NEUROPATHOLOGY

Developmental Disorders & CNS Trauma

Selective Vulnerability: CELLS / Selective Vulnerability: REGIONS
Neurons – generally the most susceptible to injury / Global ischemia – excitotoxic injury to hippocampal neurons along with selective injury to cerebellar Purkinje cells
Oligodendroglia – selectively injured in:
1)  Multiple sclerosis
2)  Leucodystrophies
3)  Autoimmune attack: acute disseminated encephalomyelitis (ADEM)
4)  Infection: progressive multifocal leucoencephalopathy (PML) – caused by papova / Hunington disease: caudate nucleus and putamen
Astrocytes – generally are the most resistant to injury / Parkinson disease: substantia nigra
Amyotrophic lateral sclerosis – motor neurons

1)  Neuronal reaction to axonal injury (central chromatolysis)

  1. Follows damage to axon
  2. Margination of Nissl substance with central clearing of the cytoplasm
  3. Peripheral displacement of the nucleus

2)  Axonal swellings

  1. Occur at axonal breakages
  2. Follow closed-head trauma, with stretching and snapping of long fibers
  3. Shaken baby syndrome is an example
  4. Neuronal degenerations such as primary cerebellar degenerations
  5. Vitamin E deficiency (rare)

3)  Neuronal inclusions

  1. Viral
  2. Herpes, rabies, CMV, measles (SSPE)
  3. Filaments
  4. Irregular inclusions: neurofibrillary tangle (Alzheimer disease)
  5. Round inclusions: Lewy body, Pick body
  6. Lewy body in Parkinson’s
  7. Pick body in Pick disease
  8. Neuronal “storage” diseases

4)  Neuronal metabolic storage diseases

  1. Glycogenoses (Pompe)
  2. Sphingolipidoses (Tay-Sachs)
  3. Sulfatidoses (Gaucher, Niemann-Pick)
  4. Mucopolysaccharidoses (Hurler)

5)  Trans-synaptic degeneration of neurons

  1. Secondary degeneration of a neuron connected to a dying neuron
  2. Antegrade or retrograde
  3. Primarily in “dedicated” tracts in CNS
  4. Dedicated means 1on1 nerve interactions (classic example would be the optic neurons)
  5. Potentially reversible

6)  Oligodendroglial inclusions

  1. Viral
  2. PML – caused by papova virus
  3. Filaments
  4. Glial cell inclusions (GCIs) in some non-Alzheimer neurodegenerative diseases such as corticobasal degeneration, multiple system atrophy, and others

7)  Astrocytic reactions

  1. Gliosis: hypertrophy and hyperplasia with synthesis of glial filaments
  2. Rosenthal fibers: swellings of processes with heat-shock proteins
  3. “Alzheimer type II Glia” – seen in liver failure
  4. Glial cytoplasmic inclusions
  5. Elaboration of cytokines

8)  Microglial reactions

  1. Constitute in part the innate immune system of the brain (bone marrow derived cells)
  2. CNS equivalents of macrophages
  3. Respond to challenge with
  4. Hypertrophy and hyperplasia
  5. Elaboration of cytokines
  6. phagocytosis
  7. Also involved in synaptic remodeling

9)  Ependymal reactions (cells which line the ventricles)

  1. Ependymal “granulations”
  2. Fusion of ependymal surfaces
  3. Viral inclusions

Patterns of reaction to disease
By NEURONS
1)  Central chromatolysis
2)  Inclusions
3)  Trans-synaptic degeneration / By AXONS
1)  Swellings / By GLIA
1)  Inclusions
2)  Gliosis
3)  Immune responses

Pathophysiology of CNS Herniation

1)  Anything that increases pressure inside the skull (hydrocephalus, brain swelling, mass lesion) will compress the brain and result in herniation

2)  Types of herniation

  1. Subfalcine herniation of cingulate gyrus
  2. Transtentorial herniation of UNCUS
  3. In extreme cases, the midbrain can be pushed against the contralateral tentorium resulting in necrosis
  4. This can create a false localizing sign with pathology on the opposite side of the body
  5. Herniation of cerebellar tonsils through foramen magnum

3)  Transtentorial herniation of the Uncus

  1. Herniation palsy of the 3rd cranial nerve
  2. As the midbrain descends, the 3rd cranial nerve is stretched over the edge of the tentorium
  3. This results in papillary dilation on the side of the mass lesion
  4. Vascular consequences:
  5. As the midbrain and pons descend, the basilar artery does not follow because it is ‘tethered’ above by the Circle of Willis
  6. The fine pontine penetrating arterioles are broken leading to pontine hemorrhage and death

4)  Hydrocephalus

  1. Marked dilation of the ventricular system due to obstruction of CSF flow
  2. Causes of hydrocephalus
  3. Occlusion of CSF flow
  4. Aqueduct of Sylvius (most common area creating hydrocephalus because it is the smallest hole)
  5. Arachnoid granulations – where CSF is reabsorbed at the superior sagittal sinus
  6. Can occur during meningitis
  7. Increased CSF flow (rare)
  8. Compensatory to brain atrophy

Pediatric and Perinatal Neuropathology

Causes of congenital brain malformations:

Genetics:
1)  Chromosomal (6%)
2)  Single gene (2%) / Environmental:
1)  Nutrition – folic acid deficient
2)  Disease – diabetes
3)  Toxins – alcohol, smoking
4)  Infections – rubella, toxoplasmosis, CMV, syphilis
5)  Radiation / Unknown (most cases**)

Embryology and Pathology of time periods

Time Period / Defects
7 days: Implantation
22-28 days: Neural tube formation / 1)  Anencephaly – absence of brain and cranial vault
2)  Spina bifida – bony defect in spine (most common)
a)  Posterior neuropore defect – cystic, skin-covered lesion on back may contain meningeal elements only (meningocele), or meningeal and neural elements (myelomeningocele)
i.  Myelomeningocele – absence of vertebral arches and herniation of meninges and malformed spinal cord into cystical lesion
3)  Encephalocele – brain and ventricle stick out of hole that never closed in skull
4)  Arnold-Chiari Malformation – hydrocephalus, widened foramen magnum, cerebella vermis herniation, ‘notch’ in cervical spinal cord
a)  Can survive and function normally
4-8 weeks: Organogensis / 1)  Holoprosencephaly – one large cerebral sphere instead of 2 hemispheres
2)  Olfactory aplasia – absence of gyri recti
3)  Agenesis of the corpus callosum – also has absence of cingulate gyrus
4)  Dandy-Walker malformation - enlargement of the fourth ventricle, the space containing cerebrospinal fluid between the medulla and the cerebellum, a partial or complete absence of the cerebellar vermis – slow motor development and large heads
8 weeks-birth: Migration of neuroblasts / 1)  Agyria (no gyri) or Lissencephaly (smooth brain)
2)  Pachygria (broad or coarse gyri) -
3)  Heterotopias – the grey matter lining the lateral ventricle is abnormal
4)  Polymicrogyria – note “busy” appearance of cortical gyral pattern
a)  Not compatible with normal intelligence
b)  The neuronal and molecular layers, but not the pia or meninges, wind up and down forming miniature pseudogyri within the true gyri
c)  Can also have Focal Polymicrogyria which is compatible with normal functioning
10 weeks: Susceptible to destructive lesions
Early = 10-25 weeks
Late = after 25th week / EARLY
1)  Porencephaly – basically the same as schizencephaly, except that the destructive event has left a hole (‘pore’)
a)  Note abnormal gyri that ‘radiate’ out from the lesion
2)  Schizencephaly –a destructive event (probably ischemic) has left symmetric clefts (‘schisms’) in the brain
3)  Hydrancephaly –
LATE
1)  Germinal matrix hemorrhage – right next to ventricles
2)  Choroid plexus hemorrhage
3)  Parenchymal hemorrhage
4)  Periventricular ‘leucomalacia’ – dead area in white matter
20 weeks on: Myelination / 1)  Delayed myelination
a)  A response to almost any chronic insult
b)  No long-term sequelae
i.  Myelination in the temporal lobes may be delayed until 2nd decade
Birth Trauma / 1)  Tearing of tentorium
2)  Linear tears of white matter
3)  Tears of the spinal cord and cerebellar peduncles
Down Syndrome / 1)  Chromosomal defect
2)  Small brain
3)  Reduced dendritic complexity
a)  Displayed by Camera Lucida drawings
4)  Premature Alzheimer changes (30s and 40s)

Other Perinatal Neuropathology

Leucodystrophies / Neuronal ‘storage’ diseases
Pathology / Myelin loss / Distended neurons
Clinical signs / Long tract signs:
1)  Ataxia
2)  Pyramidal signs
3)  Sparing of subcortical U-fibers* / Grey matter signs:
1)  Developmental delay
2)  Mental retardation
3)  Dementia
4)  Seizures
Types of diseases / 1)  Metachromatic leucodystrophy
a)  Myelin breakdown products stain red-brown with cresyl violet stain
2)  Krabbe’s (Globoid cell) leucodystrophy
a)  Perivascular macrophages are distended with myelin breakdown products
3)  Adrenoleucodystrophy
a)  Later onset** (others occur early)
b)  Peroxisome defect**

CNS Trauma & Demyelinating Diseases

Learning Objectives:

1)  Define the terms concussion and contusion

  1. Concussion – transient functional impairment
  2. No demonstratable anatomic abnormality
  3. Amnesia for the moment of injury
  4. Contusion – focal necrosis of gyral crests
  5. Sparing of sulci
  6. Old lesions are depressed and yellow (hemosiderin)

2)  Define “contre-coup contusion” and explain its pathogenesis

a.  Contre-coup contusions

  1. Coup Lesions – at the site of trauma
  2. Contre-coup – opposite the site of trauma
  3. These usually result from falls from a standing position (direction of force pushes opposite side of brain against skull)

3)  Internal vs. External injury

  1. Diffuse axonal injury – results from angular acceleration within skull: shaking or oblique impacts
  2. Involves long axon tracts of deep white matter, corpus callosum, cerebral peduncles, & brain stem
  3. Microscopically there are axonal swellings
  4. Present in 50% of patients who develop coma after trauma
  5. May explain persistent vegetative state in absence of gross lesions*
  6. In milder form may explain concussion
  7. Skull fractures –
  8. Damage to vessels à bleeding
  9. Damage to dura à infection
  10. Damage to brain

c.  Post-traumatic syndromes

  1. Post-traumatic hydrocephalus
  2. Post-traumatic dementia: “punch-drunk” syndrome (dementia pugilistica)
  3. Post-traumatic epilepsy, meningioma, infection
  4. Post-traumatic psychiatric disorders

4)  Define the pathogenic, anatomic, and clinical differences between epidural and subdural hematomas

Epidural Hematoma / Subdural Hematoma
Pathogenesis / Always associated with skull fracture / Trauma may be mild, without skull fracture
Anatomical damage / Results from tearing of middle meningeal artery / Tearing of meningeal bridging veins
Clinical Difference / There may be a “lucid interval” of several hours / May become chronic
1)  Evolution:
a)  Lysis of clot (1 week)
b)  Early organization (2 weeks)
c)  Hylanized connective tissue (1-3months)
2)  Often re-bleed, resulting in different stages of organization
Most common site*

5)  Describe the gross and microscopical pathology of multiple sclerosis and of other demyelinating conditions

a.  Multiple sclerosis

  1. A disease of young adults (20-40)
  2. Irregular, but progressive course
  3. No constant clinical picture – relapsing
  4. Chronic Autoimmune destruction of myelin
  5. Lesions separated in “time and space”
  6. Axonal preservation in MS
  7. Has acute and chronic pathological features

b.  Acute disseminated encephalomyelitis

  1. An acute, monophasic autoimmune disease with destruction of myelin
  2. No repeated or chronic attacks, people get better or die
  3. May follow viral infections or vaccines
  4. Fatal in 15-20% of cases
  5. Small hemorrhages begin to appear

c.  Central Pontine myelinolysis

  1. Formerly common in alcoholics
  2. Results from overly rapid correction of hyponatremia - IATROGENIC

6)  Describe and explain the evolution of MS lesions

  1. Axonal preservation occurs – if it was an infarct there would be loss of myelin and axons
  2. Many of the oligodendrocytes disappear after the immune attack, but some hold on but don’t generate myelin
  3. Remyelination does occur, but the axons have very thin myelin sheaths
  4. Never myelinates as good the 2nd time aroun
  5. The deficient during the initial attacks is worse than afterwards because of the inflammation
  6. Acutely, the attack is full of inflammatory cells, edema, cytokines causing the inflammation
  7. There is still deficit afterwards b/c of loss of myelin, but there isn’t inflammation anymore
  8. Macrophages come in and strip the myelin off
  9. Lesions do not appear to attack specific anatomic boundaries, it just spreads out and attacks myelin
  10. Chronic lesions have sclerotic astrocytes with limited macrophages
  11. Bv is sclerotic and irregular
  12. Axons begin to disappear in chronic MS

7)  Compare and contrast MS and acute disseminated encephalomyelitis

8)  Explain the etiology of central pontine myelinolysis, and discuss prevention of this disease

  1. This is due to a metabolic problem with serum sodium concentration
  2. With the rapid correction of sodium in alcoholics comes the disease
  3. Metabolites need to be added slowly over a period of time to prevent the disease

Cerebrovascular Diseases

Learning Objectives:

1)  Define stroke, ischemia, hypoxia, and anoxia

  1. Stroke (apoplexy) –
  2. A transient ischemic attack (TIA) is a temporary (<24hrs) deficit due to temporarily decreased perfusion
  3. Caused by
  4. Brain infarction 80%
  5. Intracerebral hemorrhage 10%
  6. Subarachnoid hemorrhage 7%
  7. Misc 3%
  8. Stroke is the 3rd leading cause of death in the elderly and the most prevalent neurological disorder
  9. Ischemia – decrease or lack of blood
  10. Hypoxia – decrease or lack of oxygen
  11. Anoxia – no oxygen

2)  List the different causes of stroke and discuss their relative prevalence, their gross and histological features, and their pathophysiology

Causes of Stroke / Prevalence / Gross features / Pathophysiology
Brain Infarction
1)  Thrombic
2)  Embolic / 80% / Acute (week 1)– softening, blurred grey-white margin, swelling with midline shifts
Subacute (weeks2&3) – tissue disintegrates, sharp demarcation of infracted area
Chronic (weeks 4+) – cavitation, Gliosis (firm tissue)
Thrombosis @ carotid bifurcation is the most common
Embolism – most often from the heart / Thrombotic – caused by atherosclerosis
Embolic – caused by mural thrombi, valvular vegetations, fat emboli
Patterns of injury:
1)  Focal infarction
a.  Outcome is focal deficit (classic stroke)
2)  Focal patterns resulting from intermediate degrees of global ischemia
a.  Hippocampal and cerebellar injury
b.  Laminar necrosis
c.  Watershed infarction
3)  Global (entire brain) infarction
a.  Ischemic/hypoxic encephalopathy (TIA or brain death)
Intracerebral hemorrhage
-  Due to hypertension / 10% / Bleeding into the basal ganglia, pons, and cerebellum / 1)  From hypertension
a.  Basal ganglia (common for hypertensive hemorrhages)
b.  Pontine and cerebellar
2)  From berry aneurysms
a.  Massive subarachnoid hemorrhage
3)  From vascular malformations
a.  Arteriovenous malformation
b.  Cavernous angioma
c.  Venous malformation
Subarachnoid hemorrhage
-  Due to ruptured berry aneurysm / 7% / Massive, clinically significant subarachnoid hemorrhage is almost always due to rupture of a berry aneurysm ** / Focal subarachnoid hemorrhage is common overlying contusions, infarcts, infectious foci
Berry (secular) aneurysm – involves Circle of Willis, found in 2% of adults, etiology unknown
1)  Aneurysm wall consists of vascular intima and adventitia, with absent smooth muscle and elastic
2)  Warning symptoms due to leakage or nerve compression (worst headache ever, vomiting, loss of consciousness)
3)  Sudden death (25-50%)
4)  Acute vasospasm leading to infarctions (and focal deficits)
5)  Rebleeding occurs in survivors
Miscellaneous / 3%

3)  Describe the different types of vascular malformation in the CNS. Differentiate them according to types of component vessels and clinical signs and symptoms

Arteriovenous malformation / Cavernous Angioma / Venous Angioma / Capillary telangiectasis
Component vessels / Arteries and veins / Veins / Veins / Capillaries
Clinical signs / Arterial pressure blood shunted into venous system à veins dilate and sclerose in response / Abnormal, dilated and hyalinized veins arranged compactly with no intervening brain tissue / Abnormal, dilated veins dispersed in brain tissue / Dilated, but otherwise normal capillaries dispersed in normal brain tissue
Symptoms / Abnormal veins prone to leakage, causing seizures and massive hemorrhages / Can cause hemorrhage / DO NOT cause hemorrhage / Virtually never causes symptoms
Notes / Lesions are congenital, but: can be silent for many years, symptoms typically occur in young adults / NO intervening neural parenchyma / Throughout intervening brain tissue, do not generally bleed / Usually an incidental finding on autopsy

4)  Describe the pathophysiological, histological, and clinical consequences of hypertension on the brain