Therapeutic decision making in autoimmune and inflammatory disorders of the central nervous system in children.

ABSTRACT Autoimmune and inflammatory disorders of the central nervous system can result in significant morbidity and mortality. Through the recognition of syndromes using diagnostic biomarkers, the clinician is now able to use immune suppressive therapies to improve outcomes. However, the therapeutic decision-making process is complex. The clinician has to balance the risk of disease, with the risk of treatment side effects. To achieve this balance, it is important to understand the natural history of disease, the risk of residual disability, the risk of relapse, and risk of a fatal outcome. It is also important to have some understanding of the pathological processes, as some of the entities have more reversible processes, whereas others have destructive processes. This review will assess the dynamic nature of this decision-making process, and compare some of the more severe diseases such as neuromyelitis optica, anti-N-methyl-D-aspartate receptor encephalitis and opsoclonus myoclonus ataxia syndrome, with disorders with more favourable outcomes such as Sydenham chorea and post-infectious cerebellar ataxia

Therapeutic decision making in autoimmune and inflammatory disorders of the central nervous system in children.

ABSTRACT Autoimmune and inflammatory disorders of the central nervous system can result in significant morbidity and mortality. Through the recognition of syndromes using diagnostic biomarkers, the clinician is now able to use immune suppressive therapies to improve outcomes. However, the therapeutic decision-making process is complex. The clinician has to balance the risk of disease, with the risk of treatment side effects. To achieve this balance, it is important to understand the natural history of disease, the risk of residual disability, the risk of relapse, and risk of a fatal outcome. It is also important to have some understanding of the pathological processes, as some of the entities have more reversible processes, whereas others have destructive processes. This review will assess the dynamic nature of this decision-making process, and compare some of the more severe diseases such as neuromyelitis optica, anti-N-methyl-D-aspartate receptor encephalitis and opsoclonus myoclonus ataxia syndrome, with disorders with more favourable outcomes such as Sydenham chorea and post-infectious cerebellar ataxia

Movement Disorders Presenting in Childhood.

PURPOSE OF REVIEW: This article provides an overview of movement disorders that present in childhood. Key clinical features are discussed, and a brief guide to management strategies is provided. Recent advances in the field of pediatric movement disorders are also a focus of the article. RECENT FINDINGS: Advances in genetic technologies and cell biology have contributed greatly to the elucidation of underlying disease mechanisms in childhood movement disorders. This article discusses the expanding spectrum of both genetic and acquired movement disorders that present in childhood, including benign, acquired, genetic, and psychogenic movement disorders. SUMMARY: Movement disorders in childhood comprise a wide spectrum of both genetic and acquired diseases, ranging from benign self-limiting conditions to more progressive phenotypes associated with significant morbidity and mortality. Elucidation of the underlying cause is achieved through accurate history, detailed clinical examination, review of video footage (including home videos), and, where appropriate, neuroimaging and laboratory investigations. Early accurate diagnosis will facilitate the instigation of appropriate management strategies

Cerebrospinal fluid metabolomics: detection of neuroinflammation in human central nervous system disease.

The high morbidity and mortality of neuroinflammatory diseases drives significant interest in understanding the underlying mechanisms involved in the innate and adaptive immune response of the central nervous system (CNS). Diagnostic biomarkers are important to define treatable neuroinflammation. Metabolomics is a rapidly evolving research area offering novel insights into metabolic pathways, and elucidation of reliable metabolites as biomarkers for diseases. This review focuses on the emerging literature regarding the detection of neuroinflammation using cerebrospinal fluid (CSF) metabolomics in human cohort studies. Studies of classic neuroinflammatory disorders such as encephalitis, CNS infection and multiple sclerosis confirm the utility of CSF metabolomics. Additionally, studies in neurodegeneration and neuropsychiatry support the emerging potential of CSF metabolomics to detect neuroinflammation in common CNS diseases such as Alzheimer's disease and depression. We demonstrate metabolites in the tryptophan-kynurenine pathway, nitric oxide pathway, neopterin and major lipid species show moderately consistent ability to differentiate patients with neuroinflammation from controls. Integration of CSF metabolomics into clinical practice is warranted to improve recognition and treatment of neuroinflammation

The connection between galaxy environment and the luminosity function slopes of star-forming regions

We present the first study of GALEX far ultra-violet (FUV) luminosity functions of individual star-forming regions within a sample of 258 nearby galaxies spanning a large range in total stellar mass and star formation properties. We identify ~65,000 star-forming regions (i.e., FUV sources), measure each galaxy's luminosity function, and characterize the relationships between the luminosity function slope (alpha) and several global galaxy properties. A final sample of 82 galaxies with reliable luminosity functions are used to define these relationships and represent the largest sample of galaxies with the largest range of galaxy properties used to study the connection between luminosity function properties and galaxy environment. We find that alpha correlates with global star formation properties, where galaxies with higher star formation rates and star formation rate densities (Sigma_SFR) tend to have flatter luminosity function slopes. In addition, we find that neither stochastic sampling of the luminosity function in galaxies with low-number statistics nor the effects of blending due to distance can fully account for these trends. We hypothesize that the flatter slopes in high Sigma_SFR galaxies is due to higher gas densities and higher star formation efficiencies which result in proportionally greater numbers of bright star-forming regions. Finally, we create a composite luminosity function composed of star-forming regions from many galaxies and find a break in the luminosity function at brighter luminosities. However, we find that this break is an artifact of varying detection limits for galaxies at different distances.Science and Technology Facilities CouncilThis is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/mnras/stw169

Cerebrospinal fluid metabolites in tryptophan-kynurenine and nitric oxide pathways: biomarkers for acute neuroinflammation.

Aim To explore the cerebrospinal fluid (CSF) metabolite features in acute neuroinflammatory diseases and identify potential biomarkers to diagnose and monitor neuroinflammation. Method A cohort of 14 patients (five females, nine males; mean [median] age 7y 9mo [9y], range 6mo–13y) with acute encephalitis (acute disseminated encephalomyelitis n=6, unknown suspected viral encephalitis n=3, enteroviral encephalitis n=2, seronegative autoimmune encephalitis n=2, herpes simplex encephalitis n=1) and age-matched non-inflammatory neurological disease controls (n=14) were investigated using an untargeted metabolomics approach. CSF metabolites were analyzed with liquid chromatography coupled to high resolution mass spectrometry, followed by subsequent multivariate and univariate statistical methods. Results A total of 35 metabolites could be discriminated statistically between the groups using supervised orthogonal partial least squares discriminant analysis and analysis of variance. The tryptophan-kynurenine pathway contributed nine key metabolites. There was a statistical increase of kynurenine, quinolinic acid, and anthranilic acid in patients with encephalitis, whereas tryptophan, 3-hydroxyanthrnailic acid, and kynurenic acid were decreased. The nitric oxide pathway contributed four metabolites, with elevated asymmetric dimethylarginine and argininosuccinic acid, and decreased arginine and citrulline in patients with encephalitis. An increase in the CSF kynurenine/tryptophan ratio (p<0.001), anthranilic acid/3-hydroxyanthranilic acid ratio (p<0.001), asymmetric dimethylarginine/arginine ratio (p<0.001), and neopterin (p<0.001) strongly predicted neuroinflammation. Interpretation The combination of alterations in the tryptophan-kynurenine pathway, nitric oxide pathway, and neopterin represent a useful potential panel for neuroinflammation and holds potential for clinical translation practice. What this paper adds The kynurenine/tryptophan and anthranilic acid/3-hydroxyanthranilic acid ratios hold great potential as biomarkers of neuroinflammation. Elevation of the asymmetric dimethylarginine/arginine ratio in acute brain inflammation shows dysregulation of the nitric oxide pathway

Anti-NMDA-R encephalitis: an encephalitis lerthargica-like illness

Posters: no. P14A girl of 3 years and 9 months with a 3-day history of fever and upper respiratory tract infection (URTI) was admitted with a generalised tonic-clonic convulsion, and delirium with screaming, non-sense talking, and agitation. For the first week after admission, she was lethargic with fluctuating awareness and mutism during the day but poor sleep at night. Workup for acute encephalopathy including autoimmune, infective, toxicology, metabolic and vasculitic screening showed negative findings. Erythrocyte sedimentation rate was markedly elevated and ...published_or_final_versionThe 1st Hong Kong Neurological Congress cum 22nd Annual Scientific Meeting of the Hong Kong Neurological Society, Hong Kong, 6-8 November 2009. In Hong Kong Medical Journal, 2009, v. 15 n. 6, suppl. 7, p. 47, abstract P1

The origin of [C II] 157 μm emission in a five-component interstellar medium : the case of NGC 3184 and NGC 628

With its relatively low ionization potential, C+ can be found throughout the interstellar medium (ISM) and provides one of the main cooling channels of the ISM via the [C II] 157 mu m emission. While the strength of the [C II] line correlates with the star formation rate, the contributions of the various gas phases to the [C II] emission on galactic scales are not well established. In this study we establish an empirical multi-component model of the ISM, including dense H II regions, dense photon dissociation regions (PDRs), the warm ionized medium (WIM), low density and G(0). surfaces of molecular clouds (SfMCs), and the cold neutral medium (CNM). We test our model on ten luminous regions within the two nearby galaxies NGC 3184 and NGC 628. on angular scales of 500-600 pc. Both galaxies are part of the Herschel. key program. KINGFISH,. and are complemented by a large set of ancillary ground-and space-based data. The five modeled phases together reproduce the observed [C II] emission quite well, overpredicting the total flux slightly (about 45%) averaged over all regions. We find that dense PDRs are the dominating component, contributing 68% of the [C II] flux on average, followed by the WIM and the SfMCs, with mean contributions of about half of the contribution from dense PDRs, each. CNM and dense H II regions are only minor contributors with less than 5% each. These estimates are averaged over the selected regions, but the relative contributions of the various phases to the [C II] flux vary significantly between these regions

Comparing [C II], H I, and CO dynamics of nearby galaxies

The HI and CO components of the interstellar medium (ISM) are usually used to derive the dynamical mass M-dyn of nearby galaxies. Both components become too faint to be used as a tracer in observations of high-redshift galaxies. In those cases, the 158 mu m line of atomic carbon ([CII]) may be the only way to derive M-dyn. As the distribution and kinematics of the ISM tracer affects the determination of M-dyn, it is important to quantify the relative distributions of HI, CO, and [CII]. HI and CO are well-characterized observationally, however, for [CII] only very few measurements exist. Here we compare observations of CO, HI, and [CII] emission of a sample of nearby galaxies, drawn from the HERACLES, THINGS, and KINGFISH surveys. We find that within R-25, the average [CII] exponential radial profile is slightly shallower than that of the CO, but much steeper than the HI distribution. This is also reflected in the integrated spectrum ("global profile"), where the [CII] spectrum looks more like that of the CO than that of the HI. For one galaxy, a spectrally resolved comparison of integrated spectra was possible; other comparisons were limited by the intrinsic line-widths of the galaxies and the coarse velocity resolution of the [CII] data. Using high-spectral-resolution SOFIA [CII] data of a number of star forming regions in two nearby galaxies, we find that their [CII] linewidths agree better with those of the CO than the HI. As the radial extent of a given ISM tracer is a key input in deriving M-dyn from spatially unresolved data, we conclude that the relevant length-scale to use in determining M-dyn based on [CII] data, is that of the well-characterized CO distribution. This length scale is similar to that of the optical disk

GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome

OBJECTIVE: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. METHODS: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. RESULTS: Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. CONCLUSIONS: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia