Kim Chong Hwa MD,PhD

Sejong general hospital, Division of endocrine &

metabolism

Classification and definition of diabetic neuropathies

Painful diabetic peripheral neuropathy

Diabetic autonomic neuropathy

Emerging markers of DPN: focus on small fiber

st1

2

st1 stesfaye, 2010-10-16

The Toronto Diabetic Neuropathy Expert Group Meeting - 2009

Introduction to TDNEG meeting

Diagnosis of DSPN for clinical practice & research

Risk reduction

Pain treatments

Pathogenic treatments

Conclusions

The Toronto Diabetic Neuropathy Expert Group Meeting - 2009The Toronto Diabetic Neuropathy Expert Group Meeting - 2009

The Toronto Diabetic Neuropathy Expert Group Meeting - 2009The Toronto Diabetic Neuropathy Expert Group Meeting - 2009

Introduction to TDNEG meeting

Diagnosis of DSPN for clinical practice & research

Risk reduction

Pain treatments

Pathogenic treatments

Conclusions

Focal and Multifocal

neuropathies

Diabetic Polyneuropathy (DPN)

Entrapmenteg median ulnar peroneal

Distal Symmetrical Polyneuropathy (DSPN)

(Typical DPN)

Multiple lesionsmononeuritis multiplex

Radiculoplexus neuropathies: LS, thoracic, cervical

Mono-neuropathy

AtypicalDPNs

Autonomic

Classification of Diabetic Polyneuropathy (DPN): Classification of Diabetic Polyneuropathy (DPN):

The Toronto Diabetic Neuropathy Expert Group Meeting The Toronto Diabetic Neuropathy Expert Group Meeting

1 APN of poor glycemic control

2 APN of rapid glycemic control

Atypical DPNs: Acute Painful NeuropathiesAtypical DPNs: Acute Painful Neuropathies

Acute onset within weeks; in both Type 1 and 2DM

Persistent burning and shooting pain, allodynia, and

hyperalgesia +++

Nocturnal exacerbation of symptoms and depression

Often severe weight loss

Sensory loss is mild or absent

May be impotence and autonomic neuropathy

Nerve conduction studies are normal or mildly impaired

TDT is usually impaired

Complete resolution of symptoms within 1 year

Treatment: same as chronic PN; BSC; reassurance APN = Acute painful neuropathies; BSC = Best supportive care; PN = Polyneuropathy;

TDT = Transmission disequilibrium test.Tesfaye et al. Diabetologia 1996

Distal Symmetrical

Polyneuropathythy

(DSPN) 50% of DM

Associated with retinopathy &

nephropathy

Microvascular complications are

preventable by rigorous glycemic

control

Risk covariates are CVR and chronic

glycemic exposure

strongest risk factor for foot

ulcer(FU) and amputation

Symmetric, length dependent,

sensory-motor neuropathy Diabetes Care 2010; 33: 2285-93

1.Clinical practice

- Identification of those at risk for FU

2. Epidemiological studies

3.Research Studies

- RCTs, Longitudinal Studies

- Accurate quantification of severity

Diagnosis of DSPN

Tesfaye et al. Diabetes Care 2010; 33: 2285-93

Symptoms of DSPN

Sensory symptoms Numbness

Paraesthesia

Pain (burning, stabbing, shooting, deep aching)

Unusual sensations (tightly wrapped, swelling, etc)

Allodynia

Inability to identify objects in hands

Motor symptoms Difficulty climbing stairs

Difficulty lifting/handling small objects

Sensory modality Nerve fiber Instrument

Vibration A (large) 128Hz TF

Pain (pinprick) C (small) Neuro-tips

Pressure A, A (large) 10g MF

Light touch A, A (large) Wisp of cotton

Cold A (small) Cold TF

Examination:Bedside sensory tests

10g Monofilament

Inexpensive, easy to use,

rapid and reproducible.Smieja et al. J Gen Intel Med 1999

Dorsum 1st toe.

Score 0-8.

5/8 - probability of DPNPerkins et al. Diabetes Care 2001

Predicts foot ulceration. 3 year

RR for foot ulceration = 15Rith-Najarian et al. Diabetes Care 1992

Clinical assessment: SummaryClinical assessment: Summary

History Signs

Sensory symptoms

Motor symptoms

Assessment of disability

Exclude other causes

of neuropathy

InspectionReflexes

Sensory

vibration

light touch

pinprick

10g Monofilament

Assess footwear

Scored clinical assessment: useful in epidemiological studies

Neuropathy Disability Score(NDS)

Toronto Clinical Scoring System(TCSS)

Michigan Neuropathy Scoring

Instrument(MNSI)

1.

2.

3.

Neuropathy Disability Score Neuropathy Disability Score

pain (neuro-tips) 0-1

vibration (128Hz TF) 0-1

warm / cold rods 0-1

ankle reflexes 0-1-2

maximum score = 10

Over 2 years RR CI

Previous FU 3.1 (2.2 - 4.3)

NDS 6/10 2.2 (1.6 - 3.4)

Abnormal 10g MF 1.8 (1.4 - 2.4)

Abnormal ankle reflex 1.6 (1.2 - 2.0)

NW England Study (n=9710)

Young et al. Diabetologia 1993

Abbott et al. Diab Medicine 2002

Quantitative sensory tests:Quantitative sensory tests:

Thresholds for:

vibration

thermal

heat - pain

cold - pain

touch - pressure

electrical impulses

Thermal testing small fiber function

cold

warm

provide quantitative measures of sensationprovide quantitative measures of sensation

Strengths

measures both small fibre and large fiber deficit

relatively simple, less discomfort

useful tool for screening large populations

Limitations

less objective (psychophysical)

less reproducible

no standardization of various systems

(reliant on normative values for each lab)

Report of Am Acad Neurol, Neurology 2003

Quantitative sensory testing:Quantitative sensory testing:

Vibration Perception Threshold:useful in epidemiological studiesVibration Perception Threshold:useful in epidemiological studies

Detects sub-clinical DPN

Predicts foot ulceration

0-15V - low risk

16-25V - intermediate

>25V - high risk (x7)

Young et al. Diabetes Care 1994

Abbott et al. Diabetes Care 1998

Predicts mortality

Coppini et al. J Clin Epidemiol 2000

Nerve conduction studies:

Strengths most objective, accurate, reproducible, sensitive Daube JR 1999

correlate with clinical endpoints Perkins et al. 2001

represent pathological hallmark of DSPN Malik et al. 1989

diagnostic sensitivity improved by incorporation

of anthropometric factors, F-wave testing etc.

Limitations measures only large fiber function

limited availability for routine testing

some discomfort

impact of external factors (eg limb temp. etc)

Essential for research studies of DSPNEssential for research studies of DSPN

Diagnostic certainty of DSPN

Possible

Symptoms or signs of DSPN

Probable

Symptoms and signs of DSPN

Confirmed

Symptoms or signs of DSPN and NC abnormality

Subclinical

NC abnormality only

Possible

Symptoms or signs of DSPN

Probable

Symptoms and signs of DSPN

Confirmed

Symptoms or signs of DSPN and NC abnormality

Subclinical

NC abnormality only

The Toronto Diabetic Neuropathy Expert Group Meeting The Toronto Diabetic Neuropathy Expert Group Meeting

Tesfaye et al. Diabetes Care 2010; 33: 2285-93

Staging DSPNusing confirmed DSPN criteria

Grade 0 = no abnormality of NC, e.g., 5 NC nds < 95th percentile or

another suitable NC criterion.

Grade 1a = abnormality of NC, e.g., 5 NC nds 95th percentile,

without symptoms or signs.

Grade 1b = NC abnormality of 1a plus neurologic signs but without

symptoms.

Grade 2a = NC abnormality of 1a with or without signs (but if present

less than 2b) and with symptoms.

Grade 2b = NC abnormality of 1a, a moderate degree of weakness

(i.e., 50%) of ankle dorsiflexion with or without symptoms

Tesfaye et al. Diabetes Care 2010; 33: 2285-93

Is clinical examination of the PNS reliable for research studies?

Clinical vs Neurophysiological Trial 1

Dyck et al., Muscle and Nerve 2010; 42:157-64.

1. Clinical diagnoses is not always reprodiceableeven when performed by experts!

2. Specific approaches to improving proficiency (clinical exam or NC) are needed and should be tested.

Conclusions from the Clinical vs Neurophysiological Trial 1

Dyck et al., Muscle and Nerve 2010; 42:157-64.

Emerging markers of DPN:

Focus on small fibers

Nerve biopsy - unmyelinsted fiber damage, invasive, highly specilaized procedure-EM

Skin biopsy - minimally invasive, morphometricquantification of intraepidermal nerve fibers(IENF)-number of IENF per length of section(IENF/mm)

Corneal confocal microscopy - noninvasive, small sensory corneal nerve fiber

Nerve axon reflex/flare response C-nociceptivefiber, laser Doppler imaging flare test

Definition of Small fiber neuropathy(SFN)

Possible : presence of length-dependent symptoms and/or clinical signs of small fiber damage

Probable : presence of length-dependent symptoms, clinical signs of small fiber damage, and normal sural NC study

Definite : presence of length-dependent symptoms, clinical signs of small fiber damage, normal sural NC study, and altered IENF density at the ankle and /or abnormal quantitative sensory testing thermal thresholds at the foot

The Toronto Diabetic Neuropathy Expert Group Meeting - 2009The Toronto Diabetic Neuropathy Expert Group Meeting - 2009

Introduction to TDNEG meeting

Diagnosis of DSPN for clinical practice & research

Risk reduction

Pain treatments

Pathogenic treatments

Conclusions

NeuropathyDiabetic Control

Nerve Fiber Loss: The cause of insensitivity in DPN1

1. Veves A, Giurini JM, Logerfo JW. Diabetic Foot. 2nd Edition, Chapter: Diabetic Neuropathy, p10529

Photomicrographs of capillaries from nerve biopsies showing a closed capillary in the diabetic nerve

Microvascular defects in DPN1

DPNDiabetic Control

1. Cameron NA, et al. Diabetologia. 2001;44:197388

Control DPN

1. Tesfaye S, et al. Diabetologia. 1993;36:126674

Microvascular abnormalities in DPN1

Impaired blood flow in established DPN1

Normal Established DPN

1. Tesfaye S, et al. Diabetologia. 1993;36:126674

Risk factors for incident neuropathy:The EURODIAB PCS

Risk factors for incident neuropathy:The EURODIAB PCS

Tesfaye et al. N Engl J Med 2005; 352: 341-50

Total cholesterol

Triglycerides

BMI

Diabetes duration

Change in HbA1c

HbA1c

Smoking

Hypertension1.57

1.38

1.48

1.36

1.40

1.27

1.21

1.15

Model 1:

without CVD

and retinopathy

Odds ratios (95% CI)Odds ratios (95% CI)

n=1101 with type 1 DM; FU: 7.30.6 yrs

Glycaemic control and

management of cardiovascular

risk factors are important

The Toronto Diabetic Neuropathy Expert Group Meeting - 2009

The Toronto Diabetic Neuropathy Expert Group Meeting - 2009

The diagnosis of DSPN depends on whether it is in the context of clinical practice or research

In research studies: Diagnosis of DSPN does not suffice severity must also be estimated.

Neurologists and diabetologists need to reconsider how to more validly and reproducibly diagnose DSPN and estimate severity.

CVR factors appear to be important in the pathogensis of DSPN

Conclusions

Thanks for your attention