CNS Histology and Pathology of Infection Flashcards
Name the components of the covering of the CNS and identify their relationships, including layers and spaces.
- Dura: thick, tough outer layer
- Arachnoid: looser cellular layer with projections into underlying pia and granulations
- Pia: thin layer attached to brain which anchors strands of arachnoid trabeculae
- Epidural space: not present in brain because dura is attached to skull
- Subdural space: potential space where blood can collect after injury
- Subarachnoid space: contains CSF
- Virchow-Robin space: the part of the subarachnoid space that follows vessels into the brain parenchyma
What are arachnoid granulations?
Arachnoid granulations occupy the dural sinuses that arise from layers of the dura and absorb CSF to send it back into circulation. They can calcify with age but this is not necessarily pathological.
Describe the morphology of neurons. How are they arranged in the CNS?
Neurons contain dendrites, a cell body, and an axon and exhibit variability in size and shape. Most are multipolar and have a large central nucleus and a large nucleolus. They also contain Nissl substance (active rough ER) in the cell body.
Neurons are organized in various ways to perform different functions in the CNS.
How are neurons in the neocortex organized?
The neocortex contains six layers that vary depending on the function of that part of the neocortex.
- Molecular layer
- External granular layer
- External pyramidal layer
- Internal granular layer
- Internal pyramidal layer
- Plexiform layer
How are neurons in the hippocampus organized?
Hippocampal cortex is referred to as an archicortex and is composed of four regions based on the cytoarchitecture of the single layer of pyramidal cells which comprise it and their interconnections.
How are neurons in the cerebellar cortex organized?
The cerebellar cortex is organized into three layers:
- Molecular layer: contains processes
- Purkinje layer: contains large cells which project into the molecular layer
- Granule layer: contains small cells
Describe the histological appearance of astrocytes and oligodendrocytes.
Astrocytes are located in both white and gray matter and their processes are not easily visible in sections. They appear to be bare nuclei.
Oligodendrocytes are much larger, contain cytoplasm, and have densely hyperchromatic nuclei.
Describe the functional significance of astrocytes and oligodendrocytes.
Astrocytes extend foot processes around the basement membranes of blood vessels so they are important structurally. They also mediate metabolic exchange between neurons and the blood.
Oligodendrocytes are responsible for myelinating neuronal processes in the CNS. They are likely involved in both structural and metabolic support.
What are ependymal cells? What are choroid plexus cells?
Ependymal cells are cuboidal and line the ventricles of the brain and the central canal. They are glial derived but form an epithelial-like layer with villi. They can have elongated processes that link the ventricular, vascular, and intraparenchymal compartments of the CSF by extending into the subependymal vasculature.
The choroid plexus cells make up projections of vascular stroma derived from the meninges and are responsible for secreting CSF.
Describe the ways neurons respond to injury.
- Acute ischemic injury: produces “red neurons” with small pycnotic nucleus
- Chronic injury: results in cell death and loss
- Neuronal inclusions: lipofushin accumulations along the perikaryal edge, cytoplasmic flame shaped inclusions (neurofibrillary tangles), intranuclear and cytoplasmic viral inclusions, cytoplasmic round inclusions (Lewy bodies)
How do glial cells respond to injury?
Glial cells undergo gliosis. Astrocytes are the main effectors of reaction to injury in the CNS through both hypertrophy and hyperplasia.
What are the inflammatory infiltrates in the CNS?
- Neutrophils (acute)
- Mononuclear cells (chronic), specifically microglia which react to injury by hyperplasia and becoming elongated
- Granulomatous inflammation
What are the four ways that infectious organisms access the CNS?
- Hematogenous spread if it can cross BBB
- Local extension (severe infection of paranasal sinuses or middle ear)
- Retrograde transport from PNS
- Direct implantation (injury, surgery)
What predisposing factors interfere with normal defense mechanisms?
- Immunosuppression
- Mechanical devices/surgical interventions
- Anatomical congenital malformations
- Hyposplenism and asplenia
Define:
- Pachymeningitis
- Meningitis/leptomeningitis
- Encephalitis
- Cerebritis
- Pachymeningitis: spread of infection into the dura mater
- Meningitis/leptomeningitis: inflammation of pia and arachnoid
- Encephalitis: inflammation of brain parenchyma with mononuclear cells (typically viral)
- Cerebritis: inflammation of the brain parenchyma with neutrophils (typically bacterial)
Define:
- Myelitis
- Poliomyelitis
- Ganglionitis
- Radiculitis
- Myelitis: inflammation of the spinal cord
- Poliomyelitis: inflammation of the spinal gray matter
- Ganglionitis: inflammation of the dorsal root ganglion
- Radiculitis: inflammation of the intradural spinal nerve roots
What are the different types of inflammatory infiltrates? What etiologic organisms are they associated with?
- Neutrophils: acute inflammation due to bacterial meningitis, cerebritis, or abscess
- Mononuclear cells: lymphocytes and plasma cells associated with chronic inflammation due to viral meningitis or encephalitis
- Granulomatous inflammation: due to mycobacteria, spirochetes, fungi, or parasites
- Microglial nodules: viral encephalitis
What does the image below represent? In what cerebral spaces can this infection occur? What organisms cause it and what cells respond to it?
Acute bacterial meningitis
- Epidural space (abscess)
- Subdural space (abscess or empyema)
- Subarachnoid space (meningitis)
- Parenchyma (abscess or cerebritis)
Caused by:
- S. pneumoniae
- N. meningiditis
- H. influenzae
Presents with neutrophils in leptomeningeal space
What does the image below represent? What is the source of this infection? What organisms cause it? How is the CNS affected?
Bacterial abscess due to a mass forming acute infection
Source:
- Local (sinusitis otitis or mastoiditis)
- Hematogenous (septic emboli from bacterial endocarditis)
Caused by:
- S. aureus
- Streptococci
Presents witih:
- Lesions with liquefactive necrosis surrounded by a fibrotic capsule
- Mass effect can cause herniation
- Vascular congestion, necrosis, edema, inflammation with neutrophils early on
- Late findings involve lymphocytes, macrophages, and granulation tissue
How does tuberculosis meningitis present?
Tuberculosis meningitis is the most common form of mycobacterial infection and involves the basal aspect of the brain with cranial nerve involvement.
Characterized by necrotizing granulomas, lymphocytes, multinucleated giant cells, and fibrosis.
What kinds of neurosyphilis exist?
Tertiary syphilis in 10% of untreated individuals
- Meningovascular neurosyphilis: chronic basal meningitis with obliterative endarteritis
- Paretic neurosyphilis: lesions associated with parenchymal damage in the cortex with neuronal loss, gliosis, and iron deposits
- Tabes dorsalis: damage to dorsal roots and posterior columns
What is neuroborreliosis? What causes it? How does it present?
Lyme disease is caused by Borrelia burgdorferi
Presents with:
- Aseptic lymphocytic meningitis
- Facial nerve palsy
- Neuropathies/polyradiculitis
- Encephalopathy
Describe lymphocytic aseptic meningitis.
Acute infection of the meninges associated with increased lymphocytes and mononuclear cells in CSF and an absence of bacteria or fungi. Typically caused by viral infection and is usually less severe than bacterial meningitis.
Neurosyphilis and Lyme disease are types of lymphocytic meningitis caused by bacterial agents.
What are the two classes of viral encephalitis? What causes each type? Describe the pathology.
Seasonal: arbovirus
- West Nile virus
- Japanese encephalitis
- Eastern and western equine encephalitis
- La Crosse encephalitis
- St. Louis encephalitis
Nonseasonal
- HSV 1, 2, 6
- VZV, EBV, CMV
- Rabies
- H1N1
Presentation: chills, malaise, headache, fever, altered consciousness, seizures, focal neurological signs, and coma.
Pathology: perivascular inflammatory infiltrate, microglial nodules, intranuclear viral inclusions, neuronophagia, gliosis, meningitis with or without parenchyma infection
Describe the unique features of herpetic encephalitis (HSV-1). CMV encephalitis? VZV encephalitis?
Herpetic encephalitis (HSV-1):
- Bilateral, asymmetrical hemorrhagic necrosis of temporal lobes
- Presents with features of encephalitis and focal neurological signs
CMV encephalitis:
- Significant only congenitally and in immunosuppressed patients
VZV encephalitis:
- Rare with varicella, may occur in immuno-suppressed zoster patients
What does this image show? What disease is this a classical histological feature of?
Negri bodies are sharply delineated round to oval eosinophilic inclusions present in neuronal cytoplasm in patients infected with rabies.
What is poliomyelitis?
Acute poliomyelitis is a lesion in the spinal cord grey matter that involves chronic perivascular inflammation of parenchyma and meninges, microglial nodules, neuronophagia, blood vessel congestion, and possible hemorrhage.
How do CNS fungal infections manifest?
- Diffuse encephalitis
- Leptomeningitis
- Fungal mycetoma of meninges
- Granulomas
- Abscesses
- Septic infarcts
- Hemorrhages
Which fungus is this? Describe its pattern of infiltration and microscopic presentation.
Aspergillus
- Disseminates hematologically and fungal hyphae infiltrate blood vessels
- Causes vascular thrombosis, hemorrhage, and infarctions–fibrous capsules rarely form
Which fungus is shown below? How is it different from Aspergillus? How does it spread to the CNS and how does it present?
Mucor (zygomycosis or mucormycosis) is similar to aspergillus but hyphae are wider and non-septate
Spread:
- Rhinocerebral
- Hematological
Presentation:
- Early: facial swelling and hyperemia, ulceration or necrosis of skin/mucosa, orbital symptoms, headaches, nuchal rigidity
- Late: Seizures, aphasia, hemiplegia, lethargy, disorientation, coma, death
Describe amebic encephalitis clinically and histologically.
Organism: Naegleria fowleri is aquired by swimming in warm fresh water than contains the amebae
Presentation:
- Fulminant, acute meningoencephalitis
- Cerebral swelling
- Hemorrhagic necrosis of frontal and olfactory bulbs
Histology:
- Unicellular organism in subarachnoid space (looks like macrophage)
Describe cysticercosis.
Infection with cysticerci (larvae of tapeworm Taenia solium) is the most common helminthic CNS disease.
Presents with parenchymal, meningeal, ventricular, and (rarely) spinal corde cysts.
What CNS infections occur in immunocompromised hosts?
- Cryptococcal meningitis
- Toxoplasmosis
- HIV encephalitis
- Progressive multifocal encephalitis
What infections is represented below? Describe the pathology.
Cryptococcal meningitis (Cryptococcus neoformans) is the most common fungal infection of the CNS. Clinical presentation is variable.
Pathology:
- Minimal inflammatory reaction with lymphocytes, plasma cells, eosinophils, and mutlinucleated giant cells
- Collections of organisms produce gelatinous pseudocystic dilations of Virchow-Robin spaces
How does toxoplasmosis typically present?
Infection usually comes from undercooked meat or cat feces. Only infects congenitally and the immunosuppressed. Most common pattern is brain abscesses presenting as multiple ring-enhancing lesions.
What disease classically presents with the histology below?
HIV Encephalitis: involves subcortical white matter, basal ganglia, and brainstem
Pathology:
- Multinucleated giant cells
- Leukoencephalopathy with patchy demyelination and gliosis
- Low grade inflammation with perivascular and parencymal lymphocytes and microglial nodules
Describe the pathology of progressive multifocal leukoencephalopathy.
JC Virus infects oligodendrocytes preferentially
Pathology:
- Ill defined demyelinating lesions
- Lipid laden macrophages
- Intranuclear viral inclusions
- Bizarre astrocytes
What cells produce CSF? How does it circulate? Describe its composition.
Epithelial cells of the choroid plexus are specialized ependymal cells. CSF circulates from the lateral ventricles to the third ventricle to the fourth ventricle and exits and circulates through the subarachnoid space. It exits the subarachnoid space through arachnoid granulations and drains into the dural venous sinuses. CSF is completely turned over every 5-7 hours.
Formation of CSF involves ultrafiltration of plasma across the fenestrated capillary wall and then the choroid plexus epithelial cells secrete/transport components into the ventricle. The ultrafiltrate is outside of the blood brain barrier and cannot diffuse freely past the choroid plexus cells. CSF composition is tightly regulated and has lower concentrations of amino acids and potassium and very low amounts of protein.
What are the four physiologic roles of CSF?
- Physical support (suspends brain so it is not completely resting on skull base)
- Protection: acts as a shock absorber and buffers to protect brain from changes in intracranial pressure
- Extracellular homeostasis: the brain has a low threshold for injury so extracellular envrionment must be tightly regulated
- Excretion: CSF removes waste from the brain as it turns over
What is the difference between the blood-brain barrier and the blood-CSF barrier?
There are two routes of entry into the CNS: via the capillaries of the brain or through the blood supply to the choroid plexus. The capillaries of the blood brain barrier have tight junctions between non-fenestrated capillaries and endothelial cell, a thick basement membrane, and astrocyte endfeet to prevent entry of most molecules. Large charged molecules are excluded while lipid soluble molecules readily cross.
The blood-CSF barrier involves the selective transport of molecule from the ultrafiltrate into the CSF by choroid cells.
What does the CSF get evaluated for? How does a lumbar puncture work?
Evaluate for:
- CNS infection
- Subarachnoid hemorrhage
- CNS malignancy
- Demyelinating disease
Insert needle into subarachnoid space below level of spinal cord (L3/L4 or L4/L5) and measure opening pressure during tap.
Contraindications include elevated intracranial pressure which may lead to cerebral herniation
Describe the gross features of normal and abnormal CSF.
Normal: clear, colorless, watery
Abnormal:
- Cloudy: CNS infection
- Bloody: subarachnoid hemorrhage
- Xanthochromia: discolored due to melanoma or bilirubin
- Viscous: metastatic mucinous adeno-carcinoma
Describe the microscopic evaluation of normal and abnormal CSF.
Normal:
- 0-5 WBC and 0 RBC per uL
- 40–80% lymphocytes, 15-40% monocytes, 0-5% neutrophils
Abnormal:
- Pleocytosis: elevation in total cell counts
- Altered cell differential
Describe the chemical analysis of normal and abnormal CSF.
Normal:
- Glucose: 60 mb/dL (60% plasma glucose)
- Protein: 30 mg/dL
Abnormal:
- Decreased glucose suggests immune response to bacteria
- Increased protein suggests increased permability of BBB or blood-CSF barrier, decreased reabsorpiton at arachnoid granulations. or increased synthesis of immunoglobulin
Describe the microbiology of CSF.
Assays:
- Gram stain
- Culture
- Latex agglutination antigen assay
Describe the molecular analysis of CSF.
Targeted detection of a viral pathogen using PCR followed by a gel or fluorescence.
What types of meningitis exist? Which are more common? Which are more lethal? What are the symptoms of meningitis?
- Viral meningitis: more common, less lethal
- Bacterial meningitis: less common, more lethal
- Fungal meningitis
- Mycobacterial meningitis
- Non-infectious meningitis: medications, malignancies
Meningitis presents with: fever, headache, altered mental status, still neck, photophobia
What are the bacteral pathogens that cause meningitis in different age groups?
- Neonates: group B strep, E. coli, Listeria monocytogenes
- Children and adults: S. pneumoniae, N. meningitidis, H. influenzae
- Older adults and immunosuppressed: S. pneumoniae, L. monocytogenes
What viral pathogens cause meningitis? How are they spread?
- Enterovirus: fecal-oral or respiratory
- Herpesvirus: direct inoculation of skin or mucosa
- Arbovirus: spread by arthropods
What classes of pathogens cause HIV associated meningitis? Give examples of each.
- Fungal: C. neoformans, C. immitis, H. capsulatum
- Bacterial: L. monocytogenes, T. pallidum, M. tuberculosis
- Viral: CMV, VZV
Describe the CSF findings in bacterial, viral, and fungal meningitis.
Bacterial:
- High opening pressure
- > 1000 WBC/ul (neutrophils)
- Low glucose, high protein
Viral:
- Normal opening pressure
- 10-200 WBC/ul (lymphocytes)
- Normal glucose and protein
Fungal:
- Variable opening pressure
- 10-200 WBC/ul (lymphocytes)
- High glucose, high protein
Describe how pathogens cross the blood brain barrier.
- Bacterial surface proteins attach to endothelial cells and undergo transcellular migration
- Cross barriers by hiding inside a circulating cell
- Cross physicially disrupted barriers (trauma, surgery, etc.)
