diabetic neuropathy · 2015-02-07 · diabetic neuropathy new insights and a paradigm shift...
TRANSCRIPT
Diabetic NeuropathyNew Insights and a Paradigm Shift
Professor Solomon Tesfaye MB ChB MD FRCPResearch Lead - Academic Directorate of Diabetes amp Endocrinology
Sheffield Teaching Hospitals and University of Sheffield
Royal Hallamshire Hospital
Sheffield UK
Diabetic Complications
Diabetic
Retinopathy
NOT the Leading cause
of blindness in working-
age adults
Diabetic Nephropathy
Leading cause of
end-stage renal diseaseDiabetic
Peripheral
Neuropathy
Leading cause of non-traumatic
lower extremity amputations
Cardiovascular
Disease
Stroke
2-4 fold increase in CV mortality and stroke
bull In the UK the numbers of amputations have been rising from 5700 in 200910 to over 6000 in 201011 It is projected that there will be over 7000 amputations in people with diabetes in England by 201415 [1]
bull Only 50 per cent of people with diabetes who have an amputation survive for two years [2]
1 Putting feet first Diabetes UK 2013
2 Rayman G et al Fast-Track-for-a-Foot-Attack 2013
Brownrigg JR et al Diabetologia 2012
Diabetic Polyneuropathy (DPN)
Symmetric length dependent sensory-motor neuropathy
strongest risk factor for FU and amputation
6
7
8
9
10
11
12
Intraepidermal nerve fiber density and sural SNCV and SNAP
in recently diagnosed Type 2 diabetic patients
IEN
FD
(fi
bers
mm
)
Diabetic (n=86)
Control (n=48)
Plt0001
35363738394041424344454647484950Skin biopsy
Sura
l SN
CV
(m
s)
4
5
6
7
8
9
10
11
12
Sura
l SN
AP (
microV
)
Plt0001
P=0006
Ziegler et al Diabetes 2014 632454-63
111
55
148
239
161
220
0
5
10
15
20
25
30
NGT i-IFG i-IGT IFG+IGT New DM Known DMn=577 n=55 n=183 n=46 n=62 n=177
MONICAKORA Augsburg Survey F4 (Age 61-82 yr n=1100)
NGT= normal glucose tolerance
i-IFG= isolated impaired fasting glucose
i-IGT= isolated impaired glucose tolerance
vibration andor pressure sensation
Bongaerts et al Diabetes Care 2012 35 1891-3
The prevalence of DPN in pre-diabetes and diabetes
The diabetic foot ulcer worse than some cancers
Armstrong DG et al Int Wound J 2007 4 286-7
Tesfaye et al N Engl J Med 2005 352 341-50
Total cholesterol
Triglycerides
BMI
Diabetes duration
Change in HbA1c
HbA1c
Smoking
Hypertension157
138
148
136
140
127
121
115
Model 1
without CVD
and retinopathy
Odds ratios (95 CI)
n=1101 with T1 DM Follow up 73plusmn06 yrs
Bedside Instruments
Diagnostic certainty of DPN
PossibleSymptoms or signs of DPN
ProbableSymptoms and signs of DPN
ConfirmedSymptoms or signs of DPN and NC abnormality
SubclinicalNC abnormality only
The Toronto Diabetic Neuropathy Consensus Panel
Tesfaye et al Diabetes Care 2010 33 2285-93
Nerve Conduction microanlbuminuria
equivalent for DPN
Weisman A et al Plos 1 2013 8 (3) e58783
ldquoIndividual NCS parameters or
their simple combinations
are valid measures for
identification and future
prediction of DPNrdquo
bull N=406 (345 T2DM)
bull Followed 109 without DPN
for 4 years
bull 25 developed clinical DPN
Reliability of a new POCD (DPN-Check)
for the detection of DPN
ldquoDPN Check demonstrated excellent reliability and acceptable accuracyrdquo
Lee JA et al Plos 1 2014
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Diabetic Complications
Diabetic
Retinopathy
NOT the Leading cause
of blindness in working-
age adults
Diabetic Nephropathy
Leading cause of
end-stage renal diseaseDiabetic
Peripheral
Neuropathy
Leading cause of non-traumatic
lower extremity amputations
Cardiovascular
Disease
Stroke
2-4 fold increase in CV mortality and stroke
bull In the UK the numbers of amputations have been rising from 5700 in 200910 to over 6000 in 201011 It is projected that there will be over 7000 amputations in people with diabetes in England by 201415 [1]
bull Only 50 per cent of people with diabetes who have an amputation survive for two years [2]
1 Putting feet first Diabetes UK 2013
2 Rayman G et al Fast-Track-for-a-Foot-Attack 2013
Brownrigg JR et al Diabetologia 2012
Diabetic Polyneuropathy (DPN)
Symmetric length dependent sensory-motor neuropathy
strongest risk factor for FU and amputation
6
7
8
9
10
11
12
Intraepidermal nerve fiber density and sural SNCV and SNAP
in recently diagnosed Type 2 diabetic patients
IEN
FD
(fi
bers
mm
)
Diabetic (n=86)
Control (n=48)
Plt0001
35363738394041424344454647484950Skin biopsy
Sura
l SN
CV
(m
s)
4
5
6
7
8
9
10
11
12
Sura
l SN
AP (
microV
)
Plt0001
P=0006
Ziegler et al Diabetes 2014 632454-63
111
55
148
239
161
220
0
5
10
15
20
25
30
NGT i-IFG i-IGT IFG+IGT New DM Known DMn=577 n=55 n=183 n=46 n=62 n=177
MONICAKORA Augsburg Survey F4 (Age 61-82 yr n=1100)
NGT= normal glucose tolerance
i-IFG= isolated impaired fasting glucose
i-IGT= isolated impaired glucose tolerance
vibration andor pressure sensation
Bongaerts et al Diabetes Care 2012 35 1891-3
The prevalence of DPN in pre-diabetes and diabetes
The diabetic foot ulcer worse than some cancers
Armstrong DG et al Int Wound J 2007 4 286-7
Tesfaye et al N Engl J Med 2005 352 341-50
Total cholesterol
Triglycerides
BMI
Diabetes duration
Change in HbA1c
HbA1c
Smoking
Hypertension157
138
148
136
140
127
121
115
Model 1
without CVD
and retinopathy
Odds ratios (95 CI)
n=1101 with T1 DM Follow up 73plusmn06 yrs
Bedside Instruments
Diagnostic certainty of DPN
PossibleSymptoms or signs of DPN
ProbableSymptoms and signs of DPN
ConfirmedSymptoms or signs of DPN and NC abnormality
SubclinicalNC abnormality only
The Toronto Diabetic Neuropathy Consensus Panel
Tesfaye et al Diabetes Care 2010 33 2285-93
Nerve Conduction microanlbuminuria
equivalent for DPN
Weisman A et al Plos 1 2013 8 (3) e58783
ldquoIndividual NCS parameters or
their simple combinations
are valid measures for
identification and future
prediction of DPNrdquo
bull N=406 (345 T2DM)
bull Followed 109 without DPN
for 4 years
bull 25 developed clinical DPN
Reliability of a new POCD (DPN-Check)
for the detection of DPN
ldquoDPN Check demonstrated excellent reliability and acceptable accuracyrdquo
Lee JA et al Plos 1 2014
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
bull In the UK the numbers of amputations have been rising from 5700 in 200910 to over 6000 in 201011 It is projected that there will be over 7000 amputations in people with diabetes in England by 201415 [1]
bull Only 50 per cent of people with diabetes who have an amputation survive for two years [2]
1 Putting feet first Diabetes UK 2013
2 Rayman G et al Fast-Track-for-a-Foot-Attack 2013
Brownrigg JR et al Diabetologia 2012
Diabetic Polyneuropathy (DPN)
Symmetric length dependent sensory-motor neuropathy
strongest risk factor for FU and amputation
6
7
8
9
10
11
12
Intraepidermal nerve fiber density and sural SNCV and SNAP
in recently diagnosed Type 2 diabetic patients
IEN
FD
(fi
bers
mm
)
Diabetic (n=86)
Control (n=48)
Plt0001
35363738394041424344454647484950Skin biopsy
Sura
l SN
CV
(m
s)
4
5
6
7
8
9
10
11
12
Sura
l SN
AP (
microV
)
Plt0001
P=0006
Ziegler et al Diabetes 2014 632454-63
111
55
148
239
161
220
0
5
10
15
20
25
30
NGT i-IFG i-IGT IFG+IGT New DM Known DMn=577 n=55 n=183 n=46 n=62 n=177
MONICAKORA Augsburg Survey F4 (Age 61-82 yr n=1100)
NGT= normal glucose tolerance
i-IFG= isolated impaired fasting glucose
i-IGT= isolated impaired glucose tolerance
vibration andor pressure sensation
Bongaerts et al Diabetes Care 2012 35 1891-3
The prevalence of DPN in pre-diabetes and diabetes
The diabetic foot ulcer worse than some cancers
Armstrong DG et al Int Wound J 2007 4 286-7
Tesfaye et al N Engl J Med 2005 352 341-50
Total cholesterol
Triglycerides
BMI
Diabetes duration
Change in HbA1c
HbA1c
Smoking
Hypertension157
138
148
136
140
127
121
115
Model 1
without CVD
and retinopathy
Odds ratios (95 CI)
n=1101 with T1 DM Follow up 73plusmn06 yrs
Bedside Instruments
Diagnostic certainty of DPN
PossibleSymptoms or signs of DPN
ProbableSymptoms and signs of DPN
ConfirmedSymptoms or signs of DPN and NC abnormality
SubclinicalNC abnormality only
The Toronto Diabetic Neuropathy Consensus Panel
Tesfaye et al Diabetes Care 2010 33 2285-93
Nerve Conduction microanlbuminuria
equivalent for DPN
Weisman A et al Plos 1 2013 8 (3) e58783
ldquoIndividual NCS parameters or
their simple combinations
are valid measures for
identification and future
prediction of DPNrdquo
bull N=406 (345 T2DM)
bull Followed 109 without DPN
for 4 years
bull 25 developed clinical DPN
Reliability of a new POCD (DPN-Check)
for the detection of DPN
ldquoDPN Check demonstrated excellent reliability and acceptable accuracyrdquo
Lee JA et al Plos 1 2014
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Diabetic Polyneuropathy (DPN)
Symmetric length dependent sensory-motor neuropathy
strongest risk factor for FU and amputation
6
7
8
9
10
11
12
Intraepidermal nerve fiber density and sural SNCV and SNAP
in recently diagnosed Type 2 diabetic patients
IEN
FD
(fi
bers
mm
)
Diabetic (n=86)
Control (n=48)
Plt0001
35363738394041424344454647484950Skin biopsy
Sura
l SN
CV
(m
s)
4
5
6
7
8
9
10
11
12
Sura
l SN
AP (
microV
)
Plt0001
P=0006
Ziegler et al Diabetes 2014 632454-63
111
55
148
239
161
220
0
5
10
15
20
25
30
NGT i-IFG i-IGT IFG+IGT New DM Known DMn=577 n=55 n=183 n=46 n=62 n=177
MONICAKORA Augsburg Survey F4 (Age 61-82 yr n=1100)
NGT= normal glucose tolerance
i-IFG= isolated impaired fasting glucose
i-IGT= isolated impaired glucose tolerance
vibration andor pressure sensation
Bongaerts et al Diabetes Care 2012 35 1891-3
The prevalence of DPN in pre-diabetes and diabetes
The diabetic foot ulcer worse than some cancers
Armstrong DG et al Int Wound J 2007 4 286-7
Tesfaye et al N Engl J Med 2005 352 341-50
Total cholesterol
Triglycerides
BMI
Diabetes duration
Change in HbA1c
HbA1c
Smoking
Hypertension157
138
148
136
140
127
121
115
Model 1
without CVD
and retinopathy
Odds ratios (95 CI)
n=1101 with T1 DM Follow up 73plusmn06 yrs
Bedside Instruments
Diagnostic certainty of DPN
PossibleSymptoms or signs of DPN
ProbableSymptoms and signs of DPN
ConfirmedSymptoms or signs of DPN and NC abnormality
SubclinicalNC abnormality only
The Toronto Diabetic Neuropathy Consensus Panel
Tesfaye et al Diabetes Care 2010 33 2285-93
Nerve Conduction microanlbuminuria
equivalent for DPN
Weisman A et al Plos 1 2013 8 (3) e58783
ldquoIndividual NCS parameters or
their simple combinations
are valid measures for
identification and future
prediction of DPNrdquo
bull N=406 (345 T2DM)
bull Followed 109 without DPN
for 4 years
bull 25 developed clinical DPN
Reliability of a new POCD (DPN-Check)
for the detection of DPN
ldquoDPN Check demonstrated excellent reliability and acceptable accuracyrdquo
Lee JA et al Plos 1 2014
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
6
7
8
9
10
11
12
Intraepidermal nerve fiber density and sural SNCV and SNAP
in recently diagnosed Type 2 diabetic patients
IEN
FD
(fi
bers
mm
)
Diabetic (n=86)
Control (n=48)
Plt0001
35363738394041424344454647484950Skin biopsy
Sura
l SN
CV
(m
s)
4
5
6
7
8
9
10
11
12
Sura
l SN
AP (
microV
)
Plt0001
P=0006
Ziegler et al Diabetes 2014 632454-63
111
55
148
239
161
220
0
5
10
15
20
25
30
NGT i-IFG i-IGT IFG+IGT New DM Known DMn=577 n=55 n=183 n=46 n=62 n=177
MONICAKORA Augsburg Survey F4 (Age 61-82 yr n=1100)
NGT= normal glucose tolerance
i-IFG= isolated impaired fasting glucose
i-IGT= isolated impaired glucose tolerance
vibration andor pressure sensation
Bongaerts et al Diabetes Care 2012 35 1891-3
The prevalence of DPN in pre-diabetes and diabetes
The diabetic foot ulcer worse than some cancers
Armstrong DG et al Int Wound J 2007 4 286-7
Tesfaye et al N Engl J Med 2005 352 341-50
Total cholesterol
Triglycerides
BMI
Diabetes duration
Change in HbA1c
HbA1c
Smoking
Hypertension157
138
148
136
140
127
121
115
Model 1
without CVD
and retinopathy
Odds ratios (95 CI)
n=1101 with T1 DM Follow up 73plusmn06 yrs
Bedside Instruments
Diagnostic certainty of DPN
PossibleSymptoms or signs of DPN
ProbableSymptoms and signs of DPN
ConfirmedSymptoms or signs of DPN and NC abnormality
SubclinicalNC abnormality only
The Toronto Diabetic Neuropathy Consensus Panel
Tesfaye et al Diabetes Care 2010 33 2285-93
Nerve Conduction microanlbuminuria
equivalent for DPN
Weisman A et al Plos 1 2013 8 (3) e58783
ldquoIndividual NCS parameters or
their simple combinations
are valid measures for
identification and future
prediction of DPNrdquo
bull N=406 (345 T2DM)
bull Followed 109 without DPN
for 4 years
bull 25 developed clinical DPN
Reliability of a new POCD (DPN-Check)
for the detection of DPN
ldquoDPN Check demonstrated excellent reliability and acceptable accuracyrdquo
Lee JA et al Plos 1 2014
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
111
55
148
239
161
220
0
5
10
15
20
25
30
NGT i-IFG i-IGT IFG+IGT New DM Known DMn=577 n=55 n=183 n=46 n=62 n=177
MONICAKORA Augsburg Survey F4 (Age 61-82 yr n=1100)
NGT= normal glucose tolerance
i-IFG= isolated impaired fasting glucose
i-IGT= isolated impaired glucose tolerance
vibration andor pressure sensation
Bongaerts et al Diabetes Care 2012 35 1891-3
The prevalence of DPN in pre-diabetes and diabetes
The diabetic foot ulcer worse than some cancers
Armstrong DG et al Int Wound J 2007 4 286-7
Tesfaye et al N Engl J Med 2005 352 341-50
Total cholesterol
Triglycerides
BMI
Diabetes duration
Change in HbA1c
HbA1c
Smoking
Hypertension157
138
148
136
140
127
121
115
Model 1
without CVD
and retinopathy
Odds ratios (95 CI)
n=1101 with T1 DM Follow up 73plusmn06 yrs
Bedside Instruments
Diagnostic certainty of DPN
PossibleSymptoms or signs of DPN
ProbableSymptoms and signs of DPN
ConfirmedSymptoms or signs of DPN and NC abnormality
SubclinicalNC abnormality only
The Toronto Diabetic Neuropathy Consensus Panel
Tesfaye et al Diabetes Care 2010 33 2285-93
Nerve Conduction microanlbuminuria
equivalent for DPN
Weisman A et al Plos 1 2013 8 (3) e58783
ldquoIndividual NCS parameters or
their simple combinations
are valid measures for
identification and future
prediction of DPNrdquo
bull N=406 (345 T2DM)
bull Followed 109 without DPN
for 4 years
bull 25 developed clinical DPN
Reliability of a new POCD (DPN-Check)
for the detection of DPN
ldquoDPN Check demonstrated excellent reliability and acceptable accuracyrdquo
Lee JA et al Plos 1 2014
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
The diabetic foot ulcer worse than some cancers
Armstrong DG et al Int Wound J 2007 4 286-7
Tesfaye et al N Engl J Med 2005 352 341-50
Total cholesterol
Triglycerides
BMI
Diabetes duration
Change in HbA1c
HbA1c
Smoking
Hypertension157
138
148
136
140
127
121
115
Model 1
without CVD
and retinopathy
Odds ratios (95 CI)
n=1101 with T1 DM Follow up 73plusmn06 yrs
Bedside Instruments
Diagnostic certainty of DPN
PossibleSymptoms or signs of DPN
ProbableSymptoms and signs of DPN
ConfirmedSymptoms or signs of DPN and NC abnormality
SubclinicalNC abnormality only
The Toronto Diabetic Neuropathy Consensus Panel
Tesfaye et al Diabetes Care 2010 33 2285-93
Nerve Conduction microanlbuminuria
equivalent for DPN
Weisman A et al Plos 1 2013 8 (3) e58783
ldquoIndividual NCS parameters or
their simple combinations
are valid measures for
identification and future
prediction of DPNrdquo
bull N=406 (345 T2DM)
bull Followed 109 without DPN
for 4 years
bull 25 developed clinical DPN
Reliability of a new POCD (DPN-Check)
for the detection of DPN
ldquoDPN Check demonstrated excellent reliability and acceptable accuracyrdquo
Lee JA et al Plos 1 2014
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Tesfaye et al N Engl J Med 2005 352 341-50
Total cholesterol
Triglycerides
BMI
Diabetes duration
Change in HbA1c
HbA1c
Smoking
Hypertension157
138
148
136
140
127
121
115
Model 1
without CVD
and retinopathy
Odds ratios (95 CI)
n=1101 with T1 DM Follow up 73plusmn06 yrs
Bedside Instruments
Diagnostic certainty of DPN
PossibleSymptoms or signs of DPN
ProbableSymptoms and signs of DPN
ConfirmedSymptoms or signs of DPN and NC abnormality
SubclinicalNC abnormality only
The Toronto Diabetic Neuropathy Consensus Panel
Tesfaye et al Diabetes Care 2010 33 2285-93
Nerve Conduction microanlbuminuria
equivalent for DPN
Weisman A et al Plos 1 2013 8 (3) e58783
ldquoIndividual NCS parameters or
their simple combinations
are valid measures for
identification and future
prediction of DPNrdquo
bull N=406 (345 T2DM)
bull Followed 109 without DPN
for 4 years
bull 25 developed clinical DPN
Reliability of a new POCD (DPN-Check)
for the detection of DPN
ldquoDPN Check demonstrated excellent reliability and acceptable accuracyrdquo
Lee JA et al Plos 1 2014
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Bedside Instruments
Diagnostic certainty of DPN
PossibleSymptoms or signs of DPN
ProbableSymptoms and signs of DPN
ConfirmedSymptoms or signs of DPN and NC abnormality
SubclinicalNC abnormality only
The Toronto Diabetic Neuropathy Consensus Panel
Tesfaye et al Diabetes Care 2010 33 2285-93
Nerve Conduction microanlbuminuria
equivalent for DPN
Weisman A et al Plos 1 2013 8 (3) e58783
ldquoIndividual NCS parameters or
their simple combinations
are valid measures for
identification and future
prediction of DPNrdquo
bull N=406 (345 T2DM)
bull Followed 109 without DPN
for 4 years
bull 25 developed clinical DPN
Reliability of a new POCD (DPN-Check)
for the detection of DPN
ldquoDPN Check demonstrated excellent reliability and acceptable accuracyrdquo
Lee JA et al Plos 1 2014
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Diagnostic certainty of DPN
PossibleSymptoms or signs of DPN
ProbableSymptoms and signs of DPN
ConfirmedSymptoms or signs of DPN and NC abnormality
SubclinicalNC abnormality only
The Toronto Diabetic Neuropathy Consensus Panel
Tesfaye et al Diabetes Care 2010 33 2285-93
Nerve Conduction microanlbuminuria
equivalent for DPN
Weisman A et al Plos 1 2013 8 (3) e58783
ldquoIndividual NCS parameters or
their simple combinations
are valid measures for
identification and future
prediction of DPNrdquo
bull N=406 (345 T2DM)
bull Followed 109 without DPN
for 4 years
bull 25 developed clinical DPN
Reliability of a new POCD (DPN-Check)
for the detection of DPN
ldquoDPN Check demonstrated excellent reliability and acceptable accuracyrdquo
Lee JA et al Plos 1 2014
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Nerve Conduction microanlbuminuria
equivalent for DPN
Weisman A et al Plos 1 2013 8 (3) e58783
ldquoIndividual NCS parameters or
their simple combinations
are valid measures for
identification and future
prediction of DPNrdquo
bull N=406 (345 T2DM)
bull Followed 109 without DPN
for 4 years
bull 25 developed clinical DPN
Reliability of a new POCD (DPN-Check)
for the detection of DPN
ldquoDPN Check demonstrated excellent reliability and acceptable accuracyrdquo
Lee JA et al Plos 1 2014
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Reliability of a new POCD (DPN-Check)
for the detection of DPN
ldquoDPN Check demonstrated excellent reliability and acceptable accuracyrdquo
Lee JA et al Plos 1 2014
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Assessing sudomotor function
Abnormality Abnormality Normal
SUDOSCAN
Neuropad
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
bull Clinical methods detect neuropathy when it is too late
bull We need a microalbuminuria equivalent objective and
quantifiable measure of DPN
bull Therefore large prospective studies are required to
examine if these simple POCDs that appear to detect
DPN in cross sectional studies can predict the
development of clinical neuropathy
Summary
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Preventative Approaches for Neuropathy in
Diabetes with Alpha-lipoic Acid
(PANDA Study)
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Painful diabetic neuropathy
a disabling problem for many patients
SleepMood
Chronic Pain
Co-morbidities
Medicationside effects
Sexual functioning
Walkingability
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Diabetic control Neuropathy
1 Clinical features
2 Electrophysiology
3 Quantitative Sensory
Testing (QST)
Cameron NA et al Diabetologia 2001441973ndash88
Tesfaye S et al Diabetologia 1993361266ndash1274
Painful DPN vs Painless DPN12
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Artery
Vein
Anatomy of the peripheral nerve
CapillaryYagihashi S J Diab Invest 2011218-32
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Impaired Blood Flow in Established DPN
Normal Established DPN
Tesfaye S et al Diabetologia 1993361266ndash1274
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Rajbhandari SM et al Pain199983627ndash629
Clinical examination and
small-fibre tests
may be normal
Painful Diabetic Neuropathy
lsquogone ndash but not forgottenrsquo
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Pathogenesis of Diabetic Neuropathy
Peripheral
lesionsCentral
lesions
Diabetic insult may be more generalised
+
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Tesfaye S et al Lancet 19963481696-701
0
10
20
30
40
50
60
70
80
90
100
on
VA
S S
core
plt001
off
Editorial Lundenberg T Lancet 1996 3481672-3
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Spinal Cord Atrophy
4 0
4 5
5 0
5 5
6 0
6 5
7 0
Cro
ss-s
ecti
onal are
a (
mm
2)
C D DPN
191010
Eaton S et al Lancet 200135835-6
C vs DPN (p=0016)
D vs DPN (p=007)
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Dead or Damaged
SENSORY LOSS
Regenerating
Normal
HYPEREXCITABILITY
ECTOPIC
CROSS TALK
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Peripheral activity causes central
hyperexcitability hellip
I
Peripheral nerve
II
III
IV
V
VIX
XIVII
VIII
Dorsal rootSpinal cord
Aδ
Aδ
Aαβ
C
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
The Thalamus
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Thalamic blood flow in painful and painless DPN
Selvarajah et al Diabetes Care 2011
Poster number 1134
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Stimulus causes neural activation resulting in a change in oxygenation of
blood in the activated region
Functional Magnetic Resonance Imaging -how does it work
fMRI is sensitive to the oxygenation of blood thus
indirectly measures areas of increased neural activation
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Simple fMRI experiment
Time
Brain
Activity
Kwong et al 1992
neural activity change O2 blood fMRI signal
+++
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Neuroanatomy of acute pain processing
Tracey amp Mantyh Neuron 2007
Hard core
S1 and S2
Thalamus
Insula
Anterior cingulate cortex
Prefrontal cortex
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Coghill et al J Neurophysiology 1999
more nociception
= more pain
= more activation
More Pain = More fMRI signal
fMRI as a READ-OUT of
peripheral nociceptive input
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Courtesy of Prof Irene Tracey
Nociception leads to pain how much pain experienced depends upon
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Context
- pain beliefs
- expectation
- placebo
Mood
- depression
- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
- catastrophising
Chemical amp Structure
- neurodegeneration
- metabolic eg
opiodergic
dopaminergic
- maladaptive plasticity
Injury
- peripheral amp
central
- sensitisation
A or C
nociceptive input
Amplified input
PainExperience
NociceptiveModulation
Nociception leads to pain how much pain experienced depends upon
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Placebo analgesia was related toincreased activity during anticipation of pain relief in the PFC
followed by decreased activity in pain-sensitive brain regions
including the thalamus insula and anterior cingulate cortex
Wager et al Science 2004 303(5661)1162-1167
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Naloxone reverses placebo analgesiaEippert et al Neuron 2009 63 533ndash543
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Resting state functional connectivity
Fox et al 2005
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Neuroimaging analysis Painful DN vs HV
SP
Mm
ip[-
90
21
72
-1
26
21
7
41
42
19
]
lt
lt lt
SPMT14
painful foot
SPMresultsPainfulfootHeight threshold T = 2624494 plt001 (unc)Extent threshold k = 0 voxels
Design matrix
05 1 15
2
4
6
8
10
12
14
contrast(s)
10
1
2
3
4
5
6
7
8
Painful DN Healthy
Volunteer
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
bull Increased connectivity
Anterior cingulate cortex medial
prefrontal cortex medial temporal
gyrus and precuneus
bull Decreased connectivity
Posterior cingulate cortex
Resting state fMRI showing disruption of
Default Mode connectivity in painful DN
Post cingulate gyrus
(-14 -30 32)
Precuneus
(14 -58 36)
Medial prefrontal Cortex
(-6 34 -16)
TFCE Cluster level p lt 0001
Oral presentation 22 ndash Abstract 131
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
ACC Connectivity relates
to pain severity and HADS A
CC
DM
N c
on
necti
vit
y (
Z)
HADS-A
r = 063
AC
C D
MN
con
necti
vit
y (
Z)
HADS-D
r = 064
AC
C D
MN
con
necti
vit
y (
Z)
NTSS
r = 037
AC
C D
MN
con
necti
vit
y (
Z)
Pain catastrophising scale
r = 057
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
fMRI activation patterns in
response to heat pain applied to the foot
Cluster level Corrected p lt 005
Uncorrected for display purposes
Painful Insensate
-62 -6 18
HV
-6 -38 58
Painless DN
-10 -46 76
Painful Sensate
-12 -46 78
Oral presentation 22 ndash Abstract 132
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
HV
-10 -38 80
Painful sensate
-12 -46 78
Painful Insensate
-58 -14 36
Painless DN
-12 -44 58
Cluster level Corrected p lt 005
Uncorrected for display purposes
fMRI activation patterns in
response to heat pain applied to the THIGH
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
PERIPHERAL
ACTIVITY
Tissue damage
Nerve damage
Allodynia
Decreased threshold
to peripheral
stimuli
Increased
spontaneous
activity
Expansion of
receptive
field
Hyperalgesia
Spontaneous
pain
CENTRAL
SENSITISATION(spinal
Supraspinal
cortical)
Injury Symptoms
ATROPHY Loss of
sensationNerve loss
Tesfaye et al Diabetes Care 2013
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
NEUROPATHY
PAIN
bull burning
bull shootingstabbing
bull deep aching
bull dysesthesias
bull asleep numbness
bull Distalsymmetric
bull nocturnal-exacer
INSENSITIVITY
symptomatic pathogenic
Risk
Reduction
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Albers et al Diabetes Care 2010
0
5
10
15
20
25
30
35
40
Intensive
Standard
DCCTBaseline
DCCTEnd
EDICYear 13-14
w
ith D
PN
plt005
DCCTEDIC Reduced incidence of DPN following previous intensive treatment (ldquometabolic memoryrdquo)
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Steno Type 2 Study 78 yr follow-up
Effects of multifactorial intervention on progression of
neuropathy and microangiopathy
00 05 10 15 20 25
Intensive
therapy better
Conventional
therapy better
Relative Risk
Variable (95 CI) P-Value
Nephropathy 039 (017-087) 0003
Retinopathy 042 (021-086) 002
AN 037 (018-079) 0002
DPN 109 (054-222) 066
BP lt13080
HbA1c lt65
TClt45 mmoll
Gaeligde et al N Engl J Med 2003 348 383-93
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Smith et al Diabetes Care 2006 29 1294-9
Baseline
12 Months
IENFD8mm
IENFD15mm
Epidermal ldquoreinnervationldquo after 1 year (n=32)
Correlation between improvementin intraepidermal nerve fiber density
(IENFD) and improvement in pain
r=04
Lifestyle intervention in IGT with painful DPN
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Disease modifying treatments for DN
Hyperglycemia
Free transition metal
ions
Autoxidation
AGE formation
Endogenous scavengers
Reactive Oxygen Species
Diabetes
Polyol
pathway
flux
Dyslipidemia EFA dysmetabolism
NEUROPATHY
DAG
PKC szlig
AII
ET
NO
PGI 2
EDHF
Vascular
dysfunctionNerve and ganglion
blood flow
Endoneurial hypoxia
Ischemia
reperfusionA-V shuntingONOO-
Cameron et al Diabetologia 2001 441973-88
PKCszligInhibitor
ARIs
Antioxidants
ALA METANX
Benfothiamine
Linoleic acid
GLA
DGLA
AA
GLA
ACE-I ARB
C-Peptide
AGE
inhibitors
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
SNRIs
Duloxetine ndash indicated for DPNP (FDAEMEA Japan)
Venlafaxine
Anticonvulsants
Pregabalin ndash indicated for DPNP (FDAEMEA Japan)
Topiramate
Oxcarbazepine
Lamotrigine
Sodium Valproate
Lacosamide
Tapentadol ndash indicated for DPNP (FDA)
Botulinum Toxin
VEGF gene transfer
Sativex
New Medications tested for painful DPN
(2004ndash2014)
VEGF = Vascular endothelial growth factor
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Anxiety
Depression
Anger
Fear
Loss of confidence
Psychological
VasculopathyPVDIHDCVA
Visual lossObesity
Nephropathy
Autonomic neuropathy
Ulcers
UnsteadinessandFalls
Job loss
Marital disharmony
Isolation
Loss of social status
Social
CVA = Cerebrovascular accident IHD = Ischaemic heart disease PVD = Peripheral vascular disease
Multidimensionality of Painful DPN
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
MDT Doctor Nurse
Physiotherapist
Pain Specialist
Psychologist
Podiatrist
Counselling
Behavioural
Therapy
Glycaemic
Control
Lifestyle
Change
Neuromodulation
Complementary
Therapies
Pharmacotherapy
Physical
Therapy
Assistive
Devices
Multimodal approach to managing
Painful diabetic neuropathy
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Conclusions (1)
Do not ignore painless neuropathy
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
bullProspective studies are required if POCD predict
new-onset DN
bullDiabetic ldquoperipheralldquo neuropathy is a misnomer
bullT1DM DN can be stopped by glucose control but
T2DM DN appears less responsive This is likely
because the neuropathic process in T2DM starts
early Life style intervention metabolic control
and potential disease modifying agents must be
started early
Conclusions (2)
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Diffusion Tensor Imaging
Tractography
Volumetric
measures
Conclusion 3 Advanced MRI paradigm shift
Resting FMRI
Task FMRI
Perfusion Imaging
Magnetic Resonance
Spectroscopy
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
Dr D SelvarajahDr M Greig
Dr J Elliott
Dr Rajiv Gandhi Dr P ShilloDr Atakilt Tekle
Dr S Eaton Prof S Rajbhandari Sr L Brady Dr C Quattrini
Dr M Oleolo Dr L Thomas Prof J Marques Dr T Cash
Dr L Scott
σας ευχαριστώ
Thank You
σας ευχαριστώ
Thank You