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Anatomy of Peripheral Nerves

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Peripheral nerves consist of fascicles that contain myelinated and unmyelinated axons.
Endoneurium is the small amount of matrix that is present between individual axons. The
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 nerve trunk and gives off
vascular connective tissue septa that traverse the nerve and separate fascicles from one
another.

Did You Know?

20 million Americans suffer from
Single myelinated axon Normal nerve peripheral neuropathy!

Axons thicker than one micron in the CNS and peripheral nervous system (PNS) are 30% of cases, the cause is diabetes!
myelinated. Myelin is a spiral sheet of cell membrane wrapped around the axon. In the CNS, 60-70% of diabetics have some
myelin is produced by oligodendroglial cells and in the PNS by Schwann cells. Each nervous system damage in the U.S.
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 The annual medical expenses for
diabetic neuropathy symptoms in the
regenerates more efficiently. Nodes of Ranvier are points of discontinuity between adjacent
U.S. are as high as $13.7 billion
myelin sheaths in which the axon is not covered by myelin. Unmyelinated axons are covered annually. (this does not include the
by Schwann cell cytoplasm, but there is no spiraling of Schwann cell membrane around them. other 70% of non diabetic cases!)

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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 See below for details!
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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RER = In the nervous system, the

endoplasmic reticulum is found within
the cell body of a nerve.

Acute Wallerian Wallerian

neuropathy degeneration 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.

Lipid material in Axonal Traumatic

acute neuropathy sprouts 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.

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
Demyelinative segmental demyelination leads to decrease of conduction velocity
neuropathy 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.

"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 Hypertrophic
(hypertrophic neuropathy). The central axon is often
neuropathy neuropathy
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.

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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.

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
End stage axonal demyelinative neuropathies show hypertrophic changes. Thus, in most
neuropathy 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, sarcoidosis, myxedema, acromegaly).
4. Cancer (paraneoplastic neuropathy).
5. Infections (leprosy, lyme disease, AIDS, herpes zoster).
6. Dysproteinemia (myeloma, cryoglobulinemia).
7. Nutritional deficiencies and alcoholism.
8. Compression and trauma.
9. Toxic industrial agents and drugs.
10. Inherited neuropathies.

Diabetic Neuropathy

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
Arteriole in diabetic neuropathies is poorly understood. Many of them have an
diabetic nerve 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

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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.

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
Guillain-Barre the Miller-Fisher syndrome (MFS). AIDP accounts for 90% of GBS. It
begins with paresthesias in the toes and fingertips, followed by rapidly
syndrome
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

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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.

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
Amyloid neuropathy 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

Polyarteritis nodosa and other vasculitides often involve peripheral

Necrotizing arteritis
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.

Further reading from source: ( www.neuropathology-web.org )

Lauria G, Lombardi R. "Skin biopsy: a new tool for diagnosing peripheral neuropathy." BMJ 2007;334:1159-62

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