PERIPHERAL NERVE PATHOLOGY

ANATOMY OF PERIPHERAL NERVES

Axons thicker than one micron in the CNS and peripheral nervous
system (PNS) are myelinated. Myelin is a spiral sheet of plasma
membrane wrapped around the axon (Figure 12.1). In the CNS,
myelin is produced by oligodendroglial cells and in the PNS by
Schwann cells. Each oligodendrocyte makes multiple segments of
myelin that wrap around many axons. Each Schwann cell makes one
segment of myelin. This is one reason why peripheral myelin
regenerates more efficiently. Nodes of Ranvier are points of
discontinuity between adjacent myelin sheaths in which the axon is
not covered by myelin. Unmyelinated axons are still surrounded by
Schwann cell cytoplasm, but there is no spiraling of Schwann cell
membrane around them.

The structure of central and peripheral myelin is essentially the same.

Chemically, myelin is composed of 70 percent lipids and 30 percent
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
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.

Peripheral nerves consist of many fascicles that contain myelinated

and unmyelinated axons (Figure 12.2). Endoneurium is the small
amount of collagen that is present between individual axons.
Perineurium is a sheath of special, fiber-like cells that ties the axons
of each fascicle together. Epineurium is the connective tissue that
surrounds the entire trunk of a peripheral nerve and gives off vascular
connective tissue septa that traverse the nerve and separate fascicles
from one another.

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 its myelin sheath, undergoes a series of changes
leading to its complete structural disintegration and chemical
degradation (Figures 12.3 and 12.4).

This process is called Wallerian degeneration. The neuronal body of

the transected axon enlarges. Nissl granules disperse, and the
nucleus is displaced peripherally . This cellular change which is called
central chromatolysis 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. 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 cells and axonal
sprouts fill the gap, forming a traumatic neuroma (Figure 12.5).

Wallerian degeneration was initially described in experimental

axotomy. Neuropathies characterized by Wallerian degeneration
include those which are caused by trauma, cooling, infarction of
peripheral nerve (diabetic mononeuropathy, vasculitis) and neoplastic
infiltration.

Distal axonopathy. When the neuronal body is injured from whatever

cause, pathology 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. Distal axonopathy involves more severely large
axons that have the highest metabolic and nutritional demands. Many
clinically important neuropathies caused by drugs and industrial
poisons such as pesticides, acrylamide, organic phosphates and
industrial solvents are characterized by distal axonopathy.
Segmental demyelination, initially described in experimental lead
poisoning, is breakdown and loss of myelin over a few segments. The
axon remains intact and there is no change in the neuronal body.
Segmental demyelination causes loss of saltatory conduction.
Recovery, due to remyelination, is faster and more complete than
Wallerian degeneration. Remyelinating axons have thin myelin
sheaths
(Figures 12.6 and 12.7).

The status of myelin can be best evaluated with teased fiber

preparations of peripheral nerves (Figure 12.8) and by electron
microscopy (Figures 12.6 and 12.7). Neuropathies characterized by
segmental demyelination include acute and chronic inflammatory
demyelinative neuropathies,diphtheritic neuropathy, metachromatic
leukodystrophy and Charcot-Marie-Tooth disease.

"Onion bulb" formations are concentric layers of Schwann cell

processes and collagen around an axon (Figures 12.7 and 12.9).
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. 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 (paresthesias), and weak or absent
tendon reflexes. The most helpful laboratory study is CSF
examination. Because cranial and spinal roots bathe in CSF,
demyelinative neuropathies that involve roots cause elevation of CSF
protein. Also, inflammation in the roots causes CSF pleocytosis. 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. 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. Its transection leaves a patch of
hypesthesia in the lateral aspect of the foot that is usually well
tolerated. Nerve biopsy should be the last resort.
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 (Figure 12.4).

Advanced axonal neuropathy shows loss of axons and increased

endoneurial collagen (Figure 12.10).

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

 1. Autoimmunity (inflammatory demyelinative
polyradiculoneuropathies).

2. Vasculitis (connective tissue diseases).

3. Systemic illness (diabetes, uremia, liver disease, myxedema,

acromegaly).

4. Cancer (paraneoplastic neuropathy).

5. Infections (leprosy, lyme disease, AIDS, herpes zoster).

6. Dysproteinemia (myeloma,cryoglobulinemia).

7. Sarcoidosis.

8. Nutritional deficiencies and alcoholism.

9. Compression and trauma.

10. Toxic industrial agents and drugs.

11. Inherited neuropathies.

The most common neuropathy in clinical practice is diabetic

neuropathy. The inherited neuropathies are rare as a group and
include lysosomal storage diseases, peroxisomal disorders and familial
amyloidoses. Neuropathy, in these diseases, is a symptom 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.

IMMUNE MEDIATED NEUROPATHIES

These common neuropathies are presumed to be immune disorders in

which antibodies 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. However, a cell mediated response probably
plays a role also. The two main entities in this group are the Guillain-
Barr syndrome (GBS) and chronic inflammatory demyelinative
neuropathy (CIDP). 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.
The Guillain-Barr Syndrome (GBS) is not a single disease entity. It
includes four variants: Acute inflammatory demyelinative
polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN),
acute motor-sensory axonal neuropathy (AMSAN) and the Miller-
Fisher syndrome (MFS). AIDP accounts for 90 percent 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. Peripheral nerves show
perivenular mononuclear cells, demyelination (myelin proteins are the
source of elevated CSF protein) and macrophages. Axonal damage is
variable and may be severe. The pathology is most severe in spinal
roots and plexuses and less pronounced in more distal nerves (Figure
12.11).

In the phase of recovery, there are thin myelin sheaths, indicating

myelin regeneration (Figure 12.6).

AMAN and AMSAN show axonal damage with little inflammation.

About 20 to 30 percent 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. Antiganglioside 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 and other
reactions that damage these structures. Anti-GM1 antibodies are
found in the serum of GBS patients. GBS following CMV infections has
anti GM2 antibodies. 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. GBS is
thought to be reversible, but approximately five percent 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.
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). GBS and
CIDP (see below) are the counterparts of MS for the peripheral
nervous system.

Chronic inflammatory demyelinative polyradiculoneuropathy (CIDP)

follows a chronic or relapsing course over many months or years and
may cause severe permanent disability. 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 axon loss.
Inflammation is variable, sometimes absent. In the active phase of the
disease, the CSF shows elevated protein.

The inflammatory demyelinative neuropathies are important, because

timely intervention with plasma exchange can prevent death in 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 MOTOR-SENSORY NEUROPATHIES

Charcot-Marie-Tooth disease (CMT - Hereditary Motor Sensory

Neuropathy type 1) 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,

axon loss and onion bulbs (Figure 12.9). In longstanding cases there is
gross thickening of nerves. The most common form of CMT1 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
other genes. An X-linked form is caused by mutation of a gap junction
protein, connexin. A deletion of the PMP22 gene causes hereditary
neuropathy with pressure palsies. Defects of the PO myelin protein
gene on chromosome 1 cause 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.

VASCULITIC NEUROPATHY

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,
(Figure 12.12) 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.