Pedal and Lower Extremity Manifestations of Diabetes Mellitus

KHURRAM H. KHAN

TARA BLITZ-HERBEL

Management of diabetes in the past century has significantly changed diabetes from a primary cause to a secondary cause of mortality. With the introduction of insulin in the 1920s, not only could mortality from diabetes be prevented, but individuals were able to live a longer and more normal life. Although life span had increased with the advent of insulin, complications such as infections of lower extremity not previously seen began to emerge. These complications were even more apparent in patients with uncontrolled diabetes. The ramifications of uncontrolled diabetes include blindness, renal failure, stroke, and lower extremity amputations.¹

The staggering growth of obesity in the United States directly influences the birth and growth of type 2 diabetes mellitus as an epidemic. Studying the past couple of decades confirms that 90% of individuals diagnosed with diabetes mellitus have type 2. Research has demonstrated that there is a 4.5% increased risk of developing type 2 diabetes for every kilogram of body mass gained.²

With regard to foot complication, foot ulcers and amputation is the main prevention goal. Over 85% of all diabetic-related lower extremity amputations were preceded by ulceration. It is well noted that quick resolution of a foot ulcer combined with appropriate intervention to reduce the rate of recurrence can lower the risk of developing a secondary infection and can decrease the probability of lower extremity amputation in the patient with diabetes.³

The multidisciplinary health care team approach for the treatment of the diabetic foot ulcer is efficacious and may improve the outcome and long-term prognosis of these patients. The foot specialist or primary care provider is often the first professional contacted for evaluation and management of the diabetic foot ulcer and therefore can serve as an effective “gatekeeper” for the purpose of integrating the other specialties in the treatment of this pathology.⁴ This chapter incorporates the essential principles of diabetic wound care recommended by the American Diabetes Association (ADA), the Agency for Health Care Policy and Research, the Center for Disease Control (CDC), and the U.S. Department of Health and Human Services (HHS).

Epidemiology

Diabetes is the sixth leading cause of death in the United States. From 1990 to 2014, the prevalence of diabetes increased from 4.9% to 9.3%. According to the newest statistics from the 2014 CDC, 29.1 million Americans have diabetes, which is about 1 in every 11 people, and 1 out of 4 diabetics do not know they have the disease; 86 million Americans have prediabetes, which is 1 out of 3 adults in the United States, and of those 86 million 9 out of 10 do not realize they have prediabetes.⁵

The total medical costs and lost work and wages for people diagnosed with diabetes were estimated at 245 billion dollars. The risk of death for adults with diabetes is 50% higher than for adults without diabetes.⁵

In 2010, about 73,000 nontraumatic lower limb amputations were performed in adults aged 20 years or older with diagnosed diabetes.⁵

In 1991, the HHS, Public Health Service, published a report on “Diabetes and Chronic Disabling Conditions.” Healthy People 2000 listed the national health promotion and disease prevention objectives. One goal of the Healthy People 2000 initiative was to reduce the incidence of diabetes to 2.5 cases per 1,000 people and reduce the prevalence to 25 cases per 1,000 people. These objectives were never met. Healthy People 2010 sought to continue on those goals and they too were never met. We are awaiting Healthy People 2020.⁶,⁷

Neuropathy

Many types of neuropathies can be associated with diabetes including polyneuropathy (many nerves affects both limbs), mononeuropathy (asymmetric and localized to one or several branches of a nerve trunk), and multifocal neuropathy (start in specific parts of the limb—usually the symptoms are more severe on one side of the body).⁸ Peripheral neuropathy is the most common type of neuropathy affecting diabetic patients. It is a key factor in the development of diabetic foot ulcerations. Neuropathy is generally considered to be a multifactorial disorder.⁹

Over the past 20 years, there have been three main theories to explain diabetic neuropathy: the polyol pathway theory, the microvascular theory, and the glycosylation end product theory. It has become increasingly apparent that several pathophysiologic factors probably operate simultaneously, and it may be too simplistic to attempt to explain the many clinical presentations and pathologic findings of diabetic neuropathy by a single theory.¹⁰

The causes are probably different for different types of diabetic neuropathy. Nerve damage is likely caused by a combination of factors: metabolic factors, such as high blood glucose, long duration of diabetes, abnormal blood fat levels, and possibly low levels of insulin¹¹; 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 all may play a role in the cause of neuropathy.¹²

The effects of these mechanisms produce a combination of sensory, motor, and autonomic deficits.

Characteristics of diabetic neuropathy are symmetrical, stocking and glove distribution that starts distal and progresses proximally. Symptoms may not be present at diagnosis and are usually found on clinical exam. It is a length-dependent process, and its sensory manifestations are most pronounced in the lower limbs and, in more severe cases, in the fingers and hands.¹³

Sensory deficiency as a result of diabetic peripheral polyneuropathy is a commonly associated finding and has been identified as an important risk factor in the development of diabetic foot ulcers. The probability of developing wounds increases dramatically when sensation is lost in the presence of faulty biomechanics and resultant deformity.

Various diagnostic tests are employed when the clinician is assessing the level and degree of peripheral sensory neuropathy. Two of the more commonly used tests are the 5.07 Semmes-Weinstein Monofilament and the Vibration Perception Threshold exam. The Semmes-Weinstein device is a simple monofilament of nylon that delivers 10 g of force when applied to the skin and is an easily reproduced exam. A number of cross-sectional studies have assessed the sensitivity of the 10-g monofilament to identify feet at risk of ulceration. Sensitivities vary from 86% to 100%.¹⁴

The Vibration Perception Threshold exam is commonly performed with a graduated Rydel-Seiffer tuning fork.¹⁵ This fork uses a visual optical illusion to allow the assessor to determine the intensity of residual vibration on a 0 to 8 scale at the point of threshold (disappearance of sensation),¹⁶ but is more accurately performed with a calibrated electrical device known as the Biothesiometer. These tests should be repeated two to three times yearly for progressively developing neuropathic conditions and for those at identified high risk for developing loss of protective sensation in their feet.¹⁷

A small fiber neuropathy occurs when damage to the peripheral nerves predominantly or entirely affects the small myelinated (Aδ) fibers or unmyelinated C fibers. The specific fiber types involved in this process include both small somatic and autonomic fibers. The sensory functions of these fibers include thermal perception and nociception. These fibers also are involved in a number of autonomic and enteric functions.¹⁸

Diagnosis of small fiber neuropathy is determined primarily by the history and physical exam, specifically asking questions such as, Do your feet ever feel numb? Do they ever tingle? Do they ever burn? Do they ever feel as if insects are crawling on them?¹⁷

Functional neurophysiologic testing and skin biopsy evaluation of intraepidermal nerve fiber density can provide diagnostic confirmation.¹⁹

That is the absence of protective sensation with no significant vascular disease, no history of ulceration or Charcot arthropathy, and no foot deformity, a patient is 1.7 times more likely to ulcerate.¹⁷

Type 2 diabetic patients may have muscle weakness at the ankle and knee related to presence and severity of peripheral neuropathy. Motor deficit is exemplified by weakness of the anterior tibial compartment and pedal intrinsic muscular atrophy, leading to digital instability and associated increased peak pressures around the resultant deformities. High compressive and frictional forces occur around the areas of deformity. These deformities can include simple foot ailments such as bunions, hammer toes, and prominent metatarsals.²⁰ Long-term insulin-dependent diabetes mellitus patients have increased endurance but reduced strength and work performance of leg muscles. The combined effect of the motor abnormalities is suggested to give rise to functional impairment, including an increased risk of falls and injuries.²¹ Patients with absent protective sensation, no significant vascular disease, no history of ulceration or Charcot arthropathy, and a foot deformity present (focus of stress) are 12.1 times more likely to ulcerate.¹⁷

Recognizing biomechanically altered gait patterns and prescribing the appropriate off-loading is imperative if one is to attain healing of an ulcer and decrease the probability of developing a new one.²²

Hyperkeratosis often forms at the site of pressure or shear and repetitive injury. Calluses on the sole of the feet and corns on the top or sides of toes are important clues that an area may be at risk of ulceration. The presence of callus formation was associated with an 11-fold increased risk of developing an ulcer. Likewise, simple debridement of the callus tissue achieved a 26% reduction in peak pressure at the site of the callus.²³

Clinical symptoms of autonomic neuropathy generally do not occur until long after the onset of diabetes. Subclinical autonomic dysfunction can, however, occur within a year of diagnosis in type 2 diabetic patients and within 2 years in type 1 diabetic patients. Autonomic neuropathy affects bodily functions including cardiovascular (resting tachycardia, exercise intolerance, orthostatic hypotension, silent myocardial ischemia), genitourinary (incontinence,
frequent urination), gastrointestinal (difficulty swallowing, gastroparesis—stomach is slow to empty), and reproductive (erectile dysfunction).²⁴

Sudomotor foot complications including dry, fissured skin are secondary to insufficient sweat gland activity. The fissured skin can lead to ulceration and infection if left untreated. Bounding pedal pulses and a pathologic increase in pedal perfusion can develop from decreased arteriolar tone and the resultant uncontrolled vasodilatation reactive to the autonomic dysfunction.²⁵

Vascular Disease

The risk factors associated with development of peripheral atherosclerosis disease are similar to those associated with the development of coronary atherosclerosis.²⁶ These are:

Genetics
Obesity
Diabetes
Smoking
Dyslipidemia
Hypertension
Hypercoagulability
Hyperhomocysteinemia

Cardiovascular disease is the leading cause of morbidity and mortality in patients with diabetes mellitus. Patients with diabetes mellitus have two to four times higher risk of cardiovascular disease and up to three times increase in mortality than in the case of nondiabetics. The accelerated rate of atherosclerosis seen in diabetes mellitus predisposes patients to coronary artery disease and to higher rates of myocardial infarction (MI) and death.²⁷,²⁸,²⁹,³⁰

Peripheral arterial disease (PAD) is also a major risk factor for lower extremity amputation, especially in patients with diabetes. Moreover, even for the asymptomatic patient, PAD is a marker for systemic vascular disease involving coronary, cerebral, and renal vessels, leading to an elevated risk of events, such as MI, stroke, and death.³¹

The endothelial cell lining of the arterial vasculature is a biologically active organ. Most patients with diabetes, including those with PAD, demonstrate abnormalities of endothelial function and vascular regulation and abnormalities of endothelial function can render the arterial system susceptible to atherosclerosis and its associated adverse outcomes.³¹

The most common symptom of PAD is intermittent claudication, defined as pain, cramping, or aching in the calves, thighs, or buttocks that appears reproducibly with walking exercise and is relieved by rest. More extreme presentations of PAD include rest pain, tissue loss, or gangrene; these limb-threatening manifestations of PAD are collectively termed critical limb ischemia.³¹

PAD is often more subtle in its presentation in patients with diabetes than in those without diabetes. In contrast to the focal and proximal atherosclerotic lesions of PAD found typically in other high-risk patients, the lesions in diabetic patients are more likely to be more diffuse and distal. Persons with diabetes and lower extremity PAD have a very consistent pattern noted anatomically: multisegmental occlusion distal to the trifurcation of the popliteal artery at the level just distal to the knee.³¹

The initial assessment of PAD in patients with diabetes should always begin with a thorough history and physical. Ensure a complete walking history comparing function today with that in years past to assess functional status and claudication symptoms, which may or may not be the classical variation. In regard to physical exam, the absence of both pedal pulses is highly suggestive of vascular disease.³²

Noninvasive vascular studies are a helpful screening tool for peripheral vascular disease in the patient with diabetes. The ankle-brachial index (ABI), is the ratio of the systolic blood pressure in the ankle divided by the systolic blood pressure at the arm and is a reproducible and reasonably accurate, noninvasive measurement for the detection of PAD and the determination of disease severity.³³

The diagnostic criteria for PAD based on the ABI are interpreted as follows:

Normal if 0.91 to 1.30
Mild obstruction if 0.70 to 0.90
Moderate obstruction if 0.40 to 0.69
Severe obstruction if <0.40
Poorly compressible if >1.30

It has been validated against angiographically confirmed disease and found to be 95% sensitive and almost 100% specific. There are some limitations, however, in using the ABI. Calcified, poorly compressible vessels in the elderly and some patients with diabetes may give you false values. The ABI may also be falsely negative in symptomatic patients with moderate aortoiliac stenoses. These issues complicate the evaluation of an individual patient, but are not prevalent enough to detract from the usefulness of the ABI as an effective test to screen for and to diagnose PAD in patients with diabetes. In diabetic patients, an ABI within normal range needs to be taken in context with history and physical to ensure proper diagnosis.³⁴

Angiograms and other invasive vascular studies are more conclusive and are generally warranted in patients who are most likely going to benefit from a peripheral arterial bypass. Coordinated care with an interventional radiologist and a vascular specialist is an integral component of the team approach.³⁵,³⁶ No angiographic factors were predictive of limb salvage.³⁷ Vascular reconstructive surgery of the impaired limb may be required prior to debridement and/or partial amputation foot surgery. Other options include endovascular surgery (i.e., stents/balloon angioplasty) for which long-term yields have not currently been reported. Vasodilator medications have not been found to promote wound healing in the ischemic foot. Treatment for such patients is individualized taking into account all the contributing factors.

Musculoskeletal Complications of Diabetes Mellitus

Diabetes leads to changes in connective tissue by glycosylation of proteins, microvascular abnormalities with damage to blood vessels and nerves, and collagen accumulation in skin and periarticular structures.³⁸ Musculoskeletal complications are most commonly seen in patients with a long-standing history of type 1 diabetes. Some have a known direct association with diabetes.³⁸

Limited Joint Mobility

Limited joint mobility in the hands is also known as diabetic cheiroarthropathy, and is characterized by thick, tight, waxy skin mainly on the dorsal aspect of the hands, with flexion deformities of the metacarpophalangeal and interphalangeal joints (increased resistance to passive extension of the joints). In the early stages, paresthesias and slight pain develop from causes thought to be multifactorial, most likely increased glycosylation of collagen in the skin and periarticular tissue and decreased collagen degradation.³⁹

Dupuytren Disease (Contracture)

Dupuytren disease is a fibroproliferative disorder of unknown origin causing palmar nodules and flexion contracture of the digits. About 5% of individuals with Dupuytren disease are diabetic, with an increased prevalence that is proportional to the duration of the diabetes. The association with diabetes mellitus is well recorded, with a reported prevalence of between 3% and 32%.⁴⁰

Carpal Tunnel Syndrome

Carpal tunnel syndrome and diabetic polyneuropathy are common conditions in patients with type 1 and type 2 diabetes. The prevalence of carpal tunnel syndrome is thought to be higher in patients with diabetic polyneuropathy than in the general population, and the treatment less successful,⁴¹ but recent studies seem to disparage the relationship. A retrospective, case-control study looked at all patients diagnosed with carpal tunnel syndrome between January 2011 and July 2012 and compared them with a control group of herniated nucleus pulposus patients. A total of 997 patients with carpal tunnel syndrome and 594 controls were included. Prevalence of type 2 diabetes was 11.5% in the carpal tunnel syndrome group versus 7.2% in the control group (odds ratio [OR] 1.67; 95% confidence interval [CI] 1.16 to 2.41). In multivariate analyses adjusting for gender, age, and body mass index, type 2 diabetes was not associated with carpal tunnel syndrome (OR 0.99; 95% CI 0.66 to 1.47). No differences in duration of diabetes mellitus, microvascular complications, or glycemic control between groups were detected.⁴²

Frozen Shoulder

One of the most disabling musculoskeletal problems seen in diabetics is adhesive capsulitis, which is also known as frozen shoulder, shoulder periarthritis, or obliterative bursitis. It is characterized by progressive, painful restriction of shoulder movement, specifically external rotation and abduction. The thickened joint capsule is closely applied and adherent to the humeral head, resulting in considerable reduction in the volume of the glenohumeral joint.⁴³

High compressive and frictional forces occur around areas of deformity. These deformities can include simple foot ailments such as bunions, hammer toes, and prominent metatarsals.⁴⁴ Multiple techniques are available to off-load areas of increased peak pressure. Use of simple felt or plastazote insoles for redistribution of weight-bearing forces is common in the treatment of the acute ulcer.⁴⁵ Recently, some removable walking casts have been shown to be very effective and statistically as efficacious as the total contact cast.⁴⁶ However, the total contact cast is still considered the gold standard for off-loading since it is a custom-molded device and applied on a weekly basis to allow for regular wound care to the site.⁴⁷,⁴⁸ Once healed, long-term management of the patient may incorporate use of custom-molded orthoses and/or specialized supportive footwear to decrease the probability of redeveloping an ulcer.⁴⁹

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