Diabetic Neuropathy

Etiology, Pathogenesis, Clinical FeaturesTop

Diabetic neuropathy is the most frequent chronic complication of diabetes mellitus (DM), present in 20% of patients with type 1 DM after 20 years of disease duration and in 10% to 15% of newly diagnosed patients with type 2 DM (50% after 10 years of disease duration). Metabolic abnormalities and changes in blood vessels supplying the nerves result in segmental demyelination, axonal atrophy and degeneration, and atrophy of neurons of the anterior horns and intervertebral ganglia; they may be accompanied by features of neuronal regeneration and changes in blood vessels supplying the nerves. Causative factors include persistent hyperglycemia, microvascular insufficiency, oxidative stress and nitrosative stress (related to an excess of nitric oxide), defective neurotropism, and autoimmune-mediated nerve destruction.

Diabetic neuropathy is a diagnosis of exclusion. The most important differential diagnoses include neuropathies caused by alcohol abuse, uremia, hypothyroidism, vitamin B12 deficiency, peripheral arterial disease, cancer, inflammatory and infectious diseases, and use of neurotoxic drugs. Nondiabetic neuropathies may be present in patients with DM and may be treatable. Nondiabetic neuropathies common in DM include pressure palsies, chronic inflammatory demyelinating polyneuropathy, radiculoplexus neuropathy, and treatment-induced, acute, painful small-fiber neuropathies.

Diabetic neuropathy is classified as peripheral or autonomic.

1. Diabetic peripheral neuropathy: The most frequent type of diabetic neuropathy. Up to 50% of patients may be asymptomatic. The most common symptoms include paresthesia and dysesthesia of the hands and feet, neuropathic pain (burning, lancinating, tingling, or shooting), painful muscle cramps and acute pain attacks, superficial and deep sensory deficits (anesthesia, hyperalgesia or allodynia), muscle weakness, hyporeflexia or areflexia, trophic changes, and autonomic disturbances. The symptoms are chronic, not related to exercise, and usually worsen at night. The loss of protective sensation indicates the presence of distal sensorimotor polyneuropathy, which is considered a risk factor for diabetic foot ulceration. If this is not recognized and if preventive foot care is not implemented, patients are at risk for injuries to and infection of their insensate feet. Diabetic peripheral neuropathy has also been strongly associated with falls and fractures.

Classification of diabetic peripheral neuropathy:

1) Distal symmetric polyneuropathy: Accounting for 75% of cases of diabetic neuropathies, distal symmetric polyneuropathy is also the most important cause in the development of foot ulcers. It is defined by the presence of distal symmetric symptoms, signs of peripheral nerve dysfunction, or both, in patients with DM after other causes have been excluded. It is classified as primarily small-fiber, primarily large-fiber, and mixed small-fiber and large-fiber neuropathy. Tests for assessing the involvement of small and large fibers:

a) Small-fiber function: Pinprick and temperature sensation.

b) Large-fiber function: Vibration perception, ankle reflex, proprioceptive sensation, and 10-g monofilament testing.

2) Mononeuropathy: Isolated cranial or peripheral (cranial neuropathies, carpal tunnel syndrome, and ulnar, femoral, or peroneal entrapment) and mononeuritis multiplex. These are more prevalent in the older population, have an acute onset with localized pain, and a self-limiting course with resolution in 6 to 8 weeks.

3) Radiculopathy or polyradiculopathy: Radiculoplexus neuropathy (lumbosacral polyradiculopathy, proximal motor amyotrophy) and thoracic radiculopathy. Proximal motor amyotrophy primarily affects the elderly and most commonly men, has an acute or gradual onset, and usually manifests with severe pain in the thighs, hips, and buttocks followed by significant weakness of the proximal muscles of the lower limbs and inability to rise from the sitting position.

Assessment of peripheral neuropathy should be performed at diagnosis of type 2 DM and after 5 years of postpubertal duration of type 1 DM. Follow-up should be done every 6 to 12 months. Diagnostic studies include assessment of the sense of touch (plantar) using a 10-g monofilament (eg, Semmes-Weinstein 5.07 monofilament applied at selected locations on the foot for ~1.5 second using a force that causes bending of the monofilament), testing the sense of vibration with a tuning fork (128 Hz, applied at the lateral malleolus and medial malleolus, superior portion of the tibia, and bases of the big toe and fifth toe), and testing the sense of temperature using a double-tipped metal or plastic probe. When previous tests are inconclusive and another type of neuropathy is suspected, nerve conduction studies (NCS) and electromyography (EMG) may be performed. Atypical features include motor greater than sensory neuropathy, rapid onset, or asymmetric presentation.

2. Diabetic autonomic neuropathy: Major clinical manifestations include hypoglycemia unawareness, resting tachycardia, orthostatic hypotension, gastroparesis, constipation, diarrhea, neurogenic bladder, and sudomotor dysfunction with either increased or decreased sweating.

1) Involving the cardiovascular system: Associated with cardiovascular mortality, arrhythmia, silent ischemia, myocardial dysfunction, and any major cardiovascular event independently of other cardiovascular risk factors. The key features are orthostatic hypotension (a fall in systolic blood pressure by >20 mm Hg or in diastolic blood pressure >10 mm Hg upon standing up from a supine position without an appropriate increase in heart rate), syncope, resting tachycardia (>100 beats/min), and sudden death (malignant arrhythmia). The diagnostic study performed is the Ewing cardiovascular test battery, which detects absence of heart rate variability on deep respiration, getting up, and Valsalva maneuver, as well as orthostatic hypotension when standing up from a supine position, or absence of blood pressure increase on squeezing a dynamometer.

2) Involving the gastrointestinal (GI) system: This usually manifests as delayed gastric emptying, esophageal dysmotility, gastroparesis, constipation, diarrhea, and/or fecal incontinence. Diagnostic workup includes contrast barium studies, gastric ultrasonography, gastrointestinal manometry, electrogastrography, and radionuclide gastric emptying study (to assess retention of gastric contents). Consider upper GI endoscopy to exclude organic causes of gastric outlet obstruction or peptic ulcer disease before considering specialized testing for gastroparesis.

3) Involving the genitourinary system: One of the most frequent causes of erectile dysfunction (ED) and/or retrograde ejaculation, which is seen in ~50% of men with DM. In women it may result in vaginal dryness (increased pain during intercourse, decreased sexual arousal, inadequate lubrication) and loss of libido. Consider hormonal evaluation to exclude hypogonadism in men with symptoms of low libido or with ED refractory to pharmacologic treatments. Urogenital neuropathy also causes urinary retention (this is assessed using ultrasonography performed after voiding), urinary incontinence, and bladder dysfunction (nocturia, frequent urination, urination urgency, weak urinary stream). Urodynamic studies may also be considered if the diagnosis is unclear. All patients with recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder should be assessed for the presence of neuropathy.

4) Other, which may involve the eyes (including abnormal pupil reactions to light) as well as sudomotor dysfunction (distal hypohidrosis/anhidrosis, abnormal perspiration, and gustatory sweating).

Assessment of autonomic neuropathy should be done in all patients with microvascular and neuropathic complications. Recognition and treatment of autonomic neuropathy may improve symptoms, reduce sequelae, and improve quality of life.

TreatmentTop

1. Good DM control and lifestyle modifications (exercise and healthy dietary plan) are of key importance for all patients. Glucose control has been shown to prevent diabetic peripheral neuropathy and cardiac autonomic neuropathy in type 1 DM and to modestly slow their progression in type 2 DM without reversal of neuronal loss. Avoid hypoglycemia, particularly for primary prevention. Consider using an angiotensin-converting enzyme inhibitor (ACEI) only when blood pressure does not meet the target level (130/80 mm Hg) or other indications for ACEIs. Evaluate the risk of falls by assessing gait and balance, cognitive function, concomitantly used drugs, and presence of neuropathic pain.

2. Symptomatic treatment of painful polyneuropathy:

1) Treatment of neuropathic pain: Table 1 (also see Pain Management: Basic Principles). Pregabalin (300-600 mg/d) and duloxetine (60-120 mg/d) are both approved by the United States Food and Drug Administration (FDA), Health Canada, and the European Medicines Agency for the treatment of neuropathic pain in DM. Other therapies include antiepileptic drugs (gabapentin 900-3600 mg/d), tricyclic antidepressants (amitriptyline 25-100 mg/d, imipramine 25-150 mg/d, nortriptyline 50-150 mg/d, desipramine 25-150 mg/d), certain opioids (tramadol, tapentadol), venlafaxine (75-225 mg/d), carbamazepine, and topical capsaicin or nitrates.Evidence 1Weak recommendations (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due the risk of bias, imprecision, and indirectness (lack of long-term data). Bril V, England J, Franklin GM, et al; American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011 May 17;76(20):1758-65. doi: 10.1212/WNL.0b013e3182166ebe. Epub 2011 Apr 11. Review. Erratum in: Neurology. 2011 Aug 9;77(6):603. Dosage error in article text. PubMed PMID: 21482920; PubMed Central PMCID: PMC3100130. American Diabetes Association. 11. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019 Jan;42(suppl 1):S124-S138. doi: 10.2337/dc19-S011. Review. PubMed PMID: 30559237. Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017 Jan;40(1):136-154. doi: 10.2337/dc16-2042. Review. PubMed PMID: 27999003. Vinik AI, Nevoret ML, Casellini C, Parson H. Diabetic neuropathy. Endocrinol Metab Clin North Am. 2013 Dec;42(4):747-87. doi: 10.1016/j.ecl.2013.06.001. Review. PubMed PMID: 24286949. Carbone F, Van den Houte K, Clevers E, et al. Prucalopride in Gastroparesis: A Randomized Placebo-Controlled Crossover Study. Am J Gastroenterol. 2019 Aug;114(8):1265-1274. doi: 10.14309/ajg.0000000000000304. PMID: 31295161. Chan YC, Lo YL, Chan ES. Immunotherapy for diabetic amyotrophy. Cochrane Database Syst Rev. 2017 Jul 26;7(7):CD006521. doi: 10.1002/14651858.CD006521.pub4. PMID: 28746752; PMCID: PMC6483238. Cavalli E, Mammana S, Nicoletti F, Bramanti P, Mazzon E. The neuropathic pain: An overview of the current treatment and future therapeutic approaches. Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738419838383. doi: 10.1177/2058738419838383. PMID: 30900486; PMCID: PMC6431761. Nonsteroidal anti-inflammatory drugs (eg, oral ibuprofen 400-800 mg tid, oral naproxen 500 mg bid) or acetaminophen (INN paracetamol) (1 g orally tid) are only short-term alternatives if pain is too intense.

2) Alpha-lipoic acid (INN thioctic acid) 600 mg/d IV for the first 2 to 4 weeks followed by oral administration may be tried as an alternative. It may be useful in reduction of oxidative stress-induced nerve damage exacerbated by chronic hyperglycemia.

3. Symptomatic treatment of autonomic neuropathy:

1) Syncope: see Syncope and Other Causes of Transient Loss of Consciousness.

2) Orthostatic hypotension: Nonpharmacologic and pharmacologic measures are used. Patients should stand up and rise slowly, ensure adequate fluid and salt intake, and avoid medications that aggravate hypotension. Compressive garments over the legs and abdomen may be used. Other measures include keeping the head of the bed elevated at 30 degrees, dorsiflexion of the ankles, and avoiding hot showers. Pharmacologic options include fludrocortisone, midodrine, and droxidopa.

3) Gastroparesis: Nutritional management and referral to a dietitian (a low-fiber, low-fat eating plan with frequent small-volume meals and foods with small particle size; in severe cases a semiliquid or liquid diet), prokinetic drugs (eg, domperidone, metoclopramide), erythromycin, and prucalopride can be used. Newer studies provided evidence for prucalopride, a 5-HT4 receptor agonist used for constipation, to improve gastric emptying rate and symptoms. Prokinetic agents should be used at the lowest doses and for the shortest duration, if possible. Avoid drugs with adverse effects on GI motility (opioids, anticholinergics, tricyclic antidepressants, glucagon-like peptide-1 [GLP-1] receptor agonists, and pramlintide). In patients with severe gastroparesis, surgical treatment and stimulation of gastric bioelectrical activity/gastric pacing can be considered. In certain severe cases enteral feeding or total parenteral nutrition may be needed.

4) Abnormal intestinal motility: Nutritional management (eg, gluten-free diet, lactose restriction), cholestyramine, clonidine, octreotide, antidiarrheal drugs (loperamide), pancreatic enzymes, antibiotics; each may be tried if other interventions fail despite the lack of convincing evidence of efficacy.

5) Atonic bladder: Avoidance of urine retention, parasympathomimetic drugs (eg, bethanechol), catheterization (an intermittent or indwelling catheter).

6) ED: Phosphodiesterase-5 (PDE-5) inhibitors (avanafil, sildenafil, tadalafil, vardenafil). Patients using nitrates for underlying coronary heart disease should not use PDE-5 inhibitors since they can lead to severe hypotension. Consider intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses in advanced cases through referral to a urologist.

7) Sudomotor dysfunction: Botulinum toxin, vasodilator drugs, moisturizing creams, and topical antimuscarinic agents (glycopyrrolate).

4. Symptomatic treatment of atypical neuropathies:

1) Mononeuropathies: Cranial neuropathies usually resolve spontaneously over several months. Nerve entrapments may require surgical decompression. In both cases anti-inflammatory medications and glucocorticoid injections may be needed in selected patients.

2) Diabetic radiculoplexus neuropathy, also known as diabetic amyotrophy: Typically presents with acute, asymmetric, focal onset of pain and weakness involving the proximal legs, along with weight loss and autonomic failure. Usually self-limiting, with improvement in symptoms with medical management and physical therapy. In severe cases immunosuppressants such as oral prednisone, IV methylprednisolone, and IV immunoglobulins (IVIGs) can be used; however, the evidence remains limited.

TablesTop