Central Nervous System

Patterns of Cellular Injury

• Neurons
– Acute neuronal injury
• “Red neurons”, eosinophilic cytoplasm
• Spheroids, disruption of axonal transport
• Central chromatolysis, axonal injury
– Neurodegenerative diseases
• Intracellular inclusions
• Dystrophic neurites
– Viral infections—inclusions
– Aging--lipofuscin
 Patterns of Cellular Injury
• Astrocytes
– Repair and scar formation (gliosis)
• Hypertrophy and hyperplasia
• Gemistocytic astrocyte, bright pink cytoplasm
• Minimal extracellular matrix deposition
• Limited fibroblast involvement
• Long standing gliosis
– Fibrillary astrocytes and Rosenthal fibers
– Degenerative change
• Corpora amylacea in astrocytic processes
 Patterns of Cellular Injury
• Oligodendrocytes
– Produce myelin
– Multiple neurons per cell
• Ependymal cells
– Line ventricles
– Disruption triggers subependymal astrocyte
proliferation (ependymal granulations)
• Choroid plexus
– Secretes CSF
 Patterns of Cellular Injury
• Microglia
– Phagocytes
• Bone marrow derived
– Activated by tissue injury
– Microglial nodules
• Aggregates at site of tissue injury
• Congregate around portions of dying neurons
– Neuronophagia
 Cerebral Edema
• Accumulation of excess fluid within the brain
parenchyma
– Vasogenic edema
• Integrity of blood-brain barrier is disrupted
• Fluid shifts from vascular compartment to intercellular
spaces
• Inflammation or tumors
– Cytotoxic edema
• Membrane injury
• Increased intracellular fluid
• Hypoxic/ischemic insult or toxins
– Often occur together
 Hydrocephalus
• Accumulation of excessive CSF within the
ventricular system
– Impaired flow
– Impaired resorption
– Excess production (rarely)
• Before suture closure
– Enlargement of head
• After suture closure
– Expansion of ventricles
– Increased intracranial pressure
 Hydrocephalus
• Noncommunicating hydrocephalus
– Obstruction within ventricular system
– Enlargement of ventricles proximal to block
• Communicating hydrocephalus
– Reduced resorption
– All ventricles enlarged
• Hydrocephalus ex vacuo
– Secondary to loss of brain parenchyma
 Herniation
• Focal expansion of brain causes it to be
displaced in relation to dural folds or bony
structures
– Occurs when volume of brain exceeds limits
permitted by compression of veins and
displacement of CSF
– Intracranial pressure rises
– Usual result is compromise of blood supply to
“pushed” tissue
 Herniation
• Subfalcine (cingulate) herniation
– Unilateral or asymmetric expansion of a
cerebral hemisphere
– Cingulate gyrus displaced under edge of falx
cerebri
– Associated with compression of anterior
cerebral artery branches
 Herniation
• Transtentorial (uncinate) herniation
– Medial aspect of temporal lobe compressed against
free edge of tentorium cerebelli
– Oculomotor nerve is compromised on side of lesion
(CN III palsy and “blown” pupil)
– Posterior cerebral artery may be compressed
• Primary visual cortex
– May compress contralateral cerebral peduncle
(hemiparesis ipsilateral to herniation)
– Duret hemorrhages in midbrain and pons
• Midline or paramedian hemorrhages from tearing of
penetrating veins and arteries
 Herniation
• Tonsilar herniation
– Displacement of cerebellar tonsils through the
foramen magnum
– Brainstem compression
– Compromises respiratory and cardiac centers
in medulla
 Cerebrovascular Diseases
• Any abnormality of the brain caused by a
pathologic process involving blood vessels
– Thrombotic occlusion of vessels
– Embolic occlusion of vessels
– Vascular rupture
• Occlusion of vessels
– Loss of oxygen and metabolic substrates resulting in
infarction
• Hemorrhage
– Direct tissue damage and secondary ischemia
 Cerebrovascular Diseases
• Brain requires a continuous supply of glucose
and oxygen
• Oxygen is the limiting substance
– Functional hypoxia
• Low partial pressure of oxygen
• Impaired oxygen carrying capacity
• Inhibition of oxygen use by tissues
– Ischemia, transient or permanent
• Interruption of normal circulatory flow
– Reduced perfusion pressure
– Vascular obstruction
 Global Cerebral Ischemia
• Widespread ischemic/hypoxic injury resulting from a
generalized reduction in cerebral perfusion
• Outcome varies with severity of insult
• Neurons are much more sensitive to hypoxia than glial
cells
• Most sensitive
– Pyramidal cells of CA1 of hippocampus
– Purkinje cells of the cerebellum
– Pyramidal cells of neocortex
• Border zone (“watershed”) infarcts
– Wedge shaped infarcts at edge of arterial perfusion fields
– ACA-MCA border
 Global Cerebral Ischemia
• Morphology
– Brain swollen, poor demarcation between
gray and white matter
– Microscopic of irreversible ischemic injury
(infarction)
• Early (12-24 hours): red neurons, infiltration of
neutrophils
• Subacute (24 hr-2wks): necrosis, macrophages,
vascular proliferation, reactive gliosis
• Repair (>2wks): removal of necrotic tissue,
disorganization, gliosis
 Focal Cerebral Ischemia
• Arterial occlusion leading to focal ischemia
or infarction
– Embolization
• More common
• Sources: cardiac mural thrombi, atheromatous
plaques, paradoxical emboli, cardiac surgery, other
material (tumor, fat, air)
• Middle cerebral artery most frequently involved
– Branch points, preexisting luminal stenoses
 Focal Cerebral Ischemia
– In situ thrombosis
• Atherosclerosis
– Carotid bifurcation, origin of MCA, basilar artery

• Infarcts are divided into two large groups

– Nonhemorrhagic
– Hemorrhagic
• Hemorrhage is due to reperfusion of ischemic
tissue
 Focal Cerebral Ischemia
• Morphology
– Macroscopic
• 0-6 hrs: nothing
• 6-48 hrs: pale, soft swollen, indistinct gray-white
matter junction
• 2-10 days: gelatinous, friable, affected area is
defined as edema resolves
• 10 days-3 wks: tissue liquefies leaving cavity
– Microscopic (see previous)
 Intracranial Hemorrhage
• Hemorrhage can occur at a variety of sites
• Each site has associated causes
 Primary Brain Parenchymal
Hemorrhage
• Peak incidence at age 60
• Rupture of small intraparenchymal vessel
• Hypertension is most common underlying
cause (15% of deaths with chronic HTN)
• Basal ganglia, thalamus, pons, cerebellum
• Location and size determine clinical
manifestations
 Cerebral Amyloid Angiopathy
• Amyloidogenic peptides deposit in the
walls of small and medium caliber
meningeal and cortical vessels
• Weakens vessel walls
• Spares vasculature of white and deep gray
matter
• Often referred to as lobar hemorrhages
due to involvement of cerebral cortex
 Saccular Aneurysms
• Most frequent cause of clinically significant
subarachnoid hemorrhage is rupture of a
saccular aneurysm
• 90% occur in the anterior circulation
• Multiple aneurysms occur in 20-30% of cases
• Associated with disorders of extracellular matrix
proteins
• Increased risk in individuals with autosomal
dominant polycystic kidney disease
 Saccular Aneurysms
• Overall, 1.3% per year rate of bleeding
– Risk increases with size
– 10mm has 50% per year rate of bleeding
• Subarachnoid hemorrhage has additional acute
risk of ischemia due to vasospasm of other
vessels
• Healing phase involves risk of obstruction of
CSF flow and resorption
• 25-50% of individuals die with first rupture
• Sudden, excruciating headache
 Saccular Aneurysms
• Morphology
– Thin walled out-pouching of an artery
– Muscular wall and internal elastic lamina are
absent from the sac
– Sac is thickened hyalinized intima
 Vascular Malformations
• Arteriovenous malformations (AVM)
– Enlarged blood vessels separated by gliotic tissue
– M:F is 2:1
– Presents most often between 10 and 30 yrs of age
• Seizure disorder, intracerebral hemorrhage, subarachnoid
hemorrhage
– Large AVM can cause high output heart failure in
infants
– Most dangerous vascular malformation
– Can be in subarachnoid space, extend into brain, or
entirely within brain
 Vascular Malformations
• Cavernous hemangiomas
– Distended loosely organized vascular channels
without intervening nervous tissue
– Occur in cerebellum, pons, subcortical regions
– Low flow, no AV shunting
• Capillary telangiectasias
– Thin walled vascular channels separated by normal
brain parenchyma
– Pons
• Venous angiomas
– Ectatic venous channels
 Hypertensive Cerebrovascular
Disease
• Effects of hypertension on the brain
– Massive hypertensive intracerebral
hemorrhage
– Lacunar infarcts
– Slit hemorrhages
– Hypertensive encephalopathy
 Hypertensive Cerebrovascular
Disease
• Arterio- and Arteriolo- sclerosis
– Deep penetrating vessels of basal ganglia,
white matter, and brain stem
– Hyaline change makes vessel walls weaker
– Charcot-Bouchard microaneurysms
• Less than 300 microns in diameter
• May rupture and bleed
 Hypertensive Cerebrovascular
Disease
• Lacunar infarcts
– Small cavitary infarcts just a few millimeters
wide
– Deep gray matter, internal capsule, deep
white matter, pons
– Can be silent or cause significant neurological
impairment
• Slit hemorrhage
– Small hemorrhage that heals leaving a slit-like
cavity
 Hypertensive Cerebrovascular
Disease
• Acute hypertensive encephalopathy
– Acute cerebral dysfunction
– Increased intracranial pressure
– Petechiae and fibrinoid necrosis of arterioles
in gray and white matter
 Vasculitis
• Infectious arteritis
• Systemic vasculitis
• Primary angiitis of the CNS
– Involves multiple small to medium
parenchymal and subarachnoid vessels
– Diffuse encephalopathic picture
– Steroids and immunosuppressive treatment
 Trauma
• Significant cause of death and disability
• Severity and site of injury affect outcome
• Variables: shape of object, force of
impact, head in motion
• Penetrating or blunt, open or closed
• External appearance doesn’t necessarily
correlate with extent of brain injury
• Parenchymal and/or vascular injury
 Traumatic Parenchymal Injury
• Contusions
– Brain impacts the skull
• Coup and contrecoup
• Rapid tissue displacement and vascular rupture
– Hemorrhage, tissue injury, edema
– Crests of gyri
• Orbital gyri of frontal lobe, temporal lobe (esp. tips)
• Laceration
– Penetration of brain
• Tissue tearing, vascular disruption, hemorrhage
• Linear path
 Traumatic Parenchymal Injury
• Diffuse axonal injury
– Widespread damage to axons within the brain
• Angles of lateral ventricles or brainstem most
commonly affected
– Movement of one region relative to another
• Angular acceleration alone can cause this without
impact
• Axonal disruption (integrity or function) and
hemorrhage
– 50% of patients who develop coma shortly
after trauma
 Traumatic Parenchymal Injury
• Concussion
– Reversible altered consciousness from head
injury in the absence of contusion
– Transient neurological dysfunction
• Loss of consciousness
• Temporary respiratory arrest
• Loss of reflexes
– Complete neurological recovery
• Amnesia for the event
– Pathogenesis unknown
 Traumatic Vascular Injury
• Direct trauma and disruption of the vessel
wall
• May occur in one or more compartments
– Epidural
– Subdural
– Subarachnoid
– Intraparenchymal
 Traumatic Vascular Injury
• Epidural hematoma
– Torn vessel in the dura
• Middle meningeal artery
– Often with skull fracture
– Blood under arterial pressure separates dura from the
inner surface of the skull
• Smooth inner contour that compresses brain
– Patients can be lucid for several hours between
trauma and development of neurological signs
• Neurosurgical emergency
 Traumatic Vascular Injury
• Subdural hematoma
– Tearing of bridging veins caused by rapid movement
of the brain
• Bleed into the subdural space
• Most common over lateral aspect of cerebral hemispheres
• 10% bilateral
– Increased risk
• Brain atrophy—stretched veins
• Infants—thin walled veins
– Become manifest within 48 hours of injury
• Signs attributable to pressure on the brain
• Headache, confusion, sometimes localizing
• Progressive neurological deterioration, rarely with acute
decompensation
 Traumatic Vascular Injury
• Subdural hematoma
– Bleeding is usually self-limited
– If not evacuated, hematoma will organize over time
• Fibroblasts grow in from dura
• Granulation tissue matures and forms “subdural membranes”
– Subdural hematomas frequently rebleed becoming
chronic subdural hematomas
– Symptomatic subdural hematomas are treated by
removing the organizing blood and tissue
 Malformations
• Neural tube defects
– Failure of a portion of the neural tube to close or
reopening after successful closure
– Involve some combination of neural tissue, meninges,
and overlying bone or soft tissues
– Most frequent CNS malformations
– Folate deficiency during initial weeks of gestation is
risk factor
– Early detection by ultrasound and α-fetoprotein
– 4-5% recurrence risk in subsequent pregnancies
 Neural Tube Defects
• Spinal cord involvement most common
– Spina bifida occulta
• Asymptomatic bony defect
– Myelomeningocele
• Extension of CNS tissue through a defect in the
vertebral column
– Problems with motor and sensory in lower limbs,
bowel/bladder control
– Infection risk from thin or ulcerated overlying skin
 Neural Tube Defects
• Brain end of neural tube
– Anencephaly
• Absence of brain and top of skull
– Encephalocele
• Diverticulum of malformed CNS tissue extending
through a defect in the cranium
– Posterior more common than anterior
 Forebrain Malformations
• Microencephaly
– Abnormally small brain
– Associated with chromosome abnormalities, fetal
alcohol syndrome, in utero HIV infection
• Lissencephaly (agyria)
– Absence of normal gyration and smooth surfaced
brain
– Disruption of normal neuronal migration and
differentiation
• Abnormally thickened cortex and only four layered
– Pachygyria is a less widespread form
 Forebrain Malformations
• Polymicrogyria
– Increased number of irregularly formed gyri
– Altered cortical architecture
• Holoprosencephaly
– Disruption of normal midline patterning
• Mild forms may just have absence of olfactory bulbs and
related structures
• In severe forms the brain may not be divided into lobes or
hemispheres
– Midline facial defects
• Mutations in sonic hedgehog linked to some cases
 Posterior Fossa Anomalies
• Most commonly result in misplaced or absent
cerebellum and hydrocephalus
• Arnold-Chiari malformation
– Chiari type II malformation
• Small posterior fossa, misshapen midline cerebellum with
downward extension of vermis through foramen magnum
• Hydrocephalus and lumbar myelomeningocele are typically
also present
– Chiari I malformation
• Low-lying cerebellar tonsils extend through the foramen
magnum
• Obstruction of CSF flow and compression of medulla
• Headache and cranial nerve deficits
 Posterior Fossa Anomalies
• Dandy-Walker malformation
– Enlarged posterior fossa
– Cerebellar vermis is absent (or rudimentary
anterior portion)
– Large midline cyst
• Lined with ependyma and is contiguous with
leptomeninges on its outer surface
– Dysplasia of brainstem nuclei are commonly
found
 Spinal Cord Abnormalities
• Hydromyelia
– Expansion of the central canal
• Syringomyelia (syrinx)
– Fluid filled cleft-like cavity in the inner portion of the
spinal cord
– May also be acquired
• Associated with destruction of adjacent gray and
white matter, surrounded by reactive gliosis
• Cervical cord most often affected
 Perinatal Brain Injury
• Cerebral palsy
– Nonprogressive neurological motor disorder
characterized by spasticity, dystonia,
ataxia/athetosis, and paresis attributable to
injury occurring during the prenatal and
perinatal periods
 Perinatal Brain Injury
• Intraparenchymal hemorrhage
– Within germinal matrix of premature infants
– May extend to ventricles and subarachnoid space
– Sometimes leading to hydrocephalus
• Periventricular leukomalacia
– Infarcts in the supratentorial periventricular white
matter, esp. in premature infants
– Leaves chalky yellow plaques in white matter with
calcifications
– If involves gray matter too, large cystic lesions can
develop throughout the hemispheres (multicystic
encephalopathy)
 Infections
• Nervous tissue damaged by
– Direct injury of neurons or glia
– Microbial toxins
– Effects of inflammatory response
– Immune-mediated mechanisms
• Routes of entry
– Hematogenous (most common)
• Arterial or venous less commonly
– Direct implantation
• Post-traumatic
– Local extension from skull, spine, or malformation
– Peripheral nerves
 Epidural and Subdural Infections
• Bacterial or fungal
• Usually by direct local spread
• Epidural abscess
– Commonly associated with osteomyelitis
– Spinal epidural abscess can cause cord compression
• Subdural empyema
– May produce a mass effect
– Thrombophlebitis of bridging veins→infarction of brain
 Meningitis
• Inflammatory process of leptomeninges
and CSF in the subarachnoid space
– Meningoencephalitis is spread of infection
from the meninges to the underlying brain
– Usually an infection, can be chemical
– Infectious meningitis
• Acute pyogenic
• Aseptic
• Chronic
 Acute Pyogenic Meningitis
• Wide range of bacteria
• Most likely depends on age
– Neonates: E. coli, group B streptococci
– Elderly: S. pneumoniae, Listeria monocytogenes
– Adolescents/young adults: Neisseria meningitides
• Systemic signs of infection superimposed on
meningeal irritation and neurological impairment
• CSF: neutrophils, ↑ protein, ↓glucose, bacteria
• Exudate in leptomeninges over surface of brain
 Acute Pyogenic Meningitis
• When fulminant, inflammatory cells may
infiltrate leptomeningeal veins, spread to
the brain, or extend to the ventricles
• Phlebitis may lead to thrombosis and
hemorrhagic infarction of the brain
• Untreated, it may be fatal
• Effective antimicrobial treatment greatly
reduces mortality
 Aseptic Meningitis
• Aseptic is a misnomer
– Clinical term for an illness comprising meningeal
irritation, fever, and alterations of consciousness of
relatively acute onset without recognizable organisms
• Less fulminant, usually self-limiting, and usually
treated symptomatically
• CSF: lymphocytosis, moderately elevated
protein, normal glucose
• Pathogen can be identified in about 70% of
cases, usually an enterovirus
 Chronic Meningitis
• Tuberculous meningitis
– CSF: pleiocytosis (↑ leukocytes) of mononuclear cells
or neutrophils and mononuclear cells, ↑ protein, ↓
glucose
– May have an intraparenchymal mass (tuberculoma)
– Usually affects basal meninges
• Meninges contain infiltrate of lymphocytes, plasma cells, and
macrophages
• Possibly even well-formed granulomas
– Cause of arachnoid fibrosis that may lead to
hydrocephalus
 Chronic Meningitis
• Neurosyphilis
– Tertiary stage of syphilis, occurs in about 10% of
untreated infections
– Meningovascular neurosyphilis is a major
manifestation
• Chronic meningitis usually involving the base of the brain
• Cerebral gummas may occur in relation to the meninges and
extend into the brain
– Paretic neurosyphilis is the parenchymal disease
• Insidious progressive loss of mental and physical functions
with mood alterations, terminating in dementia
 Chronic Meningitis
– Tabes dorsalis
• Damage to sensory nerves in dorsal roots
– Impaired proprioception
» Locomotor ataxia
– Impaired pain sensation
» Joint damage, skin damage
– Lightning pains
– Absence of deep tendon reflexes
– HIV infection increases risk of neurosyphilis
• Increased rate of progression and severity of
disease
 Parenchymal Infections
• Any type of microbial organism can potentially
infect the brain
• Different types of organisms generally have
different patterns of involvement
– Viruses are most diffuse
– Bacteria (when not meningitis) are most localized
– Other are more mixed
– Immunosuppression leads to more widespread
involvement of any particular agent
 Brain Abscess
• Nearly always caused by bacteria
• Destructive lesions
– Progressive focal signs
– Signs of increased intracranial pressure
– CSF: ↑ WBC and protein, glucose normal
• Complications
– ICP, herniation can be fatal
– Rupture, ventriculitis, meningitis, venous
sinus thrombosis
 Viral Encephalitis
• Parenchymal infection of brain that also always
is associated with meningeal inflammation
(meningoencephalitis)
• Most show perivascular and parenchymal
mononuclear infiltrates, microglial nodules, and
neuronophagia
• Various viruses may have
– Inclusion bodies
– Specific cell types or particular areas involved
– Immune-mediated injury
– Congenital malformation
 Arboviruses
• Arthropod-borne viruses (mostly
mosquitoes)
– Eastern and Western equine encephalitis
– West Nile virus
• Patients develop generalized as well as
focal signs
 Herpes Simplex Type 1
• Most common in children and young
adults
• Affects inferior and medial temporal lobes
and orbital gyri of frontal lobe
– Alterations in mood, memory, and behavior
• Necrotizing and often hemorrhagic
• Inclusions in neurons and glia
 Herpes Simplex Type 2
• Usually manifests in adults as meningitis
• Disseminated severe encephalitis in
neonates born by vaginal delivery to
women with primary active genital
infections
 Cytomegalovirus
• Fetuses and immunocompromised individuals
• Tends to localize in the paraventricular
subependymal regions
– Severe hemorrhagic necrotizing ventriculoencephalitis
and choroid plexitis
• In utero infection
– Periventricular necrosis produces severe brain
destruction
– Microcephaly and periventricular calcification
 Rabies
• Enters CNS by ascending along the peripheral nerves
from the wound site
– Incubation usually a few months
• Initially, malaise, fever, headache
• Advances to extreme CNS excitability
– Slightest touch is painful
– Violent motor responses
– Aversion to swallowing (hydrophobia)
• Progresses to alternating mania and stupor
• Coma and death from respiratory center failure
• Negri bodies: viral inclusions seen in pyramidal cells in
the hippocampus and Purkinje cells of cerebellum
 HIV
• Patterns of direct injury to brain
– Aseptic HIV-1 meningitis
• 10% of individuals 1-2 weeks after seroconversion
– HIV-1 meningoencephalitis (subacute
encephalitis)
• AIDS-dementia complex
• Microglial nodules, multinucleated giant cells
• Neuronal death from cytokines and chemokines
– Vacuolar myelopathy
• Resembles combined subacute degeneration
 Progressive Multifocal
Leukoencephalopathy
• Caused by JC virus
• Infects oligodendrocytes
– Demyelination is primary effect
• Immunocompromised individuals
– Reactivation of virus
• Focal and relentlessly progressive
neurological symptoms and signs
 Fungal Encephalitis
• Usually in the immunosuppressed
• Granulomas or abscesses often with meningitis
• Organisms
– Candida albicans: microabscesses
– Mucor: direct extension in diabetics with ketoacidosis
– Aspergillus fumigatus: widespread hemorrhagic
infarcts, angioinvasive
– Cryptococcus neoformans: AIDS (can be fulminant or
indolent), India ink prep of CSF to visualize
– Also: Histoplasma, Coccidioides, Blastomyces
 Other Meningoencephalitides
• Cerebral Toxoplasmosis
– AIDS
• Cysticercosis
– Tenia solium (tapeworm)
– Cysts in brain and meninges
• Amebic
– Naegleria
• Swimming in non-flowing warm fresh water
– Acanthamoeba
• Chronic granulomatous meningoencephalitis
 Prion Diseases
• Disorders associated with abnormal forms
of a normal cellular protein called prion
protein (PrPc)
• Abnormal form acts as an infectious agent
– It propagates itself and damages cells that
contain it
• Most cases are sporadic or associated
with mutations in the gene that encodes
PrPc
 Prion Diseases
• PrPc changes conformation to PrPsc
• PrPsc can then induce conformational change in
other PrPc molecules to PrPsc
• PrPsc is resistant to protease digestion
• PrPsc aggregates and damages the cell
• Leads to cytoplasmic vacuoles and eventual
neuronal death
• PrPc to PrPsc change occurs spontaneously at an
extremely low rate (sporadic cases)
• Mutation of gene for PrPc allows change at a
high rate (familial cases)
 Prion Diseases
• Creutzfeldt-Jakob Disease (CJD)
– Rapidly progressive dementia
• Begins with subtle changes in memory and
behavior
– 85% of cases are sporadic
– 1 in 1 million annual incidence
– Peak incidence in seventh decade
– Uniformly fatal, average 7 months
– Spongiform transformation of the cerebral
cortex and deep gray matter
 Prion Diseases
• Variant Creutzfeldt-Jakob Disease (vCJD)
– Starting in 1995, a series of cases of a CJD-like
illness appeared in the United Kingdom
– Differed from CJD
• Young adults
• Behavioral disorders were prominent in early disease stages
• Slower progression
– New disease was the consequence of exposure to
bovine spongiform encephalopathy
– Spongiform change and absence of inflammation, like
CJD, plus cortical amyloid plaques surrounded by
spongiform change
 Tumors
• ½ to ¾ are primary, the rest are metastatic
– Annual incidence
• 10-17/100,000 intracranial
• 1-2/100,000 intraspinal
– Larger proportion of childhood cancers (20%)
• Adult and childhood tumors differ in
histological subtype and location
– Childhood: more likely posterior fossa
– Adults: more likely supratentorial
 Tumors
• Unique characteristics
– Histological distinction between benign and malignant
is more subtle
– Low-grade lesions (low mitotic rate, cellular uniformity,
slow growth) may still infiltrate large regions of the
brain → serious deficits and poor prognosis
– Anatomic site can have lethal consequences even if
the tumor is benign histologically
– Pattern of spread
• Rarely metastasize outside of the CNS
• Seeding through the subarachnoid space can occur
 Gliomas
• Astrocytomas
– Fibrillary astrocytomas
• 80% of adult primary tumors
• 4th through 6th decades
• Cerebral hemispheres
• Seizures, headache, focal deficits
• Histological differentiation correlates with clinical
course and outcome
– Astrocytoma (grade I and II)
– Anaplastic astrocytoma (grade III)
– Glioblastoma multiforme (grade IV)
 Gliomas
• Astrocytomas
– Fibrillary astrocytomas
• Well differentiated
– Static or slowly progressive
– Mean survival >5 years
– Tumor usually progresses to higher grade with time
• Gliobastoma
– Mean survival 8-10 months
– <10% at 2 years
 Gliomas
• Astrocytomas
– Fibrillary astrocytomas
• Infiltrative tumors that extend beyond grossly
apparent margins expanding and distorting brain
• Gray, high grade tumors have necrosis and
hemorrhage
• High grade tumors are contrast enhancing on
imaging studies
 Gliomas
• Astrocytomas
– Pilocytic astrocytomas
• Relatively benign, often cystic tumors
• Children and young adults
• Cerebellum, usually
• Also 3rd ventricle, optic nerves, occasionally
cerebral hemispheres
• Symptomatic recurrence is often due to cyst
enlargement rather than solid component
 Gliomas
• Oligodendroglioma
– 5-15% of gliomas
– 4th and 5th decades
– Cerebral hemispheres, white matter preference
– Several years of neurological complaints, often with
seizures
– Better prognosis than astrocytomas
• Mean survival 5-10 years
– “Fried egg” appearance of tumor cells, delicate
network of capillaries
– 90% have calcifications
 Gliomas
• Ependymomas
– Arise next to ventricular system and central canal of
spinal cord
– In 1st two decades, occur near 4th ventricle
– Adults, occur in spinal cord most commonly
• Neurofibromatosis type 2 association
– CSF dissemination is common
– Supratentorial and spinal cord tumors have better
outcome than posterior fossa tumors
– Solid or papillary mass
– Rosettes and perivascular pseudorosettes
 Neuronal Tumors
• Central neurocytoma
– Low grade adjacent to ventricular system
• Ganglioneuromas
– Mature looking neurons with a mixture of glial
elements
• Dysembryoplastic neuroepithelial tumor
– Distinctive low grade tumor of childhood
– Superficial temporal lobe
– “Floating neurons” in myxoid background
 Medulloblastoma
• 20% of pediatric brain tumors
• Occurs exclusively in the cerebellum
– Children, midline tumors
– Adults, lateral tumors
• Largely undifferentiated, highly malignant
• Untreated, dismal prognosis
– Tumor is very radiosensitive
– Resection and radiation, 75% 5 year survival
• Similar tumors called CNS primitive
neuroectodermal tumors can occur elsewhere in
the CNS
 Primary CNS Lymphoma
• 2% of extranodal lymphomas, 1% of intracranial
tumors
• Most common CNS neoplasm in
immunosuppressed individuals
– Nearly all EBV driven
• Most are diffuse large B cell lymphomas
• Aggressive, poor response to chemotherapy
• Multiple sites within the CNS are often involved
– Outside involvement is a rare and late complication
 Germ Cell Tumors
• Primary brain germ cell tumors occur
along the midline
– Pineal (male predominance) and suprasellar
region
• 90% occur in first 2 decades
• Classification is similar to that used in the
testes (seminoma is called germinoma in
CNS)
 Meningiomas
• Benign tumors of adults
• Attached to the dura usually, also can be seen in
the ventricles
• Derived from arachnoid meningothelial cells
• Vague non-localizing or focal symptoms from
brain compression
• Prognosis depends on size, location, surgical
accessibility, and histological grade
• Many histological patterns
– Psammoma bodies
 Metastatic Tumors
• ¼ to ½ of intracranial tumors
• Most common primaries (80%)
– Lung, breast, skin (melanoma), kidney, GI
tract
• In the brain
– Sharply demarcated masses
– Often at gray matter-white matter junction
– Usually surrounded by a zone of edema
– Surrounded by reactive gliosis
 Paraneoplastic Syndromes
• Most commonly associated with small cell
carcinoma of the lung
• Some characteristic patterns affecting the
CNS and PNS
– Subacute cerebellar degeneration → ataxia
– Limbic encephalitis → subacute dementia
– Subacute sensory neuropathy → altered pain
sensation
 Diseases of Myelin
• Most diseases of CNS myelin do not
significantly involve the peripheral nerves,
and vice versa
• Two broad groups
– Demyelinating diseases
• Preferential damage to previously normal myelin
– Dysmyelinating diseases (leukodystrophies)
• Myelin is not properly formed or has abnormal
turnover kinetics
 Multiple Sclerosis
• Autoimmune demyelinating disorder
• Distinct episodes of neurological deficits,
separated in time, attributable to white
matter lesions that are separated in space
• Prevalence 1/1000
• Age of onset: young adulthood to 50
• Twice as common in women
 Multiple Sclerosis
• Believed to be caused by a combination of
environmental and genetic factors
– 1st degree relative: 15x risk
– 25% concordance rate among monozygotic twins
– Link to HLA-DR2
• T cell mediated delayed type hypersensitivity
reaction to myelin proteins is thought to be
central to the pathogenesis of MS
 Multiple Sclerosis
• Morphology
– MS is a white matter disease
– Affected areas show plaques
• Well-circumscribed, glassy, gray-tan, irregularly-
shaped lesions
• Commonly occur beside ventricles
• Also frequent in optic nerves, optic chiasm, brain
stem, ascending and descending fiber tracts,
cerebellum, and spinal cord
 Multiple Sclerosis
• Clinical
– Relapsing-remitting disease with gradual neurological
deterioration
– Common neurological symptoms and signs
• Unilateral visual impairment (optic neuritis)
• Cranial nerve signs
• Ataxia
• Disruption in conjugate eye movement (internuclear
ophthalmoplegia)
• Motor and sensory impairment of trunk and limbs
• Problems with voluntary control of bladder function
 Multiple Sclerosis
– CSF
• Mildly elevated protein, increased gamma-globulin
• Oligoclonal bands
– Antibodies directed against a variety of targets
– Marker of disease activity
– Unclear of role in disease mechanism
 Other Acquired Demyelinating
Diseases
• Post-infectious immune-mediated
demyelination
– Acute disseminated encephalomyelitis
• Acute onset, diffuse involvement a week or two
after antecedent infection
• May be fatal in 20% of cases
– Acute necrotizing hemorrhagic
encephalomyelitis
• More devastating disorder
• Young adults and children
 Other Acquired Demyelinating
Diseases
• Central pontine myelinolysis
– Non-immune process resulting in loss of
myelin in central pons
– Most often due to rapid correction of
hyponatremia
– Seen in alcoholism and severe electrolyte or
osmolar imbalance
– Often presents with rapidly evolving
quadraplegia
 Leukodystrophies
• Inherited dysmyelinating diseases
– Abnormal myelin synthesis or turnover
– Lysosomal enzymes, peroxisomal enzymes,
mutations in myelin proteins
• Much of the pathology is found in the white
matter
• Affected children are normal at birth but then
begin to miss developmental milestones
– Wide range of problems develop due to diffuse
involvement of white matter
 Nutritional Diseases
• Thiamine deficiency
– Wernicke encephalopathy
• Abrupt development of confusion, abnormalities of eye
movement, and ataxia
• Hemorrhage and necrosis in mammillary bodies
– Korsakoff syndrome
• Consequence of untreated Wernicke encephalopathy
• Profound memory disturbances
• Largely irreversible
• Lesions in medial dorsal nucleus of thalamus
– Wernicke-Korsakoff syndrome is often applied
because of the link
– Chronic alcoholism association
 Nutritional Diseases
• Vitamin B12 deficiency
– Subacute combined degeneration of the
spinal cord
• Involves ascending and descending fiber bundles
• Symptoms develop over weeks
– Slight ataxia
– Numbness and tingling in lower extremities
– Can progress to spastic weakness of lower extremities
– Complete paraplegia can occur
– Improvement with vitamin replacement therapy
– Poor recovery if complete paraplegia has developed
 Degenerative Diseases and
Dementias
• Dementia
– Memory impairment and other cognitive deficits with
preservation of a normal level of consciousness
– Dementia always represents a pathologic process
– Not all forms of dementia are degenerative
• Degenerative disorders represent an underlying cellular
degeneration of neurons in the brain
• Vascular disorders are an important cause of dementia
 Alzheimer Disease
• Most common cause of dementia in the elderly
• Clinical course
– Insidious impairment of higher intellectual functions,
with alterations in mood and behavior
– Progressive disorientation, memory loss, and aphasia
indicate severe cortical dysfunction
– Over the next 5 to 10 years, profoundly disabled,
mute, immobile
– Death usually occurs from pneumonia or other
infection
 Alzheimer Disease
• Incidence
– 3% for age 65-74
– 19% for age 75-84
– 47% for age >85
• Clinical assessment and imaging allow for
accurate diagnosis in 80-90% of cases
– Pathological examination of brain needed for
definitive diagnosis
• Most cases are sporadic, some familial (5-10%)
• Rarely symptomatic before age 50
 Alzheimer Disease
• Morphologic changes in brain and
dementia are initiated by the accumulation
of a peptide, β amyloid (Aβ)
• Aβ is derived from a larger membrane
protein, amyloid precursor protein (APP)
– Two processing paths
• Cleaved by α- and γ-secretase → no Aβ
• Cleaved by β- and γ-secretase → Aβ
• Generation and accumulation of Aβ occurs slowly
with advancing age
 Alzheimer Disease
• Familial
– Mutations in APP or components of γ-secretase (presenilin-1 or
presenilin-2) increase rate of Aβ accumulation
• Alzheimer disease occurs in almost all individuals with
trisomy 21 (Down syndrome) who survive beyond age 45
– APP gene is on chromosome 21
• Sporadic
– Allele of apolipoprotein, ε4 (ApoE4), associated with 30% of
cases—how is unknown
– SORL1 associated with late onset, deficiency of SORL1 protein
may alter intercellular trafficking of APP
 Alzheimer Disease
• Affects of Aβ on neurons
– Small aggregates alter neurotransmission and
can be toxic to neurons and synaptic endings
– Larger deposits, plaques, lead to neuronal
death, inflammatory response, may have
mechanical effects on axons and dendrites
altering region to region communication
– Leads neurons to hyperphosphorylate the
microtubule binding protein tau
 Alzheimer Disease
• Tau protein
– Hyperphosphorylated tau redistributes within the
neuron
• From axon to dendrites and cell body
• Aggregates into tangles
• Results in neuronal dysfunction and cell death
• Development of plaques and tangles occur in
parallel are responsible for the development of
the clinical signs and symptoms
– They develop well in advance of clinical presentation
 Alzheimer Disease
• Morphology
– Neuritic plaques, diffuse plaques,
neurofibrillary tangles, neuronal loss, and glial
reaction
– Pattern of progression
• Entorhinal cortex, hippocampal formation and
isocortex, then neocortex
 Frontotemporal Dementias
• Degeneration and atrophy of the frontal
and temporal lobes
– Deterioration of language and changes in
personality
– Followed by memory disturbances
• Some caused by mutations of gene for tau
protein
• Some have disease defining inclusions of
abnormal accumulations of tau
 Parkinsonism
• Clinical syndrome characterized by diminished
facial expression (masked facies), stooped
posture, slowness of voluntary movement,
festinating gait (progressive, shortened,
accelerated steps), rigidity, and “pill-rolling”
tremor
• Seen in a number of conditions that have
damage to dopaminergic neurons in the
substantia nigra or their projections to the
striatum
 Idiopathic Parkinson Disease
• Most common neurodegenerative disorder associated
with Parkinsonism
• Progressive Parkinsonism in absence of a toxic or other
known etiology and clinical response to L-
dihydroxyphenylalanine (L-DOPA)
• Most cases are sporadic
– Autosomal dominant and recessive forms exist
– AD form associated with α-synuclein mutations
• Lewy bodies
– A diagnostic histological feature of Parkinson disease
– Neuronal inclusions containing α-synuclein
– Suggests defective degradation in the proteosome may play a
role in the disease (other genes support this, parkin and UCHL-
1)
 Idiopathic Parkinson Disease
• Morphology
– Pallor of substantia nigra and locus ceruleus
• Loss of pigmented neurons and gliosis
– Lewy bodies
• Contain α-synuclein and other proteins including
neurofilament and ubiquitin
• Seen in remaining neurons of substantia nigra and locus
ceruleus
• Also seen in cholinergic cells of basal nucleus of Meynert
and other brain stem nuclei
• Similar structures can be seen in cerebral cortical neurons,
esp. cingulate and parahippocampal gyri
 Idiopathic Parkinson Disease
• Clinical
– L-DOPA is effective for symptomatic relief but doesn’t
change progressive nature of the disease
– 10-15 years of progressive motor slowing until near
immobility
– Death usually result of infection or trauma from falls
– 10-15% develop dementia
• Fluctuating course and hallucinations
• Attributed to widely disseminated Lewy bodies in the cerebral
cortex
 Huntington Disease
• Inherited autosomal dominant disorder
• Progressive movement disorders and
dementia, with degeneration of striatum
(caudate and putamen)
– Chorea affecting all parts of the body
– May develop Parkinsonism
• Relentlessly progressive resulting in death
after an average of 15 years
 Huntington Disease
• All have a trinucleotide repeat expansion
in the gene for huntingtin located on
4p16.3
• Polymorphic CAG trinucleotide repeat in
the gene that encodes a polyglutamine
tract in the protein
– Normal alleles have 11 to 34 copies
– Disease alleles this can increase to hundreds
– More repeats earlier onset of disease
 Huntington Disease
• Unclear how expanded polyglutamine tract
causes disease
– Binds to and sequesters transcription factors
– Functional abnormalities in mitochondria
– Aggregates of abnormal protein trigger
apoptosis
• Huntingtin is expressed widely throughout
the body
 Huntington Disease
• Morphology
– Striking atrophy of the caudate nucleus
– Less dramatic atrophy of putamen
– Secondary ventricular dilation (lateral and 3rd)
– Neurons that use GABA are especially
affected
 Huntington Disease
• Clinical
– Onset in 4th or 5th decade
– Motor symptoms precede cognitive
impairment
– Choreiform movements
– Forgetfulness and thought and affective
disorders, may progress to severe dementia
– Increased risk of suicide
– Infection most common cause of death
 Spinocerebellar Degenerations
• Heterogeneous group of disorders
– Includes several distinct diseases
• Affects cerebellar cortex, spinal cord, other
brain regions, and peripheral nerves
• Degeneration of neurons without distinct
pathological changes in the affected areas
with mild gliosis
• Many are caused by expansion of CAG
repeats
 Friedreich Ataxia
• Autosomal recessive
• Begins in 1st decade with gait ataxia and
followed by hand clumsiness and
dysarthria
– Deep tendon reflexes are diminished to
absent, extensor plantar reflex is present
– Loss of joint position and vibratory sense
– Pain, temperature, and light touch may be
diminished
 Friedreich Ataxia
– High incidence of cardiac disease and
diabetes
– Most patients are wheelchair bound within 5
years
• Caused by a GAA trinucleotide repeat
expansion (intronic) in a protein that is
involved in determining iron levels in cells
– Results in low protein levels
 Motor Neuron Diseases
• Series of diseases that affect lower motor
neurons in the spinal cord and brain stem
and upper motor neurons in the motor
cortex
• Sensory systems and cognitive functions
are usually unaffected
• Types with dementia do occur
 Amyotrophic Lateral Sclerosis
• Most common form of neurodegeneration
affecting the motor system
– Loss of both upper and lower motor neurons
– Men slightly more than women
– Onset in 5th decade or later
– Most are sporadic, 5-10% familial (AD)
• Half of familial cases have mutation of superoxide
dismutase, SOD1
 Amyotrophic Lateral Sclerosis
• Morphology
– Loss of anterior horn neurons
– Degeneration of lateral corticospinal tracts
• Clinical
– Weakness of hands
– Cramping and spasticity of arms and legs
– Diminished muscle strength and bulk with
fasciculations
– 50% 5 year survival
 Bulbospinal Atrophy
• Kennedy disease
• X-linked adult onset disease affecting
lower motor neurons
• Affected individuals manifest androgen
insensitivity
– Gynecomastia, testicular atrophy,
oligospermia
• Trinucleotide repeat disorder
– Polyglutamine repeat in androgen receptor
 Spinal Muscular Atrophy
• Distinctive group of autosomal recessive motor
neuron diseases that begin in childhood and
adolescence
• Loss of motor neurons and weakness
associated with muscle fiber atrophy that often
involves entire fascicles
• Werdnig-Hoffmann disease (SMA1) is the most
common form
– Onset at birth or within 4 months
– Leads to death within 3 years
• All forms are associated with mutations of SMN
gene on chromosome 5
 Familial Tumor Syndromes
• Inherited diseases characterized by the
development of hamartomas and neoplasms
throughout the body
• Those with particular involvement of the nervous
system follow
• Because of involvement of the nervous system
and cutaneous manifestations, they have been
grouped under the term “neurophakomatoses”
• Most are linked to loss of tumor suppressor
genes
 Neurofibromatosis Type 1
• Autosomal dominant
• Characterized by
– Neurofibromas (plexiform and solitary)
– Gliomas of the optic nerve
– Pigmented nodules of the iris (Lisch nodules)
– Cutaneous hyperpigmented macules (café au
lait spots)
• One of the more common genetic
disorders, 1 in 3000
 Neurofibromatosis Type 1
• Neurofibromas have a propensity to undergo
malignant change
• NF1 gene is a tumor suppressor gene
– Thought to be involved in G-protein dependent signal
transduction pathways
• Disease is highly variable
– Individuals with a mutated gene may have no
symptoms while others have progressive with spinal
deformities, disfiguring lesions, and compression of
vital structures including the spinal cord
 Neurofibromatosis Type 2
• Autosomal dominant
• Tumors
– Bilateral vestibular schwannomas (acoustic
neuromas)
– Multiple meningiomas
– Gliomas (ependymomas) of spinal cord
• Frequency of 1 in 40,000-50,000
• NF2 gene on chromosome 22
– Also mutated in sporadic meningiomas and
schwannomas
 Tuberous Sclerosis
• Autosomal dominant
• Hamartomas and benign tumors
– Cortical and subependymal hamartomas
• Seizures are associated with cortical lesions
– Renal angiomyolipomas
– Retinal glial hamartomas
– Pulmonary lesions
– Cardiac rhabdomyomas
 Tuberous Sclerosis
• Cysts of liver, kidneys, pancreas
• Cutaneous lesions
– Angiofibromas
– Shagreen patches (leathery thickenings)
– Hypopigmented areas (ash-leaf patches)
– Subungual fibromas
• Mutations of tumor suppressor genes,
TSC1 (hamartin) and TSC2 (tuberin)
– Interact and regulate signaling pathways
 von Hippel-Lindau Disease
• Autosomal dominant
• Hemangioblastomas involving the cerebellar
hemispheres, retina, and less commonly the
brain stem and spinal cord
• Cysts of pancreas, liver, kidney
• High risk of renal cell carcinoma
• Frequency of 1 in 30,000-40,000
• Mutations in tumor suppressor gene VHL
– Also associated with adrenal pheochromocytoma
– Gene controls angiogenesis, esp. in response to
hypoxia