Consensus statement from the international consensus meeting on post-traumatic cranioplasty.

BACKGROUND: Due to the lack of high-quality evidence which has hindered the development of evidence-based guidelines, there is a need to provide general guidance on cranioplasty (CP) following traumatic brain injury (TBI), as well as identify areas of ongoing uncertainty via a consensus-based approach. METHODS: The international consensus meeting on post-traumatic CP was held during the International Conference on Recent Advances in Neurotraumatology (ICRAN), in Naples, Italy, in June 2018. This meeting was endorsed by the Neurotrauma Committee of the World Federation of Neurosurgical Societies (WFNS), the NIHR Global Health Research Group on Neurotrauma, and several other neurotrauma organizations. Discussions and voting were organized around 5 pre-specified themes: (1) indications and technique, (2) materials, (3) timing, (4) hydrocephalus, and (5) paediatric CP. RESULTS: The participants discussed published evidence on each topic and proposed consensus statements, which were subject to ratification using anonymous real-time voting. Statements required an agreement threshold of more than 70% for inclusion in the final recommendations. CONCLUSIONS: This document is the first set of practical consensus-based clinical recommendations on post-traumatic CP, focusing on timing, materials, complications, and surgical procedures. Future research directions are also presented.

Head down tilt 15° in experimental intracerebral hemorrhage: a randomized noninferiority safety trial.

BACKGROUND AND PURPOSE: Head down tilt 15° (HDT15°), applied before recanalization, increases collateral flow and improves outcome in experimental ischemic stroke. For its simplicity and low cost, HDT15° holds considerable potential to be developed as an emergency treatment of acute stroke in the prehospital setting, where hemorrhagic stroke is the major mimic of ischemic stroke. In this study, we assessed safety of HDT15° in the acute phase of experimental intracerebral hemorrhage. METHODS: Intracerebral hemorrhage was produced by stereotaxic injection of collagenase in Wistar rats. A randomized noninferiority trial design was used to assign rats to HDT15° or flat position (n = 64). HDT15° was applied for 1 h during the time window of hematoma expansion. The primary outcome was hematoma volume at 24 h. Secondary outcomes were mass effect, mortality, and functional deficit in the main study and acute changes of intracranial pressure, hematoma growth, and cardiorespiratory parameters in separate sets of randomized animals (n = 32). RESULTS: HDT15° achieved the specified criteria of noninferiority for hematoma volume at 24 h. Mass effect, mortality, and functional deficit at 24 h showed no difference in the two groups. HDT15° induced a mild increase in intracranial pressure with respect to the pretreatment values (+2.91 ± 1.76 mmHg). HDT15° had a neutral effect on MRI-based analysis of hematoma growth and cardiorespiratory parameters. CONCLUSIONS: Application of HDT15° in the hyperacute phase of experimental intracerebral hemorrhage does not worsen early outcome. Further research is needed to implement HDT15° as an emergency collateral therapeutic for acute stroke.

Cerebellar tumour-like aggregate of glycosaminoglycans in a MPS IIIB patient: a case report.

INTRODUCTION: Mucopolysaccharidosis (MPS) IIIB is a lysosomal disorder in which a deficiency in α-N-acetylglucosaminidase impairs the degradation of heparan sulphate, which accumulates in tissues causing multiple organs dysfunction. This disease is associated with significant central nervous system (CNS) abnormalities, but a presentation with a tumour-like lesion has never been reported so far. CLINICAL PRESENTATION: The present report describes the case of a 5-year-old girl suffering from MPS IIIB who developed a cerebellar lesion with evident mass effect. She underwent surgery with a subsequent notable improvement of her clinical picture. Surprisingly, the pathological analysis revealed the lesion to have the typical MPS features. CONCLUSION: This case would describe a neglected possible presentation of MPS IIIB with a lesion mimicking a neoplasm, which could even be successfully treated with surgery.

Adverse Effects and Surgical Complications in Pediatric Patients Undergoing Vagal Nerve Stimulation for Drug-Resistant Epilepsy.

Vagal nerve stimulation (VNS) is an effective treatment for drug-resistant epilepsy that is not suitable for resective surgery, both in adults and in children. Few reports describe the adverse effects and complications of VNS. The aim of our study was to present a series of 33 pediatric patients who underwent VNS for drug-resistant epilepsy and to discuss the adverse effects and complications through a review of the literature.The adverse effects of VNS are usually transient and are dependent on stimulation of the vagus and its efferent fibers; surgical complications of the procedure may be challenging and patients sometimes require further surgery; generally these complications affect VNS efficacy; in addition, hardware complications also have to be taken into account.In our experience and according to the literature, adverse effects and surgical and hardware complications are uncommon and can usually be managed definitely. Careful selection of patients, particularly from a respiratory and cardiac point of view, has to be done before surgery to limit the incidence of some adverse effects.

Effect of a new synbiotic supplement on symptoms, stool consistency, intestinal transit time and gut microbiota in patients with severe functional constipation: a pilot randomized double-blind, controlled trial.

BACKGROUND: Data on the benefits of synbiotics in functional constipation are conflicting. The aim of this study was to assess whether the administration of the synbiotic supplement Psyllogel Megafermenti(®) normalized stool consistency and decreased intestinal transit time (ITT) in patients with severe functional constipation, based on its ability to impact on the gut microbiota. METHODS: We conducted a pilot randomized, double-blind, controlled trial. After a 2-week run-in period, patients from a tertiary care setting with severe functional constipation fulfilling the Rome III Diagnostic Criteria in the past year were randomly assigned to receive by mouth 2 bags/day of Psyllogel Megafermenti(®) (Group A) or 2.8 g of maltodextrin twice daily (Group B) for 8 weeks. Primary endpoints were increase of bowel evacuations with normal stool consistency and volume, and ITT reduction. Secondary endpoints included symptom improvement according to the Rome III Diagnostic Criteria, reduction of the Agachan-Wexner score and changes in gut microbiota composition. RESULTS: Twenty-nine patients completed the study: 17 were allocated to Group A and 12 to Group B. A statistically significant increase in stools with normal consistency was observed only in Group A (p = 0.001), even when considering patients with normal stools ≤50 % of time at baseline. In Group A, a significant reduction in ITT was also found (p = 0.022). According to polymerase chain reaction-denaturing gradient gel electrophoresis profiling of stool samples, 50 % of the patients treated with synbiotics harbored all the probiotic species of the study product. CONCLUSIONS: An 8-week treatment with Psyllogel Megafermenti(®) improved the main clinical parameters of functional constipation in patients extremely homogeneous for disorder severity and underlying pathophysiology ( Eudract.ema.europa.eu , No. 2008-000913-30).

Influenza A (H1N1) encephalitis with severe intracranial hypertension.

The swine-origin influenza A (H1N1) virus was responsible for the pandemic infection in 2009. We report a case of encephalitis diagnosed as the H1N1 virus infection in a young child. The H1N1 virus infection can be causative of the encephalitis, as with other influenza virus infections. For patients presenting with influenza-like illness accompanied by mental status changes or seizures, high suspicion for unusual presentations of influenza A virus infection and careful monitoring, including EEG and intracranial pressure monitoring, are essential for reducing complications.

The role of surgery when endovascular treatment is considered the first choice therapy for ruptured intracranial aneurysms.

AIM: Nowadays endovascular therapy is more and more considered as first choice treatment for ruptured intracranial aneurysms. The aim of this study was to understand the impact that endovascular treatment (EVT), chosen as first therapeutic strategy, has had in the selection of ruptured intracranial aneurysms submitted to surgery at our Institution and what role neurosurgeons still play in this setting. METHODS: From 1998 to 2002, 272 consecutive patients were treated at the Hospital of Toulouse for ruptured intracranial aneurysms: 222 by embolization and 50 by surgery. The two groups were homogeneous for sex, age and aneurysms multiplicity. RESULTS: The patients of the surgical group had a worst clinical-radiological status at the treatment time than those treated by EVT. Clipping was performed for different reasons: 16% for failure of attempted EVT; 32% for intracranial hematoma requiring surgical evacuation; 30% for aneurysm morphology unsuitable for EVT and 22% for absence of the endovascular operator. Aneurysms of the middle cerebral artery (MCA) represented the main surgical group. The aneurysms judged unsuitable for EVT and addressed to surgery had often a complex morphology representing a challenge also for surgery. Mid-term outcome is significantly better for patients treated by EVT. CONCLUSION: The results show that microsurgery continues to have a role in the treatment of ruptured intracranial aneurysms even when EVT is the first choice. The precarious clinical conditions of the patients submitted to surgery and the frequent complexity of their aneurysms explain their worst outcome. This would advise training dedicated vascular Neurosurgeons to guaranty a high level treatment when EVT is not possible.

Cortical areas involved in Arabic number reading.

OBJECTIVE: Distinct functional pathways for processing words and numbers have been hypothesized from the observation of dissociated impairments of these categories in brain-damaged patients. We aimed to identify the cortical areas involved in Arabic number reading process in patients operated on for various brain lesions. METHODS: Direct cortical electrostimulation was prospectively used in 60 brain mappings. We used object naming and two reading tasks: alphabetic script (sentences and number words) and Arabic number reading. Cortical areas involved in Arabic number reading were identified according to location, type of interference, and distinctness from areas associated with other language tasks. RESULTS: Arabic number reading was sustained by small cortical areas, often extremely well localized (<1 cm(2)). Over 259 language sites detected, 43 (17%) were exclusively involved in Arabic number reading (no sentence or word number reading interference detected in these sites). Specific Arabic number reading interferences were mainly found in three regions: the Broca area (Brodmann area 45), the anterior part of the dominant supramarginal gyrus (Brodmann area 40; p < 0.0001), and the temporal-basal area (Brodmann area 37; p < 0.05). Diverse types of interferences were observed (reading arrest, phonemic or semantic paraphasia). Error patterns were fairly similar across temporal, parietal, and frontal stimulation sites, except for phonemic paraphasias, which were found only in supramarginal gyrus. CONCLUSION: Our findings strongly support the fact that the acquisition through education of specific symbolic entities, such as Arabic numbers, could result in the segregation and the specialization of anatomically distinct brain areas.

Review of language organisation in bilingual patients: what can we learn from direct brain mapping?

Although the majority of people worldwide are bilingual, the brain representation of language in bilingual persons is still a matter of debate. Since the beginning of the studies conducted on bilinguals, most authors denied that learning a new language requires a new semantic processing or the involvement of new cortical areas. In this paper, we review neurosurgical studies using direct electrocortical or subcortical stimulation techniques for brain mapping in bilingual subjects and compare this data with that obtained from other brain mapping methods. The authors focused on the most controversial issue whether multiple languages are represented in common or distinct cerebral areas. Seven direct brain mapping studies from different teams focused on bilingualism and multilingualism. All these studies showed that even if cerebral representation of language in multilingual patients could be grossly located in the same cortical region, it was possible to individualise distinct language-specific areas by direct cortical stimulation in the dominant frontal and temporo-parietal regions. Task- and language-specific sites were also described, demonstrating an important specialisation of some cortical areas. Using subcortical stimulation, some authors were able to find specific white matter tracts for different languages. Finally, all authors recommend in bilingual patients who need brain mapping for neurosurgical purpose to test all languages in which the subjects are fluent.

Cortical and subcortical motor mapping in rolandic and perirolandic glioma surgery: impact on postoperative morbidity and extent of resection.

AIM: Surgery for gliomas located inside or in proximity of motor cortex or tracts requires cortical and subcortical mapping to locate motor function; direct electrical stimulation of brain cortex or subcortical pathways allows identification and preservation of motor function. In this study we evaluated the effect which subcortical motor mapping had on postoperative morbidity and extent of resection in a series of patients with gliomas involving motor areas or pathways. METHODS: One hundred and forty-six patients were included in the study. Intraoperative findings of primary motor cortex or subcortical tracts were reported, together with incidence of new postoperative deficits at short (1 week) and long term (1 month) examination. The relationship between intraoperative identification of subcortical motor tracts and extent of resection was reported. RESULTS: The motor strip was found in 133 patients (91%) and subcortical motor tracts in 91 patients (62.3%). New immediate postoperative motor deficits were documented in 59.3% of patients in whom a subcortical motor tract was identified intra-operatively and in 10.9% of those in whom subcortical tracts were not observed; permanent deficits were observed in 6.5% and 3.5%, respectively. A total resection was achieved in 94.4% of patients with high-grade gliomas and in 46.1% of those with low-grade gliomas.

Long-term inhibition of glioma growth by systemic administration of human PEX.

AIM: The growth of gliomas depends on the balance of factors stimulating or inhibiting angiogenesis, tumor cell invasion and proliferation. The administration of endogenous inhibitors to experimental human gliomas in animal models resulted in a significant inhibition of tumor growth. It is becoming apparent that resistance can develop over time to many types of endogenous inhibitors and seems to be influenced by the tumor type and system of delivery. METHODS: We recently isolated a potent endogenous inhibitor, called human PEX, from human glioma cells in culture. Human PEX is a potent inhibitor of angiogenesis, tumor and endothelial cell proliferation and migration. In this paper, we investigated the ability of human PEX to sustain inhibition of glioma growth for a prolonged period of time. We initially developed a recombinant form of the inhibitor and showed that this form had similar in vitro and in vivo activities to the natural one. Human PEX was then administered to nude mice intracranial human glioma model, in combination with metronomic chemotherapy, for a period of 185 days, starting 15 days after tumor cells implantation. RESULTS: Our data showed that the systemic administration of human PEX mantained a very prolonged inhibition of glioma growth (50% survival of animals treated with 2 mg/kg/days was 160 days vs 24 days of the control) and had a synergistic effect with low dose chemotherapy. Histological analysis of tumors, showed that treatment with PEX was associated with a decrease of vascularity, cell proliferation, and increase in apoptosis. CONCLUSION: These data indicate that human PEX controls tumor growth by separate mechanisms. In addition, treatment with PEX produced well delineated tumors, indicating the persistence of a direct anti-invasive effect of the molecule even after a prolonged period of treatment.

Hyperlipidaemic state and cardiovascular risk in primary biliary cirrhosis.

BACKGROUND: Primary biliary cirrhosis (PBC), a chronic cholestatic liver disease, is frequently associated with severe hypercholesterolaemia but the clinical significance of this finding is unclear. AIMS: To characterise changes in serum lipid profile over time and to assess the risk of cardiovascular disease in PBC. SUBJECTS AND METHODS: We studied a cohort of 400 PBC patients for 6.2 years (range 4 months to 24 years) by serial determinations of serum lipid levels and registration of all cardiovascular events. Subjects included in an Italian prospective population based study served as controls. RESULTS: At presentation, 76% of patients had serum cholesterol levels >5.2 mmol/l. Hyperbilirubinaemic patients had higher total cholesterol and lower high density lipoprotein (HDL) cholesterol levels (p<0.001). With time, disease progression was associated with a reduction in total (p<0.001) and HDL (p<0.05) cholesterol. The incidence of cardiovascular events was similar to that of the general population (cerebrovascular events: standardised ratio 1.4; 95% confidence interval 0.5-3.7; coronary events: 2.2; 0.9-4.3). Hypertension was associated with an increased risk of cardiovascular events (3.8; 1.6-8.9). Association with moderate hypercholesterolaemia was of borderline significance (3.8; 0.9-17) whereas severe hypercholesterolaemia was not associated with increased risk (2.4, 0.5-11). CONCLUSIONS: In PBC, serum cholesterol levels markedly increase with worsening of cholestasis, and decrease in the late disease stages, despite a severe reduction in biliary secretion. Marked hypercholesterolaemia, typical of severe longstanding cholestasis, is not associated with an excess risk of cardiovascular disease while less advanced patients with moderate hypercholesterolaemia are exposed to an increased cardiovascular risk. Putative protective factors in PBC patients with severe hypercholesterolaemia should be assessed.

Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2.

Angiogenesis, tumor cell proliferation, and migration are the hallmarks of solid tumors, such as gliomas. This study demonstrates that a fragment derived from the autocatalytic digestion of matrix metalloproteinase (MMP)-2, called PEX, acts simultaneously as an inhibitor of glioma angiogenesis, cell proliferation, and migration. PEX is detected in the cultured medium of various human glioma, endothelial, breast, and prostate carcinoma cell lines. PEX is purified from the medium of glioma cell lines by chromatography, where PEX is constitutively expressed as a free and a TIMP-2-bound form. In human glioma tissue, PEX expression correlates with histological subtype and grade and with alpha v beta 3 integrin expression to which it is bound. Systemic administration of PEX to s.c. and intracranial human glioma xenografts results in a 99% suppression of tumor growth with no signs of toxicity. Thus, PEX is a very promising candidate for the treatment of human malignant gliomas.

Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo.

This study evaluates the efficacy of the combination of an antiangiogenic drug and conventional chemotherapeutics for the treatment of experimental human gliomas. As an antiangiogenic, we used recombinant human PEX, a fragment of matrix metalloproteinase-2 that we have previously shown to have a significant antimitotic, anti-invasive, and antiangiogenic properties against human glioblastoma in vitro and in vivo. We used carboplatin and etoposide as the two chemotherapeutic drugs routinely used in our institution (Ospedale Maggiore de Milano) for the treatment of malignant gliomas. Conventional chemotherapeutic drugs were administered at high dose or at a low and semicontinuous regimen. Combined treatment of high-dose chemotherapy and PEX did not produce an improvement of survival in comparison with chemotherapy alone, but it was associated with a decrease in tumor volume, vascularity, and proliferative index and an increased apoptosis. All of these animals experienced severe side effects. The longest survival was documented in animals submitted to low and semicontinuous chemotherapy and antiangiogenic treatment. This regimen was associated with no side effects, marked decrease in tumor volume, vascularity, and proliferative index, and an increased apoptosis. Our data suggest that low-dose chemotherapy in combination with PEX can be successfully used against human malignant glioma in vivo.

Effects of alpha, beta and gamma recombinant interferons on CEA production from HT-29 human colon adenocarcinoma cell line.

The human colon adenocarcinoma derived cell line HT-29 is a good in vitro model for the study of CEA production and release under various experimental conditions. Many studies indicate that CEA secretion is correlated with cell proliferation and seems to depend on the growth conditions and differentiation characteristics induced by the culture medium. The present study demonstrates that recombinant interferons alpha, beta and gamma (rIFN alpha, rIFN beta, rIFN gamma) can modify CEA production and release by HT-29 cell-line. rIFN gamma in particular causes an enhancement of CEA production and release in the culture medium. This dose-depending effect is in some way correlated to cell growth inhibition since the enhancement of CEA expression in the interferon treated cells is evident in the presence of a reduction in cell proliferation. The activity of rIFN alpha and rIFN beta on CEA release is much less remarkable than that demonstrated by rIFN gamma, and is probably only due to the fact that HT-29 colon adenocarcinoma cells respond poorly to the effects of rIFN alpha and rIFN beta at the doses we used. These findings suggest that CEA production, expression and release can be modulated in a variety of ways under the influence of different rIFN treatment and this situation must be taken into account in immunodiagnostic and immunotherapeutic applications of anti-CEA monoclonal antibodies in the cancer patient.