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Background\ud \ud Glutathione (GSH) is an important brain antioxidant and a number of studies have reported its measurement by edited and nonedited localized 1H spectroscopy techniques within a range of applications in healthy volunteers and disease states. Good test–retest reproducibility is key when assessing the efficacy of treatments aimed at modulating GSH levels within the central nervous system or when noninvasively assessing changes in GSH content over time.\ud \ud \ud \ud Purpose\ud \ud To evaluate the intraday (in vitro and in vivo) and 1-month apart (in vivo) test–retest reproducibility of GSH measurements from GSH-edited MEGA-PRESS acquisitions at 3 T in a phantom and in the brain of a cohort of middle-aged and older healthy volunteers.\ud \ud \ud \ud Study Type\ud \ud Prospective.\ud \ud \ud \ud Subjects/Phantoms\ud \ud A phantom containing physiological concentrations of GSH and metabolites with overlapping spectral signatures and 10 healthy volunteers (4 F, 6 M, 55 ± 14 years old).\ud \ud \ud \ud Field strength/Sequence\ud \ud GSH-edited spectra were acquired at 3 T using the MEGA-PRESS sequence.\ud \ud \ud \ud Assessment\ud \ud The phantom was scanned twice and the healthy subjects were scanned three times (on two separate days, 1 month apart). GSH was quantified from each acquisition, with the in vivo voxels placed at the primary motor cortex (PMC) and the occipital cortex (OCC).\ud \ud \ud \ud Statistical Tests\ud \ud Mean coefficients of variation (CV) were used to assess short-term (in vitro and in vivo) and longer-term (in vivo) test–retest reproducibility.\ud \ud \ud \ud Results\ud \ud In vitro, the CV was 2.3%. In vivo, the mean intraday CV was 3.3% in the PMC and 2.4% in the OCC, while the CVs at 1 month apart were 4.6% in the PMC and 7.8% in the OCC.\ud \ud \ud \ud Data Conclusion\ud \ud GSH-edited MEGA-PRESS spectroscopy allows measurement of GSH with excellent precision.\ud \ud \ud \ud Evidence Level\ud \ud 1\ud \ud \ud \ud Technical Efficacy\ud \ud Stage 2

We have previously shown that 67% of patients with newly diagnosed coeliac disease (CD) presenting to gastroenterologists have evidence of neurological dysfunction. This manifested with headache and loss of co-ordination. Furthermore 60% of these patients had abnormal brain imaging. In this follow-up study, we re-examined and re-scanned 30 patients from the original cohort of 100, seven years later. There was significant reduction in the prevalence of headaches (47% to 20%) but an increase in the prevalence of incoordination (27% to 47%). Although those patients with coordination problems at baseline reported improvement on the gluten free diet (GFD), there were 7 patients reporting incoordination not present at baseline. All 7 patients had positive serology for one or more gluten-sensitivity related antibodies at follow-up. In total, 50% of the whole follow-up cohort were positive for one or more gluten-related antibodies. A comparison between the baseline and follow-up brain imaging showed a greater rate of cerebellar grey matter atrophy in the antibody positive group compared to the antibody negative group. Patients with CD who do not adhere to a strict GFD and are serological positive are at risk of developing ataxia, and have a significantly higher rate of cerebellar atrophy when compared to patients with negative serology. This highlights the importance of regular review and close monitoring.

Background\ud \ud Osteolysis causes recurrent pain and disability after total hip arthroplasty. We investigated the effect of the human monoclonal antibody denosumab on osteolytic lesion activity in patients undergoing revision total hip arthroplasty surgery to show the biological proof of concept for a non-surgical treatment for the disease.\ud \ud \ud Methods\ud \ud We did a phase 2, randomised, double-blind, placebo-controlled, proof of concept superiority trial at Sheffield Teaching Hospitals, Sheffield, UK. Eligible patients aged 30 years or older and scheduled for revision surgery for symptomatic, radiographically confirmed osteolysis were randomly allocated (1:1) to subcutaneous denosumab (60 mg single-dose) or placebo by an independent pharmacist using a random number table. The primary outcome was the between-group difference in osteoclast number per mm of bone surface of biopsies taken from the osteolytic membrane–bone interface at surgery 8 weeks later, measured by quantitative histomorphometry in all patients who underwent revision surgery. Adverse events were analysed in all randomly assigned participants. This trial is registered with the EU Clinical Trials Register (EudraCT 2011-000541-20).\ud \ud \ud Findings\ud \ud Between Dec 12, 2012, and June 24, 2018, 51 patients were assessed for eligibility, of whom 24 were randomly assigned to study treatment. Two patients had their revision surgery cancelled for unrelated reasons, leaving 22 patients (ten in the denosumab group) for analysis of the primary outcome. There were 83% fewer osteoclasts at the osteolysis membrane–bone interface in the denosumab versus the placebo group (median 0·05 per mm [IQR 0·11] vs 0·30 mm [0·40], p=0·011). No deaths or treatment-related serious adverse events occurred. Seven adverse events, including one severe adverse event, occurred in four (36%) of 11 patients in the denosumab group. In the placebo group ten adverse events, including three severe adverse events, occurred in five (38%) of 13 patients.\ud \ud \ud Interpretation\ud \ud To our knowledge, this is the first clinical trial of an investigational drug for osteolysis that shows tissue-specific biological efficacy. These results justify the need for future trials that target earlier-stage disease to test for clinical efficacy in reducing the need for revision surgery.\ud \ud \ud Funding\ud \ud Amgen.

Background\ud \ud Clinical phenotypic heterogeneity represents a major barrier to trials in motor neuron disease (MND) and objective surrogate outcome measures are required, especially for slowly progressive patients. We assessed responsiveness of clinical, electrophysiological and radiological muscle-based assessments to detect MND-related progression.\ud \ud \ud \ud Materials and methods\ud \ud A prospective, longitudinal cohort study of 29 MND patients and 22 healthy controls was performed. Clinical measures, electrophysiological motor unit number index/size (MUNIX/MUSIX) and relative T2- and diffusion-weighted whole-body muscle magnetic resonance (MR) were assessed three times over 12 months. Multi-variable regression models assessed between-group differences, clinico-electrophysiological associations, and longitudinal changes. Standardized response means (SRMs) assessed sensitivity to change over 12 months.\ud \ud \ud \ud Results\ud \ud MND patients exhibited 18% higher whole-body mean muscle relative T2-signal than controls (95% CI 7–29%, p

Background & Aims\ud Celiac disease is an autoimmune disorder induced by ingestion of gluten that affects 1% of the population and is characterized by gastrointestinal symptoms, weight loss, and anemia. We evaluated the presence of neurologic deficits and investigated whether the presence of antibodies to TG6 increases the risk of neurologic defects in patients with a new diagnosis of celiac disease.\ud \ud Methods\ud We performed a prospective cohort study at a secondary-care gastroenterology center of 100 consecutive patients who received a new diagnosis of celiac disease based on gastroscopy and duodenal biopsy. We collected data on neurologic history, and patients were evaluated in a clinical examination along with magnetic resonance imaging (MRI) of the brain, MR spectroscopy of the cerebellum, and measurements of antibodies against TG6 in serum samples. The first 52 patients recruited underwent repeat MR spectroscopy at 1 year after a gluten-free diet (GFD). The primary aim was to establish if detection of antibodies against TG6 can be used to identify patients with celiac disease and neurologic dysfunction.\ud \ud Results\ud Gait instability was reported in 24% of the patients, persisting sensory symptoms in 12%, and frequent headaches in 42%. Gait ataxia was found in 29% of patients, nystagmus in 11%, and distal sensory loss in 10%. Sixty percent of patients had abnormal results from the MRI, 47% had abnormal results from MR spectroscopy of the cerebellum, and 25% had brain white matter lesions beyond that expected for their age group. Antibodies against TG6 were detected in serum samples from 40% of patients–these patients had significant atrophy of subcortical brain regions compared to patients without TG6 autoantibodies. In patients with abnormal results from MR spectroscopy of the cerebellum, those on the GFD had improvements detected in the repeat MR spectroscopy 1 year later.\ud \ud Conclusions\ud In a prospective cohort study of patients with a new diagnosis of celiac disease at a gastroenterology clinic, neurological deficits were common and 40% had circulating antibodies against TG6. We observed a significant reduction in volume of specific brain regions in patients with TG6 autoantibodies, providing evidence for a link between autoimmunity to TG6 and brain atrophy in patients with celiac disease. There is a need for early diagnosis, increased awareness of the neurological manifestations amongst clinicians and reinforcement of adherence to a strict GFD by patients in order to avoid permanent neurological disability.

Introduction\ud \ud Tremor is a common side effect of treatment with lithium. Its characteristics can vary and when less rhythmical, distinction from myoclonus can be difficult.\ud \ud \ud \ud Methods\ud \ud We identified 8 patients on long-term treatment with lithium that developed upper limb tremor. All patients were assessed clinically and electrophysiologically, with jerk-locked averaging (JLA) and cross-correlation (CC) analysis, and five of them underwent brain MRI examination including spectroscopy (MRS) of the cerebellum.\ud \ud \ud \ud Results\ud \ud Seven patients (6 female) had action and postural myoclonus and one a regular postural and kinetic tremor that persisted at rest. Mean age at presentation was 58 years (range 42–77) after lengthy exposure to lithium (range 7–40 years). During routine monitoring all patients had lithium levels within the recommended therapeutic range (0.4-1 mmol/l). There was clinical and/or radiological evidence (on cerebellar MRS) of cerebellar dysfunction in 6 patients. JLA and/or CC suggested a cortical generator of the myoclonus in seven patients. All seven were on antidepressants and three additionally on neuroleptics, four of them had gluten sensitivity and two reported alcohol abuse.\ud \ud \ud \ud Conclusions\ud \ud A synergistic effect of different factors appears to be contributing to the development of cortical myoclonus after chronic exposure to lithium. We hypothesise that the cerebellum is involved in the generation of cortical myoclonus in these cases and factors aetiologically linked to cerebellar pathology like gluten sensitivity and alcohol abuse may play a role in the development of myoclonus. Despite the very limited evidence in the literature, lithium induced cortical myoclonus may not be so rare.

Objective To assess clinical, electrophysiological and whole-body muscle MRI measurements of progression in patients with motor neuron disease (MND), as tools for future clinical trials, and to probe pathophysiological mechanisms in vivo.\ud Methods A prospective longitudinal observational clinico-electrophysiological and radiological cohort study was performed. Twenty-nine MND patients and 22 age and gender-matched healthy controls were assessed with clinical measures, electrophysiological motor unit number index (MUNIX) and T2-weighted whole-body muscle MRI, at first clinic presentation and four months later. Between-group differences and associations were assessed using age and gender-adjusted multivariable regression models. Within-subject longitudinal changes were assessed using paired t-tests. Patterns of disease spread were modelled using mixed-effects multivariable regression, assessing associations between muscle relative T2 signal and anatomical adjacency to site of clinical onset.\ud Results MND patients had 30% higher relative T2 muscle signal than controls at baseline (all-regions mean, 95%CI 15%, 45%, p

Mitochondrial disease is phenotypically and genetically heterogeneous with an estimated prevalence of 1 in 4,300.1 Mutations in the POLG gene, encoding the catalytic subunit of DNA polymerase gamma, are an important cause of mitochondrial disease. The spectrum of clinical manifestations in POLG-related mitochondrial disease is variable,2 with disease onset ranging from adulthood-onset dominant or recessive progressive external ophthalmoplegia (chronic progressive external ophthalmoplegia), ataxia-neuropathy spectrum, myoclonic epilepsy, myopathy, and sensory ataxia to childhood-onset Alpers syndrome, which is characterized by intractable seizures, psychomotor regression, and hepatic impairment. Epilepsy is a poor prognostic factor in POLG mutations,3 and the onset of epilepsy often clusters in childhood (

OBJECTIVES: Non-coeliac gluten sensitivity (NCGS) refers to patients with primarily gastrointestinal symptoms\ud without enteropathy that symptomatically benefi t from gluten-free diet (GFD). Little is known about\ud its pathophysiology, propensity to neurological manifestations, and if these differ from patients with\ud coeliac disease (CD). We investigated the clinical and immunological characteristics of patients\ud presenting with neurological manifestations with CD and those with NCGS.\ud METHODS: We compared clinical, neurophysiological, and imaging data of patients with CD and NCGS\ud presenting with neurological dysfunction assessed and followed up regularly over a period of\ud 20 years.\ud RESULTS: Out of 700 patients, 562 were included. Exclusion criteria included no bowel biopsy to confi rm\ud CD, no HLA type available, and failure to adhere to GFD. All patients presented with neurological\ud dysfunction and had circulating anti-gliadin antibodies. Out of 562 patients, 228 (41%) had\ud evidence of enteropathy (Group 1, CD) and 334 (59%) did not (Group 2, NCGS). The most common\ud neurological manifestations were cerebellar ataxia, peripheral neuropathy, and encephalopathy. There\ud was a greater proportion of patients with encephalopathy in Group 1 and with a greater proportion\ud of neuropathy in Group 2. The severity of ataxia did not differ between the two groups. Patients in\ud Group 1 had more severe neuropathy. All patients from both groups responded to gluten-free diet.\ud Anti-tissue transglutaminase (TG2) antibodies were found in 91% of patients in Group 1 and in\ud 29% of patients in Group 2. Comparison between those patients in Group 2 with HLA-DQ2/DQ8 and\ud those without as well as those with positive TG2 compared with those with negative TG2 antibodies\ud identifi ed no differences within these subgroups. Serological positivity for TG6 antibodies was similar\ud in the two groups (67 and 60%).\ud CONCLUSIONS: The neurological manifestations of CD and NCGS are similar and equally responsive to a GFD\ud suggestive of common pathophysiological mechanisms.

Background Birth-related acute profound hypoxic–ischaemic\ud brain injury has specific patterns of damage including the\ud paracentral lobules.\ud Objective To test the hypothesis that there is anatomically coherent\ud regional volume loss of the corpus callosum as a result of\ud this hemispheric abnormality.\ud Materials and methods Study subjects included 13 children\ud with proven acute profound hypoxic–ischaemic brain injury\ud and 13 children with developmental delay but no brain abnormalities.\ud A computerised system divided the corpus callosum\ud into 100 segments, measuring each width. Principal component\ud analysis grouped the widths into contiguous anatomical regions.\ud We conducted analysis of variance of corpus callosum widths as\ud well as support vector machine stratification into patient groups.\ud Results There was statistically significant narrowing of the\ud mid–posterior body and genu of the corpus callosum in children\ud with hypoxic–ischaemic brain injury. Support vector machine\ud analysis yielded over 95% accuracy in patient group stratification\ud using the corpus callosum centile widths.\ud Conclusion Focal volume loss is seen in the corpus callosum\ud of children with hypoxic–ischaemic brain injury secondary to\ud loss of commissural fibres arising in the paracentral lobules.\ud Support vector machine stratification into the hypoxic–ischaemic\ud brain injury group or the control group on the basis of\ud corpus callosum width is highly accurate and points towards\ud rapid clinical translation of this technique as a potential biomarker\ud of hypoxic–ischaemic brain injury