CNS Overview

I. Cellular Injury of the Nervous System

a. Neuronal Responses to Injury

b. White Matter Responses to Injury

c. Glial Reactions to Injury

d. Ischemic Necrosis

e. Cerebral Hemorrhages

i. Intracranial Hemorrhages

ii. Subarachnoid Hemorrhages

II. Tumors of the Nervous System

a. Primary Brain Tumors

i. Glioma

ii. Meningioma

iii. Pituitary Adenoma

iv. Schwannoma

v. Medulloblastoma

b. Tumors of the Spinal Canal

c. Disorders of the Nervous System in Systemic Cancer

i. Metastatic Tumors

ii. Nonmetastatic Involvement of the CNS

III. Infectious Disease of the Nervous System

a. Meningitis

i. Bacterial

ii. Viral

iii. Tuberculosis or Fungal Meningitis

b. Encephalitis and Encephalomyelitis

c. Specialized/Limited Infections

i. Abscesses

ii. Granulomata

iii. Spirochetes

iv. Parasites

v. Trophic Viruses

vi. Unconventional Agents

1. Kuru

2. CJD

3. BSE

vii. HIV

1. Neurological Complications

2. Opportunistic Infections

a. Cryptococcal meningitis

b. Toxoplasmosis

c. Primary CNS Lymphoma (PCNSL)

d. Progressive Multifocal Leukoencephalopathy (PML)

e. CMV

f. Neurosyphilis

IV. Neurodegenerative Disease

a. ALS

b. Alzheimer’s Disease

c. Parkinsonian Syndromes

d. Huntington’s Disease

V. Central Nervous System Trauma

a. Penetrating (Missile) Injuries

b. Blunt Head Injuries

i. Epidural Hemorrhage

ii. Subdural Hematoma

iii. Cerebral Contusions

iv. Diffuse Axonal Injury

v. Brainstem Avulsion

c. Child Abuse

d. Other

I. Cellular Injury of the Nervous System

a. Neuronal Responses to Injury

- selective neural death

- changes in neuronal cytoskeleton

- chromatolysis (cell swells, eccentrically positioned nucleus, Nissl breaks apart, synapses lost)

- transsynaptic changes

- axonal sprouting

b. White Matter Responses to Injury

- loss of myelin (oligodendrocytes, Schwann cells)

- Wallerian degeneration (PNS; orthograde = away from cell body)

c. Glial Reactions to Injury

- reactive astrocytosis (degeneration, hypertrophy, hyperplasia); GFAP: pink-glassy stain; gliosis: fibrosis

- activation of microglia (form glial stars; may à phagocytes, express MHC II)

d. Ischemic Necrosis

- brain has no glucose stores of its own (but receives 15% of CO and 20% of body’s oxygen consumption)

- gray matter is more metabolically active than white matter (therefore more susceptible to infarction)

- cerebral arteries tend to be end arteries (few anastomoses); therefore, infarcts develop at “watershed” junctions à sites of hemorrhage

- causes: atherosclerosis, polycythemia vera, sickle cell disease, coagulopathies, cardiac emboli, fat emboli, compression

Time Course

- first few hours: infarcted tissue is normal

- 4-6 hours: hyperchromatic neurons

- 12-24 hours: grossly discoloured (picked up on CT, MRI)

- 24 hours: edema (space-occupying mass)

- 1-4 days: necrotic glial cells appear; axon/myelin degeneration; well-demarcated lesion

- 5-7 days: neurons are pale; (systemic) macrophages, microglia, and blood vessels appear; edema resolving

- 8-14 days: reactive astrocytes; edema resolves

- 2 weeks+: dead tissue disappears; blood vessels are more prominent; liquefied necrotic tissue slowly removed (cystic)

e. Cerebral Hemorrhages

i. Intracranial Hemorrhages

- most often due to systemic hypertension (cocaine, elderly)

- destroy tissue via rapid acculumation of blood

- most common: lateral to putamen

- à thickening of small cerebral vessels (lacunar infarcts)

- etiologies: hypertension, Binswanger’s disease, AVM (arteriovenous malformations: no capillaries)

ii. Subarachnoid Hemorrhages

- “worst headache of my life”

- etiology: spontaneous rupture of aneurysm of large arteries of Circle of Willis (saccular/berry aneurysms: usually anterior of Circle), trauma, coagulopathies

II. Tumors of the Nervous System

- etiology: unknown (meningiomas: chromosome 22)

- morbidity/mortality related to volume, topography, proximity to CSF, accessibility (usually do not metastasize: absence of CNS lymphatics)

- volume affected by: tumor + edema + CSF obstruction

- BBB is often disrupted (allowing visualization by CT, MRI) à vasogenic edema (BBB disruption: leak plasma, H₂O)

- primary vs. metastases have similar incidence

- symptoms/manifestations: headache (w/ nausea, vomiting), papilledema, herniation (subfalcian cingulate, transtentorial uncinate, cerebellar tonsillar), unilateral papillary dilation, decreasing consciousness, changes in mental status, difficulty concentrating, seizures (general or focal), specific deficits (motor, sensory, visual, higher order), spinal cord compression (neurological emergency)

- management: examination, CT/MRI, lumbar puncture (may be contraindicated in the presence of intracranial mass lesions), biopsy

- treatment: surgery, radiation therapy (metastases), chemotherapy (BCNU: gliomas, not curative), steroids (targets edema), immunotherapy

- epidemiology

- adults: supratentorial (commonà rare: glioblastoma multiforme, meningiomas, schwannomas, astrocytomas, pituitary adenomas)

- children: infratentorial (medulloblastoma, pilocytic astrocytomas, ependymomas, mixed gliomas)

a. Primary Brain Tumors

i. Glioma

1. astrocytomas

- may arise in cerebrum, brainstem, cerebellum, spinal cord

- may be present for years (focal before à malignant)

- anaplastic astrocytomas: chromosomes 22, 13, 17p [may à glioblastoma multiforme (if Chr. 10)]

2. oligodendrogliomas

3. ependymomas

4. glioblastoma multiforme

- most malignant glioma

- chromosome 10

ii. Meningioma

- attached to dura (relatively slow and benign)

- good long-term outcome

- higher incidence in females: neoplasm contains progesterone receptors

- some forms associated with neurofibromatosis 2 (Chr. 22)

iii. Pituitary Adenoma

- optic chiasm compression, gross endocrine dysfunction

- most common: prolactinoma (amenorrhea, galactorrhea, infertility)

iv. Schwannoma

- most common: Acoustic Schwannoma

- if bilateral: associated with neurofibromatosis 2 (Chr. 22)

v. Neurofibromatosis

- autosomal dominant

Subtype	Genetics	Name	Tumors	Minor Tumors	Prevalence
NF-1	Chromosome 17	“Von Recklinghausen Neurofibromatosis”	Multiple neurofibromas Café-au-Lait spots	Piolcytic astrocytomas Optic nerve gliomas	1/3000
NF-2	Chromosome 22	“Central Neurofibromatosis”	Bilateral acoustic schwannomas Multiple meningiomas	Neurofibromas	1/50,000

vi. Medulloblastoma

- small blue cell embryonal tumor (posterior fossa)

- common in children

- proximity to 4^th ventricle à hydrocephalus

- radiosensitive

b. Tumors of the Spinal Canal

subtypes

1. extradural: metastases

2. intradural: schwannomas, meningiomas

3. intramedullary: gliomas (astrocytomas, ependymomas)

c. Disorders of the Nervous System in Systemic Cancer

i. Metastatic Tumors

- carcinomas, leukemias, lymphomas

- hematogenous spread, subarachnoid spread

- most common carcinomas that metastasize: lung, breast, melanoma (kidney, GI, rare: ovary, pancreas)

- prostate cancer spreads to bone and produces CNS symptoms by compression

ii. Nonmetastatic Involvement of the CNS

- ectopic hormone production (ACTH, ADH, PTH)

- intracranial hemorrhage (leukemia)

- opportunistic infections (immunosuppressed)

- malnutrition (vitamin B₁: Wernicke’s encephalopathy, vitamin B₁₂: subacute combined degeneration of the cord)

- radiation/chemotherapy treatment-induced

III. Infectious Disease of the Nervous System

- the BBB excludes most blood borne microorganisms (good) and antibodies/immunocompetent cells (bad)

a. Meningitis

- infection and inflammation (usually in subarachnoid space)

- pia is a remarkably effective barrier

- may be purulent, granulomatous, lymphocytic (depending on infectious agent)

i. Bacterial

neonates: E. coli, group B strep., listeria

children: H. influenzae

adults: neisseria meningitides, strep. pneumoniae

ii. Viral (= aseptic meningitis)

enteroviruses (late Summer), mumps (Spring), lymphocytic choriomeningitis (Winter)

lymphocytic infiltration of arachnoid

perivascular cuffing

iii. Tuberculosis or Fungal Meningitis

granulomatous

b. Encephalitis and Encephalomyelitis

- usually viral (also: rickettsia, spirochetal, parasitic)

- encephalitis (brain)

- encephalomyelitis (brain+spinal cord)

- usually with meningitis (perivascular cuffing), neuronophagia, inclusion body formation

- microglial nodules (HIV), inclusion body formation (herpes)

c. Specialized/Limited Infections

i. Abscesses

- blood borne (gray matter principally affected: gray-white junction)

- bacterial, necrotic, PMNs, edema, astrocytosis

- poor encapsulation (fibroblasts associated with blood vessels only)

- rupture into ventricles à meningitis

ii. Granulomata

- Tb, fungi, sarcoidosis

iii. Spirochetes

- syphilis

- chronic vasculitis, dementia, chronic arachnoiditis of posterior roots of spinal cord (tabes dorsalis)

iv. Parasites

- most common: Taenia solium à cyticercosis

- malaria, amoeba, trichinella

v. Trophic Viruses

- polio: anterior horn of spinal cord

- progressive multifocal leukoencephalopathy (PML): jc virus à oligodendrocytes; opportunistic
- HSV: temporal lobe (hemorrhagic and necrotizing)

- CMV: ependymal cells lining the ventricles and lumbar spinal roots

vi. Unconventional Agents

- transmissible spongiform encephalopathies (prions)

1. Kuru (cannibalism; New Guinea)

2. CJD (most common prion disorder of humans; rapid dementia after many years)

3. BSE (Mad Cow disease; cattle feed/by products)

vii. HIV

1. Neurological Complications

- acute aseptic meningitis

- HIV dementia, cortical atrophy, reactive astrocytosis, microglial nodules, perivascular multinucleated giant cells

- white matter degeneration (e.g. gracile tract)

2. Opportunistic Infections

- present when CD4 count < 200

a. Cryptococcal meningitis (encapsulated organisms)

b. Toxoplasmosis (necrotic abscesses: basal ganglia, cerebral hemispheres)

c. Primary CNS Lymphoma (PCNSL) (B-Cell lymphoma ß EBV)

- SPECT scans can be used to differentiate PCNSL from toxoplasmosis

d. Progressive Multifocal Leukoencephalopathy (PML) (see above)

- often the first AIDS defining illness

- bizarre giant astrocytes and oligodendrocytes

- glassy, eosinophilic cytoplasm

e. CMV

f. Neurosyphilis

IV. Neurodegenerative Disease

a. ALS

- motor neuron disease (ventral horn cells; Betz cells)

- mean age of onset: 53 yo; 10%: familial (Superoxide dismutase: SOD1)

- weakness of chest muscles and diaphragm à respiratory problems (many patients die with bronchopneumonia)

- sensations, eye movement, autonomic functions are usually spared

b. Alzheimer’s Disease

- gradual loss of memory à dementia

- deterioration thought, judgment, language skills, visual-spatial perception, mood, self-management

- other primary cortical degenerative disorders: Pick’s (frontal and interior temporal), Lewy body disorders

- 10%: familial

- associations: ApoE (E4) allele, Trisomy 21, APP gene mutations, PS1 (chromosome 14), PS2 (chromosome 1)

- cortical atrophy with shrinkage of amygdala and hippocampus (acetylcholine)

- NFT, senile amyloid plaque

c. Parkinsonian Syndromes

- classic: Parkinson’s disease (bradykinesia, rigidity, tremor), cognitive deficits (10%)

- epidemiology: men:women = 1:1

- associations: a-synuclein (chromosome 4)

- neuropathogy: loss of pigmented neurons in substantia nigra (pars compacta), presence of Lewy bodies

d. Huntington’s Disease

- autosomal dominant (chromosome 4: huntingtin – CAG triplet repeat)

- chorea, dementia, behavioral abnormalities à rigidity, abnormal eye movements à irritability, depression, mute

- affects medium spiny neurons in the striatum (caudate and putamen): GABAergic

V. Central Nervous System Trauma

a. Penetrating (Missile) Injuries

b. Blunt Head Injuries

Primary: skull fractures (found in 75% of fatal head injuries), contusions

Secondary: brain swelling, herniation, infection

i. Epidural Hemorrhage

- except for young children, requires skull fracture (dura: periosteum)

- arterial

- middle meningeal artery

- lost consciousness à lucid interval à coma with hemiplegia, mass effect, herniation

ii. Subdural Hematoma

- venous acceleration/deceleration injury

- free to travel over the surface of the brain (delineated by falx cerebri)

- direct impact to the head is not obligatory

- older injury often imposed upon newer

iii. Cerebral Contusions

- classic hallmark of blunt head injury

- focal bruises of the crests of gyri

- may be contracoup (coup will be smaller)

- distinguish from infarct (infarct: wedge-shaped, narrow band of superficial cortex fed by subarachnoid vessels)

- shrunken brown scars (depressed orange areas)

iv. Diffuse Axonal Injury

- type of blunt head injury à immediate loss of consciousness, prolonged coma, severe disability

- brain can appear externally normal (diffuse axonal injury)

- microscopically: hallmark is the presence of clusters of axonal swellings (axonal retraction balls)

v. Brainstem Avulsions

- head hyperextension à brainstem torn at ponto-medullary junction à instant death

c. Child Abuse: Shaken Baby Syndrome

- children under 3

- contributing: back and forth, twisting, impact

- retinal hemorrhages, subdural and intradural optic nerve hemorrhages, subdural hemorrhages of the brain, subarachnoid hemorrhages of the brain, diffuse axonal injury

- B-APP antibodies

d. Other (Lesions not directly attributable to impact

· cerebral edema

1. vasogenic (leaky capillaries)

2. cytotoxic (global hypoxia, DAI, trauma à abnormal osmotic equilibrium)

· cerebral herniations

· focal infarcts

· global ischemia

· infections

· fat emboli (long bone fractures à marrow enters venous circulation à cerebral vessel fat globules, hemorrhages, and microinfarcts)