1. No category

Diabetisk Neuropati
Diabetesforeningen Nov. 2015
Interessekonflikt :
Konsultation/foredrag for: Astellas, Astra-Zeneca, Grünenthal, Orion og
Pfizer,
Troels Staehelin Jensen, MD, DMSc
Dept. of Neurology &
Danish Pain Research Center
Aarhus University Hospital, Denmark
Diabetes i verden:
Diabetes: 60 mil Europæer, 26 mil Amerikanere Udgift: $465bn; Dødsårsag: 4.6 mil/år
Diabetes Komplikationer
• Kardio-vaskulær
– Hjertekar
– Stroke, Demens
– PAS
• Retinopati
• Nefropati
• Neuropati
www.idf.org
Diabetisk Neuropati typer
Distal sensori-motor
polyneuropathy
Radiculo-plexopathy
Mononeuropathia
multiplex
Autonomic
neuropathy
Callaghan et al., 2012; Peltier et al., 2014
Diabetisk Polyneuropati: en symmetrisk , længde-afhængig senso-motorisk
polyneuropati som skyldes metabolisk og mikro-kar forstyrrelse som følge af
kronisk hyperglykæmi og kardio-vaskulære risiko covariable
Toronto classification Tesfaye et al. Diabetes Care 2010
Diagnose af neuropati: Ingen guld standard
Ekslusions diagnoser:
•
Perifer vaskulær sygdom
•
Arthrose
•
Malignitet
•
Alkohol misbrug
•
Spinal stenose
•
Plantar fasciitis
knyste
kallus
Charcot fod med sår
Fissur i tør hud
Charcot led
Hammer tå
Epidemiologi
Prævalens af Neuropati: 49% ,
Prævalens af smerte sympt: 34%
Prævalens of neuropati + Smerte: 21%
N= 15.692, (Abbott et al., 2011)
Kronisk senso-motorisk
“Dying back” eller “length-dependent”
– Længste nerver først afficeret
– Terminale fibre især påvirket
– Forløb: måneder til år
– Gradvis og symmetrisk udvikling
– Symptomer: overvejende sensorisk
Symptomer
Paræstesier , følenedsættelse
Dysæstesi/allodyni I fødder og hænder
Parxysmale udstrålende smerter
Dybe knugende smerter, kramper, glasskår
Allodyni
Objektive fund
Sensorisk tab: sokke-handske formet fordeling
Hyperalgesi/allodyni
Vasomotoriske ændringer
Kraftnedsættelse
Tab af reflekser
Diabetisk distal polyneuropati
DN: Snigende sygdom
Når først skaden er sket er det for sent
Normal
5
Delvis sensorisk tab
Sensorisk tab + allodyni
Udtalt sensorisk tab
Mekanismer for smerter: perifere og centrale
Jensen & Finnerup Lancet Neurol.,2014
Spontan smerte ved DN: Forskellige mekanismer
Irritable nociceptor
Normal state
Pain from
regenerating sprouts
No regeneration
Radiculopathy and
plexopathy with
denervation of 2nd
order neuron
Degeneration and regeneration
Truini et al. 2013
Diagnose af diabetisk neuropati:
•
•
•
•
Sygehistorie
Spørgeskemaer
Klinisk undersøgelse herunder neurologisk
QST og andre tests
Start med det simple og slut med det komplekse
Michigan Neuropathy Screening Instrument (MNSI)
Questionnaire
Patient version
Score> 4 suggest neuropathy
Examination
Examiner version
Score> 2 suggest neuropathy
Stimuli, receptorer, nervefibre og klinisk undersøhgelse
Ikke smertefuld berørings stimuli
(vibration, let tryk m.m. )
Tykke myeliniserede Ab fibre
Kliniske tests
Smertefuld mekanisk
stimulation (stik)
Tynde myeliniserede
Ad fibres
Thermale
stimuli
Umyeliniserede C
fibres
Kliniske tests
Diabetisk neuropati:
Sensoriske profiler
Z-Score
4
Sensitized nociceptor pain
3
Gain of
function
2
1
0
-1
Loss of
-2
function
-3
-4
CDT HDT TSL CPT HPT PPT MPS WUR MDT VDT
QST parameter
Z-Score
4
3
Gain of
function
Deafferentation pain
2
1
0
-1
Loss of
function
-2
-3
-4
CDT
Concept from the German Pain Network
HDT TSL CPT HPT PPT MPS WUR MDT VDT
QST parameter
Smerte fænotype forbundet med mekanismer
Descending
Pathways
Central
projection
Afferent
input
Activated
microglia
Descendin
g
pathways
TLRs
CX3CR1
Ca++
Fractaline
P38 MAPK, ERK
CCL21 CCRs
P2X4
CCL2
CCK
ATP
Il-1b, Il-6, TNF-, NO, PGE2
5-HT
NA
Interneurons
BDNF
GABA 
TrkB
NK-1R EP2
Opioids
AMPA-R
GABAA-R
KCC2
Glutamate
Ca++
2
d
Pre-synaptic
neuron
NMDA-R NaV1.3
mGluR
Post-synaptic
neuron
Klassifikation af Diabetisk neuropai:
Demographics,
Type
neuropathy/pain
Body maps
Utah Neuropathy
Toronto N score
Neuropathy score
BPI, DN4, NPSI
4
ENG peroneal,
tibial, ulnar ,
median
Z-Score
3
Gain of
function
2
1
0
-1
QST, Skin Punch
Biopsy, CCM
-2
-3
Loss of
function
QST parameter
-4
CDT HDT TSL CPT HPT PPT MP WUR MDT VDT
Baroreflex
events
LAB test, DNA
Brachial-Ankle
Index
Threshold
tracking,
Autonomic
measures
mean RR
SBP
Strukturelle mål ved PDN
Hud biopsi
Cornea konfocal mikroskopi
Nomal
IGT
Asghar et al, Diabetes Care 2014
Hud biopsi:
CCM:
IENFD
eNFL
Swellings
CNFD
CNFL
CNBD
Hud biopsi ved neuropati:
IENFD, NFLD
17 neuropati:
mean age: 58.2 yrs
Propable/definite neuropathy
Daily or constant pain
Pain ≥ 4,NRS
19 kontroller:
mean age: 48.3 yrs
No central or peripheral
neurological diseases
Øget antal axonale swellings
Lauria et al., 2003, Ebenezer et al.,
2007, Karlsson et al., 2013,
Karlsson et al., in press,
S w e ilin g r a t io ( m e d ia n I Q )
Axonale ”swellings” v D, DN og PDN
0 .8
**
*
***
0 .6
0 .4
0 .2
0 .0
H e a lth y
C o n tr o ls
D ia b e tic
D ia b e tic
D ia b e tic
No
No
N e u r o p a th ic
N e u r o p a th y
N e u r o p a th ic
P a in
P a in
Karlsson et al., unpubl observations
Tegn på degeneration og regeneration af nociceptorer? Lauria et al., 2013
S w e llin g r a tio (m e d ia n I Q )
0 .8
***
****
0 .6
0 .4
0 .2
0 .0
H e a lth y
D ia b e tic
D ia b e tic
C o n tr o ls
No
N e u r o p a th y
N e u r o p a th y
Diabetisk symmetrisk senso-motorisk polyneuropathy (DSPN)
Diabetes
Condition
Symptoms or signs of DSPN. Symptoms:
negative/positive sensory symptoms. Signs: reduced
distal sensation or reduced ankle jerks
No
Unlikely
DSPN
Yes
Possible DSPN
Symptoms and signs of
neuropathy
Symptoms and signs of
neuropathy
A: Symptoms:
neuropathic symptoms
A: Symptoms:
neuropathic symptoms
B : Signs:
reduced distal sensation
or reduced ankle jerks
B : Signs:
reduced distal sensation
or reduced ankle jerks
C: : Abnormal Nerve
conduction or measure
of SFN
Confirmed
DSPN
Probable
DSPN
Expert panel on Diabetic
Neuropathy, Toronto
2009 (Tesfaye et al., 2010)
Mekanismer for neuropati ved diabetes
To Skoler: Metabolisk og en vaskulær
Gennemblødning og A-V shunt i en diabetisk N. suralis
Fig 1 and 2 Epineurale arterier og vener hos normale
Fig 3. udvidede vener og snævre arterier ved diabetisk neuropati
Fig 5.Epineural A-V shunt ved diabetisk neuropati
Tesfaye et al. Diabetologia 1993
Metabolic og vaskulære ændringer ved
diabetisk neuropati
Oxidative stress
Capillary dysfunction
Normal State
Hyperglycemia + Dyslipidemia
mitochondrial dysfunction
Oxidative stress
Modified from Callaghan et al. 2012;
Østergaard et al. 2014
Hyperemic State
CTH ↑
OEF ↓
Resting TBF ↑
Hypoxic State
CTH ↑↑↑
Resting EBF ↓↓
OEF ↑
Oxidative stress ↑ ↑
Animal models of diabetic neuropathy
C57BKS Leprdb db/db
Hyperphagia, obesity, hyperinsulinemia, hyperglycemia
Nerve conduction velocity
Dorsal root ganglion neurons
Akita DBA/2J
In vivo models
• dorsal root ganglia
• sciatic nerve
• tail nerve
• footpads
IENFD
Neuropati: Hypoksi af nerve fibre?
Type 2 DN model
C57BKS Leprdb db/db
Hyperphagia; obesity; hyperglycemia;
hyperinsulinemia
Type 1 DN model
Normal State
Hyperemic State
CTH ↑
OEF ↓
Resting TBF ↑
Akita DBA/2J
Hyperglycemia; hypoinsulinemia
Sullivan et al, 2007; Vincent et al. 2007; O’Brien et al. 2014
Hypoxic State
CTH ↑↑↑
Resting EBF ↓↓
OEF ↑
Oxidative stress ↑ ↑
Østergaard et al. 2014
Hypoksis nerve skade
Two-photon microscopy (TPM)
Optical Coherence
Tomography (OCT)
angiography (top)
and quantitative
RBC velocity map
(bottom)
Mus:
Cerebral cortex
Sciatic
nerve
Red
Blood
Cell
passage
10 µm
100 µm
TPM with oxygen sensitive dye (tissue
and vessel oxygen tension in mmHg)
TPM with fluorescent plasma dye (FITC)
Humane: CTH is measured by tracking the vascular passage of standard contrast
agents (erythrocyte-sized micro-bubbles for ultrasound and Gd-based contrast
agent for MRI). The method works in brain tissue.
Metabolomiic studier : dyr og mennesker
Oxidative stress ved T2 DN
Metaboliske forandringer hos mus
afspejler den kliniske virkelighed
•
•
•
•
•
DRG
Distal symmetric length-dependent
polyneuropathy
SCN
In a prox-distal gradient in T2DN:
Decrease in glycolytic and citric acid
cycle metabolomes from prox to distal.
Increase in FA oxidation products (Acyl
Carnitines).
Increase protein oxidation
Increase of Bioactive eicosanoids
(HETEs) HODE
Other potential metabolites: Bile acids,
phospholipids, DAG, short chain FA,
etc.
Human resources:
Plasma
urine
skin
Murine resources:
SN
DRG
Sciatic nerve
Sural nerve
Behandling af diabetisk
neuropati
Symptomatisk behandling af smerte
NeuPSIG recommendations
Smertefuld diabetsik neuropati: Hvor virker medicinen ?
Central
projection
Descending
control
Descending Control
TCA, SNRI, SSRI, opioid
Afferent input
NK1
Na+
Ectopic activity
TCA, Carb., Oxc, Lam
NMDA
2d
Opioid
Ca++
Segmental
Opioid, valproate
Hyperexcitability
TCA, opioids. memantine
Pregabalin
Pregabalin NNT meta-analysis forest plot (fixed effects)
Pain condition Drug Doses Reference
NNT (95% CI)
CPSP Pregabalin 600 mg Kim et al. 2011
27.0 (6.8 -13.6)
SCI Pregabalin 600 mg Siddall et al. 2006
7.0 (3.9-37.2)
SCI Pregabalin 600 mg Cardenas et al. 2013
7.0 (3.9-31.5)
CPSP/SCI Pregabalin 600 mg Vranken et al. 2008
3.3 (1.9-14.3)
PPN Pregabalin 300 mg Rosenstock et al. 2004
4.0 (2.6-8.7)
PPN Pregabalin 300, 600 mg Lesser et al. 2004
3.4 (2.5-5.4)
PPN Pregabalin 600 mg Richter et al. 2005
4.2 (2.7-9.4)
PPN Pregabalin 300, 600 mg Tölle et al. 2008
10.8 (5.3- -230.4)
PPN Pregabalin 600 mg Arezzo et al. 2008
3.9 (2.5-8.6)
PPN Pregabalin 600 mg Simpson et al. 2010
-26.7 (13.5- -6.7)
PPN Pregabalin 300, 600 mg Satoh et al. 2011
10.8 (4.8- -47.1)
PPN Pregabalin 300 mg Rauck et al. 2012
-12.6 (20.7- -4.8)
PPN Pregabalin 300 mg Smith et al. 2013
20.2 (5.6- -12.7)
PHN Pregabalin 600 mg Dworkin et al. 2003
3.4 (2.3-6.4)
PHN Pregabalin 300 mg Sabatowski et al. 2004
5.6 (3.4-17.3)
PHN Pregabalin 300, 600 mg van Seventer et al. 2006
4.2 (3.1-6.5)
PHN Pregabalin 300, 600 mg Stacey et al. 2008
4.0 (2.8-6.9)
PPN/PHN Pregabalin 600 mg Freynhagen et al. 2005
3.9 (2.7-7.4)
PPN/PHN Pregabalin 600 mg Guan et al. 2011
8.3 (4.2-287)
PNI Pregabalin 600 mg van Seventer et al. 2010
10.6 (5.2- -409.8)
MIXED Pregabalin 600 mg Moon et al. 2010
8.5 (4.5- 68.9)
PPN Pregabalin 600 mg PhRMA/FDA 1008-040 2007
10.1 (4.1- -22.5)
PPN Pregabalin 600 mg NCT00156078
PPN Pregabalin 300, 600 mg NCT00143156, A0081071
31.8 (7.5- -14.2)
PHN Pregabalin 300, 600 mg NCT00394901
45.3 (8.6- -13.8)
5.6 (3.6-12.5)
Combined (fixed effects)
2.5
5.0
NNT (harm)
Finnerup, et al. Lancet Neurology 2015;14:162

7.7 (6.5-9.4)
5.0
2.5
NNT (benefit)
1.7
NNT værdier for smertebehandling
70
BTX-A
18
BTX-A
473
TCAs
136
TCAs
426
Strong opioids
241
Strong opioids
380
Tramadol
SNRIs
223
Tramadol
1559
1414
SNRIs
2073
3530
374
Gabapentin
2074
Gabapentin
Pregabalin
Pregabalin
1299
Capsaicin 8%
0
2
4
6
8
10
12
14
NNT
Neuropatisk smerte
Finnerup, et al. Lancet Neurology 2015;14:162
0
2
4
6
8
10
12
14
NNT
Smertefuld diabetisk neuropati
Painful polyneuropathy: 2010
TCA
Oxycodone
Tramadol
Pregabalin
SNRI
Oxcarbazep
Memantine
SSRI
Topiramate
Dextrometh
0
2
4
6
8
10
12
NNT
Painful Diabetic polyneuropathy: 2015
TCA
Opioids
Tramadol
Pregabalin
SNRI
Gabapentin
SSRI
0
2
4
6
NNT
8
10
12
Finnerup et al. Unpublished observations.
Al medicin har bivirkninger:
Neuropathic pain management:
Adverse actions / contraindications
2d-binding
agents
Na+ blocking
agents
Adverse
effects
Sedation
Ataxia
Dizziness
Mental change
Memory
change
Headache
Weight gain
Edema
Contraindication
None
TCA
SNRI
SSRI
Sedation
Ataxia
Dizziness
Mental change
Memory
disturbance
Headache
Weight gain
Edema
Sedation
Dizziness
Mental change
Weight gain
Dry mouth
Sweating
Constipation
Blurred vision
Sexual Dist
Hypotension
Sedation
Dizziness
Mental change
Nausea
Weight loss
Sweating
Diarrhoea
Sexual Dist
Dizziness
Mental change
Nausea
Weight change
Sexual dysf.
Tachycardia
Sweating
AV-block
Porphyria
MAO inhibitors
AV-block
Cardiac failure
Recent MI
MAO inhibitors
Hepatic failure
Kidney
failurefunction
MAO ihibitors
CNS adverse action
Gastrointestinal adverse action
Other adverse actions
Neuropathic pain management:
Adverse actions / contraindications
Opioids
GABA agonists
NMDA
antagonists
Topicals
(Capsaicin 8%)
Adverse
action
Sedation
Mental change
Dependence
Tolerance
Nausea
Vomiting
Obstipation
Resp depres.
Urinary
retention
Immune
changes
Sedation
Mental change
Headache
Nausea
Paresthesia
Skin reactions
Sedation
Hallucinations
Mental changes
Psychosis
Headache
Vomiting
Local pain
Skin reaction
Tachycardia
Hypertension
Paresthesia
Contraindication
Addiction
Hepatic failure
Psychiatric
disease
CNS adverse action
Gastrointestinal adverse action
Other adverse actions
Grading of Recommendations Assessment, Development, and Evaluation (GRADE),
Drugs with strong GRADE recommendation for use and recommended as first line:
TCAs, SNRI antidepressants, pregabalin, gabapentin and gabapentin ER/enacabil.
SNRI antidepressants duloxetine and venlafaxine, pregabalin, gabapentin and gabapentin ER/enacarbil have
high quality of evidence, are positive in most clinical trials and have moderate tolerability. Serious adverse
events are possible.
Drugs with weak GRADE recommendations for use and recommended as second line:
Lidocaine patches, capsaicin high concentration patches and tramadol.
Lidocaine patches have poor quality of evidence , but high values and preferences. Capsaicin highconcentration patches have high final quality of evidence. Tramadol has moderate quality of evidence. Trials
are positive, a lower potential for misuse, abuse, and dependency than stronger opioids,8 but potential
safety concerns.
Drugs with weak GRADE recommendation for use and recommended as third line:
Strong opioids and botulinum toxin type A (BTX-A).
Strong opioids have moderate final quality of evidence and demonstrated efficacy in the short term, but low
values and preferences and potential safety concerns. BTX-A moderate quality of evidence, low NNT in
published trials, a good safety profile in neuropathic pain and high values and preferences, but one large
unpublished study was negative.
Finnerup et al., Lancet Neurol. 2015;14:162-73
IDNC: International Diabetic Neuropathy Consortium
Troels S. Jensen
Hatice Tankisi
Henning Andersen
Nanna B. Finnerup
Jan Frystyk
Leif Østergaard
Reimar W Thomsen
Morten Charles
AU
U.
Michigan
USA
Eva Feldman
Callaghan
Internat.
Diabetic
Neuropathy
Consortium
Brian
U.
Oxford
UK
David Bennett
SDU
Henning Beck-Nielsen
Sindrup
Søren
Diabetisk neuropati:
”Take home messages”
•
•
•
•
•
•
•
Diabetes hyppig, især Type 2
50% får neuropati, smerter hos 25%
Sygdommen snigende.
Når skaden er sket er det for sent
Ingen kausal behandling
Sårcentre alene løser det ikke
Forebyggelse vigtig
Tak til