Peripheral Neuropathy
Virginia Osteopathic Medical Association
2010 Spring CME Conference
May 21, 2010
Andrew Galbreath, D.O.
Sentara Neurology Specialists
Virginia Beach, VA
Opening Remarks
Objectives
To review and discuss…
1.
2.
3.
4.
5.
6.
Basic epidemiology of peripheral neuropathy
The diagnostic approach to progressive sensory and
motor dysfunction in the ambulatory care setting
Classification of nerve dysfunction
Reasonable diagnostic work-up for idiopathic diffuse PN
Updated treatment guidelines for neuropathic pain
Prognosis of PN
Epidemiology
An estimated 20 million Americans suffer from PN¹
~23.6 million people suffer from diabetes²
30% of PN is related to diabetes
30% of PN is idiopathic
Annual cost to Medicare exceeds $3.5 billion
¹The Neuropathy Association www.neuropathy.org
²American Diabetes Association www.diabetes.org
Research has been underfunded
2004 NIH funding: $35 million
2005 NIH funding: $29 million
For other neurological disorders with
similar scope (MS and epilepsy), funding
is approximately 200 times that of PN
Source: The Neuropathy Association
www.neuropathy.org
Localization of “neuropathy”
Mononeuropathy – one nerve
Mononeuritis multiplex
Radiculopathy – nerve root
Plexopathy – brachial or lumbosacral plexus
Cranial neuropathy – Bell’s Palsy, 3rd nerve
palsy
Distal symmetric peripheral neuropathy (DSPN)
–
–
–
–
Small fiber versus large fiber
Sensory only
Motor only
Sensorimotor
48 yr old man with no prior medical history…
“My feet feel like they’re too big for my shoes“
-Toes and feet are very sensitive to touch
-He gets shooting pains into his feet and toes.
-"dead" type of numbness (lack of sensation) on
various spots of his feet and ankles.
-has long standing xerostomia, but no
xerophthalmia, orthostasis, or erectile
dysfunction.
85 yr old man…
-No history of diabetes
-Overall "heaviness" of legs and lost exercise
tolerance over past 3-6 months
-Used to be able to walk 3-4 miles without trouble.
Now, can hardly walk 1/2 mile.
-Has particular difficulty ascending stairs.
-No back or limb pain, no cramping, bowel or
bladder incontinence.
-Denies symptoms or xerophthalmia, xerostomia,
excessive constipation, urinary retention, and
orthostasis.
S:
1. Numbness, or a feeling of walking on cotton wool or
2.
3.
4.
5.
6.
wearing a thick sock
Pains that can be dull, constant and boring in type, or
more spontaneous sharp, shooting, or stabbing in
nature; a sensation as if walking on pebbles
Tingling, pins and needles
Hot or cold sensations (e.g., “burning feet”; “like walking
on hot sand”
Allodynia (pain caused by an otherwise non-painful
stimulus, such as light touch or stroking); this can be
very troublesome at night when the feet and legs rub
against the bedclothes
Cramps in the calves and foot muscles.
Dyck, et. al. Peripheral Neuropathy, 4th Edition. 2005
Sensory symptoms
– Gains and/or Losses
Motor symptoms
– Gains (cramps) and/or Losses (distal
predominant)
Autonomic symptoms
– Orthostasis
– Impotence
– Anhidrosis
– Vascular instability in feet
What other conditions must be considered?
Painful feet
– Arthritis, including gout
– Morton’s Neuroma
– Tarsal tunnel syndrome
– Arterial insufficiency
Tingling in the legs
– Venous stasis/peripheral edema
– Restless leg syndrome
– idiopathic
Numbness/Weakness
– Radiculopathy
– CNS dysfunction (i.e. spinal cord pathology or stroke)
O:
General Exam:
Ulcers?
Trophic changes?
Neurological Exam:
Sensation in toes/feet
– 10-g Semmes-Weinstein monofilament
– vibration at great toes, 128 Hz tuning fork
Muscle stretch reflexes (especially ankle jerks)
Motor exam
– Bulk
– Tone
– Power
Sensory Exam
10-g Semmes-Weinstein monofilament
– 3 applications at each
site (one sham)
– Insensate if fail at
1 or more sites
Picture taken from American College of Physicians publication
http://www.acponline.org/clinicalskills/
Sensory Exam
128 Hz tuning fork
Lag time (normal less
than 10 sec)
Start/stop
Making an accurate diagnosis
History
Exam
Referral to Neurology
EDX studies
Epidermal skin fiber density
Nerve biopsy
Conditions Associated with
Painful Peripheral Neuropathy
Diabetes and Pre-Diabetes
Alcohol neuropathy
Chemotherapy
– Platinum-based
Paraproteinemia
Vasculitis and Connective Tissue Diseases
Heavy metals and other toxins
HIV
Amyloidosis
Porphyria
The work-up
Practice Parameter: Evaluation of distal
symmetric polyneuropathy: Role of
laboratory, genetic, and autonomic testing;
nerve biopsy; and skin biopsy (an
evidence-based review)
Report of the Quality Standards Subcommittee of the American
Academy of Neurology, the American Association of
Neuromuscular and Electrodiagnostic Medicine, and the
American Academy of Physical Medicine and Rehabilitation
J.D. England, MD; G.S. Gronseth, MD, FAAN; G. Franklin, MD; G.T. Carter, MD; L.J.
Kinsella, MD; J.A. Cohen, MD; A.K. Asbury, MD; K. Szigeti, MD, PhD; J.R. Lupski,
MD, PhD; N. Latov, MD; R.A. Lewis, MD; P.A. Low, MD; M.A. Fisher, MD; D.N.
Herrmann, MD; J.F. Howard Jr, MD; G. Lauria, MD; R.G. Miller, MD; M.
Polydefkis, MD, MHS; and A.J. Sumner, MD
Neurology 2009;72:1–1
Slide from presentation on www.aan.com
Background
• DSP is the most common type of neuropathy.
• Prevalence is approximately 2,400 (2.4%) per
100,000 population but rises to approximately
8,000 (8%) per 100,000 in individuals older than
55 years.
• Simple screening laboratory tests, along with
medical history, neurological examination, and
EDX studies, reveal the cause of DSP in 74 to
82% of patients with polyneuropathy.
Slide from presentation on www.aan.com
Gaps in Care
• Since there are many etiologies of
polyneuropathy, a logical clinical approach is
needed for evaluation and management.
• DSP diagnosis should be based on a
combination of clinical symptoms, signs, and
electrodiagnostic criteria.
• Laboratory test results must be interpreted within
the larger clinical context since the tests’ low
specificity limits their etiologic yield.
Slide from presentation on www.aan.com
Clinical Questions
1. What is the yield of screening laboratory tests
in the evaluation of DSP, and which tests
should be performed?
2. How accurate is genetic testing for identifying
patients with genetically determined
neuropathies?
3. Which patients with polyneuropathy should be
screened for hereditary neuropathies?
Slide from presentation on www.aan.com
Clinical Questions
What is the usefulness of clinical autonomic
testing in the evaluation of polyneuropathy,
and which tests have the highest sensitivity
and specificity?
5. What is the usefulness of nerve biopsy in
determining the etiology of distal symmetric
polyneuropathy?
6. What is the usefulness and diagnostic
accuracy of skin biopsy in the evaluation of
polyneuropathy?
4.
Slide from presentation on www.aan.com
Recommendations for lab testing:
Screening laboratory tests may be considered
for all patients with DSP (Level C).
Tests with the highest yield of abnormality:
1. blood glucose (fasting)
2. serum B12 with metabolites
(methylmalonic acid, homocysteine)
3. SPEP
(Level C).
Recommendations for lab testing:
Other tests for prediabetes such as a GTT may be
considered in patients with DSPN, especially if it is
accompanied by pain (Level C).
Clinical judgment correlated with the clinical picture will
determine which additional laboratory investigations are
necessary.
Other laboratory studies
ANA, RF, Anti-dsDNA, Anti-Ro, Anti-La,
ANCA screen, cryoglobulins
Urine for heavy metals, porphyrins
IFE/urine IFE/ plasma light chain analysis
Lab tests do not diagnose polyneuropathy
Yield of screening lab tests is variable
PRACTICE PARAMETER:
Evaluation of distal symmetric polyneuropathy:
Role of autonomic testing, nerve biopsy, and
skin biopsy (an evidence-based review)
Report of the American Academy of Neurology, American
Association of Neuromuscular and Electrodiagnostic Medicine, and
American Academy of Physical Medicine and Rehabilitation
Neurology 2009;72:1–1
Assessing Autonomic Nervous System
Cardiovagal
– Heart rate variability
Adrenergic
– Valsalva maneuver
Induces BP changes and monitors pulse reaction
Postganglionic sudomotor function
– QSART
Duration (ms)
Autonomic Testing:
R-R’ interval analysis
1000 ms
Normal
500 ms
Duration (ms)
R-R Cycles
1000 ms
500 ms
R-R Cycles
Abnormal
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 76 • SUPPLEMENT 2 APRIL 2009
Skin biopsy
“For symptomatic patients with suspected
polyneuropathy, skin biopsy may be considered
to diagnose the presence of a polyneuropathy,
particularly SFSN.”
DIAGNOSIS:
A. Lt Calf, Epidermal Nerve Fiber Density:
Skin with significantly reduced epidermal nerve fiber density, consistent with small fiber neuropathy
B. Lt Thigh, Epidermal Nerve Fiber Density:
Skin with normal epidermal nerve fiber density
EPIDERMAL NERVE FIBER DENSITY TEST:
Specimen
Result Value
ABNORMAL
LOW NORMAL
A. Lt Calf
B. Lt Thigh
1.95
13.29
< 5.4
< 6.8
5.4 - 5.7
6.8 - 8.0
Genetic Testing
www. neuromuscular.wustl.edu
What do they look like?
Treatment of DSP
What is the target?
– Pain?
– Tingling?
– Weakness?
FDA, non-FDA
Mainstream versus alternative
Oral, topical, devices, combination
Options
First line?
– Antidepressants
– Anticonvulsants
Efficacy
Adverse effects/tolerability/cost
Second line?
– Opioids
– Pain clinic referral
Antidepressants for neuropathic pain
Cochrane Database of Systematic Reviews 2007. Issue 4.
61 RCT
Results:
– TCA are effective.
NNT 3.6 for at least moderate pain relief
– DN: NNT = 1.3; PHN NNT 2.7
Relatively safe (NNH 28)
–
– Venlafexine
NNT 3.1
NNH Venlafexine 16.2
Tramadol for neuropathic pain
Cochrane Database of Systematic Reviews 2006. Issue 3.
7 trials analyzed
Results:
– Tramadol is effective
NNT 3.8 for at least 50% pain relief
Insufficient data to compare with morphine
EFNS guidelines on pharmacological treatment of
neuropathic pain
In depth review of clinical trials looking at
antidepressants and anticonvulsants in
PPN, PHN
DPN and non-diabetic PPN appear to
respond in similar fashion (except HIV
neuropathy and chemotherapy
neuropathy)
Eur J Neurol 2006; 13: 1153-1169
TCA - amitriptyline, desiprimine, nortriptyline
– Amitriptyline first introduced 1961
– NNT PPN: 2.1
Selective NE/Seratonin Reuptake Inhibitors
– Venlafexine 150-225 mg/d: NNT 4.6
– Duloxetine 60-120 mg/d: NNT 5.2
Antiepileptic drugs (AEDs)
Voltage gated calcium channel ligands
– Gabapentin 1200-3600/d: NNT: 3.9
– Pregabalin 150-600mg/d also effective but data
biased
Others
– Carbamazepine (CBZ) – 2 older studies (1960s) –
difficult to assess based on methods
– Oxcarbazepine: unclear, one study NNT 5.9
– Lamotrigine: NNT 4.0
– Topiramate: negative results in 3 large trials
Opioids
Oxycodone 37-60mg/d, NNT 2.6
Anodyne
Metanx
Why is classification important?
Treatment
Further diagnostics
Prognosis – “Will this get any better?”
Objectives
To review and discuss…
•
•
•
•
•
•
Basic epidemiology of peripheral neuropathy
The diagnostic approach to progressive sensory and
motor dysfunction in the ambulatory care setting
Classification of nerve dysfunction
Reasonable diagnostic work-up for idiopathic diffuse
PN
Updated treatment guidelines for neuropathic pain
Prognosis of PN
Website for The Neuropathy Association www.neuropathy.org
2. Website for The American Diabetes Association www.diabetes.org
3. JAMA. 2010;303(15):1526-1532.
4. Dyck, et. al. Peripheral Neuropathy, 4th Edition. 2005
5. “Diabetic Foot Ulcers” Clinical Skills Module
http://www.acponline.org/
6. Sensory exam with a quantitative tuning fork Neurology
2004;62;461-464
7. Neurology 2009;72:1–1
http://www.neurology.org/cgi/rapidpdf/01.wnl.0000336370.51010.a
1v1.pdf
8. Clev Clin J Of Med 2009; 76: S2
9. Therapath website: www.therapath.com
10. Antidepressants for neuropathic pain
Cochrane Database of Systematic Reviews 2007. Issue 4.
1.