The use of cerebral computed tomographic angiography as an ancillary investigation to support a clinical diagnosis of death using neurological criteria: a consensus guideline.

This multidisciplinary consensus statement was produced following a recommendation by the Faculty of Intensive Care Medicine to develop a UK guideline for ancillary investigation, when one is required, to support the diagnosis of death using neurological criteria. A multidisciplinary panel reviewed the literature and UK practice in the diagnosis of death using neurological criteria and recommended cerebral CT angiography as the ancillary investigation of choice when death cannot be confirmed by clinical criteria alone. Cerebral CT angiography has been shown to have 100% specificity in supporting a diagnosis of death using neurological criteria and is an investigation available in all acute hospitals in the UK. A standardised technique for performing the investigation is described alongside a reporting template. The panel were unable to make recommendations for ancillary testing in children or patients receiving extracorporeal membrane oxygenation.

Accumulation of Brain Hypointense Foci on Susceptibility-Weighted Imaging in Childhood Ataxia Telangiectasia.

BACKGROUND AND PURPOSE: SWI hypointense cerebral lesions have been reported in adults with the inherited cerebellar neurodegenerative disorder ataxia telangiectasia. This study aims to establish the prevalence, age-dependency, and spatial distribution of these lesions in children and young people with ataxia telangiectasia. MATERIALS AND METHODS: Participants with classic ataxia telangiectasia and matched controls underwent SWI acquisition at 3T at 1 or 2 time points. SWI hypointense lesions were manually labeled according to the Microbleed Anatomical Rating Scale. Differences in prevalence of lesion number between groups with ataxia telangiectasia and without ataxia telangiectasia were tested with the Fisher exact test, and differences in age between participants with ataxia telangiectasia with and without lesions were tested using independent samples Mann-Whitney U test. The relationship between age and lesion number was modeled as an exponential function. RESULTS: Analyzable SWI datasets from 17 participants with ataxia telangiectasia (with median age at first scan of 12.4 years; range, 4.6-20.2 years; 8 [47%] were female) and 22 matched healthy controls showed prevalence of SWI hypointense lesions in 41% of participants with ataxia telangiectasia and 0% in controls (P = .001, Fisher exact test). Lesions were exclusively supratentorial and predominantly lobar. Participants with ataxia telangiectasia with SWI hypointense lesions were older than those without (median age 5.2 years versus 9.3 years, U = 10.5, P = .014). An exponential curve described the relationship between age and lesion number (R 2 = 0.67). CONCLUSIONS: SWI hypointense lesions are common in children and young people with ataxia telangiectasia, accumulating from 12 years of age onward. In contrast to cerebellar-dominant neurodegeneration in ataxia telangiectasia, SWI hypointense lesions were exclusively supratentorial. Further investigation is needed to establish the clinical relevance of these imaging-detected lesions.

Large-scale network dysfunction in vascular cognitive disorder supports connectional diaschisis in advanced arteriosclerosis.

BACKGROUND AND PURPOSE: The interrelation of cognitive performance, cerebrovascular damage and brain functional connectivity (FC) in advanced arteriosclerosis remains unclear. Our aim was to investigate the associations between FC, white matter damage and cognitive impairment in carotid artery disease. METHODS: Seventy-one participants with a recent cerebrovascular event and with written informed consent underwent resting-state functional magnetic resonance imaging and the Addenbrooke's Cognitive Examination - Revised (ACE-R). Network and inter-hemispheric FC metrics were compared between cognitively normal and impaired subjects, and interrelated with cognition. In order to explore the nature of FC changes, their associations with microstructural damage of related white matter tracts and cognitive performance were investigated, followed by mediation analysis. RESULTS: Participants with global cognitive impairment showed reduced FC compared to the cognitively intact subjects within the central executive network (CEN), and between hemispheres. Patients with executive dysfunction had decreased CEN FC whilst patients with memory loss demonstrated low FC in both the CEN and the default mode network (DMN). Global performance correlated with connectivity metrics of the CEN hub with DMN nodes, and between hemispheres. Cingulum mean diffusivity (MD) was negatively correlated with ACE-R and CEN-DMN FC. The cingulum MD-cognition association was partially mediated by CEN-DMN FC. CONCLUSIONS: Long-range functional disconnection of the CEN with DMN nodes is the main feature of cognitive impairment in elderly subjects with symptomatic carotid artery disease. Our findings provide further support for the connectional diaschisis concept of vascular cognitive disorder, and highlight a mediation role of functional disconnection to explain associations between microstructural white matter tract damage and cognitive impairment.

Measuring Cerebral and Cerebellar Glutathione in Children Using 1H MEGA-PRESS MRS.

BACKGROUND AND PURPOSE: Glutathione is an important antioxidant in the human brain and therefore of interest in neurodegenerative disorders. The purpose of this study was to investigate the feasibility of measuring glutathione in healthy nonsedated children by using the 1H Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence at 3T and to compare glutathione levels between the medial parietal gray matter and the cerebellum. MATERIALS AND METHODS: Glutathione was measured using MEGA-PRESS MRS (TR = 1.8 seconds, TE = 131 ms) in the parietal gray matter (35 × 25 × 20 mm3) of 6 healthy children (10.0 ± 2.4 years of age; range, 7-14 years; 3 males) and in the cerebellum of 11 healthy children (12.0 ± 2.7 years of age; range, 7-16 years; 6 males). A postprocessing pipeline was developed to account for frequency and phase variations in the edited ON and nonedited OFF spectra. Metabolites were quantified with LCModel and reported both as ratios and water-scaled values. Glutathione was quantified in the ON-OFF spectra, whereas total NAA, total Cho, total Cr, mIns, Glx, and taurine were quantified in the OFF spectra. RESULTS: We found significantly higher glutathione, total Cho, total Cr, mIns, and taurine in the cerebellum (P < .01). Glx and total NAA were significantly higher in the parietal gray matter (P < .01). There was no significant difference in glutathione/total Cr (P = .93) between parietal gray matter and cerebellum. CONCLUSIONS: We demonstrated that glutathione measurement in nonsedated children is feasible. We found significantly higher glutathione in the cerebellum compared with the parietal gray matter. Metabolite differences between the parietal gray matter and cerebellum agree with published MRS data in adults.

Acromegaly.

Acromegaly is a rare, chronic, progressive disease characterized by an excess secretion of growth hormone (GH) and increased circulating insulin-like growth factor 1 (IGF-1) concentrations. It is caused by a pituitary adenoma in the vast majority of cases. The clinical diagnosis, based on symptoms related to GH excess, is often delayed due to the insidious nature of the disease. Consequently, patients often have established systemic complications at diagnosis with increased morbidity and premature mortality. Serum IGF-1 measurement is recommended as the initial screen for patients with suspected acromegaly. The gold standard diagnostic test remains the oral glucose tolerance test with concomitant GH measurement. Therapy for acromegaly is targeted at decreasing GH and IGF-1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, medical therapies (such as dopamine agonists, somatostatin receptor agonists and the GH receptor antagonist pegvisomant) and radiotherapy. A multidisciplinary approach is recommended with often a requirement for combined treatment modalities. With disease control, associated morbidity and mortality can be reduced. The recently published evidence-based guidelines by the Endocrine society addressed important clinical issues regarding the evaluation and management of acromegaly. This review discusses advances in our understanding of the pathophysiology of acromegaly, diagnosis of various forms of the disease and focuses on current treatment modalities, and on future pharmacological therapies for patients with acromegaly.

Endocrinopathies and renal outcomes in lithium therapy: impact of lithium toxicity.

BACKGROUND: Lithium is the mainstay of treatment for bipolar disorder, mania and an augmentation therapy in patients with treatment resistant depression. It has a narrow therapeutic index, with recognized adverse multi-system and endocrine side effects. AIM: To assess the impact of lithium therapy, in particular lithium toxicity, on the development of endocrine and renal disorders in a cohort of patients in a single tertiary referral centre in Ireland. STUDY DESIGN: A retrospective analysis was performed of the prevalence of lithium toxicity and renal, thyroid and parathyroid dysfunction in our study population. METHODS: We collected laboratory data from the Clinical Chemistry department of the Adelaide and Meath Hospital incorporating the National Children's Hospital (AMNCH), Dublin, Ireland. Our study population included all patients who had at least one serum lithium measurement from January 1st 2000 to December 31st 2014 inclusive. RESULTS: A total of 580 patients were included in the study. Among our study group, 70 patients (12.1%) had 1 toxic lithium measurement (lithium level >1.2 mmol/l). 27.8% (n > 161) of patients developed stage 3 Chronic kidney Disease (CKD) or higher, which was commoner in those patients who developed toxic lithium levels (P < 0.0001) and in those who developed hypernatraemia (P > 0.0001). 16.2% of patients (n > 94) had one serum sodium >145 mmol/l during follow up. 60 patients(10.3%) had a TSH >10 mU/l, while complete suppression of TSH (<0.05 mU/l) was observed in 22 patients (3.8%) during follow-up. 4% (n > 37) of the study population had ≥1 serum corrected calcium level > 2.55 mmol/l, and 4 patients had biochemical confirmation of primary hyperparathyroidism but PTH levels were only performed in 2.8% (n > 16) of the studypopulation. CONCLUSION: Stage 3 CKD is common in patients receiving lithium therapy. Lithium toxicity is associated with CKD and hypernatraemia. Thyroid dysfunction and hypercalcaemia are common in patients receiving lithium therapy. Patients receiving lithium therapy require surveillance of renal, thyroid and bone biochemistry.

Heterogenous patterns of recovery of thirst in adult patients with adipsic diabetes insipidus.

BACKGROUND: The natural history of adipsic diabetes insipidus (ADI) is not well described, and reports of recovery of thirst are rare. DESIGN AND METHODS: Case histories presentation. ADI was identified by demonstrating absent thirst and arginine vasopressin (AVP) responses to hypertonic saline infusion. RESULTS: Twelve patients with ADI were identified (craniopharyngioma 5, anterior communicating artery aneurysm (ACOM) repair 4, congenital 1, neurosarcoidosis 1, prolactinoma 1). Three patients died. Six patients had permanent ADI. Three patients had recovery of thirst, with a heterogenous pattern of recovery. In the first case, ADI had developed after clipping of an ACOM aneurysm. Ten years after surgery; he sensed the return of thirst; repeated hypertonic saline infusion showed recovery of thirst and AVP secretion. In the second case, a 41-year-old female with an intrasellar craniopharyngioma developed post-operative ADI with persistent hypernatremia. Two years post-operatively, she complained of thirst, and hypertonic saline infusion showed normalization of thirst but absent AVP responses, confirming recovery of thirst, but with persistent diabetes insipidus (DI). In the third case, a 29-year-old Caucasian had craniotomy and radiotherapy for craniopharyngioma and developed ADI post-operatively. Eight years post-op, she presented with thirst, seizures and pNa of 112 mmol/l. Hypertonic saline infusion showed persistent DI but thirst responses typical of compulsive water drinking; she has had recurrent hyponatraemia since then. CONCLUSIONS: We report that 3/12 patients with ADI recovered thirst after longstanding adipsia with heterogenous pattern of recovery. Both the mortality of 25% and the recovery rate of 25% should be considered when planning long-term surveillance.

Conducting clinical research in community mental health settings: Opportunities and challenges.

Tremendous progress has been made in the past decade surrounding the underlying mechanisms and treatment of neuropsychiatric disease. Technological advancements and a broadened research paradigm have contributed to the understanding of the neurochemistry, brain function and brain circuitry involved in neuropsychiatric disorders. The predominant area of unmet medical need in the United States is major psychiatric disorders, and major depressive disorder is the leading cause of disability for ages 15-44. Total spending on research and development by the pharmaceutical industry has grown exponentially during the past decade, but fewer new molecular entities (NME) for the treatment of major psychiatric disorders have received regulatory approvals compared to other therapeutic areas. Though significant expansion has occurred during the "decade of the brain", the translation of clinical trials outcomes into the community mental health setting is deficient. Randomized controlled trials (RCTs) have been the standard approach to clinical evaluation of the safety and efficacy of NMEs for the past 60 years; however, there are significant barriers and skepticism in the implementation of evidence-based outcomes into clinical practice. Recruitment of patients, shortages of experienced clinical researchers, regulatory requirements and later translation of outcomes into clinical practice are ever growing problems faced by investigators. The community mental health setting presents particular barriers in the replication of therapeutic outcomes from RCTs. The diagnostic complexity of major psychiatric diseases and the highly selective patient populations involved in clinical trials lend to the gap in translation from the "bench to the bedside". The community mental health setting lends to a diverse patient population with numerous co-morbidities and environmental factors that are unaccounted in the average RCT. While we acknowledge the enormous complexity in developing novel and innovative treatments for major psychiatric disorders, we must continue to improve the translatability of clinical trials to real world settings. Progress has been rather slow but as the gap in treatment effectiveness is reduced, so will costs and barriers in community mental health.

Metrics and textural features of MRI diffusion to improve classification of pediatric posterior fossa tumors.

BACKGROUND AND PURPOSE: Qualitative radiologic MR imaging review affords limited differentiation among types of pediatric posterior fossa brain tumors and cannot detect histologic or molecular subtypes, which could help to stratify treatment. This study aimed to improve current posterior fossa discrimination of histologic tumor type by using support vector machine classifiers on quantitative MR imaging features. MATERIALS AND METHODS: This retrospective study included preoperative MRI in 40 children with posterior fossa tumors (17 medulloblastomas, 16 pilocytic astrocytomas, and 7 ependymomas). Shape, histogram, and textural features were computed from contrast-enhanced T2WI and T1WI and diffusivity (ADC) maps. Combinations of features were used to train tumor-type-specific classifiers for medulloblastoma, pilocytic astrocytoma, and ependymoma types in separation and as a joint posterior fossa classifier. A tumor-subtype classifier was also produced for classic medulloblastoma. The performance of different classifiers was assessed and compared by using randomly selected subsets of training and test data. RESULTS: ADC histogram features (25th and 75th percentiles and skewness) yielded the best classification of tumor type (on average >95.8% of medulloblastomas, >96.9% of pilocytic astrocytomas, and >94.3% of ependymomas by using 8 training samples). The resulting joint posterior fossa classifier correctly assigned >91.4% of the posterior fossa tumors. For subtype classification, 89.4% of classic medulloblastomas were correctly classified on the basis of ADC texture features extracted from the Gray-Level Co-Occurence Matrix. CONCLUSIONS: Support vector machine-based classifiers using ADC histogram features yielded very good discrimination among pediatric posterior fossa tumor types, and ADC textural features show promise for further subtype discrimination. These findings suggest an added diagnostic value of quantitative feature analysis of diffusion MR imaging in pediatric neuro-oncology.

Patterns of accidental craniocerebral injury occurring in early childhood.

OBJECTIVE: To describe the range of intracranial injuries encountered in 0-2-year-olds in cases of accidental head injury where the mechanism of trauma was well characterised and to assess the clinical consequences. DESIGN: A retrospective review of imaging and clinical data. SETTING: Two tertiary paediatric referral centres. PATIENTS: All children aged 0-2 undergoing cranial CT as indicated by National Institute for Health and Clinical Excellence guidance for head injury from 2006 to 2011. After exclusion criteria, 149 patients were included. MAIN OUTCOME MEASURES: Rates of skull fracture, intracranial haemorrhage, parenchymal injuries and ischaemic change per type of mechanism of injury. Rates of neurological sequelae on follow-up. RESULTS: Skull fractures were demonstrated in 54 (36%) patients of whom 17 (11%) had thin underlying subdural haemorrhage (SDH). Extradural haemorrhage complicated one fracture and two cases of isolated subdural haematomas were seen without skull fracture. Radiologically evident brain parenchymal injuries were present in three patients, all with mechanisms of injury involving high levels of force; severe neurological sequelae were only seen in one patient, who had diffuse hypoxic-ischaemic damage at presentation and whose (accidental) mechanism of injury involved extensive acceleration/deceleration/translational forces. CONCLUSIONS: Skull fractures and focal SDH are relatively common following minor trauma in this age group but in the vast majority of cases there are no long-term neurological sequelae. Conversely, diffuse brain injury with severe subsequent neurological impairment was only seen in patients with a correspondingly severe mechanism of injury.

Don't neglect 'neglect'- an update on post stroke neglect.

OBJECTIVES: Post-stroke neglect is common and an independent predictor of functional outcome. Assessment of neglect is very demanding, the treatment extremely difficult and the literature vast; we performed a literature search for all aspects of this difficult subject. METHODS: We searched the PubMed, EMBASE databases and historical manuals for authoritative studies on post stroke neglect between 1951 and 2011. FINDINGS: There is a great dearth of randomised controlled data on neglect because standardised assessment does not occur frequently. Eighty-eight manuscripts were identified in the literature, which were quite heterogeneous in their content and addressing diverse aspects of this clinical entity. INTERPRETATION AND IMPLICATIONS: The most important historical papers were selected along with the most widely accepted and proven strategies for assessment and treatment. Standardised assessment of neglect does not always occur, but several useful strategies are available and are described in the following sections.

The thoracic anterior spinal cord adhesion syndrome.

OBJECTIVES: This study included a series of middle-aged male and female patients who presented with chronic anterior hemicord dysfunction progressing to paraplegia. Imaging of anterior thoracic cord displacement by either a dural adhesion or a dural defect with associated cord herniation is presented. METHODS: This is a retrospective review of cases referred to a tertiary neuroscience centre over a 19-year period. Imaging series were classified by two experienced neuroradiologists against several criteria and correlated with clinical examination and/or findings at surgery. RESULTS: 16 cases were available for full review. Nine were considered to represent adhesions (four confirmed surgically) and four to represent true herniation (three confirmed surgically). In the three remaining cases the diagnosis was radiologically uncertain. CONCLUSION: The authors propose "thoracic anterior spinal cord adhesion syndrome" as a novel term to describe this patient cohort and suggest appropriate clinicoradiological features for diagnosis. Several possible aetiologies are also suggested, with disc rupture and inflammation followed by disc resorption and dural pocket formation being a possible mechanism predisposing to herniation at the extreme end of a clinicopathological spectrum.

Targeting cognitive deficits in schizophrenia: a review of the development of a new class of medicines from the perspective of community mental health researchers.

INTRODUCTION: Schizophrenia is a chronic disorder associated with positive and negative symptoms and wide-ranging deficits in neurocognitive function. Neurocognitive deficits are considered to be the core pathophysiological symptoms of the illness. Neurocognitive deficits are also closely associated with functional outcome. At present, cognitive deficits remain one of the most important unmet therapeutic needs in schizophrenia. AREAS COVERED: Neuroscientific discoveries over the past decades have enriched our understanding of the neurobiological mechanism underlying cognitive deficits in schizophrenia. This research has identified new molecular mechanisms and processes as promising pharmacological targets. However, in spite of extensive efforts to develop a new class of cognitive-enhancing medicines for the treatment of schizophrenia over the past 5 years, no novel pharmacological agents have received the regulatory approvals required by the Food and Drug Administration. The efficacy and safety outcomes from selective Phase II clinical trials are reviewed. EXPERT OPINION: The evolving concept of neurocognition and the current guidelines for the design and methodology of clinical trials of cognitive-enhancing drugs for the treatment of individuals with schizophrenia are critically examined. The future directions in the development of cognitive-enhancing medicines for the treatment of schizophrenia from the perspective of clinicians and researchers from community mental health settings are discussed.

Is there a causal relationship between the hypoxia-ischaemia associated with cardiorespiratory arrest and subdural haematomas? An observational study.

The aim of this study was to determine the frequency of subdural haematomas (SDHs) occurring in infants presenting following atraumatic cardiorespiratory collapse. This study was a review of retrospective case notes, brain imaging and post-mortem examinations carried out in the paediatric intensive care unit (PICU) and emergency department (ED) in a tertiary paediatric centre in the UK. The study included infants and children less than 4 years old dying in the ED or admitted to the PICU after atraumatic cardiorespiratory arrest. We identified macroscopic SDHs on brain imaging or post-mortem examination. Of those children who experienced a cardiorespiratory arrest from a non-traumatic cause and met inclusion criteria, 33 presented and died in the ED and 17 were admitted to the PICU. These children had a post-mortem examination, brain imaging or both. None of these infants had a significant SDH. One child had a small clot adherent to the dura found on post-mortem and two had microscopic intradural haemorrhage, but it is unclear in each case whether this was artefact, as each had otherwise normal brains. Subdural haematoma arising in infants or young children in the context of catastrophic cardiorespiratory compromise from a non-traumatic cause was not observed.