ABSTRACT

Diabetic neuropathy (DN) is the most common form of neuropathy in developed countries and may affect about half of all patients with diabetes (DM), contributing to substantial morbidity and mortality and resulting in a huge economic burden. DN encompasses multiple different disorders involving proximal, distal, somatic, and autonomic nerves. It may be acute and self-limiting or a chronic, indolent condition. DN may progress insidiously or present with clinical symptoms and signs that may mimic those seen in many other diseases. The proper diagnosis therefore requires a thorough history, clinical and neurological examinations, and exclusion of secondary causes. Distal peripheral neuropathy (DPN) is the most common manifestation and is characteristically symmetric, glove and stocking distribution and a length-dependent sensorimotor polyneuropathy. It develops on a background of long-standing chronic hyperglycemia superimposed upon cardiovascular risk factors. Diagnosis is mainly based on a combination of symptoms and signs and occasionally neurophysiological tests are required. Apart from optimizing glycemic control and cardiovascular risk factor management, there is no approved treatment for the prevention or reversal of DPN. Even tight glycemic control at best limits the progression of DPN in patients with type 1 DM, but not to the same extent in type 2 DM. It has been estimated that between 3 and 25% of persons with DM might experience neuropathic pain. Painful DPN can be difficult to treat, and is associated with reduced quality of life, poor sleep, depression, and anxiety. Pharmacotherapy is the mainstay symptomatic treatment for painful DPN. The reported prevalence of diabetic autonomic neuropathy (DAN) varies widely (7.7 to 90%) depending on the cohort studied and the methods used for diagnosis, and can affect any organ system. Cardiovascular autonomic neuropathy (CAN) is significantly associated with overall mortality and with morbidity, including silent myocardial ischemia, coronary artery disease, stroke, DN progression, and perioperative complications. Cardiovascular reflex tests are the criterion standard in clinical autonomic testing. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Diabetic neuropathy (DN) is the most common and troublesome complication of diabetes mellitus, leading to the greatest morbidity and mortality resulting in a huge economic burden for diabetes care (1,2). It is the most common form of neuropathy in the developed world, accounting for more hospitalizations than all the other diabetes related complications combined. It is the primary risk factor for complications such as foot ulceration, which is responsible for 50-75% of non-traumatic amputations (3). In the United Kingdom, the cost of managing diabetic foot disease is greater than the combined cost of three of the four most common cancers – breast, lung and prostate (4,5). DN is a set of clinical syndromes that affect distinct regions of the nervous system, singly or combined. It may be silent and go undetected while exercising its ravages; or it may present with clinical symptoms and signs that, although nonspecific and insidious with slow progression also mimics those seen in many other diseases.

SCOPE OF THE PROBLEM

Diabetic neuropathy results in a variety of syndromes and can be subdivided into focal/multifocal neuropathies, including diabetic amyotrophy, and symmetric polyneuropathies, including sensorimotor polyneuropathy (DPN). The latter is the most common type. The Toronto Diabetic Neuropathy Expert Group defined DPN as a symmetrical, length-dependent sensorimotor polyneuropathy attributable to metabolic and microvascular alterations as a result of chronic hyperglycemia exposure (diabetes) and cardiovascular risk covariates (6). Its onset is generally insidious, and without treatment the course is chronic and progressive. The loss of small fiber-mediated sensation results in the loss of thermal and pain perception, whereas large fiber impairment results in loss of touch and vibration perception. Sensory fiber involvement may also result in “positive” symptoms, such as paresthesias and pain, although up to 50% of neuropathic patients are asymptomatic. DPN can be associated with the involvement of the autonomic nervous system, i.e., diabetic autonomic neuropathy (7,8) and in its cardiovascular form is associated with at least a three-fold increased risk for mortality (9,10). Cardiac autonomic dysfunction in patients with diabetes is strongly associated with major cardiovascular events and mortality (11).

Painful DPN which occurs in up to 34% of patients with diabetes is defined as ‘pain as a direct consequence of abnormalities in the peripheral somatosensory system in people with diabetes’ (12). Persistent neuropathic pain interferes significantly with quality of life (QOL), impairing sleep and recreation; it also significantly impacts emotional well-being, and is associated with – if not the cause of – depression, anxiety, loss of sleep, and noncompliance with treatment (13). Painful DPN can pose a significant clinical management challenge and if poorly managed can lead to mood and sleep disturbances. Hence, recognition of psychosocial problems that co-exist with neuropathic pain is critical to the management of painful DPN. For many patients, optimal management of chronic pain may require a multidisciplinary team approach with appropriate behavioral therapy, as well as input from a broad range of healthcare professionals (14).

CLASSIFICATION OF DIABETIC NEUROPATHIES

Figure 1 and Table 1 describe the classification first proposed by PK Thomas (15) and modified in a recent Position Statement by the American Diabetes Association (16).

Figure 1.

Classification of diabetic neuropathy

NATURAL HISTORY OF DIABETIC NEUROPATHIES (DN)

The natural history of DPN remains poorly understood, as there are few prospective studies that have examined this. The main reason for this is the lack of standardized methodologies for the diagnosis of DPN. Unlike diabetic retinopathy and nephropathy, the lack of simple, accurate and readily reproducible methods of measuring neuropathy is a major challenge. Furthermore, the methods currently used are not only subjective and reliant on the examiner’s interpretation but tend to diagnose DPN when it’s already well established. Nevertheless, it appears that the most rapid deterioration of nerve function occurs soon after the onset of type 1 diabetes; then within 2-3 years there is a slowing of the progress with a shallower slope to the curve of dysfunction (17). In contrast, in type 2 diabetes, slowing of nerve conduction velocities (NCVs) may be one of the earliest neuropathic abnormalities and often is present even at diagnosis. In fact, there is accumulating evidence that indicates that the risk of DPN is increased even in patients with prediabetes. In a large population study conducted in Augsburg, Southern Germany, the prevalence of DPN was 28% in subjects with known diabetes, 13% in impaired glucose tolerance (IGT), 11% among those with impaired fasting glucose and 7% in those with normal glucose tolerance (18). After diagnosis, slowing of NCV generally progresses at a steady rate of approximately 1 m/sec/year, and the level of impairment is positively correlated with duration of diabetes. Moreover, nerve conduction velocities remained stable with intensive therapy but decreased significantly with conventional therapy (19,20). In a long term follow up study of type 2 diabetes patients (9), electrophysiologic abnormalities in the lower limb increased from 8% at baseline to 42% after 10 years; in particular, a decrease in sensory and motor amplitudes (indicating axonal destruction) was more pronounced than the slowing of the NCVs. However, there now appears to be a decline in this rate of evolution. It appears that host factors pertaining to general health, management of risk factors and nerve nutrition are changing/improving. This is particularly important when doing studies on the treatment of DPN, which have always relied on differences between drug treatment and placebo, and have apparently been successful because of the decline in function occurring in placebo-treated patients (21). Recent studies have pointed out the changing natural history of DPN with the advent of therapeutic lifestyle change and the use of statins and ACE inhibitors, which have slowed the progression of DPN and drastically changed the requirements for placebo-controlled studies (22,23). It is also important to recognize that DPN is a disorder wherein the prevailing abnormality is loss of axons that electrophysiologically translates to a reduction in amplitudes and not conduction velocities; therefore, changes in NCV may not be an appropriate means of monitoring progress or deterioration of nerve function. Moreover, small, unmyelinated nerve fibers are affected early in DM and are not assessed in NCV studies. Other methods such as quantitative sensory testing, autonomic function testing, skin biopsy with quantification of intraepidermal nerve fibers (IENF), or corneal confocal microscopy are necessary to identify these patients. These techniques will be discussed in greater depth later in this chapter.

Although, the true prevalence is unknown and reports vary, it is estimated to be 30% with a range between 6-54% of patients with diabetes (24). It largely depends on the criteria and sensitivity of the diagnostic tests used to define neuropathy, the population (e.g., hospital/community or urban/rural), or the country surveyed and even the etiology of diabetes (24,25). Eleven to 13% of patients reported DN using a questionnaire based survey (26,27); 42-54% were found to have neuropathy when more sensitive measures such as nerve conduction studies were used (28,29). Neurologic complications occur equally in type 1 and type 2 diabetes mellitus and additionally in various forms of acquired diabetes (30).

The major morbidity associated with somatic neuropathy is foot ulceration, the precursor of gangrene and limb loss. Neuropathy increases the risk of amputation 1.7 fold; 12 fold if there is deformity (itself a consequence of neuropathy), and 36 fold if there is a history of previous ulceration (31). For more than a decade now, it has been recognized that a limb is lost to diabetes every 30 seconds worldwide (32). According to the International Diabetes Federation (IDF), lower-limb amputations are ten times more common in people with diabetes than in people without diabetes (32, 33). Each week in England there is about 169 amputations in people with diabetes and almost all of these individuals have DN (34). Amputation is not only devastating in its impact on the individual and their family, but also leads to loss of independence and livelihood. In low-income countries, the financial costs can be equivalent to 5.7 years of annual income, potentially resulting in financial ruin for individuals and their families (35). DN also places a substantial financial burden on health-care systems and society in general.

MODIFIABLE RISK FACTORS FOR DPN INCIDENCE AND PROGRESSION

In both type 1 and 2 diabetes, chronic hyperglycemia has a key role in the pathogenesis of DPN (36). The benefit of glucose lowering is, however, more pronounced in type 1 diabetes (78% relative risk reduction) (37) compared to type 2 (5-9% relative risk reduction) (38). In fact, the benefit of intensive glucose lowering is greatest in younger patients at early stages of the disease. This treatment effects becomes weaker once nerve damage is established. The relationship between glycemic control and DPN in type 2 diabetes is less clear cut. Even when trials have shown that tighter glucose control might have a modest beneficial effect in preventing progression of DPN in type 2 diabetes, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (39), confusion has arisen when it was reported that a self-reported history of DPN at baseline was associated with an increased risk of mortality with intensive glycemic treatment (40). This highlights the differences between the pathogenesis of DPN in type 1 and 2 diabetes and emphasizes the point that many people with type 2 diabetes develop DPN despite adequate glucose control. The presence of other risk factors, weight gain and multiple comorbidities may have significant roles to play. Although hyperglycemia and duration of diabetes play an important role in DPN, other risk factors have been identified. The EURODIAB Prospective Complications study in type 1 diabetes demonstrated that the incidence of DPN is associated with other potentially modifiable cardiovascular risk factors, including hypertriglyceridemia, hypertension, obesity and smoking (41). More recently, data from the ADDITION study also implicated similar cardiovascular risk factors in the pathogenesis of DPN in type 2 diabetes (26).

PATHOGENESIS OF DIABETIC NEUROPATHIES

Despite considerable research, the pathogenesis of diabetic neuropathy remains undetermined (42). This is one reason why, despite several clinical trials, there has been relatively little progress in the development of disease-modifying treatments (43). Historically, a number of causative factors have been identified including persistent hyperglycemia, microvascular insufficiency, oxidative and nitrosative stress, defective neurotrophism, and autoimmune-mediated nerve destruction. Figure 2 summarizes our current view of the pathogenesis of DPN (44). Detailed discussion of the different theories is beyond the scope of this Chapter and there are several excellent recent reviews (45).

Figure 2.

Pathogenesis of diabetic neuropathies. Ab, antibody; AGE, advance glycation end products; C’, complement; DAG, diacylglycerol; ET, endothelin; EDHF, endothelium-derived hyperpolarizing factor; GF, growth factor; IGF; insulin-like growth factor; NFkB, nuclear factor kB; NGF, nerve growth factor; NO, nitric oxide; NT3, neurotropin 3; PKC, protein kinase C; PGI2, prostaglandin I2; ROS, reactive oxygen species; TRK, tyrosine kinase.

CLINICAL PRESENTATION

The spectrum of clinical neuropathic syndromes described in patients with diabetes mellitus includes dysfunction of almost every segment of the somatic peripheral and autonomic nervous system (16). Each syndrome can be distinguished by its pathophysiologic, therapeutic, and prognostic features.

Generalized Symmetric Polyneuropathy

ACUTE SENSORY NEUROPATHY

Acute sensory (painful) neuropathy is considered by some authors a distinctive variant of distal symmetrical polyneuropathy (66). The syndrome is characterized by severe pain, cachexia, weight loss, depression and sexual dysfunction. It occurs predominantly in male patients and may appear at any time in the course of both type 1 and type 2 diabetes. It is self-limiting and invariably responds to simple symptomatic treatment (67). Conditions such as Fabry's disease, amyloidosis, HIV infection, heavy metal poisoning (such as arsenic), and excess alcohol consumption should be excluded. Autonomic nervous system involvement can also occur and can be very disabling.

Patients report unremitting burning, deep pain and hyperesthesia especially in the feet. Other symptoms include sharp, stabbing, lancinating pain; “electric shock” like sensations in the lower limbs that appear more frequently during the night; paresthesia; tingling; coldness, and numbness. Signs are usually absent with a relatively normal clinical examination, except for allodynia (exaggerated response to non-noxious stimuli) during sensory testing and, occasionally, absent or reduced ankle reflexes. There are no motor signs and little or no abnormality on nerve conduction studies.

Acute sensory neuropathy is usually associated with poor glycemic control but may also appear after sudden improvement of glycemia. Most commonly associated with the onset of insulin therapy, being termed "insulin neuritis", it can also occur with oral hypoglycemic treatment. Patients present with severe neuropathic pain and/or autonomic symptoms with or without an acute worsening of retinopathy. Although the pathologic basis has not been determined, one hypothesis suggests that changes in blood glucose flux produce alterations in epineural blood flow, leading to ischemia; proinflammatory cytokines from activation of microglia have also been implicated (68). Hence, rapid glycemic changes in patients with uncontrolled diabetes increases the risk of this complication and should be avoided. A 2-3% (10-42mmol/mol) decrease in HbA_1c over 3 months is associated with a 20% absolute risk of developing this complication. The risk exceeds 80% with a decreased in HbA_1c of >4% (20mmol/mol) (69). A study using in vivo epineural vessel photography and fluorescein angiography demonstrated abnormalities of epineural vessels including arteriovenous shunting and proliferating new vessels in patients with acute sensory neuropathy (68). Other authors relate this syndrome to diabetic lumbosacral radiculoplexus neuropathy (DLRPN) and propose an immune mediated mechanism (70).

The key in the management of this syndrome is achieving and maintaining blood glucose stability (71). Most patients also require medication for neuropathic pain. The natural history of this disease is resolution of symptoms within one year.

CHRONIC SENSORIMOTOR NEUROPATHY OR DISTAL SYMMETRIC POLYNEUROPATY (DPN)

The most common form of neuropathy in diabetes is a distal symmetrical polyneuropathy. It occurs in both type 1 and type 2 DM with similar frequency and may already be present at the time of diagnosis of type 2 DM (18). Sensory symptoms include numbness (‘dead feeling’), paraesthesia, and neuropathic pain (hyperalgesia, allodynia, deep aching, burning and sharp stabbing sensations). Patients do occasionally present paradoxically with a painful/painless leg i.e. painful neuropathic symptoms in the presence of severe sensory loss (72). Symptoms begin in the toes before progressing in a stocking and then a glove distribution as the disease progresses. Unsteadiness or sensory ataxia leading to increased falls risk occurs in advanced neuropathy loss of proprioception, foot deformity, and abnormal muscle sensory function (73). In the absence of painful symptoms, the onset of DPN is insidious whereby patients remain completely asymptomatic and signs discovered by a detailed neurological examination. Unfortunately, DPN is often already established or well advanced when identified by bedside clinical examination.

It is critically important to annually (at least) examine the feet of patients with diabetes as loss of protective sensation is the strongest risk factor for diabetic foot ulceration. On physical examination, a symmetrical stocking like distribution of sensory abnormalities in both lower limbs is usually seen. In more severe cases, hands may be involved. All sensory modalities can be affected, particularly vibration, touch and position perceptions (large Aα/β fiber damage); and pain, with abnormal heat and cold temperature perception (small thinly myelinated Aδ and unmyelinated C fiber damage, see Figure 3, 4 and 5; Table 3). Deep tendon reflexes may be absent or reduced, especially in the lower extremities, although this may occur with advancing age in the absence of neuropathy. When DPN is established, small muscle wasting of the foot and extensor halluces longus may be seen but severe weakness is rare and should raise the possibility of a non-diabetic etiology of the neuropathy. High arching of the foot, clawing of the toes with prominent metatarsal heads also become apparent – increasing the risk ulceration (74). A thorough assessment of patient’s footwear is essential. A poor fit, abnormal wear from internal pressure areas and foreign objects found in footwear are common causes of trauma leading to foot ulceration (75).

Figure 3. 

Clinical presentation of small and large fiber neuropathies. Aα fibers are large myelinated fibers, in charge of motor functions and muscle control. Aα/β fibers are large myelinated fibers too, with sensory functions such as perception to touch, vibration, and position. Aδ fibers are small myelinated fibers, in charge of pain stimuli and cold perception. C fibers can be myelinated or unmyelinated and have both sensory (warm perception and pain) and autonomic functions (blood pressure and heart rate regulation, sweating, etc.)

Figure 4.

Clinical manifestations of small fiber neuropathies

Figure 5.

Nerve fibers of the skin and their functions

Table 3.

Subtypes of Neuropathies

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Clinical Manifestations of Small Fiber Neuropathies: Small thinly myelinated Aδ and unmyelinated C fibers are affected. Prominent symptoms with burning, superficial, or lancinating pain often accompanied by hyperalgesia, dysesthesia, and allodynia. Progression to numbness and hypoalgesia (Disappearance of pain may not necessarily reflect nerve recovery but rather nerve death, and progression of neuropathy must be excluded by careful examination). Abnormal cold and warm thermal sensation. Abnormal autonomic function with decreased sweating, dry skin, impaired vasomotion and skin blood flow with cold feet. Intact motor strength and deep tendon reflexes. Negative nerve conduction velocity findings. Loss of cutaneous nerve fibers on skin biopsies. Can be diagnosed clinically by reduced sensitivity to 1.0 g Semmes Weinstein monofilament and prickling pain perception using the Waardenberg wheel or similar instrument. Patients at risk of foot ulceration and subsequent gangrene and amputations.

Clinical Manifestations of Large Fiber Neuropathies Large myelinated, rapidly conducting Aα/β fibers are affected and may involve sensory and/or motor nerves. Prominent signs with sensory ataxia (waddling like a duck), wasting of small intrinsic muscles of feet and hands with hammertoe deformities and weakness of hands and feet. Abnormal deep tendon reflexes. Impaired vibration perception (often the first objective evidence), light touch, and joint position perception. Shortening of the Achilles tendon with pes equinus. Symptoms may be minimal: sensation of walking on cotton, floors feeling "strange", inability to turn the pages of a book, or inability to discriminate among coins. In some patients with severe distal muscle weakness, inability to stand on the toes or heels. Abnormal nerve conduction velocity findings Increased skin blood flow with hot feet. Patients at higher risk of falls, fractures, and development of Charcot Neuroarthropathy Most patients with DPN, however, have a "mixed" variety of neuropathy with both large and small nerve fiber damages.

DIAGNOSIS OF DIABETIC NEUROPATHIES

Diabetic peripheral neuropathy can be diagnosed by the bedside with careful clinical examination of the feet and legs using simple tools within a few minutes. The basic neurological assessment comprises the general medical and neurological history, inspection of the feet, and neurological examination of sensation using simple semi-quantitative bed-side instruments such as the 10g Semmes-Weinstein monofilament, Neuropen (76) (to assess touch/pressure), NeuroQuick (77) or Tiptherm (78) (temperature), calibrated Rydel-Seiffer tuning fork (vibration), pin-prick (pain), and tendon reflexes (knee and ankle) (Table 4). In addition, assessment of joint position and motor power should also be assessed. The Rydel Seiffer tuning fork is a 128 Hz tuning fork which allows quantifiable assessment of vibration perception in the feet of diabetic patients. When vibrating, two triangles appear on the graduated scale of 0–8 which join together as the amplitude decreases. The normal range for the graduated tuning fork on the dorsal distal joint of the great toe is ≥5/8 scale units in persons 21-40 years old, ≥4.5/8 in those 41-60 years old, ≥4/8 in individuals 61-71 years old, and ≥3.5/8 scale units in those 72-82 years old (79). In resource, limited settings the simple Ipswich Touch Test can be performed by lightly touching the tips of the first, third and fifth toes (80). It is recommended that a simple foot examination to detect loss of protective foot sensation, pedal pulses, and foot deformity is performed from the diagnosis of type 2 diabetes, 5-years after the diagnosis of type 1 diabetes and annually thereafter (81,82,16). This is performed in order to determine the risk of foot ulceration and prompt early referral for foot protection, regular podiatry or specialist input.

A consensus definition of DPN has been proposed by the Toronto Diabetic Neuropathy Expert Group, see below (6). In a clinical context, the diagnosis of ‘possible’ or ‘probable’ DPN is normally sufficient without the need for specialist investigations. For research purposes further tests are needed for a diagnosis of ‘confirmed’ DPN’, ‘Subclinical’ DPN or small fiber neuropathy.

Point of Care Devices for the Diagnosis of DN

Significant progress has been made to develop point-of-care (POC) devices that are capable of diagnosing early, subclinical neuropathy. Papanas et al have recently comprehensively reviewed these devices (94). Therefore, we will briefly outline the following devices: the NeuroQuick 77, NeuroPAD (95), NC-Stat DPN-Check (96), Corneal Confocal Microscopy (CCM) (97,98), and Sudoscan (99,100).

DPN CHECK

The DPN-Check is a novel, user-friendly, handheld POC devices that performs a sural nerve conduction study in three minutes (Figure 6). It is an acceptable proxy to standard nerve conduction studies which are time-consuming, expensive, and often require patients to be seen in specialist’s clinics. The DPN check has been demonstrated to have excellent reliability with an inter- and intra-observer intraclass correlation coefficients of between 0.83 and 0.97 for sensory nerve action potentials respectively (101). It also has good validity with 95% sensitivity and 71% specificity when compared against reference standard nerve conduction study (101) for the diagnosis of DN.

Figure 6.

DPN Check device

As detailed above, nerve conduction studies are only an assessment of large nerve fiber function. DPN, on the other hand, usually involves both small and large nerve fibers, with some evidence suggesting small nerve fiber involvement early in its natural history (102,103). Small nerve fibers constitute 80-91% of peripheral nerve fibers and control pain perception, autonomic and sudomotor function. Although intraepidermal nerve fiber density measurement from lower limb skin biopsy is considered the gold standard for the diagnosis of small fiber neuropathy (104,92) it is invasive and hence not suitable for routine screening. However, a number of POC devices have been developed to assess small fiber dysfunction. These include:

NEUROQUICK

Thinly myelinated Aδ and unmyelinated C-fibers are small caliber nerves that mediate thermal sensation and nociceptive stimuli. Quantitative sensory testing of thermal discrimination thresholds is a non-invasive test used to examine impaired small nerve fiber function. NeuroQuick is a handheld device for quantitative bedside testing of cold thermal perception threshold. It allows near patient assessment of small fiber dysfunction avoiding the use of time-consuming and expensive quantitative sensory testing equipment in a laboratory. To date, one published clinical validation study has been performed in a diabetic population which suggests it is a valid and reliable screening tool for the assessment of small fiber dysfunction (77). Use of NeuroQuick was more sensitive in detecting early DPN compared to the traditional bedside screening tests such as the tuning fork or elaborate thermal testing (77). However, it is a psychophysical test that relies on the cognition/attention of the patient. Furthermore, the coefficients of variation for repeated NeuroQuick measurements ranged between 8.5% and 20.4% (77). Further studies are required to demonstrate whether the NeuroQuick is a useful screening tool to detect small fiber dysfunction in DPN.

NEUROPAD

This is a 10-minute test which measures sweat production on the plantar surface of the foot (Figure 7). It is based on a color change in a cobalt compound from blue to pink which produces a categorical output with modest diagnostic performance for DPN compared to electrophysiological assessments. If the patch remains completely or partially blue within 10 min, the result is considered abnormal (105). No training is required to administer Neuropad, nor does it require responses from the patient. Therefore, this method of assessment may be more suitable for screening in community settings and those with cognitive or communication difficulties who have to respond to other methods of assessment. A number of clinical validation studies (95, 106) have been conducted which demonstrates low sensitivity for large fiber neuropathy (50-64%) but much higher sensitivity for small fiber neuropathy (80%) 107. Neuropad has also shown good reproducibility with intra- and inter-observer coefficient of variation between 4.1% and 5.1% (108).

Figure 7.

NeuroPAD

CORNEAL CONFOCAL MICROSCOPY

Corneal confocal microscopy (CCM, Figure 8) is a noninvasive technique used to detect small nerve fiber loss in the cornea which correlates with both increasing neuropathic severity and reduced IENFD in patients with diabetes (103,109). A novel technique of real-time mapping permits an area of 3.2 mm² to be mapped with a total of 64 theoretically non-overlapping single 400 µm² images (110). There have been a number of clinical validation studies including one 3.5-year prospective study in T1DM which demonstrated relatively modest to high sensitivity (82%) and specificity (69%) of CCM for the incipient DPN (98). It has good reproducibility for corneal nerve fiber length measurements with intra- and inter-observer intraclass correlation coefficients of 0.72 and 0.73 respectively. Currently, CCM is used in specialist centers, but would suit widespread application given its easy application for patient follow-up. However, large, multicenter, prospective studies are now required to confirm that corneal nerve changes unequivocally reflect the complex pathological processes in the peripheral nerve. Moreover, the establishment of a normative database and technical improvements in automated fiber measurements and wider-area image analysis may be useful to increase diagnostic performance.

Figure 8.

Examples of corneal nerve fiber density in a patient with no diabetic neuropathy on the left and with established diabetic neuropathy on the right.

CONTACT HEAT EVOKED POTENTIALS

Contact Heat Evoked Potentials (CHEPS) has been studied in healthy controls, newly diagnosed and established patients with diabetes, and patients with the metabolic syndrome. It does appear that CHEPS is capable of detecting small fiber neuropathy in the absence of other indices, and that CHEPS correlates with quantitative sensory perception and objective tests of small fiber structure (intraepidermal nerve fiber density) (111) and function (cooling detection threshold and cold pain) (112) .

SUDOSCAN

Sudoscan®, an instrument capable of detecting chloride ion flux in response to a very low current (Figure 9), is an objective and quantitative sudomotor function test with promising sensitivity and specificity in the investigation of DPN (113). The entire evaluation takes only 2 minutes and can be done in an ambulatory setting. A measurement of electrochemical skin conductance (ESC) for the hands and feet, that are rich in sweat glands, is generated from the derivative current associated with the applied voltage. Sensitivity and specificity of foot ESC for classifying DPN were 87.5% and 76.2%, respectively. The area under the ROC curve (AUC) was 0.85 (99).

Figure 9.

SUDOSCAN test of sudomotor function being performed

SUMMARY OF POINT OF CARE DEVICES

In summary, the sensitivity of point of care devices seems acceptable and perhaps a combination of devices may be used in the future for detecting DPN. However, there is high heterogeneity and patient selection bias in most of the studies. Further studies are needed to evaluate the performance of point of care devices against Wilson criteria for screening of undiagnosed DPN at the population level. Prospective studies of hard endpoints (e.g., foot ulcerations and lower limb amputations) are also necessary to ensure that the benefits of screening are important for patients. The cost-effectiveness of implementing screening using these devices also needs to be carefully appraised. Point of care devices provide rapid, non-invasive tests that could be used as an objective screening test for DPN in busy diabetic clinics, ensuring adherence to current recommendation of annual assessment for all patients with diabetes that remains unfulfilled.

Intraepithelial Nerve Fiber Density

The importance of the skin biopsy as a diagnostic tool for DPN is increasingly being recognized (45, 135). This technique quantitates small epidermal nerve fibers through antibody staining of the pan-axonal marker protein gene product 9.5 (PGP 9.5). Though minimally invasive (3-mm diameter punch biopsy), it enables a direct study of small fibers, which cannot be evaluated by NCV studies. It has led to the recognition of the small nerve fiber syndrome as part of IGT and the metabolic syndrome (Figure 10). When patients present with the “burning foot or hand syndrome”, evaluation for glucose tolerance and the metabolic syndrome (including waist circumference, blood pressure, and plasma triglyceride and HDL-C levels) becomes mandatory. Therapeutic life style changes (136) can result in nerve fiber regeneration, reversal of the neuropathy, and alleviation of symptoms (see below).

Figure 10.

Intraepidermal nerve fiber loss in small vessel neuropathy. Loss of cutaneous nerve fibers that stain positive for the neuronal antigen protein gene product 9.5 (PGP 9.5) in metabolic syndrome and diabetes.

It is widely recognized that neuropathy per se can affect the quality of life (QOL) of patients with diabetes. A number of instruments have been developed and validated to assess QOL in DPN. The NeuroQoL measures patients’ perceptions of the impact of neuropathy and foot ulcers (137). The Norfolk QOL questionnaire for DPN is a validated tool addressing specific symptoms and the impact of large, small, and autonomic nerve fiber functions (138). The tool has been used in clinical trials and is available in several validated language versions. It was tested in 262 subjects (healthy controls, controls with diabetes, and DPN patients): differences between DN patients and both diabetes and healthy controls were significant (p<0.05) for all item groupings (small fiber, large fiber, and autonomic nerve function; symptoms; and activities of daily living (ADL). Total QOL scores correlated with total neuropathy scores. The ADL, total scores, and autonomic scores were also greater in controls with diabetes compared to healthy controls (p<0.05), suggesting that diabetes per se impacts some aspects of QO (137).

The diagnosis of DPN is mainly a clinical one with the aid of specific diagnostic tests according to the type and severity of the neuropathy. However other non-diabetic causes of neuropathy must always be excluded, depending on the clinical findings (B12 deficiency, hypothyroidism, uremia, CIDP, etc.) (Figure 11).

Figure 11.

A diagnostic algorithm for assessment of neurologic deficit and classification of neuropathic syndromes: B12, vitamin B12; BUN, blood urea nitrogen; CHEPS, Contact Heat Evoked Potentials CIDP, chronic inflammatory demyelinating polyneuropathy; EMG, electromyogram; Hx, history; MGUS, monoclonal gammopathy of unknown significance; NCV, nerve conduction studies; NIS, neurologic impairment score (sensory and motor evaluation); NSS, neurologic symptom score; QAFT, quantitative autonomic function tests; QST, quantitative sensory tests; Sudo, sudomotor function testing.

Central Nervous System Involvement

Hitherto considered a disease of the peripheral nervous system, there is now mounting evidence of central nervous system (CNS) involvement in DN (Figure 12). Several magnetic resonance imaging studies provide valuable insight into CNS alterations in DN. From the spinal cord (139,140) to the cerebral cortex, structural (141), biochemical (142,143), perfusion (144), and functional changes (145,146) have been described. Although the initial injury may occur in the peripheral nerves, concomitant changes within the CNS may have a crucial role in the pathogenesis and determining clinical phenotype and even treatment response in painful DN.

Central nervous system involvement was first recognized in the 1960’s when post-mortem autopsy studies of patients with advanced diabetes found evidence of spinal cord atrophy, demyelination, and axonal loss (147,148). These findings were largely dismissed as being secondary to poor diabetes control and infection (e.g., syphilis) rather than DN. Indeed, the pathological abnormalities in the spinal cord were reported in isolation and not examined in the context of DN related peripheral nerve changes. Subsequent studies performed in the late 70’s and 80’s utilized advances in somatosensory evoked potentials and demonstrated central (brain and spinal cord) slowing in humans with DN (149) and rodent models (150). With the advent and accessibility of demonstrated magnetic resonance imaging in the 90’s and early 00’s, investigators were able to demonstrate clear spinal cord involvement in the form of cervical cord atrophy not only in patients with established DN (140) but also in those with early subclinical DN (139). Subsequent studies have sought to apply advances multimodal magnetic resonance imaging to gain unique insights into brain involvement, particularly brain regions involved with somatosensory and nociception in DN – e.g. primary somatosensory cortex (141) and the thalamus (142). Accompanying the reduction in cervical spine volume is a reduction in primary somatosensory cortical volume in both painful and painless DN (141). Proton magnetic resonance spectroscopy studies have demonstrated evidence of thalamic neuronal dysfunction in painless but not in painful DN – indicating that preservation of thalamic neuronal function may be a prerequisite for the perception of pain in DN (142). In addition, there was also an increase in thalamic vascularity (144), altered thalamic-cortical functional connectivity (146), and a reorganization of the primary somatosensory cortex in patients with painful DN (146). Thus, the involvement of the central nervous system in DN has opened a whole new area of further research and has great potential for future patient stratification and development of new therapeutic targets.

Figure 12.

Multimodal magnetic resonance imaging studies of the central nervous system in diabetic neuropathy.

TREATMENT OF DIABETIC POLYNEUROPATHIES

Treatment of DN should be targeted towards a number of different aspects: firstly, treatment of specific underlying pathogenic mechanisms; secondly, treatment of symptoms and improvement in QOL; and thirdly, prevention of progression and treatment of complications of neuropathy.

PAINFUL DIABETIC PERIPHERAL NEUROPATHY

Sensory Profiling

For many years, sensory profiling has been the mainstay for identifying a homogenous subgroup of neuropathic pain patients in clinical pain research. The basis of this approach is that painful symptoms reflect specific pathophysiological mechanisms, which are present to varying degrees in individual patients (229,230). Detailed sensory profiling using quantitative sensory testing (QST) can be used to subgroup patients into more homogenous cohorts (pain phenotypes), which could then be targeted with treatments known to act specifically on pathophysiological pathways underlying the phenotypes (231) (Figure 13). QST refers to a battery of standardized, psychophysical tests (e.g., thermal testing, pin prick, pressure algometry, and von Frey filaments) used to assess central and peripheral nervous system sensory function (232). In DPN, QST has been used for several decades mainly for diagnosing and quantifying the extent of small and large nerve fiber impairment in individuals predominantly with painless DPN. In the context of pain somatosensory phenotyping, a standardized QST protocol was developed by the German Research Network on Neuropathic Pain (DFNS), which includes 12 sensory testing parameters (i.e., cold and warm detection thresholds, paradoxical heat sensations, thermal sensory limen procedure, cold and heat pain thresholds, mechanical detection threshold, mechanical pain threshold, mechanical pain sensitivity, dynamic mechanical allodynia, wind-up ratio, vibration detection threshold, and pressure pain threshold) (232). The positive and negative results of individual patients are obtained by comparison against a normative QST reference dataset, comprised of age- and sex-stratified healthy individuals.

Figure 13.

Schematic representation of the generation of pain. (A) Normal: Central terminals of c-afferents project into the dorsal horn and make contact with secondary pain-signaling neurons. Mechanoreceptive Aβ afferents project without synaptic transmission into the dorsal columns (not shown) and also contact secondary afferent dorsal horn neurons. (B) C-fiber sensitization: Spontaneous activity in peripheral nociceptors (peripheral sensitization, black stars) induces changes in the central sensory processing, leading to spinal-cord hyperexcitability (central sensitization, gray star) that causes input from mechanoreceptive Aβ (light touch) and Aδ fibers (punctuate stimuli) to be perceived as pain (allodynia). (C) C-fiber loss: C-nociceptor degeneration and novel synaptic contacts of Aβ fibers with “free” central nociceptive neurons, causing dynamic mechanical allodynia. (D) Central disinhibition: Selective damage of cold-sensitive Aδ fibers that leads to central disinhibition, resulting in cold hyperalgesia. Sympat, sympathetic nerve

Phenotype-Driven Therapeutic Experience in Painful DPN

Examples of studies that focused on painful DPN include an open label retrospective study using the DFNS protocol, which evaluated key phenotypic differences in sensory profiling associated with response to intravenous lidocaine in patients with severe, intractable painful DPN (235). Patients with the irritable nociceptor phenotype were more likely to respond to intravenous lidocaine, which inactivates sodium channels, compared to the non-irritable nociceptor phenotype (235). In fact, dynamic mechanical allodynia and pain summation to repetitive pinprick stimuli were the only evoked ‘gain of function’ QST parameters that informed treatment response. The presence of these sensory gain parameters suggests aberrant central processing with hyperexcitable neurons driven by abnormal sodium channel regulation, generating ectopic impulses and amplifying afferent sensory inputs. In another painful DPN study by Campbell et al. of topical clonidine, sensory profiling was performed using the capsaicin challenge test (236). The post-hoc analysis demonstrated a significant reduction in pain in the patient subgroup with increased spontaneous pain following cutaneous capsaicin administration, indicating the presence of functioning and sensitized nociceptors. Bouhassira et al. published post-hoc analysis data of treatment response based on sensory profiling using the Neuropathic Pain Symptom Inventory (NPSI) questionnaire from the Combination vs Monotherapy of pregabalin and duloxetine in Diabetic Neuropathy (COMBO-DN) study (237). This study examined the effect of high-dose duloxetine, a serotonin noradrenaline reuptake inhibitor, or pregabalin, a calcium channel blocker, as monotherapy versus combined pregabalin and duloxetine for painful DPN. The investigators showed that adding pregabalin (300 mg) to duloxetine (60 mg) improved the dimensions of ‘pressing pain’ and ‘evoked pain’ more significantly. On the other hand, increasing duloxetine from 60 mg to 120 mg daily improved the dimension ‘paresthesia/dysesthesia’ to a greater extent.

SENSORY PHENOTYPING TO PREDICT THERAPEUTIC RESPONSE

In a randomized, double-blind, placebo-controlled, and phenotype-stratified study of patients with painful DPN Demant et al. reported that oxcarbazepine was more efficacious for relief of peripheral neuropathic pain in patients with the irritable vs the nonirritable nociceptor phenotype (234). Based on this and other recent studies, current opinion with regard to neuropathic pain clinical trials recommends a detailed sensory profiling of participants at baseline; and even if there is no significant separation of a drug with placebo, a subgroup analysis can be performed to see if the drug was efficacious in a particular subgroup. If there is a clear signal that this was the case, a further, adequately powered, phenotype stratified trial would be designed.

Sensory profiling can also identify subgroups with altered endogenous pain modulation to predict treatment outcomes of drugs and other interventions that affect a given mechanism. Figure 14 describes the different nerve fibers affected and possible targeted treatments.

In a study of pain modulation in DPN, individuals were assessed using QST for conditioned pain modulation (CPM), a psychophysical paradigm in which central pain inhibition is measured via the phenomenon of ‘pain inhibiting pain,’ via the simultaneous administration of a conditioning painful stimulus at a distant body site. The pain in participants with abnormal CPM was more receptive to duloxetine, which is believed to increase descending inhibitory pain pathway activation, than individuals with normal pain modulation, although there was no comparison to placebo in this open-label study (238).

Figure 14.

Different mechanisms of pain and possible treatments. C fibers are modulated by sympathetic input with spontaneous firing of different neurotransmitters to the dorsal root ganglia, spinal cord and cerebral cortex. Sympathetic blockers (e.g., clonidine) and depletion of axonal substance P used by C fibers as their neurotransmitter (e.g., by capsaicin) may improve pain. In contrast Aδ fibers utilize Na+ channels for their conduction and agents that inhibit Na+ exchange such as antiepileptic drugs, tricyclic antidepressants, and insulin may ameliorate this form of pain. Anticonvulsants (carbamazepine, gabapentin, pregabalin, topiramate) potentiate activity of g-aminobutyric acid and inhibit Na+ and Ca2+ channels, N-methyl-D-aspartate receptors, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors. Dextromethorphan blocks N-methyl-D-aspartate receptors in the spinal cord. Tricyclic antidepressants, selective serotonin reuptake inhibitors (e.g., fluoxetine), and serotonin and norepinephrine reuptake inhibitors inhibit serotonin and norepinephrine reuptake, enhancing their effect in endogenous pain-inhibitory systems in the brain. Tramadol is a central opioid analgesic. α2 antag, α 2 antagonists; 5HT, 5-hydroxytryptamine; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; DRG, dorsal root ganglia; GABA, g-aminobutyric acid; NMDA, N-methyl-D-aspartate; SNRIs, serotonin and norepinephrine reuptake inhibitors; SP, substance P; SSRIs, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants;

Taken together, these studies support the notion that mechanism-based approaches to pain management may be feasible in painful DPN. However, in an elegant mechanistic study, Haroutounian et al examined 14 patients with neuropathic pain of mixed etiology [unilateral foot pain from nerve injury (n=7) and distal polyneuropathy (n=7)] to determine the contribution of primary afferent input in maintaining peripheral neuropathic pain (239). Each patient underwent randomized ultrasound-guided peripheral nerve block with lidocaine versus intravenous lidocaine infusion. They found that peripheral afferent input was critical for maintaining neuropathic pain, but improvement in evoked hypersensitivity was not related to improvements in spontaneous pain intensity. This suggests that further studies are needed to rationalize sensory phenotyping in order to optimize clinical trial outcomes in painful DPN. Moreover, given the rarity of the irritable-nociceptor phenotype, as determined by QST, a single assessment modality may be unlikely to help stratify patients and combining with additional modalities may be necessary (e.g., brain imaging).

General Principals of Managing Painful DPN

Managing painful symptoms in DPN may constitute a considerable treatment challenge. The efficacy of a single therapeutic agent is not the rule, and most patients require combination therapy to control the pain. The present ‘trial and error’ approach is to offer the available therapies in a stepwise fashion until an effective treatment is achieved (247,248). Effective pain treatment considers a favorable balance between pain relief and side effects without implying a maximum effect. The following general considerations in the pharmacotherapy of neuropathic pain require attention (249):

1.

The appropriate and effective drug has to be tried and identified in each patient by carefully titrating the dose based on efficacy and side effects.

2.

Lack of efficacy should be judged only after 2-4 weeks of treatment using an adequate dose.

3.

As the evidence from clinical trials suggests a ≥ 50% reduction in pain for any monotherapy, combination therapy is considered a ‘robust’ response. A reduction of pain of 30-49% may be considered a ‘clinically relevant’ response.

4.

Potential drug interactions have to be considered given the frequent use of polypharmacy in patients with diabetes.

For many patients, optimal management of chronic pain may require a multidisciplinary team approach with appropriate behavioral therapy, as well as input from a broad range of healthcare professionals. Here we highlight the common agents used to manage painful DPN and key papers to demonstrate the evidence base. The most recent guidelines for pharmacotherapy for neuropathic pain in general and specifically in painful DPN can be found elsewhere (16,250,251,252,253,254,67, 255,256).

ANTIDEPRESSANTS

Antidepressants are commonest agents used in the treatment of chronic neuropathic pain (217). The putative mechanisms of interrupting pain transmission by these agents include inhibition of norepinephrine and/or serotonin reuptake within the endogenous descending pain-inhibitory systems in the brain and spinal cord (257). Antagonism of N-Methyl-D-Aspartate receptors that mediate hyperalgesia and allodynia has also been proposed.

Tricyclic Antidepressants (TCAs)

Imipramine, amitriptyline, and clomipramine induce a balanced reuptake inhibition of both norepinephrine and serotonin, while desipramine is a relatively selective norepinephrine inhibitor. The most frequent adverse events of tricyclic antidepressants (TCAs) are anticholinergic symptoms including tiredness and dry mouth and may exacerbate cardiovascular and gastrointestinal autonomic neuropathy. The starting dose should be 25 mg (10 mg in frail patients) taken as a single night time dose one hour before sleep. The maximum dose is usually 150 mg per day and doses >100mg should be avoided in the elderly.

TCAs should be used with caution in patients with orthostatic hypotension and are contraindicated in patients with unstable angina, recent (<6 months) myocardial infarction, closed-angle glaucoma, heart failure, history of ventricular arrhythmias, significant conduction system disease, and long QT syndrome. Their use is limited by relatively high rates of adverse events and several contraindications.

Serotonin Noradrenaline Reuptake Inhibitors (SNRI)

The efficacy and safety of duloxetine has been evaluated in 7 RCTs establishing it as a mainstay treatment option in painful DPN. Several systematic reviews demonstrate a moderate strength of evidence for duloxetine reduces neuropathic pain to a clinically meaningful degree in patients with painful DPN (258,259,260). Patients with higher pain intensity tend to respond better than those with lower pain levels. The most frequent side effects of duloxetine (60/120 mg/day) include nausea (16.7/27.4%), somnolence (20.2/28.3%), dizziness (9.6/23%), constipation (4.9/10.6%), dry mouth (7.1/15%), and reduced appetite (2.6/12.4%). These adverse events are usually mild to moderate and transient. To minimize them the starting dose should be 30 mg/day for 4-5 days. In contrast to TCAs and some anticonvulsants, duloxetine does not cause weight gain, but a small increase in fasting blood glucose may occur (261).

Venlafaxine is another SNRI that has mixed action on catecholamine uptake. Compared to duloxetine, the strength of evidence for venlafaxine is lower and it could be considered an alternative if duloxetine is not tolerated. At lower doses, venlafaxine inhibits serotonin uptake and at higher doses it inhibits norepinephrine uptake (262). The extended release version of venlafaxine was found to be superior to placebo in painful DPN in non-depressed patients at doses of 150-225 mg daily, and when added to gabapentin there was improved pain, mood, and quality of life (263). In a 6-week trial comprised of 244 patients the analgesic response rates were 56%, 39%, and 34% in patients given 150-225 mg venlafaxine, 75 mg venlafaxine, and placebo, respectively. Because patients with depression were excluded, the effect of venlafaxine (150-225 mg) was attributed to an analgesic, rather than antidepressant, effect. The most common adverse events were tiredness and nausea (264); additionally, clinically important electrocardiogram changes were found in seven patients in the treatment arm.

ANTI-EPILEPTIC DRUGS

Calcium Channel Modulators (α2-δ ligands)

Gabapentin is an anticonvulsant structurally related to γ-aminobutyric acid (GABA), a neurotransmitter that plays a role in pain transmission and modulation. The exact mechanisms of action of this drug in neuropathic pain are not fully elucidated. Among others, they involve an interaction with the L-amino acid transporter system and high affinity binding to the α2-δ subunit of voltage-activated calcium channels. A Cochrane review reported 4 out of 10 patients with painful DPN achieved greater than 50% pain relief with gabapentin compared to placebo (2 out of 10). Pain was reduced by a third or more for 5 in 10 with gabapentin and 4 in 10 with placebo. Over half of those treated did not benefit from worthwhile pain relief but experienced adverse event (265).

In contrast to gabapentin, pregabalin is a more specific α2-δ ligand with a 6-fold higher binding affinity. It also has a more rapid onset with a dose-dependent linear pharmacokinetic profiled i.e., 600mg/day being more effective that 300mg/day (266). Hence, the administration (BD vs QDS) and dose titration of pregabalin in considerably easier compared to gabapentin. A recent Cochrane review reported moderate quality evidence for the efficacy of pregabalin in painful DPN compared to placebo (267). 3 or 4 in 10 people had pain reduced by half or more with pregabalin 300 mg or 600 mg daily, and 2 or 3 in 10 with placebo. Pain was reduced by a third or more for 5 or 6 in 10 people with pregabalin 300 mg or 600 mg daily, and 4 or 5 in 10 with placebo.

Common side-effects associated with the use of gabapentinoids include weight gain, edema, dizziness, and somnolence. They should be used with caution in patients with congestive cardiac failure (NYHA class III or IV) and renal impairment (dose reduction required). Pooled trial analysis of adverse events showed a higher risk of side-effects with increasing pregabalin dose but not older age (268). The misuse and abuse of gabapentinoids is a growing problem in the US and in Europe necessitating monitoring for signs of misuse/abuse and caution when used in at risk populations (269). Gabapentinoids may also increase the risk of respiratory depression, a serious concern for patients taking opioids or with underlying respiratory impairment (270,271,272).

TOPICAL CAPSAICIN

C-fibers utilize the neuropeptide substance P as their neurotransmitter, and depletion of axonal substance P (through the use of capsaicin) will often lead to amelioration of the pain. Prolonged application of capsaicin, a highly selective agonist of transient receptor potential vanilloid-1 (TRPV1), depletes stores of substance P, and possibly other neurotransmitters, from sensory nerve endings. This reduces or abolishes the transmission of painful stimuli from the peripheral nerve fibers to the higher centers (273). The 8% capsaicin patch (Qutenza) (274) is authorized for the treatment of peripheral neuropathic pain. In one RCT in painful DPN, a single application of 8% capsaicin patch applied for 30min provided modest pain relief for up to 3 months (275). Specialist trained staff are required for application which can be repeated every 2-3 months. A Cochrane review of low dose (0.025% and 0.075%) topical capsaicin cream was not able to provide any recommendations due to insufficient data (276).

LIDOCAINE

Lidocaine has unique analgesic properties. Although the exact mechanism by which intravenous lidocaine provides systemic analgesia is unknown, it is thought to have both peripheral and central mechanisms of action (277,278,279). It exhibits state-dependent binding where sodium channels that are rapidly and repeatedly activated and inactivated are more readily blocked (280). This state-dependence is thought to be very important in limiting the hyperexcitability of cells exhibiting abnormal activity. Thus, it is likely to have greater efficacy in patients with neuropathic pain (281,282) and has been used to relieve chronic pain for over 50 years (283). A Cochrane review of 30 RCT found that intravenous lidocaine (284), which is more effective than its oral analogue (mexilitine, NNT10-38) and gastrointestinal intolerance most common side effect and major factor limiting its use) (284,285) and is more effective than placebo in decreasing neuropathic pain. It was found to be generally well tolerated with little or no side effects (286). Hence, intravenous lidocaine is a recognized treatment option for patients with severe painful DPN (287), and is included in clinical guidelines (288).

Although 5% lidocaine patch is being used in patients with postherpetic neuralgia (289), there is insufficient evidence to recommend its use in those with painful DPN.

OPIOIDS

Tramadol and NMDA Receptor Antagonists

The most examined compounds in painful DPN are tramadol, oxycodone, and tapentadol. Tramadol is a centrally acting weak opioid and SNRI for use in treating moderate to severe pain. More severe pain requires administration of strong opioids such as oxycodone (µ-opioid agonist) or tapentadol (µ-opioid agonist and SNRI). There is limited data available on the efficacy of these agents from relatively small-scale studies. Recent Cochrane reviews graded the available evidence as mostly of low or very low quality and likely to overestimate the efficacy of tramadol and oxycodone in the treatment of painful DPN (290,291). Side effects typical of opioids were common including somnolence, headache, and nausea. There is an increased risk of serotonergic syndrome if tramadol and tapentadol are prescribed with other agents with serotonin reuptake inhibitor properties and thus best avoided. Nevertheless, there is role for these agents as 2^nd or 3^rd line analgesics for painful DPN in carefully selected patients unresponsive to standard treatments. Non-pharmacological and non-opioid analgesic treatments should be optimized and established and/or not tolerated/contraindicated before opioid treatment is considered (292). Regular monitoring/evaluation of efficacy is recommended particularly if treatment is longer than 3 months. Opioids are associated with less pain relief during longer trials possibly due to opioid tolerance or opioid induced hyperalgesia. Moreover, adverse outcomes such as dependence, overdose, depression, and impaired functional status were more common in patients with neuropathic pain (painful DPN 68%) receiving long-term (>90 days) vs short term (<90 days) of treatment (293). Hence, referral to specialist or centers with experience in opioid use is recommended to avoid risks.

PSYCHOLOGICAL SUPPORT

A psychological component to pain should not be underestimated. Hence, an explanation to the patient that even severe pain may remit, particularly in poorly controlled patients with acute painful neuropathy or in those painful symptoms precipitated by intensive insulin treatment. Thus, the empathetic approach addressing the concerns and anxieties of patients with neuropathic pain is essential for their successful management (294).

PHYSICAL MEASURES

The temperature of the painful neuropathic foot may be increased due to arterio-venous shunting. Cold water immersion may reduce shunt flow and relieve pain. Allodynia may be relieved by wearing silk pajamas or the use of a bed cradle. Patients who describe painful symptoms on walking as comparable to walking on pebbles may benefit from the use of comfortable footwear (255).

ACUPUNCTURE

A 10-week uncontrolled study with a follow-up period of 18-52 weeks in patients with diabetes showed significant pain relief after up to 6 courses of traditional Chinese acupuncture without any side effects (295). A single-blind placebo-controlled randomized trial of acupuncture in 45 subjects with painful DN recently reported an improvement in the outcome measures assessing pain in the acupuncture arm relative to sham treatment (296). However, Chen and colleagues warn that design flaws and lack of robust outcome measures of pain in acupuncture trials make meaningful conclusions difficult (297). Larger controlled studies are needed to confirm these early findings.

ELECTRICAL STIMULATION

Transcutaneous electrical nerve stimulation (TENS) influences neuronal afferent transmission and conduction velocity, increases the nociceptive flexion reflex threshold, and changes the somatosensory evoked potentials. In a 4-week study of TENS applied to the lower limbs, each for 30 minutes daily, pain relief was noted in 83% of the patients compared to 38% of a sham-treated group. In patients who only marginally responded to amitriptyline, pain reduction was significantly greater following TENS given for 12 weeks as compared with sham treatment. Thus, TENS may be used as an adjunctive modality combined with pharmacotherapy to augment pain relief (298).

Frequency-modulated electromagnetic nerve stimulation (FREMS) in 2 studies, including a recent double-blind randomized placebo controlled trial with 51 weeks of follow-up, proved to be a safe treatment for symptomatic diabetic neuropathy, with immediate but transient reduction in pain and no effect on nerve conduction velocities (299,300). Six out of eight trials analyzed in a recent review evaluating the use of electrical stimulation in painful DN found significant pain relief in patients treated with electrical stimulation compared with placebo or sham treatment (301).

Electrical spinal cord stimulation (SCS) was first reported in painful DPN in 1996 (302). With electrodes implanted between T9 and T11, 8 out of 10 patients reported greater than 50% pain relief. Most of these early devices utilized low-frequency stimulation (40-60Hz) with two RCTs demonstrating moderate utility (n=36 to 60) with 6-month to 24-month follow up (303,304,305) with responder attrition within 12 months (306). Modern iterations of SCS employ high-frequency stimulation (10kHz) provides pain relief without generating paresthesia (307,308,309,310). A recent RCT examine the use of 10kHz electrical SCS in patients with refractory painful DPN compared to conventional medical management in 216 randomized patients (311). 50% reduction in pain relief was observed in 5% in the control group compared to 79% in the electrical SCS group with 6 months follow up. The main limitation of this study was the lack of blinding and potential for placebo effects as an important confounding factor. Nevertheless, this is an interesting finding which should open a new area for further research. Overall complications of electrical SCS include wound infection and lead migration requiring reinsertion. Currently, therefore, this invasive treatment option should be reserved for patients who do not respond to analgesic combination pharmacotherapy.

SURGICAL DECOMPRESSION

Surgical decompression at the site of anatomic narrowing has been promoted as an alternative treatment for patients with symptomatic DPN. A systematic review of the literature revealed only Class IV studies concerning the utility of this therapeutic approach. Given the current evidence available, this treatment alternative should be considered unproven. Prospective randomized controlled trials with standard definitions and outcome measures are necessary to determine the value of this therapeutic intervention (312,313).

The odds ratios for efficacy of neuropathic pain medications are given in Figure 15. In addition, Table 5 shows the dosages of the different drugs and the commonly encountered side effects.

Figure 15.

Efficacy analysis of drugs used for the treatment of PDN

Table 5.

Treatments for Symptomatic Diabetic Polyneuropathy

Pain-Dosing and Side Effects

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Drug Class	Drug	Dose	Side Effects
Tricyclics	Amitriptyline	5-75mg nocte	Somnolence, dizziness, dry mouth, tachycardia,
	Nortriptyline	50-150mg nocte	constipation, urinary retention, blurred vision
	Imipramine	25-150mg nocte	Confusion
SNRIs	Duloxetine	30-60mg BD	Nausea, somnolence, dizziness, anorexia
Anticonvulsants	Gabapentin	300-1200mg TDS	Somnolence, dizziness, Confusion, ataxia
	Pregabalin	50-300mg BD	Somnolence, confusion, edema, weight gain
	Carbamazepine/ Oxcarbazepine	Up to 200 QDS	Dizziness, somnolence, Nausea, leukopenia
Opioids*	Tramadol	50-100mg BD/QDS	Nausea, constipation, HA Somnolence
	Oxycodone MR Tapentadol ER	10-30mg BD 50mg BD up to 500mg/24hrs	Somnolence, nausea, constipation, HA Constipation, nausea, somnolence, dizziness
Topical	Capsaicin	0.075% QDS	Local irritation
	Lidocaine	0.04% QDS	Local irritation

*

Due to increased risk of adverse outcomes caution is advised if treatment is continued for >3 months.

Guidelines for Pharmacotherapy of Painful Neuropathy

Figure 16 is a pharmacotherapy algorithm that we propose for the management of painful neuropathy in diabetes. This presumes that the cause of the pain has been attributed to DPN and that all causes masquerading as DPN have been excluded. The identification of neuropathic pain as being focal or diffuse dictates the initial course of action. Focal neuropathic pain is best treated with splinting, steroid injections, and surgery to release entrapment. Diffuse neuropathies are treated with medical therapy and in a majority of cases, need combination therapy. Essential to the DPN evaluation is the identification of the patient’s comorbidities, potential adverse events, and drug interactions. When single agents fail, combinations of drugs with different mechanisms of action should be considered. Comorbidities that accompany pain include depression, anxiety, and sleep disturbances, all of which must be addressed for successful management of pain. Treatment of peripheral neuropathic pain conditions can benefit from further understanding of the impact of pain response and QOL, including activities of daily living (ADLs) and sleep. Patients often benefit from participation in pain management groups and psychological intervention to develop/gain better coping strategies and deal with harmful/disruptive pain-related behaviors. There is currently minimal evidence for the use of combination treatment for painful DPN – hence, most guidelines recommend switching to an alternative agent. There are also few head-to-head comparator trials of commonly used agent evaluating efficacy and safety between drugs. We await the outcome of the much-anticipated OPTION-DM study – head-to-head multicenter, RCT will inform clinicians of the most cost effective monotherapy (amitriptyline, pregabalin and duloxetine) followed by combination therapy for painful DPN (314).

Figure 16.

Algorithm for the Management of Symptomatic Diabetic Neuropathy. Non-pharmacological, topical or physical therapies can be useful at any time. SNRIs, serotonin and norepinephrine reuptake inhibitors; TCA, tricyclic antidepressants.

AUTONOMIC NEUROPATHY

Introduction

The autonomic nervous system (ANS) supplies all organs in the body and consists of an afferent and an efferent system, with long efferents in the vagus (cholinergic) and short postganglionic unmyelinated fibers in the sympathetic system (adrenergic). A third component is the neuropeptidergic system with its neurotransmitters substance P (SP), vasoactive intestinal polypeptide (VIP), and calcitonin gene related peptide (CGRP) amongst others. Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes but remains among the least recognized and understood. Diabetic autonomic neuropathy (DAN) can cause dysfunction of every part of the body, and has a significant negative impact on survival and quality of life (315). The organ systems that most often exhibit prominent clinical autonomic signs and symptoms in diabetes include the pupils, sweat glands, genitourinary system, gastrointestinal tract, adrenal medullary system, and the cardiovascular system (Table 6). Clinical symptoms generally do not appear until long after the onset of diabetes. However, subclinical autonomic dysfunction can occur within a year of diagnosis in type 2 diabetes patients and within two years in type 1 diabetes patients (316).

Table 6. 

Clinical Manifestations of Autonomic Neuropathy

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Cardiovascular Central: Tachycardia/ Bradycardia Systolic and diastolic dysfunction Decreased exercise tolerance Orthostasis, Orthostatic tachycardia and bradycardia syndrome Sleep apnea Anxiety/ depression Cardiac denervation syndrome Paradoxic supine or nocturnal hypertension Intraoperative and perioperative cardiovascular instability Peripheral: Decreased thermoregulation Decreased sweating Altered blood flow Impaired vasomotion Edema

Gastrointestinal Esophageal dysmotility Gastroparesis diabeticorum Diarrhea Constipation Fecal incontinence

Genitourinary Erectile dysfunction Retrograde ejaculation Neurogenic bladder and cystopathy Female sexual dysfunction (e.g., loss of vaginal lubrication)

Sudomotor Anhidrosis Hyperhidrosis Heat intolerance Gustatory sweating Dry skin

Metabolic Hypoglycemia unawareness Hypoglycemia unresponsiveness

Pupillary Pupillomotor function impairment (e.g., decreased diameter of dark-adapted pupil) Pseudo Argyll-Robertson pupil

Microvascular flow is under the control of the ANS and is regulated by both the central and peripheral components of the ANS. Defective blood flow in the small capillary circulation is found with decreased responsiveness to mental arithmetic, cold pressor, hand grip, and heating (317). The defect is associated with a reduction in the amplitude of vasomotion (318) and resembles premature aging (277). There are differences in the glabrous and hairy skin (319) and is correctable with antioxidants (320). The clinical counterpart is a dry cold skin, loss of sweating, and development of fissures and cracks that are portals of entry for organisms leading to infectious ulcers and gangrenes. Silent myocardial infarction, respiratory failure, amputations, and sudden death are hazards for diabetes patients with cardiac autonomic neuropathy (321). Therefore, it is vitally important to make this diagnosis early so that appropriate intervention can be instituted (322).

Disturbances in the autonomic nervous system may be functional, e.g., gastroparesis with hyperglycemia and ketoacidosis, or organic wherein nerve fibers are actually lost. This creates inordinate difficulties in diagnosing, treating, and prognosticating as well as establishing true prevalence rates. Tests of autonomic function generally stimulate entire reflex pathways. Furthermore, autonomic control for each organ system is usually divided between opposing sympathetic and parasympathetic innervations, so that heart rate acceleration, for example, may reflect either decreased parasympathetic or increased sympathetic nervous system stimulation. Since many conditions affect the autonomic nervous system and autonomic neuropathy (AN) is not unique to diabetes, the diagnosis of DAN rests with establishing the diagnosis and excluding other causes (Table 7 and 8). The best studied diagnostic methods, for which there are large databases and evidence to support their use in clinical practice, relate to the evaluation of cardiovascular reflexes (Figure 17). In addition, the evaluation of orthostasis is fairly straightforward and is readily done in clinical practice (Figure 18), as is the establishment of the cause of gastrointestinal symptoms (Figure 19) and erectile dysfunction. The combination of cardiovascular autonomic tests with sudomotor function tests may allow a more accurate diagnosis of diabetic autonomic neuropathy (323). Tables 9 and 10 below present the diagnostic tests that would be applicable to the diagnosis of cardiovascular autonomic neuropathy. These tests can be used as a surrogate for the diagnosis of AN of any system since it is generally rare to find involvement (although it does occur) of any other division of the ANS in the absence of cardiovascular autonomic dysfunction. For example, if one entertains the possibility that the patient has erectile dysfunction due to AN, then prior to embarking upon a sophisticated and expensive evaluation of erectile status, a measure of heart rate and its variability in response to deep breathing would - if normal - exclude the likelihood that the erectile dysfunction is a consequence of disease of the autonomic nervous system. The cause thereof would have to be sought elsewhere. Similarly, it is extremely unusual to find gastroparesis secondary to AN in a patient with normal cardiovascular autonomic reflexes.

Table 7.

Differential Diagnosis of Diabetic Autonomic Neuropathy

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Clinical Manifestations	Differential Diagnosis
Cardiovascular Resting tachycardia, Exercise intolerance Orthostatic tachycardia and bradycardia syndromes Cardiac denervation, painless myocardial infarction Orthostatic hypotension Intraoperative and perioperative cardiovascular instability	Cardiovascular disorders Idiopathic orthostatic hypotension, multiple system atrophy with Parkinsonism, orthostatic tachycardia, hyperadrenergic hypotension Shy-Drager syndrome Panhypopituitarism Pheochromocytoma Hypovolemia Congestive heart disease Carcinoid syndrome
Gastrointestinal Esophageal dysfunction Gastroparesis diabeticorum Diarrhea Constipation Fecal incontinence	Gastrointestinal disorders Obstruction Bezoars Secretory diarrhea (endocrine tumors) Biliary disease Psychogenic vomiting Medications
Genitourinary Erectile dysfunction Retrograde ejaculation Cystopathy Neurogenic bladder	Genitourinary disorders Genital and pelvic surgery Atherosclerotic vascular disease Medications Alcohol abuse
Neurovascular Heat intolerance Gustatory sweating Dry skin Impaired skin blood flow	Other causes of neurovascular dysfunction Chaga's disease Amyloidosis Arsenic
Metabolic Hypoglycemia unawareness Hypoglycemia unresponsiveness Hypoglycemia associated autonomic failure	Metabolic disorders Other cause of hypoglycemia, intensive glycemic control and drugs that mask hypoglycemia
Pupillary Decreased diameter of dark- adapted pupil Argyll-Robertson type pupil	Pupillary disorders Syphilis

Table 8.

Diagnosis and Management of Autonomic Nerve Dysfunction

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Symptoms	Assessment Modalities	Management
Resting tachycardia, exercise intolerance, early fatigue and weakness with exercise	HRV, respiratory HRV, MUGA thallium scan, 123I MIBG scan	Graded supervised exercise, beta blockers, ACE-inhibitors
Postural hypotension, dizziness, lightheadedness, weakness, fatigue, syncope, tachycardia/bradycardia	HRV, blood pressure measurement lying and standing	Mechanical measures, clonidine, midodrine, octreotide, erythropoietin, pyridostigmine
Hyperhidrosis	Sympathetic/parasympathetic balance	Clonidine, amitryptylline, trihexyphenidyl, propantheline, or scopolamine ,botox, Glycopyrrolate

Table 9.

Diagnostic Tests of Cardiovascular Autonomic Neuropathy

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TEST	METHOD/ PARAMETERS
Resting heart rate Beat-to-beat heart rate Variation*	>100 beats/min is abnormal. With the patient at rest and supine (no overnight coffee or hypoglycemic episodes), breathing 6 breaths/min, heart rate monitored by EKG or ANSCORE device, a difference in heart rate of >15 beats/min is normal and <10 beats/min is abnormal, R-R inspiration/R-R expiration >1.17. All indices of HRV are age-dependent**.
Heart rate response to Standing*	During continuous EKG monitoring, the R-R interval is measured at beats 15 and 30 after standing. Normally, a tachycardia is followed by reflex bradycardia. The 30:15 ratio is normally >1.03.
Heart rate response to Valsalva maneuver*	The subject forcibly exhales into the mouthpiece of a manometer to 40 mmHg for 15 s during EKG monitoring. Healthy subjects develop tachycardia and peripheral vasoconstriction during strain and an overshoot bradycardia and rise in blood pressure with release. The ratio of longest R-R shortest R-R should be >1.2.
Spectral analysis of heart rate variation, very low frequency power (VLFP 0.003-0.04) and high frequency power (HFP 0.15-0.40 Hz)	Series of sequential R-R intervals into its various frequent components. It defines two fixed spectral regions for the low-frequency and high-frequency measure.
Systolic blood pressure response to standing	Systolic blood pressure is measured in the supine subject. The patient stands and the systolic blood pressure is measured after 2 min. Normal response is a fall of <10 mmHg, borderline is a fall of 10-29 mmHg, and abnormal is a fall of >30 mmHg with symptoms.
Diastolic blood pressure response to isometric exercise	The subject squeezes a handgrip dynamometer to establish a maximum. Grip is then squeezed at 30% maximum for 5 min. The normal response for diastolic blood pressure is a rise of >16 mmHg in the other arm.
EKG QT/QTc intervals Spectral analysis with respiratory frequency	The QTc (corrected QT interval on EKG) should be <440 ms. VLF peak (sympathetic dysfunction) LF peak (sympathetic dysfunction) HF peak (parasympathetic dysfunction) LH/HF ratio (sympathetic imbalance)
Neurovascular flow	Using noninvasive laser Doppler measures of peripheral sympathetic responses to nociception.

*

These can now be performed quickly (<15 min) in the practitioners' office, with a central reference laboratory providing quality control and normative values. LF, VLF, HF =low, very low and high frequency peaks on spectral analysis. These are now readily available in most cardiologist's practice.** Lowest normal value of E/I ratio: Age 20-24:1.17, 25-29:1.15, 30-34:1.13, 35-30:1.12, 40-44:1.10, 45-49:1.08, 50-54:1.07, 55-59:1.06, 60-64:1.04, 65-69:1.03, 70-75:1.02 .

Table 10.

Diagnostic Assessment of Cardiovascular Autonomic Function

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Parasympathetic	Sympathetic
Resting heart rate Beat to beat variation with deep breathing (E:I ratio) 30:15 heart rate ratio with standing Valsalva ratio Spectral analysis of heart rate variation , high frequency power (HFP 0.15-0.40 Hz) Spectral Analysis of HRV respiratory frequency	Resting heart rate Spectral analysis of heart rate variation, very low frequency power (VLFP 0.003-0.04) Orthostasis BP Hand grip BP Cold pressor response Sympathetic skin galvanic response (cholinergic) Sudorimetry (cholinergic) Cutaneous blood flow (peptidergic)

Figure 17.

This is a sample power spectrum of the HRV signal from a subject breathing at an average rate of 7.5 breaths per minute (Fundamental Respiratory Frequency, FRF = 0.125 Hz). The method using HRV alone defines two fixed spectral regions for the low-frequency (LF) and high-frequency (HF) measure (dark gray and light gray, respectively). It is clear that the high-frequency (light gray) region includes very little area under the HRV spectral curve, suggesting very little parasympathetic activity. The great majority of the HRV spectral activity is under the low-frequency (dark gray) region suggesting primarily sympathetic activity. These representations are incorrect because the slow-breathing subject should have a large parasympathetic component reflective of the vagal activity. This parasympathetic component is represented correctly by the method using both HRV and respiratory activity which defines the red and blue regions of the spectrum in the graph. The blue region defined by the FRF represents purely parasympathetic activity whereas the remainder of the lower frequency regions (red region) represents purely sympathetic activity.

Figure 18.

Evaluation of postural dizziness in patients with diabetes

Figure 19.

Evaluation of a patient with suspected gastroparesis

The role of over-activation of the autonomic nervous system is illustrated in Figure 20 (324).

Figure 20.

Role of over-activation of autonomic nervous system

There are few data on the longitudinal trends in small fiber dysfunction. Much remains to be learned of the natural history of diabetic autonomic neuropathy. Karamitsos et al (325) reported that the progression of diabetic autonomic neuropathy is significant during the 2 years subsequent to its discovery.

The mortality for diabetic autonomic neuropathy has been estimated to be 44% within 2.5 years of diagnosing symptomatic autonomic neuropathy (29). In a meta-analysis, the Mantel-Haenszel estimates for the pooled prevalence rate risk for silent myocardial ischemia was 1.96, with 95% confidence interval of 1.53 to 2.51 (p<0.001; n = 1,468 total subjects). Thus, a consistent association between CAN and the presence of silent myocardial ischemia was shown (284) (Figure 21).

Figure 21.

Relative risks and 95% CIs for studies of cardiovascular neuropathy (CAN) and mortality. Pooled relative risk for 10 studies with CAN define by two or more measures: 3.45 (95% CI 2.66–4.47). Pooled relative risk for 4 studies with CAN defined by a single measure: 1.20 (1.02–1.41). REF: Maser, R. E., Mitchell, B. D., Vinik, A. I., and Freeman, R. Diabetes Care. 2003;26(6):1895-1901.

Management of Autonomic Neuropathy

POSTURAL HYPOTENSION

The syndrome of postural hypotension is posture-related dizziness and syncope. Patients who have Type 2 diabetes mellitus and orthostatic hypotension are hypovolemic and have sympathoadrenal insufficiency; both factors contribute to the pathogenesis of orthostatic hypotension (332). Postural hypotension in the patient with diabetic autonomic neuropathy can present a difficult management problem. Elevating the blood pressure in the standing position must be balanced against preventing hypertension in the supine position.

Supportive Garments: Whenever possible, attempts should be made to increase venous return from the periphery using total body stockings. But leg compression alone is less effective, presumably reflecting the large capacity of the abdomen relative to the legs (333). Patients should be instructed to put them on while lying down and to not remove them until returning to the supine position.

Drug Therapy: Some patients with postural hypotension may benefit from treatment with 9-flurohydrocortisone. Unfortunately, symptoms do not improve until edema occurs, and there is a significant risk of developing congestive heart failure and hypertension. If fluorohydrocortisone does not work satisfactorily, various adrenergic agonists and antagonists may be used (Table 11). Enhancement of ganglionic transmission via the use of pyridostigmine (inhibitor of acetylcholinesterase) improved symptoms and orthostatic hypotension with only modest effects in supine BP for patients with POTS. Similarly, the use of β-adrenergic blockers may benefit the tachycardia, and anticholinergics, the orthostatic bradycardia. Pyridostigmine has also been shown to improve HRV in healthy young adults. If the adrenergic receptor status is known, then therapy can be guided to the appropriate agent. Metoclopramide may be helpful in patients with dopamine excess or increased sensitivity to dopaminergic stimulation. Patients with α2-adrenergic receptor excess may respond to the α2-antagonist yohimbine. Those few patients in whom ß-receptors are increased may be helped with propranolol. α2-adrenergic receptor deficiency can be treated with the α2-agonist clonidine, which in this setting may paradoxically increase blood pressure. One should start with small doses and gradually increase the dose. If the preceding measures fail, midodrine, an α1-adrenergic agonist, or dihydroergotamine in combination with caffeine may help. A particularly refractory form of postural hypotension occurs in some patients post-prandially and may respond to therapy with octreotide given subcutaneously in the mornings.

Table 11. 

Pharmacologic Treatment of Autonomic Neuropathy

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Clinical status	Drug	Dosage	Side effects
Orthostatic hypotension
	9α flouro hydrocortisone, mineralocorticoid	0.5-2 mg/day	Congestive heart failure, hypertension
	Clonidine, α2 adrenergic agonist	0,1-0,5 mg, at bedtime	Orthostatic Hypotension, sedation, dry mouth, constipation, dizziness, bradycardia.
	Octreotide, somatostatin analogue	0.1-0.5 mg/kg/day	Injection site pain, diarrhea
Orthostatic tachycardia and bradycardia syndrome
	Clonidine, α2 adrenergic agonist	0.1-0.5 mg, at bedtime	Orthostatic Hypotension, sedation, dry mouth, constipation, dizziness, bradycardia.
	Octreotide, somatostatin analogue	0.1-0.5 μg/kg/day	Injection site pain, diarrhea
Gastroparesis diabeticorum
	Domperidone, D2-receptor antagonist	10-20 mg, 30-60 min before meal and bedtime	Galactorrhea
	Erythromycin, motilin receptor agonist	250 mg, 30 minutes before meals	Abdominal cramps, nausea, diarrhea, rash
	Levosulphide, D2-receptor antagonist	25 mg, 3 times/day	Galactorrhea
Diabetic diarrhea
	Metronidazole, broad spectrum antibiotics	250 mg, 3 times/day, minimum 3 weeks	Anorexia, rash, GI upset, urine discoloration, dizziness, disulfiram like reaction.
	Clonidine, α2 adrenergic agonist	0.1 mg, 2-3 times/day	Orthostatic Hypotension, sedation, dry mouth, constipation, dizziness, bradycardia.
	Cholestyramine, bile acid sequestrant	4 g, 1-6 times/day	Constipation
	Loperamide, opiate-receptor agonist	2 mg, four times/day	Toxic megacolon
	Octreotide, somatostatin analogue	50 μg, 3 times/day	Aggravate nutrient malabsorption (at higher doses)
Cystopathy
	Bethanechol, acetylcholine receptor agonist	10 mg, 4 times/day	Blurred vision, abdominal cramps, diarrhea, salivation, and hypotension.
	Doxazosin, α1 adrenergic antagonist	1-2 mg, 2-3 times/day	Hypotension, headache, palpitation
Exercise Intolerance
	Graded supervised exercise	20 minutes, 3 times/week	Foot injury, angina.
Hyperhidrosis
	Clonidine, α2 adrenergic agonist	0.1-0.5 mg, at bedtime and divided doses above 0.2 mg	Orthostatic Hypotension, sedation, dry mouth, constipation, dizziness, bradycardia.
	Amitryptiline, Norepinephrine & serotonin reuptake inhibitor	150 mg/ day	Tachycardia, palpitation
	Propantheline, Anti-muscarinic.	15 mg/ day PO	Dry mouth, blurred vision
	Trihexyphenidyl,	2-5 mg PO	Dry mouth, blurred vision, constipation, tachycardia, photosensitivity, arrhythmias.
	Botox,
	Scopolamine, anti-cholinergic	1.5 mg patch/ 3 days; 0.4 to 0.8mg PO	Dry mouth, blurred vision, constipation, drowsiness, and tachycardia.
	Glycopyrrolate, anti-cholinergic	1-2 mg, 2-3 times daily.	Constipation, tachycardia, dry mouth.
Erectile dysfunction
	Sildenafil (Viagra), GMP type-5 phosphodiesterase inhibitor	50 mg before sexual activity, only once per day	Hypotension and fatal cardiac event (with nitrate-containing drugs), headache, flushing, nasal congestion, dyspepsia, musculoskeletal pain, blurred vision
	Tadalafil (Cialis), GMP type-5 phosphodiesterase inhibitor	10 mg PO before sexual activity only once per day.	Headache, flushing, dyspepsia, rhinitis, myalgia, back pain.
	Verdenafil (Levitra), GMP type-5 phosphodiesterase inhibitor	10 mg PO, 60 minutes before sexual activity.	Hypotension, headache, dyspepsia, priapism.

SLEEP APNEA

During sleep, increased sympathetic drive is a result of repetitive episodes of hypoxia, hypercapnia, and obstructive apnea (OSA) acting through chemoreceptor reflexes. Increased sympathetic drive has been implicated in increased blood pressure variability with repetitive sympathetic activation and blood pressure surges impairing baroreflex and cardiovascular reflex functions (284). A direct relationship between the severity of OSA and the increase in blood pressure has been noted. Furthermore, the use of continuous positive airway pressure (CPAP) for the treatment of OSA has been shown to lower blood pressure and improve cardiovascular autonomic nerve fiber function for individuals with OSA. Withdrawal of CPAP for even a short period (i.e., 1 week) has been shown to result in a marked increase in sympathetic activity (284).

GASTROPATHY

Gastrointestinal motor disorders are frequent and widespread in patients with type 2 diabetes, regardless of symptoms (334) and there is a poor correlation between symptoms and objective evidence of a functional or organic defect. The first step in management of diabetic gastroparesis consists of multiple, small feedings; decreased fat intake as it tends to delay gastric emptying; maintenance of glycemic control (335,336); and a low-fiber diet to avoid bezoar formation. Metoclopramide may be used. Domperidone (337,338) has been shown to be effective in some patients, although probably no more so than metoclopramide. Erythromycin given as either a liquid or suppository also may be helpful. Erythromycin acts on the motilin receptor, "the sweeper of the gut," and shortens gastric emptying time (339). Several novel drugs, including the ghrelin (orexigenic hormone) and ghrelin receptor agonists, motilin agonist (mitemcinal), 5-HT4-receptor agonists and the muscarinic antagonist are being investigated for their prokinetic effects (340,341). If medications fail and severe gastroparesis persists, jejunostomy placement into normally functioning bowel may be needed. Different treatment modalities for gastroparesis include dietary modifications, prokinetic and antiemetic medications, measures to control pain and address psychological issues, and endoscopic or surgical options in selected instances (342).

For additional information see the Endotext chapter entitled “Gastrointestinal Disorders in Diabetes”.

ENTEROPATHY

Enteropathy involving the small bowel and colon can produce both chronic constipation and explosive diabetic diarrhea, making treatment of this complication difficult.

Antibiotics: Stasis of bowel contents with bacterial overgrowth may contribute to the diarrhea. Treatment with broad-spectrum antibiotics is the mainstay of therapy, including tetracycline or trimethoprim and sulfamethoxazole. Metronidazole appears to be the most effective and should be continued for at least 3 weeks.

Cholestyramine: Retention of bile may occur and can be highly irritating to the gut. Chelation of bile salts with cholestyramine 4g tid mixed with fluid may offer relief of symptoms.

Diphenoxylate plus atropine: Diphenoxylate plus atropine may help to control the diarrhea; however, toxic megacolon can occur, and extreme care should be used.

Diet: Patients with poor digestion may benefit from a gluten-free diet, while constipation may respond to a high-soluble-fiber diet supplemented with daily hydrophilic colloid. Beware of certain fibers in the neuropathic patient that can lead to bezoar formation because of bowel stasis in gastroparetic or constipated patients.

For additional information see the Endotext chapter entitled “Gastrointestinal Disorders in Diabetes”.

SEXUAL DYSFUNCTION

Erectile dysfunction (ED) occurs in 50-75% of men with diabetes, and it tends to occur at an earlier age than in the general population. The incidence of ED in men with diabetes aged 20-29 years is 9% and increases to 95% by age 70. It may be the presenting symptom of diabetes. More than 50% notice the onset of ED within 10 years of the diagnosis, but it may precede the other complications of diabetes. The etiology of ED in diabetes is multifactorial. Neuropathy, vascular disease, diabetes control, nutrition, endocrine disorders, psychogenic factors as well as drugs used in the treatment of diabetes and its complications play a role (343,344). The diagnosis of the cause of ED is made by a logical stepwise progression in all instances. An approach to therapy has been presented to which the reader is referred; Figure 22 below shows a flow chart modified from Vinik et. al., 1998 (302).

Figure 22. 

Evaluation of patients with diabetes with erectile dysfunction

A thorough work-up for impotence will include: medical and sexual history; physical and psychological evaluations; blood tests for diabetes and levels of testosterone, prolactin, and thyroid hormones; tests for nocturnal erections; tests to assess penile, pelvic, and spinal nerve function; and a test to assess penile blood supply and blood pressure. The flow chart provided is intended as a guide to assist in defining the problem. The healthcare provider should initiate questions that will help distinguish the various forms of organic erectile dysfunction from those that are psychogenic in origin. Physical examination must include an evaluation of the autonomic nervous system, vascular supply, and the hypothalamic-pituitary-gonadal axis.

Autonomic neuropathy causing ED is almost always accompanied by loss of ankle jerks and absence or reduction of vibration sense over the large toes. More direct evidence of impairment of penile autonomic function can be obtained by (1) demonstrating normal perianal sensation, (2) assessing the tone of the anal sphincter during a rectal exam, and (3) ascertaining the presence of an anal wink when the area of the skin adjacent to the anus is stroked or contraction of the anus when the glans penis is squeezed, i.e., the bulbo-cavernosus reflex. These measurements are easily and quickly done at the bedside and reflect the integrity of sacral parasympathetic divisions.

Vascular disease is usually manifested by buttock claudication but may be due to stenosis of the internal pudendal artery. A penile/brachial index of <0.7 indicates diminished blood supply. A venous leak manifests as unresponsiveness to vasodilators and needs to be evaluated by penile Doppler sonography.

In order to distinguish psychogenic from organic erectile dysfunction, nocturnal penile tumescence (NPT) measurement can be done. Normal NPT defines psychogenic ED, and a negative response to vasodilators implies vascular insufficiency. Application of NPT is not so simple. It is much like having a sphygmomanometer cuff inflate over the penis many times during the night while one is trying to have a normal night's sleep and the REM sleep associated with erections. The individual may have to take home the device and become familiar with it over several nights before one has a reliable estimate of the failure of NPT.

Treatment of Erectile Dysfunction

A number of treatment modalities are available and each treatment has positive and negative effects; therefore, patients must be made aware of both aspects before a therapeutic decision is made. Before considering any form of treatment, every effort should be made to have the patient withdraw from alcohol and eliminate smoking. If possible, drugs that are known to cause erectile dysfunction should be removed. Additionally, metabolic control should be optimized.

Relaxation of the corpus cavernous smooth muscle cells is caused by NO and cGMP, and the ability to have and maintain an erection depends on NO and cGMP. The peripherally acting oral phosphodiesterase type 5 (PDE5) inhibitors block the action of PDE5, and cGMP accumulates, enhancing blood flow to the corpora cavernosum with sexual stimulation. This class of agents consists of sildenafil, vardenafil, and tadalafil. They have been evaluated in patients with diabetes with similar levels of efficacy of about 70%. A 50 mg tablet of sildenafil taken orally is the usual starting dose, 60 minutes before sexual activity. Lower doses should be considered in patients with renal failure and hepatic dysfunction. The duration of the drug effect is 4 hours. Generally, patients with diabetes require the maximum dose of each agent, sildenafil 100 mg, tadalafil 20 mg, and vardenafil 20 mg. Before prescribing a PDE5 inhibitor, it is important to exclude ischemic heart disease. These are absolutely contraindicated in patients being treated with nitroglycerine or other nitrate-containing drugs. Severe hypotension and fatal cardiac events can occur (345). Side-effects include headache, flushing, dyspepsia, and muscle pain (346). Direct injection of prostacyclin into the corpus cavernosum will induce satisfactory erections in a significant number of men. Also, surgical implantation of a penile prosthesis may be appropriate. The less expensive type of prosthesis is a semirigid, permanently erect type that may be embarrassing and uncomfortable for some patients. The inflatable type is three times more expensive and subject to mechanical failure, but it avoids the embarrassment caused by other devices.

Female Sexual Dysfunction

Women with diabetes mellitus may experience decreased sexual desire and more pain on sexual intercourse, and they are at risk of decreased sexual arousal, with inadequate lubrication (347). Diagnosis of female sexual dysfunction using vaginal plethysmography to measure lubrication and vaginal flushing has not been well established.

For additional information on this topic see the Endotext chapter entitled “Sexual Dysfunction in Diabetes”.

CYSTOPATHY

In diabetic autonomic neuropathy, the motor function of the bladder is unimpaired, but afferent fiber damage results in diminished bladder sensation. The urinary bladder can be enlarged to more than three times its normal size. Patients are seen with bladders filled to their umbilicus, yet they feel no discomfort. Loss of bladder sensation occurs with diminished voiding frequency, and the patient is no longer able to void completely. Consequently, dribbling and overflow incontinence are common complaints. A post-void residual of greater than 150cc is diagnostic of cystopathy. Cystopathy may put the patients at risk for urinary infections.

Treatment of Cystopathy

Patients with cystopathy should be instructed to palpate their bladder and, if they are unable to initiate micturition when their bladders are full, use Crede's maneuver (massage or pressure on the lower portion of abdomen just above the pubic bone) to start the flow of urine. The principal aim of the treatment should be to improve bladder emptying and to reduce the risk of urinary tract infection. Parasympathomimetics such as bethanechol are sometimes helpful, although frequently they do not help to fully empty the bladder. Extended sphincter relaxation can be achieved with an alpha-1-blocker, such as doxazosin. Self-catheterization can be particularly useful in this setting, with the risk of infection generally being low.

SWEATING DYSFUNCTION

Hyperhidrosis of the upper body, often related to eating (gustatory sweating), and anhidrosis of the lower body, are a characteristic feature of autonomic neuropathy. Gustatory sweating accompanies the ingestion of certain foods, particularly spicy foods, and cheeses. There is a suggestion that application of glycopyrrolate (an antimuscarinic compound) might benefit diabetes patients with gustatory sweating (348). Low-dose oral glycopyrrolate in the range of 1 mg to 2 mg once daily can be tolerated without problematic adverse effects to alleviate the symptoms of diabetic gustatory sweating. Although more long-term data are needed, the use of glycopyrrolate for diabetic gustatory sweating may be a viable option (349). Symptomatic relief can be obtained by avoiding the specific inciting food. Loss of lower body sweating can cause dry, brittle skin that cracks easily, predisposing one to ulcer formation that can lead to loss of the limb. Special attention must be paid to foot care.

METABOLIC DYSFUNCTION

Hypoglycemia Unawareness

Blood glucose concentration is normally maintained during starvation or increased insulin action by an asymptomatic parasympathetic response with bradycardia and mild hypotension, followed by a sympathetic response with glucagon and epinephrine secretion for short-term glucose counter regulation, and growth hormone and cortisol secretion for long-term regulation. The release of catecholamine alerts the patient to take the required measures to prevent coma due to low blood glucose. The absence of warning signs of impending neuroglycopenia is known as "hypoglycemic unawareness". The failure of glucose counter regulation can be confirmed by the absence of glucagon and epinephrine responses to hypoglycemia induced by a standard, controlled dose of insulin (350).

In patients with type 1 diabetes mellitus, the glucagon response is impaired with diabetes duration of 1-5 years; after 14-31 years of diabetes, the glucagon response is almost undetectable. Absence of the glucagon response is not present in those with autonomic neuropathy. However, a syndrome of hypoglycemic autonomic failure occurs with intensification of diabetes control and repeated episodes of hypoglycemia. The exact mechanism is not understood, but it does represent a real barrier to physiologic glycemic control. In the absence of severe autonomic dysfunction, hypoglycemia unawareness is at least in part reversible.

Patients with hypoglycemia unawareness and unresponsiveness pose a significant management problem for the physician. Although autonomic neuropathy may improve with intensive therapy and normalization of blood glucose, there is a risk to the patient, who may become hypoglycemic without being aware of it and who cannot mount a counterregulatory response. It is our recommendation that if a pump is used, boluses of smaller than calculated amounts should be used and, if intensive conventional therapy is used, long-acting insulin with very small boluses should be given. In general, normal glucose and HbA1 levels should not be goals in these patients to avoid the possibility of hypoglycemia. The use of continuous glucose monitoring with hypoglycemic alarms can be very helpful in warning patients of hypoglycemia and in preventing severe hypoglycemic reactions.

Further complicating management of some patients with diabetes is the development of a functional autonomic insufficiency associated with intensive insulin treatment, which resembles autonomic neuropathy in all relevant aspects. In these instances, it is prudent to relax therapy, as for the patient with bona fide autonomic neuropathy. If hypoglycemia occurs in these patients at a certain glucose level, it will take a lower glucose level to trigger the same symptoms in the next 24-48 hours. Avoidance of hypoglycemia for a few days will result in recovery of the adrenergic response.

For additional information on this topic see the Endotext chapter entitled “Hypoglycemia During Therapy of Diabetes”.

DIABETIC NEUROPATHIES: PROSPECTS FOR THE FUTURE

Management of DN encompasses a wide variety of therapies. Treatment must be individualized in a manner that addresses the particular manifestation and underlying pathogenesis of each patient's unique clinical presentation, without subjecting the patient to untoward medication effects. An increased understanding of the pathogenesis of DN will lead to more effective approaches to diagnose and treat this condition. Refinements and adoption of new approaches to measure quantitatively and diagnose DN early is crucial, so that appropriate therapies (risk factor modification or pathogenic) can be commenced before nerve damage is established. These tests must be validated and standardized to allow comparability between studies and a more meaningful interpretation of study results. Our ability to manage successfully the many different manifestations of DN depends ultimately on our success in uncovering the pathogenic processes underlying this disorder.

ACKNOWLEDGEMENTS

This chapter updates the original Endotext chapter on this topic written by Aaron Vinik, Carolina Casellini, and Marie-Laure Nevoret.

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