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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… Basic epidemiology of peripheral neuropathy

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peripheral neuropathy

Peripheral Neuropathy

Virginia Osteopathic Medical Association

2010 Spring CME Conference

May 21, 2010

Andrew Galbreath, D.O.

Sentara Neurology Specialists

Virginia Beach, VA

objectives
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

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

Epidemiology

¹The Neuropathy Association www.neuropathy.org

²American Diabetes Association www.diabetes.org

research has been underfunded
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
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.

48 yr old man with no prior medical history…
85 yr old man
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.

slide11
S:

Numbness, or a feeling of walking on cotton wool or 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

slide12

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
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)
slide14
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
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 exam1
Sensory Exam
  • 128 Hz tuning fork
  • Lag time (normal less than 10 sec)
  • Start/stop
making an accurate diagnosis
Making an accurate diagnosis
  • History
  • Exam
  • EDX studies
  • Epidermal skin fiber density
  • Nerve biopsy

Referral to Neurology

conditions associated with painful peripheral neuropathy
Conditions Associated withPainful 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
slide21
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

Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory, genetic, and autonomic testing; nerve biopsy; and skin biopsy (an evidence-based review)

Neurology 2009;72:1–1

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

Slide from presentation on www.aan.com

background
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
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
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 questions1
Clinical Questions
  • What is the usefulness of clinical autonomic testing in the evaluation of polyneuropathy, and which tests have the highest sensitivity and specificity?
  • What is the usefulness of nerve biopsy in determining the etiology of distal symmetric polyneuropathy?
  • What is the usefulness and diagnostic accuracy of skin biopsy in the evaluation of polyneuropathy?

Slide from presentation on www.aan.com

recommendations for lab testing
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 testing1
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
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
slide29

Lab tests do not diagnose polyneuropathy

  • Yield of screening lab tests is variable
practice parameter
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
Assessing Autonomic Nervous System
  • Cardiovagal
    • Heart rate variability
  • Adrenergic
    • Valsalva maneuver
      • Induces BP changes and monitors pulse reaction
  • Postganglionic sudomotor function
    • QSART
slide32

1000 ms

Duration (ms)

1000 ms

Duration (ms)

500 ms

500 ms

R-R Cycles

R-R Cycles

Autonomic Testing: R-R’ interval analysis

Normal

Abnormal

skin biopsy
Skin biopsy

“For symptomatic patients with suspected polyneuropathy, skin biopsy may be considered to diagnose the presence of a polyneuropathy, particularly SFSN.”

slide35

DIAGNOSIS:

  • 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 1.95 < 5.4 5.4 - 5.7

B. Lt Thigh 13.29 < 6.8 6.8 - 8.0

treatment of dsp
Treatment of DSP
  • What is the target?
    • Pain?
    • Tingling?
    • Weakness?
  • FDA, non-FDA
  • Mainstream versus alternative
  • Oral, topical, devices, combination
options
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
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
Tramadol for neuropathic painCochrane 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
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

slide45

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
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
Opioids
  • Oxycodone 37-60mg/d, NNT 2.6
why is classification important
Why is classification important?
  • Treatment
  • Further diagnostics
  • Prognosis – “Will this get any better?”
objectives1
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

slide52

Website for The Neuropathy Association www.neuropathy.org

  • Website for The American Diabetes Association www.diabetes.org
  • JAMA. 2010;303(15):1526-1532.
  • Dyck, et. al. Peripheral Neuropathy, 4th Edition. 2005
  • “Diabetic Foot Ulcers” Clinical Skills Module http://www.acponline.org/
  • Sensory exam with a quantitative tuning fork Neurology 2004;62;461-464
  • Neurology 2009;72:1–1

http://www.neurology.org/cgi/rapidpdf/01.wnl.0000336370.51010.a1v1.pdf

  • Clev Clin J Of Med 2009; 76: S2
  • Therapath website: www.therapath.com
  • Antidepressants for neuropathic pain Cochrane Database of Systematic Reviews 2007. Issue 4.
  • Tramadol for neuropathic painCochrane Database of Systematic Reviews 2006. Issue 3.
  • European Federation of Neurological SocietiesEur J Neurol 2006; 13: 1153-1169.