Neuroophthalmological manifestations of congenital aqueductal stenosis.

OBJECTIVE: Congenital aqueductal stenosis (CAS) is a common etiology of hydrocephalus that occurs in a subset of infants and may be linked to an increased incidence of ophthalmological abnormalities and delayed developmental milestones. Although hydrocephalus is common and widely studied, sparse literature exists on patients with isolated (no identifiable genetic link) CAS along with analysis of ophthalmological manifestations. In this study, the authors sought to describe the ophthalmological abnormalities and delayed developmental milestones of patients with isolated CAS. METHODS: Data of patients with CAS were prospectively entered and monitored in a surgical database maintained by the Department of Neurological Surgery at Children's Hospital of Pittsburgh from January 2005 to October 2016. Patients with a family history of congenital hydrocephalus, positive testing for genetic forms of aqueductal stenosis, other congenital abnormalities suggesting an underlying genetic syndrome, and stenosis/obstruction due to secondary causes were excluded from this study. Prenatal and perinatal history, CSF diversion history, and a variety of outcomes, including ophthalmological deficits and developmental milestones, were collected and analyzed. RESULTS: A total of 41 patients with isolated CAS were identified, with a mean follow-up duration of 6 years. Among that cohort, 26 patients (63.4%) developed neuroophthalmological complications, which were further stratified. Fourteen patients (34.1%) developed strabismus and 11 (26.8%) developed astigmatism, and 1 patient (2.4%) with papilledema was recorded. Among patients with ophthalmological abnormalities, 76.9% had delayed developmental milestones (p = 0.045). CONCLUSIONS: Patients with CAS were found to have increased risk of ophthalmological abnormalities requiring correction, along with an increased risk of delayed developmental milestones. Importantly, there was a significant correlation between the development of ophthalmological abnormalities and delayed developmental milestones that was independent of CSF diversion history. Larger patient cohort studies are required to explore whether earlier development of hydrocephalus, as is the case in CAS, causes elevated rates of neurological and ophthalmological complications, and if earlier CSF diversion correlates with improved outcomes.

Urgent Treatment for Symptomatic Carotid Stenosis: The Pittsburgh Revascularization and Treatment Emergently After Stroke (PIRATES) Protocol.

BACKGROUND: Patients with symptomatic carotid stenosis remain at high risk of early recurrent stroke without revascularization. This risk must be balanced against a higher rate of periprocedural complications associated with early revascularization. OBJECTIVE: To analyze prospectively recorded data from an institutional protocol that standardized the urgent (<48 h) treatment of patients presenting with symptomatic carotid stenosis and underwent either carotid stenting (CAS) or carotid endarterectomy (CEA). METHODS: All patients presenting over 28 mo to a comprehensive stroke center with symptomatic carotid stenosis within 48 h of index event were screened for inclusion. All patients were given dual-antiplatelet therapy. If there was clinical equipoise between CEA and CAS, patients underwent angiography and subsequently revascularization if digital subtraction angiography demonstrated ≥50% stenosis. The primary outcome was a composite of stroke or death within 30 d. RESULTS: This study included 178 patients with a diagnosis of recently symptomatic carotid stenosis; 120 patients (67%) met the criteria. A total of 59 patients underwent CEA and 61 patients underwent CAS. There were not significant differences in the primary outcome; 3 patients (5.1%) in the CEA arm and 3 patients (4.9%) in the CAS arm met the primary outcome. CONCLUSION: In this prospective analysis, urgent revascularization for symptomatic carotid stenosis can be done with equivalently low rates of stroke or death, regardless of revascularization strategy.

Incorporation of transradial approach in neuroendovascular procedures: defining benchmarks for rates of complications and conversion to femoral access.

BACKGROUND: The transradial approach (TRA) has gained increasing popularity for neuroendovascular procedures. However, the experience with TRA in neuroangiography is still in early stages in most centers, and the safety and feasibility of this approach have not been well established. The purpose of this study is to report the safety and feasibility of TRA for neuroendovascular procedures. METHODS: We reviewed charts from six institutions in the USA to include consecutive patients who underwent diagnostic or interventional neuroendovascular procedures through TRA from July 2018 to July 2019. Collected data included baseline characteristics, procedural variables, complications, and whether there was a crossover to transfemoral access. RESULTS: A total of 2203 patients were included in the study (age 56.1±15.2, 60.8% women). Of these, 1697 (77%) patients underwent diagnostic procedures and 506 (23%) underwent interventional procedures. Successfully completed procedures included aneurysm coiling (n=97), flow diversion (n=89), stent-assisted coiling (n=57), balloon-assisted coiling (n=19), and stroke thrombectomy (n=76). Crossover to femoral access was required in 114 (5.2%). There were no major complications related to the radial access site. Minor complications related to access site were seen in 14 (0.6%) patients. CONCLUSION: In this early stage of transforming to the 'radial-first' approach for neuroendovascular procedures, TRA was safe with low complication rates for both diagnostic and interventional procedures. A wide range of procedures were completed successfully using TRA.

Transradial versus transfemoral approaches for diagnostic cerebral angiography: a prospective, single-center, non-inferiority comparative effectiveness study.

BACKGROUND: Interventional cardiology produced level 1 evidence recommending radial artery-first for coronary angiography given lower vascular complications. Neuroendovascular surgeons have not widely adopted the transradial approach. This prospective, single center, non-inferiority comparative effectiveness study aims to compare the transradial and transfemoral approaches for diagnostic cerebral angiography with respect to efficacy, safety and patient satisfaction. METHODS: Consecutive patients presenting for diagnostic cerebral angiography were selected to undergo right radial or femoral access based on date of presentation. Primary outcome was ability to answer the predefined diagnostic goal of the cerebral angiogram using the initial access site and was assessed with a non-inferiority design. Secondary outcomes included technical success per vessel, complications, procedure times and patient satisfaction. RESULTS: A total of 312 patients were enrolled, 158 and 154 for right radial and femoral access, respectively. The diagnostic goal of the angiogram was achieved in 152 of 154 (99%) patients who underwent attempted femoral access compared with 153 of 158 (97%) patients who underwent radial access, confirming non-inferiority of the transradial approach. Secondary outcomes showed equivalent technical success by vessel, no major complications, and similar frequency of minor complications between the two approaches. In-room time was similar between approaches, though post-procedure recovery room time was significantly shorter for transradial patients. Patient satisfaction results significantly favored the radial approach. CONCLUSIONS: In patients undergoing diagnostic cerebral angiography, transfemoral and transradial access achieve procedural goals with similar effectiveness and safety, though patients strongly prefer the radial approach. Findings support consideration of adopting a radial-first strategy for diagnostic cerebral angiography.

Evaluation of Occipitocervical Arthrodesis Rates with Screw-based Fixation and Osteoinductive Fusion Adjuncts.

Occipitocervical (OC) instability may be associated with neurologic impairment and even death. There is a paucity of research on the rate of arthrodesis utilizing modern screw-based constructs coupled with adjuvant osteoinductive agents. We reviewed our experience with OC constructs and compared the fusion rate, functional outcome, and rate of adverse events between recombinant human bone morphogenetic protein (BMP)-2, autologous iliac crest bone graft (ICBG), a combination of BMP and ICBG, and local bone autograft alone. We performed a retrospective cohort analysis of all adult admissions for operative treatment of OC instability utilizing segmental screw-based constructs for OC arthrodesis between January 2003 and September 2012. Data concerning demographic characteristics, diagnostic and procedural details, radiographic pathology, and clinical course were abstracted from medical records. The primary end point was evidence of stable fixation and osseous union on either dynamic lateral radiographs or computed tomography (CT) imaging at most recent follow-up. Secondary end points included functional outcome as determined by Nurick scale and Neck disability index (NDI) at ≥ 1year postoperation, as well as perioperative morbidity and mortality at 30 days and 3 months. During the study period, 94 patients (mean age: 62 ± 18 years) underwent OC fixation with segmental screw-based constructs. The four fusion adjunct cohorts analyzed included local autograft alone (32%), ICBG (41%), BMP (14%), or a combination of ICBG and BMP (14%). Notably, demineralized bone matrix was also used in 61% of cases overall, but its use did not differ significantly among the four cohorts (p = 0.28). Median radiographic follow-up was 6 months postoperatively (range: 1.5-54 months). Clinical outcomes were assessed at a median postoperative follow-up of 45 months (range: 12-87 months). Overall, radiographic evidence of arthrodesis was present in 83% of patients assessed and was not significantly different between adjunct cohorts (local autograft 92%, ICBG 77%, BMP 88%, and combination of ICBG and BMP 83%; p = 0.79). This finding persisted despite adjustment for age, pathology, number of levels instrumented, and attendant procedures. Importantly, neither the presence of arthrodesis nor fusion adjunct was significantly associated with functional outcome in both univariate and adjusted regression models. Additionally, perioperative adverse events occurred in 23% of cases and did not vary significantly in incidence or severity between fusion adjunct cohorts. We present a large series of patients treated for OC instability with rigid fixation utilizing modern segmental screw-based constructs. The use of adjuvant osteoinductive agents (BMP, ICBG, or a combination) produced equivalent rates of arthrodesis, functional outcome, and adverse events compared with use of local autograft alone.

Educational Resources "Over the Head" of Neurosurgical Patients: The Economic Impact of Inadequate Health Literacy.

BACKGROUND: Health literacy is the ability with which individuals can obtain, understand, and apply basic health information. Approximately 36% of Americans have basic or below basic health literacy skills. This low health literacy is particularly prevalent in neurosurgery, a growing field of medicine with considerable complexity and a patient population commonly affected with disease-related cognitive impairment. Consequences of poor patient understanding range from increased emergency department admissions rates to reduced adherence to preoperative medication instructions. Economic implications include increasing health care expenditures, decreasing access to health care, and decreasing quality of care. Health literacy costs the United States $106-236 billion per year. METHODS: Consequences of inadequate patient understanding vary widely. This article reviews and addresses the economic impact of the failure to address low health literacy in neurosurgery. RESULTS: Various groups have proposed techniques and devised outlines to improve health literacy, such as detailing principles targeting the underlying issues of health care illiteracy. The government, through legislation including the Affordable Care Act and the National Action Plan to Improve Health Literacy, has also shown its desire to remedy the effects of insufficient health literacy. CONCLUSIONS: Despite current efforts, further action is still needed. Health literacy is a key determinant in ensuring longevity and quality of life.

Giant pseudomeningocele causing urinary obstruction in a patient with Marfan syndrome.

Defective collagen biosynthesis in Marfan syndrome predisposes to dural defects such as dural ectasia, meningocele, and pseudomeningocele; thus, an increased index of suspicion for these conditions should be present in the clinical setting of Marfan syndrome. The authors describe a young woman with Marfan syndrome who was being treated with anticoagulants for a prosthetic heart valve and who presented with a spontaneous retroperitoneal hemorrhage requiring surgical evacuation. No CSF leak was encountered at surgery, but she developed progressively more severe positional headaches over the following year. She then experienced the sudden onset of acute urinary obstruction, at which time CT revealed a 17 × 15 × 13-cm presacral pseudomeningocele communicating with the thecal sac through a sacral bone defect. An anterior surgical approach was used for drainage of the pseudomeningocele as well as for primary closure of the dural defect with a bovine pericardial patch and autologous subcutaneous fat graft. After a short period of lumbar subarachnoid drainage of the CSF, the patient was able to resume normal activity without recurrent symptoms. To the authors' knowledge, such a pseudomeningocele in a patient with Marfan syndrome has been reported only twice, and this case features the largest pseudomeningocele to date. They also review the pertinent literature regarding presentation, diagnosis, and management of these lesions.

Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance.

Leptin signaling has received considerable attention in the Alzheimer disease (AD) field. Within the past decade, the peptide hormone has been demonstrated to attenuate tau hyperphosphorylation in neuronal cells and to be modulated by amyloid-ß. Moreover, a role in neuroprotection and neurogenesis within the hippocampus has been shown in animal models. To further characterize the association between leptin signaling and vulnerable regions in AD, we assessed the profile of leptin and the leptin receptor in AD and control patients. We analyzed leptin levels in CSF, and the concentration and localization of leptin and leptin receptor in the hippocampus. Significant elevations in leptin levels in both CSF and hippocampal tissue of AD patients, compared with age-matched control cases, indicate a physiological up-regulation of leptin in AD. However, the level of leptin receptor mRNA decreased in AD brain and the leptin receptor protein was localized to neurofibrillary tangles, suggesting a severe discontinuity in the leptin signaling pathway. Collectively, our results suggest that leptin resistance in the hippocampus may play a role in the characteristic changes associated with the disease. These findings are the first to demonstrate such dysregulated leptin-signaling circuitry and provide novel insights into the possible role of aberrant leptin signaling in AD. In this study, increased leptin was found in CSF and hippocampus in Alzheimer disease indicating its physiological up-regulation, yet leptin receptor mRNA was decreased and leptin receptor protein was localized to neurofibrillary tangles, suggesting a discontinuity in the leptin signaling pathway. The lack of leptin signaling within degenerating neurons may represent a novel neuronal leptin resistance in Alzheimer disease.

Activation of the extracellular signal-regulated kinase pathway contributes to the behavioral deficit of fragile x-syndrome.

Fragile X syndrome (FXS) is a developmental disorder caused by the loss of Fragile X Mental Retardation 1 (FMR1) gene function because of a CGG repeat expansion (> 200 repeats) in the gene. The molecular mechanism(s) linking loss of FMR1 function to the molecular pathology and cognitive/behavioral disability remain unclear. Given the critical role of extracellular signal-regulated kinase (ERK) in synaptic plasticity and neurodevelopment, a number of recent studies have investigated ERK phosphorylation under basal conditions or upon mGluR-induction using neuronal and peripheral tissues from Fmr1 knockout mice and peripheral tissues from FXS patients. However, these reports have presented conflicting results. The current study is the first to focus on the levels of ERK phosphorylation in brain tissue from human FXS patients. In both human brain tissue and brain tissue from Fmr1 knockout mice there was significantly increased phosphorylation of MEK1/2 and ERK. Indeed, treating Fmr1 knockout mice with the MEK1/2 inhibitor SL327 abrogated audiogenic seizure activity, a feature of the Fmr1 knockout mice that replicates the symptom in patients with FXS. These findings suggest that activation of the ERK pathway results in some cardinal cognitive and clinical features in FXS patients and likely have profound translational implications.

Frontiers in Alzheimer's disease therapeutics.

Alzheimer disease (AD) is a progressive neurodegenerative disease which begins with insidious deterioration of higher cognition and progresses to severe dementia. Clinical symptoms typically involve impairment of memory and at least one other cognitive domain. Because of the exponential increase in the incidence of AD with age, the aging population across the world has seen a congruous increase AD, emphasizing the importance of disease altering therapy. Current therapeutics on the market, including cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, provide symptomatic relief but do not alter progression of the disease. Therefore, progress in the areas of prevention and disease modification may be of critical interest. In this review, we summarize novel AD therapeutics that are currently being explored, and also mechanisms of action of specific drugs within the context of current knowledge of AD pathologic pathways.

The cell cycle regulator phosphorylated retinoblastoma protein is associated with tau pathology in several tauopathies.

Retinoblastoma protein (pRb) is a ubiquitous 928-amino acid cell cycle regulatory molecule with diverse biologic activities. One critical function of pRb is the control of the G1-to-S phase checkpoint of the cell cycle. In the hypophosphorylated state, pRb suppresses the activity of E2F transcription factors thereby inhibiting transcription of cell cycle-promoting genes. On phosphorylation, primarily by cyclin-dependent kinases, phosphorylated pRb dissociates from E2F and permits cell cycle progression. We previously found phosphorylated pRb to be intimately associated with hyperphosphorylated tau-containing neurofibrillary tangles of Alzheimer disease (AD), the pathogenesis of which is believed to involve dysregulation of the cell cycle and marked neuronal death. Here, we used immunohistochemistry to investigate the presence of phosphorylated pRb in other distinct neurodegenerative diseases that share the common characteristic of hyperphosphorylated tau pathology and neuronal loss with AD.We found colocalized labeling of tau pathology and phosphorylated pRb in Pick disease and progressive supranuclear palsy (3 cases each), neurodegeneration with brain iron accumulation type 1 (2 cases), and Parkinson-amyotrophic lateral sclerosis of Guam, subacute sclerosing panencephalitis, frontotemporal dementia and Parkinsonism linked to chromosome 17, and dementia pugilistica (1 case each). These observations further implicate aberrant neuronal cell cycle progression in neurodegenerative diseases, particularly tauopathies, and suggest a novel target for therapeutic intervention.

Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer's disease.

Tryptophan metabolism, through the kynurenine pathway, produces neurotoxic intermediates that are implicated in the pathogenesis of Alzheimer's disease. In particular, oxidative stress via 3-hydroxykynurenine (3-HK) and its cleaved product 3-hydroxyanthranilic acid (3-HAA) significantly damages neuronal tissue and may potentially contribute to a cycle of neurodegeneration through consequent amyloid-beta accumulation, glial activation, and up-regulation of the kynurenine pathway. To determine the role of the kynurenine pathway in eliciting and continuing oxidative stress within Alzheimer's diseased brains, we used immunocytochemical methods to show elevated levels of 3-HK modifications and the upstream, rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO-1) in Alzheimer's diseased brains when compared to controls. Importantly, the association of IDO-1 with senile plaques was confirmed and, for the first time, IDO-1 was shown to be specifically localized in conjunction with neurofibrillary tangles. As senile plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer's disease, our study provides further evidence that the kynurenine pathway is involved with the destructive neurodegenerative pathway of Alzheimer's disease.

Evidence for the novel expression of human kallikrein-related peptidase 3, prostate-specific antigen, in the brain.

Human kallikrein-related peptidase 3 (hK3), also known as prostate-specific antigen (PSA), is a 33 kDa single chain glycoprotein belonging to the kallikrein family of serine proteases. With chymotrypsin-like enzymatic activity, hK3 is directly and indirectly involved in a number of diverse biological functions including male fertility, the regulation of cell proliferation, and the inhibition of angiogenesis. The gene encoding hK3, hKLK3, is located on chromosome 19 and its expression has been shown to be regulated by steroid hormones through androgen receptor-mediated transcription. hK3 was once thought to be exclusively expressed and secreted by prostatic epithelial cells, hence the initial name of prostate-specific antigen, but has since been isolated in several nonprostatic tissues and ongoing characterization of alternative splicing variants has found at least 13 distinct mRNA transcripts. The detection of hK3 in cerebrospinal fluid prompted the hypothesis that hK3 may be produced in the brain. To test this notion, in this study we used RT-PCR amplification of brain tissue total RNA and examined hK3 protein by immunohistochemical, and immunoblot analysis. RT-PCR revealed several hK3 mRNA transcripts in the brain. Confirming these findings, both immunohistochemical staining and western immunoblotting showed evidence for hK3 protein in neuronal cells. Taken together, our findings support the expression of hK3 in neuronal cells reinforcing the concept of hK3 as a ubiquitous protein with more multifarious biological activity than previously believed. Ongoing research seeks to elucidate the functional significance of hK3 in brain cells.