Search

MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease [99 females, mean age: 41 (±14) years, median EDSS: 2 (0–7.5)], 162 with AQP4-neuromyelitis optica spectrum disorder [132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0–8)], 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0–8)] and 152 healthy controls (91 females) were studied. In young patients (

Familial hypercholesterolemia (FH) remains underdiagnosed and undertreated. The optimal electronic health record (EHR) screening strategy for FH is unclear.To evaluate an LDL-C threshold-based approach of identifying patients with FH from the EHR to determine the optimal LDL-C range for FH consideration.Individuals from UT Southwestern Medical Center with an LDL-C level ≥190mg/dL at any time were enrolled in an FH registry. These 5,786 patients were divided into four categories of LDL-C (190- 219, 220 - 249, 250 - 299, and ≥ 300mg/dL) with 100 individuals randomly selected for manual chart review in each category. Chart review included 1) the presence of secondary causes of dyslipidemia, 2) diagnosis of possible/definite FH by modified Simon Broome criteria, and 3) probable/definite FH by modified Dutch Lipid Clinic Network (DLCN) criteria.Of the 400 individuals with an LDL-C level ≥190mg/dL (mean age 52 years ± 14), the presence of secondary causes increased across each LDL-C category (p0.001) with the greatest prevalence in those ≥ 300mg/dL (52%). The prevalence of possible/probable or definite FH also varied by LDL-C category, with the highest prevalence of FH by Simon Broome criteria in the 220 - 249mg/dL category (52%) and by DLCN criteria in the 250 - 299mg/dL category (46%).Among those with LDL-C ≥ 190mg/dL, the prevalence of secondary causes increased markedly with higher LDL-C, while the diagnosis of FH has a parabolic relationship. Patients with intermediate LDL-C (220 - 299mg/dL) may be the optimal group to prioritize for FH screening.

Brain pseudoatrophy has been shown to play a pivotal role in the interpretation of brain atrophy measures during the first year of disease-modifying therapy in multiple sclerosis. Whether pseudoatrophy also affects the spinal cord remains unclear. The aim of this study was to analyze the extent of pseudoatrophy in the upper spinal cord during the first 2 years after therapy initiation and compare this to the brain.A total of 129 patients from a prospective longitudinal multicentric national cohort study for whom magnetic resonance imaging scans at baseline, 12 months, and 24 months were available were selected for brain and spinal cord volume quantification. Annual percentage brain volume and cord area change were calculated using SIENA (Structural Image Evaluation of Normalized Atrophy) and NeuroQLab, respectively. Linear mixed model analyses were performed to compare patients on interferon-beta therapy (n = 84) and untreated patients (n = 45).Patients treated with interferon-beta demonstrated accelerated annual percentage brain volume and cervical cord area change in the first year after treatment initiation, whereas atrophy rates stabilized to a similar and not significantly different level compared to untreated patients during the second year.These results suggest that pseudoatrophy occurs not only in the brain, but also in the spinal cord during the first year of interferon-beta treatment.

Mechanical thrombectomy (MT) is an effective treatment in patients with acute ischemic stroke (AIS) due to emergent large-vessel occlusion in the anterior circulation. Occlusion of the anterior cerebral artery (ACA) affects up to 15% of these patients. Here we report a case of an elderly patient with an successful MT of an embolic A2-segment occlussion with the anatomic variation of a triplication. Triplication of ACA is a rare anatomical variation, and the occlusion could have been easily overlooked in case of not performing the CT-perfusion (CTP) sequences. As anatomical variations of the circle of Willis are present in most subjects, CTA alone might be limited in the acute setting, particularly for young residents performing the first view on call. This case highlights the importance of including CTP in the initial CT-diagnostic algorithm in AIS patients who are basically eligible for recanalization therapies, irrespective of inconspicuous initial findings in CTA.

The request for CT (computed tomography) diagnostic in patients with suspected COVID-19 pneumonia has become part of the daily clinical routine. We reported a case of a 61-year-old patient with flu-like symptoms and a suspected COVID-19 pneumonia. After a negative PCR-test (polymerase chain reaction), a non-contrast enhanced CT was performed which revealed a suspicious hyperdensity in the left pulmonary artery and a pneumonia in the left lower lobe. A contrast enhanced CT confirmed a pulmonary embolism. An acute pulmonary embolism is a major complication and a main differential diagnosis of COVID-19. A hyperdense pulmonary artery sign (PAS) is a sensitive sign for a pulmonary embolism. Non-enhanced chest CT scans should be checked for hyperdense PAS in suspected of COVID-19 patients.

Developmental venous anomalies (DVA) are congenital malformations of veins that drain brain parenchyma, with a prevalence up to 9.3% in normal populations and 29.5% in multiple sclerosis (MS) patients. Study purpose was to determine prevalence of DVAs in patients with clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS) and to assess whether DVAs are related to altered clinical, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) laboratory parameters. Routine neurological and MRI examinations took place in a single center in 93 patients (39 CIS, 54 RRMS). Clinical disability (n = 93), MRI (n ≤ 90), CSF (n ≤ 82) parameters and DVA status were determined and compared statistically. A total of 29 DVAs were detected in 25 patients (25/93; 26.9%), 10 in 39 CIS patients and 15 in 54 RRMS patients. Most parameters were not significantly altered in patients with DVAs; no associated higher conversion rates from CIS to MS at 1–year (p = 0.411) or 2‑year follow-up (p = 0.281) were registered. A higher prevalence of DVAs was detected in CIS and early MS patients than reported in non-MS populations, congruent to recent literature. The DVAs were not associated with significantly altered clinical outcomes, brain atrophy rates or disease progression, and no associated higher risk of CIS patients for converting to MS was found.

MRI is an important diagnostic tool for evaluation of myelin content in multiple sclerosis and other CNS diseases, being especially relevant for studies investigating remyelinating pharmacotherapies. In this study, we evaluated a new synthetic MRI–based myelin estimation in methylenetetrahydrofolate reductase deficiency as a treatable primary demyelinating disorder and compared this method with established diffusion tensor imaging in both methylenetetrahydrofolate reductase deficiency patients and healthy controls. This is the first synthetic MRI–based in vivo evaluation of treatment-associated remyelination. 1.5 T synthetic MRI and 3 T diffusion MRI were obtained from three methylenetetrahydrofolate reductase deficiency patients at baseline and 6 months after therapy initiation, as well as from age-matched healthy controls (diffusion tensor imaging: n = 14, synthetic MRI: n = 9). Global and regional synthetic MRI parameters (myelin volume fraction, proton density, and relaxation rates) were compared with diffusion metrics (fractional anisotropy, mean/radial/axial diffusivity) and related to healthy controls by calculating z-scores and z-deviation maps. Whole-brain myelin (% of intracranial volume) of the index patient was reduced to 6 versus 10% in healthy controls, which recovered to a nonetheless subnormal level of 6.6% following initiation of high-dosage betaine. Radial diffusivity was higher at baseline compared with healthy controls (1.34 versus 0.79 × 10−3 mm2/s), recovering at follow-up (1.19 × 10−3 mm2/s). The index patient’s lesion volume diminished by 58% under treatment. Regional analysis within lesion area and atlas-based regions revealed lower mean myelin volume fraction (12.7Baseline/14.71Follow-up%) and relaxation rates, higher proton density, as well as lower fractional anisotropy and higher radial diffusivity (1.08 × 10−3Baseline/0.94 × 10−3Follow-up) compared with healthy controls. The highest z-scores were observed for myelin volume fraction in the posterior thalamic radiation, with greater deviation from controls at baseline and reduced deviation at follow-up. Z-deviations of diffusion metrics were less pronounced for radial and mean diffusivity than for myelin volume fraction. Z-maps for myelin volume fraction of the index patient demonstrated high deviation within and beyond lesion areas, among others in the precentral and postcentral gyrus, as well as in the cerebellum, and partial remission of these alterations at follow-up, while radial diffusivity demonstrated more widespread deviations in supra- and infratentorial regions. Concordant changes of myelin volume fraction and radial diffusivity after treatment initiation, accompanied by dramatic clinical and paraclinical improvement, indicate the consistency of the methods, while myelin volume fraction seems to characterize remyelinated regions more specifically. Synthetic MRI–based myelin volume fraction provides myelin estimation consistent with changes of diffusion metrics to monitor short-term myelin changes on individual patient level.

BACKGROUND AND PURPOSE Progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the central nervous system from the John Cunningham virus (JCV), is a side effect of natalizumab (NTZ) treatment for relapsing-remitting multiple sclerosis (RRMS), potentially leading to a substantial increase of physical and mental disability. Nevertheless, data of neuropsychological impairment during the NTZ-PML disease course are missing. Our objective was to evaluate the neuropsychological disease course of NTZ-PML patients and to compare neuropsychological deficits of NTZ-PML patients with two different non-PML multiple sclerosis (MS) cohorts. METHODS Neuropsychological examinations of 28 NTZ-PML patients performed during different phases of the disease ([i] at PML diagnosis, [ii] during immune reconstitution inflammatory syndrome [IRIS], and [iii] post-IRIS/PML) were retrospectively analyzed and compared to those of NTZ-treated RRMS or secondary progressive MS patients with and without immunotherapy. RESULTS Compared to controls, NTZ-PML patients performed worse in neuropsychological examinations during all stages of disease, mainly affecting visuospatial ability and working memory. Furthermore, failure to eliminate the JCV from the central nervous system was associated with a progredient decline of cognition, especially working memory. CONCLUSIONS Working memory and visuospatial abilities are the core neuropsychological deficits of NTZ-PML patients in long-term follow-up. Our findings should be implemented in neurorehabilitation strategies.

BACKGROUND Access to neurological care for Parkinson disease (PD) is a rare privilege for millions of people worldwide, especially in resource-limited countries. In 2013, there were just 1200 neurologists in India for a population of 1.3 billion people; in Africa, the average population per neurologist exceeds 3.3 million people. In contrast, 60,000 people receive a diagnosis of PD every year in the United States alone, and similar patterns of rising PD cases—fueled mostly by environmental pollution and an aging population—can be seen worldwide. The current projection of more than 12 million patients with PD worldwide by 2040 is only part of the picture given that more than 20% of patients with PD remain undiagnosed. Timely diagnosis and frequent assessment are key to ensure timely and appropriate medical intervention, thus improving the quality of life of patients with PD. OBJECTIVE In this paper, we propose a web-based framework that can help anyone anywhere around the world record a short speech task and analyze the recorded data to screen for PD. METHODS We collected data from 726 unique participants (PD: 262/726, 36.1% were women; non-PD: 464/726, 63.9% were women; average age 61 years) from all over the United States and beyond. A small portion of the data (approximately 54/726, 7.4%) was collected in a laboratory setting to compare the performance of the models trained with noisy home environment data against high-quality laboratory-environment data. The participants were instructed to utter a popular pangram containing all the letters in the English alphabet, “the quick brown fox jumps over the lazy dog.” We extracted both standard acoustic features (mel-frequency cepstral coefficients and jitter and shimmer variants) and deep learning–based embedding features from the speech data. Using these features, we trained several machine learning algorithms. We also applied model interpretation techniques such as Shapley additive explanations to ascertain the importance of each feature in determining the model’s output. RESULTS We achieved an area under the curve of 0.753 for determining the presence of self-reported PD by modeling the standard acoustic features through the XGBoost—a gradient-boosted decision tree model. Further analysis revealed that the widely used mel-frequency cepstral coefficient features and a subset of previously validated dysphonia features designed for detecting PD from a verbal phonation task (pronouncing “ahh”) influence the model’s decision the most. CONCLUSIONS Our model performed equally well on data collected in a controlled laboratory environment and in the wild across different gender and age groups. Using this tool, we can collect data from almost anyone anywhere with an audio-enabled device and help the participants screen for PD remotely, contributing to equity and access in neurological care.

BACKGROUND AND PURPOSE The ongoing Coronavirus Disease 2019 (COVID‐19) pandemic is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). COVID‐19 is occasionally associated with manifold diseases of the central nervous system (CNS). We sought to present the neuroimaging features of such CNS involvement. In addition, we sought to identify typical neuroimaging patterns that could indicate possible COVID‐19‐associated neurological manifestations. METHODS In this systematic literature review, typical neuroimaging features of cerebrovascular diseases and inflammatory processes associated with COVID‐19 were analyzed. Reports presenting individual patient data were included in further quantitative analysis with descriptive statistics. RESULTS We identified 115 studies reporting a total of 954 COVID‐19 patients with associated neurological manifestations and neuroimaging alterations. A total of 95 (82.6%) of the identified studies were single case reports or case series, whereas 660 (69.2%) of the reported cases included individual information and were thus included in descriptive statistical analysis. Ischemia with neuroimaging patterns of large vessel occlusion event was revealed in 59.9% of ischemic stroke patients, whereas 69.2% of patients with intracerebral hemorrhage exhibited bleeding in a location that was not associated with hypertension. Callosal and/or juxtacortical location was identified in 58.7% of cerebral microbleed positive images. Features of hemorrhagic necrotizing encephalitis were detected in 28.8% of patients with meningo‐/encephalitis. CONCLUSIONS Manifold CNS involvement is increasingly reported in COVID‐19 patients. Typical and atypical neuroimaging features have been observed in some disease entities, so that familiarity with these imaging patterns appears reasonable and may assist clinicians in the differential diagnosis of COVID‐19 CNS manifestations.

Background: Familial hypercholesterolemia (FH) is an inherited disorder associated with increased LDL-C and premature coronary heart disease, which remains significantly underdiagnosed. Screening those with very high LDL-C may help identify those with FH, but the optimal means of applying this approach is unclear. Methods: Individuals from UT Southwestern Medical Center, a large, tertiary academic center, with an LDL-C level ≥ 190 mg/dL at any time were enrolled in an FH registry. These 5,786 patients were divided into four categories of LDL-C: 190.0 - 219.9, 220.0 - 249.9, 250.0 - 299.9, and ≥ 300.0 mg/dL. One hundred individuals were randomly selected from each category for manual chart review to determine 1) the presence of secondary causes of dyslipidemia (obstructive liver disease, nephrotic syndrome, hypothyroidism, specific medication use, other secondary cause) and 2) diagnosis of possible/definite FH by modified Simon Broome criteria and 3) probable/definite FH by modified Dutch Lipid Clinic Network (DLCN) criteria. Results: Of the 400 individuals with an LDL-C level ≥ 190 mg/dL (mean age 52 years ± 14) in this cohort, the presence of secondary causes increased across each LDL-C category ( p < 0.001) (Figure) with the greatest prevalence in those ≥ 300.0 mg/dL (52%). The prevalence of FH also varied by LDL-C category, with the highest prevalence of FH by Simon Broome criteria in the 220.0 - 249.9 mg/dL category (52%) and by DLCN criteria in the 250.0 - 299.9 mg/dL category (46%). Conclusions: Amongst those with LDL-C ≥ 190 mg/dL, the prevalence of secondary causes increases with higher LDL-C, while the diagnosis of FH has a parabolic relationship. Patients with intermediate LDL-C (220 - 299 mg/dL) may be the optimal group to prioritize for FH screening using an LDL-C based approach.

Purpose As conventional quantitative magnetic resonance imaging (MRI) parameters are weakly associated with cognitive impairment (CI) in early multiple sclerosis (MS), we explored microstructural white matter alterations in early MS or clinically isolated syndrome (CIS) comparing patients with or without CI. Methods Based on a preceding tract-based spatial statistics analysis (3 Tesla MRI) which contrasted 106 patients with early MS or CIS and 49 healthy controls, diffusion metrics (fractional anisotropy, FA, mean diffusivity, MD) were extracted from significant clusters using an atlas-based approach. The FA and MD were compared between patients with (Ci_P n = 14) and without (Cp_P n = 81) cognitive impairment in a subset of patients who underwent CI screening. Results The FA was reduced in Ci_P compared to Cp_P in the splenium of corpus callosum (p = 0.001), right parahippocampal cingulum (p = 0.002) and fornix cres./stria terminalis (0.042), left posterior corona radiata (p = 0.012), bilateral cerebral peduncles, medial lemniscus and in cerebellar tracts. Increased MD was detected in the splenium of corpus callosum (p = 0.01). The CI-related localizations overlapped only partially with MS lesions. Conclusion Microstructural white matter alterations at disease onset were detectable in Ci_P compared to Cp_P in known cognitively relevant fiber tracts, indicating the relevance of early treatment initiation in MS and CIS.

ObjectiveTo investigate cross-sectional associations of CSF levels of neurofilament light chain (NfL) and of the newly emerging marker chitinase 3–like protein 1 (CHI3L1) with brain and spinal cord atrophy, which are established MRI markers of disease activity in MS, to study CHI3L1 and NfL in relapsing (RMS) and progressive MS (PMS), and to assess the expression of CHI3L1 in different cell types.MethodsIn a single-center study, 131 patients with MS (42 RMS and 89 PMS) were assessed for NfL and CHI3L1 concentrations in CSF, MRI-based spinal cord and brain volumetry, MS subtype, age, disease duration, and disability. We included 42 matched healthy controls receiving MRI. CHI3L1 expression of human brain cell types was examined in 2 published single-cell RNA sequencing data sets.ResultsCHI3L1 was associated with spinal cord volume (B = −1.07, 95% CI −2.04 to −0.11, p = 0.029) but not with brain volumes. NfL was associated with brain gray matter (B = −7.3, 95% CI −12.0 to −2.7, p = 0.003) but not with spinal cord volume. CHI3L1 was suitable to differentiate between progressive or relapsing MS (p = 0.015, OR 1.0103, CI for OR 1.002–1.0187), and its gene expression was found in MS-associated microglia and macrophages and in astrocytes of MS brains.ConclusionsNfL and CHI3L1 in CSF were differentially related to brain and spinal cord atrophy. CSF CHI3L1 was associated with spinal cord volume loss and was less affected than NfL by disease duration and age, whereas CSF NfL was associated with brain gray matter atrophy. CSF NfL and CHI3L1 measurement provides complementary information regarding brain and spinal cord volumes.Classification of evidenceThis study provides Class II evidence that CSF CHI3L1 is associated with spinal cord volume loss and that CSF NfL is associated with gray matter atrophy.

Upper cervical cord area (UCCA) atrophy is a prognostic marker for clinical progression in longstanding multiple sclerosis (MS). The objectives of the study were to quantify UCCA atrophy and evaluate its impact in clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS); to compare converting CIS patients with stable CIS, and to study changes of UCCA and brain white matter (WM) and grey matter (GM) at 2-year follow-up. 110 therapy-naive patients including 53 CIS [6 ± 6 months after symptom onset (SO)] and 57 early RRMS (SO: 12 ± 9 months) underwent sagittal 3D-T1w brain MR (3T). Mean UCCA (C1-C3 level), WM and GM, disability status (EDSS), pyramidal and sensory functional scores, motoric fatigue were assessed at baseline (BL), 12 and 24 months. Volumes were compared with 34 age- and gender-matched healthy controls to assess atrophy. RRMS (78.1 ± 8.7 mm(2), p = 0.011) and converting CIS (77.3 ± 8.0 mm(2), p = 0.046) presented with baseline UCCA atrophy, when compared with controls (82.7 ± 5.2 mm(2)), but not stable CIS (82.6 ± 7.4 mm(2), p = 0.998). Baseline WM was reduced in RRMS (509.3 ± 25.7 ml vs. CONTROLS 528.4 ± 24.1 ml, p = 0.032). Baseline UCCA correlated negative with muscular weakness and fatigability in all patients and RRMS. EDSS exceeding 3 was associated with lower baseline UCCA. Longitudinal atrophy rates were higher in UCCA than in brain volumes. Early cervical cord atrophy in CIS and RRMS was confirmed and may represent a potential new risk marker for conversion from CIS to MS. Baseline atrophy and atrophy change rates were higher in UCCA compared to WM and GM, suggesting that cervical cord volumetry might become an additional MRI marker relevant in future clinical studies in CIS and early MS.

Anti-N-methyl-D-aspartate receptor encephalitis (Anti-NMDARE) is a synaptic autoimmune encephalitis syndrome mainly affecting young females. An underlying tumor, most commonly ovarian teratomas in young females, may indicate a paraneoplastic syndrome. Prognostic factors of the clinical course of disease and outcome play a central role in view of early administration of second-line immunotherapy and intensive-care therapy. We report a case of severe Anti-NMDARE associated with unfavorable predictors including an extreme delta brush (EDB) electroencephalographic-pattern and high anti-NMDAR-antibody titers in the cerebral spinal fluid (CSF), which necessitated the admission to an intensive care unit. In spite of the poor prognosis, the patient completely recovered; we attribute this to an early escalation to second-line immunotherapy with rituximab and multidisciplinary intensive-care therapy. The present case underlines the relevance of multidisciplinary management for individuals with Anti-NMDARE.

\(\bf Objective\) To report the course of 3 recent Japanese and European cases of fingolimod-associated progressive multifocal leukoencephalopathy (PML) and to analyze its risk factors and increased incidence in Japan. \(\bf Methods\) Case series and literature review. \(\bf Results\) Fingolimod-associated PML may cause both supratentorial and infratentorial lesions and a pronounced disability. Diagnosis can be challenging because PML lesions (especially infratentorial) can be initially misdiagnosed as extensive MS lesions. Immune reconstitution inflammatory syndrome (IRIS) develops a few weeks after fingolimod discontinuation and is usually mild. Age factor and therapy duration seem to be relevant because most reported patients were older than 45 years and were treated with fingolimod for more than 3 years. Combined IgG/IgM deficiency has been identified as a possible further predisposing condition in 1 case. Another patient developed an endogenous fungal skin infection, as a sign of generally compromised cellular immune response, shortly before PML. None of the reported patients had lymphocyte counts below 200/μl. Two of the 3 reported and 4 of the 21 (19%) registered fingolimod-PML cases occurred in Japan (estimated risk of 0.652 per 1,000 compared with 0.083 per 1.000 worldwide). \(\bf Conclusions\) The risk of PML under fingolimod is low, but there are no reliable predictors. Despite a mild IRIS phase, it causes profound disability. Patients older than 45 years, especially with known comorbid immunodeficiencies or manifestation of other opportunistic infections, should be monitored more closely. Increased surveillance and identification of further risk factors are urgently needed in Japan.

BACKGROUND AND PURPOSE Cerebral atrophy has been suggested to be a reliable magnetic resonance imaging (MRI) predictor of subsequent disability in all stages of multiple sclerosis (MS). However, no accepted methodology for routine clinical use exists to date. We sought an easy to apply and fast technique to evaluate cerebral ventricular volume in patients with MS with similar accuracy as a semiautomatic volumetric method. METHODS The study included 104 patients, 61 diagnosed with MS and 43 with clinically isolated syndrome. In addition, 30 healthy controls were enrolled. Physical disability was assessed with the expanded disability status scale and cognitive disability with the Multiple Sclerosis Inventory Cognition (MUSIC) test. All subjects received standardized 3-dimensional (3D) MR-imaging on a 3 T scanner. Third ventricle volume (3VV) was obtained from 3D T1-weighted images using a semiautomated technique, and compared against planimetric assessment of the width of the third ventricle aligned (a3VW) and unaligned (u3VW) to anatomical landmarks. RESULTS a3VW was obtained within seconds with excellent intra- and interrater agreement, and outperformed volumetric measurements regarding the differentiation of MS patients from healthy controls. a3VW had the strongest correlations with 3VV (r = .78, P < .001) and showed moderate inverse correlation with MUSIC cognition score (r = −.310, P < .005). CONCLUSIONS a3VW is a time-effective and robust biomarker that has strong correlations with volumetric measurements and can be established as standard in the MRI quantification of central brain atrophy in patients with early MS.

Objective: Progressive multifocal leukoencephalopathy (PML) is an emerging complication of immunosuppressive therapies, especially natalizumab in multiple sclerosis (MS). Factors associated with functional outcome of natalizumab-associated PML (natalizumab-PML) have not been sufficiently described. Methods: We retrospectively analyzed medical records of all patients with natalizumab-PML ( n = 32) treated in our hospital since 2009. Disability measured by Expanded Disability Status Scale (EDSS) at two different time points (highest available EDSS during PML and last available EDSS after PML diagnosis) served as functional outcome parameters. Clinical, laboratory, and imaging data were analyzed for association with functional outcome by applying Spearman’s rho and multivariate regression analysis. Results: In all, 31/32 patients survived PML. A poor functional outcome was associated with higher age, higher initial John Cunningham virus (JCV) copy number in cerebrospinal fluid (CSF), and more extensive PML lesions on initial magnetic resonance imaging (MRI). No association between functional outcome and the duration of natalizumab therapy or a delayed PML diagnosis was observed. Conclusion: This study will be useful for neurological practice to estimate functional outcome or disease severity of natalizumab-PML in primary care settings.

Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs.

Short chain fatty acids (SCFA) are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here we investigate the SCFA propionic acid (PA) in multiple sclerosis (MS) as a model of general autoimmune and neurodegenerative diseases. The serum and feces of MS patients exhibited significantly reduced PA-levels, which were associated with a reduction in diversity and abundance of SCFA-producing bacteria. In a proof-of-concept study, we supplemented PA to MS patients as add-on to immunotherapy. After two weeks of PA intake, we observed a significant and sustained increase of functionally competent Treg, while Th1 and Th17 significantly decreased. Retrospective analyses of up to 3years of PA-intake revealed a reduced annual relapse rate, stabilization of disability and reduced brain atrophy. In primary neurons, differentiated from MS patient-specific induced pluripotent stem cells, PA enhanced neurite regrowth after damage, similar to the Treg key cytokine interleukin-10. Our findings suggest that PA can serve as a potent immunomodulatory and neuroprotective supplement to approved MS drugs.

\(\textbf {Background:}\) Progressive multifocal leukoencephalopathy (PML) is a severe complication of immunosuppressive therapies, especially of natalizumab in relapsing–remitting multiple sclerosis (MS). Metabolic changes within PML lesions have not yet been described in natalizumab-associated PML in MS patients. \(\textbf {Objective:}\) To study metabolic profiles in natalizumab-associated PML lesions of MS patients by \( ^{1}\)H magnetic resonance spectroscopy (\( ^{1}\)H-MRS) at different stages during the PML course. To assess changes associated with the occurrence of the immune reconstitution inflammatory syndrome (IRIS). \(\textbf {Methods:}\) 20 patients received \( ^{1}\)H-MRS and imaging at 3 T either in the pre-IRIS, IRIS, early-post-PML, or late post-PML setting. Five of these patients received individual follow-up examinations, including the pre-IRIS or IRIS phase. Clinical worsening was described by changes in the Karnofsky Performance Scale (KPS) and the expanded disability status scale (EDSS) 1 year before PML and scoring at the time of \( ^{1}\)H-MRS. \(\textbf {Results:}\) In PML lesions, increased levels of the Lip/Cr ratio, driven by rising of lipid and reduction of Creatine, were found before the occurrence of IRIS (\(\it p\) = 0.014) with a maximum in the PML–IRIS group (\(\it p\) = 0.004). By contrast, marked rises of Cho/Cr in PML lesions were detected exclusively during the IRIS phase (\(\it p\) = 0.003). The Lip/Cr ratio decreased to above-normal levels in early-post-PML (\(\it p\) = 0.007, compared to normal appearing white matter (NAWM)) and to normal levels in the late-post-PML group. NAA/Cho was reduced compared to NAWM in the pre-IRIS, IRIS, and early-post-PML group. In NAA/Cr, the same effect was seen in the pre-IRIS and early-post-PML group. These cross-sectional results were confirmed by the individual follow-up examinations of four patients. NAA/Cho, Cho/Cr, and the lipid rise relative to NAWM in PML lesions were significantly correlated with the residual clinical worsening (KPS change) in post-PML patients (Spearman correlations \(\it p\) = 0.481, \(\it p\) = 0.018; \(\it p\) = −0.505, \(\it p\) = 0.014; and \(\it p\) = −0.488, \(\it p\) = 0.020). \(\textbf {Conclusion:}\) \( ^{1}\)H-MRS detected clinically significant dynamic changes of metabolic patterns in PML lesions during the course of natalizumab-associated PML in MS patients. Lip/Cr and Cho/Cr may provide additional information for detecting the onset of the IRIS phase in the course of the PML disease.

Alemtuzumab is a pan-lymphocyte depleting anti-CD52 antibody, and is approved as an escalation therapy for patients with multiple sclerosis with active disease defined by clinical or imaging features. In phase 3 clinical trials, the drug was more effective than interferon beta-1a in reducing relapses and brain volume loss. However, concerns have been raised due to its numerous adverse effects.

Objectives Cervical cord involvement is common in neuromyelitis optica (NMO) and multiple sclerosis (MS), but its impact on disability in NMO has rarely been studied. Recent publications on NMO examined the periventricular system, areas of high aquaporin-4 expression, but not yet by using ventricle volumetry. Purpose To compare cervical cord atrophy, ventricular widening, and supra- and infratentorial brain measures between NMO and MS, and study their impact on clinical disability. Methods Magnet resonance imaging-based volumetry of upper cervical cord, third and fourth lateral ventricles, grey matter, white matter, brainstem, cerebellum and clinical status of 18 NMO and 20 MS patients, was compared between the groups and with 26 healthy controls. Patterns of ventricular widening relative to healthy controls were inspected by voxel-based morphometry of the cerebrospinal fluid. Results Cervical cord atrophy was similar in NMO and MS (75.2 ± 10.0 mm2, respectively, 76.5 ± 9.5 mm2 vs 84.1 ± 8.6 mm2 in controls).Third ventricle increase in both groups, and specific fourth ventricle widening in MS were detected. Patient groups differed in third to fourth ventricle ratio (P = 0.002). In NMO, white matter correlated inversely with the affected cord segments (P = 0.001) and with cervical cord area (P = 0.043). The disability status was explained by cervical cord area and third ventricle volume (R2=0.524) in NMO, and by grey matter and fourth ventricle volume (R2=0.565) in MS. Conclusion Cervical cord atrophy and third ventricular enlargement are both clinically relevant in NMO. Third and fourth ventricle volumetry shows differences between NMO and MS regarding the involvement of periventricular structures.

Cerebral atrophy has been suggested to be a reliable magnetic resonance imaging (MRI) predictor of subsequent disability in all stages of multiple sclerosis (MS). However, no accepted methodology for routine clinical use exists to date. We sought an easy to apply and fast technique to evaluate cerebral ventricular volume in patients with MS with similar accuracy as a semiautomatic volumetric method.The study included 104 patients, 61 diagnosed with MS and 43 with clinically isolated syndrome. In addition, 30 healthy controls were enrolled. Physical disability was assessed with the expanded disability status scale and cognitive disability with the Multiple Sclerosis Inventory Cognition (MUSIC) test. All subjects received standardized 3-dimensional (3D) MR-imaging on a 3 T scanner. Third ventricle volume (3VV) was obtained from 3D T1-weighted images using a semiautomated technique, and compared against planimetric assessment of the width of the third ventricle aligned (a3VW) and unaligned (u3VW) to anatomical landmarks.a3VW was obtained within seconds with excellent intra- and interrater agreement, and outperformed volumetric measurements regarding the differentiation of MS patients from healthy controls. a3VW had the strongest correlations with 3VV (r = .78, P.001) and showed moderate inverse correlation with MUSIC cognition score (r = -.310, P.005).a3VW is a time-effective and robust biomarker that has strong correlations with volumetric measurements and can be established as standard in the MRI quantification of central brain atrophy in patients with early MS.

Background Spontaneously hypertensive rats (SHRs) are characterized by capillary rarefaction, which may contribute to blood pressure elevation. We hypothesized that capillary rarefaction involves a suppressed angiogenesis; renin inhibition influences anti-angiogenesis homeostasis by acting on angiopoietins; transient renin blockade reduces anti-angiogenesis thereby ameliorating long-lasting blood pressure and cardiac hypertrophy in SHRs. Methods First, serum angiopoietin-1 and angiopoietin-2 were measured in 2-month old normotensive Wistar-Kyoto rats (WKYs) and SHRs after renin inhibition (aliskiren: 1 and 10mg/kg per day) or placebo. Second, 4-week old SHRs were prehypertensively treated with aliskiren (1 and 10mg/kg per day) or placebo for 4 weeks. After 4 weeks of 'drug holiday' 12-week old SHRs were given L-nitro-arginine methyl ester (L-NAME) (25mg/kg per day) for a 4-week interval to promote capillary rarefaction. Thereafter, mean arterial pressure (MAP), cardiacremodeling, capillary density, pAkt/Akt as marker for cellular survival, pro-angiogenic genes and systemic angiopoietins were investigated. Results Baseline angiopoietin levels were similar between WKYs and SHRs. Renin inhibition increased angiopoietin-1 in SHR and reduced angiopoietin-2 in both WKY and SHR blood pressure independently. Prehypertensive renin inhibition reduced MAP and cardiac hypertrophy in adult SHRs. This was associated with higher cardiac capillary density, pAkt/Akt, pro-angiogenic expression pattern and serum angiopoietin-1, whereas angiopoietin-2 was lower as compared to vehicle-pretreated SHRs. These results were independent of prehypertensive blood pressure lowering by aliskiren. Conclusion We conclude that renin inhibition modulates anti-angiogenesis signaling independently of blood pressure by increasing angiopoietin-1/angiopoietin-2 ratio. This promotes in SHR stabilization of endothelial cells, favors pro-angiogenic action and consequently results in higher capillary density. J Hypertens 29: 266-272

Purpose To evaluate, in a pilot study, the phosphorylated H2AX (γH2AX) foci approach for identifying patients with double-strand break (DSB) repair deficiencies, who may overreact to DNA-damaging cancer therapy. Methods and Materials The DSB repair capacity of children with solid cancers was analyzed compared with that of age-matched control children and correlated with treatment-related normal-tissue responses ( n = 47). Double-strand break repair was investigated by counting γH2AX foci in blood lymphocytes at defined time points after irradiation of blood samples. Results Whereas all healthy control children exhibited proficient DSB repair, 3 children with tumors revealed clearly impaired DSB repair capacities, and 2 of these repair-deficient children developed life-threatening or even lethal normal-tissue toxicities. The underlying mutations affecting regulatory factors involved in DNA repair pathways were identified. Moreover, significant differences in mean DSB repair capacity were observed between children with tumors and control children, suggesting that childhood cancer is based on genetic alterations affecting DSB repair function. Conclusions Double-strand break repair alteration in children may predispose to cancer formation and may affect children's susceptibility to normal-tissue toxicities. Phosphorylated H2AX analysis of blood samples allows one to detect DSB repair deficiencies and thus enables identification of children at risk for high-grade toxicities.

Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive skeletal muscle myopathy which is caused by mutations in the dystrophin gene. Lack of dystrophin also results to cardiomyopathy, which raises significantly the stroke risk in DMD-patients. However, data about therapeutic opportunities in the acute setting are scarce in literature. So far, only two cases receiving IV thrombolysis are described, one of them with fatal outcome. Method: Case report of a case of successful mechanical thrombectomy (MTE) in an acute ischemic stroke (AIS) patient with DMD and associated dilatative cardiomyopathy. Results: A 20-year old DMD-patient was transferred at 08:56 h to our department due to wake up stroke with severe right-sided hemiparesis and aphasia (NIHSS=20). Last-seen-normal was at 03:00 h. Cerebral CT-scan revealed only slight early ischemic changes (ASPECT-Score=8). CT-angiography detected occlusion of left middle cerebral artery (LMCA). MTE started rapidly at 9:23 h and using direct thrombus aspiration (Penumbra System®) complete recanalization was achieved 20 min later (TICI-grade 3). Considering the specific risks of general anesthesia in DMD, the procedure was performed with propofol, remifentanil and rocuronium. The patient recovered quickly from the acute symptoms, due to preexisting hypotonic tetraparesis his NIHSS-score at discharge was 12 points. Conclusions: To the best of our knowledge, this is the first report on MTE in a patient with DMD related cardioembolic stroke. In contrast to the few reports with IV thrombolysis, MTE seems to represent an optimal treatment option. Specific characteristics of DMD-patients like anesthetic regimen should be taken into account.