Comparison of posterior foraminotomy and anterior foraminotomy with fusion for treating spondylotic foraminal stenosis of the cervical spine: study protocol for a randomized controlled trial (ForaC)

Background: Cervical radiculopathy caused by spondylotic foraminal stenosis may require surgical treatment. Surgical options include anterior cervical foraminotomy and fusion or posterior cervical foraminotomy. Controversy remains regarding the preferable surgical approach. Pertinent clinical evidence is limited to low-quality observational reports. Therefore, treatment decisions are predominantly based on the individual surgeon’s preference and skill. The study objective is to evaluate the efficacy and safety of posterior foraminotomy in comparison to anterior foraminotomy with fusion for the treatment of spondylotic foraminal stenosis. Methods/design: This is a multicenter randomized, controlled, parallel group superiority trial. A total of 88 adult patients are allocated in a ratio of 1:1. Sample size and power calculations were performed to detect the minimal clinically important difference of 14 points, with an expected standard deviation of 20 in the primary outcome parameter, Neck Disability Index, with a power of 80%, based on an assumed maximal dropout rate of 20%. Secondary outcome parameters include the Core Outcome Measures Index, which investigates pain, back-specific function, work disability, social disability and patient satisfaction. Changes in physical and mental health are evaluated using the Short Form-12 (SF-12) questionnaire. Moreover, radiological and health economic outcomes are evaluated. Follow-up is performed 3, 6, 12, 24, 36, 48 and 60 months after surgery. Major inclusion criteria are cervical spondylotic foraminal stenosis causing radiculopathy of C5, C6 or C7 and requiring decompression of one or two neuroforaminae. Study data generation (study sites) and data storage, processing and statistical analysis (Department of Medical Statistics, Informatics and Health Economics) are clearly separated. Data will be analyzed according to the intention-to-treat principle. Discussion: The results of the ForaC study will provide surgical treatment recommendations for spondylotic foraminal stenosis and will contribute to the understanding of its short- and long-term clinical and radiological postoperative course. This will hopefully translate into improvements in surgical treatment and thus, clinical practice for spondylotic foraminal stenosis. Trial registration Current Controlled Trials: ISRCTN8257806

The lumbar disc herniation : gender differences and their influences on lumbar radicular pain perception

Studienzweck: Geschlechterunterschiede in der Schmerzverarbeitung wurden anhand der Quantitative Sensorischen Testung bereits untersucht. Für Patientinnen und Patienten mit lumbaler Radikulopathie liegen bislang jedoch keine evidenzbasierten Daten vor. Im Zuge der vorliegenden Arbeit wurden sowohl Sensibilitätsdefizite als auch Schmerzschwellen anhand der Quantitative Sensorischen Testung vor einer geplanten lumbalen Sequestrektomie untersucht. Methode: Die Quantitative Sensorische Testung wurde anhand des Protokolls des Deutschen Forschungsverbundes Neuropathischer Schmerz bei 50 Patientinnen und Patienten mit Lumboischialgien, die durch einen lumbalen Bandscheibenvorfall verursacht wurden, angewandt. Zudem erfolgte die Erhebung der Numerischen Rating Skala (NRS) als auch des Beck Depression Inventory einen Tag vor geplanter lumbaler Sequestrektomie. Unter der Verwendung des Kolmogorov-Smirnov Tests zur Ermittlung der Normalverteilung wurde anhand des Students t-Test, Mann-Whiteny-U-Test und des Fishers Exact Test die statistische Analyse zu den Gruppenunterschieden durchgeführt. Resultate: 20 Frauen und 30 Männer konnten in die Studie eingeschlossen werden. Zwischen den beiden Gruppen wurde präoperativ kein Unterschied im NRS für Rücken- und Beinschmerz gefunden. Hitze- und Druckschmerzschwellen waren in Frauen deutlich niedriger als in der männlichen Studienpopulation (p0.05). Eine Subgruppenanalyse konnte bei Männern, die eine periradikuläre Kortisoninfiltration erhalten hatten, eine deutliche Reduktion der Wind-up Ratio als potentieller Marker einer chronischen Schädigung zeigen (p0.05). Schlussfolgerung: Die Ergebnisse dieser Studie zeigen, dass es auch bei Patienten mit Lumboischialgien deutliche Geschlechterunterschiede gibt. Weibliche Patienten weisen insgesamt eine höhere Schmerzempfindlichkeit auf. Es empfiehlt sich, diese neuen Erkenntnisse in zukünftige Therapieentscheidungen einfließen zu lassen.Background: Previous studies have demonstrated gender differences in pain perception in quantitative sensory testing. Thus, we hypothesized that there are differences in men and women with lumbar disc herniation awaiting lumbar sequestrectomy. To elucidate the differences in pain perception between men and women using quantitative sensory testing, we carried out a prospective clinical monocentric trial. Methods: With institutional ethics approval, patients with radiculopathy awaiting lumbar sequestrectomy were examined the day before surgery. Preoperative pain was assessed using quantitative sensory testing and a series of questionnaires including the Beck Depression Inventory and a numeric rating scale (NRS) for back and leg pain. Statistical analysis was performed using the Kolmogorov-Smirnov test for normal distribution. The unpaired Students t-test, Mann-Whitney U test and Fishers exact test were used to analyze intergroup differences in the clinical and demographic characteristics and in clinical outcome variables. Results: Fifty patients (20 women and 30 men) were included in the study. The groups did not differ in NRS for back and leg pain. Heat and pressure pain thresholds were found to be lower in women than men (p 0.05). Subgroup analyses revealed decreased wind-up ratio as a potential marker for chronic changes in male patients with prior periradicular steroid application (p 0.05). Conclusions: Our results clearly indicate that sex differences in pain perception not only exist in healthy subjects, but also in patients with lumbar disc herniation. Therefore, it is essential to provide different treatment modalities to women and men.Dr. med. Anja TschuggAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersDer Arbeit wurde ein Artikel beigefügtMedical University Innsbruck, Dissertation, 2016OeBB(VLID)137949

Self-complementary adeno-associated virus serotype 6 mediated knockdown of ADAMTS4 induces long-term and effective enhancement of aggrecan in degenerative human nucleus pulposus cells: A new therapeutic approach for intervertebral disc disorders.

Inhibition of intervertebral disc (IVD) degeneration, which is often accompanied by painful inflammatory and immunopathological processes, is challenging. Current IVD gene therapeutic approaches are based on adenoviral gene delivery systems, which are limited by immune reactions to their viral proteins. Their applications in IVDs near to sensitive neural structure could provoke toxicity and immunological side-effects with neurological deficits. Self-complementary adeno-associated virus (scAAV) vectors, which do not express any viral gene and are not linked with any known disease in humans, are attractive therapeutic gene delivery vectors in degenerative IVDs. However, scAAV-based silencing of catabolic or inflammatory factor has not yet been investigated in human IVD cells. Therefore, we used scAAV6, the most suitable serotype for transduction of human nucleus pulposus (NP) cells, to knockdown the major catabolic gene (ADAMTS4) of IVD degeneration. IVD degeneration grades were determined by preoperative magnetic resonance imaging. Lumbar NP tissues of degeneration grade III were removed from 12 patients by nucleotomy. NP cells were isolated and cultured with low-glucose. Titre of recombinant scAAV6 vectors targeting ADAMTS4, transduction efficiencies, transduction units, cell viabilities and expression levels of target genes were analysed using quantitative PCR, fluorescence microscopy, fluorescence-activated cell sorting, 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assays, quantitative reverse transcription PCR, western blot and enzyme-linked immunosorbent assays during 48 days of post-transduction. Transduction efficiencies between 98.2% and 37.4% and transduction units between 611 and 245 TU/cell were verified during 48 days of post-transduction (p<0.001). scAAV6-mediated knockdown of ADAMTS4 with maximum 87.7% and minimum 40.1% was confirmed on day 8 and 48 with enhanced the level of aggrecan 48.5% and 30.2% respectively (p<0.001). scAAV6-mediated knockdown of ADAMTS4 showed no impact on cell viability and expression levels of other inflammatory catabolic proteins. Thus, our results are promising and may help to design long-term and less immunogenic gene therapeutic approaches in IVD disorders, which usually need prolonged therapeutic period between weeks and months

Transduction efficiencies of the recombinant scAAV6 vectors in NP cells.

<p>1 x 10⁵ NP cells were seeded and transduced with 5000 vg/c GFP packing recombinant scAAV6 vectors: AAV6-Ctrl (encoding non-target control shRNA) or AAV6-ADAMTS4 (encoding the shRNA targeting ADAMTS4). For both vectors similar transduction efficiencies were determined by fluorescence microscopy and FACS (Fig 2a & 2b). Fluorescence micrographs were acquired every 2 days for the first 16 days and weekly up to 48 days and the highest transduction efficiencies were recorded on day 8 of post-transduction (Fig 2a): A) untreated NP cells, B) NP cells treated with AAV6-Ctrl and C) NP cells treated with AAV6-ADAMTS4. For quantitative evaluation of the transduction efficiencies, GFP positive NP cells were quantified by FACS on day 8, 16, 24, 32 and 48 (Fig 2b). Data represent the mean with standard deviation (SD) of three independent experiments, each performed in triplicate. Error bars indicate SD values.</p

Transduction units and cell viabilities of the recombinant scAAV6 vectors.

<p>1 x 10⁵ NP cells were transduced with recombinant scAAV6 vectors AAV6-Ctrl or AAV6-ADAMTS4 at a viral dose of 5000 vg/c. NP cells were harvested on day 2, 8, 16, 24, 32 and 48 of post-transduction to determine the number of transduction units by qPCR and cell viabilities by MTT assay. Comparable numbers of transduction units per cell (TU/cell) were determined in AAV6-Ctrl or AAV6-ADAMTS4 treated NP cells (Fig 3a). Equivalent numbers of viable cells were determined in AAV6-Ctrl or AAV6-ADAMTS4 treated and untreated NP cells (Fig 3b). Data represent the mean values with standard deviation (SD) of three independent experiments, each performed in triplicate. Error bars indicate SD values.</p

Enhancement of aggrecan induced by scAAV6 mediated knockdown of ADAMTS4.

<p>Viral dose of 5000 vg/c from recombinant scAAV6 vectors AAV6-Ctrl or AAV6-ADAMTS4 were used for transduction of 1 x 10⁵ NP cells. On day 3 of post-transduction, treated and untreated NP cells were transferred to scaffold and harvested on day 8, 16, 24, 32 and 48. The Enhancement of aggrecan level induced by ADAMTS4 Knockdown was controlled by RT-qPCR (Fig 5a) and western blot (Fig 5b). AAV6-ADAMTS4 mediated knockdown of ADMATS4 induced enhancement of aggrecan at mRNA and protein levels. Moreover, plotting the mRNA levels of ADMATS4 and aggrecan against the number of transduction units per cell (TU/cell) showed a direct correlation between the TU/cell, ADAMTS4 knockdown and enhancement of aggrecan level (Fig 5c). Data represent the mean values with standard deviation (SD) of three independent experiments, each performed in triplicate (*, p < 0.001).</p

Samples of lumbar NP tissues recruited from 12 patients.

<p>Samples of lumbar NP tissues recruited from 12 patients.</p