Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations


Presentation on theme: "Spine Surgical Research at New England Baptist Hospital David H. Kim, MD Chief of Medical Education Spine Section, Dept of Orthopaedic Surgery."— Presentation transcript:

1 Spine Surgical Research at 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 Pain and Morbidity David H. Kim, MD Louis Jenis, MD Robert Banco, MD Sharon Koogler Kelsey Miller Scott Tromanhauser, MD

3 Introduction Frequently reported complications Frequently reported complications –chronic pain –numbness –cosmetic appearance No consensus regarding incidence of pain or functional significance No consensus regarding incidence of pain or functional significance Principal factor driving search for viable bone graft alternatives Principal factor driving search for viable bone graft alternatives Few prospective studies of bone graft harvest site complications; no prospective study of functional disability 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 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 Prospectively study rates of ICBG harvest pain & morbidity –rates & severity of pain –numbness –cosmetic complaints –functional limitations

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

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

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

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

11 Results Mean harvest site VAS pain scores 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: 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: 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 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 Mean pain scores progressively decline over first postop year Harvest site pain remains functionally limiting in many patients one year following surgery Harvest site pain remains functionally limiting in many patients one year following surgery Rates for functional limitation are higher than those previously reported 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 Pain is genetically determined Genes that modulate pain sensitivity in humans 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) 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 15 single nucleotide polymorphisms 15 single nucleotide polymorphisms Pain protective haplotype in 15.4% Pain protective haplotype in 15.4% Distribution follows Hardy-Weinberg Equilibrium in general population Distribution follows Hardy-Weinberg Equilibrium in general population Associated with less pain following lumbar discectomy Associated with less pain following lumbar discectomy Homozygotes reduced experimental pain sensitivity Homozygotes reduced experimental pain sensitivity [Tegeder et al, Nature Med 2006] [Kim & Dionne, Mol Pain 2008]

24 Study Design Prospective cohort study Prospective cohort study 100 patients undergoing surgical treatment for lumbar DDD 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 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 15 single nucleotide polymorphisms (SNPs) in noncoding regions of GCH1 distributed evenly across gene 14 of 15 loci informative in study population 14 of 15 loci informative in study population

26 GCH1 Allele Frequencies Standard Locus Allele Frequency Error GCH1_1 C GCH1_1 G GCH1_2 A GCH1_2 C GCH1_3 C GCH1_3 T GCH1_4 C GCH1_4 T GCH1_5 C GCH1_5 T GCH1_6 A GCH1_6 G GCH1_7 G GCH1_7 T GCH1_8 C GCH1_8 T GCH1_9 C GCH1_9 T GCH1_10 A GCH1_10 G GCH1_11 A GCH1_11 T GCH1_12 C GCH1_12 G GCH1_13 A GCH1_13 G GCH1_14 C GCH1_14 T Standard Locus Allele Frequency Error

27 GCH1 Genotype Frequencies HWD Standard Locus Genotype Frequency Coeff Error GCH1_1 C/C GCH1_1 C/G GCH1_1 G/G GCH1_2 A/A GCH1_2 A/C GCH1_2 C/C GCH1_3 C/C GCH1_3 C/T GCH1_3 T/T GCH1_4 C/C GCH1_4 C/T GCH1_4 T/T GCH1_5 C/C GCH1_5 C/T GCH1_5 T/T GCH1_6 A/A GCH1_6 A/G GCH1_6 G/G GCH1_7 G/G GCH1_7 G/T GCH1_7 T/T GCH1_8 C/C GCH1_8 C/T GCH1_8 T/T GCH1_9 C/C GCH1_9 C/T GCH1_9 T/T GCH1_10 A/A GCH1_10 A/G GCH1_10 G/G GCH1_11 A/A GCH1_11 A/T GCH1_11 T/T GCH1_12 C/C GCH1_12 C/G GCH1_12 G/G GCH1_13 A/A GCH1_13 A/G GCH1_13 G/G GCH1_14 C/C GCH1_14 C/T GCH1_14 T/T HWD Standard Locus Genotype Frequency Coeff Error

28 Linkage disequilibrium measure, δ δ := cov(I 1, I 2 ) = p 1 p 2 – h 12 = h 11 h 22 – h 12 h 21 δ := cov(I 1, I 2 ) = p 1 p 2 – h 12 = h 11 h 22 – h 12 h 21Where: –I 1, I 2 denote two loci –p 1 p 2 denote allele frequencies –h 12 denotes haplotype frequency –δ = 0 → linkage equilibrium –δ ≠ 0 → linkage disequilibrium

29 Linkage disequilibrium measure, D D = x 11 – p 1 q 1 D = x 11 – p 1 q 1 A1A1A1A1 A2A2A2A2Total B1B1B1B1 x 11 =p 1 q 1 + D x 21 =p 2 q 1 - D q1q1q1q1 B2B2B2B2 x 12 =p 1 q 2 - D x 22 =p 2 q 2 + D q2q2q2q2 Total p1p1p1p1 p2p2p2p21

30 Lewontin’s D' Extension for diploid cells Extension for diploid cells D depends on allele frequency D depends on allele frequency D' = D/D max when D ≥ 0 D' = D/D max when D ≥ 0 D' = D/D min when D < 0 D' = D/D min when D < 0 Where: D max = lesser of p 1 q 2 or p 2 q 1 D min = greater of (-)p 1 q 1 or (-)p 2 q 2 D min = greater of (-)p 1 q 1 or (-)p 2 q 2

31 Correlation coefficient between loci pairs r 2 = D 2 /(p 1 p 2 q 1 q 2 ) r 2 = D 2 /(p 1 p 2 q 1 q 2 )

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

33 Test for HWE Number Number of of Hetero- Allelic Chi- Pr > Locus Indiv Alleles PIC zygosity Diversity Square DF ChiSq GCH1_ GCH1_ GCH1_ GCH1_ GCH1_ GCH1_ GCH1_ GCH1_ GCH1_ GCH1_ GCH1_ GCH1_ GCH1_ GCH1_ GCH1 allele procedure marker summary

34 Results Genotype ratios for 4 SNPs significantly divergent from Hardy-Weinberg Equilibrium Genotype ratios for 4 SNPs significantly divergent from Hardy-Weinberg Equilibrium –Underrepresented: rs (minor allele frequency, MAF 22%) p= rs (minor allele frequency, MAF 22%) p= rs (MAF 22%); p= rs (MAF 22%); p= rs (MAF 22%); p= rs (MAF 22%); p= –Overrepresented: homozygous carriers of GCH1 rs (MAF 14%); p= homozygous carriers of GCH1 rs (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 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 Allelic variations in GCH1 may both predispose and protect patients from developing chronic pain associated with lumbar DDD

36 Thank you!


Download ppt "Spine Surgical Research at New England Baptist Hospital David H. Kim, MD Chief of Medical Education Spine Section, Dept of Orthopaedic Surgery."

Similar presentations


Ads by Google