CENTRAL NERVOUS SYSTEM CNS PATHOLOGY

Macroglia:

▪  astrocytes oligodendrocytes, ependyma (from neuroectoderm)

 

Astrocytes

-gray and white matter

-star shaped

-detect with GFAP

-form glial scars in areas of “astrogliosis”: astrocyte hypertrophy and hyperplasia, ↑, vesicular nucleus with prominent nucleolus, ↑bright pink cytoplasm around eccentric nucleus

Rosenthal fibers:

-thick eosinophilic structures in astrocytic processes

-assoc/ gliosis, pilocytic astrocytoma

 

Corpora amylacea:

-Round basophilic PAS+ lamellated structures at ends of astrocytic processes

-assoc/ degenerative change in astrocyte

 

Alzheimer type II astrocyte:

-Found in hyperammonemia of chronic liver disease

-↑nucleus (2 – 3 X normal), pale staining chromatin, intra-nuclear glycogen droplet, prominent nuclear membrane and nucleolus

Oligodendrocytes

-wrap around axons to form myelin akin to schwann cells in PNS

-small round lymphocyte like nuclei often in linear arrays

Ependymal cells

-Columnar, line ventricular system

-prod CSF

 

MicroglIa

-from monocytes in bone marrow (mesoderm)

 

Cerebral Edema

Vasogenic – disrupted blood-brain barrier eg. adjacent to abscess/neoplasm

Cytotoxic – generalized hypoxia/ ischemia

 

Raised ICP can result in:

Subfalcine herniation → can compress Anterior Cerebral Artery

Transtentorial (uncal) herniation – compression of 3^rd nerve

Tonsillar – compression of brain stem

Neural Tube Defects

Anencephaly – absence of brain and calvarium leaving area cerebrovasculosa

Encephalocele – diverticulum of CNS through calvarium

Spina Bifida

-Occulta = asymptomatic bony defect

-Myelomeningocele = extension of CNS through bony defect

-Meningocele = extension of only meninges through bony defect

 

Forebrain Anomalies

Polymicrogyria – small, and unusually numerous gyri with four or fewer gray matter layers

Megalencephaly and microencephaly

Holoprosencephaly – incomplete separation of the hemispheres

Agenesis of the corpus callosum – “bat wing” deformity of lateral ventricles

 

Posterior fossa abnormalities

Arnold-Chiari malformation

Small posterior fossa misshapen midline cerebellum with downward extension of vermis through foramen magnum leading to hydrocephalus, and a myelomeningocele

 

Dandy-Walker malformation

Enlarged posterior fossa, expanded roofless 4^th ventricle in place of rudimentary vermis

 

Syringomyelia and hydromyelia

Syringomyelia – fluid filled cleft like cavity within cord

Hydomyelia – multi-segmental or confluent expansion of ependymal lined central canal of cord

 

Perinatal Brain Injury

Intraparenchymal hemorrhage in germinal matrix – increased risk in premature infants

Periventricular white matter infarcts – aka leukomalacia  – especially in premature babies

 
Trauma ( skull fracture, parenchymal & vascular injury)

Parenchymal Injury

Concussion:

-instantaneous but transient neurologic dysfunction including loss of conciousness, respiratory arrest, and loss of reflexes

Contusion and Laceration:

-common over orbital gyri and in temporal lobes

-wedge shaped on cut section

-“coup and contracoup”

-old lesions are depressed, retracted, yellowish brown lesion over crests of gyri and are called plaque jaune

Diffuse Axonal Injury:

-axonal swelling and focal hemorrhage in deep centroaxial white matter like corpus callosum

 

Vascular Injury

Epidural hematoma: middle meningeal artery

Subdural hematoma: bridging veins from surface of brain traverse subarachnoid and dura on way to sagittal sinus

 

CerebrovascuLar Disease

1. Hypoxia, Ischemia, Infarction

2. Intracranial Hemorrhage

3. Hypertensive Cerebrovascular Disease

 

1. Hypoxia, Ischemia, Infarction

 

Functional hypoxia→ low inspired pO2, impaired oxygen carrying capacity etc

Ischemia→ transient or permanent / low perfusion pressure or vessel obstruction

1.  Global cerebral ischemia is from generalized reduction in cerebral perfusion

2.  Focal cerebral ischemia is from cessation of blood flow to a focal area of brain (eg large vessel thrombosis/embolus or small vessel vasculitis)

Path features of infarct:

Early:Pyramidal cells (hippocampus),  Pyramidal neurons of neocortex, Purkinje cells (cerebellum)→red neurons (degenerating neurons), karyorrhexis

Subacute: granulation tissue, mφ, gliosis

Late:mφ + gliosis + loss of tissue

 

2. Intracranial Hemorrhage

Classification

1. Intraparenchymal Hemorrhage

- Rupture of small vessel usually due to hypertension

2. Subarachnoid Hemorrhage and Berry Aneurysms

- intraparenchymal hemorrhage

- ACA, MCA, ICA, basilar tip

 

Risk factors for berry aneurysms:

1. PCKD
2. Marfan’s
3. Ehlers Danlos
4. Coarctation of the Aorta

 

3. Vascular Malformations

AVM: presents as seizures/bleed in 10 to 30 year olds

Cavernous hemangiomas

Capillary telangiectasias

Hypertensive Cerebrovascular Disease

Pathology

1. Intracranial hemorrhage (see above)

2  Lacunar infarcts

→ deep penetrating arteries in basal ganglia and cortex develop arteriolar sclerosis

3. Slit hemorrhages

→rupture of sm. calibre bv

4. Hypertensive encephalopathy

→multiple infarcts which over time result in “vascular multi-infarct dementia”

Micro:

1. cerebral atherosclerosis

2. bv thrombosis/embolization

3. arteriolar sclerosis

 

Infections

Meningitis

→viral or bacterial

Organsisms:

Neonates: E.coli, group B strep

Infants/children: H.flu,

Young adults: Neisseria

Elderly: Strep pneumo

Spinal tap (bacteria): purulent w/ ↑neuts, ↑pr, ↓glucose

Routes to infection:

1. hematogenous (most common)

2. direct implantation (eg. septic lumbar puncture)

3. local extension (eg. air sinus)

4. peripheral nervous system (eg. HSV, rabies)

Suppurative infections:

Abcess, subdural empyema, extradural abcess (eg. arising from adjacent sinusitis)

Specific infections:

TB→ meninogoencephalitis, obliterative endarteritis

Syphillis→base of brain, cerebral convexities, spinal leptomeninges

HSV1→temporal lobe and orbital gyri

CMV→ependymal and subependymal regions

Poliovirus→anterior horn motor neurons

Rabies→widespread neuronal degeneration, esp. basal ganglia, midbrain, medulla

 

Crutzfeldt-Jakob (CJD) (Prion disease)

Clin: subtle changes in memory and behaviour followed by rapidly progressive dementia with startle myoclonus – fatal with average duration of 7 months

Genetics:

-PrP alpha helix transforms → beta pleated sheet

-Can do so spontaneously but can be accelerated by mutation

-Infectious because they can induce conformational change in normal PrP

-PRNP gene on chromosome 20

Path:

Spongiform transformation:

-caudate and putamen

-small, microscopic vacuoles of varying sizes

-NO inflm

SS: Congo red & PAS→Kuru plaques are extracellular aggregates of abN pr in the cerebellum

EM: vacuoles are intracytoplasmic and membrane bound

 

Demyelinating Diseases

Multiple Sclerosis

Clin: “time and space”

Distinct episodes of neurologic deficit separated in time attributable to white matter lesions that are separated in space

Gross:

spinal cord: depressed, glassy, gray irregular plaques

cortex: adj lateral ventricles, optic chiasm, brainstem

Micro:

-active plaque: myelin breakdown + lipid laden mφ with PAS+ debris, perivasc. cuffs, preservation of axons, loss of oligodendrocytes

-inactive plaque: no myelin, ↓oligodendrocytes, astrocytic proliferation (gliosis)

-shadow plaques: border between normal and white matter not sharply circumscribed

Pathogenesis – immune, genetic and environmental

Others:

• Acute disseminated encephalomyelitis
• Acute necrotizing hemorrhagic encephalomyelitis
• Central Pontine Myelinosis

 

Degenerative Diseases

Alzheimer Disease

Clinical

-late-onset sporadic, familial (early, late), AD-assoc/ trisomy 21 (extra copy of APP results in ↑amyloid b peptide

Pathology

Gross

-cortical atrophy in cortical, parietal, and temporal lobes

-ventrical enlargement

Micro

1. Neurofibrillary Tangles:

-aggregates of microfilaments in the cytoplasm of neurons, displace nucleus→flame shape

-hyperphosphorylated “paired helical filaments” such as tau, MAP, Ub, amyloid b peptide

→freq ubiquitinated

-found in pyramidal cells, often flame-shaped/globular filamentous shape

-hippocampus, amygdala

2. Senile plaques:

-structure=clear halo + dystrophic neurites + central amyloid core (amyloid b peptide)

-diffuse plaques® smaller dense amyoid cores only

-hippocampus, amygdala

 

3. Amyloid angiopathy

 

4. Granulovacuolar degeneration

-cytoplasmic granules in pyramidal neurons (hippocampus)

 

5. Hirano bodies

-glassy, eosinophilic body in pyramidal neurons (hippocampus)

 

Culprits

1.amyloid b peptide is a secretase product of amyloid precursor protein

2.presenilins 1 and 2 on chromosomes 14 and 1 lead to increased amyloid b peptide and early onset familial Alzheimer dz

3.Apolipoprotein E on chromosome 19 → mechanism unclear

 

Pick’s Disease

Clin: -rare progressive dementia

-early onset behavioral (frontal) and language (temporal) disturbances

Gross:

Frontal and temporal gyri→knife edge atrophy, sparing of the posterio 2/3 of superiotemporal gyrus

Bilateral atrophy of caudate nucleus and putamen

Micro:

-neuronal loss most severe in outer three layers

-surviving neurons show basophilic inclusions in the cytoplasm ++staining with Ag (Pick bodies)

 

 

basal ganglia and brain stem

Name 5 degenerative diseases that affect the basal ganglia and brain stem.

1.     Idiopathic Parkinsons

2.     Progressive Supranuclear Palsy

3.     Corticobasal Degeneration

4.     Multiple System Atrophy

5.     Huntington Disease

 

Parkinson Disease

-degeneration of dopaminergic neurons in substantia nigra

Macro

-loss of pigmentation in substancia nigra and locus ceruleus

Micro

-loss of cholinergic neurons

-astrocytic gliosis

-accumulation of neuromelanin in macrophages

-Lewy body inclusions →dense core surrounded by a clear halo→ IHC: a-synuclein and Ub positive

-substancia nigra, locus ceruleus, nucleus of Meynert

 

Progressive Supranuclear Palsy (PSP)

Clinical:

-look surprised (vertical gaze palsy), progressive dementia, progressive dysphagia

-often die from aspiration pneumonia

Macro

-widespread neuronal loss

-loss of pigment in the substancia nigra and the locus ceruleus

-atrophy of midbrain and pons

Micro

-neurofibrillary tangles usually only seen on IHC

 

Huntington Disease

Genetics: AD inheritance

-HD gene (chr. 4) contains CAG trinucleotide repeat expansions

-the larger the expansion the earlier the onset of disease

-expansions occur during spermatogenesis

Clin: progressive movement disorder and dementia, jerky choreiform movements

Path:

-striking atrophy of the caudate nucleus and less so of putamen

-loss of striatal neurons (GABA + substance P OR enkephalin neurons)

 

Spinocerebellar Degeneration/ ataxia

Name 2 diseases and their mode of inheritance.

1.   Friedrich Ataxia – autosomal recessive

2.             Ataxia-Telaniectasia – autosomal recessive

 

Name 3 degenerative diseases affecting the motor neurons.

1. ALS

2. Bulbospinal Atrophy

3. Spinal Muscular Atrophy

 
Alzheimer’s→ tau, Ub, β-AP,

Pick’s → Pick bodies → tau

Parkinson’s → Lewy bodies → α-synuclein, Ub

PSP → tau

 

Effects of alcohol:

Brain:

▪ Wernicke encephalopathy: chronic thymine deficiency (confusion and ataxia)

-small petechial hemorrhages in the mammillary bodies, periventricular white matter (3rd and 4th ventricles)

▪ Korsakoff psychosis: confabulation and retrograde amnesia

▪ Cerebellar degeneration

▪ Central pontine myelinolysis (assoc/ binge drinking, electrolyte imbalances)

▪ Polyneuropathy

 

Endocrine

-“feminization” (lower circulating testosterone) → loss of pubic hair, gynecomastia

 

Heart:

Arrythymias

Dilated cardiomyopathy

 

Muscle

Proximal myopathy

 

Liver:

Alcoholic steatosis, hepatitis, cirrhosis

 

GI tract:

Esophagus: reflux esophagitis, Mallory Weiss tears

 

Pancreas:

Acute pancreatitis
CNS TUMOURS

SUPRATENTORIAL

CHILD:

Pleomorphic Xanthoastrocytoma

• young people, in temportal lobes ® good px.
• involves cortex and leptomeninges
• fibrillary background, pleomorphic, hyaline giant cells
• lipid laden giant cells ® looks scary
• multinucleated cells
• no mitoses, no necrosis
• GFAP +
• ·Ddx: SEGA, glioblastoma

 

SEGA: Subependymal Giant Cell Astrocytoma

• lateral ventricle ® may obstruct foramen of Monro in lateral ventricle
• giant cells located in subependymal nodules ”candle gutterings“ benign
• giant nuclei and prominent nucleoli® ganglion-like, rounded (gemistocytic-like) or spindly profiles, glassy cytoplasm

IHC: GFAP +/-

·                      assoc/ tuberous sclerosis, AML, LAM

Genetics:

mutations in genes for tuberin and hamartin

 

ADULT:

Astrocytoma (Grade II/IV)

Name THREE types of variants.

Clin:               adults, cerebrum

Gross: firm or soft +/- cystic degeneration

·                      gross margin: may appear to be well circumscribed, but microscopic margin ill-defined: gradually diminishes in cellularity

Micro:           mild nuclear atypia with pleomorphism, increased glial nuclei, nuclei not round

▪NO necrosis, NO microvascular proliferation

▪rare mitoses, Ki-67 low, GFAP+

▪fibrillary processes

Variants:

▪ fibrillary: ▪fibrillary processes + fibrillary background

▪ protoplasmic:

-few processes, occur in gray matter instead of white matter

▪ gemistocytic:

-large cells with abundant eosinophilic cytoplasm and atypical, eccentric nuclei

IHC: GFAP+ fibrillary processes

Ddx: gliosis, oligodendroglioma

 

Anaplastic Astrocytoma (Grade III/IV)

·                      increased cellularity, atypia, mitoses (most important) ­Ki67 index

·                      NO necrosis, NO microvascular proliferation

 

Glioblastoma Multiforme (Grade IV/IV)

• very short clinical course (unless arising from diffuse)
• T1 ring enhancing lesion (increased vascularity)
• increased cellularity, atypia, mitoses

·                      pseudopalisading necrosis (neoplastic cells around necrotic tumour) “glomeruloid”

·                      microvascular proliferation (glomerular like tufts or more blood vessels or thickened blood vessels) required for diagnosis

 

Oligodendroglioma (Grade II/IV)

Clin: adults, usu. have several years of epileptic seizures

cortex, white matter, frontal lobe most often ® young adults

• respond well to PCV therapy
• round with granular cytoplasm

·                      often associated with astrocytomas

Micro:

·                      fried egg cells (perinuclear halo- not seen on fozens!)/honeycomb pattern, not fibrillar

·                      chicken wire vascularity

·                      calcifications

IHC:              GFAP, vim + (GFAP is also + in intermingling astrocytes)

·                      “mini-gemistocytes”

·                      ® do better stage-for-stage than astrocytomas (ddx)

 

Anaplastic oligodendroglioma (Grade III/IV)

• significant mitoses OR necrosis OR microvascular proliferation
• no processes

Oligoastrocytoma

• oligodendroglioma + astrocytoma

 

SEGA

 

CNS Lymphoma

 

-mostly B-type

-poor prognosis

-often have angiocentric growth pattern

 

metastatic tumour

 

INFRATENTORIAL (CEREBELLUM)

BOTH:

Choroid plexus papilloma

Clin: children ® often present with hydrocephalus

Gross: villous fronds (like cauliflower) grows into ventricular system

Micro: papillary FV cores lined by round/columnar cells

-only mild atypia (like normal choroid plexus only more exuberant growth)

IHC: CK (CAM5.1 and AE1/3)+, transthyretin +

Choroid plexus carcinoma: very rare!

 

child

Pilocytic Astrocytoma (Grade I/IV)

Clin: children

Location: cerebellum

Gross: well-circumscribed -cystic lesion with mural nodule

Micro:

1. biphasic pattern:

- microcysts  + bipolar cells with hair-like projections (often fascicular arrangement) (strongly GFAP +)

2. Rosenthal fibres (brightly eosinophilic, corkscrew shape)

3. Eosinophilic, hyaline globules

4. diffuse neovascularization

 

Ependymoma (Grade II/IV)

Clin: children ® poor prog

Location: floor of 4^th ventricle

Gross solid or papillary floor of the 4th ventricle

-better demarcated than astrocytomas but close to vital pontine and medullary nuclei

-but, intraspinal tumors, this sharp demarcation makes total removal feasible

Micro:

• rosettes and perivascular pseudorosettes uniform, round to oval nuclei with abundant granular chromatin
• dense fibrillary background
• dystrophic calcification
• GFAP +, VIM +, S100+ expression

Variants

Myxopapillary ependymomas (Grade I/IV)

Gross/location:  filum terminale

Micro: papillary elements in a mucinous-myxoid background, admixed with ependymoma-like cells

Prog: good

Ddx: chordoma (no physalliferous cells found in myxo epd.)

Anaplastic ependymomas (Grade III/IV)

• increased cell density, high mitotic rates, areas of necrosis, and less evident ependymal differentiation

 

Medulloblastoma (Grade IV/IV)

Clin: children

Gross: in midline&cerebellum, well-circumscribed and friable

Micro: -undifferentiated, very densely packed, medium blue cells

-neurosecretory granules and H-W rosettes

Prog: poor®drop metastases

Variants:desmoplastic medulloblastoma® nodules surrounded by fibrosis

IHC: NF, synapto

Gen: c-myc, n-myc

 

Subependymomas

Clin/location: incidentally in the fourth ventricle of men at autopsy

Gross: well circumscribed

Micro: huddling of tumour cells in fibrillary background

 

other tumours

Meningiomas

▪ arise from arachnoid cells

▪ solitary

Risk factors: sporadic, NF2, radiation therapy

Gross: extraaxial, encapsulated and well circ., or en-plaque

Grade I variants:

Sam the transsexual fibbed about her microsurgery and liposuction to become a man.

Psammomatous:

Transitional: menigothelial and fibroblastic features. Whorls

Fibroblastic: spindle cells with thick bundles of collagen. Ddx: schwannomas.

Microcystic:

Angiomatous: >50% vessels. Ddx: hemangioblastoma

Lipomatous:

Meningothelial: most common. Syncytial and epithelial cells. Whorls.

Grade II variants:

Atypical (4-20 mitoses, necrosis, atypia, cellular), clear cell, chordoid

Grade III variants:

Anaplastic (20 + mitoses OR anaplastic features), rhabdoid, papillary.

 

Craniopharyngioma

Grade I of IV, sellar region

Adamantinous: children, peripheral cells show nuclear palisading + central cells: loose “stellate reticulum”

Papillary: 50+ years, resembles squamous papilloma

 

Retinoblastoma

-infants

-mutant alleles in retinoblastoma (Rb) gene

Hereditary retinoblastoma→ germline mutation in one allele; “second hit”

Clin:

White reflex in affected eye; also retinal detachment

Invades optic nerve mets to cranial vault, bone

Micro: sheets, trabeculae and nests of small blue cells, rossettes

IHC: NSE, synaptophysin, S100, GFAP, high Ki-67

 

Pituitary Adenomas

Micro:

-diffuse, sinusoidal (trabecular)

-round, uniform nuclei, variable amount of cytoplasm

-microadenoma if < 10mm

Hormones secreted: GH (acromegaly), PRL (galactorrhea-menorrhea), ACTH (Cushing syndrome), FSH, LH, TSH (hypothroidism) {the last 3 share common alpha subunit, beta subunit is different in each and thus confers specificity)

Pituitary carcinoma: usu. ACTH or prolactin-secreting

Pituitary apoplexy

H/A. ocular deficits, altered LOC

caused by hemorrhagic infarct of the pituitary

assoc/ ACTH and null cell adenomas

 

Gangliocytoma

Micro: ganglion cells + glial stroma (astrocytoma, oligodendroglioma)

 

 

NEUROBLASTOMA

-most common tumour < 1 yr

Clin: adrenals, parasymp. chain (most common second location is paravertebral), ↑catecholamine metabolites (eg. VMA, HVA

Gross: –sharply demarcated mass with fibrous pseudocapsule, brain-like soft cut surface

–hemorrhage, necrosis, cyst formation (more prevalent in poorly differentiated)

–calcification with increasing size

Micro: soft, brain-like tissue

-solid sheets of small round blue cells

-H-W rosettes

-neuropil

-gangioneuroma (abundant Schwannian stroma and ganglion cells)

-maturing gangion cells

3 major categories from immature → mature:

–neuroblastoma

–ganglioneuroblastoma

–ganglioneuroma

IHC: S100, variable NSE, chrA, syn

Poor prognosis:

–↑ mitosis, karyorhexis

– MYCN amplification*

– diploid or tetraploid

- 1p loss

– ↓ TRK-A,C expression

 

 
NEUROCUTANEOUS SYNDROMES

Name FOUR types.

1. Neurofibromatosis I and II
2. Tuberous sclerosis
3. von Hippau Lindau syndrome
4. Sturge-Weber

 

Neurofibromatoses

NF1

• gene NF1® chromosome 17
• neurofibromas throughout body ®plexiform or solitary
• cafe au lait spots ® hyperpigmented spots (increased melanin in basal layer)
• Lisch nodules® pigmented nodules on the iris
• many other tumours: neuroblastoma, ganglioneuroma, Wilms, lipoma, GIST, pheochromocytoma

 

NF2

• gene NF2® chromosome 22q12
• bilateral acoutic (actually vestibular)CNVIII schwannomas
• multiple meningiomas
• gliomas ® usu. ependymomas

Tuberous Sclerosis

-AD transmission or sporadic

Genetics:

TSC1: hamartin, TSC2: tuberin

Pathology:

Brain and Retina → hamartomas (glial)

Lungs & Heart → myomas

Kidneys → angiomyolipomas, cysts
Liver & Pancreas → cysts

Skin → angiofibromas

 

Von Hippel-Lindau:

• multifocal and bilateral
• VHL tumour suppressor gene is hypermethylated or mutated
• maps to 3p25

Features of von Hippel Lindau syndrome

“PHEONA the HIPPO SQUISHES THE CYSTS and makes a BLOODY mess”

PHEONA→ pheochromocytomas

HIPPO→ Hippel

CYSTS→ multicystic kidneys

BLOODY→ retinal hemangiomas, cerebellar hemangioblastomas

Sturge-Weber

-skin and brain angiomas

-in trigeminal nerve distribution

EYE

Retinoblastoma