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CRPS/RSDCRPS/RSDdiagnosis, diagnosis,
pathophysiology and pathophysiology and treatmenttreatment
Norman HardenNorman HardenCenter for Pain StudiesCenter for Pain Studies
Rehabilitation Institute of ChicagoRehabilitation Institute of ChicagoNorthwestern UniversityNorthwestern University
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Pain and Autonomic Dysfunction:Pain and Autonomic Dysfunction:
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The ‘Budapest’ Criteria: now the ‘new’ IASP
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• Diagnostic criteria (Budapest)Diagnostic criteria (Budapest) ResearchResearch
SymptomsSymptoms• Factor 1Factor 1 Positive sensory symptomsPositive sensory symptoms• Factor 2Factor 2 Vascular symptomsVascular symptoms• Factor 3Factor 3 Edema, sweating abnormalitiesEdema, sweating abnormalities• Factor 4Factor 4 Motor, trophic changesMotor, trophic changes
SignsSigns• Factor 1Factor 1 Positive sensory signsPositive sensory signs• Factor 2Factor 2 Vascular signsVascular signs• Factor 3Factor 3 Edema, sweating abnormalitiesEdema, sweating abnormalities• Factor 4Factor 4 Motor, trophic changesMotor, trophic changes
= 4 symptoms= 4 symptoms Sens. 0.70Sens. 0.70 Spec. 0.94Spec. 0.94
2 signs2 signs
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Mechanistic Hypothesis: Mechanistic Hypothesis: CRPS maintained CRPS maintained and reinforced by nested positive feed forward (afferent and reinforced by nested positive feed forward (afferent nociceptors), and feed back (efferent sympathetic nerves) nociceptors), and feed back (efferent sympathetic nerves) loopsloops
PainPaininflammationinflammation(NE, others)(NE, others)
EphapsesEphapses
GangliaGanglia
DorsalDorsal LateralLateralhorn horn hornhorn
Brain stemBrain stemHypothalamusHypothalamus
Limbic system, cortexLimbic system, cortex
Aff
eren
t Efferen
t
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Sensory Changes in CRPSSensory Changes in CRPS
AllodyniaAllodynia
HyperalgesiaHyperalgesia
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Peripheral Peripheral Sensitization/InflammationSensitization/Inflammation
Marchand F. et al. Nat. Rev. Neurosci. 6, 2005
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Neuropathic Pain Neuropathic Pain
Marchand F. et al. Nat. Rev. Neurosci. 6, 2005
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The Tetrapartite Synapse in Nerve The Tetrapartite Synapse in Nerve InjuryInjury
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Central Sensitization: Areas active in CRPSCentral Sensitization: Areas active in CRPS
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DecreasedDecreased regional anisotropy regional anisotropy and connectivity in CRPSand connectivity in CRPS
Decreased FA in CRPS, localized to a portion of the left callosal fibers (purple, shown in different orientations and magnifications; p < 0.05 corrected)
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*same patient, don’t ask…
Vasomotor changes
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qThermographyqThermography; ‘Fully ; ‘Fully Objective’Objective’
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Laser Doppler:Laser Doppler: ‘fully ‘fully objective’objective’
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EdemaEdema
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Volumeter;Volumeter; ‘fully objective’ ‘fully objective’
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Sudomotor changes Sudomotor changes
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qSART: qSART: ‘fully objective’‘fully objective’
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nail growth hair growth skin changes
nail growth hair growth skin changes
Trophic Changes(Dys)
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Sudeck’s atrophySudeck’s atrophy
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3 Phase Bone Scan? How 3 Phase Bone Scan? How about Bone Densitometryabout Bone Densitometry
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Periquet, et-al. Painful Sensory Neuropathy. Neurology 1999; 53: 1641-Periquet, et-al. Painful Sensory Neuropathy. Neurology 1999; 53: 1641-16471647
Intraepidermal nerve fiber density
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MDNI may be MDNI may be epiphenomenaepiphenomena
• Minor small fiber loss may be due to Minor small fiber loss may be due to nutritional changes (relative nutritional changes (relative ischemia due to chronic ischemia due to chronic vasoconstriction)vasoconstriction)
• MND may be due to MND may be due to inflammation/cytokine damage inflammation/cytokine damage (nociceptive and/or neurogenic (nociceptive and/or neurogenic inflammation)inflammation)
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Peripheral Inflamma-
tionIL1
Spinal Cord
TNFα
Brain
SNS
IL10
IL6
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BlistersBlisters
Blister formation to measure
mediators of inflammation
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Measurement of IL-6 and Measurement of IL-6 and TNF-TNF-α in blistersα in blisters
2626
1
10
100
1000
10000
non-involved CRPS1
1
10
100
1000
10000
non-involved CRPS1
IL-6 TNF-
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Motor DisturbanceMotor Disturbance
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Motor changes:Motor changes:
• WeaknessWeakness
• BradykinesiaBradykinesia
• DystoniaDystonia
• Tremor/myoclonusTremor/myoclonus
• secondary~contracturesecondary~contracture
• etcetc
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BradykinesiaBradykinesia
September 19, 2007September 19, 2007 2929
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van Hilten (2010)TREND Pain Medicine
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Sympathetically Maintained Sympathetically Maintained PainPain
• Pain that is caused, ‘mediated’ or Pain that is caused, ‘mediated’ or maintained by activity of the maintained by activity of the sympathetic nervous system (or its sympathetic nervous system (or its peripheral receptors)peripheral receptors)
• Either: hyperactivity of the SNS Either: hyperactivity of the SNS efferentsefferents
• Or: receptor up regulation in Or: receptor up regulation in peripheryperiphery
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Effects of Sympathetic and Peptidergic Nerve Fibers Effects of Sympathetic and Peptidergic Nerve Fibers on Skin and Immune Cellson Skin and Immune Cells
Postsynaptic sympathetic nerve terminal
Peptidergic / sensory nerve fiber
NK1
NK12
222
NE
NE NE
NESP
SP
keratinocyte
macrophagemono
Th 2
Th 1
TNFIl-12Il-1
TNFIlIl-6, Il-3Il-8, TGF
IlIl-10, Il-13
IFNIl-10Il-6
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Conceptual Model of CRPS: An Autoantibody-Mediated Neuroinflammatory Disorder
Goebel A Rheumatology 2011;50:1739-1750
© The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
90% of CRPSPatients have an Autoantibodyto one of twoNeurotransmitterReceptors
55% of CRPSPatients have Autoantibodiesto Both
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Hypothesis: Hypothesis: CRPS maintained and reinforced by CRPS maintained and reinforced by nested positive feed forward (afferent nociceptors) and nested positive feed forward (afferent nociceptors) and feed back (efferent sympathetic nerves) loopsfeed back (efferent sympathetic nerves) loops
PainPaininflammationinflammation(NE, others)(NE, others)
Ephapses, MNDEphapses, MND
GangliaGanglia
DorsalDorsal LateralLateralhorn horn hornhorn
Brain stemBrain stemHypothalamusHypothalamus
Limbic system, cortexLimbic system, cortex
Aff
eren
t Efferen
t
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Chronic Pain is a Chronic Pain is a Bio-Psycho-Social Bio-Psycho-Social DiseaseDisease
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Identify Crucial Psychosocial Targets
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Psychological Factors Psychological Factors associated with CRPSassociated with CRPS
– 75% of the articles reviewed mentioned 75% of the articles reviewed mentioned depression, anxiety, or life stress as associated depression, anxiety, or life stress as associated with the disorder in adults and children.with the disorder in adults and children.
– Correlations between Depression (BSI) and Correlations between Depression (BSI) and MPQ-Affective pain intensity were significantly MPQ-Affective pain intensity were significantly stronger in both CRPS groups compared to the stronger in both CRPS groups compared to the LBP group (.60/.66 vs .42)LBP group (.60/.66 vs .42)
Similar effect was noted for correlations between Similar effect was noted for correlations between Anxiety (BSI) and MPQ-Affective. Anxiety (BSI) and MPQ-Affective. Bruehl et al. (1996Bruehl et al. (1996))
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PsychopathologyPsychopathology
Fear
Anxiety
Anger
Frustration
Catastrophizing
Depression
Failure to Cope
Kinesiophobia
Drug abuse, OIH. etc
Fear
Anxiety
Anger
Frustration
Catastrophizing
Depression
Failure to Cope
Kinesiophobia
Drug abuse, OIH. etc
Modified: Raja SN et al. Anesthesiology. 2002;96:1254-1260.Modified: Raja SN et al. Anesthesiology. 2002;96:1254-1260.
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Strength of white matter connections Strength of white matter connections between the right VMPFC to the right between the right VMPFC to the right
NAc are related to anxiety in CRPSNAc are related to anxiety in CRPS
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Anxiety as a surrogate of sympathetic activityAnxiety as a surrogate of sympathetic activity
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Altered body perception (Candy McCabe)Altered body perception (Candy McCabe)
Enlarged area on cheek
Grossly distorted hand
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Interdisciplinary Team ApproachInterdisciplinary Team Approach
Psych
RN
MD
OTPT
RT
SW
Voc
PATIENT
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“MALIBU” ALGORITHM
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Interventional Pain Therapy Interventional Pain Therapy
Minimally Invasive TherapiesMinimally Invasive Therapies– Sympathetic / Somatic nerve blocksSympathetic / Somatic nerve blocks– IV Regional nerve blocks IV Regional nerve blocks
More Invasive TherapiesMore Invasive Therapies– Epidural / Plexus Catheter BlocksEpidural / Plexus Catheter Blocks– Neurostimulation/NeuromodulationNeurostimulation/Neuromodulation– Intrathecal Drug InfusionIntrathecal Drug Infusion
Surgical TherapiesSurgical Therapies– SympathectomySympathectomy– Motor Cortex StimulationMotor Cortex Stimulation
Burton A. Interventional therapies. Complex Regional Pain Syndrome: Treatment Guidelines. RSDSA press. 2006:51-62..
Velasco F. Pain, 2009, Volume 147, Issue 1, Pages 91-98
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Intrathecal BaclofenIntrathecal Baclofen
- Dystonia in CRPS that can Dystonia in CRPS that can not be treated by more not be treated by more conservative measures can conservative measures can be alleviated through be alleviated through intrathecal Baclofenintrathecal Baclofen
- In patients with dystonia In patients with dystonia baclofen possibly improves baclofen possibly improves pain, disability and quality of pain, disability and quality of life. life.
Van Hilten BJ et al. N Engl J Med. 2000 Aug 31;343(9):625-30.
Van Rijn MA et al. Pain. 2009; 143: 41-47.
from Van Rijn. Pain, 2009; 143:41-47
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Spinal cord stimulationSpinal cord stimulation-- Spinal cord stimulation (SCS) has a modest, Spinal cord stimulation (SCS) has a modest,
time limited effect on pain scores but no time limited effect on pain scores but no effect on health-related quality of lifeeffect on health-related quality of life
Kemler MA. N Engl J Med. 2006 Jun 1;354(22):2394-6.Kemler MA. J Neurosurg 108:292–298, 2008
.
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Today’s dogma Today’s dogma will be will be
tomorrow’s tomorrow’s heresy…heresy…
D.J.DalessioD.J.Dalessio