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Diabetic Somatic Neuropathies

¹ Division of Endocrinology, Metabolism and Diabetes, University of Miami School of Medicine, Miami, Florida
² University Department of Medicine, Manchester Royal Infirmary, Manchester, U.K
³ Department of Neuroscience, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York

Address correspondence and reprint requests to Andrew J.M. Boulton, MD, FRCP, Division of Endocrinology, University of Miami School of Medicine, P.O. Box 016960 (D-110). E-mail: aboulton{at}med.miami.edu

Abbreviations: AGE, advanced glycation end product • AR, aldose reductase • ARI, AR inhibitor • CIDP, chronic inflammatory demyelinating polyneuropathy • CMAP, compound muscle action potential • CTS, carpal tunnel syndrome • DAG, 1,2-diacylglycerol • DCCT, Diabetes Control and Complications Trial • DN, diabetic neuropathy • DPN, diabetic distal sensory polyneuropathy • GLA, -lipoic acid • ICNT, intermediate cutaneous nerve of the thigh • IGT, impaired glucose tolerance • IL, interleukin • LA, lipoic acid • MMP, matrix metalloproteinase • MNSI, Michigan Neuropathy Screening Instrument • MRI, magnetic resonance imaging • NAD, neuroaxonal dystrophy • NCV, nerve conduction velocity • NDS, Neuropathic Disability Score • NGF, nerve growth factor • NIS, Neuropathy Impairment Score • PKC, protein kinase C • PNS, Peripheral Nerve Society • QOL, quality of life • QST, quantitative sensory testing • RAGE, AGE receptor • SNAP, sensory nerve action potential • SSRI, selective serotonin-reuptake inhibitor • STZ, streptozotocin • VEGF, vascular endothelial growth factor • VPT, vibration perception threshold

	SECTION 1: INTRODUCTION

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The neuropathies are among the most common of the long-term complications of diabetes, affecting up to 50% of patients (1–4). Their clinical features vary immensely, and patients may present to a wide spectrum of specialties, from dermatology to podiatry, for example, or from urology to cardiology. Neuropathies are characterized by a progressive loss of nerve fibers, which may affect both principle divisions of the peripheral nervous system. This review will focus on the somatic neuropathies; those affecting the autonomic division were recently reviewed by Vinik et al. (5). There is increasing evidence that measures of neuropathy, such as electrophysiology and quantitative tests, are predictors of not only end points, including foot ulceration, but also of mortality (6).

The epidemiology and natural history of diabetic neuropathy (DN) remain poorly defined, partly because of poor patient selection and the variable criteria for what constitutes a diagnosis of DN. These aspects, as well as the pathogenesis of DN, will be covered in detail in this review. Studies have confirmed the major contribution of prolonged hyperglycemia in the etiopathogenesis of neuropathy and neuropathic pain (7–9,10), and this and other putative mechanisms will be discussed.

The clinical features, diagnosis, and management of the focal and multifocal neuropathies will be described. A major portion of this review will discuss the clinical features, assessment, and management of the patient with the most common form of DN, diabetic distal sensory polyneuropathy (DPN). The late sequelae of DPN and their prevention will also be described.

Finally, practical guidelines for the screening of DPN in clinical practice will be provided. For further details on this topic, please refer to recent reviews (11–18).

	SECTION 2: DEFINITIONS AND CLASSIFICATION OF THE DNs

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A. Definitions
Members of an international consensus meeting on the outpatient diagnosis and management of DN agreed on a simple definition of DN as "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes " (19). It was also agreed that neuropathy cannot be diagnosed without a careful clinical examination—absence of symptoms cannot be equated with absence of neuropathy, as asymptomatic neuropathy is common. The importance of excluding nondiabetic causes was emphasized in the Rochester Diabetic Neuropathy Study, in which up to 10% of peripheral neuropathy in diabetic patients was deemed to be of nondiabetic causation (1).

A more detailed definition of neuropathy was previously agreed upon at the San Antonio Consensus Conference: "diabetic neuropathy is a descriptive term meaning a demonstrable disorder, either clinically evident or subclinical, that occurs in the setting of diabetes mellitus without other causes for peripheral neuropathy. The neuropathic disorder includes manifestations in the somatic and/or autonomic parts of the peripheral nervous system" (20). It is generally agreed that DN should not be diagnosed on the basis of one symptom, sign, or test alone: a minimum of two abnormalities (from symptoms, signs, nerve conduction abnormalities, quantitative sensory tests, or quantitative autonomic tests) is recommended by Dyck (21). Certainly, for clinical trials or epidemiological studies, one of these two abnormalities should include quantitative tests or electrophysiology.

B. Classification of DNs
Numerous classifications of the variety of syndromes affecting the peripheral nervous system in diabetes have been proposed in recent years. Some have been based on presumed etiology, topographical features, or pathological features. However, until we have a clear understanding of the etiopathogenesis of neuropathy, classifications based on the clinical manifestations are most commonly used (22–25). Three slightly different clinical classifications are presented in Table 1. Table 1A describes a purely clinical classification (11,22), whereas Table 1B bases its classification on a mixture of clinical and anatomical findings (25). The classification proposed by Thomas (23,24) will be used throughout this review (Table 1C). This classification is based on the premise that DN is not a unitary condition but is the result of a number of disturbances in the peripheral nervous system as a consequence of hyperglycemia.

Generalized symmetrical polyneuropathies.
Chronic sensorimotor neuropathy is the most common form of DN that is discussed in detail below. It is usually of insidious onset and may be present at the diagnosis of type 2 diabetes in >10% of subjects (8,26). Whereas up to 50% of patients may be asymptomatic, 10–20% may experience troublesome sensory symptoms that require specific treatment. Sensorimotor neuropathy is often accompanied by autonomic dysfunction. Late sequelae of neuropathy, which include insensate foot ulceration, Charcot (neuropathic) arthropathy, and occasionally even amputation (27), are also discussed below.

Acute sensory neuropathy is a distinct variety of the symmetrical polyneuropathies with an acute or subacute onset characterized by severe sensory symptoms, usually with few if any clinical signs. The natural history is one of gradual improvement of these symptoms with establishment of stable glycemic control.

Autonomic neuropathy is also common, though rarely severely symptomatic. Autonomic neuropathy was a topic of focus in a recent technical review by Vinik et al. (5) and will not be further described here.

Focal and multifocal neuropathies.
All the neuropathies under this heading are recognized as being more common in older type 2 diabetic patients. Focal limb neuropathies are often, but not always, due to entrapment (e.g., carpal tunnel syndrome), indicating the greater susceptibility of diabetic nerve to compression. Recent data suggest that there is a threefold risk of having diabetes in 514 patients with carpal tunnel syndrome compared with a normal control group (28). Among the cranial nerves, those supplying the external ocular muscles are most commonly involved. Thoracolumbar radiculoneuropathies may present with girdle-like pain, occasionally with motor weakness of abdominal wall muscles. Proximal motor neuropathy (amyotrophy) may be unilateral or asymmetrically bilateral with pain, wasting, and weakness that may be relatively acute in onset. All of these focal/multifocal neuropathies are discussed in greater detail below.

It seems probable that chronic inflammatory demyelinating polyneuropathy (CIDP) occurs more commonly in people with diabetes (24,29), although a case-control study has not been performed. Its features, differential diagnosis, and management will be discussed in more detail below.

C. Consensus statements and staging of neuropathy
There have been a number of consensus and committee reports relating to DN in the last two decades, the best known of which is probably the San Antonio Conference (20), which discussed definitions, measurements, and classification primarily for clinical research. The use of standardized measurement techniques was recommended, and a further development conference was convened in 1992 to review the standardization of procedures and approaches used for epidemiological and clinical studies (30). Both of these meetings were jointly sponsored by the American Diabetes Association and the American Academy of Neurology.

An international group of experts in DN held a consensus meeting to develop guidelines for the management of diabetic peripheral neuropathy by the practicing clinician (19). The agreed clinical stages of DPN are shown in Table 2. This clinical staging is in general agreement with that proposed by Dyck (21,31), for use in both clinical practice and epidemiological studies or controlled clinical trials. Thus, the clinical "no neuropathy" is equivalent to Dyck’s N0 or N1a; "clinical neuropathy" is equivalent to N1b, N2a, or N2b; and "late complications" is equivalent to Dyck’s N3 (Table 3).

	SECTION 3: PATHOGENESIS OF DN

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This section will focus predominantly on the pathogenesis of DPN. Studies in animal models and cultured cells provide a conceptual framework for the cause and treatment of DN (35). However, limited translational work in diabetic patients continues to generate much debate and controversy over the cause(s) of human DN, and to date we have no effective treatment.

A. Hyperglycemia
Longitudinal data from the Rochester cohort support the contention that the duration and severity of exposure to hyperglycemia are related to the severity of neuropathy only (36). Similarly, in a study of newly diagnosed patients with type 2 diabetes followed up from baseline and at 5 and 10 years, the overall severity, and not the development of neuropathy, was related to the degree of hyperglycemia (8). Recent studies in patients with impaired glucose tolerance (IGT) provide important insights into the role of the degree of glucose dysmetabolism and the development of neuropathy. In a study of patients with IGT, the sural nerve amplitude and myelinated fiber density do not differ significantly from those with normal glucose tolerance, suggestive of a glycemic threshold for the development of neuropathy (37). However, of 121 patients with a painful neuropathy and electrodiagnostic evidence of axonal injury together with epidermal nerve fiber abnormalities, 25% had IGT (38). The neuropathy associated with IGT is milder than the neuropathy associated with newly diagnosed diabetes, and small nerve fiber involvement may be the earliest detectable sign of neuropathy (39). Improving hyperglycemia by more intensive insulin therapy (7) or pancreatic transplantation (40) improves electrophysiology in patients with type 1 diabetes. However, the evidence is not clear in type 2 diabetes. In the VA Cooperative Study on Type 2 Diabetes Mellitus (VACSDM), 153 patients randomized to intensive versus conventional therapy achieved a 2.07% difference in HbA_1c over 2 years, but failed to demonstrate a significant difference in the progression of either somatic or autonomic neuropathy (41). Similarly, the more recent Steno-2 Study failed to demonstrate a benefit of multifactorial intervention, including glycemic control, on measures of somatic neuropathy (42). The U.K. Prospective Diabetes Study (UKPDS) represents the largest interventional study in type 2 diabetes that has assessed the effects of improved glycemic control, but the neuropathy data have not yet been reported (26).

B. Other pathogenetic mechanisms
Polyol pathway.
Animal models of diabetes consistently demonstrate an association between increased flux through the polyol pathway and a reduction in nerve conduction velocity (NCV), both of which can be ameliorated with aldose reductase inhibitors (ARIs) (43). However, in humans the situation is not clear. A recent study has demonstrated enhanced aldose reductase (AR) but minimal sorbitol dehydrogenase expression in the peripheral nerve of diabetic patients (44). In one of the earliest clinical studies, sorbitol and fructose levels were increased in only one-third of the sural nerve biopsies studied and could not be related to clinical, neurophysiological, or pathological severity of neuropathy (45). Postmortem sciatic nerves from diabetic patients demonstrated a significant increase in glucose, fructose, and sorbitol compared with normal subjects (46). In nerve obtained at amputation, glucose, fructose, and sorbitol were significantly higher in diabetic patients than in nondiabetic patients (47), but concentrations differed markedly from those in postmortem samples (46). In a recent study of patients with normal glucose tolerance, IGT, and type 2 diabetes, only the diabetic patients demonstrated an elevation in nerve sorbitol, indicating a glycemic threshold for activation of this pathway (37). Linear regression analysis has demonstrated a significant inverse correlation between nerve sorbitol and myelinated fiber density (48). Moreover, it would appear that those at greatest risk of developing the complications are those with a higher set point for AR activity (49). Polymorphisms in the promoter region leading to a highly significant decrease in the frequency of the Z+2 allele have been demonstrated in patients with overt neuropathy compared with those without neuropathy (50).

With regard to intervention, a metaanalysis of all randomized controlled trials of ARIs identified 19 trials, testing four different ARIs for 4–208 weeks (median 24 weeks). It demonstrated a small but statistically significant reduction in decline of median (0.66 m/s, 95% CI 0.18–1.14 m/s) and peroneal (0.53, 0.02–1.04) motor NCV without benefit in sensory nerves (51). The clinical relevance of an effect on motor but not sensory nerve function is questionable, especially as the latter is primarily responsible for the most common manifestations of human DN: severe pain and the insensate extremity, leading to ulceration and eventual amputation (52).

Possible reasons for this marginal benefit may be related to the lack of a targeted approach identifying those most genetically susceptible to alterations in AR activity and, therefore, those most likely to benefit from AR inhibition (50). Furthermore, the degree of AR inhibition may determine the improvement observed. Thus, in a randomized, placebo-controlled, double-blinded, multiple-dose, clinical trial with zenarestat, dose-dependent increments in sural nerve sorbitol suppression were accompanied by significant improvement in NCV, and in doses producing >80% sorbitol suppression, there was a significant increase in the density of small-diameter myelinated fibers of the sural nerve (53). More recently, fidarestat, a potent ARI, significantly improved median nerve F-wave conduction velocity and minimal latency, as well as symptoms of numbness, spontaneous pain, paresthesiae, and hyperesthesia, in 279 diabetic patients (54).

Myoinositol.
While myoinositol deficiency has been proposed to play a role in the pathogenesis of DN, there is little evidence to support this contention. In a sural nerve biopsy study, myoinositol levels did not vary among patients with normal glucose tolerance, IGT, and type 2 diabetes (37).

Glycation.
Hyperglycemia results in the formation of advanced glycation end products (AGEs), which in turn act on specific receptors (RAGEs), inducing monocytes and endothelial cells to increase the production of cytokines and adhesion molecules (55). Glycation has also recently been shown to have an effect on matrix metalloproteinases (MMPs), in particular MMP-2, which degrades type IV collagen, but also on membrane type 1 MMP, tissue inhibitors of MMPs (TIMP)-1 and -2, and transforming growth factor-ß (TGF-ß) (56). Other effects include prevention of epidermal growth factor-induced autophosphorylation and activation of extracellular signal-regulated kinases (ERKs) (55). In experimental diabetes, these changes can be prevented by AGE inhibitors, such as the nucleophilic compounds pyridoxamine, tenilsetam, 2,3-diaminophenazone, or aminoguanidine (56,57). Alternatively, the administration of recombinant RAGE hinders the AGE-RAGE interaction (56,57). Human sural nerves obtained from diabetic and nondiabetic amputation specimens demonstrate normal furosine, an early reversible glycation product, but significantly elevated pentosidine levels in both cytoskeletal and myelin protein (58). Enhanced staining for carboxymethyllysine in the perineurium, endothelial cells, and pericytes of endoneurial microvessels, as well as myelinated and unmyelinated fibers, has been shown to correlate with a reduction in myelinated fiber density in peripheral nerve from five patients with type 2 diabetes compared with five nondiabetic control subjects (59). Pyrraline, an AGE, is also increased in postmortem samples of optic nerve from diabetic patients (60). Intervention trials have focused on nephropathy, and no trial data are currently available for human DN.

Oxidative stress.
An increasing body of data supports the role of oxidative stress in the pathogenesis of DN in animal models (35). Again, there is emerging evidence that single-nucleotide polymorphisms of the genes for mitochondrial (SOD2) and extracellular (SOD3) superoxide dismutases may confer an increased risk for the development of neuropathy (61). This may partially explain the lack of benefit observed with a number of antioxidants. However, benefits have been observed with -lipoic acid (LA), a powerful antioxidant that scavenges hydroxyl, superoxide, and peroxyl radicals and regenerates glutathione. In the ALADIN II study, diabetic patients with symptomatic polyneuropathy were randomly assigned to 5 days of intravenous LA followed by oral treatment for 2 years and demonstrated a significant improvement in sural sensory NCV, sensory nerve action potential (SNAP), and tibial motor NCV but not neuropathic disability score (NDS) (62). ALADIN III randomized 509 diabetic patients to LA intravenously for 3 weeks, followed by oral treatment compared with placebo. It showed no change in the total symptom score, but did show an improvement in the neuropathy impairment score after 3 weeks of intravenous therapy, which was maintained until the end of the study (63). Most recently, the SYDNEY study has demonstrated a significant improvement in the neuropathy symptom score, neuropathy impairment score, and one attribute of nerve conduction after daily intravenous treatment with racemic LA for 5 days/week for 14 treatments (64).

Vascular factors.
The most direct evidence that improving tissue blood flow may improve DN is derived from large-vessel revascularization studies, which have shown an improvement in NCV in one study (65) but not in another (66). However, a longer-term follow-up of the latter study did show a prevention of worsening of peroneal NCV (67). There are of course a number of pharmacological treatments that can achieve a similar effect. Angiotensin-converting enzyme (ACE) inhibitors mediate increased flow-dependent release of endothelium-derived relaxing factor (EDRF) and endothelium-dependent vessel relaxation. In a double-blind, placebo-controlled clinical trial of trandalopril over 12 months, peroneal motor NCV, M-wave amplitude, F-wave latency, and sural nerve amplitude improved significantly (68). Recently, the Appropriate Blood Pressure Control in Diabetes (ABCD) trial assessed the effects of intensive versus moderate blood pressure control with either nisoldipine or enalapril and surprisingly failed to prevent progression of DN, retinopathy, and neuropathy (69).

1,2-Diacylglycerol (DAG) induced activation of protein kinase C (PKC); in particular, PKC-ß has been proposed to play a major role in DN (35). However, even in nerve from diabetic animals, a fall in DAG levels and a consistent pattern of change in PKC activity has not been observed (70). Despite this, inhibition of PKC-ß in diabetic rats appears to correct reduced nerve blood flow and NCV (71). Based on the findings of a phase II clinical trial demonstrating some benefit in diabetic patients with neuropathy (72), multicenter, randomized, double-blind, placebo-controlled trials are under way and are due to complete in 2005.

An increasing body of evidence suggests that conventional risk factors for macrovascular disease (such as deranged lipids) are also important in the pathogenesis and progression of human DN (73). Recent studies show that hydroxymethylglutaryl CoA reductase inhibitors may enhance endothelial cell nitric oxide bioavailabilty (76), prevent AGE-induced nuclear factor (NF)-ß-induced protein-1 activation and upregulation of vascular endothelial growth factor (VEGF) mRNA (75), and thereby ameliorate experimental DN (74). Simvastatin has shown a trend toward slower progression of neuropathy measured by vibration perception threshold (VPT) but no change in the status of clinical neuropathy (76). Paradoxically, as a cautionary note, recent observational data suggest a link between chronic statin use and an increased risk of peripheral neuropathy (77).

Growth factors.
Neurotrophins promote the survival of specific neuronal populations by inducing morphological differentiation, enhancing nerve regeneration, stimulating neurotransmitter expression, and altering the physiological characteristics of neurons. Initially, the skin of diabetic patients with sensory fiber dysfunction demonstrated a depletion of nerve growth factor (NGF) (78). However, subsequent studies have shown a significant increase in skin NGF mRNA (79) and neurotrophin-3 concentrations (80) and normal sciatic nerve ciliary neurotrophic factor (CNTF) levels (81). In situ hybridization studies have also demonstrated an increased expression of both trkA, the high-affinity receptor for NGF, and trkC, the receptor for NT-3, in the skin of diabetic patients, which has been proposed to reflect a compensatory response (82). Despite these apparently contradictory findings, a phase II clinical trial of recombinant human NGF in 250 diabetic patients with symptomatic diabetic polyneuropathy demonstrated a significant improvement in the sensory component of the neurological examination, in two quantitative sensory tests, and in a rather vague end point, "the clinical impression of most subjects that their neuropathy had improved" (83). However, a phase III trial in 1,019 diabetic patients with sensory polyneuropathy failed to demonstrate a significant benefit (84). More recently a randomized, double-blind, placebo-controlled study of brain-derived neurotrophic factor (rhBDNF) in 30 diabetic patients demonstrated no significant improvement in nerve conduction and quantitative sensory and autonomic function tests, including the cutaneous axon reflex (85).

Insulin-like growth factors.
In cultured Schwann cells and the streptozotocin (STZ)-induced diabetic rat, insulin-like growth factor (IGF)-1 demonstrates a protective effect via phosphatidylinositol (PI) 3-kinase in preventing glucose-mediated apoptosis (86). Both the STZ-diabetic and the BB/W rat develop severe hyperglycemia and a deficiency in circulating IGF-1 levels and reproducibly develop neuroaxonal dystrophy (NAD) in nerve terminals of the prevertebral sympathetic ganglia and the distal portions of noradrenergic ileal mesenteric nerves. In contrast, the Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes, also develops severe hyperglycemia comparable to that in the STZ- and BB/W-diabetic rats but maintains normal levels of plasma IGF-1 and fails to demonstrate NAD in sympathetic ganglia and ileal mesenteric nerves as assessed by quantitative ultrastructural techniques (87). However, IGF-1 and IGF-1 receptor mRNA levels have not been shown to differ in the sural nerve of diabetic patients compared with control subjects (88).

C-peptide.
Impaired insulin/C-peptide action has emerged as a prominent pathogenetic factor. Preclinical studies have demonstrated a range of actions that include effects on Na(+)/K(+)-ATPase activity, endothelial nitric oxide synthase, expression of neurotrophic factors, regulation of molecular species underlying the degeneration of the nodal apparatus in type 1 diabetic nerves, as well as DNA binding of transcription factors and modulation of apoptotic phenomena (89,90). These findings have recently been effectively translated into benefits in patients with type 1 diabetes with the demonstration of a significant improvement in sural sensory NCV and vibration perception but without a benefit in either cold or heat perception after 12 weeks of daily subcutaneous C-peptide treatment (91).

VEGF.
VEGF was originally discovered as an endothelial-specific growth factor with a predominant role in angiogenesis. However, recent observations indicate that VEGF also has direct effects on neurons and glial cells, stimulating their growth, survival, and axonal outgrowth (92). Thus, with its potential for a dual impact on both the vasculature and neurons, it could represent an important therapeutic intervention in DN. Both the STZ-induced diabetic rat and the alloxan-induced diabetic rabbit have demonstrated restoration of nerve vascularity, blood flow, and both large- and small-fiber dysfunction 4 weeks after intramuscular gene transfer of plasmid DNA encoding VEGF-1 or VEGF-2, with confirmed constitutive overexpression of both transgenes in tissue (93). In contrast, immunohistochemistry of sciatic nerves and dorsal root ganglia from STZ-induced diabetic rats demonstrates intense VEGF staining in cell bodies and nerve fibers, whereas controls express no or very little VEGF, and animals treated with insulin or NGF show significantly lower immunostaining for VEGF (94). Thus, there is an intrinsic capacity to upregulate VEGF, but this appears insufficient and may require exogenous delivery possibly via gene therapy. A phase I/II, single-site, dose-escalating, double-blind, placebo-controlled study to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes with or without macrovascular disease involving the lower extremities is currently under way and will involve 192 patients over a period of 4 years (95).

Immune mechanisms.
Studies suggest that sera from type 2 diabetic patients with neuropathy contains an autoimmune immunoglobulin that induces complement-independent, calcium-dependent apoptosis in neuronal cells (96). The expression of these cytotoxic factors has been related to the severity of neuropathy and the type of neuronal cell killed (97). Thus, it has been suggested that such toxic factors may contribute to DN by acting in concert with hyperglycemia to damage sensory/autonomic neurons (97).

	SECTION 4: FOCAL AND MULTIFOCAL NEUROPATHIES

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A number of rare neuropathies referred to as the focal and multifocal neuropathies will now be discussed in detail, particularly with regard to clinical presentation and management.

Factors leading to the development of the compression neuropathies relate to either the peripheral nerve itself or the structures surrounding it at the point of compression. Many of the animal models of entrapment are based on acute compression, the mechanics of which differ considerably in terms of nerve stretch, tethering, and associated ischemia involved in entrapment. Therefore, translation of these experimental findings to entrapment neuropathies in diabetic patients should be interpreted with caution.

A. Mononeuropathies
Carpal tunnel syndrome.
This is the most common entrapment neuropathy encountered in diabetic patients and occurs as a result of median nerve compression under the transverse carpal ligament. Idiopathic carpal tunnel syndrome (CTS) occurs in patients with rheumatoid arthritis, hypothyroidism, and obesity. In 20–30% of diabetic patients, it can be demonstrated electrophysiologically but presents as a clinically relevant problem in 5.8% (98). Painful paresthesiae of the fingers may progress to a deep-seated ache, which radiates up the forearm or, very rarely, the arm. This occurs primarily at night but may be initiated during the day by repetitive flexion and extension of the wrist. Motor weakness is uncommon but thenar muscle wasting occurs particularly in the elderly. Two common clinical tests include the Phalen (forearms held vertically and hands held in complete flexion for 1 min; positive if paresthesiae develop in the median territory within 30 s) or Tinel (percussion at the wrist and palm induces paresthesiae in the median nerve territory) tests, but they have a high false-positive rate. Electrophysiological studies measure the speed of conduction across the carpal tunnel, and median sensory nerve conduction studies are compared with radial and/or ulnar sensory latencies. Their interpretations are made difficult if there is a coexisting peripheral neuropathy affecting the upper limbs or if there are no symptoms of CTS. Demyelination is thought to be the primary pathological abnormality. Treatment options include wrist splints, which have limited application because they cannot be worn during the day, but can be effective for nocturnal symptoms. Injections of cortisone into the carpal tunnel may provide short-lived relief, and in the majority of cases, repeat injections are required. Surgical sectioning of the transverse carpal ligament provides variable degrees of pain relief but does not particularly benefit muscle wasting or sensory loss.

Ulnar neuropathy.
The second most common entrapment neuropathy (2.1%) occurs as a result of ulnar nerve compression immediately distal to the ulnar groove beneath the edge of the flexor carpi ulnaris aponeurosis in the cubital tunnel. It may develop as a result of deformity at the elbow joint secondary to fracture or as a consequence of prolonged pressure during surgery, and it has been most commonly associated with alcoholism. Typical symptoms include painful paresthesiae in the fourth and fifth digits associated with hypothenar and interosseous muscle wasting. The pathology is a combination of demyelination and axonal degeneration. The key electrophysiological findings include low amplitude ulnar sensory nerve action potentials, reduced sensory NCV, and fibrillation potentials in the interossei (99). Management of patients is primarily conservative, with advice to avoid pressure to this area, as the results of surgery are very poor. However, if symptoms and signs progress, then a number of approaches may be used: medial epicondylectomy, transaction of the flexor carpi ulnaris aponeurosis, and ulnar nerve transposition (100).

Radial neuropathy.
Radial neuropathy is rare (0.6%), occurring as a consequence of radial nerve compression in the spiral groove. It presents with the characteristic motor deficits of wrist drop with very occasional sensory symptoms of paresthesiae in the dermatomes supplied by the superficial radial nerve. Causes of idiopathic radial neuropathy include humeral fracture, blunt trauma over the posterolateral aspect of the arm, and external compression. Electrophysiological assessment demonstrates a predominant effect on amplitude rather than the conduction velocity, suggestive of predominantly axonal degeneration associated with secondary demyelination (101). Management is conservative with pressure relief.

Common peroneal neuropathy.
This is the most common of all limb mononeuropathies. Involvement of the motor fibers in the common peroneal nerve results in weakness of the dorsiflexors and "foot drop," but loss of the motor supply to the tibialis anterior muscle also leads to weakness in eversion. This is accompanied by a sensory deficit but characteristically no pain or paresthesiae. Diabetes is a relatively uncommon cause (5–12% of cases) of peroneal nerve palsy (102). Common causes include external compression at the fibular head during anesthesia (in bed-ridden patients) and inappropriately placed plasters following lower-limb fractures. An important differential is a radiculopathy involving the L5 root. Features that define L5 involvement include pain in the lower back and additional loss of inversion. Electrophysiological studies suggest demyelination with conduction block in mild lesions with a marked loss of amplitude presumably secondary to axonal degeneration in more severe lesions (103). Because the majority of these lesions are caused by external pressure that, if relieved, will result in resolution of the motor deficit within 3–6 months, a conservative approach is advocated with removal of pressure and a foot brace in the interim.

Lateral femoral cutaneous neuropathy.
Compression of the lateral femoral cutaneous nerve (meralgia paraesthetica) is uncommon and results in pain, paresthesiae, and sensory loss in the lateral aspect of the thigh (104). Obesity is the most common cause, followed by trauma due to external injury of the nerve, as it runs down the lateral aspect of the thigh. Most will resolve spontaneously and are therefore managed conservatively.

Other nerves that may be involved include the sciatic and obturator nerves. They can be a cause of significant motor deficit; however, they are extremely rare and their management is conservative.

B. Cranial neuropathies
Cranial neuropathies in diabetic patients are extremely rare (0.05%) and occur in older individuals with a long duration of diabetes (105).

Ocular neuropathies.
Cranial nerves III, IV, and VI are affected, and among diabetic patients, the relative frequency is oculomotor (3.3%) and abducent (3.3%) nerve occurring with equal and greater frequency than the trochlear nerve (2.1%) (106). The classical presentation of oculomotor nerve palsy is that of an acute-onset diplopia with ptosis and pupillary sparing associated with ipsilateral headache. While pupillary sparing is often quoted as a means of differentiating diabetic from other structural (aneurysm, tumor, or mass) ophthalmoplegias, 14–18% of diabetic patients do develop pupillary dysfunction (107). Resolution of neurological deficits occurs over 2.5 months and recurrence can occur in 25% of patients (107). A clear understanding of the underlying pathology and pathogenesis of this condition is limited due to the difficulties in obtaining tissue in such patients. Based on four single postmortem case reports demonstrating centrofascicular pallor of myelin staining in paraffin-embedded sections, it is assumed that focal demyelination occurs secondary to ischemia (108). This is supported by more recent studies in plastic sections offering clearer pathological detail (109). However, this conclusion should be interpreted with caution as acute ischemic injury should result in axonal degeneration. Furthermore, pallor in staining should not be interpreted as demyelination, as this has not been confirmed using teased fiber analysis. A recent study of oculomotor nerve specimens from 8 diabetic patients without oculomotor nerve palsy compared with 15 nondiabetic patients has shown subperineurial as opposed to centrofascicular alteration. Microfasciculation has been demonstrated and suggests chronic injury due to ischemia (110). Management is expectant with strong reassurance to the patient for recovery. Maintaining optimal glycemic control as well as minimizing the other stronger risk factors for ischemia, including hypertension and hyperlipidemia, may aid recovery.

Facial neuropathy.
In most series of idiopathic facial neuropathy or Bell’s palsy, diabetes is well represented, ranging from 6% (111) to 48.8% (112). The main neurological findings are those of acute-onset unilateral weakness of facial muscles, widening of the palpebral fissure, and secondary corneal irritation. This is accompanied by varying degrees of disturbance in taste and hyperacusis. The presence of hypertension and severity of paralysis at onset, but not diabetes, determines the degree of recovery at 1 year (113). Neurophysiological studies demonstrate reduced or absent compound muscle action potentials (CMAPs) in the nasalis muscle, which can actually be used to determine outcome. Thus, CMAP >30% results in 90–100% recovery, CMAP 10–30% results in <50% recovery, and CMAP <10% results in virtually no recovery. This is associated with prolongation of the R1 and R2 latencies of the trigeminal "blink reflex" (114). If the presentation is acute for <1 week, 7–14 days of prednisone may be administered but with attention to optimizing glycemic control.

Other cranial nerves.
Other cranial nerves may be affected in diabetes. However, their relatively infrequent involvement warrants an awareness of their occurrence but will not be discussed in detail. Thus, olfactory and optic nerve involvement has been described. More recently, corneal confocal microscopy has been used to show significant degeneration of small myelinated and unmyelinated fibers in the cornea of diabetic patients with increasing neuropathic severity (115). There are also reports of an increased frequency of trigeminal neuralgia in diabetic patients. Hearing loss as a result of VIII nerve involvement has also been described (116). Vagal nerve involvement manifests as part of diabetic autonomic neuropathy. Vocal cord paralysis has also been attributed to recurrent laryngeal nerve involvement.

C. Diabetic amyotrophy
Clinical features.
Diabetic amyotrophy typically occurs in patients with type 2 diabetes aged 50–60 years and presents with severe pain and uni- or bilateral muscle weakness and atrophy in the proximal thigh muscles (117).

Pathogenesis.
Factors contributing to the development of diabetic amyotrophy (proximal motor neuropathy) (118,119) are poorly understood. Somewhat polarized views have evolved. One proposal has implicated ischemia based on an early case report that demonstrated infarcts in the proximal femoral, sciatic, and obturator nerves and lumbosacral plexus (120); other investigators have proposed a metabolic basis for a more subacute, symmetrical disorder affecting the distal branches of the proximal motor nerves (121). A conciliatory view is derived from reports of patients with an initial rapid evolution with subsequent slow progression of symptoms and signs over several months, indicating a combination of both vascular and metabolic factors (117,122).

Neurophysiology.
Needle electrode sampling reveals different responses depending on the stage of this condition. In the early stages, spontaneous fibrillation and reduced motor unit recruitment occur, suggestive of denervation. In later stages, there is an increase in amplitude of the motor unit potential, indicating reinnervation via collateral sprouting. Electrophysiological studies demonstrate a reduction in femoral NCV (123). Additionally, however, femoral nerve stimulation produces an attenuated compound muscle action potential of the quadriceps muscle, supporting the occurrence of axonal pathology (124).

Pathology.
Recent reports have demonstrated an epineurial vasculitis in the intermediate cutaneous nerve of the thigh (ICNT) in a proportion of patients with amyotrophy (124–126). Centrofascicular degeneration of the ICNT has been observed in association with an inflammatory infiltrate and occlusion of epineurial blood vessels (124,125). These studies have highlighted the heterogeneous nature of myelinated and unmyelinated fiber damage as some patients showed an almost complete loss of fibers, whereas others demonstrated a moderate reduction with regeneration both proximally in the ICNT and distally in the sural nerve (124,125). Another study demonstrated a reduction or absence of CMAPs in the tibial and peroneal nerves and also in the sensory action potential of the sural nerve, with relative preservation of NCVs, suggestive of axonal degeneration rather than demyelination (127). This was confirmed on pathological examination of the sural nerve, which demonstrated multifocal fiber loss and dystrophic fibers with predominantly axonal degeneration and secondary demyelination associated with abortive regeneration represented by the formation of microfasciculi and perineurial scarring (125). One may question the relevance of distal findings in the sural nerve for a condition that affects proximal lumbosacral nerve segments. Thus, in contrast, a recent study in the intermediate cutaneous nerve of 15 patients with diabetic amyotrophy has shown multifocal fiber loss, but teased fiber studies have primarily demonstrated demyelination (128).

The other major finding that has provided a novel perspective on the pathogenesis of this condition has been derived from immunohistological studies. In the study by Said et al. (126), all ICNT biopsies demonstrated an inflammatory infiltrate composed of B- and T-cells and occasional macrophages. In another study, which included 12 patients with diabetic amyotrophy, the sural nerve demonstrated a mononuclear cell infiltrate in 4 patients and a perivascular infiltrate of activated T-cells expressing both interleukin (IL)-2 and major histocompatibility complex class II antigens in 6 patients (129). There was, however, no evidence of infiltration with B-cells or polymorphonuclear cells. The majority of nerves from patients also showed staining for tumor necrosis factor (TNF)-, IL-6, and IL-1ß. Furthermore, C3d and C5b-9 complement protein was found within endoneurial and epineurial blood vessel walls in all patients (129). Dyck et al. (127) demonstrated epineurial vascular and perivascular mononuclear inflammatory infiltrates, which stained positive for leukocytes. There were also additional features of a necrotizing vasculitis (arteriolar, venular, and capillary wall infiltration with inflammatory cells) with hemosiderin deposition. Together these changes suggested a microscopic vasculitis, and levels of IL-1ß and IL-6 were increased in these patients (127). A recent study has demonstrated a polymorphonuclear vasculitis with transmural infiltration of postcapillary venules with IgM deposition along the endothelium as well as in the endoneurium and subperineurial regions, indicating increased permeability and immune-mediated nerve damage (128). There was additional deposition of activated complement (C5b-9) in the same areas, indicating an active immune-mediated vasculitis.

Management.
Current therapies lack a robust evidence base to support the use of any therapy, because the rarity of this condition precludes controlled clinical trials. The main aim of therapy is to control pain, and this can be achieved through nonsteroidal antiinflammatory agents (ibuprofen and naproxen), opioids (codeine phosphate and morphine elixir), or tricyclic antidepressants (amitriptyline and imipramine). Other agents that may be useful include tramadol and gabapentin (see Section 5B, no. 8). Measures that putatively affect the underlying pathology include an improvement in glycemic control. This has been particularly advocated in patients on oral hypoglycemic agents who are recommended for conversion to insulin therapy. Based on the observations of vasculitis in a proportion of patients, immunosuppressive therapy has been recommended using initial intravenous, followed by high-dose oral corticosteroids, or intravenous immunoglobulin. Reports of a dramatic improvement in neurological function (130) have resulted in the initiation of a multicenter clinical trial of immunotherapy in the U.S., due to report in 2004 (131).

D. Diabetic truncal radiculoneuropathy
Clinical features.
Diabetic truncal radiculoneuropathy affects middle-aged to elderly diabetic patients and appears to have a predilection for men. Pain is a primary feature and is acute in onset but may evolve over several months. It is aching or burning in quality, may be superimposed with lancinating stabs, and demonstrates nocturnal exacerbation with cutaneous hyperesthesia. It occurs in a girdle-like distribution over the lower thoracic or abdominal wall, usually unilateral but sometimes bilaterally. On rare occassions, it may result in motor weakness with bulging of the abdominal wall (11). Profound weight loss may accompany the onset of symptoms. Clinical examination demonstrates heterogeneous neurological findings ranging from no abnormality to sensory loss and hyperesthesia in a complete dermatomal pattern, but may sometimes just involve the distribution of the ventral or dorsal rami (132). Resolution of symptoms generally occurs within 4–6 months.

Pathogenesis.
Clinically, this condition bares strong similarities to diabetic amyotrophy, but due to the lack of pathological studies, its pathogenesis is based more on inference than on actual evidence. The acute onset suggests a vascular cause, although its occurrence in patients with generally poorer glycemic control suggests a metabolic basis.

Electrophysiology.
Electromyography demonstrates denervation potentials in the intercostal, anterior abdominal wall, and paraspinal muscles (133). There are no reported conduction studies of the intercostal nerves in this condition.

Pathology.
There are no pathological studies on this condition. Therefore, one may only infer the site of the lesion. In those patients demonstrating denervation of the paraspinal muscles, a lesion of the dorsal primary rami is probable (134). However, those who do not demonstrate this feature may demonstrate lesions more distally in the intercostal or subcostal nerves. From the sensory deficits, it is clear that the lesions may vary and involve posterior primary rami of the spinal nerves or intercostal nerves (132). The cause may be ischemia, and the contiguous dermatomal involvement may be explained by the occlusion of a single intercostal artery supplying several truncal nerves.

Management.
There is no evidence to support the use of any therapy. Because the natural history is for spontaneous resolution within 4–6 months, and as there are strong similarities to diabetic amyotrophy, the approach to management is very similar to that for the latter. The main aim of therapy is to control pain. Again, an improvement in glycemic control has been advocated, as has immunosuppressive therapy with corticosteroids or intravenous immunoglobulin.

E. CIDP
Diabetic patients occasionally develop clinical and electrodiagnostic features suggestive of CIDP (29). It is important to recognize that this subgroup, unlike those with diabetic polyneuropathy, is treatable (135). Many of the clinical, electrophysiological, and nerve biopsy criteria are not sufficiently helpful in the differential diagnosis of these two conditions. However, when an unusually severe and progressive polyneuropathy develops in diabetic patients, one must consider CIDP.

Although electrodiagnosis is an important element in the diagnosis of CIDP, current electrodiagnostic criteria alone appear to be insufficient for defining many cases of CIDP and therefore certainly should not be relied on to differentiate from diabetic polyneuropathy (136).

Nerve biopsies in CIDP demonstrate segmental demyelination and remyelination, onion bulbs, and inflammatory infiltrates, but they are also present in diabetic polyneuropathy (137). The presence of increased numbers of macrophages indicating a macrophage-associated demyelination may be helpful, as this is a characteristic feature of CIDP not observed in diabetic polyneuropathy (137).

Treatment of CIDP requires long-term immunomodulatory therapy with combinations of corticosteroids, azathioprine, plasmapheresis, and intravenous immune globulin but does produce relatively rapid and substantial improvement in neurological deficits and electrophysiology (138,139).

	SECTION 5: DISTAL SYMMETRICAL POLYNEUROPATHY

TOP SECTION 1: INTRODUCTION SECTION 2: DEFINITIONS AND... SECTION 3: PATHOGENESIS OF... SECTION 4: FOCAL AND... SECTION 5: DISTAL SYMMETRICAL... SECTION 6: NEUROPATHY AND... SECTION 7: CONCLUSIONS References

 
A. Acute sensory neuropathy
Acute sensory (painful) neuropathy is a distinctive variant of DPN that warrants a separate discussion (23,24,140). Although many of the symptoms of acute sensory and chronic sensorimotor neuropathy are similar, there are clear differences in the mode of onset, accompanying signs, and prognosis, which are summarized in Table 4 (140–142). Pain is the outstanding complaint in all patients, who also experience severe weight loss, depression, and, frequently in males, erectile dysfunction. Common complaints include constant burning discomfort (especially in the feet), severe hyperesthesiae, and deep aching pain, and many experience sudden, sharp, stabbing, or "electric shock"-like sensations in the lower limbs. All symptoms are prone to nocturnal exacerbation, with bed clothes irritating hyperesthetic skin. Clinical examination is usually relatively normal, with allodynia on sensory testing, a normal motor exam, and occasionally reduced ankle reflexes.

Conversely, it may develop after sudden improvement of glycemic control; the term "insulin neuritis" is unfortunate, as it may follow improvement of glycemic control induced by oral hypoglycemic agents. Both of these observations are in keeping with the hypothesis that blood glucose flux is important in the genesis of neuropathic pain (10).

Sural nerve biopsies have been performed in patients with acute painful neuropathy (141,144) and show active degeneration of both myelinated and unmyelinated fibers. No correlations were demonstrated between pain and either active degeneration of myelinated fibers or regenerative activity in myelinated or unmyelinated axons. Thus, it is difficult to reconcile these findings with the suggestion that acute painful neuropathy is an example of a "small-fiber neuropathy." Indeed, a recent review concluded that painful neuropathy is not restricted to selective involvement of small or large fibers (145). There is also a suggestion that acute painful neuropathy may be related to neural ischemia precipitated by sudden improvement of glycemic control. Using in vivo epineurial vessel photography and fluorescein angiography, Tesfaye et al. (146) demonstrated severe abnormalities of epineurial vessels in acute painful neuropathy, with arteriovenous shunting and proliferating neural "new vessels" that resembled new vessels seen in retinopathy. One hypothesis for the genesis of neuropathic pain in such cases is that sudden changes in blood glucose control result in alterations in their blood flow, leading to a "steal" effect with arteriovenous shunting thus rendering the endoneurium ischemic.

In the management of this condition, achieving stable blood glucose control is most important: stability may well be the key feature as blood glucose flux (as assessed by the "M" value) is associated with pain (10,147). Additionally, most patients require medications for their neuropathic pain (these medications are detailed below). The natural history of this condition is very different from the much more common chronic sensorimotor neuropathy: its onset is acute or subacute, but the severe symptoms resolve in less than a year (140,141).

B. Chronic sensorimotor neuropathy (DPN)
Chronic sensorimotor neuropathy is the most common manifestation of the DNs that is usually insidious in onset and may be the presenting feature in people with type 2 diabetes (10,26). Many patients are asymptomatic, and a neurological deficit may be discovered by chance during a routine neurological exam, although they may even present with a neuropathic complication such as a painless foot ulcer. It is a length-dependent process, and its sensory manifestations are most pronounced in the lower limbs and, in more severe cases, in the fingers and hands.

The following subsections will focus on the clinical presentation and assessment of chronic sensorimotor neuropathy; methods of quantitative sensory testing, electrophysiological study, and other methods of assessment; and treatments of chronic sensorimotor neuropathy.

1. Clinical presentation of chronic sensorimotor neuropathy (DPN).
Symptoms.
DPN occurs in both type 1 and type 2 diabetes and is more common with increasing age and duration of diabetes. These symptoms tend to be intermittent and of similar character but with lesser intensity than those described under painful neuropathy. In a large population survey, Harris et al. (148) reported that 30% of type 1 diabetic patients and 36% of male and 40% of female type 2 diabetic patients experienced neuropathic symptoms. However, 10% of males and 12% of females in the nondiabetic population reported similar symptoms.

As in acute sensory neuropathy, painful symptoms tend to be more pronounced at night, but in addition, patients with DPN may experience "negative" symptoms such as numbness or "feet feel dead." Patients often find it difficult to describe the symptoms as they are different than the pain that they have previously experienced. Though not often mentioned in older texts, unsteadiness is increasingly being recognized as a manifestation of DPN, due to disturbed proprioception and possibly abnormal muscle sensory function (149). Such unsteadiness has been quantified (150–152) and may result in repetitive minor trauma or falls and in late complications such as trauma or Charcot’s neuroarthropathy.

Signs.
On clinical examination, there is usually a symmetrical sensory loss to all modalities in a stocking distribution. In severe cases, this may extend well above the ankle and also involve the hands. The ankle reflexes are usually reduced or absent, and the knee reflexes may also be absent in some cases. Motor weakness is unusual, although small muscle wasting in the feet and also the hands may also be seen in more advanced cases. Any pronounced motor signs should raise the possibility of a nondiabetic etiology of the neuropathy, especially if asymmetrical (1,19).

In more severe cases, with loss of proprioception, patients may demonstrate a positive Romberg’s sign.

As DPN is often accompanied by distal (sympathetic) autonomic neuropathy (140), signs of autonomic dysfunction are often apparent on examinations: these might include warm dry skin (in the absence of peripheral vascular disease) and the presence of plantar callus under pressure-bearing areas. The "at-risk" foot for neuropathic ulceration might also have a high arch (pes cavus) and clawing of the toes (153). However, it must be emphasized that all patients with DPN with or without obvious foot deformities must be considered as being at risk of neuropathic complications, such as Charcot’s neuroarthopathy or foot ulceration (27,153).

2. Clinical assessment of DPN.
Symptoms.
As noted above, many patients have difficulty in describing the symptoms of neuropathy. Pain and paresthesiae are personal experiences, and there is marked variation in the description of symptoms between individuals with similar pathological lesions. This has important implications for the assessment of symptoms: Huskisson (154) clearly stated that "[p]ain is a personal psychological experience and an external observer can play no part in its direct measurement." When recording symptoms in clinical practice, physicians must therefore avoid the temptation to "interpret" or "translate" patient reports; instead, they should record the patient’s description verbatim.

A number of simple symptom screening questionnaires are available to record symptom quality and severity. A simplified neuropathy symptom score that was used in the European prevalence studies could also be useful in clinical practice (2,4). The Michigan Neuropathy Screening Instrument (MNSI) is a brief 15-item questionnaire that can be administered to patients as a screening tool for neuropathy (155). Other similar symptom scoring systems have also been described (156).

Simple visual analog or verbal descriptive scales may be used to follow patients’ responses to treatment of their neuropathic symptoms (156–158). However, it must always be remembered that identification of neuropathic symptoms is not useful as a diagnostic or screening tool in the assessment of DN, as shown by Franse et al. (159).

It is well recognized that both symptoms and deficits may have an adverse effect on quality of life (QOL) in DN (160). The NeuroQol, a recently developed and validated QOL instrument, also includes a symptom checklist and may be used as an outcome measure in future clinical studies (161).

Signs.
The use of composite scores to assess clinical signs was pioneered by Dyck and colleagues (21,162), who first described the NDS and later the Neuropathy Impairment Score (NIS). A modified NDS has been used in several large studies (2,4,52) and can also be used in the community by a trained nonspecialist (Fig. 1). It has been shown to be the best predictor of foot ulceration and the best neuropathic end point in a large prospective community study (52). The maximum NDS is 10, with a score of 6 or more being predictive of foot ulcer risk.

View larger version (30K): [in this window] [in a new window]   Figure 1— The modified NDS.

Whatever methodology is used in the assessment and documentation of neuropathic signs, it should be noted that the neurological exam of the lower limbs is the important aspect in the clinical diagnosis of DN (166).

Simple devices for clinical screening.
The dividing line between simple devices used in daily clinical practice and QST is difficult to define. For the purposes of this review, QST will be defined as procedures requiring a power source where the intensity and characteristics of the stimuli are well controlled and where the detection threshold is determined in parametric units that can be compared with established "normal" values (167).

Although the simple handheld screening devices are less sensitive than the more sophisticated QST devices described below, they have the advantage of being relatively inexpensive, easy to operate, and easily portable; therefore, their use in clinical practice is increasing.

The most widely used device in clinical practice is the Semmes-Weinstein monofilament (168,169). The filament assesses pressure perception when gentle pressure is applied to the handle sufficient to buckle the nylon filament. Although filaments of many different sizes are available, it is the one that exerts 10 g of pressure, the value most commonly used to assess pressure sensation in the diabetic foot. It is also referred to as the 5.07 monofilament because, during calibration, the filaments are calibrated to exert a force measured in grams that is 10 x log of the force exerted at the tip; hence, 5.07 exerts 10 g of force.

A number of cross-sectional studies have assessed the sensitivity of the 10-g monofilament to identify feet at risk of ulceration. Sensitivities vary from 86 to 100% (170–172), although there is no consensus as to how many sites should be tested. The most common algorithm recommends four sites per foot: generally the hallux and metatarsal heads 1, 3, and 5 (169). However, the most recent study (172) suggested that there is little advantage gained from multiple site assessments. There is also no universal agreement as to what constitutes an abnormal result (i.e., one, two, three, or four abnormal results from the sites tested). Despite these problems, the 10-g monofilament is widely used for the clinical assessment of neuropathy.

A final caution on the use of the filaments: Booth and Young (173) identified that filaments manufactured by certain companies do not actually buckle at 10 g of force. Indeed, several tested filaments buckled at <8 g. Thus, care must be taken when selecting suppliers of filaments.

The graduated Rydel-Seiffer tuning fork is used in some centers to assess neuropathy (174,175). This fork uses a visual optical illusion to allow the assessor to determine the intensity of residual vibration on a 0–8 scale at the point of threshold (disappearance of sensation). Hilz et al. (174) reported that results with this instrument correlated well with other QST measures.

The tactile circumferential discriminator assesses the perception of calibrated change in the circumference of a probe (a variation of two-point discrimination). Vileikyte et al. (176) reported a 100% sensitivity in the identification of patients at risk of foot ulceration. Similarly, this device also demonstrated good agreement with other measures of QST.

Finally, the recently reported Neuropen is a clinical device that assesses pain using both a Neurotip at one end of the "pen" and a 10-g monofilament at the other end. This was shown to be a sensitive device for assessing nerve function when compared with the simplified NDS (177).

3. QST.
The progressive loss, or change, in sensation is the hallmark of DPN. QST measures can be used to identify the sensory modalities affected and to estimate the magnitude of the deficit. In the diabetic population, vibration, thermal, and pain thresholds have proven valuable in the detection of subclinical neuropathy (178,179), in tracking the progression of neuropathy in large cohorts (180,181), and in predicting patients "at risk" for foot ulceration (182,183). In addition, QST measures have played a key role as primary efficacy end points in a series of multicenter clinical trials evaluating the prevention or treatment of diabetic polyneuropathy (74,91).

The strengths of QST are well documented (rev. in 167) and include 1) the accurate control of stimulus characteristics; 2) the ability to assess multiple modalities; 3) the use of well-established psychophysical procedures to enhance sensitivity; 4) the capacity to measure function over a wide dynamic range of intensities, thus supporting the evaluation of multiple degrees of neuropathy; 5) the ability to measure sensation at multiple anatomical sites, enabling the exploration of a potential distal-to-proximal gradient of sensory loss; and 6) for most measures, the availability of data from large, age-matched, "normal" comparison groups. The limitations of QST are also clear. No matter what the instrument or procedure used, QST is only a semiobjective measure, affected by the subject’s attention, motivation, and cooperation, as well as by anthropometric variables such as age, sex, body mass, and history of smoking and alcohol consumption (184,185). Expectancy and subject bias are additional factors that can exert a powerful influence on QST findings (186). Further, QST is sensitive to changes in structure or function along the entire neuroaxis from nerve to cortex; it is not a specific measure of peripheral nerve function (167).

There have been several reviews of QST procedures (167,187–189) and several "consensus expert panels" have considered the value of QST as a method of assessing sensory neuropathy (20,30,33,34). A discussion of the merits of specific instruments or testing algorithms is beyond the scope of this review. However, it is noteworthy that a recent study comparing VPTs using two very different instruments and procedures reported similar sensitivity to mild DPN and consistent correlation of each VPT measure with sural NCV (190).

Recently, a consensus subcommittee of the American Academy of Neurology (34) stated "QST testing for vibratory and cooling thresholds receives a Class II rating as a diagnostic test. Further, QST is designated as safe, effective and established, with a type B strength of recommendation. However, QST is unacceptable as the sole criteria to define diabetic neuropathy."

Vibration thresholds.
The relationship between elevated VPT and DN has been documented for almost 100 years. When tested in the 50- to 300-Hz range, VPT reflects the activation of mechanoreceptors (i.e., Pacinian and Meissner corpuscles), conduction in large-diameter myelinated peripheral axons, and transmission through the dorsal column spinal pathways.

Multiple studies have documented the relation between loss of vibration sensation and the progression of a variety of indicators of DPN (191,192). Dyck et al. (193) used computer-assisted QST to evaluate three large cohorts and identified a "strong and consistent correlation" between sensory loss and other markers of DN. These studies confirmed that vibration thresholds are especially sensitive to mild or subclinical neuropathy. Davis et al. (194) also demonstrated that vibratory thresholds can detect subclinical neuropathy in children and adolescents with type 1 diabetes. Boulton et al. (195) documented that vibration thresholds provided a strong indication of "risk" for future ulceration across a wide range of ages and durations of diabetes. In a 4-year prospective study (182), patients with baseline threshold elevated above a fixed value (i.e., 25 V with the biosthesiometer) were seven times more likely to develop foot ulcers. This observation is supported by the recent evaluation of 187 type 2 diabetic patients that used multivariate logistic regression to document that an elevated VPT score was the strongest predictor of foot ulceration (i.e., relative risk of 25.4) (183). The strength of the relationship between elevated VPT and foot ulceration is illustrated by the finding, in 1,035 type 1 and type 2 diabetic patients, that each 1-unit increase in vibration threshold (voltage scale) at baseline increased the hazard of foot ulceration by 5.6% over a 1-year study period (196).

Thermal thresholds.
Although most mechanoreceptors and free nerve endings can be stimulated by thermal energy, true cutaneous thermoreceptors are orders of magnitude more sensitive to shifts in temperature. Separate cold and warm thermoreceptors have been identified (197) and generally characterized by small receptor fields. Thermal energy is conducted in thinly myelinated A or unmyelinated C fibers and is principally transmitted in the crossed anterolateral tracts of the spinal cord. The sensation of pain can also be driven by high-intensity stimulation of thermoreceptors, especially those sensitive to warming; this activation can be assessed by measuring heat-pain thresholds (198).

As is the case with vibration, altered thermal thresholds have been well documented in patients with DN defined by other criteria (179,191,193), and their elevation has been associated with progression of neuropathy and ultimately with foot ulceration (199). Abnormal thermal thresholds have been reported in 75% of subjects with moderate-to-severe DPN, and elevated heat-pain thresholds were detected in 39% of these subjects (200). Generally, there is a high correlation between elevated thermal and vibration thresholds, but these measures can be dissociated, suggesting a predominant small- or large-fiber neuropathy in individual patients. The symptoms of neuropathic pain have been associated with altered thermal thresholds (201), but, as stated earlier, painful neuropathy likely involves both small- and large-diameter neurons (145). Lowered heat-pain thresholds have been reported in patients with DN, and this condition may be an important indication of hypersensitivity associated with early changes in distal nerve segments (193).

It is technically more challenging to measure thermal thresholds compared with vibration thresholds; the evaluation generally takes longer and the smallest detectable difference has been reported as approximately double that of vibration (201). Computer-assisted procedures may be especially valuable in examining thermal thresholds (202).

4. Electrophysiology.
Whole nerve electrophysiologic procedures (e.g., NCV, F-waves, sensory, and/or motor amplitudes) have emerged as an important method of tracing the onset and progression of DPN (203). Multiple consensus panels have recommended the inclusion of electrophysiology in the evaluation of DPN, as well as the use of these procedures as surrogate measures in multicenter clinical trials (20,33). These procedures have also been used extensively to explore the mechanisms of dysfunction and the value of various therapeutic interventions in chemical and genetic animal models of hyperglycemia.

An appropriate battery of electrophysiologic tests supports the measurement of the speed of both sensory and motor conduction, the amplitude of the propagating neural signal, the density and synchrony of muscle fibers activated by maximal nerve stimulation, and the integrity of neuromuscular transmission (rev. in 204,205). These are objective, parametric, noninvasive, and highly reliable measures. However, "standard" procedures, such as maximal NCV, reflect only a limited aspect of neural activity and then only in a small subset of large-diameter and heavily myelinated axons. Even in large-diameter fibers, NCV is insensitive to many pathologic changes known to be associated with DPN. For example, there is strong evidence linking DPN with a reduction in Na⁺/K⁺ adenosine triphosphatase activity (206). This deficit would primarily diminish the ability of neurons to rapidly reestablish appropriate transmembrane ion gradients after activation. Standard NCV, which essentially evaluates single pulses, could be unaffected at a time point when assessment of refractory cycles and axonal recovery would document altered function (207).

A key role for electrophysiological assessment is to rule out other causes of neuropathy or to identify neuropathies superimposed on DPN. Unilateral conditions, such as entrapments, are far more common in diabetic patients (208). Sharma et al. (209) report that the odds of occurrence of CIDP were 11 times higher among diabetic than nondiabetic patients. The symmetry of electrophysiological measures, and the nature and magnitude of the deficits, can help identify additional causes for neurological deficits and can be valuable in selecting appropriate subjects for clinical trials.

Mechanisms of NCV slowing.
The principal factors that influence the speed of NCV are 1) the integrity and degree of myelination of the largest diameter fibers, 2) the mean cross-sectional diameter of the responding axons, 3) the representative internodal distance in the segment under study, and 4) the microenvironment at the nodes, including the distribution of ion channels.