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Painful PeripheralNeuropathy

Division of Pain Medicine

Department of Anesthesiology

University Hospitals ofCleveland

Salim Hayek, MD, PhD

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Painful Peripheral Neuropathy

Salim Michel Hayek, MD, PhDDivision of Pain Medicine

Department of Anesthesiology

University Hospitals of Cleveland

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Conflicts of Interest

None Relevant to this talk

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Learning Objectives

Pathophysiology

Epidemiology

Diagnosis

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Gorson KC, Ropper AH. Idiopathic distal small fiber neuropathy. Acta NeurologicaScandinavica. 1995;92(5):376-382

Peripheral Neuropathies

Large Fiber (LFN)Small Fiber (SFN)

Most common painful neuropathyDistal painful peripheral neuropathy Painful Feet and later may handsBurning pain, pins and needles: + symptoms

Numbness: -symptomsMixed Fiber Neuropathies (MFN)

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Nerve Fiber Types

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Gregg EW et al., Diabetes Res Clin Pract 2007; 77:485488

Peripheral Neuropathy

15 to 20 million people in the UnitedStates over age 40 have some type of

peripheral neuropathyNon-Painful

Painful: Small Fiber Neuropathy (SFN)

pain, burning, tingling, and numbness in alength-dependent or stocking-glovedistribution

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Tavee J & Zhou L, Cleve Clin J Med. 2009 May;76(5):297-305

SFNClinical Finding

Often normalNeurologic exam

EMGNCS

Erroneous diagnoses:

Plantar fasciitisVascular insufficiencyDegenerative lumbosacral spine disease

A fibersA fibers

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Lopate G et al., Muscle Nerve. 2006 May;33(5):672-6Low PA et al., Diabetes Care. 2004 Dec;27(12):2942-7.

SFN Prevalence

Sjogrens: 45% have pure SFN withburning painDiabetes: neuropathy in 50-70%, not all

with burning pain

Inferred prevalence:Diabetes is at approx 6% of population (CDC)Distal burning pain occurs in 15-20% of

diabetics, or ~1% of entire population

Of patients referred for the evaluation ofSFN, about 1/3 have diabetes 3-5%Italian study found prevalence of 3% (Beghi,

1995)

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Gorson KC, Ropper AH. Idiopathic distal small fiber neuropathy. Acta NeurologicaScandinavica. 1995;92(5):376-382

SFN Pathophysiology

Degeneration of smallUnmyelinated C-Fibers

Thinly myelinated A- Fibers~Autonomic fibers

When progression from small fiber to largefiber neuropathy occurs, a symptomatic

change from "positive" to "negative"neuropathic symptoms is observed clinically

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Distal Symmetric Polyneuropathy:Small Fiber

First: pain and hyperalgesia Later: loss of sensitivity

oHeat/Cold

oLight touch/pinprick

Autonomic symptoms

Predisposes to diabetic footdisease

Electrophysiology may notdetect nerve damage

VinikVinik. In:Diabetes and Carbohydrate Metabolism. 2002.

A fibers

A & C fibers

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SFN Symptoms

Vague discomfort, length-dependent numbness in toes, pebbles

burning pain: stocking/gloves

Worse at night

tightness around feet

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SFN Exam

Allodynia

Hyperalgesia

pinprick/thermal sensation

Mild in vibratory sense

Motor strength, DTR andproprioception are WNL

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Tavee J & Zhou L, Cleve Clin J Med. 2009 May;76(5):297-305.

Autonomic Symptoms

HistoryDry eye, dry mouth, orthostatic dizziness,

constipation, bladder incontinence, sexualdysfunction, trouble sweating, skindiscoloration (red or white)

Physical Exam

Orthostatic hypotension, dry, shiny anddiscolored atrophic skin (vasomotor orsudomotor abnormalities)

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Rathmann W et al., Diabet Med. 1993 Nov;10(9):820-4

Autonomic Prognosis is poor

If an autonomic neuropathy is part ofthe small fiber neuropathy, the

prognosis is quite poor5 Studies conducted between 1980

and 1993 showed 23% to 56%

mortality at 5 years!

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Vinik In: Diabetes and Carbohydrate Metabolism, 2002

Distal Symmetric Polyneuropathy:Large Fiber

Sensory and/or motor nervesFeet usually affected first

Vibration perceptionPosition sense (proprioception)Muscle Wasting (hammertoes)~Deep seated gnawing pain

May interfere with ADLAbnormalities detected by EMG

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Causes of SFN Diabetes mellitus/pre-DM Dysthyroidisms

Alcoholism Amyloidosis B12 deficiency Celiac disease Paraproteinemia Restless leg syndrome Paraneoplastic syndrome Neurotoxic drug exposure Hereditary Infectious

HIV Hepatitis C

Autoimmune diseases Sjgren's disease Scleroderma SLE

Not length-dependent

Idiopathic SFN ~50% of cases, no etiology can be found despite extensive medical work up

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Tavee J & Zhou L, Cleve Clin J Med. 2009 May;76(5):297-305Sumner CJ et al., Neurology 2003; 60:108-111

SFN often precedes Diabetes

Impaired glucose tolerance (IGT) 2nd hour>140 mg/dl and

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Why Early Nerve Involvement?Pancreatic Peri-Islet Schwann Cells

Winer S et al. Nature Medicine 9:198, 2003

T ll tt k S h ll

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T-cells attack Schwann cellsbefore pancreatic Beta-cells

Green = T-cells (CD3)

Red = Schwann cell (GFAP)

Blue = Beta-cell (Insulin)

Winer S et al. Nature Medicine 9:198, 2003

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Tesfaye S et al., N Engl J Med. 2005 Jan 27;352(4):341-50Smith AG et al., J Neurol Sci. 2008 Oct 15;273(1-2):25-8

Metabolic Syndrome

HTN + Hyperlipidemia + Obesity +Insulin Resistance (DM or pre DM)

Risk factor forCardiovascular disease

Cerebrovascular disease

Small Fiber Neuropathy (more importantrole for dyslipidemia)

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Diagnosis: Skin Biopsy (IENFD)

Int Epi m N Fib D nsit

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SkinBiopsy2 mm

punchbiopsiesstained/

smallfiberscounted

IntraEpi erma Nerve Fiber DensityIENFD

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Walk D et al., Neurol Sci. 2007 Apr 15;255(1-2):23-6

Skin Biopsy Correlates with Exam

106 patients & 45 controlsubjects

Defined as a syndrome of Idiopathic symmetric

burning,

Paresthesias, hyperalgesia,or allodynia in a length-dependent distribution

Normal strength, reflexes,and nerve conduction

Excluded DM, B12

Divided into nl & abnlsensation to pin & vibration Best discrimination

occurred at 8/mm Modest correlation

foot/calf

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Key Points

Small Fiber Neuropathy (SFN) is a majorcause of neuropathic pain

Diabetic Painful Neuropathy is ~ SFNPre-diabetic neuropathy is a frequentcause of SFNSkin biopsy (IENFD) is important in

diagnosisBehavioral modification, Pharmacotherapy

and SCS are potential treatments

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Thank You!!

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