1. CRPS/RSD diagnosis, pathophysiology and treatment Norman Harden Center for Pain Studies Rehabilitation Institute of Chicago Northwestern University

2. Pain and Autonomic Dysfunction:

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

4. Diagnostic criteria (Budapest)Diagnostic criteria (Budapest) Research ResearchSymptoms Factor 1Positive sensory symptomsFactor 1Positive sensory symptoms Factor 2Vascular symptomsFactor 2Vascular symptoms Factor 3Edema, sweating abnormalitiesFactor 3Edema, sweating abnormalities Factor 4Motor, trophic changesFactor 4Motor, trophic changesSigns Factor 1Positive sensory signsFactor 1Positive sensory signs Factor 2Vascular signsFactor 2Vascular signs Factor 3Edema, sweating abnormalitiesFactor 3Edema, sweating abnormalities Factor 4Motor, trophic changesFactor 4Motor, trophic changes = 4 symptomsSens. 0.70Spec. 0.94  2 signs

5. Mechanistic Hypothesis: CRPS maintained and reinforced by nested positive feed forward (afferent nociceptors), and feed back (efferent sympathetic nerves) loops Pain inflammation (NE, others) EphapsesGanglia DorsalLateral horn horn Brain stem Hypothalamus Limbic system, cortex Afferent Efferent

6. Sensory Changes in CRPS AllodyniaHyperalgesia

7. Peripheral Sensitization/Inflammation Marchand F. et al. Nat. Rev. Neurosci. 6, 2005

8. Neuropathic Pain Marchand F. et al. Nat. Rev. Neurosci. 6, 2005

9. The Tetrapartite Synapse in Nerve Injury

10. Central Sensitization: Areas active in CRPS

11. 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)

12. *same patient, don’t ask… Vasomotor changes

13. qThermography; ‘Fully Objective’

14. Laser Doppler: ‘fully objective’

15. Edema Edema

16. Volumeter; ‘fully objective’

17. Sudomotor changes

18. qSART: ‘fully objective’

19. nail growth hair growth skin changes nail growth hair growth skin changes Trophic Changes (Dys)

20. Sudeck’s atrophy

21. 3 Phase Bone Scan? How about Bone Densitometry

22. Periquet, et-al. Painful Sensory Neuropathy. Neurology 1999; 53: 1641-1647 Intraepidermal nerve fiber density

23. MDNI may be epiphenomena Minor small fiber loss may be due to nutritional changes (relative ischemia due to chronic vasoconstriction) 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) MND may be due to inflammation/cytokine damage (nociceptive and/or neurogenic inflammation)

24. Peripheral Inflamma- tion IL 1 Spinal Cord TNF α Brain SNS IL 10 IL 6

25. Blisters  Blister formation to measure  mediators of inflammation

26. Measurement of IL-6 and TNF-α in blisters 26 IL-6 TNF- 

27. Motor Disturbance

28. Motor changes: Weakness Weakness Bradykinesia Bradykinesia Dystonia Dystonia Tremor/myoclonus Tremor/myoclonus secondary~contracture secondary~contracture etc etc

29. Bradykinesia September 19, 200729

30. van Hilten (2010) TREND Pain Medicine

31. Sympathetically Maintained Pain Pain that is caused, ‘mediated’ or maintained by activity of the sympathetic nervous system (or its peripheral receptors) Pain that is caused, ‘mediated’ or maintained by activity of the sympathetic nervous system (or its peripheral receptors) Either: hyperactivity of the SNS efferents Either: hyperactivity of the SNS efferents Or: receptor up regulation in periphery Or: receptor up regulation in periphery

32. Effects of Sympathetic and Peptidergic Nerve Fibers on Skin and Immune Cells Postsynaptic sympathetic nerve terminal Peptidergic / sensory nerve fiber NK1 22 22 22 22 NE SP keratinocyte macrophage mono Th 2 Th 1 TNF  Il-12 Il-1 TNF  Il   Il-6, Il-3 Il-8, TGF  Il  Il-10, Il- 13 IFN  Il-10 Il-6

33. 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 CRPS Patients have an Autoantibody to one of two Neurotransmitter Receptors 55% of CRPS Patients have Autoantibodies to Both

34. Hypothesis: CRPS maintained and reinforced by nested positive feed forward (afferent nociceptors) and feed back (efferent sympathetic nerves) loops Pain inflammation (NE, others) Ephapses, MND Ganglia DorsalLateral horn horn Brain stem Hypothalamus Limbic system, cortex Afferent Efferent

35. Chronic Pain is a Bio-Psycho-Social Disease

36. Identify Crucial Psychosocial Targets

37. 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) Similar effect was noted for correlations between Anxiety (BSI) and MPQ-Affective. Bruehl et al. (1996)

38. Psychopathology 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.

39. Strength of white matter connections between the right VMPFC to the right NAc are related to anxiety in CRPS

40. Anxiety as a surrogate of sympathetic activity

41. Altered body perception (Candy McCabe) Enlarged area on cheek Grossly distorted hand

42. Interdisciplinary Team Approach Psych RN MD OT PT RT SW Voc PATIENT

43. “MALIBU” ALGORITHM

44. 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

45. 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. 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

46. 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.

47. Today’s dogma will be tomorrow’s heresy… D.J.Dalessio D.J.Dalessio