Kim Chong Hwa MD,PhD Sejong general hospital, Division of endocrine & metabolism

Transcription

1 Kim Chong Hwa MD,PhD Sejong general hospital, Division of endocrine & metabolism

2 st1 Classification and definition of diabetic neuropathies Painful diabetic peripheral neuropathy Diabetic autonomic neuropathy Emerging markers of DPN: focus on small fiber

3 슬라이드 2 st1 stesfaye,

4 The Toronto Diabetic Neuropathy Expert Group Meeting

5 The Toronto Diabetic Neuropathy Expert Group Meeting Introduction to TDNEG meeting Diagnosis of DSPN for clinical practice & research Risk reduction Pain treatments Pathogenic treatments Conclusions

6 The Toronto Diabetic Neuropathy Expert Group Meeting Introduction to TDNEG meeting Diagnosis of DSPN for clinical practice & research Risk reduction Pain treatments Pathogenic treatments Conclusions

7 Classification of Diabetic Polyneuropathy (DPN): The Toronto Diabetic Neuropathy Expert Group Meeting Focal and Multifocal neuropathies Diabetic Polyneuropathy (DPN) Mononeuropathy Multiple lesions mononeuritis multiplex AtypicalD PNs Autonomic Radiculoplexus neuropathies: LS, thoracic, cervical Entrapment eg median ulnar peroneal Distal Symmetrical Polyneuropathy (DSPN) (Typical DPN)

8 Atypical DPNs: Acute Painful Neuropathies 1 APN of poor glycemic control 2 APN of rapid glycemic control 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

9 Distal Symmetrical Polyneuropathythy (DSPN) 50% of DM strongest risk factor for foot ulcer(fu) and amputation Associated with retinopathy & nephropathy Risk covariates are CVR and chronic glycemic exposure Microvascular complications are preventable by rigorous glycemic control Symmetric, length dependent, sensory-motor neuropathy Diabetes Care 2010; 33:

10 Diagnosis of DSPN 1. Clinical practice - Identification of those at risk for FU 2. Epidemiological studies 3. Research Studies - RCTs, Longitudinal Studies - Accurate quantification of severity Tesfaye et al. Diabetes Care 2010; 33:

11 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

12 Examination:Bedside sensory tests Sensory modality Nerve fiber Instrument Vibration Aß (large) 128Hz TF Pain (pinprick) C (small) Neuro-tips Pressure Aß, Aα (large) 10g MF Light touch Aß, Aα (large) Wisp of cotton Cold Aδ (small) Cold TF

13 10g Monofilament Inexpensive, easy to use, rapid and reproducible. Smieja et al. J Gen Intel Med 1999 Predicts foot ulceration. 3 year RR for foot ulceration = 15 Rith-Najarian et al. Diabetes Care 1992 Dorsum 1 st toe. Score /8 - probability of DPN Perkins et al. Diabetes Care 2001

14 Clinical assessment: Summary History Sensory symptoms Motor symptoms Assessment of disability Exclude other causes of neuropathy Signs Inspection Reflexes Sensory vibration light touch pinprick 10g Monofilament Assess footwear

15 Scored clinical assessment: useful in epidemiological studies Neuropathy Disability Score(NDS) Toronto Clinical Scoring System(TCSS) Michigan Neuropathy Scoring Instrument(MNSI)

16 Neuropathy Disability Score Young et al. Diabetologia 1993 pain (neuro-tips) 0-1 vibration (128Hz TF) 0-1 warm / cold rods 0-1 ankle reflexes maximum score = 10 Over 2 years NW England Study (n=9710) RR CI Previous FU 3.1 ( ) NDS 6/ ( ) Abnormal 10g MF 1.8 ( ) Abnormal ankle reflex 1.6 ( ) Abbott et al. Diab Medicine 2002

17 Quantitative sensory tests: provide quantitative measures of sensation Thresholds for: vibration thermal heat - pain cold - pain cold warm touch - pressure electrical impulses Thermal testing small fiber function

18 Quantitative sensory testing: 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

19 Vibration 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

20 Nerve conduction studies: Essential for research studies of DSPN Strengths most objective, accurate, reproducible, sensitive Daube JR 1999 correlate with clinical endpoints Perkins et al represent pathological hallmark of DSPN Malik et al 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)

21 Diagnostic certainty of DSPN The Toronto Diabetic Neuropathy Expert Group Meeting 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 Tesfaye et al. Diabetes Care 2010; 33:

22 Staging DSPN using confirmed DSPN criteria Grade 0 = no abnormality of NC, e.g., Σ 5 NC nds < 95th percentile or another suitable NC criterion. Grade 1a = abnormality of NC, e.g., Σ 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:

23 Clinical vs Neurophysiological Trial 1 Is clinical examination of the PNS reliable for research studies? Dyck et al., Muscle and Nerve 2010; 42:

24 Conclusions from the Clinical vs Neurophysiological Trial 1 1. Clinical diagnoses is not always reprodiceable even when performed by experts! 2. Specific approaches to improving proficiency (clinical exam or NC) are needed and should be tested. Dyck et al., Muscle and Nerve 2010; 42:

25 Emerging markers of DPN: Focus on small fibers Nerve biopsy - unmyelinsted fiber damage, invasive, highly specilaized procedure-em Skin biopsy - minimally invasive, morphometric quantification 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-nociceptive fiber, laser Doppler imaging flare test

26 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

27 The Toronto Diabetic Neuropathy Expert Group Meeting Introduction to TDNEG meeting Diagnosis of DSPN for clinical practice & research Risk reduction Pain treatments Pathogenic treatments Conclusions

28 Nerve Fiber Loss: The cause of insensitivity in DPN 1 Diabetic Control Neuropathy 1. Veves A, Giurini JM, Logerfo JW. Diabetic Foot. 2 nd Edition, Chapter: Diabetic Neuropathy, p105 29

29 Microvascular defects in DPN 1 Photomicrographs of capillaries from nerve biopsies showing a closed capillary in the diabetic nerve Diabetic Control DPN 1. Cameron NA, et al. Diabetologia. 2001;44:

30 Microvascular abnormalities in DPN 1 Control DPN 1. Tesfaye S, et al. Diabetologia. 1993;36:

31 Impaired blood flow in established DPN 1 Normal Established DPN 1. Tesfaye S, et al. Diabetologia. 1993;36:

32 Risk factors for incident neuropathy: The EURODIAB PCS Hypertension Smoking HbA1c Change in HbA 1c Diabetes duration BMI Triglycerides Total cholesterol Odds ratios (95% CI) n=1101 with type 1 DM; FU: 7.3±0.6 yrs Model 1: without CVD and retinopathy Tesfaye et al. N Engl J Med 2005; 352:

33 The Toronto Diabetic Neuropathy Expert Group Meeting Glycaemic control and management of cardiovascular risk factors are important

34 Conclusions 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

35 Thanks for your attention