Continuing Education Activity

About 2.4 percent of the population is affected by peripheral neuropathy. The prevalence increases to 8 percent in older populations. Peripheral neuropathy can be a manifestation of a wide range of pathologies that require further evaluation and/or treatment. Furthermore, peripheral neuropathies must be addressed before they result in complications, such as falls with subsequent hip fractures or pedal infections necessitating amputation. Interprofessional team members must recognize and evaluate peripheral neuropathy so that any underlying cause can be addressed and complications can be prevented, in turn improving outcomes for patients. This activity highlights considerations when evaluating and treating patients with peripheral neuropathies and demonstrates the critical role that interprofessional care teams play in caring for patients suffering from peripheral neuropathies.

Objectives:

• Identify the etiology of peripheral neuropathy.
• Describe the appropriate evaluation of a patient with peripheral neuropathy.
• Explain the treatment and management options available for peripheral neuropathy.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients with peripheral neuropathy.

Introduction

Peripheral neuropathies encompass disorders of peripheral nerve cells and fibers, which manifest secondary to a wide range of pathologies. These nerves include cranial nerves, spinal nerve roots & ganglia, nerve trunks & division, along with nerves of the autonomic nervous system.[1] There are several methods used to classify peripheral neuropathies, including categorizing them as mono-neuropathies, multifocal neuropathies, and polyneuropathies. Further subclassifications can be made by separating peripheral neuropathies as axonal, demyelinating, or mixed, which is essential for treatment and management purposes.[2] The most frequently encountered symptoms of peripheral neuropathy include numbness and paresthesias; pain, weakness, and loss of deep tendon reflexes may accompany these symptoms. Peripheral neuropathies usually develop over months to years, while some may develop more rapidly and be progressive in nature. Peripheral neuropathies have a broad range of severity and clinical manifestations, as they can affect motor, sensory, and autonomic fibers.

Etiology

Peripheral neuropathies stem from a variety of origins, including metabolic, systemic, and toxic causes. Underlying etiologies to consider include: 

• Diabetes mellitus
• Chronic alcoholism
• Nutritional deficiencies (e.g., B1, B6, B12, and vitamin E)
• Inflammatory conditions (e.g., vasculitis)
• Hypothyroidism
• Autoimmune disease (e.g., Sjogren syndrome, lupus, rheumatoid arthritis)
• Infections (e.g.,  Lyme disease, Epstein-Barr virus, hepatitis C, shingles, leprosy, HIV)
• Guillain-Barre syndrome
• Toxins (heavy metals, chemicals)
• Chemotherapy agents
• Medications (antibiotics, cardiovascular medications)
• Tumors (secondary to compression or associated paraneoplastic syndromes)
• Inherited conditions (e.g., Charcot-Marie-Tooth disease, familial amyloidosis)
• Trauma/injury
• Multiple myeloma and its treatments
• Monoclonal gammopathy of undetermined significance (MGUS)

In some cases, a direct cause may not be apparent.

Epidemiology

About 2.4% of the world population is affected by peripheral nerve disorders; the prevalence increases to 8.0% in older populations.[3] Diabetic neuropathy occurs in approximately half of individuals with chronic type 1 and type 2 diabetes. Globally, leprosy remains a common cause of peripheral neuropathy, with the highest prevalence in South East Asia.

The most common genetic sensorimotor polyneuropathy is Charcot-Marie-Tooth disease, specifically, type 1a. The most common mononeuropathy is carpal tunnel syndrome. 

Pathophysiology

The exact pathophysiology of peripheral neuropathy is contingent on the underlying disease. Although a wide assortment of distinct diseases can ultimately lead to peripheral neuropathies, the mechanisms in which peripheral nerves suffer injury exhibit similar patterns. These reactions include segmental demyelination, along with Wallerian and axonal degeneration. 

• Segmental Demyelination: This process refers to the process of degeneration of the myelin sheath, with sparing of the nerve axon. This type of reaction can present in mononeuropathies, sensorimotor, or, principally, motor neuropathies. These are often inflammatory and sometimes immune-mediated. About 20% of symmetrical peripheral neuropathies result from damage to the myelin. Examples include Charcot-Marie-Tooth and neuropathy associated with monoclonal gammopathy of undetermined significance.
• Wallerian Degeneration: This occurs after a nerve axon degenerates due to a lesion or physical compression; the portion distal to the axon passively wastes away, likely due to a lack of nutrients from the cell body. This reaction results in focal mononeuropathy that is secondary to trauma or infarction of the nerve.[4] Wallerian degeneration is immunohistochemically distinct by the localization of neuropeptide Y-Y1 receptor markers.[5] 
• Axonal Degeneration, also known as the dying-back phenomenon: This type of degeneration usually manifests as symmetrical polyneuropathy (around 80%) and tends to cause weakness, most notably weakness in dorsiflexion of the ankles and foot, with accompanied trophic changes to muscle. The axon degenerates in a pattern that starts distal and progresses proximally; this is thought to be because the most distal portion of the axon is particularly vulnerable due to its distance from the cell body, which provides metabolic support.[6] A proposed mechanism is that insult to the nerve causes impaired delivery of local axonal survival factors, resulting in an increased level of calcium intra-axonal, leading to a calcium-dependent cytoskeletal breakdown.[7] Examples of diseases causing axonal degeneration include diabetes, HIV, HCV, and Guillain-Barre syndrome.[8]

History and Physical

The clinical presentation of peripheral neuropathy widely varies depending on the underlying disease process. Patients may complain of symptoms initially starting in their digits and progressing to their proximal limbs. Symptoms range and include changes in sensation, weakness, atrophy, pain, numbness, and even autonomic disturbances. Clinically, these symptoms may resemble that of myelopathies, radiculopathies, autoimmune diseases, and diseases of muscles. Advanced disease may progress to reduced or absent deep tendon reflexes, stocking-glove pattern sensory loss, muscle wasting, and weakness.[3] Obtaining a thorough history is vital in helping to uncover the primary cause of neuropathy. Aside from a meticulous review of past medical history, providers should inquire about toxic exposures, present and past medications, trauma, dietary and nutritional deficiencies, and alcohol use.

Evaluation

Evaluating patients with neuropathy involves a detailed history and physical, including a review of current and past medications. Although there are no standard laboratory or imaging studies to test for peripheral neuropathies, the following studies may aid in the diagnosis and help narrow down the underlying cause of the neuropathy (e.g., inflammatory, infectious, metabolic):  

• Complete Blood Count (Macrocytic anemia may clue the clinician to vitamin B12 or folate deficiency, or even alcohol abuse)
• Metabolic Panels such as BMP or CMP (Look for electrolyte imbalances that can contribute to neuropathy along with renal failure as uremia can also lead to neuropathy).[9]
• HbA1c Testing (Diabetes is a common cause of neuropathy)
• Testing for vitamin and mineral deficiencies such as copper, thiamine, pyridoxine, folate, B12, and vitamin E, which play fundamental roles in nervous system development and maintenance. 
• Heavy metal toxicities such as mercury, lead, and arsenic are known to cause peripheral nerve toxicities along with CNS disturbances.[9]
• Infectious workup for Lyme disease, Epstein-Barr virus, hepatitis C, HIV, and syphilis as a long-standing disease may manifest with peripheral neuropathies and paresthesias.[10][11][12]
• Thyroid function testing.[13]
• Antibody testing for specific autoimmune diseases known to cause peripheral neuropathies such as Sjogren syndrome, lupus, and rheumatoid arthritis.[14]
• Nerve conduction study and electromyography (EMG)
• MRI or CT scans in cases where compression of the nerve is of concern
• Nerve biopsy
• Genetic testing (for inherited neuropathies)
• Urine Test (looking for Bence-Jones proteins as multiple myeloma and its treatments can cause peripheral neuropathy)

Treatment / Management

Treatment of peripheral neuropathies should focus on the treatment of the underlying disease process. For example, glucose control in diabetic neuropathy and alcohol cessation in alcoholic neuropathy. Nutritional deficiencies can have therapy with supplementation of the depleted vitamins or minerals. Unfortunately, not all peripheral neuropathies are reversible. Physical therapy and occupational therapy can be initiated to aid in the improvement of a patient's overall strength and function. Chronic inflammatory demyelinating neuropathy is treated using corticosteroids initially but can also be treated using intravenous immunoglobulin, plasma exchange, and some immunosuppressant drugs.[15]

A referral to a pain specialist can be beneficial for those patients who are suffering from neuropathic pain. Neuropathic pain, particularly in those suffering from small-fiber neuropathies, does not typically respond to simple analgesics. Instead, effective treatment for pain associated with peripheral neuropathies can be with membrane stabilizers, certain anti-epileptics, and tricyclic antidepressants.[16] Transcutaneous electrical nerve stimulation (TENS) is also an option as a noninvasive intervention for pain relief.

Differential Diagnosis

Differentials to consider greatly vary depending on clinical presentation. Symptoms of peripheral neuropathies may resemble that of myelopathies, radiculopathies, autoimmune diseases, and diseases of muscles.

Prognosis

In those diseases where peripheral nerves suffer damage through Wallerian or axonal degeneration, the prognosis is poorer, as the recovery of the nerve is more challenging. For clinical improvement to take place, the axon must regenerate itself and reinnervate the affected muscle or organ. The prognosis of diseases which occur secondary to segmental demyelination is more favorable because remyelination is achieved more quickly, allowing the return of function of the axon.

Complications

Complications of peripheral neuropathies include pain, altered sensation, muscle atrophy, and weakness. Diabetic peripheral neuropathy is infamous for complications, including foot ulcers which can lead to gangrenous digits and limbs, sometimes progressing to amputation.

Consultations

Consultations and referrals to consider for patients suffering from peripheral neuropathy include:

• Neurologist
• Chronic pain physician
• Physical therapy
• Occupational therapy
• Endocrinologist 
• Rheumatologist
• Psychiatry & addiction medicine (for those with alcohol-induced peripheral neuropathy)
• Infectious disease specialist
• Surgeon (for neuropathy secondary to compression)
• Hematology/oncology (for those with neuropathy related to cancer)

Deterrence and Patient Education

Patients require education on the signs and symptoms of peripheral neuropathy. Patients should be made aware that they have an increased risk of injury due to loss of sensation; they should be conscious of any new cuts or damage to their skin as wound healing can be delayed, and the risk for infection increases. Recommend always wearing socks with closed-toed shoes to decrease the risk of infection. Patients should take caution when exposing themselves to hot or cold environments to avoid burns and frostbite. Patients with diabetes should receive counseling on managing their diabetes appropriately. Patients with alcohol-induced neuropathy should get information on cessation.

Pearls and Other Issues

• Charcot-Marie-Tooth is the most commonly inherited cause of peripheral neuropathy[17]

• Demyelinating neuropathies are commonly inflammatory in nature and often treatable[3]

• Neurophysiological tests can differentiate axonal from demyelinating neuropathies

• Overall, the most common polyneuropathy is diabetic sensorimotor polyneuropathy[3]

• Peripheral neuropathy can be divided into mono-neuropathies, multifocal neuropathies, and poly-neuropathies, with further subclassifications into axonal, demyelinating, or mixed types.

• Neuropathic pain can be effectively treated with membrane stabilizers, certain anti-epileptics, and tricyclic antidepressants

Enhancing Healthcare Team Outcomes

A wide range of disease processes can lead to peripheral neuropathies, which routinely require an interprofessional team approach to diagnosis and treatment. This team should include physicians, specialists, specialty-trained nurses, and, when necessary, pharmacists, all working collaboratively to achieve optimal patient care and outcomes. [Level 5] Neuropathies can be both painful and debilitating for patients. Thus it is vital to acquire a prompt diagnosis of the underlying condition followed by the initiation of appropriate treatment(s) to reverse, slow, or stop the progression of the disease. Identifying patients most at risk for neuropathies and implementing a preventative approach to their care can undoubtedly improve outcomes for patients, as seen in the case of diabetic neuropathy. As primary care providers and nurse practitioners are often the first to work up these patients, it is imperative that they are familiar with the full range of etiologies that play a role in the development of peripheral neuropathies, including testing and referrals to the appropriate specialists.