Transcript An Update on Stroke - CME Medical Conferences & Primary

Peripheral Neuropathy and
Neuropathic Pain Management
Laurence J. Kinsella, M.D., F.A.A.N.
Outline:
l
l
l
l
l
l
Case study
Anatomy of the peripheral nerve
Approach to Neuropathy
Overview of nerve conduction studies and
electromyography
Laboratory Testing
Treatment
Case 1
l
l
l
l
l
l
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
Audience Question
Why does he have to pick up his feet
so high to clear steps?
1. Spastic weakness from spinal cord injury
2. Bilateral foot drop from neuropathy
3. Orthopedic ankle injuries
Case 1
l
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.
Plays tennis weekly, golf in the summer, fishes
with grand kids - active lifestyle!
Examination
l
l
l
l
l
l
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
Audience Question
Which tests are most likely to give a
diagnosis?
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
Evaluation
l
l
l
l
l
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
l
Hereditary distal symmetric demyelinating
polyneuropathy (Charcot Marie Tooth)
l
Treatment - Nortriptyline and genetic
counseling
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.
l
Neuromuscular Junction
– Myasthenia Gravis
– Lambert-Eaton
– Myasthenic
– Muscle
– Polymyositis
– Rhabdomyolysis
l
Sensory Ganglionitis
- Syphilis, SS
paraneoplastic
Myelin Sheath
- Guillain-Barré Syndrome
- CIDP
- MCBN
Motor neuron Disease
– ALS/WNV
– Polio
– West Nile Virus
Axonal Neuropathy
– Diabetes
– Alcohol
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.
Peripheral Neuropathies
l
l
l
l
l
30% - hereditary
25% - cryptogenic
15% - diabetes
13% - inflammatory
demyelinating (CIDP, GBS)
5% - multifocal motor
neuropathy
l
l
l
l
2% - vitamin B12
deficiency
1.5% - drug-induced
1% - sensory
neuronopathy
7% - Other (T4, vasculitis,
infectious, toxin,
paraneoplastic)
Examination
l
l
l
l
l
l
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
l
l
l
l
l
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
l
l
l
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
l
l
l
l
l
l
“Level I”
blood glucose, HbA1C
B12, methylmalonic acid,
ESR, CRP, RF, ANA
TSH with reflex T4
Immunofixation
electrophoresis (IFE)
EMG/NCS
l
l
l
l
l
l
l
l
l
“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
l
l
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?
74%
Audience
Question
This man demonstrates a focal neuropathy.
What is the diagnosis?
24%
1. Diabetic thoracic
radiculopathy
2%
w
id
Bl
ac
k
Va
r
D
ia
be
Thoracic T9 shingles
with depigmentation
ow
zo
st
ic
el
la
tic
th
o
ra
...
...
3. Black widow
spider bite
sp
...
2. Varicella zoster
Mononeuropathy Multiplex
l
l
l
l
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
Audience Question
What is the most likely cause for this
woman’s bilateral wrist drop?
1. Compressive neuropathy
2. Vasculitis
3. Lead toxicity
Occurred after 4400
sit ups!
Distal Symmetric
Polyneuropathy
l
l
l
l
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
l
l
l
2 part test
Nerve conduction of superficial nerves transcutaneously
sensory and motor nerves tested
Nerve conduction Studies
l
l
l
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
l
l
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).
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).
EMG - Normal
l
Normal spontaneous
activity - silent
l
Normal Motor Unit 3 phases
l
Normal firing of
multiple units, filling
screen
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
Neuropathic Pain Prevalence
57 year old auto dealer
l
l
l
l
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
l
l
l
l
l
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
l
l
l
l
l
l
l
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.
Lab evaluation
l
l
l
l
l
l
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
l
l
l
severe loss of small fibers
Thigh - 3.71 fibers/mm (nl > 8)
Calf - 0.0 fibers/mm (nl > 5)
dermal
plexus
thigh
dermal plexus
calf
Outcome
l
l
l
l
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
l
l
l
l
l
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
l
NCS are normal - test of largest fibers (1A)
Normal Epidermal Nerve Fiber
Density (ENFD)
l
l
l
epidermal nerve Unmyelinated
fiber density
C fibers
(ENFD)
Calf > 5 fibers/mm
(≥ 5th percentile)
Thigh > 8
fibers/mm
Subepidermal
nerve plexus
Example of Normal ENF Density
l
l
l
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
l
l
l
l
l
l
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
l
l
l
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.
©
l
l
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
l
l
l
l
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
Therapies for Regeneration?
l
l
l
l
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
l
Anticonvulsants
– Pregabalin (Lyrica®)
50-200 mg BID (FDA)
– Gabapentin (Neurontin®)
100-1200 mg TID
– Topiramate 100-400 mg
l
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
l
Opioid Analgesics
– Tramadol 50-100 mg TID
– OxyContin 20-40 mg BID
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
l
l
l
l
l
l
l
Tricyclic Antidepressants
carbamazepine
tramadol
gabapentin
capsaicin
SSRI
mexiletine
2.6
2.6
3.4
3.7
5.9
6.7
38
Sindrup SH, Jensen TS. Neurology 2000
Duloxetine (Cymbalta®)
l
l
l
l
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®)
l
l
l
l
l
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®)
l
l
Off-label indication for
neuropathic pain
Range from
300-1200 mg TID
l
l
l
l
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®)
l
l
l
l
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
l
l
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
Sindrup SH, Jensen TS. Pharmacologic treatment of
pain in polyneuropathy. Neurology 2000;55:915-920.
What can the patient do?
l
l
l
l
l
No more than 4 drinks /week
(may worsen neuropathy)
exercise
avoid smoking
good diet
vitamins/supplements?
l
l
l
l
l
l
wash feet daily
Thorlo socks
soft shoes
orthotics/ shoe inserts
magnetic insoles
cut toenails straight
across
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
Questions from the
Audience?
References
1. 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.
2. Management of chronic pain syndromes: issues and interventions.
Pain Med. 2005 Jul-Aug;6 Suppl 1:S1-S20;
3. Dworkin RH, et al. Advances in neuropathic pain: diagnosis,
mechanisms, and treatment recommendations. Arch Neurol
2003;60:1524-34.
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. 2007;105:1805-1815.
6. Sindrup SH, Jensen TS. Pharmacologic treatment of pain in
polyneuropathy. Neurology 2000;55:915-920.
7. Barohn RJ. Approach to peripheral neuropathy and neuronopathy.
Semin Neurol 1998;18:7-18.