David Lacomis, MD
Nerve Biopsy
 Major indication is “vasculitis”
 May not show specific cause of neuropathy in most
cases
Nerve Biopsy
 Processing
 Paraffin sections
o Inflammation
 Semi-thin, plastic sections (most useful)
o Axon-loss
o Demyelination
o Inflammation
o Inclusions
 Teased Fibers
o Demyelination and axonal degeneration
Organization of Peripheral Nerve
(H & E-Stained Paraffin-Embedded Section)
cross-section of 4 fascicles
 Individual axons are surrounded by endoneurial connective tissue.
 Perineurial connective tissue (yellow arrow) surrounds fascicles.
All fascicles are bundled in loose epineurial connective tissue
(black arrow) that contains the larger blood vessels in addition to
capillaries that can also be seen in the perineurium and
endoneurium.
Sural Nerve Cross-Section
(Trichrome)
 The sheaths of myelinated axons stain red
while the connective tissue stains blue.
 Higher power shows myelinated
axons more clearly.
Cross-Section: 1 Micron Thick (Toluidine Blue)
 Normal dist. of myelinated fibers in a 74 year-old woman.
 Younger people have more myelinated axons.
 Large-fibers (7 microns or larger) make up 40% and small-fibers
compose 60% of myelinated axons. Unmyelinated fibers are
also present in the nerve fascicle, but they are difficult to see
without ultrastructural study.
 There is normally a
bimodal distribution
of myelinated fiber
diameters.
 The thickness of the
myelin sheath is
generally
proportional to the
axon diameter.
 In some forms of
polyneuropathy,
such as hereditary
motor sensory
neuropathy type I,
the large myelinated
fibers may be
preferentially
affected, while in
amyloidosis, for
example, the small
myelinated fibers
may be
preferentially
affected.
Normal Anatomy of a
Single Axon
 The myelinated segments are
called internodes.
 Internode length increases
as does the axon diameter.
 For large axons, the
internodal length ranges
between 0.35 and 1.83 mm
and is approximately 1/3 of
that size for smaller
myelinated axons.
 Especially in the elderly,
there is significant variability
in internodal length.
 One Schwann cell associated
with unmyelinated axons
(REMAK cells) may surround
more than one axon.
 The unmyelinated fibers
actually outnumber
myelinated fibers
approximately 4 to 1.
Normal Single Teased
Fibers from the Sural
Nerve
 Due to osmication, the myelin sheath stains dark.
 Nodes of Ranvier border each internodal segment.
Ultrastructural Study
of a Normal Myelinated Fiber
 Normal myelin sheath thickness and axon contents
 The inner mesaxon (yellow arrow) is where the myelin
sheath begins to overlap itself.
 The outer mesaxon (red arrow) in the site is where the last
turn of the Schwann cell cytoplasm overlaps itself.
 At the Schmidt-Lanterman
incisures, the state of the
myelin sheath is noted.
 Reich’s Pi granules are normal variants and
are structures present in the Schwann cell
cytoplasm.
 They increase with age.
 They appear to be of lysosomal origin.
(H&E, Paraffin)
 Polyglucosan bodies may be normal or seen in great
numbers in a storage disease. The bodies are also PAS+.
 Renaut bodies are fibrillary structures present in
the subperineurial area.
 They are composed predominantly of fibroblasts.
 They are lightly staining with H&E.
 Renaut bodies are also lightly stained with Trichrome.
 In contrast to amyloid deposits, they do not stain with
Congo Red.
 These structures are normal variants.
 They do appear to be more common in areas of focal
nerve compression and with aging.
Renaut Body
(Toluidine Blue-Stained Section)
Axonal Degeneration
(H&E- Stained Paraffin Section)
 Shows myelin
ovoids due to
contraction of the
myelin sheath as
the underlying
axon degenerates.
 This phenomenon
occurs in
Wallerian
degeneration
distal to the site
of axonal
transection, and it
also occurs in
axonal
polyneuropathies.
 In teased fibers,
linear myelin
ovoids are seen
in a patient with
an axonal
polyneuropathy.
 Myelin ovoids
may begin in the
paranodal areas
or adjacent to
the SchmidtLanterman
incisures.
Myelin Ovoid in a Patient
with Diabetic Neuropathy
 Significant dropout in large and small
myelinated axons is present as well as a
degenerating axon with debris-laden cytoplasm.
Axonopathy
 Note
fragmentation
of the myelin
sheath,
contraction of
the axon, and
increased
contents in the
Schwann cell
cytoplasm.
 Further fragmentation of the myelin sheath
is shown in a degenerating axon.
Axonal Polyneuropathy
 Perivascular macrophages containing Pi-like granules
and lipid deposits are present, probably as a result of
ingesting contents of degenerating myelinated axons.
Ultrastructural Examination
in a Patient with Axonal Polyneuropathy
 Examination
reveals an
increase in
endoneurial
collagen, a
severe dropout
in myelinated
axons, and flat
stacks of
Schwann cell
cytoplasm,
consistent with
a loss of the
unmyelinated
fibers.
Cross-Section of Axonal Sprouts
Muscle
Nerve regeneration occurs within the Schwann cell tube.
Midroni G et al. Biopsy Diagnosis of Peripheral Neuropathy. Butterworth-Heinemann. 1995.
Denervated Schwann Cell Bands
(Bands of Bungner)
 More rounded stacks of Schwann cell
processes, sometimes in association with
multiple axons within a single Schwann cell
tube, are characteristic of Bands of Bungner.
 These bands are due to multiplication of
Schwann cells of denervated myelinated and
unmyelinated axons that had previously
regenerated (see previous slide).
 If regeneration does not occur, these bands
will totally collapse.
Muscle
Cross-section
of sprouting
nerve that then
degenerated
Cluster of Regenerating Myelinated Axons
 Clusters are defined by the presence of three or more closely
opposed myelinated axons, generally within a single Schwann
cell basal lamina.
 Eventually, the basal lamina will disintegrate and each
myelinated axon will have its own basement membrane.
Microfasciculation of Regenerating Axons
 Seen in diabetic neuropathies and ischemic neuropathies.
 Shown here are multiple microfascicles as well as thinly
myelinated fibers and a dropout in myelinated fibers. Thinly
myelinated fibers are often indicative of remyelination, but the
remyelinating process is better seen with teased fibers.
Myelin Ovoids in Diabetic Polyneuropathy
End-Stage Diabetic Polyneuropathy
 A regenerating group of myelinated fibers is isolated in a
nerve that is severely damaged in diabetic polyneuropathy.
Diabetic Polyneuropathy

 Very few remaining axons are present.
 Also note the thickening of the capillary (arrow).
 Also associated with thickening of the perineurium ().
*
 Overt degeneration of the perineurium may also
be seen in diabetic polyneuropathy.
Demyelinating Neuropathy
 Segmental demyelination is shown in two internodes.
Onion Bulbs
 Redundant layers
of Schwann cell
processes are
noted surrounding
myelinated axons.
 Onion bulbs are
indicative of
demyelination and
remyelination.
 They may be seen
with inherited
demyelinating
polyneuropathies
or other more
chronic acquired
demyelinating
neuropathies such
as chronic
inflammatory
demyelinating
polyneuropathy
(CIDP).
Inflammatory Neuropathies
 Mononuclear inflammatory cells are seen adjacent to
myelinated axons of the lumbar roots in a patient
with Guillain-Barré Syndrome.
 Vesicular demyelination is noted in a
patient with Guillain-Barré Syndrome.
 In GBS, macrophages will strip the myelin
from the axon.
Chronic Inflammatory Demyelinating Polyneuropathy
 Onion bulbs, which are present in this
specimen, may be seen in approximately
15-40% of patients.
 Significant axon loss as is shown here is
quite common.
 Teased fibers show a mixture of
demyelination and axonal loss.
 Thus, the pathologic findings of CIDP are
mixed and often do not allow a definitive
pathologic diagnosis.
Chronic Inflammatory Demyelinating Polyneuropathy
 Endoneurial and perivascular inflammation is seen in
approximately 10 to 50% of patients with CIDP (leukocyte
common antigen immunohistochemistry).
Necrotizing Vasculitis
 An artery with fibrinoid necrosis and
inflammatory cell invasion within the vascular
wall is shown in the epineurium.
 Necrotizing vasculitis is also seen in an intramuscular artery
from the same patient.
 The diagnostic yield in patients with suspected peripheral
nervous system vasculitis is increased when both muscle and
nerve are biopsied.
Patchy Loss of Myelinated Axons in a Patient with
Vasculitic Polyneuropathy
 The fascicular loss is thought to be due to endoneurial ischemia
within the central region of the fiber or in sectors.
 Such a spatial pattern of loss is also seen in some patients with
diabetic polyneuropathy.
 Thus, this is thought to be a feature of an ischemic process.
 Subperineurial edema is an early
feature in vasculitic neuropathy.
Paraneoplastic Neuropathy
DRG Neuron
 Lymphocytic dorsal root ganglionitis is typical
of paraneoplastic sensory neuropathy.
Sarcoidosis
 Sural nerve specimen shows a typical
perivascular granuloma in the epineurium.
 Multinucleated giant cells are not commonly
seen in neural sarcoidosis.
Perineuritis
 Perineuritis manifested as a sensory neuropathy is
associated with patchy infiltration of the perineurial
lamellae by epitheliod cells and lymphocytes.
 An example of toxic neuropathy is that
induced by amiodarone.
 In this particular neuropathy, there is a
demyelinating element and lipid inclusions
can be seen in Schwann cell cytoplasm.
 Most toxic neuropathies, however, cause
an axonal polyneuropathy.
Amyloid Polyneuropathy
 Endoneurial Congo Red positive staining is present.
 The Congo Red positive material has the characteristic features
of apple-green birefringence with polarized light.
Leprosy
 Bacilli can be seen within
perineurial cells, endothelial cells,
and within macrophages in this
disorder.
 Leprosy is the most common
cause of neuropathy in many third
world countries.
CMT-1
Normal
 HMSN-I or Charcot-Marie Tooth disease type I is a
chronic demyelinating polyneuropathy in which
many onion bulbs are commonly seen.
Onion Bulbs in CMT-1
 Genetic studies may be more useful in diagnosing some
inherited neuropathies. This image reveals FISH in a
patient with a duplicated PMP 22 segment on
chromosome 17 due to CMT 1a.
 In hereditary liability to pressure palsies, due to a
deleted PMP22 segment, numerous sausage-like
swellings or tomaculae are present on teased
fiber preparations.