Diabetic Neuropathy: Practice Essentials, Background, Anatomy
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Practice Essentials
Diabetic neuropathy is the most common complication of diabetes mellitus (DM), affecting as many as 50% of patients with type 1 and type 2 DM. Diabetic peripheral neuropathy involves the presence of symptoms or signs of peripheral nerve dysfunction in people with diabetes after other possible causes have been excluded. [1] In some cases patients are symptomatic long before routinely performed clinical examination reveals abnormalities.
Familial Hypercholesterolemia: Practice Essentials, Background, Pathophysiology
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Practice Essentials
Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes severe elevations in total cholesterol and low-density lipoprotein cholesterol (LDLc). [1, 2, 3]
Xanthomas are noted commonly on the Achilles tendons and metacarpal phalangeal extensor tendons of the hands of patients with untreated FH. See the image below.
Metacarpophalangeal joint tendon xanthomas in a 45
Metacarpophalangeal joint tendon xanthomas in a 45-year-old man with heterozygous familial hypercholesterolemia.
Signs and symptoms
Homozygous FH
Signs and symptoms of homozygous FH in children include the following:
Symptoms consistent with ischemic heart disease, peripheral vascular disease, cerebrovascular disease, or aortic stenosis
Articular symptoms such as tendonitis or arthralgias
Unusual skin lesions, such as cutaneous xanthomas at birth or by early childhood (eg, planar xanthomas, tuberous xanthomas; later, tendon xanthomas)
Corneal arcus may be present and is sometimes circumferential
Murmur of aortic stenosis may be present
Most patients with homozygous FH do not survive adulthood beyond age 30 years unless treated with unusual methods, such as liver transplantation, LDL apheresis, or ileal bypass surgery to dramatically lower their LDLc levels.
Heterozygous FH
Children with heterozygous FH do not have symptoms related to coronary heart disease (CHD), and most do not develop tendon xanthomas or corneal arcus. However, one parent will have severe hypercholesterolemia and will also probably have either a personal or family history for premature coronary artery disease (CAD).
Signs and symptoms of heterozygous FH in adults include the following:
Long-standing history of severe hypercholesterolemia dating back to childhood
If no previous acute coronary event, symptoms consistent with ischemic heart disease, especially in the presence of other cardiovascular risk factors (especially smoking)
Past or present symptoms of recurrent Achilles tendonitis or arthritic complaints
If heterozygous FH is left untreated, tendon xanthomas (Achilles tendons, metacarpophalangeal [MCP] extensor tendons) will occur by the third decade of life in more than 60% of patients
Xanthelasmas
See Clinical Presentation for more details.
Diagnosis
The diagnosis of both homozygous and heterozygous FH is based primarily on the finding of severe LDLc elevations in the absence of secondary causes of hypercholesterolemia.
A probable diagnosis of heterozygous FH can be made if the LDLc level is greater than 330 mg/dL or if tendon xanthomas are present in a patient with an LDLc level above the 95th percentile. Definitive diagnosis can be made only with gene or receptor analysis. However, a substantial increase in serum triglyceride levels should raise the possibility of another lipid disorder.
Testing
Findings on lipid analysis in patients with FH include the following:
Homozygous FH: Severely elevated cholesterol levels (total cholesterol and LDLc levels >600 mg/dL); triglyceride levels within the reference range
Heterozygous FH: Elevated LDLc levels commonly greater than 250 mg/dL; in patients younger than 20 years, an LDLc level higher than 200 mg/dL is highly suggestive of heterozygous FH or, possibly, familial ligand defective apoB-100; in adults, LDLc levels higher than 290-300 mg/dL suggest heterozygous FH
LDL receptor analysis can be used to identify the specific LDL receptor defect, and LDL receptor or apoB-100 studies can help distinguish heterozygous FH from the similar syndrome of familial defective apoB-100.
In August 2013, the European Atherosclerosis Society (EAS) published a consensus statement for screening and treatment of heterozygous FH. [4, 5] The recommendations for screening for heterozygous FH include patients with [4, 5] :
A family member presenting with diagnosed FH;
Plasma cholesterol in an adult ≥8mmol/L (≥310 mg/dL);
Plasma cholesterol in a child ≥6mmol/L (≥230 mg/dL);
Premature CHD;
Tendon xanthomas; or
Sudden premature cardiac death.
See Workup for more detail.
Management
The goal of FH treatment is to reduce the risk of CHD or risk of a CHD-equivalent condition (eg, carotid artery disease, diabetes, peripheral arterial disease). [6, 7, 8]
Risk categories for developing CHD are as follows:
High risk: CHD or CHD risk equivalent (10-year risk >20%)
Moderately high risk: More than 2 risk factors (10-year risk 10-20%)
Moderate risk: More than 2 risk factors (10-year risk 10%)
Lower risk: 0-1 risk factor
Homozygous FH
The following are used in the management of homozygous FH:
Lifestyle changes: Recommended for cardiovascular benefits [9, 10]
High doses of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) combined with bile acid sequestrants, ezetimibe, and niacin [11]
Anti–proprotein convertase subtilisin/kexin type 9 (anti-PCSK9) monoclonal antibodies (specifically, evolocumab and alirocumab) can be used as an adjunct to diet and maximally tolerated statin therapy, [12] or
Mipomersen, or
Lomitapide
Estrogen replacement therapy in postmenopausal women
LDL apheresis for selective removal of lipoproteins that contain apo-B (when the LDL receptors are absent or nonfunctional)
The following are procedures used in the treatment of homozygous FH:
Portacaval anastomosis
Liver transplantation (rarely)
Investigative therapies for homozygous and heterozygous FH include probucol, which causes regression of cutaneous and tendon xanthomas in patients with both homozygous and heterozygous FH but no long-term benefits for reduced coronary atherosclerosis, and gene therapy.
Heterozygous FH
The following are used in the management of heterozygous FH:
Lifestyle modification, including diet (limited saturated fats, trans fats, and cholesterol); weight management; aerobic/toning exercises
HMG-CoA reductase inhibitors (statins) (eg, simvastatin, atorvastatin, or rosuvastatin), and one or more other LDL lowering medications, or
Adenosine triphosphate-citrate lyase (ACL) inhibitor (eg, bempedoic acid) added to maximally tolerated statin therapy, or
Bile acid sequestrants, or
Ezetimibe, or
Niacin
Estrogen replacement therapy in postmenopausal women
Consider LDL apheresis for the following patients:
Those with documented CHD whose LDLc level cannot be lowered below 200 mg/dL by conventional therapy
Those without CHD but who have an LDLc level greater than 300 mg/dL
The 2013 EAS consensus statement for treatment of heterozygous FH includes the following recommendations [4, 5] :
An LDL target of < 3.5 mmol/L (< 135 mg/dL) for children with FH (age 8–10);
An LDL target of < 2.5 mmol/L (< 100 mg/dL) for adults with FH; and
An LDL target of < 1.8 mmol/L (< 70 mg/dL) for adults with known CHD or diabetes.
See Treatment and Medication for more details.
Background
Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes severe elevations in total cholesterol and low-density lipoprotein cholesterol (LDLc). [1, 2, 3] Although moderate hypercholesterolemia is a common finding in industrialized countries, heterozygous FH occurs in approximately 1 in 200-250 persons in the general population, about two-fold higher than previously thought. [13]
Because FH is associated with a high risk for premature coronary artery disease (CAD), health professionals should be alert to the signs found during a physical examination and to the laboratory values suggestive of FH. [14] Early detection and aggressive management to lower the LDLc level helps prevent or slows the progression of coronary atherosclerosis. Moreover, if the first-degree relatives of a patient with FH are screened, other gene carriers can be identified and treated. [15]
Pathophysiology
FH is a disorder of absent or grossly malfunctioning low-density lipoprotein (LDL) receptors. The LDL receptor gene is located on the short arm of chromosome 19, and the protein is composed of 860 amino acids. It is the primary determinant of hepatic LDL uptake, which normally processes approximately 70% of circulating LDL. Two ligands on LDL bind to the receptor, apolipoprotein B-100 (apoB-100) and apoE. The LDL receptor also binds another ligand, apoE, and is, therefore, more accurately termed the B,E receptor. ApoE is found on most lipoproteins other than LDL, including very low-density lipoprotein (VLDL) and chylomicrons and their remnants, intermediate-density lipoprotein (IDL), and a subclass of high-density lipoprotein (HDL). The LDL receptor binds apoE with higher affinity than apoB-100, and some mutations in the receptor may spare uptake of LDL by allowing binding to apoE. [16, 17, 18]
Goldstein and Brown discovered the LDL receptor and determined that FH was caused by an autosomal dominant mutation. [19, 20] Since then, more than 1700 mutations have been identified, with 79% of of them probably expressed as a hypercholesterolemic phenotype. Defects in the genes encoding apoB and proprotein convertase subtilisin/kexin type 9 (PCSK9) are responsible for approximately 5% and less than 1% of FH cases, respectively. [13] LDL receptor function varies from nonexistent up to about 25% of normal receptor activity. [21]
Five classes of mutations have been defined as follows:
Class 1 includes null alleles that result in complete absence of the LDL receptor.
Class 2 includes defective transport alleles, which disrupt normal folding of the receptor and cause either failure in transport to the cell surface or successful transport of truncated, mutated receptors.
Class 2a mutations completely block the transport of the receptor from the endoplasmic reticulum to the Golgi apparatus.
Class 2b mutations result in a partial blockade of transport of the receptor from the endoplasmic reticulum to the Golgi apparatus.
Class 3 includes defective binding alleles that affect binding of LDL and, in some cases, binding of VLDL as well.
Class 4 includes defective internalization alleles that affect the concentration of normal receptors in clathrin-coated pits for internalization by the hepatocyte.
Class 5 includes defective recycling alleles that prevent dissociation of the receptor and the ligand and thereby interrupt recycling of the receptor.
Frequency
United States
The prevalence of heterozygous FH has been thought to be approximately 1 case per 500 persons, although it has been more recently estimated at 1 case per 299 persons. [22] The prevalence of homozygous FH is 1 case per 1 million persons.
International
The prevalence of heterozygous FH in Europe approximates that of the United States, but certain regions, such as Iceland and Finland, or populations have a higher incidence. The prevalence of heterozygous FH among French Canadians is 1 case per 270 persons and is 1 case per 170 persons in Christian Lebanese. Due to the founder effect and relatively isolated populations, 3 distinct populations within South Africa have an extremely high prevalence of FH: 1 case per 67 in Ashkenazi Jews and 1 case per 100 persons in both Afrikaners and South African Indians.
Mortality/Morbidity
Homozygous FH
Severe and widespread atherosclerosis affects all major arterial beds, including the carotid, coronary, femoral, and iliac.
Children are at risk for early coronary events, and sudden death or acute myocardial infarction may occur in patients as young as 1-2 years. Without heroic interventions to lower blood cholesterol levels, survival beyond young adulthood is unlikely.
Valve abnormalities are common, particularly aortic stenosis.
Accumulation of cholesterol in nonvascular tissue is of less clinical significance. Corneal arcus and planar, tendon, and tuberous xanthomas are present early in childhood and sometimes at birth. Recognition of the cutaneous manifestations of FH permits early diagnosis and treatment to prevent the otherwise severe and inevitable cardiovascular complications. [23, 24]
Heterozygous FH
Premature CAD is the most serious and preventable manifestation. Untreated men are likely to develop symptoms by the fourth decade of life. The onset of symptoms in women lags behind men by approximately 10-15 years. No accurate estimates of mortality rates are available.
Cholesterol deposition in nonvascular tissue is common, although heterozygous children do not usually have physical manifestations; adults do not invariably develop them. Corneal arcus is the most frequent finding, particularly in patients older than 30 years, but this finding is also common in older patients and African Americans without hypercholesterolemia. Similarly, xanthelasmas (palpebral xanthomas) can occur in older individuals with normal cholesterol levels. Neither xanthelasma nor corneal arcus is of clinical significance, except possibly cosmetically.
Xanthomas, most commonly of the Achilles tendon and extensor tendons of the hands, are rare in children and common in untreated adults. Tendon xanthomas may occur with other conditions such as familial defective apoB-100 and type III hyperlipoproteinemia. These deposits can cause Achilles tendonitis and articular symptoms, particularly of the hands, wrists, knees, and ankles. [25]
Race
Certain populations with Finnish, Lebanese, Ashkenazi Jewish, Afrikaner, or French Canadian origins have a higher prevalence of FH.
Sex
The gene for FH is on chromosome 19; therefore, the inheritance pattern is the same for males and females.
In heterozygous FH, the consequences of severe hypercholesterolemia manifest earlier in men than in women because of the sex protection that benefits women until the postmenopausal years. Although a woman with no other major risk factors for CAD may not develop symptomatic CAD during her lifetime, men are rarely so fortunate.
Homozygous girls and boys have the same risk for a very early cardiovascular event.
Age
The consequences of a defective LDL receptor and subsequent elevations of LDLc are present at birth, but age is relevant because the longer patients live with extremely elevated LDLc levels, the higher their risk of CAD.
Early diagnosis and treatment to lower LDL levels and treat other coronary risk factors slows the progression of coronary atherosclerosis.
Signs and symptoms
In type 1 DM, distal polyneuropathy typically becomes symptomatic after many years of chronic prolonged hyperglycemia, whereas in type 2, it may be apparent after only a few years of known poor glycemic control or even at diagnosis. Symptoms include the following:
Sensory – Negative or positive, diffuse or focal; usually insidious in onset and showing a stocking-and-glove distribution in the distal extremities
Motor – Distal, proximal, or more focal weakness, sometimes occurring along with sensory neuropathy (sensorimotor neuropathy)
Autonomic – Neuropathy that may involve the cardiovascular, gastrointestinal, and genitourinary systems and the sweat glands
Physical examination should include the following assessments:
Peripheral neuropathy testing – Gross light touch and pinprick sensation; vibratory sense; deep tendon reflexes; strength testing and muscle atrophy; dorsal pedal and posterior tibial pulses; skin assessment; Tinel testing; cranial nerve testing
Autonomic neuropathy testing – Objective evaluation of cardiovagal, adrenergic, and sudomotor function in a specialized autonomic laboratory; may be preceded by bedside screening to assess supine and upright blood pressure and heart rate, with measurement of sinus arrhythmia ratio
Two classification systems for diabetic neuropathy are the Thomas system and the symmetrical-versus-asymmetrical system. The Thomas system (modified) is as follows:
Hyperglycemic neuropathy
Generalized symmetrical polyneuropathies
Sensory neuropathy
Sensorimotor neuropathy
Autonomic neuropathy
Focal and multifocal neuropathies
Superimposed chronic inflammatory demyelinating polyneuropathy
Distal symmetrical sensorimotor polyneuropathy is commonly defined according to the following 3 key criteria:
The patient must have diabetes mellitus consistent with a widely accepted definition
Severity of polyneuropathy should be commensurate with duration and severity of diabetes
Other causes of sensorimotor polyneuropathy must be excluded
Pure autonomic diabetic neuropathy is rare.
Asymmetrical neuropathies include the following:
Median neuropathy of the wrist (carpal tunnel syndrome)
Other single or multiple limb mononeuropathies
Thoracic radiculoneuropathy
Lumbosacral radiculoplexus neuropathy
Cervical radiculoplexus neuropathy
Diabetic polyneuropathy is commonly staged as follows:
NO - No neuropathy
N1a - Signs but no symptoms of neuropathy
N2a - Symptomatic mild diabetic polyneuropathy; sensory, motor, or autonomic symptoms; patient is able to heel-walk
N2b - Severe symptomatic diabetic polyneuropathy; patient is unable to heel-walk)
N3 - Disabling diabetic polyneuropathy
See Clinical Presentation for more detail.
Diagnosis
Laboratory tests that may be helpful include the following:
Fasting plasma glucose
Hemoglobin A1c
Complete blood count
Complete metabolic panel (electrolytes and liver function panel)
Vitamin B-12 and folate levels
Thyroid function tests
Erythrocyte sedimentation rate
C-reactive protein
Serum protein electrophoresis with immunofixation electrophoresis
Antinuclear antibody
Anti-SSA and SSB antibodies
Rheumatoid factor
Paraneoplastic antibodies
Rapid plasma reagin
Genetic screens
Hematology screen (for anemia)
Sequential multiple analysis-7 (renal function and electrolyte imbalances)/complete metabolic panel (CMP)
Other diagnostic modalities that may be considered are as follows:
Electromyography and nerve conduction velocity testing
Electrophysiologic studies
Magnetic resonance imaging
Computed tomography (including single-photon emission computed tomography)
Nuclear imaging
Doppler imaging
Microdialysis
Electrocardiography
Nerve and skin biopsy (now rarely recommended for clinical purposes)
See Workup for more detail.
Management
Key components of the management of diabetic neuropathy include the following:
Foot care, including regular follow-up, patient education, and referral as appropriate
Tight, stable glycemic control (most important for slowing progression of neuropathy)
Pain management (eg, with pregabalin, gabapentin, sodium valproate, dextromethorphan, morphine sulfate, tramadol, oxycodone, duloxetine, topical capsaicin, transdermal lidocaine)
Treatment of diabetic gastroparesis (eg, with erythromycin, cisapride [not available in the United States], metoclopramide, polyethylene glycol 3350, tegaserod [currently available only on an emergency basis])
Experimental therapies include aldose reductase inhibitors, alpha-lipoic acid, actovegin, and spinal cord stimulators.
Treatment of autonomic dysfunction must address the following:
Erectile dysfunction
Orthostatic hypotension
Gustatory sweating
Surgical treatment may be considered as follows:
Aggressive debridement or amputation for recalcitrant foot necrosis or infection
Jejunostomy for intractable gastroparesis
Implantation of a penile prosthesis for ongoing impotence
Bracing, special boots, or, in some cases, surgery for Charcot foot
Pancreatic transplantation for diabetes with end-stage renal disease
See Treatment and Medication for more detail.
Background
Neuropathies are characterized by a progressive loss of nerve fiber function. A widely accepted definition of diabetic peripheral neuropathy is "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes." [2, 3]
Neuropathies are the most common complication of diabetes mellitus (DM), affecting up to 50% of patients with type 1 and type 2 DM. In type 1 diabetes mellitus, distal polyneuropathy typically becomes symptomatic after many years of chronic prolonged hyperglycemia. Conversely, patients with type 2 diabetes mellitus may present with distal polyneuropathy after only a few years of known poor glycemic control; sometimes, these patients already have neuropathy at the time of diagnosis. (See Clinical Presentation.)
Neuropathies severely decrease patients' quality of life (QOL). Furthermore, while the primary symptoms of neuropathy can be highly unpleasant, the secondary complications (eg, falls, foot ulcers, cardiac arrhythmias, and ileus) are even more serious and can lead to fractures, amputations, and even death in patients with DM.
Since diabetic neuropathy can manifest with a wide variety of sensory, motor, and autonomic symptoms, a structured list of symptoms can be used to help screen all diabetic patients for possible neuropathy (see History). Physical examination of patients with suspected distal sensory motor or focal (ie, entrapment or noncompressive) neuropathies should include assessments for both peripheral and autonomic neuropathy (see Physical Examination).
Multiple consensus panels recommend the inclusion of electrophysiologic testing in the evaluation of diabetic neuropathy. An appropriate array of electrodiagnostic tests includes both nerve conduction testing and needle EMG of the most distal muscles usually affected. (See Workup.)
Management of diabetic neuropathy should begin at the initial diagnosis of diabetes. The primary care physician needs to be alert for the development of neuropathy—or even its presence at the time of initial diabetes diagnosis—because failure to diagnose diabetic polyneuropathy can lead to serious consequences, including disability and amputation. In addition, the primary care physician is responsible for educating patients about the acute and chronic complications of diabetes (see Patient Education). Patients with diabetic peripheral neuropathy require more frequent follow-up, with particular attention to foot inspection to reinforce the need for regular self-care. (See Treatment Strategies and Management.)
Management of diabetic neuropathy includes 2 approaches: therapies for symptomatic relief and those that may slow the progression of neuropathy. Of all treatments, tight and stable glycemic control is probably the most important for slowing the progression of neuropathy. Many medications are available for the treatment of diabetic neuropathic pain, although most of them are not specifically approved by the United States Food and Drug Administration for this use. Nonpharmacologic treatment includes rehabilitation, which may comprise physical, occupational, speech, and recreational therapy. (See Medication.)
Anatomy
A review of the anatomy of the peripheral nervous system can facilitate understanding of the classification of diabetic peripheral neuropathy. Peripheral neurons can be categorized broadly as motor, sensory, or autonomic.
Motor neurons originate in the central nervous system (CNS) and extend to the anterior horn of the spinal cord. From the anterior horn, they exit the spinal cord (via ventral roots) and combine with other fibers in the brachial or lumbar plexuses and innervate their target organs through peripheral nerves.
Sensory neurons originate at the dorsal root ganglia (which lie outside the spinal cord) and follow a similar course with motor neurons. Sensory neurons are subdivided into categories according to the sensory modality they convey (see the Table below).
Autonomic neurons consist of sympathetic and parasympathetic types. In the periphery, preganglionic fibers leave the CNS and synapse on postganglionic neurons in the sympathetic chain or in sympathetic ganglia.
The smaller fibers are affected first in DM. With continued exposure to hyperglycemia, the larger fibers become affected. Fibers of different size mediate different types of sensation, as shown in the table below.
Pathophysiology
The factors leading to the development of diabetic neuropathy are not understood completely, and multiple hypotheses have been advanced. [4, 5, 6, 7, 8, 9, 10, 11, 12, 13] It is generally accepted to be a multifactorial process. Development of symptoms depends on many factors, such as total hyperglycemic exposure and other risk factors such as elevated lipids, blood pressure, smoking, increased height, and high exposure to other potentially neurotoxic agents such as ethanol. Genetic factors may also play a role. [14] Important contributing biochemical mechanisms in the development of the more common symmetrical forms of diabetic polyneuropathy likely include the polyol pathway, advanced glycation end products, and oxidative stress.
Polyol pathway
Hyperglycemia causes increased levels of intracellular glucose in nerves, leading to saturation of the normal glycolytic pathway. Extra glucose is shunted into the polyol pathway and converted to sorbitol and fructose by the enzymes aldose reductase and sorbitol dehydrogenase. [15] Accumulation of sorbitol and fructose lead to reduced nerve myoinositol, decreased membrane Na+/K+ -ATPase activity, impaired axonal transport, and structural breakdown of nerves, causing abnormal action potential propagation. This is the rationale for the use of aldose reductase inhibitors to improve nerve conduction. [16]
Advanced glycation end products
The nonenzymatic reaction of excess glucose with proteins, nucleotides, and lipids results in advanced glycation end products (AGEs) that may have a role in disrupting neuronal integrity and repair mechanisms through interference with nerve cell metabolism and axonal transport. [17]
Oxidative stress
The increased production of free radicals in diabetes may be detrimental via several mechanisms that are not fully understood. These include direct damage to blood vessels leading to nerve ischemia and facilitation of AGE reactions. Despite the incomplete understanding of these processes, use of the antioxidant alpha-lipoic acid may hold promise for improving neuropathic symptoms. [18, 19, 20]
Related contributing factors
Problems that are a consequence of or co-contributors to these disturbed biochemical processes include altered gene expression with altered cellular phenotypes, changes in cell physiology relating to endoskeletal structure or cellular transport, reduction in neurotrophins, and nerve ischemia. [21] Clinical trials of the best-studied neurotrophin, human recombinant nerve growth factor, were disappointing. With future refinements, however, pharmacologic intervention targeting one or more of these mechanisms may prove successful.
In the case of focal or asymmetrical diabetic neuropathy syndromes, vascular injury or autoimmunity may play more important roles. [22]
A cross-sectional, case-control study by Gastoł et al indicated that in patients with type 1 diabetes mellitus (DM), epigenetic factors are involved in the development of autonomic neuropathy. T1DM patients with autonomic neuropathy showed differences in gene methylation compared with T1DM patients without neuropathy. For example, in the NINJ2 gene, which is involved in nerve regeneration, patients with autonomic neuropathy had significantly greater methylation in the first axon than did the other patients with type 1. In addition, two genes involved in nerve functionality, BRSK2 and CLDN4, showed decreased methylation (in the region of the first intron of BRSK2 and the 5’UTR regions of CLDN4) in the patients with neuropathy. [23]
A study by Groener et al of sciatic nerve lesions in diabetic polyneuropathy indicated that lesion load positively correlates with the duration of diabetes, attaining clinical relevance “once a critical amount of nerve fascicles is affected.” [24]
Etiology
Risk factors that are associated with more severe symptoms include the following [25] :
Poor glycemic control
Advanced age
Hypertension
Long duration of DM
Dyslipidemia
Smoking
Heavy alcohol intake
HLA-DR3/4 phenotype
Tall height
Development of symptoms depends on many factors, such as total hyperglycemic exposure and other risk factors such as elevated lipids, blood pressure, smoking, increased height, and high exposure to other potentially neurotoxic agents such as ethanol. Genetic factors may also play a role. [14]
Peripheral neuropathies have been described in patients with primary DM (types 1 and 2) and in those with secondary diabetes of diverse causes, suggesting a common etiologic mechanism based on chronic hyperglycemia. The contribution of hyperglycemia has received strong support from the Diabetes Control and Complications Trial (DCCT). [26]
An association between impaired glucose tolerance and peripheral neuropathy has been construed as further evidence of a dose-dependent effect of hyperglycemia on nerves, although this relationship remains an area of some controversy for type 2 diabetes and prediabetes. [27, 28, 29, 30]
A study by Jende et al indicated that in patients with type 1 diabetes, the predominant nerve lesions of distal symmetrical diabetic neuropathy develop in relation to poor glycemic control and nerve conduction loss, while in type 2 diabetes, these lesions arise in association with lipid metabolism changes. [31]
A study by Pai et al indicated that in adults with type 2 diabetes, an association exists between variability in fasting plasma glucose and the risk for painful diabetic peripheral neuropathy. Using the coefficient of variation (CV) for fasting plasma glucose, the investigators found that, after consideration of HbA1c, the odds ratios for the development of painful diabetic peripheral neuropathy were 4.08 and 5.49 for the third and fourth CV quartiles, respectively, compared with the first quartile. [32]
A study by Altaf et al indicated that obstructive sleep apnea (OSA) is linked to small-fiber neuropathy in type 2 diabetes, with poly–adenosine diphosphate ribose polymerase activation being a possible mechanism behind OSA’s association with diabetic peripheral neuropathy and endothelial dysfunction. [33]
A study by Dabelea et al found that among teenagers and young adults who had been diagnosed with type 1 or type 2 diabetes during childhood or adolescence, the age-adjusted prevalence of peripheral neuropathy was greater in those with type 2 diabetes than in patients with type 1 diabetes (17.7% vs 8.5%, respectively). After modifications had been made for established risk factors measured over time, the odds ratio for peripheral neuropathy in patients with type 2 diabetes versus those with type 1 was 2.52. [34]
Epidemiology
United States statistics
A large American study estimated that 47% of patients with diabetes have some peripheral neuropathy. [35] Neuropathy is estimated to be present in 7.5% of patients at the time of diabetes diagnosis. More than half of cases are distal symmetric polyneuropathy. Focal syndromes such as carpal tunnel syndrome (14-30%), [36, 37, 38] radiculopathies/plexopathies, and cranial neuropathies account for the rest. Solid prevalence data for the latter 2 less-common syndromes is lacking.
The wide variability in symmetric diabetic polyneuropathy prevalence data is due to lack of consistent criteria for diagnosis, variable methods of selecting patients for study, and differing assessment techniques. In addition, because many patients with diabetic polyneuropathy are initially asymptomatic, detection is extremely dependent on careful neurologic examination by the primary care clinician. The use of additional diagnostic techniques, such as autonomic or quantitative sensory testing, might result in a higher recorded prevalence. [39, 40]
International statistics
In a cohort of 4400 Belgian patients, Pirart et al found that 7.5% of patients already had neuropathy when diagnosed with diabetes. [41] After 25 years, the number with neuropathy rose to 45%. In the United Kingdom, the prevalence of diabetic neuropathy among the hospital clinic population was noted to be around 29%. [42] A study by Pan et al found that in Beijing, peripheral neuropathy had prevalence rates of 21.92% and 35.34% in patients with type 1 and type 2 diabetes, respectively. [43]
Diabetic neuropathy in racial minorities
No definite racial predilection has been demonstrated for diabetic neuropathy. However, members of minority groups (eg, Hispanics, African Americans) have more secondary complications from diabetic neuropathy, such as lower-extremity amputations, than whites. [25] They also have more hospitalizations for neuropathic complications.
Sex differences in diabetic neuropathy
DM affects men and women with equal frequency. However, male patients with type 2 diabetes may develop diabetic polyneuropathy earlier than female patients, [44] and neuropathic pain causes more morbidity in females than in males.
Diabetic neuropathy and advancing age
Diabetic neuropathy can occur at any age but is more common with increasing age and severity and duration of diabetes.
Prognosis
Patients with untreated or inadequately treated diabetes have higher morbidity and complication rates related to neuropathy than patients with tightly controlled diabetes. Repetitive trauma to affected areas may cause skin breakdown, progressive ulceration, and infection. Amputations and death may result.
Treating diabetic neuropathy is a difficult task for the physician and patient. Most of the medicines mentioned in the Medication section do not lead to complete symptom relief. Clinical trials are under way to help find new ways to treat symptoms and delay disease progression.
Mortality is higher in people with cardiovascular autonomic neuropathy (CAN). The overall mortality rate over periods up to 10 years was 27% in patients with DM and CAN detected, compared with a 5% mortality rate in those without evidence of CAN. Morbidity results from foot ulceration and lower-extremity amputation. These 2 complications are the most common causes of hospitalization among people with DM in Western countries. Severe pain, dizziness, diarrhea, and impotence are common symptoms that decrease the QOL of a patient with DM. In patients with diabetic peripheral neuropathy, the prognosis is good, but the patient's QOL is reduced.
In a Canadian study of patients with painful diabetic neuropathy being managed in a tertiary care setting, Mai et al found that at 12-month follow-up, significant improvement in pain and function had been achieved in almost one third of these individuals. That included pain reduction of 30% or greater in 37.2% of patients, functional improvement (reduction of 1 or greater on the Pain Interference Scale) in 51.2% of patients, and achievement of both of these measures in 30.2% of patients. Polypharmacy was found to be essential to symptom management and included the use of analgesic antidepressants and anticonvulsants. [45]
For more information, go to Diabetic Foot.
for more information, go to Diabetic Foot Infections.
Patient Education
Controlling diet and nutrition are paramount to improving the secondary complications of diabetes, including neuropathy. Patients with diabetic neuropathy should work with nutritionists or their primary care physicians to develop a realistic diet for lowering blood glucose and minimizing large fluctuations in blood glucose.
Patients with diabetic neuropathy should be encouraged to remain as active as possible. However, those with significant sensory loss or autonomic dysfunction should be cautioned about exercising in extreme weather conditions, which may result in injury. For example, patients with extremity numbness may not be aware of frostbite injuries during prolonged cold exposure, or those with abnormal sweating may become easily overheated in hot conditions. In most cases, consultation with the patient's regular physician is reasonable before the initiation of a regular exercise program.
Patients with diabetic neuropathy need to be educated on all aspects of their condition, and they need to know that it is very much affected by poor glycemic control. Prevention of diabetic neuropathy is potentially best achieved by having near-euglycemic control from the onset of DM. Even in patients with symptoms of diabetic neuropathy, controlling blood glucose to euglycemic levels reduces pain significantly. When a person has poor control and becomes euglycemic quickly, pain may be exacerbated (possibly due to an insulin effect), but this pain disappears in a few days. The bottom line for patients is that medications are imperfect. Many result in no pain relief for certain patients. However, glucose control is something that the patient can achieve that may reduce pain.
The importance of protection and care of insensitive feet cannot be overemphasized. Patients should be instructed to trim their toenails with great care and to be fastidious about foot hygiene. Any fungal or bacterial infection mandates prompt medical attention. The need for well-fitting shoes should be stressed.
Diabetic polyneuropathy is often associated with diabetic retinopathy and nephropathy. Patients with neuropathy should be counseled to seek appropriate eye care and discuss renal care and follow-up with their primary care physicians or endocrinologists.
Patient education should begin in the primary care office. The following outline reviews some common questions and answers that can serve as a springboard for discussion.
What is diabetic neuropathy?
Diabetic neuropathy is nerve damage caused by diabetes. In the United States, diabetes is one of the most common causes of nerve damage, also known as peripheral neuropathy. Diabetic neuropathy can affect nerves that supply feeling and movement in the arms and legs. It can also affect the nerves that regulate unconscious vital functions such as heart rate and digestion.
How does diabetic neuropathy occur?
Doctors have been studying this problem for many years, but they do not yet understand exactly how diabetes damages nerves. However, they have observed that good control of blood sugar levels helps prevent diabetic neuropathy and slows its progression, especially in patients with type 1 diabetes.
What are the symptoms?
Symptoms of diabetic neuropathy may include the following:
Numbness or loss of feeling (usually in the feet and legs first, then the hands)
Pain
Muscle weakness
Low blood pressure and dizziness when rising quickly from sitting or lying down
Rapid or irregular heartbeats
Trouble having an erection
Nausea or vomiting
Difficulty swallowing
Constipation or diarrhea
Pain from diabetic neuropathy may range from minor discomfort or tingling in toes to severe pain. Pain may be sharp or lightning-like, deep and aching, or burning. Extreme sensitivity to the slightest touch can also occur (allodynia).
A study by D’Amato et al indicated that among diabetes-related complications and comorbidities, painful diabetic polyneuropathy is the greatest determinant of depression in patients with diabetes. The study involved 181 patients, including 25 with painful diabetic polyneuropathy and 46 with the painless form of the condition. [46]
How can I help prevent diabetic neuropathy?
The following steps may help to prevent or slow the worsening of diabetic neuropathy [47] :
Control diabetes; try to keep blood sugar at a normal level
Maintain normal blood pressure
Exercise regularly, according to the healthcare provider's recommendation
Stop smoking
Limit the amount of alcohol intake because excessive alcohol also can cause neuropathy or make it worse
Eat a healthy diet and avoid elevated levels of triglycerides in the blood
Maintain a healthy weight
Keep follow-up appointments with the healthcare provider
How is diabetic neuropathy treated?
No treatment is currently available to reverse neuropathy. The best approach is to control the diabetes and other risk factors.
Muscle weakness is treated with support, such as braces. Physical therapy and regular exercise may help patients maintain the muscle strength they have.
Pain medications may help make pain more tolerable. Medications can be used to treat nausea, vomiting, and diarrhea.
Men who have trouble having erections because of neuropathy should talk to their healthcare providers. Medications can help a man achieve and maintain an erection, or prosthetic devices can be put in the penis.
Preventing injuries such as burns, cuts, or broken bones is especially important, because patients with neuropathy have more complications from simple injuries and may not heal as quickly as healthy individuals.
How can I take care of myself?
Diabetes patients can take the following self-care measures:
Work with primary care physicians and endocrinologists to control glucose levels
Examine the skin of feet and lower legs regularly to look for injuries
See a healthcare provider promptly for calluses, sores on the skin, or other potential problems so they can be treated properly.
Wear good-fitting, comfortable shoes that protect the feet
How long will the problem last?
Once a person has neuropathy, the symptoms will persist indefinitely, but most people with diabetic neuropathy are able to lead active, fulfilling lives. Keeping blood sugar under good control may stop neuropathy from worsening.
For excellent patient education resources, visit eMedicineHealth's Diabetes Center and Men's Health Center. Also, see eMedicineHealth's patient education articles, Diabetes Mellitus and Diabetic Foot Care.
Diabetic Neuropathy Clinical Presentation: History, Physical Examination, Classification of Diabetic Neuropathy
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History
In type 1 diabetes mellitus, distal polyneuropathy typically becomes symptomatic after many years of chronic prolonged hyperglycemia. Conversely, patients with type 2 diabetes mellitus may present with distal polyneuropathy after only a few years of known poor glycemic control; sometimes, these patients already have neuropathy at the time of diagnosis.
Since diabetic neuropathy can manifest as a wide variety of sensory, motor, and autonomic symptoms, a structured list of symptoms can be used to help screen all diabetic patients for possible neuropathy.
Sensory symptoms
Sensory neuropathy usually is insidious in onset and shows a stocking-and-glove distribution in the distal extremities. Sensory symptoms may be negative or positive, diffuse or focal. Negative sensory symptoms include feelings of numbness or deadness, which patients may describe as being akin to wearing gloves or socks. Loss of balance, especially with the eyes closed, and painless injuries due to loss of sensation are common. Positive symptoms may be described as burning, prickling pain, tingling, electric shock–like feelings, aching, tightness, or hypersensitivity to touch.
Motor symptoms
Motor problems may include distal, proximal, or more focal weakness. In the upper extremities, distal motor symptoms may include impaired fine hand coordination and difficulty with tasks such as opening jars or turning keys. Foot slapping and toe scuffing or frequent tripping may be early symptoms of foot weakness. Symptoms of proximal limb weakness include difficulty climbing up and down stairs, difficulty getting up from a seated or supine position, falls due to the knees giving way, and difficulty raising the arms above the shoulders.
In the most common presentation of diabetic neuropathy with symmetrical sensorimotor symptoms, minor weakness of the toes and feet may be seen; severe weakness is uncommon and should prompt investigation into other causes, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), or vasculitis. More severe weakness may be observed in asymmetrical diabetic neuropathy syndromes. Motor neuropathy may occur along with sensory neuropathy (sensorimotor neuropathy).
Autonomic symptoms
Autonomic neuropathy may involve the cardiovascular, gastrointestinal, and genitourinary systems and the sweat glands. Patients with generalized autonomic neuropathies may report ataxia, gait instability, or near syncope/syncope. In addition, autonomic neuropathies have further symptoms that relate to the anatomic site of nerve damage—gastrointestinal, cardiovascular, bladder, or sudomotor.
Gastrointestinal autonomic neuropathy may produce the following symptoms [48] :
Dysphagia
Abdominal pain
Nausea/vomiting
Malabsorption
Fecal incontinence
Diarrhea
Constipation
Cardiovascular autonomic neuropathy may produce the following symptoms [49] :
Persistent sinus tachycardia
Orthostatic hypotension
Sinus arrhythmia
Decreased heart variability in response to deep breathing
Near syncope upon changing positions from recumbent to standing
Bladder neuropathy (which must be differentiated from prostate or spine disorders) may produce the following symptoms:
Poor urinary stream
Feeling of incomplete bladder emptying
Straining to void
Sudomotor neuropathy may produce the following symptoms:
Heat intolerance
Heavy sweating of head, neck, and trunk with anhidrosis of lower trunk and extremities
Gustatory sweating
Physical Examination
Physical examination of patients with suspected distal sensory, motor, or focal (ie, entrapment or noncompressive) neuropathic symptoms should include assessments for both peripheral and autonomic neuropathy. [50]
Peripheral neuropathy testing
Testing for peripheral neuropathy begins with assessment of gross light touch and pinprick sensation. The first clinical sign that usually develops in diabetic symmetrical sensorimotor polyneuropathy is decrease or loss of vibratory and pinprick sensation over the toes. As disease progresses, the level of decreased sensation may move upward into the legs and then from the hands into the arms, a pattern often referred to as "stocking and glove" sensory loss. Very severely affected patients may lose sensation in a "shield" distribution on the chest.
Vibratory sense in the feet is tested with a 128-Hz tuning fork placed at the base of the great toenail. Test protective sensation with 5.07 Semmes-Weinstein monofilament, briefly applying the tip perpendicular to the plantar surface of the foot, using sufficient force (10 g) to buckle the monofilament. Inability to perceive the tuning fork or the monofilament identifies patients who are at increased risk (ie, 60% in the next 3 years) of developing a foot ulcer. [51] The 2 tests should be performed at least every year. [52]
Test deep tendon reflexes. With neuropathy, these are commonly hypoactive or absent. Perform strength testing and examine for distal intrinsic extremity muscle atrophy, since weakness of small foot muscles may develop. Check dorsal pedal and posterior tibial pulses.
Examine the skin for dryness, tinea pedis, cracks, onychomycoses, acute erythema and tenderness, and fluctuance under calluses.
Perform Tinel testing. Paresthesias or pain suggests median nerve injury.
Perform cranial nerve testing. Have the patient walk on the heels and toes; heel-toe walking tests not only distal lower-extremity strength but balance, as well.
Perkins et al recommended conducting annual screening for diabetic neuropathy using superficial pain sensation testing, monofilament testing, or vibration testing by the on-off method. These researchers also validated a scoring system to document and monitor neuropathy in the clinic. [53] Dyck et al described case report forms for recording symptoms and signs of neuropathy that might be useful in longitudinal follow-up of individual patients. [54]
Autonomic neuropathy testing
Testing for autonomic neuropathies is performed objectively in a specialized autonomic laboratory, evaluating cardiovagal, adrenergic, and sudomotor function. However, the clinician may first perform bedside screening to assess if further, more specialized testing is necessary.
Blood pressure and heart rate measurements with the patient supine and upright are compared. Blood pressure measurements in patients with autonomic neuropathy may show orthostatic hypotension with reduced compensatory tachycardia. Testing for orthostatic hypotension is particularly important in patients with longstanding diabetes mellitus. [55]
The sinus arrhythmia (SA) ratio is measured with the patient breathing 6 times per minute while the heart rate is monitored with a continuous ECG strip. The longest R-R interval during expiration and the shortest R-R interval during inspiration are measured, and the average of the 6 breaths is taken. The SA ratio is R-R expiration/R-R inspiration. The normal ratio is 1:2.
Classification of Diabetic Neuropathy
Diabetic neuropathies are heterogeneous in type; thus, several classifications of diabetic neuropathy have been created and recognized. [56, 2, 50] Two classification systems will be presented here: the Thomas system and symmetrical-versus-asymmetrical neuropathies.
Thomas system
A classification system by Thomas [57] combines anatomy and pathophysiology. It is presented below with a few modifications:
Hyperglycemic neuropathy (acute)
Generalized symmetrical polyneuropathies
Sensory neuropathy
Sensorimotor neuropathy (chronic, symmetric)
Autonomic neuropathy (cardiovascular, gastrointestinal, genitourinary, sudomotor)
Focal and multifocal neuropathies: this category includes cranial neuropathy, proximal motor neuropathy (amyotrophy), thoracic or lumbar radiculopathies, and focal limb neuropathies (entrapment neuropathies)
Superimposed chronic inflammatory demyelinating polyneuropathy (CIDP)
Symmetrical versus asymmetrical neuropathies
Another generally accepted classification of diabetic neuropathies divides them broadly into symmetrical and asymmetrical neuropathies.
Symmetrical polyneuropathies involve multiple nerves diffusely and symmetrically. Distal symmetrical sensorimotor polyneuropathy is the most common manifestation of diabetic neuropathy. The syndrome has been defined in many ways, but 3 key criteria are commonly accepted:
The patient must have diabetes mellitus by one of the widely accepted definitions such as those outlined by the American Diabetes Association or World Health Organization [58, 59]
The severity of polyneuropathy should be commensurate with the duration and severity of the diabetes
Other causes of sensorimotor polyneuropathy must be excluded
Distal symmetrical sensorimotor polyneuropathy affects sensory, motor, and autonomic functions in varying degrees, with sensory abnormalities predominating. Chronic symmetrical symptoms affect peripheral nerves in a length-dependent pattern, with the longest nerves affected first. Patients commonly present with painful paresthesias and numbness, which begin in the toes and ascend proximally in a stocking-like distribution over months and years.
When sensory symptoms ascend above the knees, similar symptoms develop in the hands, progressing proximally in a glove-like distribution. At a very late stage, the anterior aspect of the trunk and vertex of the head may be affected. The loss of sensation in the feet predisposes to development of foot ulcers and gangrene. [60] In addition, mild weakness of foot muscles and decreased ankle and knee reflexes occur commonly. With impaired proprioception and vibratory perception, gait may be affected (sensory ataxia).
Small-fiber neuropathy is a distal symmetrical neuropathy involving predominantly small-diameter sensory fibers (A delta and C fibers). It manifests as painful paresthesias that patients perceive as burning, stabbing, crushing, aching, or cramplike, with increased severity at night. There is loss of pain and temperature sensation with relative sparing of distal reflexes and proprioception.
Although some degree of autonomic involvement is present in most patients with distal symmetrical diabetic polyneuropathy, patients may not notice autonomic problems, and pure autonomic diabetic neuropathy is rare. Manifestations of autonomic neuropathy may include orthostatic hypotension, resting tachycardia, loss of normal sinus arrhythmia ratio, anhidrosis, bowel or bladder dysfunction, and small pupils sluggishly reactive to light.
In diabetic neuropathic cachexia, the patient experiences a precipitous and profound weight loss followed by severe and unremitting cutaneous pain, small-fiber neuropathy, and autonomic dysfunction. This condition occurs more often in older men; impotence is common. Muscle weakness is uncommon. The condition usually improves with prolonged glycemic control; however, symptoms are often refractory to other pharmacologic treatment. Limited anecdotal improvement is reported with nonpharmacologic treatments such as sympathectomy, spinal cord blockade, and electrical spinal cord stimulation. Recovery may be incomplete and prolonged over many months
Asymmetrical neuropathies include single or multiple cranial or somatic mononeuropathies. Syndromes include the following:
Median neuropathy of the wrist (carpal tunnel syndrome)
Other single or multiple limb mononeuropathies
Thoracic radiculoneuropathy
Lumbosacral radiculoplexus neuropathy
Cervical radiculoplexus neuropathy
These syndromes are distinguished from typical distal diabetic polyneuropathy by the following characteristics:
They often have a monophasic course
Some are associated with inflammatory angiitis and ischemia (eg, lumbosacral radiculoplexus neuropathy) and may appear acutely or subacutely
They have a weaker association with total hyperglycemic exposure than symmetrical polyneuropathies
Cranial mononeuropathy most often involves cranial nerves (CN) III, IV, VI, VII, or II. Disease of CN III, IV, and VI manifests as acute or subacute periorbital pain or headache followed by diplopia. Muscle weakness is typically in the distribution of a single nerve, and pupillary light reflexes are usually spared. Complete spontaneous recovery usually occurs within 3 months.
Facial neuropathy manifests as acute or subacute facial weakness (taste is not normally affected) and can be recurrent or bilateral. Most patients recover spontaneously in 3-6 months.
Anterior ischemic optic neuropathy manifests as acute visual loss or visual-field defects (usually inferior altitudinal). The optic disc appears pale and swollen; flame-shaped hemorrhages may be present.
For more information, see Macular Edema, Diabetic.
Somatic mononeuropathies include focal neuropathies in the extremities caused by entrapment or compression at common pressure points or by ischemia and subsequent infarction. Entrapment and compression tend to occur in the same nerves and at the same sites as in individuals without diabetes. Median nerve entrapment at the wrist (carpal tunnel syndrome) is more common in patients with diabetes and can be treated in the same manner as in patients without diabetes. Symptoms are often bilateral. The susceptibility to ulnar nerve entrapment at the elbow or common peroneal nerve entrapment at the fibular head is not definitely increased among patients with diabetes.
Neuropathy secondary to nerve infarction presents acutely, usually with focal pain associated with weakness and variable sensory loss in the distribution of the affected nerve. Multiple nerves may be affected (mononeuritis multiplex).
Diabetic thoracic radiculoneuropathy presents as burning, stabbing, boring, beltlike, or deep aching pain that usually begins unilaterally and may subsequently become bilateral. Skin hypersensitivity and allodynia (pain with normally innocuous touch) may occur. Numbness follows a dermatomal distribution, most prominent in distal distribution of intercostal nerves. Single or multiple spinal roots are involved. Contiguous territorial extension of symptoms may occur in a cephalad, caudal, or contralateral direction. In the trunk, thoracoabdominal neuropathy or radiculopathy may cause chest and/or abdominal pain in the distribution of thoracic and/or upper lumbar roots. Weakness presents in the distribution of the affected nerve root, such as bulging of the abdominal wall from abdominal muscle paresis (thoracic root). Patients older than 50 years are affected most often; it is more common in diabetes mellitus type 2 and is often associated with significant weight loss. There isoftencoexistingdiabeticdistalsymmetrical polyneuropathy.
Diabetic radiculoplexus neuropathy may occur in the cervical or lumbosacral distributions and is referred to in the literature by various designations, including diabetic amyotrophy, Bruns-Garland syndrome, and diabetic plexopathy. The most frequent initial symptom is sudden, severe, unilateral pain in the hip/lower back or shoulder/neck. Weakness then develops days to weeks later. Atrophy of the limb musculature may occur. Allodynia, paresthesias, and sensory loss are common.
Symptoms usually begin unilaterally and may later spread to the opposite side. Reflexes in the affected limb may be depressed or absent. This condition often occurs in patients older than 50 years with poorly controlled diabetes. It is more common in men than in women. Significant weight loss occurs in 50% of patients. The course is generally monophasic, with improvement over many months; however, some residual deficits often remain.
For more information, see Diabetic Lumbosacral Plexopathyhere.
Staging
Different clinical neurologic scales can be used to assess the severity of diabetic polyneuropathy. [56]
A common staging scale of diabetic polyneuropathy is as follows [61] :
NO - No neuropathy
N1a - Signs but no symptoms of neuropathy
N2a - Symptomatic mild diabetic polyneuropathy; sensory, motor, or autonomic symptoms; patient able to heel walk
N2b - Severe symptomatic diabetic polyneuropathy (as in N2a, but patient unable to heel walk)
N3 - Disabling diabetic polyneuropathy
Diabetic Neuropathy Differential Diagnoses
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Diagnostic Considerations
Establishing the diagnosis of diabetic neuropathy requires careful evaluation, because in 10-26% of diabetic patients with neuropathy, the neuropathy may have another cause. [35, 62, 63, 64, 65]
The differential diagnoses to consider vary with the presentation.
Cranial mononeuropathy includes the following:
Intracranial aneurysms
Bell palsy
Thoracoabdominal neuropathy includes the following:
Herpes zoster
Spinal tumors
Myocardial infarction
Acute cholecystitis
Acute appendicitis
Diverticulitis
Lumbosacral radiculoplexopathy includes the following:
Anterior disk protrusion
Spinal cord tumors
Malignant nerve root infiltrations
Inflammatory neuropathies
Peripheral neuropathy includes the following:
Pernicious anemia
Vitamin B-6 intoxication
Alcoholism
Uremia
Chemical toxins
Nerve entrapment and compression of benign etiology
Hepatitis
Idiopathic
Congenital (various hereditary sensory motor neuropathies)
Paraneoplastic syndrome
Syphilis
HIV/AIDS
Medication (eg, chemotherapy, isoniazid)
Spine disease (eg, radiculopathy, stenosis, arteriovenous [AV] fistula)
Cardiovascular autonomic neuropathy (in addition to some listed above) includes the following:
Myocardial infarction
Neuropathic arrhythmias (eg, Wolff-Parkinson–White syndrome, sick sinus syndrome)
Volume depletion
Drugs
Gastrointestinal neuropathy includes the following:
Gastrointestinal malignancy
Peptic ulcer disease
Postsurgical vagotomy
Electrolyte imbalance
Bladder dysfunction includes the following:
Bladder outlet obstruction
Prostate cancer
Spinal cauda equine syndrome
Mononeuropathy includes the following:
For more information, see Diabetic Lumbosacral Plexopathy.
Diabetic Neuropathy Workup: Approach Considerations, Hemoglobin A1c and Fasting Plasma Glucose, Basic Laboratory Screening Tests
Approach Considerations
Fasting plasma glucose and hemoglobin A1c are important laboratory screening tests for diabetic neuropathy.
Imaging studies rarely help the physician diagnose or manage diabetic neuropathy. However, in the appropriate clinical setting, MRI of the cervical, thoracic, and/or lumbar regions may help exclude another cause for symptoms mimicking diabetic neuropathy.
Multiple consensus panels recommend the inclusion of electrophysiologic testing in the evaluation of diabetic neuropathy. An appropriate array of electrodiagnostic tests includes both nerve conduction testing and needle EMG of the most distal muscles usually affected.
In a systematic review of 5 studies of noninvasive screening tools for detecting peripheral neuropathies in pediatric patients with type 1 diabetes, Hirschfeld and colleagues found that the diagnostic utility of the Rydel-Seiffer tuning fork and 10-g Semmes-Weinstein monofilament was low, while that of biothesiometry and a finer (1-g) monofilament was acceptable. Sensitivities and specificities of these screening tools were as follows: [66, 67]
Tuning fork: 87-99% (sensitivity); 1-19% (specificity)
Coarse monofilament: 16% (sensitivity); 64% (specificity)
Fine monofilament: 73% (sensitivity); 87% (specificity)
Biothesiometer: 61-80% (sensitivity); 64-76% (specificity)
Hemoglobin A1c and fasting plasma glucose are important laboratory screening tests for diabetic neuropathy. Hemoglobin A1c measurement is useful to assess the adequacy of recent diabetes control; levels are likely to be elevated in patients with diabetic neuropathies. In some cases, especially with asymmetrical syndromes, the severity of the elevation does not always correlate with the severity of the nerve disease.
A 3-hour glucose tolerance test may be more sensitive in borderline cases. A urinalysis is also helpful to screen for nephropathy and proteinuria.
Basic Laboratory Screening Tests
Testing is tailored depending on the clinical presentation. Examples of tests suggested as basic screening tools to exclude common causes of neuropathy other than diabetes include the following:
Complete blood cell count
Complete metabolic panel (electrolytes and liver function panel)
Vitamin B-12 and folate levels
Thyroid function tests
Erythrocyte sedimentation rate
C-reactive protein
Serum protein electrophoresis with immunofixation electrophoresis
Antinuclear antibody
Anti-SSA and SSB antibodies
Rheumatoid factor
Paraneoplastic antibodies
Rapid plasma reagin
Genetic screens
Hematology screen to check for anemia
Sequential multiple analysis-7 (SMA7) to check renal function and electrolyte imbalances/complete metabolic panel (CMP)
Electromyography and Nerve Conduction Studies
Nerve conduction studies (NCS) and electromyography (EMG) can document the characteristics of the neuropathy (eg, axonal, demyelinating) and the localization (eg, mononeuropathy versus radiculopathy or distal neuropathy) and, possibly, the severity and even prognosis for morbidity. Multiple consensus panels recommend the inclusion of electrophysiologic testing in the evaluation of diabetic neuropathy. These same panels recommend the use of nerve conduction velocity (NCV)/EMG procedures in clinical research studies. An appropriate array of electrodiagnostic tests includes both nerve conduction testing and needle EMG of the most distal muscles usually affected.
Conventional nerve conduction velocity studies
Conventional NCV testing includes measurement of the speed of both motor and sensory conduction. The amplitude of the distal response is also measured. The proximal component of conduction can be investigated with H-reflex (S1 root) or F-wave (motor pathways only) response.
Needle electromyography
Needle EMG is performed in the distal muscles in cases of generalized neuropathy and entrapment, in the proximal limb muscles in amyotrophy, and in the paraspinal and limb muscles in suspected radiculopathy. The examiner searches for abnormal spontaneous potentials, voluntary motor unit recruitment, and motor unit configuration. In weak patients, the recruitment characteristics can often help distinguish a neuropathic from a myopathic process.
Nerve conduction study findings
Findings on nerve conduction studies depend on the pattern of nerve damage. Patients with distal symmetrical sensorimotor polyneuropathy from predominant axonal loss have reduced or absent sensory nerve action potentials, especially in the legs. With progression of neuropathy, compound motor action potential amplitudes may also be reduced and abnormalities may be observed in the hands. These changes reflect length-dependent degeneration of large-diameter myelinated nerve fibers.
Conduction velocities are generally within the normal range or only mildly slowed in distal symmetrical polyneuropathy. If conduction velocities are less than 70% of the lower limit of normal, or if conduction block is present, the patient may have superimposed peripheral nerve demyelination in addition to the more typical axonal loss seen in distal symmetrical polyneuropathy. Generalized demyelinating changes on nerve conduction studies should prompt further evaluation for CIDP. Focal slowing of conduction velocity at common sites of entrapment may indicate one of the mononeuropathy syndromes discussed above.
In patients with diabetes, nerve conduction study abnormalities may be found even in the absence of clinical symptoms of polyneuropathy. In a prospective study by Walter-Höliner et al of 38 children and adolescents with type 1 diabetes, clinical neurologic examination revealed diabetic peripheral neuropathy in 13.2% of the group, compared with 31.6% of patients when diagnosis was made using nerve conduction velocity testing. Thus, the latter test demonstrated the widespread existence of subclinical diabetic peripheral neuropathy in the study’s patients. [68]
Electromyographic sampling of distal lower extremity muscles may reveal acute and ongoing denervation in the form of positive sharp waves and fibrillation potentials (spontaneous discharges). Reinnervation changes such as large-amplitude, long-duration, and polyphasic motor unit potentials reflect chronicity. Abnormalities in paraspinal muscles (eg, spontaneous discharges) usually reflect disease in spinal nerve roots.
Some studies have proposed that the severity of electrophysiologic abnormalities not only correlates with symptoms but also predicts the level of morbidity related to DM. Most authors suggest the NCV results to be stable or worsening over time; however, in 1998, Tkac found that the NCV levels could improve with glycemic control. [69]
Electrophysiologic Studies
Electrophysiologic studies are the most sensitive, reliable, and reproducible measures of nerve function. [70] Electrophysiologic findings usually correlate with morphologic changes on nerve biopsy. Common early findings are abnormal nerve conduction studies or reduced variability of heart rate with deep breathing or Valsalva maneuver. Although electrodiagnostic studies can characterize and quantitate nerve dysfunction, they cannot distinguish diabetic neuropathy from neuropathy of other causes.
Composite scores, combining clinical, quantitative sensory, [40] and electrophysiologic measures, are often used in natural history and efficacy studies. Examples include the Neuropathy Impairment Score in the Lower Limbs + 7 and the Michigan Diabetic Neuropathy score. [50, 71]
MRI and CT
Plexus MRI may be helpful to exclude other problems (eg, tumor) in patients with radiculoplexus neuropathy syndromes. For patients who cannot have MRI, CT myelography is an alternative to exclude compressive lesions and other pathology in the spinal canal. In cranial nerve palsies, brain imaging, usually with MRI, is helpful to exclude intracranial aneurysms, compressive lesions, and infarcts.
Nuclear Imaging
Scintigraphic techniques are used to detect and quantify cardiac autonomic neuropathy (for research purposes). Techniques include radiolabeled analogs of norepinephrine, 123I-metaiodobenzylguanidine (MIBG), and 11C-hydroxyephedrine. Adrenergic nerve terminals of the heart actively take up these compounds. Combining this technique with single-photon emission computed tomography (SPECT) scanning allows detection of decreased innervation of the heart.
Doppler Imaging
Laser Doppler can be used to measure skin perfusion. In this test, skin blood flow is measured by continuous laser Doppler assessment in response to several stimuli.
Microdialysis
Microdialysis has been used to study nitric oxide release, which participates in vasodilation of the microvasculature. In this test, probes are inserted into the dermis (with an ISO-NO Mark II oxide meter, a microsensor that measures nitric oxide release from single cells).
Electrocardiography
Electrocardiography may reveal prolongation of the QT interval. This is secondary to imbalance between right and left heart sympathetic innervation. This abnormality is thought to increase risk of arrhythmias. A screening ECG is advisable for patients with longstanding DM.
Nerve and Skin Biopsy
A nerve biopsy can be obtained, typically of the sural nerve, to confirm and help diagnose the neuropathic stage (ie, mild, moderate, severe). However, this is an invasive procedure and carries the risk of producing chronic pain, numbness, and cold insensitivity in the distribution of the sural nerve. Thus, with NCV/EMG and QST available, the sural nerve biopsy is rarely needed for diagnostic purposes any longer.
A skin biopsy can be obtained for research purposes only. Immunohistochemistry is used to quantify the cutaneous nerves to provide a morphologic assessment of diabetic neuropathies. This tool is new for clinical research, and it is used as an endpoint in diabetic neuropathy. The procedure requires only a 3-cm skin biopsy and enables a direct study of small nerve fibers (ie, C-fibers) that produce pain and temperature sensation.
Biopsy rarely is recommended for clinical purposes. Reasons for this move away from biopsies in clinical trials include the invasive nature of the procedure with its attendant risks, discomfort to the patient, cost, problems with reproducibility due to sampling error, and availability of other methods to obtain similar information. This study is performed primarily when the etiology of the neuropathy is in question or in research settings. Several studies have looked at biopsies, mainly of the sural nerve in humans. These studies were performed in advanced neuropathy; vessels were found to be thickened, and nerves were found to have undergone severe damage. Indications of nerve regrowth were small and weak.
Future Approaches
The following additional diagnostic approaches for diabetic neuropathy are currently in use or under intense study. Details of these techniques are beyond the scope of this review.
Skin punch biopsy/intraepidermal nerve fiber density testing [72] and immunohistochemical staining of peripheral nerves
Quantitative sensory testing
Imaging using MRI and ultrasonography
Diabetic Neuropathy Treatment & Management: Approach Considerations, Glycemic Control, Diabetic Neuropathic Pain Management
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Approach Considerations
Management of diabetic neuropathy should begin at the initial diagnosis of diabetes. The primary care physician needs to be alert for the development of neuropathy—or even its presence at the time of initial diabetes diagnosis—because failure to diagnose diabetic polyneuropathy can lead to serious consequences, including disability and amputation. [73, 74, 75, 76]
Consider any patient with clinical evidence of diabetic peripheral neuropathy to be at risk for foot ulceration, and provide education on foot care. [77] If necessary, refer the patient to a podiatrist. Admit patients for an infected diabetic foot ulcer or gangrene.
For more information, see Diabetic Foot.
For more information, see Diabetic Foot Infections.
Patients with diabetic peripheral neuropathy require more frequent follow-up, with particular attention to foot inspection to reinforce the need for regular self-care. The provision of regular foot examinations and reinforcement of the educational message on foot care have been shown in several studies to significantly reduce rates of ulceration and even amputation. [78]
The primary care physician is responsible for educating patients about the acute and chronic complications of diabetes, [51] including the psychological impact of sexual dysfunction in both men and women. The importance of involving a neurologist (preferably with expertise in peripheral neuropathy) in the treatment of patients with diabetic neuropathy cannot be overemphasized.
Glycemic Control
Of all treatments, tight and stable glycemic control is probably the most important for slowing the progression of neuropathy. [79] Because rapid swings from hypoglycemia to hyperglycemia have been suggested to induce and aggravate neuropathic pain, the stability of glycemic control may be as important as the actual level of control in relieving neuropathic pain. The Diabetes Control and Complications Trial (DCCT) demonstrated that tight blood sugar control in patients with type 1 diabetes decreased the risk of neuropathy by 60% in 5 years. [26, 80] The effect of tight glycemic control on polyneuropathy in patients with type 2 diabetes or those with impaired glucose tolerance/impaired fasting glucose is not as clear and requires further prospective study. [81]
A 2012 Cochrane review indicates that tight glycemic control prevents the development of clinical neuropathy and reduces nerve conduction and vibration threshold abnormalities in patients with either type 1 or type 2 diabetes. However, tight glucose control also increases the risk of severe hypoglycemic episodes, and this should be considered when assessing its risk/benefit ratio. [82]
Diabetic Neuropathic Pain Management
Many medications are available for the treatment of diabetic neuropathic pain. Oral agents include antidepressants and anticonvulsant drugs. According to the 2011 guideline issued by the American Academy of Neurology (AAN), American Academy of Physical Medicine and Rehabilitation (AANEM) and the American Academy of Physical Medicine and Rehabilitation (AAPMR) guideline for the treatment of painful diabetic neuropathy (PDN), pregabalin is recommended for treatment of diabetic neuropathic pain. The drug has been proven effective and can improve quality of life. However, physicians should determine if the drug is clinically appropriate for their patients on a case-by-case basis. Gabapentin and sodium valproate should also be considered for diabetic neuropathy pain management.
According to a Cochrane review evaluating gabapentin for chronic neuropathic pain and fibromyalgia, gabapentin leads to significant pain relief in patients with chronic neuropathic pain when compared with a placebo. Although patients frequently experience adverse side effects, these are usually tolerable, and serious side effects were not increased when compared with side effects associated with the placebo. [83]
According to the 2011 AAN/AANEM/AAPMR guideline, dextromethorphan, morphine sulfate, tramadol, and oxycodone should be considered for PDN treatment. No one opioid is recommended over another.
Topical therapy with capsaicin or transdermal lidocaine may be useful in some patients, especially those with more localized pain or those in whom interactions with existing oral medications is a concern. The 2011 AAN/AANEM/AAPMR guideline recommends that both of these agents be considered in for treatment of PDN. In clinical trials, capsaicin has been effective in reducing pain in PDN, but many patients cannot tolerate the side effects, such as burning pain on contact with warm/hot water or in hot weather. Any of these medications may be associated with adverse effects, and patients should be counseled about possible problems before initiating treatment. [84, 63] Patients should be assessed every 6 weeks so that adverse effects can be monitored if possible. Decrease or increase drug dose if indicated.
For many of these medications, use for neuropathic pain is off-label; they were approved by the Food and Drug Administration for other indications. Many are in the news for questionable side effects (eg, increased blood pressure and edema from salt retention with fludrocortisones). Nevertheless, multiple clinical studies show benefit for the use of these medications in the treatment of neuropathic pain. Use of these medications is well within the standard of care in most medical communities. A number of medications are currently undergoing evaluation in clinical trials. Some are licensed for use in other countries.
In a review of 6 trials (2220 patients) on duloxetine's effects on painful diabetic peripheral neuropathy (3 trials) and fibromyalgia (3 trials), Lunn et al concluded that 60 mg of duloxetine daily can relieve the pain of peripheral neuropathy in the short-term, calculating a 1.65 risk ratio for a 50% pain reduction at 12 weeks. [85] Adverse events were common and dose dependent, according to the authors, but serious ones were rare. The 2011 AAN/AANEM/AAPMR guideline recommends considering the antidepressants amitriptyline, venlafaxine, and duloxetine for the treatment of PDN, although data are insufficient to recommend one of these agents over the others.
There was no difference identified between gabapentin and tricyclic antidepressants in the achievement of pain relief of diabetic neuropathy or postherpetic neuralgia in a study by Chou et al. The authors performed a meta-analysis of head-to-head trials comparing the results of gabapentin and tricyclic antidepressants for pain relief in diabetic neuropathy. [86] . Pregabalin has similar efficacy as gabapentin for most part.
Pain Control in Pregnancy
During pregnancy, prescribing medicine for pain control is difficult. The best hope for pain control in rare cases of young women with severe neuropathy is to control their blood glucose diligently and try to control pain with acetaminophen. At the end of the third trimester, the physician can prescribe amitriptyline, gabapentin, and other medications as indicated if the benefit clearly outweighs the risk to the fetus. Physical therapy may be effective in pregnant patients by increasing their circulation.
To see complete information on Diabetes Mellitus and Pregnancy, please visit our main article.
Diabetic Gastroparesis
Erythromycin and metoclopramide are used to treat diabetic gastroparesis. Additionally, MiraLax (polyethylene glycol 3350) is gaining increasing popularity as the first-line agent for severe constipation and lower motor unit bowel. [48]
A newer agent, tegaserod (Zelnorm), may be helpful in patients with chronic ileus. In early 2010, however, tegaserod marketing was suspended because of a meta-analysis showing an excess number of serious cardiovascular adverse events, including angina, myocardial infarction, and stroke, in those taking tegaserod compared with placebo. Tegaserod is currently available only on an emergency basis. For more information, see the FDA Postmarket Drug Safety Information for Patients and Providers.
Dietary Supplements
Vitamin supplementation is being studied to see if that can have an impact. One study of zinc sulfide showed improvement in glycemic control in 60 patients. [87] Certain B vitamins are often prescribed in an attempt to reduce paresthesias.
Experimental Therapies
Aldose reductase inhibitors
Aldose reductase inhibitors block the rate-limiting enzyme in the polyol pathway that is activated in hyperglycemic states. Numerous studies of aldose reductase inhibitors (eg, alrestatin, sorbinil, tolrestat, epralrestat) have been published in the past 30 years, but many of the earlier trials had problems related to poor study design (eg, enrolling patients with advanced neuropathy who were unlikely to benefit from treatment).
These medications are not currently available in the United States. [88, 89] Epralrestat is currently marketed only in Japan. Epalrestat reduces intracellular sorbitol accumulation, which has been implicated in the pathogenesis of late-onset complications of diabetes mellitus. Epalrestat 150 mg/day for 12 weeks improved motor and sensory nerve conduction velocity and vibration threshold compared with baseline and placebo in patients with diabetic neuropathy. Subjective symptoms, including pain, numbness, hyperesthesia, coldness in the extremities, muscular weakness, dizziness, and orthostatic fainting, were also improved. [90, 91]
Alpha-lipoic acid
In a multicenter placebo-controlled trial of the antioxidant alpha-lipoic acid, Ziegler and colleagues reported short-term symptomatic relief of neuropathy symptoms in patients with type 2 diabetes and symptomatic neuropathy. [18] Other studies of this drug are ongoing.
Actovegin
A deproteinized derivative of calf blood, actovegin contains inorganic substances (eg, electrolytes, trace elements) and organic components (eg, amino acids, oligopeptides, nucleosides, glycosphingolipids). Actovegin also contains inositol phospho-oligosaccharides (IPOs), which are thought to elicit central and peripheral insulin effects. Ziegler et al found that treatment with actovegin improved neuropathic symptoms, vibration perception threshold, sensory function, and quality of life in 567 patients with type 2 diabetes mellitus and diabetic polyneuropathy. In this multicenter, randomized, double-blind trial, sequential intravenous (2000 mg/d) and oral (1800 mg/d) actovegin treatment was given over 160 days. [84]
Spinal cord stimulators and other therapies
Pain medicine specialists have been experimenting with spinal cord stimulator implants in severely painful cases. [92] One such study of 10 patients showed that median background and peak pain scores at the end of the study were, respectively, 77 and 81 with the stimulator off and 23 and 20 with the stimulator on. Exercise tolerance significantly improved at 3 months (n = 7, median increase 85%) and at 6 months. Further study is necessary. [93] Alternative and complementary therapies for pain (eg, acupuncture) are under investigation. [94, 21]
Treatment of Autonomic Dysfunction
Erectile dysfunction
Although several modalities are available, erectile dysfunction from diabetic neuropathy is a very difficult condition to treat. All other causes of impotence must be excluded. Once the diagnosis has been confirmed, the oral agent sildenafil Viagra) and related phosphodiesterase type 5 (PDE5) inhibitors can be used (if not contraindicated in the patient). Older methods such as vacuum devices or intracavernosal papaverine injections may be tried. Referral to a urologist is suggested.
Orthostatic hypotension
Symptomatic orthostatic hypotension can be troubling in patients with diabetic neuropathy. Increasing the dietary fluid and salt intake, along with use of compression stockings, may help. If these modalities do not improve symptoms, then medication may help. [55]
Gustatory sweating
Glycopyrrolate is an antimuscarinic compound that can be used for the treatment for diabetic gustatory sweating. When applied topically to the affected area, it results in a marked reduction in sweating while eating a meal.
Surgical Treatment
Surgery is indicated in patients with infected foot ulcers when the infection cannot be controlled medically. Aggressive debridement or amputation may be necessary if signs of necrosis or infection do not improve with IV antibiotics. [95, 96]
Jejunostomy may be performed in patients with intractable gastroparesis (ie, severe nausea and vomiting, severe weight loss). This will allow patients to be fed enterally, bypassing the paralytic stomach.
When impotence is a continual problem, the patient may pursue the option of a penile prosthesis.
The feet of patients with DM often become insensate and are highly susceptible not only to ulcers but also to the Charcot foot (ie, a foot that loses its structure secondary to trauma and acute arthropathy) from frequent and multiple traumas. Charcot foot, which occurs not only in diabetic peripheral neuropathy but in other types of severe neuropathy as well, can be treated with bracing or special boots. In some cases, surgery is used to correct the deformity. [97, 98]
For more information, see Diabetic Foot.
For more information, see Diabetic Foot Infections.
Pancreatic Transplantation
Pancreatic transplantation in patients with diabetes and end-stage renal disease can stabilize neuropathy and in some instances improve motor, sensory, and autonomic function for as long as 48 months after uremia plateaus. [78]
Rehabilitation
Physical therapy
Physical therapy may be a useful adjunct to other therapy, especially when muscular pain and weakness are a manifestation of the patient's neuropathy. The physical therapist can instruct the patient in a general exercise program to maintain his or her mobility and strength. An aquatic therapist can also be helpful.
Although the American Diabetes Association recommends moderate to vigorous exercise for patients with diabetes to help manage the disease, a literature review by Johnson and Takemoto indicated that in patients who have been inactive or cannot achieve such intensity levels, low-intensity aerobic therapy can improve sensation in the feet and reduce pain and tingling in the lower limbs. [99, 100]
In addition to exercise, the patient also should be educated on independent pain management and relaxation strategies to assist with pain control. Transcutaneous electrical nerve stimulation (TENS) may be a recommended modality for patients with neuropathic pain, and the physical therapist can be helpful in teaching and monitoring the patient in its use. In a 1999 case report, Somers and Somers found that application of TENS to the skin of the lumbar region was an effective treatment for the pain of diabetic neuropathy, but no controlled studies have confirmed this finding. [101] The 2011 AAN/AANEM/AAPMR guideline supports TENS as probably effective as a treatment for PDN. [102]
In cases of foot ulcers, physical therapy may be indicated for wound care. Treatments may consist of whirlpool, Unna boots (if necessary, although not commonly used), and debridement. For patients with autonomic neuropathy, balance training and fall prevention education is paramount.
Brace assessment and orthotic or prosthetic training are useful when appropriate, and walking-aid assessment and implementation may be necessary.
Occupational therapy
Occupational therapy may be necessary in cases where there is severe loss of functional status. When only the lower limbs are involved, patients may need home modifications and equipment. When the upper limbs are involved, patients may need more extensive functional restoration and adaptive equipment. When secondary complications require amputation of a limb, even more intensive functional retraining is required.
Speech therapy
Involvement of a speech therapist rarely is indicated, but professionals from this discipline can help with patients affected by gastroparesis or dysphagia.
Recreational therapy
A recreational therapist may help the patient with performance of community activities. Many patients with chronic disease, especially elderly patients, become isolated and are at risk for comorbid conditions such as depression.
Complications of Disease
Peripheral neuropathy can lead to foot ulcers and leg amputations. When a foot ulcer shows signs of infection (eg, thick yellow drainage, erythema around the wound, fever, necrotic tissue), the patient often fares much better by being admitted to a hospital, having the extent of infection assessed (eg, with MRI), and receiving IV antibiotics and foot debridement (if necessary).
Autonomic neuropathy is associated with dizziness and falling with resultant injuries, nausea and vomiting, severe diarrhea, and dehydration, all of which can lead to hyperosmolar nonketotic diabetic coma or diabetic ketoacidosis and death. Cardiovascular autonomic neuropathy can cause death.
Consultations
Most diabetic patients benefit from consultation with an endocrinologist at periodic intervals, and those with more brittle diabetes may benefit from regular endocrinology consultations to assist in diabetes management.
Patients with diabetes who develop neuropathy should see a neurologist early in the course of neuropathy. Patients with neuropathy symptoms or signs that seem out of proportion to the severity of diabetes should be evaluated by a neurologist to help exclude other underlying causes of neuropathy.
Physical medicine and rehabilitation physicians provide a functional-based comprehensive evaluation and treatment program for patients with diabetic neuropathy. Ulcer management may warrant consultation with a specialist at a wound clinic or perhaps a vascular surgeon. A cardiologist should monitor patients who have electrocardiographic abnormalities and/or suggestion of cardiac autonomic neuropathy. A gastroenterologist can monitor patients with intractable GI problems, such as gastroparesis and diarrhea.
Consultation with the appropriate specialist is also advisable if there are questions about the diagnosis of a particular form of neuropathy, or if the patient does not tolerate first-line medications.
Long-Term Monitoring
Patients with diabetic neuropathy should have regular monitoring by a primary care physician. Patients should be monitored every 4 weeks to 3 months to try to assess whether therapy is working to decrease pain or nausea or vomiting and also to taper off medications for painful peripheral neuropathy. Objective measures of function and improvement should be taken at every visit. Examine the patient's feet and assess with monofilament and tuning fork on every visit when the patient comes in for DM care. Monitoring patients closely for glycemic control is essential. [71]
Confocal microscopy of the cornea lends itself to longitudinally assessing progression of neuropathy. Furthermore, improvements in risk factors such as glycated hemoglobin (HbA1c) levels may be associated with morphological repair of nerve fibers. [103]
Diabetic Neuropathy Medication: Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), Analgesic, Topical, Anticonvulsant, Antidepressant, Tricyclic, Antidepressant, Selective Serotonin/norepinephrine Reuptake Inhibitor (SSNRI), Antidepressant, Serotonin Reuptake Inhibitor, Antiarrhythmic Agent, Class I-b, Prokinetic Agents, Antidepressant, Tetracyclic, Synthetic Adrenocortical Steroids, Cholinergic Agent, Laxative, Bowel Evacuant
Medication Summary
For the treatment of diabetic neuropathy, acute cases may be able to be managed with standard analgesics, but other agents will likely be necessary for chronic pain. Occasionally, muscle relaxants may be of benefit in the first 2 weeks of therapy.
Each type of pain or a combination of pain types should be treated. Reevaluation of the painful neuropathy should be performed every 6 weeks. [104] Every effort should be made to taper and eventually to stop therapies. Therapies may need to be reinstated at later dates if symptoms flare up.
The pharmacologic agents listed below are commonly used for the symptomatic treatment of diabetic neuropathy. Most are not specifically approved by the United States Food and Drug Administration for this use, however. [18, 86, 88, 89, 73, 27, 20, 105, 106, 107]
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Class Summary
In patients with acute painful neuropathy, simple analgesics such as nonsteroidal anti-inflammatory drugs [NSAIDs] and acetaminophen may provide pain control. [104] They also may be used as first-line therapy in painful peripheral neuropathy. With chronic painful neuropathy, simple analgesics are typically not effective. More often, chronic neuropathic pain requires treatment with off-label medications.
NSAIDs may help decrease inflammation caused by diabetic neuropathy. They also decrease pain.
For relief of mild-to-moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which results in a decrease of prostaglandin synthesis.
Analgesic, Topical
Class Summary
Identifying the type of pain can direct the course of therapy. Dysesthetic pain can be relieved with capsaicin cream (Dolorac, Capsin, Zostrix) applied qid. Capsaicin cream may cause pain during the initial few applications; patients need to be made aware of this potential effect. Additionally, few patients comply with the frequent dosing, and the cream is messy on socks and shoes. Several recent studies have advocated topical administration of lidocaine as treatment of postherpetic neuralgia. Lidocaine gel (5%) in placebo-controlled study showed significant relief in 23 patients studied. Lidocaine tape also decreases severity of pain.
Natural chemical derived from plants of Solanaceae family. By depleting and preventing reaccumulation of substance P in peripheral sensory neurons, may render skin and joints insensitive to pain. Substance P thought to be chemomediator of pain transmission from periphery to CNS.
Anticonvulsant
Class Summary
Gabapentin (Neurontin) has been reported to work excellently in the treatment of dysesthetic pain. [105] Carbamazepine (Tegretol, Carbatrol, Epitol) has been used mainly for partial seizures and can be used in peripheral neuropathy as a third-line agent if all other agents fail to reduce or improve symptoms of diabetic neuropathy. Carbamazepine is a potentially effective treatment for chronic neuropathic pain. [108] However, the studies evaluating carbamazepine for chronic neuropathic pain must be interpreted with caution.
Pregabalin (Lyrica) is approved for the treatment of pain due to generalized diabetic peripheral neuropathy and may be considered as a first-line agent in diabetic peripheral neuropathic pain. [109]
In October 2017, the FDA approved Lyrica CR (pregabalin extended-release tablets) for the treatment of diabetic peripheral neuropathy, as well as postherpetic neuralgia. The agency based its approval of the drug, which is taken once daily, on the success of a randomized, placebo-controlled trial involving patients with postherpetic neuralgia, with pain intensity improving by at least 50% in 73.6% of those patients treated with Lyrica CR and in 54.6% of patients in the placebo group. [110]
According to the 2011 American Academy of Neurology (AAN)/American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM)/American Academy of Physical Medicine and Rehabilitation (AAPMR) guideline, lamotrigine (Lamictal) should probably not be recommended for diabetic neuropathy treatment due to relative inefficacy in pain control when compared with placebo. [111]
May stabilize neuronal membranes and treat neuralgia by increasing efflux or decreasing influx of sodium ions across cell membranes in motor cortex during generation of nerve impulses. When serum level in or near therapeutic range, adjust dose in 30- to 50-mg increments. Small-dose increments may cause greater than expected increases in serum concentration (ie, Michaelis-Menten drug kinetics). Steady-state serum levels may take up to 3 wk to occur because half-life is concentration dependent.
Antidepressant, Tricyclic
Class Summary
For paresthetic pain, tricyclic antidepressants such as imipramine (Tofranil), nortriptyline (Pamelor, Aventyl), and amitriptyline (Elavil) have been shown to be useful as analgesics for paresthetic pain. [107]