms of Creutzfeldt-Jakob disease (CJD)
SCRAPIE in sheep/goats, BOVINE SPONGIFORM ENCEPHALOPATHY in cattle ("mad cow" disease)
Change in PrP from native PrPc form to an abnormal configuration - PrPsc (scrapie) or PrPres (protease resistant)
PrPsc can initiate transformation of other PrPc molecules
Creutzfeldt-Jakob Disease
Rapidly progressive dementia, sporadic in 85% of cases
Iatrogenic transmission - deep implantation electrodes, contaminated preparations of human growth hormone
Clinical presentation - subtle changes in memory and behavior, rapidly progress to dementia
Periodic sharp and slow wave complexes in the EEG
Uniformly fatal, average duration of 7 months
Creutzfeldt-Jakob Disease - morphology
Microscopic examinationSPONGIFORM TRANSFORMATION of cerebral cortex and deep gray matter structures (caudate, putamen) In advanced cases - severe neuronal loss, reactive gliosis, expansion of vacuolated areas into cystlike spaces ("status spongiosus")
No inflammatory infiltrate
Immunohistochemistry: proteinase K-resistant PrPsc in tissue
Western blot (on tissue extracts after partial protease digestion)
Prion disease (CJD)
Variant CJD (vCJD)
young adults, slow progression, microscopy similar to CJD but with abundant cortical amyloid plaques
SUMMARY different routes and disease patterns
Bacterial infections - meningitis, cerebral abscesses, or chronic meningoencephalitis
Viral infections - meningitis or meningoencephalitis
HIV - directly with meningoencephalitis or opportunistic infections (toxoplasmosis, CMV) or CNS lymphoma
Prion diseases - transmitted by altered form of normal cellular protein - sporadic, transmitted, or inherited
Recommended Reading: Robbins and Cotran Pathologic Basis of Disease 8E, p1299-1309Required Reading: Robbins Basic Pathology 9E, p824 - 832