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

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Presentation on theme: "Peripheral Neuropathy and Neuropathic Pain Management Laurence J. Kinsella, M.D., F.A.A.N."— Presentation transcript:

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

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

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

4 Why does he have to pick up his feet so high to clear steps? Audience Question 1.Spastic weakness from spinal cord injury 2.Bilateral foot drop from neuropathy 3.Orthopedic ankle injuries

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

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

7 Patient is asked to dorsiflex

8 Which tests are most likely to give a diagnosis? Audience Question 1.NCS/EMG, genetic testing for CMT1A, examination of family members 2.NCS/EMG, antibody testing for GM1, MAG, autoimmune disorders 3.NCS/EMG, 2 hour glucose tolerance test, HbA1C

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

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

11 The sensorimotor Apparatus l 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 l Neuromuscular Junction –Myasthenia Gravis Sensory Ganglionitis –Lambert-Eaton - Syphilis, SS –Myasthenic paraneoplastic –MuscleMyelin Sheath –Polymyositis - Guillain-Barré Syndrome - CIDP –Rhabdomyolysis- MCBN l Motor neuron Disease –ALS/WNV –Polio –West Nile Virus Axonal Neuropathy –Diabetes –Alcohol

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

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

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

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

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

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

20 This man demonstrates a focal neuropathy. What is the diagnosis? Audience Question 1.Diabetic thoracic radiculopathy 2.Varicella zoster 3.Black widow spider bite Thoracic T9 shingles with depigmentation

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

22 What is the most likely cause for this woman’s bilateral wrist drop? Audience Question 1.Compressive neuropathy 2.Vasculitis 3.Lead toxicity Occurred after 4400 sit ups!

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


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

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

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

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

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

31 Neuropathic Pain Prevalence

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

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

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

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

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

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

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

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

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

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 l Impaired glucose tolerance on 2 hour OGTT > 140 mg/dl or impaired fasting glucose ( ) l Found in 25-56% of patients with idiopathic neuropathy l 35-65% when the neuropathy is painful l Hughes found less of an effect after controlling for age and sex –Found differences in triglycerides l Most are overweight l ?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 l 32 pts with prediabetic neuropathy l Lifestyle intervention-diet and exercise l Baseline and 1 year –skin biopsies of thigh and calf –NCS, QST, QSART, OGTT, lipids Diabetes Care Jun;29(6):

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

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

46 Therapies for Regeneration? l Diet and Exercise for Prediabetic SFN l Alpha Lipoic Acid 600mg daily shows moderate benefit for neuropathic pain (NNT 2.7) l Topiramate up to 400 mg daily - modest response - 30% less pain for 50% of patients (NNT 7.4) l 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): Vinik A, Neurodiab 2005

47 Drugs for symptomatic relief l Anticonvulsants –Pregabalin (Lyrica ® ) mg BID (FDA) –Gabapentin (Neurontin ® ) mg TID –Topiramate mg l Tricyclic Antidepressants –Nortriptyline 10 to 60 mg q HS –Amitriptyline, desipramine, doxepin Other Antidepressants –Duloxetine (Cymbalta ® ) mg /Day (FDA) –Venlafaxine (Effexor ® ) 150 mg BID l Opioid Analgesics –Tramadol mg TID –OxyContin mg BID

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 l Tricyclic Antidepressants 2.6 l carbamazepine2.6 l tramadol 3.4 l gabapentin 3.7 l capsaicin 5.9 l SSRI 6.7 l mexiletine 38 Sindrup SH, Jensen TS. Neurology 2000

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

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

52 Gabapentin (Neurontin ® ) l Off-label indication for neuropathic pain l Range from mg TID l Begin with 300 mg qHS and rapidly titrate over several weeks TID to 50% pain reduction or side effect or 3600 mg daily. l Side Effects - sleepiness, ataxia l Very well-tolerated drug l 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 ® ) l Fewer anticholinergic side effects than amitriptyline l Less sedating l Begin with 10 mg q HS x 1 week, then increase by 10 q week to max of mg l Pt instructed to increase med until 50% pain reduction or side effect l SE - dry mouth, blurred vision, lightheadedness, palpitations, urinary hesitancy, worsening glaucoma, insomnia l Age > 70, History of Coronary Artery Disease - use caution Sindrup SH, Jensen TS. Pharmacologic treatment of pain in polyneuropathy. Neurology 2000;55:

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

55 Symptomatic Treatment of Painful Neuropathies Treatment recommendations l It is essential to start a given medication at a low dose, and gradually titrate to efficacy l Set expectations - 50% improvement l 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 l In general, when a patient remains pain-free for 3 months on a current treatment regimen, consider a slow taper

56 Questions from the Audience?

57 References 1.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; 3.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.

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