Testing the effectiveness of a new multidisciplinary cognitive rehabilitation approach for people with Multiple Sclerosis: the ReBrain protocol

doi:10.21203/rs.3.rs-1642912/v1

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Testing the effectiveness of a new multidisciplinary cognitive rehabilitation approach for people with Multiple Sclerosis: the ReBrain protocol

https://doi.org/10.21203/rs.3.rs-1642912/v1

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Background: Cognitive impairment is common in Multiple Sclerosis (MS), occurring in up to 65% of patients. The cognitive domains affected most commonly in MS include information processing speed (often first target of progressive cognitive decline), learning and episodic and working memory.

The management of cognitive impairment still relies on rehabilitative strategies, which have been reported to be effective in ameliorating cognitive domains but, even if strongly recommended for MS management and standard care, multidisciplinary treatment, including physiotherapy, occupational therapy, speech and swallow therapy, neuropsychology, built on cognitive rehabilitation principles, has scarce scientific evidence.

Methods and analysis: A total of 30people with Multiple Sclerosis (MS) will be randomly assigned to ReBrain group and standard care group. They both consist in multidisciplinary rehabilitation protocol with two hours twice a week for 12 weeks sessions including physiotherapy, occupational therapy, neuropsychological therapy and speech and swallow therapy. ReBrain treatments follow principle of cognitive rehabilitation, combining restorative and compensatory strategies, specific exercises of executive attention stimulation and holistic approach. Evaluation scales will be assessed immediately before (baseline visit, T0), after the booster session (T1, 12 weeks after baseline visit), at three months (T2, 24 weeks after baseline visit).

Discussion: ReBrain protocol may improve cognitive performance, motor control and reduce the impact of cognitive impairment on everyday activities of people with MS.

Ethics committee approval: N. Registro CER Liguria: 470/2021 DB id 11839

cognitive rehabilitation

multiple sclerosis

multidisciplinary rehabilitation

cognitive impairment

Cognition is often affected in people with MS, including processing speed, attention, executive function, working memory and long-term memory (immediate and delayed recall memory). These impairments can be combined in different ways resulting in lost self-esteem and decreased quality of life, through the reduction of participation and employability ^1,2

Despite its high prevalence, there are no disease modifying therapies (DMT) effective for treating cognitive dysfunction so alternative treatment approaches are needed for mitigating this symptom and its impact on daily living skills. As consequently, the management of cognitive disturbance mainly relies on rehabilitative strategies, which have been reported to be effective in ameliorating these functional domains³ ^4,5.

Cognitive rehabilitation (CR) is an intervention that aims to improve cognitive impairment through using compensatory and restorative approaches. Although it has modest level of evidence, it has shown consistent beneficial effect⁶. It is a part of a global approach that takes into account the abilities and disabilities of an individual, as well as the personal and social factors affecting function. It is more than just dealing with cognitive factors, rather, it is a holistic approach and process ^6,7.

The last reviews about the impact of CR⁶ in MS are often focused on the neuropsychological treatment, exercise training and computer based interventions while studies examining the impact of multidisciplinary treatment are very few ^3,8. Cognitive disorders management could potentially involve, as holistic approach and process, other diverse disciplines of the rehabilitation care process, such as occupational therapy and speech and swallow therapy^9,10, but its efficiency remains speculative due to methodological variability and lack of ecologically valid outcome measures and investigation over long follow-up periods. Bagert and colleagues (2002) described strategies for dealing with cognitive problems, provided by occupational therapists, speech- language therapists, psychologists and CR specialists, making the important difference between remedial and compensatory approaches¹¹. Frequently therapists have to face cognitive impairment during rehabilitation treatment: more consistent evidence of effectiveness for cognitive multidisciplinary rehabilitation is needed to enforce the use of a tool recommended in clinical practice such as multidisciplinary approach⁴.

This is why it could be useful to build CR programs including physiotherapy, speech and swallow therapy, neuropsychological therapy and occupational therapy to face the impact on every aspect of daily living of cognitive impairment and study the real effectiveness of these programs. For example, in a more recent review about CR in MS ⁵ occupational therapy isn’t mentioned, but Deluca et al. 2020 ⁵ stated that the substantial real life impact of cognitive deficits in MS underlines the importance of effectively managing MS-related cognitive impairment. MS Society (National MS Society, s.d.) has recommended remedial interventions and accommodations that can be made to manage cognitive impairment and improve everyday functioning in both adult and paediatric MS population .

The correlation between cognitive impairments and fatigue management, depression, participation in activities of daily living (ADL) could have the key role to ameliorate the cognitive rehabilitation approach (through ecological evaluations and ecological intervention from different professional points of view). There are some works focusing on differences between objective and self-perceived cognitive performance: the existing discrepancy provides justification to consider both aspects, the goals of occupational therapy and neuropsychological interventions may not be the only improvement of cognitive test performances, but facilitating coping strategies and maximising self-perceived function. Some authors contend that research has shown correlations between psychological factors and biological disease progression, suggesting that a reduction in stress levels through improved perceptions of cognitive performance is crucial ¹⁰.

Furthermore, better cognitive functioning could be related to better movement strategies and motor control and viceversa ^12–14.

Given that most trials did not investigate effects of multidisciplinary cognitive rehabilitation the purpose of this observational study is to examine the effect of a cognitive rehabilitation approach applied in every kind of treatment combined in a defined multidisciplinary rehabilitation protocol (ReBrain).

The specific research questions are as follows:

In people with MS (PwMS) is multidisciplinary cognitive rehabilitation useful to improve processing speed, one of the most common early symptoms reported from clinicians in MS people evaluation and very often underestimated by patients¹⁵?
Are there any benefits on other cognitive domains (such as executive functions, verbal learning, verbal and visuo-spatial memory), on motor control and on perceived deficit impact in everyday life activities?
Are there any long-term benefits beyond the intervention period?

A pilot observational study will be carried out. Outpatients of the Italian MS Society Rehabilitation Center of Genoa (Italy) who show during standard clinical procedures (medical visit or rehabilitative intervention) signs of possible cognitive deficit will be enrolled by the study coordinator. During the medical visit the eligibility criteria will be checked and those patient who met the inclusion criteria will start the baseline assessment. The total assessment will last about 60 minutes in each time-points.

Participants will be randomly allocated into either experimental ReBrain group or standard therapy group. Outcome measures will be collected at baseline (T0), at the end of the period of intervention (T1) and 12-week after treatment end (T2).

Study participants and recruitment

Participant eligibility

Participants will be recruited among those followed as outpatients at the Italian MS Society (AISM) Rehabilitation Service of Genoa.

Inclusion criteria are:

Diagnosis of MS (according to 2017 revised Mc Donald criteria ¹⁶)
Age ≥18 years
Written informed consent
Symbol digit modalities test <38¹⁷
EDSS < 6
Fluent Italian speaker and good language comprehension

Exclusion criteria are:

Severe cognitive compromise (Mini Mental State Examination <19)
Psychosis or other serious psychiatric conditions
One or more relapses in the previous 3 months
Current pregnancy
MS diagnosis for less than three months

Intervention

Both ReBrain protocol and standard care will be run by psychologists, physiotherapists, occupational therapists and speech and swallow therapists of the Italian MS Society Rehabilitation Center of Genoa (Italy) who have a strong expertise in MS rehabilitation. Therapists involved in ReBrain treatments have an additional expertise in CR and cognitive impairment management.

Rebrain protocol is a CR multidisciplinary protocol which consist of 20 physiotherapy, 12 occupational therapy, 4 speech and swallow, 12 neuropsychological treatments in 2 hour twice a week sessions to maximize the effects of interventions in retaining memory of what they do during treatments. Content of the session will be organized as follow:

First and second week: Speech and swallow therapy 1 h and 1 h neuropsychological (or occupational therapy) training (twice a week)
From 3rd to 6th week 1 h neuropsychological training (or occupational therapy) and 1 hour physiotherapy (twice a week)
From 7th to 12th week 1 h occupational therapy (or neuropsychological training) and 1 hour physiotherapy (twice a week)

Standard care: The control condition will consist of a standard care protocol based on motor control and compensatory strategies to minimize the impact on participation of Multiple Sclerosis symptoms. The intervention will consist of 12 weeks, 2-hour twice a week sessions. This control program matched the study intervention in number of sessions and schedule (but not in session content) in order to control the non-specific effects of ReBrain.First and second week: Speech and swallow therapy 1 h and 1 h neuropsychological (or occupational therapy) training (twice a week)

From 3rd to 6th week 1 h neuropsychological training (or occupational therapy) and 1 hour physiotherapy (twice a week)
From 7th to 12th week 1 h occupational therapy (or neuropsychological training) and 1 hour physiotherapy (twice a week)

ReBrain session contents:

Neuropsychological therapy: the psychologist, with a restorative approach, will use Rehacom (Hasomed, Germany), a computerized rehabilitation software for cognitive intervention, paper and pencil exercises (if the patient has a low technology attitude) and mindfulness techniques^4,5,18
Physiotherapy: cognitive-motor dual task exercises, techniques for the activation of the attentive-executive system will be conducted by the physiotherapist during the sessions; they will work on balance and strengthening combining cognitive stimulation^19,20²¹.
Occupational therapy: Occupational therapy interventions will be focused mainly on activity and participation and it will range from ADL training to fatigue and stress management. Compensatory strategies will be also trained during the session to optimize the cognitive functioning at work/home, techniques for the activation of the attentive-executive system will be conducted by the occupational therapist during the sessions²²^23–25.
Speech and swallow therapy: during the session the therapist will focus the intervention on breathing control training the patients with proprioceptive exercises. Breathing control has a key role on paying attention^26,27. An active control on it could be an important tool to face cognitive fatigue and anxiety during cognitive performance and communication.

Measures

To evaluate the effectiveness of the ReBrain protocol we will use the Italian versions of BICAMS ^28,29 including Symbol Digit Modalities Test (SDMT) California Verbal Learning Test-II (CVLT-II), Brief Visual-Memory Test-Revised (BVMT-R), Shortened Balance Evaluation System Test (MiniBEST)³⁰), Perceived Deficits Questionnaire (PDQ), HospitalAnxiety and Depression Scale (HADS)³¹, Frontal Assessment Battery (FAB) , Multiple Sclerosis Quality of Life 54-items questionnaire (MSQOL-54³².

Primary Outcome Measure

SDMT is widely used because it is easy to administer, reliable and also evaluates information processing speed. slowed cognitive processing is a very common cognitive symptom of MS. Validity research shows that SDMT is a good measure of processing speed or efficiency. SDMT is the neuropsychological test most sensitive to MS cognitive disorder, it has demonstrated remarkable sensitivity in detecting not only the presence of brain damage, but also changes in cognitive functioning over time and in response to treatment ^33,34.

Secondary Outcome Measures

Mini-BESTest assesses dynamic balance, a unidimensional construct and includes items addressing anticipatory postural adjustments, reactive postural control, sensory orientation, dynamic gait
CVLT-II^29,35 is a comprehensive, detailed assessment of verbal learning and memory deficits in older adolescents and adults. It assesses encoding, recall and recognition in a single modality of item presentation (auditory-verbal). The CVLT-II is considered to be a more sensitive measure of episodic memory than other verbal learning tests. It was designed to not only measure how much a subject learned, but also reveal strategies employed and the types of errors made.
BVMT-R²⁹: assesses visuospatial learning and memory in adults.
FAB consists of six subtests exploring conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy.
PDQ: specifically for MS in order to provide a self-report measure of cognitive dysfunction. This instrument provides an assessment of several domains of cognitive functioning that are frequently affected in MS: attention, retrospective memory, prospective memory, and planning and organization. The full-length PDQ consists of 20 items
HADS ³¹is a well-validated measure that consists of two seven-item subscales to assess anxiety and depressive levels. Higher scores indicate higher levels of depressive or anxiety symptoms [40]. Unlike many similar measures, the HADS excludes somatic symptoms of anxiety and depression, which may overlap with physical illness.
MSQOL-54 ³²is a health-related QoL measure that comprises the generic Short-Form 36-item (SF-36), plus 18 MS-specific items . The 54 items are organized into 12 multi-item and two single item subscales. As for the SF-36, two composite scores (Physical Health Composite, PHC, and Mental Health Composite, MHC) are derived by combining scores of the relevant subscales. The MSQOL-54 has well documented validity in terms of content, constructs, reliability, discrimination and responsiveness.

Clinical information and measures

The following information will be also provided by the PwMS medical doctor at T0: EDSS score ³⁶, MS course (relapsing remitting, primary progressive, secondary progressive), presence/type of co-pathologies, and ongoing treatment. The physiatrist will update occurrence of new relapses at each time-point.

Dropout and suspension criteria

Subjects will have the right to withdraw from the study at any time during the intervention period. Additionally, the subject will be excluded if any unexpected worsening of motor or cognitive symptoms occur.

Statistical analysis

Descriptive statistics will be calculated for general and clinical variables. Specifically, continuous variables will be summarised by their mean and SD, or median and interquartile range; categorical variables will be summarised as numbers and percentages.

The normality assumption will be tested with the Shapiro-Wilk test. Between-group comparisons will be carried out using M-ANOVA.

Our primary end-point is the between-arm difference in T0 - T2 changes in SDMT

Longitudinal changes will be analyzed using repeated measures hierarchical (patients nested in clusters) generalized linear mixed models, accounting for the cluster effect (using a random intercepts for clusters).

All group comparisons will be carried out according to the intention-to-treat principle, i.e. participants will be analysed in the arm (ReBrain or standard care) to which they were assigned. In addition, we will: carry out a per protocol analysis; assess the sensitivity of the results to excluding patients who missed three or more ReBrain sessions. No interim analysis has been planned.

This study will examine the efficacy of a multidisciplinary CR protocol in facing the impact of cognitive impairment in PwMS.

Although previous studies have investigated the effects on cognition of physiotherapy, neuropsychological therapy and occupational therapy^4,5,7; studies investigating the effects of these kind of treatment together are very scarce.

We will analyze SDMT variation before and after the treatment period because the information elaboration speed is one of the first aspects affected in MS and that probably causes a cascade effect on other cognitive functions³³.

Possible limitations of this study are the following.

The high commitment required to patients for 3 months (two hours/twice a week) could negatively affect treatment adherence and compliance. But consistent evidence suggests that a more intensive treatment lead to significant improvements in PwMS with cognitive impairments.

With such a mixed and multidisciplinary intervention including physiotherapy, neuropsychological therapy and occupational therapy, it may be not clear to disentangle the specific contribution of each kind of treatment on patients’ improvement, on the other side each professional contribute with its own specific compensatory or remedial approach in consolidating the strategies to face the impact of cognitive impairment on everyday life, according to recent literature.

In conclusion the result of this trial may contribute to make important advance in cognitive rehabilitation building a rationale for multidisciplinary cognitive rehabilitation, as in standard care management of people with MS; to prepare the ground for a multicentric RCT study using the same protocol as ReBrain; to give the suggestion to all the professionals involved in MS care that a cognitive approach could be useful in every kind of treatment

Sitography

https://www.nationalmssociety.org/Symptoms-Diagnosis/MS-Symptoms/Cognitive-Changes

Conflicts of interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article

Contributors

VB: conceptualization, validation, writing - original draft, review and editing, visualization, data curation; JP: methodology, formal analysis, data curation, review and editing; MG: conceptualization, rehabilitative treatments, resources; SA: rehabilitative treatments, resources; AV: rehabilitative treatments, resources; LP: review and editing; MMB: review and editing; TA: review and editing; MB: review and editing, supervision; GB: review and editing, project administration, supervision.

Consent for publication

The consent for publication is included in the documentation required in the ethics committee

Ethics committee approval

N. Registro CER Liguria: 470/2021 DB id 11839

Acknowledgments

The author wishes to thank the staff of the Italian Multiple Sclerosis Society Rehabilitation Center of Genoa and Dr. Giampaolo Brichetto, Director of the Center, for their contributions to study planning.

Availability of data and material

Data will not be available in order to not compromise individual privacy of participants.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Editorial decision: Major revision
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Testing the effectiveness of a new multidisciplinary cognitive rehabilitation approach for people with Multiple Sclerosis: the ReBrain protocol

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