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 Local extension can occur from infection in an air sinus (mastoid or frontal), from an infected tooth, from a surgical site in the cranium or spine causing osteomyelitis, bone erosion, and propagation of the infection into the CNS, or from a congenital malformation (meningo-myelocele)

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 Epidural abscess: associated with osteomyelitis, arises from adjacent focus of infection like sinusitis/surgical procedure. In spinal epidural space, it causes spinal cord compression (neurosurgical emergency) Subdural Empyema: infections of skull/air sinuses spread to subdural space and a large empyema may produce mass effect. Also, thrombophlebitis of bridging veins may lead to venous occlusion/infarction of brain

Inflammation of lepto-meninges and CSF in subarachnoid space Meningitis Inflammation of lepto-meninges and CSF in subarachnoid space Complications – seizures, focal neurologic deficits, cranial nerve palsies, sensorineural hearing loss, communicating/non-communicating hydrocephalus Infectious meningitis: acute pyogenic (bacterial) aseptic (viral) chronic (tuberculous, spirochetal, or cryptococcal) Chemical meningitis: in response to a nonbacterial irritant

Acute Pyogenic Meningitis (Bacterial Meningitis) In neonates: E.coli, group B streptococci In 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 Untreated pyogenic meningitis can be fatal, however, effective antimicrobial agents have markedly reduced the mortality

Morphology Brain Abscesses Meningoencephalitis: spread into brain 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 Pus in the subarachnoid space Brain abscesses following neonatal group B streptococcus meningitis

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 Microscopic examination: Gelatinous /fibrinous exudate in subarachnoid space at base of brain, discrete white granules scattered over leptomeninges Microscopic examination: Lymphocytes, plasma cells, and macrophages Granulomas with caseous necrosis and giant cells Acid fast bacilli Thick exudate at the base of the brain in TB meningitis

Neurosyphilis Paretic neurosyphilis Tabes dorsalis 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 Individuals with HIV infection are at increased risk for neurosyphilis, and the rate of progression and severity of the disease seem to be accelerated

Morphology Meningovascular neurosyphilis Obliterative endarteritis with perivascular plasma cells and lymphocytes Cerebral 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 Spirochetes are rarely demonstrated in tissue sections

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 infections Predisposing conditions Direct implantation, local extension (mastoiditis, paranasal sinusitis) or hematogenous spread (from heart, lungs, bones or after tooth extraction) Predisposing conditions Acute bacterial endocarditis: multiple abscesses Cyanotic congenital heart disease: right-to-left shunt with loss of pulmonary filtration of organisms Chronic pulmonary sepsis: bronchiectasis Clinically: progressive focal deficits, signs of raised intracranial pressure With surgery and antibiotics, the otherwise high mortality rate can be reduced, with earlier intervention leading to better outcomes

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 With increased intracranial pressure, herniation can be fatal Abscess rupture can lead to ventriculitis, meningitis, and venous sinus thrombosis

Viral Encephalitis Associated with meningeal inflammation – MENINGOENCEPHALITIS Microscopy: perivascular and parenchymal mononuclear cell infiltrates, microglial nodules, and neuronophagia Certain viruses may form inclusion bodies The nervous system is particularly susceptible to viruses such as rabies and polio Intrauterine viral infection may cause congenital malformations, as occurs with rubella 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 Generalized neurologic symptoms (seizures, confusion, delirium, and stupor or coma) as well as focal signs (reflex asymmetry and ocular palsies)

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 A: Adult HSV encephalitis – hemorrhagic necrosis of the temporal and frontal lobes B: Perivascular mononuclear cells and brain necrosis C: Cowdry type A intranuclear 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 The dependence on route of delivery indicates that the infection is acquired during passage through the birth canal rather than transplacentally 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: Shingles Post-herpetic neuralgia Granulomatous arteritis leads to infarcts In immunosuppressed patients causes acute encephalitis Shingles: painful, vesicular skin eruption in the distribution of one/few dermatomes, usually self-limited Post-herpetic neuralgia: persistent pain syndrome in the affected region

Cytomegalovirus Morphology : Fetuses / immunosuppressed In utero: periventricular necrosis and calcification, microcephaly Morphology : In immunosuppressed patient - subacute encephalitis, with CMV inclusion-bearing cells A: Fetal CMV encephalitis – microcephaly and abnormal gyral pattern B: Fetal CMV encephalitis – microcephaly, abnormal gyral pattern hydrocephalous and periventricular calcifications

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 In acute disease, death can occur from paralysis of respiratory muscles

Rabies Extraordinary CNS excitability Severe encephalitis transmitted to humans by the bite of rabid animal Virus ascends along peripheral nerves from wound site Negri body Incubation period depends on distance between wound and brain, may take few months Hydrophobia: contracture of the pharyngeal musculature may create an aversion to swallowing even water 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) HIV envelope glycoproteins cause the membranes of HIV infected macrophages to fuse forming multinucleated giant cells

Progressive Multifocal Leukoencephalopathy (PML) JC virus, a polyomavirus Infects oligodendrocytes causes demyelination In immunosuppressed Most people show serologic evidence of exposure to JC virus during childhood, and it is believed that PML results from virus reactivation because of immunosuppression 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)

associated with AIDS CSF - few cells, high level of protein India Ink stain of CSF showing encapsulated yeast Mucicarmine stain of brain infected with C. neoformans CSF - few cells, high level of protein Mucoid encapsulated yeasts in CSF seen by INDIA INK (In tissue sections: PAS, mucicarmine, silver stains)

A, Whole-brain section showing the numerous areas of tissue destruction (“soap bubbles”) associated with the spread of organisms in the perivascular spaces. B, At higher magnification it is possible to see the cryptococci in the lesions. Fungal capsule is characteristic for Cryptococcus and forms "Soap bubble abcesses”

Mucicarmine stain of cryptococci (staining red) in a Virchow-Robin perivascular space of the brain (soap-bubble lesion)

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 Biopsy should be obtained from periphery of lesion, to find viable organisms, since the lesion of toxoplasmosis is often necrotic in the center MRI image post contrast shows a ring enhancing mass with "target appearance" in the left lentiform nucleus with marked surrounding edema Biopsy: shows tachyzoites, crescent-shaped 4-8 microns organisms with a nucleus (arrow)

Cysticercosis Morphology 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 Symptoms can intensify when the organism dies within the cyst, as happens after therapy

Other protozoal infections Amebic meningoencephalitis - different patterns with different species Naegleria: swimming in non-flowing warm fresh water rapidly fatal necrotizing encephalitis Acanthamoeba: chronic granulomatous meningoencephalitis

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 If mutation in the gene encoding PrPc, then the change occurs at a higher rate - familial forms of prion disease

Proposed mechanism for the conversion of PrPc through protein-protein interactions. The initiating molecules of PrPsc may arise through inoculation (as in directly transmitted cases) or through an extremely low-rate spontaneous conformational change. The effect of the mutations in PrPc is to increase the rate of the conformational change once PrPsc is able to recruit and convert other molecules of PrPc into the abnormal form of the protein. Although the model is drawn with no other proteins involved, it is possible that other proteins play critical roles in the conversion of Prpc to PrPsc.

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 Worldwide annual incidence of about 1 per million, peak incidence in 7th decade

Creutzfeldt-Jakob Disease - morphology Microscopic examination SPONGIFORM 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)

A, Histology of CJD showing spongiform change in the cerebral cortex (Inset: high magnification of neuron with vacuoles) B: Spongiform change Prion disease (CJD)

Variant CJD (vCJD) Amyloid plaques (see inset) in the regions of spongiform change young adults, slow progression, microscopy similar to CJD but with abundant cortical amyloid plaques

different routes and disease patterns 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, p1299-1309 Required Reading: Robbins Basic Pathology 9E, p824 - 832