gms | German Medical Science

Objective: Various forms of spinal dysraphism and intradural surgery can lead to the fixation of intrathecal nervous structures within the spinal canal, thus leading to neurologic signs of “tethered cord syndrome” (TCS). So far traction resulting in ischemia and further hypoxia in affected neural structures are considered the main driving forces for developing clinical relevant TCS. The aim of this study was to identify further specific mediators of molecular lesion cascades that may contribute to the development of TCS.

Methods: Ethical approval was obtained. Specimens from 14 TCS-surgeries were investigated; only patients with previous myelomeningocele repair were included. Clinical characteristics were obtained retrospectively and included neurological status, bowel/bladder-dysfunction, contractures/spacities of lower extremities and back pain or leg pain. Furthermore MRI scans were retrospectively evaluated for tethering signs like i.e. syrinx and conus position. Normal adult spinal cords (sc) (n=4) served as controls. Sections were immunostained with neural, glial, neural crest, mesenchymal and epithelial markers (GFAP, Vimentin, neurofilament (NF 200kD), NeuN, synaptophysin, CNPase). Immunohistochemistry and real-time RT-PCR for inflammatory cytokines (interleukin-1beta (IL-1b), IL-1R1, tumor necrosis factor-alpha (TNF-α), TNF-R1), and hypoxia inducible factors (HIF-1a/-2a) were performed. Further apoptotic marker cleaved-PARP and Caspase-3 were immunostained. Data were analyzed qualitatively and semi-quantitatively. Double-fluorescence-labeling confirmed cellular expression patterns with markers for neuronal, astrocytic and microglial cells.

Results: The investigated specimen exhibited significant gliosis with strong GFAP- and Vimentin-immunolabeling. IL-1b and TNF-α and their receptors became detectable in cellular composites of intrathecal nervous structures on significantly elevated level (p<0,05 and p<0,001 vs. control). TNF-R showed significant induction on mRNA level in real-time RT-PCR. The investigated cytokines were co-stained with NeuN (TNFα/TNF-R1/IL-1b/IL1-R1) and GFAP (IL-1b) as well as CD68 (IL-1b/IL1-R1) as a marker for microglial cells. Hypoxia-inducible factors HIF-1a and HIF-2a were also induced in TCS specimen co-stained with neuronal and microglial markers.

Conclusion: Pro-inflammatory and hypoxia-induced cytokines might influence symptomatology and outcome of patients with TCS. As specific molecular composites of the underlying pathophysiology they potentially offer new therapeutic opportunities.