1. Peripheral Neuropathy Andrew Galbreath, D.O. Sentara Neurology Specialists Virginia Beach, VA Virginia Osteopathic Medical Association 2010 Spring CME Conference May 21, 2010

2. Opening Remarks

3. Objectives To review and discuss… 1. 1. Basic epidemiology of peripheral neuropathy 2. 2. The diagnostic approach to progressive sensory and motor dysfunction in the ambulatory care setting 3. 3. Classification of nerve dysfunction 4. 4. Reasonable diagnostic work-up for idiopathic diffuse PN 5. 5. Updated treatment guidelines for neuropathic pain 6. 6. Prognosis of PN

4. Epidemiology An estimated 20 million Americans suffer from PN¹ ~23.6 million people suffer from diabetes² 30% of PN is related to diabetes 30% of PN is idiopathic Annual cost to Medicare exceeds $3.5 billion ¹The Neuropathy Association www.neuropathy.orgwww.neuropathy.org ²American Diabetes Association www.diabetes.org

5. Research has been underfunded 2004 NIH funding: $35 million 2005 NIH funding: $29 million For other neurological disorders with similar scope (MS and epilepsy), funding is approximately 200 times that of PN Source: The Neuropathy Association www.neuropathy.org

6. Localization of “neuropathy” Mononeuropathy – one nerve Mononeuritis multiplex Radiculopathy – nerve root Plexopathy – brachial or lumbosacral plexus Cranial neuropathy – Bell’s Palsy, 3 rd nerve palsy Distal symmetric peripheral neuropathy (DSPN) – –Small fiber versus large fiber – –Sensory only – –Motor only – –Sensorimotor

9. “My feet feel like they’re too big for my shoes“ -Toes and feet are very sensitive to touch -He gets shooting pains into his feet and toes. -"dead" type of numbness (lack of sensation) on various spots of his feet and ankles. -has long standing xerostomia, but no xerophthalmia, orthostasis, or erectile dysfunction. 48 yr old man with no prior medical history…

10. 85 yr old man… -No history of diabetes -Overall "heaviness" of legs and lost exercise tolerance over past 3-6 months -Used to be able to walk 3-4 miles without trouble. Now, can hardly walk 1/2 mile. -Has particular difficulty ascending stairs. -No back or limb pain, no cramping, bowel or bladder incontinence. -Denies symptoms or xerophthalmia, xerostomia, excessive constipation, urinary retention, and orthostasis.

11. S: 1. 1. Numbness, or a feeling of walking on cotton wool or wearing a thick sock 2. 2. Pains that can be dull, constant and boring in type, or more spontaneous sharp, shooting, or stabbing in nature; a sensation as if walking on pebbles 3. 3. Tingling, pins and needles 4. 4. Hot or cold sensations (e.g., “burning feet”; “like walking on hot sand” 5. 5. Allodynia (pain caused by an otherwise non-painful stimulus, such as light touch or stroking); this can be very troublesome at night when the feet and legs rub against the bedclothes 6. 6. Cramps in the calves and foot muscles. Dyck, et. al. Peripheral Neuropathy, 4 th Edition. 2005

12. Sensory symptoms –Gains and/or Losses Motor symptoms –Gains (cramps) and/or Losses (distal predominant) Autonomic symptoms –Orthostasis –Impotence –Anhidrosis –Vascular instability in feet

13. What other conditions must be considered? Painful feet –Arthritis, including gout –Morton’s Neuroma –Tarsal tunnel syndrome –Arterial insufficiency Tingling in the legs –Venous stasis/peripheral edema –Restless leg syndrome –idiopathic Numbness/Weakness –Radiculopathy –CNS dysfunction (i.e. spinal cord pathology or stroke)

14. O: General Exam: Ulcers? Trophic changes? Neurological Exam: Sensation in toes/feet – –10-g Semmes-Weinstein monofilament – –vibration at great toes, 128 Hz tuning fork Muscle stretch reflexes (especially ankle jerks) Motor exam – –Bulk – –Tone – –Power

15. Sensory Exam 10-g Semmes-Weinstein monofilament –3 applications at each site (one sham) –Insensate if fail at 1 or more sites Picture taken from American College of Physicians publication http://www.acponline.org/clinicalskills/

16. Sensory Exam 128 Hz tuning fork Lag time (normal less than 10 sec) Start/stop

17. Making an accurate diagnosis HistoryExam EDX studies Epidermal skin fiber density Nerve biopsy Referral to Neurology

18. Conditions Associated with Painful Peripheral Neuropathy Diabetes and Pre-Diabetes Alcohol neuropathy Chemotherapy –Platinum-based Paraproteinemia Vasculitis and Connective Tissue Diseases Heavy metals and other toxins HIVAmyloidosisPorphyria

20. The work-up

21. Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory, genetic, and autonomic testing; nerve biopsy; and skin biopsy (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation Report of the Quality Standards Subcommittee of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation J.D. England, MD; G.S. Gronseth, MD, FAAN; G. Franklin, MD; G.T. Carter, MD; L.J. Kinsella, MD; J.A. Cohen, MD; A.K. Asbury, MD; K. Szigeti, MD, PhD; J.R. Lupski, MD, PhD; N. Latov, MD; R.A. Lewis, MD; P.A. Low, MD; M.A. Fisher, MD; D.N. Herrmann, MD; J.F. Howard Jr, MD; G. Lauria, MD; R.G. Miller, MD; M. Polydefkis, MD, MHS; and A.J. Sumner, MD Slide from presentation on www.aan.com Neurology 2009;72:1–1

22. Background DSP is the most common type of neuropathy. Prevalence is approximately 2,400 (2.4%) per 100,000 population but rises to approximately 8,000 (8%) per 100,000 in individuals older than 55 years. Simple screening laboratory tests, along with medical history, neurological examination, and EDX studies, reveal the cause of DSP in 74 to 82% of patients with polyneuropathy. Slide from presentation on www.aan.com

23. Gaps in Care Since there are many etiologies of polyneuropathy, a logical clinical approach is needed for evaluation and management. DSP diagnosis should be based on a combination of clinical symptoms, signs, and electrodiagnostic criteria. Laboratory test results must be interpreted within the larger clinical context since the tests’ low specificity limits their etiologic yield. Slide from presentation on www.aan.com

24. Clinical Questions 1. What is the yield of screening laboratory tests in the evaluation of DSP, and which tests should be performed? 2. How accurate is genetic testing for identifying patients with genetically determined neuropathies? 3. Which patients with polyneuropathy should be screened for hereditary neuropathies? Slide from presentation on www.aan.com

25. Clinical Questions 4. What is the usefulness of clinical autonomic testing in the evaluation of polyneuropathy, and which tests have the highest sensitivity and specificity? 5. What is the usefulness of nerve biopsy in determining the etiology of distal symmetric polyneuropathy? 6. What is the usefulness and diagnostic accuracy of skin biopsy in the evaluation of polyneuropathy? Slide from presentation on www.aan.com

26. Recommendations for lab testing: Screening laboratory tests may be considered for all patients with DSP (Level C). Tests with the highest yield of abnormality: 1. blood glucose (fasting) 2. serum B12 with metabolites (methylmalonic acid, homocysteine) 3. SPEP (Level C).

27. Recommendations for lab testing: Other tests for prediabetes such as a GTT may be considered in patients with DSPN, especially if it is accompanied by pain (Level C). Clinical judgment correlated with the clinical picture will determine which additional laboratory investigations are necessary.

28. Other laboratory studies ANA, RF, Anti-dsDNA, Anti-Ro, Anti-La, ANCA screen, cryoglobulins Urine for heavy metals, porphyrins IFE/urine IFE/ plasma light chain analysis

29. Lab tests do not diagnose polyneuropathy Yield of screening lab tests is variable

30. PRACTICE PARAMETER: Evaluation of distal symmetric polyneuropathy: Role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review) Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation Neurology 2009;72:1–1

31. Assessing Autonomic Nervous System Cardiovagal –Heart rate variability Adrenergic –Valsalva maneuver Induces BP changes and monitors pulse reaction Postganglionic sudomotor function –QSART

32. 1000 ms 500 ms R-R Cycles Duration (ms) Autonomic Testing: R-R’ interval analysis 1000 ms 500 ms Duration (ms) R-R Cycles NormalAbnormal

33. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 76 SUPPLEMENT 2 APRIL 2009

34. Skin biopsy “For symptomatic patients with suspected polyneuropathy, skin biopsy may be considered to diagnose the presence of a polyneuropathy, particularly SFSN.”

35. DIAGNOSIS: A.Lt Calf, Epidermal Nerve Fiber Density: Skin with significantly reduced epidermal nerve fiber density, consistent with small fiber neuropathy B. Lt Thigh, Epidermal Nerve Fiber Density: Skin with normal epidermal nerve fiber density EPIDERMAL NERVE FIBER DENSITY TEST: Specimen Result Value ABNORMAL LOW NORMAL A. Lt Calf 1.95 < 5.4 5.4 - 5.7 B. Lt Thigh 13.29 < 6.8 6.8 - 8.0

36. Genetic Testing

37. www. neuromuscular.wustl.edu

38. What do they look like?

40. Treatment of DSP What is the target? –Pain? –Tingling? –Weakness? FDA, non-FDA Mainstream versus alternative Oral, topical, devices, combination

41. Options First line? –Antidepressants –Anticonvulsants Efficacy Adverse effects/tolerability/cost Second line? –Opioids –Pain clinic referral

42. Antidepressants for neuropathic pain Cochrane Database of Systematic Reviews 2007. Issue 4. 61 RCT Results: –TCA are effective. NNT 3.6 for at least moderate pain relief –DN: NNT = 1.3; PHN NNT 2.7 Relatively safe (NNH 28) – –Venlafexine NNT 3.1 NNH Venlafexine 16.2

43. Tramadol for neuropathic pain Cochrane Database of Systematic Reviews 2006. Issue 3. 7 trials analyzed Results: –Tramadol is effective NNT 3.8 for at least 50% pain relief Insufficient data to compare with morphine

44. EFNS guidelines on pharmacological treatment of neuropathic pain In depth review of clinical trials looking at antidepressants and anticonvulsants in PPN, PHN DPN and non-diabetic PPN appear to respond in similar fashion (except HIV neuropathy and chemotherapy neuropathy) Eur J Neurol 2006; 13: 1153-1169

45. - amitriptyline, desiprimine, nortriptyline TCA - amitriptyline, desiprimine, nortriptyline – –Amitriptyline first introduced 1961 – –NNT PPN: 2.1 Selective NE/Seratonin Reuptake Inhibitors – –Venlafexine 150-225 mg/d: NNT 4.6 – –Duloxetine 60-120 mg/d: NNT 5.2

46. Antiepileptic drugs (AEDs) Voltage gated calcium channel ligands –Gabapentin 1200-3600/d: NNT: 3.9 –Pregabalin 150-600mg/d also effective but data biased Others –Carbamazepine (CBZ) – 2 older studies (1960s) – difficult to assess based on methods –Oxcarbazepine: unclear, one study NNT 5.9 –Lamotrigine: NNT 4.0 –Topiramate: negative results in 3 large trials

47. Opioids Oxycodone 37-60mg/d, NNT 2.6

48. Anodyne

49. Metanx

50. Why is classification important? Treatment Further diagnostics Prognosis – “Will this get any better?”

51. Objectives To review and discuss… Basic epidemiology of peripheral neuropathy The diagnostic approach to progressive sensory and motor dysfunction in the ambulatory care setting Classification of nerve dysfunction Reasonable diagnostic work-up for idiopathic diffuse PN Updated treatment guidelines for neuropathic pain Prognosis of PN

52. 1. 1. Website for The Neuropathy Association www.neuropathy.orgwww.neuropathy.org 2. 2. Website for The American Diabetes Association www.diabetes.orgwww.diabetes.org 3. 3. JAMA. 2010;303(15):1526-1532. 4. 4. Dyck, et. al. Peripheral Neuropathy, 4 th Edition. 2005 5. 5. “Diabetic Foot Ulcers” Clinical Skills Module http://www.acponline.org/ http://www.acponline.org/ 6. 6. Sensory exam with a quantitative tuning fork Neurology 2004;62;461-464 7. 7. Neurology 2009;72:1–1 http://www.neurology.org/cgi/rapidpdf/01.wnl.0000336370.51010.a 1v1.pdf 8. 8. Clev Clin J Of Med 2009; 76: S2 9. 9. Therapath website: www.therapath.com 10. 10. Antidepressants for neuropathic pain Cochrane Database of Systematic Reviews 2007. Issue 4. 11. 11. Tramadol for neuropathic pain Cochrane Database of Systematic Reviews 2006. Issue 3. 12. 12. European Federation of Neurological Societies Eur J Neurol 2006; 13: 1153-1169.