Dan Ziegler

Institute of Clinical Diabetes Research, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, DUsseldorf, Germany

CLASSIFICATION, EPIDEMIOLOGY, AND CLINICAL IMPACT OF DIABETIC NEUROPATHY

Diabetic neuropathy has been defined as a demonstrable disorder, either clinically evident or subclinical, that occurs in the setting of diabetes mellitus without other causes for peripheral neuropathy. It includes manifestations in the somatic and/or autonomic parts of the peripheral nervous system (1), which are classified along with clinical criteria. However, due to the variety of the clinical syndromes with possible overlaps there is no universally accepted classification. The most widely used classification of diabetic neuropathy, proposed by Thomas (2), has recently been modified (3). This proposal differentiates between rapidly reversible, persistent symmetric polyneuropathies, and focal or multifocal neuropathies (Table 1). The distal symmetric sensory or sensorimotor polyneuropathy (DSP) represents the most relevant clinical manifestation affecting approximately 30% of the hospital-based population and 20% of community-based samples of diabetic patients (4). The incidence of DSP is approximately 2% per year. The most important etiological factors that have been associated with DSP are poor glycemic control, visceral obesity, diabetes duration and height, with possible roles for hypertension, age, smoking, hypoinsulinemia, and dyslipidemia (4). Moreover, DSP is related to both lower-extremity impairments such as diminished position sense and functional limitations such as walking ability (5). There is accumulating evidence suggesting that not only surrogate markers of microangiopathy such as albuminuria but also those used for polyneuropathy such as nerve conduction velocity (NCV) and vibration perception threshold (VPT) may predict mortality in diabetic patients (6,7). Elevated VPT also predicts the development of neuropathic foot ulceration, one of the most common causes for hospital admission and lower limb amputations among diabetic patients (8). Pain associated with diabetic neuropathy exerts a substantial impact on the quality of life, particularly by causing considerable interference in sleep and enjoyment of life (9). Chronic neuropathic pain is present in 16% to 26% of diabetic patients (10,11). Pain is a subjective symptom of major clinical importance as it is often this complaint that motivates patients to seek health care. However, in a recent survey from the United Kingdom only 65% of diabetic patients received treatment for their neuropathic pain, although 96% had reported the pain to their physician (10). Pain treatment consisted of antidepressants in 43.5% of the cases, anticonvulsants in 17.4%, opiates in 39%, and alternative treatments in 30%. While 77% of the patients reported persistent pain over 5 years, 23% were pain free over at least 1 year (10). Thus, neuropathic pain persists in the majority of diabetic patients over periods of several years.

CLINICAL MANIFESTATIONS Distal Symmetric Polyneuropathy

The term "hyperglycemic neuropathy" is being used to describe sensory symptoms in poorly controlled diabetic patients that are rapidly reversible following institution of near-normoglycemia (3). The most frequent form is the DSP commonly associated with autonomic involvement. The onset is insidious, and, in the absence of intervention, the course is chronic and progressive. It seems that the longer axons to the lower limbs are more vulnerable toward the nerve lesions induced by diabetes (length-related distribution). This notion is supported by the correlation found between the presence of DSP and height. DSP typically develops as a

TABLE 1 Classification of Diabetic Neuropathies

Rapidly reversible

Hyperglycemic neuropathy Persistent symmetric polyneuropathies Distal somatic sensory/motor polyneuropathies involving predominantly large fibers Autonomic neuropathies Small fiber neuropathies Focal/multifocal neuropathies Cranial neuropathies Thoracoabdominal radiculopathies Focal limb neuropathies Proximal neuropathies Compression and entrapment neuropathies

Source: From Ref. 3.

dying-back neuropathy, affecting the most distal extremities (toes) first. The neuropathic process then extends proximally up the limbs and later it may also affect the anterior abdominal wall and then spread laterally around the trunk. Occasionally are the upper limbs involved with the fingertips being affected first (glove-and-stocking distribution). Variants including painful small-fiber or pseudosyringomyelic syndromes and an atactic syndrome (diabetic pseudotabes) have been described. Small-fiber unmyelinated (C) and thinly myelinated (A8) fibers as well as large-fiber myelinated (Aa, Ap) neurons are typically involved. However, it is as yet uncertain whether the various fiber type damage develops following a regular sequence, with small fibers being affected first, followed by larger fibers, or whether the small-fiber or large-fiber involvement reflects either side of a continuous spectrum of fiber damage. However, there is evidence suggesting that small fiber neuropathy may occur early, often presenting with pain and hyperalgesia before sensory deficits or nerve conduction slowing can be detected (3). The reduction or loss of small fiber-mediated sensation results in loss of pain sensation (heat pain, pin-prick) and temperature perception to cold (A8) and warm (C) stimuli. Large-fiber involvement leads to nerve conduction slowing and reduction or loss of touch, pressure, two-point discrimination, and vibration sensation which may lead to sensory ataxia (atactic gait) in severe cases. Sensory fiber involvement causes "positive" symptoms such as paresthesiae, dysesthesiae (hypersensitivity), and pain as well as "negative" symptoms such as numbness.

Persistent or episodic pain that typically may worsen at night and improve during walking is localized predominantly in the feet. The pain is often described as a deep-seated aching but there may be superimposed lancinating stabs or it may have a burning thermal quality (12). In a clinical survey including 105 patients with painful polyneuropathy the following locations of pain were most frequent: 96% feet, 69% balls of feet, 67% toes, 54% dorsum of foot, 39% hands, 37% plantum of foot, 37% calves, and 32% heels. The pain was most often described by the patients as "burning/hot," "electric," "sharp," "achy," and "tingling," was worse at night time and when tired or stressed (9). The average pain intensity was moderate, approximately 5.75/10 on a 0 to 10 scale, with the "least" and "most" pain 3.6 and 6.9/10, respectively. Allodynia (pain due to a stimulus which does not normally cause pain, e.g. stroking) may occur. The symptoms may be accompanied by sensory loss, but patients with severe pain may have few clinical signs. Pain may persist over several years (13) causing considerable disability and impaired quality of life in some patients (9), whereas it remits partially or completely in others (14,15), despite further deterioration in small fiber function (15). Pain remission tends to be associated with sudden metabolic change, short duration of pain or diabetes, preceding weight loss, and less severe sensory loss (14,15).

Compared to the sensory deficits, motor involvement is usually less prominent and restricted to the distal lower limbs resulting in muscle atrophy and weakness at the toes and foot. Ankle reflexes are frequently reduced or absent. At the foot level, the loss of the protective sensation (painless feet), motor dysfunction, and reduced sweat production due to autonomic involvement result in a markedly increased risk of callus and foot ulcers. Thus, the neuropathic patient is a high-risk patient to develop severe and potentially life-threatening foot complications such as ulceration, osteoarthropathy (Charcot foot), and osteomyelitis as well as medial arterial calcification and neuropathic edema. Because DSP is the major contributory factor for diabetic foot ulcers and the lower limb amputation rates in diabetic subjects are 15 times higher than in the non-diabetic population, an early detection of DSP by screening is of paramount importance (8). This is even more imperative due to the fact that many patients with DSP are asymptomatic or have only mild symptoms. In view of these causation pathways the majority of amputations should be potentially preventable if appropriate screening and preventative measures were adopted.

Acute Painful Neuropathy

Acute painful neuropathy has been described as a separate clinical entity (16). It is encountered infrequently in both type 1 and type 2 diabetic patients presenting with continuous burning pain particularly in the soles ("like walking on burning sand") with nocturnal exacerbation. A characteristic feature is a cutaneous contact discomfort to clothes and sheet which can be objectified as hypersensitivity to tactile (allodynia) and painful stimuli (hyperalgesia). Motor function is preserved, and sensory loss may be only slight, being greater for thermal than for vibration sensation. The onset is associated with and preceded by precipitous and severe weight loss. Depression and impotence are constant features. The weight loss has been shown to respond to adequate glycemic control, and the severe manifestations subsided within 10 months in all cases. No recurrences were observed after follow-up periods of up to 6 years (16). The syndrome of acute painful neuropathy seems to be equivalent to "diabetic cachexia" as described by Ellenberg (17). It has also been described in girls with anorexia nervosa and diabetes in association with weight loss (18).

The term insulin neuritis was used by Caravati (19) to describe a case with precipitation of acute painful neuropathy several weeks following the institution of insulin treatment. Sural nerve biopsy shows signs of chronic neuropathy with prominent regenerative activity (20) as well as epineurial arterio-venous shunting and a fine network of vessels, resembling the new vessels of the retina, which may lead to a steal effect rendering the endoneurium ischemic (21). This may happen in analogy to the transient deterioration of a preexisting retinopathy following rapid improvement in glycemic control.

Focal and Multifocal Neuropathies

Most of the focal and multifocal neuropathies tend to occur in long-term diabetic patients of middle age or older. The outlook for most of them is for recovery, either partial or complete, and for eventual resolution of the pain that frequently accompanies them. With this in mind, physicians should always maintain an optimistic outlook in dealing with patients with these afflictions (22).

Cranial Neuropathy

Palsies of the third cranial nerve (diabetic ophthalmoplegia) are painful in about 50% of the cases (23). The onset is usually abrupt. The pain is felt behind and above the eye, and at times precedes the ptosis and diplopia (with sparing of pupillary function) by several days. Oculomotor findings reach their nadir within a day or at most a few days, persist for several weeks, and then begin gradually to improve. Full resolution is the rule and generally takes place within 3 to 5 months (22). The fourth, sixth, and seventh cranial nerves are next in frequency.

Mononeuropathy of the Limbs

Focal lesions affecting the limb nerves, most commonly the ulnar, median, radial, and peroneal may be painful, particularly if of acute onset, as may entrapment neuropathies such as the carpal tunnel syndrome which is associated with painful paresthesias (12).

Diabetic Truncal Neuropathy

Mononeuropathy of the trunk (thoracoabdominal neuropathy or radiculopathy) presents with an abrupt onset, with pain or dysesthesias being the heralding feature sometimes accompanied by cutaneous sensory impairment or hyperesthesia. Pain has been described as deep, aching, or boring, but also the descriptors of jabbing, burning, sensitive skin, or tearing have been used. The neuropathy is almost always unilateral or predominantly so. As a result, the pain felt in the chest or the abdomen may be confused with pain of pulmonary, cardiac, or gastrointestinal origin. Sometimes it may have a radicular or girdling quality, half encircling the trunk in a root-like distribution. Pain may be felt in one or several dermatomal distributions, and, almost universally, it is worst at night. Rarely, abdominal muscle herniation may occur predominantly in middle-aged men, involving three to five adjacent nerve roots between T6 and T12 (24). The time from first symptom to the peak of the pain syndrome is often just a few days, although occasionally spread of the pain to adjacent dermatomes may continue for weeks or even months. Weight loss of 15 to 40 pounds occurs in >50% of the cases. The course of truncal neuropathy is favorable, and pain subsides within months with a maximum of 1.5 to 2 years (22).

Diabetic Amyotrophy

Asymmetric or symmetric proximal muscle weakness and muscle wasting (iliopsoas, obturator, and adductor muscles) are easily recognized clinically in the syndrome of lower limb proximal motor neuropathy (synonyms: Bruns-Garland syndrome, diabetic amyotrophy, proximal diabetic neuropathy, diabetic lumbosacral plexopathy, ischemic mononeuropathy multiplex, femoral-sciatic neuropathy, femoral neuropathy). Pain is nearly universal in this syndrome. Characteristically, it is deep, aching, constant, and severe, invariably worse at night, and may have a burning, raw quality. It is usually not frankly dysesthetic and cutaneous. Frequently, pain is first experienced in the lower back or buttock on the affected side, or may be felt as extending from hip to knee. Although severe and tenacious, the pain of proximal motor neuropathy has a good prognosis. Concurrent distal sensory polyneuropathy is frequently present. Weight loss is also a frequently associated feature and may be as much as 35 to 40 pounds. The weight is generally regained during the recovery phase (22).

Patients with proximal or multifocal diabetic neuropathy show marked ischemic nerve lesions with vasculitis and inflammatory infiltration of mononuclear cells (25,26) and T cells of the CD8+ cell type (27). Activated endoneurial lymphocytes express immunoreactive cytokines and major histocompatibility class II antigens (27). To classify these changes Krendel (28) coined the term diabetic inflammatory vasculopathy which he describes as a "multifocal axonal neuropathy" caused by inflammatory vasculopathy, predominantly encountered in type 2 diabetic patients, indistinguishable from diabetic proximal neuropathy or mononeuritis multiplex. Separated from this form is the "demyelinating neuropathy" without vascular inflammation, predominantly encountered in type 1 diabetic patients, indistinguishable from chronic inflammatory demyelinating polyneuropathy (29). These findings suggest that immunological mechanisms may be implicated in the pathogenesis of these neuropathies.

Central Nervous System Dysfunction

Relatively little attention has been directed toward impairment of the central nervous system (CNS) in diabetic patients with DSP. Previous autopsy studies in diabetic patients have demonstrated diffuse degenerative lesions in the CNS including demyelination and loss of axon cylinders in the posterior columns (30,31), degeneration of cortical neurons (32), and abnormalities in the midbrain and cerebellum (32,33) which have been described as "diabetic myelopathy" (31) and "diabetic encephalopathy" (32,34).

Studies that evaluated CNS function in diabetic patients using evoked potentials in response to stimulation of peripheral nerves, event-related potentials, and neuropsychological tests have yielded variable results as to the existence of spinal or supraspinal (central) conduction deficits or cognitive dysfunction. However, we have shown that the degree of dysfunction along the somatosensory afferent pathways in type 1 diabetic patients depends on the stage of peripheral neuropathy, is not related to the duration of diabetes or glycemic control, and can be characterized by an alteration of the cortical sensory complex and peripheral rather than spinal or supraspinal conduction deficits (35). We also demonstrated evidence of cognitive dysfunction with increasing degree of DSP in diabetic patients using event-related potentials (P300 latency) and neuropsychological tests. The P300 latency as an electrophysiological index of cognitive dysfunction was normal in diabetic patients without DSP but was significantly prolonged in those with stage 1 (asymptomatic) and stage 2 (symptomatic) DSP (36). Dejgaard et al. (37) using magnetic resonance imaging, have found an increased frequency of subcortical and brainstem lesions in type 1 diabetic patients with peripheral neuropathy. Using positron emission tomography and [18F]-2-deoxy-2-fluoro-D-glucose we have shown reduced cerebral glucose metabolism in type 1 diabetic patients with DSP as compared with newly diagnosed diabetic patients and healthy subjects (38). Eaton et al. (39) found a smaller cross-sectional chord area at C4/5 and T3/4 as assessed magnetic resonance imaging in patients with DSP as compared to those without DSP and controls. Thus, there is accumulating evidence suggesting that neuropathic involvement at central and spinal levels is a feature of DSP. However, it is not clear whether these are primary or secondary events in DSP.

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