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01-02-2019 | Original Article

Expression profiles of pro-inflammatory and pro-apoptotic mediators in secondary tethered cord syndrome after myelomeningocele repair surgery

Authors: Gesa Cohrs, Bea Drucks, Jan-Philip Sürie, Christian Vokuhl, Michael Synowitz, Janka Held-Feindt, Friederike Knerlich-Lukoschus

Published in: Child's Nervous System | Issue 2/2019

Abstract

Purpose

The literature on histopathological and molecular changes that might underlie secondary tethered cord syndrome (TCS) after myelomeningocele (MMC) repair surgeries remains sparse. To address this problem, we analyzed specimens, which were obtained during untethering surgeries of patients who had a history of MMC repair surgery after birth.

Methods

Specimens of 12 patients were analyzed in this study. Clinical characteristics were obtained retrospectively including pre-operative neurological and bowel/bladder-function, contractures and spasticity of lower extremities, leg and back pain, syringomyelia, and conus position on spinal MRI. Cellular marker expression profiles were established. Further, immunoreactivities (IR) of IL-1ß/IL-1R1, TNF-α/TNF-R1, and HIF-1α/-2α were analyzed qualitatively and semi-quantitatively by densitometry. Co-labeling with cellular markers was determined by multi-fluorescence-labeling. Cytokines were further analyzed on mRNA level. Immunostaining for cleaved PARP and TUNEL was performed to detect apoptotic cells.

Results

Astrocytosis, appearance of monocytes, activated microglia, and apoptotic cells in TCS specimens were one substantial finding of these studies. Besides neurons, these cells co-stained with IL-1ß and TNF-α and their receptors, which were found on significantly elevated IR-level and partially mRNA-level in TCS specimens. Staining for HIF-1α/-2α confirmed induction of hypoxia-related factors in TCS specimens that were co-labeled with IL-1ß. Further, hints for apoptotic cell death became evident by TUNEL and PARP-positive cells in TCS neuroepithelia.

Conclusions

Our studies identified pro-inflammatory and pro-apoptotic mediators that, besides mechanical damaging and along with hypoxia, might promote TCS development. Besides optimizing surgical techniques, these factors should also be taken into account when searching for further options to improve TCS treatment.

Hertzler DA II, DePowell JJ, Stevenson CB, Mangano FT (2010) Tethered cord syndrome: a review of the literature from embryology to adult presentation. Neurosurg Focus 29:E1. https://doi.org/10.3171/2010.3.FOCUS1079 CrossRefPubMed

Bowman RM, Mohan A, Ito J, Seibly JM, McLone DG (2009) Tethered cord release: a long-term study in 114 patients. J Neurosurg Pediatr 3:181–187. https://doi.org/10.3171/2008.12.PEDS0874 CrossRefPubMed

Bowman RM, McLone DG, Grant JA et al (2001) Spina bifida outcome: a 25-year prospective. Pediatr Neurosurg 34:114–120. https://doi.org/10.1159/000056005 CrossRefPubMed

Shurtleff DB, Duguay S, Duguay G, Moskowitz D, Weinberger E, Roberts T, Loeser J (1997) Epidemiology of tethered cord with meningomyelocele. Eur J Pediatr Surg 7(Suppl 1):7–11. https://doi.org/10.1055/s-2008-1071200 CrossRefPubMed

Hudgins RJ, Gilreath CL (2004) Tethered spinal cord following repair of myelomeningocele. Neurosurg Focus 16:E7CrossRef

Lew SM, Kothbauer KF (2007) Tethered cord syndrome: an updated review. Pediatr Neurosurg 43:236–248. https://doi.org/10.1159/000098836 CrossRefPubMed

Herman JM, McLone DG, Storrs BB, Dauser RC (1993) Analysis of 153 patients with myelomeningocele or spinal lipoma reoperated upon for a tethered cord. Presentation, management and outcome. Pediatr Neurosurg 19:243–249CrossRefPubMed

Tani S, Yamada S, Knighton RS (1987) Extensibility of the lumbar and sacral cord. Pathophysiology of the tethered spinal cord in cats. J Neurosurg 66:116–123. https://doi.org/10.3171/jns.1987.66.1.0116 CrossRefPubMed

Kang JK, Kim MC, Kim DS, Song JU (1987) Effects of tethering on regional spinal cord blood flow and sensory-evoked potentials in growing cats. Childs Nerv Syst 3:35–39CrossRefPubMed

10.

Yamada S, Zinke DE, Sanders D (1981) Pathophysiology of “tethered cord syndrome”. J Neurosurg 54:494–503. https://doi.org/10.3171/jns.1981.54.4.0494 CrossRefPubMed

11.

Guthkelch AN, Pang DVJ (1981) Influence of closure technique on results in myelomeningocele. Childs Brain 8:350–355PubMed

12.

Samuels R, McGirt MJ, Attenello FJ et al (2009) Incidence of symptomatic retethering after surgical management of pediatric tethered cord syndrome with or without duraplasty. Childs Nerv Syst 25:1085–1089. https://doi.org/10.1007/s00381-009-0895-6 CrossRefPubMed

13.

Yamada S, Won DJ, Pezeshkpour G, Yamada BS, Yamada SM, Siddiqi J, Zouros A, Colohan ART (2007) Pathophysiology of tethered cord syndrome and similar complex disorders. Neurosurg Focus 23:1–10. https://doi.org/10.3171/FOC-07/08/E6 CrossRef

14.

Dolan EJ, Transfeldt EE, Tator CH, Simmons EH, Hughes KF (1980) The effect of spinal distraction on regional spinal cord blood flow in cats. J Neurosurg 53:756–764. https://doi.org/10.3171/jns.1980.53.6.0756 CrossRefPubMed

15.

Kocak A, Kilic A, Nurlu G et al (1997) A new model for tethered cord syndrome: a biochemical, electrophysiological, and electron microscopic study. Pediatr Neurosurg 26:120–126CrossRefPubMed

16.

Schneider SJ, Rosenthal AD, Greenberg BM, Danto J (1993) A preliminary report on the use of laser-Doppler flowmetry during tethered spinal cord release. Neurosurgery 32:214–218CrossRefPubMed

17.

Yamada S, Knerium DS, Mandybur GM, Schultz RL, Yamada BS (2004) Pathophysiology of tethered cord syndrome and other complex factors. Neurol Res 26:722–726. https://doi.org/10.1179/016164104225018027 CrossRefPubMed

18.

Maurya VP, Rajappa M, Wadwekar V, Narayan SK, Barathi D, Madhugiri VS (2016) Tethered cord syndrome—a study of the short term effects of surgical detethering on markers of neuronal injury and electrophysiologic parameters. World Neurosurg. https://doi.org/10.1016/j.wneu.2016.07.005

19.

Kowitzke B, Cohrs G, Leuschner I, Koch A, Synowitz M, Mehdorn HM, Held-Feindt J, Knerlich-Lukoschus F (2016) Cellular profiles and molecular mediators of lesion cascades in the placode in human open spinal neural tube defects. J Neuropathol Exp Neurol 75:827–842. https://doi.org/10.1093/jnen/nlw057 CrossRefPubMed

20.

Kwon B, Kim DH, Vaccaro AR (2005) The pathophysiology of tethered cord syndrome: ischemia or apoptosis? Semin Spine Surg 17:8–12. https://doi.org/10.1053/j.semss.2005.01.001 CrossRef

21.

Knerlich-Lukoschus F, Von Der Ropp-Brenner B, Lucius R et al (2010) Chemokine expression in the white matter spinal cord precursor niche after force-defined spinal cord contusion injuries in adult rats. Glia 58:916–931. https://doi.org/10.1002/glia.20974 CrossRefPubMed

22.

Knerlich-Lukoschus F, Juraschek M, Blömer U, Lucius R, Mehdorn HM, Held-Feindt J (2008) Force-dependent development of neuropathic central pain and time-related CCL2/CCR2 expression after graded spinal cord contusion injuries of the rat. J Neurotrauma 25:427–448. https://doi.org/10.1089/neu.2007.0431 CrossRefPubMed

23.

Qian BJ, You L, Shang FF, Liu J, Dai P, Lin N, He M, Liu R, Zhang Y, Xu Y, Zhang YH, Wang TH (2015) Vimentin regulates neuroplasticity in transected spinal cord rats associated with micRNA138. Mol Neurobiol 51:437–447. https://doi.org/10.1007/s12035-014-8745-2 CrossRefPubMed

24.

Pineau I, Sun L, Bastien D, Lacroix S (2010) Astrocytes initiate inflammation in the injured mouse spinal cord by promoting the entry of neutrophils and inflammatory monocytes in an IL-1 receptor/MyD88-dependent fashion. Brain Behav Immun 24:540–553. https://doi.org/10.1016/j.bbi.2009.11.007 CrossRefPubMed

25.

Reis JL, Correia-Pinto J, Monteiro MP, Costa M, Hutchins GM (2008) Vascular and apoptotic changes in the placode of myelomeningocele mice during the final stages of in utero development. J Neurosurg Pediatr 2:150–157. https://doi.org/10.3171/PED/2008/2/8/150 CrossRefPubMed

26.

Ribotta MGMG, Menet VV, Privat AA (2004) Glial scar and axonal regeneration in the CNS: lessons from GFAP and vimentin transgenic mice. Acta Neurochir Suppl 89:87–92. https://doi.org/10.1007/978-3-7091-0603-7_12 CrossRefPubMed

27.

Pekny M, Wilhelmsson U, Pekna M (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565:30–38. https://doi.org/10.1016/j.neulet.2013.12.071 CrossRefPubMed

28.

Herx LM, Rivest S, Yong VW (2000) Central nervous system-initiated inflammation and neurotrophism in trauma: IL-1 beta is required for the production of ciliary neurotrophic factor. J Immunol 165:2232–2239. https://doi.org/10.4049/jimmunol.165.4.2232 CrossRefPubMed

29.

Bastien D, Lacroix S (2014) Cytokine pathways regulating glial and leukocyte function after spinal cord and peripheral nerve injury. Exp Neurol 258:62–77. https://doi.org/10.1016/j.expneurol.2014.04.006 CrossRefPubMed

30.

Basu A, Krady JK, Levison SW (2004) Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res 78:151–156. https://doi.org/10.1002/jnr.20266 CrossRef

31.

Giulian D, Woodward J, Young DG, Krebs JF, Lachman LB (1988) Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization. J Neurosci 8:2485–2490CrossRefPubMed

32.

Sato A, Ohtaki H, Tsumuraya T, Song D, Ohara K, Asano M, Iwakura Y, Atsumi T, Shioda S (2012) Interleukin-1 participates in the classical and alternative activation of microglia/macrophages after spinal cord injury. J Neuroinflammation 9:65. https://doi.org/10.1186/1742-2094-9-65 CrossRefPubMedPubMedCentral

33.

Huang SL, Peng J, Yuan GL, Ding XY, He XJ, Lan BS (2015) A new model of tethered cord syndrome produced by slow traction. Sci Rep 5:9116. https://doi.org/10.1038/srep09116 CrossRefPubMedPubMedCentral

34.

Imtiyaz HZ, Simon MC (2010) Hypoxia-inducible factors as essential regulators of inflammation. Curr Top Microbiol Immunol 345:105–120. https://doi.org/10.1007/82-2010-74 CrossRefPubMedPubMedCentral

35.

Basu A, Lazovic J, Krady JK, Mauger DT, Rothstein RP, Smith MB, Levison SW (2005) Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury. J Cereb Blood Flow Metab 25:17–29. https://doi.org/10.1038/sj.jcbfm.9600002 CrossRefPubMed

36.

Minami M, Kuraishi Y, Yabuuchi K, Yamazaki A, Satoh M (1992) Induction of interleukin-1 beta mRNA in rat brain after transient forebrain ischemia. J Neurochem 58:390–392CrossRefPubMed

37.

Legos JJ, Whitmore RG, Erhardt JA, Parsons AA, Tuma RF, Barone FC (2000) Quantitative changes in interleukin proteins following focal stroke in the rat. Neurosci Lett 282:189–192. https://doi.org/10.1016/S0304-3940(00)00907-1 CrossRefPubMed

38.

Auron PE (1998) The interleukin 1 receptor: ligand interactions and signal transduction. Cytokine Growth Factor Rev 9:221–237. https://doi.org/10.1016/s1359-6101(98)00018-5 CrossRefPubMed

39.

Dehne N, Brüne B (2009) HIF-1 in the inflammatory microenvironment. Exp Cell Res 315:1791–1797. https://doi.org/10.1016/j.yexcr.2009.03.019 CrossRefPubMed

40.

Chen K-B, Uchida K, Nakajima H, Yayama T, Hirai T, Watanabe S, Guerrero AR, Kobayashi S, Ma WY, Liu SY, Baba H (2011) Tumor necrosis factor-α antagonist reduces apoptosis of neurons and oligodendroglia in rat spinal cord injury. Spine (Phila Pa 1976) 36:1350–1358. https://doi.org/10.1097/BRS.0b013e3181f014ec CrossRef

41.

Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10:45–65. https://doi.org/10.1038/sj.cdd.4401189 CrossRefPubMed

42.

Knerlich-Lukoschus F, Noack M, von der Ropp-Brenner B et al (2011) Spinal cord injuries induce changes in CB1 cannabinoid receptor and C-C chemokine expression in brain areas underlying circuitry of chronic pain conditions. J Neurotrauma 28:619–634. https://doi.org/10.1089/neu.2010.1652 CrossRefPubMed

43.

Knerlich-Lukoschus F (2015) Chemokines and their receptors: important mediators to be aware of in neuroregenerative approaches for spinal cord injury. Neural Regen Res 10:562–564. https://doi.org/10.4103/1673-5374.155423 CrossRefPubMedPubMedCentral

44.

Cohrs G, Sürie J-P, Vokuhl C, Held-Feindt J, Synowitz M, Knerlich-Lukoschus F (2018) Establishing a retinoic induced mmc model in rats for investigating molecular lesion cascades during the post-neurulation fetal and perinatal development. Childs Nerv Syst 34:995–1094CrossRef

45.

Sharma U, Pal K, Pratap A, Gupta DK, Jagannathan NR (2006) Potential of proton magnetic resonance spectroscopy in the evaluation of patients with tethered cord syndrome following surgery. J Neurosurg 105:396–402. https://doi.org/10.3171/ped.2006.105.5.396 CrossRefPubMed

46.

Pal K, Sharma U, Gupta DK, Pratap A, Jagannathan NR (2005) Metabolite profile of cerebrospinal fluid in patients with spina bifida: a proton magnetic resonance spectroscopy study. Spine (Phila Pa 1976) 30:E68–E72. https://doi.org/10.1097/01.brs.0000152161.08313.04 CrossRef

47.

Baigrie RJ, Lamont PM, Kwiatkowski D, Dallman MJ, Morris PJ (1992) Systemic cytokine response after major surgery. Br J Surg 79:757–760. https://doi.org/10.1002/bjs.1800790813 CrossRefPubMed

48.

Clementsen T, Krohn CD, Reikerås O (2006) Systemic and local cytokine patterns during total hip surgery. Scand J Clin Lab Invest 66:535–542. https://doi.org/10.1080/00365510600889635 CrossRef

49.

Arishima Y, Setoguchi T, Yamaura I, Yone K, Komiya S (2006) Preventive effect of erythropoietin on spinal cord cell apoptosis following acute traumatic injury in rats. Spine (Phila Pa 1976) 31:2432–2438. https://doi.org/10.1097/01.brs.0000239124.41410.7a CrossRef

50.

Hattermann K, Knerlich-Lukoschus F, Lucius R, Mehdorn M, Held-Feindt J (2015) Erythropoietin and CCL3 antagonise their functional properties during neuroinflammation. Neurol Res 37:1025–1028. https://doi.org/10.1179/1743132815Y.0000000070 CrossRefPubMed

51.

Yang L, Yan X, Xu Z, Tan W, Chen Z, Wu B (2016) Delayed administration of recombinant human erythropoietin reduces apoptosis and inflammation and promotes myelin repair and functional recovery following spinal cord compressive injury in rats. Restor Neurol Neurosci 34:647–663. https://doi.org/10.3233/RNN-150498 CrossRef

Title: Expression profiles of pro-inflammatory and pro-apoptotic mediators in secondary tethered cord syndrome after myelomeningocele repair surgery
Authors: Gesa Cohrs
Bea Drucks
Jan-Philip Sürie
Christian Vokuhl
Michael Synowitz
Janka Held-Feindt
Friederike Knerlich-Lukoschus
Publication date: 01-02-2019
Publisher: Springer Berlin Heidelberg
Published in: Child's Nervous System / Issue 2/2019
Print ISSN: 0256-7040
Electronic ISSN: 1433-0350
DOI: https://doi.org/10.1007/s00381-018-3984-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Expression profiles of pro-inflammatory and pro-apoptotic mediators in secondary tethered cord syndrome after myelomeningocele repair surgery

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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