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Spine Surgical Research at New England Baptist Hospital

Spine Surgical Research at New England Baptist Hospital. David H. Kim, MD Chief of Medical Education Spine Section, Dept of Orthopaedic Surgery. Iliac Crest Bone Graft Harvest Related Pain and Morbidity . David H. Kim, MD Louis Jenis, MD Robert Banco, MD Sharon Koogler Kelsey Miller

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Spine Surgical Research at New England Baptist Hospital

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  1. Spine Surgical Researchat New England Baptist Hospital David H. Kim, MD Chief of Medical Education Spine Section, Dept of Orthopaedic Surgery

  2. Iliac Crest Bone Graft Harvest Related Painand Morbidity David H. Kim, MD Louis Jenis, MD Robert Banco, MD Sharon Koogler Kelsey Miller Scott Tromanhauser, MD

  3. Introduction • Frequently reported complications • chronic pain • numbness • cosmetic appearance • No consensus regarding incidence of pain or functional significance • Principal factor driving search for viable bone graft alternatives • Few prospective studies of bone graft harvest site complications; no prospective study of functional disability

  4. Comparative Use of Bone Graft Alternative

  5. Introduction • Bone graft harvest site complications & fusion rates are two most important variables in cost-benefit calculations for high-priced technology such as recombinant growth factor

  6. Purpose • Prospectively study rates of ICBG harvest pain & morbidity • rates & severity of pain • numbness • cosmetic complaints • functional limitations

  7. Study Design • Prospective cohort study • Study population • patients undergoing autologous ICBG harvest as part of elective spinal surgery

  8. Study Population • 135 adult patients prospectively enrolled • 12 month postop f/u period • 5 patients failed f/u • 130 patients in final study group • Female/male: 71/59 • Lumbar/cervical: 116/14

  9. Outcome Measures • Visual analogue scale (VAS) for pain from ICBG harvest site • 12 month f/u questionnaire regarding symptoms & effect on functional activities.

  10. Methods • Preoperative demographic data • Postoperative VAS pain scores at 6 wk, 6 mo, & 12 mo f/u • 12 mo f/u questionnaire • Full-time research assistant

  11. Results • Mean harvest site VAS pain scores • 6 wks: 2.63 (S.D. 2.76) • 6 mos: 1.77 (S.D. 2.42) • 12 mos: 1.54 (S.D. 2.39)

  12. Harvest Site Pain N=129

  13. Harvest Site Pain by Primary Surgical Site

  14. Harvest Site Pain by Age

  15. Harvest Site Pain by Sex

  16. Harvest Site Pain by Diagnosis

  17. Results • 12 mo f/u: • 16.5% more severe pain from harvest site than primary surgical site • 3.9% bothered by scar appearance • 29.1% noticeable numbness • 11.3% bothersome numbness

  18. Results • Functional disability due to persistent harvest site pain: • 18.8% walking • 10.3% job • 19.0% recreational activity • 21.5% household chores • 10.8% sexual activity • 5.1% irritation from clothing

  19. Conclusions • High rate of persistent pain & morbidity from iliac crest bone graft harvest when associated with elective spine surgery • Mean pain scores progressively decline over first postop year • Harvest site pain remains functionally limiting in many patients one year following surgery • Rates for functional limitation are higher than those previously reported

  20. Polymorphic Variation of the GTP Cyclohydrolase 1 Gene in Patients Undergoing Surgical Treatment for Lumbar Degenerative Disc Disease David H. Kim, MD; Mitchell Max, PhD; Inga Peter, PhD; Inna Belfer, PhD; Robert Banco, MD; Scott Tromanhauser, MD; Louis Jenis, MD; Carolyn Schwartz, ScD New England Baptist Hospital, Boston, USA National Institutes of Health, Bethesda, USA

  21. Introduction • Pain is genetically determined • Genes that modulate pain sensitivity in humans • COMT[Diatchenko et al, Hum Mol Genet 2005; Zubieta et al, Science 2003] • Mc1r[Mogil et al, Proc Natl Acad Sci USA 2003] • GCH1[Tegeder et al, Nature Med 2006]

  22. GCH1 • GTP cyclohydrolase (GCH1) • Rate-limiting enzyme in BH4 synthesis • BH4 essential cofactor for tyrosine, tryptophan, and phenylalanine hydroxylases, iNOS • Expression in brain, spinal cord, and peripheral nerve [Lentz & Kapatos, Neurochem Int 1996; Hwang et al, Synapse 1998] • Loss of function mutation causes hereditary progressive dystonia with marked diurnal fluctuation (HPD) aka dopa responsive dystonia [Ichinose et al, Nature Gen 1994]

  23. GCH1 and Pain Sensitivity [Kim & Dionne, Mol Pain 2008] [Tegeder et al, Nature Med 2006] 15 single nucleotide polymorphisms Pain protective haplotype in 15.4% Distribution follows Hardy-Weinberg Equilibrium in general population Associated with less pain following lumbar discectomy Homozygotes reduced experimental pain sensitivity

  24. Study Design • Prospective cohort study • 100 patients undergoing surgical treatment for lumbar DDD • Moderate to severe LBP > 6 months • Failed nonoperative treatment (activity modification, NSAIDs, PT, injection) • MRI evidence of 1-2 level DDD • Venous blood sample, DNA extraction, GCH1 DNA sequence analysis

  25. Results 15 single nucleotide polymorphisms (SNPs) in noncoding regions of GCH1 distributed evenly across gene 14 of 15 loci informative in study population

  26. GCH1 Allele Frequencies Standard Locus Allele Frequency Error GCH1_1 C 0.7813 0.0264 GCH1_1 G 0.2188 0.0264 GCH1_2 A 0.2833 0.0352 GCH1_2 C 0.7167 0.0352 GCH1_3 C 0.7789 0.0265 GCH1_3 T 0.2211 0.0265 GCH1_4 C 0.2188 0.0264 GCH1_4 T 0.7813 0.0264 GCH1_5 C 0.3495 0.0321 GCH1_5 T 0.6505 0.0321 GCH1_6 A 0.3495 0.0330 GCH1_6 G 0.6505 0.0330 GCH1_7 G 0.0806 0.0205 GCH1_7 T 0.9194 0.0205 Standard Locus Allele Frequency Error GCH1_8 C 0.1389 0.0305 GCH1_8 T 0.8611 0.0305 GCH1_9 C 0.7857 0.0322 GCH1_9 T 0.2143 0.0322 GCH1_10 A 0.3187 0.0334 GCH1_10 G 0.6813 0.0334 GCH1_11 A 0.7865 0.0274 GCH1_11 T 0.2135 0.0274 GCH1_12 C 0.9194 0.0205 GCH1_12 G 0.0806 0.0205 GCH1_13 A 0.5852 0.0379 GCH1_13 G 0.4148 0.0379 GCH1_14 C 0.8000 0.0262 GCH1_14 T 0.2000 0.0262

  27. GCH1 Genotype Frequencies HWD Standard Locus Genotype Frequency Coeff Error GCH1_1 C/C 0.5729 -0.0374 0.0129 GCH1_1 C/G 0.4167 -0.0374 0.0129 GCH1_1 G/G 0.0104 -0.0374 0.0129 GCH1_2 A/A 0.1000 0.0197 0.0222 GCH1_2 A/C 0.3667 0.0197 0.0222 GCH1_2 C/C 0.5333 0.0197 0.0222 GCH1_3 C/C 0.5684 -0.0383 0.0131 GCH1_3 C/T 0.4211 -0.0383 0.0131 GCH1_3 T/T 0.0105 -0.0383 0.0131 GCH1_4 C/C 0.0104 -0.0374 0.0129 GCH1_4 C/T 0.4167 -0.0374 0.0129 GCH1_4 T/T 0.5729 -0.0374 0.0129 GCH1_5 C/C 0.0860 -0.0361 0.0225 GCH1_5 C/T 0.5269 -0.0361 0.0225 GCH1_5 T/T 0.3871 -0.0361 0.0225 GCH1_6 A/A 0.0968 -0.0253 0.0229 GCH1_6 A/G 0.5054 -0.0253 0.0229 GCH1_6 G/G 0.3978 -0.0253 0.0229 GCH1_7 G/G 0.0108 0.0042 0.0095 GCH1_7 G/T 0.1398 0.0042 0.0095 GCH1_7 T/T 0.8495 0.0042 0.0095 HWD Standard Locus Genotype Frequency Coeff Error GCH1_8 C/C 0.0667 0.0474 0.0202 GCH1_8 C/T 0.1444 0.0474 0.0202 GCH1_8 T/T 0.7889 0.0474 0.0202 GCH1_9 C/C 0.6374 0.0200 0.0195 GCH1_9 C/T 0.2967 0.0200 0.0195 GCH1_9 T/T 0.0659 0.0200 0.0195 GCH1_10 A/A 0.0879 -0.0136 0.0223 GCH1_10 A/G 0.4615 -0.0136 0.0223 GCH1_10 G/G 0.4505 -0.0136 0.0223 GCH1_11 A/A 0.5843 -0.0343 0.0133 GCH1_11 A/T 0.4045 -0.0343 0.0133 GCH1_11 T/T 0.0112 -0.0343 0.0133 GCH1_12 C/C 0.8495 0.0042 0.0095 GCH1_12 C/G 0.1398 0.0042 0.0095 GCH1_12 G/G 0.0108 0.0042 0.0095 GCH1_13 A/A 0.3523 0.0098 0.0259 GCH1_13 A/G 0.4659 0.0098 0.0259 GCH1_13 G/G 0.1818 0.0098 0.0259 GCH1_14 C/C 0.6105 -0.0295 0.0122 GCH1_14 C/T 0.3789 -0.0295 0.0122 GCH1_14 T/T 0.0105 -0.0295 0.0122

  28. Linkage disequilibrium measure, δ δ := cov(I1, I2) = p1p2 – h12 = h11h22 – h12h21 Where: I1, I2 denote two loci p1p2 denote allele frequencies h12 denotes haplotype frequency δ = 0 → linkage equilibrium δ ≠ 0 → linkage disequilibrium

  29. Linkage disequilibrium measure, D D = x11 – p1q1

  30. Lewontin’s D' Extension for diploid cells D depends on allele frequency D' = D/Dmax when D ≥ 0 D' = D/Dmin when D < 0 Where: Dmax = lesser of p1q2 or p2q1 Dmin = greater of (-)p1q1 or (-)p2q2

  31. Correlation coefficient between loci pairs r2 = D2/(p1p2q1q2)

  32. Linkage disequilibrium of GCH1 in patients with lumbar DDD Haploview results with confidence interval method

  33. GCH1 allele proceduremarker summary --------Test for HWE-------- Number Number of of Hetero- Allelic Chi- Pr > Locus Indiv Alleles PIC zygosity Diversity Square DF ChiSq GCH1_1 96 2 0.2834 0.4167 0.3418 4.6063 1 0.0319 GCH1_2 90 2 0.3236 0.3667 0.4061 0.8490 1 0.3568 GCH1_3 95 2 0.2851 0.4211 0.3444 4.7095 1 0.0300 GCH1_4 96 2 0.2834 0.4167 0.3418 4.6063 1 0.0319 GCH1_5 93 2 0.3513 0.5269 0.4547 2.3454 1 0.1257 GCH1_6 93 2 0.3513 0.5054 0.4547 1.1563 1 0.2822 GCH1_7 93 2 0.1373 0.1398 0.1483 0.3055 1 0.5805 GCH1_8 90 2 0.2106 0.1444 0.2392 14.1226 1 0.0002 GCH1_9 91 2 0.2800 0.2967 0.3367 1.2861 1 0.2568 GCH1_10 91 2 0.3400 0.4615 0.4342 0.3594 1 0.5488 GCH1_11 89 2 0.2794 0.4045 0.3358 3.7224 1 0.0537 GCH1_12 93 2 0.1373 0.1398 0.1483 0.3055 1 0.5805 GCH1_13 88 2 0.3676 0.4659 0.4855 0.1429 1 0.7054 GCH1_14 95 2 0.2688 0.3789 0.3200 3.2237 1 0.0726

  34. Results Genotype ratios for 4 SNPs significantly divergent from Hardy-Weinberg Equilibrium Underrepresented: rs10483639 (minor allele frequency, MAF 22%) p=0.0319 rs752688 (MAF 22%); p=0.0300 rs4411417 (MAF 22%); p=0.0319 Overrepresented: homozygous carriers of GCH1 rs12147422 (MAF 14%); p=0.0002

  35. Conclusions As a group, patients presenting for surgical treatment of lumbar DDD demonstrate significant divergence from HWE and the general population for a set of polymorphisms in the pain-modulating gene GCH1 Allelic variations in GCH1 may both predispose and protect patients from developing chronic pain associated with lumbar DDD

  36. Thank you!

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