Continuing Education Activity

Peripheral neuropathy encompasses a broad range of clinical pathologies potentially presenting with peripheral nervous system dysfunction. Patients with peripheral neuropathy often present with varying degrees of numbness, tingling, aching, burning sensation, weakness of limbs, hyperalgesia, allodynia, and pain. Neuropathic pain has been characterized as superficial, deep-seated, or severe, unremitting pain with exacerbation at night. While metabolic disorders represent the predominant etiology of extremity pain caused by an underlying peripheral neuropathy clinical pathology, broad clinical consideration is given to many clinical conditions. There are many possible causes of peripheral neuropathy; the most prevalent subtype, diabetic peripheral neuropathy (DPN), can lead to significant complications ranging from paresthesia to loss of limb and life. 

Because peripheral neuropathy is so common in patients with diabetes, the American Diabetes Association (ADA) recommends clinicians evaluate patients with type 2 diabetes when they are diagnosed; in patients with type 1 diabetes, clinicians should assess for peripheral neuropathy 5 years after diagnosis and then annually. Peripheral neuropathy is primarily diagnosed clinically. Diabetic peripheral neuropathy management consists of several strategies. The aim of this activity is to enhance healthcare learners' competence in selecting appropriate diagnostic tests, managing peripheral neuropathy, and fostering effective interprofessional teamwork to improve outcomes.

Objectives:

• Identify the pathophysiology of diabetic peripheral neuropathy.

• Implement evidence-based treatment strategies for diabetic peripheral neuropathy.

• Determine the potential complications of diabetic peripheral neuropathy.

• Implement collaboration strategies with interprofessional team members to provide well-coordinated care and enhance patient outcomes.

Introduction

Peripheral neuropathy encompasses a broad range of clinical pathologies potentially presenting with peripheral nervous system dysfunction.[1] Patients with peripheral neuropathy often present with varying degrees of numbness, tingling, aching, burning sensation, weakness of limbs, hyperalgesia, allodynia, and pain. This pain has been characterized as superficial, deep-seated, or severe, unremitting pain with exacerbation at night.[2] While metabolic disorders represent the predominant etiology of extremity pain caused by an underlying peripheral neuropathy 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 (DPN), can lead to significant complications ranging from paresthesia to loss of limb and life.[2] 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.[3][4][5] DPN is primarily diagnosed clinically through history and neurological assessment of small fiber sensation with temperature changes or pinpricks, large fiber sensation with vibrations, and ulceration risk with pressure testing using a 10 g monofilament. Neurology consultation and specialized testing, including nerve conduction studies and intraepidermal nerve fiber density testing, are only indicated for patients with atypical clinical features (eg, rapid symptom onset, severe neuromotor impairment, and asymmetrically abnormal sensation).[6]

The exact cause of DPN is not known. Proposed theories include metabolic, neurovascular, and autoimmune pathways have been proposed. Mechanical compression (eg, carpal tunnel), genetics, and social and lifestyle factors such as chronic alcohol consumption and smoking have all been implicated. Perpetually high blood serum glucose leads to insulin resistance, promoting oxidative stress, inflammation, and cell damage.[7] First, the distal sensory and autonomic nerve fibers are damaged; the damage continues with proximal progression, leading to a gradual loss of protective sensation in the skin and foot joints. DPN management consists of several strategies, including preventative measures (eg, patient education, proper foot care, correct shoe wear, and annual foot exam), glucose control, dietary modifications, weight loss, and pain control. Half of the diabetic peripheral neuropathies may be asymmetric.[6] If not recognized and preventative foot care is not implemented, patients have an increased risk of injury due to their insensate feet.[8][9]

Etiology

Metabolic disorders represent the most common clinical category of etiologies, causing extremity pain from underlying peripheral neuropathy conditions. Several causes of PN exist, but diabetes mellitus is the most common etiology. Other underlying etiologies include:

• Alcohol use disorder [10]
• Nutritional deficiencies (eg, low B12, high B6) [11]
• Guillain-Barre syndrome [12]
• Toxins (eg, chemotherapy) and overdose [13][14][15][16]
• Hereditary or genetic conditions (eg, Charcot Marie Tooth disease, amyloidosis, porphyria) [17][18][19][20][21][22]
• Infection (eg, HIV)[23][24][25]
• Inflammatory conditions (eg, lupus and rheumatoid arthritis) [26][27]][28]
• Hypothyroidism [29][30][31][32]
• Malignancy
• Trauma [33][34]

Diabetic Peripheral Neuropathy Risk Factors 

Risk factors for DPN include:

• Advanced age
• Hypertension
• Peripheral vascular disease
• Smoking
• Dyslipidemia
• Poor glucose control
• Long-standing diabetes
• Obesity
• Excessive alcohol consumption
• Positive HLA-DR3/4 genotype

Epidemiology

At the time a patient is diagnosed with diabetes, the literature estimates that 10% to 20% of these patients are concomitantly diagnosed with DPN; however, studies analyzing patients with long-standing diabetes mellitus report that DPN has a higher prevalence in those patients. After 5 years, 26% have peripheral neuropathy, and 41% of patients with diabetes have neuropathy at 10 years. The literature reports that 50% to 66% of patients with diabetes mellitus will eventually develop DPN during their lifetime.[35] DPN can occur in both type 1 and type 2 diabetes, but the prevalence is higher in individuals with type 2 diabetes due to the longer duration and higher rates of comorbidities.[36] Diabetes mellitus is also the most common cause of Charcot neuroarthropathy, with an incidence of 0.1% to 0.4% and as high as 29% in patients with peripheral neuropathy.[37]

About half of patients with DPN can clinically present with asymmetric sensory changes.[38][39] Obesity and genetic factors increase the risk of developing diabetes. Peripheral and autonomic neuropathies are some of the leading causes of morbidity in diabetes mellitus. At 5 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.[40][41][42]

Pathophysiology

DPN encompasses sensory, motor, and autonomic neuropathy. Increased serum glucose leads to insulin resistance, dyslipidemia, and oxidative stress of the endoplasmic reticulum and mitochondria. These processes contribute to accumulating reactive oxygen species (ROS), inflammation, and cellular damage. The infiltrated macrophages inside peripheral nerve cells trigger cytokine and chemokine production, promoting inflammation and nerve fiber damage.[7] In addition, implicated causes of peripheral nerve damage include advanced glycosylation end products and disturbance of hexosamine, protein kinase C, and polymerase pathways. Neurovascular impairment with poor repair processes and endothelial dysfunction also have been implicated.[39]

Toxicokinetics

Transient hyperglycemia is often tolerated by normal compensatory physiological function and homeostatic mechanisms of blood sugar control. However, serum glucose can have toxic effects such as neuropathy in chronically elevated states. For patients diagnosed early with type 1 diabetes, tight glucose control can reduce the risk of diabetic peripheral neuropathy by 78%.[36] 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%.[36][43]

History and Physical

Because peripheral neuropathy is so common in patients with diabetes, the American Diabetes Association (ADA) recommends clinicians evaluate patients with type 2 diabetes when they are diagnosed; in patients with type 1 diabetes, clinicians should assess for peripheral neuropathy 5 years after diagnosis and then annually. Peripheral neuropathy is primarily diagnosed clinically through history and neurological assessment of small fiber sensation with temperature changes or pinpricks, large fiber sensation with vibrations, and ulceration risk with pressure testing using a 10 g monofilament.[6]

Clinical History

Clinicians should perform a complete medical history, including diabetes, obesity, dyslipidemia, and hypertension. Furthermore, a review of systems and medications captures most of the underlying causes of DPN. Other risk factors for peripheral neuropathy should also be noted (eg, older age and diabetes control). Characteristic symptoms of peripheral neuropathy include burning, numbness, or tingling in the feet that worsens at night.[6] 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). Clinical features of peripheral neuropathy and distal sensory peripheral neuropathy are present in about 80% of DPN patients, often described as a "stocking-glove distribution," which can take several years to develop.[44]

Physical Examination

A lower extremity neurological physical exam should include muscle strength, reflex, and sensation evaluation, including light touch with a monofilament, vibratory sensation, and proprioception. A dermatological exam demonstrating dry/cracked skin may point to autonomic neuropathy, while pedal deformities (eg, hammertoes) suggest motor neuropathy.[44]

Small fiber sensation is assessed with temperature changes or pinprick testing. A patient's risk for developing ulcers is evaluated by determining the individual's ability to feel pressure. Since the protective sensation is lost after sensory impairment, the standard Semmes-Weinstein 5.07 monofilament 10 g of pressure protective sensation test may be accurately sensed even after developing a neurotrophic ulcer.[6]

Large fibers are assessed through vibratory sensation.[6] Simply timing the duration that a vibrating 128 Hz tuning fork is felt at the dorsal hallux interphalangeal joint, normally 18 seconds in most individuals, 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. In contrast, 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.[45]

Autonomic Symptoms

Autonomic neuropathy is also prevalent in diabetes and can affect the gastrointestinal, cardiovascular, and genitourinary organs. Common symptoms in each organ system 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, cervical neuropathy, and impairment of cranial nerves III, IV, VI, and VII

Evaluation

Neurology consultation and specialized testing, including nerve conduction studies and intraepidermal nerve fiber density testing, are only indicated for patients with atypical clinical features (eg, rapid symptom onset, severe neuromotor impairment, and asymmetrically abnormal sensation).[6] Electromyography and nerve conduction studies are suggested for severe or rapidly progressive symptoms or motor weakness.

Intraepidermal nerve fiber density is the preferred test for small fiber neuropathy evaluation. Intraepidermal nerve fiber density measurement 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.[46][47]

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 levels.

Treatment / Management

DPN management consists of several strategies, including preventative measures (eg, patient education, proper foot care, correct shoe wear, and annual foot exam), glucose control, dietary modifications, weight loss, and pain control. Many patients with neuropathy have mild to moderate numbness symptoms yet retain protective sensation in their feet. Patients may only need reassurance and education regarding the cause of the numbness. Periodic follow-up is essential. Peripheral arterial disease and radiculopathy should be ruled out. With improved glycemic control, paresthesias and dysesthesias may diminish within one year. In 2022, the Current Pain and Headache Reports proposed a treatment algorithm for painful diabetic neuropathy.[48] The algorithm is divided into conservative, pharmacologic, and interventional therapies, subcategorized as first, second, and third-line treatment.

Conservative Therapy

• First-line therapy: Physical therapy
  • Weight-bearing exercises
  • Tai chi massage therapy
• Second-line therapy: Health management
  • Optimization of glucose
  • Properly manage comorbidities
  • Weight loss
  • Healthy diet
• Third-line therapy: Minimally invasive treatment
  • Acupuncture
  • Transcutaneous electrical nerve stimulation (TENS)

 Pharmacological Therapy

• First-line agents
  • Gabapentinoids (eg, pregabalin and gabapentin)
  • Duloxetine
• Second-line agents
  • Serotonin and norepinephrine reuptake inhibitors (eg, venlafaxine)
  • Tricyclic antidepressants (eg, amitriptyline)
  • Tapentadol
  • Capsaicin patch 8%
  • Lidocaine patch 5%
• Third- and Fourth-line agents
  • Tramadol
  • Opioid
  • Intravenous agents (eg, lidocaine, ketamine)

Interventional Therapy

• First-line therapy: Dorsal column spinal cord stimulation
  • Typically 10 kHz
  • Tonic waveforms
• Second-line therapy: Other neuromodulation options
  • Burst spinal cord stimulation
  • Dorsal root ganglion spinal cord stimulation
  • Peripheral nerve stimulation
• Third-line therapy: Intrathecal drug delivery system
  • Intrathecal morphine, fentanyl, or hydromorphone
  • Intrathecal ziconatide

DPN can affect other body areas, including the digestive, endocrine, and vascular systems. Diabetic gastroparesis may be managed with erythromycin and metoclopramide.[49][50] Tegaserod is a newer agent but is only available on an emergency basis because of serious adverse cardiac effects.[51] Erectile dysfunction is managed with phosphodiesterase inhibitors, but not everyone has a response. A penile prosthesis may be of benefit.[52] 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.[53]

Alternative Therapies

Some patients may also benefit from supplements, but studies are scarce. Omega-3 polyunsaturated fatty acid oral supplements (ie, fish oil) have perhaps the best evidence in attenuating sensory loss and reducing the incidence of peripheral neuropathy.[54] One randomized controlled trial reported a significant increase in corneal nerve fiber length in patients with dry eye disease compared to placebo.[55] Several studies have linked vitamin D deficiency with an increased risk for diabetic peripheral neuropathy, diabetic ulcer, and cardiovascular autonomic neuropathy.[56] In addition, a single high-dose intramuscular injection of vitamin D supplementation 600,000 IU has significantly improved patients' quality of life and perception of foot problems.[57] There is moderate evidence that alpha lipoic acid supplementation decreases pain with little to no adverse effects.[58][59][60] 

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 significantly improved nerve fiber density and monofilament sensation.[61] Scant evidence shows that supplementation with vitamins C and E prevents diabetic complications. There is no evidence that taking vitamin B12 oral supplements improves DPN.[62] Depleting substance P with topical capsaicin cream may help some patients who can tolerate the initially increased burning.[63][64][65] For patients with painful diabetic peripheral neuropathy, a capsaicin 8% patch in serial treatments can provide modest improvements in pain and sleep quality.[66][67]

Differential Diagnosis

Differential diagnoses of DPN include the following:

• Alcohol-associated neuropathy
• Nutritional linked neuropathy
• Uremic neuropathy
• Vasculitic linked neuropathy
• Vitamin B12 deficiency
• Toxic metal neuropathy

Staging

While numerous classifications have attempted to categorize different types of diabetic neuropathies, most experts agree that a classification based on the clinical manifestation is the most appropriate.[68] The following classification of diabetic neuropathies described initially by Thomas is the most accepted today:

• Rapidly reversible
  • hyperglycemic neuropathy
• Generalized symmetrical polyneuropathies
  • Chronic sensorimotor 
  • Acute sensory
  • Autonomic
  • Prediabetic or impaired glucose tolerance neuropathy
• Focal and multifocal neuropathies
  • Cranial
  • Thoracolumbar radiculoneuropathy
  • Focal limb
  • Proximal motor (eg, amyotrophy)
• Superimposed chronic inflammatory demyelinating neuropathy [69]

The most common type of DPN is generalized symmetrical sensorimotor polyneuropathy.[70] The staging of diabetic neuropathy was described by Dyck and divided into 4 stages:[71]

• Stage 0: no neuropathy
• Stage 1: asymptomatic neuropathy
• Stage 2: symptomatic neuropathy
• Stage 3: disabling neuropathy

Prognosis

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

Complications

Common complications of DPN include the following:

• Amputations of the toes, foot, or leg
• Infections of the foot
• Falls secondary to dizziness
• Diarrhea, failure to thrive, and dehydration
• Pain
• Cardiovascular neuropathy can cause death

Deterrence and Patient Education

Preventative strategies are an essential aspect of DPN management. According to the 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 3 to 4 months. Patients should be educated on monitoring blood sugar levels and self-examining their feet daily 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. Clinicians should make patients aware of the contributing role of alcohol and smoking in peripheral neuropathy and recommend a plan to quit as needed. 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 also 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 and therapeutic shoes and insoles have helped 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 nurse proficient in diabetes management 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 use portable glucose monitors. The pharmacist should offer education about the medications, their benefits, and their adverse effects.

Compliance with medication therapy to treat diabetes 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 with 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.[72][73] 

Outcomes

In general, patients with diabetes mellitus 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 diabetes mellitus with autonomic neuropathy, especially those who have cardiac dysfunction. The overall mortality rates are 15% to 30% over 10 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.[70][74]