PATHOLO

CNS PART 2
Dr. Roberto Demigillo | AY 2023-2024 | Term 1

PRION DISEASES
● Creutzfeldt Jakob Disease
● 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)

COMMON FEATURES OF PRION DISEASES

● Infectious agents with apparently DNA
● Dementia
● Prion protein (PrP) accumulation
● “Spongiform” changes in neurons and glia
● Transmibble, 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
○ Due to ingestion or transmission
○ Influences neighboring proteins to
become like it (?)
○ Like a virus (?)
● Prion proteins = normal; prion = abnormal (?)
CREUTZFELDT-JAKOB (CJD)
● 1 million per incidence, 7th decade
○ Usually in the elderly population
● Sporadic cases, not epidemic
○ Sporadic = rare
● Transmitted!
● Familial cases well documented
○ Hereditary
● Rapidly progressive dementia (in elderly)
● Grey matter (is affected)
● Cerebellar ataxia also, usually
○ Ataxia = problems in gait and balance
● Fatal, no treatment known, like all prion
diseases
DEMYELINATING DISEASES
● Multiple sclerosis
● MS variants
○ Acute disseminated encephalomyelitis
(ADEM)
○ Acute necrotizing hemorrhagic
encephalomyelitis (ANHE)
○ Many, many many others
● Demyelination is a non-specific reaction to many
types of CNS injury, and demyelination also
causes edema

MULTIPLE SCLEROSIS
● Cause: ?
● USA prevalence: 1:1000
● F>>>M, ages: 30’s, 40’s
● Spongiform appearance ● Immune response primarily against CNS myelin
○ Neurons and glial cells are diminished (white matter)
because they are taken over by prion ○ Autoimmune
proteins ● Regional area of white matter demyelination is
called “PLAQUE”
● Increased CSF gamma globulin, i.e., oligoclonal
bands
○ Autoimmune response is generated in
the CSF
● Often presents with visual problems
● exacerbations/remissions
○ Exacerbations = full blown disease
○ Remissions = delay or diminishing
manifestations

● Microscopic images of MS
○ w/o myelination, there’s no efficient
transmission
○ Manifests as paralysis, decreased
cognition, etc

● MRI is usually the diagnostic modality

○ White areas are plaques
○ White matter is affected
○ Demyelination causes increased MRI
signals
● Myelin stain
○ Myelinated white matter stains blue
○ Areas that are not blue are the
demyelinated areas

CNS DEGENERATIVE DISEASES

● Cortex (dementias)
● Basal ganglia and brain stem (parkinsonian)
● Spinocerebbellar (ataxias)
● Motor neurons (muscle atrophy)

CORTEX (DEMENTIAS)
● Alzheimer disease
○ Caucasians are usually affected
● Frontotemporal
● Pick disease (also primarily frontal)
● Progressive supranuclear palsy (PSP)
○ Affect cranial nerves
○ Rare degenerative tauopathy
■ Accumulation of tau proteins
(tauopathy)
○ Gradual deterioration and death of
certain areas of the brain
 ■ Basal ganglia and cortex,
cranial nerves
● Cortico basal degeneration (CBD)
● Vascular dementias (MID)

ALZHEIMER DISEASE
● Commonest cause of dementias (majority)
● Sporadic, 5-10% familial
● Cortical (grey matter) atrophy
● Neuritic plaques (extraneuronal)
○ Accumulation of tau proteins
● Neurofibrillary tangles (intraneuronal)
● Amyloid (i.e., beta amyloid)
○ Protein that accumulates
● Normal brain
● Brown areas are the beta amyloid

● Brain w/ alzheimer
○ Prominent sulci due to cortical atrophy
○ Gyri became smaller

● Beta amyloids
○ Plaque accumulations (arrows)
○ Extraneuronal (top)
○ Intraneuronal (bottom)
■ Hairlike extensions (?)
■ Neurofibrillary tangle
● Neurofibrillary tangles
VASCULAR DEMENTIA
● Associated with multiple infarcts hence the
name MID (multiple infarct dementia)
○ Lacunar infarcts
○ Cortical microinfarcts
○ Multiple embolic infarcts
■ embolic/embolism = traveling
blood clot
● Most common location
is peripheral limbs
○ Prolonged
standing
○ Sedentary
position
● Second commonest form of alzheimer
● Displaces the nucleus due to increased ● Can be seen in the gray matter
accumulation

BASAL GANGLIA AND BRAIN STEM

● Parkinsonism
○ Parkinson disease
● Tangle is a hyperphosphorylation of a neuron
○ Multiple system atrophy
microtubule that causes it to precipitate or
○ Huntington disease
accumulate

PARKINSONISM
● Is a clinical syndrome, not a disease
○ Diminished facial expression
 ○ Stooped posture
○ Slowness of voluntary movement
○ Slowness of voluntary movement
○ “Festinating” gait (short, fast)
■ Small steps, but fast (?)
○ Rigidity (cogwheel)
○ “Pillrolling” tremor
■ Like rolling a pill in their fingers
(?)
● The above clinical findings involve pathology of
the substantia nigra and include
○ Parkinson disease
○ Multiple system atrophy
○ Postencephalitic parkinsonism ● Normal (left); Parkinson (right)
○ Progr. Supranus. Palsy, Cort. Basal ○ Pallor = decreased dopamine
Degen. (cortical disorders)

PARKINSON DISEASE
● Pallor of the substantia nigra (and locus
coeruleus)
○ Pallor = diminishing color/whitish
discoloration; paleness
● Lewy bodies (alpha-synuclein protein)
● Brainstem (normal)
○ Blackish coloration

● Lewy body
○ Eosinophilic inclusion body
■ Alpha synuclein
○ Pathognomonic of Parkinson disease

● Brainstem w/ pallor (left)

○ Decreased dopamine

● Parkinsonism symptoms, i.e.,

○ Cogwheel rigidity
○ Intention tremor
● Progressive
● Hallucinations
● Dementia
● Symptomatic response to L-DOPA
● Normal locus coeruleus (right); abnormal (left) ○ L-DOPA = synthetic dopamine which is
responsive to parkinson disease
patients
MULTIPLE SYSTEM ATROPHY
● MSA
● Wide spectrum of diseases CNS DEGENERATIVE DISEASES
○ Affects many organs
● Glial cytoplasmic inclusions (GCIs) in SPINOCEREBELLAR DEGENERATIONS (ATAXIAS)
oligodendrocytes (alpha synuclein) ● Spine to cerebellum (ascending/afferent)
○ Myelin is affected ● Problems in coordination of muscles due to
○ Decreased axonal transmission to the damage of the ascending tract
target cells ● Spinocerebellar ataxias
● Clinically, ● Friedrich ataxia
○ Parkinsonism symptoms ● Ataxia-Telangiectasia
○ Autonomic dysfunction ○ Dilation of blood vessels that are
■ Problems in parasympathetic superficial
and sympathetic stimulation ○ Co-disease
● Brownish tint (antibody-antigen complexes) ● Manifests in:
○ Cerebellar cortex
○ Spinal cord
○ Peripheral nerves
● Features:
○ Ataxia (mainly)
■ Loss of extremity muscle
coordination
○ Spasticity
■ Loss of muscle tone
■ Increased stimulation of
muscles
○ Neuropathies
■ Nerve pain at the terminal ends
HUNTINGTON DISEASE of target cells
● Classic familial genetic disease ■ Manifests in the hands
● Progressive motor loss and dementia ■ Vitamin B6 treatment
● Chorea, i.e., jerky movements
○ Fasta and short movements of limbs
MOTOR NEURONS)
● Progressive, fatal ● ALS (amyotrophic lateral sclerosis, i.e., Lou
● Atrophy of basal ganglia, i.e., corpus striatum Gehrig’s disease)
● Ventricular enlargement due to loss of the tissue ○ Can’t feel sensation of temperature
part of the basal ganglia ● Bulbospinal atrophy (Kennedy syndrome)
● Autosomal dominant (?) ○ Mutation of androgen receptor
○ Problems in endocrine and genital
development
○ Androgen insensitivity syndrome
● Spinal muscular atrophy

AMYOTROPHIC LATERAL SCLEROSIS

● Unknown etiology
● Progressive muscle atrophy due to motor
neuron loss (lower, upper)
● 5-10% familial
● Hand weakness → diaphragm
○ Life threatening because it affects the
contraction of the lungs
○ Respiration rate is lower
● Anterior horn cells reduced and gliotic
○ Denervation
 ○ Anterior horn delivers responses from
CNS to target cell (efferent)
● White matter is affected
● Numerous blebs in the anterior horn cells
○ Reduction in neurons
● Cerebral cortex to spine is affected (descending
tract)

● Vitamin B12 deficiency (vibratory sense)

○ Posterior column demyelination
○ Large amount of white spots
○ Subacute combined degeneration
○ Tuning fork used to assess vibratory
sense

GENETIC METABOLIC DISEASES

● Neuronal storage diseases
○ Classical autosomal recessive enzyme
deficiencies
● Leukodystrophies
● Diabetes – increased/decreased glucose
○ Abnormal myelin synthesis
● Hepatic failure (NH4+)
○ Clear discoloration
○ Metabolic/hepatic encephalopathy
● Mitochondrial encephalopathies
● CO (cortex, hippocampus, Purkinje cells)
○ Mitochondrial gene mutation
○ Consistent binding of oxygen
○ Competes w/ hemoglobin
LEUKODYSTROPHIES
● CH3-OH, Methanol (retinal ganglion cells)
● Characterized by progressive degeneration of
● CH3-CH2–OH (acute/chronic, direct/nutritional)
myelinated white matter
● Radiation (brain most resistant to Rad. Rx)
● Imperfect growth/development of myelin
● Chemo (methotrexate + radiation)
● Types:
○ Krabbe
CNS TUMORS
○ Metachromatic-
● Gliomas (do not metastasize out of the CNS)
○ Adreno-
○ Astrocytes (I, II, III, IV)
○ Pelizaeus-Merzbacher
○ Oligodendroglioma
○ Canavan
○ Ependymoma
● Neuronal (neuroblastoma)
ACQUIRED TOXIC/METABOLIC CNS DISEASES
● Poorly differentiated (medulloblastoma)
● Vitamin B1 deficiency (Wernicke-Korsakoff)
● Meningiomas
○ Hemorrhagic mammillary bodies
● Lymphomas
○ Affect microglia
● Metastatic
○ Comes from distant organs that plant
tumors to CNS
○ Most common tumors
● Important to differentiate between primary vs
metastatic tumors
 ○ Need to find if px has tumors anywhere ○ Associated w/ gliosis
else ● Satellitosis?
● Symptoms (very vague) ○ Polar attractions of cancer cells (causes
○ Headache them to stick together)
○ Vomiting ● Delineation?
○ Mental changes ○ Gliosis = diffused involvement
○ Motor problems ○ Glioma = has borders (?)
○ Seizures
○ Increased intracranial pressure
○ Any localizing CNS abnormality
● How to detect CNS tumors
○ History
○ Physical
○ Neurologic exam
○ Lumbar Puncture (including cytology)
■ CSF analysis
■ Examination of cells
○ CT
○ MRI ● Glioma (picture above)
○ Brain angiography ○ Well circumscribed border
■ Insert dye to assess evaluation ○ Slight hyperchromasia
of vascular flow ○ Large nuclei
○ Biopsy (confirmatory) ○ Features of mitosis
● Questions for assessing CNS tumors
○ Benign? Malignant? Primary vs.
metastatic?
○ Location?
○ Age?
○ X-ray density? MRI signals?
○ Calcifications?
○ Vascularity?
○ Necrosis?
○ Liquefaction?
○ Edema?
○ Compression of neighbors?
● Pilocytic astrocytoma (picture above)
GLIOSIS VS GLIOMA ○ Increased proliferation of
● Age? astrocytes/glial cells
● White vs. grey matter? ○ Neoplastic tumor
● Gross texture? ■ New growth
● Vascularity? ○ Benign
● Mitoses?
● (N/C. pleomorphism, hyperchromasia)
○ If nucleus gets bigger but not cytoplasm,
it indicates an ongoing development of a
cancer
○ Pleomorphism
■ Irregular shaped and size of
cells
○ Hyperchromasia
■ Basophilic staining of nucleus
● Calcifications?
○ Seen in glioma
● Cysts?
● Glioblastoma
○ Nucleus is elongated
○ Malignant
○ Mitotic figures
○ Nuclei are scattered and cells have
different sizes and shapes
○ Hemorrhage
○ Calcifications
○ Hyperchromasia
○ Presence of nucleolus
○ Presence of necrosis
○ Many blood vessels
■ Need to supply for nutrition
○ Microvascular proliferation
● Central necrosis (picture below)
○ Sign of rapid growth
○ Outgrows its blood supply
○ Liquefies centrally like an abscess
○ Highly aggressive tumor (white spot)
○ Dark spots are the liquid
○ Can produce transtentorial herniation
NON ASTROCYTIC GLIOMA
● 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
○ Normal (left); abnormal (right)
● Ependymoma ○ Rosetting (?) (flower like)
○ Seen in the ventricles ■ Hallmark for embryonic tumors
○ Normal (left); abnormal (right) ■ True rosette (homer wright
rosette) - clear space inside
● neuroblastoma
■ Pseudo rosette (perivascular
rosette) - has blood vessel
inside
● ependymoma

○ Choroid plexus tumors

○ Overproduction of CSF
○ Usually localized to one area of the
brain
○ Develops from cells that line hollow
cavities at the bottom of the brain and
the canal containing the spinal cord
○ Can be slow growing or fast growing ● Medulloblastoma
○ May be located in the ventricles (cavities ○ Midline cerebellar tumor in children (3-4
in the center of the brain) yrs old)
○ May block the ventricles, causing ○ Primitive neuroectodermal tumor
hydrocephalus (water on the brain) ○ Found in occipital lobe, 4th ventricle,
○ Sometimes extends to the spinal cord cerebellum (posterior lobes)
○ 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

● Neuroblastoma
○ Neoplasm of the neuron
○ primitive/embryonic ● Meningiomas
○ Cellular origin is neuron precursor ○ Tumor of the brain covering (meninges)
○ Occur where dura is
○ Very vascular
○ Benign (can be 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 PSAMOMMA
bodies
■ PSAMOMMA - calcification or
deposits of calcium seen in
tumors
● Papillary carcinoma of
○ Whorling pattern (picture above)
the thyroid
● HIV
● Serous carcinoma of
○ Granuloma formation
the ovary
○ Tumor that arise from HIV
● Meningioma
○ Toxoplasma pseudotumor
● Adrenal tumors
○ Encephalitic pseudotumor
● Etc.
○ Lymphoma
■ EBV

METASTATIC CNS TUMORS

● Lung*
● Breast
● Melanoma
● Kidney
● GI

PARANEOPLASTIC SYNDROMES
● Small cell; lung
● Lymphomas
● Breast CA
● Purkinje cell degeneration
● Encephalitis, limbic system
● Sensory neuron degeneration, DRG (dorsal root
ganglion)
● Eye movement disorders
● Hypercalcemia
● Water salt imbalance

FAMILIAL TUMOR SYNDROMES

● NF1
○ Neurofibromas
○ Gliomas
● NF2
○ Schwannomas
○ Meningiomas
● Tuberous sclerosis, i.e., CNS and somatic
hamartomas
● Von-Hippel-Lindau, CNS
○ Hemangioblastomas, chiefly cerebellar