The Management of Diabetic Neuropathy and Glycemic Control in Long-Term Care Facilities (Part II of III)
The prevalence of diabetes mellitus is estimated at 180 million, and the World Health Organization projects that prevalence will double from that level by the year 2030.1 Approximately half of the patients with diabetes mellitus will develop a preventable but devastating complication called diabetic peripheral neuropathy (DPN).2
This educational activity recaps the epidemiology, classification, diagnosis, and pathology of diabetic neuropathy and summarizes the optimal pharmacological and nonpharmacological methods of treatment.
Defining the Challenge
Definition and Prevalence
DPN is often defined as “the presence of symptoms or signs of peripheral nerve dysfunction in patients with diabetes after the exclusion of other causes.”3 There are several challenges to using this definition. Clinicians detect peripheral nerve dysfunction based on patients’ presenting symptoms and/or physical examination.4 Most often, symptom- and/or physical examination–based scales are used, but these may lack sensitivity.4,5 Some experts advocate using a large panel of different tests together to maximize sensitivity, and scales may be supplemented by electrodiagnostic studies such as nerve conductions, electromyography (which is sensitive for large-diameter sensory and motor fiber dysfunction), autonomic testing, and epidermal nerve fiber density testing (which is sensitive for small fiber dysfunction).6
A second challenge comes from the “exclusion of other causes.”3 Diabetes mellitus can affect sensory nerves, motor nerves, and autonomic nerves. Distal symmetric polyneuropathy typically leads to both small and large nerve fiber damage. Frequently, combinations of nerves are affected in what is termed polyneuropathy.7
Classification systems have been proposed based upon the types and patterns of peripheral nerves involved.3 For every one of these sites of pathology, there will be a list of potential causes. A detailed description of all the causes of every type of peripheral nerve dysfunction that can be seen in a patient with diabetes mellitus is beyond the scope of this monograph. However, there are certain patterns of neuropathy that are highly unlikely to be related to diabetes mellitus. The most common presentation of DPN (and its differential diagnoses) is presented later in this monograph.
The challenges of the definition of DPN, as the challenge of ascertainment bias, make the true prevalence of DPN difficult to know. Dyck and colleagues attempted to determine the extent of diabetic neuropathies in a community-based study of 380 patients with clinically recognized diabetes mellitus.8 Of these patients, 102 had insulin-dependent diabetes mellitus (IDDM), and 278 had non–insulin-dependent diabetes mellitus (NIDDM). Two-thirds of the IDDM patients had some type of neuropathy; of these patients, 54% had polyneuropathy, 22% had asymptomatic carpal tunnel syndrome, 11% had symptomatic carpal tunnel syndrome, 7% had visceral autonomic neuropathy, and 3% had other neuropathies. Patients with NIDDM had similar rates of neuropathies: polyneuropathy (45%), asymptomatic carpal tunnel syndrome (29%), symptomatic carpal tunnel syndrome (6%), visceral autonomic neuropathy (5%), and other neuropathies (3%).
DPN Presentation Is Typically Sensory and Insidious in Onset
Chronic sensorimotor polyneuropathy is the most common form of DPN.3 Up to 50% of the patients with this type of neuropathy experience painful symptoms such as burning pain, electrical or stabbing sensations, paresthesia, hyperesthesia, and deep aching pain. From 10% to 20% have symptoms severe enough to require treatment.9 In most patients, the pain is worse at nighttime.3
DPN presentation is mainly sensory and insidious in onset.3 Symptoms begin in the toes and the feet and gradually extend proximally.10 Later, the fingers and hands may become affected, again with proximal spread. Usually, when extensive, the anterior abdominal wall may be involved, and sensory loss gradually spreads laterally around the trunk. Patients may lose their ability to feel, identify, or manipulate smaller objects.11 They can gradually lose the capacity to ascertain temperature or sense painful or threatening stimuli. The loss of innervation can lead to atrophy of essential pedal muscles, resulting in deformities (eg, hammertoes) that leave patients vulnerable to ulceration.11,12 Sensorimotor neuropathy is the main risk factor for developing diabetic foot ulcers, which are the predominant risk factor for lower-extremity amputations in diabetes patients.
Motor involvement is less frequent than sensory involvement.10 However, when severe, this neuropathy causes weakness of distal leg muscles.
The autonomic nervous system may become widely involved itself in diabetic neuropathy.11 Diabetic autonomic neuropathy can develop in patients with type 1 or type 2 diabetes. While autonomic neuropathy can occur at any stage of diabetes, those over age 40 years who have had the disease for more than 25 years and have difficulty controlling their blood sugar run the highest risk.13
Most patients have symptoms that are not severe, but some have significant morbidity and even mortality, especially with cardiovascular autonomic neuropathy (CAN).3 Symptoms of autonomic neuropathy range from cardiac (ie, early fatigue, weakness with exercise, and postural hypotension) to gastrointestinal (ie, gastroparesis, erratic glucose control, abdominal pain, early satiety, nausea, vomiting, constipation, and diarrhea). Other symptoms include sexual, bladder, and sudomotor dysfunction.
Cardiovascular Autonomic Neuropathy
CAN affects both the sympathetic and parasympathetic innervation of the heart and coronary vessels.11 Primary symptoms of CAN are orthostatic hypotension and decreased heart rate variability, and CAN may contribute to left ventricular dysfunction, silent or asymptomatic myocardial infarction, and exercise intolerance.11,14 There is evidence that the disease process may begin early in the course of diabetes but remains asymptomatic until later stages.11,14
Gastrointestinal Autonomic Neuropathy
Diabetic autonomic neuropathy can affect the entire gastrointestinal system. Symptoms range from mild discomfort to disabling impairment of daily activities. Gastroesophageal dysfunction manifests as gastroesophageal reflux disease in roughly 30% of diabetes patients.15 Delayed gastric emptying and gastric retention, which are present in one-fourth of patients with diabetes, can result in early satiety, bloating, epigastric pain (heartburn), nausea, vomiting, and anorexia.16 Gastroparesis can also complicate pharmacotherapy by delaying the absorption of glucose or antidiabetic medication.
Diabetic mononeuropathy has an acute onset, usually is asymmetric, and involves the cranial, truncal, and peripheral nerves.17 The neuropathy generally resolves spontaneously in 3 to 12 months, but in rare cases may last for years.
Cranial neuropathies are rare, and include the III, IV, VI, and VII cranial nerves.3 Cranial neuropathy affects the nerves connected with the brain that control sight, eye movement, hearing, and taste.18 Most often, cranial neuropathy affects the nerves that control the eye muscles. Neuropathy starts with pain on one side of the face near the affected eye. Later, the eye muscle becomes paralyzed, resulting in double vision. Nevertheless, symptoms of this type of neuropathy usually resolve within 2 or 3 months.
Truncal neuropathy usually presents subacutely with painful paresthesia in variable size patches in the trunk, either unilaterally or bilaterally.19 Associated involvement of motor nerve fibers can lead to bulging of the abdominal wall in the paresthetic areas. Clinicians should check for a patch of sensory abnormality in the region of the symptoms.
Proximal neuropathies may develop in long-standing diabetics with poor metabolic control and may lead to weight loss.20 A prominent feature is pain that is often severe and located in the hips and thighs.20,21 Proximal neuropathy causes weakness in the legs and often leaves patients unable to emerge from a sitting to a standing position without aid. The length of the recovery period varies, depending on the type of nerve damage.
Early Detection of DPN Is Critical
Boulton and colleagues offer the following reasons to emphasize the importance of early detection and management of DPN3:
• Nondiabetic neuropathies may occur in diabetics, thereby confusing the diagnostic process
• A number of treatment options exist for symptomatic DPN
• Up to half of DPN may be asymptomatic, leading to injuries the patient does not perceive, and contributing to amputations for complications of diabetes
• Autonomic neuropathies may involve multiple organ systems
• Morbidity and mortality increase with autonomic neuropathy, particularly if CAN is present
Diagnosing chronic DPN requires clinicians to exclude nondiabetic causes.3 Other forms of neuropathy, including chronic inflammatory demyelinating polyneuropathy, vitamin B12 deficiency, hypothyroidism, and uremia, occur in more frequency in diabetics than in the general population and require ruling out. The differential diagnosis includes various forms of hereditary neuropathy, as well as numerous causes of acquired neuropathy.22
The diagnosis of DPN is made on the basis of a careful clinical examination and, when indicated, electrodiagnostic studies.3 The combination of using more than one test has a > 87% sensitivity in detecting DPN.
Table 1 lists the procedures clinicians should perform for all of their diabetic patients on an annual basis.3
Diagnosing Diabetic Neuropathy
Diagnosing diabetic neuropathy requires clinicians to perform a thorough physical examination, elicit patient history, and use clinical judgment; it does not necessarily hinge on any particular neurologic test or finding.17 Some patients such as Vivian (Figure 1) present with severe pain but only minimal neurologic deficits, while others present with foot ulcers but have no pain or neurologic symptoms.
A complete medical evaluation enables clinicians to classify the diabetes, detect the presence of diabetes complications, review previous treatment and glycemic control in patients with established diabetes, assist in formulating a management plan, and provide a basis for continuing care.4
Table 2 lists the factors clinicians should consider when evaluating patients presenting with symptoms of diabetic neuropathy.17
No single test can definitely diagnose diabetic neuropathy, and clinical judgment must play a role.5 Good communication skills are important when assessing patients presenting with symptoms of diabetic neuropathy. Patient descriptions of burning, tingling, or pain would suggest diabetic neuropathy. However, clinicians should understand that there are other potential causes of diabetic neuropathy that must be excluded before a diagnosis of diabetic neuropathy is made. Conditions with symptoms resembling diabetic neuropathy that must be excluded include malignant disease, toxic causes, and infections, particularly human immunodeficiency virus. The patient’s history may suggest other diagnoses as well, such as postherpetic neuralgia. Other pain syndromes that may mimic diabetic peripheral neuropathic pain include tarsal tunnel syndrome, osteoarthritis, idiopathic distal small fiber neuropathy, and erythromelalgia.
Several diagnostic tests can be used to determine the presence and type of diabetic neuropathy.17 Clinicians should review patients’ symptoms to determine if neuropathy is present and to what extent. It is important to remember that all other potential causes of, for example, muscle weakness and numbness, be ruled out before making a diagnosis of diabetic neuropathy.
All patients with diabetes should receive an annual foot examination in which the foot is assessed for skin sensation using a monofilament (Semmes-Weinstein 5.07
[10-g]), skin integrity (calluses and sores, especially between toes), bone deformities or deformities in the foot’s structure or biomechanics, and vibration perception.3,4,17 Ankle reflexes should also be tested. Quantitative sensory testing (responses to pressure, vibration, and temperature) can be used to determine loss of sensation or sensitivity of nerves.
Tools Clinicians Can Use to Measure Pain
Clinicians also have a variety of tools to assess pain, including the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Neuropathic Pain Scale (NPS), Neuropathic Pain Questionnaire (NPQ), and the Brief Pain Inventory for Diabetic Peripheral Neuropathy.5 Other tools also used to measure neuropathic pain include the Neuropathic Pain Symptoms Inventory and the Neuropathic Pain Diagnostic Questionnaire (DN4).23,24
Based on existing data, the LANSS has the most empirical support as a measure that distinguishes patients with and without neuropathic pain.5 The NPS has the most empirical support as a measure of treatment outcome. The LANSS includes 7 items (5 symptom items and 2 examination items).25 Usually, the examination items are done by a clinician, but the modified version (the self-report LANSS [S-LANSS]) allows patients to use the scale themselves. The purpose of the LANSS is to assess whether the pain that is experienced is predominantly due to nerve damage or not. Both the LANSS and S-LANSS are scored out of 24; a score of 12 or more strongly suggests neuropathic pain. Clinicians can access the S-LANSS at: http://www.neurocentre.com/slanss/slanss.pdf.
To validate the LANSS, Bennett and colleagues asked 200 patients with chronic pain to complete the S-LANSS unaided.26 A researcher then administered the S-LANSS scale and the NPS in interview format. The S-LANSS scale correctly identified 75% of pain types when self-completed and 80% when used in interview format.
The NPS is designed to assess distinct pain qualities associated with neuropathic pain.27 The NPS is a 10-item questionnaire that has 2 global pain domains (intensity and unpleasantness), 8 pain qualities (sharp, hot, dull, cold, sensitive, deep, surface, and itchy pain), and is able to differentiate patients from different diagnostic groups.
Like the LANSS and NPS, the NPQ also distinguishes neuropathic pain patients from nonneuropathic pain patients.28 The NPQ consists of 12 items that include 10 related to sensations or sensory responses, and 2 related to affect. The NPQ demonstrated a 67% sensitivity and 74% specificity compared to clinical diagnosis in the validation sample. The short form of the NPQ maintained similar discriminative properties with only 3 items (numbness, tingling pain, and pain increase in response to touch).29
The Brief Pain Inventory for Diabetic Peripheral Neuropathy assesses the severity of pain, its impact on daily functioning, and other aspects of pain.5 It includes 11 items (a 4-item pain severity scale and a 7-item pain interference scale). The pain severity scale uses worst pain, least pain, average pain, and pain now, with worst pain being most predictive of mild, moderate, and severe pain.
The DN4, which was developed in France, consists of 7 items related to symptoms and 3 related to clinical examination.24 A total score of 4 out of 10 or more suggests neuropathic pain.
The primary risk factor for diabetic neuropathy is hyperglycemia.4 The length of time a patient has diabetes also increases the risk of neuropathy, but the association between duration and prevalence may depend in part upon patient age, which itself is a risk factor.30
Nerve damage in diabetic neuropathy is likely due to a combination of factors21:
• Metabolic factors (high blood glucose, long duration of diabetes, abnormal blood fat levels, and possibly low levels of insulin)
• Neurovascular factors, leading to damage to the blood vessels that carry oxygen and nutrients to nerves
• Autoimmune factors that cause inflammation in nerves
• Mechanical injury to nerves, such as carpal tunnel syndrome
• Inherited traits that increase susceptibility to nerve disease
• Lifestyle factors, such as smoking or alcohol use
Consequences of DPN Can Be Severe
Diabetic neuropathies can lead to a series of serious complications, including death.3,31 Among the most serious complications is amputation of a limb.32 Because nerve damage caused by DPN affects a patient’s ability to feel, cuts and sores may go unnoticed and become infected or ulcerated. Because diabetes reduces blood flow to feet, the risk of infection is high. Infections that cause tissue death (ie, gangrene) may require amputation of a toe, foot, or limb. Another complication associated with diabetic neuropathies includes Charcot joint, which ensues after a joint (usually in the foot) deteriorates.
Other conditions that may accompany diabetic neuropathies include sexual dysfunction, urinary tract infections, urinary incontinence, hypoglycemia unawareness, low blood pressure, digestive problems, increased or decreased perspiration, and social isolation.32
Diabetic Neuropathy Imposes Barriers to Quality of Life
Like most chronic pain syndromes, diabetic neuropathy impacts patients’ quality of life (QOL). A 1998 study found that QOL was significantly more impaired in patients with diabetic neuropathy who registered higher degrees of impairment measures such as emotional reactions, energy, pain, physical mobility, and sleep compared to diabetic patients without neuropathy.33 Another study of 105 patients with painful diabetic neuropathy reported high levels of interference with sleep and enjoyment of life, and moderate interference with mobility, employment, and recreational and social activities.34
Diabetic Neuropathy Is Preventable
The Diabetes Control and Complications Trial (DCCT) demonstrated that tight control of glycemia may result in a greater than 60% reduction in the risk of developing clinical neuropathy in patients with type 1 diabetes.3,35 A follow-up study to DCCT, Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC), demonstrated a lower prevalence of neuropathy in the intensively treated group when assessed either by questionnaire (1.8% vs 4.7%; P < 0.0001) or examination (17.8% vs 28.0%; P < 0.0001).36
The UK Prospective Diabetes Study (UKPDS) 33 obtained similar findings in patients with type 2 diabetes, reporting significant reductions in microvascular and neuropathic complications with intensive glucose-lowering therapy.37
Both the DCCT and UKPDS demonstrated that long-term intensive glucose control improved measures of autonomic function in both DPN and diabetic autonomic neuropathy.35,37 Acute sensory neuropathy has a strong association with blood glucose levels maintaining euglycemia, and often results in the resolution of painful symptoms.3
Controlling Blood Glucose, Blood Pressure, and Cholesterol Reduces Risk of Diabetic Neuropathy
Several studies also confirm how intensive therapy combining tight control of blood glucose, blood pressure, and cholesterol can benefit diabetic neuropathy. In the Steno-2 study published in 2008, Gæde and colleagues randomly assigned 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy over a mean treatment period of 7.8 years.38 Intensive combined therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio [HR] 0.43; 95% confidence interval [CI], 0.19-0.94; P = 0.04) and a lower risk of cardiovascular events (HR 0.41; 95% CI, 0.25-0.67; P < 0.001). Intensive therapy also reduced the relative risk of autonomic neuropathy to 0.53 (P = 0.004), but the relative risk of peripheral neuropathy was 0.97 (P = 0.89).
Another 2008 study conducted by the Action in Diabetes and Vascular Disease (ADVANCE) Collaborative Group revealed that intensive glucose and blood pressure control significantly reduced microvascular events.39 However, the effect was primarily due to a reduction in nephropathy; new or worsening neuropathy was unchanged by intensive treatment (2353 with intensive treatment vs 2311 with standard treatment). Stratton and colleagues showed that the incidence of clinical complications was significantly tied to glycemic control.40 In their 2000 study (UKPDS 35) in nearly 4600 patients, the authors concluded that each 1% reduction in updated mean A1C was associated with risk reductions of 21% for any endpoint related to diabetes (95% CI, 17-24; P < 0.0001), 21% for deaths related to diabetes (95% CI, 15-27; P < 0.0001), 14% for myocardial infarction (95% CI, 8-21; P < 0.0001), and 37% for microvascular complications (95% CI, 33-41; P < 0.0001).
Tight Glycemic Control Is Key When Managing the Elderly
Approximately 1 in 5 nursing home residents has diabetes.41 Of these patients, 90% have shown signs of coronary artery disease, stroke, and/or peripheral vascular disease. Elderly patients suffer from higher rates of all complications of diabetes, including autonomic neuropathy, nephropathy, retinopathy, erectile dysfunction, and foot ulcers.42
Suh and colleagues compared the prevalence of type 2 diabetes mellitus in the U.S. elderly population between 1988 to 1994 and 1999 to 2004, and assessed glycemic control and comorbid conditions in this population.43 After adjusting for patient characteristics, including duration of diabetes mellitus, patients with nephropathy or renal insufficiency were 40% less likely to achieve their A1C goal compared to those without. Approximately half of the elderly population diagnosed with type 2 diabetes had an A1C of 7% or higher.
Although many elderly diabetics do not maintain glycemic control, they are unaware of the problem because common symptoms of hyperglycemia might be absent.44 Symptoms may include nonspecific lethargy, functional decline, weakness, and confusion.
Maintaining glycemic control in elderly patients offers several benefits and should be a high treatment priority.44 Although tight glycemic control offers several benefits, including prevention of acute complications of hyperglycemia (ie, dehydration, mental status changes, and infection risk) and faster wound healing, clinicians should keep in mind the greater susceptibility elderly patients have to the adverse effects of hypoglycemia.
What A1C Goals Should Patients Pursue?
When patients achieve their A1C goals, patient outcomes have been shown to generally improve. The UKPDS 35 demonstrated that reducing A1C levels by 1% led to a 21% reduction in the risk of diabetes-related complications and deaths.40 While the American Diabetes Association (ADA) recommends an A1C target of < 7%, the potential advantages and drawbacks of intensifying a treatment regimen to achieve the target should be considered for each individual patient, as outlined in Table 3.4
Clinicians should also realize that the ADA’s recommendation has not changed following the recent announcement of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study that reported deaths in patients with type 2 diabetes receiving intensive glycemic therapy.45
Diabetes Care: Improving but Still Falling Short of the Mark
Despite the results of the DCCT trial,35 nearly 30% of commercial managed care patients have poor glycemic control (A1C > 9.5%).46 Fortunately, according to a new analysis of National Health and Nutrition Examination Survey (NHANES) data published in 2008, glycemic control has improved during the current decade. The predictive margin for having A1C < 7.0% has increased from 37.0% in 1999-2000 to 49.7% in 2001-2002, and still higher to 55.7% between 2003 and 2004.47 Clearly there is still work to be done to optimize prevention of DPN.