Painful peripheral neuropathy

1. Painful Peripheral Neuropathy Clinton Pong Tufts/Cambridge Health Alliance December 2012, PGY-3 FM

2. Objectives • By the end of this session, learners will be able to: • Develop and refine a differential diagnosis for peripheral neuropathy • Discuss the workup for common & typical cases • Perform a comprehensive diabetic foot exam o by ADA/NDEP standards • Treat painful peripheral neuropathy

3. Definition Pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system (“Dysfunction” includes nociceptive and psychogenic conditions) Nociceptive = Response to tissue injury Neuropathic = Pathologic or maladaptive pain • International Association for the Study of Pain • [Classification of Chronic Pain: Descriptions of chronic pain syndromes and definitions of pain terms. 2nd ed. 2002. ]

4. Symptoms Neuralgias Neuropathies • Can be spontaneous, episodic or continuous • Abnormal tactile and thermal sensations • Numbness • Tingling • Pins and Needles • Burning • Shooting • Electric shock-like sensation • Motor nerves may also cause painful cramps Nociceptive aberrancy • Dysesthesia, hyperalgesia and allodynia • Painful percept evoked by stimuli below nociceptor threshold

5. Classifications • Timing o Acute o Sub-acute o Chronic • Nerve Injury o Neuropraxia o Axonotmesis o Neuronotmesis o Wallerian degeneration • Acquired o Metabolic o Infectious o Inflammatory o Toxic o Mechanical o Traumatic • Hereditary • Location o Axonal vs Myelin o Large vs Short-diameter fibers • Large = vib/prop • Small = pain/temp • Both = light touch o Nerve Trunk vs Nerve Root o Sensory vs Motor Nerves • Focal o Mononeuropathy • Multifocal o Mononeuropathy multiplex • Generalized o Polyneuropathy

6. Epidemiology • Only 3 prevalence studies on peripheral neuropathy o Italy: ~8% of Italians 55+ y/o with a PCP going for surgery have peripheral neuropathy o Bombay India: 2.4% of Indians surveyed door-to-door met criteria • Carpal tunnel syndrome and DM most common o Sicily: 7% of Sicilians surveyed door-to-door met criteria • DM neuropathy dx’ed in 0.3% • My best numbers are seen on the next slide o (x% of cases = overall percentage gathered from small studies on incidence for underlying dx of peripheral neuropathy) o (x% of [diagnosis] = overall percentage of patients with dx that have peripheral neuropathy) o Best study was in Oklahoma on elderly • n=795 • JABFP Sept-Oct 2004 Peripheral neuropathy Diagnosis

7. Differential dx Common Other interesting ones • Diabetes (30% of cases) o 2/3 of DM • Idiopathic (30% of cases) • Post herpetic neuralgia • Mechanical o Disc compression o OA [(+) in 19.9% of OK elderly] o Inflammation o Carpal tunnel (5.8% of ♀, 0.6% of ♂) • GI/Malnutrition o Alcoholic (1/3 of Spanish alcoholics) o B12 (5% of OK elderly) o B6 • Infectious o Hep B/C (1.3% of OK elderly) o Lyme disease, HIV, CMV, Leprosy, Chagas • Drugs/Toxins/Chemotx o Isoniazid, Hydralazine, Lithium, Flagyl, Amitriptyline, statins, retroviral, Dapsone o Taxol, Vincristine o EtOH, arsenic, cyanide, Pb, Hg, thallium • Immune-mediated (6.3% of OK elderly) o Guillain-Barré o MGUS/MM, Sjogrens, Lupus, Vasculitic • Inflammatory o Parsonage-Turner • Cancer-related o Paraproteinemic (discovered in 10% of (-) workup cases) o Paraneoplastic syndrome • Hereditary (0.6% of OK elderly) o Charcot Marie Tooth, Fabry’s, famillial amyloid neuropathy, porphyria

8. http://www.aafp.org/afp/1998/0215/p755.html

9. http://www.aafp.org/afp/1998/0215/p755.html

10. Diagnosis (DynaMed) • Other tests o CBC, Lytes, BUN/Cr, BG, LFTs, Ca, Mag Phos o HIV o Lyme o CXR o Heavy metals, lead, coproporphyrin • If (+)Family history o Initial genetic testing to consider (AAN level A) • CMT1A dupllication/HNPP deletion • Cx32 (GJB1) • MFN2 • Specialist tests o Autonomic testing (AAN level B) o Nerve biopsy (AAN level U) • Sural nerve bx may be useful but cause persistent pain o Affected management in 60% o 33% reported increased pain at biopsy site 6 mo later o Skin biopsy (AAN level C) • Highest yield (AAN level C) o Blood glucose • A1c (26% yield*) o Serum B12 with metabolities (methymalonic acid +/- homocysteine) • 2% yield* o Serum protein immunofixation electrophoresis • 3% yield* • If (-)diabetes (AAN level C) o Consider test for impaired glucose tolerance o 2hr GTT (61-62% yield*) • 0% yield* o TSH, ESR, Folate • EMG/NCS (level 3[lacking-direct]) o Confirmed dx in 59% o Changed dx in 14% o Expanded dx in 18% *yield from a small study from a tertiary referral center in Utah Arch Intern Med 2004 May 10;164(9):1021

11. Case 1 • (these are all risk factors for bilateral sensory deficits) o 65-74 yo: 26% o 75-84 yo: 36% o 85+ yo: 54% • In addition to o Hx of DM o B12 deficiency o Rheumatoid arthritis o Absence of hx of HTN o Income <$15,000 • 85 year old Caucasian male veteran who complains of restless legs and progressive trouble with balance and walking • PMH of HLD • Meds: statin, fibrate • Routine CPEX notable for: • Increasing BMI from 30 to 35 • Absence of Achilles reflex and loss of fine touch • Gait: normal, timed get-up-and-go is 10 seconds J Am Fam Pract 2004 Sep-Oct;17(5):309 n=795

12. Idiopathic • ?age-related? • Clinical research focusing on impaired glucose tolerance as a culprit o Fasting >110 & <125 or 2hr GTT >140 &<199 (75g load) • 35-50% of pt with idiopathic sensory neuropathy have IGT • Painful sensory neuropathy of small caliber afferent fibers in the lower limbs • In early stages, DTR, muscle strength and EMG/NCS are spared

13. Case 2 • 48 yo Italian-American male with PMH of diabetes comes in for routine diabetes exam o Lives in the North End and works as a bank teller; walks to work every day for ~20 min/day. His 75 yo mother cooks “pastas and calzones” for him but he has been trying to have smaller portions. o He saw the podiatrist once last year and was told he had “elephantiasis.” • Meds: metformin, ACEi, BB • PE significant for: o Morbid obesity (BMI 45) o Markedly swollen 3+ non-weeping lower extremities with leathery alligator like hyperkeratotic plaques by the heels and lower legs; unable to examine the entire leg. Onychomycosis, Xerosis. Nails are all long and dystrophic with discoloration and absent hair growth from the shins inferiorly. Left great toenail bleeding o Monofilament sensation absent bilaterally on 0/5 points detected • Labs: o A1c 6.5%, LDL 108, BUN/Cr 23/0.9, Albumin 3.9, Urine Alb/Cr 6,

14. Diabetes • 2/3 of all diabetes patients have a peripheral nervous disorder o (also includes dysautonomia, painless foot neuropathy) o Progressive • 5 years after diagnosis: 4% • 20 years after dx: 15% • Etiology (proposed pathways) o Persistent hyperglycemia activates polyol pathway for neural accumulation of fructose & sorbitol o Autoimmune damage o Endoneural vascular ischemic damage • Intensive treatment lowers incidence by 60% o Diabetes Control and Complications Trial (DCCT) • a ten-year clinical study that concluded in 1993 • ANY sustained lowering of the blood glucose helps, even if the person has a history of poor control • follow-up study shows reduction in microvascular changes persist for at least four years after, despite increasing blood glucose levels o United Kingdom Prospective Diabetes Study (UKPDS) • significantly lower prevalence of neuropathy at 9 and 15 years than patients randomized to conventional therapy

15. Diabetes syndromes • Diabetic neuropathic cachexia o Acute onset: Severe diffuse neuropathic pain in lower extremities o Spreads to all the lower limbs/trunk and hands, typically worsening at night o Severe weight loss (up to 60%!) o Depression o Lasts for several months and slowly subsides over 8-12 months o Tx: aggressive insulin infusion • Painful lumbosacral radiculoplexus neuropathy o Acute onset: severe asymmetric deep aching pain localized proximally in the lower limb o May have associated proximal weakness and wasting in the same area • Painful diabetic neuropathy o 11% of insulin-treated population o 25% of hospital diabetic clinic population o Small fiber distal symmetric polyneuropathy • Long-lasting/unremitting, burning, shooting • often with allodynia/hyperalgesia, alteration of thermal perception and autonomic dysfunction • Cold/warm/painful hypesthesia

16. Uremic neuropathy • 80% of pt with advanced renal failure have a sensory motor axonal polyneuropathy • Characterized by cramps and restlessness in legs, dysesthesia • Concomitant DM may cause a severe motor polyneuropathy with intense cramps

17. http://ndep.nih.gov/publications/PublicationDetail.aspx?PubId=116

18. Upper panel: For performance of the 10-g monofilament test, the device is placed perpendicular to the skin, with pressure applied until the monofilament buckles. Boulton A J et al. Dia Care 2008;31:1679-1685 Copyright © 2011 American Diabetes Association, Inc.

21. http://ndep.nih.gov/publications/PublicationDetail.aspx?PubId=116 http://ndep.nih.gov/media/FootExamForm.pdf

22. Case 3 pt 1 • 53 yo Caucasian male with PMH of Bipolar disorder, EtOH abuse and seizure disorder (s/p trigeminal neuralgia “surgery decompression) presents with shoulder pain o Two years ago, he broke his arm after a seizure + fall at home with progressively worse right neck, shoulder and arm pain o 8/10 Burning debilitating pain radiating down the right shoulder and arm to the elbow and encompasses the upper arm bicep/tricep o Denies clumsiness/dropping things in the right hand o Currently tried lidocaine patch, tylenol, tramadol and neurontin and flexeril without relief

23. Case 3 pt 2 • CPEX: o CN II-XII intact o Tone: normal without cogwheeling/spasticity o Normal 2+ reflexes in biceps/triceps/brachioradialis bilaterally o Strength: 5/5 except right deltoid 4+/5, biceps 4+/5, due to pain o No atrophy, no tremor o Psych exam normal • MRI: o Cervical degenerative disc disease, uncoverterbral joint and facet arthritis, post operative changes at C5-6 with an anterior fusion o Cg-7 disc herniation and focal spinal stenosis with cord deformity o Mild cord atrophy and myelomalacia at C6-7

24. Case 3 pt 3 • EMG/NCS: o Motor conduction studies of both ulnar and right median nerves are nromal. Sensory conduction studies of both ulnar and radial nervers demonstrate very reduced amplitudes. The right ulnar latency is mildly reduced. The right Median sensory response is moderately reduced o Concentric needle EMG studies of the right upper extremity demonstrate mild chronic denervative changes in the APB and FDI. The C5-7 paraspinal muscles are normal. • Impression: o Consistent with the presence of an axonal, predominantly sensory, peripheral neuropathy in the upper extremities. o There is no evidence for a right cervical radiculopathy

25. Cervical radiculopathy • Annual incidence 83 per 100,000 o in Rochester NY (1976-1990) n=561 o Higher in men than women o Highest in 50-54 years of age o C6-C7 affected in 64% of cases o Recurrence common 32% within 5 years o Luckily, 90% had few or no symptoms at follow up • (mild cases likely to be underrepresented)

26. Alcohol • Spanish study of Incidence: 1/3 of alcoholics in a hospital clinic fulfilled EP criteria • Mainly the consequence of nutritional deficiency o Thiamine o B6 o B12 • Sensory motor axonal neuropathy affecting all fiber types • Severe burning/stabbing, associated w/ hyperalgesia/allodynia • Sensory ataxia

27. Case 4 pt 1 • L.R. 76 yo PMH of DM, COPD, chronic back pain presents to the ED with leg weakness, numbness and gait instability. • 2 months ago, she had facial numbness around her lips with weakness with swallowing and an inability to tell if food was inside or outside her mouth. She also had numbness of her right hand. • 1 month ago, she had a whole body pain. Within two weeks, she developed numbness in her hands and feet and had difficulty walking with weakness in both legs. • She reports that this all started when she got “bunch of shots.”

28. Case 4 pt 2 • “Bilateral Bell’s Palsy” resolved with a five-day course of steroids • LP showed cytoalbuminologic dissociation with protein of 90 and 0 WBCs • EMG/NCS impression: mild chronic generalized sensory motor polyneuropathy, axonal in nature. • Diagnosed with Guillain-Barre and was given a course of IVIG that improved her gait mobility • She was not diagnosed with CIDP • 2 years later, she is able to stand up, but still has chronic pain in her lower legs and can only ambulate for about 10-20 steps.

29. Guillain-Barré Syndrome (GBS) • Epidemiology o Annual incidence of 1-2 per 100,000 population o 40-66% due to C. jejuni, also linked to Shigella, CMV o Very rarely linked to vaccines (except for vaccinia old-rabies w/ myelin and 1976 US Swine flu vaccine) • England: n=200+ cases, imm vs nonimm, OR of 1.8 [95% CI 0.7-4.4] • HPI o Preceding URI or GI infection o 85% of pts repots moderate/severe pain at onset • S/sx: o 1) stabbing, deep dorsal LBP radiating into the limbs o 2) Dysesthetic extremity pain with burning/tingling o 3) Joint/muscle pain o Characteristic: Weakness of limb and respiratory muscles • Mortality previously ~1/3 of pts; down to 5-10% with vent support

30. Case 5 pt 1 • RI is a 84 yo male with PMH of HTN/zoster, home visit • A couple of years ago, he had a shingles outbreak on his leg and the pain was so bad that he lost nearly fifty pounds (down to 170#) and feels that the loss of appetite was secondary to the pain. • His kidneys were “blocked up” around the same time and was on HD for a few months and was given a “bladder bag” and has Q6 week visits at SH for foley changes after declining suprapubic surgery • He still has some residual pain from the zoster and lives independently. Otherwise well, no back pain

31. Case 5 pt 2 • Old vesicular patch scar pattern on the left-medial anterior thigh • Large inguinal hernia easily reducible, foley draining clear yellow urine • Neuro exam intact. No sensory changes to light touch or sensitivity over the zoster scar • BUN/Cr 38/2.1, Alk phos 1301, SPEP/UPEP negative except total protein high at 59.6 • PSA: 88.3 • MRI chest: multiple bone through the thoracic and lumbar spine concerning for ossesous neoplastic disease

32. VZV-Postherpetic neuralgia • Ganglionopathy • Acute phase o Acute neuralgia at site of inflammation o Lasts for several weeks • Long-lasting neuropathic pain o 3+ months after healing of the skin lesion o Major or complete sensory loss o Hyperalgesia/allodynia (light stroking or warming)

33. Cancer Drugs (Large fiber neuropathy) • Paclitaxel o Ascending distal paraesthesiae/dysesthesia with burning pain/allodynia to cold or mechanical stimulation o Vibration/pin/cold sensation are impaired o Stocking-glove distribution • Cisplatin o Painless ataxia • Vincristine o Large fiber sensory/motor neuropathy o Muscle aches • Paraneoplastic polyneuropathies • Acute sensory ganglionopathy o 90% of the time, it precedes other symptoms of cancer o Anti-Hu neuronal antibody (+) o Most commonly SCLC o More rarely: ovarian, breast or lymphoma • Paraproteinemic neuropathy o SPEP(+) in 10% of unexplained neuropathies

34. Treatment (1) • Opioids (level 2[mid-level]) o “Timely and fearless use” for acute ganglionopathy and plexopathy • Tramadol o 50-100mg Q6hr prn pain, max dose 400mg/day o Antagonize nociceptive nerve trunk injury • Steroids o In cases of acute inflammatory component to nerve injury • Capsaicin (Zostrix) 0.025% (A-1) o Up to 3-4x/day x 4-6 weeks, apply with gloves and don’t rub eyes o Chili pepper extract depleting substance P/VIP/CCK/somatostatin stores • TCAs (Amitrip/Nortrip/Desip) (level 2[mid-level], A-2) o Start at 10mg Qhs and increased up to 25mg Qhs and by 25mg increments as tolerated o May experience relief in 2 weeks

35. Treatment (2) • Anticonvulsants: unknown MOA • Gabapentin (Neurontin) (A-2) o 300mg Qhs x2 nights, then 300mg BID x2 days, increase to 300mg TID and additional 300mg doses as tolerated o ADR: leukopenia, somnolence/dizziness/ataxia/fatigue • Pregabalin (Lyrica) (A-2) o 100mg Qhs o Titrated over 2 weeks to max of 600mg Qhs o ADR: somnolence/dizziness, headache, dry mouth, peripheral edem • Botulinum toxin (Botox) (Level 2[mid-level]) • Clonazepam (no RCTs) • Phenytoin (no RCTs)

36. CAM treatment (evidence-harm) • 43% of pt with peripheral neuropathy use CAM • Megavitamins (35%) o Vitamin B complex (B-100) (B-2) one tab BID • for deficiency syndromes • Caution: High dose B6 (1000mg/d) can cause toxic neuropathy! o Acetyl-L-carnitine 500 BID-1000TID (A-1) • For chemo-induced and DM neuropathy o Alpha-lipoic acid 600-1800 PO Daily (A-1) o Benfotiamine-B1 50-100 TID (B-1) • For DM neuropathy o Vitamin E 400-800 IU Daily (B-2) • Magnets (30%) o Magnetic insoles (A-1) • Acupuncture (30%) (B-1) o Beta-endorphin release • Herbals (22%) o Geranium oil (Neutragen PN) topically several times a day (level 1[likely-reliable])C-1) • Reduces neuropathic foot pain for up to 4 hours o Evening Primrose Oil 360mg PO daily of GLA from EPO (A-1) • Chiropractor (21%)

37. Objectives • By the end of this session, learners will be able to: • Develop and refine a differential diagnosis for peripheral neuropathy • Discuss the workup for common & typical cases • Perform a comprehensive diabetic foot exam o by ADA/NDEP standards • Treat painful peripheral neuropathy

38. Take Home Points • Think systematically • High-yield actions: o Drug review: chemotx, INH, B6, Hydralazine, Metronidazole, Lithium, Amitriptyline o Labs: fasting glucose, A1c, BUN/Cr, CBC, ESR, UA, B12 and TSH o Order for EMG/NCS o Refer to Neuro (if considering: autonomic eval, LP, CXR, EKG, PFT: FVC) • By prevalence, think about: o Diabetes (30% of cases) o Idiopathic (30% of cases) o Consider • Post herpetic neuralgia, Mechanical (Disc compression, OA, Inflammation, Carpal tunnel), Alcoholic, B12

39. References • DynaMed: Peripheral Neuropathy (Accessed December, 2012) • AAN/AANEM National Guideline Clearinghouse 2009 Jun1:13615 • Arch Intern Med 2004 May 10;164(9):1021 • Boulton et al. Comprehensive Foot Examination and Risk Assessment. Diabetes Care August 2008 vol. 31 no. 8 1679-1685 o http://care.diabetesjournals.org/content/31/8/1679.long • Martyn C et al. Epidemiology of peripheral neuropathies. Neuroepidemiology. J. Neuro/Neurosurg/Psych. 1997; 62:310-318 • Marchettini, P. et al., Painful Peripheral Neuropathies. Current Neuropharmacology. 2006. 4 175- 181. o http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430688/pdf/CN-4-3-175.pdf • Mold J et al. Prevalence, Predictors and Consequences of Peripheral Sensory Neuropathy in Older Patients. JABFP Sept-Oct 2004. 17;5: 309-318 • PONCELET, AN. An Algorithm for the Evaluation of Peripheral Neuropathy. Am Fam Physician. 1998 Feb 15;57(4):755-764. o http://www.aafp.org/afp/1998/0215/p755.html • Schaumberg H., et al. Sensory Neuropathy from Pyridoxine Abuse — A New Megavitamin Syndrome. N Engl J Med 1983; 309:445–8. o http://www.nejm.org/doi/pdf/10.1056/NEJM198308253090801 • Rakel. Integrative Medicine. 2nd edition. Chapter 15: Peripheral Neuropathy pp 157-168 • Feet Can Last a Lifetime – A Health Care Provider’s Guide to Preventing Diabetes Foot Problems o http://ndep.nih.gov/publications/PublicationDetail.aspx?PubId=116 o http://ndep.nih.gov/media/FootExamForm.pdf

40. Questions? • Please comment on: • 1. What was the most important thing you learned today? • 2. What question remains uppermost in your mind afterward? • 3. What is the muddiest point in today's lecture?