Peripheral Neuropathy

Introduction

Peripheral neuropathy is among the most common reasons patients seek out medical care. The overall prevalence in the general population is estimated to be 2.8% and increases to 8% in those older than 55 years of age. There are many causes of peripheral neuropathy, with diabetic neuropathy, vitamin deficiencies, dysproteinemias, toxin-induced (including chemotherapeutics), trauma-related, and inherited gene mutations being among those most commonly diagnosed.

Peripheral neuropathies can easily be divided in mononeuropathies, or those affecting one nerve, and polyneuropathies, which involve many or most of the nerves of the body to some extent. Multiple mononeuropathy or mononeuropathy multiplex involve two or more nerves in different parts of the body. The pattern of neuropathy is important in deciding an appropriate treatment for each patient, especially in creating a treatment plan that may involve nerve stimulation.

Dorsal root ganglion (DRG) stimulation is gaining favor as the potential treatment of choice for polyneuropathy that is refractory to conservative management. However, it lacks the specificity that is desired when treating a peripheral mononeuropathy. Evidence continues to grow in favor of peripheral nerve stimulation (PNS) for patients who suffer from these peripheral mononeuropathies.

Clinical Presentation

The clinical presentation of peripheral neuropathy will vary greatly with the vast number of causes and the wide range of nerves that may be diseased. This difference in patient presentation of symptoms and physical exam can help guide the clinician’s differential diagnosis. A careful history will also enable the medical provider to create a sensible differential diagnosis from the many causes. When diagnosing the cause of polyneuropathy or mononeuropathy, the following diseases, drugs, genetic disorders, and toxins should be considered.

• Diseases

  • Human immunodeficiency virus (HIV), carcinomas, liver disease, diabetes mellitus, end-stage renal disease, hypothyroidism, leprosy, Lyme disease, lymphoma, monoclonal gammopathy, porphyria, syphilis, vitamin deficiencies (B6 and B12)

• Drugs

  • Amiodarone, chloroquine, digoxin, heroin, hydralazine, isoniazid, lithium, metronidazole, misoprostol, nitrofurantoin, phenytoin, procainamide, statins, vincristine, vitamin excess (B6)

• Genetic disorders

  • Charcot-Marie-Tooth disease, metachromatic leukodystrophy, neuropathy with liability to pressure palsies, Refsum disease

• Toxins

  • Diphtheria toxin, ethanol, heavy metals (arsenic, lead, mercury, gold), organophosphates, tetanus, tic paralysis

• Other

  • Direct nerve damage from traumatic injury, idiopathic polyneuropathy.

Most of the systemic diseases listed earlier will present as polyneuropathy, with the most common being diabetes mellitus, hypothyroidism, and nutritional deficiencies. These more common causes should be ruled out before moving toward a rarer cause. These polyneuropathies can present with both positive (pain, burning) and negative (numbness) symptoms and most commonly cause symptoms that are initially distal and become more proximal with progression of the disease.

Mononeuropathy most commonly occurs as the result of damage to a single peripheral nerve. This is most commonly a result of compression or history of trauma to an isolated nerve. Thus, the presentation of symptoms tends to be unilateral and affecting a discrete and recognizable pattern of nerve innervation. For example, a patient with a mononeuropathy of the right saphenous nerve should have symptoms affecting the medial right lower extremity. The typical positive and negative symptoms described in polyneuropathy are also seen in mononeuropathies. Pain or a burning sensation, pins and needles, loss of sensation, diminished coordination, and weakness in the affected area are among the symptoms most commonly reported.

Acute onset of symptoms is most commonly a result of trauma to the individual nerve, while a more insidious onset of symptoms is seen with chronic compression of the nerve. Mechanical damage to the nerve is the most common inciting source for a mononeuropathy, but as with any disease process the cause can be multifactorial. Localized or systemic infection that leads to invasion of isolated peripheral nerves is among other commonly described causes. A localized ischemic event, including one caused by a vascular disorder, can also be the source. Metabolic disorders including diabetes can predispose an already vulnerable nerve to further injury, along with autoimmune disorders such as systemic lupus erythematosus. Local invasion of tumors and cancer cells may directly compromise the integrity of an individual nerve. The treatment of cancer with radiation therapy and chemotherapeutic agents may also overtly cause a mononeuropathy or contribute to neurologic impairment.

It is also possible to have multiple mononeuropathies if two or more peripheral nerves are injured. This is termed multiple mononeuropathy or mononeuritis multiplex. Such a presentation may result in difficulty in differentiating from polyneuropathy, depending on the location of the nerves affected. A polyneuropathy will typically affect a group of nerves in one location and is often symmetrical, while multiple mononeuropathy will show pathology in multiple isolated peripheral nerves. For example, a patient may have a bilateral median nerve compression from bilateral carpal tunnel syndrome. This would cause symptoms in a bilateral median nerve distribution, while other local nerves show no pathology, thus causing multiple mononeuropathies.

Anatomy

Peripheral nerves extend from the central nervous system to provide sensory feedback and motor function and to assist in the regulation of the autonomic nervous system. Each peripheral nerve is made up of many nerve fibers or axons, which are extensions projecting from cell bodies that are held within the central nervous system or the ganglia of the peripheral nervous system. The axons of the peripheral nervous system are myelinated by Schwann cells. This myelination allows for saltatory conduction and more rapid transmission of nerve signals to the periphery (efferent) or centrally (afferent).

Peripheral neuropathy happens as a result of damage to nerve axons or destruction to the myelination of the axons. Nerve injury leads to a number of proposed mechanisms that are believed to contribute to neuropathy. First, following the injury there is an increase in sodium, potassium, and calcium channels at the site of injury. This increased concentration of channels at the site of injury leads to neurons becoming hyperexcitable and the generation of ectopic activity. Second, sympathetic sprouting occurs at the cell bodies of the injured nerve axons within the dorsal root ganglia. This in part accounts for sympathetically mediated pain associated with peripheral neuropathies. Third, the nerve injury leads to altered expression of genes, leading to increased activity of the N-methyl-D-aspartate receptor. All of these changes also lead to alterations in the central processing of pain, leading to reduced activation thresholds and increased sensitivity to pain.

Diagnosis

Determining the underlying cause of a neuropathy may be even more important than just diagnosing the neuropathy itself. Clinical distribution (length-dependent, length-independent, or multifocal) and clinical modality (motor, sensory, autonomic, or some combination) can help in guiding the medical provider to the underlying cause.

Most patients will describe a length-dependent peripheral neuropathy that is symmetric in nature and progresses distally to more proximally. This neuropathy typically affects the lower extremities first and may progress to involve the hands. The majority of these neuropathies are also sensory-predominant. In these cases, patients do not typically require specialty consultation for management of their disease and symptoms. Sensory symptoms either with or without motor weakness in a length-independent distribution are more likely to require specialist evaluation.

Patients who describe a length-independent mononeuropathy should be further worked up to find any underlying cause. This will most commonly involve some traumatic event or evidence of nerve compression. These patients may benefit from PNS, but proceeding with stimulation without determining the underlying cause may put the patient at risk for further nerve damage.