Peripheral Neuropathies

The body receives important proprioceptive and sensory information via the peripheral nervous system. This system transmits sensory information from the muscles and tissues to the central nervous system. Peripheral neuropathies hinder the transmission of this afferent sensory information. These neuropathies can lead to significant deficits in sensory and motor function. These neuropathies are diseases of the peripheral nerve that can be the result of disease or acute trauma. In this disorder, patients often report numbness, prickling and pain. These altered sensations that occur without an external sensory stimulus are called paresthesias. Peripheral neuropathies also lead to a deficit in proprioception which can lead to gait ataxia. This gait ataxia will significantly affect the patient's quality of life and must compensate for the lack of sensory information.


Peripheral Nervous System
The body is supplied information about the external and internal environment through the Peripheral Nervous System (PNS). It is anatomically separate from the Central Nervous System (CNS). The PNS is divided into somatic and autonomic divisions. The somatic division of the PNS contains the sensory neurons that innervate the skins, muscles and joints. The cell bodies of these sensory neurons are in the dorsal root and cranial ganglion. They will then convey information to the CNS about muscle and limb position and touch. In the somatic division, the PNS is responsible for visceral control of the smooth muscles, viscera and endocrine glands. The somatic division also contains the sympathetic, parasympathetic and enteric systems. Both of these divisions lie outside the pial membrane of the spinal cord and brainstem. In this article, we will mainly be concerned with the somatic portion of the PNS.

Fredericks, CM: Pathology of Motor Systems

Jenkins, TW:Functional Mammalian Neuroanatomy

Peripheral Nerve
A peripheral nerve is composed of nerve fibers, layers of connective tissue and blood vessels. Each peripheral nerve contains both myelinated and unmyelinated neurons. The axons of myelinated fibers are covered in layers of Schwann Cells, which are interrupted at nodes of Ranvier. Normal function of a peripheral nerve depends upon the integrity of the myelin sheath which increases the speed of conduction. Unmyelinated nerve fibers are covered by whole Schwann cells, not by myelin. These unmyelinated fibers convey information about sharp pain and temperature. In most nerves, around 75% of fibers are unmyelinated. Each peripheral nerve is composed of thousands of nerve fibers of many types each with their own particular morphologic and functional characteristics.

Each nerve fiber of a peripheral nerve are surrounded by layers of connective tissue. Individual fibers are surrounded by endoneurium which provides support and is important for guidance during regeneration. Groups of fibers are packed in bundles, fascicles, which are surrounded by the strong connective perineurium. This layer protects the nerve fibers from toxins, antigens and viruses. The bundles of fasciles are surrounded by the epineurium which is the outermost layer. This layer serves as a cushion during movements by protecting the fasciles from external trauma and maintaining oxygen supply through the epineural blood vessels. The epineurium is thicker at the bones and joints because there is a greater need for protection. The spinal nerve roots have thinner epineuriums and are therefore more susceptible to trauma.

Axonal Transport
Structural components, organelles, nutrients and neurotransmitters are all transported along the axon from the cell body to the nerve terminal. This is called antegrade axonal transport. If there are deficits in the transport of materials, neuronal function can be disturbed. In retrograde axonal transport, is transport from the periphery toward the cell body. Spent neurotransmitter vesicles are returned to the cell body via this system. The substances that are exchanged between axons and the tissues they innervate are called trophic factors. Defects in the transport of materials along the axon can alter and disturb neuronal function.

The Dorsal Column Medial Leminiscal System conveys information about the perception of touch and proprioception. In the spinal cord, the large-diameter dorsal root ganglion axons diverge from the smaller sensory afferents used for pain and temperature sense. The large fibers will ascend ipsilaterally and will ascend via the cuneate or gracile fasicle. The cuneate fasicle is located laterally and contains fibers from the upper thoracic and cervical segments of the spinal cord. The gracile fasicle located more medially and contains fibers that ascend via sacral, lumbar and lower thoracic segments. The cunate fasicle will terminate in the cuneate nucleus and the gracile fasicle will terminate in the gracile nucleus which are both located in the lower medulla. 2nd order neurons in thee cuneate and gracile nuclei then decussate and ascend to the ventral posterior lateral nucleus of thalamus via the medial lemniscus. Neurons in the thalamus then send information to the primary somatic sensory cortex in the post-central gyrus to be integrated and understood.
The anterolateral system conveys information about pain and temperature. These dorsal root ganglion neurons have smaller axons and cell bodies than those transmitting touch and proprioception. The neurons in the spinal cord decussate and ascend on the contralateral side. They ascend via the spinothalamic or spinoreticular tract. The spinothalamic tract conveys information about painful and thermal stimuli directly to the VPL of the thalamus. These neurons then project to the primary somatosensory cortex. Axons in the spinoreticular tract synapse on the reticular formation of the pons and sends information to the posterior nuclei of the thalamus (Kandel).

Development of Peripheral Neuropathy

Christopher M. Fredericks describes in his article the classification and pathology of peripheral neuropathies. Peripheral nueropathies can be classified into those that affect the axon and those that affect its surrounding myelin or Schwann cells. Those disorders that affect the axon axonopathies and are the most common.

These are disorders of the peripheral nerve that affect the axon. Wallerian Degeneration and Axonal Degeneration are both classified as axonopathies.

Wallerian Degeneration
A type of axonopathy is Wallerian Degeneration. This degeneration is a result of acute traumatic lesions in which the axon is interrupted. This interruption may be a result of a transaction of the nerve by laceration, by local crushing or ischemia. If the materials cannot be transported due to the interruption, the materials synthesized by the cell body cannot be transported along the axon. After two weeks, the synapses formed by the distal segment have degenerated completely. If the injury occurs close to the cell body, neuronal cell death may occur. Wallerian degeneration proceeds more rapidly in the peripheral nerves and the degeneration is complete in a few weeks. This is in contrast to the cranial nerves where degeneration is spread out over several months.

The table below is a classification of acute traumatic peripheral nerve injury.
This type of injury is based upon mechanical trauma. Neurotmesis is a severance of all essential structures in the neuron including the axon and endoneurium

Class I
Class II
Class III
Reversible blockade of nerve conduction
Variable loss of sensory, motor and
sympathetic nerve function
Result of crushing injuries
Common result of stab wounds
Decreased strength, absence of deep tendon reflexes,
Loss of sensation
Muscle atrophy, absence of deep tendon reflexes
Decreased strength, absence of deep tendon reflexes,
Loss of sensation
Generally no permanent damage, recovery
spontaneous and within 3 months
Schwann cells and endoneurium entact,
regeneration generally effective. Recovery slow (months-year)
Axons regenerate to original form
Damage to connective tissue layers and Schwann cells.
Prognosis poor and function may not be restored
Adapted from Schaumber HH, Spencer PS, and Thomas PK:Disorders of peripheral nerves, Philadelphia, 1983, FA Davis.

After the injury or disruption has occurred, regeneration is initiated by the growth of new branches from the proximal segment of the interrupted axon. As many as twenty-five branches may grow from a single axon during regeneration. Regeneration is quicker in a crushing injury because more of the nerve fibers remain intact. Many of the sprouts will not go to appropriate destinations. In the case of motor fibers, some may innervate muscle fibers other than those they originally supplied resulting in inappropriate movement. If the regeneration is incomplete or defective, there can also be incorrect localized sensation. These faulty branchings will eventually disappear. The rates of regeneration vary from 1-8mm/day depending upon the specific nerve and location (Darcy).

Axonal Degeneration
Axonal disintegration may develop slowly with chronic disease or long term damage to the nervous system. This type of degeneration occurs with toxins and certain metabolic disorders. The degeneration usually starts in the distal part of axon and moves toward the cell body. There may eventually be deterioration of the myelin or Schwann cells. The most distal regions of the longest and largest axons are the most susceptible to degeneration. If the neuronal degeneration is prolonged, it may result in cell death.

As with axonal degeneration, in demyelination disorders, the distal regions supplied by the largest nerves will be most likely lose function. In demyelination, the action potentials in different axons of the nerve will conduct at slightly different velocities. The nerve will then lose its normal synchrony of conduction. Slowing and temporal dispersion will result. Tendon reflexes and sensing vibration depend on synchrony of the action potentials. Without this synchrony, there will be a slowing of conduction velocity. In regeneration of the myelin, the sheath will be thinner than the original. The recovery following demyelination is usually rapid. Guillain–Barré syndrome is a type of demyelinating neuropathy.

Common Neuropathies
Diabetic Neuropathy-Diabetes may be the most common cause of peripheral neuropathy.Unfortunately, diabetic polyneuropathy will develop in 50% of patients with long term diabetes. These patients will most often suffer from distal sensory disturbances. The large distal nerve fibers are affected which results in diminished feeling in the legs, lessened muscle stretch reflexes and a loss in joint position sense. Patients will sometimes report a deep pain in the legs along with burning sensations in the feet. Diabetic neuropathy is a combination of demyelination and axonal degeneration.
Alcoholic Polyneuropathy- This type of neuropathy consists of many of the same symptoms as other polyneuropathies. It is primarily an axonal degenerative neuropathy. It has been theorized that the alcohol has toxic effects upon the nerve axons. Also, the poor nutritional state of alcoholics may also contribute to the neuropathy.
Guillain–Barré syndrome- This is a rapid poylneuropathic disorder. It originates as rapid progressive muscle weakness. The weakness begins in the lower body but quickly ascends to the upper body. Some patients will have mild distal weakness while others will have complete quadriplegia. Recovery will begin 2-4 weeks after progression of the disease has stopped. All peripheral nerves may be affected by most of the lesions develop in the ventral roots and proximal nerve trunks. This syndrome is considered to be an autoimmune disorder and may be triggered by a virus. The exact cause is unknown.

Signs and Symptoms

Peripheral neuropathies can be further classified into two categories, mononeuropathies and polyneuropathies. In mononeuropathies, the disorder stems from a single nerve trunk. They also are often the result of direct trauma to the nerve Motor and sensory symptoms are limited because this neuropathy is only stemming from a single trunk. Tendon reflexes are usually unaffected. With polynueropathies, there are widespread bilateral symptoms and are usually the result of toxic substances, metabolic disorders and particular immune reactions.

Negative Signs and Symptoms-The most common motor symptom is persistent weakness. In polyneuropathies, weakness is symmetrical and begins distally in the feet and legs.Later, the hands and forearms will be affected. This is called the glove and stocking syndrome. This syndrome is demonstrated in the picture below.
Harvard Medical School (2010)
Positional, vibratory, pain and temperature perception may all be diminished.Vibratory sense is often more affected than positional sense. If the polyneuropathy worsens, sensory loss may spread to the abdomen and head.

Positive Signs and Symptoms

Peripheral neuropathy may lead to the abnormal generation of action potentials in motor and sensory neurons. Involuntary activation of the muscles may accompany muscle weakness. Repetitive activation of multiple motor units may also occur leading to muscle stiffness. The repetitive activation of motor units may arise from the damaged regions of the peripheral nerves. A common complaint of peripheral neuropathies is abnormal sensation. These consist of numbness, tingling and prickling and are most common in the hands and feet. Patients will also complain of pain as a result of their peripheral neuropathy. This pain can be spontaneous or can be brought on by stimulation of the skin.
Other Signs and Symptoms
Gait ataxia may result as a loss of proprioception. With the interrupted conduction from the large distal peripheral nerves, there is a severe loss of proprioceptive input. This loss will lead to gait disturbances. There may also be a loss of tendon reflexes due to the loss of muscle spindle afferent input. Muscle spindle afferent input is also important in position-sense of the body.


Electromyographic (EMG) readings are used to demonstrate the presence of normal innervations to the muscle. As the denervated muscle becomes reinnervated, the EMG pattern changes in a way that details how far along in recovery the patient is. Demyelinating neuropathies have abnormal nerve conduction with normal amplitudes. Axonal neuropathies have normal nerve conduction with abnormal amplitudes.
Sensory testing is also used to determine how far along in the regeneration process the patient has progressed. The Tinel Sign is a provocation test used on regenerating nerves. The test consists of tapping on the end of the regenerating nerve. A positive sign is a response of pain or tingling over the distal end of the nerve. If there is no sensation, than there has been no reinervation of that nerve (Umphred).


Demyelinating neuropathies primarily affect the myelin sheath which result in slowed conduction in myelinated nerves. Axonal neuropathies involve the neuron processes themselves and both unmyelinated and myelinated fibers are affected. Nerve conduction studies such as an EMG, can distinguish between the two types. Most metabolic and systemic diseases produce axonal nueropathies whereas demyelinating neuropathies are a result of inflammation of the myelin sheath.
These neuropathies can lead to positive and negative symptoms. The tingling and painful sensations associated with this disorder can be debilitating. In addition, the absence of proprioceptive input from the damaged peripheral nerves can lead to gait ataxia. The severity of the ataxia is based upon the total peripheral neuropathy deficit.


Paresthesia- abnormal sensations, such as numbness and tingling that occur spontaneously without an external sensory stimulus
Somatic Division- Portion of PNS that contains the sensory neurons that innervate skin, muscles and joints.
Dorsal Column Medial Leminiscal System- the ascending pathway responsible for perception of touch and proprioception
Anterolateral System- Ascending pathway that conveys information about pain and temperature
Antegrade Axonal transport- Structural components, organelles, nutrients and neurotransmitters are all transported along the axon from the cell body to the nerve terminal
Neurotmesis- severance of all essential structures in the neuron, including the axon and endoneurium.
Endoneurium- provides support for nerve fibers and is important in the guidance of axons during regeneration
Epineurium- the outermost layer of connective tissues of a spinal nerve. It serves as a cushion and protects fibers during movement.
Axonopathies- disorders of the peripheral nerve that affect the axon
Wallerian Degeneration- acute traumatic lesions in which the axon is abruptly terminated
Mononeuropathies- disorders that stem from a single nerve trunk
Polyneuropathies- damage to the peripheral nerve system is more diffuse and often result from demyelination.
Stocking and Glove Syndrome- peripheral polyneuropathy that affects the hands and feet
Guillain–Barré syndrome- a rapidly developing polyneuropathy. The weakness and paralysis begins distally but then moves proximally


1) What percent of nerve fibers are unmyelinated?
a) 25%
b) 40%
c) 75%
d) 100%

2) Which of the following common polyneuropathies is a rapidly evolving paralytic disorder?
a) Diabetic Neuropathy
b) Alcoholic Neuropathy
c) Mononeuropathy
d) Guillain–Barré syndrome

3)Which syndrome describes the most distal muscles being affected first, then later the hands and forearms?
a) Epineurium syndrome
b) Stocking and Glove Syndrome
c) Wallerian Degeneration
d) Tinel Syndrome

4) What sign is used to determine if the regenerating axon has been reinervated?
a) Tinel Sign
b) Aging Sign
c) Polyneuropathy Sign
d) Carpal Tunnel Sign

5) Which ascending sensory tract conveys information about pain and temperature?
b) Anterolateral
c) Vestibulospinal
d) Reticulospinal

True or False
6)The epineurium is the outermost layer of connective tissue surrounding the spinal nerve.

7) Class III acute trauma peripheral nerve injuries will always lead to successful neuronal regeneration.

8) Polyneuropathies primarily result from acute trauma to the nerve.

Short Answer

9) What is the difference between mononeuropathies and polyneuropathies?

10)What is the difference between axonopathies and demyelination?

11) Name several negative and postive signs associated with peripheral neuropathy.

9)Mononeuropathies- disorders that stem from a single nerve trunk
Polyneuropathies- damage to the peripheral nerve system is more diffuse and often result from demyelination.

10) Axonopathies are disorders that affect the axon. These would be such disorders such as laceration to the nerve or crushing injury.
Demyelintation is a disintegration of the myelin sheath surrounding the axon. This would slow down the conduction veloctiy. These are more of a result of metabolic disorders and autoimmune disorders.

11) Negative signs-absence of joint position sense. Vibratory sense diminished. Positional, temperature and pain sensation may be absent. Absence of tendon reflex.
Positive signs- tingling, prickling and pain.

Further Readings
This video details the process of EMG. It overviews the entire process and shows an example of the test being performed.

Smith, E., Beck, S., & Cohen, J. (2008). The total neuropathy score: a tool for measuring chemotherapy-induced peripheral neuropathy. Oncology Nursing Forum, 35(1), 96-102. Retrieved from EBSCOhost.
This article lists some of the effects chemotherapy has upon the peripheral nervous system.Chemotherapy would have toxic effect on the peripheral nerves and could lead to demyelination.
This website lists some of the basic questions and mechanisms associated with peripheral neuropathy.
This website lists some of the basic questions and mechanisms specifically associated with diabetic neuropathy.


Fredericks, C.M.: Pathology of ,motor systems principles and clinical presentation. Philadelphia: F.A Davis, 1996. Print.

Gelb, DJ. (2000). Introduction to clinical neurology. Boston: Butterworth Heinemann.

Kandel, ER. (2000). Principles of neural science. Mc-Graw Hill: New York.

Masdeu, JC, Sudarsky, L, & Wolfson, L. (1997). Gait disorders of aging and therapeutic strategies. New York: Lippincott & Raven.

Parry, GJ. (1999). Motor disorders. Philadelphia: Lippincott Williams & Wilkins.

Schaumber HH, Spencer PS, and Thomas PK:Disorders of peripheral nerves, Philadelphia, 1983, FA Davis.

Umphred, DA. (1995). Neurological rehabilitation. New York: Mosby.

When nerves get damaged. Peripheral neuropathy causes strange feelings of numbness and sometimes pain. (2010). Harvard Health Letter / From Harvard Medical School, 35(9), 4-6. Retrieved from EBSCOhost.