new developments in peripheral neuropathy developments in peripheral neuropathy jeffrey a. niezgoda,...

New Developments in Peripheral Neuropathy

Jeffrey A. Niezgoda, MD FACHM, MAPWCA, [email protected] 1

Jeffrey A. Niezgoda, MDFACHM, MAPWCA, CHWS

Basic Statistics and Demographics

Review Pathophysiology

Discuss DPN Assessment

Demonstrate a Novel Screening Device

Management & Benefits of Treatment

Outline & Overview

The World of Non-Healing Wounds Chronic Disease Trends – a growing problem

4STRICTLY CONFIDENTIAL

Neuropathy

Microvascular disease

Retinopathy, Nephropathy

Protein glycosylation

Macrovascular disease – CAD, CVD, PVD

Immunopathy – susceptibility to infection

Major Complications of Diabetes Mellitus

Diabetes in America, 2nd Ed., 1995CDC: Diabetes Surveillance, 1999



Ulceration

Infection

Lower extremity amputation

Charcot foot (Osteoarthropathy)

Diabetes Related Major Lower Extremity Complications

Frykberg, Armstrong et al: Diabetic Foot Disorders: a Clinical Practice GuidelineJ Foot Ankle Surgery (Supplement 1) 39: October 2000, 2003

25% lifetime occurrence of lower extremity ulceration

0.5- 3.0% annual cumulative incidence of ulcer

Ulceration leads to longer hospitalizations

Foot ulcers are the precursor to amputation in 85% of lower extremity amputation in diabetic patients 7-20% of ulcers subsequently require an amputation

Diabetes is the leading cause of non-traumatic amputation and over 60% of all are diabetic and averaging 82,000 per year

Lower Extremity Amputation

Frykberg R, Zgonis T, Armstrong D, et al, Diabetic Foot Disorders: A clinical Practice Guideline (2006 revision), J of Foot and Ankle Surgery Supplement, 2006, Volume 45;5: s1-66.

Toe amputations are most common amputation (2.6/1000)

Below the knee (1.6/1000), AKA (0.8/1000)

15-20 times higher in DM than non-DM

Direct and indirect costs for diabetic foot disease can easily exceed $6 billion/year

$20,000- 60,000 per event, greater cost the higher the amputation

Diabetes Related Amputation

Frykberg RG et al, Functional outcome in the elderly following lower extremity amputation, J Foot Ankle Surg, 1998;37:181-185.

Among first-time amputees: 30-50% will require additional amputations within 1-3 years

50% will die within five years of an initial major amputation

It has been estimated that 50% to 75% of lower extremity amputations could be prevented…

by modifying risk factors and improving care

among individuals with diabetes.

Diabetes Related Amputation

Frykberg RG et al, Functional outcome in the elderly following lower extremity amputation, J Foot Ankle Surg, 1998;37:181-185.

Peripheral Arterial Disease (PAD)

Peripheral Neuropathy (DPN)

Foot Pathology/Deformities

These factors will commonly contribute to the development of Diabetic Foot Ulcers

that can take several paths depending on the underlying factors

Etiology: Lower Extremity Ulcers Pathways to Amputation

Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation: basis for prevention. Diabetes Care 1990;13(5):513-521.



DeFronzo RA, Reasner C, The Diabetes Control and Complications Trial Study: Implications for the diabetic foot, J Foot Ankle Surg, 10=994;33:551-556.LoGerfo FW, Gibbons GW, Vascular disease of the lower extremities in diabetes mellitus, Endocrinol Metab Clin North Am, 1996;25:439-445.Rosenbloom AL, Silverstein JH, Connective tissue and joint disease in diabetes Mellitus, Endo and Metab Clin, 1996;25:473-483.

Diabetic Neuropathy

Diabetic Neuropathy Definition

“The presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after other

causes have been excluded”

Boulton AJ et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005 Apr;28(4):956-62.

Diabetic NeuropathyEtiology

Multifactor

Exact mechanism not completely understood

Manifestations Subclinical

Clinical

Significant impact on quality of life

Significant financial cost



Causes of Diabetic NeuropathyMetabolic

High blood glucose, long duration of diabetes, abnormal lipids, and possibly low levels of insulin

Neurovascular damage to the blood vessels that carry

oxygen and nutrients to nerves

Autoimmune inflammation in nerves, oxidative stress

Mechanical Direct trauma/injury to nerves

Lifestyle smoking or alcohol use

Etiology & Pathophysiology

Unger J. Pathogenesis, diagnosis, and treatment of painful diabetic peripheral neuropathy. Applied Neurology 2007;(Suppl 1)

Alterations in nerve blood flow

Schwann cell (SC) dysfunction: Primary demyelination, secondary segmental demyelination due to impairment of axonal control of myelination, remyelination, SC proliferation, atrophy of denervated bands of SC, basal lamina hypertrophy.

Neuronal degeneration & progressive impairment of regeneration (esp. thin myelinated fibres)

Neuronal damage caused by hyperglycemia (activation of the polyol pathway, synthesis of AGE products, excess activation of PKC-driven pathways, microangiopathy of the vasa nervorum)

Oxidative stress

Etiology & Pathophysiology

Perivascular lymphocytic inflammation involves two epineurial arterioles. (Hematoxylin and eosin, ×25.)

Semi-thin transverse section illustrates selective involvement of one fascicle, with marked loss of myelinated fibers, a pattern highly suggestive of nerve ischemia.

Reduced nerve function results in the Insensate Foot

DM Neuropathy is the MOST IMPORTANT RISK FACTOR leading to ulceration

DM Neuropathy is present in more than 80% of DM patients with foot ulcerations

Increases amputation risk 1.7 fold 12 fold increase in amputation if deformity is present

36 fold increased amputation risk if history of prior ulcer

Diabetic Neuropathy

Levin, 1995



Sensory Neuropathy LOPS “Loss of Protective Sensation”

Begins in feet can follow to hands

Motor Neuropathy Presents with Contracted digits

Intrinsic Muscular wasting, weakness, foot drop

Autonomic Neuropathy Decrease natural body oil production & sweat

Anhidrosis: decrease perspiration and excess drying

Diabetic Tri-Neuropathy ManifestationsPain and/or paresthesias

Numbness

Autonomic neuropathy dry/scaling skin

Motor changes

Edema formation

DFU Evaluation EssentialsWound Assessment

Classification, culture, radiologic, R/O osteomyelitis

Vascular Assessment pulses, toe and ankle pressures, TCOM’s, venous or arterial

symptoms

Dermatologic Assessment Interdigital area, skin quality, integrity, atrophy callus, ulcerative or

pre ulcerative changes and toenails

Musculoskeletal Assessment deformities such as hammer toes, bunions, evaluate pressure areas,

muscle strength, weakness, contractures, joint ROM and gait

Neurological Assessment evaluate sensory perception, DTR’s, loss of protective sensation

Boulton 2004Frykberg 2000

Detection of Neuropathy

Brush TestObjective:The brush test can be used to

identify mechanical allodynia.

Pinprick TestObjective:The pinprick test is used to

identify hyperalgesia andhypoesthesia.



Objective:Hot/Cold test is used to identify

thermal allodynia (the abnormal sensation of pain from the stimulus of hot or cold).

Cruccu G, Anand P, Attal N, et al. EFNS guidelines on neuropathic pain assessment. Eur J Neurol 2004;11:153-162.Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:1524-34.

Hot/Cold TestObjective:The vibration test can evaluate

the integrity of large nerve fibres.1

This test is a rapid, reliable assessment, requiring less than 60 seconds to administer. 2

Aring AM, Jones DE, Falko JM. Evaluation and prevention of diabetic neuropathy. Am Fam Physician 2005;71(11):2123-28.Perkins BA, Olaleye D, Zinman B, Bril V. Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care 2001;24(2):250-56.

Vibration Test

Monofilament TestObjective:The two-site Semmes-Weinstein

(SW) monofilament test is used to identify loss of sensitivity for people with diabetes.

SW monofilaments come in several strengths, including: 4.17, 5.07, and 6.1 (1, 10 and 75gm force respectively).Less than 7 of 10 pressure

sites patient has an absent protective threshold.

Lee S, Kim H, Choi S, Park Y, Kim Y, Cho B. Clinical usefulness of the two-site Semmes-Weinstein monofilament test for detecting diabetic peripheral neuropathy. J Korean Med Sci 2003;18:103-7.

Four studies were identified which directly compared SWME with NCS and encompassed 1065 patients with, and 52 patients without diabetes mellitus.

Sensitivity ranging from 57-93% 57% (95% CI, 44% to 68%) to 93% (95% CI, 77% to 99%)

Specificity ranging from 75-100% 75% (95% CI, 64% to 84%) to 100% (95% CI, 63% to 100%)

Positive predictive value (PPV) ranging from 84-100% 84% (95% CI, 74% to 90%) to 100% (95% CI, 87% to 100%)

Negative predictive value (NPV) ranging from 36-94% 36% (95% CI, 29% to 43%) to 94% (95% CI, 91% to 96%)

Semmes Weinstein Monofilament Examination

Yuzhe Feng, Felix J. Schlösser, MD, PhD, Bauer E. Sumpio, MD, PhD. The Semmes Weinstein monofilament examination as a screening tool for diabetic peripheral neuropathy. Journal of Vascular Surgery Volume 50, Issue 3, September 2009, Pages 675–682.e1



Conclusion of the meta analysis: Current literature suggests that nerve conduction study

is the gold standard for diagnosing DPN

Semmes Weinstein Monofilament Examination

Yuzhe Feng, Felix J. Schlösser, MD, PhD, Bauer E. Sumpio, MD, PhD. The Semmes Weinstein monofilament examination as a screening tool for diabetic peripheral neuropathy. Journal of Vascular Surgery Volume 50, Issue 3, September 2009, Pages 675–682.e1

A non-invasive device which quickly assesses sudomotor (sweat gland) function via Reverse Iontophoresis and Chronoamperometry

Sudomotor function is used as a marker for small fiber peripheral neuropathy

Abnormal sweat response is often associated with populations at risk for diabetes

Sudoscan

Iontophoresis using an electric charge to open up skin pores for a

drug to enter through the skin

Reverse Iontophoresis using a small electric charge to draw OUT ions (in our

case chloride) from the sweat glands

Chronoamperometry incremental step up of the electric charge used to

measure the current produced

SudoscanMeasuring sweat gland function as a biomarker for

Autonomic Nervous System function

Sympathetic innervation Thin, Unmyelinated C-fibers: no protective coating –

easily damaged

Long: from spine to soles of feet: sensitive to length-dependent damage (dying back disorders)

Therefore sweat dysfunction will be the first detectable damage to the small fibers of the peripheral nervous system

BEFORE ANY CLINICAL SIGNS OR SYMPTOMS

Sudorimetry

Illigens et al. Clin Auton Res 2009

Conditions may cause abnormal Sudoscan results from temporary or permanent nerve damage

ConfoundersSuperficial pain (C-fiber type)

Electric shock, burning, allodynia

Autonomic dysfunction

Thermal imperceptions

Decreased Sweating

Normal strength and reflexes

Small Fiber Neuropathy



Large v Small FiberIt is critical to measure small fibers:

Large fiber neuropathy may signal advanced disease

Detect neuropathy as early as possible in order to correct the underlying disease and possibly reverse the neuropathy

Prevent progression of the neuropathy to ulcers, amputations

Decrease mortality from autonomic neuropathy

Small Fiber Assessment

All patients should be assessed for diabetic peripheral neuropathy starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter

ADA Recommendations

Diabetes Care 2016;39(Suppl. 1):S72–S80 | DOI: 10.2337/dc16-S012

Exclude non-diabetic etiologies

Stabilize DM/ Metabolic control

Diet & Exercise

Pain management

Management Strategy

Pharmaceutical ManagementParameters Significance

Tight glucose control Can reverse the changes but only if the neuropathy and diabetes is recent in onset.

Tricyclic antidepressants (TCA’s) Amitriptyline, Nortriptyline Effective but suffer from multiple side effects that are dosage dependent

Serotonin reuptake inhibitor (SSRI’s) Fluoxetine, Paroxetine, Sertraline and CitalopramFDA not approved, no more efficacious than placebo in several controlled trials.

Antiepileptic drugs (AED’s) Gabapentin & PregabalinEmerging as first line treatment for painful neuropathy.

Methylcobalamin Exerts neuroprotective effects, regeneratesmyelin sheath

Managing Neuropathic Pain: New Approaches For Today's Clinical PracticeCharles E. Argoff, MD, www.medscape.com

Pain Management LadderMonotherapy Combinations Additional

Measures

First-line TCA Low-dose TCA+ AEParacetamol

Acupuncture

Physiotherapy

Anti-epileptic (AE)

Second-line Alternative Antidepressant

Opioid with TCA or AE

Opioid

Capsaicin

Third-line Alternative Opioids Intrathecal drug delivery

Neuromodulation



Intensive glycemic control was associated with a reduction of 40% - 60% in the development or progression of neuropathy

The reduction in complications (Risk of DPN and CAN (64% and 45%, respectively, P<0.01) persisted despite the return of the hemoglobin A1c to pretreatment levels Legacy Effect: Aggressive early intervention to

produce later rewards

Detection & Treatment Matters

Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol. 1995;38(6):869. Neuropathy and related findings in the DCCT EDIC study. ,Martin CL, Albers JW, Pop-Busui R, DCCT/EDIC Research Group Diabetes Care. 2014 Jan;37(1):31-8.

Understanding, Detecting and Treating Diabetic Peripheral Neuropathy is CRITICAL to successful attainment of the goal of amputation prevention.

Small Fiber screening can significant contribute to care of the patient with DFU.

Sudoscan is available for clinical use to screen for small fiber neuropathy.

Summary

Thank You

new developments in peripheral neuropathy developments in peripheral neuropathy jeffrey a. niezgoda,...

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