Clinical and biological predictors of Cladribine effectiveness in Multiple Sclerosis: A real-world, single Centre study considering a two-year interval from year-2 dosing.

OBJECTIVES: Cladribine tablets (CLAD) for adult patients with highly active relapsing multiple sclerosis (RMS) have been available in Italy since 2018. We aimed to assess predictors of no-evidence-of-disease-activity-3 (NEDA-3) status after 24 months of the last dose of CLAD. RESULTS: We included 88 patients (70.5% female, mean age at CLAD start 35.4 ± 11.4). Eighteen patients were treatment naïve, 48 switched to CLAD from a First line Disease Modifying Drug (DMD), and 22 from Second line DMDs. All patients were observed for a median follow-up time of 2.4 (1-4) years after the last dose of CLAD. Forty-nine patients (55.7%) showed NEDA at the last available follow-up. Naïve patients (p = 0.001), those with a lower number of previous DMDs (p < 0.001) and, even though not significantly, those switching from first line DMDs (p = 0.069) were more likely NEDA3 at the last available follow-up. In a subgroup of 30 patients (34%), Serum Light Neurofilaments (sNFL) levels showed a decrease from baseline to the 24 months of follow-up, statistically significant from baseline to the sixth month, and from the first to the second year detection. sNFL levels at 12th month showed a strong inverse correlation with the time to NEDA3 loss. CONCLUSIONS: Our experience provides information for the 2-years after the last dose of CLAD, confirming a higher effectiveness of CLAD when placed early in the treatment algorithm. Given the ongoing expansion of the therapeutic landscape in MS, sNfL could support individualized decision-making, used as blood-based biomarker for CLAD responses in clinical practice.

Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom.

AIM: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). METHODS: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. RESULTS: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. CONCLUSIONS: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

There are several medications used to treat people with relapsing remitting multiple sclerosis, such as interferon-based therapies (Betaferon/Betaseron (US), Rebif, Avonex, Extavia), glatiramer acetate (Copaxone), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera), collectively named BRACETD. Other treatments for multiple sclerosis (MS) have a narrower use, such as natalizumab (Tysabri) or fingolimod (Gilenya), among others.This study objective was to assess how well natalizumab and fingolimod helped treating MS (clinical effectiveness) and subsequently estimate what the cost of these treatments is in comparison to the benefit they bring to people with rapidly evolving severe MS that use them in the United Kingdom (UK) (cost-effectiveness).We used an international disease registry (MSBase), which collects clinical data from people with MS in various centers around the world to compare the effectiveness of natalizumab, fingolimod and BRACETD treatments. We used a technique called propensity score matching to obtain results from comparable patient groups. People treated with natalizumab had better disease control, namely with fewer relapses and higher improvement on their disability level, than patients on fingolimod or BRACETD. Conversely, there were no differences between each group of people on a measure called disability worsening.Based on these clinical results, we built an economic model that simulates the lifetime costs and consequences of treating people with MS with natalizumab in comparison with fingolimod. We found that using natalizumab was less costly and was more effective compared to using fingolimod in UK patients.

Risk of multiple sclerosis relapses when switching from fingolimod to cell-depleting agents: the role of washout duration.

BACKGROUND: Fingolimod (FTY) induces sequestration of lymphocytes in secondary lymphoid organs and the average lymphocyte recovery following discontinuation takes 1-2 months. It has been hypothesized that the therapeutic effects of subsequent cell-depleting agents may be compromised if initiated before lymphocyte recovery has occurred. OBJECTIVE: To assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent in relation to washout duration using data from the Italian MS Register. METHODS: The risk of relapses was assessed in relation to different washout durations (< 6, 6-11, 12-17 and > / = 18 weeks) in patients starting alemtuzumab, rituximab, ocrelizumab or cladribine following FTY discontinuation. RESULTS: We included 329 patients in the analysis (226F, 103 M; mean age 41 ± 10 years). During the cell-depleting treatment, the incidence rate ratio for a relapse was significantly greater in patients with a washout period of 12-17 and > / = 18 weeks compared to the reference period (< 6 weeks). The risk of a relapse was significantly influenced by the occurrence of relapses during FTY treatment and by washout length, with hazard ratios markedly increasing with the washout duration. CONCLUSION: The risk of relapses increases with the washout duration when switching from FTY to lymphocyte-depleting agents.

Perampanel during pregnancy: Description of four cases.

Perampanel (PER) is approved in Italy as an adjunctive treatment for focal-onset seizures (FOS) and generalized tonic-clonic seizures (GTCs), and it could be an alternative to valproate in young women diagnosed with idiopathic generalized epilepsy. Nevertheless, clinical data about the outcome of pregnancies in women exposed to PER are lacking. Here, we report retrospectively collected data from four women suffering from FOS who were exposed to PER during pregnancy. Three pregnancies were carried out with PER as add-on therapy during the entire gestation (8 mg/day in two patients and 6 mg/day in one), without seizure frequency variations. The fourth patient started PER 2 mg/day as monotherapy during the 13th week of pregnancy due to seizure relapse and continued it until delivery with complete seizure control. All pregnancies showed good outcomes, and their newborns did not possess major congenital malformations. Apgar scores and auxological parameters at birth were normal. Fetal pathology in follow-up during pregnancies was absent in all cases. In our patients PER was well tolerated and appeared safe for the fetuses and did not result in major malformations or adverse events at birth. Nevertheless, this is a report involving a small number of patients and it does not suggest the general use of PER is safe during pregnancy.

Detection of disability worsening in relapsing-remitting multiple sclerosis patients: a real-world roving Expanded Disability Status Scale reference analysis from the Italian Multiple Sclerosis Register.

BACKGROUND AND PURPOSE: In relapsing-remitting multiple sclerosis patients (RRMS) disability progressively accumulates over time. To compare the cumulative probability of 6-month confirmed disability-worsening events using a fixed baseline or a roving Expanded Disability Status Scale (EDSS) reference, in a real-world setting. METHODS: A cohort of 7964 RRMS patients followed for 2 or more years, with EDSS scores recorded every 6 months, was selected from the Italian Multiple Sclerosis Register. The overall probability of confirmed disability-worsening events and of confirmed disability-worsening events unrelated to relapse was evaluated using as reference a fixed baseline EDSS score or a roving EDSS score in which the increase had to be separated from the last EDSS assessment by at least 6 or 12 months. RESULTS: Using a fixed baseline EDSS reference, the cumulative probability of 6-year overall confirmed disability-worsening events was 33.2%, and that of events unrelated to relapse was 10.9% (33% of overall confirmed disability-worsening events). Using a roving EDSS, the proportions were respectively 35.2% and 21.3% (61% of overall confirmed disability-worsening events). CONCLUSIONS: In a real-world setting, roving EDSS reference scores appear to be more sensitive for detecting confirmed disability-worsening events unrelated to relapse in RRMS patients.

Anti-inflammatory disease-modifying treatment and disability progression in primary progressive multiple sclerosis: a cohort study.

BACKGROUND AND PURPOSE: Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti-inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti-inflammatory disease-modifying treatment on disability outcomes in PPMS. METHODS: Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease-modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention-to-treat and an as-treated approach in paired, pairwise-censored analyses. RESULTS: Of the 1284 included patients, 533 were matched (treated, n = 195; untreated n = 338). Median on-study pairwise-censored follow-up was 3.4 years (quartiles 1.2-5.5). No difference in the hazard of experiencing 3-month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0; 95% confidence interval (CI), 0.6-1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6-1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7-1.6, P = 0.69). CONCLUSION: Our pooled analysis of disease-modifying agents suggests that these therapies have no substantial effect on short- to medium-term disability outcomes in PPMS.

Lymphocyte subsets as biomarkers of therapeutic response in Fingolimod treated Relapsing Multiple Sclerosis patients.

We investigated, lymphocyte count (LC) and lymphocyte subpopulations (LS) in a real life setting of Fingolimod (FTY) treated Relapsing MS (RMS) patients. Peripheral blood counts with LS, relapses and MRI scans were recorded in a cohort of 119 FTY patients, during one year of treatment. Simple and multivariate logistic regression models, were performed. ROC analysis identified cut-off values of LS predicting a higher risk of relapses and of Gd+ lesions. We demonstrated a FTY-induced re-modulation of the immune system, suggesting that LS in RMS FTY treated patients can predict the clinical response to the drug.

The role of neutralizing antibodies to interferon-ß as a biomarker of persistent MRI activity in multiple sclerosis: a 7-year observational study.

PURPOSE: During interferon-ß (IFN-ß) therapy, up to 45 % of patients may develop neutralizing antibodies (NAbs), associated with a decreased efficacy of the drug. We investigated in a real-life setting the impact of NAbs on magnetic resonance imaging (MRI) outcomes in a population of 567 IFN-ß-treated relapsing-remitting (RR) multiple sclerosis (MS) patients up to 7 years. We also evaluated NAbs' role as a biomarker of the persistence of MRI disease activity. METHODS: Patients' sera were tested for NAbs' presence by cytopathic effect (CPE) assay every 6-12 months. MRI scans were performed every 12 months. Generalized hierarchical linear models accounting for within-patient correlation were used to analyze T1 gadolinium-enhancing and new T2 lesions. Moreover, further tests were carried out to assess the overall outcome difference from year 1 to year 7 according to NAb status and the possible interaction between NAb status and time of follow-up. RESULTS: Seventy-five patients (13.2 %) became NAb positive (NAb+) during the follow-up. Considering T1 gadolinium-enhancing (GD+) lesions, we observed a significantly higher incidence in NAb+ patients (52 %, p = 0.0091). Also for new T2 lesions, we found a higher incidence in NAb+ patients (50 %, p = 0.0075). The negative impact of NAbs on the MRI outcomes considered did not change during the follow-up. CONCLUSIONS: Our 7-year results show the negative effect of NAbs on MRI measures of disease activity and confirm their role as a surrogate marker of IFN-ß treatment efficacy.

Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity.

BACKGROUND: The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting. METHODS: We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0-10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months. RESULTS: A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3-2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%). CONCLUSIONS: Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.

Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis.

BACKGROUND AND PURPOSE: Early relapse outcomes in long-term stable patients switching from interferon ß/glatiramer acetate (IFNß/GA) to oral therapy are unknown. OBJECTIVE: The objective of this study was to compare early relapse and progression in multiple sclerosis (MS) patients switching to oral therapy following a period of stable disease on IFNß/GA, relative to a propensity-matched comparator of patients remaining on IFNß/GA. METHODS: The MSBase cohort study is a global, longitudinal registry for MS. Time to first 6-month relapse in previously stable MS patients switching from platform injectables ('switchers') to oral agents were compared with propensity-matched patients remaining on IFNß/GA ('stayers') using a Cox marginal model. RESULTS: Three-hundred and ninety-six switchers were successfully matched to 396 stayers on a 1:1 basis. There was no difference in the proportion of patients recording at least one relapse in the first 1-6 months by treatment arm (7.3% switchers, 6.6% stayers; P = 0.675). The mean annualized relapse rate (P = 0.493) and the rate of first 6-month relapse by treatment arm (hazard ratio 1.22, 95% confidence interval 0.70, 2.11) were also comparable. There was no difference in the rate of disability progression by treatment arm (hazard ratio 1.43, 95% confidence interval 0.63, 3.26). CONCLUSION: This is the first study to compare early relapse switch probability in the period immediately following switch to oral treatment in a population previously stable on injectable therapy. There was no evidence of disease reactivation within the first 6 months of switching to oral therapy.

BREMSO: a simple score to predict early the natural course of multiple sclerosis.

BACKGROUND AND PURPOSE: Early prediction of long-term disease evolution is a major challenge in the management of multiple sclerosis (MS). Our aim was to predict the natural course of MS using the Bayesian Risk Estimate for MS at Onset (BREMSO), which gives an individual risk score calculated from demographic and clinical variables collected at disease onset. METHODS: An observational study was carried out collecting data from MS patients included in MSBase, an international registry. Disease impact was studied using the Multiple Sclerosis Severity Score (MSSS) and time to secondary progression (SP). To evaluate the natural history of the disease, patients were analysed only if they did not receive immune therapies or only up to the time of starting these therapies. RESULTS: Data from 14 211 patients were analysed. The median BREMSO score was significantly higher in the subgroups of patients whose disease had a major clinical impact (MSSS≥ third quartile vs. ≤ first quartile, P < 0.00001) and who reached SP (P < 0.00001). The BREMSO showed good specificity (79%) as a tool for predicting the clinical impact of MS. CONCLUSIONS: BREMSO is a simple tool which can be used in the early stages of MS to predict its evolution, supporting therapeutic decisions in an observational setting.

Natalizumab discontinuation and disease restart in pregnancy: a case series.

BACKGROUND: The humanized monoclonal alpha4-integrin antibody Natalizumab (NTZ) (Tysabri(©) , Biogen Idec, Cambridge, MA, USA) has shown to be effective in multiple sclerosis (MS) therapy; however, the interruption of the drug has been related to a disease restart. This risk has to be carefully considered in case of accidental or desired pregnancies. AIM OF THE STUDY: To report the risk of disease restart in patients who interrupted NTZ because of pregnancy and discuss the implication of NTZ choice in female childbearing patients with MS. METHODS: Clinical histories and MRI images of four pregnant women with MS who interrupted NTZ. RESULTS: Despite pregnancy is usually related with disease stability, the cases presented here showed an abrupt increase of disability with high number of MRI lesions, some of them with a mass effect. CONCLUSIONS: We recommend that female patients on childbearing age must be informed before starting NTZ treatment of the risk of a return of disease activity when the drug is discontinued. The risk occurs even during pregnancy a condition that is considered as protective for women with MS.

Cerebrospinal fluid neurofilament tracks fMRI correlates of attention at the first attack of multiple sclerosis.

BACKGROUND: Identifying markers of cognitive dysfunction in multiple sclerosis (MS) is extremely challenging since it means supplying potential biomarkers for neuroprotective therapeutic strategies. OBJECTIVE: The aim of this study is to investigate the relationship between fMRI correlates of attention performance and cerebrospinal fluid (CSF) neurofilament light chain (NFL) levels in patients with clinically isolated syndrome (CIS) suggestive of MS. METHODS: Twenty-one untreated, cognitively preserved CIS patients underwent BOLD-fMRI while performing the Variable Attentional Control (VAC) task, a cognitive paradigm requiring increasing levels of attentional control processing. CSF NFL was assessed by ELISA technique. SPM8 random-effects models were used for statistical analyses of fMRI data (p<0.05 corrected). RESULTS: Repeated-measures ANOVA on imaging data showed an interaction between attentional control load and NFL levels in the right putamen. At the high level of attentional control demand CIS patients with "low NFL levels" showed greater activity in the putamen compared with subjects with "high NFL levels" (p=0.001). These results are independent of cognitive impairment index. CONCLUSIONS: Our findings suggest a relationship between CSF NFL levels and load-dependent failure of putaminal recruitment pattern during sustained attention in CIS and suggest a role of CSF NFL as a marker of subclinical abnormality of cognitive pathway recruitment in CIS.

Implementation of the 'Sapere Migliora' information aid for newly diagnosed people with multiple sclerosis in routine clinical practice: a late-phase controlled trial.

BACKGROUND: The SIMS-Trial showed that the 'Sapere Migliora' information aid (IA) for newly diagnosed people with multiple sclerosis (PwMS) effectively improved patient knowledge and satisfaction with care. OBJECTIVES: The objectives of this paper are to assess the effectiveness of the IA in clinical practice and to compare the whole IA with the take-home booklet/website component alone. METHODS: After updating the IA and replacing the CD with a website, a prospective, open-label non-randomised controlled trial compared the whole IA (group A, five SIMS-Trial centres) to take-home (group B, 16 centres). One month after the intervention, participants completed the MS Knowledge Questionnaire (MSKQ), care satisfaction questionnaire (COSM-R) (primary study outcomes), Hospital and Anxiety Depression Scale, and ad hoc questionnaire appraising the IA. RESULTS: We enrolled 159 newly diagnosed PwMS (May 2012-March 2013). Drop-outs were four of 77 (5%, group A) and 11/82 (13%, group B). Primary endpoint (highest tertile both for MSKQ and COSM-R section 2 scores) was achieved by 38/77 (49%) group A and 33/82 (40%) group B (p = 0.25). Attainment of secondary outcomes was also similar between groups. CONCLUSIONS: This study shows that the entire IA is not superior to the booklet/website alone, and that both are comparable in efficacy to the intervention arm of the SIMS-Trial. TRIAL REGISTRATION NUMBER: ISRCTN78940214.

Computer-assisted rehabilitation of attention in patients with multiple sclerosis: results of a randomized, double-blind trial.

BACKGROUND: There is controversial information on the efficacy of cognitive rehabilitation in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to test a home-based computerized program for retraining attention dysfunction in MS. METHODS: Relapsing-remitting patients who failed > 2 tests of attention on an extensive neuropsychological battery were randomized to specific or nonspecific computerized training (ST, n-ST), in one-hour sessions, twice a week for three months. Outcome measures included neuropsychological assessment, depression, fatigue, everyday activities and a visual analogue scale assessing attentive performance (VAS). Assessments were repeated after the interventions and after a further three months. Statistical analysis included the analysis of variance (ANOVA) for repeated measures. RESULTS: Eighty-eight out of 102 randomized patients completed the study (69 women, age 40.9 ± 11.5 years, disease duration 13.0 ± 8.7 years, Expanded Disability Status Scale score 2.7 ± 1.5). Fifty-five patients were randomized to ST, 33 to n-ST. A benefit of the ST was observed on the Paced Auditory Serial Addition Test (p < 0.002). However, patient self-report did not reveal differences between ST and n-ST patient groups. CONCLUSION: Although our program trained different attention components, we could detect some improvements exclusively on tasks of sustained attention. Moreover, patient self-perceived results may be independent of the training program.

Anxiety state affects information processing speed in patients with multiple sclerosis.

The aim of this study was to investigate the impact of anxiety on the cognitive performance of a clinical sample of relapsing-remitting (RR) MS patients. One hundred ninety patients (140 females) were included in the study and assessed through the beck depression inventory, the state-trait anxiety inventory and the Rao's brief repeatable battery which assesses cognitive domains most frequently impaired in MS. As for neuropsychological performance, a total of 76 (40%) subjects fulfilled our criterion for cognitive impairment. Tests most frequently failed by cognitive impairment (CI) patients were those assessing complex attention and information processing speed [Simbol Digit Modalities Test (SDMT), Paced Auditory Serial Auditory Test (PASAT) 3 and 2] and verbal memory. In the univariate analysis, state anxiety was related to failure on the SDMT (p = 0.042), and marginally, to failure on the PASAT-3 (p = 0.068), and to the presence of CI (p = 0.082). Moderate/severe depression was detected in 38 (20%) patients and fatigue in 109 (57%). Higher depression scores were related to impairment on the ST (OR = 1.05; 95% CI 1.01-1.10; p = 0.029).

Verbal fluency deficits in clinically isolated syndrome suggestive of multiple sclerosis.

BACKGROUND: Little is known about relationships between Cognitive Impairment (CI) and verbal fluency measures in patients with a Clinically Isolated Syndrome (CIS) suggestive of Multiple Sclerosis. The aim of this study was to assess the extent of verbal fluency deficits and their predictive value for the presence of a CI in a population of CIS patients. METHODS: CI was detected by the Rao's Brief Repeatable Battery (BRB) and the Stroop Test (ST) in 100 CIS patients. The BRB includes the Word List Generation (WLG) test for semantic verbal fluency. The FAS test was used to investigate phonemic verbal fluency. CI was defined as the failure in at least 3 tests on BRB (without WLG to exclude criterion contamination bias) and ST. RESULTS: Eleven patients failed in at least 3 of the BRB tests and were classified as cognitively impaired. The comparison of Receiver Operating Characteristic curves showed that the Area Under the Curve (AUC) of the WLG was not significantly different from the AUC of the FAS (0.787 vs 0.755; p=N.S.). A cut-off <17 words for the WLG achieved 64% of sensitivity and a 79% of specificity, and a cut-off <28 words achieved 82% of sensitivity and a 66% of specificity in discriminating patients with CI. CONCLUSIONS: Verbal fluency deficits occur early in the disease course and may predict the presence of CI in CIS patients.