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diabetic neuropathy

Etiology: risk factors [4] 1) longer duration of diabetes mellitus 2) poor glycemic control 3) increased serum triglycerides 4) increased body-mass index 5) smoking 6) hypertension 7) intensive treatment of poorly-controlled diabetes (diabetes type 1 or diabetes type 2) [10] 8) metformin may increase risk of diabetic neuropathy by diminishing plasma vitamin B12 [12] 9) prediabetes not a risk factor [13] Epidemiology: 1) most common form of peripheral neuropathy 2) more than 50% of patients with diabetes develop peripheral neuropathy [18] Pathology: 1) sensorimotor neuropathy a) decreased motor & sensory nerve conduction velocity & amplitude b) demyelination & axonal damage c) C-fibers in particular affected d) small & large sensory nerve fibers affected [2] e) distal motor nerver fibers less affected [2] 2) affects nerve roots as well as peripheral nerves (radiculopathy) 3) autonomic neuropathy 4) small fiber neuropathy 5) may be role for AKR1B1 (aldehyde reductase) 6) diminished sweat gland innervation correlates with severity of neuropathy [9] 7) different forms of neuropathy may coexist in the same patient Physical examination: - assessment for distal symmetric diabetic polyneuropathy - at onset in type 2 diabetes - within 5 years in type 1 diabetes [21] - examine feet for ulcerations & other lesions - monofilament exam of the diabetic foot is 67% sensitive in predicting ulceration in the next 3-4 years (see diabetic foot) - vibration sensation using a 128-Hz tuning fork [21] Clinical manifestations: 1) predominantly sensory neuropathy - neuropathic pain, paresthesias often worst at night [24] 2) stocking-glove or radicular distribution (symmetric) 3) generally occurs early in the course of diabetes [3] 4) early painful dysesthesias may give way to hypesthesia [3] 5) bilateral loss of sensation a) pain b) touch c) temperature d) proprioception 6) minimal weakness, except weakness of intrinsic muscles of the feet - exception is diabetic amyotrophy - distal weakness may be observed in advanced disease 7) may present as mononeuropathy, most often median nerve or ulnar nerve 8) loss of pressure, pain & temperature sensation 9) loss of ankle reflex [2] 10) manifestations of autonomic neuropathy a) diabetic gastroparesis b) alternating diarrhea & constipation c) urinary incontinence or retention d) impotence, erectile dysfunction e) orthostatic hypotension without reflex tachycardia f) loss of hypoglycemic awareness g) hyperhidrosis or hypohydrosis h) sudden death 11) cranial neuropathy (especially isolated cranial nerve 6) [2] Laboratory: 1) increased glycosylated proteins - hemoglobin A1c in blood 2) advanced glycosylation end products or pigments (AGE) 3) increased sorbitol 4) decreased myoinositol 5) complete blood count 6) serum vitamin B12 [12] - unnecessary with classic presentation of symmetric distal polyneuropathy, normal complete blood count & discontinuation of metformin [2] Special laboratory: - nerve conduction studies & EMG unnecessary for patients with classic symptoms [2] Management: 1) improved glycemic control [2,26] a) neuropathy is 60% less common in tightly-controlled diabetics b) near-normal glycemia prevents (type 1 diabetes) or retards neuropathy (type 2 diabetes) c) metformin may exacerbate diabetic neuropathy d) GRS8 says not effective for pain control [3] 2) frequent foot examinations - screening test for loss of pressure sensation 3) pharmaceutical agents for dysesthesia* a) pregabalin or duloxetine 1st-line therapy [21] but evidence not strong (see below) - gabapentin & pregabalin predispose elderly to falls [28] - combinations of pregabalin with duloxetine or amitrityline equally effective [32] b) tricyclic antidepressants (TCA) are the most effective [8] 1] avoid in patients with cardiovascular disease, arrhythmias [2] - risk of arrhythmias, heart block, & sudden death [2] 2] amitriptyline 10-25 mg QHS - up to 150 mg (amitriptyline or desipramine) for painful neuropathy 3] desipramine 10-25 mg QHS 4] tricyclic antidepressants predispose elderly to falls [28] c) anticonvulsants - valproate - carbamazepine - gabapentin (Neurontin) [2,3] - pregabalin (Lyrica) [5] - effective when gabapentin not tolerated [3] - FDA-approved for diabetic neuropathy whereas gabapentin is not [17] - number needed to treat is 5 [3] - venlafaxine or duloxetine superior to pregabalin [17] d) serotonin-norepinephrine reuptake inhibitors (SNRIs) atypical antidepressants 1] duloxetine (Cymbalta) (seems to be favorate of ref [2]) 2] venlafaxine can be added to gabapentin [11] e) amitriptyline, pregabalin & duloxetine of similar efficacy 1] cognitive function slightly worse with pregabalin 2] adverse effects (particularly fatigue, dizziness, & somnolence) more common with pregabalin 3] duloxetine associated with insomnia [14] 4] doses needed for duloxetine & pregabalin may be twice that of the FDA-approved maximal doses for diabetic neuropathy [14] f) serotonin-reuptake inhibitor (SSRI) - paroxetine [2] g) capsaicin topical [2,11] h) SNRIs or TCAs reduce pain more than anticonvulsants or capsaicin [17] i) mexiletine j) topiramate may be of benefit in some patients k) salsalate is an anti-inflammatory agent that lowers HgbA1c l) duloxetine, venlafaxine, pregabalin, oxcarbazepine, TCAs, atypical opioids (tapentadol), & botulinum toxin all more effective than placebo [22] m) opiates should be reserved for patients who fail other treatment modalities [5] n) alpha-lipoic acid 600 mg QD of no benefit [6] 4) electrical stimulation - transcutaneous electrical stimulation [11] - implantable spinal cord stimulation at 10 kHz (high frequency) + medical management > 75% effective in reducing pain over 6 months [29] - HFX spinal cord stimulation FDA-approved - Proclaim XR spinal cord stimulation FDA-approved [33] 5) control modifiable risk factors a) exercise [2] b) management of dyslipidemia [2] c) management of weight, obesity [2] 6) orthostatic hypotension - volume expansion with salt & fludrocortisone (Florinef) * evidence for comparative effectiveness is not strong [17] * adverse effects problematic with virtually all agents [17]

Related

diabetes mellitus diabetic gastroparesis

Specific

diabetic amyotrophy/lumbar polyradiculopathy; diabetic lumbosacral radiculoplexus neuropathy (DLRPN) diabetic mononeuropathy diabetic polyneuropathy

General

microvascular complication of diabetes mellitus peripheral nerve disease; peripheral neuropathy chronic neurologic disease

References

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  13. Journal Watch, April 4, 2012, Massachusetts Medical Society - Callaghan BC et al. The evaluation of distal symmetric polyneuropathy: A physician survey of clinical practice. Arch Neurol 2012 Mar; 69:339 PMID: 22083798 - Dyck PJ et al. Impaired glycemia and diabetic polyneuropathy: The OC IG Survey. Diabetes Care 2012 Mar; 35:584 PMID: 22355020
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