Through the orbit and beyond: Current state and future perspectives in endoscopic orbital surgery on behalf of the EANS frontiers committee in orbital tumors and the EANS skull base section.

Introduction: Orbital surgery has always been disputed among specialists, mainly neurosurgeons, otorhinolaryngologists, maxillofacial surgeons and ophthalmologists. The orbit is a borderland between intra- and extracranial compartments; Krönlein's lateral orbitotomy and the orbitozygomatic infratemporal approach are the historical milestones of modern orbital-cranial surgery. Research question: Since its first implementation, endoscopy has significantly impacted neurosurgery, changing perspectives and approaches to the skull base. Since its first application in 2009, transorbital endoscopic surgery opened the way for new surgical scenario, previously feasible only with extensive tissue dissection. Material and methods: A PRISMA based literature search was performed to select the most relevant papers on the topic. Results: Here, we provide a narrative review on the current state and future trends in endoscopic orbital surgery. Discussion and conclusion: This manuscript is a joint effort of the EANS frontiers committee in orbital tumors and the EANS skull base section.

Epstein Barr virus associated smooth muscle tumors in the central nervous system: a case report and systematic review of the literature.

PURPOSE: Epstein Barr virus (EBV)-associated smooth muscle tumors (SMT) in the central nervous system are rare tumors. EBV-associated SMT mainly occur in patient with compromised immune status. We report on a case of a HIV positive patient, who developed multiple EBV-SMTs, intracranially and in the spine. We systematically review the literature on the topic. CASE REPORT: A 46 years old female with HIV was imaged for complaints of headaches for 2 years, when an intracranial lesion was found. The patient was followed with sequential MRI scans before an excision was performed 5 years later. Pathology revealed an EBV-associated SMT. Multiple other lesions appearing in the brain and in the spine over years were treated by stereotactic radiosurgery or by surgery. At the time of this report, the patient is alive under HARRT treatment without recurrence. METHODS: A systematic PRISMA guided literature research was conducted on the topic reviewing multiple databases for EBV-associated SMT located in brain or spine. We identified 52 patients from the literature and performed a pooled analysis. RESULTS: All patients in this cohort except one were immuno-suppressed from HIV, post-transplant therapy or because of CIS. Female predominance and a median age of 35 years was identified as was frequent multifocality. Therapeutic strategies varied but were mostly multidisciplinary with surgery. CONCLUSION: Based on our results, EBV-associated SMT should be included in the differential diagnosis of intracranial lesions mimicking meningiomas in immuno-suppressed patients. Stereotactic radiosurgery can be offered as an alternate treatment option for suitable lesions. Long-term surveillance via MRI scanning is recommended for follow up.

Relationship between Cough-Associated Changes in CSF Flow and Disease Severity in Chiari I Malformation: An Exploratory Study Using Real-Time MRI.

BACKGROUND AND PURPOSE: Currently no quantitative objective test exists to determine disease severity in a patient with Chiari I malformation. Our aim was to correlate disease severity in symptomatic patients with Chiari I malformation with cough-associated changes in CSF flow as measured with real-time MR imaging. MATERIALS AND METHODS: Thirteen symptomatic patients with Chiari I malformation (tonsillar herniation of ≥5 mm) were prospectively studied. A real-time, flow-sensitized pencil-beam MR imaging scan was used to measure CSF stroke volume during rest and immediately following coughing and relaxation periods (total scan time, 90 seconds). Multiple posterior fossa and craniocervical anatomic measurements were also obtained. Patients were classified into 2 groups by neurosurgeons blinded to MR imaging measurements: 1) nonspecific Chiari I malformation (5/13)-Chiari I malformation with nonspecific symptoms like non-cough-related or mild occasional cough-related headache, neck pain, dizziness, paresthesias, and/or trouble swallowing; 2) specific Chiari I malformation (8/13)-patients with Chiari I malformation with specific symptoms and/or objective findings like severe cough-related headache, myelopathy, syringomyelia, and muscle atrophy. The Spearman correlation was used to determine correlations between MR imaging measurements and disease severity, and both groups were also compared using a Mann-Whitney U test. RESULTS: There was a significant negative correlation between the percentage change in CSF stroke volume (resting to postcoughing) and Chiari I malformation disease severity (R = 0.59; P = .03). Mann-Whitney comparisons showed the percentage change in CSF stroke volume (resting to postcoughing) to be significantly different between patient groups (P = .04). No other CSF flow measurement or anatomic measure was significantly different between the groups. CONCLUSIONS: Our exploratory study suggests that assessment of CSF flow response to a coughing challenge has the potential to become a valuable objective noninvasive test for clinical assessment of disease severity in patients with Chiari I malformation.

Src homology domain-containing phosphatase 2 suppresses cellular senescence in glioblastoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) signalling is frequently altered during glioblastoma de novo pathogenesis. An important downstream modulator of this signal cascade is SHP2 (Src homology domain-containing phosphatase 2). METHODS: We examined the The Cancer Genome Atlas (TCGA) database for SHP2 mutations. We also examined the expression of a further 191 phosphatases in the TCGA database and used principal component and comparative marker analysis available from the Broad Institute to recapitulate the TCGA-defined subgroups and identify the specific phosphatases defining each subgroup. We identified five siRNAs from two independent commercial sources that were reported by the vendor to be pre-optimised in their specificity of SHP2 silencing. The specificity and physiological effects of these siRNAs were tested using an in vitro glioma model. RESULTS: TCGA data demonstrate SHP2 to be mutated in 2% of the glioblastoma multiforme's studied. Both mutations identified in this study are likely to be activating mutations. We found that the four subgroups of GBM as defined by TCGA differ significantly with regard to the expression level of specific phosphatases as revealed by comparative marker analysis. Surprisingly, the four subgroups can be defined solely on the basis of phosphatase expression level by principal component analysis. This result suggests that critical phosphatases are responsible for the modulation of specific molecular pathways within each subgroup. Src homology domain-containing phosphatase 2 constitutes one of the 12 phosphatases that define the classical subgroup. We confirmed the biological significance by siRNA knockdown of SHP2. All five siRNAs tested reduced SHP2 expression by 70-100% and reduced glioblastoma cell line growth by up to 80%. Profiling the established molecular targets of SHP2 (ERK1/2 and STAT3) confirmed specificity of these siRNAs. The loss of cell viability induced by SHP2 silencing could not be explained by a significant increase in apoptosis alone as demonstrated by terminal deoxyribonucleotidyl transferase-mediated nick-end labelling and propidium iodide staining. Src homology domain-containing phosphatase 2 silencing, however, did induce an increase in ß-galactosidase staining. Propidium iodide staining also showed that SHP2 silencing increases the population of glioblastoma cells in the G1 phase of the cell cycle and reduces the population of such cells in the G2/M- and S-phase. CONCLUSION: Src homology domain-containing phosphatase 2 promotes the growth of glioblastoma cells by suppression of cellular senescence, a phenomenon not described previously. Selective inhibitors of SHP2 are commercially available and may be considered as a strategy for glioblastoma therapy.

Phenomenology of hallucinations, illusions, and delusions as part of seizure semiology.

In partial epilepsy, a localized hypersynchronous neuronal discharge evolving into a partial seizure affecting a particular cortical region or cerebral subsystem can give rise to subjective symptoms, which are perceived by the affected person only, that is, ictal hallucinations, illusions, or delusions. When forming the beginning of a symptom sequence leading to impairment of consciousness and/or a classic generalized seizure, these phenomena are referred to as an epileptic aura, but they also occur in isolation. They often manifest in the fully awake state, as part of simple partial seizures, but they also can be associated to different degrees of disturbed consciousness. Initial ictal symptoms often are closely related to the physiological functions of the cortical circuit involved and, therefore, can provide localizing information. When brain regions related to sensory integration are involved, the seizure discharge can cause specific kinds of hallucinations, for example, visual, auditory, gustatory, olfactory, and cutaneous sensory sensations. In addition to these elementary sensory perceptions, quite complex hallucinations related to a partial seizure can arise, for example, perception of visual scenes or hearing music. By involving psychic and emotional spheres of human perception, many seizures also give rise to hallucinatory emotional states (e.g., fear or happiness) or even more complex hallucinations (e.g., visuospatial phenomena), illusions (e.g., déjà vu, out-of-body experience), or delusional beliefs (e.g., identity change) that often are not easily recognized as epileptic. Here we suggest a classification into elementary sensory, complex sensory, and complex integratory seizure symptoms. Epileptic hallucinations, illusions, and delusions shine interesting light on the physiology and functional anatomy of brain regions involved and their functions in the human being. This article, in which 10 cases are described, introduces the fascinating phenomenology of subjective seizure symptoms.

Survival and transmitter expression of rat cholinergic medial septal neurons despite removal of hippocampus in the early postnatal period.

It has been shown that target-derived neurotrophins are not necessary for the survival of septohippocampal cholinergic neurons in adult rats. In this study, we have removed the hippocampus in early postnatal rats by unilateral excitotoxic N-methyl-D-aspartate lesions at postnatal days 5, 10 and 20. At postnatal day 70, numerous cholinergic neurons (60% of controls) were present in the medial septum on the lesioned side. This suggests that there is only a limited influence of target-derived neurotrophic factors to these cells also in development.

Pyramidal neurons in layer 5 of the rat visual cortex. I. Correlation among cell morphology, intrinsic electrophysiological properties, and axon targets.

Previous work has established two structure/function correlations for pyramidal neurons of layer 5 of the primary visual cortex of the rat. First, cells projecting to the superior colliculus have thick apical dendrites with a florid terminal arborization in layer 1, whereas those projecting to the visual cortex of the opposite hemisphere have thinner apical dendrites that terminate below layer 1, without a terminal tuft (e.g., Hallman et al.: J Comp Neurol 272:149, '90). Second, intracellular recording combined with dye injection has revealed two classes of cells: the first has a thick, tufted apical dendrite and fires a distinctive initial burst of two or more impulses, of virtually fixed, short interspike interval, in response to current injection; and the other, with a slender apical dendrite lacking a terminal tuft, tends to have a longer membrane time constant and higher input resistance, and does not fire characteristic bursts (e.g., Larkman and Mason: J Neurosci 10:1407, '90). The present study combined intracellular recording in isolated slices of rat visual cortex and injection of carboxyfluorescein, to reveal soma-dendritic morphology, with prior injection of rhodamine-conjugated microspheres into the superior colliculus or contralateral visual cortex to label neurons according to the target of their axons. This permitted a complete correlation of morphology, intrinsic electrophysiological properties, and identity of the projection target for individual pyramidal cells. Neurons retrogradely labeled from the opposite visual cortex were found in all layers except layer 1 while those labeled from the superior colliculus lay exclusively in layer 5. Within layer 5 interhemispheric cells were more concentrated in the lower half of the layer but extensively overlapped the distribution of corticotectal cells. Every cell studied that projected to the superior colliculus was of the bursting type and had a thick apical dendrite with a terminal tuft. Every cell in this study projecting to the opposite visual cortex was a "nonburster" and had a slender apical dendrite with fewer oblique branches that ended without a terminal tuft, usually in the upper part of layer 2/3. Interhemispheric cells also had rounder, less conical somata and generally had fewer basal dendrites than corticotectal neurons. Many cells with the physiological and morphological characteristics of interhemispheric cells were not back-labeled from the opposite visual cortex, implying that pyramidal cells of this type can have other projection targets (e.g., other cortical sites in the ipsilateral hemisphere).(ABSTRACT TRUNCATED AT 400 WORDS)

Pyramidal neurons in layer 5 of the rat visual cortex. II. Development of electrophysiological properties.

Two major classes of pyramidal neurons can be distinguished in layer 5 of the adult rat visual cortex. Cells of the "thick/tufted" type have stout apical dendrites with terminal tufts, and most of them project to the superior colliculus (Larkman and Mason: J Neurosci 10:407, '90; Kasper et al.: J Comp Neurol, this issue, 339:459-474). "Slender/untufted" cells have thinner apical trunks with no obvious terminal tufts, and a substantial proportion of them project to the contralateral visual cortex. These two types also differ in their intrinsic electrophysiological features. In this study we describe the postnatal maturation of the electrophysiological and synaptic properties of layer 5 pyramidal neurons and relate these findings to the morphological development and divergence of the two cell types. Living slices were prepared from the visual cortex of rats aged between postnatal day 3 (P3) and young adults and maintained in vitro. Stable intracellular impalements were obtained from a total of 63 pyramidal cells of layer 5 at various ages, which were injected with biocytin so that morphological and electrophysiological data could be obtained from the same cell. Before P15, injection of a single cell sometimes stained a cluster of neurons of similar morphology, probably as a result of dye coupling. The incidence of such clustering and the number of neurons within each cluster decreased with age. There was no obvious difference in electrophysiological properties between cells in clusters and age-matched, noncoupled neurons. From P5, the apical dendrites of neurons could easily be classified as "thick/tufted" or "slender/untufted." On average, the resting potential became more negative, and membrane time constant and input resistance decreased with age. Electrophysiological differences between the "thick/tufted" and "slender/untufted" cell types did not become apparent until the third postnatal week, after which the "thick/tufted" cells on average had lower input resistances and slightly faster time constants than "slender/untufted" cells. The current-voltage relations of the neurons became progressively more nonlinear during maturation, with both rapid inward rectification and time-dependent rectification or "sag" becoming more prominent. There were also changes in the amplitude and waveform of action potentials, which generally approached adult values by 3 weeks of age. Action potential threshold became more negative, both in absolute terms and relative to the resting membrane potential. Action potentials became larger in peak amplitude and of shorter duration, with both rise and fall times decreasing progressively during development.(ABSTRACT TRUNCATED AT 400 WORDS)

Pyramidal neurons in layer 5 of the rat visual cortex. III. Differential maturation of axon targeting, dendritic morphology, and electrophysiological properties.

This paper describes the early morphological and physiological development of pyramidal neurons in layer 5 of the rat visual cortex in relation to the targets chosen by their axons. Cells were prelabeled by retrograde transport from the superior colliculus or the contralateral visual cortex and intracellularly injected either in fixed slices or after recording in living slices. In the adult, corticotectal cells have thick apical dendrites with an extensive terminal arborization extending into layer 1, and fire characteristic bursts of action potentials when injected with a depolarizing current; interhemispheric cells have slender apical dendrites that terminate without a terminal tuft, usually in layer 2/3, and they display a more regular firing pattern (Kasper et al.: J Comp Neurol, this issue, 339:459-474). At embryonic day E18 (when axons of the two classes of cells are already taking different routes towards their targets) and E21, pyramidal-like cells throughout the cortical plate all have similar soma-dendritic morphology, with spindle-shaped cell bodies and few, short basal dendrites but apical dendrites that all end in distinct tufts in the marginal zone. At postnatal day P3, after the axons of both cell classes have reached their targets, all pyramidal neurons in layer 5 still have distinct terminal arborizations in layer 1, though they vary in complexity and extent. The somata are now more mature (round to ovoid in shape), and the basal dendritic tree has extended. As early as P5, all cells studied could be clearly classified as tufted or untufted (considerably earlier than previously reported; Koester and O'Leary: J Neurosci 12:1382, '92), and these features correlated precisely with the projection target, as in the adult. Measurement showed that although interhemispheric cells lose their terminal tufts, in general the trunks of their apical dendrites do not withdraw but continue to grow, at roughly the same rate as those of corticotectal cells. The two classes of layer 5 pyramidal neurons differentiate from each other in three distinct phases: pathway selection by axons precedes the loss of the apical tuft by interhemispheric cells, and these morphological characteristics are established 10 days before the onset of burst-firing in corticotectal cells. These three steps may be guided by different molecular signals.