Risk of Aneurysm Rupture (ROAR) study: protocol for a long-term, longitudinal, UK multicentre study of unruptured intracranial aneurysms.

INTRODUCTION: Unruptured intracranial aneurysms (UIA) are common in the adult population, but only a relatively small proportion will rupture. It is therefore essential to have accurate estimates of rupture risk to target treatment towards those who stand to benefit and avoid exposing patients to the risks of unnecessary treatment. The best available UIA natural history data are the PHASES study. However, this has never been validated and given the known heterogeneity in the populations, methods and biases of the constituent studies, there is a need to do so. There are also many potential predictors not considered in PHASES that require evaluation, and the estimated rupture risk is largely based on short-term follow-up (mostly 1 year). The aims of this study are to: (1) test the accuracy of PHASES in a UK population, (2) evaluate additional predictors of rupture and (3) assess long-term UIA rupture rates. METHODS AND ANALYSIS: The Risk of Aneurysm Rupture study is a longitudinal multicentre study that will identify patients with known UIA seen in neurosurgery units. Patients will have baseline demographics and aneurysm characteristics collected by their neurosurgery unit and then a single aggregated national cohort will be linked to databases of hospital admissions and deaths to identify all patients who may have subsequently suffered a subarachnoid haemorrhage. All matched admissions and deaths will be checked against medical records to confirm the diagnosis of aneurysmal subarachnoid haemorrhage. The target sample size is 20 000 patients. The primary outcome will be aneurysm rupture resulting in hospital admission or death. Cox regression models will be built to test each of the study's aims. ETHICS AND DISSEMINATION: Ethical approval has been given by South Central Hampshire A Research Ethics Committee (21SC0064) and Confidentiality Advisory Group support (21CAG0033) provided under Section 251 of the NHS Act 2006. The results will be disseminated in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN17658526.

A benchtop brain injury model using resected donor tissue from patients with Chiari malformation.

The use of live animal models for testing new therapies for brain and spinal cord repair is a controversial area. Live animal models have associated ethical issues and scientific concerns regarding the predictability of human responses. Alternative models that replicate the 3D architecture of the central nervous system have prompted the development of organotypic neural injury models. However, the lack of reliable means to access normal human neural tissue has driven reliance on pathological or post-mortem tissue which limits their biological utility. We have established a protocol to use donor cerebellar tonsillar tissue surgically resected from patients with Chiari malformation (cerebellar herniation towards the foramen magnum, with ectopic rather than diseased tissue) to develop an in vitro organotypic model of traumatic brain injury. Viable tissue was maintained for approximately 2 weeks with all the major neural cell types detected. Traumatic injuries could be introduced into the slices with some cardinal features of post-injury pathology evident. Biomaterial placement was also feasible within the in vitro lesions. Accordingly, this 'proof-of-concept' study demonstrates that the model offers potential as an alternative to the use of animal tissue for preclinical testing in neural tissue engineering. To our knowledge, this is the first demonstration that donor tissue from patients with Chiari malformation can be used to develop a benchtop model of traumatic brain injury. However, significant challenges in relation to the clinical availability of tissue were encountered, and we discuss logistical issues that must be considered for model scale-up.

In vitro model of traumatic brain injury to screen neuro-regenerative biomaterials.

Penetrating traumatic brain injury (pTBI) causes serious neurological deficits with no clinical regenerative therapies currently available. Tissue engineering strategies using biomaterial-based 'structural bridges' offer high potential to promote neural regeneration post-injury. This includes surgical grade materials which can be repurposed as biological scaffolds to overcome challenges associated with long approval processes and scaleup for human application. However, high throughput, pathomimetic models of pTBI are lacking for the developmental testing of such neuro-materials, representing a bottleneck in this rapidly emergent field. We have established a high throughput and facile culture model containing the major neural cell types which govern biomaterial handling in the central nervous system. We show that induction of traumatic injuries was feasible in the model, with post-injury implantation of a surgical grade biomaterial. Cellular imaging in lesions was achievable using standard epifluorescence microscopy methods. Key pathological features of pTBI were evident in vitro namely immune cell infiltration of lesions/biomaterial, with responses characteristic of cell scarring, namely hypertrophic astrocytes with GFAP upregulation. Based on our observations, we consider the high-throughput, inexpensive and facile pTBI model can be used to study biomaterial 'implantation' and evaluate neural cell-biomaterial responses. The model is highly versatile to test a range of laboratory and clinical grade materials for neural regeneration.

Stem cell sprays for neurological injuries: a perspective.

Injuries to the brain and spinal cord have major clinical consequences with high costs for healthcare systems. Neural cell transplantation therapies have significant translational potential to promote regeneration post-injury with clinical trials commencing for various pathologies. However, there are challenges associated with current clinical approaches used for systemic or direct delivery of transplant cells to neural tissue in regenerative applications. These include risks associated with surgical microinjection into neural tissue (e.g. haemorrhage, cell clumping) and high cell loss due to systemic clearance or with cell passage through fine gauge needles into densely packed neural tissue. This article presents lines of evidence supporting the concept that cell spray delivery technology can offer significant translational benefits for neural transplantation therapy, versus current cell delivery methods. Potential benefits include rapid/homogenous cell delivery, release over large surface areas, minimal invasiveness, compatibility with neurosurgical procedures in acute injury, no predictable clinical complications and the capacity to combine cell therapies with drug/biomolecule delivery. Accordingly, we consider that the development of cell spray delivery technology represents a key goal to develop advanced cell therapies for regenerative neurology.

Sudden-onset paraplegia in a 72-year-old male with a spinal dural arteriovenous fistula: illustrative case.

BACKGROUND: Spinal dural arteriovenous fistulas (SDAVFs) are rare vascular malformations of the spine but account for up to 80% of all vascular malformations involving the spine. Few case reports of SDAVFs have been reported in the literature, and even fewer have been described with sudden onset of symptoms. OBSERVATIONS: The authors described the case of a 72-year-old male with sudden-onset bilateral paraplegia and sensory loss with subsequent inability to bear weight and an initial suspicion of cauda equina syndrome, which was eventually diagnosed as an SDAVF using magnetic resonance imaging. During open surgery, it was difficult to identify the feeder vessels. A postoperative scan showed persistence of the fistula, and the patient had to receive redo ligation with good postoperative status. LESSONS: Sudden-onset paraplegia is not the typical presentation of SDAVF. All doctors need to be aware of the possibility of an acute presentation with SDAVF, especially with the high likelihood of misdiagnosis and resultant worse outcome due to treatment delays. A high index of suspicion is required to ensure early recognition as well as initiation of treatment.

Duroplasty in iatrogenic dorsal spinal cord herniation: illustrative case.

BACKGROUND: The case report detailed an unusual presentation of an iatrogenic dorsal cord herniation at the level of the thoracic cord after insertion of an epidural catheter 8 months before presentation to the neurosurgical clinic. OBSERVATIONS: Only 13 cases of iatrogenic dorsal cord herniation, most of which occurred after spinal surgery, have been described in the literature. This was the first case of a spinal cord hernia described after the insertion of an epidural catheter. In this case study, the authors described a 38-year-old man who presented with progressive lower limb weakness, sensory deficits, perianal numbness, and urinary/fecal incontinence. He was diagnosed with a spinal cord hernia that reherniated after an initial sandwich duroplasty repair. Definitive repair was made after his re-presentation using an expansile duroplasty. LESSONS: In patients with previous spinal instrumentation who present with neurological symptoms, spinal cord herniation should be considered a likely differential despite its rarity. In this case, a simple duroplasty was insufficient to provide full resolution of symptoms and was associated with recurrence. Perhaps a combination of graft and expansile duroplasty may be used for repair, especially when associated with a tethered cord and in the presence of significant adhesions.

Extramedullary malignant melanotic schwannoma of the spine: Case report and an up to date systematic review of the literature.

BACKGROUND: Melanotic schwannoma is a rare variant of schwannoma. Extramedullary melanotic schwannoma originates in the vicinity of nerve roots mimicking other intervertebral disc disorders. Therefore, T1 and T2-weighted MRI sequences become an essential tool for diagnosis. Aside from case reports, no large studies exist to provide consensus on the signal intensities in T1 and T2-weighted MR imaging. Moreover, no clear evidence is available to delineate prognosis. Here, a case report is presented together with a subsequent systematic review of the literature regarding this rare entity. CASE DESCRIPTION: A 45-year old female presented with a one-year history of insidious onset of neck pain and paraesthesia. Magnetic resonance imaging confirmed an extramedullary lesion along the C6 nerve root with T1-weighted hyperintensity and T2-weighted hypointensity. Despite two surgical decompressions and adjuvant immunotherapy, the patient unfortunately passed away due to metastatic progression. DISCUSSION: According to the systematic review conducted, in over half of the cases of extramedullary melanotic schwannoma, there is local reoccurrence and/or distal metastasis. Moreover, in 64.7% and 70.6% of the cases, the T1-weighted image of the lesion appears hyperintense and hypointense on a T2-weighted image, respectively. It is an aggressive variant of schwannoma, one of the most commonly observed extramedullary tumours presenting to neurosurgical practice. CONCLUSION: Our results highlight that specific T1 and T2-weighted imaging findings can provide valuable information, enabling early suspicion, influencing the surgical aims and strategy and the timely commencement of relevant immunotherapy. Considering the poor prognosis, early adjuvant therapy with other modalities should be considered.

Safe nanoengineering and incorporation of transplant populations in a neurosurgical grade biomaterial, DuraGen PlusTM, for protected cell therapy applications.

High transplant cell loss is a major barrier to translation of stem cell therapy for pathologies of the brain and spinal cord. Encapsulated delivery of stem cells in biomaterials for cell therapy is gaining popularity but experimental research has overwhelmingly used laboratory grade materials unsuitable for human clinical use - representing a further barrier to clinical translation. A potential solution is to use neurosurgical grade materials routinely used in clinical protocols which have an established human safety profile. Here, we tested the ability of Duragen Plus™ - a clinical biomaterial used widely in neurosurgical duraplasty procedures, to support the growth and differentiation of neural stem cells- a major transplant population being tested in clinical trials for neurological pathology. Genetic engineering of stem cells yields augmented therapeutic cells, so we further tested the ability of the Duragen Plus™ matrix to support stem cells engineered using magnetofection technology and minicircle DNA vectors- a promising cell engineering approach we previously reported (Journal of Controlled Release, 2016 a &b). The safety of the nano-engineering approach was analysed for the first time using sophisticated data-independent analysis by mass spectrometry-based proteomics. We prove that the Duragen Plus™ matrix is a promising biomaterial for delivery of stem cell transplant populations, with no adverse effects on key regenerative parameters. This advanced cellular construct based on a combinatorial nano-engineering and biomaterial encapsulation approach, could therefore offer key advantages for clinical translation.

Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: results of the Subcutaneous Interleukin-1Ra in SAH (SCIL-SAH) study.

OBJECTIVE Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular event with long-term morbidity and mortality. Patients who survive the initial bleeding are likely to suffer further early brain injury arising from a plethora of pathological processes. These may result in a worsening of outcome or death in approximately 25% of patients and may contribute to longer-term cognitive dysfunction in survivors. Inflammation, mediated by the cytokine interleukin-1 (IL-1), is an important contributor to cerebral ischemia after diverse forms of brain injury, including aSAH. Its effects are attenuated by its naturally occurring antagonist, IL-1 receptor antagonist (IL-1Ra [anakinra]). The authors hypothesized that administration of additional subcutaneous IL-1Ra would reduce inflammation and associated plasma markers associated with poor outcome following aSAH. METHODS This was a randomized, open-label, single-blinded study of 100 mg subcutaneous IL-1Ra, administered twice daily in patients with aSAH, starting within 3 days of ictus and continuing until 21 days postictus or discharge from the neurosurgical center, whichever was earlier. Blood samples were taken at admission (baseline) and at Days 3-8, 14, and 21 postictus for measurement of inflammatory markers. The primary outcome was difference in plasma IL-6 measured as area under the curve between Days 3 and 8, corrected for baseline value. Secondary outcome measures included similar area under the curve analyses for other inflammatory markers, plasma pharmacokinetics for IL-1Ra, and clinical outcome at 6 months. RESULTS Interleukin-1Ra significantly reduced levels of IL-6 and C-reactive protein (p < 0.001). Fibrinogen levels were also reduced in the active arm of the study (p < 0.002). Subcutaneous IL-1Ra was safe, well tolerated, and had a predictable plasma pharmacokinetic profile. Although the study was not powered to investigate clinical effect, scores of the Glasgow Outcome Scale-extended at 6 months were better in the active group; however, this outcome did not reach statistical significance. CONCLUSIONS Subcutaneous IL-1Ra is safe and well tolerated in aSAH. It is effective in reducing peripheral inflammation. These data support a Phase III study investigating the effect of IL-1Ra on outcome following aSAH. Clinical trial registration no.: EudraCT: 2011-001855-35 ( www.clinicaltrialsregister.eu ).

The challenges that parents of children with epilepsy face: A qualitative study.

OBJECTIVE: This qualitative study explored the challenges that Greek parents/caregivers of children with controlled epilepsy (CwE) face regarding the disorder. METHODS: Interviews were conducted based on open-ended questions guided by a review of the literature. A total of 91 parents/caregivers were recruited by neurologists at the neurology clinics of two Athens public hospitals. A hermeneutic phenomenological approach was used to explore parent/caregiver experiences. The data were grouped and analyzed through a textual interpretation. RESULTS: Two key challenges were identified for parents of CwE: the disclosure of epilepsy and the absence of adequate information about coping with epilepsy. Parents in Greece were hesitant to reveal their child's epilepsy to school staff and their wider social milieu. Also, although satisfied with the patient-centered approach they experienced with their hospital doctor, parents/caregivers found that they needed more education about the existing sources of psychosocial and emotional support to cope with their child's epilepsy personally and as a family. Finally, the parents/caregivers who let their child know about the epilepsy and discussed the implications with the child found that parent-child communication improved. CONCLUSION: This study provides valuable insight into the impact of epilepsy on parents of CwE, which might help hospital and school staff support families with greater understanding, sensitivity, and skill. The findings suggest that Greek authorities should staff hospitals and schools with experts and more systematically advertise sources of information about epilepsy and ways to cope with it.

Teachers' knowledge about epilepsy in Greece: Information sources and attitudes towards children with epilepsy during school time.

AIM: The aim of this study was to explore the sources of information for the educators in Greek primary and secondary schools with regard to epilepsy, first aid to seizures, and pupils' health conditions. METHOD: A semistructured anonymous 52-item questionnaire was sent to 100 public primary and secondary Greek schools from all districts. Two thousand thirty-seven teachers were approached; 446 questionnaires returned. The data were analyzed with SPSS20. Also, 70 head teachers were phone-interviewed with an open-ended unstructured questionnaire. The derived data were analyzed using mixed methodology. RESULTS: Twenty-two percent of the addressed educational community responded to the questionnaire, mostly women (66.6%). More responses came from urban areas (71.5%). The main source for the teachers to obtain information about epilepsy was found to be personal experience (37.75%) and internet (34.93%). Only a small percentage was referred to courses (6.2%). Eighty point three percent of the educators knew what epilepsy is, and 88.1% had the right view about the nature of the illness. However, 92% of the educators replied that they have not had adequate first aid training. Although 80.3% of the teachers believed that the school personnel are aware of the pupils' medical history, 85.48% of the teachers considered that they are informed about the pupils' condition from the parents/carers, and only 5.53% believed that the information came from the family doctor. Ninety-five point seventy percent of the educators declared a wish for further information and training about epilepsy. CONCLUSION: Knowledge and attitudes of the educators towards epilepsy are improved compared with those reported in previous studies conducted in Greece. However, there are still areas of uncertainty which need improvement. The necessity for more information about epilepsy and pupils' medical history along with appropriate training about seizure incidents seems crucial for the Greek educational community. Educational campaigns about epilepsy could improve teachers' knowledge of epilepsy to develop a well-informed and tolerant community. Further research in the field is necessary to provide teachers with accurate information about the illness and the ways to cope with it.

Intradural extramedullary cavernoma of a lumbar nerve root mimicking neurofibroma. A report of a rare case and the differential diagnosis.

BACKGROUND CONTEXT: Intradural extramedullary (IDEM) cavernomas are rare vascular malformations. They are well-circumscribed dark berry-like lesions with a histologic appearance of sinusoidal vascular channels. Neurofibromas are the most common IDEM tumors, originating from all nerve elements and leading to firm enlargement of the affected nerve root. These lesions are completely different; however, they may involve the spinal nerve roots or the major nerve trunks. Any similarities in clinical findings are based on different pathophysiology. PURPOSE: To present a rare resemblance of an IDEM cavernoma to a neurofibroma. STUDY DESIGN: This is a case report with review of the literature focused on the differential diagnosis. METHODS: A 79-year-old patient presented with acute sensorimotor disturbance from L2-S1 levels. The investigations showed an L2-L3 lesion occupying the canal. Findings resembled a neurofibroma and a surgical resection was decided. RESULTS: The complete surgical resection revealed a vascular lesion originating from a nerve root. The histology confirmed an IDEM cavernoma. This is a unique case as such a clinical resemblance and a macroscopical appearance has not been reported for an IDEM cavernoma as yet. The patient showed full postoperative recovery from his initial symptoms. CONCLUSIONS: Intradural extramedullary cavernoma is a rare cause of compression to spinal cord or nerve roots. Its manifestation characteristics are well defined and should always be part of the differential diagnosis. Intraoperative findings aid the diagnosis in nontypical cases before the final histology. The nontraumatic and nerve tissue sparing surgical resection warrants optimal postoperative results and excellent prognosis.

Upper cervical cord enterogenous cyst mimicking transient ischaemic attacks.

A 76-year-old woman presenting with tetraparesis, left-sided hemisensory loss and occasional neck pain was urgently admitted to our department. A cervical spine MRI scan revealed a partially cystic lesion compressing the cord at the C2-4 level. The lesion was surgically excised. The histopathological diagnosis was that of an enterogenous cyst. No postoperative complications were noted and the patient significantly recovered from the preoperative tetraparesis. Eleven months before surgery, a waxing and waning presentation of the myelopathic signs with normal neuroradiological findings on a non-contrast-enhanced head CT scan, had unfortunately led to the misdiagnosis of transient ischaemic attacks and ischaemic stroke which delayed the treatment of an essentially benign disease the total surgical excision of which not only is usually curative but also improves the preoperative signs and symptoms.

Venous anastomotic circle, multiple varices and oculomotor palsy--a rare coincidence.

Oculomotor nerve palsy due to a venous varix arising from flow anomalies caused by a dural arteriovenous fistula (AVF) is a rare phenomenon. We report a case of surgical third nerve palsy with a rare underlying AVF as the cause and discuss in detail the patho-anatomy and its significance. A tentorial dural AVF mimicking the arterial circle was found with multiple varix formation causing compressive oculomotor palsy. This was treated successfully with Onyx™ injection with a satisfactory angiographic result and complete resolution of symptoms.

Intraparenchymal myxopapillary ependymoma: case report.

OBJECTIVE AND IMPORTANCE: Myxopapillary ependymoma is a histological variant of ependymoma found in the cauda equina region. The most characteristic histological feature of myxopapillary tumors is the abundance of intercellular and perivascular mucin and the arborizing vasculature, which tends to form papillae. Primary intracerebral myxopapillary ependymomas are extremely rare; only three cases have been reported in the previous literature. CLINICAL PRESENTATION: A 68-year-old man presented with disorientation and dizziness caused by a cystic left frontal intraparenchymal lesion. This proved to be a myxopapillary ependymoma. Similarities to previously reported cases are discussed, as are the findings on magnetic resonance imaging. There is also a literature review of the histological findings, natural history, and outcome of surgically treated myxopapillary ependymoma. INTERVENTION: The lesion was totally removed. After surgery, the patient was neurologically intact and had an uneventful recovery. CONCLUSION: This is the fourth reported case of histologically proven primary myxopapillary intracranial ependymoma.