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Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an extremely rare, autosomal recessive neurodegenerative disorder. It is caused by biallelic pathogenic variants in the ADPRS gene, which encodes an enzyme involved in DNA repair, and is characterized by exacerbations in relation to physical or emotional stress, and febrile illness. We report a 24-year-old female, who was compound heterozygous for two novel pathogenic variants revealed by whole exome sequencing. Additionally, we summarize the published cases of CONDSIAS. In our patient, onset of symptoms occurred at 5 years of age and consisted of episodes of truncal dystonic posturing, followed half a year later by sudden diplopia, dizziness, ataxia, and gait instability. Progressive hearing loss, urinary urgency, and thoracic kyphoscoliosis ensued. Present neurological examination revealed dysarthria, facial mini-myoclonus, muscle weakness and atrophy of hands and feet, leg spasticity with clonus, truncal and appendicular ataxia, and spastic-ataxic gait. Hybrid [18F]-fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) of the brain revealed cerebellar atrophy, particularly of the vermis, with corresponding hypometabolism. MRI of the spinal cord showed mild atrophy. After informed consent from the patient, we initiated experimental, off-label treatment with minocycline, a poly-ADP-polymerase (PARP) inhibitor, which has shown beneficial effects in a Drosophila fly model. The present case report expands the list of known pathogenic variants in CONDIAS and presents details of the clinical phenotype. Future studies will reveal whether PARP inhibition is an effective treatment strategy for CONDIAS., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Fingolimod is a frequently used disease-modifying therapy in relapsing-remitting multiple sclerosis. However, case reports and small observational studies indicate a highly increased risk of disease reactivation after discontinuation. We aimed to investigate the risk of radiological disease reactivation in patients discontinuing fingolimod. We performed a nationwide cohort study in Denmark, including patients who discontinued fingolimod between January 2014 and January 2023. Eligibility was a diagnosis with relapsing-remitting multiple sclerosis and two MRIs performed respectively within 1 year before and after discontinuing fingolimod. The included patients were compared with those discontinuing dimethyl fumarate with the same eligibility criteria in an unadjusted and matched propensity score analysis. Matching was done on age, sex, Expanded Disability Status Scale, MRI data, cause for treatment discontinuation, treatment duration and relapse rate. The main outcome was the presence of new T 2 lesions on the first MRI after treatment discontinuation. To identify high-risk patients among those discontinuing fingolimod, we made a predictive model assessing risk factors for obtaining new T 2 lesions. Of 1324 patients discontinuing fingolimod in the study period, 752 were eligible for inclusion [mean age (standard deviation), years, 41 (10); 552 females (73%); median Expanded Disability Status Scale (Q1-Q3), 2.5 (2.0-3.5); mean disease duration (standard deviation), years, 12 (8)]. Of 2044 patients discontinuing dimethyl fumarate in the study period, 957 were eligible for inclusion, presenting similar baseline characteristics. Among patients discontinuing fingolimod, 127 (17%) had 1-2 new T 2 lesions, and 124 (17%) had ≥3 new T 2 lesions compared with 114 (12%) and 45 (5%), respectively, for those discontinuing dimethyl fumarate, corresponding to odds ratios (95% confidence interval) of 1.8 (1.3-2.3) and 4.4 (3.1-6.3). The predictive model, including 509 of the 752 patients discontinuing fingolimod, showed a highly increased risk of new T 2 lesions among those with disease activity during fingolimod treatment and among females under 40 years. This nationwide study suggests that discontinuing fingolimod in some cases carries a risk of developing new T 2 lesions, emphasizing the importance of clinical awareness. If feasible, clinicians should prioritize the prompt initiation of new disease-modifying therapies, particularly among young females., Competing Interests: M.F.W.-H. has served on the scientific advisory board for Sanofi and has received honoraria for lecturing for Novartis and Sanofi. R.P.H. has served on the scientific advisory board for Novartis and received honoraria for lecturing for Novartis and Sanofi. A.H. has served on the scientific advisory board for Merck and received honoraria for lecturing for Biogen and Merck. A.R.L. reports no competing interests. M.M. has served on the scientific advisory board for Biogen, Sanofi, Roche, Novartis, Merck and AbbVie, has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi and Genzyme and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck and Novartis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Purpose: The endocannabinoid system (ECS) has been found altered in patients with multiple sclerosis (MS). However, whether the ECS alteration is present in the early stage of MS remains unknown. First, we aimed to compare the ECS profile between newly diagnosed MS patients and healthy controls (HCs). Next, we explored the association of the ECS, biomarkers of inflammation, and clinical parameters in newly diagnosed MS patients., Methods: Whole blood gene expression of ECS components and levels of endocannabinoids in plasma were measured by real-time quantitative polymerase chain reaction and ultra-high-pressure liquid chromatography-mass spectrometry, respectively, in 66 untreated MS patients and 46 HCs., Results: No differences were found in the gene expression or plasma levels of the selected ECS components between newly diagnosed MS patients and HCs. Interferon-γ, encoded by the gene IFNG, correlated positively (ρ = 0.60) with the expression of G protein-coupled receptor 55 (GPR55), and interleukin1β (IL1B) correlated negatively (ρ = -0.50) with cannabinoid receptor 2 (CNR2) in HCs., Conclusions: We found no alteration in the peripheral ECS between untreated patients with MS and HC. Furthermore, our results indicate that the ECS has a minor overall involvement in the early stage of MS on inflammatory markers and clinical parameters when compared with HCs., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

We conducted this Systematic Review to create an overview of the currently existing Artificial Intelligence (AI) methods for Magnetic Resonance Diffusion-Weighted Imaging (DWI)/Fluid-Attenuated Inversion Recovery (FLAIR)-mismatch assessment and to determine how well DWI/FLAIR mismatch algorithms perform compared to domain experts. We searched PubMed Medline, Ovid Embase, Scopus, Web of Science, Cochrane, and IEEE Xplore literature databases for relevant studies published between 1 January 2017 and 20 November 2022, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We assessed the included studies using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Five studies fit the scope of this review. The area under the curve ranged from 0.74 to 0.90. The sensitivity and specificity ranged from 0.70 to 0.85 and 0.74 to 0.84, respectively. Negative predictive value, positive predictive value, and accuracy ranged from 0.55 to 0.82, 0.74 to 0.91, and 0.73 to 0.83, respectively. In a binary classification of ±4.5 h from stroke onset, the surveyed AI methods performed equivalent to or even better than domain experts. However, using the relation between time since stroke onset (TSS) and increasing visibility of FLAIR hyperintensity lesions is not recommended for the determination of TSS within the first 4.5 h. An AI algorithm on DWI/FLAIR mismatch assessment focused on treatment eligibility, outcome prediction, and consideration of patient-specific data could potentially increase the proportion of stroke patients with unknown onset who could be treated with thrombolysis.

Introduction: Patients with MS are MRI scanned continuously throughout their disease course resulting in a large manual workload for radiologists which includes lesion detection and size estimation. Though many models for automatic lesion segmentation have been published, few are used broadly in clinic today, as there is a lack of testing on clinical datasets. By collecting a large, heterogeneous training dataset directly from our MS clinic we aim to present a model which is robust to different scanner protocols and artefacts and which only uses MRI modalities present in routine clinical examinations., Methods: We retrospectively included 746 patients from routine examinations at our MS clinic. The inclusion criteria included acquisition at one of seven different scanners and an MRI protocol including 2D or 3D T2-w FLAIR, T2-w and T1-w images. Reference lesion masks on the training ( n = 571) and validation ( n = 70) datasets were generated using a preliminary segmentation model and subsequent manual correction. The test dataset ( n = 100) was manually delineated. Our segmentation model https://github.com/CAAI/AIMS/ was based on the popular nnU-Net, which has won several biomedical segmentation challenges. We tested our model against the published segmentation models HD-MS-Lesions, which is also based on nnU-Net, trained with a more homogenous patient cohort. We furthermore tested model robustness to data from unseen scanners by performing a leave-one-scanner-out experiment., Results: We found that our model was able to segment MS white matter lesions with a performance comparable to literature: DSC = 0.68, precision = 0.90, recall = 0.70, f1 = 0.78. Furthermore, the model outperformed HD-MS-Lesions in all metrics except precision = 0.96. In the leave-one-scanner-out experiment there was no significant change in performance ( p < 0.05) between any of the models which were only trained on part of the dataset and the full segmentation model., Conclusion: In conclusion we have seen, that by including a large, heterogeneous dataset emulating clinical reality, we have trained a segmentation model which maintains a high segmentation performance while being robust to data from unseen scanners. This broadens the applicability of the model in clinic and paves the way for clinical implementation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hindsholm, Andersen, Cramer, Simonsen, Askløf, Magyari, Madsen, Hansen, Sellebjerg, Larsson, Langkilde, Frederiksen, Højgaard, Ladefoged and Lindberg.)

Background: Our aim was to propose criteria to distinguish multiple sclerosis (MS) from acute disseminated encephalomyelitis (ADEM) at onset based on age at onset, sex, cerebrospinl fluid (CSF)-specific oligoclonal bands, and MRI., Methods: A neuroradiologist undertook retrospective evaluation of the baseline magnetic resonance imaging (MRI) in a nationwide cohort of children with medical record-validated MS (n = 67) and monophasic ADEM (n = 46). Children with ADEM had at least 5 years of follow-up for relapse. We used forward stepwise conditional logistic regression to develop our criteria based on age at onset, sex, CSF-specific oligoclonal bands, and MRI. We undertook sensitivity analyses using children with ADEM including encephalopathy and polyfocal neurological deficits and in those with onset between 11 and 17 years of age. We estimated accuracy statistics from our criteria and all previously proposed MRI criteria to distinguish MS and ADEM., Results: The best performing criteria to differentiate MS from ADEM were scoring at least three points in the following categories: presence of CSF-specific oligoclonal bands (2 points), occipital lesion (1 point), age 11-17 years (1 point), female sex (1 point). These criteria gave highly reliable discrimination with sensitivity of 95% (95% CI=89%-100%), specificity of 100% (95% CI=100%-100%), and area under the curve of 98% (95% CI=95%-100%). The best performing MRI criteria had area under the curve of 84% (95% CI=78%-91%). Previously proposed MRI criteria had the following areas under the curve: Callen (75%), KIDMUS (82%), and McDonald 2017 criteria (68%)., Conclusion: Combining sex, age at onset, CSF-specific oligoclonal bands, and MRI gives highly reliable differentiation between pediatric MS and monophasic ADEM at onset., Competing Interests: Declaration of Competing Interest Dr. Boesen has served on a scientific advisory board for Teva; has received speaker honoraria for lecturing from Novartis, and support for congress participation from Teva, Novartis and Roche. Dr. Blinkenberg has served on scientific advisory boards for Genzyme, Roche, Biogen, Merck, Novartis and Teva; has received speaker honoraria from Genzyme, Biogen, Merck, Novartis, Teva and Roche; has received consulting honoraria from the Danish Multiple Sclerosis Society, Biogen, Teva, Roche and Merck; and has received funding for travel from Genzyme, Roche and Biogen. Dr Magyari has served on the scientific advisory board for Biogen, Sanofi-Genzyme, Teva, Roche, Novartis, and Merck; has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi-Genzyme, and support for congress participation from Biogen, Sanofi-Genzyme, Teva, and Roche. Drs. Langkilde and Ilginiene report no disclosures., (Copyright © 2022. Published by Elsevier B.V.)

A 23-year-old man presented with right eye blurred vision; he was diagnosed with acute posterior multifocal placoid pigment epitheliopathy (APMPPE), and his symptoms resolved with prednisolone. Two months later, he developed a right arm weakness that resolved after 3 weeks. MR scan of brain identified changes suggesting multiple sclerosis, with four hyperintense FLAIR lesions; there was contrast enhancement of two lesions and no diffusion restriction. Cerebrospinal fluid showed mononuclear pleocytosis. We eventually diagnosed these as APMPPE-associated CNS lesions. APMPPE is a rare inflammatory chorioretinopathy that rarely can resemble multiple sclerosis clinically and radiologically., Competing Interests: Competing interests: SEM, AI, KH, AL and SH report no conflicts of interest. JRC reports receiving speaker honoraria from Biogen and being a member of the steering committee of the DanNORMS study (NCT04688788) and receiving grants from the Medicine Fund of the Danish Regions., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: MRI of the nervous system is the critical in distinguishing pediatric MS from acute disseminated encephalomyelitis (ADEM). Our aim was to propose MRI criteria to distinguish MS from monophasic ADEM based on the first MRI and to validate previously proposed MRI criteria., Methods: A neuroradiologist undertook retrospective evaluation of the MRI at the first demyelinating event in children (<18 years) with medical record-validated MS and ADEM in Denmark during 2008-15. We used forward stepwise logistic regression to identify MRI categories that differed significantly between MS and ADEM. We estimated accuracy statistics for all MRI criteria to distinguish MS from ADEM., Results: The monophasic ADEM cohort (n=46) was nationwide and population-based during 2008-15; the median age at onset of 5.3 years (range 0.8‒17.2) and children had at least five years of follow-up to ensure a monophasic disease course. Children with MS (n=67) had a median age at onset of 16.3 years (range 3.3‒17.9). Having at least two categories best distinguished MS from monophasic ADEM by an area under the curve of 83% to 89%: (a) corpus callosum long axis perpendicular lesion; (b) only well-defined lesions; (c) absence of basal ganglia or thalamus lesion OR, (a) corpus callosum long axis perpendicular lesion; (b) only well-defined lesions; (c) absence of diffuse large lesions; (d) black holes. The Callen, KIDMUS, and IPMSSG criteria performed well. The McDonald 2017, Barkhof, MAGNIMS, and Verhey criteria had poorer performance., Conclusion: This study provides Class II evidence that MRI has good performance in differentiating MS from monophasic ADEM at onset., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aim: Children with dyskinetic cerebral palsy (CP) are often severely affected and effective treatment is difficult, due to different underlying disease mechanisms. Comprehensive systematic movement disorder evaluations were carried out on patients with this disorder., Methods: Patients born from 1995 to 2007 were identified from the Danish Cerebral Palsy Register and referrals to the neuropaediatric centre, Rigshospitalet, Copenhagen. They were classified by gross motor function, manual functional ability, communication ability, dystonia and spasticity. Electromyography was carried out on the upper and lower limbs. Magnetic resonance imaging scans were revised, and aetiological searches for underlying genetic disorders were performed., Results: We investigated 25 patients with dyskinetic CP at a mean age of 11.7 years. Dystonia, spasticity and rigidity were found in the upper limbs of 21, four and six children, respectively, and in the lower limbs of 18, 18 and three children. The mean total Burke-Fahn-Marsden score for dystonia was 45.02, and the mean Disability Impairment Scale level was 38% for dystonia and 13% for choreoathetosis. Sustained electromyography activity was observed in 20/25 children. Stretching increased electromyography activity more in children with spasticity. There were 10 re-classifications., Conclusion: The children had heterogenic characteristics, and 40% were reclassified after systematic movement disorder evaluation., (© 2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objectives: To assess the ability of the biomarkers neuron-specific enolase (NSE), tau, neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP) to predict postoperative cognitive dysfunction (POCD) at discharge in patients who underwent cardiac surgery., Design: Post hoc analyses (with tests being prespecified before data analyses) from a randomized clinical trial., Setting: Single-center study from a primary heart center in Denmark., Participants: Adult patients undergoing elective or subacute on-pump coronary artery bypass grafting and/or aortic valve replacement., Interventions: Blood was collected before induction of anesthesia, after 24 hours, after 48 hours, and at discharge from the surgical ward. The International Study of Postoperative Cognitive Dysfunction test battery was applied to diagnose POCD at discharge and after three months. Linear mixed models of covariance were used to assess whether repeated measurements of biomarker levels were associated with POCD. Receiver operating characteristic (ROC) curves were applied to assess the predictive value of each biomarker measurement for POCD., Measurements and Main Results: A total of 168 patients had biomarkers measured at baseline, and 47 (28%) fulfilled the POCD criteria at discharge. Patients with POCD at discharge had significantly higher levels of tau (p = 0.02) and GFAP (p = 0.01) from baseline to discharge. The biomarker measurements achieving the highest area under the ROC curve for prediction of POCD at discharge were NFL measured at discharge (AUC, 0.64; 95% confidence interval [CI], 0.54-0.73), GFAP measured 48 hours after induction (AUC, 0.64; 95% CI, 0.55-0.73), and GFAP measured at discharge (AUC, 0.64; 95% CI, 0.54-0.74), corresponding to a moderate predictive ability., Conclusions: Postoperative serum levels of tau and GFAP were significantly elevated in cardiac surgery patients with POCD at discharge, however, the biomarkers achieved only modest predictive abilities for POCD at discharge. Postoperative levels of NSE were not associated with POCD at discharge., Competing Interests: Conflict of Interest H.Z. has served on scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, and CogRx; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. K.B. has served as a consultant or on advisory boards for Abcam, Axon, Biogen, Lilly, MagQu, Novartis, and Roche Diagnostics and is a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg. The other authors report no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: MRI allows demonstration of dissemination in space and time at the first demyelinating event. However, no pediatric MS study has investigated the validity of MS-specific outcomes described in MRI radiological reports that clinicians rely on to make the MS diagnosis and to assess the MS treatment effect. Our aim was to validate MS-specific outcomes in hospital MRI reports in pediatric MS by comparing MS-specific outcomes in MRI reports with secondary MRI review., Methods: A senior consultant and a resident neurologist extracted data on MS-specific outcomes from MRI reports at baseline and follow-up in children with MS onset during 2008-15 in Denmark. Gold standard was an expert neuroradiologist's secondary MRI review. We estimated percent agreement and Kappa values by comparing data extracted from hospital MRI reports (what we wanted to test) with results from the secondary MRI reviews (our gold standard)., Results: Among 55 children with MS, we included 44 baseline and 48 follow-up MRIs. The median age at MS onset was 16.3 years (range 9.2‒17.9). Agreement between the MRI reports and the secondary MRI review ranged 68%-100% for MS-specific outcomes; agreement was higher when MRI outcomes were present. Kappa values ranged from 0.42 ("moderate") to 1.00 ("excellent"). Kappa for fulfillment of the McDonald 2017 criteria was 0.60 on baseline MRI, and 0.53 on follow-up MRI. Kappa for a new lesion on follow-up MRI was 0.41., Conclusion: Agreement was moderate to good for most MS-specific outcomes between MS neurologists' data extraction from hospital MRI radiological reports compared with a neuroradiologist's secondary MRI review. The agreement was moderate for both fulfilling the McDonald 2017 criteria and acquiring a new lesion on follow-up MRI. We recommend structured MRI reporting in children suspected of acquired demyelinating syndromes to increase validity of hospital MRI reports and clinical use., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients., Methods: We conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related., Results: From April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated., Conclusion: CNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes suggested autoimmune-mediated mechanisms., (© 2021. The Author(s).)

Background: Tight junction proteins contribute to maintenance of epithelial and endothelial barriers such as the intestinal barrier and the blood brain barrier (BBB). Increased permeability of these barriers has been linked to disease activity in MS and there is currently a lack of easily accessible biomarkers predicting disease activity in MS., Aim: To investigate whether levels of circulating tight junction proteins occludin and zonula occludens-1 (ZO-1) are associated with biomarkers of inflammation and disease activity; and to determine whether they could serve as clinical biomarkers., Methods: We prospectively included 72 newly diagnosed patients with relapsing remitting MS or clinically isolated syndrome with no prior disease modifying therapy (DMT) use and 50 healthy controls (HCs). Patients were followed with blood samples, 3 tesla MRI, and clinical evaluation for 12 months. Occludin, ZO-1, calprotectin and soluble urokinase-type plasminogen activator receptor (suPAR) were measured by ELISA; serum neurofilament light (NfL) and IL-6 by single-molecule array (SIMOA). The mRNA expression of IFNG, IL1R1, IL10, IL1B, ARG1 and TNF was measured by quantitative real time polymerase chain reaction (qPCR) in whole blood., Results: Plasma occludin levels were higher in MS patients compared with HCs. After 12 months on DMT, occludin levels were reduced by approximately 25% irrespective of 1st or 2nd line DMT (p<0.001). Furthermore, NfL and calprotectin levels were significantly reduced by 31% and 29%, respectively. Occludin and ZO-1 did not correlate with biomarkers of inflammation and did not predict disease activity at baseline or after 12 months., Conclusions: Higher levels of occludin suggest an increased permeability of the BBB and/or the intestinal barrier in MS patients. The reduction of occludin after 12 months on DMTs might reflect repair of these barriers upon treatment. However, plasma levels of ZO-1 and occludin could not predict clinical or MRI disease activity as determined by regression and ROC-curve analysis. Our results do not indicate a clear clinically relevant role for circulating tight junction proteins as biomarkers of disease activity in MS and further investigations in larger cohorts are needed to clarify this issue., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Spinal cord lesions are included in the diagnosis of multiple sclerosis (MS), yet spinal cord MRI is not mandatory for diagnosis according to the latest revisions of the McDonald Criteria. We investigated the distribution of spinal cord lesions in MS patients and examined how it influences the fulfillment of the 2017 McDonald Criteria. Seventy-four patients with relapsing-remitting MS were examined with brain and entire spinal cord MRI. Sixty-five patients received contrast. The number and anatomical location of MS lesions were assessed along with the Expanded Disability Status Scale (EDSS). A Chi-square test, Fischer's exact test, and one-sided McNemar's test were used to test distributions. MS lesions were distributed throughout the spinal cord. Diagnosis of dissemination in space (DIS) was increased from 58/74 (78.4%) to 67/74 (90.5%) when adding cervical spinal cord MRI to brain MRI alone ( p = 0.004). Diagnosis of dissemination in time (DIT) was not significantly increased when adding entire spinal cord MRI to brain MRI alone ( p = 0.04). There was no association between the number of spinal cord lesions and the EDSS score ( p = 0.71). MS lesions are present throughout the spinal cord, and spinal cord MRI may play an important role in the diagnosis and follow-up of MS patients.

Multiple sclerosis (MS) is a chronic immune-mediated disease characterized by demyelination and neuroaxonal damage in the central nervous system. The etiology is complex and is still not fully understood. Accumulating evidence suggests that our gut microbiota and its metabolites influence the MS pathogenesis. Short-chain fatty acids (SCFAs), such as acetate, propionate and butyrate, are metabolites produced by gut microbiota through fermentation of indigestible carbohydrates. SCFAs and kynurenine metabolites have been shown to have important immunomodulatory properties, and propionate supplementation in MS patients has been associated with long-term clinical improvement. However, the underlying mechanisms of action and its importance in MS remain incompletely understood. We analyzed serum levels of SCFAs and performed targeted metabolomics in relation to biomarkers of inflammation, and clinical and MRI measures in newly diagnosed patients with relapsing-remitting MS before their first disease modifying therapy and healthy controls (HCs). We demonstrated that serum acetate levels were nominally reduced in MS patients compared with HCs. The ratios of acetate/butyrate and acetate/(propionate + butyrate) were significantly lower in MS patients in a multivariate analysis (orthogonal partial least squares discriminant analysis; OPLS-DA). The mentioned ratios and acetate levels correlated negatively with the pro-inflammatory biomarker IFNG , indicating an inverse relation between acetate and inflammation. In contrast, the proportion of butyrate was found higher in MS patients in the multivariate analysis, and both butyrate and valerate correlated positively with proinflammatory cytokines ( IFNG and TNF ), suggesting complex bidirectional regulatory properties of SCFAs. Branched SCFAs were inversely correlated with clinical disability, at a nominal significance level. Otherwise SCFAs did not correlate with clinical variables or MRI measures. There were signs of an alteration of the kynurenine pathway in MS, and butyrate was positively correlated with the immunomodulatory metabolite 3-hydroxyanthranilic acid. Other variables that influenced the separation between MS and HCs were NfL, ARG1 and IL1R1 , D-ribose 5-phosphate, pantothenic acid and D-glucuronic acid. In conclusion, we provide novel results in this rapidly evolving field, emphasizing the complexity of the interactions between SCFAs and inflammation; therefore, further studies are required to clarify these issues before supplementation of SCFAs can be widely recommended., Competing Interests: AO has received support for congress participation from Roche and Novartis. SG has received support for congress participation from Merck. FS has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. ABO has served on scientific advisory boards for Biogen Idec, Novartis and Sanofi Genzyme; has received research support from Novartis; has received speaker honoraria from Biogen Idec, Novartis and TEVA; and has received support for congress participation from, Merck, TEVA, Biogen, Roche, Novartis and Sanofi Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Olsson, Gustavsen, Nguyen, Nyman, Langkilde, Hansen, Sellebjerg, Oturai and Bach Søndergaard.)

Objectives: Cardiac surgery is associated with risk of cerebral injury and mean arterial pressure (MAP) during cardiopulmonary bypass (CPB) is suggested to be associated with cerebral injury. The 'Perfusion Pressure Cerebral Infarcts' (PPCI) trial randomized patients undergoing coronary artery bypass grafting (CABG) and/or aortic valve replacement to a MAP of 40-50 or 70-80 mmHg during CPB and found no difference in clinical or imaging outcomes between the groups. We here present PPCI trial predefined secondary end points, consisting of biomarkers of brain injury., Methods: Blood was collected from PPCI trial patients at baseline, 24 and 48 h after induction of anaesthesia and at discharge from the surgical ward. Blood was analysed for neuron-specific enolase, tau, neurofilament light and the glial marker glial fibrillary acidic protein. Linear mixed models were used to analyse differences in biomarker value changes from baseline between the 2 MAP allocation groups., Results: A total of 193 (98%) patients were included. We found no differences in biomarker levels over time from baseline to discharge between the 2 MAP allocation groups (PNSE = 0.14, PTau = 0.46, PNFL = 0.21, PGFAP = 0.13) and the result did not change after adjustment for age, sex and type of surgery., Conclusions: We found no significant differences in levels of biomarkers of neurological injury in patients undergoing elective or subacute CABG and/or aortic valve replacement randomized to either a target MAP of 40-50 mmHg or a target MAP of 70-80 mmHg during CBP., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: It is essential to distinguish acute disseminated encephalomyelitis (ADEM) from MS early. Our aim was to determine MRI features at baseline and follow-up to distinguish pediatric ADEM from MS stratified according to age at onset., Methods: Using hospital ICD-10 codes for acquired demyelinating syndromes from a nationwide register and subsequent chart review, we identified 52 children (<18 years) with ADEM and 66 children with MS. We undertook a retrospective analysis of MRI scans at onset and at follow-up. The MRI rater was a senior neuroradiologist blinded to clinical characteristics., Results: At baseline, children with ADEM had more diffuse poorly demarcated lesions, particularly in the basal ganglia/thalamus (p = 0.001) and cerebellar peduncles (p < 0.0001). Further, longitudinal extensive transverse myelitis was strongly associated with ADEM (p<0.0001). Children with ADEM had fewer contrast-enhancing lesions (p = 0.0004), occipital lesions (p = 0.01), optic nerve lesions (p = 0.01), periventricular lesions, well-defined lesions only (p<0.0001), and fewer fulfilled dissemination in time according to the McDonald 2017 criteria (p = 0.005). On baseline MRI, dissemination in space and time was fulfilled in 17% of children with ADEM and in 34% of children with MS (p = 0.06), and 60% of children with ADEM fulfilled the criterion for dissemination in space. The mean time from baseline MRI to follow-up MRI was 1.0 year for children with ADEM and 2.1 years for children with MS. On follow-up MRI, 85% of children with ADEM had partial or complete T2 lesion resolution, but in the 58% without complete resolution lesions were predominantly frontal. Only 47% of children with MS had partial or complete T2 lesion resolution, and therefore more MRI features differed between children with ADEM and MS on follow-up. MRI had the greatest distinguishing value after age 11 years because MS is exceptional in the first decade of life., Conclusion: Age at onset and the timing of MRI in relation to disease onset are critical in the interpretation of MRI to distinguish between ADEM and MS., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: There is a lack of reliable biomarkers predicting disability and disease activity in multiple sclerosis (MS). Recent evidence suggests an involvement of intestinal and pulmonary epithelial barrier function related to immune activation and the pathophysiology of MS. Blood biomarkers of epithelial barrier function have, however, not been widely studied in MS., Objective: To examine biomarkers of inflammation and epithelial barrier function in relapsing remitting MS (RRMS) patients compared with healthy controls (HCs), and to assess associations between biomarkers and disease activity., Methods: A panel of 30 biomarkers were measured in serum or plasma from 49 newly diagnosed, untreated RRMS patients and 58 HCs with electrochemiluminescence or ELISA. Neurofilament light chain (NfL) was measured with single-molecule array. Validation was performed in a second independent cohort of 68 newly diagnosed, treatment naive RRMS patients and 50 HCs. Patients were divided into groups of active and inactive disease based on NfL levels and the presence of gadolinium enhancing magnetic resonance imaging lesions., Results: Patients with active MS showed significantly higher serum levels of calprotectin and soluble urokinase plasminogen activator receptor compared with inactive MS in the exploratory cohort. Validation confirmed higher levels of calprotectin in active compared with inactive MS, and HCs. Biomarkers of intestinal and pulmonary epithelial barrier function did not differ significantly between groups., Conclusions: The measured biomarkers of epithelial barrier function do not seem to play a major role in the pathophysiology of MS, but serum calprotectin could represent a clinically useful biomarker of innate immune activation and disease activity., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To assess the association between total volume and number of gaseous microemboli (GME) in the cardiopulmonary bypass (CPB) circuit and the occurrence of new postoperative cerebral infarctions and postoperative cognitive dysfunction (POCD) in patients undergoing cardiac surgery., Design: Predefined subanalyses of the randomized controlled Perfusion Pressure Cerebral Infarcts (PPCI) trial., Setting: Primary heart center in a university hospital., Participants: A total of 143 adult patients undergoing cardiac surgery with CPB., Interventions: Patients were allocated 1:1 to a low-target mean arterial pressure (MAP) of 40 to 50 mmHg or a high-target MAP of 70 to 80 mmHg during CPB with a fixed pump flow of 2.4 liters per minute per square meter body surface area plus 10% to 20%., Measurements and Main Results: The total volume and number of GME in the CPB circuit were assessed by the Bubble Counter Clinical 200® (GAMPT GmbH). New cerebral infarcts were identified by diffusion-weighted magnetic resonance imaging (DWI) 3 to 6 days after surgery. The median number of GME per patient was 8069 (range 1,523-204,095) with a median total volume of 1.2 μL (range 0.07-48 μL). A total of 66 (46%) patients had DWI detected cerebral infarcts postoperatively, and 36 (28%) patients had POCD after 7 days. The authors found no significant association between volume or number of GME with MAP target allocation, presence of cerebral infarction, or POCD., Conclusions: The authors found no significant associations between volume or number of GME with the occurrence of cerebral infarction or cognitive dysfunction in cardiac surgery patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Anti-myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) can be found in different immune-mediated inflammatory CNS disorders. The full range of clinical manifestations may not have been fully discovered yet., Methods: In a cross-sectional study 184 adults (age ≥ 16) were tested for anti-MOG antibody (Ab) with a cell-based assay. To define the relevant target population for anti-MOG antibody testing in a neurology clinic, we divided the entire study population based on the presenting symptoms and classified cases followed for multiple sclerosis (MS) according to the clinical features and response to disease-modifying therapy., Results: We identified eight (4.4%) MOG-Ab positive cases in the whole cohort. All eight cases had first manifestations suggestive of neuromyelitis optica spectrum disorder (NMOSD), but had highly variable disease courses and responses to therapy. This included a patient with chronic relapsing inflammatory optic neuropathy (CRION) responding only to therapy with infliximab. Four (3%) out of 134 cases followed for MS who tested positive for anti-MOG Ab showed atypical features and had poor response to therapy., Conclusion: A broad range of clinical and radiological features of anti-MOG associated disorder was observed in a single centre. MOG-Ab testing should be considered in patients with an NMOSD phenotype and in MS patients presenting atypical features. The potential use of infliximab therapy for MOG-Ab disease should be further investigated., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Physical activity and alternate-day fasting/caloric restriction may both ameliorate aspects of the metabolic syndrome, such as insulin resistance, visceral fat mass accumulation, and cognitive impairment by overlapping mechanisms. The purpose of this study was to test the hypothesis that alternate-day caloric restriction (ADCR) with overall energy balance would reduce insulin resistance and accumulation of visceral fat, in addition to improving cognitive functions, after 8 consecutive days in bed. Healthy, lean men (n = 20) were randomized to 1) 8 days of bed rest with three daily isoenergetic meals (control group, n = 10); and 2) 8 days of bed rest with 25% of total energy requirements every other day and 175% of total energy requirements every other day (ADCR group). Oral glucose tolerance testing, dual-energy X-ray absorptiometry (DXA) scans, magnetic resonance imaging of the abdomen and brain, V̇o 2max , and tests for cognitive function were performed before and after bed rest. In addition, daily fasting blood samples and 24-h glucose profiles by continuous glucose monitoring system were assessed during the 8 days of bed rest period. Bed rest induced insulin resistance, visceral fat accumulation, and worsening of mood. No positive effects emerged from ADCR on these negative health outcomes. Compared with the control group, ADCR was associated with improved and steadier glycemic control on fasting days and higher glycemic fluctuation and indexes of insulin resistance on overeating days. In contrast to our hypothesis, the metabolic impairment induced by 8 days of bed rest was not counteracted by ADCR with overall energy balance., New & Noteworthy: Alternate-day caloric restriction without overall energy reduction does not ameliorate the metabolic impairment induced in lean men by 8 days of bed rest., (Copyright © 2017 the American Physiological Society.)

Background: Cerebrospinal fluid (CSF) biomarkers have been suggested to predict multiple sclerosis (MS) after clinically isolated syndromes, but studies investigating long-term prognosis are needed., Objective: To assess the predictive ability of CSF biomarkers with regard to MS development and long-term disability after optic neuritis (ON)., Methods: Eighty-six patients with ON as a first demyelinating event were included retrospectively. Magnetic resonance imaging (MRI), CSF leukocytes, immunoglobulin G index and oligoclonal bands were registered. CSF levels of chitinase-3-like-1, osteopontin, neurofilament light-chain, myelin basic protein, CCL2, CXCL10, CXCL13 and matrix metalloproteinase-9 were measured by enzyme-linked immunosorbent assay. Patients were followed up after 13.6 (range 9.6-19.4) years and 81.4% were examined, including Expanded Disability Status Scale and MS functional composite evaluation. 18.6% were interviewed by phone. Cox regression, multiple regression and Spearman correlation analyses were used., Results: Forty-six (53.5%) developed clinically definite MS (CDMS) during follow-up. In a multivariate model MRI (p=0.0001), chitinase 3-like 1 (p=0.0033) and age (p=0.0194) combined predicted CDMS best. Neurofilament light-chain predicted long-term disability by the multiple sclerosis severity scale (p=0.0111) and nine-hole-peg-test (p=0.0202). Chitinase-3-like-1 predicted long-term cognitive impairment by the paced auditory serial addition test (p=0.0150)., Conclusion: Neurofilament light-chain and chitinase-3-like-1 were significant predictors of long-term physical and cognitive disability. Furthermore, chitinase-3-like-1 predicted CDMS development. Thus, these molecules hold promise as clinically valuable biomarkers after ON as a first demyelinating event., (© The Author(s), 2015.)

Due to the high temporal and spatial resolution in multislice computed tomography it is possible to perform high-quality computer tomography angiography (CTA) of the cerebral and cervical vessels. Compared to digital subtraction angiography (DSA), a method that is still considered to be the golden standard, CTA is faster and can be performed using a minimal invasive technique. In this paper we outline the clinical indications for performing CTA (aneurysms, stroke, vasospasms, arterio-venous malformations, dissection). Examples of scan protocols are given both for angiography of the cerebral vessels alone and for angiography of the cervical and cerebral vessels in combination. Postprocessing methods for evaluating the images in 2D and 3D are described. Finally CTA is compared to other modalities (DSA, magnetic resonance angiography and Doppler ultrasound).

Unipolar depression is moderately heritable. It is unclear whether structural brain changes associated with unipolar depression are present in healthy persons at risk of the disorder. Here we investigated whether a genetic predisposition to unipolar depression is associated with structural brain changes. A priori, hippocampal volume reductions were hypothesized. Using a high-risk study design, magnetic resonance imaging brain scans were obtained from 59 healthy high-risk subjects having a co-twin with unipolar depression, and 53 healthy low-risk subjects without a first-degree family history of major psychiatric disorder. High-risk twins had smaller hippocampal volumes than low-risk twins (p<0.04). The finding was most pronounced in DZ twins. Groups did not differ on global brain tissue volumes or regional tissue volumes assessed in exploratory voxel-wise whole cerebrum analyses. In conclusion, hippocampal volume reduction may index a predisposition to develop depression and thus may be predictive of future onset of the disorder. Further studies are needed to elucidate the role of (shared) environmental and genetic factors., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Background: Enlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode schizophrenia. Studies investigating brain structure in antipsychotic-naive patients have generally focused on the striatum. In this study, we examined whether ventricular enlargement and hippocampal and caudate volume reductions are morphological traits of antipsychotic-naive first-episode schizophrenia., Methods: We obtained high-resolution 3-dimensional T1-weighted magnetic resonance imaging scans for 38 antipsychotic-naive first-episode schizophrenia patients and 43 matched healthy controls by use of a 3-T scanner. We warped the brain images to each other by use of a high-dimensional intersubject registration algorithm. We performed voxel-wise group comparisons with permutation tests. We performed small volume correction for the hippocampus, caudate and ventricles by use of a false discovery rate correction (p < 0.05) to control for multiple comparisons. We derived and analyzed estimates of brain structure volumes. We grouped patients as those with (n = 9) or without (n = 29) any lifetime substance abuse to examine the possible effects of substance abuse., Results: We found that hippocampal and caudate volumes were decreased in patients with first-episode schizophrenia. We found no ventricular enlargement, differences in global volume or significant associations between tissue volume and duration of untreated illness or psychopathology. The hippocampal volume reductions appeared to be influenced by a history of substance abuse. Exploratory analyses indicated reduced volume of the nucleus accumbens in patients with first-episode schizophrenia., Limitations: This study was not a priori designed to test for differences between schizophrenia patients with or without lifetime substance abuse, and this subgroup was small., Conclusion: Reductions in hippocampal and caudate volume may constitute morphological traits in antipsychotic-naive first-episode schizophrenia patients. However, the clinical implications of these findings are unclear. Moreover, past substance abuse may accentuate hippocampal volume reduction. Magnetic resonance imaging studies addressing the potential effects of substance abuse in antipsychotic-naive first-episode schizophrenia patients are warranted.

An increased percentage of blood CD8+ T cells from patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) was found to express CD26 and CD69. The percentage of CD26 or CD69 positive CD8+ T cells was higher in patients with MRI evidence of disease dissemination in space or with active MRI lesions than in the remaining patients. Treatment of MS with interferon (IFN)-beta resulted in a decrease in the percentage of CD26 and CD71 positive CD8+ T cells and an increase in the percentage of CD8+ T cells that expressed interleukin (IL)-10 and IL-13. CD8+ T cell activation in MS may be linked to disease activity already at disease onset, and is regulated by treatment with IFN-beta.

We studied CD4 T cell activation in patients with clinically isolated syndromes (CIS) suggesting an initial attack of multiple sclerosis. The percentage of blood CD26+ CD4 T cells was increased in these patients, and correlated with magnetic resonance imaging disease activity and clinical disease severity. In contrast, the percentage of CD25+ CD4 T cells in cerebrospinal fluid correlated negatively with the cerebrospinal fluid concentration of myelin basic protein and the presence of IgG oligoclonal bands. These results suggest that distinct systemic and intrathecal T cell activation states correlate with disease activity and risk of subsequently developing MS in CIS patients.

It is well known that morphological changes at the cellular level occur in muscle of patients with mitochondrial myopathy (MM), but changes in muscle structure with fat infiltration and gross variation of muscle fiber size with giant fibers, normally encountered in the muscular dystrophies, have typically not been associated with mitochondrial disease. We investigated gross and microscopic muscle morphology in thigh muscles by muscle biopsy and MRI in 16 patients with MM, and compared findings with those obtained in muscular dystrophy patients and healthy subjects. Changes of muscle architecture, similar to those found in the group of muscular dystrophy patients occurred consistently in patients with a high mutation load for single, largescale deletions of mtDNA, but were absent in all patients with the 3243A-->G mtDNA point mutation. Dystrophic changes of muscle architecture were also present in one MM patient with a unique, sporadic mutation in the mtDNA tRNA(Met) gene. These findings provide evidence that morphological changes in muscle of MM patients are common and may resemble those of muscular dystrophies, but that development of dystrophic-like changes in muscle relate to genotype.

The volume of cortical activation as detected by functional magnetic resonance imaging (fMRI) in the visual cortex has previously been shown to be reduced following optic neuritis (ON). In order to understand the cause of this change, we studied the cortical activation, both the size of the activated area and the signal change following ON, and compared the results with results of neuroophthalmological testing. We studied nine patients with previous acute ON and 10 healthy persons served as controls using fMRI with visual stimulation. In addition to a reduced activated volume, patients showed a reduced blood oxygenation level dependent (BOLD) signal increase and a greater asymmetry in the visual cortex, compared with controls. The volume of visual cortical activation was significantly correlated to the result of the contrast sensitivity test. The BOLD signal increase correlated significantly to both the results of the contrast sensitivity test and to the Snellen visual acuity. Our results indicate that fMRI is a useful method for the study of ON, even in cases where the visual acuity is severely impaired. The reduction in activated volume could be explained as a reduced neuronal input; however, the greater asymmetry might point to a cortical reorganization as a consequence of neuronal damage. Future fMRI studies in ON will add to the understanding of the neural adaptive behaviour following ON.

Conventional magnetic resonance imaging (MRI) is still the standard technique in the diagnosis and follow-up of patients with multiple sclerosis (MS), despite low pathological specificity and poor correlation to the disability. The results of T2- and T1-weighted imaging with and without contrast and the lesion characteristics are presented in this review. The numerous differential diagnoses and the diagnostic MRI criteria are also reviewed.

Conventional magnetic resonance imaging (MRI) techniques have proved important in the diagnosis and in the follow-up in clinical trials of patients with multiple sclerosis (MS). However, these techniques have low specificity for the pathological changes in the MS lesions, and the correlation between conventional MRI and the disability is poor. The last ten years have seen the development of new techniques with improved sensitivity and increased pathological specificity, such as magnetisation transfer imaging (MTI), magnetic resonance spectroscopy (MRS), diffusion-weighted imaging, and functional magnetic resonance imaging (fMRI). These techniques and their contribution to the knowledge about the pathophysiology of MS are described in this review.

The first case of combined centronuclear myopathy and multiple sclerosis is reported. The difficulties of diagnosing multiple sclerosis in patients with muscular disorders associated with the central nervous system involvement are discussed.