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CRPS/RSD
diagnosis, pathophysiology
and treatment
Norman Harden
Center for Pain Studies
Rehabilitation Institute of Chicago
Northwestern University
Pain and Autonomic Dysfunction:
The ‘Budapest’ Criteria: now the ‘new’ IASP
• Diagnostic criteria (Budapest)
Research
Symptoms
• Factor 1
• Factor 2
• Factor 3
• Factor 4
Positive sensory symptoms
Vascular symptoms
Edema, sweating abnormalities
Motor, trophic changes
Signs
• Factor 1
• Factor 2
• Factor 3
• Factor 4
Positive sensory signs
Vascular signs
Edema, sweating abnormalities
Motor, trophic changes
= 4 symptoms
 2 signs
Sens. 0.70
Spec. 0.94
Mechanistic Hypothesis:
CRPS maintained and
reinforced by nested positive feed forward (afferent nociceptors),
and feed back (efferent sympathetic nerves) loops
Pain
inflammation
(NE, others)
Ganglia
Dorsal
horn
Lateral
horn
Brain stem
Hypothalamus
Limbic system, cortex
Efferent
Afferent
Ephapses
Sensory Changes in CRPS
Allodynia
Hyperalgesia
Peripheral Sensitization/Inflammation
Marchand F. et al. Nat. Rev. Neurosci. 6, 2005
Neuropathic Pain
Marchand F. et al. Nat. Rev. Neurosci. 6, 2005
The Tetrapartite Synapse in Nerve Injury
Central Sensitization: Areas active in CRPS
Decreased regional anisotropy and
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)
Vasomotor changes
*same patient, don’t ask…
qThermography; ‘Fully Objective’
Laser Doppler: ‘fully objective’
Edema
Volumeter; ‘fully objective’
Sudomotor changes
qSART: ‘fully objective’
(Dys)Trophic
nail growth
hair growth
skin changes
Changes
Sudeck’s atrophy
3 Phase Bone Scan? How about
Bone Densitometry
Intraepidermal nerve fiber density
Periquet, et-al. Painful Sensory Neuropathy. Neurology 1999; 53: 1641-1647
MDNI may be epiphenomena
• Minor small fiber loss may be due to
nutritional changes (relative ischemia due
to chronic vasoconstriction)
• MND may be due to inflammation/cytokine
damage (nociceptive and/or neurogenic
inflammation)
Peripheral
Inflammation
IL1
TNFα
Spinal
Cord
Brain
IL6
IL10
SNS
Blisters
 Blister formation to measure
 mediators of inflammation
Measurement of IL-6 and TNF-α
in blisters
10000
10000
TNF-
IL-6
1000
1000
100
100
10
10
1
1
non-involved
CRPS1
non-involved
CRPS1
26
Motor Disturbance
Motor changes:
• Weakness
• Bradykinesia
• Dystonia
• Tremor/myoclonus
• secondary~contracture
• etc
Bradykinesia
September 19, 2007
29
van Hilten (2010)
TREND
Pain Medicine
Sympathetically Maintained Pain
• Pain that is caused, ‘mediated’ or
maintained by activity of the sympathetic
nervous system (or its peripheral
receptors)
• Either: hyperactivity of the SNS efferents
• Or: receptor up regulation in periphery
Effects of Sympathetic and Peptidergic Nerve Fibers on Skin
and Immune Cells
Postsynaptic
sympathetic nerve
terminal
Peptidergic / sensory nerve
fiber
SP
NE
NE
NE
NE
b2
b2
mono
Th 1
2
SP
b2
NK1
keratinocyte
NK1
macrophage
Il-10
Il-6
IFNg
Th 2
Il-4, Il-10, Il13
TNF
Il-12
Il-1
TNF, Il1
Il-6, Il-3
Il-8,
TGFb
Conceptual Model of CRPS: An Autoantibody-Mediated Neuroinflammatory Disorder
90% of CRPS
Patients have
an Autoantibody
to one of two
Neurotransmitte
Receptors
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]
55% of CRPS
Patients have
Autoantibodies
to Both
Hypothesis:
CRPS maintained and reinforced by nested
positive feed forward (afferent nociceptors) and feed back
(efferent sympathetic nerves) loops
Pain
inflammation
(NE, others)
Ganglia
Dorsal
horn
Lateral
horn
Brain stem
Hypothalamus
Limbic system, cortex
Efferent
Afferent
Ephapses, MND
Chronic Pain is a
Bio-Psycho-Social
Disease
Identify Crucial Psychosocial Targets
Psychological Factors associated
with CRPS
– 75% of the articles reviewed mentioned
depression, anxiety, or life stress as associated
with the disorder in adults and children.
– Correlations between Depression (BSI) and
MPQ-Affective pain intensity were significantly
stronger in both CRPS groups compared to the
LBP group (.60/.66 vs .42)
Similar effect was noted for correlations between
Anxiety (BSI) and MPQ-Affective. Bruehl et al. (1996)
Psychopathology
Fear
Anxiety
Anger
Frustration
Catastrophizing
Depression
Failure to Cope
Kinesiophobia
Drug abuse, OIH. etc
Modified: Raja SN et al. Anesthesiology. 2002;96:1254-1260.
Strength of white matter connections
between the right VMPFC to the right NAc
are related to anxiety in CRPS
Anxiety as a surrogate of sympathetic activity
Altered body perception (Candy McCabe)
Enlarged area on cheek
Grossly distorted hand
Interdisciplinary Team Approach
OT
Psych
PT
Voc
RT
PATIENT
MD
SW
RN
“MALIBU” ALGORITHM
Interventional Pain Therapy

Minimally Invasive Therapies
– Sympathetic / Somatic nerve blocks
– IV Regional nerve blocks

More Invasive Therapies
– Epidural / Plexus Catheter Blocks
– Neurostimulation/Neuromodulation
– Intrathecal Drug Infusion

Surgical Therapies
– Sympathectomy
– Motor 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 Baclofen
- Dystonia in CRPS that can not be
treated by more conservative
measures can be alleviated
through intrathecal Baclofen
- In patients with dystonia
baclofen possibly improves pain,
disability and quality of life.
from Van Rijn. Pain, 2009; 143:41-47
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.
Spinal cord stimulation
- Spinal cord stimulation (SCS) has a modest, time
limited effect on pain scores but no effect 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
Today’s dogma
will be
tomorrow’s
heresy…
D.J.Dalessio