Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology.

Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.

Sequence variant at 8q24.21 associates with sciatica caused by lumbar disc herniation.

Lumbar disc herniation (LDH) is common and often debilitating. Microdiscectomy of herniated lumbar discs (LDHsurg) is performed on the most severe cases to resolve the resulting sciatica. Here we perform a genome-wide association study on 4,748 LDHsurg cases and 282,590 population controls and discover 37 highly correlated markers associating with LDHsurg at 8q24.21 (between CCDC26 and GSDMC), represented by rs6651255[C] (OR=0.81; P=5.6 × 10-12) with a stronger effect among younger patients than older. As rs6651255[C] also associates with height, we performed a Mendelian randomization analysis using height polygenic risk scores as instruments to estimate the effect of height on LDHsurg risk, and found that the marker's association with LDHsurg is much greater than predicted by its effect on height. In light of presented findings, we speculate that the effect of rs6651255 on LDHsurg is driven by susceptibility to developing severe and persistent sciatica upon LDH.

[Visits to an emergency department due to head injuries]. / Komur á brádadeild Landspítala vegna áverka á höfdi.

INTRODUCTION: Head injury is a common consequence of accidents and violence. It can result in permanent disability and is one of the leading causes of premature death worldwide. Our aim was to review all visits to Landspitali University Hospital (LUH) from head injuries, to study the incidence, nature and severity of head injuries. MATERIAL AND METHODS: A retrospective study on all visits of Reykjavik's inhabitants to LUH for head injuries in the years 2000-2005 and 2008-2009. Data were collected from patient records at LUH. One main diagnosis was used if head injury diagnoses were many. They were categorised into 5 groups; soft tissue injury, eye injury, injury to cranium, intracranial- and cranial nerve injury and multiple trauma. RESULTS: During the study period 35.031 patients presented with head injuries to LUH. Males were 67%. Mean age was 26 years (0-107). The highest rate was among infants and children aged 0-4 years (20.8%), followed by 5-9 years (11,5%) and 20-24 years (9.4%). The annual incidence decreased between the study periods from 4.2% to 3.3%. The annual incidence for admitted head injury patients decreased from 181/year/100.000 inhabitants to 110/year/100.000 inhabitants. Most often injuries were caused by accidents (80,5%) and violence (12.7%). Soft tissue injury was the most common injury (65%), followed by eye injury (15%) and intracranial- and cranial nerve injury (14%). The injuries that most frequently led to hospital admission were intracranial bleeding (90.1%), followed by skull fracture (79.2%). CONCLUSION: Accidents and violence caused most head injuries and they are more common among men than women. Patients with intracranial haemorrhage were usually admitted. Incidence of hospital visits and admissions because of head injuries in Reykjavik has decreased over the last decade. Key words: Head injury, accident, violence, brain injury, intracranial bleeding.

Meningiomas engaging major venous sinuses.

BACKGROUND: Meningiomas with growth onto or into the major venous sinuses, that is, venous meningiomas, provide management problems regarding their radical removal and preservation of venous drainage. The relationship to venous structures often precludes radical surgery; the risk of recurrence and aggressive histology is greater for parasagittal meningiomas than in other locations. Older series reflect the conflict between radical surgery and subtotal removal followed by the "wait-and-scan" approach for the residual. This review summarizes our experience of a more contemporary series of venous meningiomas, after to the introduction of gamma-knife radiosurgery, for residual tumors and a long follow-up of 10 years. METHODS: Treatment, histopathology, and follow-up data of 100 consecutive patients undergoing surgery for venous meningiomas were prospectively collected. Gamma-knife surgery was considered as a direct postsurgical adjunct or as an adjunct after a period of radiological follow-up. The proliferation marker MIB-1 was prospectively analyzed. Two patients were lost to follow-up after 5 years, and 98 were followed until their death or a minimum of 10 years. RESULTS: The 6-month outcome was good-to-excellent in 94 patients; one patient died. Eighteen patients died within 10 years. Ten had aggressive or anaplastic meningiomas. In 10 years, tumor recurrence or progression was noted in 23 patients. One important reason was that only 42% of patients undergoing Simpson grade 1 removal had free resection margins at microscopic examination. Patients with Simpson grade 1 surgery had a recurrence rate of 10%. Patients with deliberate nonradical surgery (Simpson grade IV) had a tumor recurrence rate of 72%, whereas a combined treatment of direct gamma-knife radiosurgery after a tailored microsurgical resection (Simpson IV gamma) allowed return to a low recurrence rate of 10%. The tumor proliferation indices (MIB-1/Ki-67) were prognostically relevant for recurrence after either microsurgery or gamma-knife radiosurgery. CONCLUSION: Surgical microscopic radicality was unexpectedly difficult to achieve. Gamma-knife radiosurgery was a useful adjunct but only in patients with tumors of low proliferative index. It should probably be used as part of the initial surgical management. As expected, treatment results for these patients seem to have improved during the last decades but recurrence and malignancy remained a problem, which is not always solved by repeated radiosurgery.

Neuronavigation for arteriovenous malformation surgery by intraoperative three-dimensional ultrasound angiography.

OBJECTIVE: Neuronavigational devices have traditionally used preoperative imaging with limited possibilities for adjustment to brain shift and intraoperative manipulation of the surgical lesions. We have used an intraoperative imaging and navigation system that uses navigation on intraoperatively acquired three-dimensional ultrasound data, as well as preoperatively acquired magnetic resonance imaging scans and magnetic resonance angiograms. The usefulness of this system for arteriovenous malformation (AVM) surgery was evaluated prospectively. METHODS: Nine consecutive patients with Spetzler Grade 1 (n = 3), 2 (n = 3), 3(n = 2) or 4 (n = 1) AVMs underwent operation using this intraoperative imaging and navigation system. The system provides real-time rendering of three-dimensional angiographic data and can visualize such projections in a stereoscopic (virtual reality) manner using special glasses. The experiences with this technology were analyzed and the outcomes assessed. Angiographic reconstructions of three-dimensional images were obtained before and after resection. RESULTS: Conventional navigation on the basis of preoperative magnetic resonance angiography was helpful to secure positioning of the bone flap; stereoscopic visualization of the same data represented a powerful means to construct a mental three-dimensional picture of the extent of the AVM and the feeder anatomy even before skin incision. Intraoperative ultrasound corresponded well to the intraoperative findings and allowed confirmation of feeding vessels in surrounding gyri and rapid identification of the perinidal dissection planes, regardless of brain shift. The latter feature was particularly helpful because the intraoperative navigational identification of surgical planes leads to minimal exploration into the nidus or dissection at a greater distance from the malformation. Application of the system was thought to increase surgical confidence. In two patients, postresection ultrasound prompted additional nidus removal. Ultrasound angiography seemed to allow some degree of resection control, although its sensitivity was not thought to be sufficient. All AVMs were radically removed without new permanent morbidity. CONCLUSION: The complexities of handling the pathological vessels of AVMs were ameliorated by intraoperative three-dimensional ultrasound and navigation because the three-dimensional outline of the vasculature (feeders, nidus, and draining veins) provided a means to adapt resection strategies, define dissection planes, and interpret intraoperative findings. It is difficult to provide a scientifically valid definition of "added value." However, in our experience, the added confidence and the improved mental image of the lesion that resulted from this technology improved the quality and flow of surgery.

Combination of microsurgery and Gamma Knife surgery for the treatment of intracranial chondrosarcomas.

OBJECT: Intracranial chondrosarcomas have a high risk of recurrence after surgery. This retrospective study of patients with intracranial chondrosarcoma was conducted to determine the long-term results of microsurgery followed by Gamma Knife surgery (GKS) for residual tumor or recurrence. METHODS: The authors treated nine patients whose median age was 36 years. Seven patients had low-grade chondrosarcomas (LGCSs), whereas mesenchymal chondrosarcomas (MCSs) were diagnosed in two. Radiosurgery was performed in eight patients, whereas one patient declined further surgical intervention and tumor-volume reduction necessary for the GKS. The patients were followed up for 15 to 173 months (median 108 months) after diagnosis and 3 to 166 months (median 88 months) after GKS. Seven patients had residual tumor tissue after microsurgery, and two operations appeared radical. In the two latter cases, tumors recurred after 25 and 45 months. Thus, definite tumor control was not achieved after surgery alone in any patient, whereas the addition of radiosurgery allowed tumor control in all six patients with LGCSs. Two of these patients experienced an initial tumor regrowth after GKS; in both cases the recurrences were outside the prescribed radiation field. The patients underwent repeated GKS, and subsequent tumor control was observed. An MCS was diagnosed in the remaining two patients. Complications after microsurgery included diplopia, facial numbness, and paresis. After GKS, one patient had radiation necrosis, which required microsurgery, and two patients had new cranial nerve palsies. CONCLUSIONS: Tumor control after microsurgery alone was not achieved in any patient, whereas adjuvant radiosurgery provided local tumor control in six of eight GKS-treated patients. Tumor control was not achieved in the two patients with MCS. Similar to other treatments for intracranial chondrosarcoma, morbidity after micro- and radiosurgical combination therapy was high and included severe cranial nerve palsies.

Gamma knife surgery for dural arteriovenous shunts: 25 years of experience.

OBJECT: The aim of this study was to assess the clinical efficacy of gamma knife surgery (GKS) in the treatment of dural arteriovenous shunts (DAVSs). METHODS: From a database of more than 1600 patients with intracranial arteriovenous shunts that had been treated with GKS, the authors retrospectively and prospectively identified 53 patients with 58 DAVSs from the period between 1978 and 2003. Four patients were lost to follow-up evaluation and were excluded from the series. Thus, this study is based on the remaining 49 patients with 52 DAVSs. Thirty-six of the shunts drained into the cortical venous system, either directly or indirectly, and 22 of these were associated with intracranial hemorrhage on patient presentation. The mean prescription radiation dose was 22 Gy (range 10-28 Gy). All patients underwent a clinical follow-up examination. In 41 cases of DAVS a follow-up angiography study was performed. At the 2-year follow-up visit, 28 cases (68%) had angiographically proven obliteration of the shunt and in another 10 cases (24%) there was significant flow regression. Three shunts remained unchanged. There was one immediate minor complication related to the administration of radiation. Furthermore, one patient had a radiation-induced complication 10 years after treatment, although she recovered completely. There was one posterior fossa bleed 2 months after radiosurgery; a hematoma, as well as a lesion, was evacuated, and the patient recovered uneventfully. A second patient had an asymptomatic occipital hemorrhage approximately 6 months postradiosurgery. The clinical outcome after GKS was significantly better than that in patients with naturally progressing shunts (p < 0.01, chi-square test); figures on the latter have been reported previously. CONCLUSIONS: Gamma knife surgery is an effective treatment for DAVSs, with a low risk of complications. Major disadvantages of this therapy include the time elapsed before obliteration and the possibility that not all shunts will be obliterated. Cortical venous drainage from a DAVS, a risk factor for intracranial hemorrhage, is therefore a relative contraindication. Consequently, GKS can be used in the treatment of both benign DAVSs with subjectively intolerable bruit and aggressive DAVSs not responsive to endovascular treatment or surgery.

Expression and growth dependency of the insulin-like growth factor I receptor in craniopharyngioma cells: a novel therapeutic approach.

Craniopharyngioma is a rare benign intracranial epithelial tumor that, however, often recurs and sometimes kills the affected patients, one-third of which are children. In many cases, the patients acquire growth hormone deficiency and postoperatively need substitution. Generally, growth hormone promotes local release of insulin-like growth factor I (IGF-I), which in turn activates the IGF-I receptor (IGF-IR) if present. Together, these circumstances raise the question whether IGF-IR may be involved in craniopharyngioma growth. To address this issue, we analyzed phenotypically well-characterized primary low-passage craniopharyngioma cell lines from nine different patients for IGF-IR expression and IGF-I dependency. Two of the cell lines showed no/very low expression of the receptor and was independent on IGF-I, whereas five cell lines exhibited a strong expression and was clearly contingent on IGF-I. The two remaining cell lines had low receptor expression and IGF-I dependency. Upon treatment with an IGF-IR inhibitor, cells with high IGF-IR expression responded promptly with decreased Akt phosphorylation followed by growth arrest. These responses were not seen in cells with no/very low receptor expression. Growth of cell lines with low IGF-IR expression was only slightly affected by IGF-IR inhibition. Taken together, our data suggest that IGF-IR may be involved in the growth of a subset of craniopharyngiomas and points to the possibility of the involvement of IGF-IR inhibitors as a treatment modality to obtain complete tumor-free conditions before growth hormone substitution.

Gamma knife radiosurgery for craniopharyngiomas: long-term results in the first Swedish patients.

OBJECT: The purpose of this study was to assess the long-term treatment efficacy and morbidity of patients who undergo gamma knife radiosurgery (GKS) for craniopharyngioma. METHODS: Twenty-one consecutive Swedish patients were evaluated retrospectively: 11 children (< or = 15 years) and 10 adults. The time from diagnosis to the most recent follow-up imaging study was 6.3 to 34.3 years (mean 18.2 years, median 16.8 years). Tumor volumes and morbidity from GKS or other treatments were assessed at the time of the most recent imaging study or at the time of a subsequent new treatment. The observation period ranged from 0.5 to 29 years (mean 7.5 years, median 3.5 years). The prescription dose ranged from less than 3 Gy to 25 Gy. The mean tumor volume was 7.8 cm3 (range 0.4-33 cm3). There were 22 tumors in 21 patients treated with GKS. Five of these tumors were reduced in size, three were unchanged, and 14 increased. Tumor progression correlated with a low dose to the tumor margin. Eleven (85%) of 13 tumors that received a dose of less than 6 Gy to the margin increased in size, whereas only three (33%) of nine tumors that received 6 Gy increased. This difference was statistically significant (p = 0.01). In five of six patients tumors that became smaller after GKS there were no recurrences within a mean follow-up period of 12 years. Nine (82%) of 11 tumors in children ultimately increased after GKS, compared with five (50%) of 10 in adults. In eight patients there was a deterioration of visual function. In all except one this could be related to a volume increase but radiation-induced damage could not be excluded as a factor in any of them. Four patients developed pituitary deficiencies. CONCLUSIONS: Gamma knife radiosurgery is effective in controlling growth of craniopharyngiomas with a minimum dose of 6 Gy. The findings also suggest that other stereotactic techniques, such as cyst aspiration and intracystic treatment, are only of value in reducing tumor volume in preparation for safe GKS.