Neoehrlichiosis associated with ocrelizumab in a patient with multiple sclerosis: A case report.

OBJECTIVE: To describe a case of neoehrlichiosis, an emerging opportunistic tick-borne infection, in a patient with multiple sclerosis (MS) treated with ocrelizumab. METHODS: This is a case study. RESULTS: Our patient developed clinical infection over several months while on ocrelizumab and was ultimately diagnosed with neoehrlichiosis, caused by the bacteria Neoehrlichia mikurensis. Resolution of symptoms began within a few days after the initiation of antibiotic treatment. CONCLUSION: We describe the first probable case of ocrelizumab-associated neoehrlichiosis in a patient with MS. Clinicians should be aware of this potentially debilitating and life-threatening infection in patients receiving CD20-depleting therapy.

Linking lesions in sensorimotor cortex to contralateral hand function in multiple sclerosis: a 7†T MRI study.

Cortical lesions constitute a key manifestation of multiple sclerosis and contribute to clinical disability and cognitive impairment. Yet it is unknown whether local cortical lesions and cortical lesion subtypes contribute to domain-specific impairments attributable to the function of the lesioned cortex. In this cross-sectional study, we assessed how cortical lesions in the primary sensorimotor hand area relate to corticomotor physiology and sensorimotor function of the contralateral hand. Fifty relapse-free patients with relapsing-remitting or secondary-progressive multiple sclerosis and 28 healthy age- and sex-matched participants underwent whole-brain 7 T MRI to map cortical lesions. Brain scans were also used to estimate normalized brain volume, pericentral cortical thickness, white matter lesion fraction of the corticospinal tract, infratentorial lesion volume and the cross-sectional area of the upper cervical spinal cord. We tested sensorimotor hand function and calculated a motor and sensory composite score for each hand. In 37 patients and 20 healthy controls, we measured maximal motor-evoked potential amplitude, resting motor threshold and corticomotor conduction time with transcranial magnetic stimulation and the N20 latency from somatosensory-evoked potentials. Patients showed at least one cortical lesion in the primary sensorimotor hand area in 47 of 100 hemispheres. The presence of a lesion was associated with worse contralateral sensory (P = 0.014) and motor (P = 0.009) composite scores. Transcranial magnetic stimulation of a lesion-positive primary sensorimotor hand area revealed a decreased maximal motor-evoked potential amplitude (P < 0.001) and delayed corticomotor conduction (P = 0.002) relative to a lesion-negative primary sensorimotor hand area. Stepwise mixed linear regressions showed that the presence of a primary sensorimotor hand area lesion, higher white-matter lesion fraction of the corticospinal tract, reduced spinal cord cross-sectional area and higher infratentorial lesion volume were associated with reduced contralateral motor hand function. Cortical lesions in the primary sensorimotor hand area, spinal cord cross-sectional area and normalized brain volume were also associated with smaller maximal motor-evoked potential amplitude and longer corticomotor conduction times. The effect of cortical lesions on sensory function was no longer significant when controlling for MRI-based covariates. Lastly, we found that intracortical and subpial lesions had the largest effect on reduced motor hand function, intracortical lesions on reduced motor-evoked potential amplitude and leucocortical lesions on delayed corticomotor conduction. Together, this comprehensive multilevel assessment of sensorimotor brain damage shows that the presence of a cortical lesion in the primary sensorimotor hand area is associated with impaired corticomotor function of the hand, after accounting for damage at the subcortical level. The results also provide preliminary evidence that cortical lesion types may affect the various facets of corticomotor function differentially.

Ocrelizumab treatment in multiple sclerosis: A Danish population-based cohort study.

BACKGROUND AND PURPOSE: Real-world evidence regarding the effectiveness and safety of ocrelizumab for the treatment of multiple sclerosis (MS) is limited. The aim was to evaluate the effectiveness and safety of ocrelizumab treatment for MS in a real-world setting. METHODS: A nationwide population-based cohort study was conducted where clinical and magnetic resonance imaging data of MS patients enrolled prospectively in the Danish Multiple Sclerosis Registry who initiated ocrelizumab treatment between January 2018 and November 2020 were analyzed. RESULTS: A total of 1104 patients (85.7% relapsing-remitting MS [RRMS], 8.8% secondary progressive MS [SPMS], 5.5% primary progressive MS [PPMS]) were included, with a median follow-up period of 1.3 years. At baseline, the mean age was 41.4 years in the RRMS group, 44.5 years in the PPMS group and 50.3 years in the SPMS group. Median Expanded Disability Status Scale score was 2.5, 3.5 and 5.5, respectively. Most RRMS and SPMS patients had received previous disease-modifying therapies (87.5% and 91.8%, respectively), whereas PPMS patients were mostly treatment naïve (78.7%). After ocrelizumab initiation, 9.3% of the patients experienced a relapse and 8.7% a 24 weeks confirmed disability worsening. Conversely, 16.7% showed a 24 weeks confirmed disability improvement. After ~1 year of treatment, most patients (94.5%) were free of magnetic resonance imaging activity. Ocrelizumab was generally well tolerated, as side effects were only reported for 10% of patients, mostly consisting of infusion-related reactions and infections. CONCLUSIONS: It is shown that most MS patients treated with ocrelizumab are clinically stabilized and with an adverse event profile consistent with the experience from the pivotal clinical trials.

Employment, health visits, mental health, and mortality in parents with a chronically ill child: a Danish nationwide population-based cohort study.

Chronic diseases in children can impact their parents; this may be overlooked in a clinical setting. Our aim was to investigate associations of chronic diseases in children with their parents' employment, health care utilization, mental health, and mortality. In a matched cohort study using nationwide and population-based data in Denmark, we included parents to children (< 18 years) with acute disseminated encephalomyelitis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease, and rheumatoid arthritis/juvenile idiopathic arthritis during 2008-2015. The reference group was parents to unaffected children. Outcomes were parental employment (early retirement, cash benefits, income), health care utilization (e.g., general practitioner, or hospital visits), mental health (visits to psychiatry/psychology clinics, antidepressant drug redemptions), and mortality. We included 13,769 parents with a chronically ill child and 138,606 control parents. Annual income was unaffected for two-parent families after the child's disease onset, but two-parent families had increased hazard of early retirement of 25% (95% CI = 1.01-1.54; p = 0.04). Parents with a chronically ill child had (a) increased rate of antidepressant drug redemptions or psychology/psychiatry visits (hazard ratio 1.37; 95% CI = 1.28-1.46 at 1-year follow-up); (b) increased health care utilization, with an increased marginal mean in primary care of 1% (95% CI = 1.00-1.02; p = 0.005), hospital-affiliated visits of 19% (95% CI = 1.14-1.24; p < 0.0001), and hospital admissions of 14% (95% CI = 1.09-1.20; p < 0.0001); and (c) 69% increased mortality hazard (95% CI = 1.30-2.18; p < 0.0001) in parents younger than 50 years with no comorbidities, albeit small in absolute numbers. CONCLUSION: Pediatric chronic diseases were negatively associated with parental employment, mental health, and mortality, and increased health care utilization. WHAT IS KNOWN: • Studies on the impact of pediatric chronic diseases on parental health are qualitative. • Knowledge is unavailable regarding the impact on parental work, health care utilization, and mortality. WHAT IS NEW: • Among 13,769 parents with a chronically ill child and 138,606 control parents, parents with a chronically ill child had 37% increased antidepressant drug redemptions, and these parents <50 years without comorbidities had 69% increased mortality hazard. • Medical doctors should consider the parental health condition and societal challenges related to having child with a chronic disease.

School performance, psychiatric comorbidity, and healthcare utilization in pediatric multiple sclerosis: A nationwide population-based observational study.

BACKGROUND: Pediatric multiple sclerosis (MS) may hamper educational achievements due to psychiatric comorbidity and cognitive impairment. Our aims were to investigate school performance, psychiatric comorbidity, and healthcare utilization following pediatric MS and to differentiate between disability in MS and that arising from a non-brain-related chronic disease. METHODS: We included all children (<18 years) with MS onset during 2008-2015 in Denmark with a medical record-validated MS diagnosis. The control groups were children from the general population or children with non-brain-related chronic diseases. Outcomes were register-based on 9-12 grade point average, psychiatric comorbidity, and healthcare visits. RESULTS: Cohorts were children with MS (n = 92), control children matched to children with MS (n = 920), children with non-brain-related chronic diseases (n = 9108), and "healthy" children with neither MS nor brain-related chronic disease (n = 811,464). School performance in grades 9-12 was similar, but children with MS compared to those with non-brain-related chronic disease had an almost doubled hazard for psychiatric comorbidity (hazard ratio = 1.87; 95% confidence interval = 1.38-2.53; p < 0.0001) and a higher rate of all hospital visits (p < 0.0001) but a lower rate of hospital admissions (p = 0.001). CONCLUSION: Children with MS have a seemingly standard school performance but increased psychiatric comorbidity and a high rate of healthcare utilization.

Predictors of treatment outcome in patients with paediatric onset multiple sclerosis.

BACKGROUND: Disease-modifying therapies (DMT) are increasingly used for children with multiple sclerosis (MS) even though most double-blinded randomized controlled trials evaluating efficacy, safety and dosing strategy of a specific drug have included adults. OBJECTIVE: To investigate predictors of treatment outcomes in patients with paediatric onset MS treated with DMTs. METHODS: Prospective cohort study from the nationwide Danish Multiple Sclerosis Registry including all patients with a MS diagnosis who initiated treatment with an approved DMT before the age of 18 (N = 137) and followed until their 25th birthday. Selected baseline predictors were tested in univariate and multivariate regression models. RESULTS: Multivariate analyses showed that being female and having disease duration for 2 or more years prior to DMT initiation predicted a higher relapse rate. In addition, disease duration and baseline expanded disability status scale (EDSS) predicted both confirmed disability worsening and improvement. We found no difference in treatment outcome between children with MS onset before and after the age of 13 years. CONCLUSIONS: The efficacy of DMT in paediatric onset MS patients is comparable to that seen in adult onset MS patients. Earlier treatment start is associated with a beneficial prognosis in the paediatric cohort.

Infections seem to be more frequent before onset of pediatric multiple sclerosis: A Danish nationwide nested case-control study.

BACKGROUND: Infections are suspected environmental triggers for multiple sclerosis (MS). The relationship between the timing and cumulative number of childhood infections regarding pediatric MS risk is uninvestigated. OBJECTIVES: To investigate whether childhood infections contribute to pediatric MS. METHODS: A nationwide nested case-control study with detailed MS case ascertainment including chart review was undertaken. For each MS case, we selected five control children using density sampling from the entire Danish population, matching controls to children with MS by sex and birthdate. We analyzed data with the cumulative number of childhood infections as exposure and MS as outcome. Hazard ratios (HRs) including 95% confidence intervals (CIs) were estimated using Cox regression. RESULTS: We identified 212 children with MS and 1,060 controls. Median age at MS onset was 15.3 years (range: 7.6-17.8 years); 72% were girls. Each infection during the preceding 3 years increased the hazard for MS by 11% (95% CI = 1.01-1.22, p = 0.04); having 5+ infections compared with 0-4 infections in the preceding 3 years doubled the hazard for MS (HR: 2.18; 95% CI = 1.12-4.30, p = 0.02). CONCLUSION: Children with MS appeared to have more infections in the 3 years preceding MS clinical onset; accordingly, immune response to infections may influence MS pathogenesis.

Pediatric-onset multiple sclerosis and other acquired demyelinating syndromes of the central nervous system in Denmark during 1977-2015: A nationwide population-based incidence study.

BACKGROUND: The incidence of acquired demyelinating syndromes (ADS) including multiple sclerosis (MS) has never been investigated in a Danish pediatric population. OBJECTIVES: We estimated the nationwide age- and sex-specific incidence of pediatric ADS including MS. METHODS: Data were sourced from the Danish Multiple Sclerosis Registry, providing cases of pediatric MS for 1977-2015, and the National Patient Register, providing cases of ADS during 2008-2015. All medical records were reviewed to validate the register-based diagnoses. RESULTS: We identified 364 cases of pediatric MS occurring during 1977-2015 (incidence rate = 0.79 per 100,000 person-years). MS was exceptionally rare before puberty, but the incidence rose considerably from 9 years in girls and 11 years in boys. The female-to-male ratio was 2.5; the median age at onset was 16 years (range = 7-17 years). The MS incidence rate was relatively stable through the study period. During 2008-2015, we identified 219 ADS cases. The incidence was 2.29 per 100,000 person-years with considerable differences in the age peaks for the separate ADS. CONCLUSION: The incidence rates of MS and other ADS in Denmark were higher than those reported for some other European countries. Referral bias and classification differences may account for this disparity, in particular the age-intervals and the definition of onset.

Implications of the International Paediatric Multiple Sclerosis Study Group consensus criteria for paediatric acute disseminated encephalomyelitis: a nationwide validation study.

AIM: The International Paediatric Multiple Sclerosis Study Group (IPMSSG) has proposed criteria for acute disseminated encephalomyelitis (ADEM) not evaluated in clinical practice. Our objective was to assess epidemiological implications of the IPMSSG criteria for ADEM in a cohort study using prospectively collected data. METHOD: We identified all diagnosed cases of ADEM in Denmark between 2008 and 2015 from the Danish National Patient Register by International Classification of Diseases 10 codes assigned to acute demyelinating episodes, and we reviewed all medical records to validate ADEM. RESULTS: We found 52 children up to the age of 18 years with a verified clinical diagnosis of ADEM (incidence rate 0.54/100 000 person-years; all had abnormal brain magnetic resonance imaging). Only 18 (35%) fulfilled the IPMSSG criteria regarding encephalopathy and polyfocal neurological deficits. Among all 52 children with ADEM, 33 per cent had clinical sequelae after a median follow-up of 4 years 6 months (range: 10mo-8y 3mo). Surprisingly, none progressed to multiphasic ADEM or multiple sclerosis, but median age at end of follow-up was only 10 years 9 months (range: 2y-24y 3mo). INTERPRETATION: Among 52 children with ADEM, none converted to multiphasic ADEM or multiple sclerosis (median follow-up: 4y 6mo; range: 10mo-8y 3mo). Applying the IPMSSG criteria to all children with a diagnosis of ADEM leaves 65 per cent of the cases without a diagnosis and lowers the incidence rate of paediatric ADEM. WHAT THIS PAPER ADDS: The incidence of paediatric acute disseminated encephalomyelitis (ADEM) was 0.54 per 100 000 person-years in children younger than 18 years. Only 35 per cent of children with ADEM fulfilled the International Paediatric Study Group consensus criteria. ADEM in clinical practice was primarily based on magnetic resonance imaging findings. Paediatric neurologists diagnosed ADEM in the absence of encephalopathy. None of the children with ADEM progressed to multiple sclerosis/multiphasic ADEM during follow-up.

Association of Cortical Lesions With Regional Glutamate, GABA, N-Acetylaspartate, and Myoinositol Levels in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Cortical lesions contribute to disability in multiple sclerosis (MS), but their impact on regional neurotransmitter levels remains to be clarified. We tested the hypothesis that cortical lesions are associated with regional glutamate and gamma-aminobutyric acid (GABA) concentrations within the affected cortical region. METHODS: In this cross-sectional study, we used structural 7T MRI to segment cortical lesions and 7T proton MR-spectroscopy of the bilateral sensorimotor hand areas to quantify regional GABA, glutamate, N-acetylaspartate, and myoinositol concentrations in patients with MS (inclusion criteria: diagnosis of relapsing-remitting [RR] or secondary progressive MS [SPMS]; age 18-80 years) and age and sex-matched healthy controls. Data were collected at a single center between August 2018 and September 2020. Linear mixed-effects models were used to test for associations between metabolite concentrations and cortical lesion volumes within the same MR-spectroscopy voxel. RESULTS: Forty-seven patients with MS (34 RRMS, 13 SPMS; 45.1 ± 12.5 years; 31 women) and 23 healthy controls (44.4 ± 13 years, 15 women) were studied. In patients, higher regional glutamate and lower regional GABA concentrations were associated with larger cortical lesion volume within the MR-spectroscopy voxel [glutamate: 0.61 (95% CI 0.19-1.03) log(mm3), p = 0.005, GABA: -0.71 (-1.24 to -0.18) log(mm3), p = 0.01]. In addition, lower N-acetylaspartate levels [-0.37 (-0.67 to -0.07) log(mm3), p = 0.016] and higher myoinositol levels [0.48 (0.03-0.93) log(mm3), p = 0.037] were associated with a larger regional cortical lesion volume. Furthermore, glutamate concentrations were reduced in patients with SPMS compared with healthy participants [-0.75 (-1.3 to -0.19) mM, p = 0.005] and patients with RRMS [-0.55 (-1.07 to -0.02) mM, p = 0.04]. N-acetylaspartate levels were lower in both patients with RRMS [-0.81 (-1.39 to -0.24) mM, p = 0.003] and SPMS [-1.31 (-2.07 to -0.54) mM, p < 0.001] when compared with healthy controls. Creatine-normalized N-acetylaspartate levels were associated with performance in the 9-hole peg test of the contralateral hand [-0.004 (-0.007 to -0.002) log(s), p = 0.002], and reduced mean creatine-normalized glutamate was associated with increased Expanded Disability Status Scale (R = -0.39, p = 0.02). DISCUSSION: Cortical lesions are associated with local increases in glutamate and a reduction in GABA concentration within the lesional or perilesional tissue. Further studies are needed to investigate the causal relationship between cortical lesions and changes in neurotransmitter concentrations.

Clinically silent PML and prolonged immune reconstitution inflammatory syndrome in a patient with multiple sclerosis treated with natalizumab.

We report the case of a woman with natalizumab-treated multiple sclerosis (MS) and clinically silent progressive multifocal leukoencephalopathy (PML) with an unusually long preclinical phase, followed by acute symptoms due to development of immune reconstitution inflammatory syndrome (IRIS). Furthermore, the course of the IRIS was prolonged and continued to progress even five months after natalizumab treatment was ceased. This case shows that PML and IRIS can have a considerably variable course in natalizumab-treated MS patients and underlines the need for PML screening in JC virus antibody-positive patients in order to detect clinically silent cases.

Expanded functional coupling of subcortical nuclei with the motor resting-state network in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) impairs signal transmission along cortico-cortical and cortico-subcortical connections, affecting functional integration within the motor network. Functional magnetic resonance imaging (fMRI) during motor tasks has revealed altered functional connectivity in MS, but it is unclear how much motor disability contributed to these abnormal functional interaction patterns. OBJECTIVE: To avoid any influence of impaired task performance, we examined disease-related changes in functional motor connectivity in MS at rest. METHODS: A total of 42 patients with MS and 30 matched controls underwent a 20-minute resting-state fMRI session at 3 Tesla. Independent component analysis was applied to the fMRI data to identify disease-related changes in motor resting-state connectivity. RESULTS: Patients with MS showed a spatial expansion of motor resting-state connectivity in deep subcortical nuclei but not at the cortical level. The anterior and middle parts of the putamen, adjacent globus pallidus, anterior and posterior thalamus and the subthalamic region showed stronger functional connectivity with the motor network in the MS group compared with controls. CONCLUSION: MS is characterised by more widespread motor connectivity in the basal ganglia while cortical motor resting-state connectivity is preserved. The expansion of subcortical motor resting-state connectivity in MS indicates less efficient funnelling of neural processing in the executive motor cortico-basal ganglia-thalamo-cortical loops.

Comparison of Translocator Protein Expression Between Tumefactive Multiple Sclerosis and Glioblastoma.

ABSTRACT: This figure presents a comparison of molecular imaging of the translocator protein (TSPO) and contrast-enhanced MRI in 2 patients with tumefactive multiple sclerosis and glioblastoma, respectively. In the case of the tumefactive multiple sclerosis patient, TSPO uptake is primarily located centrally, while in the glioblastoma patient, TSPO uptake is predominantly situated peripherally to the central necrotic area. These findings suggest that TSPO imaging could be a noninvasive imaging technique for distinguishing between these 2 diagnoses.

Autologous hematopoietic stem cell transplantation of patients with aggressive relapsing-remitting multiple sclerosis: Danish nation-wide experience.

BACKGROUND: Autologous hematopoietic stem cell treatment (AHSCT) is considered an effective treatment option for patients with aggressive relapsing-remitting multiple sclerosis (RRMS). Still there are few randomized and controlled studies of AHSCT to shed light on the safety and efficacy of the treatment, and therefore experiences from single centers are important. AIM: To describe the Danish experience with AHSCT regarding patient characteristics, safety, and efficacy. METHOD: Nationwide retrospective single center study of patients with multiple sclerosis (MS) treated with AHSCT. RESULTS: A total of 32 patients were treated with AHSCT from May 2011 to May 2021. Seven were treated with carmustine, etoposide, cytarabine arabinoside, and melphalan (BEAM) as well as antithymocyte globulin (ATG). Twenty-five patients were treated with cyclophosphamide (CY) and ATG. In the whole cohort, relapse-free survival (RFS) was 77% (95% CI: 64-94%), worsening-free survival (WFS) was 79% (95% CI: 66-96%), MRI event-free survival (MFS) was 93% (95% CI: 85-100%), and no evidence of disease (NEDA-3) was 69% (95% CI: 54-89%) at the end of year two post-AHSCT. We had no treatment related mortality and only few severe adverse events (AEs). CONCLUSION: AHSCT of patients with aggressive RRMS was an effective and relatively safe treatment with few serious AEs and no mortality in Danish patients.

Validation of MRI radiological reports in pediatric MS according to the McDonald 2017 criteria: A Danish nationwide multicenter cohort study.

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.

Magnetic resonance imaging criteria at onset to differentiate pediatric multiple sclerosis from acute disseminated encephalomyelitis: A nationwide cohort study.

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.

Oligoclonal bands, age 11-17 years, occipital lesion, and female sex differentiate pediatric multiple sclerosis from acute disseminated encephalomyelitis: A nationwide cohort study.

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.

Mapping grip-force related brain activity after a fatiguing motor task in multiple sclerosis.

BACKGROUND: Motor fatigue is common in multiple sclerosis (MS), but its pathophysiology is still poorly understood. Here we used functional magnetic resonance imaging (fMRI) to delineate how the acute induction of motor fatigue alters functional activity of the motor system and how these activity changes are related to motor fatigue. METHOD: Forty-four right-handed mildly disabled patients with relapsing-remitting MS and 25 healthy controls performed a maximal tonic precision grip with their right hand until they developed motor fatigue. Before and after the fatiguing task, participants performed a non-fatiguing tonic grip force task, producing 15-20% of their maximum grip force based on visual feedback. Task related brain activity was mapped with blood-oxygen level dependent fMRI at 3 T. Statistical parametric mapping was used to identify relative changes in task-related activation from the pre-fatigue to the recovery MRI session. RESULTS: Following fatigue induction, task performance was perturbed in both groups, and task-related activation increased in the right (ipsilateral) primary motor hand area. In patients with MS, task-related activity increased bilaterally during the recovery phase in the ventrolateral portion of the middle putamen and lateral prefrontal cortex relative to controls. The more patients increased task-related activity in left dorsal premotor cortex after the fatiguing task, the less they experienced motor fatigue during daily life. CONCLUSION: Patients with MS show enhanced functional engagement of the associative cortico-basal ganglia loop following acute induction of motor fatigue in the contralateral hand. This may reflect increased mental effort to generate movements in the recovery phase after fatigue induction. The ability to recruit the contralateral dorsal premotor cortex after fatigue induction may constitute a protective mechanism against experiencing motor fatigue in everyday life.

Blood-brain barrier permeability changes in the first year after alemtuzumab treatment predict 2-year outcomes in relapsing-remitting multiple sclerosis.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), early disease control reduces the risk of permanent disability. The blood-brain barrier (BBB) is compromised in MS, and its permeability is a potential biomarker. OBJECTIVE: To investigate BBB permeability measured by MRI as a marker of alemtuzumab efficacy. METHODS: Patients with RRMS initiating alemtuzumab treatment were recruited prospectively. BBB permeability was assessed as the Patlak-derived influx constant (Ki) by dynamic contrast-enhanced MRI before and 6, 12, and 18 months after the first course of alemtuzumab. No Evidence of Disease Activity-3 (NEDA-3) status was ascertained two years after treatment initiation. RESULTS: Patients who maintained NEDA-3 status at two years (n = 7) had a larger decrease in Ki between baseline and six months (-0.029 ml/100 g/min [CI -0.005 - -0.053]) and between baseline and 12 months in normal appearing white matter (0.043 [CI 0.022 - -0.065]), than those who experienced disease activity (n = 8). ROC curve analysis of the Ki change between baseline and 12 months in NAWM predicted a loss of NEDA status at 2 years with 86% sensitivity and 86% specificity (AUC 0.98, p = 0.002). CONCLUSION: BBB permeability predicted alemtuzumab efficacy at two years, indicating that BBB permeability is a biomarker of treatment response in RRMS.