patoloji-ders-notlari

Title

Serdar Balcı

Infectious Diseases of CNS

Serdar BALCI, MD

Infectious Diseases of CNS

Agents specific for CNS
- Rabies
Other agents
- Staphylococcus aureus
Damage to nervous tissue
- direct injury of neurons or glial cells by the infectious agent or microbial toxins
- consequence of the host innate or adaptive immune response

How do infectious agents reach the nervous system

Hematogenous spread
- Arterial blood supply
  - The most common means of entry
- Retrograde venous spread
  - Anastomoses between veins of the face
  - Venous sinuses of the skull
Direct implantation of microorganisms
- Traumatic introduction of foreign material
- Iatrogenic
  - Lumbar puncture needle
Local extension
- Infections of the skull or spine
- Air sinuses
  - Most often the mastoid or frontal
- Infected teeth
- Cranial or spinal osteomyelitis
- Congenital malformations
  - Meningomyelocele
Peripheral nerves
- Viruses
  - Rabies
  - Herpes zoster viruses

Epidural and Subdural Infections

Bacterial or fungal infections

Usually as a consequence of direct local spread

Epidural Infections

Epidural abscesses
- Arise from an adjacent focus of infection
- Sinusitis or osteomyelitis
Abscesses of spinal epidural space
- Cause spinal cord compression
- Neurosurgical emergency

Subdural Infections

Subdural empyema
- When infections of the skull or air sinuses spread to the subdural space
- Arachnoid and subarachnoid spaces are unaffected
- Large subdural empyema may produce a mass effect
Thrombophlebitis in the bridging veins that cross the subdural space
- Venous occlusion
- Infarction of the brain

Meningitis

Inflammatory process involving the leptomeninges within the subarachnoid space
Meningoencephalitis
- If spreads into the underlying brain
Meningitis can be infectious or chemical
Infectious meningitis
- acute pyogenic (usually bacterial)
- aseptic (usually viral)
- chronic (usually tuberculous, spirochetal, or cryptococcal)

Acute Pyogenic Meningitis (Bacterial Meningitis)

Most likely organisms vary with patient age
Neonates
- Escherichia coli, group B streptococci
Adolescents and in young adults
- Neisseria meningitidis
Older individuals
- Streptococcus pneumoniae, Listeria monocytogenes
Systemic signs of infection
Meningeal irritation and neurologic impairment
- headache, photophobia, irritability, clouding of consciousness, and neck stiffness
Lumbar puncture
- increased pressure
Examination of the CSF
- Abundant neutrophils, elevated protein, and reduced glucose
- Bacteria may be seen on a smear or can be cultured

Acute meningitis

Exudate is within the leptomeninges over the surface of the brain

Meningeal vessels are engorged and prominent

Tracts of pus can be followed along blood vessels on the brain surface

When the meningitis is fulminant

-inflammatory cells infiltrate the walls of the leptomeningeal veins

-may spread into the substance of the brain (focal cerebritis)

-may extend to the ventricles, producing ventriculitis

Robbins Basic Pathology

Acute meningitis

Neutrophils
- fill the entire subarachnoid space in severely affected areas
- predominantly around the leptomeningeal blood vessels in less severe cases
Gram stain reveals varying numbers of the causative organism
Bacterial meningitis may be associated with abscesses in the brain
Phlebitis also may lead to venous occlusion and hemorrhagic infarction of the underlying brain
If treated early, there may be little or no morphologic residuum

Aseptic Meningitis (Viral Meningitis)

Meningeal irritation, fever, and alterations in consciousness
Relatively acute onset
Less fulminant than in pyogenic meningitis
Examination of the CSF
- Lymphocytosis
- moderate protein elevation
- normal glucose level
Typically self-limiting disease
Believed to be of viral origin in most cases
- often difficult to identify the responsible virus
No distinctive macroscopic characteristics
- brain swelling, seen in only some instances
Microscopic examination
- no recognizable abnormality
- mild to moderate leptomeningeal lymphocytic infiltrate

Chronic Meningitis

Mycobacteria

Spirochetes

They may involve the brain parenchyma

Tuberculous Meningitis

Generalized signs and symptoms of headache, malaise, mental confusion, and vomiting
__ in CSF__
- moderate increase cellularity
- mononuclear cells
- mixture of polymorphonuclear and mononuclear cells
- protein level is elevated
- glucose content typically is moderately reduced or normal
Mycobacterium tuberculosis
- Tuberculoma
  - well-circumscribed intraparenchymal mass associated with meningitis
- cause of arachnoid fibrosis
  - produce hydrocephalus
Subarachnoid space
- gelatinous or fibrinous exudate
- most often at the base of the brain
- obliterate the cisterns and encasing cranial nerves
- discrete white granules scattered over the leptomeninges
- Arteries show obliterative endarteritis
  - inflammatory infiltrates
  - marked intimal thickening
Microscopic examination
- mixtures of lymphocytes, plasma cells, and macrophages
- well-formed granulomas
- caseous necrosis and giant cells

Spirochetal Infections

Neurosyphilis
- tertiary syphilis
- 10% of persons with untreated Treponema pallidum
- HIV infection
  - increased risk for neurosyphilis
  - more aggressive and severe
Meningovascular neurosyphilis
- involves the base of the brain
- obliterative endarteritis rich in plasma cells and lymphocytes
Paretic neurosyphilis
- parenchymal involvement
- neuronal loss
- marked proliferation of rod-shaped microglial cells
- progressive loss of mental and physical functions
- mood alterations
  - delusions of grandeur
- severe dementia
Tabes dorsalis
- damage to the sensory nerves in the dorsal roots
- impaired joint position sense and locomotor ataxia
- loss of pain sensation
  - skin and joint damage (Charcot joints)
- sensory disturbances, “lightning pains”
- absence of deep tendon reflexes

Neuroborreliosis

Borrelia burgdorferi
Lyme disease
Neurologic signs and symptoms are highly variable
- aseptic meningitis
- facial nerve palsies
- mild encephalopathy
- polyneuropathies

Brain Abscesses

Nearly always caused by bacterial infections
Direct implantation of organisms
Local extension from adjacent foci (mastoiditis, paranasal sinusitis)
Hematogenous spread (usually from a primary site in the heart, lungs, or distal bones, or after tooth extraction)
Predisposing conditions
- Acute bacterial endocarditis
  - septic emboli are released
  - multiple abscesses
- Cyanotic congenital heart disease
  - right-to-left shunt
  - loss of pulmonary filtration of organisms
- Chronic pulmonary infections
  - Bronchiectasis
  - source of microbes that spread hematogenously
Destructive lesions
Progressive focal deficits
General signs of increased intracranial pressure
CSF
- white cell count and protein levels are usually high
- glucose content tends to be normal
Increased intracranial pressure and progressive herniation can be fatal
Abscess rupture can lead to ventriculitis, meningitis, and venous sinus thrombosis

N Engl J Med 2014;371:447-56

Robbins Basic Pathology

Central liquefactive necrosis

İnflammatory cells

Edema and granulation tissue, vascularization

Fibrous capsule

Zone of reactive gliosis

Viral Encephalitis

Parenchymal infection
Meningoencephalitis
- almost invariably associated with meningeal inflammation
Most characteristic histologic features
- perivascular and parenchymal mononuclear cell infiltrates
- microglial nodules
- neuronophagia

Robbins Basic Pathology

**perivascular cuffing of lymphocytes **

**microglial nodules **

Robbins Basic Pathology

Herpes encephalitis showing extensive destruction of inferior frontal and anterior temporal lobes

Robbins Basic Pathology

HIV encephalitis: Accumulation of microglia forming a microglial nodule and multinucleate giant cell

Robbins Basic Pathology

Arboviruses

Arthropod-borne viruses
Epidemic encephalitis
- tropical regions
Eastern and Western equine encephalitis
West Nile virus infection
Perivascular lymphocytic meningoencephalitis (sometimes with neutrophils)
Multifocal gray and white matter necrosis
Often associated with neuronophagia
Microglial nodules
Phagocytosis of neuronal debris
In severe cases necrotizing vasculitis, focal hemorrhages

HSV-1 encephalitis

most common in children and young adults
alterations in mood, memory, and behavior
- involvement of the frontal and temporal lobes
Recurrent HSV-1 encephalitis
- associated with inherited mutations Toll-like receptor signaling
Inferior and medial regions of the temporal lobes, orbital gyri of the frontal lobes
Necrotizing and often hemorrhagic
Perivascular inflammatory infiltrates
Large eosinophilic intranuclear viral inclusions (Cowdry type A bodies) in neurons and glial cells

HSV-2

Meningitis in adults

Disseminated severe encephalitis neonates born by vaginal delivery to women with active primary HSV genital infections

Varicella-zoster virus (VZV)

chickenpox during primary infection

Latent infection in neurons of dorsal root ganglia

Reactivation in the distribution of one or a few dermatomes

Cytomegalovirus

Fetuses and immunosuppressed persons
All cells within the CNS (neurons, glial cells, ependyma, and endothelium) are susceptible to infection
Intrauterine infection
- periventricular necrosis
- microcephaly with periventricular calcification
Adults
Subacute encephalitis
Most severe in the periventricular region
Lesions can be hemorrhagic, contain typical viral inclusions

Poliovirus

Enterovirus
Secondarily invades the nervous system
- damages motor neurons in the spinal cord and brain stem
- flaccid paralysis
Postpolio syndrome
- 25-35 years after the initial illness

Rabies Virus

Virus enters the CNS by ascending along the peripheral nerves from the wound site

Incubation period depends on the distance between the wound and the brain

Human Immunodeficiency Virus

Direct effects of virus on the nervous system
Opportunistic infections
Primary CNS lymphoma
HIV-associated neurocognitive disorder
- HIV infection of microglial cells in the brain
- Activation of innate immune responses
- Cytokine-induced inflammation and toxic effects of HIV-derived proteins

HIV encephalitis

Chronic inflammatory reaction
Widely distributed infiltrates of microglial nodules
Foci of tissue necrosis and reactive gliosis
Microglial nodules also found in the vicinity of small blood vessels
- abnormally prominent endothelial cells
- perivascular foamy or pigment-laden macrophages
Subcortical white matter, diencephalon, and brain stem
Macrophage-derived multinucleate giant cell
Multifocal or diffuse areas of myelin pallor with associated axonal swellings and gliosis
HIV is present in CD4+ mononuclear and multinucleate macrophages and microglia

Polyomavirus and Progressive Multifocal Leukoencephalopathy

JC virus
- Polyomavirus
- infects oligodendrocytes
Demyelination
Exposure to JC virus during childhood → PML results from virus reactivation in immunosuppressed persons
Virus also infects astrocytes
- bizarre giant forms with irregular, hyperchromatic, sometimes multiple nuclei that can be mistaken for tumor

Patchy, irregular, ill-defined areas of white matter destruction that enlarge as the disease progresses

Each lesion is an area of demyelination

Robbins Basic Pathology

Center

-scattered lipid-laden macrophages

-reduced number of axons

Edges

-greatly enlarged oligodendrocyte nuclei whose chromatin is replaced by glassy-appearing amphophilic viral inclusions

Robbins Basic Pathology

Fungal Encephalitis

Parenchymal granulomas or abscesses
Often associated with meningitis
Candida albicans
- Produces multiple microabscesses
- With or without granuloma formation
Mucormycosis
- Rhinocerebral infections
- Infection of the nasal cavity or sinuses of a diabetic patient with ketoacidosis
- May spread to the brain through vascular invasion or by direct extension through the cribriform plate
Aspergillus fumigatus
- Widespread septic hemorrhagic infarctions
In endemic areas
- Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis
- Immunosuppression

Cryptococcus neoformans

Both meningitis and meningoencephalitis
immunosuppression
Can be fulminant and fatal in as little as 2 weeks
May exhibit indolent behavior, evolving over months or years
Mucoid encapsulated yeasts can be visualized on India ink preparations
Extension into the brain follows vessels in the Virchow-Robin spaces
- Organisms proliferate, these spaces expand, giving rise to a “soap bubble”–like appearance

Robbins Basic Pathology

Cerebral Toxoplasmosis

Toxoplasma gondii
immunosuppressed adults
newborns who acquire the organism transplacentally from a mother with an active infection
Adults
- Abscess
- Edema around lesions
Newborns
- Chorioretinitis, hydrocephalus, and intracranial calcifications

Robbins Basic Pathology

Free tachyzoites are demonstrated by immunohistochemical staining

Bradyzoites are present as a pseudocyst

Robbins Basic Pathology

Cysticercosis

End-stage infection by the tapeworm Tenia solium

Develop into mature tapeworms, they encyst

Common within the brain and subarachnoid space

Mass lesion and can cause seizures

Intense inflammatory infiltrate in the surrounding brain, often including eosinophils

Associated with marked gliosis

Amebiasis

Naegleria spp.
- rapidly fatal necrotizing encephalitis
Acanthamoeba
- chronic granulomatous meningoencephalitis

Prion Diseases

Sporadic, familial, iatrogenic, and variant forms of Creutzfeldt-Jakob disease (CJD)
Animal diseases
- **Scrapie in sheep **
- Bovine spongiform encephalopathy in cattle (“mad cow disease”)
The agent in prion diseases is an abnormal form of a cellular protein
- Prion protein (PrP)
May undergo a conformational change from its normal shape (PrP c ) to an abnormal conformation called PrP sc ( sc for scrapie)
PrP normally is rich in α-helices, but PrP sc has a high content of β-sheets
- a characteristic that makes it resistant to proteolysis
When PrP sc physically interacts with PrP molecules it induces them to also adopt the PrP sc conformation
- “infectious nature” of PrP sc
Over time accumulation of a high burden of pathogenic PrP sc molecules in the brain

Robbins Basic Pathology

Sporadic cases of prion disease (sCJD)

PrP c also may change its conformation spontaneously

**Extremely low rate **

Early-onset familial forms of prion disease (fCJD)

Certain mutations in the gene encoding PrP c ( PRNP ) accelerate the rate of spontaneous conformational change

α-Helical PrPc may spontaneously shift to the β-sheet PrPsc conformation, an event that occurs at a much higher rate in familial disease associated with germ line PrP mutations

Robbins Basic Pathology

PrPsc may also be from exogenous sources, such as contaminated food, medical instrumentation, or medicines. Once present, PrPsc converts additional molecules of PrPc into PrPsc through physical interaction

Robbins Basic Pathology

formation of pathogenic PrPsc aggregates

Robbins Basic Pathology

Creutzfeldt-Jakob Disease

Rapidly progressive dementing illness
Sporadic in approximately 85% of cases
Worldwide annual incidence of about 1 per million
>70 years of age
Familial forms caused by mutations in PRNP may present in younger people
The progression to death in CJD usually is so rapid
- little macroscopic evidence of brain atrophy

Pathognomonic finding is a spongiform transformation of the cerebral cortex and deep gray matter structures (caudate, putamen)

Uneven formation of small, apparently empty, microscopic vacuoles of varying sizes within the neuropil and sometimes in the perikaryon of neurons

Robbins Basic Pathology

Advanced cases

Severe neuronal loss

Reactive gliosis

Expansion of the vacuolated areas into cystlike spaces (“status spongiosus”)

No inflammatory infiltrate is present

Immunohistochemical staining demonstrates the presence of proteinase K–resistant PrP sc in tissue

Western blotting of tissue extracts after partial protease digestion allows detection of diagnostic PrP sc .

Variant Creutzfeldt-Jakob Disease

Starting in 1995, cases of a CJD-like illness appeared in the United Kingdom
Neuropathologic findings and molecular features of these new cases were similar to those of CJD
This new disorder differed from typical CJD in several important respects
- The disease affected young adults
- Behavioral disorders figured prominently in early disease stages
- Neurologic syndrome progressed more slowly than in other forms of CJD
Consequence of exposure to the prion disease of cattle, called bovine spongiform encephalopathy
Transmission by blood transfusion
Similar pathologic appearance to that in other types of CJD
- spongiform change
- absence of inflammation
In vCJD, however, there are abundant cortical amyloid plaques, surrounded by the spongiform change

Variant CJD (vCJD) is characterized by amyloid plaques (see inset) that sit in the regions of greatest spongiform change

Robbins Basic Pathology

Autopsy Pathology: A Manual and Atlas

Rubin’s Pathology 7th Ed Clinicopathologic Foundations Of Medicine