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

Pain and Autonomic Dysfunction:Pain and Autonomic Dysfunction:

The ‘Budapest’ Criteria: now the ‘new’ IASP

• 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

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

Sensory Changes in CRPSSensory Changes in CRPS

AllodyniaAllodynia

HyperalgesiaHyperalgesia

Peripheral Peripheral Sensitization/InflammationSensitization/Inflammation

Marchand F. et al. Nat. Rev. Neurosci. 6, 2005

Neuropathic Pain Neuropathic Pain

Marchand F. et al. Nat. Rev. Neurosci. 6, 2005

The Tetrapartite Synapse in Nerve The Tetrapartite Synapse in Nerve InjuryInjury

Central Sensitization: Areas active in CRPSCentral Sensitization: Areas active in CRPS

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)

*same patient, don’t ask…

Vasomotor changes

qThermographyqThermography; ‘Fully ; ‘Fully Objective’Objective’

Laser Doppler:Laser Doppler: ‘fully ‘fully objective’objective’

EdemaEdema

Volumeter;Volumeter; ‘fully objective’ ‘fully objective’

Sudomotor changes Sudomotor changes

qSART: qSART: ‘fully objective’‘fully objective’

nail growth hair growth skin changes

nail growth hair growth skin changes

Trophic Changes(Dys)

Sudeck’s atrophySudeck’s atrophy

3 Phase Bone Scan? How 3 Phase Bone Scan? How about Bone Densitometryabout Bone Densitometry

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

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)

Peripheral Inflamma-

tionIL1

Spinal Cord

TNFα

Brain

SNS

IL10

IL6

BlistersBlisters

Blister formation to measure

mediators of inflammation

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-

Motor DisturbanceMotor Disturbance

Motor changes:Motor changes:

• WeaknessWeakness

• BradykinesiaBradykinesia

• DystoniaDystonia

• Tremor/myoclonusTremor/myoclonus

• secondary~contracturesecondary~contracture

• etcetc

BradykinesiaBradykinesia

September 19, 2007September 19, 2007 2929

van Hilten (2010)TREND Pain Medicine

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

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

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: journals.permissions@oup.com

90% of CRPSPatients have an Autoantibodyto one of twoNeurotransmitterReceptors

55% of CRPSPatients have Autoantibodiesto Both

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

Chronic Pain is a Chronic Pain is a Bio-Psycho-Social Bio-Psycho-Social DiseaseDisease

Identify Crucial Psychosocial Targets

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))

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.

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

Anxiety as a surrogate of sympathetic activityAnxiety as a surrogate of sympathetic activity

Altered body perception (Candy McCabe)Altered body perception (Candy McCabe)

Enlarged area on cheek

Grossly distorted hand

Interdisciplinary Team ApproachInterdisciplinary Team Approach

Psych

RN

MD

OTPT

RT

SW

Voc

PATIENT

“MALIBU” ALGORITHM

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

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

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