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

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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.

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Abbreviations

CD3:

Cluster of differentiation 3

CD11b/Integrin αM:

Cluster of differentiation 11b

CD68:

Cluster of differentiation 68

CKPan:

Cytokeratin Pan

CNPase:

2′,3′-Cyclic nucleotide 3′-phosphodiesterase

cPARP:

Cleaved poly-ADP-ribose polymerase

CSF:

Cerebrospinal fluid

CT:

Cycle of threshold

DAB:

Diaminobenzidine

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GFAP:

Glial fibrillary acidic protein

H&E:

Hematoxylin-eosin

HIF:

Hypoxia-inducible factor

IHC:

Immunohistochemistry

IL-1ß:

Interleukin-1 beta

IL-1R1:

Interleukin-1 beta receptor type 1

IR:

Immunoreactivity

MMC:

Myelomeningocele

NeuN:

Neuronal nuclear protein

NF200kD:

Neurofilament 200-kD fragment

RT:

Room temperature

RT-PCR:

Reverse transcription polymerase chain reaction

SD:

Standard deviation

SDS:

Sodium dodecyl sulfate

TCS:

Tethered cord syndrome

TNF-α:

Tumor necrosis factor alpha

TNF-R1:

Tumor necrosis factor receptor type 1

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling

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Acknowledgments

The authors thank Fereshteh Ebrahim, Brigitte Rehmke, and Silvia Iversen for their excellent technical assistance. At this point, we would also like to pay tribute to the memory of Professor Ivo Leuschner who, due to his expertise, cordiality and human warmth, had always been an esteemed discussion and cooperation partner, who passed away too soon in January 2017.

Funding

This work was funded by Familie Mehdorn Stiftung 2015 (to G.C. and F.K.L.).

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Author notes

  1. Gesa Cohrs and Bea Drucks contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, University Hospital of Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, House 41, 24105, Kiel, Germany

    Gesa Cohrs, Bea Drucks, Jan-Philip Sürie, Michael Synowitz, Janka Held-Feindt & Friederike Knerlich-Lukoschus

  2. Department of Pathology, University Hospital of Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, House 14, 24105, Kiel, Germany

    Christian Vokuhl

  3. Deparment of Pediatric Neurosurgery, Asklepios klinik Sankt Augstin GmbH, Arnold-Janssen-Str. 29, 53757, Sankt Augustin, Germany

    Friederike Knerlich-Lukoschus

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  1. Gesa Cohrs
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  2. Bea Drucks
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  3. Jan-Philip Sürie
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  6. Janka Held-Feindt
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Correspondence to Friederike Knerlich-Lukoschus.

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Cohrs, G., Drucks, B., Sürie, JP. et al. Expression profiles of pro-inflammatory and pro-apoptotic mediators in secondary tethered cord syndrome after myelomeningocele repair surgery. Childs Nerv Syst 35, 315–328 (2019). https://doi.org/10.1007/s00381-018-3984-6

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