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EsaMervaala
MillaRosengård-Bärlund

Diabetic Neuropathy

Essentials

  • The diagnosis of diabetic neuropathy is based on the diagnosis of diabetes, typical symptoms and clinical findings, as well as exclusion of other causes leading to neuropathy.
  • Neuropathy that affects the large fibres can be verified objectively by ENMG Clinical Neurophysiology in Diagnostics and small fibre neuropathy by quantitative sensory threshold testing or skin biopsy.
  • Diabetic neuropathy may be the first sign of type 2 diabetes or impaired glucose tolerance.
  • Up to 50% of cases of diabetic neuropathy are asymptomatic.
  • The loss of protective sensation as a consequence of peripheral neuropathy is the most important risk factor of diabetic foot ulcer.
  • Diabetic neuropathy increases morbidity and mortality.
  • It is important to identify neuropathy early and possibly prevent developing neuropathy.

Epidemiology

  • At least 50% of all patients with diabetes develop some manifestation of neuropathy as a late complication
    • As symptomatic in approximately 30%
    • As subclinical in 75-80%, i.e. it can be detected in clinical examination or as abnormalities in ENMG
    • 13-35% of all patients with diabetes and 30-50% of patients with diabetic neuropathy have neuropathic pains.
    • Painful small fibre neuropathy may develop in 10-30% already during prediabetes.
  • The prevalence of neuropathy increases with patient's age and duration of diabetes.

Distal symmetric polyneuropathy

  • By far the most common form of neuropathy: accounts for 80-90% of all neuropathies associated with diabetes.
  • Occurs in approximately 30-50% of all patients with diabetes.
  • Usually neuropathy associated with diabetes has features of both small fibre and large fibre neuropathies.

Symptoms

  • Pains beginning predominantly distally, paraesthesias, dysaesthesias and restless legs are common, but some neuropathic patients may be symptomless.
  • Together with the decreased sensation, paradoxical sensory hypersensitivity may also occur.

Findings

  • Sensory disturbances
    • Vibration and position sense in lower limbs are affected at first, other sensory modalities later on. Sense of touch is investigated with monofilament examination (picture 2). The monofilament examination is predictive of diabetic foot ulcers at least equally well as vibration perception treshold testing.
  • Tendon reflex deficits
    • The achilles tendon reflex is the first to become diminished or absent.
  • Postural and loading abnormalities of the foot
    • Sensory disturbance associated with sensory neuropathy predisposes to skin injuries. As the protective sensation is lacking, the patient may continue loading the already injured area.
    • Also dryness of skin and its cracks, caused by autonomic neuropathy, predispose to skin injuries.
    • As the neuropathy progresses, motor neuropathy may lead to postural abnormalities of the foot.
    • Motor neuropathy may also cause ataxia and balance difficulties and thus increase the risk of falls and fractures.
    • Charcot neuroarthropathy is a severe complication of diabetic neuropathy.
    • See also Treatment of the Diabetic Foot Polyneuropathies.

Diagnosis

  • The diagnosis is based on typical symptoms and signs. Symmetric, glove and stocking sensory loss which usually can be detected with monofilament examination.
  • In typical diabetic peripheral neuropathy, an ENMG examination is not required. ENMG may be needed in differential diagnosis, for example in the case of asymmetric or rapidly progressing symptoms or if a more precise picture of the severity of the neuropathy is needed.

Differential diagnosis

  • See also Polyneuropathies Polyneuropathies.
  • The symptoms of diabetic polyneuropathy do not differ from the symptoms of other neuropathies. Conditions that should be ruled out include e.g. deficiency of vitamin B12 and folate, excessive alcohol consumption, renal failure and hypothyroidism.
  • The aetiology is often multifactorial.

Small fibre neuropathy

  • Often the first manifestation of diabetic neuropathy
  • Typical symptoms include burning pain and paraesthesias in the feet as well as disturbances in the sensation of cold and warm
  • Increases the risk of foot ulcers, gangrene and amputations.
  • May already be present in prediabetes (elevated fasting glucose or impaired glucose tolerance). If a patient has symptoms of small fibre neuropathy, it is recommended to perform a 2-hour oral glucose tolerance test.
  • In a small share of patients, a rapid correction of hyperglycaemia that has lasted long is associated with small fibre neuropathy. It may occur in any type of diabetes (including a new diagnosis) and irrespective of the hyperglycaemia treatment method. Symptoms typically start 2-8 weeks after the correction of glucose balance and slowly resolve within 1-2 years.
  • The diagnosis of small fibre neuropathy is based on typical symptoms. It is confirmed, as necessary, by quantifying intraepidermal nerve fibers density in a skin biopsy or by quantitative sensory threshold testing.

Mononeuropathies and other rarer forms of diabetic neuropathy

  • Mononeuropathies caused by diabetes include:
    • Painful neuropathy of the femoral nerve, causing weakness of the quadriceps muscle, which resolves spontaneously
    • Mononeuropathy of the facial area
    • Diabetic ophthalmoplegia, a paresis of nerves that move the eye, resulting in diplopia as a symptom.
    • Disturbances may also occur in other peripheral nerves as single or multiple mononeuropathies. These are usually resolved within weeks or months.
  • Mononeuritis may cause girdle pain or muscular weakness in the abdominal or chest area (truncal radiculopathy). Diabetic amyotrophy causes reduced muscle strength and pain in the thigh region.
  • Possible nerve entrapment and radicular symptoms originating from the back should be kept in mind as differential diagnostic options.
  • Patients with diabetes have an increased risk to develop painful nerve entrapments. Carpal tunnel syndrome is the most common of these.

Autonomic neuropathy

  • Cardiovascular autonomic neuropathy is often subclinical and, nevertheless, one of the most serious complications of diabetes.

Symptoms and findings

  • Diminished or abolished pulse rate variability
  • Orthostatic hypotension
  • Disturbances in intestinal function, diarrhoea, constipation
  • Disturbances in gastric motility, gastroparesis, nausea after meals as well as wide variation in the patient's blood glucose levels
  • Urinary disturbances
  • Erectile dysfunction
  • Sweating disturbances
  • Weakening or disappearance of hypoglycaemic symptoms

Diagnosis

  • History (symptoms, control of diabetes, other possible underlying factors)
  • Clinical examination
    • In the orthostatic test, the systolic blood pressure decreases more than 20 mmHg and/or a rise in pulse rate is absent Brief Orthostatic Test.
    • A resting pulse rate above 90/min may be suggestive of autonomic neuropathy.
    • If gastroparesis is suspected, it is essential to rule out mechanical obstruction with gastroscopy and, as necessary, MRI of the small intestine. In unclear cases, slowed gastric emptying can be confirmed with double-isotope scintigraphy.
  • The diagnosis of cardiovascular autonomic neuropathy can be confirmed with tests of the autonomic nervous system, which include, for example, decrease of pulse rate variability during forced inhalation and exhalation and the orthostatic test Brief Orthostatic Test.

Treatment of diabetic neuropathy Antidepressants for Neuropathic Pain, Tramadol for Neuropathic Pain, Opioids for Neuropathic Pain, Anticonvulsants for Diabetic Neuropathy

  • Optimal glucose balance is the basis of the prevention and treatment of neuropathy since no drug has been shown to slow down the development of neuropathy or heal already occurred nerve damage.
  • Treatment of all risk factors of cardiovascular diseases in their own right prevents neuropathy Comprehensive Treatment and Follow-Up of Type 2 Diabetes.
  • Diabetic mononeuropathy, radiculopathy and painful smallfibre neuropathy associated with rapid correction of glucose balance usually resolve spontaneously.
  • First-line drugs in the treatment of neuropathic pain comprise tricyclic antidepressant, pregabalin and gabapentin. If these do not help or are unsuitable, it is worthwhile to try with tramadol, duloxetine or venlafaxine. If even these prove ineffective and the pain is difficult to cope with, a therapeutic trial with strong opioids should be considered. See also Chronic Pain (e.g., the use of strong opioids).
  • Relaxation exercises and transcutaneous nerve stimulation (TNS) may help some patients.
  • The treatment of autonomic neuropathy is usually symptomatic.
    • In orthostatic hypotension, any medication affecting the vascular system should be optimized and sufficient fluid volume should be taken care of. Treatments include compression stockings, venous tone increasing etilefrine, midodrine and, in severe situations a mineralocorticoid (fludrocortisone).
    • Treatment of gastroparesis comprises nutritional counselling. Pharmacotherapy consists of metoclopramide or low-dose erythromycin. In selected cases, neurostimulation therapy may be beneficial.
    • For treatment of impotence, see Erectile Dysfunction.
  • Smoking and large quantities of alcohol may aggravate neuropathy.
  • Treatment of risk factors for atherosclerosis will also decrease the patient's risk of developing neuropathy.

    References

    • Jensen TS, Karlsson P, Gylfadottir SS et al. Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management. Brain 2021;144(6):1632-1645. [PubMed]
    • Feldman EL, Callaghan BC, Pop-Busui R et al. Diabetic neuropathy. Nat Rev Dis Primers 2019;5(1):41. [PubMed]
    • Patel K, Horak H, Tiryaki E. Diabetic neuropathies. Muscle Nerve 2021;63(1):22-30. [PubMed]
    • Callaghan BC, Cheng HT, Stables CL et al. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol 2012;11(6):521-34. [PubMed]
    • Vinik AI, Nevoret ML, Casellini C et al. Diabetic neuropathy. Endocrinol Metab Clin North Am 2013;42(4):747-87. [PubMed]
    • Pop-Busui R, Boulton AJ, Feldman EL et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care 2017;40(1):136-154. [PubMed]
    • Finnerup NB, Attal N, Haroutounian S et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14(2):162-73. [PubMed]
    • Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol 2021;17(7):400-420. [PubMed]