An In-vivo 1H-MRS short-echo time technique at 7T: Quantification of metabolites in chronic multiple sclerosis and neuromyelitis optica brain lesions and normal appearing brain tissue.

Magnetic Resonance Spectroscopy (MRS) allows for the non-invasive quantification of neurochemicals and has the potential to differentiate between the pathologically distinct diseases, multiple sclerosis (MS) and AQP4Ab-positive neuromyelitis optica spectrum disorder (AQP4Ab-NMOSD). In this study we characterised the metabolite profiles of brain lesions in 11 MS and 4 AQP4Ab-NMOSD patients using an optimised MRS methodology at ultra-high field strength (7T) incorporating correction for T2 water relaxation differences between lesioned and normal tissue. MS metabolite results were in keeping with the existing literature: total N-acetylaspartate (NAA) was lower in lesions compared to normal appearing brain white matter (NAWM) with reciprocal findings for myo-Inositol. An unexpected subtlety revealed by our technique was that total NAA differences were likely driven by NAA-glutamate (NAAG), a ubiquitous CNS molecule with functions quite distinct from NAA though commonly quantified together with NAA in MRS studies as total NAA. Surprisingly, AQP4Ab-NMOSD showed no significant differences for total NAA, NAA, NAAG or myo-Inositol between lesion and NAWM sites, nor were there any differences between MS and AQP4Ab-NMOSD for a priori hypotheses. Post-hoc testing revealed a significant correlation between NAWM Ins:NAA and disability (as measured by EDSS) for disease groups combined, driven by the AP4Ab-NMOSD group. Utilising an optimised MRS methodology, our study highlights some under-explored subtleties in MRS profiles, such as the absence of myo-Inositol concentration differences in AQP4Ab-NMOSD brain lesions versus NAWM and the potential influence of NAAG differences between lesions and normal appearing white matter in MS.

Electroconvulsive therapy related autobiographical amnesia: a review and case report.

Introduction: While short-term cognitive impairment following electroconvulsive therapy (ECT) is well described and acknowledged, the relationship between ECT and persistent memory impairment, particularly of autobiographical memory, has been controversial. Methods: We describe the case of a 70-year-old consultant neurophysiologist, AW, who developed prominent, selective autobiographical memory loss following two courses of ECT for treatment-resistant depression. Results: His performance on standard measures of IQ, semantic and episodic memory, executive function and mood was normal, while he performed significantly below controls on measures of episodic autobiographical memory. Conclusions: Explanations in terms of mood-related memory loss and somatoform disorder appear unlikely. We relate AW's autobiographical memory impairment, following his ECT, to reports of similar autobiographical memory impairment occurring in the context of epilepsy, and emphasise the importance of using sensitive approaches to AbM assessment.

Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease.

IMPORTANCE: Neuromyelitis optica spectrum disorders (NMOSD) can present with very similar clinical features to multiple sclerosis (MS), but the international diagnostic imaging criteria for MS are not necessarily helpful in distinguishing these two diseases. OBJECTIVE: This multicentre study tested previously reported criteria of '(1) at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or (2) the presence of a subcortical U-fibre lesion or (3) a Dawson's finger-type lesion' in an independent cohort of relapsing-remitting multiple sclerosis (RRMS) and AQP4-ab NMOSD patients and also assessed their value in myelin oligodendrocyte glycoprotein (MOG)-ab positive and ab-negative NMOSD. DESIGN: Brain MRI scans were anonymised and scored on the criteria by 2 of 3 independent raters. In case of disagreement, the final opinion was made by the third rater. PARTICIPANTS: 112 patients with NMOSD (31 AQP4-ab-positive, 21 MOG-ab-positive, 16 ab-negative) or MS (44) were selected from 3 centres (Oxford, Strasbourg and Liverpool) for the presence of brain lesions. RESULTS: MRI brain lesion distribution criteria were able to distinguish RRMS with a sensitivity of 90.9% and with a specificity of 87.1% against AQP4-ab NMOSD, 95.2% against MOG-ab NMOSD and 87.5% in the heterogenous ab-negative NMOSD cohort. Over the whole NMOSD group, the specificity was 89.7%. CONCLUSIONS: This study suggests that the brain MRI criteria for differentiating RRMS from NMOSD are sensitive and specific for all phenotypes.

Socioeconomic deprivation is an independent risk factor for behavioral problems in children with epilepsy.

AIM: The aim of this study was to examine whether socioeconomic deprivation in children with epilepsy (CWE) increases risk for behavioral problems independent of seizure factors. METHODS: A cross-sectional study was done in which parents of children attending a specialist epilepsy clinic were invited to complete a child behavior checklist (CBCL) questionnaire about their child. Medical and sociodemographic data on CWE were obtained through their pediatric neurologists. Home postal code was used to obtain quintiles of Scottish Index of Multiple Deprivation 2012 (SIMD2012) scores for individuals. Lower (1-3) quintiles correspond to higher socioeconomic deprivation. Regression analysis was used to investigate whether a lower quintile was an independent risk factor for scores >63 (significant behavioral problem). RESULTS: Parents of 87 children (42 male, mean age of 10.5years) were enrolled. Fifty-nine percent had total scores >63. A higher proportion of children from quintiles 1-3 compared to those from quintiles 4-5 had externalizing (49% vs. 25%, p=0.02) and total (54% vs. 30%, p=0.02) scores >63. Adjusted OR of quintiles 1-3 vs. 4-5 for scores >63=14.8, 95% CI=3.0, 68.0. Fewer children with scores >63 and from quintiles 1-3 were known to the child and adolescent mental health service (CAMHS) compared to those in quintiles 4-5 (p=0.01). INTERPRETATION: Socioeconomic deprivation was an independent risk factor for behavioral problems in CWE. Children with epilepsy and behavioral problems who lived in socioeconomically deprived areas received less help.

Opioid-free anaesthesia.

Adverse effects of perioperative opioids have led to the pursuit of 'opioid-free anaesthesia'. While early studies have shown that effective analgesia can be achieved without using opioids, with some reduction in unwanted effects, further research is needed to elucidate which patients may benefit most and how.

A-utrophin up-regulation in mdx skeletal muscle is independent of regeneration.

Duchenne muscular dystrophy is a fatal childhood disease caused by mutations that abolish the expression of dystrophin in muscle. Utrophin is a paralogue of dystrophin and can functionally replace it in skeletal muscle. A method to induce utrophin up-regulation in muscle should therefore be therapeutically useful in Duchenne muscular dystrophy. The search for such a method needs to be informed by an understanding of the mechanisms controlling utrophin expression in muscle. Two full length utrophin isoforms are expressed: A and B. A-utrophin is up-regulated in dystrophin deficient skeletal muscle and we sought to test the hypothesis that this up-regulation occurs as a consequence of ongoing regeneration. We measured utrophin expression by immunohistochemistry and immunoblotting in the oesophageal outer muscular layer and in gamma-irradiated limb muscle from mdx mice. Skeletal muscle in these tissues is dystrophin deficient but not regenerating; we found that A-utrophin up-regulation still occurred. We conclude that utrophin up-regulation in skeletal muscle does not depend on regeneration. An alternative hypothesis involving competition for binding sites between utrophin and dystrophin is discussed. These results have important implications for future studies aiming to effect therapeutic utrophin up-regulation in Duchenne muscular dystrophy patients.

Concentric and single fiber needle electrodes yield comparable jitter results in myasthenia gravis.

The single fiber needle electrode (SFNE), which is designed to isolate single muscle fiber action potentials, has played an important role in the diagnosis of myasthenia gravis (MG). However, the concentric needle electrode (CNE) has been recently adopted by some workers to study neuromuscular instability in MG, and reference data have also been obtained in healthy subjects. In this study we wanted to establish whether data acquired using the SFNE is comparable to that obtained using the CNE when studying patients with MG. We established reference data for our laboratory using the CNE for orbicularis oculi (OO) and extensor digitorum communis (EDC). We compared data from 24 MG patients using both SFNE and CNE and found no significant differences in mean jitter values for either muscles. We correlated the neurophysiological data obtained by either electrode with various clinical assessments, the ice pack test, OO and EDC strength measurement, and MGFA classification of disease, and we found no significant relation. We compared discomfort scores for the two needle electrodes for each muscle and found that the discomfort scores for CNE are significantly lower (P = 0.0004). We conclude that the CNE is a useful alternative electrode for studying single fiber potentials, but more reference data from normal control subjects is desirable. Muscle Nerve, 2008.

A- and B-utrophin have different expression patterns and are differentially up-regulated in mdx muscle.

Duchenne muscular dystrophy (DMD) is a fatal childhood disease caused by mutations that abolish the expression of dystrophin in muscle. Utrophin is a paralogue of dystrophin and can functionally replace it in skeletal muscle. A method to induce utrophin up-regulation in muscle should therefore be therapeutically useful in DMD. We have previously shown that there are two full-length utrophin mRNA species: A and B. Here we describe the generation and characterization of antibodies specific to A- and B-utrophin. We show that both mRNA isoforms are translated into full-length proteins, which have very different expression patterns. B-utrophin is expressed in vascular endothelial cells; A-utrophin is expressed at the neuromuscular junction, choroid plexus, pia mater, and renal glomerulus. We have analyzed the expression of A- and B-utrophin protein and RNA in dystrophin-deficient tissues. We conclude that (i) the previously described expression patterns of utrophin represent a composite of A- and B-utrophin, (ii) A- but not B-utrophin is up-regulated in dystrophin-deficient striated muscle, and (iii) this up-regulation occurs post-transcriptionally with an additional transcriptional component in skeletal muscle. These results have important implications for understanding the biology of utrophin and are crucial for future studies aiming to effect its therapeutic up-regulation in DMD patients.

Function and genetics of dystrophin and dystrophin-related proteins in muscle.

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and alpha-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.