Radiologically isolated syndrome in children: Clinical and radiologic outcomes.
ABSTRACT: To describe clinical and radiologic outcomes of children with incidental findings on neuroimaging suggestive of CNS demyelination (termed "radiologically isolated syndrome" or RIS).Clinical and radiologic data were obtained from a historical cohort of children with no symptoms of demyelinating disease who had MRI scans that met the 2010 MRI criteria for dissemination in space for MS.We identified 38 children (27 girls and 11 boys) with RIS now being prospectively followed at 16 sites in 6 countries. The mean follow-up time was 4.8 ± 5.3 years. The most common reason for initial neuroimaging was headache (20/38, 53%). A first clinical event consistent with CNS demyelination occurred in 16/38 children (42%; 95% confidence interval [CI]: 27%-60%) in a median of 2.0 years (interquartile range [IQR] 1.0-4.3 years). Radiologic evolution developed in 23/38 children (61%; 95% CI: 44%-76%) in a median of 1.1 years (IQR 0.5-1.9 years). The presence of ?2 unique oligoclonal bands in CSF (hazard ratio [HR] 10.9, 95% CI: 1.4-86.2, p = 0.02) and spinal cord lesions on MRI (HR 7.8, 95% CI: 1.4-43.6, p = 0.02) were associated with an increased risk of a first clinical event after adjustment for age and sex.We describe the clinical characteristics and outcomes of children with incidental MRI findings highly suggestive of CNS demyelination. Children with RIS had a substantial risk of subsequent clinical symptoms and/or radiologic evolution. The presence of oligoclonal bands in CSF and spinal cord lesions on MRI were associated with an increased risk of a first clinical event.
Project description:Background:Steps towards the development of diagnostic criteria are needed for children with the radiologically isolated syndrome to identify children at risk of clinical demyelination. Objectives:To evaluate the 2005 and 2016 MAGNIMS magnetic resonance imaging criteria for dissemination in space for multiple sclerosis, both alone and with oligoclonal bands in cerebrospinal fluid added, as predictors of a first clinical event consistent with central nervous system demyelination in children with radiologically isolated syndrome. Methods:We analysed an international historical cohort of 61 children with radiologically isolated syndrome (≤18 years), defined using the 2010 magnetic resonance imaging dissemination in space criteria (Ped-RIS) who were followed longitudinally (mean 4.2 ± 4.7 years). All index scans also met the 2017 magnetic resonance imaging dissemination in space criteria. Results:Diagnostic indices (95% confidence intervals) for the 2005 dissemination in space criteria, with and without oligoclonal bands, were: sensitivity 66.7% (38.4-88.2%) versus 72.7% (49.8-89.3%); specificity 83.3% (58.6-96.4%) versus 53.9% (37.2-69.9%). For the 2016 MAGNIMS dissemination in space criteria diagnostic indices were: sensitivity 76.5% (50.1-93.2%) versus 100% (84.6-100%); specificity 72.7% (49.8-89.3%) versus 25.6% (13.0-42.1%). Conclusions:Oligoclonal bands increased the specificity of magnetic resonance imaging criteria in children with Ped-RIS. Clinicians should consider testing cerebrospinal fluid to improve diagnostic certainty. There is rationale to include cerebrospinal fluid analysis for biomarkers including oligoclonal bands in planned prospective studies to develop optimal diagnostic criteria for radiologically isolated syndrome in children.
Project description:There are limited data to guide clinicians in differentiating tumefactive multiple sclerosis (TMS) from CNS neoplasms. Identifying distinguishing features will inform diagnosis and management and avoid unnecessary diagnostic biopsy. Our study aimed to determine the clinical and radiologic features that differentiate TMS from glioma and CNS lymphoma (CNSL) in patients who present with tumefactive lesions.We retrospectively reviewed all patients with tumefactive lesions and histologically proven or clinically diagnosed TMS, glioma, or CNSL at our tertiary center from 1999 to 2012. Two independent blinded neuroradiologists rated MRI brain scans at presentation. We correlated patients' demographic, clinical, laboratory, and radiologic data to final diagnosis.A total of 133 patients (10 TMS, 85 glioma, 38 CNSL) were analyzed. Patients with TMS were younger and a greater proportion were women. Presenting symptoms did not distinguish between diagnoses. TMS lesions were smaller compared to glioma and CNSL, had no or mild mass effect, and were always associated with contrast enhancement. Radiologic features that were more frequent in TMS lesions were incomplete rim (open-ring) enhancement, incomplete peripheral diffusion restriction, and mixed T2 signal and CT hypoattenuation of MRI-enhancing components (all p < 0.05).Radiologic features but not presenting symptoms are useful in distinguishing TMS from CNS neoplasms.
Project description:With the development of magnetic resonance imaging (MRI) and publications about radiologically isolated syndrome (RIS), a lot of patients are referred to multiple sclerosis (MS) tertiary centers to confirm diagnosis of RIS or MS when brain T2 abnormalities are identified, whatever their characteristics. We evaluate prospectively the occurrence of RIS or MS and sensitivity, specificity and predictive value of McDonald criteria in diagnosis for patients presenting with incidental brain MRI T2 lesions.The authors ran standardized procedures on 220 consecutive patients addressed by general practitioners or neurologists to confirm RIS or MS diagnosis on brain MRI and give a therapeutic advice. All patients underwent neurological tests, extensive blood screening, cerebrospinal fluid (CSF) examination, visual evoked potential (VEP) and follow-up MRI after 3, 6, 12 and 24 months to consider dissemination in time and space.Patient characteristics were: 165 women and 55 men, mean age: 42.7 years old (23-59). The major symptom motivating MRI was headaches (39%), sensitive atypical manifestations or pain (12%), mood disorders (10%), transient visual symptoms (9%), fatigue (8%), hormonal screening (6%), vertigo (6%), cranial trauma (5%), and dummy run for clinical study (5%). After a structured analysis of T2 lesions, the suspected diagnosis was: inflammatory disease 45%, vascular 33%, non-pathological 19%, genetic 2%, and metabolic 1%. Extensive screening confirmed the proposed diagnosis in 97% of cases. Among all the 220 proposed RIS patients, only 35.4% fulfilled the 2010 McDonald criteria, and 8% can be categorized as RIS. Dissemination in time criteria was present for 82.7% of MS patients and 36% of RIS patients but none of the vascular or non-pathological T2 abnormalities.Even if RIS was initially suspected on MRI, only a third of the patients had an inflammatory disease. Most of the patients had either non-specific T2 lesions or a non-inflammatory disease. Others were initially well categorized but had experienced clinical symptoms that could possibly be considered as a first clinical event. Overdiagnosis of MS can lead to propose an inappropriate disease-modifying therapy.
Project description:The improved availability of MRI in medicine has led to an increase in incidental findings. Unexpected brain MRI findings suggestive of multiple sclerosis (MS) without typical symptoms of MS were recently defined as radiologically isolated syndrome (RIS). The prevalence of RIS is uncertain. The aim of this study was to determine the prevalence of RIS at a university hospital in a region with a high prevalence for MS and describe the long-term prognosis of the identified patients.Retrospective cohort study conducted in 2012.All brain MRI examinations performed at Karolinska University Hospital in Huddinge, Stockholm, Sweden during 2001 were retrospectively screened by a single rater for findings fulfilling the Okuda criteria. The sample year was chosen in order to establish the long-term prognosis of the patients identified. The examinations of interest were re-evaluated according to the Barkhof criteria by a neuroradiologist with long experience in MS.In total 2105 individuals were included in the study. Ages ranged from 0 to 90 years with a median age of 48 years. Only one patient with RIS was identified, equivalent to a prevalence of 0.05% in the studied population, or 0.15% among patients aged 15-40 years. The patient with RIS developed symptoms consistent with MS within 3 months accompanied with radiological progression and was diagnosed with MS.RIS, according to present criteria, is an uncommon finding in a tertiary hospital setting in a high-prevalence region for MS where awareness and clinical suspicion of MS is common. In order to study the prognosis of RIS, multicentre studies, or case-control studies are recommended.
Project description:OBJECTIVE: To report the 5-year risk and to identify risk factors for the development of a seminal acute or progressive clinical event in a multi-national cohort of asymptomatic subjects meeting 2009 RIS Criteria. METHODS: Retrospectively identified RIS subjects from 22 databases within 5 countries were evaluated. Time to the first clinical event related to demyelination (acute or 12-month progression of neurological deficits) was compared across different groups by univariate and multivariate analyses utilizing a Cox regression model. RESULTS: Data were available in 451 RIS subjects (F: 354 (78.5%)). The mean age at from the time of the first brain MRI revealing anomalies suggestive of MS was 37.2 years (y) (median: 37.1 y, range: 11-74 y) with mean clinical follow-up time of 4.4 y (median: 2.8 y, range: 0.01-21.1 y). Clinical events were identified in 34% (standard error=3%) of individuals within a 5-year period from the first brain MRI study. Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age [hazard ratio (HR): 0.98 (95% CI: 0.96-0.99); p=0.03], sex (male) [HR: 1.93 (1.24-2.99); p=0.004], and lesions within the cervical or thoracic spinal cord [HR: 3.08 (2.06-4.62); p=<0.001] were identified as significant predictors for the development of a first clinical event. INTERPRETATION: These data provide supportive evidence that a meaningful number of RIS subjects evolve to a first clinical symptom. An age <37 y, male sex, and spinal cord involvement appear to be the most important independent predictors of symptom onset.
Project description:We describe the prevalence and range of incidental intracranial abnormalities identified through MRI of the brain in a large group of children screened for a clinical trial.We included 953 children between 5 and 14 years of age who were screened with MRI of the brain for the Silent Infarct Transfusion Trial. All had sickle cell anemia or sickle beta-null thalassemia. MRI scans were interpreted by 3 neuroradiologists. MRI scans reported to have any abnormality were reviewed by 2 study neuroradiologists. Incidental findings were classified into 4 categories, that is, no, routine, urgent, or immediate referral recommended. Cerebral infarctions and vascular lesions were not considered incidental and were excluded.We identified 63 children (6.6% [95% confidence interval: 5.1%-8.4%]) with 68 incidental intracranial MRI findings. Findings were classified as urgent in 6 cases (0.6%), routine in 25 cases (2.6%), and no referral required in 32 cases (3.4%). No children required immediate referral. Two children with urgent findings underwent surgery in the subsequent 6 months.In this large cohort of children, incidental intracranial findings were identified for 6.6%, with potentially serious or urgent findings for 0.6%.
Project description:OBJECTIVE: To examine the clinical features of pediatric CNS demyelination associated with positive myelin oligodendrocyte glycoprotein (MOG) antibodies and to examine the functional effects of MOG antibody on oligodendrocyte cytoskeleton. METHODS: We measured MOG antibody using a fluorescence-activated cell sorting live cell-based assay in acute sera of 73 children with CNS demyelination (DEM) (median age 8 years, range 1.3-15.3) followed for a median of 4 years. We used MO3.13 cells to examine immunoglobulin (Ig) G effects on oligodendrocyte cytoskeleton using 3D deconvolution imaging. RESULTS: MOG antibodies were found in 31/73 patients with DEM (42%) but in 0/24 controls. At first presentation, MOG antibody-positive patients were more likely to have bilateral than unilateral optic neuritis (ON) (9/10 vs 1/5, respectively, p = 0.03), less likely to have brainstem findings (2/31 vs 16/42, p = 0.005), more likely to have a raised erythrocyte sedimentation rate >20 mm/h (9/19 vs 3/21, p = 0.05), less likely to have intrathecal oligoclonal bands (0/16 vs 5/27, p = 0.18), and less likely to be homozygous or heterozygous for human leukocyte antigen DRB1*1501 (3/18 vs 7/22, p = 0.46). MOG antibody positivity varied according to clinical phenotype, with ON and relapsing ON most likely to be seropositive. Two relapsing MOG antibody-positive patients treated with mycophenolate mofetil remain in remission and have become MOG antibody seronegative. Oligodendrocytes incubated with purified IgG from MOG antibody-positive patients showed a striking loss of organization of the thin filaments and the microtubule cytoskeleton, as evidenced by F-actin and β-tubulin immunolabelings. CONCLUSIONS: MOG antibody may define a separate demyelination syndrome, which has therapeutic implications. MOG antibody has functional effects on oligodendrocyte cytoskeleton.
Project description:In multiple sclerosis (MS), the inflammation and demyelination of the central nervous system (CNS) develop in distinct ways. This makes diagnosing patients difficult, imperative to initiating early and proper treatment. Several common features exist, among them a profound infiltration of monocytes into the CNS mediating demyelination and tissue destruction. In the periphery, monocytes are divided into three subsets depending on expression of CD14 and CD16, representing different stages of activation and differentiation. To investigate their involvement in MS, peripheral blood mononuclear cells (PBMCs) from 61 patients with incipient, untreated MS and 22 symptomatic control (SC) patients as well as 6 patients with radiologically isolated syndrome (RIS) were characterized ex vivo. In addition, paired serum and cerebrospinal fluid (CSF) samples were analyzed with a panel of biomarkers. In PBMC samples, we demonstrate decreased levels of nonclassical monocytes with a concomitant significant decrease of human endogenous retrovirus (HERV) H3 envelope epitopes on this monocyte subset compared with SC and RIS. The observed HERV expression is present on nonclassical monocytes irrespective of MS and thus presumably a result of the inflammatory activation. For the other surface markers analyzed, we found significantly decreased expression between classical and nonclassical monocytes. In matched samples of CSF a highly significant increase in levels of soluble markers of activation and inflammation is shown, and notably this is not the case for the serum samples. Of the soluble markers investigated, interleukin (IL)-12/IL-23p40 had the highest discriminatory power in differentiating patients with MS from SC and RIS, almost comparable to the immunoglobulin G index.
Project description:OBJECTIVE: In multiple sclerosis (MS), central nervous system (CNS), cerebrospinal fluid (CSF), and blood display TCR clonal expansions of CD8(+) T cells. These clones have been assumed - but never demonstrated - to be similar in the three compartments. Addressing this key question is essential to infer the implication of peripheral clonally expanded CD8(+) T cells in the disease. METHODS: For the first time, TCR V? repertoire from paired blood (purified CD8(+) and CD4(+) T cells), CSF and CNS (22 lesions, various inflammatory and demyelination statuses) samples from three MS patients was studied using complementary determining region 3 (CDR3) spectratyping and high-throughput sequencing. In parallel, blood and CNS clonally expanded CD8(+) T cells were characterized by fluorescent staining. RESULTS: TCR V? repertoire analysis revealed strong sharing of predominant T-cell clones between CNS lesions, CSF, and blood CD8(+) T cells. In parallel, we showed that blood oligoclonal CD8(+) T cells exhibit characteristics of pathogenic cells, as they displayed a bias toward a memory phenotype in MS patients, with increased expression of CCR5, CD11a and Granzyme B (GZM-B) compared to non oligoclonal counterparts. CNS-infiltrating T cells were mainly CD8 expressing CD11a and GZM-B. INTERPRETATION: This study highlights the predominant implication of CD8(+) T cells in MS pathophysiology and demonstrates that potentially aggressive CD8(+) T cells can be easily identified and characterized from blood and CSF samples.
Project description:B cells are implicated in the etiology of multiple sclerosis (MS). Intrathecal IgG synthesis, cerebrospinal fluid (CSF) oligoclonal bands and lesional IgG deposition suggest a role for antibody-mediated pathology. We examined the binding of IgG1 monoclonal recombinant antibodies (rAbs) derived from MS patient CSF expanded B cell clones to central nervous system (CNS) tissue. MS rAbs displaying CNS binding to mouse and human CNS tissue were further tested for their ability to induce complement-mediated tissue injury in ex vivo spinal cord explant cultures. The staining of CNS tissue, primary human astrocytes and human neurons revealed a measurable bias in MS rAb binding to antigens preferentially expressed on astrocytes and neurons. MS rAbs that recognize myelin-enriched antigens were rarely detected. Both myelin-specific and some astrocyte/neuronal-specific MS rAbs caused significant myelin loss and astrocyte activation when applied to spinal cord explant cultures in the presence of complement. Overall, the intrathecal B cell response in multiple sclerosis binds to both glial and neuronal targets and produces demyelination in spinal cord explant cultures implicating intrathecal IgG in MS pathogenesis.