CNS normal histology

CNS
NORMAL HISTOLOGY
DR. THOMAS K ABRAHAM
DR. THOMAS K. ABRAHAM

Outline
Embryology
Various tissue organizations
Features in ageing
Special stains
References

BASIC EMBRYOLOGY

Central Nervous System
The central nervous system appears at
the beginning of the third week as a
slipper-shaped plate of thickened
ectoderm.
The neural plate, in the mid dorsal
region in front of the primitive node.
Its lateral edges soon elevate to form the
neural folds.

Sites of flexion
S C
H B
During the 3rd and 4th week of embryonic life
M B
cervical flexure
cephalic flexure

prosencephalon

Cerebrum
Neocortex
Paleocortex
(Limbic/Olfactory)
Archicortex
(Hippocampal)

Cerebral Cortex

Cerebral Cortex
The vast majority (>90%) of cerebral cortex in humans is
neocortex
All neocortical areas—also called isocortex—go through
developmental periods in which their elements are laid
down in six layers.
Cerebral cortex contains two dominant neuronal types:
the granular(stellate) cell and the pyramidal cell.

Pyramidal cells
Account for two thirds of cerebral cortical neurons and are the primary output.
They have prominent apical dendrites that extend toward the cortical surface.
Their axons extend long distances to terminate within the ipsilateral or
contralateral cortex or travel to subcortical regions.
Granular cells
 Are smaller and are considered to be the primary interneurons of the
neocortex.
 Other less common neurons are the horizontal cells (of Cajal), common in the
superficial cortex in development;
 Fusiform cells, most frequent in the deepest cortical layers

1. The molecular layer
2. Outer granular cell layer
3. Outer pyramidal cell
4. Inner granular cell layer
5. Inner pyramidal cell layer
6. Multiforme layer

The practice of neuropathology requires basic
familiarity with neocortical structure.
The six layers of the cortex, from the surface to the
white matter, are more histologically apparent in some
regions than others.
Best appreciated in considerably thicker sections than
are normally cut for routine surgical neuropathology.

White Matter
The white matter of the CNS is relatively uniform.
It is generally more deeply eosinophilic than the overlying
cortex, and its matrix is coarser.
Individual axons themselves are difficult to appreciate on
H&E sections of normal brain.
Oligodendrocytes, fibrillary astrocytes, and microglia are
all oriented along the length of axons with a fairly rigid
periodicity.

• Sweeping linear arrays of
axons are the backbone of
the white matter but
cannot be readily
identified on hematoxylin
and eosin stains.
• Oligodendrocytes,
astrocytes, and microglia
are dispersed linearly
along the length of axons
with a fairly rigid
periodicity.

Neurofilament
immunohistochemistry or
Silver stains can highlight
axons

Neuropathological work-up
Tissue should always be fixed in formalin(10%).
On bloc resections should be carefully orientated and cut
perpendicular to the cortical surface (3 – 5 mm section thickness)
Include areas with macroscopically visible changes- blurred grey-
white matter border or increased cortical thickness.
Remaining unfixed tissue slices should be snap frozen in liquid
nitrogen and long-term stored at –80 °C to allow molecular-biological
or genetic analysis.
Paraffin sections of 4 – 7 μm are most appropriate for histochemical
and immunohistochemical stains.
Clinical Neuropathology, Vol. 30 – No. 4/2011 (164-177): Neuropathological work-up of focal cortical dysplasias using the new
ILAE consensus classification system

A,B: : Normal
appearing neocortex
C,D: Perpendicular Cut
Distinct microcolumnar
arrangements
E,F: Tangential Cut
Tangential altered
neocortical
architecture
FOCAL CORTICAL DYPLASIA
(Nissl-LFB NeuN).

CELL TYPES
Neurons Glia
The brain parenchyma consists of predominantly 2 cell types

NEURONES
PARTS
Cell Body
Dendrite
Axon

TYPES OF NEURONS
Pyramidal
Cortical
granular(stellate)
Betz cells
Purkinje
Anterior horn
cells

PYRAMIDAL NEURONES
Large, triangular cell
bodies
Prominent apical
dendrite
Numerous finer
branching basal
dendrites.
Abundant cytoplasm
Large nucleus with open
chromatin
Prominent nucleolus

CORTICAL GRANULAR NEURONS
Neurons are the smaller counterparts of Pyramidal
neurons in the cortex
Being interneurons, they have numerous shorter processes
that remain within the confines of the cortex.

BETZ CELLS Largest neurons of cerebral
cortex
Found in the primary motor
cortex where they dwarf their
neighboring cortical pyramidal
cells
The amounts of cytoplasm
and Nissl substance and the
number of visible processes
far exceed normal pyramidal
cells.
Betz cells are upper motor
neurons.

GLIA
Nerve glue- providing structural and functional support for neuronal elements.
Glia account for approximately 90% of all CNS
Glia are divided into the macroglia or true glia and
The microglia, which are actually of hematopoietic rather than true glial
derivation.

GLIA
Macroglia
Astrocytes
Oligodendrocytes
EpendymaMicroglia

ASTROCYTES
Multipolar / Starlike
Numerous processes
Abundant cytoplasm
Part of the BBB and Brain-CSF barrier
Abundant cytoplasmic Intermediate filament -> Stains GFAP
Based on location and morphology: 2 family types
Protoplasmic Astrocytes: cerebral cortex
Fibrillary astrocytes: white matter.

Resting
state
-Scant cytoplasm
-Cytoplasmic processes not
seen.
-Oblong nuclei
-Chromatin is lighter than
oligodendrocytes
-Absent nucleoli
Reactive
Seen in response to injury
-Proliferation and
hypertrophy of Astrocytes
-H&E: visible cytoplasm
(PATHOLOGICAL)

REACTIVE
ASTROCYTOSIS
Gemistocytic
Piloid gliosis
Alzheimer type
II
Bergmann
gliosis
Crueuzfeldt
cells

GEMISTOCYTIC ASTROCYTES
Eccentrically placed
cell bodies.
Large amounts of
brightly eosinophilic
cytoplasm.

PILOID GLIOSIS
Chronic lesion is often more fibrillar in nature
 Rosenthal fibers can be seen
It is most often encountered adjacent to slow-growing neoplasms
E.g., craniopharyngioma, ependymoma, hemangioblastoma)
And benign cystic lesions (e.g., pineal cyst, spinal syrinx)

-Highly fibrillar form of reactive gliosis
-Dense, elongate astrocytic processes that are tightly packed
together
-Associated with numerous Rosenthal fibers

ALZHEIMER TYPE II ASTROCYTES
Elevated blood ammonia, usually related to renal or hepatic
disease.
They are present in highest concentration in the basal
ganglia.
Cytoplasmic hypertrophy is not prominent in this form of
astrocytosis .
The nuclei have no appreciable cytoplasm.

 Alzheimer type II
astrocytes (arrow)
 Enlarged, Clear
nuclei
 Seen in states of
hyperammonemia.

BERGMANN GLIA
Speicalized astrocytes
Cells are only one to two layers thick and can go
unnoticed in resting states.
 In response to cerebellar injury, especially to
individual Purkinje cell loss
The reactive proliferation of this cell layer is referred
to as Bergmann gliosis.

 Purkinje cells have
been replaced by
one to three layers
of Bergmann glia.
 Oval nuclei with
long coarse
cytoplasmic
processes radiating
toward the pial
surface (left side).

CREUTZFELDT CELLS
Creutzfeldt cells are another form of reactive astrocytes
Abundant cytoplasm and “granular mitoses,” the
fragmenting of nuclear material that gives the impression of
multiple micronuclei
They are not specific, but are seen most often in active
inflammatory diseases (classic in demyelinating disease).
Not to be mistaken them for the mitoses of an infiltrating
astrocytoma.

 Creutzfeldt cells
(‘granular mitoses’)
 Fragmented
nuclear material
(arrow)
 Can be mistaken
for mitotic figures.

Oligodendrocytes
From Greek, meaning 'cells with a few branches‘
Myelinating cells of the CNS and are therefore more numerous
in white than in gray matter.
In the white matter, oligodendrocytes are disposed along the
length of axonal processes
Whereas in the cerebral cortex, they are scattered within the
neuropil and concentrated immediately surrounding neuronal
cell bodies (satellite cells)

Round dark nuclei.
Few with
perinuclear halo.
Cytoplasm blends
with the neuropil.

Microglia
Not neuroepithelial in origin.
Derived from a monocyte–macrophage lineage.
They serve as APC for immune surveillance and participate
in inflammatory responses
Particularly against viral pathogens.
In the resting state, microglia are easily overlooked
because of their small size and bland appearance, yet they
account for nearly 20% of the cellular population.

 Microglia have thin, elongated, and
hyperchromatic nuclei
 Stands out from the neuropil
(arrow).
 Microglia are most readily identified
in their reactive state, when they are
referred to as “rod cells.”
 The rod like quality of activated
microglia is also appreciated on
cytologic preparations (arrows).

Ventricular System

Ependyma
Greek word- means literally “upper garment”.
Originate from inner (germinal) zone of neuroepithelium
Tanycytes Special group of ependymal cells at the bottom of
the 3rd ventricle. Have long extensions into nervous tissue.
Within the supra- and infratentorial compartments,
ependymal are fairly homogeneous, varying slightly by anatomic
location in their cell height and degree of ciliation.

 Cuboidal to
columnar glial cells
 Nuclei are oval and
hyperchromatic
 Cytoplasm is pale
to eosinophilic

 On their ventricular
(apical) surface,
microscopically
visible cilia and
microvilli
 Lateral surfaces are
tethered to one
another by
desmosomes,
forming a functional
CSF–brain barrier.

Ependymal rosettes
 May be found subjacent to the
ependymal lining of the
ventricular system.
 They are particularly common
in at the tips of the lateral
ventricular horns, especially
the occipital horns and at the
lateral angles of the fourth
ventricle.
 These normal rosette clusters
are occasionally sampled in
surgical specimens and should
not be misinterpreted as
evidence of disease.

Central Canal Of The Spinal Cord
A. In the child, the central canal is widely patent and exhibits the ciliated columnar ependymal lining
expected in a young individual.
B. In contrast, the central canal of adults is typically obliterated over much of its length, with only
residual small nests and occasional rosettes of ependymal cells.

Spinal cord:
In Adults-
 collection of
poorly organized
ependymal cells
 Can be mistaken
for a neoplasm

Choroid Plexus
The choroid plexus is a functionally differentiated region of
ependyma.
Extends into the ventricular space as frondlike tufts of epithelium
Secrete the ultrafiltrate of CSF.
Individual cells are found as a single layer on a fibrovascular core.
Microvilli extend from the apical surface.
Tight junctions and desmosomes are present between choroid
plexus cells to ensure a viable blood–CSF barrier.

 Single layer
 Large pink cells
 cobblestone-like
surface.
 Small bland,
basally located
nuclei
 Fibrovascular
core

Thalamus

Thalamus
The thalamus is the main integrator and relay of sensory
information to the cortex and has over 50 individual nuclei, each
with its own specific function.
 Classic divisions are the anterior, medial, ventrolateral, and
posterior groups of nuclei.
Not among these larger categories are the midline, intralaminar,
and reticular nuclei.
The histologic appearance of each of the lobes is relatively similar.

Thalamic neurons
Projection
neurons
Interneurons

The thalamus has
large projection
neurons as well as a
less frequent
population of
smaller, inhibitory
interneurons.

Hippocampus

“cornu Ammonis” –
horn of (the ancient
Egyptian god) Amun-
”The hidden one”.
Hippocampus (Latin)
(hippokampos), from
hippos- “horse”
kampos,- “sea monster”.

CA3
CA2
CA1
H
DF
SUB
ALV
H/CA4- Hilum
SUB- Subiculum
ALV- Alveus
DF- Dentate
fascia

Pituitary Gland

Parts of Pituitary

Nests of round or polyhedral cells, and an
intervening network of vascular sinusoids
Normal adenohypophysis
Admixture of cells of eosinophilic, basophilic, and
chromophobic type within acini.

Cell nests are
surrounded by
reticulin.

Pituitary Panel
GH ACTH FSH/LH PRL TSH

Brightly eosinophilic growth hormone
(GH) cells comprise much of the lateral wings
Their cytoplasm is rich in GH-immunopositive
granules ( GH immunostain)
G
H

Normal prolactin
(PRL) cells occur in
both densely (top)
and sparsely
(bottom)
granulated cells
(PRL immunostain)
P
R
L
O
A
C
T
I
N

A
C
T
H
Normal ACTH cells are
amphophilic to
basophilic and exhibit
a prominent, pale,
spherical lysosome
(arrow).

F
S
H
Normal
FSH/LH cells
vary in
immunoreactivity for
gonadotropins and
are often
seen to partly
envelope PRL cells
(arrow; FSH
immunostain).

T
S
H
Normal TSH cells typically contain
PAS- positive lysosomes (PASD)
TSH stain

Normal neurohypophysis
This consists of non-
myelinated
nerve fibers and a
meshwork of
capillaries adjacent to
which the fibers
terminate. Also
present are
specialized astrocytes
(pituicytes)

Cerebellum

Histologic appearance is
homogeneous and relatively
simple throughout.
Outermost is the molecular layer
The Purkinje cell layer is at the
junction of the molecular layer
and the deeper granular cell
layer
Purkinje cells are large neurons
that have widely arborizing
dendritic trees that extend into
the molecular layer,
Granular cells of the cerebellum
are the most common neuronal
cell in the CNS.

ML
WM
PCL
GCL
The cerebellar cortex
contains:
 Sparsely cellular
Molecular layer(ML)
 Purkinje cell layer
(PCL),
 Granular cell layer
(GCL), and
 White matter (WM).

PURKINJE CELLS
Purkinje cells are large,
histologically distinctive
neurons of the cerebellum.
Cell bodies sit at the
interface of the molecular and
internal granular cell layers.
Each neuron has a prominent
pink cell body and an
expansive dendritic tree with
thick processes that extend
into the molecular layer

GRANULAR NEURONS
Tiny and densely
packed, often
displaying a linear
arrangement or loose
rosettes around
delicate neuropil
Perinuclear cytoplasm
is sparse, giving the
appearance of only
nuclei on H&E stains.

Meninges

Pia mater

Dura mater
A thick, monotonous
layer of dense fibrous
connective tissue
Layered collagen
scattered interspersed
flattened fibroblasts

Arachanoid mater
Delicate fibrous bands
(arrow)
Traverse the
subarachnoid space
(star),
Embed subarachnoid
vessels
Have attachments to
both underlying pia and
overlying dura

Pia mater
Thin, fine coating
on the surface of
the brain
Brightly
eosinophilic
Merges with the
arachnoid

Meningothelial cells
Scattered within the arachnoid membranes throughout the
neuroaxis, but they are most concentrated at the outermost layers
of the arachnoid just under the adjacent dura, where they are
called arachnoid cap cells.
Meningothelial cells are epithelioid to slightly spindled and are
typically seen in small clusters (10–20 cells), where they have a
tendency to form whorls and psammoma bodies, similar to their
neoplastic counterparts in meningiomas.

 They are typically
spindled to polygonal
cells
 Moderate amounts of
eosinophilic cytoplasm
 Bland oval nuclei
 Usually occur in small
clusters.

Melanocytes
Melanocytes are normal, neural crest-derived constituents of
the human Leptomeninges.
They are intimately associated with pia and subarachnoid
membranes and are widely scattered in most supratentorial
regions and noted histologically only following intense
searching.
Almost always seen as individual dendrite-shaped cells rather
than clusters.

 Melanocytes (arrow) are
infrequent
 Flattened, highly pigmented cells
of the pia and arachnoid
membranes
 Generally dispersed individually
 Highest density over the ventral
brainstem.

Spinal Cord

ANTERIOR HORN CELLS
Large, lower motor neurons
(alpha motor neurons) that
populate all levels of the spinal
cord in the anterior horns
Long axonal processes

White mater vs Grey mater

Features of the Aging Nervous System

Corpora amylacea Perivascular mineralization

Microvascular mineralization Neurofibrillary tangles

Amyloid plaques

Special Stains

la reazione nera”
The Black Stain “la reazione nera”
formulated by Golgi in 1873

Ramon y Cajal improved on Golgi’s silver stain, and developed a
Gold chloride-Mercury stain for astrocytes.

Special Stains in Neuropathology Today

Commonly Used Special Stains

References
Histology for Pathologists- Stacy. E. Mills.
Practical surgical Neuropathology- Arie Perry.
A reference book of Neuropathology- David Ellison.
Clinical Neuropathology, Vol. 30 – No. 4/2011 (164-177): Neuropathological work-up of focal
cortical dysplasias using the new ILAE consensus classification system.

Thank you

CNS normal histology

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