1. 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)

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. Neuroborreliosis Borrelia burgdorferi - pathogen of Lyme disease
Neurologic symptoms are highly variable and include aseptic meningitis, facial nerve palsies, mild encephalopathy, and polyneuropathies

12. 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

13. 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

14. 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

15. 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)

16. 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

17. 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

18. 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

19. 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

20. 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, years after resolution of initial illness
In acute disease, death can occur from paralysis of respiratory muscles

21. 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

22. 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

23. 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)

24. 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)

25. 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)

26. 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”

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

28. 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)

29. 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

30. 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

31. 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

32. 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.

33. 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

34. 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)

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

36. 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

37. 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, p
Required Reading: Robbins Basic Pathology 9E, p