Guy R. Pupp, DPM, FACFAS

Program Director

Podiatry Residency

Providence Hospital, Michigan

Diabetic Neuropathy

NO FINANCIAL DISCLOSURES

An estimated 285 million people worldwide had

diabetes in 2010, according to the International

Diabetes Federation. The federation predicts as

many as 438 million will have diabetes by 2030.

Nearly 110 million wounds! U.S… Yr. 2050: 48 Million DM, 9.6 Million Ulcers

Amputation secondary to NEUROPATHY and PAD

Misdiagnosed CLI

BKA associated with NEUROPATHY and PAD

Neuropathic Ulcers…B-K Amputation?

Diabetic Foot Ulcers One of the most common complications of diabetes

Annual incidence 1% to 4%1-2

Lifetime risk 15% to 25%3-4

~15% of diabetic foot ulcers result in lower extremity amputation3,5

~85% of lower limb amputations in patients with diabetes are proceeded by ulceration6-7

Peripheral neuropathy is a major contributing factor in diabetic foot ulcers1-7

Other factors: foot deformity, callus, trauma, and peripheral vascular disease

1. Reiber and Ledoux. In The Evidence Base for Diabetes Care. Williams et al, eds. Hoboken, NJ: John Wiley & Sons; 2002:641–665.

2. Boulton et al. NEJM. 2004;351:48.3. Sanders. J Am Podiatry Med Assoc. 1994;84:322.

4. Boulton et al. Lancet. 2005;366:1719.5. Ramsey et al. Diabetes Care 1999;22:382.6. Pecoraro et al. Diabetes Care. 1990;13:513.7. Apelqvist and Larsson. Diabetes Metab Res Rev. 2000:16:S75.

Diabetic Peripheral Neuropathy:

What is it?

• Nerve damage and dysfunction secondary to diabetes mellitus type 1 or 2

– Consensus definition: “the presence of an abnormality of nerve conduction and a symptom or symptoms or a sign or signs of neuropathy confirm Distal Symmetrical Polyneuropathy (DSPN). If nerve conduction is normal, a validated measure of small fiber neuropathy may be used.”

Tesfaye S, et al. Diabetes Care 2010;33:2285-2293..

Diabetic Neuropathy:

The Forgotten Complication

Results of the 2005 ADA National Survey

• Only one in four survey respondents who experience symptoms of diabetic neuropathy have been diagnosed with the condition.

• The majority of respondents who experience symptoms (56%) remain unaware of the term DIABETIC NEUROPATHY.

• 62% believe that their symptoms are associated with their diabetes, but only 42% have been told by their physician that diabetes is the cause.

• Approximately one in seven people who said they talked to their doctor about their symptoms and pain reported that no cause was mentioned.

May 10, 2005 /PR Newswire via COMTEX.

Neuropathy is Commonly Underdiagnosed

For every mistake made for not knowing, 10 are made

for not looking

Endocrinologists

Non-endocrinologists

Co

rre

ct

dia

gn

os

is (

%)

0

20

40

60

80

100

No neuropathy

(n=4628)Non-severeneuropathy

(n=2209)

Severeneuropathy

(n=541)

Herman et al. Diabetes Care. 2005;28:1480.Breathnach CS and Moynihan JB. Ulster Med J 2012;81(3):149-153.

- J.A. Lindsay

Clinical Unmet Needs in DM Neuropathy

• There are a wide range of treatments available forneuropathic pain

• This prescribing pattern suggests that there is no one treatment that addresses all the factors

• Despite a spectrum of drugs available with different modes of action, many patients remain inadequately treated in several aspects of the disease

Increasinglevel ofimportance

Improvedefficacy

Improved sideeffect profile

Reduced time toonset of action

Fewer drug-druginteractions

Reduced pillburden

Datamonitor Research 2008.

Clinical Impact of DPN Total Symptoms

DPN

Painfulneuropathicsymptoms

NeuropathicdeficitsImpairment

DisabilityHandicap

FootUlcers...Charcot

Infection(skin, bone)

Quality

of life

Surgery, Amputation96,000/y

AtaxiaWeakness

Falls

Mortality

Cost $37B

Fractures

Vinik, et al. Endo & Metab 2006;2(5):269-81.

Vinik, Aaron. Frontiers in Endocrinology 2012;3:1-3.

Vinik A, et al. Endocrinol Metab Clin N Am 2013;42:747-787.

NEUROPATHY…Charcot…Ulcer...Osteo…BKA

Some Effects of Amputation on

Quality of Life

Limitation of daily activities

Impairment of physical activity

Early Retirement

Reduced Income

Loss of Social Contacts

Impairment of Sexual Activity

Aging, Disease and Falls • Risk of falling typically increases when (age-related) diseases emerge

• One third of people >65y fall annually

• Each day in the US 63 people die from a fall- related injury

• An additional 1800 are hospitalized

• The commonest causes of falling are:

Hypertension

Diabetes

Polypharmacy

• Therefore we need to compensate for both age- and disease-related factors that can impact on balance and stability

Neuropathy in Diabetes

Tromp AM, et al. J Clin Epidemiol 2001;54:837-44.

Centers for Disease Control and Prevention website at http://www.cdc.gov/injury/wisqars

Reaction Time- Hand- Foot

Proprioception

Lower Limb Strength- Ankle dorsi-flexion- Knee flexion- Knee Extension

Sensation

Vision- Visual Acuity

- Contrast Sensitivity

Postural Sway

Clinical Tests

VisionSomatosensoryVestibular Auditory

Neurological

Perc

epti

on

Cognition

Pro

prio

ceptio

n

Strength

Motor

Balance & Mobility Cardiorespiratory

Polyp

harm

acy

Risk Factors for Falls

Distal Symmetric Diabetic Neuropathies

Subtypes:

Neuropathy

Large-fiber

MYELINATED SENSORY-MOTOR

Deep-seated pain (A- type)

Wasting and weakness

Numbness, pins and needles,

tingling & ataxia

Impaired vibration perception

Loss of position sense

Loss of reflexes

Impaired nerve conduction velocity

Interferes with normal life

Risk of falling and fractures

Small-fiber

UNMELINATED SENSORY ONLY

Superficial pain (C-fiber type)

Electric shock, burning, allodynia

Autonomic dysfunction

Thermal imperception

Normal strength and reflexes

Electrophysiogically silent

Quantitative sensory testing and

skin biopsies

Produces symptoms

Leads to morbidity and mortality

Vinik A, et al. Endo & Metab 2006;2(5):269-281.

Large Fiber NeuropathyCarry info regarding position and vibration

-weakness…<DTR, <Vib

-”numbness without pain”

Diagnosis: EMG, NCV

Simple Tests of Large-Fiber Function

Controls (n=11)Diabetic controls (n=8)Diabetic neuropathy (n=14)

0

20

40

60

80

100

120

140

160

180

2-minutewalk

Dis

tan

ce (

m)

*

30

0

5

10

15

20

25

Tandemstand

1- footstand

Balancewalk

Foottapping

Tim

e (

s) *

†

* *

Resnick et al. Muscle Nerve. 2002;25:43.

* P<0.05 vs nondiabetic controls; †P<0.01 vs nondiabetic controls

SMALL FIBER NEUROPATHY

Carry info regarding pain and temperature

-stocking/glove effect

-Electrical studies are WNL

Diagnosis: Clinical info

Skin biopsy

Differential Dx of Small Fiber Neuropathy

MS

Raynauds

FMS

RSD/CRPS

Restless Leg

Neuroma

Therapath Neuropathology Report, 2004.

CAUSES OF SMALL FIBER NEUROPATHY

AutoimmuneSarcoidSjogren’s SyndromeInflammatory Bowel DiseaseLyme DisEtOH abuseDrugs,ToxinsAmyloidosisLupusVasculitis

Bakkers M et al. J. Neurol 2010, 12: 2086-90

Small Fiber Neuropathy

– Pain is C-fiber type, burning, superficial, allodynia

– Early hyperesthesia and hyperalgesia, impaired neurovascular function

– late hypoesthesia and hypoalgesia

– Impaired warm thermal and pain thresholds, decreased IENF

– Decreased sweating

– Normal strength, reflexes and EMG!!!

Vinik, A.I., et al. Exp. Clin. Endocrinol Diabetes 2001;109(Suppl 2):S451-S473.

The Use of 1 and 10g Monofilament Test

DIABETIC NEUROPATHY

Diabetic Neuropathy: A Small Fiber Disease

Normal Skin

Biopsy

Small Fiber

Neuropathy Biopsy

Normal innervation with small nerve

fibers seen in the epidermis (arrows).

Skin biopsy specimens with protein

gene product 9.5 immunostaining.

A specimen from a patient with small

fiber neuropathy shows denervation

with no small nerve fibers seen in the

epidermis

Tavee J , Zhou L Cleveland Clinic Journal of Medicine 2009;76:297-305

Work-up for Peripheral Neuropathy:

A1c (Glycohemoglobin)

CBC

Chemistry Profile

TSH

B12, Folic Acid Level

Serum Protein Electrophoresis (SPEP)

Sedimentation Rate, ANA, RPR, RA

Heavy Metal Screen (Lead, Arsenic, Mercury)

*EMG/NCV

*Biopsy/CSF

*Genetic screening

Pain Can Directly Lead to Sleep and Psychological Symptom Problems

Paradigm of pain

Sleep interference can

directly result from

chronic pain and

exacerbate pain

Psychological symptoms

are strongly associated

with NeP, anxiety and

depression

Management strategies of NeP patients

is to improve overall patient functionality

and treat all comorbidities to improve QOL

Argoff CE. Clin J Pain. 2007;23(1):15-22.

Vinik modified from Nicholson B, Verma S. Pain Med. 2004;5(Suppl

1):S9-S27.

Moulin DE, et al. Pain Res Manag. 2007;12(1):13-21.

Vinik, et al. Clinical Thera

2013;35(5):612-623.

Vinik, et al. Pain Med. In Press 2013.

Depression, Anxiety, Sleep –More Commonly Present with Neuropathy than Not

Castro M, et al. Arq Neuropsiquiatr. 2009;67(1):25-28

38.5%

61.5%

27.3%

72.8%

7.0%

93.0%

0%

20%

40%

60%

80%

100%

Not Depressed Depressed Not Anxious Anxious Normal Abnormal

N=400

DEPRESSION ANXIETY SLEEPING PATTERNS

%

DNAssociation of Metformin and Clinically Worsened DPN

The Neuropathy Impairment Scale

has been designed in an effort to

maximize the measurement of

potential changes in all motor,

sensory and reflex activity in the

lower limbs. Total score ranges

from normal = 0 to maximum of

16.

n = 122

• A prospective study of 122 symptomatic DPN patients compared those who had >6 months of metformin to those without metformin

• Metformin-associated cobalamindeficiency may contribute to the clinical burden of DPN (P<0.001).

• The severity of DPN positively correlates to increases in the cumulative metformin dose (P<0.001)

Wile DJ, et al. Diabetes Care 2010;33:156-61.Bril, Vera. Eur Neurol 1999;41(Suppl 1):8-13.

Diabetic Neuropathy Treatment Options

TCAs, Pregabalin

Opioids

Gabapentin / Duloxetine

Pain Management

Glucose Management

Medical Foods (Metanx)

Vitamins (B12, Folic acid…)

Topical Compounds

Adapted from Tavakoli M and Malik R. Expert Opin Pharmacother. 2008;9(17):2969-2978..

Fonseca VA, et al. Am J Med 2013;126(2):141-149.

Interventional Tx-Regional N Blocks-Sympathetic Blocks-Spinal Cord Stimulators-Infusion Therapy

SURGERY-Tarsal Tunnel Deconpression

-Neurolysis

Metanx®-Methylfolate 3 mg

Methylcobalamin 2 mg

Pyridoxal 5’ –phosphate 35 mg

Nutritional support specifically modified for the management of the distinct nutrient needs that result from the disease or condition, as determined by medical evaluation.

Medical Food – Regulated by FDA

• Metanx® is dispensed by prescription under supervision of a HCP

• Metanx® addresses the underlying condition such as endothelial dysfunction / DPN

• Metanx® is scientifically recognized in peer-reviewed literature

U.S. Food and Drug Administration. Guidance for Industry: Frequently Asked Questions About Medical Foods. Available at:

http://www.fda.gov/Food/Guidanceregulation/GuidanceDocumentsRegulatoryInformation/Medical Foods/ucm054048.htm Accessed May 23, 2014.

Clinical Case Outcome I

Baseline 6 months

Patient received baseline skin punch biopsy and given L-methylfolate, Me-Cbl, P-5-P (Metanx®)

twice daily and followed for six months. Left image represents baseline skin punch biopsy at

left calf. Right image represents six month follow up skin punch biopsy. Patient average

increase of 3.75 nerve fibers per mm. Skin Punch Biopsy Analysis and Images Performed by

Therapath, LLC

Metanx® is a medical food dispensed by prescription for the clinical dietary management of endothelial

dysfunction in patients with diabetic peripheral neuropathy. Use under medical supervision. Jacobs AM and Cheng D. Rev Neurol Dis. 2011;8(1/2):39-47.

Metanx® Administration to PregabalinPartial-Responders for Management of DPNP

Results from a 20 week, open label trial of Metanx® in 24 patients with a partial response to pregabalin.

After nutritional management with Metanx®:

The average absolute pain reduction after 20 weeks in the study group was 3.0 compared to .25 in the control group (P<0.001)

After 20 weeks, the study group experienced greater pain relief compared to the active control group, 87.5% vs. 25.0% reduction in NPS respectively (P=0.005)

Jacobs, AM, Cheng D. J Diabetes Mellit 2013;3(3):134-38.

0

-0.5

-1

-1.5

-2

-2.5

-3

-3.50 20

Weeks

Pai

n R

edu

ctio

n

P<0.001

Pregabalin

L-methylfolate,

Me-CBl, P-S-P/

Pregabalin

Significant Change in Neuropathic Pain

Summary and Conclusions: Diabetic Neuropathies

Diabetic neuropathies are a heterogeneous group of disorders that occur in about 50% of patients with diabetes. Approximately 40% are painful.

DPN is the most common form of neuropathy and is a mixed sensorimotor neuropathy involving small and large fibers, with each fiber having a different etiology and producing its own constellation of features.

The pathogenesis is being unraveled and therapy directed at oxidative/nitrosative stress and autonomic imbalance have lead to major breakthroughs in management with the ability to reduce cardiovascular events, regenerate nerves, stop falls and reduce foot ulceration. There are promising agents in the wings including gene therapy that address the core pathogenic mechanisms and are potential targets for therapy in the future.

Tesfaye S and Selvarajah D. Diabetes Metab Res Rev 2012;28(Suppl 1):8-14.Boulton AJM, et al. Diabetes Care 2005;28(4):956-962.

Vinik and Casellini. Diabetes, Metabolism Syndrome & Obesity 2013;6:57-78.

Guy R. Pupp, DPM, FACFAS

Program Director

Podiatry Residency

Providence Hospital, Michigan

Diabetic Neuropathy