Peripheral NeuropathyPeripheral Neuropathy

Andrew Galbreath, D.O.Andrew Galbreath, D.O.

Sentara Neurology SpecialistsSentara Neurology Specialists

Virginia Beach, VAVirginia Beach, VA

Virginia Osteopathic Medical Association2010 Spring CME Conference

May 21, 2010

Opening RemarksOpening Remarks

Objectives

To review and discuss…

1. Basic epidemiology of peripheral neuropathy2. The diagnostic approach to progressive sensory and

motor dysfunction in the ambulatory care setting3. Classification of nerve dysfunction4. Reasonable diagnostic work-up for idiopathic diffuse PN5. Updated treatment guidelines for neuropathic pain6. 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.org²American Diabetes Association www.diabetes.org

Research has been underfundedResearch has been underfunded

2004 NIH funding: $35 million2004 NIH funding: $35 million

2005 NIH funding: $29 million2005 NIH funding: $29 million

For other neurological disorders with For other neurological disorders with similar scope (MS and epilepsy), funding similar scope (MS and epilepsy), funding is approximately 200 times that of PNis approximately 200 times that of PN

Source: The Neuropathy Associationwww.neuropathy.org

Localization of “neuropathy”

Mononeuropathy – one nerveMononeuritis multiplexRadiculopathy – nerve rootPlexopathy – brachial or lumbosacral plexusCranial neuropathy – Bell’s Palsy, 3rd nerve palsyDistal symmetric peripheral neuropathy (DSPN)– Small fiber versus large fiber– Sensory only– Motor only– Sensorimotor

“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…

-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

wearing a thick sock2. 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

3. Tingling, pins and needles4. Hot or cold sensations (e.g., “burning feet”; “like walking

on hot sand”5. 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

6. Cramps in the calves and foot muscles.

Dyck, et. al. Peripheral Neuropathy, 4th Edition. 2005

Sensory symptomsSensory symptoms– Gains and/or LossesGains and/or Losses

Motor symptomsMotor symptoms– Gains (cramps) and/or Losses (distal predominant)Gains (cramps) and/or Losses (distal predominant)

Autonomic symptomsAutonomic symptoms– OrthostasisOrthostasis– ImpotenceImpotence– AnhidrosisAnhidrosis– Vascular instability in feetVascular instability in feet

What other conditions must be considered?

Painful feetPainful feet– Arthritis, including goutArthritis, including gout– Morton’s NeuromaMorton’s Neuroma– Tarsal tunnel syndromeTarsal tunnel syndrome– Arterial insufficiencyArterial insufficiency

Tingling in the legsTingling in the legs– Venous stasis/peripheral edemaVenous stasis/peripheral edema– Restless leg syndromeRestless leg syndrome– idiopathicidiopathic

Numbness/WeaknessNumbness/Weakness– RadiculopathyRadiculopathy– CNS dysfunction (i.e. spinal cord pathology or stroke)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 ExamSensory Exam

10-g Semmes-Weinstein monofilament– 3 applications at each 3 applications at each

site (one sham)site (one sham)– Insensate if fail at Insensate if fail at

1 or more sites1 or more sites

Picture taken from American College of Physicians publication http://www.acponline.org/clinicalskills/

Sensory ExamSensory Exam

128 Hz tuning fork128 Hz tuning fork

Lag time (normal less Lag time (normal less than 10 sec)than 10 sec)

Start/stop Start/stop

Making an accurate diagnosisMaking an accurate diagnosis

HistoryHistory

ExamExam

EDX studiesEDX studies

Epidermal skin fiber densityEpidermal skin fiber density

Nerve biopsyNerve biopsy

Referral to Neurology

Conditions Associated withConditions Associated withPainful Peripheral NeuropathyPainful Peripheral Neuropathy

Diabetes and Pre-DiabetesDiabetes and Pre-Diabetes

Alcohol neuropathyAlcohol neuropathy

ChemotherapyChemotherapy– Platinum-basedPlatinum-based

ParaproteinemiaParaproteinemia

Vasculitis and Connective Tissue DiseasesVasculitis and Connective Tissue Diseases

Heavy metals and other toxinsHeavy metals and other toxins

HIVHIV

AmyloidosisAmyloidosis

PorphyriaPorphyria

The work-up

Practice Parameter: Evaluation of distal Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of symmetric polyneuropathy: Role of

laboratory, genetic, and autonomic testing; laboratory, genetic, and autonomic testing; nerve biopsy; and skin biopsy (an nerve biopsy; and skin biopsy (an

evidence-based review)evidence-based review)

Report of the Quality Standards Subcommittee of the American Report of the Quality Standards Subcommittee of the American Academy of Neurology, the American Association of Academy of Neurology, the American Association of

Neuromuscular and Electrodiagnostic Medicine, and the Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation 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. 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, 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. 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, Herrmann, MD; J.F. Howard Jr, MD; G. Lauria, MD; R.G. Miller, MD; M. Polydefkis,

MD, MHS; and A.J. Sumner, MD MD, MHS; and A.J. Sumner, MD

Slide from presentation on www.aan.comNeurology 2009;72:1–1

BackgroundBackground

• 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 CareGaps 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 QuestionsClinical Questions

1. 1. What is the yield of screening laboratory tests What is the yield of screening laboratory tests in the evaluation of DSP, and which tests in the evaluation of DSP, and which tests should be performed? should be performed?

2. 2. How accurate is genetic testing for identifying How accurate is genetic testing for identifying patients with genetically determined patients with genetically determined neuropathies? neuropathies?

3. 3. Which patients with polyneuropathy should be Which patients with polyneuropathy should be screened for hereditary neuropathies? screened for hereditary neuropathies?

Slide from presentation on www.aan.com

Clinical QuestionsClinical Questions

4.4. What is the usefulness of clinical autonomic What is the usefulness of clinical autonomic testing in the evaluation of polyneuropathy, testing in the evaluation of polyneuropathy, and which tests have the highest sensitivity and which tests have the highest sensitivity and specificity? and specificity?

5.5. What is the usefulness of nerve biopsy in What is the usefulness of nerve biopsy in determining the etiology of distal symmetric determining the etiology of distal symmetric polyneuropathy?polyneuropathy?

6.6. What is the usefulness and diagnostic What is the usefulness and diagnostic accuracy of skin biopsy in the evaluation of accuracy of skin biopsy in the evaluation of polyneuropathy? 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 testing: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 studiesOther laboratory studies

ANA, RF, Anti-dsDNA, Anti-Ro, Anti-La, ANA, RF, Anti-dsDNA, Anti-Ro, Anti-La, ANCA screen, cryoglobulinsANCA screen, cryoglobulins

Urine for heavy metals, porphyrinsUrine for heavy metals, porphyrins

IFE/urine IFE/ plasma light chain analysisIFE/urine IFE/ plasma light chain analysis

Lab tests do not diagnose polyneuropathyLab tests do not diagnose polyneuropathy

Yield of screening lab tests is variableYield 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 Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and RehabilitationElectrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation

Neurology 2009;72:1–1

Assessing Autonomic Nervous SystemAssessing Autonomic Nervous System

CardiovagalCardiovagal– Heart rate variabilityHeart rate variability

AdrenergicAdrenergic– Valsalva maneuverValsalva maneuver

Induces BP changes and monitors pulse reactionInduces BP changes and monitors pulse reaction

Postganglionic sudomotor functionPostganglionic sudomotor function– QSARTQSART

1000 ms

500 ms

R-R Cycles

Dur

ation

(ms)

Autonomic Testing: Autonomic Testing: R-R’ interval analysisR-R’ interval analysis

1000 ms

500 ms

Dur

ation

(ms)

R-R Cycles

NormalNormal

Abnormal 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 neuropathyB. Lt Thigh, Epidermal Nerve Fiber Density:

Skin with normal epidermal nerve fiber density

EPIDERMAL NERVE FIBER DENSITY TEST:Specimen Result Value ABNORMAL LOW NORMALA. Lt Calf 1.95 < 5.4 5.4 - 5.7B. Lt Thigh 13.29 < 6.8 6.8 - 8.0

Genetic TestingGenetic Testing

www. neuromuscular.wustl.edu

What do they look like?What do they look like?

Treatment of DSPTreatment of DSP

What is the target?What is the target?– Pain?Pain?– Tingling?Tingling?– Weakness? Weakness?

FDA, non-FDAFDA, non-FDA

Mainstream versus alternativeMainstream versus alternative

Oral, topical, devices, combinationOral, topical, devices, combination

OptionsOptions

First line?First line?– AntidepressantsAntidepressants– AnticonvulsantsAnticonvulsants

EfficacyEfficacy

Adverse effects/tolerability/costAdverse effects/tolerability/cost

Second line?Second line?– OpioidsOpioids– Pain clinic referralPain clinic referral

Antidepressants for neuropathic pain Antidepressants for neuropathic pain Cochrane Database of Systematic Reviews Cochrane Database of Systematic Reviews 2007. Issue 4.2007. Issue 4.

61 RCT61 RCT

Results:Results:– TCA are effective.TCA are effective.

NNT 3.6NNT 3.6 for at least moderate pain relief for at least moderate pain relief– DN: NNT = 1.3DN: NNT = 1.3; PHN NNT 2.7; PHN NNT 2.7

Relatively safe (NNH 28)Relatively safe (NNH 28)–

– Venlafexine Venlafexine

NNT 3.1NNT 3.1

NNH Venlafexine 16.2NNH Venlafexine 16.2

Tramadol for neuropathic painTramadol for neuropathic painCochrane Database of Systematic Reviews Cochrane Database of Systematic Reviews 2006. Issue 3.2006. Issue 3.

7 trials analyzed7 trials analyzed

Results:Results:– Tramadol is effectiveTramadol is effective

NNT 3.8NNT 3.8 for at least 50% pain relief for at least 50% pain relief

Insufficient data to compare with morphineInsufficient data to compare with morphine

EFNS guidelines on pharmacological treatment of EFNS guidelines on pharmacological treatment of neuropathic painneuropathic pain

In depth review of clinical trials looking at In depth review of clinical trials looking at antidepressants and anticonvulsants in antidepressants and anticonvulsants in PPN, PHNPPN, PHN

DPN and non-diabetic PPN appear to DPN and non-diabetic PPN appear to respond in similar fashion (except HIV respond in similar fashion (except HIV neuropathy and chemotherapy neuropathy and chemotherapy neuropathy)neuropathy)

Eur J Neurol 2006; 13: 1153-1169

TCA - - amitriptyline, desiprimine, nortriptylineamitriptyline, 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 ligandsVoltage gated calcium channel ligands– GabapentinGabapentin 1200-3600/d: 1200-3600/d: NNT: 3.9NNT: 3.9– Pregabalin 150-600mg/d also effective but data biasedPregabalin 150-600mg/d also effective but data biased

OthersOthers– Carbamazepine (CBZ) – 2 older studies (1960s) – Carbamazepine (CBZ) – 2 older studies (1960s) –

difficult to assess based on methodsdifficult to assess based on methods– Oxcarbazepine: unclear, one study Oxcarbazepine: unclear, one study NNT 5.9NNT 5.9– Lamotrigine: Lamotrigine: NNT 4.0NNT 4.0– Topiramate: negative results in 3 large trialsTopiramate: negative results in 3 large trials

OpioidsOpioids

Oxycodone 37-60mg/d, Oxycodone 37-60mg/d, NNT 2.6NNT 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

1. 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.a1v1.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.

11. Tramadol for neuropathic painCochrane Database of Systematic Reviews 2006. Issue 3.

12. European Federation of Neurological SocietiesEur J Neurol 2006; 13: 1153-1169.