Chronic Distal Symmetrical Neuropathy
This is the most common neuropathic syndrome and what is meant in clinical practice by the phrase "diabetic neuropathy." Clinical manifestations (14) and measurements (15,16) of distal symmetrical neuropathy have recently been reviewed. There is a "length-related" pattern of sensory loss, with sensory symptoms starting in the toes and then extending to involve the feet and legs in a stocking distribution. In more severe cases, there is often upper limb involvement, with a similar progression proximally starting in the fingers. Although the nerve damage can extend over the entire body including the head and face, this is exceptional. Subclinical neuropathy detectable by autonomic function tests is usually present. However, clinical autonomic neuropathy is less common. Autonomic neuropathy is considered in more detail in Chapter 24. As the disease advances, overt motor manifestations, such as wasting of the small muscles of the hands and limb weakness become apparent. However, subclinical motor involvement detected by magnetic resonance imaging appears to be common, and thus, motor disturbance is clearly part of the functional impairment caused by distal symmetrical neuropathy (17).
The main clinical presentation of distal symmetrical neuropathy is sensory loss, which the patient may not be aware of, or may be described as "numbness" or "dead feeling." However, some may experience a progressive buildup of unpleasant sensory symptoms including tingling (paraesthesae); burning pain; shooting pains down the legs; lancinating pains; contact pain often with day-time clothes and bedclothes (allodynia); pain on walking often described as "walking barefoot on marbles," or
"walking barefoot on hot sand," sensations of heat or cold in the feet; persistent achy feeling in the feet; and cramp-like sensations in the legs. Occasionally, pain can extend above the feet and may involve the whole of the legs, and when this is the case there is usually upper limb involvement also. There is a large spectrum of severity of these symptoms. Some may have minor complaints such as tingling in one or two toes; others may be affected with the devastating complications, such as "the numb diabetic foot," or severe painful neuropathy that does not respond to drug therapy.
Diabetic neuropathic pain is characteristically more severe at night, and often prevents sleep (18,19). Some patients may be in a constant state of tiredness because of sleep deprivation (18,19). Others are unable to maintain full employment (18-21). Severe painful neuropathy can occasionally cause marked reduction in exercise threshold thus interfere with daily activities (20). This is particularly the case when there is an associated disabling, severe postural hypotension because of autonomic involvement (9). Not surprisingly therefore, depressive, symptoms are not uncommon (21). Although, subclinical autonomic neuropathy is commonly found in patients with distal symmetrical neuropathy (22), symptomatic autonomic neuropathy is uncommon.
It is important to appreciate that many subjects with distal symmetrical neuropathy may not have any of the above symptoms, and their first presentation may be with a foot ulcer (7). This underpins the need for carefully examining and screening the feet of all people with diabetes, in order to identify those at risk of developing foot ulceration (7). The insensate foot is at risk of developing mechanical and thermal injuries, and patients must therefore be warned about these and given appropriate advice regarding foot care (7,23). A curious feature of the neuropathic foot is that both numbness and pain may occur, the so called "painful, painless" leg (23). It is indeed a paradox that the patient with a large foot ulcer may also have severe neuropathic pain. In those with advanced neuropathy, there may be sensory ataxia. The unfortunate sufferer is affected by unsteadiness on walking, and even falls particularly if there is associated visual impairment because of retinopathy.
Neuropathy is usually easily detected by simple clinical examination (15,16,23). Shoes and socks should be removed and the feet examined at least annually and more often if neuropathy is present. The most common presenting abnormality is a reduction or absence of vibration sense in the toes. As the disease progresses there is sensory loss in a "stocking" and sometimes in a "glove" distribution involving all modalities. When there is severe sensory loss, proprioception may also be impaired, leading to a positive Romberg's sign. Ankle tendon reflexes are lost and with more advanced neuropathy, knee reflexes are often reduced or absent.
Muscle strength is usually normal during the early course of the disease, although mild weakness may be found in toe extensors. However, with progressive disease there is significant generalized muscular wasting, particularly in the small muscles of the hand and feet. The fine movements of fingers would then be affected, and there is difficulty in handling small objects. However, wasting of dorsal interossei is usually because of entrapment of the ulnar nerve at the elbow. The clawing of the toes is believed to be as a result of unopposed (because of wasting of the small muscles of the foot) pulling of the long extensor and flexor tendons. This scenario results in elevated plantar pressure points at the metatarsal heads that are prone to callus formation and foot ulceration (7). Deformities such as a bunion can form the focus of ulceration and with more extreme deformities, such as those associated with Charcot arthropathy, the risk is further increased (24). As one of the most common precipitants to foot ulceration is inappropriate footwear, a thorough assessment should also include examination of shoes for poor fit, abnormal wear, and internal pressure areas or foreign bodies (7).
Autonomic neuropathy affecting the feet can cause a reduction in sweating and consequently dry the skin that is likely to crack easily, predisposing the patient to the risk of infection (7). The "purely" neuropathic foot is also warm because of artero/venous shunting first described by Ward (25). This results in the distension of foot veins that fail to collapse even when the foot is elevated. It is not unusual to observe a gangrenous toe in a foot that has bounding arterial pulses, as there is impairment of the nutritive capillary circulation because of arterio-venous shunting. The oxygen tension of the blood in these veins is typically raised (26). The increasing blood flow brought about by autonomic neuropathy can sometimes result in neuropathic oedema, which is resistant to treatment with diuretics, but may respond to treatment with ephedrine (27).
Some authorities have advocated the existence of "small-fiber neuropathy" as a distinct entity (28,29), usually within the context of young type 1 patients. A prominent feature of this syndrome is neuropathic pain, which may be very severe, with relative sparing of large-fiber functions (vibration and proprioception). The pain is described as burning, deep, and aching. The sensation of pins and needles (paraesthesae) is also often experienced and contact hypersensitivity may be present. Rarely, patients with small-fiber neuropathy might not have neuropathic pain, and some might occasionally have foot ulceration. Autonomic involvement is common, and severely affected patients may be disabled by postural hypotension and/or gastrointestinal symptoms. The syndrome tends to develop within a few years of diabetes as a relatively early complication.
On clinical examination there is little evidence of objective signs of nerve damage, apart from a reduction in pinprick and temperature sensation, which are reduced in a "stocking" and "glove" distribution. There is relative sparing of vibration and position sense (because of relative sparing of the large diameter Ap fibers). Muscle strength is usually normal and reflexes are also usually normal. However, autonomic function tests are frequently abnormal and affected male patients usually have erectile dysfunction. Electrophysiological tests support small-fiber dysfunction. Sural sensory conduction velocity may be normal, although the amplitude may be reduced. Motor nerves appear to be less affected. Controversy still exists regarding whether small-fiber neuropathy is a distinct entity or an earlier manifestation of chronic sensory motor neuropathy (28,29). Said et al. (28) studied a small series of subjects with this syndrome and showed that small-fiber degeneration predominated morphometrically. Veves et al. (30) found a varying degree of early small-fiber involvement in all diabetic polyneuropathies, which was confirmed by detailed sensory and autonomic function tests. Therefore it is unclear, whether this syndrome is in fact distinct or merely represents the early stages of distal symmetrical neuropathy that has been detected by the prominence of early symptoms.
The natural history of chronic distal symmetrical neuropathy remains poorly understood. This is mainly because there is paucity of well conducted prospective studies that have sought to examine this (6). In addition, the inadequate knowledge regarding the pathogenesis of distal symmetrical neuropathy is also a contributory factor, although several mechanisms have been suggested (31-35), and the list of potential mechanisms is constantly growing. Unlike in diabetic retinopathy and nephropathy, the scarcity of simple, accurate, and readily reproduciable methods of measuring neuropathy further complicates the problem (15,16). One study (36) reported that neuropathic symptoms remain or get worse over a 5-year period in patients with chronic distal symmetrical neuropathy. A major drawback of this study was that it involved highly selected patients from a hospital base. A more recent study reported improvements in painful symptoms with worsening of quantitative measures of nerve function for a duration of 3.5 years (37). Neuropathic pain was assessed using a visual analog scale, and small-fiber function by thermal limen, heat pain threshold, and weighted pinprick threshold. At follow-up, 3.5 years later one third of the 50 patients at baseline had died or were lost to follow-up. Clearly, this is a major drawback. There was symptomatic improvement in painful neuropathy in the majority of the remaining patients. It should be noted that many of the subjects were being treated with pain relieving drugs that may have influenced the findings. However, despite this symptomatic improvement, small fiber function as measured by the aforementioned tests deteriorated significantly. Thus, there was a dichotomy in the evolution of neuropathic symptoms and neurophysiological measures.
Are Painful and Painless Neuropathies Distinct Entities?
One of the complexities of distal symmetrical neuropathy is the variety of presentation to the clinician. A relative minority present with pain as the predominant symptom (38). There is controversy as to whether the clinical, neurophysiological, peripheral nerve haemodynamic/morphometric findings are distinctly different in subjects with painful and painless diabetic neuropathy. Young et al. (39) reported that patients with painful neuropathy had a higher ratio of autonomic (small-fiber) abnormality to elec-trophysiological (large-fiber) abnormality. In contrast, they found that electrophysio-logical parameters were significantly worse in patients with foot ulceration compared with those with painful neuropathy. They concluded that in distal symmetrical neuropathy, the relationship between large-fiber and small-fibre damage is not uniform, and that there may be different etiological influences on large- and small-fibre neuropathy in diabetic subjects, with the predominant type of fibre damage determining the form of the presenting clinical syndrome (39). This view is supported by the study of Tsigos et al. (40) who also suggested that painful and painless neuropathies represent two distinct clinical entities with little overlap. However, a contrary view was expressed by Veves et al. (41) who found that painful symptoms were frequent in diabetic neuropathy, irrespective of the presence or absence of foot ulceration, and that these symptoms may occur at any stage of the disease. They concluded that there is a spectrum of presentations from varying degrees of painful neuropathy to predominantly painless neuropathy associated with foot ulceration, and that much overlap is present (41). The author's clinical observations support this view, as painful symptoms are often similarly present in patients with and without foot ulceration, suggesting that painless and painful neuropathy represent extreme forms of the same syndrome. Thus, an important clinical point is that the neuropathic foot with painful symptoms is just as vulnerable to foot ulceration as the foot with absence of painful neuropathic symptoms. The crucial determining factor is elevation of vibration perception threshold (42) and not the presence or absence of painful symptoms. Indeed, the "painful-painless" foot with ulceration, is frequently observed in the diabetic foot clinic, a phenomenon first described by Ward (23).
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