CNS

• Normal
CNS
–Neurons
–Glia
• Astrocytes
• Oligodendrocytes
• Ependymal Cells
• Microglia

• Pathology (13 Questions)

Classical Disease Patterns
• Degenerative
• Inflammatory
• Neoplastic
Classical CNS Disease Patterns

• Degenerative
• Inflammatory
• Neoplastic
• Traumatic
• 1) What are general patterns of CNS cell pathology?

• 2) What are the consequences of ↓↑ CNS pressure?

• 3) What are common patterns of CNS malformations?
• 4) What are common perinatal CNS injuries?
• 5) What are the patterns of CNS trauma?
• 6) What are the patterns of CNS vascular disease?
• 7) What are the patterns of CNS infection?
___________________________________________________
• 8) What are the patterns of CNS prion disease?
• 9) What are the patterns of CNS demyelinating disease?
• 10) What are the patterns of CNS degenerative disease?
• 11) What are the CNS genetic metabolic diseases?
• 12) What are the CNS acquired metabolic/toxic diseases?
• 13) What are the CNS tumors?
CELLULAR REACTIONS
• Neurons
– Acute (RED neuron, karyolysis)
– Subacute, chronic, cell loss, gliosis
– Axonal
– Inclusions (lipid, prot., carb., viruses)

• Glia, “gliosis”
– Swelling
– Fibers
– Inclusions
ACUTE NEURONAL INJURY

“RED” NEURONS
CEREBRAL EDEMA
(normal weight 1200-1300 grams)

• Vasogenic (disrupted BBB)

Intravascular INTER-cellular
• Cytotoxic
 INTRA-cellular
 CEREBRAL EDEMA
• Subfalcine (SUPRA-tentorial)
• Cingulate (TENTORIAL)
• Cerebellar tonsilar (SUB-tentorial,
or INFRA-tentorial)
 CEREBRAL EDEMA
• DDX: • SYMPTOMS
–EVERYTHING –HEADACHE
–HALLUCINATIONS
–COMA
–DEATH
HYDROCEPHALUS
HYDROCEPHALUS
• Impaired RESORPTION
• Increased PRODUCTION

• OBSTRUCTION
• COMMUNICATING (entire)
• NON-COMMUNICATING (part)
• HIGH Pressure
• NORMAL Pressure
CNS MALFORMATIONS
• Neural Tube
– Anencephaly, Encephalocele, Spina Bifida
• Forebrain
– Polymicrogyria, Holoprosencephaly, Agenesis of
Corpus Callosum
• Posterior Fossa (Infratentorial)
– Arnold Chiari (infratentorial herniation), Dandy-
Walker (cerebellar cyst)
• Syringomyelia/Hydromyelia
SPINA
BIFIDA
POLYMICROGYRIA
HOLOPROSENCEPHALY
SYRINGOMYELIA
(note “SYRINX”)
 PERINATAL Brain Injuries
• Intraparenchymal Hemorrhage
• Intraventricular hemorrhage (premies)
• Periventricular “leukomalacia” (i.e.,
infarcts)

• Cerebral “Palsy” refers to

nonprogressive diffuse cerebral
pathology apparent at childbirth
 CNS TRAUMA
• Skull Fractures
• Parenchymal Injuries
• Traumatic Vascular Injury
• Sequelae
• Spinal Cord Trauma
 BRAIN TRAUMA
• Contusion (bruise)
• Laceration (tear)
• Coup/Contre-Coup
• Concussion
“HAIRLINE” “DEPRESSED”,
aka
“DISPLACED”
 HEMATOMAS/HEMORRHAGE
• EPIDURAL (fx)
• SUBDURAL (trauma NO fx)
• SUBARACHNOID (arterial, no trauma)
• INTRAPARENCHYMAL (any)
• INTRAVENTRICULAR (no trauma, rare
in adults, common in premies)
EPIDURAL HEMATOMA
SUBDURAL
HEMATOMA
SUBARACHNOID
INTRAPARENCHYMAL
INTRAPARENCHYMAL
INTRAVENTRICULAR
CNS TRAUMA SEQUELAE
• Hydrocephalus (WHY?)

• Dementia (Punch Drunk Syndrome)

• Diffuse Axonal Injury (white matter)

SPINAL CORD TRAUMA
• Parallels BRAIN patterns of
injury on a cellular basis
• Usually secondary to spinal
column displacement
• Level of injury mirrors motor
loss: Death Quadriplegia 
Paraplegia
 Cerebrovascular Diseases
(CVA, “Stroke”)
• Ischemic (Thrombotic)
(↓ blood and 02)
– Global
– Focal (regional):
– ACUTE: edema  neuronal microvacuolization  pyknosis 
karyorrhexis  neutrophils
– CHRONIC: macrophages  gliosis

• Hemorrhagic (rupture of artery/aneurysm)

THROMBOTIC
MCA
HEMORRHAGIC
ACA
 A) EDEMA

B) “RED” NEURONS

C) POLYs

D) MONO’s (MACs)

E) GLIOSIS

Histopathologic
progression of
CNS infarcts
HYPERTENSIVE CVA
• Intracerebral
• Basal Ganglia Region
(lenticulostriate arteries of internal
capsule, putamen)
HYPERTENSIVE CVA
LACUNAR INFARCTS
“SLIT” HEMORRHAGE(s)
 SUBARACHNOID
HEMORRHAGE
• Rupture of large intracerebral
arteries which are the primary
branches of the anatomical circle
(of Willis)

• Congenital (“berry” aneurysms)

• Atherosclerotic (atherosclerotic
aneurysms, or direct wall rupture)
 HYPERTENSIVE
ENCEPHALOPATHY
• ACUTE
– Headaches
– Confusion
– Anxiety
– Convulsions
• CHRONIC
– Dementia (MID, Multi-Infarct-Dementia)
– Gait Disturbances
– Basal Ganglia symptoms
 CNS INFECTIONS
• ACUTE MENINGITIS
• ACUTE FOCAL SUPPURATIVE
• CHRONIC BACTERIAL
• VIRAL
• FUNGAL
• OTHER
 INFECTIONS
• Meningitis (generally* bacterial)
– E. coli, Strep B (neonates)
– H. influenzae (children)
– Neisseria meningitidis (adults)
– Strep. pneumoniae, Listeria (elderly)
– PMNs in CSF, INCREASED protein, REDUCED glucose
• Encephalitis (generally viral)
– Arboviruses, HSV, CMV, V/Z, polio, rabies, HIV
– Lymphs and macrophages in perivascular “Virchow-
Robbins” spaces
• Meningoencephalitis
* viral, chemical, tumoral
 ACUTE FOCAL SUPPURATIVE
CNS INFECTIONS

• CEREBRAL ABSCESSES
– Local (mastoiditis, sinusitis)
– Hematogenous (tooth extraction, sepsis)
– Staph, Strep
– Often fibrous capsule, liquid center
• SUBDURAL EMPYEMA (IN SINUSITIS)
• EXTRADURAL ABSCESS
(IN OSTEOMYELITIS)
SUBDURAL EMPYEMA
 CHRONIC BACTERIAL
Meningo-encephalits

• TB, brain and meninges

• SYPHILIS, gummas in brain
• LYME DISEASE (Neuro-Borreliosis)
TUBERCULOMA
 VIRAL
Meningo-encephalitis
• ARBO VIRUSES (West Nile, Equines, Venez., many more)
• HSV1
• HSV2
• V/Z
• CMV
• POLIO
• RABIES
• HIV
• Progressive Multifocal Leukoencephalopathy (JC)
• Subacute Sclerosing Panencephalitis (Measles)
 VIRAL
ENCEPHALITIS
PERIVASCULAR
LYMPHOCYTIC
“CUFFING”
Bitemporal encephalitis is HSV until proven otherwise!
HSV = TEMPORAL lobe(s)
 PERIVASCULAR
GIANT CELLS
in WHITE MATTER in
HIV
ENCEPHALITIS
 PROGRESSIVE MULTIFOCAL
LEUKOENCEPHALOPATHY (PML)
• JC Polyoma virus is the cause (JCV)

• Primarilly affects oligodendocytes

• Ergo, demyelination is the main

feature
PML
SUBACUTE SCLEROSING
PANENCEPHALITIS (SSPE)
• VERY rare since measles eradicated
• Thought to be caused by measles virus
 FUNGAL
MENINGO-ENCEPHALITIS
•CRYPTOCOCCUS
•CANDIDA
• ASPERGILLIS
• MUCOR

(Mostly in immunocompromised hosts)

CRYPTOCOCCUS
MICROABSCESSES
 OTHERS
• MALARIA
• TOXOPLASMOSIS (in HIV)
• AMEBIASIS
• TRYPANOSOMES
• RICKETTSIAE
• ECHINOCOCCUS
CNS II
• 1) What are general patterns of CNS cell pathology?
• 2) What are the consequences of ↓↑ CSF pressure?
• 3) What are common patterns of CNS malformations?
• 4) What are common perinatal CNS injuries?
• 5) What are the patterns of CNS trauma?
• 6) What are the patterns of CNS vascular diseases?
• 7) What are the patterns of CNS infection?

• 8) What are the patterns of CNS prion diseases?

• 9) What are the patterns of CNS demyelinating
diseases?
• 10) What are the patterns of CNS degenerative
diseases?
• 11) What are the CNS genetic metabolic diseases?
• 12) What are the CNS acquired metabolic/toxic
diseases?
• 13) What are the CNS tumors?
 PRION DISEASES
• Creutzfeldt-Jakob Disease (CJD)
• Gerstmann-Straussler-Scheinker syn. (GSS)
• Fatal familial insomnia
• Kuru, human variety (cannibalism)
• Scrapie (sheep and goats)
• Mink transmissible encephalopathy
• Chronic wasting disease (deer and elk)
• Bovine Spongiform Encephalopathy (BSE)
 PRION DISEASES:
common features
• Infectious agents with apparently
no DNA
• DEMENTIA
• Prion Protein (PrP) accumulation
• “SPONGIFORM” changes in
neurons and glia
• TRANSMISSIBLE, FATAL, NO Rx
PRION PROTEIN
Normally found in
humans
Exact structure
known, 208 amino
acids
Specific
chromosome, #20,
specific genes also
known
Requires a
conformational
change to
accumulate and do
damage
 CJD (Creutzfeldt-Jakob)
• 1 per million incidence, 7th decade
• Sporadic cases, not epidemic
• Transmitted!
• Familial cases well documented
• Rapidly progressive dementia
• Grey Matter
• Cerebellar ataxia also, usually
• FATAL, no treatment known, like ALL
prion diseases
 DEMYELINATING DISEASES
• MS (MULTIPLE SCLEROSIS)
• MS variants
• ACUTE DISSEMINATED
ENCEPHALOMYELITIS (ADEM)
• ACUTE NECROTIZING HEMORRHAGIC
ENCEPHALOMYELITIS (ANHE)
• Many, many, many others. Remember:
DEMYELINATION is a NON-SPECIFIC
reaction to MANY types of CNS injury, and
demyelination also causes edema
• Cause: ?
MS
• USA prevalence: 1:1000
• F>>M, Ages: 30’s, 40’s
• Immune response primarily against CNS myelin
(white matter)
• Regional area of white matter demyelination is
called “PLAQUE”
• Increased CSF gamma globulin, i.e., oligoclonal
bands
• Often presents with VISUAL problems
• EXACERBATIONS/REMISSIONS
PLAQUES, MS
CNS DEGENERATIVE DISEASES
• CORTEX (dementias)
• BASAL GANGLIA and BRAIN
STEM (parkinsonian)
• SPINOCEREBELLAR (ataxias)
• MOTOR NEURONS (muscle
atrophy)
CNS DEGENERATIVE DISEASES

• CORTEX (dementias)
–ALZHEIMER DISEASE
– Frontotemporal
– Pick Disease (also primarily frontal)
–Progressive Supranuclear Palsy (PSP)
–CorticoBasal Degeneration (CBD)
– Vascular Dementias (MID)
 ALZHEIMER DISEASE
• Commonest cause of dementias (majority)
• Sporadic, 5-10% familial
• CORTICAL (grey matter) ATROPHY
• NEURITIC PLAQUES*
(extraneuronal)
• NEUROFIBRILLARY TANGLES
(intraneuronal)
• AMYLOID!!! (i.e., “BETA” amyloid)
Neuritic plaques Neuritic plaques, stained with
anti- beta amyloid
immunostain
 OTHER CORTICAL DEMENTIAS
(tau gene/protein, tau-opathies)
• FRONTOTEMPORAL
• PICK DISEASE (LOBAR ATROPHY)
• PROGRESSIVE SUPRANUCLEAR
PALSY (PSP)
• CORTICOBASAL DEGENERATION
(CBD)

• VASCULAR DEMENTIA (MID)

VASCULAR DEMENTIA
• Associated with multiple infarcts,
hence the name MID (Multiple
Infarct Dementia)
– Lacunar infarcts
– Cortical microinfarcts
– Multiple embolic infarcts
• SECOND commonest form of
dementia after Alzheimer
CNS DEGENERATIVE DISEASES

• BASAL GANGLIA and

BRAIN STEM
–Parkinsonism
–Parkinson Disease
–Multiple System Atrophy
–Huntington Disease
 Parkinsonism
• Is a clinical “syndrome”, NOT a disease
– Diminished facial expression
– Stooped posture
– Slowness of voluntary movement
– “Festinating” gate (short, fast)
– Rigidity (cogwheel)
– “Pillrolling” tremor
• The above clinical findings involve
pathology of the SUBSTANTIA NIGRA, and
include:
–PARKINSON DISEASE
– MULTIPLE SYSTEM ATROPHY
– POSTENCEPHALIC PARKINSONISM
– Progr. Supranuc. Palsy, Cort. Basal Degen.
(cortical disorders)
 PARKINSON DISEASE
•PALLOR of the
SUBSTANTIA NIGRA
(and LOCUS COERULEUS)
• LEWY BODIES (alpha-synuclein
protein)
 LOCUS COERULEUS* in PONS
(CERULEUS**)
* 254,000 ** 76,000
 PARKINSON DISEASE
• Parkinsonism symptoms, i.e.,
– cogwheel rigidity
– intention tremor
• Progressive
• Hallucinations
• Dementia
• Symptomatic response to L-DOPA
 MULTIPLE SYSTEM ATROPHY
• MSA
• WIDE SPECTRUM of diseases
• GLIAL CYTOPLASMIC
INCLUSIONS (GCIs) in
oligodendrocytes (alpha synuclein)
• Clinically,
– parkinsonism symptoms
– autonomic dysfunction
 HUNTINGTON DISEASE
• Classical familial,
genetic disease
• Progressive motor
loss and dementia
• “chorea”, i.e.
“jerky” movements
• Progressive, fatal
• Atrophy of basal
ganglia, i.e., corpus
striatum
Cortical (basal ganglia) atrophy
Ventricular enlargement
CNS DEGENERATIVE DISEASES

• SPINOCEREBELLAR
DEGENERATIONS (ATAXIAS)
–Spinocerebellar ataxias
–Friedrich Ataxia
–Ataxia-Telangiectasia
SPINOCEREBELLAR DEGENERATIONS

• Cerebellar cortex
• Spinal cord
• Peripheral nerves

• FEATURES:

–ATAXIA (loss of extremity muscle

coordination)
– SPASTICITY
– NEUROPATHIES
CNS DEGENERATIVE DISEASES
• MOTOR NEURONS
–ALS (Amyotrophic Lateral
Sclerosis, i.e., Lou Gehrig’s
disease)
– BulboSpinal Atrophy (Kennedy
Syndrome)
– Spinal Muscular Atrophy
Amyotrophic Lateral Sclerosis
• Unknown etiology
• Progressive muscle atrophy due to motor
neuron loss (lower, upper)
• 5-10% familial
• Lou Gehrig had it, so does Steven Hawking
• Hand weakness diaphragm
• Anterior horn cells reduced and gliotic
 A.L.S., DEMYELINATION IN
CORTICOSPINAL TRACTS

ALS, pathologic changes in anterior horn cells

GENETIC METABOLIC DISEASES
• NEURONAL STORAGE DISEASES
– (classical autosomal recessive enzyme deficiencies)

• “LEUKO”-DYSTROPHIES
– (abnormal “myelin” synthesis)

• MITOCHONDRIAL
ENCEPHALOPATHIES
– (mitochondrial gene mutations)
LEUKODYSTROPHIES
• Krabbe
• Metachromatic-
• Adreno-
• Pelizaeus-Merzbacher
• Canavan
 ACQUIRED TOXIC/METABOLIC
CNS DISEASES
• Vitamin B1 deficiency (Wernicke-Korsakoff)
• Vitamin B12 deficiency (vibratory sense)
• Diabetes Increased/Decreased GLUCOSE
• Hepatic Failure (NH4+)
• CO (Cortex, hippocampus, Purkinje cells)
• CH3-OH, Methanol (Retinal ganglion cells)
• CH3-CH2-OH (acute/chronic, direct/nutrit’l)
• Radiation (Brain MOST resistant to Rad. Rx.)
• Chemo (Methotrexate + Radiation)
128 Hz
 CNS TUMORS
• GLIOMAS (do not metastasize out of the
CNS)
III, IV)
– Astrocytes (I, II,
– Oligodendroglioma
– Ependymoma
• NEURONAL (neuroblastoma)
• POORLY DIFFERENTIATED (medulloblastoma)
• MENINGIOMAS
• LYMPHOMAS
• METASTATIC
 CNS
• SYMPTOMS?
TUMORS
– Headache
– Vomiting
– Mental Changes
– Motor Problems
– Seizures
– Increased Intracranial Pressure
–ANY localizing CNS abnormality
 CNS TUMORS
• History
• Physical
• Neurologic exam
• LP (including cytology)
• CT
• MRI
• Brain angiography
• Biopsy
 CNS TUMORS
• Benign? Malignant?, Primary vs. met?
• Location?
• Age?
• X-ray Density? MRI signals?
• Calcifications?
• Vascularity?
• Necrosis?
• Liquefaction?
• Edema?
• Compression of neighbors?
 GLIOSIS vs. GLIOMA
• Age?
• White vs. Grey Matter?
• Gross texture?
• Vascularity?
• Mitoses?
• (N/C, Pleomorphism, Hyperchromasia)
• Calcifications?
• Cysts?
• Satellitosis?
• Delineation?
 NON
ASTROCYTIC
GLIOMAS
 OLIGODENDROGLIOMA
Occurs frequently in the
frontal or temporal lobes

Can be classified as low

grade or high grade

Common among men and

women in their 20s-40s, but
can occur in children

More common in men than

women

Accounts for two percent of

all brain tumors

May be associated with 1p or

19q chromosomal losses
 EPPENDYMOMA
Usually localized to one area of the brain

Develops from cells that line the hollow

cavities at the bottom of the brain and the
canal containing the spinal cord

Can be slow growing or fast growing

May be located in the ventricles (cavities in

the center of the brain)

May block the ventricles, causing

hydrocephalus (water on the brain)

Sometimes extends to the spinal cord

Common in children, and among men and
women in their 40s and 50s

Occurrence peaks at age five and again at age

34

Accounts for two percent of all brain tumors

Zoom
Me!
•
MENINGIOMAS
Occur where dura is
• Very vascular
• BENIGN, but………….(can be damned invasive)
• Can invade skull, etc.
• Only invade (displace) brain in areas adjacent to
dura, i.e., parasagittal, falx, tentorium, venous
sinuses
• Small, firm, and well defined like a SUPERBALL

• Often (usually?) have PSAMMOMA bodies

HIV
 METASTATIC CNS
TUMORS

•LUNG
• BREAST
• MELANOMA
• KIDNEY
• GI
“PARA”NEOPLASTIC SYNDROMES
• Purkinje Cell
•SMALL Degeneration
CELL, • Encephalitis, Limbic
System
LUNG • Sensory Neuron
• LYMPHOMAS Degeneration, DRG
• BREAST CA • Eye Movement
Disorders
FAMILIAL TUMOR SYNDROMES
• NF1
– Neurofibromas
– Gliomas
• NF2
– Schwannomas
– Meningiomas
• Tuberous Sclerosis, i.e., CNS and
somatic “hamartomas”
• Von-Hippel-Lindau, CNS
hemangioblastomas, chiefly cerebellar