Continuing Education Activity

Peripheral neuropathy (PN) encompasses a broad range of clinical pathologies potentially presenting with peripheral nervous system dysfunction. Patients with PN often present with varying degrees of numbness, tingling, and/or burning in the extremities. While metabolic disorders represent the predominant etiology of extremity pain caused by an underlying PN clinical pathology, broad clinical consideration is given to many clinical conditions. Although there are many possible causes of peripheral neuropathy, the most prevalent subtype, diabetic peripheral neuropathy, can lead to significant complications. The exact cause of diabetic peripheral neuropathy is not known. Mechanical compression (e.g., carpal tunnel), genetics, and social and lifestyle factors such as chronic alcohol consumption and smoking have been implicated. This activity reviews the evaluation and management of diabetic neuropathy and the role of interprofessional team members in collaborating to provide well-coordinated care and enhance patient outcomes.

Objectives:

• Review the pathophysiology of diabetic neuropathy.
• Summarize the treatment of diabetic neuropathy.
• Describe the potential complications of diabetic neuropathy.
• Outline the management of diabetic neuropathy and the role of interprofessional team members in collaborating to provide well-coordinated care and enhance patient outcomes.

Introduction

Peripheral neuropathy (PN) encompasses a broad range of clinical pathologies potentially presenting with peripheral nervous system dysfunction.[1] Patients with PN often present with varying degrees of numbness, tingling, and/or burning in the extremities. While metabolic disorders represent the predominant etiology of extremity pain caused by an underlying PN clinical pathology, broad clinical consideration is given to many clinical conditions.

Although there are many possible causes of peripheral neuropathy, the most prevalent subtype, diabetic peripheral neuropathy, can lead to significant complications. Early assessment of symptoms of peripheral polyneuropathy helps avoid neuropathic foot ulcers to combat potential morbidity and mortality resulting from the pathophysiologic poor wound healing potential, which can lead to limb compromise, local to systemic infection, septicemia, and even death.

The exact cause of diabetic peripheral neuropathy is not known. Proposed theories include metabolic, neurovascular, and autoimmune pathways have been proposed. Mechanical compression (e.g., carpal tunnel), genetics, and social and lifestyle factors such as chronic alcohol consumption and smoking have all been implicated. Perpetually high blood serum glucose appears to lead to damaged small blood vessels, compromising oxygen and nutrients to the nerves. First, the distal sensory and autonomic nerve fibers are damaged; the damage then continues with proximal progression leading to a gradual loss of protective sensation in both the skin and foot joints. Half of the diabetic peripheral neuropathies may be asymmetric. If they are not recognized and preventative foot care is not implemented, patients have an increased risk of injury due to their insensate feet.[2][3][4]

Etiology

Metabolic disorders represent the most common clinical category of etiologies, causing extremity pain from underlying PN conditions.   

Several causes of PN exist, but diabetes mellitus (DM) is the most common etiology. Other underlying etiologies worth considering include:

• Alcohol use disorder
• Nutritional deficiencies (e.g., low B12, high B6)
• Guillain-Barre syndrome
• Toxins (chemotherapy) and overdose
• Hereditary or genetic conditions (e.g., Charcot Marie Tooth disease, amyloidosis, porphyria)
• Infection (HIV)
• Inflammatory conditions (lupus, rheumatoid arthritis)
• Hypothyroidism
• Malignancy

Risk factors for PN include:

• Advanced age
• Hypertension
• Peripheral vascular disease
• Smoking
• Dyslipidemia
• Poor glucose control
• A long duration of diabetes
• Heavy intake of alcohol
• Positive HLA-DR3/4 genotype

Epidemiology

At the time of diagnostic DM onset in patients, the literature reports about 10% to 20% of patients being concomitantly diagnosed with PN. However, studies analyzing patients with DM at an increasing duration of stages of the disease in terms of chronicity report increasing prevalence rates for the DM and PN association. After five years, 26% have peripheral neuropathy, and 41% of patients with diabetes have neuropathy at ten years. The literature reports that 50% to 66% of patients with DM will eventually develop PN during their lifetime.[5]

Clinically, about half of patients with diabetic PN can present with asymmetric sensory changes.[6][7] Obesity and genetic factors increase the risk of developing diabetes. Peripheral and autonomic neuropathies are one of the leading causes of morbidity in diabetes mellitus. At five years, the risk of death for patients with a diabetic foot ulcer is 2.5 times as high as the risk of death for a patient with diabetes who does not have a foot ulcer. The rate of emergency department visits for diabetic foot ulcers and associated infection exceeds the rates for congestive heart failure, renal disease, depression, and most forms of cancer.[8][9][10]

Pathophysiology

Diabetic peripheral neuropathy encompasses sensory, motor, and autonomic neuropathy. Implicated causes of peripheral nerve damage include oxidate stress damage, accumulation of sorbitol, advanced glycosylation end products, and a disturbance of hexosamine, protein kinase C, and polymerase pathways. Neurovascular impairment with poor repair processes and endothelial dysfunction also have been implicated.[7]

Toxicokinetics

Transient hyperglycemia is often tolerated by normal compensatory physiological function and homeostatic mechanisms of blood sugar control. However, in chronically elevated states, it can have toxic effects such as neuropathy. For patients diagnosed early with type 1 diabetes mellitus, tight glucose control can reduce the risk of diabetic peripheral neuropathy by 78%.[11] In contrast, typically, with a later diagnosis of long-standing hyperglycemia or type 2 diabetes, tight glucose control only reduces the risk by 5% to 9%.[11]

History and Physical

Symptoms of burning, numbness, or tingling in the feet tend to worsen at night are characteristic. Patients with pedal paresthesias and dysesthesia often describe a nonspecific constellation of symptoms resulting in difficulty with ambulation and other basic activities of daily living (ADL). The characteristic polyneuropathy and distal sensory peripheral neuropathy are present in about 80% of DM PN patients. This is often described as a "stocking-glove distribution," which can take several years to develop.[12]

Since the protective sensation is lost after sensory impairment, the standard Semmes-Weinstein 5.07 monofilament 10 grams of pressure protective sensation test may be accurately sensed even after a neurotrophic ulcer has developed. Simply timing the duration that a vibrating 128 Hz tuning fork is felt at the dorsal hallux interphalangeal joint (usually 18 seconds) can be used to detect sensory deficits earlier and quantify severity. Decreased light touch sensation or loss of ankle reflexes tend to occur earlier in the disease process, while the detectable loss of protective sensation tends to occur later in the disease, sometimes even after a neuropathic ulcer develops. Needle electromyography (EMG) and nerve conduction velocity testing can be both painful and expensive and mainly test the large myelinated fibers. Epidermal nerve fiber density testing can be performed to evaluate the small unmyelinated fibers.[13]

Autonomic Symptoms

Autonomic neuropathy is also very common in diabetes and can affect the gastrointestinal, cardiovascular, and genitourinary organs. Typical symptoms include:

• GI: Abdominal discomfort, dysphagia, nausea, fecal incontinence, constipation, diarrhea
• Cardiac: Hypotension, sinus tachycardia, variable heart rate, syncope
• Bladder: Weak urinary stream, straining to void, incomplete emptying of bladder, 
• Skin: Heat intolerance, gustatory sweating, extreme diaphoresis
• Nervous: Carpal tunnel syndrome, radiculopathy, lumbosacral, and cervical neuropathy. In addition, cranial nerves 3,4,6, and 7 may be affected.

Evaluation

The medical history review of systems and medications captures most of the causes of peripheral neuropathy. Electromyography and/or nerve conduction studies are suggested if there are severe or rapidly progressive symptoms or motor weakness. Minor symptoms may not need laboratory workup. Persistent unexplained symptoms may warrant laboratory investigation, including serum glucose, hemoglobin A1c, complete blood count, erythrocyte sedimentation rate, rapid plasma reagin, serum electrophoresis, and vitamin B1, B6, and B12 level. A lower extremity neurological physical exam should be performed to include muscle strength, reflex evaluation, and sensation evaluation (light touch with a monofilament, vibratory sensation, and proprioception). A dermatological exam demonstrating dry/cracked skin may point to autonomic neuropathy, while pedal deformities (hammertoes) suggest motor neuropathy.[12]

Measurement of epidermal nerve fiber density (ENFD) by skin biopsy can be considered in patients with idiopathic cases. The number and morphology of axons within the epidermis can be evaluated, and intraepidermal nerve fiber density is compared to age-dependent normal values.[14][15]

Treatment / Management

Many patients with neuropathy have mild to moderate numbness symptoms yet still retain protective sensations in their feet. They may only need reassurance and education as to the cause of the numbness. Periodic follow-up is essential. With improved glycemic control, paresthesias and dysesthesias may diminish within one year. After peripheral arterial disease and radiculopathy are ruled out, painful symptoms that disturb sleep or activities of daily living can be treated with pregabalin, gabapentin, or anti-depressants.[16] These medications have been shown to reduce the symptoms by 30% to 50% in many patients. Some patients also respond to the over-the-counter antioxidant alpha-lipoic acid. Additionally, although classified as a medical food, the prescription containing L-methyl folate, pyridoxal 5'-phosphate, and methylcobalamin for the dietary management of endothelial dysfunction has been shown to improve nerve fiber density and monofilament sensation significantly.[17]

Depleting substance P with topical capsaicin cream may help some patients who can tolerate the initially increased burning.[18][19][20] For patients with painful diabetic peripheral neuropathy, a capsaicin 8% patch in serial treatments can provide modest improvements in pain and sleep quality.[21][16]

Diabetic gastroparesis may be managed with erythromycin and metoclopramide. Tegaserod is a newer agent but is only available on an emergency basis because of serious adverse cardiac effects.

Some patients may benefit from the use of vitamins, especially zinc.

Erectile dysfunction is managed with phosphodiesterase inhibitors, but not everyone has a response. A penile prosthesis may be of benefit.

Orthostatic hypotension may be managed by increased salt and fluid intake and compression stockings. If that fails, steroids may be required. Glycopyrrolate is used to manage sweating but often does not work.

• All infected diabetic foot ulcers need debridement or amputation
• Gastroparesis may be managed by a jejeunostomy tube, especially in patients losing weight.
• A pancreas transplant is an option and has been shown to stabilize autonomic function.
• Physical therapy is a must for all patients with PN, especially those with muscle pain and weakness. Also, occupational therapy may be necessary when there is a functional loss. Speech therapy is needed to help patients with dysphagia and the risk of aspiration.

Differential Diagnosis

• Alcohol-associated neuropathy
• Nutritional linked neuropathy
• Uremic neuropathy
• Vasculitic linked neuropathy
• Vitamin B-12 deficiency
• Toxic metal neuropathy

Staging

Staging

1. NO: No neuropathy
2. N1a: Signs but no symptoms of neuropathy
3. N2a: Mild polyneuropathy or autonomic neuropathy, patient able to walk on heels
4. N2b: Severe polyneuropathy and patient unable to walk on heels
5. N3: Disabling polyneuropathy

Prognosis

Poorly treated diabetics have higher morbidity and complication rates associated with PN than well-controlled diabetics. PN often leads to skin breakdown, infection, ulceration, and eventually to amputation. Further, the treatment of PN is not satisfactory, and adverse cardiac events are common. Less than a third of patients achieve good pain control. For most patients with PN, the quality of life is poor.

Complications

• Amputations of the toes, foot, or leg
• Infections of the foot
• Dizziness falls
• Diarrhea, failure to thrive, dehydration
• Pain
• Cardiovascular neuropathy can cause death

Deterrence and Patient Education

According to American Diabetes Association, people with diabetes should have a complete foot examination annually and a visual examination of the feet at each visit, usually every three to four months. Patients should be educated well on monitoring blood sugar levels and performing self-examination of their feet every day to look for ulcers, wounds, or broken skin. They should also follow a diet plan and take medications on time, as advised by the doctor. They should be made aware of the contribution role of alcohol and smoking in peripheral neuropathy and advised a plan to quit if required. Moreover, abnormally fitting shoes should not be worn by the patient.

Pearls and Other Issues

The lower extremities are especially prone to the repetitive microtrauma-induced complications of polyneuropathy. There is an increased propensity to develop not only recurrent neuropathic ulcers but Charcot neuroarthropathy and, to a lesser extent, motor neuropathy. Additionally, as patients age, their nails become dystrophic, and the risk of subungual ulcerations, gangrene, and osteomyelitis increases with decreased protective sensation. Periodic pedal-focused examinations are essential. Professional foot care, along with therapeutic shoes and insoles, have helped to reduce the lower limb amputation rates in patients with diabetes mellitus.

Enhancing Healthcare Team Outcomes

Diabetic neuropathy affects many organ systems and is best managed by an interprofessional team. Because there is no cure for the disorder, the key is prevention. All people with diabetes should have a dietary consult and receive education on what foods they should eat and what to avoid. The diet should be realistic and focused on lowering blood glucose levels. The patients should also enter a rehabilitation program or some exercise. Losing weight makes it easier to control blood sugars and lowers blood pressure and lipids. A podiatry consult is vital as protection of the foot is necessary. Further, all people with diabetes should be informed about avoiding trauma and undergoing any invasive procedure on the feet without prior clearance from the endocrinologist. In addition, the patient should be told to avoid cold or hot temperatures.

A dedicated diabetic nurse should educate the patient about all aspects of diabetes and the importance of euglycemia. Patients should be taught how to monitor their blood glucose and how to use portable glucose monitors. The pharmacist should offer education about the medications, their benefits, and their adverse effects.

Compliance with diabetic medications is vital. Finally, patients who develop neuropathy also tend to have nephropathy and retinopathy- hence, all people with diabetes should be referred to a nephrologist and ophthalmologist. There should be open communication between the interprofessional team so that all patients are provided the available standard of care with minimal morbidity. Foot and nail care nurses monitor patients, provide education, and inform the team of the patient's condition. Pharmacists educate patients about the use of medications and the importance of compliance.[22][23] [Level 5]

Outcomes

In general, patients with diabetes mellitus (DM) who are not compliant with treatment or undertreated usually tend to have a poorer outcome than patients who undergo treatment. The neuropathy frequently results in skin breakdown, ulceration, and, eventually, an infection. Amputation of the toes and limbs is not uncommon. However, the actual treatment of diabetic neuropathy is not perfect, and often most treatments do not work. Complete relief from symptoms of neuropathy is rare. Overall, the mortality rates are highest in patients with DM with autonomic neuropathy, especially those who have cardiac dysfunction. The overall mortality rates are 15% to 30% over ten years, but there is also significant morbidity from limb amputation. Other symptoms that make the quality of life poor include syncopal attacks, diarrhea, constipation, and continuous pain.[2][24] [Level 5]