Peripheral Nerve Disorders

There are many types of peripheral neuropathy, often brought on by diabetes; genetic predispositions (hereditary causes); exposure to toxic chemicals, alcoholism, malnutrition, inflammation (infectious or autoimmune), injury, and nerve compression; and by taking certain medications such as those used to treat cancer and HIV/AIDS. Mayo Clinic researchers are working toward earlier and better diagnosis and treatment, and ultimately prevention of these debilitating nerve diseases. The following are the major types of peripheral neuropathy:

• Neuropathy is the disease of the nervous system in which there is a disturbance in the function of a nerve or particular group of nerves. The three major forms of nerve damage are: peripheral neuropathy, autonomic neuropathy, and mononeuropathy. The most common form is peripheral neuropathy, which mainly affects the feet and legs.
• Sciatica is pain, tingling, or numbness produced by an irritation of the sciatic nerve. Sciatica is a pain in the leg due to irritation of the sciatic nerve. Sciatica most commonly occurs when a branch of the sciatic nerve is compressed at the base of the spine.
• Carpal tunnel syndrome occurs when tendons in the wrist become inflamed after being aggravated. Tendons can become aggravated when the carpals (a tunnel of bones) and the ligaments in the wrist narrow, pinching nerves that reach the fingers and the muscle at the base of the thumb.
• Polyneuropathy is any illness that attacks numerous nerves in the body, sometimes causing weakness and/or pain. It tends to be a systemic problem that affects more than one nerve group at a time. Polyneuropathies are relatively symmetric, often affecting sensory, motor, and vasomotor fibers simultaneously.
• Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions usually result from diabetic microvascular injury involving small blood vessels that supply nerves (vasa nervorum).
• Autonomic neuropathy is a group of symptoms caused by damage to nerves supplying the internal body structures that regulate functions such as blood pressure, heart rate, bowel and bladder emptying, and digestion.
• Postherpetic neuralgia is pain that persists after an episode of shingles (herpes zoster) has resolved, resulting from damaged nerve fibers from the shingles.
• Thoracic outlet syndrome is a condition in which the nerves or vessels behind the collar bone (clavicle) become compressed or stretched, causing pain, weakness, or numbness in the arm on the same side. The thoracic outlet is an area at the top of the rib cage, between the neck and the chest. Several anatomical structures pass through this area, including the esophagus, trachea, and nerves and blood vessels that lead to the arm and neck region.

Ongoing research

The Peripheral Nerve Research Laboratory (PNRL), under the direction of Peter James Dyck, M.D., has engaged in research on peripheral nerve and its diseases for the last 40 years. Initial studies were done in collaboration with E. H. Lambert, but in recent years, they have been done in association with Phillip A. Low, M.D., P. James B. Dyck, M.D., and Christopher Klein, M.D. The research focusing on human diseases can be categorized as follows:

1. Experimental neuropathies including permanent axotomy, lead intoxication, ischemia, regeneration, irradiation.
2. Natural history, gene identification, and treatment of inherited neuropathies such as Charcot-Marie-Tooth syndrome types 1, 2 and other; and hereditary sensory neuropathy (HSN) including congenital insensitivity to pain, HSN with dementia, inherited brachial plexus neuropathy, progressive muscular atrophy, and spastic paraplegia.
3. Diabetic sensorimotor polyneuropathy, including its natural history, course, outcome, pathogenic factors, risk factors, and treatment trials.
4. Diabetic multifocal neuropathies including the natural history, underlying mechanisms, and treatment trials of the disease.
5. Acute and chronic immune neuropathies–their natural history, pathologic alterations, outcome, and treatment trials. The diseases studied include AIDP (Gillian-Barr syndrome), chronic inflammatory demyelinating polyneuropathy (CIDP) and idiopathic axonal polyneuropathy (CIAP), multifocal motor neuropathy (MMN), chronic inflammatory multiple mononeuropathy (CIMM, also called MADSAM), or chronic inflammatory sensory polyradiculopathy (CISP). The laboratory did the first prospective controlled double-blind trials of CIDP.
6. Monoclonal gammopathy of unknown significance with neuropathy (MGUS neuropathy), including its natural history, pathologic alterations, and treatment trials. Dr. Dyck’s laboratory did the first prospective double-blind trials of treatment.
7. Studies of other approaches for evaluations of symptoms, deficits, disabilities, and outcomes in neuropathy—using symptoms scores (e.g., NSS, NSC, and others), impairment scores (e.g., NIS), composite scores of nerve conduction, quantitative sensation testing, and disability scores This laboratory has been a leading reading and quality assurance center for many multi-center trials.

Caterina Giannini, M.D., is doing research focused on tumors of the central and peripheral nervous system and the pathologic features predictive of patient outcome. She is conducting correlative studies to determine the clinical significance of histologic and genetic variables in brain tumor tissue, in particular in the setting of clinical trials of patients with gliomas. Dr. Giannini is responsible for the Mayo Clinic Brain Cancer SPORE Tissue Core for the collection of fresh and fixed brain tissues for research. The Brain SPORE Tissue Core also supports high-throughput tissue microarray construction, laser capture microdissection, immunohistochemistry, FISH, in situ hybridization, and a variety of other techniques. A recent research development, in collaboration with the Mayo lymphoma SPORE investigators, has been the study of primary CNS malignant lymphoma cytogenetics, including low- and high-grade B-cell lymphomas.

Phillip Low, M.D., focuses his research on peripheral nerve microenvironment with particular emphasis on the basic mechanisms underlying the pathogenesis of diabetic neuropathy. His specific hypothesis is that diabetic neuropathy is mediated by oxidative injury to nerve target, especially sensory neuron. A related focus is on the pathophysiology of ischemic neuropathies and mechanisms of neuroprotection. Techniques used include immunohistochemical, molecular, microelectrode, and autoradiographic methods of studying nerve tissues. Another area of focus is human and experimental autonomic dysfunction. In the Autonomic Physiology Laboratory, he is studying the pathophysiology of orthostatic intolerance and its amelioration. Diseases studied include multiple system atrophy, autoimmune autonomic neuropathy, and postural tachycardia syndrome. The lab has the capabilities to non-invasively measure beat-to-beat blood pressure and flow (systemic, splanchnic-mesenteric, cerebral), heart rate, cardiac output, stroke volume, total peripheral resistance, as well as sudorometric and laser Doppler methods of measuring sudomotor and vasomotor activity. Direct measurements of muscle sympathetic activity are available using microneurography of peripheral nerve.

Brachial plexus injuries

Mayo Clinic in Minnesota has two laboratory research projects under way that are related to brachial plexus injuries.

Nerve Conduits. Mayo has developed a multichanneled nerve tube for peripheral nerve repair. This nerve tube is made of PCLF [poly(caprolactone fumarate)], a new biomaterial invented at Mayo Clinic in Rochester that is flexible and easy to suture. The current line of research is investigating the influence of structure on the support of regeneration for the possibility of bridging larger gaps and improving regeneration by separate guidance of regenerating axons. Use of a nerve conduit would decrease disadvantages of autograft, the current gold standard, such as donor-site morbidity (pain, sensory abnormality, separate incisions, etc.) and limited availability.

Choline Acetyltransferase (CAT) Assay: Application for Diagnosis and Treatment of Brachial Plexus Injuries. This research project is evaluating the relationship between CAT activity level in injured nerves and muscle function in a rat nerve repair model. The measurement of CAT activity in brachial plexus nerves can determine the level of motor fibers present. If there is a relationship between the level of CAT activity and functional recovery of muscle, then high CAT activity areas of the nerve can be targeted to specific muscles to improve motor activity.