The
structure of central and peripheral myelin is
essentially the same. Myelin is composed of 70% lipids
and 30% protein. There are some important differences in
myelin proteins between CNS and PNS. These differences
explain why an allergic reaction against PNS myelin does
not cause central demyelination and vice versa; and why
inherited metabolic disorders of myelin proteins
that affect peripheral nerves do not damage central
myelin. On the other hand, lipids are similar between
PNS and CNS myelin. For this reason, metabolic disorders
of myelin lipids, such as metachromatic leukodystrophy,
affect both, the central white matter and peripheral
nerves.
The
myelin sheath acts as an electrical insulator,
preventing short-circuiting between axons. More
important, it facilitates conduction. The nodes of
Ranvier are the only points where the axon is uncovered
by myelin and ions can be exchanged between it and the
extracellular fluid. Depolarization of the axonal
membrane at the nodes of Ranvier boosts the action
potential that is transmitted along the axon and is the
basis of saltatory (jumping)
conduction.
Pathological Patterns of Neuropathy
The
pathology of peripheral neuropathy follows three basic
patterns: Wallerian degeneration, distal axonopathy, and
segmental demyelination.
Wallerian degeneration.
The neuronal cell body maintains the axon through the
axoplasmic flow. When an axon is transected, its distal
part, including the myelin sheath, undergoes a series of
changes leading to its complete structural
disintegration and chemical degradation.
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Acute neuropathy |
Wallerian degeneration |
Wallerian degeneration |
Changes also occur in the neuronal body. The RER
disaggregates and the neuronal body balloons. The
cytoplasm becomes smooth and the nucleus is displaced
toward the periphery of the cell. This process is called
central chromatolysis and reflects activation of
protein synthesis in order to regenerate the axon.
Cytoskeletal proteins and other materials flow down the
axon. The proximal stump elongates at a rate of 1 to 3
mm per day. Schwann cells distal to the transection also
proliferate and make new myelin.
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Lipid
material in acute neuropathy
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Axonal
sprouts |
Traumatic
neuroma |
The
degree of regeneration and recovery depends on how well
the cut ends are put together and on the extent of soft
tissue injury and scarring around the area of
transection. If reconstruction is not good, a haphazard
proliferation of collagen, Schwann cell processes, and
axonal sprouts fill the gap, forming a traumatic
neuroma. Wallerian degeneration was initially
described in experimental axotomy. Neuropathies
characterized by Wallerian degeneration include those
that are caused by trauma, infarction of peripheral
nerve (diabetic mononeuropathy, vasculitis) and
neoplastic infiltration.
In
distal axonopathy, degeneration of axon and myelin
develops first in the most distal parts of the axon and,
if the abnormality persists, the axon "dies back". This
causes a characteristic distal ("stocking-glove")
sensory loss and weakness. Neurofilaments and organelles
accumulate in the degenerating axon (probably due to
stagnation of axoplasmic flow). Eventually the axon
becomes atrophic and breaks down. Severe distal
axonopathy resembles Wallerian degeneration. At an
advanced stage, there is loss of myelinated axons. Many
clinically important neuropathies caused by drugs and
industrial poisons such as pesticides, acrylamide,
organic phosphates, and industrial solvents are
characterized by distal axonopathy.
Distal
axonopathy is thought to be caused by pathology of the
neuronal body resulting in its inability to keep up with
the metabolic demands of the axon. This explains why the
disease begins in the most distal parts of nerves, and
large axons that have the highest metabolic and
nutritional demands are more severely affected. However,
this question is not settled. It is hard to imagine how
the relatively miniscule neuronal body can keep up with
the metabolic demands of the enormous mass of the axon.
Furthermore, the neuronal body is just as dependent on
the distal axon and its synapses for trophic
interactions that keep it alive and functioning.
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Demyelinative
neuropathy |
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Segmental demyelination,
originally described in experimental lead poisoning, is
characterized by breakdown and loss of myelin over a few
segments. The axon remains intact and there is no change
in the neuronal body. The loss of saltatory
conduction that results from segmental demyelination
leads to decrease of conduction velocity
and conduction block. Deficits develop
rapidly but are reversible because Schwann cells make
new myelin. However, in many cases, demyelination leads
to loss of axons and permanent deficits. The nerve, in
segmental demyelination, shows demyelinated axons,
thin-regenerating-myelin, "onion bulbs"(see below) and,
in severe cases, loss of axons. The status of myelin can
be evaluated with teased fiber preparations of
peripheral nerves and by electron microscopy.
Neuropathies characterized by segmental demyelination
include acute and chronic inflammatory demyelinative
neuropathies, diphtheritic neuropathy,
metachromatic leukodystrophy and
Charcot-Marie-Tooth
disease.
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Hypertrophic neuropathy |
Hypertrophic neuropathy |
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"Onion
bulb" formations
are concentric layers of Schwann cell processes and
collagen around an axon. This proliferation is caused by
repetitive segmental demyelination and regeneration of
myelin and can cause gross thickening of peripheral
nerves (hypertrophic neuropathy). The central
axon is often demyelinated or has a thin layer of
myelin. Onion bulb formations are the histological
hallmark of Charcot-Marie-Tooth disease, but are
also seen in other hereditary neuropathies (Dejerine-Sottas
disease, Refsum disease), in diabetic neuropathy, and in
chronic inflammatory demyelinative neuropathy.
The
pathology of peripheral neuropathy is reflected in the
spinal cord. Acute axonal neuropathy causes cental
chromatolysis. Axonal neuropathy and distal axonopathy
involving the bipolar neurons of the dorsal root ganglia
cause degeneration of the central axons of these neurons
in the gracile and cuneate tracts of the spinal cord.
This lesion is associated with loss of position and
vibration sense and sensory ataxia.
Neuropathies can be classified on the basis of their
pathological changes into axonal (Wallerian degeneration
and distal axonopathy), demyelinative, or mixed.
Approach for the
Investigation of Peripheral Neuropathy
The
goal of the investigation of peripheral neuropathy is to
establish the diagnosis of peripheral neuropathy,
determine if it is an axonal or demyelinative process,
and find its cause.
Clinically,
neuropathy causes weakness and atrophy of
muscle, loss of sensation or altered sensation
(pain, paresthesias), and weak or absent tendon
reflexes. Nerve conduction studies can
distinguish demyelinative neuropathy (slowing of
conduction velocity or conduction block) from axonal
neuropathy (low-action potential amplitudes).
Electromyography (EMG) can distinguish denervation
atrophy from primary muscle disease. CSF examination
is helpful, especially in inflammatory demyelinative
neuropathies. Because cranial and spinal roots bathe in
CSF, demyelinative neuropathies that involve roots cause
elevation of CSF protein. Also, inflammation in nerve
roots causes CSF pleocytosis. Careful history taking
with attention to family history, environmental
exposure, and systemic illness, combined with
neurological examination and laboratory studies can
determine the etiology in most peripheral neuropathies.
When the diagnosis is in doubt, a nerve biopsy
studied by light microscopy, electron microscopy,
morphometry, and teased fiber preparations can give more
definitive information. The sural nerve is usually
chosen for biopsy because it is superficial and easy to
find and it is predominantly sensory. Sural nerve biopsy
leaves a patch of hypesthesia in the lateral aspect of
the foot that is usually well tolerated.
Diabetic and other neuropathies affect predominantly
small myelinated and unmyelinated fibers that convey
pain and temperature sensation. Degeneration in these
"small fiber neuropathies" involves the most distal
portions of nerve fibers that are found in different
organs and tissues (somatic fibers) rather than fibers
in major nerves. Nerve conduction studies and EMG in
such cases may be normal and the sural nerve biopsy may
be difficult to interpret. The diagnosis can be made
with a skin biopsy. A 3-4 mm plug of skin is
removed with a punch and sectioned with a microtome. The
sections are treated with antibodies to Protein Gene
Product 9.5 which reveal small nerve fibers that
penetrate the epidermis. The density of these fibers is
reduced in small fiber neuropathies.
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End stage
axonal neuropathy |
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The
pathological changes of most peripheral neuropathies
(axonal degeneration, segmental demyelination or a
combination of these) are not specific. In any active
neuropathy, there are macrophages removing myelin and
axon debris. Advanced axonal neuropathy shows loss of
myelinated axons and increased endoneurial collagen.
Some chronic demyelinative neuropathies show
hypertrophic changes. Thus, in most neuropathies, the
sural nerve biopsy can only establish the diagnosis of
neuropathy and distinguish axonal from demyelinative and
acute from chronic neuropathy, but cannot determine the
cause of neuropathy. Only a few peripheral neuropathies
show disease-specific pathological changes allowing a
specific diagnosis. These neuropathies include acute and
chronic inflammatory demyelinative neuropathies,
hereditary motor and sensory neuropathies, vasculitis,
sarcoid neuropathy, leprosy, amyloid neuropathy,
neoplastic invasion of peripheral nerves, metachromatic
leukodystrophy, adrenomyeloneuropathy, and giant axonal
neuropathy.
Principal Causes of
Peripheral Neuropathy
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1.
Autoimmunity (inflammatory demyelinative
polyradiculoneuropathies).
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2.
Vasculitis (connective tissue diseases).
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3.
Systemic illness (diabetes, uremia, sarcoidosis,
myxedema, acromegaly).
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4.
Cancer (paraneoplastic neuropathy).
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5.
Infections (leprosy, lyme disease, AIDS, herpes
zoster).
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6.
Dysproteinemia (myeloma, cryoglobulinemia).
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7.
Nutritional deficiencies and alcoholism.
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8.
Compression and trauma.
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9.
Toxic industrial agents and drugs.
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10. Inherited neuropathies.
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Diabetic Neuropathy
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Arteriole in
diabetic nerve |
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The
most common cause of neuropathy in clinical practice is
diabetes. Peripheral neuropathy develops in more than
half of long term diabetics. Diabetes causes several
types of neuropathy, which include chronic symmetrical
polyneuropathy, proximal neuropathy (diabetic amyotrophy),
mononeuropathies, and cranial radiculopathies. The
pathogenesis of diabetic neuropathies is poorly
understood. Many of them have an ischemic basis. A
prominent finding in diabetic neuropathy is thickening
of arterioles due to increased deposition of basement
membrane material, similar to changes that occur in
brain arterioles and glomerular capillaries.
Nonenzymatic glycation of neural structures and other
biochemical changes in diabetes probably play a role
also.
Inflammatory
Demyelinative Neuropathies
These
uncommon neuropathies are presumed to be immune
disorders in which antibodies and activated
T-lymphocytes, reacting with antigens present on
peripheral nerves, elicit an inflammatory and macrophage
reaction that destroys myelin and axons. The strongest
evidence of a humoral immune reaction in these
neuropathies is that plasma exchange results in
significant clinical improvement. The participation of
cellular immunity is underlined by the pesence of
T-lymphocytes around blood vessels in affected nerves.
The two main entities in this group are the
Guillain-Barré syndrome and chronic inflammatory
demyelinative neuropathy. An experimental model of
demyelinative neuropathy, experimental allergic
neuritis (EAN), can be produced by injecting animals
with myelin and Freund adjuvant or purified peripheral
myelin protein P2. EAN is a cell-mediated immune
reaction.
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Guillain-Barre
syndrome |
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The
Guillain-Barré Syndrome(GBS)
is not a single disease entity. It includes several
variants: Acute inflammatory demyelinative
polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN),
and the Miller-Fisher syndrome (MFS). AIDP accounts for
90% of GBS. It begins with paresthesias in the toes and
fingertips, followed by rapidly advancing weakness and
areflexia. Weakness reaches a plateau within four weeks,
after which recovery begins. Some cases are fulminant,
evolving in one or two days. At the height of their
disease, many patients are completely paralyzed and
unable to breathe. Even with modern intensive care,
approximately 5% of patients die from respiratory
paralysis, cardiac arrest (probably due to autonomic
dysfunction), sepsis, and other complications. Ten
percent of those who recover have residual weakness.
Though easy to diagnose in its classical form, GBS is
often missed because of atypical clinical features which
include ophthalmoplegia, ataxia, sensory loss, and
dysautonomia. Plasma exchange (presumably
removing the offending antibodies) and intravenous
immunoglobulin are the treatments of choice. The two key
laboratory abnormalities in GBS are decreased
nerve conduction velocity or conduction block and
elevated CSF protein with relatively few cells (albuminocytologic
dissociation).
Peripheral nerves show perivenular mononuclear cells,
demyelination (myelin proteins are the source of
elevated CSF protein), and macrophages. Axonal damage,
which accounts for the permanent deficits, is variable
and may be severe. The pathology is most severe in
spinal roots and plexuses and less pronounced in more
distal nerves. In the phase of recovery, the nerve
contains thin myelin sheaths, indicating myelin
regeneration. AMAN shows axonal damage with little
inflammation.
About
20% to 30% of GBS cases are preceded by an infection
with Campylobacter Jejuni. An equal
number are preceded by Cytomegalovirus (CMV) infection.
The rest are preceded by Mycoplasma and other
infections, or vaccinations. The bacterial wall of C.
jejuni contains GM1 ganglioside. Anti-ganglioside
antibodies, generated in the course of the infection,
cross-react with GM1 ganglioside present in the axonal
membrane at the nodes of Ranvier and in paranodal
myelin. This contact elicits inflammation that damages
these structures. Anti-GM1 antibodies are found in the
serum of GBS patients. GBS following CMV infections has
anti-GM2 antibodies.
Chronic inflammatory demyelinative
polyradiculoneuropathy (CIDP)
follows a chronic or relapsing course over many months
or years and may cause severe permanent disability.
Nerve conduction studies show decreased conduction
velocity, conduction block, and prolonged distal
latencies and F waves. In the active phase of the
disease, the CSF shows elevated protein without
increased cells. Pathologically, peripheral nerves show
demyelination, thin (incompletely regenerated) myelin,
and hypertrophic changes due to recurrent attacks of
demyelination with intervals of repair. In chronic
cases, there is significant axonal loss. Inflammation is
variable, sometimes absent. The pathology is most severe
in proximal nerve segments and spinal roots and may not
be full blown in the sural nerve biopsy. CIDP is thought
to represent an autoimmune T-cell and antibody reaction
against unknown myelin antigens. Its treatment consists
of plasma exchange, intravenous immunoglobulin, and
corticosteroids.
The
GBS and CIDP are the counterparts of MS for the
peripheral nervous system. They are important, because
timely intervention with plasma exchange can prevent
death in the GBS and severe permanent disability in CIDP.
There are standardized criteria for their diagnosis,
based on the clinical, CSF, nerve conduction, and biopsy
findings.
Hereditary Neuropathies
The
inherited neuropathies are rare as a group and include
lysosomal storage diseases, peroxisomal
disorders, and familial amyloidoses. Neuropathy, in
these diseases, is a component of a systemic metabolic
defect. The inherited neuropathies include also a group
of diseases called hereditary motor and sensory
neuropathies, in which neuropathy is the main or
only abnormality. The most common entity in this group
and the most common overall familial neuropathy is
Charcot-Marie-Tooth disease.
Charcot-Marie-Tooth
disease
(CMT) is not a single entity but a group of inherited
neuropathies that are divided into 3 phenotypes, CMT1,
CMT2, and X-linked CMT. CMT1 is the most common
inherited peripheral neuropathy. It involves 1 in 2500
persons and is autosomal dominant. It causes weakness
and atrophy of distal muscles, especially those
innervated by the peroneal nerve ("stork leg"), pes
cavus, sensory loss, and action tremor in some patients.
It begins in childhood or adolescence and progresses
slowly, involving other nerves. It is compatible with a
normal lifespan. Nerve conduction studies show decreased
conduction velocity. The nerve biopsy in CMT1 shows
demyelination, myelin regeneration (thin myelin), axonal
loss, and onion bulbs. In longstanding cases
there is gross thickening of nerves, hence the term
hypetrophic neuropathy.
CMT1
is genetically diverse. Its most common form is due to
duplication of a segment of chromosome
17 (17p11.2-p12) that contains the gene for a 22 kd
peripheral myelin protein, PMP22. This
protein probably also plays a role in Schwann cell
differentiation. CMT1 patients have three copies of the
normal gene and presumably produce 1.5 times as much
PMP22 as normal people do. Other forms of CMT1 are
caused by mutations of the PMP22 gene or mutations of
the Myelin Protein Zero (MPZ) gene. CMT2 is a distal
axonopathy with a diverse genetic background. X-linked
CMT is caused by mutation of a gap junction protein,
connexin 32. A deletion of the PMP22 gene causes
hereditary neuropathy with pressure palsies. Autosomal
dominant and autosomal recessive mutations of PMP22, MPZ,
and other genes cause CMT3 (Dejerine-Sottas
disease), a severe infantile demyelinative hypertrophic
neuropathy. These molecular abnormalities underline the
importance of myelin proteins for structural stability
of myelin and show how diverse genetic abnormalities can
cause a similar phenotype.
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Amyloid
neuropathy |
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Familial amyloid neuropathies
(FAP) are a group of familial systemic amyloidoses with
involvement of peripheral nerves. The most common FAP is
caused by an autosomal dominant mutation of the
transthyretin gene on 18q11. The mutant protein
is deposited in the form of amyloid and damages
peripheral nerves, the heart, kidneys, gastrointestinal
tract, and other organs. In nerves, amyloid damages
first and most severely small fibers, causing loss of
pain and temperature sensation and autonomic
dysfunction. Transthyretin is produced in the liver.
Liver transplantation arrests the progression of the
disease.
Vasculitic Neuropathy
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Necrotizing
arteritis |
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Polyarteritis nodosa
and
other vasculitides often involve peripheral nerves
causing single or multiple mononeuropathies (due to
nerve ischemia), asymmetric polyneuropathy, and distal
symmetric polyneuropathy. A sural nerve biopsy along
with a muscle biopsy are the best tissues for
establishing the diagnosis of vasculitis. The nerve
biopsy is diagnostic in over half of patients with
systemic vasculitis and clinical neuropathy, and the
diagnostic yield increases with the addition of a muscle
biopsy. Such biopsies show necrotizing arteritis,
perivascular inflammatory infiltrates, hemorrhage and
hemosiderin deposition, neovascularization in epineurial
arteries, and variable changes in nerve fascicles,
depending on the severity and stage of neuropathy. The
muscle shows vasculitis and denervation atrophy.
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Further
reading from source: (
www.neuropathology-web.org
)
Lauria G, Lombardi R. "Skin biopsy: a new tool for
diagnosing peripheral neuropathy."
