1. Peripheral Neuropathy and Neuropathic Pain Management
Laurence J. Kinsella, M.D., F.A.A.N.

2. Outline: Case study Anatomy of the peripheral nerve
Approach to Neuropathy
Overview of nerve conduction studies and electromyography
Laboratory Testing
Treatment

3. Case 1 75 year old man with numbness in the feet for 5 years.
Numbness ascending up to knees for 3 years
Unsteady walking, esp. at night.
Has to lift the legs high over steps to prevent falling
No back pain
Cramping of small muscles of hands/feet

4. Why does he have to pick up his feet so high to clear steps?50
250
Audience Question
Why does he have to pick up his feet so high to clear steps?
Spastic weakness from spinal cord injury
Bilateral foot drop from neuropathy
Orthopedic ankle injuries

5. Case 1
PMHx/SH - HTN; s/p CABG 1997; mild diabetes for 1 year, diet controlled; 2 oz scotch per night for 40 years, no tobacco.
Plays tennis weekly, golf in the summer, fishes with grand kids - active lifestyle!

6. Examination
MS/CN wnl
Motor exam shows distal wasting of foot muscles with pes cavus, hammer toes. “Yea, I got my mother’s feet.”
Toe flexion is weak, produces cramp
Distal sensory loss to foot filament, light touch, pinprick, vibration, position sense
Ankle reflexes absent
Abnormal tandem gait

7. Patient is asked to dorsiflex

8. Which tests are most likely to give a diagnosis?48
250
Audience Question
Which tests are most likely to give a diagnosis?
NCS/EMG, genetic testing for CMT1A, examination of family members
NCS/EMG, antibody testing for GM1, MAG, autoimmune disorders
NCS/EMG, 2 hour glucose tolerance test, HbA1C

9. Evaluation B12, MMA, TSH - normal NCS - absent sural sensory
slowed conduction velocities,
peroneal and tibial motor nerves
EMG - Distal muscle fibrillation and polyphasic motor units.
Lumbar MRI - normal.
Genetic Assay for Charcot Marie Tooth deletion abnormal.

10. Diagnosis
Hereditary distal symmetric demyelinating polyneuropathy (Charcot Marie Tooth)
Treatment - Nortriptyline and genetic counseling

11. The sensorimotor Apparatus
The 1a and 1b afferents carry sensory information from the tendon, synapse with the Renshaw interneuron, excite the alpha motor neuron causing contraction of the muscle.

12. Neuromuscular Junction
Myasthenia Gravis Sensory Ganglionitis
Lambert-Eaton Syphilis, SS
Myasthenic paraneoplastic
Muscle Myelin Sheath
Polymyositis Guillain-Barré Syndrome - CIDP
Rhabdomyolysis - MCBN
Motor neuron Disease
ALS/WNV
Polio
West Nile Virus
Axonal Neuropathy
Diabetes
Alcohol

13. Anatomy of the Peripheral Nerve
The peripheral nerve is a bundle of myelinated and unmyelinated axons, akin to a telephone cord. The axon carries the signal, the myelin insulates and speeds conduction.

14. Peripheral Neuropathies
2% - vitamin B12 deficiency
1.5% - drug-induced
1% - sensory neuronopathy
7% - Other (T4, vasculitis, infectious, toxin, paraneoplastic)
30% - hereditary
25% - cryptogenic
15% - diabetes
13% - inflammatory demyelinating (CIDP, GBS)
5% - multifocal motor neuropathy

15. Examination
Supine and standing BP and P - screen for autonomic neuropathy
Cranial nerves - rarely affected
Motor-distal greater than proximal weakness (contrast with myopathy)
Sensory - test foot filament score, vibration, cold tuning fork
Distal areflexia
Focal weakness, sensory loss in distribution of single nerve

16. Semmes - Weinstein Foot Filament
10 sites per foot tested
10 gram filament for feet, 5 gram for hands
Score each foot 0-10
Record and follow sites with sensory loss
Correlates with loss of protective sensation

17. Approach to Neuropathy
Is it focal (CTS), multifocal (vasculitis), or generalized (diabetes)?
Is it acute (GBS, CTS) or chronic (diabetes)?
What diseases does the patient have (EtOH, diabetes, thyroid, RA)?

18. Evaluation of Neuropathy
“Level I”
blood glucose, HbA1C
B12, methylmalonic acid, ESR, CRP, RF, ANA
TSH with reflex T4
Immunofixation electrophoresis (IFE)
EMG/NCS
“Level II”
Glucose tolerance test
CMT1a genetic analysis
GM1, MAG, Hu, HIV antibodies
MRI lumbar/cervical spine
Lumbar puncture
Bone survey (if IFE abnl)
Nerve/muscle biopsy
Anti-Gliadin antibodies

19. Mononeuropathy
Once a mononeuropathy is suspected (single limb paresthesias, weakness, pain) the NCS/EMG serves as an extension of the physical exam
Is the lesion a mononeuropathy, plexopathy, or radiculopathy?

20. This man demonstrates a focal neuropathy. What is the diagnosis?
Audience Question 50
250
This man demonstrates a focal neuropathy. What is the diagnosis?
Diabetic thoracic radiculopathy
Varicella zoster
Black widow spider bite
Thoracic T9 shingles with depigmentation

21. Mononeuropathy Multiplex
Multiple focal nerve injuries
Ulnar neuropathy + peroneal neuropathy
Multiple compression injuries, hereditary liability to pressure palsies, Polyarteritis nodosa, vasculitis
Requires extensive evaluation for rheumatologic disease

22. What is the most likely cause for this woman’s bilateral wrist drop?
Audience Question 53
250
What is the most likely cause for this woman’s bilateral wrist drop?
Compressive neuropathy
Vasculitis
Lead toxicity
Occurred after 4400 sit ups!

23. Distal Symmetric Polyneuropathy
sensory symptoms of numbness, burning, tingling begin in toes, ascend to knees, then hands- “glove and stocking”
“walking on bunched-up socks”
distal leg weakness, areflexia at ankles
sensory loss leads to ulcers, Charcot joints

25. NCS/EMG
2 part test
Nerve conduction of superficial nerves transcutaneously
sensory and motor nerves tested

26. Nerve conduction Studies
Latency - time from the impulse to the response of the CMAP
Amplitude - The height of the CMAP - indicates the number of functioning axons
Conduction Velocity - the distance between two points along the nerve divided by the latency difference

27. Nerve Conduction Studies
Prolonged latency and conduction velocity suggest pathology of the myelin sheath, which is most commonly affected in entrapment and demyelinating neuropathy.
Reduced CMAP indicates a loss of axons, suggesting a more severe and longstanding compression or degeneration (axonal neuropathy).
Answer to TQ#2

28. Electromyography
A concentric needle is inserted into a variety of limb muscles, looking for evidence of denervation (fibrillations, fasciculations, positive waves, polyphasic MUPs with reduced recruitment).

29. EMG - Normal Normal spontaneous activity - silent
Normal Motor Unit -3 phases
Normal firing of multiple units, filling screen

30. EMG - Abnormal Fibrillations - single muscle fibers contract
Polyphasic MUPs - reorganization of motor units due to axon loss and reinnervation
Rapid firing of single, polyphasic MUPs - indicates axon loss

31. Neuropathic Pain Prevalence

32. 57 year old auto dealer 2nd opinion for tarsal tunnel release
6 years of progressive numbness and burning feet
Began in toes, now up to ankles
Recently moved into hands and arms

33. 57 year old auto dealer PMHx - CAD, HTN, Chol, GERD
Meds - nifedipine, Atenolol (Tenormin), Atorvastatin (Lipitor®), Gabapentin (Neurontin®), Loratadine (Claritin®), Omeprazole (Prilosec®), Aspirin
Seen by 15 physicians (3 neurologists)
NCS/EMG x4 negative, except min. denervation of foot muscles
Recommended tarsal tunnel release

34. Exam Normal strength, reflexes
Pinprick < right ankle, left mid calf
PS 50% normal responses
Rydell-Seiffer tuning fork
L toe - 1/8, R toe - 2/8 (nl > 4/8)
Semmes-Weinstein filament score 7/10 (nl 10)
Callus left sole
Phalen’s in both hands
Neurology 2004;62:461.
Answer to TQ#1

35. Lab evaluation TG 225 (< 150) BMP normal x Cr 1.5
Impaired fasting glucose 123 ( mg/dl)
2 hour glucose tolerance test nl 105 (< 140 mg/dl)
HbA1c (< 6.0)
B12, methylmalonic acid, Immunofixation electrophoresis, liver function tests, HCV, anti gliadin antibody normal

36. Skin biopsy dermal plexus severe loss of small fibers
Thigh fibers/mm (nl > 8)
Calf fibers/mm (nl > 5)
thigh
dermal plexus
calf

37. Outcome
Small fiber neuropathy - idiopathic vs prediabetic vs. hypertriglycidemia
Gabapentin (Neurontin®) 300 mg TID, Duloxetine (Cymbalta®) 20 mg q AM
Marked improvement in pain
Counseled to lose 10% body weight, exercise

38. Small Fiber Neuropathy
Affects A-delta (thinly myelinated), unmyelinated C fibers
Burning, aching, lancinating pain in feet
Exam often normal, x pinprick, cold sensation.
Vibration, position sense less common
Usually distal > proximal
Exception - proximal > distal subtype, burning face and tongue, assoc dysautonomia
NCS are normal - test of largest fibers (1A)

39. Normal Epidermal Nerve Fiber Density (ENFD)
Calf > 5 fibers/mm (≥ 5th percentile)
Thigh > 8 fibers/mm
Unmyelinated C fibers
Subepidermal nerve plexus

40. Example of Normal ENF Density
41 M with paresthesias up to waist, dizziness
Normal Valsalva ratio, R-R interval by deep breathing
Normal IENF density 7.07 (nl > 5.0/mm)
Dermal plexus
Terminal fibers

41. Nerve Fiber Density Consistent with Small Fiber Neuropathy
70 year old man with burning feet, normal NCS

42. Glucose Intolerance is an important cause of SFN
Impaired glucose tolerance on 2 hour OGTT > 140 mg/dl or impaired fasting glucose ( )
Found in 25-56% of patients with idiopathic neuropathy
35-65% when the neuropathy is painful
Hughes found less of an effect after controlling for age and sex
Found differences in triglycerides
Most are overweight
?metabolic syndrome
Novella SP, Muscle Nerve 2001
Singleton JR, Muscle Nerve 2001
Sumner CJ, Neurology 2003
Smith AG, Muscle Nerve 2004
Hughes RA, Brain 2004

43. Skin Biopsy can document recovery of neuropathy
32 pts with prediabetic neuropathy
Lifestyle intervention-diet and exercise
Baseline and 1 year
skin biopsies of thigh and calf
NCS, QST, QSART, OGTT, lipids
Diabetes Care Jun;29(6):

44. Distal IENFD improved 0.3 ± 1.1 fibers/mm, and the proximal IENFD improved 1.3 ± 2.2 fibers/mm (*P < 0.004).
Improvement in proximal thigh IENFD was observed in 70% of subjects compared with 31% for the ankle.
Diabetes Care Jun;29(6):

45. Treatment Diet and Exercise Control lipids
AACE recommendation – metformin, others
Neuropathic pain management
Duloxetine 60 mg daily
Pregabalin
Gabapentin, TCAs
Opioids may be needed
IVIG, Solu-Medrol experimental
Answer to TQ#3

46. Therapies for Regeneration?
Diet and Exercise for Prediabetic SFN
Alpha Lipoic Acid 600mg daily shows moderate benefit for neuropathic pain (NNT 2.7)
Topiramate up to 400 mg daily - modest response - 30% less pain for 50% of patients (NNT 7.4)
Nerve regeneration documented in small series using skin bx
Tang J, et al Alpha lipoic acid may improve symptomatic diabetic polyneuropathy. Neurologist. 2007;13(3):
Raskin P, et al. Topiramate vs placebo in painful diabetic neuropathy:
analgesic and metabolic effects. Neurology. 2004;63(5):865-73
Vinik A, Neurodiab 2005

47. Drugs for symptomatic relief
Anticonvulsants
Pregabalin (Lyrica®) mg BID (FDA)
Gabapentin (Neurontin®) mg TID
Topiramate mg
Tricyclic Antidepressants
Nortriptyline 10 to 60 mg q HS
Amitriptyline, desipramine, doxepin
Other Antidepressants
Duloxetine (Cymbalta®) mg /Day (FDA)
Venlafaxine (Effexor®) mg BID
Opioid Analgesics
Tramadol mg TID
OxyContin mg BID
Answer to TQ#3

48. Topical analgesics High potency Capsaicin 0.25% in Lidocaine cream
Capsaicin or 0.075% QID x 1 month trial
Lidoderm Patch q 12 hrs
5% Ketoprofen Cream
Doxepin 5% (Zonalon® cream) x 1-2 weeks
Ketamine ( mg/gm) cream
Magnetic Insoles
Dworkin, Arch Neurol 2003;60:
Lynch M, et al. Topical Amitriptyline and Ketamine in
Neuropathic Pain Syndromes: An Open-Label Study. 
The Journal of Pain, Volume 6, Issue 10, Pages

49. Number Needed to Treat (NNT) to give 50% improvement
Tricyclic Antidepressants 2.6
carbamazepine 2.6
tramadol
gabapentin
capsaicin
SSRI
mexiletine
Sindrup SH, Jensen TS. Neurology 2000

50. Duloxetine (Cymbalta®)
60 or 120 mg./ day
First FDA indication for DPN
Placebo 30% pain reduction, drug 50%
Side effects - nausea, somnolence, dizziness, dry mouth
Pain Jul;116:109-18

51. Pregabalin (Lyrica®) Binds Ca Channels, reduces NT release
FDA indication for diabetic neuropathic pain, Post herpetic neuralgia
50  100 mg TID
Few drug interactions
SE - dizziness, somnolence, ataxia
Gajraj. Pregabalin: Its Pharmacology and Use in Pain Management Anesth. Analg. 2007;105:

52. Gabapentin (Neurontin®)
Off-label indication for neuropathic pain
Range from mg TID
Begin with 300 mg qHS and rapidly titrate over several weeks TID to 50% pain reduction or side effect or 3600 mg daily.
Side Effects - sleepiness, ataxia
Very well-tolerated drug
Generic price reduction
Vinik et al. Use of Antiepileptic Drugs in the Treatment of
Chronic Painful Diabetic Neuropathy
J. Clin. Endocrinol. Metab. 2005;90:

53. Nortryptiline (Pamelor®)
Pt instructed to increase med until 50% pain reduction or side effect
SE - dry mouth, blurred vision, lightheadedness, palpitations, urinary hesitancy, worsening glaucoma, insomnia
Age > 70, History of Coronary Artery Disease - use caution
Fewer anticholinergic side effects than amitriptyline
Less sedating
Begin with 10 mg q HS x 1 week, then increase by 10 q week to max of mg
Sindrup SH, Jensen TS. Pharmacologic treatment of pain in polyneuropathy. Neurology 2000;55:

54. What can the patient do?
No more than 4 drinks /week (may worsen neuropathy)
exercise
avoid smoking
good diet
vitamins/supplements?
wash feet daily
Thorlo socks
soft shoes
orthotics/ shoe inserts
magnetic insoles
cut toenails straight across

55. Symptomatic Treatment of Painful Neuropathies
Treatment recommendations
It is essential to start a given medication at a low dose, and gradually titrate to efficacy
Set expectations - 50% improvement
If a patient experiences partial pain relief with 1 drug as monotherapy, a combination of 2 or more drugs with complementary mechanisms can often yield better results in terms of efficacy
In general, when a patient remains pain-free for 3 months on a current treatment regimen, consider a slow taper
These recommendations apply despite agent used treating neuropathic pain.

56. Questions from the Audience?

57. References
Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain Jul;116:
Management of chronic pain syndromes: issues and interventions. Pain Med Jul-Aug;6 Suppl 1:S1-S20;
Dworkin RH, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:
Lynch M, et al. Topical Amitriptyline and Ketamine in Neuropathic Pain Syndromes: An Open-Label Study.  J Pain 2005; 6:
Gajraj. Pregabalin: Its Pharmacology and Use in Pain Management Anesth. Analg. 2007;105:
Sindrup SH, Jensen TS. Pharmacologic treatment of pain in polyneuropathy. Neurology 2000;55:
Barohn RJ. Approach to peripheral neuropathy and neuronopathy. Semin Neurol 1998;18:7-18.