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Neuropsychological rehabilitation for multiple sclerosis

  1. Eija M Rosti-Otajärvi1,
  2. Päivi I Hämäläinen2,*

Editorial Group: Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group

Published Online: 11 FEB 2014

Assessed as up-to-date: 28 MAY 2013

DOI: 10.1002/14651858.CD009131.pub3


How to Cite

Rosti-Otajärvi EM, Hämäläinen PI. Neuropsychological rehabilitation for multiple sclerosis. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD009131. DOI: 10.1002/14651858.CD009131.pub3.

Author Information

  1. 1

    Tampere University Hospital, Department of Neurology and Rehabilitation, Tampere, Finland

  2. 2

    Finnish MS Association, Masku neurological rehabilitation centre, Masku, Finland

*Päivi I Hämäläinen, Masku neurological rehabilitation centre, Finnish MS Association, Seppäläntie 90, Masku, 21250, Finland. paivi.hamalainen@ms-liitto.fi.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 11 FEB 2014

SEARCH

 
Characteristics of included studies [ordered by study ID]
Benedict 2000

MethodsRCT; single-centre trial
Country: USA

Study dates not reported


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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

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

Study dates not reported


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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

MethodsRCT; single-centre trial
Country: Italy

Study dates not reported


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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

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

Study was conducted between September 2000 and September 2001


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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

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

Study dates not reported


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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

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

Study dates not reported


ParticipantsN = 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


InterventionsIntervention: 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 


OutcomesPrimary 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

MethodsRCT; single-centre trial
Country: Denmark

Study dates not reported


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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

MethodsRCT; single-centre trial
Country: Great Britain

Study dates not reported


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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

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

Participant examinations between June 2007 and December 2008


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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


OutcomesSee 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

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

Study dates not reported


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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

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

Participant recruitment between years 1994 and 1996


ParticipantsN = 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)


InterventionsIntervention: 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


OutcomesPrimary 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

MethodsRCT; multi-centre trial
Country: Finland

Participant recruitment between November 2010 and April 2011


ParticipantsN = 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)


InterventionsIntervention: 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


OutcomesPrimary 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

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

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


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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

MethodsRCT; single-centre trial
Country: Italy

Participant recruitment between January 2001 and May 2002


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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

MethodsRCT; single-centre trial
Country: USA

Study dates not reported


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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

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

Study dates not reported


ParticipantsN = 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)


InterventionsIntervention: 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


OutcomesPrimary 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

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

Study dates not reported


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesPrimary 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

MethodsSame study as Vogt 2008


ParticipantsN = 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


InterventionsIntervention: 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


OutcomesSame 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

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

MethodsRCT; single-centre trial
Country: France

Participants50 patients with MS (age 18 to 55, disease duration > 6 months and ≤ 15 years), 25 healthy controls

InterventionsIntervention: 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

OutcomesPrimary 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 informationBruno Brochet: bruno.brochet@chu-bordeaux.fr

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

Notes

Shevil 2013

Trial name or titleDevelopment and evaluation of a cognitive rehabilitation program for persons with multiple sclerosis

MethodsRCT; single-centre trial
Country: Israel

Participants50 patients with MS (18 years of age or older) with self reported cognitive difficulties

InterventionsSelf 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

OutcomesPrimary 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

 
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 Test
4150Std. Mean Difference (IV, Fixed, 95% CI)0.02 [-0.30, 0.34]

    1.4 Divided attention
146Std. Mean Difference (IV, Fixed, 95% CI)-0.05 [-0.63, 0.53]

    1.5 Avoiding distractions
146Std. Mean Difference (IV, Fixed, 95% CI)-0.05 [-0.63, 0.53]

    1.6 Inhibition
146Std. Mean Difference (IV, Fixed, 95% CI)0.23 [-0.35, 0.81]

    1.7 Shifting attention
146Std. Mean Difference (IV, Fixed, 95% CI)-0.14 [-0.72, 0.44]

    1.8 Trail Making A
123Std. Mean Difference (IV, Fixed, 95% CI)-0.28 [-1.10, 0.54]

    1.9 Trail Making B
123Std. Mean Difference (IV, Fixed, 95% CI)0.01 [-0.81, 0.82]

    1.10 Stroop/colour-word
123Std. 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 time
146Std. 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 forward
290Std. Mean Difference (IV, Fixed, 95% CI)0.55 [0.11, 0.99]

    3.2 Digit span forward
160Std. 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 backward
290Std. Mean Difference (IV, Fixed, 95% CI)0.34 [-0.09, 0.78]

    4.3 Corsi blocks backward
130Std. Mean Difference (IV, Fixed, 95% CI)0.38 [-0.34, 1.10]

    4.4 Verbal auditory working memory
146Std. Mean Difference (IV, Fixed, 95% CI)0.59 [0.00, 1.19]

    4.5 Visual working memory
146Std. Mean Difference (IV, Fixed, 95% CI)0.52 [-0.07, 1.11]

    4.6 Auditory working memory
146Std. 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 memory
160Std. 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 Battery
160Std. 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 reproduction
160Std. 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 Test
130Std. 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 Planning
146Std. Mean Difference (IV, Fixed, 95% CI)0.08 [-0.50, 0.66]

    8.3 Time estimation
146Std. 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 Naming
146Std. 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 Scale
120Std. Mean Difference (IV, Random, 95% CI)1.27 [0.29, 2.24]

    10.2 Chicago Mood Depression Inventory
177Std. Mean Difference (IV, Random, 95% CI)0.0 [-0.45, 0.45]

    10.3 Allgemeine Depressionskala
130Std. Mean Difference (IV, Random, 95% CI)0.05 [-0.66, 0.77]

    10.4 Zung Depression Scale
146Std. Mean Difference (IV, Random, 95% CI)-0.31 [-0.89, 0.27]

    10.5 Beck Depression Inventory II
123Std. 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 Life
120Std. Mean Difference (IV, Fixed, 95% CI)0.47 [-0.42, 1.36]

    11.2 Functional Assessment of MS
130Std. Mean Difference (IV, Fixed, 95% CI)-0.13 [-0.84, 0.59]

    11.3 54-item MS Quality of Life Questionnaire/mental health composite
177Std. 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 functions
130Std. Mean Difference (IV, Fixed, 95% CI)0.18 [-0.54, 0.90]

    12.2 Modified Fatigue Impact Scale
130Std. Mean Difference (IV, Fixed, 95% CI)0.19 [-0.53, 0.91]

    12.3 Fatigue Severity Scale/raw score
146Std. Mean Difference (IV, Fixed, 95% CI)-0.25 [-0.83, 0.33]

    12.4 Fatigue Severity Scale/delta score
123Std. 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 Inventory
123Mean Difference (IV, Fixed, 95% CI)4.40 [-3.87, 12.67]

 
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 Test
177Std. 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 retrieval
177Mean 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 recall
177Mean 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 recall
177Std. Mean Difference (IV, Fixed, 95% CI)-0.30 [-0.75, 0.15]

    4.2 10/36 Spatial Recall Test/delayed recall
177Std. 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 Inventory
177Mean 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 composite
177Mean Difference (IV, Fixed, 95% CI)-9.40 [-28.38, 9.58]

 
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 answers
119Std. Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.92, 0.88]

    1.2 Paced Auditory Serial Addition Test 3'/raw score
2159Std. Mean Difference (IV, Fixed, 95% CI)0.07 [-0.24, 0.39]

    1.3 Paced Auditory Serial Addition Test 2'/raw score
2159Std. Mean Difference (IV, Fixed, 95% CI)0.21 [-0.10, 0.53]

    1.4 Paced Auditory Serial Addition Test 3'/z-score
142Std. Mean Difference (IV, Fixed, 95% CI)0.01 [-0.61, 0.62]

    1.5 Test battery of attention/alertness without cueing
142Std. Mean Difference (IV, Fixed, 95% CI)0.23 [-0.39, 0.85]

    1.6 Symbol Digit Modalities Test
2159Std. Mean Difference (IV, Fixed, 95% CI)0.19 [-0.12, 0.51]

    1.7 Trail Making A
198Std. Mean Difference (IV, Fixed, 95% CI)0.26 [-0.14, 0.67]

    1.8 Trail Making B
198Std. Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.44, 0.36]

    1.9 Stroop/colour-word interference time
198Std. Mean Difference (IV, Fixed, 95% CI)0.11 [-0.29, 0.51]

    1.10 Test of Everyday Attention/incompatibility
120Std. 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 time
119Std. Mean Difference (IV, Fixed, 95% CI)0.0 [-0.90, 0.90]

    2.2 2-back/reaction time
140Std. Mean Difference (IV, Fixed, 95% CI)0.25 [-0.44, 0.95]

    2.3 Preference shifting/reaction time
140Std. Mean Difference (IV, Fixed, 95% CI)0.07 [-0.62, 0.77]

    2.4 Response shifting/reaction time
140Std. Mean Difference (IV, Fixed, 95% CI)0.25 [-0.45, 0.94]

    2.5 Test Battery of Attention/object alternation
142Std. 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 forward
120Mean 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/commissions
140Std. Mean Difference (IV, Fixed, 95% CI)0.24 [-0.46, 0.94]

    4.2 WAIS/digit span backward
120Std. Mean Difference (IV, Fixed, 95% CI)-0.20 [-1.08, 0.68]

    4.3 Test of Everyday Attention/working memory
120Std. 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 Test
119Std. Mean Difference (IV, Fixed, 95% CI)0.34 [-0.57, 1.25]

    5.2 California Verbal Learning Test/learning trials
282Std. Mean Difference (IV, Fixed, 95% CI)0.41 [-0.05, 0.88]

    5.3 California Verbal Learning Test/total
161Std. Mean Difference (IV, Fixed, 95% CI)0.16 [-0.34, 0.67]

    5.4 Hopkins Verbal Learning Test - revised
128Std. Mean Difference (IV, Fixed, 95% CI)0.08 [-0.66, 0.82]

    5.5 Buschke Selective Reminding Test/consistent long-term retrieval
198Std. Mean Difference (IV, Fixed, 95% CI)0.24 [-0.16, 0.65]

    5.6 Buschke Selective Reminding Test/free recall
120Std. 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 Test
119Std. Mean Difference (IV, Random, 95% CI)0.34 [-0.57, 1.25]

    6.2 Brief Visuospatial Memory Test - revised/total
161Std. Mean Difference (IV, Random, 95% CI)-0.04 [-0.54, 0.47]

    6.3 10/36 Spatial Recall/total correct
2118Std. 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 recall
2103Std. Mean Difference (IV, Fixed, 95% CI)0.38 [-0.02, 0.77]

    7.2 Brief Visuospatial Memory Test - revised/delayed
161Std. Mean Difference (IV, Fixed, 95% CI)0.06 [-0.44, 0.57]

    7.3 Buschke Selective Reminding Test/delayed recall
2118Std. Mean Difference (IV, Fixed, 95% CI)0.15 [-0.22, 0.52]

    7.4 10/36 Spatial Recall/delayed
2118Std. 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 answers
119Std. Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.92, 0.88]

    8.2 Preference shifting/trials to criterion
140Std. Mean Difference (IV, Fixed, 95% CI)-0.33 [-1.03, 0.37]

    8.3 Response shifting/trials to criterion
140Std. Mean Difference (IV, Fixed, 95% CI)0.18 [-0.52, 0.87]

    8.4 Sorting Test from the Delis-Kaplan Executive Function System
161Std. Mean Difference (IV, Fixed, 95% CI)-0.30 [-0.81, 0.21]

    8.5 Test of Everyday Attention/flexibility errors
120Std. 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 Test
161Std. 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 Test
120Std. 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 Questionnaire
1225Std. Mean Difference (IV, Fixed, 95% CI)-0.08 [-0.36, 0.20]

    11.2 Memory Functioning Questionnaire/overall rating
128Std. Mean Difference (IV, Fixed, 95% CI)-0.40 [-1.15, 0.35]

    11.3 Everyday Memory Questionnaire/patient's report
1217Std. Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.31, 0.26]

    11.4 Dysexecutive Memory Questionnaire/patient's report
1223Std. Mean Difference (IV, Fixed, 95% CI)0.01 [-0.27, 0.30]

    11.5 Strategy Subscale of the Multifactorial Memory Questionnaire
161Std. Mean Difference (IV, Fixed, 95% CI)0.30 [-0.21, 0.81]

    11.6 Multiple Sclerosis Neuropsychological Questionnaire
2159Std. Mean Difference (IV, Fixed, 95% CI)0.26 [-0.06, 0.58]

    11.7 Perceived Deficits Questionnaire
198Std. 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 report
1177Std. Mean Difference (IV, Fixed, 95% CI)0.04 [-0.28, 0.36]

    12.2 Dysexecutive Syndrome Questionnaire/carer's report
1179Std. Mean Difference (IV, Fixed, 95% CI)-0.01 [-0.33, 0.31]

    12.3 Multiple Sclerosis Neuropsychological Questionnaire - Informant
198Std. 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 Inventory
4187Mean 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 score
142Std. 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 score
198Std. 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 Scale
119Std. Mean Difference (IV, Random, 95% CI)-0.51 [-1.43, 0.41]

    15.2 Fatigue Severity Scale
142Std. Mean Difference (IV, Random, 95% CI)-0.05 [-0.66, 0.57]

    15.3 Fatigue Scale for Motor and Cognitive Fatigue/total
198Std. 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/state
128Mean 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 score
198Std. Mean Difference (IV, Fixed, 95% CI)0.03 [-0.38, 0.43]

    17.2 Control subscale of the Multiple Sclerosis Self Efficacy Scale
161Std. Mean Difference (IV, Fixed, 95% CI)0.07 [-0.44, 0.58]

 
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 answers
119Std. 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 Test
2159Std. Mean Difference (IV, Fixed, 95% CI)0.11 [-0.21, 0.42]

    1.5 Trail Making A
198Std. Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.50, 0.31]

    1.6 Trail Making B
198Std. Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.50, 0.30]

    1.7 Stroop/colour-word interference time
198Std. 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 time
119Std. Mean Difference (IV, Fixed, 95% CI)0.56 [-0.36, 1.49]

    2.2 2-back/reaction time
120Std. Mean Difference (IV, Fixed, 95% CI)-0.51 [-1.49, 0.46]

    2.3 Preference shifting/reaction time
120Std. Mean Difference (IV, Fixed, 95% CI)-0.04 [1.00, 0.91]

    2.4 Response shifting/reaction time
120Std. 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/commissions
120Mean 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 Test
119Std. Mean Difference (IV, Fixed, 95% CI)0.47 [-0.45, 1.38]

    4.2 Hopkins Verbal Learning Test - revised
128Std. Mean Difference (IV, Fixed, 95% CI)-0.12 [-0.87, 0.62]

    4.3 California Verbal Learning Test/learning trials
120Std. Mean Difference (IV, Fixed, 95% CI)0.41 [-0.55, 1.38]

    4.4 California Verbal Learning Test/total
161Std. Mean Difference (IV, Fixed, 95% CI)0.33 [-0.18, 0.84]

    4.5 Buschke Selective Reminding Test/consistent long-term retrieval
198Std. 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 Test
119Std. Mean Difference (IV, Fixed, 95% CI)0.05 [-0.85, 0.95]

    5.2 Brief Visuospatial Memory Test - revised/total
161Std. Mean Difference (IV, Fixed, 95% CI)0.05 [-0.46, 0.55]

    5.3 10/36 Spatial Recall/total correct
198Std. 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/delay
161Std. Mean Difference (IV, Fixed, 95% CI)0.26 [-0.24, 0.77]

    6.2 Brief Visuospatial Memory Test - revised/delayed
161Std. Mean Difference (IV, Fixed, 95% CI)0.20 [-0.30, 0.71]

    6.3 Buschke Selective Reminding Test/delayed
198Std. Mean Difference (IV, Fixed, 95% CI)0.20 [-0.21, 0.60]

    6.4 10/36 Spatial Recall/delayed
198Std. 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 answers
119Std. Mean Difference (IV, Random, 95% CI)-0.65 [-1.58, 0.28]

    7.2 Preference shifting/trials to criterion
120Std. Mean Difference (IV, Random, 95% CI)0.75 [-0.24, 1.74]

    7.3 Response shifting/trials to criterion
120Std. Mean Difference (IV, Random, 95% CI)-0.37 [-1.34, 0.59]

    7.4 Sorting Test from the Delis-Kaplan Executive Function System
161Std. 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 Test
161Std. 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 Questionnaire
1209Std. Mean Difference (IV, Random, 95% CI)-0.09 [-0.38, 0.20]

    10.2 Memory Functioning Questionnaire/overall memory
128Std. Mean Difference (IV, Random, 95% CI)-0.43 [-1.18, 0.32]

    10.3 Everyday Memory Questionnaire/patient's report
1208Std. Mean Difference (IV, Random, 95% CI)0.01 [-0.28, 0.31]

    10.4 Dysexecutive Syndrome Questionnaire/patient's report
1215Std. Mean Difference (IV, Random, 95% CI)-0.01 [-0.30, 0.27]

    10.5 Strategy Subscale of the Multifactorial Memory Questionnaire
161Std. Mean Difference (IV, Random, 95% CI)0.17 [-0.34, 0.68]

    10.6 Multiple Sclerosis Neuropsychological Questionnaire
2159Std. Mean Difference (IV, Random, 95% CI)0.16 [-0.51, 0.83]

    10.7 Perceived Deficits Questionnaire
198Std. 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 report
1163Std. Mean Difference (IV, Fixed, 95% CI)0.04 [-0.29, 0.36]

    11.2 Dysexecutive Syndrome Questionnaire/carer's report
1166Std. Mean Difference (IV, Fixed, 95% CI)-0.03 [-0.36, 0.29]

    11.3 Multiple Sclerosis Neuropsychological Questionnaire - Informant
198Std. 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 Inventory
3145Mean 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 score
198Mean 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 Scale
119Std. Mean Difference (IV, Random, 95% CI)-0.56 [-1.49, 0.36]

    14.2 Fatigue Scale for Motor and Cognitive Fatigue/total score
198Std. 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/state
128Mean 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 score
198Std. Mean Difference (IV, Fixed, 95% CI)0.12 [-0.28, 0.53]

    16.2 Control subscale of the Multiple Sclerosis Self Efficacy Scale
161Std. Mean Difference (IV, Fixed, 95% CI)0.13 [-0.38, 0.64]

 
Summary of findings for the main comparison. Cognitive training versus any control for multiple sclerosis

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

ControlCognitive training versus any control

AttentionThe mean attention score in the control groups was 12.6The 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)
⊕⊕⊝⊝
low1

Information processing speedThe mean information processing speed score in the control groups was -410.9The 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 low1,2,3
Time-related scores were entered as negative variables.

Memory spanThe mean memory span score in the control groups was 5.8The 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)
⊕⊕⊝⊝
low3,4

Working memoryThe mean working memory score in the control groups was 8.6The 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 low1,3

Immediate verbal memoryThe mean immediate verbal memory score in the control groups was 4.3The 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)
⊕⊕⊝⊝
low3,4

Executive functionsThe mean executive functions score in the control groups was -6.6The 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 low1,3
Error scores were entered as negative variables.

DepressionThe mean depression score in the control groups was -28.0The 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 low1,2,3
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.

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

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

ControlCognitive 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)
⊕⊕⊕⊝
moderate1

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 low2,3
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 low2,3

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)
⊕⊕⊕⊝
moderate1

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)
⊕⊕⊝⊝
low1,3,4

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)
⊕⊕⊝⊝
low1,4
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 low1,3,4
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.

 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.
 
Table 1. Description of participants

Number of participantsSexAge 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

 EDSS: Expanded Disability Status Scale
MS: multiple sclerosis
 
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

 
Table 3. Four most commonly used outcome measures in the 20 studies

MeasureNumber 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%)

 *Other outcome measures were also used in all studies.
 
Table 4. Results of the study Jonsson 1993

StudyMain resultOther results

Jonsson 1993Immediate 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)

 

 
Table 5. Results of the studies of Benedict 2000 and Mendoza 2001

StudyMain resultOther 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

 
Table 6. Recommendations for future studies of neuropsychological rehabilitation

NoRecommendation

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