Central Nervous System Neurons

Department of Pathology Axonal Reaction

Acute cell injury (Red Neuron)
Atrophy & Neuronal
Degeneration
Intraneuronal Deposits

Glial Cell: Astrocyte

Gray & white matter
Star-shaped, imparted by its
multiple, branching cytoplasmic
processes
(+) GFAP

Astrocytes: Response to Injury

Gliosis
Rosenthal Fibers
Corpora amylacea
Cells Alzheimer Type II Astrocytes
Neurons
Glial Oligodendrocytes
Astrocytes Main cellular component of the
Oligodendrocytes white matter
Ependymal Cells Production & maintenance of
Microglial CNS myelin
Endothelial Cells
Microglia
Neuron Mesoderm-derived cells (bone
marrow)
Irregular/spindly nuclei
CD4+

Microglia: Response to Injury

Proliferation
Developing elongated nuclei (Red
Nuclei)
Forming Aggregates (microglial
nodules)
Neuronophagia

Ependyma
Lines the ventricular system and the
central canal of the spinal cord
Single layer of cuboidal to columnar
cells (variably ciliated)

Common Pathophysiologic
Complications of Brain Pathology

Herniations
Cerebral edema
Hydrocephalus
Cellular Reactions to Injury

Herniation
Subfalcine
Expansion of a cerebral
hemisphere leading to
displacement of the cingulate
gyrus
Compression of the anterior
cerebral artery
Transtentorial (Uncal or Uncinate)
Space-occupying lesion in the
temporal lobe or more lateral
portion of the cerebral
hemisphere.
Clinical Consequences of Transtentorial
Herniation
Alteration in consciousness to the
point of coma, secondary to
compression of the midbrain by the
impinging uncus
Stretching or compression of the
oculomotor nerve (ipsilateral,
contralateral or both)
Compression of contralateral cerebral
peduncle against the free edge of the
tentorium
Aqueductal compression and
hydrocephalus further raising ICP
Intermittent compression of the post
cerebral artery
Duret Hemorrhages
Herniation
Tonsillar Herniation (Coning)
One or both cerebellar tonsils
are displaced into the foramen
magnum, with compression of
the medulla and its vital
respiratory center
Transcarvarial
Extracranial (Calvarial) Herniation
Shift of the brain through an
extracranial defect
These are generally post
traumatic or post surgical. The
brain can become ischemic and
infarct. Post trauma patients or
patients with significant
intracranial mass effect may
undergo craniectomy to remove
the ipsilateral, overlying bone .
This will allow the brain to
decompress through the defect.
This gross specimen correlates
with the CT of the brain shifting
through the cranial defect
Cerebral Edema
Vasogenic
Increased vascular permeability
Cytotoxic
Altered cell regulation of fluid
Interstitial
Transudation of fluid from the
ventricular system across the
ependymal lining
Morphology: Cerebral Edema
Vasogenic Edema
Soft & Swollen brain
Gyri are flattened, sulci are
widened, ventricles are
compressed
Widened extracellular space
between the normally closely
apposed myelinated
fibers,distention of endothelial
cells and pericapillary astrocytic
foot processes and breakdown
of myelin
Cytotoxic Edema
Most evident in the gray matter
Cells are swollen and
vacoulated.
Interstitial Edema
Abnormal flow of fluid around
the lateral ventricles when there
is an abnormal flow of fluid from
the interventricular space.
Hydrocephalus
 Enlargement of ventricles with an
associated increase in volume of CSF
500 ml/day
140-150 ml (renewed q 6-8 hours)
Secreted by the choroid plexus
Types:
Non-communicating-blockage
anywhere along the ventricular
system
Communicating obstruction is
along the subarachnoid path of
CSF flow, including the sites of
its absorption
Causes of Hydrocephalus
Infants and Children
Congenital malformation
Intrauterine or perinatal
infection
Vascular diseases
Neoplasm
Adults
Sudden or gradual obstruction
of flow
Elderly
Normal pressure hydrocephalus
Mental slowness, incontinence,
gait disturbance
Hydrocephalus ex vacou
Cerebral atrophy, extensive tissue
loss, compensatory expansion of the
ventricular system
Morphology of Hydrocephalus
Interruption of the ependymal lining
with ependymal granulations,
interstitial periventricular edema with
thinning out of the myelin fibers
Malformations & Developmental
Diseases
Neural Tube Defects
Forebrain Abnormalities
Posterior Fossa Abnormalities
Syringomyelia & Hydromyelia
Neural tube defects
Anencephaly
Encephalocoele
Spinal Dysraphism or Spina
Bifida
Myelomeningocoele
(Meningomyelocoele)
Meningocoele
Forebrain Abnormalities
Polymicrogyria
Megalencephaly/ Microcephaly
Lissencephaly (Agyria)
Neuronal Heterotopias
Holoprosencephaly
Agenesis of the Corpus callusom
Posterior Fossa Abnormalities
Arnold-Chiari Malformation
(Chiari Type II)
Dandy-Walker Malformation
Syringomyelia & Hydromyelia
Neural Tube Defects
Etiology: unknown
Screening:
Maternal Blood Samples for
alpha feto protein
Recurrence rate: 4-5%
Risk factor: Folate Deficiency
Anencephaly
Malformation of the anterior end of the
neural tube, with the absence of brain
& calvarium
1-5/ 1000 live births
More common in females
Develop at 28 days of gestation
Area cerebrovasculosa -consists of
scattered primitive neuroglial tissue
elements within an irregular vascular
proliferation.
Encephalocoele
Defect in the cranium
Diverticulum of malformed CNS tissue
Occurs in the occipital region or in the
posterior fossa
Spinal Dysraphism or Spina bifida
Two Forms:
Asymptomatic bony defect
(spina bifida occulta)
A severe malformation with a
flattened disorganized segment
of the spinal cord associated
with an overlying meningeal out
pounching
Meningocoele/Myelomenigocoele
Myelomeningocoele
(Meningomyelocoele)
Extension of CNS tissue through
a defect in the vertebral column
Meningocoele
Meningeal extrusion Neuronal Heterotopias
Stranded clusters of neurons
Strewn along the path of migration

Holoprosencephaly
Incomplete separation of cerebral
hemispheres across the midline
Forebrain abnormalities Midline facial abnormalities including
cyclopias
Polymicrogyria Arrhincephaly
Loss of the normal external contour of Trisomy 13 and Trisomy 18
the convolutions
Small, unusually numerous , irregularly
formed convolutions
Gray matter few layers, with
entraptment of apparent meningeal Holoprosencephaly
tissue at points of fusion
Localized tissue injury during the time
of neuronal migration.

Megalencephaly/Microcephaly
Microcephaly
Abnormally small brain
Chromosomal abnormalities,
fetal alcohol syndrome, HIV
infection in utero
Reduced neurons
Macrocephaly Agenesis of the Corpus Callosum
Lissencephaly (Agyria) Absence of white matter bundles that
Decreased to total absence of carry cortical projections from one
gyri hemisphere to the other.
Smooth brain X-ray: Mishapped lateral ventricles
(bat-wing deformity)
Lissencephaly (Agyria) Lipoma may occupy the defect

Posterior Fossa Abnormalities

Posterior Fossa Abnormalitites: Arnold-

Chiari Malformation
Chiari Type II malformation
 Small posterior fossa, malformed
midline cerebellum with extension of
the vermis through the foramen
magnum
Hydrocephalus & Lumbar
myelomeningocoele
Dandy-Walker Malformation
Enlarged porterior fossa
Absent cerebellar vermis or
rudimentary form
Large midline cyst
Syringomyelia/Hydromyelia
Hydromyelia
Segmental or continous
expansion of the ependymal-
lined central canal of the cord
Syringomyelia
Formation of cleft-like cavity in
the inner portion of the cord
Syringobulbia
Slit-like cavity extend into the
brainstem
Signs & Symptoms: Syrinx
Syrinx cavities associated with
intraspinal tumors, degenerative
diseases.
Sensory loss of pain and temperature
in the upper extremeties, retention of
the position sense, and absence of
motor deficits, due to early
involvement of the crossing anterior
spinal commisural fibers
Perinatal Injury
Perinatal Brain Injury
Cerebral Palsy non progressive
neurologic motor deficit with onset
during the perinatal period, regardless
of etiology
Intraparenchymal Hemorrhage within
the germinal matrix, near the junction
of thalamus and caudate nucleus
Periventricular leukomalacia (PVL)
chalky white plaques consists of
discrete regions of white matter
necrosis and mineralization
Perinatal Ischemic Lesion
Gliotic gyri (ulegyria)
Status marmoratus
Intraventricular Hemorrhage (IVH)
Periventricular leukomalacia
Shock lesions
Trauma
Skull Fractures
Diastatic
Displaced skull fractures
Concussion
Clinical syndrome brought about by
closed head injury
Reversible and unassociated with
permanent structural damage
Transient neurologic dysfunction, loss
of consciousness, respiratory arrest &
loss of reflexes
Neurologic recovery: complete
Amnesia: persist
Direct Parenchymal Injury
Contusion
Transmission of kinetic energy
to the brain
Laceration
Penetration of an object and
tearing of tissue
Coup injury injury at the
point of impact
Contrecoup injury
damage to the brain
opposite the point of
impact White Matter Injury
Axonal retraction balls
Contussion Demostrated by silver staining
Contrecoup lesion in the frontal and Angular acceleration without impact
temporal poles are (arrows) are Axonal swelling
located opposite to a small coup lesion Decreased number of microglia
over the cerebellum Degeneration of fiber tracts

Laceration Epidural Hematoma

Tissue loss Middle meningeal injury
Temporal area
Histologic Morphology: Contusion Lucid for several hours before
24 hours- evidence of neuronal injury neurologic deficits
24-48 hours axonal swelling, Expand rapidly: Neurological
infiltrates emergency
Plaque jaune
Depress, retracted,yellowish- Subdural Hematoma
brown patches involving the Bridging veins
crests of gyri most commonly Manifest within the 1st 48 hours of
located at the sites of contre- injury
coup lesions Nonlocalizing sign, slowly progressive
neurologic deterioration
Course of Organization:
Lysis of clot
Fibroblast
Plaque jaune
Granulation tissue
Complication: Rebleeding

Other Traumatic Injury to the Brain

Traumatic subarachnoid hemorrhage
with intraparenchymal damage
Spinal cord Injury
Cerebrovascular Diseases

Hypoxia, Ischemia & Infarction

Intracranial Hemorrhage
Hypertensive Cerebrovascular Disease

Cerebrovascular Diseases
Third leading cause of death (after
heart disease and cancer).
Three categories:
 Thrombosis Interruption of the normal
Embolism circulatory flow
Hemorrhage
Two processes: Acute Ischemic Injury
Hypoxia, ischemia and Ischemic (Hypoxic) Encephalopathy
infarction Generalized reduction of
Hemorrhage cerebral perfusion with
widespread damage
Cerebral Infarction
Focal ischemic necrosis that
follows reduction or cessation of
blood flow to the localized area
of the brain

Ischemic (Hypoxic) Encephalopathy

Mild: transient postischemic
confusional state with eventual
recovery
Global: widespread brain necrosis
Focal: localized area
Brain Death
Diffuse cortical Injury flat EEG
Brain Stem Damage
Absent reflexes
Respiratory drive
Respirator Brain
Soft, puree- like tissue that does
not fix and take stain well
Morphology of Hypoxic Brain
Swollen (Widened gyri,
narrowed sulci)
Poor demarcation of gray &
white matter
12-24 hours
Hypoxia, Ischemia & Infarction Acute neuronal cell
15% of the resting cardiac output change (red
20% of the total body oxygen neuron)-
consumption microvascularizatio
Normal cerebral function: 8-10 n, eosinophilia,
seconds after cerebral ischemia nuclear pyknosis &
Irreversible brain damage: 6-8 minutes karyorrhexis
30-60 minutes after reduction of blood 24 hours to 2 weeks
sugar to zero Necrosis of tissue,
influx of
macrophages,
Mechanism of O2 deprivation vascular
proliferation,
Functional Hypoxia reactive gliosis
>2 weeks
Low inspired partial pressure of
O2 Repair
Impaired O2 carrying capacity
Sensitivity of Cells to injury
Inhibition of O2 use by tissue
Neurons most sensitive
Ischemia (Transient or Permanent)
Astrocytes
 Olgodendrocytes
Respirator Brain
Ischemic (Hypoxic) Encephalopathy
Watershed or Border Zone Infarcts
Wedge-shape areas of
coagulation necrosis that occur
in those region of the brain and
spinal cord that lie distal to the
arterial irrigation.
Cerebral Infarction
Stroke
Clinical term that refers to the
sudden development of a
neurologic deficit caused by
abnormality of the blood supply
Thrombosis or Embolism
Thrombosis
extracerebral carotid
system
Atherosclerosis
Arteritis Tb &
Syphilis
Embolus intracranial
vessels
Shower embolization (fat embolism)
generalized cerebral dysfunction
Spinal cord infarction - Hypoperfusion
Hemorrhagic (Red) Infarct
Multiple, confluent, petechial
hemorrhages typically
associated with embolic events
Reperfusion
Anticoagulation is
contraindicated
White (Pale, Bland) Infarct
Associated with thrombosis
6 hours of irreversible injury
48 hours
Pale, soft, and swollen, and the
corticomedullary junction
becomes distinct
2-10 days
Gelatinous and friable
10 days 3 weeks
Tissue liquefies and eventually
removed leaving a fluid-filled
cavity
12 hours
Ischemic neuronal damage and
edema
Loss of the usual tinctorial
characteristics of white & gray
matter structures
Swelling of endothelial & glial
cells, mainly astrocytes
Disintegration of myelinated
fibers
48 hours
Phagocytic cells, adventitial
histiocytes and activated
microglial
Months
Nuclear and cytoplasmic
enlargement subsides
Non Traumatic Intracranial Hemorrhage
Intraparenchymal Hemorrhage
80% arterial hypertension
Intracerebral arteriovenous
malformations
Tumor
Hemorrhagic diathesis
Amyloid angiopathy
Hypertensive Intracerebral Hemorrhage
Putamen 50-60%
Thalamus
Pontine tegmentum
Cerebellar hemispheres
Ganglionic hemorrhages
Complication: Charcot Bourchard
Aneurysm
Extravasation of blood with
compression of the adjacent
parenchyma
Subarachnoid Hemorrhage (SAH)
Rupture of berry aneurysm
Extension from a traumatic hematoma
Rupture hypertensive intracerebral
hemorrhage into the ventricular
system
Vascular malformation
Hematologic disorder
 Tumor collagenized walls, devoid of nervous
tissue
Berry Aneurysm Cerebellum, pons and subcortical
Saccular or congenital aneurysm regions
Other uncommon aneurysms:
Atherosclerotic (fusiform) Hypertensive Cerebrovascular Disease
Mycotic or traumatic aneurysm Acute Hypertensive Encephalopathy
Dissecting aneurysm Clinicopathologic syndrome
Pathogenesis: Unknown arising in the hypertensive
Age & Hypertension patient characterized by
Collagen disorders evidence of diffuse cerebral
74% of patient: Rupture dysfunction
5th decade Headaches, confusion, vomiting,
convulsions, coma
Females
Cause of Death: Cerebral
20-30% multiple
edema with Herniation
Headache
Healing Phase: meningeal fibrosis and Binswanger Disease
scarring, causing obstruction of CSF Pattern of injury is in the subcortical
flow white matter with axonal & myelin loss
Thin walled outpouchings of the artery
Few mm to 2-3 cm Lacunar Infarcts
Bright red,shiny surface and a thin Lake like spaces 15 mm wide
translucent wall Non cortical area of the brain
Rupture occurs in the apex of the sac
Slit Hemorrhages
Due to rupture of small caliber blood
vessels
Hemorrhage ---------slit like spaces
Focal tissue destruction, pigment
laden macrophages and gliosis

Infections

Route of Entry
Vascular Malformations
Arteriovenous malformations (AVMs)
Most important
Abnormally tortous, Meningitis
misshapen vessels
Males affected 2x than
females
10-30 y.o
Seizure, intracerebral
and/or subarachnoid
bleed
Cavernous angiomas
Capillary telangiectasia
Cavernous Hemangioma
Greatly distended, loosely organized
vascular channels with thin
Hematogenous
Direct Implantation
Local Extension
PNS rabies & herpes simplex
Etiology
Infants: E.coli & Group B strep
Infants & Children: H. influenzae
Adolescents & young adults:
Neisseria meningitidis
Elderly: Streptococcus
pneumoniae & Listeria
monocytogenes
SSx of menigeal irritation:
headache, photophobia,
irritability, clouding of
consciousness, neck stiffness

Bacterial Meningitis
N. meningitidis
Viral Meningitis
Nonbacterial or aseptic
Lymphocytic pleocytosis, moderate
protein elevation, normal protein
Enterovirus (echovirus, coxsackie,
polio)
Brain swelling
Lymphocytic Infiltrates in the
leptomeninges
Brain Abscess
Direct implantation of the organism,
local extension from adjacent foci
(mastoiditis) or hematogenous
Predisposing factors:
Acute bacterial endocarditis
Cyanotic heart disease
Chronic pulmonary sepsis
Tuberculosis
Gelatinous or fibrinous exudates often
at the base of the brain
Granuloma formation
Meningoencephalitis
Signs & Symptoms:
Headache
Malaise
Mental confusion
Vomiting
Complications:
Arachnoid fibrosis
hydrocephalus
Obliterative endarteritis
Arterial occusion - infarction
CSF
Pleocytosis
Elevated protein
Sugar : Normal or reduced
Neurosyphilis
Tertiary stage of syphilis
Impaired cell mediated
immunity
Patterns of CNS involvement:
Meningovascular syphilis
Heubner arteritis
Paretic neurosyphilis
Widespread individual
cell death and
consequently brain
atrophy
Progrssive loss of mental
functions, mood
alteration (delusion of
grandeur) and
terminating in severe
dementia
Argyll Robertson pupil
Loss of cortical neurons
with proliferation of
microglia and gliosis
General paresis of the
insane
Tabes Dorsalis
Damage to the sensory
nerve in the dorsal roots
Impaired position sense
and ataxia (locomotor
ataxia)
Loss of pain sensation
(Charcot joints)
Viral Meningoencephalitis
Spongiform Encephalopathies: Post polio syndrome: 25-35 years after
Creutzfeldt-Jacob Dse & Kuru resolution of the initial illness

Spongiform change in the gray matter Rabies

Prion Cebrebral edema
Abnormal form of a normal IP: 1-3 months
cellular protein and is relatively Hippocampal neurons and the
resistant to digestion by cerebellar Purkinje cells are the places
proteinase K Negri bodies are most likely to appear.
Severe neuronal loss
Reactive astrocytosis Fungal Infections
Kuru plaques 3 basic patterns
Chronic meningitis
Herpes Simplex Virus Vasculitis
Parenchymal invasion

Aspergillus

CMV
Fetus and immunosuppresed
individuals Toxoplasmosis
Periventricular necrosis
Severe brain destruction -
microcephaly and
periventricular calcification

Cytomegalovirus

Cysticercosis

Poliomyelitis
Picornavirus group
ofenterobacteriaciae Demyelinating Disease
Anterior motor neuron of the spinal Multiple Sclerosis
cord Dysmyelinating Diseas (Leukodystrophies)
Meningeal irritation Myelinolytic Diseases (Spongy
CSF: Aseptic meningitis Myelinopathies)
Demyelinating Diseases Globoid cell leukodystrophy (Krabbes
Acquired conditions characterized by Disease)
preferential damage to myelin with Beta-galactocerebrosidase
preservation of the axons Onset:
Causes: 6 months old
Auto-immune SSx:
Infection rigidity, decreased alertness,
fatal (2 y.o.)
Multiple Sclerosis Brain:
20-40 y.o. Demyelination & globoid bodies
Female (multinucleated histiocytes
Chronic remitting or chronic around the blood vessels)
progressive
Oligoclonal bands in CSF containing Krabbe Disease
excessive protein (IgG and Myelin
Basic Protein)
Etiology: autoimmune
(?) viral

Relapsing episodes of paresthesia,

visual disturbance (optic nerve) and
incoordination.
Metachromatic Leukodystrophy
Dysmyelinating Disease
(Leukodystrophies)

Adrenoleukodystrophy (ALD)
X- linked
Young boys
Adrenal (glucocorticoid) failure:
Accumulation of long chain fatty acids
Pronounced lymphocytic infiltrates
Large plaques of demyelination and
dies within 3 years
Adult forms: Slowly developing spastic
paralysis, cerebellar ataxia, peripheral
neuropathy.
Leukodystrophies
Krabbe Disease
Metachromatic Leukodystrophy (MLD)
Classic Metachromatic
Late infantile presentation lack of encepathalomyopathies
Adrenoleukodystrophy
arylsulfatase A
Systemic especially gallbladder, Pelizaeus-Merzbacher Disease
kidney & neuronal lipidosis Canavan Disease
 Granulovacoular degeneration
Mitochondrial Encephalomyopathies Hirano bodies
Leigh Syndrome
Myoclonic epilepsy and ragged red Picks Disease
fibers Peak incidence at 60 y.o.
Mitochondrial encephalomyopathy, Male = female
lactic acidosis and stroke-like episodes AD
Kearns-Sayre Syndrome Profound dementia
Sharply demarcated focal (lobar)
Leigh Syndrome subacute necrotizing atrophy
encephalopathy Pick bodies: subtle, swollen,
filamentous, eosinophilic bodies in the
cytoplasm of the neurons

Degenerative Disease of Basal Ganglia

& Brain Stem
Parkinsonism
Clinical syndrome characterized
by: diminished facial expression,
stooped posture, slowness of
voluntary movement,
festinating gait, rigidity & pill
rolling tumor
Damage to the nigrostriatal
dopaminergic system
Degenerative Disease
Parkinsons Disease
Alzheimers Disease
Picks Disease

Degenerative diseases
Diseases of the gray matter
characterized by progressive loss of
neurons with associated changes of
the white matter tracts Huntingtons Disease
Hallmark in diagnosis: presence of AD
protein aggregates that are resistant 35-40 y.o.
to degeneration
Chorea, psychiatric changes
Dementia
(promiscousness, violence, sociopathic
behaviour, depression) later confusion,
Alzheimers Disease
memory deficit and dementia.
Most common cause of dementia in
Marked atrophy of the caudate nuclei
elderly
& putamen
Marked atrophy (frontal lobes)
Cell loss, senile plaques, neurofibrillary Spinocerebellar Degeneration
tangles, granulovacoular
degeneration, amyloid angiopathy Degenerative Diseases affecting the
Hirano bodies eosinophilic football Motor Neurons
shaped structures Amyotrophic Lateral Sclerosis
Cerebral amyloid angiopathy Bulbospinal Atropy
 Dehydration
Amyotrophic Lateral Sclerosis Hepatic encephalopathy
Bunina Bodies Alzheimer Type II astrocytosis
PAS positive cytoplasmic
inclusions that appear to be a Toxic Disorders
remnant of autophagic vacoules Carbon monoxide
Methanol
Genetic Metabolic Diseases Degeneration of the retinal
Neuronal Storage Disease ganglion cells
Leukodystrophies Formate
Mitochondrial encephalopathies Ethanol
Cerebellar atropy and loss of
Toxic & Acquired Metabolic Diseases granule cells predominantly of
Vitamin Deficiencies the anterior vermis
Thiamine (Vitamin B1) Bergmann gliosis
Beri-beri Radiation
Wernicke encephalopathy Combine Methotrexate and Radiation-
benign, abrupt Induced Injury
Hemorrhage &
necrosis in the
mamillary bodies
Psychotic
symptoms
Ophthalmoplegia
Korsakoff syndrome
memory disturbance and
confabulation
Vitamin B12
Slight ataxia, spastic
weakness of the lower
extremeties
Swelling of the myelin
layers
Degeneration of the
axons of both ascending
tracts of the posterior
columns and descending
pyramidal tracts

Wernicke encephalopathy
Periventricular hemorrhages
and discoloration of mamillary
bodies.
Fibrillary gliosis

Neurologic Sequelae of Metabolic

Disturbance
Hypoglycemia
Hippocampus & Purkinje fibers
of the cerebellum
Hyperglycemia
Ketoacidosis & hyperosmolar
coma