1. Complex Regional Pain Syndrome Type 1 Anke GJ De Bruijn

2. Pain Stimulus Mediators Receptor Spinal cord Higher centers Cerebral cortex Limbic system Emotion Perception Transduction Transmission Modulation

3. Complex Regional Pain Syndrome Definition 72 different names: –Sudeck’s atrophy –Posttraumatic dystrophy –Sympathetic reflex dystrophy –Shoulder-hand syndrome Veldman criteria, IASP criteria, Bruehl criteria Veldman et al. 1993; Beek et al. 2002; Reinders et al. 2002

4. IASP Conference Orlando 1993 Complex Regional Pain Syndrome Spontaneous, continuing pain or allodynia/hyperalgesia, disproportionate to inciting event Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity Exclusion of medical conditions that would otherwise account for the degree of pain and dysfunction Type 1 without, type 2 with nerve injury Stanton Hicks et al. 1995

5. Bruehl criteria Complex Regional Pain Syndrome Continuing pain disproportionate to inciting event Sensory (allodynia, hypesthesia) Vasomotor (skin color changes, temperature) Sudomotor (edema/swelling, sweating) Motor/trophic signs and symptoms (weakness, dystonia, nail/hair growth) At least one symptom in each category At least one sign in two or more categories Bruehl et al. 1999

6. Complex Regional Pain Syndrome Epidemiology 1-2% following fracture 7-35% following Colles’ fracture 10-26% spontaneous Other causes: MI, CVA, reperfusion syndrome 8000 estimated new patients per year in NL Female : Male ≈ 3:1 Veldman et al. 1993

8. Pathophysiology CRPS CNS Dorsal horn Neurogenic inflammation Blood vessel Substance P CGRP Nerve injury to C and Aδ fibres Neuropeptides Higher centers

9. Neuropeptides Animal model Loose ligation of sciatic nerve in the rat Changing expression neuropeptides CRPS symptoms appear Increase skin blood flow is blocked by Capsaicin NK1 receptor antagonist decreases CRPS symptoms Verge et al. 2002; Daemen et al. 1998; Kingerly et al. 2003

10. Neuropeptides Patient model Infusion of Substance P aggravates CRPS Depletion of Substance P with Capsaicin decreases CRPS Symptoms Bradykinin, Neuropeptide Y, CGRP and VIP increased Transcutaneous electric stimulation increases neuropeptides release Blair et al. 1998; Weber et al. 2001; Cheslie et al. 1990; Rumsfield et al. 1991

11. Pathophysiology CRPS CNS Dorsal horn Neurogenic inflammation Pro- inflammatory agents Mastcells Blood vessel IL6 TNFalfa Pro-inflammatory agents Higher centers

12. Inflammatory response Animal Model Loose ligation of sciatic nerve in the rat Increase in cytokines: especially IL-6 and TNFalfa Wagner et al. 1996; Sommer et al. 1997; Shubayev et al. 2001; Cui et al. 2000

13. Inflammatory response Patient model IL-6 and TNFalfa are significantly higher in a CRPS extremity Tryptase is significantly higher in CRPS Succesful treatment with anti-TNF Huygen et al. 2002; Huygen et al. submitted 2003; Huygen et al. 2003

14. Free radicals Animal model Infusion of tert-butylhydroperoxide in rat paws induces: –Increased skin temperature –Increased volume –Skin redness –Impaired function –Pain Van der Laan et al. 1998

15. Free radicals Patient model CRPS resembles “local” sepsis, free radicals are possibly involved in sepsis DMSO 50% relieves clinical symptoms in the warm phase N-acetylcysteine relieves clinical symptoms in the cold phase Goris et al. 1987; Zuurmond et al. 1996; Perez et al. 2003

16. Pathophysiology CRPS CNS Dorsal horn Blood vessel 3 Motor dysfunction 2 Sympathetic disorder Sensitization GABA Sensitization Higher centers 1 Sensory dysfunction Neuropeptides Cytokines

17. Sensory dysfunction Animal model Loose ligation of sciatic nerve in the rat Changes in the dorsal horn under influence of neuropeptides and cytokines Verge et al. 2002; Sorkin et al. 2002

18. Sensory dysfunction Patient model > 70% glove or stocking like pattern Allodynia and/or hyperalgesia Central mechanisms Veldman et al. 1993; Boas et al. 1996; Thimineur et al. 1998; Rommel et al. 1999,2001

19. Sympathetic dysfunction Animal model Loose ligation of sciatic nerve in the rat CRPS symptoms Sympathetic dysfunction is caused by denervation induced hypersensitivity of catecholamines Kurvers et al. 1998

20. Sympathetic dysfunction Patient model Density of alpha receptors in the skin of CRPS patients is greater than in control subjects Decreased sympathetic activity in acute phase induces hypersensitivity to catecholamines Drummond et al. 1996; Birklein et al. 2001

21. Motor dysfunction Patient model Dystonia, weakness, myoclonus and tremor Changes in CNS by abnormal input can result in a neglect like syndrome Clinical picture of disuse is diffucult to discern from CRPS 1 Changes in sensory and motor integration in spinal cord, involvement of GABA system Swartzman et al. 1990; Galer et al. 1995; Butler et al. 1996; Hilten et al. 2000

22. Immunologic considerations Patient model Genetic abnormality (HLA-DR2) on chromosome 6 is more often found in chronic CRPS HLA-DQ1 is significantly increased in CRPS Association HLA-DR13 in CRPS Significant association TNF2 allele in warm CRPS and even homozygote in CRPS patients with  2 extremities affected Seropositivity Parvovirus B12 is associated with CRPS Mailis et al. 1994; Kemler et al. 2000; Hilten et al. 2000; Vaneker et al. 2002; van de Vusse et al. 2001

23. Drug-induced CRPS Case reports Phenobarbital –Improvement on withdrawal or treatment with Gabapentin –Described since 1966 Isoniazide Cyclosporin A in renal transplant patients Heroin induced rhabdomyolysis Cocain injected intra-arterially Van der Korst et al. 1966; Rovetta et al. 2001; Lee et al. 2001; Gay et al. 2000; Marshall et al. 2000

24. Psychological factors Patient model No evidence that these factors play an aetiological role Psychological and/or emotional factors are able to intensify pain in CRPS Prospective studies for psychological and psychiatric factors in CRPS Bruehl et al. 2002; Bruehl et al. 1992; Beerthuizen et al. 2003

25. Pathophysiology CRPS CNS Dorsal horn Neurogenic inflammation Pro- inflammatory agents Mastcells Blood vessel Substance P CGRP IL6 TNFalfa Motor dysfunction Sympathetic disorder Nerve injury GABA Higher centers Sensory dysfunction

26. Therapy CRPS Limited effect sympathetic blocks, radical scavengers (mannitol, DMSO, acetylcysteine), vasodilators, prednisone, acupuncture and lymphe drainage Analgetics: antidepressants, carbamazepine Limited effect vitamin C in prevention Proven effect calcium regulators (Bisphosphonates) Calcitonine relieves pain effectively Capsaicin Forouzanfar et al. 2002; Perez et al. 2001

27. Complex Regional Pain Syndrome type 1 Future Diagnosis, gold standard, epidemiology Pathophysiology: –Pathway analysis, genetics, adverse drug reactions Interventions, antagonists, synthesis inhibitors

28. Trend Project (Trauma Related Neuronal Dysfunction) Knowledge consortium with multi-disciplinary approach: –Epidemiology –Assessment technologies –Pharmacotherapeutics –Proteomics –Genetics

29. PhD project Epidemiology Incidence and prevalence Disease course Applied treatments and effectiveness Intrinsic and extrinsic factors that precipitate and sustain CRPS Phenotype spectrum

30. IPCI Database Integrated Primary Care Information Database Longitudinal observational database Electronic patient records of 150 GP’s: 500.000 patients in the Netherlands Coded and anonymous data on demographics, symptoms, diagnosis (from GP and specialist), physical examination, discharge letters, referrals and prescriptions

31. Complex Regional Pain Syndrome type 1 Future Diagnosis, gold standard, epidemiology Pathophysiology: –Pathway analysis, genetics, adverse drug reactions Interventions, antagonists, synthesis inhibitors Trend and Infobiomed join forces? –Integration patient data and molecular data?

32. END