Painful Peripheral

NeuropathyClinton Pong

Tufts/Cambridge Health Alliance

December 2012, PGY-3 FM

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

Definition

• International Association for the Study of Pain• [Classification of Chronic Pain: Descriptions of chronic pain syndromes and definitions of

pain terms. 2nd ed. 2002. ]

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 injuryNeuropathic = Pathologic or maladaptive pain

SymptomsNeuralgias 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

Classifications• Timing

o Acuteo Sub-acuteo Chronic

• Nerve Injuryo Neuropraxiao Axonotmesiso Neuronotmesiso Wallerian degeneration

• Acquiredo Metabolico Infectiouso Inflammatoryo Toxico Mechanicalo Traumatic

• Hereditary

• Locationo Axonal vs Myelino Large vs Short-diameter fibers

• Large = vib/prop• Small = pain/temp• Both = light touch

o Nerve Trunk vs Nerve Rooto Sensory vs Motor Nerves

• Focalo Mononeuropathy

• Multifocalo Mononeuropathy multiplex

• Generalizedo Polyneuropathy

Epidemiology• Only 3 prevalence studies on peripheral

neuropathyo Italy: ~8% of Italians 55+ y/o with a PCP going for surgery have

peripheral neuropathyo Bombay India: 2.4% of Indians surveyed door-to-door met criteria

• Carpal tunnel syndrome and DM most commono 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 slideo (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 neuropath

yDiagnosis

Differential dxCommon Other interesting ones

• Diabetes (30% of cases)o 2/3 of DM

• Idiopathic (30% of cases)

• Post herpetic neuralgia• Mechanical

o Disc compressiono OA [(+) in 19.9% of OK elderly]o Inflammationo Carpal tunnel (5.8% of ♀, 0.6% of ♂)

• GI/Malnutritiono Alcoholic (1/3 of Spanish alcoholics)o B12 (5% of OK elderly)o B6

• Infectiouso Hep B/C (1.3% of OK elderly) o Lyme disease, HIV, CMV, Leprosy, Chagas

• Drugs/Toxins/Chemotxo Isoniazid, Hydralazine, Lithium, Flagyl,

Amitriptyline, statins, retroviral, Dapsoneo Taxol, Vincristineo EtOH, arsenic, cyanide, Pb, Hg, thallium

• Immune-mediated (6.3% of OK elderly)

o Guillain-Barré o MGUS/MM, Sjogrens, Lupus, Vasculitic

• Inflammatoryo Parsonage-Turner

• Cancer-relatedo 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

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

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

Diagnosis (DynaMed)

• Other testso CBC, Lytes, BUN/Cr, BG, LFTs, Ca, Mag

Phoso HIVo Lymeo CXRo Heavy metals, lead, coproporphyrin

• If (+)Family historyo Initial genetic testing to consider (AAN

level A)• CMT1A dupllication/HNPP deletion• Cx32 (GJB1)• MFN2

• Specialist testso 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 latero 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

toleranceo 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 UtahArch Intern Med 2004 May 10;164(9):1021

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 too Hx of DMo B12 deficiencyo Rheumatoid

arthritiso Absence of hx of

HTNo 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

Idiopathic• ?age-related?

• Clinical research focusing on impaired glucose tolerance as a culprito 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

Case 2• 48 yo Italian-American male with PMH of diabetes

comes in for routine diabetes examo 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,

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 &

sorbitolo Autoimmune damageo 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 levelso United Kingdom Prospective Diabetes Study (UKPDS)

• significantly lower prevalence of neuropathy at 9 and 15 years than patients randomized to conventional therapy

Diabetes syndromes• Diabetic neuropathic

cachexiao Acute onset: Severe diffuse

neuropathic pain in lower extremitieso Spreads to all the lower limbs/trunk

and hands, typically worsening at night

o Severe weight loss (up to 60%!)o Depressiono Lasts for several months and slowly

subsides over 8-12 monthso Tx: aggressive insulin infusion

• Painful lumbosacral radiculoplexus neuropathyo 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 neuropathyo 11% of insulin-treated

populationo 25% of hospital diabetic clinic

populationo 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

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

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

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.

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

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

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

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 paino Two years ago, he broke his arm after a seizure + fall at home with

progressively worse right neck, shoulder and arm paino 8/10 Burning debilitating pain radiating down the right shoulder and

arm to the elbow and encompasses the upper arm bicep/tricepo Denies clumsiness/dropping things in the right hando Currently tried lidocaine patch, tylenol, tramadol and neurontin and

flexeril without relief

Case 3 pt 2• CPEX:

o CN II-XII intacto Tone: normal without cogwheeling/spasticityo Normal 2+ reflexes in biceps/triceps/brachioradialis bilaterallyo Strength: 5/5 except right deltoid 4+/5, biceps 4+/5, due to paino No atrophy, no tremoro Psych exam normal

• MRI: o Cervical degenerative disc disease, uncoverterbral joint and facet

arthritis, post operative changes at C5-6 with an anterior fusiono Cg-7 disc herniation and focal spinal stenosis with cord deformityo Mild cord atrophy and myelomalacia at C6-7

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

Cervical radiculopathy• Annual incidence 83 per 100,000

o in Rochester NY (1976-1990) n=561o Higher in men than womeno Highest in 50-54 years of ageo C6-C7 affected in 64% of caseso Recurrence common 32% within 5 yearso Luckily, 90% had few or no symptoms at follow up

• (mild cases likely to be underrepresented)

Alcohol• Spanish study of Incidence: 1/3 of alcoholics in a

hospital clinic fulfilled EP criteria• Mainly the consequence of nutritional deficiency

o Thiamineo B6o B12

• Sensory motor axonal neuropathy affecting all fiber types

• Severe burning/stabbing, associated w/ hyperalgesia/allodynia

• Sensory ataxia

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.”

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.

Guillain-Barré Syndrome (GBS)

• Epidemiologyo Annual incidence of 1-2 per 100,000 populationo 40-66% due to C. jejuni, also linked to Shigella, CMVo 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]

• HPIo Preceding URI or GI infectiono 85% of pts repots moderate/severe pain at onset

• S/sx: o 1) stabbing, deep dorsal LBP radiating into the limbso 2) Dysesthetic extremity pain with burning/tinglingo 3) Joint/muscle paino Characteristic: Weakness of limb and respiratory muscles

• Mortality previously ~1/3 of pts; down to 5-10% with vent support

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

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

VZV-Postherpetic neuralgia

• Ganglionopathy• Acute phase

o Acute neuralgia at site of inflammationo Lasts for several weeks

• Long-lasting neuropathic paino 3+ months after healing of the skin lesiono Major or complete sensory losso Hyperalgesia/allodynia (light stroking or warming)

CancerDrugs

(Large fiber neuropathy)

• Paclitaxelo Ascending distal

paraesthesiae/dysesthesia with burning pain/allodynia to cold or mechanical stimulation

o Vibration/pin/cold sensation are impaired

o Stocking-glove distribution

• Cisplatino Painless ataxia

• Vincristineo Large fiber sensory/motor

neuropathyo Muscle aches

• Paraneoplastic polyneuropathies

• Acute sensory ganglionopathyo 90% of the time, it precedes other

symptoms of cancero Anti-Hu neuronal antibody (+)o Most commonly SCLCo More rarely: ovarian, breast or

lymphoma

• Paraproteinemic neuropathyo SPEP(+) in 10% of unexplained

neuropathies

Treatment (1)• Opioids (level 2[mid-level])

o “Timely and fearless use” for acute ganglionopathy and plexopathy

• Tramadolo 50-100mg Q6hr prn pain, max dose 400mg/dayo Antagonize nociceptive nerve trunk injury

• Steroidso 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 eyeso 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 toleratedo May experience relief in 2 weeks

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 Qhso Titrated over 2 weeks to max of 600mg Qhso ADR: somnolence/dizziness, headache, dry mouth, peripheral edem

• Botulinum toxin (Botox) (Level 2[mid-level])• Clonazepam (no RCTs)• Phenytoin (no RCTs)

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 neuropathyo 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%)

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

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 TSHo Order for EMG/NCSo 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

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 1679-1685o 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=116o http://ndep.nih.gov/media/FootExamForm.pdf

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?