13.5.4 Diabetic neuropathy

Diabetic neuropathy is a major complication of diabetes and a cause of considerable morbidity and mortality (1). Diabetic neuropathy is not a single entity but includes several neuropathic syndromes (Fig. 13.5.4.1). In clinical practice, the commonest presentation of neuropathy is chronic distal symmetrical polyneuropathy, also known as diabetic peripheral neuropathy (DPN). The neuropathic syndromes depicted in Fig. 13.5.4.1 have varied presentations and pathogenesis. This chapter will cover these syndromes although the main focuses will be: (1) DPN, which is the main initiating factor for foot ulceration and a cause of troublesome painful neuropathic symptoms; and (2) autonomic neuropathy.

There is much variation in the prevalence of DPN. Where electrophysiology is employed the prevalence rates will be in excess of 50% (2), whereas when clinical parameters or quantitative sensory testing are employed both clinic- and population-based studies show similar prevalence rates at about 30% (3). The EURODIAB Prospective Complications Study investigated 3250 type 1 patients and found a prevalence rate of 28% for DPN (4). The study also showed that over a 7.3-year period, about a quarter of type 1 diabetic patients developed DPN (5). The development of DPN was also associated with modifiable cardiovascular risk factors such as hypertension, hyperlipidaemia, obesity, and cigarette smoking (Fig. 13.5.4.2) (5). Based on recent epidemiological studies, correlates of DPN include age, duration of diabetes, poor glycaemic control, retinopathy, albuminuria, and vascular risk factors (5).

Classification of the various syndromes of diabetic neuropathy is difficult. The variations and overlap in aetiology, clinical features, natural history, and prognosis have meant that most classifications are necessarily oversimplified. Nevertheless, classification assists in the planning of clinical management.

Figure 13.5.4.1 shows a modified clinical classification of diabetic polyneuropathy (6). Watkins and Edmonds (7) have suggested a classification for diabetic neuropathy based on the natural history of the various syndromes, which separates them into three distinct groups (Box 13.5.4.1).

DPN is the commonest neuropathic syndrome. 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 upper limb involvement, with a similar progression proximally. 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. As the disease advances, overt motor manifestations such as wasting of the small muscles of the hands and limb weakness become apparent. Subclinical motor involvement detected by MRI appears to be common, and thus motor disturbance is clearly part of the functional impairment caused by DPN (8).

The main clinical presentation of DPN is sensory loss which the patient may not be aware of, or may be described as ‘asleep numbness’ or ‘dead feeling’. However, some may experience a progressive build-up of unpleasant sensory symptoms including tingling (paraesthesiae or ‘pins and needles’). Box 13.5.4.2 summarizes the ‘positive’ and ‘negative’ symptoms of DPN. There is a large spectrum of severity of these symptoms.

Diabetic neuropathic pain is characteristically more severe at night, and often prevents sleep (9). Some patients may be in a constant state of tiredness because of sleep deprivation (9). Others are unable to maintain full employment. Severe painful neuropathy can cause marked reduction in exercise threshold so as interfere with daily activities. This is particularly the case when there is an associated disabling, severe postural hypotension due to autonomic involvement. Not surprisingly therefore, depressive symptoms are not uncommon. It is important to appreciate that many subjects with DPN may not have any of the above symptoms, and their first presentation may be with a foot ulcer (10). This underpins the need for carefully examining and screening the feet of all people with diabetes. The insensate foot is at risk of developing mechanical and thermal injuries, and patients must therefore be warned about these and given appropriate advice with regard to foot care (10). A curious feature of the neuropathic foot is that both numbness and pain may occur, the so called ‘painful, painless’ leg. 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, unsteadiness on walking, and even falls.

DPN is usually easily detected by simple clinical examination (Box 13.5.4.3) (11). Bare feet should be 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 (though this may also be lost with old age in nondiabetic people) and with more advanced neuropathy, knee reflexes are often reduced or absent.

Muscle strength is usually normal early in the course of the disease, although mild weakness may be found in toe extensors. With progressive disease there is significant generalized muscular wasting, particularly in the small muscles of the hand and feet. Wasting of dorsal interossei is usually due to entrapment of the ulnar nerve at the elbow. Clawing of the toes is believed to be due to unopposed 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. Deformities such as a bunion can form the focus of ulceration and with more extreme deformities, such as those associated with Charcot arthropathy (12), the risk is further increased. 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.

Autonomic neuropathy affecting the feet can cause a reduction in sweating and consequently dry skin that is likely to crack easily, predisposing the patient to the risk of infection. The ‘purely’ neuropathic foot is also warm due to arteriovenous shunting first described by Ward et al. (13). 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 due to arteriovenous shunting. The oxygen tension of the blood in these veins is typically raised. The increasing blood flow brought about by autonomic neuropathy can sometimes result in neuropathic oedema (13).

Before attributing the neuropathy to diabetes other common causes of neuropathy must be excluded. The absence of other complications of diabetes, rapid weight loss, excessive alcohol intake and other atypical features in either the history or clinical examination should direct the physician to search for other causes of neuropathy (Box 13.5.4.4).

Acute painful neuropathies are transient neuropathic syndromes characterized by an acute onset of pain (over weeks) in the lower limbs. They are relatively rare compared to chronic DPN. There are two distinct syndromes, the first of which occurs within the context of poor glycaemic control, and the second with rapid improvement in glycaemic control.

This occurs usually in diabetic individuals with poor glycaemic control. There is often an associated severe weight loss. Ellenberg coined the description of this condition as ‘neuropathic cachexia’ (14). Patients typically experience persistent burning pain associated with allodynia (contact pain). The pain is most marked in the feet but often affects the whole of the lower extremities. As in chronic DPN, the pain is typically worse at night and often results in depression.

In acute painful neuropathies sensory loss is usually mild or absent. There are usually no motor signs, although ankle jerks may be absent. Nerve conduction studies are usually normal or mildly abnormal. Temperature discrimination threshold (small fibre function) is affected more commonly than vibration perception threshold (large fibre function). There is complete resolution of symptoms within 12 months, and weight gain is usual with continued improvement in glycaemic control with the use of insulin.

The term ‘insulin neuritis’ is a misnomer as the condition can follow rapid improvement in glycaemic control with oral hypoglycaemic agents and is better termed ‘acute painful neuropathy of rapid glycaemic control’ (15). The natural history of acute painful neuropathies is an almost guaranteed improvement in contrast to chronic DPN (15). Presentation is with burning pain, paraesthesiae, allodynia, often with a nocturnal exacerbation of symptoms; and accompanying depression. There is no associated weight loss, sensory loss is often mild or absent, and there are no motor signs. There is little or no abnormality on nerve conduction studies. Prognosis is good with usually complete resolution of symptoms within 12 months. The management of painful symptoms is as in chronic DPN.

The existence of ‘small fibre neuropathy’ as a distinct entity has been advocated (16), usually within the context of young type 1 patients and prediabetes (17). A dominant feature of this syndrome is neuropathic pain, which may be severe, with relative sparing of large fibre functions (vibration and proprioception). The pain is described as burning, deep, and aching. The sensation of pins and needles (paraesthesiae) is often experienced. Contact hypersensitivity may be present. 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 (and indeed in prediabetes) 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 (due to relative sparing of the large diameter Aβ fibres). Muscle strength and reflexes are usually normal. Autonomic function tests are frequently abnormal and affected male patients usually have erectile dysfunction. Electrophysiological tests are usually normal. Controversy still exists as to whether small fibre neuropathy is a distinct entity or an earlier manifestation of DPN (16).

Asymmetrical (or focal) neuropathies have a relatively rapid onset, and complete recovery is usual. This contrasts with chronic DPN, where there is usually no improvement in symptoms several years after onset. Unlike DPN their presence is not related to the presence of other diabetic complications. Asymmetrical neuropathies predominantly affect middle aged/older patients and are more common in men (18). A high index of suspicion for a nondiabetic cause is advised.

The syndrome of progressive asymmetrical proximal leg weakness and atrophy was first described by Garland (19), who coined the term ‘diabetic amyotrophy’. This condition has also been named as ‘proximal motor neuropathy’ or ‘femoral neuropathy’. The patient presents with severe pain which is felt deep in the thigh, but can sometimes be of burning quality and extend below the knee. The pain is usually continuous and often causes insomnia and depression. Both type 1 and type 2 patients over the age of 50 are affected (19). There is an associated weight loss which can be severe, and can raise the possibility of an occult malignancy.

On examination there is profound wasting of the quadriceps with marked weakness in these muscle groups, although hip flexors and hip abductors can also be affected. Thigh adductors, glutei, and hamstring muscles may be involved. The knee jerk is usually reduced or absent. The profound weakness can lead to difficulty from getting out of a low chair or climbing stairs. Sensory loss is unusual, and if present indicates a coexistent DPN.

Other causes of quadriceps wasting such as nerve root and cauda equina lesions and occult malignancy causing proximal myopathy syndromes (e.g. polymyositis) should be excluded. MRI of the lumbosacral spine is now mandatory in order to exclude focal nerve root entrapment and other pathologies. An erythrocyte sedimentation rate (ESR), an X-ray of the lumbar/sacral spine, a chest X-ray, and ultrasound of the abdomen may also be required. Electrophysiological studies may demonstrate increased femoral nerve latency and active denervation of affected muscles. CSF protein is often elevated.

The cause of diabetic proximal motor neuropathy is not known. It tends to occur within the background of DPN. It is suggested that the combination of focal features superimposed on diffuse peripheral neuropathy may suggest vascular damage to the femoral nerve roots, as a cause of this condition.

There is scarcity of prospective studies that have looked at the natural history of proximal motor neuropathy. Pain usually starts to settle after about 3 months, and usually settles by 1 year, while the knee jerk is restored in 50% of the patients after 2 years. Recurrence is a rare event. Management is largely symptomatic and supportive. There is still controversy as to whether the use of insulin therapy influences the natural history of this syndrome. Some patients benefit from physiotherapy that including extension exercises to strengthen the quadriceps. The management of pain in diabetic amyotrophy is similar to that of painful DPN (see below).

The commonest cranial mononeuropathy is the third cranial nerve palsy. The patient presents with pain in the orbit, or sometimes with a frontal headache (20). There is typically ptosis and ophthalmoplegia, although the pupil is usually spared. Recovery usually occurs over 6 months. It is important to exclude any other cause of third cranial nerve palsy (aneurysm or tumour) by CT or MRI, where the diagnosis is in doubt. Fourth, sixth and seventh cranial nerve palsies have also been described in diabetic subjects, but the association with diabetes is not as strong as that with a third cranial nerve palsy.

Diabetic thoracoabdominal neuropathy (truncal radiculopathy) is characterized by an acute onset pain in a dermatomal distribution over the thorax or the abdomen (21). The pain is usually asymmetrical, and can cause local bulging of the muscle. There may be patchy sensory loss and other causes of nerve root compression should be excluded. Recovery is usually the rule within several months, although symptoms can sometimes persist for a few years.

The patient typically has pain and paraesthesia in the hands, which sometimes radiate to the forearm and are particularly marked at night. In severe cases, clinical examination may reveal a reduction in sensation in the median territory in the hands, and wasting of the muscle bulk in the thenar eminence. The clinical diagnosis is confirmed by median nerve conduction studies and treatment involves surgical decompression. There is generally a good response to surgery, although painful symptoms may relapse more commonly than in the nondiabetic population.

The ulnar nerve is also vulnerable to pressure damage at the elbow resulting in wasting of the dorsal interossei, particularly the first dorsal interosseous. This is confirmed by ulnar electrophysiological studies. Rarely, the patients may present with wrist drop due to radial nerve palsy after prolonged sitting or while unconscious during hypoglycaemia. In the lower limbs the common peroneal (lateral popliteal) is the most commonly affected nerve resulting in foot drop. Unfortunately, complete recovery is not usual. The lateral cutaneous nerve of the thigh is occasionally also affected with entrapment neuropathy in diabetes. Phrenic nerve involvement in association with diabetes has been described.

Despite considerable research, the pathogenesis of diabetic neuropathy remains undetermined. Morphometric studies have demonstrated that distal symmetrical neuropathy is characterized by pathological changes including: (1) axonal loss distally, with a ‘dying back’ phenomenon, (2) a reduction in myelinated fibre density, and (3) focal areas of demyelination on teased fibre preparations. Nerve regenerative activity may also be seen with the emergence of ‘regenerative clusters’, containing groups of myelinated axons and nonmyelinated axons sprouts. However, the small and unmyelinated fibres that make up around 80% of all nerve fibres have proved more difficult to assess.

Figure 13.5.4.3 shows current thinking regarding the pathogenesis of diabetic neuropathy (22). Hyperglycaemia stimulates the production of advanced glycosylated end products, activates protein kinase C, enhances polyol pathway activity, and induces a dysregulation of reactive oxygen and nitrogen generating pathways (nitrosative stress). These processes impair the capacity of the vascular endothelium to produce biologically active nitric oxide, which adversely affects vascular relaxation.

The view that microvessel disease may be central to the pathogenesis of diabetic neuropathy is not new. Severe neural microvascular disease has been demonstrated in subjects with clinical diabetic neuropathy (23). Several workers have reported basal membrane thickening of endoneurial capillaries, degeneration of pericytes and hypoplasia and swelling of endothelial cells and sometimes vessel closure. The degree of microvascular disease has been correlated with the severity of neuropathy.

In vivo studies looking at the exposed sural nerve in human subjects have demonstrated epineural arteriovenous shunting, which appears to result in a ‘steal’ phenomenon diverting blood from the nutritive endoneurial circulation (24). The consequent impairment of nerve blood flow causes a fall in endoneural oxygen tension. There is a strong correlation between nerve conduction velocity and lower limb transcutaneous oxygenation measurements in diabetes; macrovascular disease appears to exacerbate neuropathy and surgical restoration of perfusion improves nerve conduction velocity (25). A recent epidemiological study has also found a strong correlation between diabetic neuropathy and cardiovascular risk factors including; body weight, hypertension, smoking, and hypertriglyceridaemia (5).

Abnormalities of autonomic function are very common in subjects with longstanding diabetes, however, clinically significant autonomic dysfunction is uncommon. Several systems are affected (Box 13.5.4.5). Autonomic neuropathy has a gradual onset and is slowly progressive. The prevalence of diabetic autonomic neuropathy depends on the type of population studied, and a number of tests of autonomic function employed. In the EURODIAB study the prevalence of autonomic neuropathy defined as the presence of two abnormal cardiovascular autonomic function tests, was 24%, and the prevalence increased with age, duration of diabetes, glycaemic control, and presence of cardiovascular risk factors (5).

Cardiovascular autonomic neuropathy a serious complication of longstanding diabetes and causes postural hypotension and may be a cause of sudden death.

It is now generally accepted that a fall in systolic blood pressure of >20 mmHg is considered abnormal. Coincidental treatment with tricyclic antidepressants for neuropathic pain, and diuretics may exacerbate postural hypotension. The symptoms of postural hypotension can be disabling for some patients who may not be able to walk for more than a few minutes. Severely affected patients are prone to unsteadiness and falls. The degree of dizziness does not appear to correlate with the postural drop in blood pressure. There is increased mortality in subjects with postural hypotension.

The management of subjects with postural hypotension is challenging. Current treatments include: (1) removing any drugs that may result in orthostatic hypotension, such as diuretics, B-blockers; (2) advising patients to get up from the sitting or lying position slowly, and crossing the legs; (3) increasing sodium intake up to 10 g (185 mmol) per day and fluid intake of 2–2.5 l/day (caution in elderly patients with heart failure); (4) the use of custom fitted elastic stockings extending to the waist; (5) treatment with fludrocortisone (starting at 100 μgm/day) and 6) in severe cases the α₁ adrenal receptor agonist, midodrine or octreotide, may be effective.

Five cardiovascular autonomic function tests are now widely used for the assessment of autonomic function. These tests are noninvasive, and all that is required is an electrocardiogram machine, an aneroid pressure gauge attached to a mouthpiece, a hand grip dynamometer, and sphygmomanometer. See Table 13.5.4.1 (26).

Autonomic neuropathy can reduce oesophageal motility (dysphagia and heartburn), and cause gastroparesis (reduced gastric emptying, vomiting, swings in blood sugar) (27). The diagnosis of gastroparesis is often made on clinical grounds by the evaluation of symptoms and sometimes the presence of succussion splash, while barium swallow and follow through, and gastroscopy may reveal a large food residue in the stomach. Gastric motility and emptying studies may aid diagnosis.

Management of diabetic gastroparesis include: optimization of glycaemic control; the use of antiemetics (metoclopramide and domperidone), and the use of the cholinergic agent which stimulates oesophageal motility (erythromycin which may enhance the activity of the gut peptide, motilin). Gastric electrical stimulation (GES) has recently been introduced as a treatment option in patients with drug refractory gastroparesis.

Severe gastroparesis causing recurrent vomiting, is associated with dehydration, swings in blood sugar and weight loss, and is an indication for hospital admission. The patient should be adequately hydrated with intravenous fluids and blood sugar should be stabilized, antiemetics could be given intravenously and if the course of the gastroparesis is prolonged, total parenteral nutrition or feeding through a gastrostomy tube may be required.

The usual presentation is that of diarrhoea which tends to be worse at night, or alternatively some may present with constipation. Both the diarrhoea and constipation respond to conventional treatment. Diarrhoea associated with bacterial overgrowth may respond to treatment with a broad spectrum antibiotic.

Autonomic bladder dysfunction is a rare complication of autonomic neuropathy and may result in hesitancy of micturition, increased frequency of micturition and in serious cases with urinary retention associated with overflow incontinence. Such a patient is prone to urinary tract infections. Ultrasound scan of the urinary tract and urodynamic studies may be required. Treatments include mechanical methods of bladder emptying by applying suprapubic pressure, or the use of intermittent self-catheterization. Anticholinesterase drugs such as neostigmine or pyridostigmine may be useful.

Increased sweating usually affecting the face, and often brought about by eating (gustatory sweating) can be embarrassing to patients. Oral anticholinergic agents, including oxybutynin, propantheline, and glycopyrrolate, have improved symptoms; however adverse reactions limit their use. Clonidine has also been used with some success but is also limited by side effects including hypotension and dry mouth (27). Systemic side effects have led to the investigation of nonsystemic approaches. Topical glycopyrrolate, a quaternary ammonium, antimuscarinic compound has been shown to significantly decrease the incidence, severity, and frequency of sweating with eating and is tolerated well. Botulinum toxin has been used for gustatory sweating, though in most literature it is limited to use in unilateral, surgical-related cases.

Unfortunately, currently available treatment approaches for PDN may not completely abolish the pain (28). Neuropathic pain can be very disabling and an empathic approach is essential. Psychological support is an important aspect of the overall management plan (28). Box 13.5.4.6 presents a summary of pharmacological treatment options.

There is now little doubt that good blood sugar control prevents/delays the onset of diabetic neuropathy (29). In addition, painful neuropathic symptoms may also improved by improving metabolic control, if necessary with the use of insulin in type 2 diabetes.

Tricyclic compounds are regarded as one of the first-line treatment agents (30). A number of double-blind clinical trials have confirmed their effectiveness beyond any doubt. As these drugs do have unwanted side effects such as drowsiness, dry mouth, and postural hypotension, patients should be started on imipramine or amitriptyline at a low dose (10–25 mg taken before bed), the dose gradually titrated if necessary up to 100 mg/day. Caution should be taken in elderly patients and in those with cardiovascular disease. The mechanism of action of tricyclic compounds in improving neuropathic pain is not fully understood.

Serotonin–noradrenaline reuptake inhibitors (SNRIs), such as duloxetine, relieve pain by increasing synaptic availability of 5-hydroxytryptamine and noradrenaline in the descending pathways that are inhibitory to pain impulses. Duloxetine is licensed for the treatment of painful diabetic neuropathy. The efficacy of duloxetine in painful neuropathy has been investigated (28) with the 60 mg/day and 120 mg/day doses being effective in relieving painful symptoms. Duloxetine is contraindicated in those with liver disease.

Older anticonvulsants, including sodium valproate and carbamazepine, though effective, tend to have more side effects. Gabapentin and pregabalin bind to the α-2-δ subunit of the calcium channel, reducing calcium flux, and thus resulting in reduced neurotransmitter release in the hyperexcited neuron. Gabapentin has been used to treat painful neuropathy for over a decade (28). More recently pregabalin at 300–600 mg/day has been found effective in several clinical trials and is licensed for the treatment of painful diabetic neuropathy. Side effects of include dizziness, somnolence, and peripheral oedema.

The antioxidant α-lipoic acid: at a dose of 600 mg per day orally or IV has also been found to be useful in reducing neuropathic pain.

The opiate derivative tramadol (50–100 mg four times per day) has been found effective in relieving neuropathic pain. Another opioid, oxycodone slow release, has also been shown to be effective in the management of neuropathic pain. Recently, the combination of morphine and gabapentin, and oxycodone and gabapentin were found to be more effective than either on its own in the management of diabetic neuropathic pain.

Topical capsaicin works by depleting substance ‘P’ from nerve terminals, and there may be worsening of neuropathic symptoms for the first 2–4 weeks of application. Topical capsaicin (0.075%) applied sparingly three to four times per day to the affected area has been found to relieve neuropathic pain (31).

Intravenous lidocaine at a dose of 5 mg/kg body weight administered over 30 min, with a cardiac monitor in situ, has been found to be effective in relieving neuropathic pain for up to two weeks. This form of treatment is useful in subjects that are having severe pain which is not responding to the above agents, although it does necessitate bringing the patient into hospital.

Neuropathic pain can sometimes be extremely severe. Unfortunately some patients are not helped by conventional pharmacological treatment. Such patients may respond to electrical spinal cord stimulation which relieves both background and peak neuropathic pain (32).

In England and Wales, the 2009 National Institute for Health and Clinical Excellence (NICE) guideline on the management of type 2 diabetes (33) advocates a formal enquiry annually about the development of neuropathic symptoms that may be causing distress. It also encourages clinicians to be alert to the psychological consequences of painful DPN and the need to offer psychological support according to the needs of the individual. A newly published NICE guideline on the pharmacological management of neuropathic pain in adults in nonspecialist settings (34) provides updated guidance on the treatment of painful DPN and other neuropathic pain conditions. For the purposes of the newer guideline, ‘nonspecialist settings’ are defined as ‘primary and secondary care services that do not provide specialist pain services. Non-specialist settings include general practice, general community care and hospital care’ (34). The guideline recommends the following regarding pharmacological care of painful DPN.