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Disc degeneration alters disc height and mechanics of the spinal column and is associated with lower back pain. In preclinical studies gel-like materials or resorbable polymer-based implants are frequently used to rebuild the nucleus pulposus, aiming at tissue regeneration and restoration of tissue function. To compare the outcome of tissue repair, freeze-dried resorbable polyglycolic acid–hyaluronan (PGA/HA) implants without any bioactive components or bioactivated fibrin (fibrin-serum) was used in a degenerated disc disease model in New Zealand white rabbits. Animals with partial nucleotomy only served as controls. The T2-weighted/fat suppression sequence signal intensity in the nuclear region of operated discs as assessed by magnet resonance imaging was reduced in operated compared to healthy discs, indicating loss of water and did not change from week 1 to month 6 after surgery. Quantification of histological and immunohistochemical staining indicated that the implantation of PGA/HA leads to significantly more repair tissue compared to nucleotomy only. Type II collagen content of the repair tissue formed after PGA/HA or fibrin-serum treatment is significantly increased compared to controls with nucleotomy only. The data indicate that intervertebral disc augmentation after nucleotomy has a positive effect on repair tissue formation and type II collagen deposition as shown in the rabbit model. [ABSTRACT FROM AUTHOR]

Owing to failure to achieve positive long-term effects, the currently performed treatment methods for lumbar facet joint syndrome (LFJS) are still under debate. Interspinous distraction devices unload the facet joints. Thus, these devices might be an alternative surgical treatment method for LFJS. The aim of this study was to evaluate the clinical and radiological outcome of an interspinous distraction device for the treatment of LFJS. Subjects had verified single level LFJS at level L4-5. They received percutaneous facet joint denervation (PFJD). If pain persisted, they were offered implantation of an interspinous device (Coflex) and/or repeat PFJD. Clinical and radiological outcome was determined before and after PFJD or surgery up to 2 years afterwards in all cases. Forty-one patients with LFJS at L4-5 underwent PFJD. Twenty patients with persisting pain underwent a subsequent surgery for implantation of an interspinous device. Five patients with recurrent pain at 6-12 months opted for an additional PFJD. Three obese patients (body weight > 100 kg) had persistent pain at 3 months after surgery and received additionally dorsal semi-dynamic stabilization. The clinical outcome improved significantly in the surgically treated patients; however, it did not differ compared with patients receiving PFJD only after 24 months.Radiological evaluation revealed a restricted range of motion (ROM) of the operated and an elevated ROM of the adjacent segment. Surgical or device-related complications were not observed. In conclusions, the implantation of an interspinous Coflex device in case of recurrent facet joint pain succeeds to improve facet joint pain in clinical shortand mid-term settings. However, it does not exceed the outcome of denervated patients. [ABSTRACT FROM AUTHOR]

In posterior lumbar interbody fusion, cage migrations and lower fusion rates compared to autologous bone graft used in the anterior lumbar interbody fusion procedure are documented. Anatomical and biomechanical data have shown that the cage positioning and cage type seem to play an important role. Therefore, the aim of the present study was to evaluate the impact of cage positioning and cage type on cage migration and fusion. We created a grid system for the endplates to analyze different cage positions. To analyze the influence of the cage type, we compared "closed" box titanium cages with "open" box titanium cages. This study included 40 patients with 80 implanted cages. After pedicle screw fixation, 23 patients were treated with a "closed box" cage and 17 patients with an "open box" cage. The follow-up period averaged 25 months. Twenty cages (25%) showed a migration into one vertebral endplate of <3 mm and four cages (5%) showed a migration of > or =3 mm. Cage migration was highest in the medio-medial position (84.6%), followed by the postero-lateral (42.9%), and the postero-medial (16%) cage position. Closed box cages had a significantly higher migration rate than open box cages, but fusion rates did not differ. In conclusion, cage positioning and cage type influence cage migration. The medio-medial cage position showed the highest migration rate. Regarding the cage type, open box cages seem to be associated with lower migration rates compared to closed box cages. However, the cage type did not influence bone fusion. [ABSTRACT FROM AUTHOR]

Study Design: This was a single-center prospective randomized controlled study., Objective: The aim was to compare the efficacy of endoscopic facet joint denervation (FJD) with that of the percutaneous technique in terms of pain, functional disability, and quality of life in patients with low back pain (LBP)., Summary of Background Data: Different controlled studies in patients with LBP have shown short-term benefits from percutaneous FJD. Observational studies have demonstrated that endoscopic FJD may be more effective. As the superiority of the endoscopic technique has not been clearly demonstrated in previous studies, a prospective randomized controlled study was conducted., Materials and Methods: For this study, 40 patients with LBP lasting more than 6 months duration and at least 50% pain reduction on the visual analog scale after medial branch block under fluoroscopy, were assigned randomly to receive percutaneous or endoscopic FJD. The primary outcome was pain, as indicated by visual analog scale. Secondary outcomes were functional disability, as assessed by the Oswestry Disability Index (ODI), Roland-Morris Disability Questionnaire (RDQ), and quality of life, as assessed by the Short Form Health Survey (SF-36)., Results: After the intervention, the pain level decreased significantly in both groups ( P <0.001); however, the effect was still significant in the endoscopic group (EG) and diminished to lower than the statistical significance in the percutaneous group (PG) after 12 months. The ODI and RDQ scores also improved significantly in both groups ( P <0.001). However, the ODI and RDQ were significantly better ( P <0.001) in the EG after 12 months. In the SF-36, we observed significant improvement in both groups three months after the intervention. The effect decreased after six months in the PG and was predominantly not demonstrable after 12 months, whereas in the EG there was still a strong significant improvement on all scales ( P <0.001) after 12 months., Conclusion: Percutaneous and endoscopic FJD reduced pain and improved functionality and quality of life. However, the effects decreased or disappeared in the PG after 12 months, whereas there was still a strong significant improvement in the EG., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Study:  The sacroiliac joint (SIJ) may be the primary source of pain in 15 to 25% of patients with axial low back pain. Furthermore, 75% of patients who have had fusion surgery develop SIJ pain within 10 years. Treatment options include SIJ blocks, radiofrequency (RF) denervation, and fusion. The RF techniques range from ablation of the nerves supplying the joint, creating lesions to the joint itself, or a combination of both techniques. However, different clinical studies could only identify a limited or, in some cases, no effect in decreasing of pain intensity and duration of the effect., Methods:  In this retrospective study, we selected 23 patients with SIJ pain, with a duration of more than 12 months and a 50% pain reduction on the Numeric Rating Scale (NRS) after diagnostic block. All patients received endoscopic ablation of the medial branch L5/S1 and the lateral branches, exiting the sacral foramina on S1/S2 and S2/S3 on both sides while using only one incision on each side. Telephone interviews were conducted with all patients. The outcome was determined with Odom's criteria, percent reduction NRS, subjective assessment of the patient, and duration of the effect., Results:  According to Odom's criteria, 79% of the patients showed acceptable to excellent results and confirmed that denervation helped them to manage their daily lives better. The average pain reduction in the responder group was 57% with an average duration of 13.4 months., Conclusion:  In this retrospective study, we could demonstrate the practicability and effectiveness of endoscopic SIJ denervation in the treatment of SIJ pain using only one incision for three levels on each side. Further studies should investigate if this procedure is more effective than percutaneous RF., Competing Interests: Dr. Woiciechowsky reports grants from RiwoSpine, during the conduct of the study, and personal fees from presentations and workshops, outside the submitted work., (Thieme. All rights reserved.)

Background and Study Aims:  Low back pain is well documented as an extremely common health problem. The most frequently used treatment is radiofrequency denervation for chronic low back pain. However, different clinical studies could only show a limited to no improvement regarding the decrease of pain intensity and duration of the effect. The main reasons for these limited effects seem to be due to the size of the lesion and difficulties in locating the exact placement of the cannula near the medial branch as well as or additional pathologies. Using an endoscope, it is possible to coagulate the facet joints and the medial branch under visual control and consider other pathologies such as extraspinal synovial cysts., Patients:  In this retrospective study, we included 28 patients with low back pain, with a duration > 6 months and a 50% pain reduction on the numeric analog scale (NAS) after a diagnostic block. All patients received endoscopic facet joint denervation of three facets on the left and right side using only one incision on each side with an exploration of the surrounding tissue. Telephone interviews were conducted with all patients. The outcome was determined with Odom's criteria, percentage reduction NAS, subjective assessment of the patient, and duration of the effect., Results:  According to Odom's criteria, 68% of the patients showed "acceptable" to "excellent" results and confirmed that denervation helped them manage their daily lives better. The average pain reduction in the responder group was 47% with an average duration of 7.8 months., Conclusion:  In this retrospective study, we demonstrated the practicability and effectiveness of the endoscopic facet joint denervation procedure in the treatment of chronic low back pain using only one incision for three facets. Further studies should investigate if this procedure is more effective than percutaneous radiofrequency denervation., Competing Interests: Christian Woiciechowsky reports grants from RiwoSpine, during the conduct of the study, and personal fees from presentations and workshops, outside the submitted work. Leonie Mercedes Richter has declared no conflicts of interest for this article., (Georg Thieme Verlag KG Stuttgart · New York.)

OBJECTIVE Recent studies have described encouraging outcomes after cervical total disc replacement (cTDR), but there are also critical debates regarding the long-term effects of heterotopic ossification (HO) and the prevalence of adjacent-level degeneration. The aim in this paper was to provide 4-year clinical and radiographic outcome results on the activ C disc prosthesis. METHODS A total of 200 subjects underwent single-level activ C (Aesculap AG) implantation between C-3 and C-7 for the treatment of symptomatic degenerative disc disease. Clinical and radiographic assessments were performed preoperatively, intraoperatively, at discharge, and again at 6 weeks, 6 months, 1 year, 2 years, and 4 years. Radiographic evaluations were done by an independent core laboratory using a specific software for quantitative motion analysis. RESULTS Neck Disability Index (NDI) and visual analog scale (VAS) score for neck and arm pain decreased significantly from baseline to the 4-year follow-up. The mean improvement for NDI was 20, for VAS severity and frequency of neck pain 26.4 and 28, and for VAS severity and frequency of arm pain 30.7 and 35.1, respectively. The neurological situation improved for the majority of patients (86.4%); 76.1% of cases were asymptomatic. Subsequent surgical interventions were reported in 7% of the cases, including device removals in 3%. In 2.5% a subsidence greater than 3 mm was recorded; 1 of these cases also had a migration greater than 3 mm. No device displacement, expulsion, disassembly, loose or fractured device, osteolysis, or facet joint degeneration at the index level was observed. Segmental lordotic alignment changed from -2.4° preoperatively to -6.2° at 4 years, and postoperative height was maintained during the follow-up. Advanced HO (Grade III and IV) was present in 27.1% of the cases; 82.4% showed segmental mobility. A progression of radiographic adjacent-segment degeneration occurred in 28.2%, but only 4.5% required surgical treatment. CONCLUSIONS The activ C is a safe and effective device for cervical disc replacement confirming the encouraging results after cTDR. Clinical trial registration no.: NCT02492724 ( clinicaltrials.gov ).

Degeneration of intervertebral discs (IVDs) occurs frequently and is often associated with lower back pain. Recent treatment options are limited and treat the symptoms rather than regenerate the degenerated disc. Cell-free, freeze-dried resorbable polyglycolic acid (PGA)-hyaluronan implants were used in an ovine IVD degeneration model. The nucleus pulposus of the IVD was partially removed, endoscopically. PGA-hyaluronan implants were immersed in autologous sheep serum and implanted into the disc defect. Animals with nucleotomy only served as controls. The T2-weighted/fat suppression sequence signal intensity index of the operated discs, as assessed by magnetic resonance imaging (MRI), showed that implantation of the PGA-hyaluronan implant improved (p = 0.0066) the MRI signal compared to controls at 6 months after surgery. Histological analysis by haematoxylin and eosin and safranin O staining showed the ingrowth of cells with typical chondrocytic morphology, even cell distribution, and extracellular matrix rich in proteoglycan. Histomorphometric analyses confirmed that the implantation of the PGA-hyaluronan scaffolds improved (p = 0.027) the formation of regenerated tissue after nucleotomy. Disc heights remained stable in discs with nucleotomy only as well as after implantation of the implant. In conclusion, implantation of cell-free polymer-based implants after nucleotomy induces nucleus pulposus tissue regeneration and improves disc water content in the ovine model., (Copyright © 2012 John Wiley & Sons, Ltd.)

Aim: New techniques for biological repair in the treatment of degenerative disc disease (DDD) have been developed recently. The question arises whether it is possible to find a predictive marker to identify a patient population which could benefit from this new treatment option. Standard magnetic resonance imaging (MRI) fails to differentiate between pathologic painful and asymptomatic aging discs. Neurological symptoms contribute to identifying the pathological level. In this preliminary translational research study we analysed the gene expression of structure proteins and inflammatory mediators as well as histological features of lumbar intervertebral discs in symptomatic patients with various signs of degeneration in the MRI., Methods: Specimens of intervertebral disc tissue were obtained from 20 patients undergoing lumbar nucleotomy. Preoperatively, a group selection based on four pre-defined MRI-criteria was performed: Group 1 (mild signs of degeneration), group 2 (moderate), group 3 (moderate-severe), group 4 (severe)., Results: An increase of the expression of structural proteins and inflammatory markers could be observed in MRI-groups 2 and 3. Gene expression of collagen type I and II and aggrecan went along with levels of cyclooxygenase-2 (COX-2) and (fibroblast growth factor-2) FGF-2 expression. Histological examination showed signs of granulation tissue in only 35% of cases, but no differences between the groups., Conclusion: Our findings implicate that the gene expression of structural proteins might correlate with the appearance of inflammatory mediators in symptomatic patients with moderate disc changes in the MRI in this preliminary clinical subset. The assessment of cell activity and protein expression in a larger number of patients could be next step to support and supplement the present data.

Closure and biological repair of anulus fibrosus (AF) defects in intervertebral disc diseases is a therapeutic challenge. The aim of our study was to evaluate the anabolic properties of bioactive factors on cartilaginous matrix formation by AF cells. Human AF cells were harvested from degenerated lumbar AF tissue and expanded in monolayer culture. AF cell differentiation and matrix formation was initiated by forming pellet cultures and stimulation with hyaluronic acid (HA), human serum (HS), fibroblast growth factor-2 (FGF-2), transforming growth factor-β3 (TGF-β3) and TGF-β3/FGF-2 for up to 4 weeks. Matrix formation was assessed histologically by staining of proteoglycan, type I and type II collagens and by gene expression analysis of typical extracellular matrix molecules and of catabolic matrix metalloproteinases MMP-2 and MMP-13. AF cells, stimulated with HS, FGF-2 and most pronounced with TGF-β3 or TGF-β3/FGF-2 formed a cartilaginous matrix with significantly enhanced expression of matrix molecules and of MMP-13. Stimulation of AF cells with TGF-β3 was accompanied by induction of type X collagen, known to occur in hypertrophic cartilage cells having mineralizing potential. HA did not show any chondro-inductive characteristics. These findings suggest human serum, FGF-2 and TGF-β3 as possible candidates to support biological treatment strategies of AF defects., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Object: Biological repair strategies for the treatment of degenerated intervertebral discs are of growing interest. In addition to the development of nucleus pulposus implants to restore disc height and relieve pain, there is growing demand for an appropriate method for reconstructing the anulus fibrosus (AF). The aim of this pilot study was to evaluate the applicability of a resorbable 3D polymer of pure polyglycolic acid (PGA) combined with hyaluronan for the use in cell-free and cell-based regeneration and repair of the AF., Methods: Adult human AF cells were expanded in vitro using human serum and rearranged three dimensionally in hyaluronan-PGA scaffolds that were stabilized with fibrin for in vitro analyses. The capacity of dedifferentiated AF cells to redifferentiate was evaluated after 2 weeks of culture, using propidium iodide/fluorescein diacetate staining, gene expression analysis of typical marker genes, and histological staining of proteoglycans., Results: The propidium iodide/fluorescein diacetate staining demonstrated that vital human AF cells were evenly distributed within the construct. The induction of typical AF marker genes such as collagen Types I-III indicated the initiation of AF redifferentiation by 3D assembly in hyaluronan-PGA. Histological analysis of the constructs showed initial formation of an AF-like matrix comprising proteoglycans., Conclusions: The results suggest that the 3D arrangement of human AF cells in resorbable hyaluronan-PGA scaffolds cultured in the presence of human serum is an excellent system for AF cell redifferentiation.

Intervertebral disc degeneration is considered a major source of low back pain. We therefore examined an absorbable polyglycolic acid (PGA) biomaterial for its utility to support disc tissue regeneration. Microdiscectomy for lumbar disc herniation was performed in six patients. Intervertebral disc cells were isolated and in vitro cell expansion was accomplished using human serum and FGF2. In a fibrin-hyaluronan solution, disc cells were loaded on PGA scaffolds and cultured for 2 weeks. Formation of disc tissue was documented by histological staining of the extracellular matrix as well as gene expression analysis of typical disc marker genes. The use of human serum and FGF2 ensures efficient isolation and expansion of human disc cells. During this phase, dedifferentiation of the disc cells was observed. Subsequent 3D tissue culture of disc cells in PGA scaffolds, however, is accompanied by the induction of typical disc marker genes, resulting in tissue containing glycosaminoglycans and collagens. Propidium iodide/fluorescein diacetate (PI/FDA) staining documented that 3D assembly of disc cells in PGA scaffolds allows prolonged culture and high viability of disc cells. Disc cells from tissue of the nucleus compartment can be reliably isolated and expanded in vitro with FGF. In combination with a fibrin-hyaluronan solution and loaded on a PGA scaffold, disc cells from expansion culture commence a redifferentiation process. PGA-based scaffolds could be useful as temporal matrices for regenerative disc repair approaches., (Copyright © 2010 John Wiley & Sons, Ltd.)

Object: The object of this study was to characterize the regenerative potential of cells isolated from herniated disc tissue obtained during microdiscectomy. The acquired data could help to evaluate the feasibility of these cells for autologous disc cell transplantation., Methods: From each of 5 patients (mean age 45 years), tissue from the nucleus pulposus compartment as well as from herniated disc was obtained separately during microdiscectomy of symptomatic herniated lumbar discs. Cells were isolated, and in vitro cell expansion for cells from herniated disc tissue was accomplished using human serum and fibroblast growth factor-2. For 3D culture, expanded cells were loaded in a fibrin-hyaluronan solution on polyglycolic acid scaffolds for 2 weeks. The formation of disc tissue was documented by histological staining of the extracellular matrix as well as by gene expression analysis of typical disc marker genes., Results: Cells isolated from herniated disc tissue showed significant signs of dedifferentiation and degeneration in comparison with cells from tissue of the nucleus compartment. With in vitro cell expansion, further dedifferentiation with distinct suppression of major matrix molecules, such as aggrecan and Type II collagen, was observed. Unlike in previous reports of cells from the nucleus compartment, the cells from herniated disc tissue showed only a weak redifferentiation process in 3D culture. However, propidium iodide/fluorescein diacetate staining documented that 3D assembly of these cells in polyglycolic acid scaffolds allows prolonged culture and high viability., Conclusions: Study results suggested a very limited regenerative potential for cells harvested from herniated disc tissue. Further research on 2 major aspects in patient selection is suggested before conducting reasonable clinical trials in this matter: 1) diagnostic strategies to predict the regenerative potential of harvested cells at a radiological or cell biology level, and 2) clinical assessment strategies to elucidate the metabolic state of the targeted disc.

Degeneration of the intervertebral disc is the most common cause of lower back pain. Interestingly, all available treatments are limited to treat the symptoms and not the underlying biologic alterations of the disc. Freeze-dried resorbable non-woven polyglycolic acid (PGA) - hyaluronan implants were used in a degenerated disc disease (DDD) model in New Zealand white rabbits. The constructs were immersed in allogenic serum and implanted into the disc defect. Animals with discectomy only served as controls. The T2-weighted/fat suppression sequence signal intensity of the operated discs as assessed by magnet resonance imaging decreased in both groups one week after the operation compared to a healthy disc. After 12 months the implanted group showed an increase of 51% in the signal intensity compared to the 1-week results whereas the signal intensity in the sham group remained on the same level from one week to 12 months. Histological and quantitative immunohistochemical examination after 12 months indicated cell migration into the defect and showed formation of disc repair tissue. In controls, repair tissue containing type II collagen was not evident. In conclusion, the implantation of polymer-based constructs after discectomy induces tissue regeneration resulting in improvement of the disc water content., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Object: A variety of anterior, posterior, and combined approaches exist to decompress the spinal cord, restore sagittal alignment, and avoid kyphosis, but the optimal surgical strategy remains controversial. The authors compared the anterior and posterior approach used to treat multilevel cervical spondylotic myelopathy (CSM), focusing on sagittal alignment and clinical outcome., Methods: The authors studied 48 patients with CSM who underwent multilevel decompressive surgery using an anterior or posterior approach with instrumentation (24 patients in each group), depending on preoperative sagittal alignment and direction of spinal cord compression. In the anterior group, a 1-2-level corpectomy was followed by placement of an expandable titanium cage. In the posterior group, a multilevel laminectomy and posterior instrumentation using lateral mass screws was performed. Postoperative radiography and clinical examinations were performed after 1 week, 12 months, and at last follow-up (range 15-112 months, mean 33 months). The radiological outcome was evaluated using measurement of the cervical and segmental lordosis., Results: Both the posterior multilevel laminectomy (with instrumentation) and the anterior cervical corpectomy (with instrumentation) improved clinical outcome. The anterior group had a significantly lower preoperative cervical and segmental lordosis than the posterior group. The cervical and segmental lordosis improved in the anterior group by 8.8 and 6.2 degrees, respectively, and declined in the posterior group by 6.5 and 3.8 degrees, respectively. The loss of correction was higher in the anterior than in the posterior group (-2.0 vs -0.7 degrees, respectively) at last follow-up., Conclusions: These results demonstrate that both anterior and posterior decompression (with instrumentation) are effective procedures to improve the neurological outcome of patients with CSM. However, sagittal alignment may be better restored using the anterior approach, but harbors a higher rate of loss of correction. In cases involving a preexisting cervical kyphosis, an anterior or combined approach might be necessary to restore the lordotic cervical alignment.

Study Design: : Different biologic strategies exist to treat degenerative disc disease. Tissue engineering approaches favor autologous chondrocyte transplantation. In our one-step-approach, a resorbable cell-free polyglycolic acid (PGA)-based implant is immersed in serum from whole blood and implanted into the disc defect directly after discectomy., Objectives: : The aim of our study was to investigate the capacity of a cell-free implant composed of a PGA felt, hyaluronic acid, and serum to recruit disc cells and stimulate repair tissue formation in vivo after microdiscectomy in a rabbit model., Summary of the Background Data: : Disc tissue has a limited ability to regenerate after the degeneration process was once initiated. Therefore, we developed a cell-free resorbable implant that is able to attract local cells into the defect and induce proper repair tissue formation., Methods: : The cell-free implant consisting of PGA and hyaluronic acid was immersed in allogenic serum and implanted into the disc defect after discectomy in New Zealand white rabbits. One week and 6 months after the operation, the disc height index and the T2-weighted signal intensity index were determined using plane radiographs and magnetic resonance imaging. Finally, discs were explanted and investigated histologically. Animals with discectomy only served as controls., Results: : In our animal studies, we could demonstrate that the T2-weighted signal intensity of the operated discs decreased in both groups 1 week after surgery. However, after 6 months, the T2-weighted signal intensity index increased by 45% in the implanted group whereas the index decreased further by 11% in the sham group. This corresponded to changes in the disc height index. Furthermore, the histologic examinations indicated cell migration into the defect and showed tissue regeneration., Conclusion: : The implantation of a cell-free PGA-hyaluronic acid implant immersed in serum after discectomy induces regeneration, resulting in improvement of the disc water content and preservation of the disc height 6 months after surgery.

Objective: Even without contrast enhancement on MRI scans gliomas can show histological features of anaplasia. These tumors are heterogeneous regarding anaplastic and non-anaplastic areas. Increased amino acid uptake was shown to be associated with dismal prognosis in gliomas. We investigated histological correlates of tumor grading in biopsies obtained from regions with maximum amino acid uptake revealed by F-18-fluoro-ethyl-tyrosin positron emission tomography (FET-PET)., Methods: We included 22 patients with non-contrast enhancing lesions on MRI scans. PET was performed 10 min after FET injection, and the area of maximum FET uptake was chosen as the biopsy target. In 13 patients neuronavigated biopsies were obtained during tumor resection. Nine patients had a stereotactic biopsy. The ratio of maximum standardized uptake value (SUV) to background was calculated. Histological specimens were classified and graded according to world health organization (WHO) criteria. We investigated cell and vascular density, mitotic activity, proliferation index, microvascular proliferation, nuclear pleomorphism, necrosis and immunoreactivity of LAT1 (SLC7A5), an amino acid transporter with prognostic impact in gliomas., Results: 12 of the 22 non-contrast enhancing gliomas corresponded to anaplastic astrocytomas WHO grade III. Vascular and cellular density was correlated highly to the SUV ratio (P = 0.0015 and P = 0.0021, respectively), but with no nuclear pleomorphism, mitotic activity, Mib-1 immunoreactivity, or microvascular proliferation. Thus, no correlation was found between FET uptake and tumor grade., Conclusion: FET-PET correlates with vascular and cell density in non-contrast enhancing gliomas. Although tumor grade cannot be predicted, clinical use of FET PET as an indicator for neovascularization should be addressed in future studies.

Objective: The influence of the degree of resection on survival in patients with glioblastoma multiforme is still under discussion. The highly controlled 5-aminolevulinic acid study provided a unique platform for addressing this question as a result of the high frequency of "complete" resections, as revealed by postoperative magnetic resonance imaging scans achieved by fluorescence-guided resection and homogeneous patient characteristics., Methods: Two hundred forty-three patients with glioblastoma multiforme per protocol from the 5-aminolevulinic acid study were analyzed. Patients with complete and incomplete resections as revealed by early magnetic resonance imaging scans were compared. Prognostic factors that might cause bias regarding resection and influence survival (e.g., tumor size, edema, midline shift, location, age, Karnofsky Performance Scale score, National Institutes of Health Stroke Scale score) were used for analysis of overall survival. Time to reintervention (chemotherapy, reoperation) was analyzed further to exclude bias regarding second-line therapies., Results: Treatment bias was identified in patients with complete (n = 122) compared with incomplete resection (n = 121), i.e., younger age and less frequent eloquent tumor location. Other factors, foremost preoperative tumor size, were identical. Patients without residual tumor survived longer (16.7 versus 11.8 mo, P < 0.0001). In multivariate analysis, only residual tumor, age, and Karnofsky Performance Scale score were significantly prognostic. To account for distribution bias, patients were stratified for age (>60 or

Recent data suggest that ubiquitin has anti-inflammatory properties and therapeutic potential after severe trauma and brain injuries. However, direct evidence for its neuroprotective effects has not yet been provided. We hypothesized that ubiquitin treatment is neuroprotective, and thus reduces brain edema formation and cortical contusion volume after closed traumatic brain injuries. To test this hypothesis, a focal cortical contusion was induced using a controlled cortical impact (CCI) model in Sprague-Dawley rats. Animals (n = 27) were randomized to either 1.5 mg/kg ubiquitin or vehicle (placebo) intravenously within 5 min after CCI. Blood pressure, arterial blood gases (ABG) and intracranial pressure (ICP) were monitored. Ubiquitin serum and cerebrospinal fluid levels were measured by ELISA. Brain water content was quantified gravimetrically after 24 h and cerebral contusion volume was determined in triphenyltetrazolium-chloride stained brains after 7 days. All animals recovered to normal activity. ICP and cerebral perfusion pressures were normal at the end of the observation period. Ubiquitin serum and CSF levels at 24 h and 7 days after CCI were similar in both groups. With ubiquitin brain water content of the injured hemisphere was slightly lower (n = 6/group; 79.97 +/- 0.29% vs. 81.11 +/- 0.52%; p = 0.08). Cortical contusion volume was significantly lower with ubiquitin (n = 7-8/group; 32.88 +/- 2.1 mm(3) vs. 43.96 +/- 4.56 mm(3); p = 0.025). This study shows that ubiquitin treatment after brain injury has direct neuroprotective effects, as demonstrated by improved brain morphology 7 days after brain injury. In connection with its beneficial effects in our previous studies, these data suggest ubiquitin as a promising candidate protein therapeutic for the treatment of brain injuries.

Severe head injury (SHI) leads to systemic immunosuppression, which is processed by central mechanisms and is associated with a high risk of pneumonia. The timely identification of an immunodepressed condition in SHI patients might help prevent infections by changing the intensive care strategy. The aim of this prospective study is to evaluate a new method for identifying immunodepression and predicting pneumonia. We correlated interleukin (IL)-6 levels determined by the standard test (Immulite) and performed by specialized laboratories with those obtained using the new bedside test (PicoScan) with the occurrence of pneumonia in patients with SHI. Thirty-two patients with isolated SHI were investigated. Analyses were performed on serum samples taken 2 to 24 hours after trauma. Pearson correlation coefficient was 0.924 (P<0.001) for IL-6 values determined by PicoScan versus Immulite and Spearman rho was 0.572 for visual interpretation versus Immulite (P=0.01). Immulite and PicoScan have a positive predictive value of 91% and 100%, respectively, and a negative predictive value of 76% and 86%. The present study investigated for the first time the determination of IL-6 concentrations by PicoScan in patients. Our findings show a good correlation with the results of the standard Immulite test and suggest that the PicoScan may be used as a handy tool to predict pneumonia in SHI patients.

The immunosuppressant drug tacrolimus (FK-506) failed to show an anti-edematous effect despite suppressing pro-inflammatory cytokines in cerebrospinal fluid following focal traumatic brain injury. By questioning the role of the inflammatory response as a pharmacological target, we investigated the effects of FK-506 on immune cell infiltration in brain-injured rats. Following induction of a cortical contusion, male Sprague-Dawley rats received FK-506 or physiological saline intraperitoneally. Brains were removed at 24 h, 72 h or 7 days, respectively. Frozen brain sections (7 microm) were stained immunohistologically for markers of endothelial activation (intercellular adhesion molecule-1--ICAM-1), neutrophil infiltration (His-48), and microglial and macrophage activation (Ox-6; ED-1), respectively. Immunopositive cells were counted microscopically. Contusion volume (CV) was quantified morphometrically 7 days after trauma. Inflammatory response was confined to the ipsilateral cortex and hippocampal formation, predominating in the contusion and pericontusional cortex. Strongest ICAM-1 expression coincided with sustained granulocyte accumulation at 72h which was suppressed by FK-506. Ox-6+ cells prevailing at 72 h were also significantly reduced by FK-506. ED-1+ cells reaching highest intensity at 7 days were significantly attenuated at 72 h. Cortical CV was not influenced. FK-506 significantly decreased post-traumatic local inflammation which, however, was not associated with a reduction in cortical CV. These results question the importance of post-traumatic local immune cell infiltration in the secondary growth of a cortical contusion.

Cerebral metastases are a frequent complication of lung cancer. They often determine patients' prognosis and need urgent therapeutic intervention. Based on histologic type, former therapies, age and performance of the patient, the number of cerebral lesions and the extracerebral tumour activity, individualized treatments are applied. For patients who suffer from non-small cell lung cancer and a single CNS lesion the best results can be achieved if they are surgically resected or receive radiosurgery. Their survival time can be markedly increased in comparison to patients who undergo whole brain irradiation. If multiple metastases are seen in CT or MRI, whole brain irradiation is the therapy to choose. Furthermore it should be initiated if small cell lung cancer metastasizes to the brain. More aggressive local treatment options appear promising, but a clear role for them has not yet been defined. Systemic chemotherapy gains more attention in the treatment of small and non-small cell lung cancer with brain metastases. How to increase the efficacy through simultaneous application of chemo- and radiotherapy is tested in current trials. This article gives an overview on clinical presentation and diagnosis of cerebral metastases in lung cancer and reviews current treatment options.

Leukocyte migration into inflamed tissues comprises dynamic interactions between immune and endothelial cells through events controlled by adhesion molecules, e.g., P- and E-selectins, which mediate Th1 cells recruitment after injury. Since miscarriage is known to be a Th1 event and selectins are expressed at the murine foetal-maternal interface, the purpose of our study was to investigate whether blocking P- and E-selectins before implantation could inhibit Th1 migration into the foetal-maternal interface and thus prevent foetal rejection. DBA/2J-mated CBA/J females were treated with monoclonal antibodies (mAbs) against P-selectin or with both, anti-P- and anti-E-selectins combined on days 2 and 4 of pregnancy. PBS-treated females served as controls. Our data revealed a significant improvement in pregnancy outcome in both treated groups compared to the control, which is due to the effectiveness of the mAb against P-selectin, since the treatment with anti-E-selectin alone could not prevent abortion. We further observed that there was diminished Th1 cytokine production by decidual immune cells in all treated groups in comparison to the controls. Our data first confirm the important role of P-selectin in mediating the extravasation of abortive cells, while opening new therapeutic opportunities.

Tolerance mechanisms allowing pregnancy success resemble those involved in allograft acceptance. Heme oxygenase (HO) is a tissue-protective molecule, which allows graft acceptance and is known to have antiapoptotic effects on several cell types. We previously reported down-regulated levels of HO-1 and HO-2 in placenta from allopregnant mice undergoing abortion. In this study, we analyzed whether the up-regulation of HO-1 by cobalt-protoporphyrin (Co-PP) during implantation window can rescue mice from abortion. Induction of HO-1 by Co-PP treatment prevented fetal rejection, whereas the down-regulation of HOs by zinc-protoporphyrin application boosted abortion. The beneficial effect of HO-1 induction was not related to a local shift to Th2-profile or to a change in the NO system. Interestingly, the expression of the antiapoptotic/cytoprotective molecule Bag-1 as well as the levels of neuropilin-1, a novel marker for T regulatory cells, were up-regulated after Co-PP treatment. Our data strongly support a very important role for HO-1 in fetal allotolerance and suggest that HO-1 might be protective by up-regulating tissue protective molecules, i.e., Bag-1, and by activating T regulatory cells rather than by changing the local cytokine profile.

Study Design: Retrospective study of 20 patients with degenerative cervical spinal canal stenosis who were treated with corpectomy followed by the placement of a distractable titanium cage (anterior distraction device [ADD]) (Ulrich GmbH & Co. KG, Ulm, Germany)., Objective: To investigate the efficacy of distractable titanium cages for reconstruction following decompressive cervical corpectomy., Summary of Background Data: Anterior corpectomy and reconstruction for extensive spinal canal stenosis are standard techniques. The reconstruction is commonly performed with bone graft and anterior plating. Alternatively, different fusion cages have gained acceptance in spine surgery. However, in traditionally designed cages, an over-distraction of the involved segment is necessary to place the cage into the defect, and to achieve tight contact between cage and endplates. The new designed cage (ADD) can be distracted in situ. Therefore, the height of the cage can be adjusted precisely to the size of the corpectomy., Methods: All patients were treated with corpectomy followed by the placement of an ADD. A cervical plate was added in 13 cases, and an "All-in-one-system" (i.e., a cage with an attached plate with 2 holes for screw fixation on both sides, ADD) was used in 7. Follow-up was 18-60 months. Clinical evaluation and radiographs were performed after 3, 6, and 12 months, and then once a year., Results: In all cases, a stable reconstruction of the anterior column was achieved, with no signs of instability on flexion/extension radiographs. However, there was one incidence of cage subsidence. According to Odom criteria, 11 patients (55%) had excellent outcome, 4 (20%) good, 3 (15%) satisfactory, and 2 (10%) poor., Conclusions: The results of the study show that distractable cages are useful vertebral body replacements because they can be adjust to the size of the corpectomy in situ and provide immediate strong anterior column support, avoiding bone graft site morbidity. The possibility of direct cage fixation without an additional plate simplifies the procedure.

The authors report the case of a 23-year-old man who presented with a C1-3 spinal mass. Following intraspinal decompression the tumor was histologically classified as an atypical meningioma (World Health Organization grade II). Two further surgical interventions resulted in almost total removal of the meningioma. In addition, radiotherapy was performed. During the 1.5-year follow-up period the diagnostic examinations identified a local tumor recurrence, an intraspinal C-6 metastasis, and a segmental instability with anterior C2-3 slippage and C3-4 kyphosis. The tumor was resected and occipitocervical stabilization was performed. Histological examination showed no change in malignancy. Despite additional hydroxyurea-based chemotherapy, the patient presented 4 months later with a hemiparesis and a massive recurrence of the tumor mass involving the posterior fossa and the upper thoracic spine. Because there were no further therapeutical options, the patient died. The authors discuss more aggressive therapeutic options in addition to surgery in patients with metastatic atypical meningiomas. The results in the reported case indicate that meningiomas associated with cerebrospinal fluid metastasis may represent a higher grade of malignancy.

Objective: Intra-operative movements due to mechanical ventilation or manipulations are a limiting factor for accurate spinal navigation or robotic-assisted spinal surgery. The purpose of this study was to assess the accuracy of an intra-operative spinal fixation device in an experimental setup., Materials and Methods: We developed a fixation device, attached to the operating table, that combines soft tissue retraction with spinal process fixation. Using a lumbar spine cadaver, tightness of fixation was evaluated using two measurement systems. Accuracy measurements using changes in spatial co-ordinates of implanted reference markers were performed in three segments, following different manipulations of the spine. In addition, for intra-operative movements of the spine during mechanical ventilation, the range of motion was determined in 10 patients during lumbar interbody fusion., Results: The spine frame was easy to use and did not restrict screw insertion. Mean deviations of the markers' in all segments were measured at between 0.35 and 0.8 mm, following pedicle screw insertion and lateral traction. Intra-operative range of motion of the spine was measured with a mean value of 8.7 +/- 3.3 mm., Conclusion: Using our spine frame, a rigid fixation following manipulation of the spine was demonstrated. By overcoming the intra-operative movement-dependent inaccuracy, safety in navigated spine surgery and robotic-assisted procedures might be improved.

There is a bi-directional communication between the immune and central nervous system. In this context, it is known that patients with traumatic brain injury suffered from systemic immunodepression and an increased risk to develop infectious complications. We investigated the role of an increased intracranial pressure (ICP) and sympathetic activation on systemic immune changes. A sustained increase in ICP was achieved by inflation of a subdural balloon. At different time points, plasma levels of the anti-inflammatory cytokine, interleukin (IL)-10, were measured. Furthermore, the effect of a sympathetic blockade by co-administration of the beta2-adreoreceptor antagonist, propranolol, was evaluated. Finally, we examined the impact of epinephrine infusion on blood IL-10 levels. We showed that an increase in ICP with activation of the sympathetic nervous system was able to induce systemic release of IL-10. This effect was blocked by administration of the beta2-adreoreceptor antagonist. Furthermore, epinephrine infusion directly induced systemic release of IL-10. Our data suggested that sympathetic activation with release of epinephrine may induce systemic immunodepression with risk of infectious complications in brain-injured patients.

The allogeneic fetus has been considered to be an allograft and the tolerance mechanisms involved in pregnancy maintenance resemble those leading to graft acceptance. Up-regulation of Heme Oxygenase-1 (HO-1) promotes graft acceptance. Additionally, HO-1 has been proposed to have tissue-protective properties. Previous studies reported the presence of HO-1 and HO-2 in mammalian placenta and postulated a protective role for HO during pregnancy. Here, we analyze HO-1 and HO-2 expression at the feto-maternal interface from normal pregnant and abortion mice and correlate these findings with inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) expression as well as with Th1/Th2 cytokine production by immune cells. DBA/2-mated CBA/J females undergoing abortion and BALB/c-mated CBA/J females having normal pregnancies were included in our study. The mice received no treatment. On day 14 of pregnancy, the mice were sacrificed, the abortion rate was calculated and the ex vivo Th1/Th2 production by decidual immune cells was analyzed by flow cytometry. The expression of HO-1 and HO-2, iNOS and eNOS was analyzed by immunohistochemistry (IHC) and Western blot in placenta samples. The Th1/Th2 cytokines ratio was augmented in decidua from abortion mice. We further observed a significant down-regulation of HO-1, HO-2, iNOS and eNOS molecules in placental tissue from mice undergoing abortion when compared to normal pregnant mice. Since we found diminished HOs and nitric oxide synthase (NOS) levels at the feto-maternal interface from abortion mice when compared to normal pregnant mice, which were further associated with increased Th1/Th2 cytokine production, we propose HO as a putative therapeutic target in immunological abortions. Up-regulation of HO-1 or HO-2 would favour the Th2-cytokine production, which could avoid abortion onset.

Background: Degenerative spondylolisthesis of the cervical spine is rare. Patients show signs of progredient myelopathy, radiculopathy and pain. Treatment strategies include ventral, dorsal and combined fusion techniques with or without repositioning and decompression., Methods: In this study, we present 16 patients with degenerative cervical spondylolisthesis. The leading symptom was severe myelopathy in 8 patients, radiculomyelopathy in 5 patients and neck pain in 3 patients. However, neck pain was the initial symptom in all the patients and decreased when neurological symptoms became more evident. Radiographic examinations included plain radiography, MRI, CT, myelography and lateral tomography., Results: Spondylolisthesis was located five times at level C3/4, C4/5 and C5/6. In three cases spondylolisthesis was located at level C7/T1. There were two patients with spondylolisthesis on two levels. Instability could be demonstrated by flexion/extension radiography in five cases. Patients were divided into three groups according to a newly introduced classification system. The surgical approach corresponded to this classification. In ten patients the spondylolisthesis could be corrected by extension and positioning, so discectomy and fusion on one or two levels with cage, plate and screws was sufficient. In five cases a corpectomy was necessary due to severe spondylosis. In one case a combined approach with dorsal decompression and release followed by ventral fusion was applied due to additional dorsal spinal cord compression. The follow-up period was 6-52 months. After surgery, none of the patients showed any signs of neurological deterioration. In all cases, a stable fusion was achieved with no signs of instability on flexion/extension radiographs. Neurological improvement was seen in 6 of 8 patients with myelopathy and 4 of 5 patients with radiculomyelopathy. The others showed stable disease. Pain relief was seen in all patients who complained of pain preoperatively., Conclusion: The aims of treatment for cervical spondylolisthesis are spinal cord decompression (ventral, dorsal or both), correction and fusion. The used procedure should depend on the severity of the cervical deformity, degree and side of the spinal cord compression, and the possibility of correction by extension and positioning.

Background: Gliosis is a characteristic pathology in many central nervous system (CNS) diseases. Cytokines are considered to be effectors of gliosis. It has been shown that pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6 boost glia scar formation. On the other hand, anti-inflammatory cytokines, such as IL-10 and IL-1 receptor antagonist (ra), can act neuroprotectively. Furthermore, various immune mediators and neurotransmitters can modulate the onset of gliosis., Material/methods: We used 100 male Sprague-Dawley rats to investigate the mechanisms of brain-cytokine-induced astrogliosis using an in vivo model of convection-enhanced delivery of cytokines (IL-beta, IL-6, tumor necrosis factor (TNF)-alpha) into the cerebro-ventricular system. The protective effects of the anti-inflammatory cytokine IL-10 and the neurotransmitter propranolol were also investigated., Results: With this paradigm, we could clearly demonstrate that IL-6 is a key cytokine mediating astrogliosis, noticeable in the increased expression of glial fibrillary acidic protein (GFAP). Thus intra-cerebroventricular infusion of IL-6 increased GFAP expression in a dose-dependent manner. Furthermore, GFAP expression was also increased by IL-beta, which correspondingly triggered an IL-6 release into the CSF. Accordingly, TNF-alpha, which did not induce IL-6 release, also did not induce gliosis. On the other hand, substances which decrease IL-beta-induced IL-6 production, such as propranolol and IL-10, also dramatically decreased IL-beta triggered gliosis., Conclusions: IL-6 infusion, as well as IL-beta-induced IL-6 release into the CSF, increase GFAP expression in the cerebral cortex and hippocampus. Accordingly, blockade of the IL-beta-induced IL-6 release by IL-10 and propranolol decreases GFAP expression.

Investigation into the inflammatory response in the central nervous system (CNS) is a rapidly growing field, and a vast amount of information on this topic has accumulated over the past two decades. Inflammation is a particularly interesting issue in the (traditionally non-regenerating) CNS, owing to its dual role in worsening or improving regeneration and functional outcome in certain circumstances. This paper reviews the current literature on the interactions between the immune system and the CNS in physiological and pathological states. The first part will provide an overview of the cellular and molecular components of CNS inflammation, this being followed by a discussion of the concept of systemic immunodepression after neurotrauma and neurosurgery. Finally, the delicate balance of immune responses in the CNS, with an emphasis on the beneficial effects of inflammation and possible therapeutic options, will be discussed.

Although intracranial hemorrhage has frequently been found responsible for mortality in adult patients with Alagille syndrome (AGS), no specific underlying cause has been identified. We describe the case of severe subarachnoid hemorrhage in a 30-year-old woman harboring five intracranial aneurysms and multiple peripheral vascular anomalies. To evaluate a possible higher incidence of intracranial aneurysms, a study of the cerebral vasculature in all AGS patients by using noninvasive imaging techniques should be considered.

Malignant gliomas are hard to treat successfully. Like other treatments immune therapy fails presumably due to low concentration of immune modifiers within the tumor. However, convection-enhanced delivery (CED) may overcome this problem. So, we analyzed the effect of intratumoral delivery of interleukin (IL)-1beta and interferon (IFN)-gamma by CED on tumor immune cell invasion in a rat glioma model. Tumors were implanted into the left caudate nucleus and tumor growth was demonstrated by MRI. Afterwards intratumoral infusion of IL-1beta or IFN-gamma was started for 48 h. Then animals were sacrificed and the number of tumor infiltrating CD4+ and CD8+ lymphocytes as well as macrophages was analyzed by immunohistochemistry. Our results demonstrate that intratumoral cytokine infusion using CED leads to a strong tumor invasion with macrophages and lymphocytes suggesting a tumor specific immune response.

Background: Significantly increased plasma and CSF IL-6 levels reflect underlying tissue damage following clinical and experimental traumatic brain injury (TBI). Catecholamines, used under clinical conditions to maintain adequate cerebral perfusion pressure, induce a sustained IL-6 release. Thus an additional elevation in IL-6 could aggravate brain edema in the acute posttraumatic phase. We studied the changes in plasma and cerebrospinal fluid (CSF) IL-6 levels 4 and 24 hours after experimental TBI and assessed possible time-dependent effects of norepinephrine infusion on IL-6 and brain edema., Material/methods: Paired plasma and CSF IL-6 measured at 4 and 24 hours following TBI (n=10) were compared to levels in non-traumatized rats (n=5). In a placebo-controlled trial, 20 brain-injured male Sprague-Dawley rats were randomized to receive norepinephrine or NaCl for 90 minutes at 4 or 24 hours after TBI. Plasma IL-6 was measured before, during, and after the infusion period. One hour after stopping the infusion, CSF IL-6 and hemispheric swelling were determined., Results: During the first posttraumatic day, plasma and CSF IL-6 levels were significantly increased compared to non-traumatized rats, reaching the highest values at 24 hours (p<0.05). Norepinephrine infusion significantly increased plasma IL-6 at 7 and 27 hours after TBI; IL-6 was significantly elevated in CSF only at 7 hours (p<0.05). Brain edema was not aggravated., Conclusions: The norepinephrine-induced increase in plasma and CSF IL-6 suggests that concomitant norepinephrine administration needs to be considered when interpreting systemic and local changes in IL-6 levels in TBI patients.