Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder.

INTRODUCTION: Cariprazine treats acute manic and depressive episodes in bipolar I disorder (BP-I), but its efficacy in preventing relapse of mood episode remains unknown. METHODS: In this phase 3b, double-blind, placebo-controlled study, patients with BP-I with acute manic or depressive episodes (each with/without mixed features), were treated with cariprazine 3.0 mg/day during a 16-week open-label treatment period; those who achieved stable remission within 8 weeks and remained stable for at least another 8 weeks were randomized to receive cariprazine 1.5 or 3.0 mg per day or placebo in the double-blind treatment period for up to 39 weeks. The primary efficacy endpoint was time to relapse of any mood episode. Adverse events (AEs) were assessed. RESULTS: Patients (440/896) enrolled in the open-label treatment period achieved stability criteria and were randomized to receive cariprazine 3.0 mg/day (n = 148), cariprazine 1.5 mg/day (n = 147), or placebo (n = 145) in the double-blind treatment period. Relapse rates were 17.9%, 16.8%, and 19.7% in the cariprazine 3.0 mg/day, cariprazine 1.5 mg/day, and placebo groups, respectively. Neither dose of cariprazine was more effective than placebo on the primary outcome (3.0 mg/day: HR = 0.89, [95% CI: 0.5, 1.5]; 1.5 mg/day: HR = 0.83, 95% CI [0.5, 1.4]). The most frequently reported AEs (≥5%) were akathisia, headache, insomnia, and nausea in the open-label treatment period and increased weight and insomnia in the double-blind treatment period. In the open-label and double-blind treatment periods, 7.5% and 1.6% of patients experienced an AE leading to discontinuation. CONCLUSION: Cariprazine was not superior to placebo in the prevention of relapses in this study. Relapse rates were unusually low in the placebo group. Cariprazine was well-tolerated.

Act1, scene brain: astrocytes play a lead role.

Interleukin-17 (IL-17) is crucial for the progression of experimental autoimmune encephalomyelitis. In this issue of Immunity, Kang et al. (2010) report that neuroectoderm-derived astrocytes are the critical cellular element that responds to IL-17.

Targeting the GM-CSF receptor for the treatment of CNS autoimmunity.

In multiple sclerosis (MS), there is a growing interest in inhibiting the pro-inflammatory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF). We sought to evaluate the therapeutic potential and underlying mechanisms of GM-CSF receptor alpha (Rα) blockade in animal models of MS. We show that GM-CSF signaling inhibition at peak of chronic experimental autoimmune encephalomyelitis (EAE) results in amelioration of disease progression. Similarly, GM-CSF Rα blockade in relapsing-remitting (RR)-EAE model prevented disease relapses and inhibited T cell responses specific for both the inducing and spread myelin peptides, while reducing activation of mDCs and inflammatory monocytes. In situ immunostaining of lesions from human secondary progressive MS (SPMS), but not primary progressive MS patients shows extensive recruitment of GM-CSF Rα+ myeloid cells. Collectively, this study reveals a pivotal role of GM-CSF in disease relapses and the benefit of GM-CSF Rα blockade as a potential novel therapeutic approach for treatment of RRMS and SPMS.

IL-17A activates ERK1/2 and enhances differentiation of oligodendrocyte progenitor cells.

Inflammatory signals present in demyelinated multiple sclerosis lesions affect the reparative remyelination process conducted by oligodendrocyte progenitor cells (OPCs). Interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 have differing effects on the viability and growth of OPCs, however the effects of IL-17A are largely unknown. Primary murine OPCs were stimulated with IL-17A and their viability, proliferation, and maturation were assessed in culture. IL-17A-stimulated OPCs exited the cell cycle and differentiated with no loss in viability. Expression of the myelin-specific protein, proteolipid protein, increased in a cerebellar slice culture assay in the presence of IL-17A. Downstream, IL-17A activated ERK1/2 within 15 min and induced chemokine expression in 2 days. These results demonstrate that IL-17A exposure stimulates OPCs to mature and participate in the inflammatory response.

The role of antigen presenting cells in multiple sclerosis.

Multiple sclerosis (MS) is a debilitating T cell mediated autoimmune disease of the central nervous system (CNS). Animal models of MS, such as experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) have given light to cellular mechanisms involved in the initiation and progression of this organ-specific autoimmune disease. Within the CNS, antigen presenting cells (APC) such as microglia and astrocytes participate as first line defenders against infections or inflammation. However, during chronic inflammation they can participate in perpetuating the self-destructive environment by secretion of inflammatory factors and/or presentation of myelin epitopes to autoreactive T cells. Dendritic cells (DC) are also participants in the presentation of antigen to T cells, even within the CNS. While the APCs alone are not solely responsible for mediating the destruction to the myelin sheath, they are critical players in perpetuating the inflammatory milieu. This review will highlight relevant studies which have provided insight to the roles played by microglia, DCs and astrocytes in the context of CNS autoimmunity.

Cytokine control of inflammation and repair in the pathology of multiple sclerosis.

Cytokines are secreted signaling proteins that play an essential role in propagating and regulating immune responses during experimental autoimmune encephalomyelitis (EAE), the mouse model of the neurodegenerative, autoimmune disease multiple sclerosis (MS). EAE pathology is driven by a myelin-specific T cell response that is activated in the periphery and mediates the destruction of myelin upon T cell infiltration into the central nervous system (CNS). Cytokines provide cell signals both in the immune and CNS compartment, but interestingly, some have detrimental effects in the immune compartment while having beneficial effects in the CNS compartment. The complex nature of these signals will be reviewed.

Levetiracetam Prophylaxis for Children Admitted With Traumatic Brain Injury.

BACKGROUND: Prophylactic antiseizure medications (ASMs) for pediatric traumatic brain injury (TBI) are understudied. We evaluated clinical and radiographic features that inform prescription of ASMs for pediatric TBI. We hypothesized that despite a lack of evidence, levetiracetam is the preferred prophylactic ASM but that prophylaxis is inconsistently prescribed. METHODS: This retrospective study assessed children admitted with TBI from January 1, 2017, to December 31, 2019. TBI severity was defined using Glasgow Coma Scale (GCS) scores. Two independent neuroradiologists reviewed initial head computed tomography and brain magnetic resonance imaging. Fisher exact tests and descriptive and regression analyses were conducted. RESULTS: Among 167 children with TBI, 44 (26%) received ASM prophylaxis. All 44 (100%) received levetiracetam. Prophylaxis was more commonly prescribed for younger children, those with neurosurgical intervention, and abnormal neuroimaging (particularly intraparenchymal hematoma) (odds ratio = 10.3, confidence interval 1.8 to 58.9), or GCS ≤12. Six children (13.6%), all on ASM, developed early posttraumatic seizures (EPTSs). Of children with GCS ≤12, four of 17 (23.5%) on levetiracetam prophylaxis developed EPTSs, higher than the reported rate for phenytoin. CONCLUSIONS: Although some studies suggest it may be inferior to phenytoin, levetiracetam was exclusively used for EPTS prophylaxis. Intraparenchymal hematoma >1 cm was the single neuroimaging feature associated with ASM prophylaxis regardless of the GCS score. Yet these trends are not equivalent to optimal evidence-based management. We still observed important variability in neuroimaging characteristics and TBI severity for children on prophylaxis. Thus, further study of ASM prophylaxis and prevention of pediatric EPTSs is warranted.

Compliance with evidence-based guidelines for computed tomography of children with head and abdominal trauma.

INTRODUCTION: Recently, two large prospective clinical trials developed and validated prediction rules for children at very low risk for clinically important traumatic brain injuries (ciTBI) or abdominal injury for whom CT is unnecessary. Specific criteria/guidelines were identified which if met would obviate the need for CT scanning. The purpose of this study was to assess compliance at a level one pediatric center with these guidelines as a tool for quality improvement. METHODS: Records of children admitted to our pediatric trauma center one year before and two years after publication of head (Kuppermann '09) and abdominal trauma (Holmes '13) CT imaging guidelines were reviewed. Data collected included demographics, Glasgow coma score, (GCS), injury severity score (ISS), mechanism of injury, and indication for imaging based on criteria/guidelines from the prediction rule including history, symptoms, and physical exam findings. RESULTS: There were 296 total patients identified. Demographic data, GCS, ISS, and mechanism of injury were similar between both groups before and after guideline publication. Prior to publication of head trauma imaging guidelines, 20.7% of head trauma patients had no indication for head CT prior compared with 19.5% after publication of imaging guideline (p=0.85). Prior to publication of abdominal trauma imaging guidelines, 28.9% of patients had no indication for abdominal CT compared with 31.5% after publication of imaging guidelines (0.76). The rate of ciTBI requiring intervention was 4.6% before and 1.1% after guideline publication (p=0.4). The rate of abdominal injury requiring intervention was 7.9% before and 1.8% post guideline publication (p=0.2). None of the children at very low risk for ciTBI or abdominal injury required surgical intervention. CONCLUSION: At our institution compliance with evidence-based guidelines for CT of children with head and abdominal trauma is poor with a significant number of patients undergoing unnecessary imaging. This provides an opportunity for quality improvement with evidence based methods to reduce unnecessary imaging for trauma. LEVEL OF EVIDENCE: III TYPE OF STUDY: Clinical Research Paper.

Characterization of oligodendroglial populations in mouse demyelinating disease using flow cytometry: clues for MS pathogenesis.

Characterizing and enumerating cells of the oligodendrocyte lineage (OLCs) is crucial for understanding demyelination and therapeutic benefit in models of demyelinating disease in the central nervous system. Here we describe a novel method for the rapid, unbiased analysis of mouse OLCs using flow cytometry. The assay was optimized to maximize viable yield of OLCs and maintain OLC antigen integrity. Panels of antibodies were assembled for simultaneous analysis of seven antigens on individual cells allowing for characterization of oligodendroglial cells throughout the lineage. We verified the utility of the assay with cultured OLCs and through a time course of developmental myelination. Next we employed the assay to characterize OLC populations in two well-characterized models of demyelination: cuprizone-induced demyelination and experimental autoimmune encephalomyelitis (EAE). In EAE we observed a dramatic loss of mature oligodendrocytes coincident with a dramatic expansion of oligodendrocyte progenitors cells (OPCs) at the onset of disease suggesting an attempt of the host to repair myelin. This expanded OPC pool was maintained through remission and relapse suggesting an arrest in differentiation in the face of the chronic autoimmune T cell-mediated inflammatory response. These robust, reproducible changes in OLCs through disease provide a rapid quantitative global analysis of myelin-producing cells in the adult mouse brain and important information regarding effects of disease on oligodendroglial proliferation/differentiation which is useful for defining the pathogenesis and therapy of MS.

Strategies for protecting oligodendrocytes and enhancing remyelination in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) characterized by encephalitogenic leukocyte infiltration and multifocal plaques of demyelination. Patients present with debilitating clinical sequelae including motor, sensory, and cognitive deficits. For the past 30 years, immune modulating treatments have entered the marketplace and continue to improve in limiting the frequency and severity of relapses, but no cure has been found and no drug has successfully stopped chronic progressive disease. Recent work focusing on the oligodendrocyte, the myelin-producing cell, has provided needed insight into the process of demyelination, the spontaneous ability of the CNS to regenerate, and the inevitable failure of remyelination. From this a number of promising molecular targets have been identified to protect oligodendrocytes and promote remyelination. Combining immunomodulatory therapy with strategies to protect oligodendrocytes from further degeneration and enhance remyelination presents a very real means to improve clinical outcome for chronic progressive patients in the near future. Here we lay out a combination therapy approach to treating MS and survey the current literature on promising drug candidates potentially capable of mediating oligodendrocyte protection and enhancing remyelination.

Desert wildfire and severe drought diminish survivorship of the long-lived Joshua tree (Yucca brevifolia; Agavaceae).

Extreme climate events are transforming plant communities in the desert Southwest of the United States. Abundant precipitation in 1998 associated with El Niño Southern Oscillation (ENSO) stimulated exceptional alien annual plant production in the Mojave Desert that fueled wildfires in 1999. Exacerbated by protracted drought, 80% of the burned Yucca brevifolia, a long-lived arborescent monocot, and 26% of unburned plants died at Joshua Tree National Park by 2004. Many burned plants <1 m tall died immediately, and survival of all but the tallest, oldest plants declined to the same low level by 2004. Postfire sprouting prolonged survival, but only at the wetter, high-elevation sites. During succeeding dry years, herbaceous plants were scarce, and individuals of Thomomys bottae (pocket gopher) gnawed the periderm and hollowed stems of Y. brevifolia causing many of them to topple. Thomomys bottae damage reduced plant survivorship at low-elevation, unburned sites and diminished survival of burned plants in all but the driest site, which already had low survival. Accentuated ENSO episodes and more frequent wildfires are expected for the desert Southwest and will likely shift Y. brevifolia population structure toward tall, old adults with fewer opportunities for plant recruitment, thus imperiling the persistence of this unique plant community.