diabetic neuropathy
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Etiology
risk factors[4]
- longer duration of diabetes mellitus
- poor glycemic control
- increased serum triglycerides
- increased body-mass index
- smoking
- hypertension
- intensive treatment of poorly-controlled diabetes (diabetes type 1 or diabetes type 2)[10]
- metformin may increase risk of diabetic neuropathy by diminishing plasma vitamin B12[12]
- prediabetes not a risk factor[13]
Epidemiology
- most common form of peripheral neuropathy
- more than 50% of patients with diabetes develop peripheral neuropathy[18]
Pathology
- sensorimotor neuropathy
- decreased motor & sensory nerve conduction velocity & amplitude
- demyelination & axonal damage
- C-fibers in particular affected
- small & large sensory nerve fibers affected[2]
- distal motor nerver fibers less affected[2]
- affects nerve roots as well as peripheral nerves (radiculopathy)
- autonomic neuropathy
- small fiber neuropathy
- may be role for AKR1B1 (aldehyde reductase)
- diminished sweat gland innervation correlates with severity of neuropathy[9]
- 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
- predominantly sensory neuropathy
- neuropathic pain, paresthesias often worst at night[24]
- stocking-glove or radicular distribution (symmetric)
- generally occurs early in the course of diabetes[3]
- early painful dysesthesias may give way to hypesthesia[3]
- bilateral loss of sensation
- pain
- touch
- temperature
- proprioception
- minimal weakness, except weakness of intrinsic muscles of the feet
- exception is diabetic amyotrophy
- distal weakness may be observed in advanced disease
- may present as mononeuropathy, most often median nerve or ulnar nerve
- loss of pressure, pain & temperature sensation
- loss of ankle reflex[2]
- manifestations of autonomic neuropathy
- diabetic gastroparesis
- alternating diarrhea & constipation
- urinary incontinence or retention
- impotence, erectile dysfunction
- orthostatic hypotension without reflex tachycardia
- loss of hypoglycemic awareness
- hyperhidrosis or hypohydrosis
- sudden death
- cranial neuropathy (especially isolated cranial nerve 6)[2]
Laboratory
- increased glycosylated proteins
- advanced glycosylation end products or pigments (AGE)
- increased sorbitol
- decreased myoinositol
- complete blood count
- serum vitamin B12[12]
- unnecessary with classic presentation of symmetric distal polyneuropathy, normal complete blood count & discontinuation of metformin[2]
Diagnostic procedures
- nerve conduction studies & EMG unnecessary for patients with classic symptoms[2]
Management
- improved glycemic control[2][26]
- neuropathy is 60% less common in tightly-controlled diabetics
- near-normal glycemia prevents (type 1 diabetes) or retards neuropathy (type 2 diabetes)
- metformin may exacerbate diabetic neuropathy
- GRS8 says not effective for pain control[3]
- frequent foot examinations
- screening test for loss of pressure sensation
- pharmaceutical agents for dysesthesia*
- 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]
- tricyclic antidepressants (TCA) are the most effective[8]
- avoid in patients with cardiovascular disease, arrhythmias[2]
- risk of arrhythmias, heart block, & sudden death[2]
- amitriptyline 10-25 mg QHS
- up to 150 mg (amitriptyline or desipramine) for painful neuropathy
- desipramine 10-25 mg QHS
- tricyclic antidepressants predispose elderly to falls[28]
- avoid in patients with cardiovascular disease, arrhythmias[2]
- 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]
- serotonin-norepinephrine reuptake inhibitors (SNRIs) atypical antidepressants
- duloxetine (Cymbalta) (seems to be favorate of ref[2])
- venlafaxine can be added to gabapentin[11]
- amitriptyline, pregabalin & duloxetine of similar efficacy
- cognitive function slightly worse with pregabalin
- adverse effects (particularly fatigue, dizziness, & somnolence) more common with pregabalin
- duloxetine associated with insomnia[14]
- doses needed for duloxetine & pregabalin may be twice that of the FDA-approved maximal doses for diabetic neuropathy[14]
- serotonin-reuptake inhibitor (SSRI) - paroxetine[2]
- capsaicin topical[2][11]
- SNRIs or TCAs reduce pain more than anticonvulsants or capsaicin[17]
- mexiletine
- topiramate may be of benefit in some patients
- salsalate is an anti-inflammatory agent that lowers HgbA1c
- duloxetine, venlafaxine, pregabalin, oxcarbazepine, TCAs, atypical opioids (tapentadol), & botulinum toxin all more effective than placebo[22]
- opiates should be reserved for patients who fail other treatment modalities[5]
- alpha-lipoic acid 600 mg QD of no benefit[6]
- pregabalin or duloxetine 1st-line therapy[21] but evidence not strong (see below)
- 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]
- control modifiable risk factors
- orthostatic hypotension
- volume expansion with salt & fludrocortisone (Florinef)
* evidence for comparative effectiveness is not strong[17]
* adverse effects problematic with virtually all agents[17]
More general terms
- microvascular complication of diabetes mellitus
- peripheral nerve disease; peripheral neuropathy
- chronic neurologic disease
More specific terms
- diabetic amyotrophy/lumbar polyradiculopathy; diabetic lumbosacral radiculoplexus neuropathy (DLRPN)
- diabetic mononeuropathy
- diabetic polyneuropathy
Additional terms
References
- ↑ Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 1016-18
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - ↑ 4.0 4.1 Journal Watch 25(6):48, 2005 Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu- Tirgoviste C, Witte DR, Fuller JH; EURODIAB Prospective Complications Study Group. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005 Jan 27;352(4):341-50. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15673800
- ↑ 5.0 5.1 5.2 Prescriber's Letter 13(8): 2006 Diabetes Peripheral Neuropathic Pain Treatment Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220807&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 6.0 6.1 Ziegler D et al, Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy. The Sydney 2 trial. Diabetes Care 2006, 29:2365 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17065669
Ziegler D et al. Efficacy and safety of antioxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: The NATHAN 1 Trial. Diabetes Care 2011 Sep; 34:2054 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21775755 - ↑ Advisory on the utility of surgical decompression for treatment of diabetic neuropathy. American Academy of Neurology. Aug 2006 http://www.aan.com/professionals/practice/guidelines/surgicaldecom_article.pdf
- ↑ 8.0 8.1 Wong M-C et al, Effects of treatments for symptoms of painful diabetic neuropathy. Systematic review. BMJ 2007, 335:87 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17562735
- ↑ 9.0 9.1 Gibbons CH et al Quantification of sweat gland innervation: A clinical- pathologic correlation. Neurology 2009 Apr 28; 72:1479. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19398703
- ↑ 10.0 10.1 Gibbons CH and Freeman R. Treatment-induced diabetic neuropathy: A reversible painful autonomic neuropathy. Ann Neurol 2010 Apr; 67:534. PMID: https://www.ncbi.nlm.nih.gov/pubmed/20437589
- ↑ 11.0 11.1 11.2 11.3 Bril V et al Evidence-based guideline: Treatment if painful diabetic neuropathy Neurology. 2011 Apr 11 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/21482920 <Internet> http://www.neurology.org/content/early/2011/04/08/WNL.0b013e3182166ebe.full.pdf+html
- ↑ 12.0 12.1 12.2 Prescriber's Letter 18(6): 2011 CHART: Comparison of Common Meds for Diabetic Neuropathy GUIDELINES: Evidence-based guideline: Treatment of Painful Diabetic Neuropathy (2011) Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=270605&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 13.0 13.1 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: https://www.ncbi.nlm.nih.gov/pubmed/22083798
Dyck PJ et al. Impaired glycemia and diabetic polyneuropathy: The OC IG Survey. Diabetes Care 2012 Mar; 35:584 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22355020 - ↑ 14.0 14.1 14.2 Boyle J et al Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain: Impact on pain, polysomnographic sleep, daytime functioning, and quality of life. Diabetes Care 2012 Dec; 35:2451 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22991449
- ↑ Hovaguimian A, Gibbons CH. Clinical Approach to the Treatment of Painful Diabetic Neuropathy. Ther Adv Endocrinol Metab. 2011 Feb;2(1):27-38 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21709806
- ↑ Tesfaye S, Selvarajah D. The Eurodiab study: what has this taught us about diabetic peripheral neuropathy? Curr Diab Rep. 2009 Dec;9(6):432-4. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19954687
- ↑ 17.0 17.1 17.2 17.3 17.4 17.5 Griebeler ML et al. Pharmacologic interventions for painful diabetic neuropathy: An umbrella systematic review and comparative effectiveness network meta-analysis. Ann Intern Med 2014 Nov 4; 161:639 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25364885
- ↑ 18.0 18.1 Brett AS Peripheral Neuropathy in Patients with Prediabetes NEJM Journal Watch. June 4, 2015 Massachusetts Medical Society (subscription needed) http://www.jwatch.org
Lee CC et al. Peripheral neuropathy and nerve dysfunction in individuals at high risk for type 2 diabetes: The PROMISE cohort. Diabetes Care 2015 May; 38:793 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25665810 <Internet> http://care.diabetesjournals.org/content/38/5/793 - ↑ Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 2012 Jun;11(6):521-34 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22608666
- ↑ Vinik AI CLINICAL PRACTICE. Diabetic Sensory and Motor Neuropathy. N Engl J Med 2016; 374:1455-1464. April 14, 2016 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27074068 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMcp1503948
- ↑ 21.0 21.1 21.2 21.3 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27999003 <Internet> http://care.diabetesjournals.org/content/40/1/136
- ↑ 22.0 22.1 Waldfogel JM, Nesbit SA, Dy SY et al Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life. Neurology. March 24, 2017 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28341643 <Internet> http://www.neurology.org/content/early/2017/03/24/WNL.0000000000003882.short
- ↑ Kanji JN, Anglin RE, Hunt DL, Panju A. Does this patient with diabetes have large-fiber peripheral neuropathy? JAMA. 2010 Apr 21;303(15):1526-32. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/20407062
- ↑ 24.0 24.1 NEJM Knowledge+ Question of the Week. Oct 10, 2017 https://knowledgeplus.nejm.org/question-of-week/1405/
- ↑ Pasnoor M, Dimachkie MM, Kluding P, Barohn RJ. Diabetic neuropathy part 1: overview and symmetric phenotypes. Neurol Clin. 2013 May;31(2):425-45. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23642717 Free PMC Article
Pasnoor M, Dimachkie MM, Barohn RJ. Diabetic neuropathy part 2: proximal and asymmetric phenotypes. Neurol Clin. 2013 May;31(2):447-62. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23642718 Free PMC Article - ↑ 26.0 26.1 Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012 Jun 13;(6):CD007543. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22696371 Free PMC Article
- ↑ NINDS Diabetic Neuropathy Information Page https://www.ninds.nih.gov/Disorders/All-Disorders/Diabetic-Neuropathy-Information-Page
- ↑ 28.0 28.1 28.2 Randolph AC, Lin YL, Volpi E, Kuo YF. Tricyclic antidepressant and/or gamma-aminobutyric acid-analog use is associated with fall risk in diabetic peripheral neuropathy. J Am Geriatr Soc 2019 Jun; 67:1174-1181 PMID: https://www.ncbi.nlm.nih.gov/pubmed/30694557 https://onlinelibrary.wiley.com/doi/abs/10.1111/jgs.15779
- ↑ 29.0 29.1 Monaco K High Frequency Spinal Stimulation Succeeds in Diabetic Neuropathy. Pain relief was significant and durable in SENZA-PDN trial. MedPage Today May 29, 2021 https://www.medpagetoday.com/meetingcoverage/aace/92853
Petersen E, et al Neuromodulation for treatment of painful diabetic neuropathy - sustained benefits of 10kHz spinal cord stimulation in a randomized controlled trial. American Association of Clinical Endocrinology (AACE) 2021. - ↑ Khdour MR. Treatment of diabetic peripheral neuropathy: a review J Pharm Pharmacol. 2020 Jul;72(7):863-872 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32067247 Review.
- ↑ Iqbal Z, Azmi S, Yadav R et al. Diabetic peripheral neuropathy: epidemiology, diagnosis, and pharmacotherapy. Clin Ther. 2018;40(6):828-849 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29709457 https://www.clinicaltherapeutics.com/article/S0149-2918(18)30140-1/fulltext
- ↑ 32.0 32.1 Tesfaye S et al. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): A multicentre, double-blind, randomised crossover trial. Lancet 2022 Aug 27; 400:680. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36007534 PMCID: PMC9418415 Free PMC article https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01472-6/fulltext
- ↑ 33.0 33.1 Whitlock Burton K FDA Clears Spinal Cord Stimulator for Diabetic Neuropathy. Medscape. January 26, 2023 https://www.medscape.com/viewarticle/987551
- ↑ ElSayed NA, Aleppo G, Aroda VR, et al. 12. Retinopathy, neuropathy, and foot care: standards of care in diabetes - 2023. Diabetes Care. 2023;46:S203-S215. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36507636
- ↑ Diabetic Neuropathies: The Nerve Damage of Diabetes http://diabetes.niddk.nih.gov/dm/pubs/neuropathies/index.htm