Quality of life and functional independence in amyotrophic lateral sclerosis: A systematic review

Journal Pre-proof QUALITY OF LIFE AND FUNCTIONAL INDEPENDENCE IN AMYOTROPHIC LATERAL SCLEROSIS: A SYSTEMATIC REVIEW ´ ´ Jessica Paloma Rosa Silva, Jose´ Bomfim Santiago Junior, Elizabete Lima dos Santos, Fernanda Oliveira de Carvalho, Iandra Maria Pinheiro de Franc¸a Costa, Deise Maria Furtado de Mendonc¸a

PII:

S0149-7634(18)30944-8

DOI:

https://doi.org/10.1016/j.neubiorev.2019.12.032

Reference:

NBR 3645

To appear in:

Neuroscience and Biobehavioral Reviews

Received Date:

9 December 2018

Revised Date:

8 November 2019

Accepted Date:

29 December 2019

´ Please cite this article as: Rosa Silva JP, Santiago Junior JB, dos Santos EL, de Carvalho FO, de Franc¸a Costa IMP, de Mendonc¸a DMF, QUALITY OF LIFE AND FUNCTIONAL INDEPENDENCE IN AMYOTROPHIC LATERAL SCLEROSIS: A SYSTEMATIC REVIEW, Neuroscience and Biobehavioral Reviews (2020), doi: https://doi.org/10.1016/j.neubiorev.2019.12.032

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QUALITY OF LIFE AND FUNCTIONAL INDEPENDENCE IN AMYOTROPHIC LATERAL SCLEROSIS: A SYSTEMATIC REVIEW

Jéssica Paloma Rosa Silva1,3; José Bomfim Santiago Júnior3; Elizabete Lima dos Santos3; Fernanda Oliveira de Carvalho1,2; Iandra Maria Pinheiro de França Costa1;

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Deise Maria Furtado de Mendonça3*

Department of Physical Therapy, Federal University of Sergipe, Lagarto, SE, Brazil.

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Health Sciences Post-Graduation Nucleus, Federal University of Sergipe, SE, Brazil.

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Laboratory of Neurobiology of Degenerative Diseases of the Nervous System,

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Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil.

*Corresponding Author:

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Dr. Deise Maria Furtado de Mendonça Address: Av. Vereador Olimpio Grande, sem número, Centro, Itabaiana.

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Campus Professor Alberto Carvalho; Departamento de Biociências; Universidade Federal de Sergipe. Sergipe, SE, Brazil. Postal Code: 49500-000 e-mail address: [email protected]

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HIGHLIGHTS 

ALS rehabilitation treatment and impact on functional independence and/or quality of life

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Functional Independence and quality of life instruments most used to evaluate ALS

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Respiratory care, mental health, communication are the focus on ALS quality of life

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ALS Patient-Perceived outcomes about quality of life is limited by disease

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severity

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ABSTRACT

Amyotrophic Lateral Sclerosis (ALS) leads to functional capacity decline, generating

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great impact in quality of life. Quality of life is directly related to physical integrity and

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functional independence. This systematic review aimed to analyze treatment protocols and their outcomes from clinical trials with focus on ALS rehabilitation that evaluated

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the effects on quality of life and functional independence from their intervention process. A literature search was conducted through MEDLINE-PubMed, Science Direct, Web of Science and Scopus databases. A total of 3630 articles were identified. Eleven

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studies met the inclusion criteria. They focused on different aspects of quality of life or

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functional independence, which are: respiratory care, mental health, communication skills and exercises. Use of bipap and inspiratory muscle training, anxiety and depression, communication devices implementation and exercises safety and tolerability were considered as key points. However, the drastic evolution of the disease is a limiting factor to the perception of quality of life improvement by patients. Further studies should be done to validate the benefits on patients' quality of life. 2

Keywords: Neurodegenerative Diseases, Neurodegeneration, Motor Neuron Disease, Rehabilitation

1. INTRODUCTION Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration and death of upper and lower motor neurons (Saberi

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et al., 2015; Hardiman et al., 2017). In most cases, patients evolve to death on average within 3 to 5 years after the onset of symptoms (Bendotti et al., 2016; Mehta et al.,

2017). The disease does not have a defined etiology, but studies point to the possibility

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that the disease is multifactorial, and some environmental and genetic factors are

mentioned (Bendotti et al., 2016). The disease does not have laboratory or imaging

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biomarkers for diagnosis. The diagnosis of ALS is made by means of clinical

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manifestations and complementary tests such as electroneuromiography (ENMG) (Brooks, 1994; Makki and Benatar, 2007). There is no cure for ALS and Riluzole is so far the only approved drug used in this population, however it only prolongs the

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patient's survival time in about 3 months (Miller et al., 2012; Hardiman et al., 2017; Schultz, 2018). Recently, Edaravone, a new drug resource with Riluzole-like action, has

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been approved for intravenous treatment, but there are still few descriptions of its

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efficacy in the literature (Rothstein, 2017; Dash et al., 2018; Okada et al., 2018; Schultz, 2018).

ALS symptoms are quite heterogeneous, with the most common symptoms

being muscle weakness, spasticity, atrophy and fasciculations (Bandeira et al., 2010; Hardiman et al., 2017). The relentless decline of functional capacity with relative cognition and sensitivity preservation is perceived in patients with ALS. It is possible to

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assume that patients with a progressive and disabling disease such as ALS are unable to enjoy living and invariably experience a decrease in their quality of life (Mello et al., 2009; Felgoise et al., 2010). Thus, it is of fundamental importance an appropriate multidisciplinary diagnosis, care and therapies with the purpose of providing greater functionality and consequent improvement in the quality of life of these patients (Felgoise et al., 2010; Morris, 2015). ALS is part of a group of diseases that have a negative effect on muscle control,

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which has a dramatic adverse effect on the function and well-being of those with this diagnosis. The disease produces significant impacts in different spheres, such as

economic, social, emotional and family life, affecting aspects of the functionality and

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quality of life of patients (Bandeira et al., 2010; Silva et al., 2014).

Quality of life is defined through the individuals' understanding of their lives and

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the context in which they are inserted, associated with their goals, expectations,

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standards and concerns broadly related to their physical and psychological conditions, independence level, social relations and personal beliefs (The WHOQOL Group, 1995) (Figure 1). This concept is directly related to functional independence, which is

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characterized by the functional activities that patients point as fundamental for the maintenance of their physical and psychological well-being (Orient-López et al., 2006).

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All of which is carried out congruently through the integration of cognitive, behavioral,

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sensory and motor resources (Cesário et al., 2006; Mcnaughton et al., 2005). Considering the non-existence of a cure for ALS, patients need a specific assistance and care based on their clinical condition, accompanying every evolutionary manifestation of the disease, in a continuous scheme of therapeutic readjustment (Majmudar and Paganoni, 2014; Soofi et al., 2018).

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In the rehabilitation process, the primary goal is to help patients to stay functionally active in a safe and effective way (Hobson and McDermott, 2018). The process should positively impact their quality of life, although the main characteristic of the disease is the reduction of mobility with a consequent decline in daily life activity and instrumental activities of daily life. This decline interferes with the subject's selfcare ability, which consists of the individual's ability to take care of themselves, providing benefits to their health and well-being and is directly linked to changes in the

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process of illness (Silva et al., 2014; Hobson and McDermott, 2018). During rehabilitation, the multidisciplinary team provides the patient with a

comprehensive and individual practice (Majmudar and Paganoni, 2014). Preserving,

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maintaining, developing or restoring the integrity of systems or functions, as well as the maintenance of functionality and quality of life are the purposes of the rehabilitation

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process (Honorato and Martins, 2008). In order to do so, it is necessary to use specific

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evaluation instruments for the variables to ascertain the actual functional stage of the patient, as well as to understand the impact of this decline on quality of life and functional independence. Based on that, it is possible to prepare an individual,

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accessible and effective therapeutic plan (Cappellato et al., 2015). The present study is based on a systematic literature review that aims to analyze

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clinical trials that evaluated treatment effects of rehabilitation programs, in its

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multidisciplinary concept, in functional independence and quality of life of patients. It was included only clinical trials that used validated instruments of measurement in their intervention process.

2. MATERIAL AND METHODS

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This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and supplemented by guidance from the Cochrane Collaboration Handbook. A protocol of this systematic review was designed a priori and was registered in the PROSPERO database (registration number CRD42019115729).

2.1. Search Strategy

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Four databases (Internet sources) were used to search for appropriate papers that fulfilled the purpose of this study. Those included the National Library of Medicine (MEDLINE-PubMed), Science Direct, Web of Science and Scopus, using different

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combinations of the following keywords: "amyotrophic lateral sclerosis",

"rehabilitation", “quality of life”, “functional independence”, "clinical trial". The

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databases were searched for studies conducted in the period up to and including

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December 2018.

The research strategy was designed to identify clinical management studies focused on ALS rehabilitation. Thus, any clinical trial using rehabilitation practices was

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eligible, while pharmacological clinical trials was excluded. Since this study was restricted to clinical trials, reviews, systematic reviews and meta-analyzes articles were

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also excluded. The population should be composed of ALS patients, with no phenotype,

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age or gender restriction. Patients should have been treated by a rehabilitation professional or a group of rehabilitation professionals. Rehabilitation program could be goal-directed to any aspect of ALS functional features and the studies must consider evaluation of impact on quality of life and functional independence after treatment. Only articles that evaluated quality of life and functional independence through validated instruments of measurement, in their intervention process, were selected.

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After articles selection, information were collected on study characteristics and design, as country, sample size, controls, the functional status of patients, diagnostic criteria, type of ALS onset, treatment protocol, number of treatment sections or time of protocol, results obtained from treatment and impact in patient functionality and in quality of life. Citations were manually limited to clinical trials of patients with ALS. Additional papers were included in our study after analyses of all references from the

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selected articles. We did not contact the authors of such articles, nor did we try to identify unpublished data.

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2.2. Study Selection

All electronic search titles, selected abstracts and full-text articles were

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independently reviewed by a minimum of two reviewers (JPRS, JBSJ, ELS).

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Disagreements over inclusion/exclusion criteria were resolved by means of a consensus among the reviewers. The following inclusion criteria were applied: clinical trials, human studies, ALS, quality of life and functional independence. Studies were excluded

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according to the following exclusion criteria: studies that did not fit the above characteristics, review articles, meta-analyzes, abstracts only, conference proceedings,

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editorials/letters, case reports. Selected abstracts and, later, selected full-text articles

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were brought to full review.

2.3 Quality assessment We assessed the risk of bias according to the Cochrane guidelines for

Randomized Controlled Trials (RCTs). Six domains for evaluation were assessed: sequence generation and allocation concealment (selection bias), blinding of

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participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective outcome reporting (reporting bias). We rated the risk of bias as low, unclear, or high according to established criteria and the total score was obtained by assigning 1 point for each “low” answer and 0 points for “unclear” or “high” answers, for a total quality score ranging from 0 to 6. A study was considered with low quality when less than 2 of 6 items were met. Two investigators independently (J.P.R.S. and D.M.F.M.) conducted this

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assessment and any disagreements were resolved by consensus.

2.4 Data extraction

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Data were extracted by one reviewer using standardized forms and then checked by a second reviewer. From all of the evaluated studies the following information was

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extracted: Study design; Population (n) of each study; Average age (in years); Time

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with ALS’ diagnosis; Treatment protocol; Number of treatment sessions; If there is presence of control group or not; Evaluation Tools (quality of life and functional

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3. RESULTS

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independence); Results; Conclusions.

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3.1. Study selection The process followed for article selection is presented in Figure 2. A total of

3,630 articles were identified: 2,045 articles on Science Direct, 468 on SCOPUS, 304 on WEB OF SCIENCE and 813 on PubMed. After deleting duplicate articles, we proceeded with the reading of 2,166 titles and abstracts. 175 articles were selected for full reading. After the assessment of the articles not shown in full, the duplicates, the

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letters to the reader, the case studies, the articles that were not in English, Spanish or Portuguese or whose subject did not include the approach of this study, nine articles remained. At the end, after adding two articles found in the manual search of the literature, a total of eleven articles were finally selected (Pinto et al., 1995; Silvoni et al., 2009; Pinto et al., 2012; Pinto and Carvalho, 2013; Londral et al., 2015; Van Groenestijn et al., 2015; Raglio et al., 2016; Bertella et al., 2017; Braga et al., 2018; Vitacca et al., 2018; Clawson et al., 2018). There was a high level of agreement on

(Kappa index > 95%).

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3.2. General characteristics of included studies

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inclusion/exclusion between the two investigators who screened the retrieved articles

The selected studies were conducted in four different countries: Portugal (5),

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Italy (4), USA (1), and Netherlands (1), and they were published between 1995 and

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2018 (Table 1).

From all evaluated studies, two were experimental, controlled, longitudinal type

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(Pinto et al., 1995; Vitacca et al, 2018). One study was experimental, controlled, longitudinal, blinded type (Silvoni et al., 2009). Four studies were experimental,

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controlled, longitudinal, randomized type (Londral et al., 2015; Raglio et al., 2016; Bertella et al., 2017; Clawson et al., 2018). Two studies were experimental, controlled,

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longitudinal, blinded, randomized type (Pinto et al., 2012; Van Groenestijn et al., 2015). One study was controlled, longitudinal, blinded, quasi-randomized type (Braga et al., 2018). Only one study used historical control (Pinto and Carvalho, 2013). Details of methodology are presented in Table 1. All studies mentioned having inclusion and exclusion criteria of participating patients but not all of them described these criteria. In six trials the sampling was 9

selected according to the criteria proposed by El Escorial Criteria (Pinto et al., 1995; Silvoni et al., 2009; Pinto et al., 2012; Londral et al., 2015; Bertella et al., 2017; Clawson et al., 2018). The work of Pinto and Carvalho (2013) does not report patient selection through the El Escorial Criteria, however, probably due to the fact that it is a short communication, since the inclusion of patients through the El Escorial Criteria evaluation seems to be a standard protocol of the group in previous works. Van Groenestijn and coworkers (2015), Raglio and coworkers (2016); Braga and coworkers

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(2018), and Vitacca and coworkers (2018) do not mention the use of the criterion. The number of patients in each study ranged from 18 to 194. The age of ALS patients from intervention groups ranged between 29 to 83, and time to diagnosis of

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ALS patients, when described, was between 20 and 36.8 months. In the evaluated

population, regarding ALS clinical subtypes, one study did not specify the clinical

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presentation of the disease and in eight studies, patients with the classic and bulbar

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forms were evaluated. In fact, two studies had a focus on patients with ALS in its bulbar form (Pinto et al., 1995; Londral et al., 2015). One of the studies reported inclusion with

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Primary Lateral Sclerosis patients in their sample (Raglio et al., 2016). However, there was a predominance of the classical form of the disease. Two studies addressed the

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educational level of the patients.

Four of the studies used ALS Functional Revised Score (ALSFRS-R) as

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determinants for inclusion or exclusion of the patients in their experiments (Pinto et al., 2012; Londral et al., 2015; Raglio et al., 2016; Braga et al., 2018). Patients who presented associated comorbidities, such as diabetes, dementia, pulmonary disturbances, absence of measurable ocular movements, cardiac insufficiency and/or forced vital capacity (FVC) of less than 80% were excluded in eight studies.

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Some of the studies had as primary objective to verify the increase or not in the quality of life of patients with ALS, from the intervention. Two of them included caregivers within this approach (Van Groenestijn et al., 2015; Londral et al., 2015). Three studies had also as objective to verify the effect of the intervention on the survival of the patients. All studies used patients of both genders, but there was a predominance

3.3 Quality of life and functional independence

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of male sex in eight of them.

Regarding the analyzed parameters, the patients were evaluated in the domains of functionality and quality of life in an isolated or associated way. Both aspects were

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evaluated concomitantly in five studies. The functionality aspect was evaluated in all studies, with ALSFRS being the most used instrument.

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Quality of life was evaluated in six studies, with variability among the

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instruments used. Only one study used the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) (Van Groenestijn et al., 2015) and only another one used

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the ALS Specific Quality of Life Instrument-Revised (ALSSQoL-R) (Clawson et al., 2018) to evaluate patients with ALS. Other studies also used the following

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questionnaires: MQoL Questionnaire, World Healt Organization Quality of Life questionnaire (WHOQOL-BREF), Analog scale for life satisfaction, Euro Qol-5D (EQ-

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5D) and Mental Component Summary (SF-36-MCS). In two of the studies, the use of more than one quality of life assessment tool was observed (Van Groenestijn et al., 2015; Londral et al., 2015). It was clear that among the instruments for functionality evaluation, the ALSFRS was the most used. However, in terms of quality of life a reduced use of ALSAQ-40 or ALSSQoL-R was observed. Details of methodology related to evaluation 11

tools and analysis are presented in Table 2. Other methodological details from studies can be found in Figure 3. In general, the studies focused on different aspects of quality of life such as respiratory care, mental health, and communication skills. Two studies were related to the safety and tolerability of moderate to intense exercise (Braga et al., 2018; Clawson

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et al., 2018).

3.3.1 Respiratory care

From the eleven studies, six were focused on respiratory function, with the

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purpose of maintaining functionality and consequently with improvement in quality of life (Pinto et al., 1995; Pinto et al., 2012; Pinto and Carvalho, 2013; Bertella et al.,

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2017; Braga et al., 2018; Vitacca et al., 2018). Two of the studies had a population of

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ALS patients with bulbar onset only (Pinto et al., 1995; Londral et al., 2015) and eight studies had a population that also included patients with spinal onset (Silvoni et al., 2009; Pinto et al., 2012; Pinto and Carvalho, 2013; Van Groenestijn et al., 2015;

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Bertella et al., 2017; Braga et al., 2018; Clawson et al., 2018; Vitacca et al., 2018).

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One of the studies evaluated the effect of bilevel intermitent positive air pressure (Bipap) in patients with bulbar ALS (Pinto et al., 1995), two were related to inspiratory

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muscle training (Pinto et al., 2012; Pinto and Carvalho, 2013), and two used noninvasive ventilation in bulbar and spinal onset ALS patients (Bertella et al., 2017; Vitacca et al., 2018). All studies have shown benefit, as vital capacity improvement, tendency to reduce nocturnal oxygen saturation abnormalities or increase of survival, among others; however, the drastic evolution of the disease limits the gain of functionality and the perception of quality of life improvement by patients. 12

3.3.2 Mental health From the eleven studies, two were focused on the psychological aspects of ALS patients, considering elements such as anxiety and depression (Van Groenestijn et al., 2015; Raglio et al., 2016). Regarding general characteristics of these studies, the study from Van Groenestijn and coworkers (2015) was not selective about clinical presentation of the disease, having bulbar and spinal onset patients. The study from

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Raglio and coworkers (2016) do not described clearly the onset, however they used

acceptable respiratory functions as one of the criteria of inclusion. None of the studies were selective for gender.

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One of the studies used a musical therapy approach and the other used Cognitive

Behavioral Therapy. Both studies used different scales to measure their outcomes, using

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as intersection points the ALSFRS, scales for assessment of quality of life, and anxiety

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and depression scales. One of the studies had an approach to caregivers concomitantly (Van Groenestijn et al., 2015). Both studies point to a great impact on patients' quality

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of life from the interventions performed but suggest that further studies should be done

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to validate these benefits.

3.3.3 Communication skills

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Two of the eleven studieswere focused on the implementation of communication devices and correlation with quality of life was performed (Silvoni et al., 2009; Londral et al., 2015). One study included only patients with bulbar ALS (Londral et al., 2015). One of the studies evaluated the impact on the quality of life of the caregiver as well (Londral et al., 2015).

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One of the studies evaluated the use of a modern tablet device, as an assistive communication device, to evaluate bulbar-onset patients (Londral et al., 2015). The other study evaluated the use of a brain computer interface in patients with ALS in early and intermediate stage of the disease (Silvoni et al., 2009). Both studies evaluated the patients' ability to maintain autonomy in communication with the use of devices and consequent impact on quality of life. Both studies consider possible benefits with the use of assistive devices and both suggest that the tools should be introduced in the early

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stages of the disease.

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3.4 Caregivers

Two studies carried out an approach with the caregiver, who mostly presented as

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the spouse of the patients, being female gender predominant among the participants

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3.5 Risk of bias

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(Van Groenestijn et al., 2015; Londral et al., 2015).

Figure 4 and Figure 5 provide a graph and a summary, respectively, of the bias

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risk of the eleven studies. Only four studies were adequate for random sequence generation, three presented a risk of uncertain bias because they did not inform the

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randomization process and four studies presented a high risk of bias in random sequence generation (selection bias). Four studies had a high risk of allocation concealment (selection bias), only three presented low risk of bias, and the other four presented a risk of uncertain bias. Most of the studies presented low risk of bias in relation to the blindness of participants and professionals and blinding the outcome assessment. Eight of the studies cited here presented a low risk of incomplete outcome and selective 14

outcome, while the remaining studies showed a high bias risk. Considering the quality score of at least two points of the studies, only the article by Silvoni et al. (2009) would be considered of low methodological quality, because it presented only one point in the bias risk analysis. The other studies could be then classified as good quality.

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4. DISCUSSION 4.1 Summary of findings

Despite the complexity of the disease for patient and family, few studies are found in the literature containing evaluation of quality of life and functionality of

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patients with ALS. The disease has a major impact on patients and families. The disease

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drastically changes the course of life of all people involved, directly or indirectly (Majmudar and Paganoni, 2014). Gradually, decreasing mobility leads to difficulty in

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carrying out activities of daily living, and sometimes breathing, communication, and eating are also impaired (Cesário et al., 2006; Bandeira et al., 2010; Felgoise et al.,

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2016; Schultz, 2018).

This systematic review had a focus on analyzing studies related to quality of life

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and functional independence evaluation and treatment of ALS patients. From the

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selected studies, considering the criteria described above, the first study was conducted only in 1995, even though the disease was described more than 125 years ago. Of course, there are many factors to be observed in the disease. However, it is necessary to focus on the quality of life and functionality of these patients. The studies comprised in this review had a good methodological design, presenting significant interventions and good number of patients, although the disease

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was described as rare. Control patients from the evaluated studies were sex and age matched and with enough number to perform quantitative analysis. Patient selection, in most of the studies, included El Escorial Criteria, the diagnostic method currently used by specialists all over the world. In addition, patients with bulbar and spinal ALS were included in most studies. There is, however, no search for patient’s evaluation specifying sporadic or familial ALS type, as well as there is no search specifying patients by genetic aspects. Since ALS has neuropathological features and genetic

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variation (Morris, 2015; Saberi et al., 2015; Hardiman et al., 2017), as even different phenotypes, these aspects interfere in the prognosis and could also be considered in future studies.

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Regarding the studies considered in this review, it was possible to observe that

the functionality aspect was evaluated in all of them, with ALSFRS being the most used

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instrument. Studies demonstrate the importance of ALSFRS, a specific tool, for

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functional evaluation of a devastating disease such as ALS. However, in terms of quality of life we observed a reduced use of specific survey. Quality of life is related to

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the individual's perception of yourself within your life context. This includes goals, expectations and concerns, for example. It is perceived that ALS is a disease that has a

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strong impact on psychic aspects of patients (Pagnini, 2013). In this way, healthy policies aimed at ALS care should be adopted.

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Quality of life in patients with ALS can be assessed from a specific

questionnaire, such as ALSAQ-40 (Jenkinson et al., 2000; Diaz-Gomez and OrtizCorredor, 2017). The domains evaluated in ALSAQ-40 measure aspects of individuals with the disease Jenkinson et al., 1999). In the studies evaluated in this review, only one chose to work with ALSAQ-40 (Van Groenestijn et al., 2015), but the most affected domains of the patients who were part of the research were not available. Perhaps in 16

future studies such aspects could be considered, since quality of life, depending on the most affected domains, may have a different meaning from one patient to another. Respiratory care, mental health, and communication skills were the focus on some papers, but exercise was also evaluated. One study evaluated resistance and endurance exercises considering safety and tolerability. Despite of safety, it was observed that there were no diferences in quality of life or ALS function in patients who practiced such exercises (Clawson et al., 2018). One other study evaluated

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Cardiopulmonary Exercise Testing (CPET) efficiency to define exercise intensity to

ALS patients and researchers reported that the use of CPET is feasible to define exercise and can improve functional outcome in ALS (Braga et a., 2018). It is well established

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that physical exercise brings many benefits, however there are evidences showing

potential hazardous of exercise to ALS patients. Though, doing to these evidences, a

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patient-specific treatment program, under fully supervising and constant monitoring,

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exercise could be incorporated into ALS rehabilitation program in a safe way. Despite not improving muscular strength of muscles already compromised by the disease, mild-

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to-moderate exercise could be important for different aspects of quality of life to ALS

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patients (Majmudar and Paganoni, 2014; Lisle and Tennison, 2015; Bello-Haas, 2018).

4.2 Is respiratory care the most important aspect of quality of life in ALS

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management?

Respiratory impairment is one of the hallmarks of ALS. Although not all

patients experience respiratory difficulties, in those who develop this condition the alteration becomes a major complication.

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Noninvasive ventilation (NIV) is a tool that can be used in the respiratory care of patients with ALS, but there is no consensus as to when it is the best moment to start. Some respiratory biomarkers have been tested as possible parameters for implantation of NIV and among them is the Diaphragmatic Compound Muscle Action Potential (DCMAP). However, in a study by Yamauchi and coworkers (2014), the efficacy of DCMAP was evaluated and the outcome was not as expected. A total of 43 patients with definite or probable ALS were investigated in relation to progression of respiratory

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failure and it was concluded that DCMAP is not always a reliable clinical indicator regarding the decision of when to introduce NIV in this population.

In one of the reviews, the researchers demonstrated the benefits of using Bipap

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in patients with bulbar ALS (Pinto et al., 1995). In this study, 20 patients with bulbar

ALS, with mean age of 57 years, were submitted to Bipap, and another 10 patients were

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treated with palliative management. The evolution of patients was evaluated every 3

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months through different assessments. Clinical parameters, bulbar and spinal Norris scorers, analog scale for life satisfaction, and Barthel score were performed. The authors

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report that clinical evolution curves and clinical parameters were not statistically different between groups, except for vital capacity value. Their results show that there is

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significant increase in total survival time and in survival from onset of diurnal disorders of gas exchanges. Despite the positive results obtained with the use of Bipap, there was

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no correlation with the increase of the quality of life perception from patients. Bertella and coworkers (2017) and Vitacca and coworkers (2018) also investigated the use of NIV in ALS patients. Bertella and coworkers, in fact, aimed to evaluate the effectiveness of acceptance and adherence to NIV in not-hospitalized ALS patients, since commonly NIV begins in an in-hospital regime. In a 3-month follow-up, these researchers observed no differences in acceptance and adherence failure between 18

groups, leading to consider that not-hospitalized initiation of NIV in ALS, regarding acceptance and adherence, is as effective as inpatient initiation. Vitacca and coworkers (2018) aimed to evaluate if NIV prescription to ALS patients with forced vital capacity ≥80% would extend the survival time when compared to later-start of NIV. In their

study, clinical and respiratory functional data were compared, over a 3-year follow-up, and they observed that early NIV prescription prolongs the free time from diagnosis to death.

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Regarding therapeutic resources in the different phases of ALS, little is known about the effectiveness of exercise to respiratory muscles. Plowman (2015), in a

literature review about exercise in patients with ALS in the period between 1960 and

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2014, observed that respiratory exercises used in the early stages of the disease, in mild

consequent increase of survival.

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and medium levels, obtained a positive significance in the functional areas with a

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In one of the reviews, the researchers evaluated respiratory exercise by the implementation of an inspiratory muscle training (Pinto et. al., 2012). The study was

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performed with a total of 26 ALS patients. Patients were divided in two groups. One group started the training protocol and did it for eight months. The other group was

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treated palliatively during the first four months and started the muscle training protocol after this time. Over eight months, patients were evaluated three times: at the beginning,

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within four months, and at the end of the training programm. ALSFRS, respiratory tests, neurophysiological measurements, fatigue and quality of life evaluation were performed. Although the researchers observed that the training was not harmful, it was observed that there was no significant difference between the two groups of patients.

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Pinto and Carvalho (2013), continuing the previous work of Pinto and coworkers (2012), evaluated the muscular training program in a long-term impact on survival. A total of 18 patients with ALS were submitted to the same muscular training program previously used by the group. A historical group was used as control. Seven patients underwent 8 months of treatment, five patients underwent 12 months, two patients at eight months, three patients at 24 months and one patient at 32 months. ALSFRS and respiratory tests were performed. The study concluded that inspiratory muscle training

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is a significant predictor of survival in early affected patients and emphasizes that the method tends to reduce nocturnal oxygen saturation abnormalities. The group suggested that the training program, as well as other exercise training programs, could bring

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cardiovascular benefits, neural and muscular adaptations and increase the release of neuroprotective molecules.

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Considering that ALS does not have laboratory or diagnostic imaging tests, one

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of the factors that can lead to medical mistrust is the loss of functionality linked to respiratory failure, which is in some cases the main manifestation of the disease leading

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to the patient in most cases to emergency invasive mechanical ventilation (Sato et al., 2014). Association of continuous monitoring techniques and therapeutic actions can

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minimize the damage caused by respiratory changes in ALS, increase survival and

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ensure improvement in quality of life. (Sanjuán-López et al., 2014; Orsini et al., 2015).

4.3 Communication versus mental healthy The reduction or loss of speech associated with functional decline leads to a

reduction in the quality of life of ALS patients. Felgoise and coworkers (2016) observed greater impact on the quality of life of patients with oral communication impairment in

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the initial phase of the disease when compared with those with physical limitations and preserved oratory (Felgoise et al., 2016). In the literature, the use of the brain-computer interface as a resource in several aspects such as communication and leisure has been described, and it was mainly observed in patients in the more advanced stages of the disease (Lancioni et al., 2015). In the early stages of the disease, when the patient has functional upper limbs, writing has been used as a form of communication between patients and caregivers (Bloch and

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Clarke, 2013). This was not different from two of the studies included in this systematic

review. Silvoni and coworkers (2009) and Londral and coworkers (2015) focused on the implementation of communication devices and correlation with quality of life. A tablet

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device and brain-computer interface were used. Both studies showed that quality of life of patients exhibited improvement, but they also suggest that the tools should be

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introduced in the early stages of the disease.

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Some ALS patients receive late care and consequently have severe limitations such as dysphonia, dysarthria, and dysphagia, the latter being responsible for events

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such as gagging and bronchoaspiration (Rubin et al., 2012; Makkonen et al., 2016). Difficulties in speech associated with motor changes or one of these dysfunctions alone

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commonly promote the manifestation of emotional decline. Nevertheless, aspects such as depression and the consequent desire to die were not observed by Rabkin and

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coworkers (2015). Although higher rates of anxiety were observed in depressed patients.

Two of the studies included in this systematic review worked on anxiety and depresssion evaluation of ALS patients and their relationship with quality of life (Van Groenestijn et al., 2015; Raglio et al., 2016). The approach from Raglio and coworkers (2016) was performed with musical therapy and Van Groenestijn and coworkers (2015) 21

used Cognitive Behavioral Therapy. In both studies, ALS patients exhibited significantly improvement after treatment when re-evaluated with quality of life scales.

4.4 General role and importance of caregivers in ALS Diseases with progressive fucntional decline like ALS lead patients to a constant support at home. In most cases, these people are spouses or first-degree family

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members. In this systematic review the findings were not different. The constant care associated with the affective relations makes depression and anxiety a common event among caregivers (Chen et al., 2015).

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Concomitant to disease progression is the decline in communication, which may have a significant impact on the caregiver-patient relationship. This may lead to deficits

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in the quality of life indices of this population. Some strategies have been developed to

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enable better communication among them. Hwang and collaborators (2014) have demonstrated the effectiveness of an auxiliary device for ocular tracking in the quality

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of life and consequent reduction of the overload of the caregivers. This would promote autonomy for the patient and consequentely greater efficiency in communication

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between patient and caregiver.

In addition to emotional and communication factors, a more drastic aggravating

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factor in the progression of the disease is the physical and motor incapacity. All of this must be considered together with the high workload that is dedicated to promoting care for such patients. In this way, caregivers should be part of ALS care program in order to create strategies to support and ensure the well-being of this population (Galvin et al., 2016). From seven studies evaluated in the present review, two of them also had caregivers as targets of their research. 22

4.5 Interventions proposed by the analyzed studies All studies proposed interventions aimed at minimizing the alterations resulting from the progression of the disease in the communication, psychological, and respiratory aspects, being the latter the most explored in most articles. Strategies such as Inspiratory Muscular Training (IMT) associated with the use of Non-Invasive

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Mechanical Ventilation (NIMV), and intermittent positive two-way air pressure (Bipap) were used to demonstrate benefits to patients. Mental health and skills improvement

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therapies have also been proposed.

5. CONCLUSION

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Until now ALS has no cure and its treatment is bascically symptomatic. Some therapies slow down the progression of the disease and, consequently, increase survival.

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ALS patients have many needs, since the disease greatly compromises motor skills, communication and, sometimes, nourishment and breathing. Invariably, the condition

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conducts to enormous decrease in functional independence and quality of life. Quality of life is related to the patient's individual perception about himself/herself in cultural

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and social context, also expectations and own interests. In this way, clinical management of ALS patients must consider an approach to quality of life improvement. Patient must be carefully evaluated in all peculiarities of ALS disease, given its devastation and darkness. Specific intruments for analysis of this population are needed and the benefit of different kind of treatments and support on quality of life must be evaluated. This systematic review approached this issue. The reviewed studies had 23

focus on different aspects of functional independence and/or quality of life, and their interventions were related to respiratory care, communication, mental healthy or exercises. It was possible to conclude that much more efforts should be invested on the quality of life of patients with ALS. The disease, for being so disabling, also impacts a lot on the caregiver. When possible, a program focused on quality of life of caregivers

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should be elaborated as well.

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Bloch, S., Clarke, M., 2013. Handwriting-in-interaction between people with ALS/MND and their conversation partners. Augment Altern Commun. 29 (1), 54-67.

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Braga, A.C.M., Pinto, A., Pinto, S., de Carvalho, M., 2018. The role of moderate aerobic exercise as determined by cardiopulmonary exercise testing in ALS. Neurol Res

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Brooks, B.R., 1994. El Escorial World Federation of Neurology criteria for the

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diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial "Clinical limits of amyotrophic lateral sclerosis" workshop contributors. J Neurol Sci. 124 (S), 96-107. Budnick, A., Dräger, D., Blüher, S., Kummer, K. 2015. Family caregivers as a target group for health promotion and prevention. Gesundheitswesen. 77 (S), 41-42. 25

Cappellato, V., Bosco, N., Chiò, A., Calvo, A., 2015. Curable or treatable? The implications of different definitions of illness when treating patients suffering from amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 17 (12), 15-20. Carvalho, T.L., de Almeida, L.M., Lorega, C.M., Barata, M.F., Ferreira, M.L., de BritoMarques, P.R., Correia, C.C., 2016. Depression and anxiety in individuals with amyotrophic lateral sclerosis: a systematic review. Trends Psychiatry Psychother. 38

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Clawson, L.L., Cudkowicz, M., Krivickas, L., Brooks, B.R., Sanjak, M., Allred, P., Atassi, N., Swartz, A., Steinhorn, G., Uchil, A., Riley, K.M., Yu, H., Schoenfeld, D.A., Maragakis, N.J, neals consortium, 2018. A randomized controlled trial of resistance and

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edaravone: revisiting the clinical pharmacokinetics of the only two amyotrophic lateral sclerosis therapeutics. Clin Pharmacokinet. 57 (11), 1385-1398. Diaz-Gomez, M.F., Ortiz-Corredor, F., 2017. Design and validation of a classification system for assessing the degree of disability of patients with amyotrophic lateral sclerosis. Rev Neurol. 64 (3), 112-118.

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Federal Council of Physiotherapy and Occupational Therapy, 1978. Resolution No.80. Approves the norms for qualification to practice the professions of physiotherapist and occupational therapist and gives other measures. Official Journal of the Union, Brasília, DF. Felgoise, S.H., Zaccheo, V., Duff, J., Simmons, Z., 2016. Verbal communication impacts quality of life in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 17 (3-4), 179-183.

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Felgoise, S.H., Chakraborty, B.H., Bond, E., Rodriguez, J., Bremer, B.A., Walsh, S.M., Lai, E.C., McCluskey, L., Simmons, Z., 2010. Psychological morbidity in ALS: the

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Honorato, E.S., Martins, E.F., 2008. Evidences for the targeting of physiotherapeutic intervention in the kinetic-functional alterations generated by Amyotrophic Lateral Sclerosis. Rev Health Care. 6 (15), 66-74. Hwang, C.S., Weng, H.H., Wang, L.F., Tsai, C.H., Chang, H.T., 2014. An eye-tracking assistive device improves the quality of life for ALS patients and reduces the caregivers' burden. J Mot Behav. 46 (4), 233-238.

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Jenkinson, C., Levvy, G., Fitzpatrick, R., Garratt, A., 2000. The amyotrophic lateral sclerosis assessment questionnaire (ALSAQ-40): tests of data quality, score reliability and response rate in a survey of patients. J Neurol Sci. 180 (1-2), 94-100. Jenkinson, C., Fitzpatrick, R., Brennan, C., Swash, M., 1999. Evidence for the validity and reliability of the ALS assessment questionnaire: the ALSAQ-40. Amyotroph Lateral Scler Other Motor Neuron Disord. 1 (1), 33-40. Lisle, S., Tennison, M., 2015. Amyotrophic lateral sclerosis: the role of exercise. Curr

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Sports Med Rep. 14 (1), 45-46. Lancioni, G.E., Simone, I.L., De Caro, M.F., Singh, N.N., O'Reilly, M.F., Sigafoos, J.,

Ferlisi, G., Zullo, V., Schirone, S., Denitto, F., Zonno, N., 2015. Assisting persons with

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Londral, A., Pinto, A., Pinto, S., Azevedo, L., De Carvalho, M., 2015. Quality of life in

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Amyotrophic Lateral Sclerosis patient and caregivers: impact of assistive communication from early stages. Muscle Nerve. 52 (6), 933-941. Majmudar, S., Wu, J., Paganoni, S., 2014. Rehabilitation in amyotrophic lateral

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Makkonen, T., Korpijaakko-Huuhka, A.M., Ruottinen, H., Puhto, R., Hollo, K., Ylinen, A., Palmio, J., 2016. Oral motor functions, speech and communication before a definitive diagnosis of amyotrophic lateral sclerosis. J Commun Disord. 61, 97-105.

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Mcnaughton, H.K., Weatherall, M., Mcpherson, K.M., 2005. Functional measures across neurologic discase states: analysis of factores in common. Archives Physical Medicine and Rehabilitation, Reston. 86 (11), 2184-2188. Mello, M.P., Orsini, M., Nascimento, O.J.M., Pernes, M., Lima, J.M.B., Heitor, C., Leite, M.A.A., 2009. The hidden patient: Quality of Life among caregivers and patients diagnosed with Amyotrophic Lateral Sclerosis. Rev Bras Neurol. 45 (4), 5-16. Mehta, P., Horton, D.K., Kasarskis, E.J., Tessaro, E., Eisenberg, M.S., Laird, S.,

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Morris, J., 2015. Amyotrophic Lateral Sclerosis (ALS) and related motor neuron diseases: an overview. Neurodiagn J. 55 (3), 180-194. Okada, M., Yamashita, S., Ueyama, H., Ishizaki, M., Maeda, Y., Ando, Y., 2018. Long-

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term effects of edaravone on survival of patients with amyotrophic lateral sclerosis. eNeurologicalSci. 11, 11-14.

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Orsini, M., Lopes, A.J., Menezes, S.L., Oliveira, A.B., Freitas, M.R., Nascimento, O.J., Guimarães, F.S., 2015. Current issues in the respiratory care of patients with amyotrophic lateral sclerosis. Arq Neuropsiquiatr. 73 (10), 873-876.

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Pagnini, F., 2013. Psychological wellbeing and quality of life in amyotrophic lateral sclerosis: a review. Int J Psychol. 48 (3), 194-205. Pinto, A.C., Evangelista, T., Carvalho, C., Alves, M.A., Sales, M.L., 1995. Respiratory assistance with a non-invasive ventilator (Bipap) in MND/ALS patients: survival rates in a controlled trial. Journal of the Neurological Sciences. 129, S19-S26. Pinto, S., Swash, M., de Carvalho, M., 2012. Respiratory exercise in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 13 (1), 33-43.

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Saberi, S., Stauffer, J.E., Schulte, D.J., Ravits, J., 2015. Neuropathology of Amyotrophic Lateral Sclerosis and its variants. Neurol Clin. 33 (4), 855-876. Sanjuán-López, P., Valiño-López, P., Ricoy-Gabaldón, J., Verea-Hernando, H., 2014. Amyotrophic lateral sclerosis: impact of pulmonary follow-up and mechanical ventilation on survival. A study of 114 cases. Arch Bronconeumol. 50 (12), 509-513. Sato, K., Morimoto, N., Deguchi, K., Ikeda, Y., Matsuura, T., Abe, K., 2014. Seven amyotrophic lateral sclerosis patients diagnosed only after development of respiratory

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of individuals with amyotrophic lateral sclerosis. Qual Life Res. 27 (4), 845-856. The WHOQOL Group 1995. The World Health Organization quality of life assessment (WHOQOL): position paper from the World Health Organization. Social Science and Medicine. 10, 1403-1409. van Groenestijn, A.C., Schröder, C.D., Visser-Meily, J.M., Reenen, E.T., Veldink, J.H., van den Berg, L.H., 2015. Cognitive behavioural therapy and quality of life in

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psychologically distressed patients with amyotrophic lateral sclerosis and their caregivers: Results of a prematurely stopped randomized controlled trial. Amyotroph Lateral Scler Frontotemporal Degener. 16 (5-6), 309-315. Vitacca, M., Montini, A., Lunetta, C., Banfi, P., Bertella, E., De Mattia, E., Lizio, A., Volpato, E., Lax, A., Morini, R., Paneroni, M., ALS RESPILOM Study Group, 2018. Impact of an early respiratory care programme with non-invasive ventilation adaptation in patients with amyotrophic lateral sclerosis. Eur J Neurol. 25 (3), 556-e33.

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Yamauchi, R., Imai, T., Tsuda, E., Hozuki, T., Yamamoto, D., Shimohama, S., 2014. Respiratory insufficiency with preserved diaphragmatic function in amyotrophic lateral

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sclerosis. Intern Med. 53 (12), 1325-1331.

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LEGENDS

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Figure 1. Summary of the different aspects relevant to a person's quality of life.

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Figure 2. Flow diagram for literature searching and screening. The flow diagram follows the PRISMA guidelines.

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Records identified through SCIENCE DIRECT = 2,045; PUBMED = 813; WEB OF SCIENCE = 304; and SCOPUS = 468: (n = 3,630)

1,464 citations duplicates

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348 studies deemed potentially relevant by title review

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1,818 citations excluded not relevant citations by title review

173 citations excluded: not relevant by abstract review

166 citations excluded: not relevant by full text review

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175 studies deemed relevant by title and abstract or needed full text to make determination

9 studies included

2 studies deemed relevant by search manual

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11 studies included in Systematic review

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Figure 3. Summary of some type of methodological information from included studies.

Figure 4. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. 36

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Figure 5. Risk of bias summary: review authors' judgements about each risk of bias

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item for each included study.

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TABLES

Study Design

Controlled, Longitudinal trial

Control Population (n)

20 ALS patients (11 males, 9 females)

10 ALS patients from total 20 patients were part of the control group

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Pinto et al., 1995, Portugal

ALS Population (n) and gender

Intervention Group Age (min and max or mean age)

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Authors, Year, Country

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Table 1. Characteristics of studies included in the Systematic Review

51 - 69 years

Treatment Protocol

Bipap support (treated group); palliative management (control group)

Number of treatment sessions or time of protocol

Results

Conclusions

Not clearly specifed since patients were part of the group until death

Analog scale of life satisfaction showed improved in treated group even after the beginning of respiratory insufficiency. Treated group presented significantly improvement of total survival and survival from diurnal abnormalities in gas exchange

Preliminary results evidenced significant importance of BIPAP to ALS patients. Researcher group suggest that further studies must go on in order to optimize the best time for introducing Bipap

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f Historical Controlled, Longitudinal Trial

Van Groenestjin et al., 2015, Netherlands

Controlled, Longitudinal, Blinded, Randomized Trial

57 years mean age

18 patients (9 males, 9 females)

Historical group of 16 ALS patients

15 patients (9 males, 6 females)

5 ALS patients from total 15 patients were submited to usual care

Not clearly specifed

57.4 years mean age

A brain-communication tool can be used in early and middle stage of the disease

Although there was no evidence of benefits, it is not possible to rule out a minor positive effect. More studies are needed

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29 - 73 years

P300-based braincomputer interface training protocol

Eight acquisition and 16 test sessions scattered over 2 weeks, 1year follow-up

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26 patients (18 males, 8 females)

13 ALS patients from total 26 patients were part of a late intervention group

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Pinto and Carvalho, 2013, Portugal

9 healthy subjects

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Pinto et al., 2012, Portugal

Controlled, Longitudinal, Blinded, Randomized Trial

21 ALS patients (16 males, 5 females)

Active inspiratory exercise program

Twice-a-day training, 8months follow-up

There was no significant difference between the two patients groups (early-intervention and late-interventions groups)

Active inspiratory exercise program

Seven patients undertook active inspiratory exercise programme for 8 months, five patients for 12 months, two patientes for 18 months, three for 24 months and one for 32 months

Inspiratpry muscle training showed to be a significant independent predictor survival in early affected-patients

More studies would be useful to corroborate this data

Cognitive behavioral therapy

Five to 10 cognitive behavioral therapy sessions, in 16 weeks

Mental quality of life of patients was significant better in cognitive behavioral therapy group. Caregiver Strain Index was significantly lower in cognitive behavioral therapy group

Cognitive behavioral therapy might be beneficial to patients. More studies would be useful to corroborate this data

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Controlled, Longitudinal, Blinded trial

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Silvoni et al., 2009, Italy

Patients and healthy subjects acquired good or excellent communications skills after the trainning program. Time since trainning acquisition and clinical status did not affected the patients brains-communication skill at early and middle stage of the diease

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f Controlled, Longitudinal, Randomized Trial

25 ALS (out)patients (14 males, 11 females)

25 ALS (in)patients (17 males, 8 females)

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Bertella et al., 2017, Italy

Braga et al., 2018, Portugal

Controlled, Longitudinal, Blinded, Quasirandomized Trial

48 ALS patients (32 males, 16 females)

24 ALS patients from total 48 patients were submited to usual care

62.9 years mean age

Active music therapy program

It was observed a positive impact of assistive communications device on quality of life in early stages of bulbar-onset ALS, considering improvement in psychological and existencial well being domains evaluated

Assistive communications tool shoud be introduced in early stages of bulbaronset ALS

There was significant improvement in quality of life of ALS patients, leading for example to reduced perception of physical symptoms

More studies would be useful to corroborate this data

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Seven to 10 months follow-up

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Raglio et al., 2016, Italy

30 ALS patients (13 males, 17 females)

15 ALS patients from total 30 patients were submited to usual care

39 - 83 years

Assistive communication device training program

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Controlled, Longitudinal, Randomized Trial

27 ALS patients (5 males, 22 females)

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Controlled, Longitudinal, Randomized Trial

Londral et al., 2015, Portugal

11 ALS patients from total 27 patients were part of a later intervention group

Twelve session, 3 times a week, 30 min each, about 1 month period

61.2 years mean age

Non-invasive nigh-time ventilation

3 months followup

60.5 years mean age

Controlled intensity aerobic exercise, with training zone determined by cardiopulmonary exercise testing (CPET)

Two times per week, 6 months follow-up

There were no differences in acceptance/adherence failure between groups. Female gender and spinal onset were predictors for non-invasive acceptance/adherence failure. There were no between-group differences in progression of respiratory impairment, symptoms and sleep quality At 6 months ALSFRS-R was higher in intervention group. Also gas exchange variables did not change in this group but had significant differences in standard care group Multiregression analyses showed the Spinal ALSFRS-R slope and Intervention group as

Early outpatient initiation of noninvasive ventilation in ALS is as effective as inpatient initiation

Aerobic exercise defined by CPET can improve functional outcome in ALS

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f Pr

59 ALS patients (39 males, 20 females)

59,55 years mean age

Randomization to resistance, endurance, or stretching/range of motion exercises

6 months followup

Vitacca et al., 2018, Italy

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Clawson et al., 2018, USA

Controlled, Longitudinal, Randomized Trial

These 59 ALS patients were their own control since they were divided into 3 groups with different intervention each

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significant predictors of ALSFRS-R at 6 months.

Controlled, Longitudinal Trial

194 ALS patients (57,73% male)

129 ALS patients from total 194 were part of a later intervention group

62.62 years mean age

Non-invasive ventilation (NIV)

3-year follow-up

All three forms of exercise were tolerable but endurance exercise was less well tolerated than Stretching/Range of Motion. Compliance was highest for both Stretching/Range of Motion and resistance exercises and less so with endurance exercises. There were no differences in the rates of disease progression among groups and secondary outcome measures Survival was significantly longer and death rate was significantly lower in ALS patients that started NIV with FVC ≥ 80% compared to those that started NIV when FVC% <80%. Furthermore, tracheotomy was protective for all patients subgroups.

All three forms of exercise are safe to be performed with the specified regimen without any worsening of outcomes as related to ALS function. All of them were tolerated with resistance and stretching/range of motion exercises showing the highest compliance over the 24 week-period

Very early NIV prescription (with FVC ≥ 80%) prolongs the free time from diagnosis to death, while tracheotomy reduces the mortality risk in all ALS patients

43

f oo pr

Quality of life

Others

Pr

Pinto et al., 1995

Functionality Bulbar and Spinal Norris Scale; Modified Barthel Score

e-

Table 2. Summary of evaluation tools and analysis developed from studies included in the Systematic Review

Clinical and Respiratory functions evaluation

Analog scale for Life Satisfaction

Silvoni et al., 2009

ALS-Functional Rating Scale (ALSFRS)

Pinto et al., 2012

ALS-Functional Rating Scale (ALSFRS); Functional Independent Measure

EuroQol-5D (EQ-5D)

ALS-Functional Rating Scale (ALSFRS)

Not evaluated

na l

Jo ur

Pinto and Carvalho, 2013

Not evaluated

Van Groenestjin et al., 2015

ALS-Functional Rating Scale (ALSFRS)

Londral et al., 2015

ALS Functional Rating Scale-revised (ALSFRSR)

Emotional Functioning (EF) subscale of the ALS AssessMent Questionare (ALSAQ-40); Health Survey Short Form, mental component summary (SF-36-MCS) McGill Quality of Life questionnaire (MQoL) to ALS patients; MQoL and World Health Organization Quality of Life

Clinical evaluations; Diferent instruments for Neuropsychological (cognitive state, attentions, executive functions, others) and Neurophysiological evaluations Clinical evaluations; Different instruments for Respiratory functions, Neurophysiological, Sleepiness and Depression evaluation

Correlation among clinical parameter, clinical evolution and respiratory functions between groups Correlation among clinical, neuropsychological and neurophysiological parameters, between groups as well as training interface communication device skill and quality of device-based communiccation Correlation among clinical parameter, clinical evolution and respiratory functions between groups

Clinical and Respiratory functions evaluation

Correlation among clinical parameter, clinical evolution and respiratory functions between groups

Hospital and Anxiety Depression Scale and Caregiver Strain Index

Correlation to compare changes between ALS groups as well comparison between caregivers groups

Modified Communication Effectiveness Index and performance in writing

Correlation to compare changes between ALS groups as well comparison between caregivers groups

44

ALS Functional Rating Scale-revised (ALSFRSR)

f

Mcgil Quality of Life Questionaire (MQoL)

Hospital and Anxiety Depression Scale; Music Therapy Rating Scale

Correlation to compare changes between ALS groups

Clinical and Respiratory functions evaluation; Sleep study; Patients’ acceptance, experience and adherence to non-invasive ventilation; Sleep Quality Assessment with a Visual Analogue Scale

Correlation among clinical evolution, acceptance and adherence to non-invasive ventilation between groups

pr

Raglio et al., 2016

oo

(WHOQoL-BREF) questionnaires to caregivers

ALS Functional Rating Scale-revised (ALSFRSR)

Not evaluated

Braga et al., 2018

ALS Functional Rating Scale-revised (ALSFRSR)

Not evaluated

Respiratory function tests and Cardiopulmonary exercise testing

Correlation among clinical parameter, clinical evolution and respiratory functions between groups

Pulmonary forced vital capacity; quantitative strength measurement; grip strength; the fatigue severity scale; the Ashworth spasticity scale and the maximum oxygen consumption

Correlation to compare changes between ALS groups

Respiratory function tests

Correlation among clinical parameter, clinical evolution and respiratory functions between groups

Pr

e-

Bertella et al., 2017

ALS Functional Rating Scale-revised (ALSFRSR)

ALS Specific Quality of Life Instrument-Revised (ALSSQoL-R)

Vitacca et al., 2018

ALS Functional Rating Scale-revised (ALSFRSR)

Not evaluated

Jo ur

na l

Clawson et al., 2018

45