Peripheral Neuropathy and Neuropathic Pain Management

1
Peripheral Neuropathy and Neuropathic Pain
Management

• Laurence J. Kinsella, M.D., F.A.A.N.

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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?
Audience Question

1. Spastic weakness from spinal cord injury
2. Bilateral foot drop from neuropathy
3. 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!

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Examination

• MS/CN wnl
• Motor exam shows distal wasting of foot muscles
  with pes cavus, hammer toes. Yea, I got my
  mothers 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

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Patient is asked to dorsiflex
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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

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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.

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Diagnosis

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

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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.

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• 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

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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.

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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

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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

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Semmes - WeinsteinFoot 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

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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)?

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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

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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?

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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
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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 womans
bilateral wrist drop?
Audience Question

1. Compressive neuropathy
2. Vasculitis
3. Lead toxicity

Occurred after 4400 sit ups!
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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

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NCS/EMG

• 2 part test
• Nerve conduction of superficial nerves
  transcutaneously
• sensory and motor nerves tested

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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

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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).

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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).

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EMG - Normal

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

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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

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Neuropathic Pain Prevalence
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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

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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

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Exam

• Normal strength, reflexes
• Pinprick lt right ankle, left mid calf
• PS 50 normal responses
• Rydell-Seiffer tuning fork
• L toe - 1/8, R toe - 2/8 (nl gt 4/8)
• Semmes-Weinstein filament score 7/10 (nl 10)
• Callus left sole
• Phalens in both hands
• Neurology 200462461.

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Lab evaluation

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

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Skin biopsy
dermal plexus

• severe loss of small fibers
• Thigh - 3.71 fibers/mm (nl gt 8)
• Calf - 0.0 fibers/mm (nl gt 5)

thigh
dermal plexus
calf
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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

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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 gt proximal
• Exception - proximal gt distal subtype, burning
  face and tongue, assoc dysautonomia
• NCS are normal - test of largest fibers (1A)

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Normal Epidermal Nerve Fiber Density (ENFD)

• epidermal nerve fiber density (ENFD)
• Calf gt 5 fibers/mm ( 5th percentile)
• Thigh gt 8 fibers/mm

Unmyelinated C fibers
Subepidermal nerve plexus
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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 gt 5.0/mm)

Dermal plexus
Terminal fibers
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Nerve Fiber Density Consistent with Small Fiber
Neuropathy
70 year old man with burning feet, normal NCS
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Glucose Intolerance is an important cause of SFN

• Impaired glucose tolerance on 2 hour OGTT gt 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

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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 Jun29(6)1294-9.
44

• Distal IENFD improved 0.3 1.1 fibers/mm, and
  the proximal IENFD improved 1.3 2.2 fibers/mm
  (P lt 0.004).
• Improvement in proximal thigh IENFD was observed
  in 70 of subjects compared with 31 for the
  ankle.

Diabetes Care. 2006 Jun29(6)1294-9.
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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

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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. 200713(3)164-167. Raskin P, et al.
Topiramate vs placebo in painful diabetic
neuropathy analgesic and metabolic effects.
Neurology. 200463(5)865-73 Vinik A, Neurodiab
2005
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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

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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 2003601524-34. 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
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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

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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 Jul116109-18

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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. 20071051805-1815.
52
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.
2005904936-4945.
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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 gt 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 200055915-920.
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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

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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

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Questions from the Audience?
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References

1. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar
   S.Duloxetine vs. placebo in patients with
   painful diabetic neuropathy. Pain. 2005
   Jul116109-18.
2. Management of chronic pain syndromes issues and
   interventions. Pain Med. 2005 Jul-Aug6 Suppl
   1S1-S20
3. Dworkin RH, et al. Advances in neuropathic pain
   diagnosis, mechanisms, and treatment
   recommendations. Arch Neurol 2003601524-34.
4. Lynch M, et al. Topical Amitriptyline and
   Ketamine in Neuropathic Pain Syndromes An
   Open-Label Study.  J Pain 2005 6 644-649
5. Gajraj. Pregabalin Its Pharmacology and Use in
   Pain Management Anesth. Analg. 20071051805-1815.
   
6. Sindrup SH, Jensen TS. Pharmacologic treatment of
   pain in polyneuropathy. Neurology
   200055915-920.
7. Barohn RJ. Approach to peripheral neuropathy and
   neuronopathy. Semin Neurol 1998187-18.