Inter-attack Interval Research Articles

Pretreatment Neurofilament Light Chain Serum Levels, Early Disease Severity, and Treatment Response in Pediatric Multiple Sclerosis.

High disease activity and frequent therapy failure in pediatric multiple sclerosis (MS) make prognostic biomarkers urgently needed. We investigated whether serum neurofilament light chain (sNfL) levels in treatment-naive pediatric patients with MS are associated with early disease severity and indicate treatment outcomes. A retrospective cohort study of patients seen in the Göttingen Center for MS in Childhood and Adolescence, Germany. Inclusion criteria were MS diagnosis according to the McDonald criteria, MS onset <18 years, and available pretreatment serum sample. sNfL levels were analyzed using a single-molecule array assay. Associations with clinical and MRI evidence of disease severity at sampling were evaluated using the Spearman correlations and nonparametric tests for group comparisons. Correlations between pretreatment sNfL and annualized relapse and new T2 lesion rate on first-line therapy, and odd ratios for switch to high-efficacy therapy were assessed. A total of 178 patients (116 women [65%]) with a mean sampling age of 14.3 years were included in the study. Pretreatment sNfL levels were above the ≥90th percentile reported for healthy controls in 80% of patients (median 21.1 pg/mL) and correlated negatively with age, but no correlation was seen with sex, oligoclonal band status, or body mass index. High pretreatment sNfL levels correlated significantly with a high number of preceding relapses, a shorter first interattack interval, a high T2 lesion count, and recent gadolinium-enhancing lesions. Of interest, sNfL levels reflected more strongly MRI activity rather than clinical activity. Pretreatment sNfL levels also correlated significantly with the relapse rate and occurrence of new/enlarging T2 lesions while on first-line injectable therapy. Odds of future therapy escalation increased from 0.14 for sNfL below 7.5 pg/mL to 6.38 for sNfL above 15 pg/mL. In patients with a recent relapse, higher sNfL levels were associated with poorer recovery 3 months after attack. The results of this study have 3 important implications: First, pretreatment sNfL levels are a valuable biomarker for underlying disease activity in pediatric patients with MS. Second, pretreatment sNfL levels in pediatric patients with MS have a predictive value for the response to first-line therapy and the necessity of future therapy escalation. Third, high sNfL levels during a relapse are associated with poor recovery in this age group.

Clinical and Magnetic Resonance Imaging Characteristics of Pediatric Acute Disseminating Encephalomyelitis With and Without Antibodies to Myelin Oligodendrocyte Glycoprotein.

BackgroundMyelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG)-associated disorders (MOGADs) have been considered as a new inflammatory disease entity of the central nervous system (CNS) and have heterogeneous clinical and imaging presentations. Acute disseminated encephalomyelitis (ADEM) is one of the most important phenotypes. Our research is aimed to compare the clinical and magnetic resonance imaging (MRI) characteristics of ADEM with or without MOG-IgG in pediatric-acquired demyelinating syndromes (ADSs).Methods and ResultsWe retrospectively reviewed the clinical characteristics, MRI features, and outcomes of pediatric patients with ADSs from March 2017 to February 2021 in our center. MOG-IgG was analyzed by transfected cell-based assay (CBA). Among 46 children with ADEM, 21 children (11 girls and 10 boys) were positive for MOG-IgG. Headache, fever, vomiting, vertigo, ataxia, and decreased muscle strength were common in all enrolled children. No significant difference existed in demographic characteristics, symptoms at an initial episode, or laboratory cerebrospinal fluid (CSF) findings between children with MOG-IgG and children without MOG-IgG. For children with MOG-IgG seropositive ADEM, cerebral MRI showed widespread, poorly demarcated bilateral lesions, especially in cortical and subcortical white matter, and spinal MRI often showed lesions spanning more than three segments. The significant difference in MRI features between the two groups was the presence of lesions in the thalamus and cortical area (p < 0.05). Most children in both groups showed clinical improvement 1 week after immunotherapy and achieved recovery during their hospital stay. Three children with MOG-IgG and four children without MOG-IgG had one or more relapsing courses with median interattack intervals of 4 (range: 1–7) months and 10 (range: 1–24) months, respectively. New clinical symptoms and lesions on cerebral and spinal MRI were found during relapsing courses in two groups. No recurrences were recorded 6–51 months after each patient’s last episode.ConclusionsThere was no significant difference in clinical characteristics between ADEM children with MOG-IgG and ADEM children without MOG-IgG. For children with MOG-IgG seropositive ADEM, cerebral MRI showed large, bilateral lesions and spinal MRI often showed lesions spanning more than three segments. Children achieved a favorable outcome regardless of MOG-IgG serostatus.

Mortality of neuromyelitis optica spectrum disorders in a Chinese population.

ObjectiveNeuromyelitis optica spectrum disorder (NMOSD) is a rapidly disabling disease. Epidemiologic studies have suggested varying NMOSD mortality across ethnic groups. However, NMOSD mortality data in China are scarce. This study’s objectives were to explore mortality and causes of death among Chinese NMOSD patients and to identify independent predictors of death.MethodsWe performed a retrospective study with a 10‐year follow‐up of Chinese NMOSD patients. A Cox proportional hazards model was used to identify independent predictors of death.ResultsFive hundred and sixty‐nine patients were included; 24 patients died during follow‐up, for overall mortality of 4.2%. In these patients, the median disease duration at the time of death was 3.4 years. The most common cause of death was secondary infection (62.5%), especially respiratory infection (45.8%). The second most common cause of death was extensive cervical myelitis with respiratory failure (16.7%). Other causes included suicide (8.3%), cancer (4.2%), cerebral embolism (4.2%), and unknown causes (4.2%). The multivariate Cox analyses indicated that a short first interattack interval (HR = 0.93, 95% CI 0.89–0.98, p = 0.003), lack of regular immunotherapy (HR = 10.34, 95% CI 4.05–26.37, p < 0.001), and older age at onset were independent predictors of death. Every increasing decade of onset age increased the risk of death 2.59 times (95% CI 1.74–3.86, p < 0.001).InterpretationInfections were more common in patients not treated with any immunotherapy, indicating that early and consequent immunotherapy might prevent death by infections, which is of great importance for further treatment of NMOSD patients to avoid undertreatment due to fear of treatment‐associated infections.

Clinical Characteristics and Disability Progression of Early- and Late-Onset Multiple Sclerosis Compared to Adult-Onset Multiple Sclerosis.

Background: Compared to the adult onset of multiple sclerosis (AOMS), both early-onset (EOMS) and late-onset (LOMS) are much less frequent, but are often under- or misdiagnosed. The aims of the present study were: 1. To compare demographic and clinical features of individuals with EOMS, AOMS and LOMS, and 2. To identify predictors for disability progression from relapsing remitting MS (RRMS) to secondary progressive MS (SPMS). Method: Data were taken from the Isfahan Hakim MS database. Cases were classified as EOMS (MS onset 18 years), LOMS (MS onset >50 years) and AOMS (MS >18 and 50 years). Patients’ demographic and clinical (initial symptoms; course of disease; disease patterns from MRI; disease progress) information were gathered and assessed. Kaplan–Meier and Cox proportional hazard regressions were conducted to determine differences between the three groups in the time lapse in conversion from relapsing remitting MS to secondary progressive MS. Results: A total of 2627 MS cases were assessed; of these 127 were EOMS, 84 LOMS and 2416 AOMS. The mean age of those with EOMS was 14.5 years; key symptoms were visual impairments, brain stem dysfunction, sensory disturbances and motor dysfunctions. On average, 24.6 years after disease onset, 14.2% with relapsing remitting MS (RRMS) were diagnosed with secondary progressive MS (SPMS). The key predictor variable was a higher Expanded Disability Status Scale (EDSS) score at disease onset. Compared to individuals with AOMS and LOMS, those with EOMS more often had one or two relapses in the first two years, and more often gadolinium-enhancing brain lesions. For individuals with AOMS, mean age was 29.4 years; key symptoms were sensory disturbances, motor dysfunctions and visual impairments. On average, 20.5 years after disease onset, 15.6% with RRMS progressed to SPMS. The key predictors at disease onset were: a higher EDSS score, younger age, a shorter inter-attack interval and spinal lesions. Compared to individuals with EOMS and LOMS, individuals with AOMS more often had either no or three and more relapses in the first two years. For individuals with LOMS, mean age was 53.8 years; key symptoms were motor dysfunctions, sensory disturbances and visual impairments. On average, 14 years after disease onset, 25.3% with RRMS switched to an SPMS. The key predictors at disease onset were: occurrence of spinal lesions and spinal gadolinium-enhancement. Compared to individuals with EOMS and AOMS, individuals with LOMS more often had no relapses in the first two years, and higher EDSS scores at disease onset and at follow-up. Conclusion: Among a large sample of MS sufferers, cases with early onset and late onset are observable. Individuals with early, adult and late onset MS each display distinct features which should be taken in consideration in their treatment.

Long-term outcome and prognosis in patients with neuromyelitis optica spectrum disorder from Serbia

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) most commonly, although not exclusively, targets optic nerves and spinal cord. Untreated, early and severe disability is common. We evaluated the long-term outcome in NMOSD patients diagnosed according to the 2015 criteria. MethodsWe retrospectively analyzed 74 patients from the hospital-based NMOSD cohort at the Clinic of Neurology, Belgrade, Serbia, who fulfilled the 2015 NMOSD criteria. We identified patients based on 2015 criteria; 51.4% of whom would not have fulfilled 2006 criteria. Median follow-up was 6.9 years. Aquaporin-4 (AQP4) IgG was tested in all patients using a cell-based indirect immunofluorescence assay. The level of neurological disability was assessed by the Expanded Disability Status Scale (EDSS) score, and by Opticospinal Impairment Scale (OSIS), visual acuity (VA) and motor function subscores. ResultsThe disease course was monophasic in 17.6% patients and relapsing in the remainder; none developed progressive disease. AQP4-IgG was detected in 89.2% of patients. 45 of 74 patients were treated with immunosuppressants, 40 with azathioprine, 3 with mycophenolate mofetil, 1 with cyclophosphamide, 1 with mitoxantrone, and 2 patients with rituximab. The median intervals from onset to EDSS 4.0, 6.0 and 7.0 were 6.5 years, 11.9, and 22.0 years, respectively. Higher baseline EDSS was associated with risk of attaining EDSS 4.0, 6.0 and 7.0; a shorter first inter-attack interval for reaching EDSS 4.0 and 6.0; longer time to the start of treatment for reaching EDSS 7.0. Worse visual acuity at the disease onset predicted faster assignment of OSIS VA = 6 and VA = 8. Severe visual deficit (OSIS VA 6) was reached earlier after optic neuritis (median time, 10.0 years) or combined opticospinal onset (median time, 11.4 years) than after myelitis onset (median time, 18.0 years) (p = 0.002). ConclusionOur results support the benefits of early diagnosis and treatment of NMOSD, especially in persons with severe optic and spinal disability at onset.

Delving Into Internet DDoS Attacks by Botnets: Characterization and Analysis

Internet distributed denial of service (DDoS) attacks are prevalent but hard to defend against, partially due to the volatility of the attacking methods and patterns used by attackers. Understanding the latest DDoS attacks can provide new insights for effective defense. But most of existing understandings are based on indirect traffic measures (e.g., backscatters) or traffic seen locally. In this paper, we present an in-depth analysis based on 50 704 different Internet DDoS attacks directly observed in a seven-month period. These attacks were launched by 674 botnets from 23 different botnet families with a total of 9026 victim IPs belonging to 1074 organizations in 186 countries. Our analysis reveals several interesting findings about today’s Internet DDoS attacks. Some highlights include: 1) geolocation analysis shows that the geospatial distribution of the attacking sources follows certain patterns, which enables very accurate source prediction of future attacks for most active botnet families; 2) from the target perspective, multiple attacks to the same target also exhibit strong patterns of inter-attack time interval, allowing accurate start time prediction of the next anticipated attacks from certain botnet families; and 3) there is a trend for different botnets to launch DDoS attacks targeting the same victim, simultaneously or in turn. These findings add to the existing literature on the understanding of today’s Internet DDoS attacks and offer new insights for designing new defense schemes at different levels.

Clinical and magnetic resonance imaging features of children, adolescents, and adults with a clinically isolated syndrome.

The diagnosis of multiple sclerosis (MS) both in children and adults is based on clinical and magnetic resonance imaging (MRI) features according to the McDonald criteria. Little is known about differences in the presentation between pre-pubertal children, adolescents, and adult patients at disease onset. To compare (1) the clinical, cerebrospinal fluid (CSF), and MRI characteristics, and (2) the diagnostic performance of the 2010 McDonald criteria between pre-pubertal, adolescent, and adult patients with a clinically isolated syndrome (CIS). We performed a retrospective analysis of the initial brain and spinal cord MRI scans from 11 pre-pubertal children, 46 adolescents, and 56 adults with a CIS. Furthermore, clinical, CSF characteristics, and the performance of the 2010 McDonald criteria were compared. The first inter-attack interval tended to increase with age. With respect to MRI presentation, significantly fewer pre-pubertal children presented with juxtacortical and callosal lesions. We found no significant differences in the fulfillment of the 2010 McDonald criteria between the groups. In this retrospective series, subtle differences between children, adolescents, and adults with a CIS were noted. Larger samples are required in order to establish distinct features of the different age groups.

Subclinical central inflammation is risk for RIS and CIS conversion to MS

Background: Subtle diffuse intrathecal inflammation is undetectable by conventional neuroimaging, and could influence multiple sclerosis (MS) disease course. Objective: To explore the role of subclinical persisting intrathecal inflammation in radiologically isolated syndrome (RIS) or clinically isolated syndrome (CIS) conversion to MS, and in early MS disease reactivation. Methods: One-hundred ninety-three subjects with RIS, CIS, relapsing–remitting (RR), or primary progressive (PP) MS were included, along with 76 matched controls. Cerebrospinal fluid (CSF) levels of interleukin-8 (IL-8), a major proinflammatory cytokine, were measured as a biomarker of intrathecal inflammation. Patients were followed up for 2 years. Clinical and imaging measures of disease progression were recorded. Results: High central contents of IL-8 were associated to clinical progression in subjects with RIS, and to the risk of conversion to MS in subjects with CIS. Asymptomatic intrathecal inflammation placed subjects at risk for MS conversion, even regardless lesion load. CSF IL-8 levels were higher in RR MS with high disease activity. Higher number of relapses in the first two years since diagnosis and shorter first inter-attack intervals were observed in patients with high levels of IL-8. Conclusion: IL-8 might provide utility in determining the presence of active intrathecal inflammation, and could be important in diagnostically undefined cases.

P008 - A prospective study on the prognosis of multiple sclerosis in Tunisia: Do we really have a distinct disease course in North Africa?

Introduction Few epidemiological data on multiple sclerosis (MS) patients are available in North Africa (NA). Studies of immigrants from NA showed a more aggressive course of MS in NA than in European patients. Objective To describe clinical, long term course characteristics and prognostic factors of MS in a Tunisian population. Methods We performed a prospective multicentric study of 437 MS patients in Tunisia between 2010 and 2012. We considered as endpoints the time to reach non-reversible disability levels corresponding to EDSS scores of 3.0, 4.0 and 6.0, and the beginning of a secondary progressive phase. We used Kaplan–Meier analyses and Cox regression models to determine the influence of the clinical variables on the time to disability onset. Results Sex ratio was 2.34. Mean age of onset was 30.3±9.5 years and the duration of illness was 8.4±6.7 years. The course was relapsing-remitting (RR) in 77% of patients, secondary progressive (SP) in 15.5% and primary progressive (PP) in 8.5%. Median time to secondary progressive onset was 19.1 years. Median times from onset of multiple sclerosis to assignment of a score of 3, 4 and 6 were 8, 10.7 and 15 years respectively. A greater number of functional systems involved at onset, progressive from as well as late age, motor, cerebellar and sphincter symptoms at onset were factors predictive of a poor outcome. A longer first inter-attack interval was associated with a better prognosis. Once EDSS 4 was reached, the time course of progressive disability was similar in patients with progressive onset and those with RR MS. Conclusion This is the first multicentric study in our country. The present study showed a similar course of MS in a North African population compared to European cohorts. Similar long term prognosis factors were found.

RELAPSING AQP4 ANTIBODY NEGATIVE NMO WITH MOG ANTIBODIES

<h3>Introduction</h3> Around 70–90% of typical NMO have aquaporin-4 antibodies (AQP4-Ab). More recently, an association between myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) and monophasic NMO has been reported. <h3>Methods</h3> We present 5 AQP4-Ab negative cases with relapsing CNS demyelinating disease (4 with NMO phenotype) associated with MOG-Ab. <h3>Results</h3> All patients were Caucasian. Four patients presented with typical NMO phenotype. One patient had a long myelitis and a further brainstem event. Median age at onset was 17 (16–39) years. The first episode of optic neuritis and longitudinally extensive myelitis developed simultaneously in 2 patients while 2 patients had inter-attack interval 1.1 and 7 years. All except one patient had a normal brain MRI. EDSS (visual) scores after disease duration (number of relapses) of 1.3 (2), 1.6 (2), 3.4 (6), 8.3 (7) and 12 (13) years were 5 (0), 4 (3), 3 (5), 4 (0) and 4 (6) respectively. <h3>Conclusions</h3> MOG-Ab can be seen in relapsing NMO and is not restricted to the monophasic subtype. The clinical and diagnostic role of MOG-Ab is still evolving.

Factors Associated With the Time to Next Attack in Neuromyelitis Optica: Accelerated Failure Time Models With Random Effects

Background and ObjectiveNeuromyelitis optica (NMO) is an inflammatory demyelinating disorder of the central nervous system with a relapsing and remitting course. We aimed to identify factors associated with the time to next attack, including the effect of the natural disease course and the diverse treatment regimens, by applying a longitudinal statistical analysis to the individual attacks of each patient.MethodsIn total, 184 acute attacks among 58 patients with either NMO or NMO spectrum disorder with anti-aquaporin-4 antibody were assessed retrospectively. Patient demographics, clinical characteristics at each attack, and type of treatment during inter-attack periods were assessed. The dependent variable was defined as the time from each attack to the next attack (inter-attack interval). An exponential accelerated failure time model with shared gamma frailty was adapted for statistical analysis.ResultsA multivariable analysis revealed that the time from each attack to the next attack in NMO increased independently by 1.31 times (95% confidence interval (CI), 1.02–1.67; p = 0.035) with each additional cumulative attack experienced, by 5.34 times (95% CI, 1.57–18.13; p = 0.007) with combined azathioprine treatment and continued oral prednisolone, and by 4.26 times (95% CI, 1.09–16.61; p = 0.037) with rituximab treatment.ConclusionThe time to next attack in NMO can increase naturally in the later stages of the disease as the number of cumulative attacks increases. Nevertheless, both combined azathioprine treatment with continued oral prednisolone and rituximab treatment were also associated with a longer time to next attack, independently of the natural disease course of NMO.

A single lesion—And yet MS?

Barts and The London School of Medicine & Dentistry 2 Newark Street, London E1 2AT, United KingdomThe cornerstone for a clinical diagnosis of multiple sclerosis(MS) is the demonstration of dissemination in space (DIS)and time (DIT) of lesions in the central nervous systemsuggestive of demyelination in the absence of a differentialdiagnosis that would better explain a patient’s symptoms(Polman et al., 2011).In a paper published in Neurology, Schmalstieg et al.(2012) reported seven cases of progressive myelopathy thatneither fulfilled standard criteria for MS nor for any of itsmany differential diagnoses (Miller et al., 2008). Rather,symptoms and signs were attributable to a solitary lesionsuggestive of demyelination in the brainstem or spinal cord.None of the reported cases developed any further lesion,neither clinically nor – where available – on MRI.The case series reported by Schmalstieg et al. consists ofquite a heterogeneous group of patients. Three had aninsidious onset, another three had relapses and remissionsreferable to the same site and one had a sub-acute coursewith partial resolution and subsequent progression after6 months. Only three of their cases had follow-up MRIconfirming short lesions in the brainstem or spinal cord,and for one patient no MRI was available at all. Of the sixcases where cerebro-spinal fluid was tested, four hadunmatched oligoclonal bands. The three cases tested forNMO immunoglobulin G had negative results. The medianfollow-up was 3 years. What unified these cases was thereported solitary lesion causing symptoms.Excluding one outlier who had been symptomatic for 27years, the average disease duration of the cohort was5.5 years, making it difficult to predict whether some of theirpatients will still develop classic DIS, thereby fulfilling currentdiagnostic criteria for MS ( Polman et al., 2011). In a recentstudy, based on the natural history cohort from LondonOntario, over 20% of patients with relapse onset MS had afirst inter-attack interval of 6 years or more (Scalfari et al.,2010). Further, we can only assume patients’ ethnicity in thestudy by Schmalstieg et al. (white Caucasian?), and that theytested negative for antibodies against HTLV-1.However, despite the incomplete nature of their auditdata, and the limited time of follow-up, Schmalstieg et al.highlight a challenge any neurologist with an interest in MSoccasionally faces: the patient with a single lesion ofpresumed demyelinaton who develops a chronic progressivesyndrome clinically undistinguishable from primary progres-sive MS – whilst never fulfilling the criterion for DIS.To some extent, the study by Schmalstieg et al. remindsus of the limited toolbox currently available to clinicians,which does not regularly include techniques such as quanti-tative and high-field MRI or optical coherence tomography,both highly sensitive tools to detect tissue damage as itcharacteristically occurs in MS. For example, whilst corticalMS lesions are well described histologically, only non-standard MRI techniques such a double inversion recovery(DIR; Boulby et al., 2004) are able to detect (a proportionof) such lesions. It would be interesting to investigate thecohort reported by Schmalstieg et al. using DIR or othernovel techniques such as phase sensitive inversion recovery(Sethi et al., 2012) to explore whether the detection ofcortical lesions could help to establish DIS, keeping in mindthat lesions in the cortex have yet to be formally incorpo-rated in a diagnostic algorithm for MS (Geurts et al., 2011).Schmalstieg et al. speculate about potential mechanismsunderlying axonal degeneration in their small cohort, but inthe absence of further data on, for example, brain atrophythe basis for this discussion remains limited. Diagnostically,however, we share their impression that of the small numberof patients in which application of standard diagnostictools does not underpin the disseminated nature of an

Clinical and psychophysiological analysis of panic attacksin patients with various mental diseases

The fact that the unilateral approach to studying panic attacks (PA) is unsound has presently become evident in the context of one specialty - neurology or psychiatry. Subjects and methods . One hundred and ninety-three patients with PA, among whom 80 (30 men and 50 women; mean age 31.5±9.66 years) fully met the inclusion-exclusion criteria, were examined. A control group comprised 36 healthy individuals (16 men and 20 women; mean age 25.9±6.73 years). The interdisciplinary approach integrating two (neurological and psychiatric) paradigms was applied to investigate PA. Clinical, psychological, and neurophysiological studies were employed. Results and discussion . The clinical picture of PA and an interattack interval was shown to encompass similar autonomic and different psychopathological manifestations caused by varying pathogenic mechanisms. The clinical manifestations of the latter most frequently correspond to neurotic, specific personality, and schizotypal disorders. It was ascertained that each group of patients with PA, which was identified by the nosological principle, was characterized by the pattern of clinical and psychophysiological characteristics and the trend in PA in addition to general manifestations. The neurophysiological signs of mental disease, in whose picture PA developed, corresponded to the progression of psychopathological and personality manifestations of PA in each consecutive group. The determinant of the pathogenesis and clinical presentation of PA in various mental diseases is psychodynamic processes, the specific features of which need to be taken into account when making diagnostic, therapeutic, prognostic, and expert decisions.

Meniere's disease

Meniere's disease is one of the most common causes of recurrent vestibular vertigo. Despite its comparatively high prevalence, this disease is frequently diagnosed late and patients do not receive timely therapy. The paper gives current diagnostic criteria for Meniere's disease. Approaches to treating the disease in its attack and an interattack interval are discussed. Emphasis is laid on the role of vestibular rehabilitation in increasing the quality of life in patients with Meniere's disease.

PAW28 The natural history of multiple sclerosis, a geographically based study. 10: relapses and long-term disability

The relationship of relapses to long-term disability in multiple sclerosis (MS) is uncertain. The reduction of relapses is a common therapeutic target but clinical trials have shown dissociation between relapse...

The natural history of multiple sclerosis, a geographically based study 10: relapses and long-term disability

The relationship of relapses to long-term disability in multiple sclerosis is uncertain. Relapse reduction is a common therapeutic target but clinical trials have shown dissociation between relapse suppression and disability accumulation. We investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from multiple sclerosis [Disability Status Scale 6, 8, 10] by analysing 28 000 patient-years of evolution in 806-bout onset patients from the London Ontario natural history cohort. Having previously shown no effect of relapse frequency among progressive multiple sclerosis subtypes, here we examined these measures in the pre-progressive or relapsing–remitting phase. Survival was compared among groups stratified by (i) early relapses—number of attacks during the first 2 years of multiple sclerosis; (ii) length of first inter-attack interval; (iii) interval between onset and Disability Status Scale 3 (moderate disability); (iv) number of attacks from the third year of disease up to onset of progression; and (v) during the entire relapsing–remitting phase. Early clinical features can predict hard disability outcomes. Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints. Attack frequencies, in the first 2 years, of 1 versus ≥3, gave differences of 7.6, 12.8 and 20.3 years in times from disease onset to Disability Status Scale 6, 8 and 10, respectively. Time to Disability Status Scale 3 highly and independently predicted time to Disability Status Scale 6, 8 and 10. In contrast, neither total number of relapsing–remitting phase attacks nor of relapses experienced during the relapsing–remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from Disability Status Scale 3 to these hard endpoints. The failure of a regulatory mechanism tied to neurodegeneration is suggested. Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to Disability Status Scale 6, 8 or 10, highlighting two distinct disease phases related to late outcome. These appear to be separated by a watershed within the relapsing–remitting phase, just a few years after clinical onset. Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression. They increase the probability of its occurrence, its latency and influence—to a lesser degree—its slope. The prevention or delay of the progressive phase of the disease is implicated as a key therapeutic target in relapsing–remitting patients.

A multifactorial prognostic index in multiple sclerosis

The ability to predict the future progression of MS represents a key issue for the neurologist. The aim of the study was to create a multifactorial prognostic index (MPI) providing the probability of a severe MS course at diagnosis based on clinical and immunological CSF parameters. 64 clinically definite relapsing-remitting (RR)MS patients (38 benign, 26 severe MS) followed up for at least 10 years were included. Clinical and demographic details, EDSS after 5 and 10 years, progression index, relapse number and rate, time to a second relapse were assessed. CSF and serum samples collected at diagnosis were examined for CSF IgM and IgG oligoclonal bands (OB) and quantitative IgM and IgG determination. Kaplan-Meier analysis showed that the probability of reaching an EDSS score of 3 or 4 was significantly influenced by the presence of IgMOB (p<0.01 and p<0.01, log-rank test) and by the symptoms at onset (p=0.04 and p=0.03, log-rank test). These results were confirmed at multivariate analysis (Cox model). Univariate logistic analysis showed that IgMOB presence predicted a severe MS course (OR=9.33, CI=2.92- 29.88), whereas sensory symptoms at onset predicted a benign MS course (OR=0.12, CI=0.02-0.56). Using multivariate logistic regression the factors found to be significant were: presence/absence of IgMOB (p<0.01), onset with sensory (p<0.01) and pyramidal symptoms (p=0.01), and first inter-attack interval (p=0.03). The individual probability of a severe evolution was thus estimated by a simple formula comprising clinical and biological markers of prognosis available at diagnosis (pyramidal and sensory symptoms, months to the 2nd episode, and IgMOB presence/absence), giving the probability of developing a severe MS course. Applied to the same patient cohort this formula showed a global error of 6/64 (9.37%). We then used another independent series of 65 RRMS patients to validate this model. In this second patient cohort, 4/45 BMS and 4/20 SMS patients were found to have been incorrectly classified (based on the formula), with a global error of 8/65 (12.31%). For the first time we created a MPI, using clinical and biological markers to predict the clinical course of MS at diagnosis. This index can support the clinician in patient counselling, therapeutic choices, as well as in patient selection criteria for clinical trials.

Comparison of the natural history and prognostic features of early onset and adult onset multiple sclerosis in Jordanian population

Objectives To assess the natural history and prognostic features of early onset multiple sclerosis (EOMS) and adult onset multiple sclerosis (AOMS) in Jordanian population. Patients and methods A retrospective analysis of 253 multiple sclerosis (MS) patients treated at the three major referral centers for MS in Jordan was performed. Twenty-six patients were excluded due to lack of follow up details. Patients under (or equal to) the age of 18 years were considered as EOMS. Clinical features of the two groups were compared and statistically analyzed. Time to reach expanded disability status score (EDSS) 3 and time to reach secondary progression were used as end points for survival analysis. Log-rank tests were performed and Kaplan–Meier survival curves were presented. Results About 44 (19.4%) patients had EOMS. The clinical characteristics of EOMS and AOMS were not significantly different. Most patients (about 88%) had relapsing remitting course. Monosymptomatic presentation was the predominant feature in both groups. Median time to reach EDSS 3 and median time to reach secondary progression were significantly longer in EOMS. Kaplan–Meier survival analysis did not show difference between the two groups. Higher EDSS score at diagnosis, shorter first inter-attack interval, and secondary progressive course were significantly unfavorable prognostic factors for both EOMS and AOMS. Conclusions The natural history and prognostic features of EOMS and AOMS are not significantly different in Jordanian population. Therefore, treatment strategies should be the same for the two groups.

The Prognostic Value of Initial Relapses on the Evolution of Disability in Patients with Relapsing-Remitting Multiple Sclerosis

The evolution of multiple sclerosis (MS) and the resulting disability are unpredictable. To identify clinical variables that could be potential prognostic factors, we followed a cohort of 288 patients diagnosed as having relapsing-remitting MS between 1990 and 2003. The end point was the first occurrence of a non-reversible EDMUS-GS score ≧3 (moderate disability). The impact of the number of MS attacks during the first 2 years of the disease as well as the first interattack interval were assessed in two Cox models, one using a fixed-in-time covariate, the other using a time-dependent covariate. Older age at onset and a higher number of MS attacks during the first 2 years of MS proved to be predictors of unfavourable prognosis. The first interattack interval had no influence on the evolution of the disability, conversely to the first relapse which had a short-term impact on the prognosis. We confirmed that the age at onset and the number of MS attacks during the first 2 years of MS are predictors of the evolution of the disability and demonstrated the importance of using time-dependent covariates.

Prognosis of multiple sclerosis: clinical factors predicting the late evolution for an early treatment decision

With the development of new immunomodulating therapies, with which early use is strongly encouraged, it is crucial to be in possession of reliable clinical predictors of multiple sclerosis evolution. Prognostic factors are important to patients wanting to be informed about their prospects; to the clinician needing to individualize patients requiring immune treatments at an early stage of the disease; and also to the researcher needing to to improve the design and analysis of the clinical therapeutic trials and observational studies. Frequentist analyses have indicated a poor prognosis for male gender, late age at onset, motor, cerebellar and sphincter involvement at onset, progressive course at onset, short inter-attack interval, high number of early attacks; and a relevant early residual disability. A recent application of a Bayesian analysis led to the construction of more detailed models of the natural history of multiple sclerosis and the estimated risk of unfavorable evolution at an individual patient level.