Introduction

The peripheral nervous system distributed throughout the body mediates motor, sensory, and autonomic (sympathetic and parasympathetic nervous system) functions. The manifestations of nerve dysfunction, or neuropathy, depend on the severity, distribution, and functions affected. Generalized peripheral neuropathy and polyneuropathy are terms that describe disorders arising from diffuse disease of the peripheral nerves, usually manifested by weakness, numbness, and autonomic (e. g. blood pressure, gastrointestinal, bladder) dysfunction. Mononeuropathy refers to focal involvement of a single nerve, usually due to a local cause such as trauma, compression, or entrapment. Peripheral neuropathy is a less specific term that is frequently used interchangeably with polyneuropathy, but can also refer to multiple mononeuropathies (mononeuritis multiplex). Polyneuropathy is a specific term that refers to a generalized, relatively homogeneous process affecting many peripheral nerves, with the distal (longest) nerves usually affected most prominently.

Symptoms

The presentation of neuropathy can vary widely depending the underlying cause, location, and mechanism of the nerve dysfunction. The symptoms can start at any age and at times there may be no symptoms. Hereditary forms of neuropathy often are detectable during childhood or adolescence although sometimes symptoms are not reported until years later. Acquired neuropathies, for example diabetic neuropathy, more typically start later in life. Neuropathies can start and progress rapidly in certain cases, such as in Guillain Barre Syndrome where weakness progresses over days to a few weeks. In other cases the symptoms may be insidious in onset and progress slowly, such as neuropathy caused by B12 deficiency and diabetes. Neuropathy may affect the myelin covering (Schwann cell insulation) of nerves, the axons (nerve cell extensions), or both and it may affect motor nerves, sensory nerves, and autonomics, individually or in combination. Polyneuropathy is typically characterized by symmetric distal (“length dependent”) sensory loss, abnormal spontaneous sensations, or weakness. Sensory symptoms, such as numbness and tingling, typically precede motor symptoms such as weakness. Individuals with neuropathy typically present with slowly progressive distal sensory loss and dysesthesias (spontaneous abnormal sensations) such as pins-and-needles, burning or shooting pain in the feet, and mild balance problems. Upper extremity involvement often follows resulting in a “stocking and glove” distribution of sensory loss. As neuropathies progress there is more proximal involvement, mild weakness of the lower legs and hand symptoms may begin. Hereditary neuropathies, such as Charcot-Marie-Tooth disease, are usually not associated with pain or tingling but are associated with slowly progressive loss of sensation, strength, and balance. Autonomic neuropathies can affect many processes such as blood pressure regulation, bowel and bladder control, erectile function, and gastric emptying. Cranial neuropathies affect the nerves that control eye movements, facial strength, facial sensation, hearing, swallowing, and pupillary constriction.

Diagnosis

A comprehensive neurologic history elucidating typical symptoms and possible underlying medical causes and a comprehensive neurologic exam in search of sensory changes, weakness, reflex loss and balance problems is the first step in evaluating a suspected neuropathy. Often a diagnostic test called an EMG (electromyogram) with nerve conduction studies is performed to clarify the type and severity of neuropathy and localize focal entrapment or compression of the nerves. In certain cases, a nerve biopsy may also be requested for diagnostic clarity. In cases of acute auto-immune or inflammatory neuropathies, such as Guillain Barre Syndrome, a spinal tap (lumbar puncture) may be helpful.

Laboratory investigations in search of systemic causes of neuropathy will also be requested and may screen for the following:

• Vitamin B12, thiamine and other nutritional deficiencies
• Metabolic causes – Diabetes, thyroid disease, renal failure
• Rheumatological disease - Lupus, Rheumatoid arthritis, Sjogren disease and small blood vessel inflammation (vasculitis)
• Infectious causes - Lyme disease, HIV, hepatitis
• Neoplastic - Multiple Myeloma, Direct and Remote effects of Cancer (Paraneoplastic neuropathy)
• Abnormal genes with familial neuropathy
• Autoantibodies (directed against nerve components)

Medications and certain toxins may also be implicated in the various causes of neuropathy and can include:

• Alcohol
• Chemotherapy
• Heavy Metals (mercury, lead and arsenic)
• Amiodarone
• Colchicine
• Dapsone
• Isoniazid
• Fluroquinolone antibiotics
• Metronidazole
• Phenytoin
• Excessive Pyridoxine (vitamin B6)
• Statins

Despite exhaustive efforts, the cause of neuropathy remains unknown in up to 50% of cases.

Treatment

Treatment is aimed at treating the underlying cause of a neuropathy where one can be identified (e.g. controlling diabetes, reducing alcohol intake, supplementing deficient nutrients, etc.). 

Treatment may also include immunosuppressant therapies (e.g. glucocorticoids, intravenous immunoglobin) for neuropathies that are inflammatory or autoimmune in origin. 

In cases of nerve entrapment or compression, surgical intervention may be warranted.  

Physical therapy evaluation is important in patients with significant weakness. Appropriate use of ankle-foot orthoses, splints, and walking assistance devices can significantly improve lifestyle in the face of significant disability.

Patients with distal polyneuropathy are at increased risk for developing foot ulcers; proper foot and nail care is especially important in this population. Regular visits to a podiatrist can also help prevent problems.

The Mediterranean diet and aerobic exercise are important lifestyle factors that may help slow progression of peripheral neuropathy. 

Neuropathic pain is usually treated symptomatically with medication in patients with bothersome pain.  Non-narcotic approaches are preferred.

Medications that are commonly prescribed for neuropathic pain are listed below along with the most commonly encountered side effects:

• Gabapentin – dizziness, fatigue, sleepiness
• Pregabalin – dizziness, sleepiness, dry mouth, swelling the extremities, fatigue, weight gain
• Duloxetine – nausea, headache, abdominal discomfort, fatigue, insomnia
• Amitriptyline – dry mouth, sedation, weight gain
• Nortriptyline – dry mouth, sedation, weight gain
• Topical anesthetics like lidocaine patches and capsaicin cream