A Randomised Computer-assisted Rehabilitation Trial of Attention in Pediatric Multiple Sclerosis: A Post-hoc Analysis.

Background: Cognitive decline is one of the most remarkable features of Multiple Sclerosis (MS) and particularly in pediatric onset MS (POMS). The Simbol Digit Modalities Test (SDMT), a simple, brief measure of information processing speed (IPS) has been proposed and it is increasingly used to explore cognitive functions in MS clinical trials. Recently a 4-point worsening on the SDMT score has been demonstrated to signicantly correlate with a clinically meaningful cognitive decline. Methods: The primary objective of this post-hoc analysis of a randomised computer-assisted rehabilitation trial for attention impairment in POMS was to test the clinical meaningfulness of the changes of SDMT scores by applying a 4-point SDMT cut-off. POMS exposed to specic computer training (ST) and nonspecic training (nST) were compared. All analyses were post hoc and not pre-specied. To evaluate the clinical meaningfulness of longitudinal changes over time of the SDMT in the ST and nST groups we applied a categorization of the delta SDMT scores (delta SDMT: SDMT score at T1 – SDMT score at T0) as follow: between -3 and 3 = not clinically signicant; ≤ - 4 = clinically signicant worsening; ≥ 4 = clinically signicant improvement. The proportion of patients reporting a clinically signicant SMDT improvement were compared between the 2 groups by using the chi-square test. Results: Twenty-ve % of POMS reported no clinically signicant changes, 12.5% a clinically signicant worsening and 62.5% patients a clinically signicant improvement in the SDMT score at the end of the training program. The proportion of patients reporting a clinically signicant improvement of the SDMT was signicantly (p=0.008) higher (100%) in patients exposed to the ST in comparison to that (25%) in nST group. Conclusions: In our RCT the use of the 4-point SDMT cut-off allows us to demonstrate the clinical meaningfulness of the results obtained by a home-based computerized program for retraining attention dysfunction in POMS patients with attention impairment. Further studies are needed to conrm the clinical validity of this cut-off and its applicability in the routine clinical practice setting


Introduction
There's a growing need to nd new and more robust disability outcome measures to be used in multiple sclerosis (MS) randomised clinical trials (RCTs) and in clinical practice. The most common outcomes currently used, annualized relapse rate and sustained Expanded disability Status Scale (EDSS) progression, miss an important dimension of MS-related disability, namely, decline in cognitive function.
Indeed, cognitive dysfunction is one of the most remarkable features of MS (1) and particularly in pediatric onset MS (POMS).
The percentage of patients with POMS with at least a mild cognitive de cit ranges from 30 to 50%. (2)(3)(4)(5)(6) Therefore, the Multiple Sclerosis Functional Composite (MSFC), including a cognitive test, the Paced Auditory Serial Addition Test (PASAT), has been suggested (7) as an alternative and more complete outcome measure in MS RCTs, but it has some limitations due to the di culty interpreting the clinical meaning of z-score change and because it seems to be not fully accepted by MS patients (8,9).
Currently the Simbol Digit Modalities Test (SDMT), a simple, brief measure of information processing speed (IPS) has been proposed (10) and it is increasingly used to explore cognitive functions in MS clinical trials, since it requires little time and no special equipment, does not demonstrate signi cant ceiling effects, has a good test-retest reliability and very low practice effects as there are alternate forms available (11) Recently a detailed analysis of the psychometric qualities, sensitivity to change and clinical meaningfulness of SMDT in comparison to the Paced Auditory Serial Addition Test (PASAT) has been performed by the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) (10). The results of this analysis proved the SDMT to be superior to the PASAT suggesting SDMT should be considered the measure of choice for MS trials in assessing IPS. In particular, they found that a 4-point worsening on the SDMT score signi cantly correlated with clinically meaningful cognitive decline as evidenced by a 5-point worsening on the Physical Component Summary (PCS) of the Health Status Questionnaire (SF-36).
Moreover, previous studies con rmed that this degree of change in the SDMT is clinically meaningful, when correlated to relapses and employment status. (12,13) In a recent double-blind RCT (14) we assessed the e cacy of a home-based computerized program for retraining attention dysfunction in a cohort of POMS patients with attention impairment. We found that after a 3-month cognitive training, the speci c computer training (ST) exposure was associated to a signi cantly more pronounced reduction of the Cognitive Impaired Index (CII) in comparison to the nonspeci c training (nST) exposure. In particular, POMS treated with a ST had a signi cant higher improvement in their performances on SDMT in comparison to those receiving a n-ST suggesting that a cognitive rehabilitation program that targets attention is a suitable tool for improving global cognitive functioning in POMS patients.
Here, we present a post-hoc analysis aimed to assess the robustness of treatment effects, applying the 4point SDMT cut-off, as proposed by MSOAC (10), on the results of our cognitive rehabilitation trial.

Study population, Procedures and intervention
A detailed description of the study population, procedures and intervention has been previously reported elsewhere (14).
Brie y, 16 POMS patients failing in at least 2/4 attention tests on a neuropsychological battery were randomized to ST or nST (15), performed at home, in one-hour sessions, twice/week for three months. A neuropsychological test battery was administered, using alternative versions of the tests, at baseline (T0), and within one week following the end of the three months training program (T1).
The neuropsychological test battery comprised tests which cover different cognitive domains.
The SDMT was administered to assess IPS.
The primary objective of this post-hoc analysis was to test the effects of our cognitive rehabilitation trial by comparing the delta SDMT scores, applying a 4-point SDMT cut-off, in ST and nST groups.

Statistical analysis
All analyses were post hoc and not pre-speci ed. To quantify the clinical impact of longitudinal changes over time of the SDMT in the cohorts of patients exposed to ST and to nST we have applied the following categorization of the delta SDMT scores (delta SDMT:=SDMT score at T1 -SDMT score at T0) by using

Results
The comparisons of baseline demographic and clinical characteristics and of the baseline NP of POMS subgroups who underwent ST and n-ST are reported in Table 1. At baseline, no differences were found between the 2 treatment arms regarding sex, age, and in terms of NP performances.
After the 3-month cognitive training, patients exposed to the ST showed a signi cant improvement in SDMT performances (p < 0.0001) in comparison to those treated with nST. By applying the 4 points cut-off of the delta SDMT scores, 4 (25%) patients reported no clinically signi cant changes, 2 (12.5%) patients a clinically signi cant worsening and 10 (62.5%) patients a clinically signi cant improvement in the SDMT score at the end of the training program.
Moreover, the overall improvement of the delta-CII was signi cantly higher in patients reporting a clinically signi cant improvement of the SDMT at the end of training in comparison to those who presented with a not clinically signi cant change and those with a clinically signi cant worsening of the SDMT (p = 0.038). (Fig. 1)

Discussion
Rehabilitation treatment with a computerized cognitive training speci cally designed to exercise the attention domain resulted in a signi cant improvement of overall cognitive performances and in particular of the SDMT scores. With this post-hoc analysis we have also demonstrated that a speci c attention training is associate with clinically meaningful changes of SDMT scores in the short term.
It is noteworthy that all patients exposed to the ST exhibited a clinically meaningful improvement of the SDMT scores in comparison to only 2/8 patients exposed to the nST at the end of the 3-month cognitive training .
To the best of our knowledge, this is the rst report of the application of the 4-point SDMT cut-off, proposed by MSOAC (10), to the results of a RCT in order to test if the degree of changes in the SDMT scores obtained after a speci c cognitive training were clinically meaningful.
The research about functional measurers capable to explore from different perspectives, including the non-motor disability, the overall impact of MS on disability has a long-lasting history.
In 1996 the MSFC was proposed as a multiple domains measure to detect and summarize walking impairment (via the time 25-foot walk test), upper extremity dexterity (via the 9-hole peg test) and cognition (via the PAST) abilities in patients with MS. (16) Thereafter, most of the RCTs performed to evaluate the e cacy of disease modifying therapies included the MSFC as an outcome measure, but due to the di culty interpreting the clinical meaning of z-score change and because it seems that MS patients not fully accept the tests (especially the PASAT), MSFC has not been extensively used in clinical practice. (8,9) The use of SDMT as an outcome measure in RCTs and observational studies has progressively gained more attention in the recent years. The SDMT performances have been found to be associated with different magnetic resonance imaging measures of MS disease progression (17)(18)(19)(20).
Given all these premises and based on its predictive validity, the very high level of sensitivity and speci city and the facility of administration, this cognitive test is often used in clinical practice to perform a basic cognitive screening helping to identify patients at high risk for cognitive impairment who need a more structured neuropsychological evaluation.
Recently, the psychometric properties of SDMT and PASAT have been compared and the former proved to be superior to the PASAT in assessing the IPS in patients with MS. (10) Furthermore, a 4-point change in the SDMT has been proved to be a cut-off able to discriminate clinically meaningful changes from test scores changes due to practice effect or simply to the chance. (10,26) In our RCT the use of the 4-point SDMT cut-off allows us to demonstrate the clinical meaningfulness of the results obtained by a home-based computerized program for retraining attention dysfunction in POMS patients with attention impairment. Further studies are needed to con rm the clinical validity of this cut-off and its applicability in the routine clinical practice setting.

Declarations
Availability of data and materials The datasets used and analysed during the current study are available from the corresponding author on reasonable request.
Authors' contributions MS de ned the study concept and design, recruited patients and collected, analysed and interpreted the data.
RGV performed the neuropsychological evaluations and collected, analysed and interpreted the data.
LM performed the study supervision and a critical revision of the manuscript for intellectual content.
PI de ned the study concept and design and collected, analysed and interpreted the data.
All authors read and approved the nal manuscript.
Ethics approval and consent to participate.
The study was conducted with approval of the institutional review board (Comitato Etico Indipendente Azienda Ospedaliero-Universitaria Consorziale Policlinico -Approval Number: 0070059/CE). Parents of the participants signed an informed consent.