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

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

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

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

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!

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

Patient is asked to dorsiflex

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

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.

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

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.

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

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.

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

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

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

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)?

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

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?

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

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

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!

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

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

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

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

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).

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

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

Neuropathic Pain Prevalence

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

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

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

Lab evaluation TG 225 (< 150) BMP normal x Cr 1.5 Impaired fasting glucose 123 (110-125 mg/dl) 2 hour glucose tolerance test nl 105 (< 140 mg/dl) HbA1c - 6.1 (< 6.0) B12, methylmalonic acid, Immunofixation electrophoresis, liver function tests, HCV, anti gliadin antibody normal

Skin biopsy dermal plexus severe loss of small fibers Thigh - 3.71 fibers/mm (nl > 8) Calf - 0.0 fibers/mm (nl > 5) thigh dermal plexus calf

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

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)

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

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

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

Glucose Intolerance is an important cause of SFN Impaired glucose tolerance on 2 hour OGTT > 140 mg/dl or impaired fasting glucose (110-125) 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

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. 2006 Jun;29(6):1294-9.

© 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. 2006 Jun;29(6):1294-9.

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

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):164-167. 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

Drugs for symptomatic relief Anticonvulsants Pregabalin (Lyrica®) 50-200 mg BID (FDA) Gabapentin (Neurontin®) 100-1200 mg TID Topiramate 100-400 mg Tricyclic Antidepressants Nortriptyline 10 to 60 mg q HS Amitriptyline, desipramine, doxepin Other Antidepressants Duloxetine (Cymbalta®) 20-60 mg /Day (FDA) Venlafaxine (Effexor®) 150 mg BID Opioid Analgesics Tramadol 50-100 mg TID OxyContin 20-40 mg BID Answer to TQ#3

Topical analgesics High potency Capsaicin 0.25% in Lidocaine cream Capsaicin 0.025 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 (30-100 mg/gm) cream Magnetic Insoles Dworkin, Arch Neurol 2003;60:1524-34. 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 644-649

Number Needed to Treat (NNT) to give 50% improvement Tricyclic Antidepressants 2.6 carbamazepine 2.6 tramadol 3.4 gabapentin 3.7 capsaicin 5.9 SSRI 6.7 mexiletine 38 Sindrup SH, Jensen TS. Neurology 2000

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. 2005 Jul;116:109-18

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;105:1805-1815.

Gabapentin (Neurontin®) Off-label indication for neuropathic pain Range from 300-1200 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;90:4936-4945.

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 60-100 mg Sindrup SH, Jensen TS. Pharmacologic treatment of pain in polyneuropathy. Neurology 2000;55:915-920.

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

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.

Questions from the Audience?

References Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005 Jul;116:109-18. Management of chronic pain syndromes: issues and interventions. Pain Med. 2005 Jul-Aug;6 Suppl 1:S1-S20; Dworkin RH, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:1524-34. Lynch M, et al. Topical Amitriptyline and Ketamine in Neuropathic Pain Syndromes: An Open-Label Study.  J Pain 2005; 6: 644-649 Gajraj. Pregabalin: Its Pharmacology and Use in Pain Management Anesth. Analg. 2007;105:1805-1815. Sindrup SH, Jensen TS. Pharmacologic treatment of pain in polyneuropathy. Neurology 2000;55:915-920. Barohn RJ. Approach to peripheral neuropathy and neuronopathy. Semin Neurol 1998;18:7-18.