Michael J. Moravan

Treatment of CNS sarcoidosis with infliximab and mycophenolate mofetil.

Objective: To describe the effects of the anti–tumor necrosis factor neutralizing antibody, infliximab, and the antiproliferative immunosuppressant, mycophenolate mofetil, in refractory neurosarcoidosis. Methods: We treated patients with biopsy-proven sarcoidosis and CNS involvement, who had failed treatment with steroids, with infliximab (5 mg/kg on weeks 0, 2, and 6, and then every 6–8 weeks thereafter). Six out of seven patients were co-treated with mycophenolate mofetil (1,000 mg PO BID). Patients underwent a review of symptoms and complete neurologic examination every 3 months and MRI scanning before and after 3–4 infusions of infliximab. Results: All patients reported significant symptomatic improvement by the fourth infusion of infliximab, including relief of headache and neuropathic pain, reversal of motor, sensory, or coordination deficits, and control of seizure activity. Furthermore, infliximab therapy was universally associated with a decrease in lesion size or suppression of gadolinium enhancement as documented by MRI. A positive treatment response was attained irrespective of location or distribution of CNS involvement by sarcoidosis (dural/leptomeningeal based vs intraparenchymal; cord vs brain; single lesion vs multifocal). There were no serious adverse effects in a follow-up period spanning 6–18 months. Conclusions: Combination treatment with mycophenolate mofetil and infliximab is a promising therapeutic approach for neurosarcoidosis. A = azathioprine; AA = African American; Cy = cyclophosphamide; E = etanercept; EDSS = Expanded Disability Status Scale; MMF = mycophenolate mofetil; MMSE = Mini-Mental State Examination; N = neurologic; O = ophthalmologic; P = pulmonary; Pq = Plaquenil; R = rheumatologic; Si = sinuses; S = steroids; TNF = tumor necrosis factor; VPS = ventriculoperitoneal shunt; W = white.

Cranial Irradiation Leads to Acute and Persistent Neuroinflammation with Delayed Increases in T-Cell Infiltration and CD11c Expression in C57BL/6 Mouse Brain

Radiotherapy is commonly employed to treat cancers of the head and neck and is increasingly used to treat other central nervous system (CNS) disorders. Exceeding the radiation tolerance of normal CNS tissues can result in sequelae contributing to patient morbidity and mortality. Animal studies and clinical experience suggest that neuroinflammation plays a role in the etiology of these effects; however, detailed characterization of this response has been lacking. Therefore, a dose–time investigation of the neuroinflammatory response after single-dose cranial irradiation was performed using C57BL/6 mice. Consistent with previous reports, cranial irradiation resulted in multiphasic inflammatory changes exemplified by increased transcript levels of inflammatory cytokines, along with glial and endothelial cell activation. Cranial irradiation also resulted in acute infiltration of neutrophils and a delayed increase in T cells, MHC II-positive cells, and CD11c-positive cells seen first at 1 month with doses ≥15 Gy. CD11c-positive cells were found almost exclusively in white matter and expressed MHC II, suggesting a “mature” dendritic cell phenotype that remained elevated out to 1 year postirradiation. Our results indicate that cranial irradiation leads to persistent neuroinflammatory changes in the C57BL/6 mouse brain that includes unique immunomodulatory cell populations.

Adult murine hippocampal neurogenesis is inhibited by sustained IL-1β and not rescued by voluntary running

Acute neuroinflammation reduces adult hippocampal neurogenesis but the role of chronic neuroinflammation, which may be more representative of ongoing processes in CNS disorders, remains relatively unknown. Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that has been shown to acutely impair neurogenesis. To further investigate the relationship between sustained IL-1β expression and adult neurogenesis, a mouse model with an IL-1β excisionally activated transgene, IL-1β(XAT), was utilized. Upon exposure to Cre recombinase, IL-1β overexpression in this model results in chronic neuroinflammation, which persists up to 12 months and causes glial activation, cellular recruitment, and deficits in learning and memory. We hypothesized that adult neurogenesis would be reduced by sustained hippocampal IL-1β overexpression and rescued by voluntary running, which has been shown to enhance neurogenesis. Hippocampal inflammation in the IL-1β(XAT) model severely impaired doublecortin (DCX) positive cells at 1 and 3 months after IL-1β induction. Furthermore, BrdU labeling demonstrated a shift in cell lineage from neuronal to astroglial in the context of sustained hippocampal IL-1β overexpression. Deletion of the IL-1 receptor prevented the decrease in DCX(+) cells. Voluntary running did not attenuate the effects of IL-1β expression demonstrated by DCX staining. These results suggest that chronic neuroinflammation severely impairs adult hippocampal neurogenesis and voluntary running is not beneficial as a therapy to rescue these effects.

Chemisorptions of bacterial receptors for hydrophobic amino acids and sugars on gold for biosensor applications: a surface plasmon resonance study of genetically engineered proteins

This paper demonstrates potential applications of two periplasmic receptor proteins from E. coli as sensing elements for biosensors using the surface plasmon resonance (SPR) technique. These molecules, namely the aspartate to cysteine mutant of the leucine-specific receptor (LS-D1C) and the glutamine to cysteine mutant of the D-glucose/D-galactose receptor (GGR-Q26C) proteins, are chemisorbed on a thin (approximately 40 nm) Au film in neutral K2HPO4 buffers. Using angle and time resolved SPR measurements; we show that adsorption behaviors of both proteins are dominated by diffusion-free second order Langmuir kinetics. We also show that the protein-modified Au films exhibit measurable SPR shifts upon binding to their respective target ligands. According to these SPR data, the kinetics of ligand binding for both LS-D1C and GGR-Q26C are governed by irreversible first order diffusion limited Langmuir model. The utility of the SPR technique for studying reactions of biological molecules is further illustrated in this work.

Delayed sub-aponeurotic fluid collections in infancy: Three cases and a review of the literature

Background: Sub-aponeurotic fluid collections (SFCs) in the neonatal period are poorly described in the literature. We describe the occurrence, possible etiologies and treatment of sub-aponeurotic fluid collections following the neonatal period. Case Description: We present 3 cases of previously healthy children who developed soft, fluctuant, extracranial masses several weeks after birth. All 3 children were seen by a pediatric neurosurgeon after parents noticed scalp masses between 5 and 9 weeks of age. All 3 children were found to be otherwise healthy. Two of the children were born via C-section and 1 child was born vaginally. The vaginal delivery was described as difficult and utilized vacuum assist. Scalp electrodes were placed in all 3 children for intensive monitoring during labor. These children received plain skull x-rays to assess for abnormalities, and 2 of the children underwent a non-contrast brain CT scan to better characterize the fluid collection. Plain x-rays and CT scans showed no abnormalities of the skull or ventricles. In both patients who underwent a CT scan, a soft tissue prominence was noted with a Hounsfield unit similar to water. All cases resolved between 5 and 9 weeks after initial presentation, with no long-term sequelae. Conclusion: SFCs presenting after the neonatal period are usually associated with benign soft tissue swellings. Use of fetal scalp electrodes has been shown to cause cerebrospinal fluid (CSF) leakage in the neonatal period and may result in delayed SFC. This condition is benign, and the recommended course of treatment is conservative management.

Unilateral subfrontal approach to anterior communicating artery aneurysms: A review of 28 patients.

Background: The pterional approach is the most common for AComm aneurysms, but we present a unilateral approach to a midline region for addressing the AComm complex. The pure subfrontal approach eliminates the lateral anatomic dissection requirements without sacrificing exposure. The subfrontal approach is not favored in the US compared to Asia and Europe. We describe our experience with the subfrontal approach for AComm aneurysms treated at a single institution.Background: The pterional approach is the most common for AComm aneurysms, but we present a unilateral approach to a midline region for addressing the AComm complex. The pure subfrontal approach eliminates the lateral anatomic dissection requirements without sacrificing exposure. The subfrontal approach is not favored in the US compared to Asia and Europe. We describe our experience with the subfrontal approach for AComm aneurysms treated at a single institution. Methods: We identified 28 patients treated for AComm aneurysms through the subfrontal approach. Patient records and imaging studies were reviewed. Demographics and case data, as well as clinical outcome at 6 weeks and 1 year were collected. Results: Mean patient age was 48 (range 21–75) years and 64% suffered subarachnoid hemorrhage (SAH). All aneurysms were successfully clipped. Gyrus rectus was resected in 57% of cases, more commonly in ruptured cases. Intraoperative rupture occurred in 11% of cases. The average operative time was 171 minutes. There were two patient deaths. Ninety-two percent of patients had a Glasgow Outcome Scale (GOS) of 5 at 6 weeks. All unruptured patients had a GOS of 5. At 12 months, 96% of all patients had a GOS of 5. Conclusions: The subfrontal approach provides an efficient avenue to the AComm region, which reduces opening and closing friction but still yields a comprehensive operative window for access to the anterior communicating region.

Ventriculosubgaleal Shunting – A Strategy to Reduce the Incidence of Shunt Revisions and Slit Ventricles: An Institutional Experience and Review of the Literature

Background/Aims: Slit ventricles and multiple episodes of shunt failure are problematic in many infants and preterm neonates shunted for hydrocephalus. We utilized ventriculosubgaleal (VSG) shunting as the initial neurosurgical intervention in neonates with hydrocephalus associated with intraventricular hemorrhage and infants with myelomeningocele. Methods: We conducted a chart review of 21 children initially treated with a VSG shunt between November 2002 and July 2009. Patient records and imaging studies were reviewed. Demographics, case data and clinical outcome were collected. Results: Five patients (27.8%) required a revision after conversion to a ventriculoperitoneal (VP) shunt. There were 9 cases of radiographic slit ventricles (45%). Average follow-up was 59.5 months (range 12–97 months). Average time interval to shunt conversion was 81.5 days. Two patients have not required conversion to a VP shunt (one with an 8-year follow-up). To date, none of these patients has required a subtemporal window or cranial vault expansion. Conclusion: Based on our results, initial management of selected hydrocephalic infants with a VSG shunt may prove to be advantageous in the long run for these children as the number of shunt revisions and the incidence of slit ventricles are significantly less than those reported in the literature.

Managing Patients With Oligometastatic Non–Small-Cell Lung Cancer

Metastatic lung cancer has long been considered incurable, with the goal of treatment being palliation. However, a clinically meaningful number of these patients with limited metastases (approximately 25%) are living long term after definitive treatment to all sites of active disease. These patients with so-called oligometastatic disease likely represent a distinct clinical group who may possess a more indolent biology compared with their more widely metastatic counterparts. Hellman and Weichselbaum proposed the existence of the oligometastatic state, on the basis of the spectrum theory of cancer spread. The literature suggests that an oligometastatic state exists in patients with non-small-cell lung cancer (NSCLC). This observation in the setting of rapidly evolving systemic therapies, including immune checkpoint inhibitors and an increasing number of targeted therapies, represents a unique clinical opportunity. Metastasis-directed therapies to address sites of disease include surgery (metastasectomy) and/or radiation therapy. Available evidence suggests that treating patients with limited or oligometastases may improve outcomes in a meaningful way; however, the majority of the randomized data includes patients with intracranial metastatic disease, and there are limited robust, randomized data available in the setting of NSCLC with only extracranial sites of metastatic disease. Ongoing randomized trials, including NRG-LU002 and the UK Conventional Care Versus Radioablation (Stereotactic Body Radiotherapy) for Extracranial Oligometastases trial, are aimed at evaluating this question further. One of the current limitations of aggressive treatment of oligometastatic NSCLC is the inability to accurately identify these patients before therapy, yet molecular markers, including microRNA profiles, are being investigated as a promising way to identify these patients.

Armored brain: A case report and review of the literature.

Background: Calcified chronic subdural hematomas occur infrequently. When the calcifications are extensive and bilateral, the condition is termed “armored brain”. We describe a case of “armored brain” incidentally discovered in an adult presenting with abdominal pain and mild headaches, long after initial placement of a ventriculo-peritoneal (VP) shunt. Case Description: A 38-year-old woman, treated at infancy with a VP shunt, presented with a 2-month history of abdominal pain associated with nausea and chills. She was neurologically intact on exam. An abdominal computed tomography (CT) scan demonstrated a rim-enhancing loculated fluid collection surrounding the patients distal VP shunt catheter tip. As a part of her initial work-up, she received a head CT to evaluate the proximal VP shunt, which demonstrated large bilateral chronic subdural hematomas with heavily calcified walls. She was eventually taken to the operating room (OR) for replacement of the distal catheter. It was felt that her acute clinical presentation was unrelated to the bilateral, calcified subdural hematomas and thus the decision was made to manage them conservatively. Conclusions: This rare complication of chronic shunting for hydrocephalus is sometimes referred to as armored brain. Surgery for armored brain is infrequently indicated and beneficial in only small subgroup of patients, with management guided by clinical presentation. Our patient fully recovered after shunt revision alone.

CIED malfunction in patients receiving radiation is a rare event that could be detected by remote monitoring

An increasing number of patients with cardiac devices require radiation therapy for treatment of a variety of cancers. This study aimed to identify the incidence and predictors of cardiac implantable electronic devices (CIED) malfunction in a real‐world population that has received radiation therapy.