Non-syndromic single-suture craniosynostosis in triplets.

INTRODUCTION: Craniosynostosis is the premature fusion of one or more cranial sutures. The cause of non-syndromic craniosynostosis has been attributed to a complex interaction among genetic, epigenetic, and environmental factors. Increased concordance rates in monozygotic twins support a genetic etiology while a concordance rate less than 100% suggests environmental and/or epigenetic influences. Here, we describe the first reported occurrence of all three children in a triplet set with non-syndromic single-suture craniosynostosis. CASE REPORT: The dichorionic triamniotic triplets were the product of a non-consanguineous marriage delivered at 35 weeks' gestation by a 38-year-old mother and consisted of a monochorionic-diamniotic pair (A and B) and a fraternal triplet (C). Three-dimensional computed tomography scans confirmed sagittal synostosis in A and B and metopic synostosis in C. All patients underwent endoscopic strip craniectomy and were discharged on the second postoperative day with helmet orthoses. Comparative genetic hybridization (CGH) and whole-exome sequencing (WES) failed to identify pathogenic copy number variants or gene mutations, respectively. DISCUSSION AND CONCLUSION: The results of the genetic testing suggest the possibility of a rare variant contributing to the risk of midline craniosynostosis shared among the triplets, with potential modifiers at other genetic loci affecting the phenotype. We speculate mutations at loci within non-coding regions not captured by our genetic analysis may have been involved. Moreover, epigenetic factors as well as environmental factors including, but not limited to, in utero head constraint could have contributed to the observed phenotype.

Atypical Presentation of a Pediatric Cerebellar Ganglioglioma.

BACKGROUND/AIMS: Gangliogliomas (GGs) are rare central nervous system tumors occurring primarily in the supratentorial compartment with infratentorial instances most often involving the brain stem. Infratentorial GGs typically present with signs and symptoms of increased intracranial pressure (ICP), cranial nerve deficits, or focal cerebellar findings; rarely, these tumors have been associated with focal seizures. METHODS: In this report, we describe an atypical presentation of a cerebellar GG in a 20-month-old male who initially presented with syncope and emesis in the absence of electrographic evidence of seizures, radiographic evidence of hydrocephalus, or elevated ICP. The epidemiology, radiographic, and pathological findings as well as the treatment of these tumors are also discussed. RESULTS: After gross total resection, the patient experienced full resolution of all his preoperative symptoms without the development of new neurological deficits. CONCLUSIONS: Unlike their supratentorial counterparts, infratentorial GGs do not commonly present with seizures although rare reports exist in the literature of seizures attributed to cerebellar GG. Moreover, cerebellar GGs may produce nonspecific symptoms in the absence of concrete diagnostic findings. Such a presentation should prompt further neurological evaluation. Most cases of isolated cerebellar GG can be successfully treated with surgical resection and carry a favorable prognosis.

Pediatric Traumatic Brain Injury Outcomes and Disparities During the COVID-19 Pandemic.

BACKGROUND: To study the impact of the COVID-19 pandemic on traumatic brain injury (TBI) patient demographic, clinical and trauma related characteristics, and outcomes. METHODS: Retrospective chart review was conducted on pediatric TBI patients admitted to a Level I Pediatric Trauma Center between January 2015 and June 2022. The pre-COVID era was defined as January 1, 2015, through March 12, 2020. The COVID-19 era was defined as March 13, 2020, through June 30, 2022. Bivariate analysis and logistic regression were performed. RESULTS: Four hundred-thirty patients were treated for pediatric TBI in the pre-COVID-19 period, and 166 patients during COVID-19. In bivariate analyses, the racial/ethnic makeup, age, and sex varied significantly across the two time periods (p < 0.05). Unwitnessed TBI events increased during the COVID-19 era. Logistic regression analyses also demonstrated significantly increased odds of death, severe disability, or vegetative state during COVID-19 (AOR 7.23; 95 % CI 1.43, 36.41). CONCLUSION: During the COVID-19 pandemic, patients admitted with pediatric TBI had significantly different demographics with regards to age, sex, and race/ethnicity when compared to patients prior to the pandemic. There was an increase in unwitnessed events. In the COVID period, patients had a higher odds ratio of severe morbidity and mortality despite adjustment for confounding factors. LEVEL OF EVIDENCE AND STUDY TYPE: Level II, Prognosis.

Early CT physics research at Massachusetts General Hospital.

Although CT imaging was introduced at Massachusetts General Hospital (MGH) quite early, with its first CT scanner installed in 1973, CT research at MGH started years earlier. The goal of this paper is to describe some of this innovative work and related accomplishments.

Traumatic carotid artery injury caused by a metal sipping straw in a pediatric patient: Anesthetic management and considerations.

CNS injury following a traumatic intraoral injury is a rare but potentially catastrophic occurrence in pediatrics. For example, intraoral trauma resulting in acute ischemic stroke (AIS) secondary to carotid artery dissection has only been described by a limited number of case reports [1]. We report the case of a 4-year-old boy who suffered a penetrating right internal carotid injury after a fall resulting in a metal straw perforating the neck and oropharynx. The patient presented in hemorrhagic shock with altered consciousness. CT Angiography revealed a right internal carotid traumatic rupture with flow occlusion and right cerebral hemispheric hypoperfusion. The patient underwent emergent neuroradiologic intervention under general anesthesia with successful reconstruction of the right carotid artery through the use of five flow diverting pipeline stents. The patient was extubated one week later with the only neurologic sequala being slight left upper extremity weakness. Anesthetic management played a vital part in this outstanding outcome. Thoughtful management is required to ensure both survival and the best possible neurologic recovery. Despite the rarity of these events, there is sufficient evidence from similar interventions and neurophysiology to guide sound management. This case report highlights these principles and areas for further investigation. Our experience may be instructive in the support of safe care under similarly rare but challenging circumstances.

Early time points perfusion imaging: theoretical analysis of correction factors for relative cerebral blood flow estimation given local arterial input function.

If local arterial input function (AIF) could be identified, we present a theoretical approach to generate a correction factor based on local AIF for the estimation of relative cerebral blood flow (rCBF) under the framework of early time points perfusion imaging (ET). If C(t), the contrast agent bolus concentration signal time course, is used for rCBF estimation in ET, the correction factor for C(t) is the integral of its local AIF. The recipe to apply the correction factor is to divide C(t) by the integral of its local AIF to obtain the correct rCBF. By similar analysis, the correction factor for the maximum derivative (MD1) of C(t) is the maximum signal of AIF and the correction factor for the maximum second derivative (MD2) of C(t) is the maximum derivative of AIF. In the specific case of using normalized gamma-variate function as a model for AIF, the correction factor for C(t) (but not for MD1) at the time to reach the maximum derivative is relatively insensitive to the shape of the local AIF.

Early time points perfusion imaging: relative time of arrival, maximum derivatives and fractional derivatives.

Time of arrival (TOA) of a bolus of contrast agent to the tissue voxel is a reference time point critical for the Early Time Points Perfusion Imaging Method (ET) to make relative cerebral blood flow (rCBF) maps. Due to the low contrast to noise (CNR) condition at TOA, other useful reference time points known as relative time of arrival data points (rTOA) are investigated. Candidate rTOA's include the time to reach the maximum derivative, the maximum second derivative, and the maximum fractional derivative. Each rTOA retains the same relative time distance from TOA for all tissue flow levels provided that ET's basic assumption is met, namely, no contrast agent has a chance to leave the tissue before the time of rTOA. The ET's framework insures that rCBF estimates by different orders of the derivative are theoretically equivalent to each other and monkey perfusion imaging results supported the theory. In rCBF estimation, maximum values of higher order fractional derivatives may be used to replace the maximum derivative which runs a higher risk of violating ET's assumption. Using the maximum values of the derivative of orders ranging from 1 to 1.5 to 2, estimated rCBF results were found to demonstrate a gray-white matter ratio of approximately 3, a number consistent with flow ratio reported in the literature.

Early time points perfusion imaging.

The aim was to investigate the feasibility of making relative cerebral blood flow (rCBF) maps from MR images acquired with short TR by measuring the initial arrival amount of Gd-DTPA evaluated within a time window before any contrast agent has a chance to leave the tissue. We named this rCBF measurement technique utilizing the early data points of the Gd-DTPA bolus the "early time points" method (ET), based on the hypothesis that early time point signals were proportional to rCBF. Simulation data were used successfully to examine the ideal behavior of ET while monkey's MRI results offered encouraging support to the utility of ET for rCBF calculation. A better brain coverage for ET could be obtained by applying the Simultaneous Echo Refocusing (SER) EPI technique. A recipe to run ET was presented, with attention paid to the noise problem around the time of arrival (TOA) of the contrast agent.

Colloid cyst curtailed: A case report of spontaneous colloid cyst regression.

BACKGROUND: Colloid cysts arise from the roof of the third ventricle and are at risk for obstructing the flow of cerebrospinal fluid (CSF) and causing increased intracranial pressure. With advancements and increased frequency of imaging, colloid cysts are sometimes discovered incidentally. In these cases, the neurosurgeon is faced with the decision of whether to intervene or manage conservatively. CASE DESCRIPTION: A 67-year-old man was discovered to have a colloid cyst when imaging was performed for transient neurologic deficits. CT and MRI brain revealed a 5mm lesion in the third ventricle with characteristics suggestive of the colloid cyst. Except for his initial presentation, the patient did not exhibit any symptoms and was followed with serial imaging. Four years after discovery, the colloid cyst regressed in size. CONCLUSION: The evolution and resolution of colloid cysts remain elusive; however, the discovery of incidental colloid cysts due to more frequent and more advanced neuroimaging emphasize the importance of this topic. The fear of conservative management is acute decompensation due to obstruction of CSF. However, surgical risks may be avoided if these asymptomatic lesions regress and resolve without intervention. Conservative management is a viable option for patients with colloid cysts, who may not only avoid surgery but who might also rarely experience cyst resolution.

Dynamics of subdural hygroma following decompressive craniectomy: a comparative study.

OBJECT: This retrospective comparative cohort study was aimed at discovering the risk factors associated with subdural hygroma (SDG) following decompressive craniectomy (DC) to relieve intracranial hypertension in severe head injury. METHODS: Sixty-eight of 104 patients who had undergone DC during a 48-month period and survived > 30 days were eligible for this study. To assess the dynamics of subdural fluid collections, the authors compared CT scanning data from and the characteristics of 39 patients who had SDGs with the data in 29 patients who did not have hygromas. Variables significant in the appearance, evolution, and resolution of this complication were analyzed in a 36-week longitudinal study. RESULTS: The earliest imaging evidence of SDG was seen during the 1st week after DC. The SDG volume peaked between Weeks 3 and 4 post-DC and was gradually resolved by the 17th week. Among the mechanisms of injury, motor vehicle accidents were most often linked to the development of an SDG after DC (p < 0.0007), and falls were least often associated (p < 0.005). Moreover, patients with diffuse brain injury were more prone to this complication (p < 0.0299) than those with an evacuated mass (p < 0.0001). There were no statistically significant differences between patients with and without hygromas in terms of age, sex, Glasgow Coma Scale score, intraventricular and subarachnoid hemorrhage, levels of intracranial pressure and cerebral perfusion pressure, timing of decompression, and the need for CSF diversion. More than 90% of the SDGs were ipsilateral to the side of the craniectomy, and 3 (8%) of 39 SDGs showed evidence of internal bleeding at approximately 8 weeks postinjury. Surgical evacuation was needed in 4 patients with SDGs. CONCLUSIONS: High dynamic accidents and patients with diffuse injury were more prone to SDGs. Close to 8% of SDGs converted themselves into subdural hematomas at approximately 2 months postinjury. Although SDGs developed in 39 (approximately 60%) of 68 post-DC patients, surgical evacuation was needed in only 4.

A review and comparison of three neuronavigation systems for minimally invasive intracerebral hemorrhage evacuation.

Advances in stereotactic navigation technology have helped to improve the ease, reliability, and workflow of neurosurgical intraoperative navigation. These advances have also allowed novel, minimally invasive neurosurgical techniques to emerge. Minimally invasive techniques for intracerebral hemorrhage (ICH) evacuation, including endoscopic evacuation and passive catheter drainage, are notable examples, and as these gain support in the literature and their use expands, stereotactic navigation will take on an increasingly important and central role. Each neurosurgical navigation system has unique characteristics. Operators may find that certain aspects are more important than others, depending on the environment in which the evacuation is performed and operator preferences. This review will describe the characteristics of three popular stereotactic neuronavigation systems and compare their advantages and disadvantages as they relate to minimally invasive ICH evacuation.

The role of IFN-gamma in immune responses to viral infections of the central nervous system.

Interferon (IFN)-gamma, is not only a marker of T(H)1 CD4, CD8 and natural killer (NK) cells, it is also a critical antiviral mediator which is central to the elimination of viruses from the CNS. In this review, we describe IFN-gamma, its receptor, signal transduction from receptor engagement, and antiviral downstream mediators. We demonstrate that although neurons are post-mitotic and non-renewing, they respond to IFN-gamma in a fashion similar to peripheral fibroblasts or lymphocytes. We have illustrated this review with details about studies on the role(s) of IFN-gamma in the pathogenesis of measles virus (MV), herpes simplex virus (HSV) type 1, and vesicular stomatitis virus (VSV) infections of the CNS. For VSV infection, IFN-gamma signals through Jaks 1 and 2 and STAT1 to activate (interferon regulatory factor) IRF-1; although viral protein synthesis is inhibited, PKR is not a critical mediator in the antiviral response to VSV in murine neurons. In contrast, induction of nitric oxide synthase (NOS) type 1 and its production of nitric oxide is essential in the elimination of viruses from neurons.

A limit on dose reduction possible with CT reconstruction algorithms without prior knowledge of the scan subject.

PURPOSE: To find an upper bound on the maximum dose reduction possible for any reconstruction algorithm, analytic or iterative, that result from the inclusion of the data statistics. The authors do not analyze noise reduction possible from prior knowledge or assumptions about the object. METHODS: The authors examined the task of estimating the density of a circular lesion in a cross section. Raw data were simulated by forward projection of existing images and numerical phantoms. To assess an upper bound on the achievable dose reduction by any algorithm, the authors assume that both the background and the shape of the lesion are completely known. Under these conditions, the best possible estimate of the density can be determined by solving a weighted least squares problem directly in the raw data domain. Any possible reconstruction algorithm that does not use prior knowledge or make assumptions about the object, including filtered backprojection (FBP) or iterative reconstruction methods with this constraint, must be no better than this least squares solution. The authors simulated 10,000 sets of noisy data and compared the variance in density from the least squares solution with those from FBP. Density was estimated from FBP images using either averaging within a ROI, or streak-adaptive averaging with better noise performance. RESULTS: The bound on the possible dose reduction depends on the degree to which the observer can read through the possibly streaky noise. For the described low contrast detection task with the signal shape and background known exactly, the average dose reduction possible compared to FBP with streak-adaptive averaging was 42% and it was 64% if only the ROI average is used with FBP. The exact amount of dose reduction also depends on the background anatomy, with statistically inhomogeneous backgrounds showing greater benefits. CONCLUSIONS: The dose reductions from new, statistical reconstruction methods can be bounded. Larger dose reductions in the density estimation task studied here are only possible with the introduction of prior knowledge, which can introduce bias.

Chondromyxoid fibroma invasion of the transverse-sigmoid sinus junction causing posterior fossa hemorrhage.

We report a 50-year-old woman with a chondromyxoid fibroma of the occipital bone, who presented with a cerebellar hemorrhage due to invasion of the adjacent sinus. Chondromyxoid fibromas are benign cartilaginous tumors. However, this case represents the first example, to our knowledge, of a chondromyxoid fibroma invading the transverse-sigmoid junction, resulting in intracranial hemorrhage. Our report highlights that the location of an intracranial chondromyxoid fibroma is an important factor in guiding surgical management.

Initial multicenter technical experience with the Apollo device for minimally invasive intracerebral hematoma evacuation.

BACKGROUND: No conventional surgical intervention has been shown to improve outcomes for patients with spontaneous intracerebral hemorrhage (ICH) compared with medical management. OBJECTIVE: We report the initial multicenter experience with a novel technique for the minimally invasive evacuation of ICH using the Penumbra Apollo system (Penumbra Inc, Alameda, California). METHODS: Institutional databases were queried to perform a retrospective analysis of all patients who underwent ICH evacuation with the Apollo system from May 2014 to September 2014 at 4 centers (Medical University of South Carolina, Stony Brook University, University of California at San Diego, and Semmes-Murphy Clinic). Cases were performed either in the neurointerventional suite, operating room, or in a hybrid operating room/angiography suite. RESULTS: Twenty-nine patients (15 female; mean age, 62 ± 12.6 years) underwent the minimally invasive evacuation of ICH. Six of these parenchymal hemorrhages had an additional intraventricular hemorrhage component. The mean volume of ICH was 45.4 ± 30.8 mL, which decreased to 21.8 ± 23.6 mL after evacuation (mean, 54.1 ± 39.1% reduction; P < .001). Two complications directly attributed to the evacuation attempt were encountered (6.9%). The mortality rate was 13.8% (n = 4). CONCLUSION: Minimally invasive evacuation of ICH and intraventricular hemorrhage can be achieved with the Apollo system. Future work will be required to determine which subset of patients are most likely to benefit from this promising technology.

Posttranscriptional regulation of neuronal nitric oxide synthase expression by IFN-gamma.

In this report, the mechanism through which interferon-gamma (IFN-gamma) regulates the expression of nitric oxide synthase (NOS-1) in neurons was examined. We have shown previously that IFN-gamma treatment of cells results in a two log inhibition of vesicular stomatitis virus (VSV) production. This inhibition of VSV replication is dependent both in vitro and in vivo on nitric oxide (NO) production by NOS-1. Furthermore, this effect is associated with the increased expression and activity of NOS-1 following IFN-gamma treatment. In vitro, exposure to IFN-gamma prior to infection with VSV is a prerequisite to establish an effective antiviral state, indicating the necessity for a priming event. Neuroblastoma cells (NB41A3) were treated with IFN-gamma or medium and examined for changes in NOS-1 protein and mRNA expression. NOS-1 protein expression was found to be increased after IFN-gamma treatment, and this was associated with increases in both neosynthesis and NOS-1 protein stability. NOS-1 transcription and mRNA levels were unaffected by IFN-gamma treatment. These data demonstrate that IFN-gamma regulates NOS-1 expression through posttranscriptional and posttranslational mechanisms.

IL-12, while beneficial, is not essential for the host response to VSV encephalitis.

In this report, the role of STAT4 and local production of interleukin (IL)-12 in the central nervous system (CNS) were examined during experimental vesicular stomatitis virus (VSV) encephalitis. We have previously shown that IL-12 treatment is beneficial both in vitro and in vivo during experimental VSV infection. This inhibition of VSV replication was dependent on the production of nitric oxide (NO) by the neuronal isoform of nitric oxide synthase (NOS-1). In vitro, IL-12 induces the phosphorylation and nuclear localization of STAT4 in neuroblastoma cell lines. STAT4 expression was not required for host survival or clearance of virus during experimental VSV encephalitis. Taken together, these data suggest that while neurons can respond directly to IL-12 in vitro by signaling through STAT4, STAT4 is not required for survival. It is likely that redundant innate host inflammatory cytokine responses compensate for the absence of IL-12 signaling.

PKR is not required for interferon-gamma inhibition of VSV replication in neurons.

In this report, the contribution of PKR to the IFN-gamma mediated inhibition of VSV replication in neurons was examined. IFN-gamma treatment of NB41A3 murine neuroblastoma cells resulted in the reduced expression of VSV protein during infection. PKR was found to be modestly upregulated in NB41A3 cells following IFN-gamma treatment. The phosphorylation state of PKR and its downstream target, eIF2alpha, were unaffected by either IFN-gamma or VSV infection. Inhibition of PKR through the use of 2-aminopurine or the expression of the Influenza A NS1 gene had no effect on the ability of IFN-gamma to inhibit the replication of VSV in vitro. These data indicate that endogenously expressed PKR is not required for the IFN-gamma mediated inhibition of VSV replication in NB41A3 neuroblastoma cells.

Mesenchymal stem cells from human fat engineered to secrete BMP4 are nononcogenic, suppress brain cancer, and prolong survival.

PURPOSE: Glioblastoma is the most common adult primary malignant intracranial cancer. It is associated with poor outcomes because of its invasiveness and resistance to multimodal therapies. Human adipose-derived mesenchymal stem cells (hAMSC) are a potential treatment because of their tumor tropism, ease of isolation, and ability to be engineered. In addition, bone morphogenetic protein 4 (BMP4) has tumor-suppressive effects on glioblastoma and glioblastoma brain tumor-initiating cells (BTIC), but is difficult to deliver to brain tumors. We sought to engineer BMP4-secreting hAMSCs (hAMSCs-BMP4) and evaluate their therapeutic potential on glioblastoma. EXPERIMENTAL DESIGN: The reciprocal effects of hAMSCs on primary human BTIC proliferation, differentiation, and migration were evaluated in vitro. The safety of hAMSC use was evaluated in vivo by intracranial coinjections of hAMSCs and BTICs in nude mice. The therapeutic effects of hAMSCs and hAMSCs-BMP4 on the proliferation and migration of glioblastoma cells as well as the differentiation of BTICs, and survival of glioblastoma-bearing mice were evaluated by intracardiac injection of these cells into an in vivo intracranial glioblastoma murine model. RESULTS: hAMSCs-BMP4 targeted both the glioblastoma tumor bulk and migratory glioblastoma cells, as well as induced differentiation of BTICs, decreased proliferation, and reduced the migratory capacity of glioblastomas in vitro and in vivo. In addition, hAMSCs-BMP4 significantly prolonged survival in a murine model of glioblastoma. We also demonstrate that the use of hAMSCs in vivo is safe. CONCLUSIONS: Both unmodified and engineered hAMSCs are nononcogenic and effective against glioblastoma, and hAMSCs-BMP4 are a promising cell-based treatment option for glioblastoma.

Harvey Cushing's early management of hydrocephalus: an historical picture of the conundrum of hydrocephalus until modern shunts after WWII.

PURPOSE: Throughout his early career, Cushing proposed a variety of methods for temporary and permanent drainage and diversion of CSF in his patients, and acknowledged that certain techniques were more suited to particular subsets of hydrocephalus. METHODS: Following IRB approval, and through the courtesy of the Alan Mason Chesney Archives, the surgical records of the Johns Hopkins Hospital, from 1896 to 1912, were reviewed. Patients operated upon by Harvey Cushing were selected for further analysis. Within this cohort, we recovered all available records for a single patient with hydrocephalus and spina bifida, who was treated with a ventriculosubgaleal shunt prior to repair of the spina bifida. RESULTS: A 3 month-old infant presented with hydrocephalus associated with spina bifida. Cushing performed serial lumbar and ventricular punctures. Following this, Cushing took the patient to the operating room for placement of a ventriculosubgaleal shunt. The patient subsequently underwent excision of the myelomeningocele sac, with post-operative mortality due to unspecified causes. CONCLUSIONS: Cushing's publications document a preference for translumbar-peritoneal drainage in patients with congenital hydrocephalus, particularly those with spina bifida. Although the placement of ventriculosubgaleal shunts has become an accepted practice for contemporary neurosurgeons, this case illustrates the challenges that early neurosurgeons faced in developing operative approaches for the treatment of congenital hydrocephalus.