Foetal amplitude-integrated electroencephalography: proof of principle of a novel foetal monitoring technique in adult volunteers.

Peripartum hypoxic neonatal brain injury cannot be accurately predicted with current foetal monitoring techniques. Neonatal brain monitoring through amplitude-integrated electroencephalography (aEEG) is utilised when brain injury is suspected. Intrapartum aEEG assessment may improve detection of foetal hypoxia, facilitating earlier intervention. Using different engineered configurations in adult volunteers (n = 18), we monitored aEEG through application of two foetal scalp electrodes (FSEs). This aided development of a novel signal splitter, our Foetal heart rate and aEEG Monitoring System (FEMS) to monitor aEEG intrapartum. We then compared FEMS with gold-standard EEG monitoring simultaneously in two adults. Average percentage of interpretable aEEG signal was 61.3%, with the FEMS obtaining 72.15%. EEG signal on the aEEG device consistently showed a similar trace to gold standard EEG. This study demonstrates feasibility of aEEG monitoring in adults with FEMS utilising FSE inputs. An intrapartum foetal study utilising FEMS is due to commence shortly. IMPACT STATEMENTWhat is already known on this subject? Cardiotography, the current gold standard in foetal monitoring, is not associated with a reduction in cerebral palsy or infant mortality rates. Neonatal amplitude-integrated electroencephalography (aEEG) is an established method of monitoring brain function to guide commencing cooling therapy in suspected hypoxic brain injury. Intrapartum animal studies have illustrated foetal EEG changes reflecting evolving hypoxia.What do the results of this study add? This study demonstrates aEEG monitoring in human adult volunteers through application of foetal scalp electrodes and use of a novel signal splitter. This Foetal heart rate and aEEG Monitoring System (FEMS) provided a good overall percentage of aEEG signal, consistently showing a similar trace to gold standard EEG.What the implications are of these findings for clinical practice and/or further research? This proof of principle study provides the first step in developing a novel intrapartum foetal monitoring technique to monitor foetal aEEG in labour. This provides an exciting prospect of transferring well established neonatal monitoring techniques to facilitate accurate brain function assessment intrapartum and early intervention to reduce hypoxic brain injury. An intrapartum foetal study of this technology is due to begin in the near future.

Evaluation of the change of outcomes over a 10-year period in patients with stage III colon cancer: pooled analysis of 6501 patients treated with fluorouracil, leucovorin, and oxaliplatin in the ACCENT database.

BACKGROUND: Since 2004, adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX or FLOX) have been the standard of care for patients with resected colon cancer. Herein we examine the change of outcomes over a 10-year period in patients with stage III colon cancer who received this regimen. PATIENTS AND METHODS: Individual patient data from the ACCENT database was used to compare the outcomes in older (1998-2003) and newer (2004-2009) treatment eras for patients with stage III colon cancer who received adjuvant FOLFOX or FLOX. The outcomes were compared between the two groups by the multivariate Cox proportional-hazards model adjusting for age, sex, performance score, T stage, N stage, tumor sidedness, and histological grade. RESULTS: A total of 6501 patients with stage III colon cancer who received adjuvant FOLFOX or FLOX in six randomized trials were included in the analysis. Patients enrolled in the new era group experienced statistically significant improvement in time to recurrence [3-year rate, 76.1% versus 73.0%; adjusted hazard ratio (HRadj) = 0.83 (95% CI, 0.74-0.92), P = 0.0008], disease-free survival (DFS) [3-year rate, 74.7% versus 72.3%; HRadj = 0.88 (0.79-0.98), P = 0.024], survival after recurrence (SAR) [median time, 27.0 versus 17.7 months; HRadj = 0.65 (0.57-0.74), P < 0.0001], and overall survival (OS) [5-year rate, 80.9% versus 75.7%; HRadj = 0.78 (0.69-0.88), P < 0.0001]. The improved outcomes remained in patients diagnosed at 45 years of age or older, low-risk patients (T1-3 and N1), left colon, mismatch repair proficient (pMMR), BRAF, and KRAS wild-type tumors. CONCLUSION: Improved outcomes were observed in patients with stage III colon cancer enrolled in clinical trials who received adjuvant FOLFOX/FLOX therapy in 2004 or later compared with patients in the older era. Prolonged SAR calls for revalidation of 3-year DFS as the surrogate endpoint of OS in adjuvant clinical trials and reevaluation of optimal follow-up of OS to confirm the trial findings based on the DFS endpoints. CLINICAL TRIALS NUMBERS: NCT00079274; NCT00096278; NCT00004931; NCT00275210; NCT00265811; NCT00112918.

Intracranial pressure monitoring and caesarean section in a patient with von Hippel-Lindau disease and symptomatic cerebellar haemangioblastomas.

Von Hippel-Lindau disease is a rare genetic disorder which gives rise to a range of tumours including central nervous system haemangioblastomas. We report a case of caesarean section in a patient with symptomatic cerebellar haemangioblastomas associated with von Hippel-Lindau disease. An intracranial pressure monitor was inserted before surgery, which enabled intracranial pressure to be monitored throughout. The anaesthetic implications of von Hippel-Lindau disease are discussed and clinical options explored.

Ruptured aneurysms and the International Subarachnoid Aneurysm Trial (ISAT): What is known and what remains to be questioned.

BACKGROUND AND PURPOSE: The International Subarachnoid Aneurysm Trial (ISAT) was a major study comparing clipping and coiling of ruptured intracranial aneurysms. The trial provided answers that were the subject of multiple letters and editorial comments. METHODS: We review the most common critiques that were published in major neurosurgical journals, trying to identify what aspects of ISAT could have been improved, and what questions remain to be studied. RESULTS: Frequent critiques include imprecise selection criteria, lack of requirement for the technical proficiency of surgical participants, lack of angiographic controls of surgically treated patients, and poorly chosen primary endpoints. Other issues that are often raised are the poor recruitment rate which endangered generalization of results, the excessive delays in performing clipping which led to rebleeding episodes, lack of blinding in the assessment of outcomes, and subjective questionnaires. Nonetheless, the design of the study as a pragmatic trial was appropriate, as was the choice of the primary endpoint. The overall trial results could not be verified for all subgroups of interest, and currently many patients who would not have been included in ISAT are treated by coiling, while other patients are treated by clipping despite ISAT results. Hence a new trial, complementary to the original ISAT, may now be indicated. CONCLUSION: ISAT was well-designed and conducted, but many questions remain. They should be addressed by a new trial.

Prediction of 60 day case-fatality after aneurysmal subarachnoid haemorrhage: results from the International Subarachnoid Aneurysm Trial (ISAT).

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with substantial case-fatality. Our purpose was to examine which clinical and neuro-imaging characteristics, available on admission, predict 60 day case-fatality in aSAH and to evaluate performance of our prediction model. We performed a secondary analysis of patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomised multicentre trial to compare coiling with clipping in aSAH patients. Multivariable logistic regression analysis was used to develop a prognostic model to estimate the risk of dying within 60 days from aSAH based on clinical and neuro-imaging characteristics. The model was internally validated with bootstrapping techniques. The study population comprised of 2,128 patients who had been randomised to either endovascular coiling or neurosurgical clipping. In this population 153 patients (7.2%) died within 60 days. World Federation of Neurosurgical Societies (WFNS) grade was the most important predictor of case-fatality, followed by age, lumen size of the aneurysm and Fisher grade. The model discriminated reasonably between those who died within 60 days and those who survived (c statistic = 0.73), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.70). Several strong predictors are available to predict 60 day case-fatality in aSAH patients who survived the early stage up till a treatment decision; after external validation these predictors could eventually be used in clinical decision making.

Venoplasty and stenting of a jugular foramen meningioma.

The authors describe a novel approach to relieving major venous sinus stenosis at the level of the jugular bulb caused by a petrous meningioma. A balloon-expandable renovascular stent was deployed via a jugular approach to restore venous outflow and thus reduce visual and vestibulocochlear symptoms. Endovascular balloon venoplasty and stenting may assess and restore cranial outflow in veins compressed by soft tumours in anatomical locations challenging to surgical resection, even in the absence of intracranial hypertension.

Intramedullary tumours in patients with neurofibromatosis type 2: MRI features associated with a favourable prognosis.

AIM: To assess the magnetic resonance imaging (MRI) features and natural history of intramedullary tumours in patients with neurofibromatosis type 2 (NF2). MATERIALS AND METHODS: Eleven NF2 patients with intramedullary spinal cord tumours were identified from the database of the multidisciplinary NF2 clinic. All the imaging studies of these patients were individually reviewed by two neuroradiologists to evaluate the size, number, location, imaging characteristics, and interval growth of the intramedullary tumours. RESULTS: Two of the 11 patients had lesions that required surgery. Both these lesions were in the cervical region, and extended over three and five segments respectively. Nine patients with a mean imaging follow-up period of 77 months had lesions that remained stable, apart from the development of small peritumoral cysts in three. The lesions were well circumscribed, often multiple, usually less than 1cm in diameter, and were most frequently found in the cervical cord. CONCLUSION: The majority of intramedullary tumours in NF2 patients are very slow growing and share certain MRI features that differ from those of progressive or symptomatic lesions.

External ventricular drain infection: the effect of a strict protocol on infection rates and a review of the literature.

External ventricular drains (EVDs), like any surgically-implanted foreign body, are at risk of infection. We present the results of a completed audit loop following introduction of an evidence-based protocol for their insertion and management. There were two phases over a 2-year period. Phase 1 was a retrospective audit of our EVD infection rate. Phase 2 was a prospective audit of the infection rate subsequent to the introduction of a protocol for the insertion and management of EVDs. In phase 1, the infection rate was 27%. In phase 2, the infection rate was 12%. This was a statistically significant reduction (p < 0.05, Chi-squared test). EVD infection is unfortunately a common clinical problem and associated with potential morbidity and mortality. This study demonstrates that adherence to an evidence-based protocol for their insertion and management is associated with a significant reduction in the infection rate.

Evaluation of quality of life and psychiatric morbidity in patients with malignant tumours of the skull base.

In general, patients with malignant tumours of the skull base have a poor prognosis. Treatment may have a disfiguring physical and disabling mental effect on patients. To evaluate the effect of treatment on physical and mental quality of life in patients with skull base malignancy, we conducted a cross-sectional patient survey of 18 patients treated for such tumours, using the University of Washington (version 4) quality of life questionnaire and the hospital anxiety and depression scale. The total quality of life score (median value) was 980 (550-1125). Patients with anterior skull base malignancy scored lower than those with lateral skull base malignancy (p=0.003). In general, the worst individual domain scores were: mood (64 per cent); activity (69 per cent); and, specifically for patients with anterior skull base malignancy, taste (54 per cent, p=0.004) and anxiety (60 per cent, p=0.034). One-third of skull base cancer patients were at risk of suffering from mental distress and psychiatric morbidity (indicated as a score of more than seven on the hospital anxiety and depression scale).

Changes in cell adhesion and extracellular matrix molecules in spontaneous spinal neural tube defects in avian embryos.

Quail embryos (embryonic days 2-2.5) with spontaneous neural tube defects (NTDs), along with age-matched normal embryos, were examined immunocytochemically for the extracellular matrix (ECM) molecules laminin, fibronectin, and chondroitin sulfate proteoglycan, the cell adhesion molecules (CAMs) E- and N-cadherin and neural CAM (NCAM), and the neural crest marker HNK-1. The embryos with NTDs were at the lower limit of the normal stage range and the affected region was about 25% shorter than in normal embryos. Open NTDs occurred in cervical and upper thoracic level, although often the ventral neural tube was morphologically normal. Widened, irregular but closed neural tubes (lower thoracic to sacral levels) showed disorganized mesenchyme-like cells centrally and often multiple lumens. Finger-like tabs projecting from the ectoderm over the neural tube also occurred at lower thoracic to sacral levels. In open NTDs, the E-cadherin-labeled epidermis was incomplete dorsally, and was continuous with the N-cadherin-labeled neural tissue, with a sharp demarcation between E- and N-cadherin-expressing regions, as in the early stages of normal primary neurulation. A sharp inverted peak of epidermis extended ventrally, closely applied to the side of the neural tissue. The intervening matrix labeled less intensely for chondroitin sulfate proteoglycan relative to laminin and fibronectin, in comparison to control embryos. In closed NTDs, the dorsal superficial cell layer (i.e., positionally epidermis) was not separated from the underlying neural tissue by a band of matrix as in control embryos. In addition, this layer expressed E-cadherin (as in normal embryos), but coexpressed N-cadherin and NCAM, which are not normally found here at this stage. This overlap region resembled the mid-dorsal tissue at earlier stages in normal secondary neurulation in the tail-bud. The tabs of tissue appeared to be localized hypertrophy of the epidermal and neural ectoderm, and also showed codistribution of E- and N-cadherin. In all these defects, matrix molecules occurred within (rather than around) the neural and epidermal epithelia. HNK-1-labeled neural crest cells were frequently absent in regions of NTDs, in contrast to control embryos. These results show that matrix and cell adhesion molecules are disturbed in spontaneous NTDs at the time of neurulation, and therefore could be involved in the generation of the defects by altering cell adhesion-dependent morphogenetic events.

Isolation and characterization of chondroitin sulfate proteoglycans from embryonic quail that influence neural crest cell behavior.

The movement of neural crest cells is controlled in part by extracellular matrix. Aggrecan, the chondroitin sulfate proteoglycan from adult cartilage, curtails the ability of neural crest cells to adhere, spread, and move across otherwise favorable matrix substrates in vitro. Our aim was to isolate, characterize, and compare the structure and effect on neural crest cells of aggrecan and proteoglycans purified from the tissues through which neural crest cells migrate. We metabolically radiolabeled proteoglycans in E2.5 quail embryos and isolated and characterized proteoglycans from E3.3 quail trunk and limb bud. The major labeled proteoglycan was highly negatively charged, similar in hydrodynamic size to chick limb bud versican/PG-M, smaller than adult cartilage aggrecan but larger than reported for embryonic sternal cartilage aggrecan. The molecular weight of the iodinated core protein was about 400 kDa, which is more than reported for aggrecan but less than that of chick versican/PG-M. The proteoglycan bore chondroitin sulfate glycosaminoglycan chains of 45 kDa, which is larger than those of aggrecan. It lacked dermatan sulfate, heparan sulfate, or keratan sulfate chains. It bound to collagen type I, like aggrecan, but not to fibronectin (unlike versican/PG-M), collagen type IV, or laminin-1 in solid-phase assays and it bound to hyaluronate in gel-shift assays. When added at concentrations between 10 and 30 microg/ml to substrates of fibronectin, trunk proteoglycan inhibited neural crest cell spreading and migration. Attenuation of cell spreading was shown to be the most sensitive and titratable measure of the effect on neural crest cells. This effect was sensitive to digestion with chondroitinase ABC. Similar cell behavior was also produced by aggrecan and the small dermatan sulfate proteoglycan decorin; however, 30-fold more aggrecan was required to produce an effect of similar magnitude. When added in solution to neural crest cells which were already spread and migrating on fibronectin, the embryonic proteoglycan rapidly and reversibly caused complete rounding of the cells, being at least 30-fold more potent than aggrecan in this activity.

Benign intracerebral cysts with ependymal lining: pathological and radiological features.

Cerebral intraparenchymal cysts without communication with the ventricles are very rare. We report four such cases with no relevant past history or evidence of infection, haemorrhage, trauma, tumour or congenital neural tube defect. At operation smooth wailed cysts with an ependymal-type lining were found. To the best of our knowledge, we present the first correlation of their pathological and radiological features (including magnetic resonance imaging). We also review the literature on these cysts.

Endosaccular treatment of inoperable intracranial aneurysms with platinum coils.

Endosaccular packing of inoperable aneurysms with electrolytic platinum coils was performed in 50 patients. Complete embolization of the aneurysms was achieved in 100% of small, 95% of large and 85% of giant aneurysms, with combined procedural and periprocedural morbidity and mortality rates of 6 and 4%, respectively. Follow-up angiography of 42 aneurysms demonstrated some degree of refilling in 17% of small, 19% of large and 50% of giant aneurysms. The risks associated with the procedure were similar in aneurysms of the carotid and vertebrobasilar circulations. This treatment should therefore be considered for all inoperable aneurysms and particularly for aneurysms involving the posterior circulation. Its long-term efficacy remains uncertain.

Effect of a new computed tomographic image transfer system on management of referrals to a regional neurosurgical service.

A computed tomographic image transfer system ('Image Link') was used to link scanners within the Oxford region, UK, to the regional neurosurgical service. 100 consecutive neurosurgical referrals were examined by this system; 43% of the emergency referrals did not require transfer, 31% were transferred electively, and 26% urgently. Most of the patients defined as potentially hazardous for transfer (10/11) did not require neurosurgical intervention. The delay by the use of the system was negligible and early detection of intracranial haematoma contributed to good outcome in some head injured patients. Overall, 3,170 miles of ambulance journey were avoided. Use of image link has led to substantial improvements in management of neurosurgical emergency referrals, cost-effectiveness of neurosurgical and ambulance facilities, and interhospital communication between doctors.