Neuropsychological rehabilitation for multiple sclerosis

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

This is an update of the Cochrane review 'Neuropsychological rehabilitation for multiple sclerosis' (first published in The Cochrane Library 2011, Issue 11).

Cognitive deficits are a common manifestation of multiple sclerosis (MS) and have a significant effect on the patient's quality of life. Alleviation of the harmful effects caused by these deficits should be a major goal of MS research and practice. 

Objectives

To assess the effects of neuropsychological/cognitive rehabilitation on health-related factors, such as cognitive performance and emotional well-being in patients with MS.

Search methods

The Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Search Co-ordinator searched their Specialised Register which, among other sources, contains trials from CENTRAL (The Cochrane Library 2013, Issue 2), MEDLINE, EMBASE, CINAHL, LILACS, PEDro and clinical trials registries (28 May 2013). We contacted authors of the studies for additional information.

Selection criteria

Randomised controlled trials (RCTs) and quasi-randomised trials evaluating the effects of neuropsychological rehabilitation in MS compared to other interventions or no intervention.

Data collection and analysis

Two review authors individually judged the eligibility of the included studies, assessed risk of bias and extracted data. We combined results quantitatively in meta-analyses according to the intervention type: 1) cognitive training and 2) cognitive training combined with other neuropsychological rehabilitation methods.

Main results

Twenty studies (986 participants; 966 MS participants and 20 healthy controls) fulfilled the inclusion criteria. The mean age of the participants was 44.6 years, mean length of education was 12.3 years and 70% of the participants were women. Most of the participants had a relapsing-remitting course of disease. The mean Expanded Disability Status Scale score was 3.2 and the mean duration of disease was 14.0 years.

On the basis of these studies, we found low-level evidence that neuropsychological rehabilitation reduces cognitive symptoms in MS. Cognitive training was found to improve memory span (standardised mean difference (SMD) 0.54, 95% confidence interval (CI) 0.20 to 0.88, P = 0.002) and working memory (SMD 0.33, 95% CI 0.09 to 0.57, P = 0.006). Cognitive training combined with other neuropsychological rehabilitation methods was found to improve attention (SMD 0.15, 95% CI 0.01 to 0.28, P = 0.03), immediate verbal memory (SMD 0.31, 95% CI 0.08 to 0.54, P = 0.008) and delayed memory (SMD 0.22, 95% CI 0.02 to 0.42, P = 0.03). There was no evidence of an effect of neuropsychological rehabilitation on emotional functions.

The overall quality, as well as the comparability of the included studies, was relatively low due to methodological limitations and heterogeneity of interventions and outcome measures. Although most of the pooled results in the meta-analyses yielded no significant findings, 18 of the 20 studies showed some evidence of positive effects when the studies were individually analysed.

Authors' conclusions

This review found low-level evidence for positive effects of neuropsychological rehabilitation in MS. The interventions and outcome measures included in the review were heterogeneous, which limited the comparability of the studies. New trials may therefore change the strength and direction of the evidence.

Résumé scientifique

Rééducation neuropsychologique pour la sclérose en plaques

Contexte

Ceci est une mise à jour de la revue Cochrane intitulée « Rééducation neuropsychologique pour la sclérose en plaques » (publiée pour la première fois dans la Bibliothèque Cochrane 2011, numéro 11).

Les troubles cognitifs sont une manifestation fréquente de la sclérose en plaques (SEP) ayant une incidence significative sur la qualité de vie des patients. L'atténuation des effets préjudiciables de ces déficits doit être un objectif majeur de la recherche et de la pratique médicale concernant la SEP.

Objectifs

Évaluer les effets de la rééducation neuropsychologique/cognitive sur les facteurs liés à la santé, tels que les performances cognitives et le bien-être émotionnel chez les patients atteints de SEP.

Stratégie de recherche documentaire

Le coordinateur de recherche d'études du groupe Cochrane sur la sclérose en plaques et les maladies rares du système nerveux central a effectué des recherches dans son registre spécialisé qui, entre autres sources, contient des essais issus de CENTRAL (Bibliothèque Cochrane 2013, numéro 2), MEDLINE, EMBASE, CINAHL, LILACS, PEDro et les registres d'essais cliniques (28 mai 2013). Nous avons contacté les auteurs des études pour obtenir des informations supplémentaires.

Critères de sélection

Essais contrôlés randomisés (ECR) et quasi randomisés évaluant les effets de la rééducation neuropsychologique dans la SEP par rapport à d'autres interventions ou à l'absence d'intervention.

Recueil et analyse des données

Deux auteurs de la revue ont individuellement jugé l'éligibilité des études incluses, évalué le risque de biais et extrait les données. Nous avons combiné les résultats quantitativement dans des méta-analyses selon le type d'intervention : 1) entraînement cognitif et 2) entraînement cognitif associé à d'autres méthodes de rééducation neuropsychologique.

Résultats principaux

Vingt études (986 participants ; 966 participants atteints de SEP et 20 témoins sains) remplissaient les critères d'inclusion. L'âge moyen des participants était de 44,6 ans, la durée moyenne de l'éducation était de 12,3 ans et 70 % des participants étaient des femmes. La plupart des participants avaient une évolution récurrente-rémittente de la maladie. Le score moyen sur l'échelle EDSS (Expanded Disability Status Scale) était de 3,2 et la durée moyenne de la maladie était de 14,0 ans.

Sur la base de ces études, nous avons trouvé des preuves de faible niveau indiquant que la rééducation neuropsychologique diminuait les symptômes cognitifs de la SEP. Il a été constaté que l'entraînement cognitif améliorait l'empan mnémonique (différence moyenne standardisée (DMS) 0,54, intervalle de confiance (IC) à 95 % 0,20 à 0,88, P = 0,002) et la mémoire de travail (DMS 0,33, IC à 95 % 0,09 à 0,57, P = 0,006). L'entraînement cognitif associé à d'autres méthodes de rééducation neuropsychologique a pu améliorer l'attention (DMS 0,15, IC à 95 % 0,01 à 0,28, P = 0,03), la mémoire verbale immédiate (DMS 0,31, IC à 95 % 0,08 à 0,54, P = 0,008) et la mémoire différée (DMS 0,22, IC à 95 % 0,02 à 0,42, P = 0,03). Il n'y avait aucune preuve d'un effet de la rééducation neuropsychologique sur les fonctions émotionnelles.

La qualité globale, tout comme la comparabilité des études incluses, étaient relativement faibles en raison de limitations méthodologiques et de l'hétérogénéité des interventions et des mesures de résultats. Bien que la plupart des résultats regroupés dans des méta-analyses n'étaient pas significatifs, 18 études sur les 20 montraient quelques preuves d'effets positifs lorsque les études étaient analysées individuellement.

Conclusions des auteurs

Cette revue a trouvé des preuves de faible niveau sur les effets positifs de la rééducation neuropsychologique dans la SEP. Les interventions et les mesures de résultats incluses dans la revue étaient hétérogènes, ce qui a limité la comparabilité des études. De nouveaux essais risquent donc de modifier la force et la direction de ces preuves.

Plain language summary

Rehabilitation for cognitive dysfunction in people with multiple sclerosis

This is an update of the Cochrane review 'Neuropsychological rehabilitation for multiple sclerosis' (first published in The Cochrane Library 2011, Issue 11).

Demyelinating disease is any condition that results in damage to the protecting covering (myelin sheath) that surrounds nerve fibers in brain and spinal cord. Multiple sclerosis (MS) has used to be regarded simply as a demyelinating disease, however recent research has shown that widespread damage to neurons (nerve cells) and grey matter changes are central features of MS. This has emphasised cognitive dysfunction, like deficits in memory or attention, as being one of the major symptoms of the disease. Cognitive deficits are common in MS, occurring in about 50% to 60% of patients. These deficits can have a multidimensional impact on patients' activities of daily living and should be taken into account in their treatment and rehabilitation. Neuropsychological rehabilitation aims to 1) reduce cognitive deficits, 2) reduce the harmful effects of cognitive impairments and 3) support patients' awareness and ability to take cognitive impairments into account in daily living.

The aim of this review was to evaluate the effects of cognitive (neuropsychological) rehabilitation in MS. We did this by considering the effects of rehabilitation on cognitive test performance and everyday cognitive performance, as well as on depression, fatigue, personality/behaviour disturbances, anxiety and quality of life.

Twenty relevant studies comprising a total of 986 participants (966 MS participants and 20 healthy controls) were identified and included in this review. Low-level evidence was found that neuropsychological rehabilitation reduces cognitive symptoms in MS. However, when analysed individually, 18 out of the 20 studies showed positive effects. Cognitive training was found to improve memory span and working memory. Cognitive training combined with other neuropsychological rehabilitation methods was found to improve attention, immediate verbal memory and delayed memory.

It is worth noting that the small numbers of patients in the studies and some methodological weaknesses reduce the level of the evidence. To further strengthen the evidence well-designed, high-quality studies are needed. 

Résumé simplifié

La rééducation pour le dysfonctionnement cognitif chez les personnes atteintes de sclérose en plaques

Ceci est une mise à jour de la revue Cochrane intitulée « Rééducation neuropsychologique pour la sclérose en plaques » (publiée pour la première fois dans la Bibliothèque Cochrane 2011, numéro 11).

Une maladie démyélisante est une affection qui se traduit par des lésions de l'enveloppe protectrice (gaine de myéline) qui entoure les fibres nerveuses dans le cerveau et la moelle épinière. La sclérose en plaques (SEP) était auparavant considérée simplement comme une maladie démyélisante, cependant les recherches récentes ont montré que les lésions généralisées de neurones (cellules nerveuses) et les changements dans la substance grise sont des caractéristiques centrales de la SEP. Cela a mis l'accent sur les dysfonctionnements cognitifs, comme les troubles de la mémoire ou de l'attention, comme étant l'un des principaux symptômes de la maladie. Les troubles cognitifs sont fréquents dans la SEP, survenant chez environ 50 % à 60 % des patients. Ils peuvent avoir un impact multidimensionnel sur les activités de la vie quotidienne des patients et doivent être pris en compte dans le traitement et la rééducation. La rééducation neuropsychologique vise à 1) réduire les déficits cognitifs, 2) réduire les effets préjudiciables des troubles cognitifs et 3) renforcer la conscience des patients et leur capacité à prendre en compte les troubles cognitifs dans leur vie quotidienne.

Le but de cette revue était d'évaluer les effets de la rééducation cognitive (neuropsychologique) dans la SEP. Nous l'avons fait en considérant les effets de la rééducation sur la performance aux tests cognitifs et sur les performances cognitives au quotidien ainsi que sur la dépression, la fatigue, les troubles de la personnalité et du comportement, l'anxiété et la qualité de vie.

Vingt études pertinentes impliquant un total de 986 participants (966 participants atteints de SEP et 20 témoins sains) ont été identifiées et incluses dans cette revue. Des preuves de faible niveau ont été découvertes indiquant que la rééducation neuropsychologique réduisait les symptômes cognitifs dans la SEP. Cependant, analysées individuellement, 18 études sur les 20 ont montré des effets positifs. Il a été constaté que l'entraînement cognitif améliorait la capacité de mémorisation à court terme et la mémoire de travail. L'entraînement cognitif associé à d'autres méthodes de rééducation neuropsychologique a pu améliorer l'attention, la mémoire verbale immédiate et la mémoire différée.

Il convient de noter que le petit nombre de patients dans les études et certaines faiblesses méthodologiques réduisent le niveau des preuves. Pour renforcer les preuves, d'autres études de bonne qualité et bien conçues sont nécessaires.

Notes de traduction

Traduit par: French Cochrane Centre 23rd June, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

எளியமொழிச் சுருக்கம்

மல்டிபிள் ஸ்கலரோசிஸ் கொண்ட மக்களில் அறிவாற்றல் பிறழ்ச்சிக்கான புனர்வாழ்வு

இது, 'மல்டிபிள் ஸ்கலரோசிஸ்ற்கான நரம்புஉளவியல் புனர்வாழ்வு' (காக்குரேன் நூலகத்தில் முதலில் வெளியிடப்பட்டது, 2011, பிரதி 11) என்ற காக்குரேன் திறனாய்வின் மேம்படுத்துதல் ஆகும்.

மூளை மற்றும் தண்டு வடத்தை சுற்றி அமைந்துள்ள நரம்பு நார்களை பாதுகாக்கும் உறை (நரம்பு கொழுப்பு) சேதம் அடைவதால் ஏற்படும் எந்த ஒரு நிலையும் நரம்பு கொழுப்பு குறைவு நோயாகும். மல்டிபள் ஸ்கேலோரோசிஸ் (எம்எஸ்) நரம்பு கொழுப்பு குறைவு நோய் என்று மிக எளிமையாக கருதப்பட்டு இருந்தது; எனினும் சமீபத்திய ஆராய்ச்சி, நியூரான்ஸ் (நரம்பணுக்கள்) மற்றும் சாம்பல் நிற திசுக்களில் ஏற்படும் மாற்றங்களே எம்எஸ்-சின் முக்கிய அம்சங்களாகும் என்று காட்டுகிறது. இவை, ஞாபகம் அல்லது செயல் கூர்மையில் ஏற்படும் குறைவுகளை போன்ற அறிவாற்றல் பிறழ்ச்சியை, நோயின் பிரதானமான அறிகுறிகளில் ஒன்றாக முக்கியப்படுத்துகிறது. அறிவாற்றல் பிறழ்ச்சிகள், எம்எஸ் கொண்ட நோயாளிகளில் 50-60 சதவீதம் வரை பரவலாகக் காணப்படுகிறது. இந்த பிறழ்ச்சிகள், ஒரு நோயாளியின் அன்றாட நடவடிக்கைகளில் ஒரு பல்பரிணாம தாக்கத்தை ஏற்படுத்தக் கூடும்,மற்றும் இவற்றை, அவர்களின் சிகிச்சை மற்றும் புனர்வாழ்வில் கருத்தில் கொள்ள வேண்டும். நரம்பு-உளவியல் புனர்வாழ்வு, 1) அறிவாற்றல் பிறழ்ச்சிகளை குறைத்தல், 2) அறிவாற்றல் குறைபாடுகளின் தீங்கு தரக் கூடிய விளைவுகளைக் குறைத்தல், 3) நோயாளிகளின் விழிப்புணர்வு மற்றும் அறிவாற்றல் குறைபாடுகளை அன்றாட வாழ்க்கையில் கருத்தில் கொள்ளக் கூடிய திறனை ஆதரித்தல் என்பன போன்றவற்றில் நோக்கம் கொண்டுள்ளது.

எம்எஸ்-சில் அறிவாற்றல் (நரம்பு-உளவியல்) புனர்வாழ்வின் விளைவுகளை மதிப்பிடுவதே இந்த திறனாய்வின் நோக்கம் ஆகும். அறிவாற்றல் சோதனை செயல்திறன் மற்றும் அன்றாட அறிவாற்றல் செயல்திறன், அத்துடன் மனச்சோர்வு, அயர்ச்சி, தனிமனித பண்பு/நடத்தை இடர்கள், பதட்டம் மற்றும் வாழ்க்கைத் தரம் ஆகியவற்றின் மேல் புனர்வாழ்வின் விளைவுகளை கருத்தில் கொண்டு நாங்கள் இதை நடப்பித்தோம்.

மொத்தம் 986 பங்கேற்பாளர்கள் (966 எம்எஸ் பங்கேற்பாளர்கள் மற்றும் 20 ஆரோக்கியமான கட்டுபாட்டு பங்கேற்பாளர்கள்) கொண்ட இருபது தொடர்புடைய ஆய்வுகள் கண்டறியப்பட்டு இந்த திறனாய்வில் சேர்க்கப்பட்டது. எம்எஸ்-இல் நரம்பு-உளவியல் புனர்வாழ்வு அறிவாற்றல் குறைவு அறிகுறிகளை குறைக்கும் என்பதற்கு குறைந்தளவு ஆதாரம் காணப்பட்டது. எனினும், தனித்தனியாக பகுப்பாய்வு செய்யப்பட்ட போது, 20 ஆய்வுகளில் 18 ஆய்வுகள் சாதகமான விளைவுகளை காட்டின. அறிவாற்றல் பயிற்சி, ஞாபக திறனையும் செயலாக்க ஞாபகத்தையும் முன்னேற்றியது என்று காணப்பட்டது. அறிவாற்றல் பயிற்சியுடன் இணைக்கப்பட்ட பிற நரம்பு-உளவியல் புனர்வாழ்வு முறைகள், கூர்மை திறன், உடனடி வார்த்தை ஞாபகம் மற்றும் தாமதமான ஞாபகத்தையும் முன்னேற்றியது என்று காணப்பட்டது.

ஆய்வுகளில் இருந்த சிறிய எண்ணிக்கையிலான நோயாளிகள் மற்றும் சில செயல்முறையியல் பலவீனங்கள்ஆதாரத்தின் தரத்தை குறைத்தன என்பது குறிப்பிட வேண்டிய விஷயமாகும். ஆதாரத்தை மேலும் வலுப்படுத்துவதற்கு, சிறந்த-வடிவமைப்பு கொண்ட உயர்-தர ஆய்வுகள் தேவைப்படுகின்றன.

மொழிபெயர்ப்பு குறிப்புகள்

மொழி பெயர்ப்பாளர்கள்: சிந்தியா ஸ்வர்ணலதா ஸ்ரீகேசவன், ப்ளசிங்டா விஜய், தங்கமணி ராமலிங்கம், ஸ்ரீகேசவன் சபாபதி.

Laički sažetak

Rehabilitacija za kognitivne disfunkcije kod osoba s multiplom sklerozom

Ovo je obnovljena verzija Cochrane sustavnog pregleda koji je prvi put objavljen u Cochrane knjižnici 2011, izdanje 11.

Demijelinizacijska bolest je bilo koje stanje koje rezultira oštećenjem zaštitnog pokrova (mijelinska ovojnica) koja okružuje živčana vlakna u mozgu i leđnoj moždini. Nekad se jednostavno smatralo da je multipla skleroza (MS) demijelinizacijska bolest, međutim nedavna istraživanja su pokazala da su rasprostranjena oštećenja neurona (živčanih stanica) i promjene sive tvari središnje značajke MS. To je stavilo naglasak na kognitivne poremećaje, poput pamćenja ili pažnje, kao jednog od glavnih simptoma bolesti. Kognitivni deficiti su zajednički kod MS i pojavljuju se u oko 50% do 60% pacijenata. Ovi deficiti mogu imati višestruki utjecaj na aktivnosti svakodnevnog života pacijenata i trebaju se uzeti u obzir u njihovom liječenju i rehabilitaciji. Ciljevi neuropsihološke rehabilitacije jest 1) smanjiti kognitivne deficite, 2) smanjiti štetne učinke kognitivnih oštećenja i 3) podržati pacijentovu svjesnost i sposobnost te uzeti u obzir kognitivna oštećenja u svakodnevnom životu.

Cilj ovog pregleda je bio procijeniti učinke kognitivne (neuropsihološke) rehabilitacije kod MS. Temeljem rezultata provedenih kliničkih pokusa analizirani su učinci rehabilitacije na rezultate kognitivnog testiranja i svakodnevnog kognitivnog učinka, kao i na depresiju, umor, osobnost / poremećaje ponašanja, anksioznost i kvalitetu života.

Pronađeno je 20 relevantnih studija koje obuhvaćaju ukupno 986 sudionika (966 MS sudionika i 20 zdravih) i uključeno u ovaj pregled. Pronađeni su dokazi loše kvalitete da neuropsihološka rehabilitacija smanjuje kognitivne simptome MS-a. Međutim, kada se promotre zasebno, 18 od 20 studija je pokazalo pozitivne učinke. Utvrđeno je da kognitivni trening poboljšava raspon memorije i radnu memoriju. Utvrđeno je da kognitivni trening u kombinaciji s drugim metodama neuropsihološke rehabilitacije poboljšava pažnju, neposredno verbalno pamćenje i odgođeno sjećanje.

Važno je napomenuti da razinu kvalitete dokaza umanjuje mali broj pacijenata u studijama i određene metodološke slabosti tih studija. Potrebne su visokokvalitetne studije kako bi se dobili dokazi visoke kvalitete u ovom području.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Ivana Sruk
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Summary of findings(Explanation)

Summary of findings for the main comparison. Cognitive training versus any control for multiple sclerosis
  1. 1Several crucial limitations in the implementation of the study.
    2High, unexplained heterogeneity.
    3Low number of participants.
    4One crucial limitation in the implementation of the study.

Cognitive training versus any control for multiple sclerosis
Patient or population: patients with multiple sclerosis
Settings: outpatient
Intervention: cognitive training versus any control
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comment
Assumed riskCorresponding risk
Control Cognitive training versus any control
AttentionThe mean attention score in the control groups was 12.6

The mean attention score in the intervention groups was

0.06 standard deviations higher

(0.1 lower to 0.23 higher)

SMD 0.06 (95% CI -0.1 to 0.23),

P = 0.46

573
(5 studies)
⊕⊕⊝⊝
low 1
 
Information processing speedThe mean information processing speed score in the control groups was -410.9

The mean information processing speed score in the intervention groups was

0.15 standard deviations higher

(0.33 lower to 0.62 higher)

SMD 0.15 (95% CI -0.33 to 0.62),

P = 0.55

176
(4 studies)
⊕⊝⊝⊝
very low 1,2,3
Time-related scores were entered as negative variables.
Memory spanThe mean memory span score in the control groups was 5.8

The mean memory span score in the intervention groups was

0.54 standard deviations higher

(0.2 to 0.88 higher)

SMD 0.54 (95% CI 0.2 to 0.88),

P = 0.002

150
(2 studies)
⊕⊕⊝⊝
low 3,4
 
Working memoryThe mean working memory score in the control groups was 8.6

The mean working memory score in the intervention groups was

0.33 standard deviations higher

(0.09 to 0.57 higher)

SMD 0.33 (95% CI 0.09 to 0.57),

P = 0.006

288
(3 studies)
⊕⊝⊝⊝
very low 1,3
 
Immediate verbal memoryThe mean immediate verbal memory score in the control groups was 4.3

The mean immediate verbal memory score in the intervention groups was

0.2 standard deviations higher

(0.02 lower to 0.41 higher)

SMD 0.2 (95% CI -0.02 to 0.41),

P = 0.08

360
(4 studies)
⊕⊕⊝⊝
low 3,4
 
Executive functionsThe mean executive functions score in the control groups was -6.6

The mean executive functions score in the intervention groups was

0.35 standard deviations higher

(0.03 lower to 0.73 higher)

SMD 0.35 (95% CI -0.03 to 0.73),

P = 0.07

112
(2 studies)
⊕⊝⊝⊝
very low 1,3
Error scores were entered as negative variables.
DepressionThe mean depression score in the control groups was -28.0

The mean depression score in the intervention groups was

0.26 standard deviations higher

(0.23 lower to 0.75 higher)

SMD 0.26 (95% CI -0.23 to 0.75),

P = 0.29

196
(5 studies)
⊕⊝⊝⊝
very low 1,2,3
Depression scores were entered as negative variables.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; SMD: standardised mean difference
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Cognitive training combined with other neuropsychological rehabilitation methods versus any control for multiple sclerosis

Summary of findings 2. Cognitive training combined with other neuropsychological rehabilitation methods versus any control for multiple sclerosis
  1. 1One crucial limitation in the implementation of the study.
    2Several crucial limitations in the implementation of the study.
    3Low number of participants.
    4High, unexplained heterogeneity.

Cognitive training combined with other neuropsychological rehabilitation methods versus any control for multiple sclerosis
Patient or population: patients with multiple sclerosis
Settings: outpatient
Intervention: cognitive training combined with other neuropsychological rehabilitation methods versus any control
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comment
Assumed riskCorresponding risk
Control Cognitive training combined with other neuropsychological rehabilitation methods versus any control
AttentionThe mean attention score in the control groups was 8.7The mean attention score in the intervention groups was
0.15 standard deviations higher
(0.01 to 0.28 higher)

SMD 0.15 (95% CI 0.01 to 0.28),

P = 0.03

894
(5 studies)
⊕⊕⊕⊝
moderate 1
 
Information processing speedThe mean information processing score in the control groups was -608.6The mean information processing speed score in the intervention groups was
0.05 standard deviations higher
(0.27 lower to 0.36 higher)

SMD 0.05 (95% CI -0.27 to 0.36),

P = 0.77

181
(3 studies)
⊕⊝⊝⊝
very low 2,3
Time-related scores were entered as negative variables.
Immediate verbal memoryThe mean immediate verbal memory score in the control groups was 32.9The mean immediate verbal memory score in the intervention groups was
0.31 standard deviations higher
(0.08 to 0.54 higher)

SMD 0.31 (95% CI 0.08 to 0.54),

P = 0.008

308
(7 studies)
⊕⊝⊝⊝
very low 2,3
 
Delayed memoryThe mean delayed memory score in the control groups was 9.5The mean delayed memory score in the intervention groups was
0.22 standard deviations higher
(0.02 to 0.42 higher)

SMD 0.22 (95% CI 0.02 to 0.42),

P = 0.03

400
(4 studies)
⊕⊕⊕⊝
moderate 1
 
Everyday cognitive performance/patient's reportThe mean everyday cognitive performance/patient's report score in the control groups was 6.0The mean everyday cognitive performance/patient's report score in the intervention groups was
0.1 standard deviations higher
(0.03 lower to 0.23 higher)

SMD 0.1 (95% CI -0.03 to 0.23),

P = 0.13

1011
(4 studies)
⊕⊕⊝⊝
low 1,3,4
 
DepressionThe mean depression score in the control groups was -8.6The mean depression score in the intervention groups was
0.25 standard deviations higher
(2.11 lower to 2.61 higher)

MD 0.25 (95% CI -2.11 to 2.61),

P = 0.84

187
(4 studies)
⊕⊕⊝⊝
low 1,4
Depression scores were entered as negative variables.
FatigueThe mean fatigue score in the control groups was -50.8The mean fatigue score in the intervention groups was
0.08 standard deviations higher
(0.44 lower to 0.59 higher)

SMD 0.08 (95% CI -0.44 to 0.59),

P = 0.77

159
(3 studies)
⊕⊝⊝⊝
very low 1,3,4
Fatigue scores were entered as negative variables.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference; SMD: standardised mean difference
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) causing damage to both white and grey matter. The average age at disease onset is 30 years (Barten 2010). MS is the most common disabling neurological disease in young and middle-aged adults, and the economic effects of the disease are noticeable (Barten 2010). MS is characterised by a marked variability in its clinical symptoms and their course, while the unpredictable nature of the disease trajectory increases the distress it causes patients.

Cognitive deficits are a common manifestation of MS, occurring in about 50% to 60% of patients (Amato 2006). The neuropathological background of the deficits is considered to relate to the variety of white and grey matter damage (Filippi 2010). There is no direct relationship between cognitive deficits and physical disability, disease duration or course of the disease (Amato 2008). On the other hand, it has been found that high primary cognitive capacity may protect cognitive functions by creating 'cognitive reserves', thus contributing to the development of functional reorganisation processes (Bonnet 2006; Sumowski 2009).

MS-related cognitive dysfunction is heterogeneous and its evolution is highly individual among patients. In longitudinal studies, both stable cognitive status (Jennekens-Schinkel 1990; Kujala 1997; Mariani 1991; Rosti 2007; Sperling 2001) and decline (Amato 2001; Feinstein 1992; Kujala 1997; Zivadinov 2001) have been reported. Memory and learning dysfunction and slowed information processing speed are regarded as the most common MS-related cognitive deficits (Calabrese 2006; Rogers 2007). Slowed information processing speed, in particular, is thought to underlie and be the core feature of cognitive problems observed in MS (DeLuca 2004; Henry 2006) and can negatively affect other aspects of cognitive function (Calabrese 2006; Feinstein 2007). Deficits in complex attention and executive functions, in visual perception and in language (verbal fluency and naming) can also occur (Fischer 2001).

The functional consequences of MS-related cognitive impairment can be striking and have a multidimensional impact on patients' activities of daily living. Thus, MS-related cognitive impairment and its recovery should be taken into account in the patient's treatment and rehabilitation regimen. Indeed, cognitive deficits may have both physical and mental effects, leading to symptoms of cognitive fatigue (DeLuca 2005), and may have an impact on (physical) independence, employment, social and recreational activities (Chiaravalloti 2008), driving skills (Kotterba 2003; Lincoln 2008) and on physical rehabilitation outcome (Langdon 1999), as well as caregiver strain (Khan 2007).

Description of the intervention

Neuropsychological rehabilitation is based on a comprehensive neuropsychological assessment where the patient's individual cognitive strengths and weaknesses are evaluated. In order to reduce the harmful effects on the patient's everyday life, neuropsychological rehabilitation involves teaching compensatory strategies, using aids, supporting the patient's awareness and counselling patients and their significant others in how to cope better with cognitive problems. While psychological interventions aim to treat mood disorders such as depression or anxiety, reduce stress, enhance self efficacy and self esteem, and improve psychological coping skills, neuropsychological interventions focus on the improvement of cognitive skills, by supporting the patient's awareness of their own cognitive strengths and weaknesses. Thus, neuropsychological rehabilitation is provided by a specialised clinical neuropsychologist.

How the intervention might work

Neuropsychological rehabilitation aims to:

  1. reduce cognitive deficits;

  2. reduce the harmful effects of cognitive impairments;

  3. support the patients' awareness of their cognitive impairment to enable them to cope in everyday living.

Functional magnetic resonance imaging (fMRI) studies on cognitive function in MS have revealed that functional brain reorganisation often takes place spontaneously to compensate for tissue damage (Penner 2007). Functional brain reorganisation after a brain injury mainly consists of an increase in the extent of brain areas activated, even recruiting additional areas (Pantano 2006). Neuroplasticity may reduce the clinical expression of cognitive symptoms and it has been speculated that cognitive rehabilitation might be seen as a procedure to enhance plasticity processes in the brain (Chiaravalloti 2012; Filippi 2012; Leavitt 2012; Parisi 2012; Penner 2007).

The scientific literature reports some evidence of cognitive rehabilitation reducing cognitive impairment. Attention and memory retraining has been shown to be effective after traumatic brain injury, as has language and perception training in persons with stroke (Cicerone 2000). Furthermore, it has been suggested that by providing patients with knowledge about their cognitive strengths and weaknesses, it is possible to increase their awareness and ability to find ways to cope with persisting neuropsychological deficits (Wilson 2008). On the other hand, teaching compensatory strategies may help patients to cope with their cognitive impairments (Wilson 2008). Finally, in order to help patients to understand and accept their cognitive problems and increase their psychological well-being, neuropsychological support in individual and group rehabilitation settings appears to be effective (Mateer 2005).

Why it is important to do this review

The effects of neuropsychological rehabilitation in MS have not been as widely studied as they have, for example, in stroke patients, where the advantages of neuropsychological rehabilitation have been more extensively evaluated (Bowen 2007; das Nair 2007; Lincoln 2000). The heterogeneous and progressive nature of MS-related cognitive deficits, in addition to the difficulty in investigating slow information processing, which appears to be the main cognitive impairment in the MS population, may explain the reluctance of researchers to conduct this type of study.

In the Cochrane review by Thomas et al (Thomas 2006), the effectiveness of psychological interventions for MS was evaluated, based on the evidence from 16 randomised controlled trials (RCTs). However, only five of these trials focused on neuropsychological interventions. This review concentrated on evaluating whether psychological interventions had an effect on quality of life, psychiatric symptoms (e.g. depression and anxiety), psychological functioning (e.g. emotions, self efficacy, self esteem) and neurological disability, and as only one component of cognitive function. In addition to Thomas 2006 another a Cochrane review focused solely on memory rehabilitation in MS (das Nair 2012a) and did not cover other cognitive functions or neuropsychological rehabilitation. Our review, on the other hand, will focus on evaluating whether neuropsychological rehabilitation has an effect on improving cognitive performance and patients' ability to cope with their cognitive deficits.

It is important to undertake this review because cognitive deficits are common in MS and may have a multidimensional impact on patients' quality of life. Medication cannot prevent cognitive deficits or their progression and simple psychological interventions do not attain the same benefits. This systematic review will evaluate the published literature on this topic and assess its quality.

This is an update of the Cochrane review 'Neuropsychological rehabilitation for multiple sclerosis' (first published in The Cochrane Library 2011, Issue 11).

Objectives

To assess the effects of neuropsychological/cognitive rehabilitation on health-related factors, such as cognitive performance and emotional well-being in patients with MS.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi-randomised trials.

We defined quasi-randomised allocation as the use of factors such as date of admission, hospital number, alternation, date of birth or assignment to comparable groups with respect to clinical and demographic factors. Quasi-randomised trials were included because of their number in the scientific literature; their exclusion would have meant discarding most of the available data. Cross-over studies were not included.

Types of participants

Patients with a clinically definite MS diagnosis according to the Poser (Poser 1983) or McDonald (McDonald 2001; Polman 2005) criteria. We included studies in the review regardless of the clinical course of the disease, or its severity or duration. Studies concerning both MS patients and other patient populations were also included only when the results for the MS patients could be separated from the other clinical population.

Types of interventions

Neuropsychological/cognitive interventions compared with a control condition were included. Studies with neuropsychological/cognitive rehabilitation as a part of multidisciplinary rehabilitation were also included when the share of the neuropsychological rehabilitation in the intervention was clearly reported. All neuropsychological rehabilitation approaches were included, such as cognitive retraining, teaching of compensatory strategies and use of aids, and neuropsychological counselling or support aimed at reducing the harmful effects of cognitive/behavioural problems (see section Description of the intervention). The target of the intervention had to be the reduction of the impairments caused by or related to the neuropsychological deficits, such as memory or attention disorders. We set no restrictions on delivery, duration, intensity or co-interventions for interventions or comparators. Psychological interventions and drug studies were excluded. We set no other criteria for the control group intervention.

Types of outcome measures

We classified assessments according to whether they were observed:

  1. immediately post-treatment (within a month post-treatment);

  2. at longer-term follow-up (second measurement more than one month post-treatment).

Primary outcomes
  • Measures of cognitive function: we selected standardised neuropsychological tests to obtain an objective and world-recognised score, in addition to self reported questionnaires to assess the perceived impact of cognitive dysfunction on everyday life

Outcome measures had to be standardised, objective research tools for measuring cognitive performance, such as the Wechsler Adult Intelligence Scale (WAIS, Wechsler 1997a), the Wechsler Memory Scale (WMS, Wechsler 1997b), the Paced Auditory Serial Addition Test (PASAT, Gronwall 1977), the Symbol Digit Modalities Test (SDMT, Smith 1973) etc. For evaluating everyday cognitive performance we selected subjective self reports and carer ratings for measuring the harmful effects of cognitive problems and/or meta-cognition experienced, such as the Multiple Sclerosis Neuropsychological Questionnaire (Benedict 2003), the Memory Functioning Questionnaire (MFQ, Gilewski 1990), the Everyday Memory Questionnaire (EMQ, Sunderland 1983), the Dysexecutive Syndrome Questionnaire (DEX, Wilson 1996) etc.

Secondary outcomes

Secondary outcomes were measures of:

  • depression (such as the Beck Depression Inventory (BDI, Beck 1961));

  • fatigue (such as the Fatigue Scale for Motor and Cognitive Functions (FSMC, Penner 2005));

  • personality disturbance (such as the NEO Personality Inventory (NEO-PI, Hogan 1969));

  • anxiety (such as the State-Trait Anxiety Inventory (STAI, Spielberger 1983)); and

  • quality of life (such as the SF-36 (Ware 1992)).

As secondary outcome measures, we also considered non-standardised measures such as return to work or activity level.

Search methods for identification of studies

We conducted a systematic search without language or date restrictions to identify all relevant published and unpublished randomised controlled trials and quasi-randomised clinical trials.

Electronic searches

The Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Trials Search Co-ordinator searched their Specialised Register (28 May 2013) which, among other sources, contains:

  1. Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 2);

  2. MEDLINE (PubMed) (1966 to 28 May 2013);

  3. EMBASE (Embase.com) (1974 to 28 May 2013);

  4. CINAHL (EBSCO host) (1981 to 28 May 2013);

  5. LILACS (Bireme) (1982 to 28 May 2013).

In addition, we searched clinical trials registries: Clinicaltrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Portal (http://apps.who.int/trialsearch/).

Information on the Specialised Register and details of the search strategies used to identify trials can be found in the 'Specialised Register' section within the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's module.

The keywords used to search for this review are listed in Appendix 1.

In addition, we performed an expanded search to identify all quasi-randomised clinical trial articles in the following databases: PubMed (Appendix 2); EMBASE (Appendix 3) and CINAHL (Appendix 4), up to 28 May 2013.

Searching other resources

In addition to the electronic searches, we examined the reference lists of the included studies. We also used personal contact with experts in the field to identify the studies.  

Data collection and analysis

Selection of studies

Two review authors (ER and PH) independently selected articles and assessed study relevance in line with the predetermined inclusion criteria. Disagreements were discussed and resolved by consensus among the review authors.

Data extraction and management

Two review authors (ER and PH) extracted data from the studies. The first author (ER) tabulated the data, which were checked and completed by the second author (PH). We reached a consensus for every item included in the final tables (Characteristics of included studies; Data and analyses).

We extracted and tabulated data concerning:

  1. participants (number, drop-outs, age, sex, years of education, MS disease course, severity and duration of the disease, exclusion criteria, research setting);

  2. interventions delivered (type, cognitive domain targeted, number/frequency/duration of sessions and follow-up times);

  3. results reported (primary and secondary outcome measures, timing of the measurements, main and secondary results).

Assessment of risk of bias in included studies

Two review authors (ER and PH) independently graded the selected studies using a simple contingency form following the domain-based evaluation described in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 (Higgins 2011). The authors compared evaluations and discussed and resolved any disagreements.

The authors assessed the following domains as 'low risk of bias', 'unclear risk of bias' or 'high risk of bias':

  1. random sequence generation (adequate use of a random component in the sequence generation);

  2. allocation concealment (adequate use of allocation concealment so that participants or investigators enrolling participants could not foresee assignment);

  3. blinding of participants, personnel and outcome assessors (knowledge of the allocated interventions was adequately prevented during the study);

  4. incomplete outcome data (acceptable drop-out rate (< 20%));

  5. selective reporting (all intended outcome data presented for intervention and control groups); and

  6. other bias (e.g. similarity in groups' baseline characteristics regarding the most important prognostic indicators; acceptable compliance with intervention).

We reported the results of the 'Risk of bias' assessments for each individual study in the 'Risk of bias' tables and presented the overall quality of the findings in Summary of findings for the main comparison and Summary of findings 2. We used the GRADE software to provide an overall grading of the quality of the evidence (GRADE 2008).

Measures of treatment effect

We analysed data using RevMan 5.2 (RevMan 2012).

The included studies evaluated different cognitive functions using various tests and rating scales. We grouped the cognitive tests employed in the included studies into cognitive domains according to the functions they are traditionally used to measure (Lezak 2004) and we evaluated the effects of neuropsychological rehabilitation separately for those domains. For data where a higher score denotes a worse performance (time-related and error variables in cognitive tests, outcome measures for depression, fatigue and anxiety) we entered the mean at the post-intervention time point as a negative variable.

The data for continuous outcomes were the mean and standard deviation (SD) of each post-intervention outcome variable and the number of participants for each treatment group at each assessment point. We entered test scores at the end of treatment and during further follow-ups in the analyses.

We analysed treatment effects using mean differences (MD) for continuous outcome variables. We calculated the standardised mean difference (SMD) when continuous outcome variables were measured with different scales. For all treatment effects, we provided 95% confidence intervals (CI).

Unit of analysis issues

We included studies with multiple intervention and control groups, which we analysed by pooling together the data from all the intervention groups into a single intervention group and from all the control groups into a single control group.

Dealing with missing data

When data were not available or were unclear in the original study reports, we contacted the authors of the studies in question in order to obtain more precise information.

Assessment of heterogeneity

We employed the I2 statistic to evaluate heterogeneity of study variables statistically. I2 values of 25%, 50% and 75% corresponded to low, medium and high levels of heterogeneity, respectively. When the I2 statistic was significant (at ≥ 50%), we calculated estimates of treatment effects using a random-effects model (which provides broader confidence intervals than a fixed-effect model). When heterogeneity was not found, we adopted a fixed-effect model.

Assessment of reporting biases

To assess possible publication bias, we created funnel plots for those outcomes with at least 10 variables.

Data synthesis

To provide a meaningful summary, two authors (ER and PH) considered whether the clinical and methodological characteristics of the included studies were similar enough for meta-analysis.

We combined results quantitatively in meta-analyses according to the intervention type:

  1. cognitive training; and

  2. cognitive training combined with other neuropsychological rehabilitation methods.

Additionally, we used descriptive analysis in reporting the results of multimodal neuropsychological rehabilitation.

Sensitivity analysis

We carried out sensitivity analyses to assess the robustness of the results by:

  1. excluding studies with inadequate concealment of allocation;

  2. excluding studies in which outcome evaluation was not blinded or blinding remained unclear;

  3. excluding studies in which loss to follow-up remained unclear or was greater than 20%.

Results

Description of studies

See the Characteristics of included studies and Characteristics of excluded studies tables.

Results of the search

The literature search process is described in Figure 1. Overall, we retrieved 6500 studies (including overlapping search results from different databases). From these, 20 studies were included. Three studies (Filippi 2012; Mattioli 2012a; Vogt 2009) were related to other included studies. Both authors of the review acted as authors in one of the evaluated studies (Mäntynen 2013). The journal titles, names of the authors and institutions, sources of funding and results were available to the review authors in all phases of the review.

Figure 1.

Flow diagram of the study selection process. Filippi 2012, Mattioli 2012a, and Vogt 2009 were related studies, so 17 were included in analyses and 3 were related studies (not included in analyses).

Included studies

The 20 studies included were published between 1993 and 2013 and conducted in 10 different countries: six in Italy, four in the United States, two in Switzerland, two in Germany and one in Denmark, Great Britain, Austria, Israel, France and Finland. One study was written in German and the others in English. All except one (Mäntynen 2013) were single-centre studies.

We obtained further information regarding the randomisation method for three studies (Benedict 2000; Mattioli 2010; Tesar 2005) through email contact with study authors. We obtained statistical data for outcome measures for four studies (Chiaravalloti 2005; Lincoln 2002: data for meta-cognition outcomes and subjective experience and carers' reports of the harmful effects of cognitive problems; Mattioli 2010; Shatil 2010: data for depression and fatigue). For Jonsson 1993 the original data were no longer available.

Participants

The 20 trials included 986 participants: 966 MS patients and 20 healthy controls. Detailed information about the participants is given in the Characteristics of included studies table and the participants' characteristics are summarised in Table 1. The number of participants in the studies varied from 15 to 240 (mean 58) and the drop-out rate ranged from 0% to 57% (mean 9%; drop-out rates were not reported in Hildebrandt 2007). The proportion of women among the participants varied from 48% to 100% (mean 70%; gender distribution was not reported in Brissart 2012). The mean age of the participants varied from 32.7 to 60.0 years (mean 44.6) and mean length of education ranged from 8.5 to 14.8 years (mean 12.3; education years were not reported in Fink 2010, Mendoza 2001 or Tesar 2005).

Table 1. Description of participants
  1. EDSS: Expanded Disability Status Scale
    MS: multiple sclerosis

Number of participantsSex

Age in years

Mean

Education in years

Mean

Severity of disease, EDSS

Mean

Duration of disease, years

Mean

986 (966 MS participants

20 healthy controls)

70% women

30% men

44.612.33.214.0

Most patients (414; 43%) had a relapsing-remitting course of disease (disease course or number of participants with a certain disease course were not reported in Mendoza 2001, Mendozzi 1998, Shatil 2010 or Stuifbergen 2012). The mean Expanded Disability Status Scale (EDSS) scores varied from 1.4 to 5.6 (mean 3.2) among patients, and the mean duration of disease from 4.7 to 17.5 years (mean 14.0; EDSS scores were not reported in Chiaravalloti 2005, Fink 2010, Lincoln 2002 or Mendoza 2001 and duration of disease in Benedict 2000, Lincoln 2002, Mendoza 2001 or Shatil 2010).

In 13 of the studies (65%), cognitive impairment, either self reported, objectively demonstrated or both, was one of the inclusion criteria. The heterogeneity of the methods used to define and evaluate cognitive impairment did not make it possible to characterise the overall degree of cognitive impairment in the study population.

Interventions

Detailed information about interventions is presented in the Characteristics of included studies table and the intervention characteristics are summarised in Table 2. Cognitive training was implemented in 18 studies (90% of the studies; Brissart 2012; Cerasa 2012; Chiaravalloti 2005; Filippi 2012; Fink 2010; Hildebrandt 2007; Jonsson 1993; Lincoln 2002; Mattioli 2010; Mattioli 2012a; Mendozzi 1998; Mäntynen 2013; Shatil 2010; Solari 2004; Stuifbergen 2012; Tesar 2005; Vogt 2008; Vogt 2009).

Table 2. Description of interventions

Cognitive training

Number of studies (%)

Learning compensatory strategies

Number of studies (%)

Multimodal neuropsychological rehabilitation

Number of studies (%)

Number of sessions

Mean

Duration of sessions

Mean

Frequency

Mean

Duration of intervention

Mean

18 (90%) (in addition to training, learning compensatory strategies in 9 studies)

Trained cognitive domains: memory, attention, visuospatial functions, executive functions, problem-solving skills)

11 (55%)2 (10%)171 hour2 times per week9.5 weeks

In nine out of the 18 studies (50%) (Brissart 2012; Chiaravalloti 2005; Fink 2010; Hildebrandt 2007; Jonsson 1993; Lincoln 2002; Mäntynen 2013; Tesar 2005; Stuifbergen 2012) the intervention programme consisted of learning compensatory strategies in addition to cognitive training. In 15 studies (83%), cognitive training was computer-assisted and in three studies it was performed as paper-pencil tasks. Computer-assisted training was conducted at home in six (40%) and in clinic in nine (60%) studies. The computer-assisted programs were: RehaCom (n = 7; Cerasa 2012; Filippi 2012; Mattioli 2010; Mattioli 2012a; Mendozzi 1998; Solari 2004; Tesar 2005), BrainStim (n = 2; Vogt 2008; Vogt 2009), Vilat-G 1.0 (n = 1; Hildebrandt 2007), ProCogSEP (n = 1; Brissart 2012), Foramen Rehab (n = 1 Mäntynen 2013) and an internet-based program (www.neuropsychonline.com) (n = 1 Stuifbergen 2012).

Cognitive training was described according to five cognitive domains:

  • Memory training: memorising and recalling of word lists, pictures and figures, routes, numbers and stories.

  • Attentional training: turned, inversed and reflected texts, 'two in one' pictures, labyrinths, searching of figures and train driving with the monitoring of distractors.

  • Visuospatial training: mosaic games and navigating tasks.

  • Training of executive functions: organising, planning and developing solution strategies employing realistic simulations of a set of scheduled dates and duties.

  • Problem-solving skills training: puzzles requiring deductive reasoning, organisation and analysis of facts.

Learning of compensatory strategies was included in 11 of the studies (55%) (Benedict 2000; Brissart 2012; Chiaravalloti 2005; Fink 2010; Hildebrandt 2007; Jonsson 1993; Lincoln 2002; Mendoza 2001; Mäntynen 2013; Tesar 2005; Stuifbergen 2012) and mostly used for memory functions. Both external (calendar, diaries, notebooks, and lists) and internal (visualisation, logical content like story building, semantic categorisation and associations) memory strategies were used. Calendars and notebooks were also used in a wider context; for example calendars were used for planning everyday activities and notebooks for recording current needs. Building routines into behaviour and self control techniques were mentioned as compensatory strategies for attentional deficits, as were simplifying activities and visualisation for problem-solving and planning deficits. Furthermore, cognitive-behavioural and neuropsychotherapeutic methods were used to process cognitive and behavioural problems and to improve their management.

Two out of 20 interventions (10%) did not include cognitive training. The methods employed in these studies were a cognitive-behavioural intervention to reduce behavioural problems (Benedict 2000) and the use of notebooks to intensify the observation of institutionalised patients' needs (Mendoza 2001).

The target of the intervention was a single cognitive function in seven studies (35%) (Cerasa 2012; Chiaravalloti 2005; Fink 2010; Mäntynen 2013; Mendozzi 1998; Vogt 2008; Vogt 2009). The primary target was usually memory function, either alone or together with other functions. In 12 studies (60%) (Brissart 2012; Filippi 2012; Hildebrandt 2007; Jonsson 1993; Lincoln 2002; Mattioli 2010; Mattioli 2012a; Mendoza 2001; Shatil 2010; Solari 2004; Stuifbergen 2012; Tesar 2005) the target was several cognitive functions, mainly tailored to the patient's individual symptoms, while in Benedict 2000 the target of the intervention was behaviour regulation.

The reported number of intervention sessions in the studies varied from eight to 36 (mean 17) and the duration of each session from 25 minutes to two hours (mean one hour; sessions and their duration were not reported in all studies). The frequency of interventions varied from five times a week to twice per month (mean two times per week; frequency was not reported in all studies). The duration of the interventions varied from four weeks to six months (mean 9.5 weeks) and the entire follow-up time from immediate follow-up to one year (mean 25.3 weeks).

Of the research settings, 15 were comparative studies with two groups (75%). In three studies (Lincoln 2002; Mendozzi 1998; Vogt 2009) there were three study groups and in one study (Vogt 2008) four (intervention and control groups of MS patients and healthy controls). The control group received no intervention in 13 of the studies (Filippi 2012; Fink 2010; Hildebrandt 2007; Lincoln 2002; Mattioli 2010; Mattioli 2012a; Mendoza 2001; Mäntynen 2013; Shatil 2010; Stuifbergen 2012; Tesar 2005; Vogt 2008; Vogt 2009) and unspecific cognitive training in five of the studies (Cerasa 2012; Chiaravalloti 2005; Jonsson 1993; Mendozzi 1998; Solari 2004). Other control interventions were: supportive psychotherapy (n = 1; Benedict 2000), neuropsychological evaluation with feedback (n = 1; Lincoln 2002), discussion program (n = 1; Brissart 2012), an intervention programme for healthy controls (n = 1; Vogt 2008) and low-intensity distributed training (n = 1; Vogt 2009).

Outcomes

Cognitive tests were used as baseline measurements in all 20 studies. Detailed information about the outcome measures is given in the Characteristics of included studies table.

Cognitive tests were used as the outcome measures in most of the studies (90%, n = 18), except for Benedict 2000 and Lincoln 2002 where neuropsychological assessment was used only to document the similarity of the compared groups at the beginning of the study. Cognitive test results acted as the sole outcome measures only in two studies (Brissart 2012; Mendozzi 1998). Instead, it was more common that both cognitive tests and self rating questionnaires were used as outcome measures.

In most of the studies (70%) outcome was evaluated with self rating mood questionnaires (n = 14; Benedict 2000; Cerasa 2012; Chiaravalloti 2005; Hildebrandt 2007; Jonsson 1993; Mäntynen 2013; Mattioli 2010; Mattioli 2012a; Mendoza 2001; Shatil 2010; Solari 2004; Tesar 2005; Vogt 2008; Vogt 2009), of which the Beck Depression Inventory (BDI; Beck 1961) was the most commonly used (n = 8; Benedict 2000; Cerasa 2012; Chiaravalloti 2005; Hildebrandt 2007; Jonsson 1993; Mäntynen 2013; Mendoza 2001; Tesar 2005). In addition, other self report questionnaires were used, such as questionnaires on fatigue (n = 7; Cerasa 2012; Hildebrandt 2007; Mäntynen 2013; Shatil 2010; Tesar 2005; Vogt 2008; Vogt 2009), quality of life (n = 6; Hildebrandt 2007; Lincoln 2002; Mäntynen 2013; Mattioli 2010; Mattioli 2012a; Solari 2004), meta-cognition/subjectively experienced harmful effects of cognitive problems (n = 4; Chiaravalloti 2005; Lincoln 2002; Mäntynen 2013; Stuifbergen 2012), anxiety (n = 3; Cerasa 2012; Chiaravalloti 2005; Jonsson 1993), personality (n = 1; Benedict 2000) and behaviour disturbances (n = 1; Benedict 2000).

In three studies (Benedict 2000; Lincoln 2002; Mäntynen 2013) a caregiver evaluated the patient's social behaviour and personality, everyday memory and executive functions, as well as the caregiver's own mood. The cognitive tests and questionnaires used varied among the studies. The four most commonly used outcome measures in the original studies are specified in Table 3.

Table 3. Four most commonly used outcome measures in the 20 studies
  1. *Other outcome measures were also used in all studies.

Measure Number of studies (%)*
Paced Auditory Serial Addition Test (PASAT)10 (50%)
Symbol Digit Modalities Test (SDMT)10 (50%)
Controlled Oral Word Association Test9 (45%)
Beck Depression Inventory (BDI)8 (42%)

Only in three studies (Fink 2010; Mäntynen 2013; Solari 2004) were the primary outcome measures determined beforehand and separated from the secondary outcome measures.

In 11 out of 20 studies (55%), the outcome was measured immediately post-treatment (within a month post-treatment) without longitudinal follow-up, while in the remaining nine studies (45%)(Chiaravalloti 2005; Fink 2010; Jonsson 1993; Lincoln 2002; Mattioli 2012a; Mäntynen 2013; Solari 2004; Stuifbergen 2012; Tesar 2005) longitudinal follow-ups were employed and varied from 11 weeks to one year post-treatment (mean 25.3 weeks).

Excluded studies

Based on the full text, 58 studies were excluded. Reasons for exclusion are reported in the Characteristics of excluded studies table.

Risk of bias in included studies

See the 'Risk of bias' graph (Figure 2) and 'Risk of bias' summary (Figure 3).

Figure 2.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

The randomisation was adequate and unpredictable only in 35% of studies (n = 7) (Benedict 2000; Cerasa 2012; Jonsson 1993; Lincoln 2002; Mäntynen 2013; Solari 2004; Stuifbergen 2012). In these studies random number tables and a sealed opaque envelope system were used as randomisation and allocation concealment methods. In six of these studies (Cerasa 2012; Jonsson 1993; Lincoln 2002; Mäntynen 2013; Solari 2004; Stuifbergen 2012) the personnel who performed the randomisation process were not involved in the study itself. However, in most of the studies (65%), the randomisation procedure was inadequate and predictable (n = 13) (Brissart 2012; Chiaravalloti 2005; Fink 2010; Filippi 2012; Hildebrandt 2007; Mattioli 2010; Mattioli 2012a; Mendoza 2001; Mendozzi 1998; Shatil 2010; Tesar 2005; Vogt 2008; Vogt 2009); non-random components such as alternation, assignment to comparable groups with respect to clinical and demographic factors, and date of admission were used in the sequence generation processes.

Blinding

In most of the studies, the blinding of participants and personnel was not possible because of the characteristics of the interventions.

In 74% of studies the blinding of the participant was not successful or it remained unclear whether it had succeeded in practice (n = 15) (Benedict 2000; Filippi 2012; Hildebrandt 2007; Jonsson 1993; Mäntynen 2013; Lincoln 2002; Mattioli 2010; Mattioli 2012a; Mendoza 2001; Mendozzi 1998; Shatil 2010; Stuifbergen 2012; Tesar 2005; Vogt 2008; Vogt 2009).

The blinding of personnel was not successful or it was reported insufficiently in most of the studies (n = 16) (Benedict 2000; Brissart 2012; Cerasa 2012; Chiaravalloti 2005; Filippi 2012; Fink 2010; Jonsson 1993; Lincoln 2002; Mattioli 2010; Mattioli 2012a; Mendoza 2001; Mendozzi 1998; Mäntynen 2013; Solari 2004; Stuifbergen 2012; Tesar 2005). The blinding of personnel was judged to be successful only in those studies where training was carried out by the participant him/herself with a computer-aided program (Hildebrandt 2007; Shatil 2010; Vogt 2008; Vogt 2009).

The blinding of outcome assessors was slightly more successful, but it remained unclear or insufficient in 30% of the studies (n = 6) (Jonsson 1993; Mendoza 2001; Shatil 2010; Tesar 2005; Vogt 2008; Vogt 2009). However, only three studies (Jonsson 1993; Mäntynen 2013; Solari 2004) reported how the blinding of the assessor had succeeded in practice. 

Incomplete outcome data

In seven studies (35%), there were no losses to follow-up (Benedict 2000; Brissart 2012; Filippi 2012; Mattioli 2010; Mattioli 2012a; Vogt 2008; Vogt 2009). In nine studies (45%), the percentage of drop-outs and withdrawals was less than 20% (Cerasa 2012; Chiaravalloti 2005; Lincoln 2002; Mendoza 2001; Mendozzi 1998; Mäntynen 2013; Solari 2004; Stuifbergen 2012; Tesar 2005). In four studies (20%) the percentage of drop-outs and withdrawals exceeded 20% or was reported insufficiently (Fink 2010; Hildebrandt 2007; Jonsson 1993; Shatil 2010).

Selective reporting

In most of the studies (80%) we did not find indications of selective reporting: all intended outcome data were present for the intervention and control groups during the intervention and follow-up phases (n = 16) (Benedict 2000; Brissart 2012; Cerasa 2012; Chiaravalloti 2005; Filippi 2012; Hildebrandt 2007; Mattioli 2010; Mattioli 2012a; Mendozzi 1998; Mäntynen 2013; Shatil 2010; Solari 2004; Stuifbergen 2012; Tesar 2005; Vogt 2008; Vogt 2009). In 10% of studies, only some of the pre-specified outcome measures were reported (n = 2) (Fink 2010; Jonsson 1993). In one study (Lincoln 2002) cognitive tests were not included as outcome measures although the intervention was cognitive training and the target was cognitive rehabilitation. Consequently, we judged that results for some key outcomes were not reported. Moreover, in one study data for all outcome measures (cognitive tests) were not reported (Mendoza 2001).

Other potential sources of bias

We did not find any other sources of bias in 65% of the studies (n = 13) (Benedict 2000; Brissart 2012; Cerasa 2012; Filippi 2012; Jonsson 1993; Mattioli 2010; Mattioli 2012a; Mendozzi 1998; Mäntynen 2013; Tesar 2005; Stuifbergen 2012; Vogt 2008; Vogt 2009). However, in six studies (30%) the intervention and control groups were not similar at baseline or their similarity remained unclear for the most important prognostic indicators. Groups differed in demographic factors, such as age (Chiaravalloti 2005; Hildebrandt 2007; Mendoza 2001; Shatil 2010; Solari 2004) and gender (Hildebrandt 2007), or baseline characteristics were not reported in sufficient detail (Brissart 2012; Fink 2010). Furthermore, in one study compliance with the intervention was weak; only 46% of participants in the intervention group participated in the intervention as planned and this should be taken into account as a potential bias (Lincoln 2002).

Effects of interventions

See: Summary of findings for the main comparison Cognitive training versus any control for multiple sclerosis; Summary of findings 2 Cognitive training combined with other neuropsychological rehabilitation methods versus any control for multiple sclerosis

Eighteen of the 20 included studies showed some evidence of positive effects when the studies were individually analysed. In two studies (Lincoln 2002; Solari 2004) no significant effect of the intervention was reported.

Cognitive training versus any control

Nine original studies (Cerasa 2012; Filippi 2012; Mattioli 2010; Mattioli 2012a; Mendozzi 1998; Shatil 2010; Solari 2004; Vogt 2008; Vogt 2009) evaluated the effects of direct cognitive training. The target of the intervention was memory (Mendozzi 1998), working memory (Vogt 2008; Vogt 2009), memory and attention (Solari 2004), attention (Cerasa 2012), attention, information processing and executive functions (Filippi 2012; Mattioli 2010; Mattioli 2012a) and several cognitive functions based on the patient's individual neuropsychological symptoms (Shatil 2010). Six of the studies (Cerasa 2012; Mattioli 2010; Mendozzi 1998; Shatil 2010; Solari 2004; Vogt 2008) were included in the meta-analyses. The studies Filippi 2012 and Mattioli 2012a were related to Mattioli 2010, and Vogt 2009 was related to Vogt 2008. These three studies (Filippi 2012; Mattioli 2012a; Vogt 2009) were not included in the meta-analyses to avoid the duplication of the results.

Everyday cognitive performance was not evaluated by these studies.

Immediate post-intervention assessment
Primary outcomes

Analyses on the effects of cognitive training compared to any control (other intervention or no intervention) showed significant positive effects of cognitive training on memory span (standardised mean difference (SMD) fixed-effect 0.54, 95% confidence interval (CI) 0.20 to 0.88, P = 0.002, Analysis 1.3) and working memory (SMD fixed-effect 0.33, 95% CI 0.09 to 0.57, P = 0.006, Analysis 1.4). Cognitive training did not result in significant effects on attention (Analysis 1.1), information processing speed (Analysis 1.2), immediate verbal memory (Analysis 1.5), immediate visual memory (Analysis 1.6), delayed memory (Analysis 1.7), executive functions (Analysis 1.8) or verbal functions (Analysis 1.9). The corresponding funnel plot for attention (Figure 4) suggests possible publication bias, as there were two small positive studies but no small negative studies published (Higgins 2011). In other words, the two smaller, less precise studies were more positive than the larger, more precise studies.

Figure 4.

Funnel plot of comparison: 1 Cognitive training versus any control, outcome: 1.1 Attention.

Secondary outcomes

Analyses on the effects of cognitive training compared to any control showed no significant differences in depression (Analysis 1.10), quality of life (Analysis 1.11), fatigue (Analysis 1.12) or anxiety (Analysis 1.13).

Longitudinal assessment

Neither of the above reported analyses showed significant differences at long-term follow-up (16 weeks). See Analysis 2.1; Analysis 2.2; Analysis 2.3; Analysis 2.4; Analysis 2.5; Analysis 2.6 and Analysis 2.7.

Cognitive training combined with other neuropsychological rehabilitation methods versus any control

Nine original studies (Brissart 2012; Chiaravalloti 2005; Fink 2010; Hildebrandt 2007; Jonsson 1993; Lincoln 2002; Mäntynen 2013; Tesar 2005; Stuifbergen 2012) evaluated the effects of cognitive training combined with other neuropsychological methods. The interventions consisted of cognitive training and learning compensatory strategies. In these studies, the targets of the intervention were working memory, verbal learning, memory, attention, problem-solving skills and several cognitive functions. Eight studies (Brissart 2012; Chiaravalloti 2005; Fink 2010; Hildebrandt 2007; Lincoln 2002; Mäntynen 2013; Tesar 2005; Stuifbergen 2012) were included in the meta-analyses. The results of one study (Jonsson 1993) are reported in an additional table (Table 4), because data were not available in the appropriate format for meta-analyses.

Table 4. Results of the study Jonsson 1993
Study Main result Other results
Jonsson 1993

Immediate follow-up

Visual perception: the intervention group improved significantly compared to the control group (P < 0.004)

Beck Depression Inventory (BDI): the intervention group improved significantly compared to the control group (P < 0.04)

 

Longitudinal follow-up (6 months)

Visuospatial memory: the intervention group improved significantly compared to the control group (P = 0.05)

BDI: the intervention group improved significantly compared to the control group (P = 0.03)

Immediate follow-up

In most cognitive tests, improvement due to learning and unspecific treatment effects

Visuospatial memory: the intervention group improved compared to the control group (trend to significance P = 0.08)

Visuomotor speed: the control group improved compared to the intervention group (trend to significance P = 0.07)

State-Trait Anxiety Inventory (STAI): no change

 

Longitudinal follow-up (6 months)

Visual perception: the intervention group improved compared to the control group (trend to significance P = 0.09)

Sum of the 11 cognitive tests: the intervention group improved compared to the control group (trend to significance P = 0.09)

 

Immediate post-intervention assessment
Primary outcomes

Analyses on the effects of cognitive training combined with other neuropsychological rehabilitation methods compared to any control (other intervention or no intervention) showed significant positive effects only for attention (SMD fixed-effect 0.15, 95% CI 0.01 to 0.28, P = 0.03, Analysis 3.1), immediate verbal memory (SMD fixed-effect 0.31, 95% CI 0.08 to 0.54, P = 0.008, Analysis 3.5) and delayed memory (SMD fixed-effect 0.22, 95% CI 0.02 to 0.42, P = 0.03, Analysis 3.7). The corresponding funnel plot for attention (Figure 5) did not suggest relevant publication bias. Cognitive training combined with other neuropsychological rehabilitation methods did not result in significant effects on information processing speed (Analysis 3.2), memory span (Analysis 3.3), working memory (Analysis 3.4), immediate visual memory (Analysis 3.6), executive functions (Analysis 3.8), visual functions (Analysis 3.9), or verbal functions (Analysis 3.10).

Figure 5.

Funnel plot of comparison: 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, outcome: 3.1 Attention.

Analyses on the effects of cognitive training combined with other neuropsychological rehabilitation methods compared to any control showed no significant differences for patient's (Analysis 3.11) or carer's (Analysis 3.12) reported everyday cognitive performance.

Secondary outcomes

Analyses on the effects of cognitive training combined with other neuropsychological rehabilitation methods compared to any control showed no significant differences for depression (Analysis 3.13), quality of life (Analysis 3.14), fatigue (Analysis 3.15), anxiety (Analysis 3.16) or impact of the disease (Analysis 3.17). The other secondary outcome, personality disturbance, was not evaluated in these studies.

Longitudinal assessment

The same analyses at long-term follow-up (mean 25.3, range 11 to 52 weeks) showed significant positive effects of cognitive training combined with other neuropsychological rehabilitation methods on immediate visual memory (SMD fixed-effect 0.35, 95% CI 0.05 to 0.65, P = 0.02, Analysis 4.5) and delayed memory (SMD fixed-effect 0.32, 95% CI 0.10 to 0.55, P = 0.005, Analysis 4.6). Effects on other outcomes were not significant. See Analysis 4.1; Analysis 4.2; Analysis 4.3; Analysis 4.4; Analysis 4.7; Analysis 4.8; Analysis 4.9; Analysis 4.10; Analysis 4.11; Analysis 4.12; Analysis 4.13; Analysis 4.14; Analysis 4.15 and Analysis 4.16. The corresponding funnel plot for attention (Figure 6) suggests possible publication bias, as there was one small negative study, but no small positive studies published (Higgins 2011).

Figure 6.

Funnel plot of comparison: 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), outcome: 4.1 Attention.

Multimodal neuropsychological rehabilitation   

Two studies (Benedict 2000; Mendoza 2001) evaluated the effects of multimodal neuropsychological rehabilitation. In Benedict 2000, the target of the intervention was behavioural problems, while in Mendoza 2001 the use of a notebook was exploited in order to intensify the observation of the actual needs of institutionalised patients. In these studies interventions were not similar enough for the results to be pooled. Thus, we used narrative presentation to report the main results of these studies in an additional table (Table 5).

Table 5. Results of the studies of Benedict 2000 and Mendoza 2001
Study Main result Other results
Benedict 2000Modified Social Aggression Scale: the intervention group improved significantly compared to the control group (P < 0.001)

Beck Depression Inventory (BDI): both groups showed modest improvement (not statistically significant); change scores did not differ between groups

Hogan Empathy Scale (HES), NEO-Personality Inventory (NEO-PI): no change

Mendoza 2001Beck Depression Inventory (BDI): significant improvement in the intervention group compared to the control group (P < 0.001)

Activity level: participants in the intervention group participated more often in voluntary unit activities than did participants in the control group (trend to significance P < 0.06)

Cognitive functions: no change

Sensitivity analyses

Exclusion of studies in which concealment of allocation had been inadequate resulted in the exclusion of four studies (Mattioli 2010; Mendozzi 1998; Shatil 2010; Vogt 2008) and thus only two studies (Cerasa 2012; Solari 2004) were included in meta-analysis evaluating the effects of cognitive training. In studies evaluating the effects of cognitive training combined with other neuropsychological rehabilitation methods five studies (Brissart 2012; Chiaravalloti 2005; Fink 2010; Hildebrandt 2007; Tesar 2005) were excluded and only three studies (Lincoln 2002; Mäntynen 2013; Stuifbergen 2012) were included in the meta-analysis. None of these analyses showed significant effects.

Exclusion of studies in which outcome evaluation was not blinded or blinding remained unclear resulted in the exclusion of two studies (Shatil 2010; Vogt 2008) and the inclusion of four studies (Cerasa 2012; Mattioli 2010; Mendozzi 1998; Solari 2004) in the meta-analysis evaluating the effects of cognitive training. Analysis revealed significant positive effects of cognitive training on memory span (SMD fixed-effect 0.63, 95% CI 0.24 to 1.02, P = 0.001) and executive functions (MD fixed-effect 22.3, 95% CI 6.16 to 38.44, P = 0.007). In studies evaluating the effects of cognitive training combined with other neuropsychological rehabilitation methods one study (Tesar 2005) was excluded and seven studies (Brissart 2012; Chiaravalloti 2005; Fink 2010; Hildebrandt 2007; Lincoln 2002; Mäntynen 2013; Stuifbergen 2012) were included in the meta-analysis. Analysis revealed significant positive effects of cognitive training combined with other neuropsychological rehabilitation methods on attention (SMD fixed-effect 0.15, 95% CI 0.01 to 0.28, P = 0.03) and immediate verbal memory (SMD fixed-effect 0.31, 95% CI 0.07 to 0.55, P = 0.01).

Exclusion of studies in which loss to follow-up remained unclear or was greater than 20% resulted in the exclusion of one study (Shatil 2010) and the inclusion of five studies (Cerasa 2012; Mattioli 2010; Mendozzi 1998; Solari 2004; Vogt 2008) in the meta-analysis evaluating the effects of cognitive training. Analysis revealed significant positive effects of cognitive training on executive functions (MD fixed-effect 22.30, 95% CI 6.16 to 38.44, P = 0.007). In studies evaluating the effects of cognitive training combined with other neuropsychological rehabilitation methods two studies (Fink 2010; Hildebrandt 2007) were excluded and five studies (Brissart 2012; Chiaravalloti 2005; Lincoln 2002; Mäntynen 2013; Tesar 2005) were included in the meta-analysis. Analysis revealed significant positive effects of cognitive training combined with other neuropsychological rehabilitation methods on attention (SMD fixed-effect 0.15, 95% CI 0.01 to 0.29, P = 0.04) and immediate verbal memory (SMD fixed-effect 0.28, 95% CI 0.01 to 0.54, P = 0.04).

Discussion

Summary of main results

This review evaluated the effects of neuropsychological rehabilitation on MS based on randomised and quasi-randomised controlled trials. Twenty studies were identified in a comprehensive and systematic literature search and analysis, the sample consisting of a total of 966 MS participants.

The review indicates that cognitive training improves memory span and working memory (see Summary of findings for the main comparison). However, although cognitive training showed significant effects on subcategories of cognitive performance, the majority of comparisons yielded no significant results.

Cognitive training combined with other neuropsychological methods was found to improve attention, immediate verbal memory and delayed memory (see Summary of findings 2). In longitudinal follow-up, positive effects of cognitive training combined with other neuropsychological rehabilitation methods were found for immediate visual memory and delayed memory.

There was no evidence of an effect of cognitive training or cognitive training combined with other neuropsychological rehabilitation methods on everyday cognitive functions, mood, fatigue, personality, anxiety or quality of life. However, although the pooled results in the meta-analyses yielded no significant findings, 18 out of the 20 studies showed positive effects when the results were individually evaluated. When interpreting the results, it must be taken into account that the cognitive training was mostly performed using computer-aided programs.

The sensitivity analyses showed that exclusion of studies where concealment of allocation was not adequate resulted in the loss of the majority of data and consequent analyses. Exclusion of studies where outcome evaluation was not blinded or where data lost at follow-up was remarkable did not result in any significant changes to the results of the analyses.

Overall completeness and applicability of evidence

Population, interventions and outcome measures in the studies

Population

The disease course, severity and duration, as well as the cognitive status of the MS patients in the included studies were heterogeneous. Over one-third of the studies (35%, n = 7) included MS patients despite their normal cognitive status. The primary aim of rehabilitation is to reduce existing symptoms or to support the management of them, so it is not meaningful to include patients without any cognitive problems. When including patients both with and without cognitive impairments, evaluation of the effectiveness of rehabilitation can be distorted. However, most of the studies (65%, n = 13) included only MS participants with either self reported or documented cognitive impairment, or both. When relying only on self reports, it should be taken into account that MS patients' self reports of their cognitive performance can be unreliable, a fact that has been noticed in many previous studies (e.g. Benedict 2003; Carone 2005; Sherman 2007).

In the studies, MS participants were mainly handled as a single group without dividing them into cognitively more homogeneous subgroups. This may also distort and flatten the results, because the effects of the neuropsychological intervention are probably different in patients with different severities of cognitive impairment. Consequently, different kinds of rehabilitation procedures may be needed for them. Only in one study (and even then not until afterwards) were the results of the intervention inspected separately in patients with mild and moderate/severe cognitive impairment (Chiaravalloti 2005). The intervention was found to be especially effective when memory deficits were moderate to severe.

Interventions

The interventions differed in all the studies included in the review. Moreover, the duration and frequency of the interventions varied significantly. In addition to heterogeneity between the studies, within-study variation also occurred. Jonsson (Jonsson 1993), Lincoln (Lincoln 2002) and Tesar (Tesar 2005) tailored the interventions according to each patient's individual symptoms. Therefore, standardisation and direct comparison of the interventions was not possible. However, two subgroups of intervention types could be created: cognitive training and cognitive training combined with other neuropsychological rehabilitation methods, for example teaching compensatory strategies. This variability also reflects the everyday reality of clinical practice; due to the heterogeneity of MS patients' neuropsychological symptoms, rehabilitation has to be tailored individually to each patient's needs. However, research settings usually focus only on specific rehabilitation methods because these can be precisely described. These kinds of study settings are not necessarily able to take into account a patient's individual needs and are not necessarily based on neuropsychological examination. Therefore, both the research settings and also the meta-analyses conducted may ignore the individual nature of neuropsychological rehabilitation and thus flatten the results. Additionally, in some studies (Brissart 2012; Benedict 2000; Cerasa 2012; Chiaravalloti 2005; Fink 2010; Jonsson 1993; Mendozzi 1998; Solari 2004) cognitive training was compared to other active treatments (e.g. specific versus unspecific cognitive training), thus masking potentially beneficial effects. When unspecific cognitive training is used as a control intervention, it should be taken into account that these tasks may partly promote the same functions as specific training. Although cognitive functions are theoretically distinguishable, they are highly complex, modular and interactive systems.

The number of intervention sessions varied from eight to 36, the duration of the rehabilitation intervention from four weeks to six months, and the frequency from two times per month to five times per week. When analysing the results with regard to the number of sessions, duration and frequency, no definite conclusions can be drawn about the effect of these factors on rehabilitation outcomes.

Outcome measures

Careful selection of outcome measures is essential because elicitation of treatment effects is naturally only possible for the factors covered by the outcome measures. Effects not evaluated by the measurements remain undocumented even if they have occurred. Cognitive tests and various questionnaires were most often used as outcome measures in the included studies. Outcome measures were mainly commonly known, validated methods. However, both the cognitive tests and the questionnaires used varied considerably between studies. The most commonly used, in 50% of studies (n = 10), were the Paced Auditory Serial Addition Test (PASAT) and the Symbol Digit Modalities Test (SDMT). The Beck Depression Inventory (BDI) was used in 40% of studies (n = 8), three of them showing a positive response to rehabilitation. However, it should be taken into account that the BDI was not originally designed to be used to show the effects of rehabilitation but to evaluate the severity of depressive symptoms (Beck 1961).

Because of the variety in the nature and aims of the neuropsychological interventions, it is only natural that a diversity of outcome measures was used. However, with multiple significance testing, the risk of making a type one error increases. In other words, there is a risk of incorrectly concluding that the intervention has had an effect. The use of a Bonferroni adjusted critical significance level can partly reduce this risk, but none of the studies adopted this method. Furthermore, the reliability of the findings can be lost if similar methods are used as training material and as outcome measures. For future meta-analyses, it would be beneficial if greater consensus could be achieved regarding the selection of standardised measures for use in outcome evaluation.

Outcome measures should be focused on the functions targeted by rehabilitation so that the effects of the intervention programme can be realistically evaluated. Only three studies (Fink 2010; Mäntynen 2013; Solari 2004) separately specified the primary outcome measure and other secondary measures. Prior definition of one or two primary outcome measures could reduce the statistical problems of multiple comparisons and make the primary findings of the study more transparent.

When evaluating the effects of a rehabilitation intervention, the aim should be to use outcomes which also measure, in addition to the severity of a symptom, its effects on everyday activities and how the patient copes with the symptom or problem. This is especially relevant for the progressive stage of disease. It is questionable whether changes in cognitive test performance also reflects real changes in everyday functions, when rehabilitation is based on individual aims relating to everyday functions (Wilson 2008). Even in studies in which the main aim of the intervention is to teach compensatory strategies, the real benefits of the intervention do not necessarily become evident when using outcome measures that do not reflect the use of such strategies (Cicerone 2000). Ideally, outcome measures should reflect meaningful functional improvements such as the use of compensatory strategies to fulfil real-life demands, performance in everyday activities, changes in level of productivity or measures of subjective well-being (Cicerone 2000).

The studies included in the present review were heterogeneous. Differences were obvious in the course and severity of the disease, as well as in the content, frequency, duration, setting and aim of the intervention, the outcome measures, the way of reporting the results and in the methodological quality of the studies. Because of this heterogeneity, it was not possible to pool the whole data set quantitatively with a meta-analysis. Meta-analysis was found to be appropriate in two subgroups: 1) studies comparing cognitive training versus any control and 2) studies comparing cognitive training combined with other neuropsychological rehabilitation methods versus any control.

Quality of the evidence

The quality of the evidence for most of the outcomes was low or very low (see Summary of findings for the main comparison and Summary of findings 2). The strength of the findings of our review is limited due to the small sample sizes and methodological weaknesses of most of the studies. However, we did not exclude studies due to their low quality because the sample was already small. Instead, we evaluated the risk of bias of each study and the quality of the evidence. This enables us to report limited evidence based on lower-quality studies which, however, is the best evidence available at the present time.

Most studies with two groups employed inappropriate randomisation methods. In these situations, the possible difference between the groups may be due to the biased selection of patients for the groups. Moreover, in several studies, the fact that the methods applied were not described in sufficient detail hampered our 'Risk of bias' assessment. However, in the most recent studies it seems that quality has slightly improved and randomisation and allocation concealment have been more successful.

The blinding of therapists or patients is usually not possible in research settings evaluating the effectiveness of rehabilitation due to the nature of the interventions. These deficiencies in blinding were also the most commonly occurring deficiencies in the evaluated research settings. However, blinding of the assessor or the person interpreting the results may be possible, and this can partly reduce the possibility of bias. This was slightly better realised in the studies, although only a single study reported how the blinding of the assessor was actually achieved. The quality domains best met in the included studies were incomplete outcome data and selective reporting, with only few studies failing to report appropriately.

Comprehensive 'Risk of bias' (e.g. The Cochrane Collaboration's 'Risk of bias' assessment tool, Higgins 2011)) and quality assessment criteria (e.g. Van Tulder 2003) can act as a guide when constructing research settings. If the criteria for a high-quality study are taken into account in the planning of a study, the basis for a successful and effective study can be created. Fulfilling all the criteria is almost impossible with neuropsychological interventions, because the treatment is based on interaction between patients and healthcare professionals (e.g. the blinding of patient and therapist is rarely possible, unlike in studies of the effects of medications). Although it may be difficult to apply the existing quality criteria to studies on the effects of rehabilitation, it is nonetheless better to operate according to some consistent criteria than without any guidelines.

Potential biases in the review process

We attempted to reduce bias in the review process by performing a comprehensive search and ensuring that two independent authors judged the relevance, risk of bias and content of the included studies. Although our search was comprehensive and we included studies identified in languages other than English, we cannot rule out the possibility that some studies have been missed. The possibility of publication bias may also have been increased by the fact that relevant studies with unclear or negative results may have remain unpublished.

To be able to create a meaningful summary of numerous separate cognitive variables and to evaluate the effects of neuropsychological rehabilitation on cognitive domains, we classified the cognitive tests employed in the included studies into cognitive domains according to the functions they are traditionally used to measure (Lezak 2004). However, although the classification was based on a theoretical background, every classification is artificial and imperfect because cognitive tests are highly multifactorial and evaluate several cognitive functions. For the meta-analyses, we used test scores observed at the end of treatment. Thus, the results describe a clinical profile observed at a specific time point instead of a change observed after the intervention. It cannot be ruled out that possible baseline imbalances may have partly affected the results.

Additionally, both authors of the review acted as authors in one of the evaluated studies (Mäntynen 2013).

Agreements and disagreements with other studies or reviews

There are three previous systematic reviews evaluating the effects of neuropsychological rehabilitation in MS. In the Cochrane review by Thomas et al (Thomas 2006), the effects of psychological interventions in MS were evaluated based on the evidence from 16 randomised controlled trials (RCTs). However, only five of these trials were of neuropsychological interventions and therefore the review did not comprehensively cover the literature on neuropsychological rehabilitation. This review concluded that there is some, although unclear, evidence for the effects of cognitive rehabilitation in MS. It was noted that the large number of outcome measures and small sample sizes hampered the interpretation.

In the review of O'Brien et al (O'Brien 2008), the effects of cognitive rehabilitation in MS were evaluated based on the evidence from 16 trials (four RCTs, five controlled clinical trials (CCTs) and seven uncontrolled studies). According to the conclusions of this review, for MS patients' verbal memory and learning, two rehabilitation methods can be recommended: 1) the story memory technique and 2) self generation (self generating/modifying the memorised material). According to this review, there is preliminary evidence, but it is not sufficient to make any recommendations about the effects of rehabilitation on attention and executive functions and general cognitive rehabilitation. In all, according to this review, cognitive rehabilitation in MS is in its infancy and more research is needed.

In the Cochrane review of das Nair et al (das Nair 2012a), the effects of memory rehabilitation in MS were evaluated based on the evidence from eight RCTs. This review did not find evidence to support the effectiveness of memory rehabilitation on memory function or functional abilities in patients with MS. However, this conclusion was arrived at because of the limited quality of some of the primary studies. According to this review further, robust RCTs of higher methodological quality are needed.

According to the present review there are preliminary positive findings for the effects of neuropsychological rehabilitation in MS. In line with the findings of the review of O'Brien et al (O'Brien 2008) our review indicates that cognitive training can in particular improve memory functions in addition to attention, while for other cognitive functions (information processing speed, executive, verbal and visual functions) no significant evidence of an effect was found. It should, however, be noted that none of the studies specifically aimed to improve those functions alone. Furthermore, consistent with previous reviews, the present review highlights the need for high-quality studies on the topic. The contradictory findings of our review and the review of das Nair et al (das Nair 2012a) may be related to the different inclusion criteria for studies as well as the fact that more original studies were included in our review.

Authors' conclusions

Implications for practice

This review found low-level evidence for the positive effects of neuropsychological rehabilitation in MS. The interventions and the outcome measures included in the review were heterogeneous and consequently clinical inferences can only be drawn from single studies. New trials may therefore change the strength and direction of the evidence. Decisions about neuropsychological rehabilitation for MS patients have to be based on theoretical and empirical knowledge in addition to research evidence.

Implications for research

This review raises concerns about the quality of the included studies which evaluated the effects of neuropsychological rehabilitation in MS. In further studies it is important to include an objective baseline assessment of the cognitive status of patients and to evaluate the effects of the intervention in a sufficiently large group of cognitively homogeneous patients. Furthermore, the course and severity of the disease and other relevant disease variables should be clearly reported in the studies. This could offer important extra information about which MS participants benefit most from rehabilitation and to which patient populations the results may be generalised, thus helping to focus limited resources on those who need and could benefit from the interventions.

The interventions should be reported in detail to enable more accurate evaluation and repetition. Additionally, a clear aim for the interventions should be defined beforehand. The primary outcome measure should assess whether the predefined aim of the intervention has been realised; in specific cognitive training this could be, for example, a few central cognitive variables targeted by the intervention. Alternatively, different questionnaires (mood, fatigue, meta-cognition etc.) can act as primary measures of more multimodal cognitive rehabilitation, depending on the targets of the intervention. One method could be to define the individual aim and to measure it using a scale such as Goal Attainment Scaling (GAS), for example. Furthermore, basic statistical information with exact numerical information and timing of assessment should also be reported for all outcome measures. Future studies should include measures for evaluating more extensive functional capacity and, in this way, possibly uncover the generalised effects on the patient's everyday functions. In addition to general measures, methods to enable us to measure the achievement of individual aims relating to everyday functions are needed. Future studies should also aim for longer follow-ups to determine the longer-lasting effects of rehabilitation interventions.

On the basis of the results of the current review, the actions specified in Table 6 are recommended to improve the quality of future studies. It should be kept in mind, however, that the currently widely used quality criteria (such as The Cochrane Collaboration's 'Risk of bias' tool (Higgins 2011) and those of Van Tulder et al (Van Tulder 2003)) are somewhat problematic in the evaluation of psychological interventions. For example, the blinding of patients and therapists is rarely possible. In future, the aim should be to modify the criteria to serve the research needs better and to raise the quality of psychological intervention studies. Regardless of the criteria used, unifying the assessment and reporting practices for establishing the effectiveness of interventions can be regarded as a gold standard. It is impossible to collect and analyse research evidence and conduct meta-analyses if the general recommendations for high-quality studies are not followed. More recent studies appear to have succeeded better than earlier studies in taking into account these quality criteria. One reason for this might be the fact that systematic reviews have made these criteria more visible and thus highlighted their importance.

Table 6. Recommendations for future studies of neuropsychological rehabilitation
No Recommendation
1The use of comprehensive risk of bias (e.g. Higgins 2011) or quality assessment criteria (e.g. Van Tulder 2003) as guiding principles in preparing the research designs
2Detailed reporting of the methods applied in the study (e.g. flow charts including exact number of patients)
3Sufficient sample sizes
4Objective baseline assessment of the cognitive status of the patients
5Evaluation of treatment effects in cognitively homogeneous groups
6Detailed reporting of the most essential disease variables
7Determination of the aim of the intervention beforehand and measuring it with the primary measure
8Detailed reporting of the content of the interventions
9Detailed reporting of the basic statistics and outcome assessment timing
10The use of outcome measures which more extensively reflect everyday functioning and the generalised effects of the interventions, thus enabling assessment of whether individual rehabilitation aims related to everyday functions have been achieved 
11Longitudinal follow-ups to evaluate the permanence of the treatment effects

Acknowledgements

We thank the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group for their help and technical support in preparing the review.

Data and analyses

Download statistical data

Comparison 1. Cognitive training versus any control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Attention5573Std. Mean Difference (IV, Fixed, 95% CI)0.06 [-0.10, 0.23]
1.1 Paced Auditory Serial Addition Test 2'297Std. Mean Difference (IV, Fixed, 95% CI)0.03 [-0.38, 0.44]
1.2 Paced Auditory Serial Addition Test 3'373Std. Mean Difference (IV, Fixed, 95% CI)0.35 [-0.12, 0.82]
1.3 Symbol Digit Modalities Test4150Std. Mean Difference (IV, Fixed, 95% CI)0.02 [-0.30, 0.34]
1.4 Divided attention146Std. Mean Difference (IV, Fixed, 95% CI)-0.05 [-0.63, 0.53]
1.5 Avoiding distractions146Std. Mean Difference (IV, Fixed, 95% CI)-0.05 [-0.63, 0.53]
1.6 Inhibition146Std. Mean Difference (IV, Fixed, 95% CI)0.23 [-0.35, 0.81]
1.7 Shifting attention146Std. Mean Difference (IV, Fixed, 95% CI)-0.14 [-0.72, 0.44]
1.8 Trail Making A123Std. Mean Difference (IV, Fixed, 95% CI)-0.28 [-1.10, 0.54]
1.9 Trail Making B123Std. Mean Difference (IV, Fixed, 95% CI)0.01 [-0.81, 0.82]
1.10 Stroop/colour-word123Std. Mean Difference (IV, Fixed, 95% CI)0.54 [-0.29, 1.38]
2 Information processing speed4176Std. Mean Difference (IV, Random, 95% CI)0.15 [-0.33, 0.62]
2.1 Signal detection time/reaction time(s)160Std. Mean Difference (IV, Random, 95% CI)0.80 [0.24, 1.36]
2.2 Response time146Std. Mean Difference (IV, Random, 95% CI)0.17 [-0.41, 0.75]
2.3 2-back (reaction time)130Std. Mean Difference (IV, Random, 95% CI)-0.02 [-0.74, 0.69]
2.4 Test of Everyday Attention (median for auditory stimulus)120Std. Mean Difference (IV, Random, 95% CI)-0.77 [-1.68, 0.15]
2.5 Test of Everyday Attention (median for visual stimulus)120Std. Mean Difference (IV, Random, 95% CI)0.21 [-0.67, 1.09]
3 Memory span2150Std. Mean Difference (IV, Fixed, 95% CI)0.54 [0.20, 0.88]
3.1 Corsi blocks forward290Std. Mean Difference (IV, Fixed, 95% CI)0.55 [0.11, 0.99]
3.2 Digit span forward160Std. Mean Difference (IV, Fixed, 95% CI)0.52 [-0.02, 1.07]
4 Working memory3288Std. Mean Difference (IV, Fixed, 95% CI)0.33 [0.09, 0.57]
4.1 2-back (numbers correct)130Std. Mean Difference (IV, Fixed, 95% CI)-0.05 [-0.76, 0.67]
4.2 Digit span backward290Std. Mean Difference (IV, Fixed, 95% CI)0.34 [-0.09, 0.78]
4.3 Corsi blocks backward130Std. Mean Difference (IV, Fixed, 95% CI)0.38 [-0.34, 1.10]
4.4 Verbal auditory working memory146Std. Mean Difference (IV, Fixed, 95% CI)0.59 [0.00, 1.19]
4.5 Visual working memory146Std. Mean Difference (IV, Fixed, 95% CI)0.52 [-0.07, 1.11]
4.6 Auditory working memory146Std. Mean Difference (IV, Fixed, 95% CI)0.08 [-0.50, 0.66]
5 Immediate verbal memory4360Std. Mean Difference (IV, Fixed, 95% CI)0.20 [-0.02, 0.41]
5.1 Buschke Selective Reminding Test (consistent long-term retrieval)3120Std. Mean Difference (IV, Fixed, 95% CI)0.26 [-0.10, 0.63]
5.2 Wechsler Memory Scale/logical memory160Std. Mean Difference (IV, Fixed, 95% CI)-0.08 [-0.62, 0.46]
5.3 Wechsler Memory Scale/verbal paired associations (easy)160Std. Mean Difference (IV, Fixed, 95% CI)0.29 [-0.25, 0.83]
5.4 Wechsler Memory Scale/verbal paired associations (hard)160Std. Mean Difference (IV, Fixed, 95% CI)0.31 [-0.23, 0.85]
5.5 Memory scale of the Luria-Nebraska Neuropsychological Battery160Std. Mean Difference (IV, Fixed, 95% CI)0.11 [-0.43, 0.65]
6 Immediate visual memory5270Std. Mean Difference (IV, Random, 95% CI)0.14 [-0.30, 0.58]
6.1 Recognition memory (Corsi)160Std. Mean Difference (IV, Random, 95% CI)0.36 [-0.18, 0.91]
6.2 Wechsler Memory Scale/visual reproduction160Std. Mean Difference (IV, Random, 95% CI)0.79 [0.23, 1.34]
6.3 10/36 Spatial Recall Test (immediate recall)3120Std. Mean Difference (IV, Random, 95% CI)-0.20 [-0.94, 0.54]
6.4 Faces Symbol Test130Std. Mean Difference (IV, Random, 95% CI)0.06 [-0.66, 0.77]
7 Delayed memory3240Std. Mean Difference (IV, Fixed, 95% CI)-0.19 [-0.45, 0.07]
7.1 Buschke Selective Reminding Test (delayed recall)3120Std. Mean Difference (IV, Fixed, 95% CI)-0.07 [-0.43, 0.29]
7.2 10/36 Spatial Recall Test (delayed recall)3120Std. Mean Difference (IV, Fixed, 95% CI)-0.31 [-0.68, 0.05]
8 Executive functions2112Std. Mean Difference (IV, Fixed, 95% CI)0.35 [-0.03, 0.73]
8.1 Wisconsin Card Sorting Test (total errors)120Std. Mean Difference (IV, Fixed, 95% CI)1.16 [0.20, 2.12]
8.2 Planning146Std. Mean Difference (IV, Fixed, 95% CI)0.08 [-0.50, 0.66]
8.3 Time estimation146Std. Mean Difference (IV, Fixed, 95% CI)0.33 [-0.25, 0.91]
9 Verbal functions4186Std. Mean Difference (IV, Fixed, 95% CI)0.20 [-0.09, 0.49]
9.1 Naming146Std. Mean Difference (IV, Fixed, 95% CI)0.19 [-0.39, 0.77]
9.2 Controlled Oral Word Association Test (phonemic)297Std. Mean Difference (IV, Fixed, 95% CI)0.21 [-0.19, 0.61]
9.3 Controlled Oral Word Association Test (semantic)243Std. Mean Difference (IV, Fixed, 95% CI)0.20 [-0.40, 0.80]
10 Depression5196Std. Mean Difference (IV, Random, 95% CI)0.26 [-0.23, 0.75]
10.1 Montgomery-Asberg Depression Rating Scale120Std. Mean Difference (IV, Random, 95% CI)1.27 [0.29, 2.24]
10.2 Chicago Mood Depression Inventory177Std. Mean Difference (IV, Random, 95% CI)0.0 [-0.45, 0.45]
10.3 Allgemeine Depressionskala130Std. Mean Difference (IV, Random, 95% CI)0.05 [-0.66, 0.77]
10.4 Zung Depression Scale146Std. Mean Difference (IV, Random, 95% CI)-0.31 [-0.89, 0.27]
10.5 Beck Depression Inventory II123Std. Mean Difference (IV, Random, 95% CI)0.85 [-0.01, 1.71]
11 Quality of life3127Std. Mean Difference (IV, Fixed, 95% CI)0.26 [-0.09, 0.61]
11.1 Multiple Sclerosis Quality of Life120Std. Mean Difference (IV, Fixed, 95% CI)0.47 [-0.42, 1.36]
11.2 Functional Assessment of MS130Std. Mean Difference (IV, Fixed, 95% CI)-0.13 [-0.84, 0.59]
11.3 54-item MS Quality of Life Questionnaire/mental health composite177Std. Mean Difference (IV, Fixed, 95% CI)0.36 [-0.09, 0.81]
12 Fatigue3129Std. Mean Difference (IV, Fixed, 95% CI)0.13 [-0.22, 0.48]
12.1 Fatigue Scale for Motor and Cognitive functions130Std. Mean Difference (IV, Fixed, 95% CI)0.18 [-0.54, 0.90]
12.2 Modified Fatigue Impact Scale130Std. Mean Difference (IV, Fixed, 95% CI)0.19 [-0.53, 0.91]
12.3 Fatigue Severity Scale/raw score146Std. Mean Difference (IV, Fixed, 95% CI)-0.25 [-0.83, 0.33]
12.4 Fatigue Severity Scale/delta score123Std. Mean Difference (IV, Fixed, 95% CI)0.79 [-0.07, 1.64]
13 Anxiety123Mean Difference (IV, Fixed, 95% CI)4.40 [-3.87, 12.67]
13.1 State Trait Anxiety Inventory123Mean Difference (IV, Fixed, 95% CI)4.40 [-3.87, 12.67]
Analysis 1.1.

Comparison 1 Cognitive training versus any control, Outcome 1 Attention.

Analysis 1.2.

Comparison 1 Cognitive training versus any control, Outcome 2 Information processing speed.

Analysis 1.3.

Comparison 1 Cognitive training versus any control, Outcome 3 Memory span.

Analysis 1.4.

Comparison 1 Cognitive training versus any control, Outcome 4 Working memory.

Analysis 1.5.

Comparison 1 Cognitive training versus any control, Outcome 5 Immediate verbal memory.

Analysis 1.6.

Comparison 1 Cognitive training versus any control, Outcome 6 Immediate visual memory.

Analysis 1.7.

Comparison 1 Cognitive training versus any control, Outcome 7 Delayed memory.

Analysis 1.8.

Comparison 1 Cognitive training versus any control, Outcome 8 Executive functions.

Analysis 1.9.

Comparison 1 Cognitive training versus any control, Outcome 9 Verbal functions.

Analysis 1.10.

Comparison 1 Cognitive training versus any control, Outcome 10 Depression.

Analysis 1.11.

Comparison 1 Cognitive training versus any control, Outcome 11 Quality of life.

Analysis 1.12.

Comparison 1 Cognitive training versus any control, Outcome 12 Fatigue.

Analysis 1.13.

Comparison 1 Cognitive training versus any control, Outcome 13 Anxiety.

Comparison 2. Cognitive training versus any control (longitudinal follow-up)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Attention1154Std. Mean Difference (IV, Fixed, 95% CI)-0.22 [-0.54, 0.10]
1.1 Paced Auditory Serial Addition Test 2'177Std. Mean Difference (IV, Fixed, 95% CI)-0.38 [-0.83, 0.07]
1.2 Symbol Digit Modalities Test177Std. Mean Difference (IV, Fixed, 95% CI)-0.06 [-0.51, 0.39]
2 Immediate verbal memory177Mean Difference (IV, Fixed, 95% CI)-0.30 [-17.77, 17.17]
2.1 Buschke Selective Reminding Test/consistent long-term retrieval177Mean Difference (IV, Fixed, 95% CI)-0.30 [-17.77, 17.17]
3 Immediate visual memory177Mean Difference (IV, Fixed, 95% CI)-1.20 [-4.86, 2.46]
3.1 10/36 Spatial Recall Test/immediate recall177Mean Difference (IV, Fixed, 95% CI)-1.20 [-4.86, 2.46]
4 Delayed memory1154Std. Mean Difference (IV, Fixed, 95% CI)-0.30 [-0.62, 0.02]
4.1 Buschke Selective Reminding Test/delayed recall177Std. Mean Difference (IV, Fixed, 95% CI)-0.30 [-0.75, 0.15]
4.2 10/36 Spatial Recall Test/delayed recall177Std. Mean Difference (IV, Fixed, 95% CI)-0.30 [-0.75, 0.15]
5 Verbal functions177Mean Difference (IV, Fixed, 95% CI)2.10 [-1.87, 6.07]
5.1 Controlled Oral Word Association Test (phonemic)177Mean Difference (IV, Fixed, 95% CI)2.10 [-1.87, 6.07]
6 Depression177Mean Difference (IV, Fixed, 95% CI)-0.40 [-5.16, 4.36]
6.1 Chicago Mood Depression Inventory177Mean Difference (IV, Fixed, 95% CI)-0.40 [-5.16, 4.36]
7 Quality of life177Mean Difference (IV, Fixed, 95% CI)-9.40 [-28.38, 9.58]
7.1 54-item MS Quality of Life Questionnaire/mental health composite177Mean Difference (IV, Fixed, 95% CI)-9.40 [-28.38, 9.58]
Analysis 2.1.

Comparison 2 Cognitive training versus any control (longitudinal follow-up), Outcome 1 Attention.

Analysis 2.2.

Comparison 2 Cognitive training versus any control (longitudinal follow-up), Outcome 2 Immediate verbal memory.

Analysis 2.3.

Comparison 2 Cognitive training versus any control (longitudinal follow-up), Outcome 3 Immediate visual memory.

Analysis 2.4.

Comparison 2 Cognitive training versus any control (longitudinal follow-up), Outcome 4 Delayed memory.

Analysis 2.5.

Comparison 2 Cognitive training versus any control (longitudinal follow-up), Outcome 5 Verbal functions.

Analysis 2.6.

Comparison 2 Cognitive training versus any control (longitudinal follow-up), Outcome 6 Depression.

Analysis 2.7.

Comparison 2 Cognitive training versus any control (longitudinal follow-up), Outcome 7 Quality of life.

Comparison 3. Cognitive training combined with other neuropsychological rehabilitation methods versus any control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Attention5894Std. Mean Difference (IV, Fixed, 95% CI)0.15 [0.01, 0.28]
1.1 Sustained attention test/correct answers119Std. Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.92, 0.88]
1.2 Paced Auditory Serial Addition Test 3'/raw score2159Std. Mean Difference (IV, Fixed, 95% CI)0.07 [-0.24, 0.39]
1.3 Paced Auditory Serial Addition Test 2'/raw score2159Std. Mean Difference (IV, Fixed, 95% CI)0.21 [-0.10, 0.53]
1.4 Paced Auditory Serial Addition Test 3'/z-score142Std. Mean Difference (IV, Fixed, 95% CI)0.01 [-0.61, 0.62]
1.5 Test battery of attention/alertness without cueing142Std. Mean Difference (IV, Fixed, 95% CI)0.23 [-0.39, 0.85]
1.6 Symbol Digit Modalities Test2159Std. Mean Difference (IV, Fixed, 95% CI)0.19 [-0.12, 0.51]
1.7 Trail Making A198Std. Mean Difference (IV, Fixed, 95% CI)0.26 [-0.14, 0.67]
1.8 Trail Making B198Std. Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.44, 0.36]
1.9 Stroop/colour-word interference time198Std. Mean Difference (IV, Fixed, 95% CI)0.11 [-0.29, 0.51]
1.10 Test of Everyday Attention/incompatibility120Std. Mean Difference (IV, Fixed, 95% CI)0.63 [-0.27, 1.53]
2 Information processing speed3181Std. Mean Difference (IV, Fixed, 95% CI)0.05 [-0.27, 0.36]
2.1 Sustained Attention Test/variation reaction time119Std. Mean Difference (IV, Fixed, 95% CI)0.0 [-0.90, 0.90]
2.2 2-back/reaction time140Std. Mean Difference (IV, Fixed, 95% CI)0.25 [-0.44, 0.95]
2.3 Preference shifting/reaction time140Std. Mean Difference (IV, Fixed, 95% CI)0.07 [-0.62, 0.77]
2.4 Response shifting/reaction time140Std. Mean Difference (IV, Fixed, 95% CI)0.25 [-0.45, 0.94]
2.5 Test Battery of Attention/object alternation142Std. Mean Difference (IV, Fixed, 95% CI)-0.27 [-0.89, 0.35]
3 Memory span120Mean Difference (IV, Fixed, 95% CI)0.40 [-0.46, 1.26]
3.1 WAIS/digit span forward120Mean Difference (IV, Fixed, 95% CI)0.40 [-0.46, 1.26]
4 Working memory280Std. Mean Difference (IV, Fixed, 95% CI)0.25 [-0.22, 0.72]
4.1 2-back/commissions140Std. Mean Difference (IV, Fixed, 95% CI)0.24 [-0.46, 0.94]
4.2 WAIS/digit span backward120Std. Mean Difference (IV, Fixed, 95% CI)-0.20 [-1.08, 0.68]
4.3 Test of Everyday Attention/working memory120Std. Mean Difference (IV, Fixed, 95% CI)0.75 [-0.16, 1.67]
5 Immediate verbal memory7308Std. Mean Difference (IV, Fixed, 95% CI)0.31 [0.08, 0.54]
5.1 Verbal Learning Test119Std. Mean Difference (IV, Fixed, 95% CI)0.34 [-0.57, 1.25]
5.2 California Verbal Learning Test/learning trials282Std. Mean Difference (IV, Fixed, 95% CI)0.41 [-0.05, 0.88]
5.3 California Verbal Learning Test/total161Std. Mean Difference (IV, Fixed, 95% CI)0.16 [-0.34, 0.67]
5.4 Hopkins Verbal Learning Test - revised128Std. Mean Difference (IV, Fixed, 95% CI)0.08 [-0.66, 0.82]
5.5 Buschke Selective Reminding Test/consistent long-term retrieval198Std. Mean Difference (IV, Fixed, 95% CI)0.24 [-0.16, 0.65]
5.6 Buschke Selective Reminding Test/free recall120Std. Mean Difference (IV, Fixed, 95% CI)1.17 [0.21, 2.14]
6 Immediate visual memory4198Std. Mean Difference (IV, Random, 95% CI)0.36 [-0.14, 0.86]
6.1 Non-Verbal Learning Test119Std. Mean Difference (IV, Random, 95% CI)0.34 [-0.57, 1.25]
6.2 Brief Visuospatial Memory Test - revised/total161Std. Mean Difference (IV, Random, 95% CI)-0.04 [-0.54, 0.47]
6.3 10/36 Spatial Recall/total correct2118Std. Mean Difference (IV, Random, 95% CI)0.77 [-0.49, 2.03]
7 Delayed memory4400Std. Mean Difference (IV, Fixed, 95% CI)0.22 [0.02, 0.42]
7.1 California Verbal Learning Test/long delay free recall2103Std. Mean Difference (IV, Fixed, 95% CI)0.38 [-0.02, 0.77]
7.2 Brief Visuospatial Memory Test - revised/delayed161Std. Mean Difference (IV, Fixed, 95% CI)0.06 [-0.44, 0.57]
7.3 Buschke Selective Reminding Test/delayed recall2118Std. Mean Difference (IV, Fixed, 95% CI)0.15 [-0.22, 0.52]
7.4 10/36 Spatial Recall/delayed2118Std. Mean Difference (IV, Fixed, 95% CI)0.22 [-0.15, 0.59]
8 Executive functions4180Std. Mean Difference (IV, Fixed, 95% CI)-0.08 [-0.39, 0.23]
8.1 Computer-aided Card-Sorting Procedure/correct answers119Std. Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.92, 0.88]
8.2 Preference shifting/trials to criterion140Std. Mean Difference (IV, Fixed, 95% CI)-0.33 [-1.03, 0.37]
8.3 Response shifting/trials to criterion140Std. Mean Difference (IV, Fixed, 95% CI)0.18 [-0.52, 0.87]
8.4 Sorting Test from the Delis-Kaplan Executive Function System161Std. Mean Difference (IV, Fixed, 95% CI)-0.30 [-0.81, 0.21]
8.5 Test of Everyday Attention/flexibility errors120Std. Mean Difference (IV, Fixed, 95% CI)0.57 [-0.32, 1.47]
9 Visual functions280Std. Mean Difference (IV, Fixed, 95% CI)0.40 [-0.04, 0.85]
9.1 Intelligence Test-revised (HAWIE-R)119Std. Mean Difference (IV, Fixed, 95% CI)0.79 [-0.16, 1.73]
9.2 Judgement of Line Orientation Test161Std. Mean Difference (IV, Fixed, 95% CI)0.29 [-0.21, 0.80]
10 Verbal functions3219Std. Mean Difference (IV, Fixed, 95% CI)0.26 [-0.01, 0.53]
10.1 Controlled Oral Word Association Test (semantic fluency)3179Std. Mean Difference (IV, Fixed, 95% CI)0.23 [-0.07, 0.52]
10.2 Controlled Oral Word Association Test (phonologic fluency)120Std. Mean Difference (IV, Fixed, 95% CI)0.05 [-0.83, 0.93]
10.3 Boston Naming Test120Std. Mean Difference (IV, Fixed, 95% CI)0.81 [-0.11, 1.73]
11 Everyday cognitive performance/patient's report41011Std. Mean Difference (IV, Fixed, 95% CI)0.10 [-0.03, 0.23]
11.1 Memory Aids Questionnaire1225Std. Mean Difference (IV, Fixed, 95% CI)-0.08 [-0.36, 0.20]
11.2 Memory Functioning Questionnaire/overall rating128Std. Mean Difference (IV, Fixed, 95% CI)-0.40 [-1.15, 0.35]
11.3 Everyday Memory Questionnaire/patient's report1217Std. Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.31, 0.26]
11.4 Dysexecutive Memory Questionnaire/patient's report1223Std. Mean Difference (IV, Fixed, 95% CI)0.01 [-0.27, 0.30]
11.5 Strategy Subscale of the Multifactorial Memory Questionnaire161Std. Mean Difference (IV, Fixed, 95% CI)0.30 [-0.21, 0.81]
11.6 Multiple Sclerosis Neuropsychological Questionnaire2159Std. Mean Difference (IV, Fixed, 95% CI)0.26 [-0.06, 0.58]
11.7 Perceived Deficits Questionnaire198Std. Mean Difference (IV, Fixed, 95% CI)0.69 [0.27, 1.10]
12 Everyday cognitive performance/carer's report2454Std. Mean Difference (IV, Fixed, 95% CI)0.03 [-0.17, 0.23]
12.1 Everyday Memory Questionnaire/carer's report1177Std. Mean Difference (IV, Fixed, 95% CI)0.04 [-0.28, 0.36]
12.2 Dysexecutive Syndrome Questionnaire/carer's report1179Std. Mean Difference (IV, Fixed, 95% CI)-0.01 [-0.33, 0.31]
12.3 Multiple Sclerosis Neuropsychological Questionnaire - Informant198Std. Mean Difference (IV, Fixed, 95% CI)0.08 [-0.32, 0.49]
13 Depression4187Mean Difference (IV, Fixed, 95% CI)0.25 [-2.11, 2.61]
13.1 Beck Depression Inventory4187Mean Difference (IV, Fixed, 95% CI)0.25 [-2.11, 2.61]
14 Quality of life2140Std. Mean Difference (IV, Fixed, 95% CI)0.16 [-0.18, 0.50]
14.1 SF-36 Health Questionnaire (short form)/mental score142Std. Mean Difference (IV, Fixed, 95% CI)0.06 [-0.56, 0.68]
14.2 Brief version of the World Health Organization Quality of Life/psychological total score198Std. Mean Difference (IV, Fixed, 95% CI)0.20 [-0.20, 0.61]
15 Fatigue3159Std. Mean Difference (IV, Random, 95% CI)0.08 [-0.44, 0.59]
15.1 Modified Fatigue Impact Scale119Std. Mean Difference (IV, Random, 95% CI)-0.51 [-1.43, 0.41]
15.2 Fatigue Severity Scale142Std. Mean Difference (IV, Random, 95% CI)-0.05 [-0.66, 0.57]
15.3 Fatigue Scale for Motor and Cognitive Fatigue/total198Std. Mean Difference (IV, Random, 95% CI)0.43 [0.03, 0.84]
16 Anxiety128Mean Difference (IV, Fixed, 95% CI)2.36 [-4.81, 9.53]
16.1 State-Trait Anxiety Inventory/state128Mean Difference (IV, Fixed, 95% CI)2.36 [-4.81, 9.53]
17 Impact of the disease2159Std. Mean Difference (IV, Fixed, 95% CI)0.04 [-0.27, 0.36]
17.1 Multiple Sclerosis Impact Scale/psychological total score198Std. Mean Difference (IV, Fixed, 95% CI)0.03 [-0.38, 0.43]
17.2 Control subscale of the Multiple Sclerosis Self Efficacy Scale161Std. Mean Difference (IV, Fixed, 95% CI)0.07 [-0.44, 0.58]
Analysis 3.1.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 1 Attention.

Analysis 3.2.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 2 Information processing speed.

Analysis 3.3.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 3 Memory span.

Analysis 3.4.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 4 Working memory.

Analysis 3.5.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 5 Immediate verbal memory.

Analysis 3.6.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 6 Immediate visual memory.

Analysis 3.7.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 7 Delayed memory.

Analysis 3.8.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 8 Executive functions.

Analysis 3.9.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 9 Visual functions.

Analysis 3.10.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 10 Verbal functions.

Analysis 3.11.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 11 Everyday cognitive performance/patient's report.

Analysis 3.12.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 12 Everyday cognitive performance/carer's report.

Analysis 3.13.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 13 Depression.

Analysis 3.14.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 14 Quality of life.

Analysis 3.15.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 15 Fatigue.

Analysis 3.16.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 16 Anxiety.

Analysis 3.17.

Comparison 3 Cognitive training combined with other neuropsychological rehabilitation methods versus any control, Outcome 17 Impact of the disease.

Comparison 4. Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Attention3790Std. Mean Difference (IV, Fixed, 95% CI)0.01 [-0.13, 0.15]
1.1 Sustained attention test/correct answers119Std. Mean Difference (IV, Fixed, 95% CI)-0.65 [-1.58, 0.28]
1.2 Paced Auditory Serial Addition Test 3'2159Std. Mean Difference (IV, Fixed, 95% CI)0.18 [-0.14, 0.49]
1.3 Paced Auditory Serial Addition Test 2'2159Std. Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.36, 0.28]
1.4 Symbol Digit Modalities Test2159Std. Mean Difference (IV, Fixed, 95% CI)0.11 [-0.21, 0.42]
1.5 Trail Making A198Std. Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.50, 0.31]
1.6 Trail Making B198Std. Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.50, 0.30]
1.7 Stroop/colour-word interference time198Std. Mean Difference (IV, Fixed, 95% CI)-0.01 [-0.41, 0.40]
2 Information processing speed279Std. Mean Difference (IV, Fixed, 95% CI)0.05 [-0.43, 0.53]
2.1 Sustained attention test/variation reaction time119Std. Mean Difference (IV, Fixed, 95% CI)0.56 [-0.36, 1.49]
2.2 2-back/reaction time120Std. Mean Difference (IV, Fixed, 95% CI)-0.51 [-1.49, 0.46]
2.3 Preference shifting/reaction time120Std. Mean Difference (IV, Fixed, 95% CI)-0.04 [1.00, 0.91]
2.4 Response shifting/reaction time120Std. Mean Difference (IV, Fixed, 95% CI)0.14 [-0.82, 1.09]
3 Working memory120Mean Difference (IV, Fixed, 95% CI)1.1 [-3.22, 5.42]
3.1 2-back/commissions120Mean Difference (IV, Fixed, 95% CI)1.1 [-3.22, 5.42]
4 Immediate verbal memory5226Std. Mean Difference (IV, Fixed, 95% CI)0.26 [-0.01, 0.53]
4.1 Verbal Learning Test119Std. Mean Difference (IV, Fixed, 95% CI)0.47 [-0.45, 1.38]
4.2 Hopkins Verbal Learning Test - revised128Std. Mean Difference (IV, Fixed, 95% CI)-0.12 [-0.87, 0.62]
4.3 California Verbal Learning Test/learning trials120Std. Mean Difference (IV, Fixed, 95% CI)0.41 [-0.55, 1.38]
4.4 California Verbal Learning Test/total161Std. Mean Difference (IV, Fixed, 95% CI)0.33 [-0.18, 0.84]
4.5 Buschke Selective Reminding Test/consistent long-term retrieval198Std. Mean Difference (IV, Fixed, 95% CI)0.26 [-0.14, 0.67]
5 Immediate visual memory3178Std. Mean Difference (IV, Fixed, 95% CI)0.35 [0.05, 0.65]
5.1 Non-Verbal Learning Test119Std. Mean Difference (IV, Fixed, 95% CI)0.05 [-0.85, 0.95]
5.2 Brief Visuospatial Memory Test - revised/total161Std. Mean Difference (IV, Fixed, 95% CI)0.05 [-0.46, 0.55]
5.3 10/36 Spatial Recall/total correct198Std. Mean Difference (IV, Fixed, 95% CI)0.62 [0.21, 1.03]
6 Delayed memory2318Std. Mean Difference (IV, Fixed, 95% CI)0.32 [0.10, 0.55]
6.1 California Verbal Learning Test/delay161Std. Mean Difference (IV, Fixed, 95% CI)0.26 [-0.24, 0.77]
6.2 Brief Visuospatial Memory Test - revised/delayed161Std. Mean Difference (IV, Fixed, 95% CI)0.20 [-0.30, 0.71]
6.3 Buschke Selective Reminding Test/delayed198Std. Mean Difference (IV, Fixed, 95% CI)0.20 [-0.21, 0.60]
6.4 10/36 Spatial Recall/delayed198Std. Mean Difference (IV, Fixed, 95% CI)0.57 [0.16, 0.99]
7 Executive functions3120Std. Mean Difference (IV, Random, 95% CI)-0.18 [-0.69, 0.32]
7.1 Computer-aided Card-Sorting Procedure/correct answers119Std. Mean Difference (IV, Random, 95% CI)-0.65 [-1.58, 0.28]
7.2 Preference shifting/trials to criterion120Std. Mean Difference (IV, Random, 95% CI)0.75 [-0.24, 1.74]
7.3 Response shifting/trials to criterion120Std. Mean Difference (IV, Random, 95% CI)-0.37 [-1.34, 0.59]
7.4 Sorting Test from the Delis-Kaplan Executive Function System161Std. Mean Difference (IV, Random, 95% CI)-0.29 [-0.80, 0.22]
8 Visual functions280Std. Mean Difference (IV, Fixed, 95% CI)0.09 [-0.35, 0.53]
8.1 Intelligence Test-revised (HAWIE-R)119Std. Mean Difference (IV, Fixed, 95% CI)0.07 [-0.83, 0.98]
8.2 Judgement of Line Orientation Test161Std. Mean Difference (IV, Fixed, 95% CI)0.10 [-0.41, 0.60]
9 Verbal functions2159Mean Difference (IV, Fixed, 95% CI)0.95 [-1.75, 3.65]
9.1 Controlled Oral Word Association Test (semantic fluency)2159Mean Difference (IV, Fixed, 95% CI)0.95 [-1.75, 3.65]
10 Everyday cognitive performance/patient's report4978Std. Mean Difference (IV, Random, 95% CI)0.11 [-0.12, 0.33]
10.1 Memory Aids Questionnaire1209Std. Mean Difference (IV, Random, 95% CI)-0.09 [-0.38, 0.20]
10.2 Memory Functioning Questionnaire/overall memory128Std. Mean Difference (IV, Random, 95% CI)-0.43 [-1.18, 0.32]
10.3 Everyday Memory Questionnaire/patient's report1208Std. Mean Difference (IV, Random, 95% CI)0.01 [-0.28, 0.31]
10.4 Dysexecutive Syndrome Questionnaire/patient's report1215Std. Mean Difference (IV, Random, 95% CI)-0.01 [-0.30, 0.27]
10.5 Strategy Subscale of the Multifactorial Memory Questionnaire161Std. Mean Difference (IV, Random, 95% CI)0.17 [-0.34, 0.68]
10.6 Multiple Sclerosis Neuropsychological Questionnaire2159Std. Mean Difference (IV, Random, 95% CI)0.16 [-0.51, 0.83]
10.7 Perceived Deficits Questionnaire198Std. Mean Difference (IV, Random, 95% CI)0.73 [0.32, 1.15]
11 Everyday cognitive performance/carer's report2427Std. Mean Difference (IV, Fixed, 95% CI)0.03 [-0.17, 0.23]
11.1 Everyday Memory Questionnaire/carer's report1163Std. Mean Difference (IV, Fixed, 95% CI)0.04 [-0.29, 0.36]
11.2 Dysexecutive Syndrome Questionnaire/carer's report1166Std. Mean Difference (IV, Fixed, 95% CI)-0.03 [-0.36, 0.29]
11.3 Multiple Sclerosis Neuropsychological Questionnaire - Informant198Std. Mean Difference (IV, Fixed, 95% CI)0.13 [-0.27, 0.53]
12 Depression3145Mean Difference (IV, Fixed, 95% CI)0.19 [-1.92, 2.31]
12.1 Beck Depression Inventory3145Mean Difference (IV, Fixed, 95% CI)0.19 [-1.92, 2.31]
13 Quality of life198Mean Difference (IV, Fixed, 95% CI)0.30 [-0.71, 1.31]
13.1 Brief version of the World Health Organization Quality of Life/psychological total score198Mean Difference (IV, Fixed, 95% CI)0.30 [-0.71, 1.31]
14 Fatigue2117Std. Mean Difference (IV, Random, 95% CI)-0.04 [-0.83, 0.75]
14.1 Fatigue Impact Scale119Std. Mean Difference (IV, Random, 95% CI)-0.56 [-1.49, 0.36]
14.2 Fatigue Scale for Motor and Cognitive Fatigue/total score198Std. Mean Difference (IV, Random, 95% CI)0.27 [-0.14, 0.67]
15 Anxiety128Mean Difference (IV, Fixed, 95% CI)6.08 [-1.57, 13.73]
15.1 State Trait Anxiety Inventory/state128Mean Difference (IV, Fixed, 95% CI)6.08 [-1.57, 13.73]
16 Impact of the disease2159Std. Mean Difference (IV, Fixed, 95% CI)0.13 [-0.19, 0.44]
16.1 Multiple Sclerosis Impact Scale/psychological total score198Std. Mean Difference (IV, Fixed, 95% CI)0.12 [-0.28, 0.53]
16.2 Control subscale of the Multiple Sclerosis Self Efficacy Scale161Std. Mean Difference (IV, Fixed, 95% CI)0.13 [-0.38, 0.64]
Analysis 4.1.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 1 Attention.

Analysis 4.2.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 2 Information processing speed.

Analysis 4.3.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 3 Working memory.

Analysis 4.4.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 4 Immediate verbal memory.

Analysis 4.5.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 5 Immediate visual memory.

Analysis 4.6.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 6 Delayed memory.

Analysis 4.7.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 7 Executive functions.

Analysis 4.8.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 8 Visual functions.

Analysis 4.9.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 9 Verbal functions.

Analysis 4.10.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 10 Everyday cognitive performance/patient's report.

Analysis 4.11.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 11 Everyday cognitive performance/carer's report.

Analysis 4.12.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 12 Depression.

Analysis 4.13.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 13 Quality of life.

Analysis 4.14.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 14 Fatigue.

Analysis 4.15.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 15 Anxiety.

Analysis 4.16.

Comparison 4 Cognitive training combined with other neuropsychological rehabilitation methods versus any control (longitudinal follow-up), Outcome 16 Impact of the disease.

Appendices

Appendix 1. Keywords

{cogniti\*} OR {awareness} OR {cognitive dissonance} OR {comprehension} OR {consciousness} OR {imagination} OR {intuition} OR {learn\*} OR {visual perception} OR {thinking} OR {psycholinguistics} OR {neuropsychol\*} OR {memor\*} OR {attenti\*} {language} OR {speech} OR {problem solving} OR {mathematics} OR {information process\*} OR {visuospat\*} OR {visuoconstruct\*} OR {execut\*} OR {metacognit\*}

AND

{rehabilit\*} OR {restitut\*} OR {remediat\*} OR {restorat\*} OR {retrain\*} OR {train\*} OR {recover\*} OR {treat\*} OR {guid\*} OR {instruct\*} OR {teach\*} OR {stimulat\*} OR {exerci\*} OR {strateg\*} OR {counsel\*} OR {therap\*} OR {intervent\*} OR {manage\*}

Appendix 2. PubMed

(1966 to 28 May 2013)
1exp demyelinating autoimmune diseases, cns/ or exp multiple sclerosis/
2(multiple sclerosis or ms).mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
31 or 2
4exp cognition/ or exp awareness/ or exp cognitive dissonance/ or exp comprehension/ or exp consciousness/ or exp imagination/ or exp intuition/ or exp learning/ or exp visual perception/ or exp thinking/ or exp psycholinguistics/
5Neuropsychology/
6exp Memory/
7Attention/
8Language/
9exp Speech/
10Problem Solving/
11exp Mathematics/
12Awareness/
136 or 11 or 7 or 9 or 12 or 8 or 4 or 10 or 5
14(cogniti* or neuropsychol* or memor* or learn* or attenti* or information process* or language or visuospat* or visuoconstruct* or problem solving or reason* or execut* or metacognit*).mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
1513 or 14
16exp Rehabilitation/
17Remedial Teaching/
18"Recovery of Function"/
19Exercise/
20exp Counseling/
2118 or 19 or 16 or 17 or 20
22(rehabilit* or restitut* or remediat* or restorat* or retrain* or train* or recover* or treat* or guid* or instruct* or teach* or stimulat* or exerci* or strateg* or counsel* or therap* or intervent* or manage*).mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
2322 or 21
243 and 23 and 15
25exp clinical trial/ or clinical trial, phase i/ or clinical trial, phase ii/ or clinical trial, phase iii/ or clinical trial, phase iv/ or controlled clinical trial/ or multicenter study/ or randomized controlled trial/
26(randomi* control* trial* or randomi* clinical trial* or random allocation* or controlled clinical trial* or clinical trial* or experimental clinical trial* or quasi experimental clinical trial* or controlled trial* or randomi*ed trial* or clinical randomi*ed trial* or controlled stud* or crossover stud* or rct or crt).mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
2725 or 26
2827 and 24
29limit 28 to humans

exp = exploded; / = vocabulary term; mp = multiple (free-text search).

Appendix 3. EMBASE

(1974 to 28 May 2013)

'crossover procedure'/exp OR 'double blind procedure'/exp OR 'single blind procedure'/exp OR 'controlled clinical trial'/de OR 'randomized controlled trial'/exp OR random*:ab,ti OR factorial*:ab,ti OR crossover:ab,ti OR 'clinical trial'/exp OR (cross:ab,ti AND over:ab,ti) OR placebo:ab,ti OR 'double blind':ab,ti OR 'single blind':ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti OR quasi experimental:ab,ti AND ('multiple sclerosis'/exp OR 'demyelinating disease'/de OR 'optic neuritis'/exp OR 'acute disseminated encephalomyelitis'/exp OR 'myelooptic neuropathy'/exp OR 'myelitis'/de OR 'multiple sclerosis':ab,ti OR 'chronic progressive multiple sclerosis':ab,ti OR 'progressive relapsing multiple sclerosis':ab,ti OR 'secondary progressive multiple sclerosis':ab,ti OR 'primary progressive multiple sclerosis':ab,ti OR 'relapsing remitting multiple sclerosis':ab,ti OR 'remitting-relapsing multiple sclerosis':ab,ti OR 'acute relapsing multiple sclerosis':ab,ti OR 'optic neurities':ab,ti OR 'neuromyelitis optica':ab,ti OR encephalomyelitis:ab,ti OR 'clinically isolated syndrome':ab,ti OR 'transverse myelitis':ab,ti OR 'devic disease':ab,ti OR 'demyelinating disease':ab,ti OR 'demyelinating disorder':ab,ti OR 'acute disseminated encephalomyelitis':ab,ti OR adem:ab,ti) NOT [medline]/lim AND (cogniti*:ab,ti OR neuropsychol*:ab,ti OR memor*:ab,ti OR learn*:ab,ti OR attenti*:ab,ti OR 'information process':ab,ti OR language:ab,ti OR visuospat*:ab,ti OR visuoconstruct*:ab,ti OR 'problem solving':ab,ti OR reason*:ab,ti OR execut*:ab,ti OR metacognit*:ab,ti) AND ('rehabilitation'/de OR 'counseling'/exp OR (rehabilit*:ab,ti OR restitut*:ab,ti OR remediat*:ab,ti OR restorat*:ab,ti OR retrain*:ab,ti OR train*:ab,ti AND recover*:ab,ti OR treat*:ab,ti AND guid*:ab,ti AND instruct*:ab,ti) OR teach:ab,ti OR stimulat*:ab,ti OR exerci*:ab,ti OR strateg*:ab,ti OR counsel*:ab,ti OR therap*:ab,ti OR intervent*:ab,ti OR manage*:ab,ti) AND [humans]/lim AND [embase]/lim

Appendix 4. CINAHL

(1981 to 28 May 2013)
1(MH "Multiple Sclerosis") or (MH "Autoimmune Diseases+")
2TX Multiple sclerosis or ms
3S1 or S2
4(MH "Cognition+") or (MH "Mental Processes+")
5(MH "Neuropsychology")
6(MH "Attention")
7(MH "Language+")
8(MH "Mathematics+")
9S4 or S5 or S6 or S7 or S8
10TX cogniti* or neuropsychol* or memor* or learn* or attenti* or information process* or language or visuospat* or visuoconstruct* or problem solving or reason* or execut* or metacognit*
11S9 or S10
12(MH "Rehabilitation+")
13(MH "Recovery")
14(MH "Counseling+")
15S12 or S13 or S14
16TX rehabilit* or restitut* or remediat* or restorat* or retrain* or train* or recover* or treat* or guid* or instruct* or teach* or stimulat* or exerci* or strateg* or counsel* or therap* or intervent* or manage*
17S15 or S16
18S3 and S11 and S17
19(MH "Clinical Trials+")
20TX randomi* control* trial* or randomi* clinical trial* or random allocation* or controlled clinical trial* or clinical trial* or experimental clinical trial* or quasi experimentasl clinical trial or controlled trial* or randomi*ed trial* or clinical randomi*ed trial* or controlled stud* or crossover stud* or rct or crt
21S19 or S20
22S18 and S21
23limiters: Human
24S22 and S23

What's new

Last assessed as up-to-date: 28 May 2013.

DateEventDescription
28 May 2013New search has been performedNew search. Six new trials have been included.
28 May 2013New citation required and conclusions have changedConclusions changed.

Contributions of authors

Both authors (ER and PH) participated in the whole review process: selection and evaluation of studies, extraction of data, analyses and writing the review.

Declarations of interest

Both authors (ER and PH) acted as authors of one of the included studies (Mäntynen 2013).

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Finnish National Insurance Institution, Finland.

    The study had financial support from the Finnish National Insurance Institution.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Benedict 2000

Methods

RCT; single-centre trial
Country: USA

Study dates not reported

Participants

N = 15; intervention: 8, control: 7. Additionally, healthy controls: 15

Age: intervention: 47.9 (6.6), control: 41.4 (12.2), healthy controls: 43.5 (9.4)

Gender (female/male): intervention: 5/3, control: 5/2, healthy controls: 11/4

Education years: intervention: 14.3 (2.1), control: 13.4 (2.2), healthy controls: 13.9 (1.8)

MS disease course: intervention: 8 SP, control: 6 SP, 1 PP

EDSS: intervention: 4.9 (2.2), control: 5.1 (2.6)

Duration of disease (years): not reported

Exclusion criteria: history of neurological disease other than MS. Drug or alcohol dependence. Psychiatric disease. Depressive disorder. Clinical MS relapse. Corticosteroid treatment within 3 weeks prior to participation

Interventions

Intervention: Neuropsychological Compensatory Training, NCT: aim - to enhance patient and caregiver understanding of MS-related deficits in cognitive functions, personality and behaviour, and to improve adaptive function by psychoeducational and cognitive-behavioural methods

3 main aims:

1) To teach the patient and caregiver to understand the neurological basis of cognitive impairment, pathological affect and abnormal social behaviour (in other words, abnormal behaviour is due to neurological injury)

2) To improve the patient's capacity to appreciate the perspective of others (social skills training exercises, attentive listening, perspective taking, facilitative communication  practiced by role-playing and audio-taping of spontaneous conversation)

3) To diminish the frequency of socially aggressive behaviour (cognitive-behavioural strategies taught to enhance patient self control and behaviour regulation)

Number of sessions: 12 x 1 h. Duration: 12 weeks. Frequency: once per week

Control: unspecific supportive psychotherapy, NSP: aim - to foster personality growth and behaviour change through emotional support and clinician empathy, and to help with stress modulation

Number of sessions, duration and frequency: same as in intervention group

Outcomes

Primary and secondary outcomes:

Beck Depression Inventory (BDI)

Hogan Empathy Scale (HES) (caregiver reported)

NEO-Personality Inventory (NEO-PI)

Modified Social Aggression Scale (caregiver reported)

Assessment timing: baseline and immediate follow-up (12 to 14 weeks)

NotesDomain targeted: behaviour regulation
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAssignment by random number table
Allocation concealment (selection bias)High riskAuthor's definition: "Patients were assigned in sequence by a randomized schedule but not by a person independent of the eligibility determination and the allocation was not concealed"
Blinding (performance bias and detection bias)
Participant
Unclear riskIt remained unclear whether participants were blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 0 (0%)
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasLow riskThe study appears to be free of other sources of bias

Brissart 2012

Methods

Quasi-randomised trial; single-centre trial
Country: France

Study dates not reported

Participants

N = 20, intervention: 10, control: 10

Age: intervention: 42.5 (5.2), control: 41.3 (8.0)

Gender: not reported

Education years: intervention: 13.0 (2.2), control: 12.4 (1.7)

MS disease course: 20 RR

EDSS: intervention: 2.9 (1.4), control: 2.9 (1.2)

Duration of disease (years): intervention: 5.0 (3.6), control: 7.2 (5.5)

Exclusion criteria: no cognitive complaint or mild or moderate cognitive impairment. Not ambulatory. Not French native speaker. Other MS disease course than RRMS. EDSS > 5.0. Disease duration > 20 years. Age over 50 years. Use of corticosteroids during the last 4 weeks before enrolment. Participation in another rehabilitation programme. Neuropsychological assessment done in the 3 months prior to inclusion. Other chronic or neurological disease than MS. Substance abuse

Interventions

Intervention: ProCog-SEP program; aim - to train cognitive functions with a computer-aided program (ProCog-SEP) and to teach cognitive compensatory strategies.

In order to optimise meta-cognition, each cognitive function was explained at the beginning of each session, in order to link exercises with everyday life. Sessions included exercises about semantic memory and lexical access, visual and verbal episodic memory, working memory, associative memory, executive functions and several cognitive functions

Number of sessions: 13 x 2 h. Duration: 6 months. Frequency: twice per month

Control: discussion program; neutral discussions and various non-cognitive exercises

Number of sessions, duration and frequency: same as in intervention group

Outcomes

Primary and secondary outcomes:

Selective Reminding Test

10/36 Spatial Recall

TEA/working memory, flexibility, incompatibility

Semantic fluency

Phonological fluency

WAIS/digit span

Boston Naming Test

Assessment timing: baseline and immediate follow-up (6 months)

NotesCognitive domain targeted: several cognitive functions
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskPatients were casually assigned by a blinded psychologist
Allocation concealment (selection bias)High riskPatients were casually assigned by a blinded psychologist
Blinding (performance bias and detection bias)
Participant
Low riskPatients were not informed of the programme in which they were included
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 0
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasUnclear riskGender distribution at baseline not reported

Cerasa 2012

Methods

RCT; single-centre trial
Country: Italy

Study dates not reported

Participants

N = 26, intervention: 13, control: 13

Age: intervention: 31.7 (9.2), control: 33.7 (10.3)

Gender (female/male): intervention: 9/3, control: 8/3

Education years: intervention: 11, control: 12

MS disease course: all RR

EDSS: intervention: 3, control: 2

Duration of disease (years): intervention: 4.3 (3.0), control: 5.1 (5.2)

Exclusion criteria: severe cognitive impairment as evaluated by a detailed neuropsychological assessment. No predominant deficits in either attention and/or information processing speed, working memory and/or executive functions (failure in at least 1 of the following tests: SDMT, TM A-B, PASAT, Stroop word-colour task). Additional impairment in other cognitive domains. Relapse and steroid treatment for at least 1 month prior to study entry. Concomitant therapy with antidepressant or psychoactive drugs. EDSS > 4.0. History of psychiatric problems. Not optimal visual acuity

Interventions

Intervention: computer-aided attention training; aim - to train attentional functions with a computer-aided program (RehaCom modules divided attention, attention and concentration, and vigilance)

Divided attention: the patient was required to stimulate a train driver and several distractions had to be taken into account, with increasing levels of difficulty

Attention and concentration: an individual picture (target) was presented and then compared with a matrix of pictures and selected from the matrix, with increasing levels of difficulty

Vigilance: the patient was trained to sustain his/her attention for a long period of time by providing response times limited to the various items. The task was to control a conveyor belt and to select the objects that differed from a sample in one or more details

Number of sessions: 12 x 1 hour. Duration: 6 weeks. Frequency: twice per week

Control: computer-aided visuomotor co-ordination tasks at home. Patients had to simply respond quickly and accurately to the appearance of target visual stimuli (numbers 2-4-6-8) on the screen by pressing the corresponding number key on the keyboard with increasing speed

Number of sessions, duration and frequency: same as in intervention group

Outcomes

Primary and secondary outcomes:

Selective Reminding Test (SRT)

10/36 Spatial Recall Test (SPART)

Symbol Digit Modalities Test (SDMT)

Controlled Oral Word Association Test (COWAT)

Paced Auditory Serial Addition Test (PASAT)

Stroop

Trail Making A+B (TM A-B)

Beck Depression Inventory II (BDI-II)

State-Trait Anxiety Inventory (STAI)

Fatigue Severity Scale (FSS)

MR imaging

Assessment timing: baseline and immediate follow-up (6 weeks)

NotesCognitive domain targeted: attention
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAssignment by computer-generated, site-stratified randomisation schedule
Allocation concealment (selection bias)Low riskParticipants were randomly allocated by assistants not involved in the study using a computer-generated allocation list
Blinding (performance bias and detection bias)
Participant
Low riskParticipants were blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 3 (12%) (intervention: 1, control: 2)
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasLow riskThe study appears to be free of other sources of bias

Chiaravalloti 2005

Methods

Quasi-randomised trial; single-centre trial
Country: USA

Study was conducted between September 2000 and September 2001

Participants

N = 29, intervention: 15, control: 14

Age: intervention: 45.1 (13.8), control: 46.0 (9.3)

Gender (female/male): intervention: 64% female, control: 57% female

Education years: intervention: 14.6 (2.7), control: 15.0 (2.8)

MS disease course: 17 RR, 4 PP, 7 SP

Ambulation index: intervention: 3.2 (2.8), control: 2.4 (2.6)

Duration of disease (years): intervention: 14.0 (8.4), control: 8.4 (5.0)

Exclusion criteria: age over 69 years. History of neurological disorder other than MS. Alcohol or drug abuse. Bipolar disorder. Psychotic disorder. Schizophrenia. Head injury resulting in more than 30 minutes loss of consciousness. No MS relapse during 1 month. No problems in new learning (the performance of MS patients should be at least 1 standard deviation lower in BSR than the normative values). Impaired attention and verbal comprehension

Interventions

Intervention: aim - to strengthen the acquisition of new information into long-term memory by improving the quality of acquisition (context and imagery). This was aimed for through learning the Story Memory Technique (SMT)

Patients were taught to:

1) Use visualisation (i.e. imagery) to facilitate new learning (sessions 1 to 4)

2) Utilise context to learn new information (e.g. story) even if information is seemingly unrelated (sessions 5 to 8)

Number of sessions: 8 x 45 min. Duration:  4 weeks. Frequency: twice per week

Control: same tasks as in intervention group but without Story Memory Technique (SMT)

Reading a story and recalling as much as possible, after which they were asked specific questions about the story

Number of sessions, duration and frequency: same as in intervention group

Outcomes

Primary and secondary outcomes:

Hopkins Verbal Learning Test-revised (HVLT-R)

Memory Functioning Questionnaire (MFQ)

Beck Depression Inventory (BDI)

State Trait Anxiety Inventory (STAI)

Assessment timing: baseline, immediate follow-up (6 weeks) and longitudinal follow-up (11 weeks)

NotesCognitive domain targeted: verbal learning and learning
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAssignment based on alternation ("odd and even numbers")
Allocation concealment (selection bias)High riskAssignment based on alternation
Blinding (performance bias and detection bias)
Participant
Low riskParticipants were blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 1 (3%) (intervention: 1, control: 0)
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasHigh riskSignificant difference between intervention and control groups in duration of disease

Filippi 2012

MethodsSame study as Mattioli 2010
ParticipantsSee Mattioli 2010
InterventionsSee Mattioli 2010. Aim of the present study - to evaluate brain changes after cognitive rehabilitation in patients with relapsing-remitting MS by using neuropsychologic assessment and structural and functional magnetic resonance (MR) imaging techniques
OutcomesSame cognitive tests as in Mattioli 2010, additionally MR imaging
NotesCognitive function targeted: attention, information processing and executive functions
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAssignment based on alternation
Allocation concealment (selection bias)High riskAssignment based on alternation
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 0 (0%)
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasLow riskThe study appears to be free of other sources of bias

Fink 2010

Methods

Quasi-randomised trial; single-centre trial
Country: Germany

Study dates not reported

Participants

N = 50, intervention: 14, placebo: 17, control: 19 

Age: 44.8 (8.2)

Gender (female/male): 41/9

Education years: not reported

MS disease course: 50 RR

EDSS: not reported

Duration of disease (years): 7.7 (7.7)

Exclusion criteria: corticosteroid treatment during the last 4 weeks before enrolment. EDSS > 7. Neuropsychiatric disorder. Dementia. Relapse during the study phase

Interventions

Intervention: aim - to ease executive deficits by self training and receiving feedback and discussing the exercises with a psychologist

Textbook exercises for executive functioning and meeting with a psychologist weekly for 1.5 hours to receive feedback and to discuss the exercises

Number of sessions: 24 x 25 to 30 min. Duration: 6 weeks. Frequency: 4 times per week

Placebo control: reaction capacity subtest of the computer-aided rehabilitation program (RehaCom). Participants had to respond fast and accurately to visual stimuli. They had to call the psychologist once a week to report the time having spent on training

Number of sessions: 30 x 40 min. Duration: 6 weeks. Frequency: 5 times per week

Control: no intervention

Outcomes

Primary outcomes:

Preference shifting, response shifting, 2-back (computer-based)

Secondary outcomes:

California Verbal Learning Test (CVLT)

Wechsler Adult Intelligence Scale/short form (WIP)

Expanded Disability Status Scale (EDSS)

Multiple Sclerosis Functional Composite (MSFC)

Brain parenchymal fraction (BRF)

Assessment timing: baseline, immediate follow-up (6 weeks) and longitudinal follow-up (1 year)

NotesCognitive domain targeted: executive functions
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskPatients were appointed to 1 of 3 groups. In title mentioned "pseudo-randomised study"
Allocation concealment (selection bias)High riskPatients were appointed to 1 of 3 groups. In title mentioned "pseudo-randomised study"
Blinding (performance bias and detection bias)
Participant
Low riskParticipants were blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
High riskDrop-outs: post-treatment: 10 (20%) (intervention: 3, placebo: 3, control: 4); 1-year follow-up: 30 (60%) (intervention: 8, placebo: 9, control: 13)
Selective reporting (reporting bias)High riskResults for some of the outcome measures (short form of the Wechsler Adult Intelligence Scale and Multiple Sclerosis Functional Composite) not reported
Other biasUnclear riskExact baseline characteristics per groups were not reported; it remained unclear whether groups were similar e.g. with regards to education

Hildebrandt 2007

Methods

Quasi-randomised trial; single-centre trial
Country: Germany

Study dates not reported

Participants

N = 42, intervention: 17, control: 25

Age: intervention: 42.4, control: 36.5

Gender (female/male): intervention: 12/5, control: 13/12

Education years: intervention: 11.6, control: 11.2

MS disease course: intervention: 17 RR, control: 25 RR

EDSS: intervention: 2.9, control: 2.7

Duration of disease (years): intervention: 5.4, control: 4.5

Exclusion criteria: EDSS over 7. Current or past medical illness or psychiatric disorder. Substance abuse. At least 4 weeks from corticosteroid treatment

Interventions

Intervention: aim - to strengthen working memory by direct exercises and teaching memory strategies. This was aimed for through computer-aided (VILAT-G 1.0) training

Patients received a compact disk (CD) for home-based training to learn a word list. Subsequently, a series of calculation tasks were presented. The calculations relied heavily on working memory, because 3 numbers had to be added or subtracted without help of paper and pencil. Moreover, the result of the previous calculation had to be remembered and compared with the actual task. After series of calculations (2 to 15) the program asked the patient to recall the word list earlier learned. Typing the memorised words in a sequence that was structured by a common semantic category was rewarded by a special feedback sentence. The number of words and calculations were self adapted to the performance level

Number of sessions: 30 x 30 min. Duration: 6 weeks. Frequency: 5 times per week

The intensity or frequency of home-based training was not controlled

Control: no intervention 

Outcomes

Primary and secondary outcomes:

Expanded Disability Status Scale (EDSS)

Multiple Sclerosis Functional Composite (MSFC) including components: Nine-Hole Peg Test (9HPT), Timed 25-Foot Walk (TWT) and Paced Auditory Serial Addition Test (PASAT)

California Verbal Learning Test (CVLT)

Test battery of attention (TAP)/object alternation and alertness test

Beck Depression Inventory (BDI)

Fatigue Severity Scale (FSS)

SF-36 Health Questionnaire (short form)

MRI-parameters (brain atrophy)

Assessment timing: baseline and immediate follow-up (8 weeks; 2 weeks post-treatment)

NotesCognitive domain targeted: working memory, learning and memory recall
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAssignment based on alternation
Allocation concealment (selection bias)High riskAssignment based on alternation
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
Low riskThere were no personnel in this study. Training was carried out by participant him/herself with computer-aided program
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs not reported
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasHigh riskSignificant difference between intervention and control groups in age and gender

Jonsson 1993

Methods

RCT; single-centre trial
Country: Denmark

Study dates not reported

Participants

N = 40, intervention:  20, control: 20

Age: intervention: 46.1 (7.3), control: 43.0 (9.0)

Gender (female/male): intervention: 9/11, control: 10/10

Education years: intervention: 10.9 (2.0), control: 12.2 (2.9)

MS disease course: 6 RR, 25 SP, 9 PP

EDSS: intervention: 5.6 (1.7), control: 5.6 (1.8)

Duration of disease (years): intervention: 15.0 (11.2), control: 15.1 (8.5)

Exclusion criteria: neurological disease other than MS. Psychiatric disease unrelated to MS. Age over 60 years. Severe visual impairment. Severe motor dysfunction of arms or hands. Very severe cognitive impairment. History of alcohol or drug abuse. Regular use of psychopharmacia or analgesics. Foreigner. No cognitive impairment verified by neuropsychological testing

Interventions

Intervention: aim - to alleviate the patient's individual neuropsychological symptoms through cognitive training and neuropsychotherapy

The cognitive training employed the common principles in cognitive rehabilitation programmes consisting of compensation, substitution and cognitive training

Cognitive training of concentration was done with compiled, inverted and mirror-written text, "two-in-one" pictures, labyrinths etc. 

Memory was trained both directly and by learning compensatory strategies (visualisation using pictures of increasing complexity, shopping lists and appointments, calendar). The calendar was also used for planning daily activities. Stories were read aloud and the patient was encouraged to visualise and then retell the stories in order to learn how to structure a text.

Patients with visuospatial difficulties were trained partly with mosaic games, being corrected and urged to work slowly and systematically, and partly with practical exercises such as walking or wheelchair driving in and outside the hospital.

Along with the cognitive training, the patients took part in neuropsychotherapy to realise and accept their present cognitive and behavioural level of functioning, learning how to best use their available resources

Number of sessions: 1 to 1.5 h each session, in all mean 17.3 h. Duration: about 6.5 weeks. Frequency: 3 times per week

Control: unspecific mental stimulation:

Watching and discussing different kinds of films. Reading and discussing newspaper articles. Playing games. Discussing personal problems and problems concerning disease acceptance

Number of sessions: 1 to 1.5 h each session, in all mean 17.1 h. Duration and frequency: same as in intervention group

Outcomes

Primary and secondary outcomes:

Wechsler Adult Intelligence Scale-revised (WAIS-R)/digit span

Sentence repetition

Associative learning

List learning

Visual gestalts, learning and retention.

WAIS-R/Block Design

Trail making

Symbol Digit Modalities Test (SDMT)

Street

WAIS-R/Similarities

WAIS-R/Picture arrangement

Beck Depression Inventory (BDI)

State-Trait Anxiety Inventory (STAI)

Assessment timing: baseline, immediate follow-up (on day 45.6 (mean) after the 1st testing) and longitudinal follow-up (6 months)

NotesCognitive domain targeted: several cognitive functions
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised assignment with sealed, opaque envelope system
Allocation concealment (selection bias)Low riskRandomised assignment with sealed, opaque envelope system
Blinding (performance bias and detection bias)
Participant
Unclear riskIt remained unclear whether participants were blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
High riskNo patient was tested and treated by the same neuropsychologist. However, the authors realised quite early that the intended blind study was not possible, since just a few words from the patient indicated which treatment had been given
Incomplete outcome data (attrition bias)
All outcomes
High riskDrop-outs: 8 (20%) (intervention: 4, control: 4)
Selective reporting (reporting bias)High riskPre-treatment evaluation was done with neuropsychological test battery including 41 measures of cognitive performance. However, post-treatment evaluation was done only with 25 cognitive tests. "We selected 25 cognitive tests from the original battery, excluding some tests with known high practice effect"
Other biasLow riskThe study appears to be free of other sources of bias

Lincoln 2002

Methods

RCT; single-centre trial
Country: Great Britain

Study dates not reported

Participants

N = 240, intervention: 79, assessment: 79, control: 82

Age (median): intervention: 43.0, assessment: 43.0, control: 40.5

Gender (female/male): intervention: 48/26, assessment: 56/16, control: 52/25

Education years: age left education (median): intervention: 16.0, assessment: 16.0, control: 16.0

MS disease course: 94 SP, 107 RR, 19 PP, 21 not known

Ambulation Index (median): intervention: 4, assessment: 4, control: 3

Duration of disease (years): not reported

Exclusion criteria: live over 20 mile radius from the hospital. Unable to co-operate with assessment at least 30 min at time. No consent to take part

Interventions

Intervention: aim - to alleviate the patient's individual neuropsychological symptom complex through cognitive training and using compensatory strategies

Patients received detailed neuropsychological assessment. The information obtained was summarised for patients and, when the patients agreed, their relatives. Formal psychological reports were sent to the professionals involved in the patients' care and to patients and their relatives

Cognitive rehabilitation programme based on individually identified problems. This included learning both external (diaries, notebooks, calendars, lists) and internal (visualisation) memory strategies. More detailed information about intervention was not reported

Number of sessions: not intensive, exact intensity or frequency, however, not reported. Duration: 4 months

Assessment: same way as in intervention group, patients received detailed neuropsychological assessment lasting 3 hours with oral and written feedback

Control: no intervention, 30 min screening assessment without feedback

Outcomes

Primary and secondary outcomes:

General Health Questionnaire (GHQ) (also caregiver ratings)

SF-36 and SF-54 Health Questionnaire

(Overall Quality of Life (OQoL), Q53 and Satisfaction with Quality of Life (SQoL), Q54

Extended Activities of Daily Living Index (EADL)

Everyday memory questionnaire (EMQ) (also caregiver ratings)

Dysexecutive Syndrome Questionnaire (DEX) (also caregiver ratings)

Memory Aids Questionnaire (MAQ)

Guy’s Neurological Disability Scale (GNDS)

Assessment timing: Baseline, immediate follow-up (4 months) and longitudinal follow-up (8 months)

NotesCognitive domain targeted: several cognitive functions
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAssignment with a computer-generated random number table
Allocation concealment (selection bias)Low riskParticipants were randomly allocated by an assistant not involved in the study using a computer-generated allocation list
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 17 (7%) (intervention: 5, assessment: 7, control: 5)
Selective reporting (reporting bias)High riskThe study did not include cognitive tests as outcome measures although intervention was cognitive rehabilitation and target cognitive training
Other biasHigh riskCompliance in the intervention was weak, only 46% of participants in the intervention group participated in the intervention as planned. This information became evident in later publication (2003) of authors

Mattioli 2010

Methods

Quasi-randomised trial; single-centre trial
Country: Italy

Participant examinations between June 2007 and December 2008

Participants

N = 20, intervention: 10, control: 10

Age (median): intervention: 42, control: 44

Gender (female/male): intervention: 10/0, control: 10/0

Education years (median): intervention: 8.0, control: 9.0

MS disease course: 20 RR

EDSS (median): intervention:  2.5, control: 1.5

Duration of disease (years) (median): intervention: 16.5, control: 18.5

Exclusion criteria: 1 or more clinical exacerbations in the previous year. Loss of visual acuity. Ongoing major psychiatric disorder. Substance abuse. Mini Mental State Examination < 24. Intact performance in Paced Auditory Serial Addition Test 2" and 3" and in Wisconsin Card Sorting Test

Interventions

Intervention: aim - to train attention, information processing and executive functions with a computer-aided program (RehaCom modules Plan a Day and Divided Attention)

Module "Plan a day": trains the patient’s ability to organise, plan and develop solution strategies employing realistic simulations of a set of scheduled dates and duties to be organised at specific places in a small city map

Module "Divided attention": the patient is required to simulate a train driver, carefully observing the control panel of the train and the countryside. Several distractions, such as crossing animals and train speed must be taken into account with increasing levels of difficulty

Number of sessions: 36 x 1h. Duration: 12 weeks. Frequency: 3 times per week

Control: no intervention

Outcomes

Primary and secondary outcomes:

Brief Repeatable Battery of Neuropsychological Tests (BRBNT) including: Selective Reminding Test (SRT), 10/36 Spatial Recall Test, Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test 2’ and 3’ (PASAT), Controlled Oral Word Association Test (COWAT)

Wisconsin Card Sorting Test (WCST)

Test of Everyday Attention (TEA)

Montgomery-Asberg Depression Rating Scale (MADRS)

Multiple Sclerosis Quality of Life Questionnaire (MSQoL)

Assessment timing: baseline, immediate follow-up (12 weeks)

NotesCognitive function targeted: attention, information processing and executive functions
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAssignment based on alternation
Allocation concealment (selection bias)High riskAssignment based on alternation
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 0 (0%)
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasLow riskThe study appears to be free of other sources of bias

Mattioli 2012a

MethodsSame study as Mattioli 2010 (longitudinal follow-up)
ParticipantsSee Mattioli 2010
InterventionsSee Mattioli 2010
Outcomes

See Mattioli 2010

Assessment timing: baseline, 3 months, 6 months

NotesCognitive function targeted: attention, information processing and executive functions
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAssignment based on alternation
Allocation concealment (selection bias)High riskAssignment based on alternation
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 0 (0%)
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasLow riskThe study appears to be free of other sources of bias

Mendoza 2001

Methods

Quasi-randomised trial; single-centre trial
Country: USA

Study dates not reported

Participants

N = 20, intervention: 10, control: 10

Age: intervention: 54.6, control: 64.7

Gender (female/male): intervention: 7/3, control: 7/3

Education years: not reported

MS disease course: not reported

EDSS: mentioned that groups did not differ, however data not reported

Duration of disease (years): not reported. Had lived in the facility for mean 5 years (intervention) and 4.8 years (control)

Exclusion criteria: primary admitting diagnosis not MS. Unable to read test stimuli. Diagnosed with a comorbid major mental disorder. Speed had deteriorated so that not able to answer test questions at sufficient verbal level. Performance on K-SNAP in the none impaired range. Unavailable at the time the protocol would be administered

Interventions

Intervention: nursing staff who cared for the participants in the intervention group were educated in neuroanatomy related to cognitive dysfunction in MS, details of the project, rationale for using memory notebooks and participant's neurocognitive strengths and weaknesses

Each participant received a large notebook that was attached to the wheelchair. Certified nursing assistants were instructed to interview the participant to whom they had been assigned and determine whether the participant had any comments or concerns to be recorded. All this information was gathered during normal morning routine. The staff were encouraged to read and write down information in the notebooks

Staff and researchers routinely reviewed the notebooks and marked the entries to indicate to the participant that his/her notebook was being read. When appropriate, the staff offered special assistance, as indicated by the participant's notebook entries

Number of sessions: neuropsychologist provided 4 x 1 h counselling for nursing staff. Intensity or frequency of other intervention not reported. Duration: 2 months

Control: no intervention, normal treatment routines

Outcomes

Primary and secondary outcomes:

Kaufman Short Neuropsychological Assessment (K-SNAP)

Hopkins Verbal Learning Test (HVLT)

North American New Adult Reading Test (NANART)

Stroop

Wechsler Memory Scale III (WMS-III)/digit span, family pictures, logical memory, letter-number sequencing

Boston Naming Test

Controlled Oral Word Association Test (COWAT)

Beck Depression Inventory (BDI)

Activity level (the number of unit events in which the participant took part)

Assessment timing: baseline, immediate follow-up (2 months)

NotesCognitive domain targeted: several cognitive functions
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskRandomly assigned to groups with the criterion of equal numbers of men and women in each condition
Allocation concealment (selection bias)High riskRandomly assigned to groups with the criterion of equal numbers of men and women in each condition
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Unclear riskIt remained unclear whether assessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 1 (5%) (intervention: 0, control: 1)
Selective reporting (reporting bias)High riskData for cognitive tests not reported
Other biasHigh riskSignificant difference between intervention and control groups in age

Mendozzi 1998

Methods

Quasi-randomised trial; single-centre trial
Country: Italy

Participant recruitment between years 1994 and 1996

Participants

N = 60, intervention (specific training): 20, unspecific training: 20, control: 20

Age: intervention: 47.9 (9.4), unspecific training: 45.9 (12.1), control: 45.4 (6.8)

Gender (female/male): intervention: 11/9, unspecific training: 12/8, control: 10/10

Education years: intervention: 12.7 (4.8), unspecific training: 13.0 (3.5), control: 11.7 (3.6)

MS disease course: RR and SP (numbers not reported)

EDSS: intervention: 3.7 (2.2), unspecific training: 4.0 (2.1), control: 3.3 (2.0)

Duration of disease (years): intervention: 12.0 (7.7), unspecific training: 10.7 (7.6), control: 10.2 (6.9)

Exclusion criteria: unstable clinical condition during 2 months prior to the first retraining session. Less than 5 years formal education. Insufficient visual function and manual dexterity to perform the neuropsychological tests. History or current clinical evidence of mental disorders. No subjective memory and attention deficits (verified also as objective memory, attention and reaction speed problems in test performances)

Interventions

Intervention: Specific Computer-assisted Memory Retraining Program, SCRP: aim - to train memory and attention with a computer-aided program (RehaCom)

Memory: objects were displayed on the screen, the patient had to memorise the location of objects. The objects were hidden. An object was displayed and the patient had to indicate the location of the hidden object corresponding to that displayed.

Attention: similar to memory task, except that objects were not hidden. The task was to locate the object exactly corresponding to the one displayed. At each response the patient received positive or negative feedback

At the end of each session, patients were presented with a histogram summarising their performance. The psychologist briefly discussed the results with the patient and set the goals for the next session

Number of sessions: 15 x 45 min. Duration: 8 weeks. Frequency: twice per week

Unspecific training: unspecific Computer-assisted Retraining Program, NCRP. Visual tracking: the patient had to move a red dot into a blue circle by operating a joystick. As soon as the 2 overlapped, the blue circle started moving and the patient had to keep the red dot within the blue circle

Reaction time: the patient had to press a key as quickly as possible on presentation of a target stimulus (go, no-go)

At the end of each session patients were presented with a histogram summarising their performance. The psychologist briefly discussed the results with the patient and set the goals for the next session

Number of sessions, duration and frequency: same as in intervention group

Control: no intervention

Outcomes

Primary and secondary outcomes:

Wechsler Memory Scale (WMS)/logical memory, digit span, visual reproduction, verbal paired associates

Corsi block’s test and recognition memory (computer-based)

Memory Scale of the Luria-Nebraska Neuropsychological Battery (LNNB)

Signal detection time (computer-based)

Raven’s progressive matrices (PM)

Assessment timing: baseline, immediate follow-up (average of 40 days post-treatment (14 weeks))

NotesCognitive domain targeted: memory
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskFirst 30 patients were randomly assigned to groups, while next 30 patients assigned to balance the groups as much as possible for sex, age and education
Allocation concealment (selection bias)High riskFirst 30 patients were randomly assigned to groups, while next 30 patients assigned to balance the groups as much as possible for sex, age and education
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
Unclear riskIt remained unclear whether personnel were blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 1 (2%) (intervention: 1, unspecific training: 0, control: 0)
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasLow riskThe study appears to be free of other sources of bias

Mäntynen 2013

Methods

RCT; multi-centre trial
Country: Finland

Participant recruitment between November 2010 and April 2011

Participants

N = 102, intervention: 60, control: 42

Age: intervention: 43.5 (8.7), control: 44.1 (8.8)

Gender (female/male): intervention: 45/13, control: 31/9

Education years: intervention: 13.6 (2.3), control: 13.8 (2.6)

MS disease course: 102 RRMS

EDSS: intervention: 0 to 4: 93.1%; 4.5 to 5.5: 6.9%, control 0 to 4: 92.5%; 4.5 to 5.5: 7.5%

Duration of disease (years): intervention: 9.2 (6.6), control 10.1 (7.1)

Exclusion criteria: other MS disease course than RRMS, EDSS > 6.0, no subjective attentional deficits (total score of questions 1, 2, 11 in the MSNQ-P < 6), not objective attentional deficits (SDMT < 50), age under 18 or over 59, history of alcohol or drug abuse, psychiatric disorder, acute relapses, neurological disease other than MS, ongoing neuropsychological rehabilitation, overall cognitive impairment (performance on all tests of the BRBNT under -1.5 SD compared to norms of healthy controls)

Interventions

Intervention: aim - to teach compensatory strategies by training attention and working memory with a computer-aided program (Foramen Rehab) and to offer psychoeducation and psychological support to promote coping with cognitive impairments.

The rehabilitation consisted of computer-based attention and working memory retraining, psychoeducation and teaching compensatory strategies, and homework assignments involving rehabilitation goals, as well as offering psychological support to promote coping with cognitive impairments. The computer-based training programme consisted of ForamenRehab cognitive software attention and memory modules

Number of sessions: 13 x 60 min. Duration: 13 weeks. Frequency: once per week

Control: no intervention

Outcomes

Primary outcomes:

Perceived Deficits Questionnaire (PDQ)

Symbol Digit Modalities Test (SDMT)
Goal Attainment Scaling (GAS); only for the intervention group

Secondary outcomes:

Buschke Selective Reminding Test (BSR)

10/36 Spatial Recall Test

Paced Auditory Serial Addition Test (2 and 3 seconds interstimulus)

Controlled Oral Word Association Test (COWAT)

Stroop

Trail making A + B

Beck Depression Inventory II (BDI-II)

Multiple Sclerosis Impact Scale (MSIS-29)

Multiple Sclerosis Neuropsychological Questionnaire - Patient (MSNQ-P) and Informant (MSNQ-I)

Brief version of the World Health Organization Quality of Life (WHOQOL-Bref)

Fatigue Scale for Motor and Cognitive Fatigue (FSMC)

Assessment timing: baseline, immediate follow-up (3 months) and longitudinal follow-up (6 months)

NotesCognitive domain targeted: attention and working memory
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAssignment with a computer-generated random number table
Allocation concealment (selection bias)Low riskParticipants were randomly allocated by a statistician not involved in the study using a computer-generated allocation list
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessing neuropsychologists were blinded to the intervention, which was also shown in their estimates; only 61.7% of them being correct
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 4 (4%) (intervention: 2, control: 2). The compliance with the intervention was 94.1%
Selective reporting (reporting bias)Low riskThe study protocol was available
Other biasLow riskThe study appears to be free of other sources of bias

Shatil 2010

Methods

Quasi-randomised trial; single-centre trial
Country: Israel

The study was conducted between 14 November 2005 and 22 November 2006

Participants

N = 107, intervention: 59, control: 48

Baseline characteristics of study completers (N = 46, intervention: 22, control: 24)

Age: intervention: 49.9 (1.9), control: 42.3 (10.7)

Gender (female/male): intervention: 17/5, control: 19/5

Education: intervention: university 16, high school 6, control: university 17, high school 7

MS disease course: RR and RP (numbers not reported)

EDSS: intervention: 2.6 (2.1), control: 2.5 (1.7)

Duration of disease (years): not reported

Exclusion criteria: other MS disease course than RR or RP. Healthy dominant hand not functioning. Did not speak Hebrew. Did not own or not able to use a personal computer at home. Did not express an interest in taking part in the study. Other neurological disease. Drug or alcohol abuse or dependence. Major depression. Known condition which required the use of psychotropic medication

Interventions

Intervention: aim - to explore unprompted adherence to a personalised, home-based, computer-aided cognitive training program (CogniFit Personal Coach, CPC) and to examine the impact of training on cognitive performance.

Patients received a CD containing the cognitive training program for home-based training. The selection of training tasks was determined by individual performance on the computer-based neuropsychological examination, hence no 2 people had the same training regimen. For each individual, the CPC assigned scores to 17 cognitive abilities that were subsequently trained by means of 21 different training tasks

The degree of difficulty of the tasks was modified automatically according to the participant's performance level

Number of sessions: 24 x 20 to 30 min. Duration: 12 weeks. Frequency: 3 times per week

Control: no intervention

Outcomes

Primary and secondary outcomes:

Neuropsychological Examination - CogniFit Personal Coach (N-CPC) composing 15 tasks measuring a wide range of cognitive abilities such as memory, attention and eye-hand co-ordination

Zung Depression Scale

Expanded Disability Scale (EDSS)

Fatigue Severity Scale (FSS)

Assessment timing: baseline, immediate follow-up (12 weeks)

NotesCognitive function targeted: several cognitive functions
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskA sufficient number of participants were first allocated for the intervention group. Participants with no home internet connection and remaining participants were allocated to the control group
Allocation concealment (selection bias)High riskA sufficient number of participants were first allocated for the intervention group. Participants with no home internet connection and remaining participants were allocated to the control group
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
Low riskThere were no personnel in this study. Training was carried out by participant him/herself with computer-aided program
Blinding (performance bias and detection bias)
Outcome assessor
Unclear riskIt remained unclear whether assessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
High riskDrop-outs: 61 (57%) (intervention: 37, control: 24). Only 37% of participants completed entire training regimen
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasHigh riskSignificant difference between intervention and control groups in age

Solari 2004

Methods

RCT; single-centre trial
Country: Italy

Participant recruitment between January 2001 and May 2002

Participants

N = 82, intervention: 42, control: 40

Age: intervention: 46.2 (9.2), control: 41.2 (10.6)

Gender (female/male): intervention: 26/14, control: 23/14

Education: intervention: elementary school 19, high school 21, control: elementary school 17, high school 20

MS disease course: 39 RR, 35 PR, 3 PP

EDSS: intervention: 3.0, control: 4.0

Duration of disease (years since first symptoms): intervention: 15.2, control: 13.5

Exclusion criteria: age under 18 or over 65 years. MMSE < 24. Education less than 8 years. Ongoing major psychiatric disorder. 1 or more relapses in 3 months prior to enrolment. Immunomodulant or immunosuppressant treatment initiated in 4 months prior to enrolment. Cognitive rehabilitation in the 6 months prior to enrolment. No subjective experience of poor attention or memory and confirmed by a score below the 80th percentile in at least 2 components of the BRBNT

Interventions

Intervention: aim - to train memory and attention with a computer-aided program (RehaCom)

Patients were treated on an individual basis as outpatients with computer-aided retraining program (RehaCom memory and attention retraining). The content of the intervention was not reported precisely

Number of sessions: 16 x 45 min. Duration: 8 weeks. Frequency: twice per week.

Control: patients were treated on an individual basis as outpatients with computer-aided retraining program (RehaCom visuo-constructional and visuomotor co-ordination retraining procedures). To minimise possible attentional and memory retraining, the visuomotor co-ordination procedure was simplified in that "puzzle" pieces were pre-disposed in the correct orientation and a black and white representation of the picture to be constructed was visible as an aid to puzzle completion.

Number of sessions, duration and frequency: same as in intervention group

Outcomes

Primary outcomes:

Brief Repeatable Battery of Neuropsychological Tests (BRBNT) including: Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Selective Reminding, 10/36 Spatial Recall and Word List Generation

Increase of 20% or more in at least 2 BRBNT test scores provided that there was no worsening by 20% or more in 2 or more of the remaining tests

Secondary outcomes:

Chicago Mood Depression Inventory (CMDI)

54-item MS Quality of Life Questionnaire (MSQOL-54)

Assessment timing: baseline, immediate follow-up (8 weeks) and longitudinal follow-up (16 weeks)

NotesCognitive function targeted: attention and memory
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAssignment with computer-generated random number table
Allocation concealment (selection bias)Low riskAssignment with computer-generated random number table
Blinding (performance bias and detection bias)
Participant
Low riskParticipants were blinded
Blinding (performance bias and detection bias)
Personnel
Unclear riskIt remained unclear whether personnel were blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 5 (6%) (intervention: 2, control: 3)
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasHigh riskSignificant difference between intervention and control groups in age

Stuifbergen 2012

Methods

RCT; single-centre trial
Country: USA

Study dates not reported

Participants

N = 63, intervention: 36, control: 27

Baseline characteristics of study completers (N = 61, intervention: 34, control: 27)

Age: all: 48.0 (8.8), no significant differences between intervention and control group

Gender (female/male): intervention: 29/5, control: 25/2

Education: intervention: high school 13 (38%), associate school 3 (9%), bachelors school 8 (24%), graduate degree 10 (29%), control: high school 7 (26%), associate school 2 (7%), bachelors school 11 (41%), graduate degree 7 (26%)

MS disease course: not reported

EDSS: all: 5.2 (1.2)

Duration of disease (years): all: 12.2 (7.4), no significant differences between intervention and control group

Exclusion criteria:

Age under 18 or over 60 years. Unable to understand and comply with the study protocol. Not clinically definite MS for at least 6 months. Unstable disease status at the time of the study entry. No subjective cognitive complaints confirmed by at least 5 ratings of  "sometimes" or more often in the PDQ. Other medical causes of dementia. Other neurological disorder. Major psychiatric disorder. Major functional limitations that precluded them from participating in the study

Interventions

Intervention: aim - to train cognitive functions with a computer-aided program as home training and to teach cognitive compensatory strategies in group sessions. The MAPSS-MS (Memory, Attention, and Problem Solving Skills for Persons with Multiple Sclerosis) had 2 components: 1) weekly group sessions focused on the efficacy for use of cognitive compensatory strategies and 2) a computer-aided cognitive training program as home training. Group sessions provided information specific to MS-related cognitive difficulties and helped participants assess their difficulties and identify strategies to manage those difficulties and improve functional performance. The computer-aided program included internet-based game-like formats of attention (auditory and visual reactions to fixed and random points and divided attention), executive (organising information, attributes and groups, sequences, serial addition and simultaneous multiple addition), memory (auditory and visual sequenced and reversed sequenced recall, colour match, trail trace, sequenced blocks and recall for objects and locations) and problem-solving skills (puzzles requiring deductive reasoning and organising and analysing facts)

Number of group sessions: 8 x 2 h. Duration: 8 weeks. Frequency: Once per week. Computer-aided cognitive home training: minimum of 45 minutes 3 times per week

Control: no intervention

Outcomes

Primary and secondary outcomes:

Minimal Assessment of Cognitive Function in MS (MACFIMS) including:

Controlled Oral Word Association Test (COWAT), Judgement of Line Orientation test (JLO), California Verbal Learning Test (CVLT-II), Brief Visuospatial Memory Test – Revised (BVMT-R), Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Sorting Test from the Delis-Kaplan Executive Function System (DKEFS)

Control Subscale of the Multiple Sclerosis Self Efficacy Scale (MSSE-Control)

Strategy Subscale of the Multifactorial Memory Questionnaire (MMQ-Strategy)

Multiple Sclerosis Neuropsychological Screening Questionnaire -patient (MSNQ-P)

NotesCognitive function targeted: memory, attention and problem solving skills
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAssignment with computer-generated random number table and sealed envelopes
Allocation concealment (selection bias)Low riskParticipants were randomly allocated by a data analyst not involved in the study using a computer-generated random number table and sealed envelopes
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 2 (3%) (intervention: 2, control: 0)
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasLow riskThe study appears to be free of other sources of bias

Tesar 2005

Methods

Quasi-randomised trial; single-centre trial
Country: Austria

Study dates not reported

Participants

N = 20, intervention: 10, control: 10

Age: intervention: 45.3 (9.2), control: 46.9 (11.2)

Gender (female/male): intervention: 7/3, control: 5/4

Education: not reported

MS disease course: 13 RR, 6 SP

EDSS: intervention: 4.5 (1.7), control: 4.4 (1.9)

Duration of disease (years): intervention: 8.0 (4.2), control: 10.4 (7.1)

Exclusion criteria: previous psychiatric history. Past drug or alcohol abuse. Other medical diagnosis than MS. Relapse during the past 30 days. Corticosteroid therapy. IQ below 85. Age over 60 years. Insufficient visual acuity. BDI > 11 scores. No mild or moderate cognitive impairments (cognitive impairment was not defined more precisely)

Interventions

Intervention: aim - to train the 2 cognitive areas most severely affected with a computer-aided program (RehaCom) and to teach compensatory strategies relevant to everyday life. The content of the intervention concerning computer-aided training was not more specifically reported

Compensation strategies:

Memory and learning: internal and external memory supports, association mechanisms

Attention: techniques for building up routines for behaviour and self control

Problem-solving and planning: simplifying and visualisation

Number of sessions: 12 x 1 h. Duration: 4 weeks. Frequency: 3 times per week

Control: no intervention

Outcomes

Primary and secondary outcomes:

Verbal learning test (VLT)

Non-verbal learning test (NVLT)

Sustained attention test (DAUF)

Computer-aided card-sorting procedure (CKV)

Mosaic test from the Hamburg Wechsler Intelligence Test-revised (HAWIE-R)

Beck Depression Inventory (BDI)

Modified Fatigue Impact Scale (MFIS)

Follow-up questionnaire

Assessment timing: baseline, immediate follow-up (4 weeks) and longitudinal follow-up (3 months)

NotesCognitive function targeted: several cognitive functions
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAssignment to comparable groups with respect to clinical and demographic factors. Independent person determined which group acted as intervention and control group
Allocation concealment (selection bias)High riskAssignment to comparable groups with respect to clinical and demographic factors. Independent person determined which group acted as intervention and control group
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
High riskPersonnel were not blinded
Blinding (performance bias and detection bias)
Outcome assessor
Unclear riskIt remained unclear whether assessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 1 (5%) (intervention: 0, control: 1)
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasLow riskThe study appears to be free of other sources of bias

Vogt 2008

Methods

Quasi-randomised trial; single-centre trial
Country: Switzerland

Study dates not reported

Participants

N = 50, intervention (MS): 15, control (MS): 15, intervention (healthy controls): 10, control (healthy controls): 10

Age: intervention (MS): 43.2 (8.8), control (MS): 46.3 (10.5), intervention (healthy controls): 39.5 (11.6), control (healthy controls): 43.4 (12.5)

Gender (female/male): intervention (MS): 11/4, control (MS): 10/5, intervention (healthy controls): 7/3, control (healthy controls): 6/4

Education (0 = secondary school, 1 = college, 2 = university): intervention (MS): 1.6 (0.5), control (MS): 1.5 (0.5), intervention (healthy controls): 1.7 (0.7), control (healthy controls): 1.6 (0.5)

MS disease course: 22 RR, 7 SP, 1 PP

EDSS: intervention (MS): 3.2 (1.8), control (MS): 3.2 (1.6)

Duration of disease (years): intervention (MS): 9.1 (5.4), control (MS): 12.1 (9.0)

Exclusion criteria: unstable symptomatic medication during previous months. Relapse or unstable disease phase within previous 3 months. Corticosteroid treatment within previous month. Other neurological or psychiatric disease. Healthy controls: neurological or psychiatric disease

Interventions

Intervention: aim - to train working memory with a computer-aided program (BrainStim) as home training

Spatial orientation (module "City Map"): trains spatial orientation by either visual or verbal instructions to be remembered and finding the path using given arrows along virtual city map

Visual object memory and the updating functions of working memory (module "Find Pairs"): the aim is to remember the location of cards that have been turned over and back again and find pairs of cards with the same image

Verbal numeric working memory (module "Memorize Numbers"): numbers that are presented for a short time have to be remembered meanwhile performing an arithmetic distraction task

The degree of difficulty of the tasks was modified automatically according to the participant's performance level

Intervention in question for both MS patients (n = 15) and healthy controls (n = 10)

Number of sessions: 16 x 45 min. (each of the 3 modules 15 min). Duration: 4 weeks. Frequency: 4 times per week

Control: no intervention

Outcomes

Primary outcomes:

Wechsler Memory Scale (WMS-R)/digit span backwards, Corsi Block forwards

Test battery of attention (TAP)/2-back Task (modified)

Paced Auditory Serial Addition Test (PASAT) from Brief Repeatable Battery of Neuropsychological Tests (BRB-N)

Faces Symbol Test (FST)

Symbol Digit Modalities Test (SDMT/from BRB-N)

Fatigue Scale for Motor and Cognitive Fatigue (FSMC)

Modified Fatigue Impact Scale (MFIS)

Allgemeinen Depressionsskala (ADS)

Functional Assessment of MS (FAMS)

Secondary outcomes:

Log files recorded during training (modules: City Map, Find Pairs and Memorise Numbers)

Assessment timing: baseline (twice within 2 weeks), immediate follow-up (4 weeks)

NotesCognitive function targeted: working memory
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAssignment to  comparable groups with regard to demographic factors (age, sex, education)
Allocation concealment (selection bias)High riskAssignment to  comparable groups with regard to demographic factors (age, sex, education)
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
Low riskThere were no personnel in this study. Training was carried out by the participant him/herself with a computer-aided program
Blinding (performance bias and detection bias)
Outcome assessor
Unclear riskIt remained unclear whether assessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 0 (0%)
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasLow riskThe study appears to be free of other sources of bias

Vogt 2009

  1. a

    BDI: Beck Depression Inventory

    BRBNT: Brief Repeatable Battery of Neuropsychological Test

    BSR: Buschke Selective Reminding Test

    EDSS: Expanded Disability Status Scale

    MMSE: Mini Mental State Examination

    MS: Multiple Sclerosis

    MSNQ-P: Multiple Sclerosis Neuropsychological Questionnaire - Patient

    MR: Magnetic Resonance (Imaging)

    PASAT: Paced Auditory Serial Addition Test

    PDQ: Perceived Deficits Questionnaire

    PP: Primary Progressive

    RR: Relapsing-Remitting

    RRSM: Relapsing-Remitting Multiple Sclerosis

    SD: Standard Deviation

    SDMT: Symbol Digit Modalities Test

    SP: Secondary progressive

    TM A-B: Trail Making A+B

MethodsSame study as Vogt 2008
Participants

N = 45, intervention (high-intensity training): 15, intervention (distributed training): 15, control: 15

Age: intervention (high-intensity training): 43.2 (8.8), intervention (distributed training): 43.4 (12.3), control: 46.3 (10.5)

Gender (female/male): intervention (high-intensity training): 11/4, intervention (distributed training): 9/6, control: 10/5

Education (0 = secondary school, 1 = college, 2 = university): intervention (high-intensity training): 1.6 (0.5), intervention (distributed training): 1.5 (0.5), control: 1.5 (0.5)

MS disease course: 36 RR, 8 SP, 1 PP

EDSS: intervention (high-intensity training): 3.2 (1.8), intervention (distributed training): 2.3 (1.1), control: 3.2 (1.6)

Duration of disease (years): intervention (high-intensity training): 9.1 (5.4), intervention (distributed training): 8.1 (6.3), control: 12.1 (9.0)

Exclusion criteria: relapse. Change in symptomatic medication within previous 3 months. Treatment with steroids within previous month. Other neurological or psychiatric disease

Interventions

Intervention: aim - to evaluate 2 different training schedules of a computer-aided (BrainStim) working memory training.

Same intervention methods as in the study of Vogt 2008. In this study computer-aided training either with high-intensity or with distributed training were compared

Number of sessions: 16 x 45 min. (both training groups). Duration: 4 weeks (high-intensity training) and 8 weeks (distributed training). Frequency: 4 times per week (high-intensity training) and twice per week (distributed training)

Control: no intervention

Outcomes

Same outcome methods as in the study of Vogt 2008

Assessment timing: baseline (twice within 2 weeks), immediate follow-up (for the high-intensity training group and control group 4 weeks, for the distributed training group 8 weeks)

NotesCognitive domain targeted: working memory. This paper is based on the same study as Vogt 2008
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAssignment to  comparable groups with regard to demographic factors (age, sex, education)
Allocation concealment (selection bias)High riskAssignment to  comparable groups with regard to demographic factors (age, sex, education)
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Personnel
Low riskThere were no personnel in this study. Training was carried out by the participant him/herself with a computer-aided program
Blinding (performance bias and detection bias)
Outcome assessor
Unclear riskIt remained unclear whether assessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs: 0 (0%)
Selective reporting (reporting bias)Low riskThe expected outcomes are reported
Other biasLow riskThe study appears to be free of other sources of bias

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    MS: multiple sclerosis

Allen 1995Case report
Allen 1998Not a controlled trial
Altinkaya 2012Abstract
Basso 2006Not a neuropsychological/cognitive intervention
Basso 2007Not a neuropsychological/cognitive intervention
Ben 2012Abstract
Birnboim 2004Case report
Bombardier 2008Not a neuropsychological/cognitive intervention
Brenk 2008Controlled clinical trial (CCT)
Brissart 2010Not a controlled trial
Chiaravalloti 2002Not a neuropsychological/cognitive intervention
Chiaravalloti 2003Not a neuropsychological/cognitive intervention
Chiaravalloti 2011Abstract
Chiaravalloti 2012Results of neuropsychological outcomes not reported (same study as Leavitt 2012)
das Nair 2012bResults of MS participants could not be separated from other neurological patient groups
Foley 1994Case report
Gordon 1997Not a neuropsychological/cognitive intervention
Goverover 2008Not a neuropsychological/cognitive intervention
Goverover 2011Within-group design
Hubacher 2011Abstract
Leavitt 2012Results of neuropsychological outcomes not reported (same study as Chiaravalloti 2012)
Lincoln 2003Case report
Longley 2012A protocol for an ongoing trial
Mattioli 2012bAbstract
Panicari 2012Abstract
Parisi 2012Results of neuropsychological outcomes not reported (same study as Mattioli 2010 and Filippi 2012)
Pierfederici 2007Abstract
Plohmann 1994Preliminary report of a study in progress at the time of publication
Plohmann 1998Not a controlled trial
Rigby 2008Not a neuropsychological/cognitive intervention
Rodgers 1996Neuropsychological/cognitive rehabilitation could not be separated from the intervention
Sastre-Garriga 2010Controlled clinical trial (CCT)
Schwartz 1999Neuropsychological/cognitive rehabilitation could not be separated from the intervention
Shevil 2009Not a controlled trial
Stuifbergen 2011Qualitative, descriptive study
Tesar 2003Not a neuropsychological/cognitive intervention
Topcular 2011Abstract
Wassem 2003Neuropsychological/cognitive rehabilitation could not be separated from the intervention

Characteristics of ongoing studies [ordered by study ID]

Brochet 2013

Trial name or titleRandomised controlled clinical trial of cognitive rehabilitation in multiple sclerosis and assessment by neuroimaging
Methods RCT; single-centre trial
Country: France
Participants50 patients with MS (age 18 to 55, disease duration > 6 months and ≤ 15 years), 25 healthy controls
Interventions

Intervention: specific cognitive rehabilitation

Rehabilitation will be focused on attention, executive functions, information processing speed and working memory based on the patient's individual neuropsychological symptoms. Sessions will include varied exercised according to complexity and presentation modality, using computerised and "paper-and-pencil" tasks and meta-cognitive training

Number of sessions: 50 x 1 h. Duration: 4 months. Frequency: 3 times per week

Control: non-specific cognitive rehabilitation

Group session without specific cognitive rehabilitation

Number of sessions, duration, frequency: same as in intervention group

Control: healthy participants

No intervention. Same evaluation procedures as patients

Outcomes

Primary outcomes: the cognitive global executive z score (after 4 months)

Secondary outcomes: brain activation, the z score of the SDMT, the daily-life cognitive questionnaire, clinical global impression of patients (after 4 and 8 months), the z cognitive global executive z score (after 8 months)

Starting dateMay 2011
Contact information

Bruno Brochet: bruno.brochet@chu-bordeaux.fr

Mathilde Deloire: mathilde.grassin@bb-luni.u-bordeaux2.fr

Notes 

Shevil 2013

  1. a

    MS: multiple sclerosis
    SDMT: Symbol Digit Modalities Test

Trial name or titleDevelopment and evaluation of a cognitive rehabilitation program for persons with multiple sclerosis
Methods RCT; single-centre trial
Country: Israel
Participants50 patients with MS (18 years of age or older) with self reported cognitive difficulties
Interventions

Self management cognitive rehabilitation group intervention. 8-week cognitive rehabilitation programme facilitated by an occupational therapist. Programme goals include increased knowledge of cognitive impairments in MS, increased self efficacy to manage cognitive changes and increased use of cognitive compensatory strategies

Control intervention: 8-week group programme that is not specifically directed to management of cognitive impairments

Outcomes

Primary outcomes: cognitive strategy use (pre-intervention, post-intervention, 3, 6, 12-month follow-up)

Secondary outcomes: cognitive self efficacy (pre-intervention, post-intervention, 3, 6, 12-month follow-up)

Starting dateFebruary 2011
Contact informationEynat Shevil:eshevil@post.tau.ac.il
Notes 

Ancillary