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peripheral nerve disease; peripheral neuropathy

Classification: 1) symmetrical distal polyneuropathy 2) focal or mononeuropathy 3) proximal sensorimotor neuropathy 4) demyelinating vs axonal 5) large fiber vs small fiber neuropathy 6) familial neuropathy 7) autonomic neuropathy Etiology: 1) axonal neuropathies - diabetes mellitus - alcohol & other toxins - vitamin B12 deficiency - paraneoplastic syndromes - hereditary, type II - dysproteinemias & paraproteinemias - pharmacologic agents (several, see selection) 2) segmental demyelination - diabetes mellitus - Guillain-Barre syndrome - chronic inflammatory polyradiculopathy - dysproteinemia & paraproteinemia - hereditary, type I - pharmacologic agents (several, see selection) 3) focal & multifocal neuropathies a) diabetes mellitus b) nerve entrapment - carpal tunnel syndrome c) mononeuritis multiplex - vasculitis d) infection - herpes zoster - Lyme disease (Borrelia burgdorferi) - acquired immune deficiency syndrome (AIDS) - leprosy - syphilis - West Nile virus 4) autonomic neuropathy - amyloidosis - diabetes mellitus - paraneoplastic syndromes 5) sensory neuropathy - Sjogren syndrome - paraneoplastic syndrome - copper deficiency - celiac disease 6) small fiber neuropathy - impaired glucose tolerance - Sjogren syndrome - familial burning feet syndrome - Fabry disease [3] 7) acquired sensorimotor neuropathy - diabetes mellitus - monoglonal gammopathy, MGUS - uremia - chemotherapy [14] 8) hereditary sensorimotor neuropathy - Charcot-Marie-Tooth disease - familial amyloidosis 9) polyradiculopathy - Guillain-Barre syndrome - chronic inflammatory demyelinating polyradiculopathy - amyloidosis - porphyria [3] 10) motor neuropathy - multifocal motor neuropathy 11) polyneuropathy a) diabetes mellitus b) vitamin B12 deficiency c) alcoholism 11) other [3] - metabolic - hypothyroidism, anemia (distal symmetric polyneuropathy), acromegaly, critical illness - nutritional - copper deficiency - pellagra (niacin deficiency) - thiamine deficiency - vitamin B6 toxicity - vitamin B12 deficiency - vitamin E deficiency - infectious - HIV1 infection, Lyme disease, leprosy - rheumatologic - systemic lupus erythematosus - rheumatoid arthrtis - polyarteritis nodosa - Sjogren's syndrome - mixed connective tissue disease - paraproteinemia & paraneoplastic disease - MGUS - POEMS syndrome - amyloidosis - lymphoma, multiple myeloma - paraneoplastic neuropathy & ganglionopathy - sarcoidosis - lead poisoning & other heavy metal poisoning - arsenic poisoning, mercury poisoning, thallium poisoning - chemotherapy-induced peripheral neuropathy 12) idiopathic (30%) [3] Epidemiology: - prevalence of polyneuropathy: [17] - 2% in persons 50-60, 31% in persons > 80 years - 31% with diabetes mellitus - 14% with vitamin B12 deficiency Pathology: - disorder of axons vs disorder of neurons (neuronopathy) Clinical manifestations: 1) paresthesias 2) tingling 3) itching 4) numbness 5) burning 7) electrical sensation 8) muscle cramps 9) pain 10) foot ulcers & deformity 11) decreased sense of vibration 12) muscle weakness/foot drop 13) skin dryness/hair loss 14) decreased stretch reflexes (deep tendon reflexes) 15) decreased sense of pain & temperature 16) decreased sense of touch & pressure 17) short steps, slow walking speed & difficulty turning [18] 18) autonomic dysfunction: constipation, orthostasis, or bladder dysfunction Laboratory: 1) complete blood count (CBC) 2) erythrocyte sedimentation rate (ESR) 3) electrolytes 4) serum glucose, hemoglobin A1c* - glucose tolerance test if serum glucose & A1c normal & small fiber neuropathy suspected [3] 5) thyroid function tests 6) serum immunoglobulins & serum protein electrophoresis* 7) urine protein electrophoresis [3] 8) serum vitamin B12* & serum folate 9) CSF analysis if neuropathy is rapidly progressive 10) see ARUP consult [9] 11) other testing as indicated - hereditary peripheral neuropathy genotyping * highest yield of initial diagnostic testing * also see ARUP consult [20] Special laboratory: 1) nerve conduction studies & electromyography a) axonal neuropathies 1] nerve conduction is normal or slightly reduced 2] electromyography shows muscle denervation b) demyelinating neuropathies 1] nerve conduction is slowed 2] electromyography reveals no muscle denervation c) combined axonal & demyelinating neuropathies are common 2) Semmes-Weinstein monofilament testing 3) nerve biopsy a) vasculitis b) sarcoidosis c) amyloidosis d) leprosy 4) 3 mm punch biopsy may reveal small fiber neuropathy [4] - distal calf biopsy for nerve conduction study-negative neuropathic feet Radiology: - chest X-ray Complications: - peripheral neuropathy is associated with excess risk of mobility impairment in the elderly [11] - peripheral neuropathy is associated with excess risk of mortality independent of diabetes mellitus associated with decreased sensation in the foot [22] - peripheral neuropathy & hearing loss are independently & additively associated with premature mortality [23] - associations may be mediated in part by impaired balance [23] Differential diagnosis: - central nervous system disease - lower motor neuron signs imply peripheral neuropathy - muscle cramps, fasciculations, muscle atrophy - lesion may include cell body of lower motor neuron within the anterior horn of the spinal cord - hyperreflexia, extensor plantar response suggests upper motor neuron & CNS pathology - sensory loss in an entire limb rather than dermatomal or stocking glove distribution suggests CNS disease - electromyography is normal in CNS disease - peripheral neuropathy - anterior lateral thigh numbness, no weakness - meralgia paresthetica - sensory loss over the palmar surface of the 1st 3 fingers & weakness with abduction & opposition of thumb - carpal tunnel syndrome (median neuropathy) - numbness of the 4th & 5th fingers & weakness of interosseus muscles - cubital tunnel syndrome (ulnar neuropathy) - paresthesias & numbness of the great toe & medial foot - tarsal tunnel syndrome (posterior tibial neuropathy) - upper & lower face weakness - Bell's palsy (cranial nerve 7 palsy) - mononeuritis multiplex (multiple non-contiguous nerve defects) - vasculitis, lymphoma, amyloidosis, sarcoidosis, HIV1, diabetes - distal, symmetric (stocking-glove) sensory or sensory & motor manifestations - axonal polyneuropathy: diabetes mellitus, alcoholism - small fiber neuropathy will present with pain only - severe unilateral leg pain, numbness, proximal weakness, atrophy, weight loss - diabetic amyotrophy - acute ascending paralysis, areflexia, paresthesias - Guillain-Barre syndrome - progressive proximal motor & sensory polyneuropathy evolving over months - chronic inflammatory demyelinating polyneuropathy - symmetric distal sensory neuropathy with paraprotein - MUGUS, multiple mylemona, amyloidosis, cyroglobulinemia Management: 1) pharmacologic agents a) avoid benzodiazepines: they lower pain threshold b) analgesics: 1] aspirin 2] acetaminophen 3] non-steroidal anti-inflammatory agents (NSAIDs) 4] opiates - morphine in combination with gabapentin [5] c) tricyclic antidepressants 1] amitriptyline 2] nortriptyline 3] may be used in conjunction with fluphenazine (Prolixin) 4] often effective at lower doses than those used for treatment of depression d) selective serotonin-reuptake inhibitors (SSRI) 1] paroxetine (Paxil) 2] fluoxetine (Prozac) e) duloxetine* first line for chemotherapy-induced painful peripheral neuropathy [10,23] f) anticonvulsants 1] carbamazepine (Tegretol) 2] valproate (Depakene) 3] phenytoin (Dilantin) g) clonidine (Catapres) h) clonazepam (Klonopin) i) gabapentin (Neurontin), pregabalin* j) mexiletine 200-400 mg PO TID k) capsaicin (topical) applied several times/day l) nortriptyline & duloxetine* better than pregabalin* or mexiletine, but no drug particularly effective [21] m) tapendolol* (extended-release) 2) physical measures: a) warm baths; b) skin care; c) appropriate clothing 3) control of diabetes 4) workup for occult malignancy if no cause found 5) patient education a) symptoms usually improve with time b) symptoms sometimes appear to worsen as nerves begin to repair themselves & recover functionality 6) placebo effects - pregabalin & placebo significantly & equally effective in HIV-related neuropathy [8] * only duloxetine, pregabalin & tapendolol FDA-approved for treatment of painful peripheral neuropathy [3]

Interactions

disease interactions

Related

age-associated changes in the peripheral nervous system nerve conduction study (NCS); electroneuronography peripheral nerve peripheral nervous system peripheral neuropathy gene mutation pharmaceutical agents causing peripheral neuropathy

Specific

chemotherapy-induced peripheral neuropathy (CIPN) chronic idiopathic ataxic neuropathy cramp fasciculation syndrome diabetic neuropathy entrapment neuropathy; nerve entrapment syndrome; pinched nerve facial nerve disorder hand & foot syndrome; palmar-plantar erythrodysesthesia; acral erythema mental neuropathy mononeuritis multiplex mononeuropathy motor neuropathy nerve injury nerve lesion nerve root injury neuralgia neuritis neurogenic arthritis (neurogenic arthropathy) nutritional neuropathy occipital neuralgia phantom limb; pseudomelia plexopathy POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, & Skin changes); Crow-Fukase syndrome polyneuropathy post Herpetic neuralgia pyridoxine neuropathy; megavitamin-B6 syndrome radiculopathy sensory neuropathy slowed nerve conduction velocity; nerve conduction block

General

peripheral nervous system (CNS) disease

References

  1. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 829-39
  2. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 1046-47
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Journal Watch 25(9):74, 2005 Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005 Mar 31;352(13):1324-34. PMID: 15800228
  5. Journal Watch, Mass Med Soc 20(1):11 (Jan 1) 2000
  6. England JD et al Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Neurology 2009 Jan 13;72(2):185-92 PMID: 19056666
  7. England JD et al Practice Parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Neurology 2009 Jan 13;72(2):177-84 PMID: 19056667
  8. Simpson DM et al. Pregabalin for painful HIV neuropathy: A randomized, double-blind, placebo-controlled trial. Neurology 2010 Feb 2; 74:413. PMID: 20124207
  9. ARUP Consult: Autoimmune Neuropathies - Neuropathic Disease deprecated reference
  10. Smith EM et al Effect of Duloxetine on Pain, Function, and Quality of Life Among Patients With Chemotherapy-Induced Painful Peripheral Neuropathy. A Randomized Clinical Trial. JAMA. 2013;309(13):1359-1367 PMID: 23549581 http://jama.jamanetwork.com/article.aspx?articleid=1674238
  11. Lauria G, Merkies IS, Faber CG. Small fibre neuropathy. Curr Opin Neurol. 2012 Oct;25(5):542-9 PMID: 22941266
  12. Ward RE et al. Sensory and motor peripheral nerve function and incident mobility disability. J Am Geriatr Soc 2014 Dec; 62:2273 PMID: 25482096
  13. Levine TD, Saperstein DS. Laboratory evaluation of peripheral neuropathy. Neurol Clin. 2013 May;31(2):363-76. PMID: 23642714
  14. Nelson R Persistent Chemo-Induced Neuropathy Impacts Functioning. Medscape Oncology. Jan 14, 2016 http://www.medscape.com/viewarticle/857235
  15. Callaghan B, McCammon R, Kerber K, Xu X, Langa KM, Feldman E. Tests and expenditures in the initial evaluation of peripheral neuropathy. Arch Intern Med. 2012 Jan 23;172(2):127-32. PMID: 22271119 Free PMC Article
  16. Callaghan BC, Burke JF, Rodgers A, Expenditures in the elderly with peripheral neuropathy: Where should we focus cost-control efforts? Neurol Clin Pract. 2013 Oct;3(5):421-430. PMID: 24175158 Free PMC Article
  17. Hanewinckel R et al. Prevalence of polyneuropathy in the general middle-aged and elderly population. Neurology 2016 Nov 1; 87:1892 PMID: 27683845
  18. Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019
  19. National Institute of Neurological Disorders and Stroke (NINDS) - NINDS Peripheral Neuropathy Information Page https://www.ninds.nih.gov/Disorders/All-Disorders/Peripheral-Neuropathy-Information-Page - Peripheral Neuropathy Fact Sheet https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet
  20. ARUP Consult: Autoimmune Neuropathies - Neuropathic Disease The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/autoimmune-neuropathies
  21. Barohn RJ, Gajewski B, Pasnoor M et al. Patient assisted intervention for neuropathy: Comparison of treatment in real life situations (PAIN-CONTRoLS): Bayesian adaptive comparative effectiveness randomized trial. JAMA Neurol 2020 Aug 17; [e-pub] PMID: 32809014 https://jamanetwork.com/journals/jamaneurology/fullarticle/2769608
  22. Hicks CW, Wang D, Matsushita K et al Peripheral Neuropathy and All-Cause and Cardiovascular Mortality in U.S. Adults. Ann Intern Med. 2020. Dec 8. PMID: 33284680 https://www.acpjournals.org/doi/10.7326/M20-1340
  23. Mold JW, Lawler FH, Liao X, Bard DE. Associations between hearing loss, peripheral neuropathy, balance, and survival in older primary care patients. J Am Geriatr Soc. 2024 Aug 14. PMID: 39143038 https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.19142