Diabetic neuropathy

See the separate Diabetic Foot article. Diabetes may cause polyneuropathy, mononeuropathy, amyotrophy and autonomic neuropathy.

Diabetic neuropathy is a common complication of both type 1 diabetes and type 2 diabetes. Neuropathy plays a major role in the development of foot ulcers, which cause an enormous effect on quality of life for the patient (especially if amputation becomes necessary) and is also responsible for a very large health and social services expenditure.

Optimal control of all metabolic factors and regular organised surveillance of all people with diabetes are essential to reduce the risk of both development and progression of diabetic neuropathy and therefore reduce the risk of disability for the patient.

Motor, sensory and autonomic fibres may all be affected by diabetic neuropathy.

Epidemiology

Neuropathies related to diabetes can affect 60-70% of people with diabetes¹. Neuropathy associated with type 2 diabetes may be present at the time of diagnosing diabetes. Neuropathy associated with type 1 diabetes usually develops more than 10 years after the diagnosis of diabetes. Diabetes is the most common cause of peripheral neuropathy in the world².

Risk factors

• Smoking.

• Age over 40 years.

• History of periods of poor glycaemic control.

• Prevalence increases with increased duration of diabetes.

• People with signs of neuropathy are likely also to have evidence of diabetic nephropathy and diabetic retinopathy.

• Hypertension.

• Coronary heart disease.

Presentation

The presentation depends on the type of neuropathy involved. 50% of people with diabetic polyneuropathy may have no symptoms and are only diagnosed by careful, regular and thorough clinical examination³.

Peripheral sensorimotor (chronic peripheral neuropathy)

• Sensory nerves are affected more than motor.

• Touch, pain and temperature sensation and proprioception in lower limbs in a glove and stocking distribution.

• Loss of ankle jerks and, later, knee jerks.

• Hands are only affected in severe long-standing neuropathy.

• Equal prevalence in types 1 and 2.

Acute diffuse painful (acute peripheral neuritis)

• Often abrupt onset and not related to duration of diabetes.

• Can resolve completely.

• Burning foot pain, often worse at night.

• Associated with poor glycaemic control but sometimes initially follows establishing good glycaemic control.

• Examination may be normal apart from hyperaesthesia.

Acute painful neuropathy of rapid improvement of blood glucose control⁴

Acute painful neuropathy resulting from rapid improvement of blood glucose control is a self-limiting condition that improves symptomatically over time.

Autonomic neuropathy

• Risk factors include hypertension and dyslipidaemia. It is more common in females.

• It may present with:
  

  • Cardiac autonomic neuropathy, which has been linked to⁵:
    

    • Resting tachycardia, postural hypotension, orthostatic bradycardia and orthostatic tachycardia.

    • Exercise intolerance.

    • Decreased hypoxia-induced respiratory drive.

    • Loss of baroreceptor sensitivity, increased intra-operative or peri-operative cardiovascular lability.

    • Increased incidence of asymptomatic myocardial ischaemia, myocardial infarction, decreased rate of survival after myocardial infarction.

    • Congestive heart failure.

  • Genitourinary:
    

    • Impotence, retrograde ejaculation, urinary hesitancy, overflow incontinence.

    • At least 25% of men with diabetes have problems with sexual function.

    • There is often no association with glycaemic control or with duration or severity of diabetes.

    • Risk factors for erectile dysfunction include increasing age, alcohol, initial glycaemic control, intermittent claudication and retinopathy.

  • Gastrointestinal:
    

    • Nausea and vomiting.

    • Abdominal distension.

    • Dysphagia.

    • Diarrhoea.

  • Gustatory sweating, anhidrosis.

• Tends to be associated with peripheral neuropathy.

• People with both types 1 and 2 are affected.

• High mortality rate (50% within three years) mainly due to chronic kidney disease but there is often no obvious cause.

• Tight glycaemic control reduces the risk.

Mononeuropathy

• External pressure or entrapment - eg, carpal tunnel syndrome.

• Isolated neuropathies of either the cranial or peripheral nerves. Mononeuropathies of cranial nerves III, IV and VI, intercostal nerves and femoral nerves are common.

• Occasionally more than one nerve is involved (mononeuritis multiplex).

Proximal motor (diabetic amyotrophy)

• Main motor manifestation.

• Severe pain and paraesthesiae in the upper legs, with weakness and muscle wasting of the thigh and pelvic girdle muscles.

• May be asymmetrical and there may be extensor plantars.

• Mainly affects middle-aged and elderly patients.

• Usually associated with a period of very poor glycaemic control, sometimes with dramatic weight loss.

• Pain and weakness gradually reduce once good glycaemic control has returned.

Differential diagnosis

• Other possible causes of neuropathy include:
  

  • Toxins (eg, alcohol, occupational, vitamin B6), medications (eg, amiodarone).

  • Hypothyroidism.

  • Pernicious anaemia.

  • Malignancies, amyloidosis.

  • Collagen vascular disease, neurosarcoidosis.

  • Tabes dorsalis, AIDS.

  • Spinal cord disease, cauda equina syndrome.

Investigations

• Full assessment of diabetes and blood pressure control. Assessment of other possible causes - eg, TFTs, B12.

• May require nerve conduction studies and electromyography.

Management⁶

• Regular surveillance for signs of neuropathy to allow early intervention.

• Tight glycaemic control.

• Prevention of foot trauma.
  

Management of painful neuropathy

May require a great deal of support for the depressing and disabling nature of the condition.

General measures

• Bed foot cradles for problems at night.

• Simple analgesia taken in advance of diurnal symptoms.

• Contact dressings.

Drug treatments recommended by the National Institute for Health and Care Excellence (NICE)⁶

• Offer a choice of amitriptyline, duloxetine, gabapentin or pregabalin as initial treatment for neuropathic pain. Note that as of April 2019, gabapentin and pregabalin became scheduled as Class C controlled substances (under the Misuse of Drugs Act 1971) and Schedule 3 under the Misuse of Drugs Regulations 2001. Before prescribing, patients should be evaluated for a history of drug abuse and observed for signs of abuse and dependence.

• If the initial treatment is not effective or is not tolerated, offer one of the remaining three drugs; consider switching again if the second and third drugs tried are also not effective or not tolerated.

• Consider tramadol only if acute rescue therapy is needed.

• Consider capsaicin cream for people with localised neuropathic pain who wish to avoid, or who cannot tolerate, oral treatments.

• Opioids other than tramadol should be avoided unless they are part of shared-care arrangements after specialist assessment.

• Patients on drug treatment should be reviewed early when starting treatment for dosage titration, or when changing dose to monitor for adverse effects and tolerability.

• Regular reviews (NICE does not specify a time interval) should also be arranged to check progress, adverse effects, mood, quality of sleep and any problems with daily activities.

When to refer
Consider referral to a pain clinic and/or condition-specific service at any stage (including initial presentation) if:

• Pain is severe.

• Pain significantly limits activity.

• The underlying condition has deteriorated.

Management of autonomic neuropathy

See the separate Autonomic Neuropathy article. In all patients, optimise control of diabetes.

• Cardiovascular effects - various cardio-active drugs are being used to reverse the effects on the cardiovascular system, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, diuretics and digoxin⁷.

• Erectile dysfunction: see the separate Erectile Dysfunction article.

• Gastroparesis⁸:
  

  • Investigation using radiological or radioisotope methods may help in the diagnosis.

  • Investigation of cardiovascular autonomic neuropathy may help in the diagnosis.

  • Drugs which increase gastric emptying are worth trying. These include metoclopramide, domperidone and erythromycin.

  • Electrical stimulation has produced benefits in some patients.

• Diabetic nocturnal diarrhoea:

  • Investigation must exclude other causes of intestinal upset.

  • May be helped by high doses of codeine, loperamide or diphenoxylate⁹.

• Gustatory sweating:

  • Explanation and counselling are often required.

  • The anticholinergic agent glycopyrrolate is sometimes effective when applied topically¹⁰.

• Postural hypotension:
  

  • NICE found limited evidence that fludrocortisone improved this condition¹¹. The outcome of a Cochrane review is awaited¹².

NICE recommends⁴¹³:

• Considering the possibility of contributory sympathetic nervous system damage for adults with diabetes who lose the warning signs of hypoglycaemia.

• Considering the possibility of autonomic neuropathy affecting the gut in type 1 diabetes in adults who have unexplained diarrhoea, particularly at night.

• Taking care when prescribing antihypertensive medicines or tricyclic antidepressants not to expose people to the risks of orthostatic hypotension as a result of the combined effects of sympathetic autonomic neuropathy and blood pressure-lowering medicines.

• In adults with diabetes who have bladder emptying problems, investigating the possibility of autonomic neuropathy affecting the bladder, unless other explanations are adequate.

• When managing the symptoms of autonomic neuropathy, including standard interventions for the manifestations encountered (eg, abnormal sweating and postural hypotension).

Acute painful neuropathy of rapid improvement of blood glucose control⁴

• Acute painful neuropathy resulting from rapid improvement of blood glucose control is a self-limiting condition that improves symptomatically over time.

• The specific treatments for acute painful neuropathy resulting from rapid improvement of blood glucose control aim to make the symptoms tolerable until the condition resolves; they may not relieve pain immediately and may need to be taken regularly for several weeks to be effective.

• Use of simple analgesics (paracetamol, aspirin) and local measures (bed cradles) are recommended as a first step; however, if trials of these measures are ineffective, they should be stopped and other measures tried.

• Diabetes control should not be relaxed to address acute painful neuropathy resulting from rapid improvement of blood glucose control in adults with type 1 diabetes.

• If simple analgesia does not provide sufficient pain relief for adults with type 1 diabetes who have acute painful neuropathy resulting from rapid improvement
  of blood glucose control, treatments for neuropathic pain should be offered (see above).

Prognosis¹⁴¹⁵

• Autonomic neuropathy is associated with a high mortality rate, mainly due to its association with chronic kidney disease, cardiopathy and hypotension.

• Diabetic peripheral neuropathy is a major cause of morbidity and increased mortality and increases the risk of burns, injuries and foot ulceration¹⁶.

• People with diabetes are more likely to undergo lower limb amputation.

Prevention

• Tight glycaemic control has been clearly shown to reduce the risk of neuropathy.

• Smoking avoidance or cessation.