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Etiology, Pathogenesis, Clinical Features, DiagnosisTop
Diabetic neuropathy is the most frequent chronic complication of diabetes mellitus. 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. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes mellitus and may be treatable. Diabetic neuropathy is classified as peripheral or autonomic.
1. Diabetic peripheral neuropathy: The most frequent type manifests with paresthesia and dysesthesia of the hands and feet, painful muscle cramps and acute pain attacks, superficial and deep sensory deficits, muscle weakness, hyporeflexia or areflexia, trophic changes, and autonomic disturbances. The symptoms are chronic, not related to exercise, and usually worsen at night. Up to 50% of diabetic peripheral neuropathy may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet.
Diabetic peripheral neuropathy classification:
1) Distal symmetric polyneuropathy, which is further classified as small-fiber and large-fiber dysfunction. To assess the involvement of small and large fibers, one may test:
a) Small-fiber function: Pinprick and temperature sensation.
b) Large-fiber function: Vibration perception, ankle reflex, and proprioceptive sensation.
2) Proximal motor neuropathy.
3) Acute mononeuropathies.
4) Entrapments (carpal tunnel syndrome).
5) Painful neuropathy (chronic pain not related to exercise, usually worsening at night).
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 s using a force that causes bending of the monofilament), testing the sense of vibration, recommended every 6-12 months, 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 the 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 and electromyography may be performed.
2. Diabetic autonomic neuropathy:
1) Involving the cardiovascular system: The key features are orthostatic hypotension and syncope. Diagnostic study performed is the Ewing cardiovascular test battery that detects the absence of heart rate variability on deep respiration, getting up, and Valsalva maneuver, as well as orthostatic hypotension when standing up, or the absence of blood pressure increase on a dynamometer squeeze.
2) Involving the gastrointestinal (GI) system: This usually manifests as delayed gastric emptying. Diagnostic studies include contrast barium studies, gastric ultrasonography, GI manometry, electrogastrography, and radionuclide studies (to assess gastric contents retention).
3) Involving the genitourinary system: One of the most frequent causes of erectile dysfunction that is seen in ~50% of men with diabetes. In women, it may result in vaginal dryness and loss of libido. It also causes urinary retention (this is assessed using ultrasonography performed after voiding).
4) Other, which may involve the eyes (including abnormal pupil reactions to light) as well as abnormal perspiration, taste, and salivation.
1. Good diabetes control is of key importance. Avoid hypoglycemia, particularly for primary prevention. Consider using an angiotensin-converting enzyme inhibitor only when blood pressure does not meet the target level (140/90 mm Hg).
2. Symptomatic treatment of painful polyneuropathy:
1) Treatment of neuropathic pain: see Pain in Patients With Cancer. There is uncertainty regarding the first-line therapy; however, it may include antiepileptic drugs (pregabalin 150-600 mg/d, gabapentin 900-1800 mg/d), tricyclic antidepressants (amitriptyline 25-150 mg/d), and opioids (eg, tramadol).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. 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 short-term alternatives if the 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.
3. Symptomatic treatment of autonomic neuropathy:
1) Syncope: see Syncope and Other Causes of Transient Loss of Consciousness.
2) Gastroparesis: Nutritional management (frequent small-volume meals; in severe cases a semiliquid or liquid diet), prokinetic drugs (eg, domperidone, metoclopramide), erythromycin, and proton pump inhibitors (PPIs) (see Peptic Ulcer Disease). Prokinetic agents should be used at the lowest doses and for the shortest duration possible, generally not exceeding 3 months. In patients with severe gastroparesis, surgical treatment and stimulation of gastric bioelectrical activity can be considered.
3) 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.
4) Atonic bladder: Avoidance of urine retention, parasympathomimetic drugs (eg, bethanechol), catheterization (an intermittent or indwelling catheter).
5) Erectile dysfunction: Phosphodiesterase type 5 inhibitors (avanafil, sildenafil, tadalafil, vardenafil). Note the interactions with nitrates in patients with coronary heart disease.
6) Abnormal perspiration: Botulinum toxin, vasodilator drugs, moisturizing creams.