Proefschrift Creemers

Huub Creemers

Optimizing quality of care for patients with ALS and their family caregivers

Uitnodiging Voor het bijwonen van de openbare verdediging van het proefschrift

Optimizing quality of care for patients with ALS and their family caregivers

Optimizing quality of care for patients with ALS and their family caregivers door Huub Creemers

op woensdag 13 januari 2016 om 14.00 uur in de Agnietenkapel Oudezijds Voorburgwal 231 te Amsterdam Na afloop bent u van harte welkom op de receptie aldaar Huub Creemers Simonshavenstraat 19 1107 VA Amsterdam huub.creemers@planet.nl

Paranimfen Antoinette Vullings-Creemers Francien Haex

Huub Creemers

Op mizing quality of care for pa ents with ALS and their family caregivers

Huub Creemers

Doctoral thesis, University of Amsterdam, The Netherlands ISBN: Copyright:

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Gildeprint − The Netherlands.

Gildeprint − The Netherlands.

Op mizing quality of care for pa ents with ALS and their family caregivers

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector MagniďŹ cus prof. dr. D.C. van den Boom ten overstaan van een door het College voor Promo es ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op woensdag 13 januari 2016, te 14.00 uur door

Hubertus Wilhelmus Joseph Creemers geboren te Venray

PROMOTIECOMMISSIE Promotores:

Prof. dr. F. Nollet Prof. dr. L.H. van den Berg

Universiteit van Amsterdam Universiteit Utrecht

Co-promotores:

Dr. J.A.J.M. Beelen Prof. dr. J.H Veldink

Universiteit van Amsterdam Universiteit Utrecht

Overige leden:

Prof. dr. A.J. Pols Prof. dr. M.A.G. Sprangers Prof. dr. S.C.C.M. Teunissen Prof. dr. J.M.A. Visser-Meily Prof. dr. M. de Visser Prof. dr. H.C.P.M. van Weert

Universiteit van Amsterdam Universiteit van Amsterdam Universiteit Utrecht Universiteit Utrecht Universiteit van Amsterdam Universiteit van Amsterdam

Faculteit der Geneeskunde

The studies presented in this thesis were carried out under the auspices of: The department of Rehabilita on, Academic Medical Center Amsterdam The department of Neurology, Rudolf Magnus Ins tute of Neuroscience, University Medical Center Utrecht The studies presented in this thesis were financially supported by: The Netherlands Organisa on for Health Research and Development (ZonMw) The Netherlands ALS Founda on The Netherlands ALS Center Department of Rehabilita on, Academic Medical Center Amsterdam

Financial support for the prin ng of this thesis is gratefully acknowledged and was provided by: Academic Medical Center Amsterdam – www.amc.nl Wellco Interna onal BV / Fi]orm – www.fi]orm.net Quo Vadis Nederland BV – www.qvn.nl Permobil Benelux BV – www.permobil.com

CONTENTS Chapter 1

General introduc on

9

Chapter 2

Prognos c factors for the course of func onal status of pa ents with ALS: a systema c review

19

Chapter 3

The provision of assis ve devices and home adapta ons to pa ents with ALS in the Netherlands: Pa ents’ perspec ves

51

Chapter 4

Cluster RCT of case management on pa ents’ quality of life and caregiver strain in ALS

65

Chapter 5

Need and value of case management in mul disciplinary ALS care: A qualita ve study on the perspec ves of pa ents, spousal caregivers and professionals

85

Chapter 6

Factors related to caregiver strain in ALS

103

Chapter 7

General Discussion

119

Summary Samenva`ng Dankwoord Curriculum Vitae / Por]olio List of publica ons

141 147 153 155 161

1 General introduc on

Chapter 1

10

General introduc on

1.1 Amyotrophic Lateral Sclerosis (ALS) Amyotrophic lateral sclerosis (ALS) is a lethal, progressive motor neuron disease (MND) that mainly causes degenera on of the upper and lower motor neurons ul mately leading to paralysis and early death. Clinically ALS presents with considerable variability in onset, presenta on of symptoms and disease progression, resul ng in a complex and diverse disability profile. Respiratory failure is the most common cause of death in ALS. The median survival me a{er symptom onset is two-three years 1,2.

Due to progressive muscle weakness and other symptoms, pa ents with ALS experience increasing difficul es in the performance of ac vi es of daily living and this may lead to restric ons in par cipa on, impending loss of autonomy and quality of life 3-5. Dysfunc onal motor neurons affect voluntary muscle ac vity, for example causing difficul es with si`ng, walking, manipula ng objects, chewing, swallowing, speaking and breathing. Besides isolated motor neuron involvement, pa ents with ALS and their families may be faced with cogni ve deteriora on and/or behavioural changes, which indicates that ALS is a mul system neurological disease 6. About 5-10% of ALS is familial, the remaining 90% of pa ents is classified as having sporadic disease. It is es mated that the Dutch ALS popula on consists of about 1400 pa ents at any me. In the Netherlands, the average annual incidence rate is 2.8 per 100.000 person-years, and a prevalence rate of 10.3 per 100.000 individuals, which is similar to the most recently published prospec ve popula on-based registers in other countries 7,8.

1.2 Mul disciplinary care for pa ents with ALS and their informal caregivers In the absence of a cure or medical interven ons to stop the progression of muscle weakness, the focus of support for pa ents with ALS is on symptoma c, neuro-pallia ve rehabilita on care 9,10. The management of ALS varies considerably around the world despite the current recommended ‘gold standard’ for ALS care; expert mul disciplinary management 11,12. As recommended within the ALS guidelines from the American Academy of Neurology (AAN) and the European Federa on of Neurological Socie es (EFNS) mul disciplinary ALS care should be available for pa ents with ALS 13,14. In the Netherlands, mul disciplinary ALS care is available na onwide, and it is es mated that at least 90-95 percent of the Dutch pa ents with ALS receive care in conformity with these interna onal guidelines, the Dutch consensus protocol for rehabilita ve management in ALS and the mul disciplinary allied health prac ce guidelines for physical, speech and occupa onal therapy in ALS (h p:// www.als-centrum.nl/kennisbank/mul disciplinaire-als-richtlijn/) 7,13-15.

The diversity in rate and degree of loss of muscle strength in different body regions, and the associated diversity and amount of disease symptoms, emphasize the urgency for evidence based mul disciplinary care for pa ents and their informal caregivers. The related range of impairments and limita ons (e.g., related to nutri on, respira on, ambula on, cogni on, well-being), that can present during the disease course, and related treatment choices further contribute to the complexity of ALS care. It is inherent that many different 11

1

Chapter 1

health care professionals (Figure – The mul disciplinary ALS team), social services, agencies, authori es, companies, organiza ons and volunteers are involved.

In ALS, op mal ming of appropriate care interven ons is of great importance for the pa ent and a serious challenge for their health care professionals. However, the progression of the disease and the func onal limita ons in me are currently diďŹƒcult to predict, which hampers informing the pa ent about the expected disease course and the proac ve provision of care interven ons 16. Earlier studies a empted to construct prognos c algorithms for survival 17,18. However, prognos c tools for the func onal course in ALS are lacking.

Figure The mul disciplinary ALS team.

1.3 The quality of ALS care The current evidence base for the management of ALS indicates that care in a mul disciplinary se`ng is most eec ve. There is some evidence for extended survival, decreased medical complica ons by symptom treatment, increased use of assis ve devices and improved QOL, related to a endance at specialized mul disciplinary clinics 13,14,19-21. Good clinical prac ce recommenda ons based on the consensus of experts are formulated with respect to the composi on of the mul disciplinary team, the frequency of contact with the pa ent and caregiver and visits of the pa ent, and the communica on and coordina on between all service providers and care specialists involved 13,14.

12

General introduc on

From previous na onal and interna onal research projects and daily clinical prac ce we know that pa ents with ALS and their informal caregivers report gaps in complex mul disciplinary and regular service provision 22-28. On the basis of data from pa ents, caregivers and health care professionals it is suggested that there is room for improvement in services with regard to coordina on of care, symptom treatment, availability of aids and adapta ons and caregiver support 22-24,29. Accordingly, to improve ALS care related to the provision of assis ve devices and home adapta ons (ADHA), it is necessary to inves gate the pa ents’ experiences during the procurement process to gain insight in the bo lenecks of this care issue.

Complex ALS care, that fails to meet the care needs of pa ents and caregivers with respect to symptom burden, care coordina on, mutual communica on between pa ents, caregivers and their care professionals and caregiver strain, might be improved through intensive case management. As far as we could ascertain, there was no evidence for case management in pa ents with ALS. However, earlier non-ALS studies suggested case management as an innova ve strategy to op mize complex care 30. Case management suppor ng tasks (e.g., family support, educa on, advocacy, psychosocial support and care coordina on) in various complex long term condi ons appeared to be beneficial on pa ent and caregiver outcomes like quality of life, quality of care and caregiver burden 31-36.

Moreover, Mitsumoto et al. (2005) 37 and Andersen et al. (2012) 14 previously recommended addi onal research with respect to the increase of empirical evidence and improvement of the quality of mul disciplinary ALS care on symptom treatment, QOL and caregiver strain.

Informal caregivers usually hold a central posi on during the disease course of pa ents with ALS. A{er the diagnosis, most of the pa ents prefer to stay in their homes un l the end of their live and caregivers make a valuable contribu on to achieve this goal. However, informal caregivers of pa ents with ALS are vulnerable as caregiving exerts substan al strain that increases during disease progression. To op mize caregiver support, insight is needed into poten ally modifiable factors associated with caregiver strain.

1.4 Aims of this thesis The overall aim of this thesis is to op mize mul disciplinary ALS care through expanding our knowledge related to previously iden fied bo lenecks in complex ALS care – aids and adapta ons, prognos ca on, quality of care, caregiver strain − and examining the care interven on case management in a mixed methods research project. Our mixed methods research project included a mul center cluster randomized controlled trial (RCT) and a qualita ve study with semi-structured interviews.

13

1

Chapter 1

The specific aims of this thesis •

To summarize the available evidence based on the scien fic literature about prognos c factors for the course of the func onal status of pa ents with ALS. (Chapter 2)

•

To explore the experiences of pa ents with ALS during the applica on and provision process of assis ve devices and home adapta ons, and par cularly to determine the problems they perceived during this procurement process. (Chapter 3)

•

To study the effect of case management on pa ents’ quality of life (QOL), caregivers’ strain, and perceived quality of care (QOC) in pa ents with ALS and their caregivers.

(Chapter 4)

•

To explore the experiences of pa ents, their caregivers and health care professionals with case management addi onal to mul disciplinary ALS care. (Chapter 5)

•

To iden fy factors for recep veness to case management and what aspects of case management have addi onal value to the usual mul disciplinary ALS care. (Chapter 5)

•

To iden fy pa ent and caregiver disease- and psychosocial-related factors associated with caregiver strain over me in ALS. (Chapter 6)

1.5 Outline of this thesis Chapter 2 describes the results of a systema c review of evidence regarding prognos c factors for the rate of func onal decline of pa ents with ALS, assessed with the ALS Func onal Ra ng Scale. In chapter 3 we explored through a na onwide survey the experiences of pa ents with ALS during the applica on and provision process of assis ve devices and home adapta ons, and par cularly determined the problems they perceived during this procurement process.

Chapter 4 , 5 and 6 are based on results from the mul center, cluster randomized controlled trial on the effec veness of case management addi onal to usual mul disciplinary ALS care.

During 12 months, pa ents with ALS and their most important informal caregiver received case management in addi on to usual care or usual care alone. In chapter 4 we present the results of the care interven on case management on outcome measures pa ents’ quality of life, caregiver strain and pa ents’ and caregivers’ quality of care. The experiences of pa ents, their caregivers and health care professionals with case management during the RCT are explored through semi-structured interviews and described in chapter 5. Furthermore, aspects of case management that may have addi onal value to usual mul disciplinary ALS care and factors for recep veness to case management are presented.

14

General introduc on

Data, collected during the RCT case management, are applied to analyse which (modiďŹ able) pa ent and caregiver factors are associated with caregiver strain. We present the results of the (longitudinal) analyses in chapter 6.

In chapter 7 the main ďŹ ndings, strengths and limita ons of this thesis are described.

Finally, the implica ons of the study ďŹ ndings for the care in ALS are discussed and future perspec ves are considered.

15

1

Chapter 1

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Andersen PM, Abrahams S, Borasio GD, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)--revised report of an EFNS task force. Eur J Neurol 2012;19:36075.

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Ng L, Khan F, Mathers S. Mul disciplinary care for adults with amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007425.

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ALS en hulpmiddelen. Een onderzoek naar de hulpmiddelenverstrekking aan mensen met ALS. (ALS and ADHA. A survey into the provision of ADHA in people with ALS. Netherlands ALS Centre and The Dutch Associa on for Pa ents with Neuromuscular Diseases) ALS Centrum Nederland en Vereniging Spierziekten Nederland. May 2004 (Dutch).

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Chapter 1 36.

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Mitsumoto H, Bromberg M, Johnston W, Tandan R, Byock I, Lyon M, Miller RG, Appel SH, Bendi J, Bernat JL, Borasio GD, Carver AC, Clawson L, Del Bene ML, Kasarskis EJ, LeGrand SB, Mandler R, McCarthy J, Munsat T, Newman D, SuďŹ t RL, Versenyi A. Promo ng excellence in end-of-life care in ALS. Amyotroph Lateral Scler Other Motor Neuron Disord. 2005 Sep;6(3):145-54.

2 Prognos c factors for the course of func onal status of pa ents with ALS: a systema c review Huub Creemers Hepke Grupstra Frans Nollet Leonard H. van den Berg Anita Beelen

Journal of Neurology 2015. Jun;262(6):1407-23. Š Reprinted with permission from Springer

Chapter 2

ABSTRACT The progressive course of Amyotrophic Lateral Sclerosis (ALS) results in an ever-changing spectrum of the care needs of pa ents with ALS. Knowledge of prognos c factors for the func onal course of ALS may enhance clinical predic on and improve the ming of appropriate interven ons. Our objec ve was to systema cally review the evidence regarding prognos c factors for the rate of func onal decline of pa ents with ALS, assessed with versions of the ALS Func onal Ra ng Scale (ALSFRS). Two reviewers independently assessed the methodological quality of the thirteen included studies using the Quality in Prognosis Studies (QUIPS) tool. The overall quality of evidence for each prognos c factor was assessed using the Grading of Recommenda ons Assessment, Development and Evalua on (GRADE) approach, considering risk of bias, imprecision, inconsistency, indirectness and publica on bias. The quality of evidence for the prognos c value of age at onset, site of onset, me from symptom onset to diagnosis, and ALSFRS-Revised baseline score was low, mainly due to the limited data and inconsistency of results in the small number of studies included. The prognos c value of ini al rate of disease progression, age at diagnosis, forced vital capacity, frontotemporal demen a, body mass index and comorbidity remains unclear. We conclude that the current evidence on prognos c factors for func onal decline in ALS is insuďŹƒcient to allow the development of a predic on tool that can support clinical decisions. Given the limited data, future prognos c studies may need to focus on factors that have a predic ve value for a decline in ALSFRS(-R) domain scores, preferably based on interna onally collected and shared data.

20

Prognos c factors for the func onal course in ALS

INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease showing signs of both upper motor neuron (UMN) and lower motor neuron (LMN) dysfunc on, resul ng in increasing muscle weakness in one or more body regions 1. Due to different rates of degenera on and progression of loss of motor neurons in brain, brainstem and spinal cord, clinical manifesta ons may vary widely between pa ents 2. Adding to the heterogeneity in motor impairments, varying degrees of cogni ve impairment and behavioural dysfunc on are present in pa ents with ALS 3.

The heterogeneity of the ALS syndrome poses a challenge to mul disciplinary, neuropallia ve, rehabilita on management 4. Because of the progressive course, the care needs form a broad and ever-changing spectrum. The ming of appropriate interven ons is important and requires accurate predic on of the individual course of the disease. In clinical prac ce, individual prognos ca on with regard to disability progression and the ming of suppor ve interven ons are largely based on the clinician’s cumulated experience. Despite a empts to construct prognos c algorithms for survival, prognos c tools for the func onal course in ALS are lacking 5,6. Evidence on prognos c factors for disability progression may enhance clinical predic on and guide clinical decision making, including pa ent counselling and treatment selec on 7,8.

The aim of our study is to iden fy factors from the literature that have a predic ve value for the course of the func onal status of pa ents with ALS.

METHODS Literature selec on We searched the literature up to March 2014 to iden fy prognos c studies of the func onal status in ALS. Two of the researchers (AB and HC) iden fied relevant ar cles by searching the computerized bibliographic databases EMBASE (1980−March 2014), CINAHL (1982−March 2014), PsycINFO (1995−March 2014), MEDLINE (1965−March 2014), and Web of Science (1988−March 2014).

A sensi ve search strategy was built on the subjoined components: 1) pa ents with Amyotrophic Lateral Sclerosis (MESH term and text word), 2) prognos c studies (we used a revised version of the Yale University School of Medicine Prognosis and Natural History Filter) and 3) the func onal status outcome – a self-compound filter of ALS-related func oning and disability assessment as measured with the ALSFRS/ALSFRS-R/ALSFRS-EX. We decided to select the ALS-FRS(-R) as outcome measure because it is a commonly used, validated, clinically meaningful, reliable and easy to administer measure of func onal status 9–12. The full search strategy is available on request.

21

2

Chapter 2

Two reviewers (HC and AB) independently screened the abstracts iden fied by the search strategy. Relevant publica ons, poten ally eligible for inclusion, were read in full by the two reviewers and in case of disagreement on inclusion, subsequently discussed during a consensus mee ng. One researcher (HC) screened the reference lists of each of the selected publica ons to retrieve relevant publica ons which had not been iden fied by the computerized search.

An eligible study aimed to iden fy prognos c factors (sociodemographic, diseasespecific, psychosocial and comorbid factors) on func onal status assessed using (versions of) the ALSFRS in pa ents with ALS who were classified according to the El-Escorial diagnos c criteria 1. This had to be designed as a longitudinal cohort study, with at least one followup measurement. Both prospec ve and retrospec ve studies were included. Results were published in English as full length ar cles between January 1960 and March 2014.

Data extrac on One reviewer (HC) used a standardized form to record informa on and data regarding study design, sample size, study popula on, pa ents’ characteris cs, treatment, outcome measure(-s), ALSFRS(-R) score(-s) at baseline, loss to follow-up, follow-up dura on, prognos c factor(-s) studied and strength of associa on between prognos c factors and ALSFRS(-R)-outcome.

Methodological quality assessment There is interna onal consensus on how to appraise the quality of prognos c studies 13,14 . The Quality in Prognosis Studies (QUIPS) tool is designed for systema c reviews of prognos c studies. We used an adapted QUIPS which contained five categories assessing poten al sources of bias conduc ng prognos c studies — pa ent selec on, study a ri on, measurement of prognos c factors, outcome measurement, sta s cal analysis and results presenta on. We considered the original QUIPS items on confounding not relevant for our study, because included studies were designed to predict a specific outcome based on a combina on of several poten al prognos c factors. In advance, we determined the key characteris cs specific for the source popula on, the baseline study sample, and the par cipants who completed the study and those who did not, in order to assess poten al risks of bias in study par cipa on and a ri on.

Two reviewers (HC, AB) independently rated the methodological quality of the selected studies. Ra ng of adequacy of repor ng in the included studies was carried out for each separate promp ng item of the six categories using yes, par al, no, or unsure. Subsequently, poten al bias for each of the six domains was rated: high quality when there was low risk of bias, moderate quality with moderate risk, and low quality when there was high risk of bias. The two reviewers discussed disagreement about whether a criterion was met, and resolved by consensus.

22

Prognos c factors for the func onal course in ALS

Data synthesis Due to the expected heterogeneity of selected studies, we performed a qualita ve bestevidence synthesis. Most important elements of this synthesis were the prognos c factors, the strength of the associa on and the methodological quality of the studies (QUIPS).

We applied the GRADE (Grading of Recommenda ons Assessment, Development, and Evalua on) approach to judge the quality of evidence across studies and to grade strength of recommenda ons in systema c reviews 14-16. Two reviewers (HC, AB) judged how the GRADE factors – phase of inves ga on, study limita ons (QUIPS; subgroup analyses), inconsistency, indirectness, imprecision, publica on bias, and moderate or large effect size – impacted the overall quality of evidence (BOX). We omi ed the factor ‘exposure-response gradient’ as it was not relevant for the quality of evidence of the prognos c studies we selected. The level of evidence was rated as high, moderate, low or very low according to the GRADE approach 17 .

BOX

The GRADE process ra ng the quality of evidence across studies.

(Modified from Huguet et al. 2013 16) Ra ng is modified downward: -Univariate analysis is applied to iden fy associa ons between a number of poten al prognos c factors and the ALSFRS(-R).

-Study limita ons; moderate or low study quality based on the QUIPS ‘risk of bias’ score 14.

-Inconsistency of results; difference in results are not clinically meaningful. Point of effect es mates are on either side of the line of no effect.

-Indirectness of evidence; the study sample does not fully represent the review ques on defined in the systema c review, but only represents a subset of the popula on of interest.

-Publica on bias likely; publica on bias exists when a prognos c factor has been inves gated in a small number of cohort studies.

-Within study imprecision; 1) sample size jus fica on is not provided and sample size of each included study < 100 pa ents, and 2) no precision in the es ma on of the effect size within each included study is reported 18.

Ra ng is modified upward: -Moderate or large effect size. For meta-analysis: pooled effect is moderate or large. For narra ve summary; moderate or large similar effect is reported by most studies.

RESULTS Selec on of studies Thirteen publica ons with a total of 5,341 pa ents were included in this review (Figure 1) 19–31 .

23

2

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Prognos c factors for the func onal course in ALS

Study characteris cs The studies were published between April 2006 and March 2014. The search yielded ten prospec ve cohort studies and three retrospec ve cohort studies. Four of the prospec ve studies were clinical trials. In one study the data were generated from three clinical trials and one observa onal study 27. The study characteris cs are summarized in Table 1. The number of study pa ents varied from 31 to 2,452. Seventy-two percent of the total number of pa ents (n = 5,341) came from observa onal studies. Mean (+SD) age of the pa ents varied between 53.9 (12.5) and 63.4 (10.2) years. One study looked at two groups of pa ents whose presented median (range) ages were 61 (45-74) and 55 (35-73) years, respec vely 29.

Bulbar type of onset varied from 16% to 40%; this was not speciďŹ ed in two studies 19,29. The sample in one study consisted of pa ents from a popula on-based ALS register (PRO-ACT; h ps://nctu.partners.org/ProACT/) 19. Dura on of follow-up varied from six months to ďŹ ve years. Most studies did not report on co-interven ons between baseline and follow-up (e.g., Riluzole use, Percutaneous Endoscopic Gastrostomy (PEG), non-invasive ven la on (NIV), mul disciplinary care). Mean (+SD) baseline ALSFRS(-R) score ranged from 27.0 (6.6) to 42.8 (5.8). Five studies included an incep on cohort â&#x20AC;&#x201D; the other studies used non-incep on cohorts. Six studies presented the ALSFRS as outcome measure for disability accumula on.

Three of these studies started pa ent recruitment prior to the revision of the ALSFRS in 1999 10. One study did not report the me period of inclusion 28.

Prognos c factors Table 2 summarizes the candidate prognos c factors studied in rela on to the outcome measures ALSFRS(-R) total score, and analysed in more than one study (n = 12). A descrip on of the candidate prognos c factors studied in rela on to the outcome measures ALSFRS(-R) total score and ALSFRS-R bulbar domain score, and analysed in single studies (n = 16), is provided as supplementary material (Appendix 1). The prognos c factors summarized involved sociodemographic characteris cs (n = 11), clinical characteris cs (n = 12), environmental factors (n = 1), psychosocial factors (n = 2) and biological markers of disease progression (n = 2). Ten studies used sta s cal analysis modelling for covariates to es mate the strength of the independent associa on between prognos c factor and outcome.

25

2

26

Prospec ve mul center cohort

Reich-Slotky, 2013 [23]

Age at diagnosis (yrs): mean 58.8 Male: 56 % Bulbar onset: 28 %

150 Age (yrs): mean 57.0 (SD 10.9) Nineteen Male: 57 % outpa ent centers Bulbar onset: 16 % BMI: mean 26.2 FVC%: mean 88

514 ALS outpa ent clinic

Retrospec ve cohort

Körner, 2013 [22]

Age (yrs): mean 63.4 (SD 10.2) Male: 60 % Bulbar onset: 36 %

186 Popula on-based ALS register

Prospec ve cohort

Age (yrs): mean 55.5 (SD 11.6) Male: 65 %

Elamin, 2013 [21]

338 PRO-ACT* database

Pa ents’ characteris cs

Age (yrs): mean 61.0 (SD 12.4) 382 Sixteen outpa ent Male: 55 % university hospitals Bulbar onset: 23.3 % Mean me to diagnosis: 9.6 mo (SD 8.1) Time since diagnosis < 6 mo

Prospec ve mul center cohort

Gomeni, 2013 [19]

Sample size (n), study popula on

Clavelou, 2013 Prospec ve [20] mul center cohort

Study design

Author, year

Table 1 Characteris cs of the included studies (n = 13).

ALSFRS-R; total and bulbar domain scores median total: 38

Riluzole 72% ALSFRS-R; None Coenzyme mean 35.44 (SD 5.22) Q10: 50%

0 (0)

175 (94)

ALSFRS; 132 (35) mean 32.82 (SD 4.66); median 34.0; range 10 − 40

Not reported ALSFRS-R; baseline score not reported

Riluzole 82.8 %

Riluzole 100 %

6 (2)

BMI

Comorbidi es; Gender; Age at diagnosis; Site of onset (bulbar versus spinal); Time to diagnosis

>6

9

Age; Gender; Site of onset (bulbar versus spinal); Baseline ALSFRS-R; Frontotemporal syndrome

Site of onset (bulbar, lower limbs, upper limbs); Gender

Baseline ALSFRS-R; %Change in ALSFRS-R from baseline at week two; %Change in ALSFRS-R from baseline at week four

18

30

12

Outcome measure(s) Loss to Follow-up Prognos c factor(s) and baseline score(s) follow-up, dura on n (%) (mo)

Not reported ALSFRS-R; mean 38.7 (SD 4.9)

Treatment

Prospec ve mul center cohort

Qureshi, 2008 [27]

UMN-ALS group (n = 20): Age at onset (yrs): mean 60; Male: 50 % Bulbar onset: 40 % Time to diagnosis (yrs): mean 2.7 Typical ALS group (n = 20): Age at onset (yrs): mean 60; Male: 50 % Bulbar onset: 25 % Time to diagnosis (yrs): mean 1.0

795 Age (yrs): mean 56.0 (SD 12.2; n = Twenty-one 596) outpa ent centers Male: 64 % Bulbar onset: 19.5 % %VC: mean 86.3 (SD 17.7)

40 One outpa ent hospital

Retrospec ve cohort

Sorarù, 2010 [26]

Riluzole 59%

Treatment

ALSFRS-R; mean 42.8 (SD 5.8)

Topiramate ALSFRS; 57 % mean 31.2 (SD 5.3) Crea ne 58 % Celecoxib 67 %

Not reported ALSFRS-R, total and domain scores Baseline total score: UMN-ALS group: mean 35.5; range 15−40 Typical ALS group: mean 37.7; range 24−45

294 (37)

8 (20)

608 (25)

103 (59)

6-12 (range)

18

Mean 32 mo (SD 36)

8

Baseline laboratory parameters

Upper Motor Neuron dominance

Age at onset; Site of onset (bulbar versus limb); Baseline ALSFRS-R; Time to diagnosis; Gender; Weight at the first visit; Height

Uric acid levels; BMI

Outcome measure(s) Loss to Follow-up Prognos c factor(s) and baseline score(s) follow-up, dura on n (%) (mo)

Age at diagnosis (yrs): mean 59.7 (SD Not reported ALSFRS-R; baseline 13.2) score not reported Male: 57 % Bulbar onset: 28 %

2,452 One outpa ent hospital

Prospec ve cohort

Pa ents’ characteris cs

Gordon, 2010 [25]

Sample size (n), study popula on 251 Age (yrs): mean 53.9 (SD 12.5) Thirty-seven Male: 63 % outpa ent centers Bulbar onset: 16 % FVC%: mean 87.1 Time since diagnosis (days): mean 294.9 Time since onset (days): mean 672.1 BMI: mean 26.8 VC > 60 % Disease dura on < 5 yrs

Study design

Paganoni, 2012 Prospec ve [24] mul center cohort

Author, year

2

27

28

Study design

Prospec ve cohort

Retrospec ve cohort

Author, year

Krampe, 2008 [28]

Rauchway, 2007 [29]

50 One neurophysiology laboratory

31 One outpa ent clinic

Sample size (n), study popula on

Not reported ALSFRS; median (minimummaximum) Group I; 28 (13−40) Group II; 36 (28−40)

Group I ALSFRS < 26: n = 14 Age at onset (yrs): median 61; Time since onset (mo): median 4; range 2−24 Group II: ALSFRS >26; n=33 Age at onset (yrs): median 55; Time since onset (mo): median 10; range = 1−24

3 (6)

17 (55)

Gender; Age at onset; Years of educa on; Time since onset; Time from diagnosis to study inclusion; FVC; Personality factors (neuro cism, extraversion, openness, agreeableness, conscien ous-ness); Depression; FTD and cogni ve performance 10 Time from onset of (median) symptoms to ini al EDX studies

12

Outcome measure(s) Loss to Follow-up Prognos c factor(s) and baseline score(s) follow-up, dura on n (%) (mo)

Melatonin ALSFRS; 100 % mean 27.0 (SD 6.6); Vitamin E range 12−38 74 % Riluzole 81 % Amitriptyline 48 % Baclofen 26 % Mg 52 % Vit C 23 % Crea ne 13 %

Treatment

Age (yrs): mean 60.3 (SD 10.4) Age at onset (yrs): mean 58.4 (SD 10.3) Male: 61 % Bulbar/mixed onset: 19/13 % Time to diagnosis (weeks): mean 52.4 (SD = 32.3) FVC%: mean 62.4 (SD 24.5; n = 20); range 13−100 Time from onset (yrs): < 6yrs

Pa ents’ characteris cs

Prospec ve cohort

Prospec ve cohort

Qureshi, 2006 [30]

De Carvalho, 2006 [31]

57 One outpa ent center

95 One outpa ent hospital

Sample size (n), study popula on

Treatment

Age (yrs): mean 61.1; range 32−78 Male: 51 % Bulbar onset: 23 % Time since onset (mo): mean 16.4; range 2−63

Not reported ALSFRS; 24 (42) Group 1: mean 34.7 (SD 1.7); range 32−37 Group 2: mean 33.3 (SD 4.7); range 24−39

None

6

12

A > 8.78% reduc on in ALSFRS score at 3 months

Sociodemographic characteris cs: Age; Age at onset; Age at diagnosis; Gender; Years of educa on; Male veterans; Marital status; Race Clinical examina on characteris cs: El Escorial criteria; Site of onset (bulbar/limb); Time to diagnosis; Baseline FVC; Baseline ALSFRS; Height; Weight; Familial ALS; History of ALS ALS risk factors (n = 12 factors) Comorbidity (n = 12 factors)

Outcome measure(s) Loss to Follow-up Prognos c factor(s) and baseline score(s) follow-up, dura on n (%) (mo)

Age (yrs): mean 54.4 (SD = 13.1) Not reported ALSFRS; Male: 63.2 % mean 31.9 (SD 5.7) Bulbar onset: 24 % Time to diagnosis (yrs): mean 0.9 (SD 0.9)

Pa ents’ characteris cs

PRO-ACT Pooled Resource Open-Access ALS Clinical Trials database (h ps://nctu.partners.org/ProACT/), mo months, yrs years, SD standard devia on, ALSFRS(-R) Amyotrophic Lateral Sclerosis(-Revised), BMI Body Mass Index, FVC% percentage forced vital capacity of predicted normal values, VC vital capacity, UMN upper motor neuron, Mg magnesium, Vit vitamin, FTD frontotemporal demen a, EDX electrodiagnos c

Study design

Author, year

2

29

30

No. of studies (par cipants)

Significant Sta s cal analysis associa on reported number of studies (par cipants)

2 [25], [30] (n = 2,547)

2 [25], [30] (n = 2,547)

Weight

Height

0

0

6 [20], [21], 0 [22], [25], [28], [30] (n = 3,660)

Gender

1 [22] (n = 514)

2 [22], [30] (n = 609)

Age at diagnosis

[21], [28], [30] Not significant

p < 0.001

[25] ALSFRS-R = −0.046 (SE = 0.013) points for every age year.

Strength of associa on

[20], [21], [22], [25], [28], [30] Not significant

[25], [30] Mixed effects [25], [30] Not significant model

[25], [30] Mixed effects [25], [30] Not significant model

[22] Mul ple linear analysis (only results from univariate analysis reported)

[21] Mul ple linear regression

[20], [25], [28], [30] Mixed effects model

[22] Mul ple linear [22] Mean ra oa = 1.01 (95 % CI = 1.00, analysis (only results 1.02); For every age year the difference in from univariate analysis ALSFRS-R decline is 1 %. reported) p = 0.015 [30] Mixed effects model [30] Not significant

Outcome: Decline in ALSFRS total score or ALSFRS-R total score Sociodemographic characteris cs Age at onset 4 [21], [25], 1 [25] [21] Mul ple linear [28], [30] (n = 1,844) regression (n = 2,764) [25], [28], [30] Mixed effects model

Prognos c factor

Table 2 Prognos c factors related to outcome measures.

‘Moderate’ evidence

‘Moderate’ evidence

‘High’ evidence

‘Very low’ evidence

‘Low’ evidence

There is ‘moderate’ evidence that height is not associated with func onal decline.

There is ‘moderate’ evidence that weight is not associated with func onal decline.

There is ‘high’ evidence that gender is not associated with a steeper func onal decline.

There is ‘very low’ evidence that older age at diagnosis is associated with a worse func onal decline.

There is ‘low’ evidence that older age at onset is associated with a steeper func onal decline.

Quality score Level of evidence (based on GRADE Considered judgment if applicable)

No. of studies (par cipants)

0

Strength of associa on

‘Low’ evidence

[20], [21] Bulbar versus limb onset (ALSFRS and ALSFRS-R); not significant.

p = 0.02

[30] The mean change in ALSFRS = −0.02 (SE = + 0.01) points/month of pa ents with bulbar onset versus limb onset.

p = 0.004

[25] Steeper change in ALSFRS-R proximal limb onset versus distal limb-onset.

Data not reported.

p = 0.02

p =0.012 [22] Mul ple linear [25] Steeper change in ALSFRS-R leg onset analysis (only results from univariate analysis versus arm onset.

Data not reported. reported)

There is ‘very low’ evidence that: - Leg onset is associated with a steeper decline in func onal status compared to arm onset.

- Proximal limb onset is associated with a steeper decline in func onal status compared to distal limb onset.

There is ‘low’ evidence that bulbar onset of disease is associated with a worse func onal decline compared to limb onset.

There is ‘low’ evidence that years of educa on is not associated with func onal decline.

Quality score Level of evidence (based on GRADE Considered judgment if applicable)

[22] Mean ra oa = 1.34 (95 % CI = 1.07, ‘Low’ evidence 1.68); Bulbar onset results in a difference in ALSFRS-R decline of 34% compared to spinal onset.

[28], [30] Mixed effects [28], [30] Not significant model

Significant Sta s cal analysis associa on reported number of studies (par cipants)

Clinical characteris cs: disease-related and func onal factors Site of onset 5 [20], [21], 3 [22], [25], [30] [20], [25], [30] Mixed [22], [25], [30] (n = 3,061) effects model (n = 3,629) [21] Mul ple linear regression

Years of educa on 2 [28], [30] (n = 126)

Prognos c factor

2

31

32

No. of studies (par cipants)

Time from 3 [22], [29], symptom onset to [30] diagnosis (n = 3,111)

Prognos c factor

3 [22], [29], [30] (n = 656)

p = 0.001

[30] For every year that elapses between symptom onset and diagnosis, the slope of the ALSFRS score declines by 0.12 points (SE = 0.036) per month.

p = 0.02

[29] A shorter interval between symptom onset and diagnosis is associated with a lower ALSFRS score at six months follow-up.

p < 0.001

[29] Mann-Whitney U-test [30] Mixed effects model

[22] Mean ra oa = 0.99 (95 % CI = 0.98, 0.99); For every month between symptom onset to diagnosis the ALSFRS-R decline decreases with 1 %.

Strength of associa on

[22] Mul ple linear analysis (only results from univariate analysis reported)

Significant Sta s cal analysis associa on reported number of studies (par cipants) ‘Low’ evidence

There is ‘low’ evidence that a longer me between symptom onset and diagnosis is associated with a milder func onal decline.

Quality score Level of evidence (based on GRADE Considered judgment if applicable)

No. of studies (par cipants)

2 [19], [31] (n = 395)

2 [22], [30] (n = 609)

Prognos c factor

Ini al rate of disease progression

Comorbidi es

1 [22] (n = 514)

2 [19], [31] (n = 395)

[30] Mixed effects model

[22] Mul variate analysis (adjusted for age at diagnosis, region of onset, me from first symptom to diagnosis)

[31] Mann-Whitney U-test

[19] Stepwise logis c regression

Significant Sta s cal analysis associa on reported number of studies (par cipants)

[12} Not significant

p = 0.04

[22] Parkinson’s disease; mean ra oa = 0.46 ‘Very low’ (95 % CI = 0.22, 0.98). Pa ents with evidence symptoms of Parkinson’s disease have a milder ALSFRS-R decline of 46 %.

p < 0.01

[31] A cut-off point of 8.78 % reduc on in ALSFRS score in 3 months (the 80th percen le and 2 SD’s above the mean) iden fies pa ents with a rapid disease progression.

[19] %change ALSFRS-R score at week 4 was an independent prognos c factor of slow disease progression at 6 months [odds ra o = 0.0797 (95 % CI = 0.0451, 0.1406), p < 0.0001] and 12 months [odds ra o = 0.3073 (95 % CI = 0.2290, 0.4123), p < 0.0001]

There is ‘very low’ evidence that ‘comorbidity Parkinson’s disease ALS’ is associated with a slower func onal decline compared to ALS with no comorbidity.

There is ‘very low’ evidence that a higher percentage change in ALSFRS(-R) score at diagnosis is associated with a faster func onal decline.

Quality score Level of evidence (based on GRADE Considered judgment if applicable)

[19] %change ALSFRS-R score at week 2 was ‘Very low’ an independent prognos c factor of slow evidence disease progression at 6 months [odds ra o = 0.0156 (95 % CI = 0.0057, 0.0424), p < 0.0001] and 12 months [odds ra o = 0.1637 (95 % CI = 0.0945, 0.2833), p < 0.0001]

Strength of associa on

2

33

34 1 [23] (n = 150)

2 [19], [25] (n = 2,176)

Nutri onal status; 2 [23], [24] BMI (n = 401)

Baseline ALSFRS-R 4 [19], [21], score [25], [30] (n = 3,071)

[23] FVC was significantly associated with the ALSFRS-R decline (data not reported).

Strength of associa on

[19] Baseline ALSFRS-R score was an ‘Low’ evidence independent prognos c factor of slow disease progression at 6 months; odds ra o = 1.116 (95 % CI = 1.032, 1.207)

[24] Not significant

BMI >30 Not significant

p = 0.03

[21], [30] Not significant

p < 0.001

p = 0.0047 [25], [30] Mixed effects model [25] β baseline ALSFRS-R = 0.0660 (SE = 0.024) points.

[21] Mul ple linear regression

[19] Stepwise logis c regression

p < 0.01

[24] Mixed effects model BMI<30; β = −0.48 (SE = 0.22) points ALSFRS-R

[23] BMI was significantly associated with ‘Very low’ ALSFRS-R reduc on over me, with a evidence minimal ALSFRS-R score decline at BMI of 30 (data not reported).

‘Very low’ evidence

There is ‘low’ evidence that a higher baseline ALSFRS-R total score is associated with a slower func onal decline.

There is ‘very low’ evidence that a BMI of 30 is associated with a minimal func onal decline compared to BMI of <30 or >30, and that a higher BMI score on BMI of <30 is associated with a slower func onal decline compared to a lower score.

There is ‘very low’ evidence that a lower FVC is associated with a worse func onal decline.

Quality score Level of evidence (based on GRADE Considered judgment if applicable)

[23] Mul variate regression model (adjusted for age at inclusion and FVC)

[28], [30] Mixed effects p = 0.01 model [28], [30] Not significant

[23] Univariate regression

Significant Sta s cal analysis associa on reported number of studies (par cipants) 1 [23] (n = 150)

No. of studies (par cipants)

Respiratory status; 3 [23], [28], FVC [30] (n = 276)

Prognos c factor

2 [21], [28] (n = 217)

Frontotemporal syndromeb / extent of FTD and cogni ve performance

1 [21] (n = 186)

[28] Mixed effects model

[21] Mul ple linear regression (n = 186)

[21] Kruskal-Wallis test (n = 98)

Significant Sta s cal analysis associa on reported number of studies (par cipants)

[21], [28] Not significant

p = 0.025

There is ‘very low’ evidence that the presence of a frontotemporal syndrome at baseline is associated with a worse func onal decline.

Quality score Level of evidence (based on GRADE Considered judgment if applicable)

[21] Median ALSFRS-R decline at 12 months ‘Very low’ is higher in pa ents with a frontotemporal evidence syndrome. Execu ve dysfunc on, −0.76; no cogni ve abnormality 0.42; nonexecu ve cogni ve impairment, −0.66 points/month.

Strength of associa on

No. number, GRADE Grading of Recommenda ons Assessment, Development and Evalua on, ALSFRS (-R) amyotrophic lateral sclerosis func onal ra ng scale (-Revised), CI confidence interval, % percentage, SE standard error, β beta; regression coefficient, FVC forced vital capacity, BMI Body Mass Index, FTD frontotemporal demen a. a Mean ra o; difference in ALSFRS-R score ra o. ALSFRS-R ra o= the deteriora on of the score per month. b Frontotemporal syndrome= comorbid FTD or execu ve dysfunc on in a pa ent without demen a.

No. of studies (par cipants)

Prognos c factor

Prognos c factors for the func onal course in ALS

2

35

Chapter 2

Methodological quality of included studies The results of our risk of bias assessment using the QUIPS tool are summarized in the ‘risk of bias table’ (Appendix 2). The overall methodological quality of five studies was judged as ‘high’, five studies scored ‘moderate’ and three studies ‘low’ quality. In almost all studies, measurement of prognos c factors and ALSFRS(-R) outcomes were performed in a similar, valid, and reliable way for all par cipants. These quality domains were classified as ‘low’ risk of bias. Due to lack of repor ng on key characteris cs of the source popula on (‘study par cipa on’) and of par cipants loss to follow-up (‘study a ri on’), bias could not be ruled out. We were, therefore, compelled to classify studies as ‘moderate’ (n = 6) and ‘high’ risk (n = 5) of selec on bias. The sta s cal analysis, model-building process or completeness of repor ng were judged to be inadequate in six studies, resul ng in ‘moderate’ to ‘high’ risk of bias. Some of the studies reviewed only presented results from univariate analysis on the prognos c factor(-s) studied, thus causing the data quality assessment to be downgraded 22,26,29,31 . One study could be classified as ‘low’ risk of bias on all quality domains 23.

Synthesis of evidence The GRADE qualita ve synthesis of evidence for factors analysed in two or more studies, resulted in a ra ng of ‘low’ quality of evidence for site of onset, age at onset, me from symptom onset to diagnosis, and ALSFRS-R score at diagnosis as independent prognos c factor for decline in ALSFRS(-R) total score (Table 3). Based on the GRADE approach, we concluded ‘high’ evidence for gender, ‘moderate’ evidence for weight and height, and ‘low’ evidence for years of educa on as factors that are not associated with a decline in ALSFRS(-R), and ‘very low’ evidence for age at diagnosis, ini al rate of disease progression, forced vital capacity (FVC), body mass index (BMI), frontotemporal demen a (FTD), and comorbidi es as prognos c factor for decline in ALSFRS(-R) total score. Age at onset and age at diagnosis could be considered as interrelated factors, represen ng the same prognos c variable. However, as the dura on of the trajectory of diagnosis might differ within cohorts of pa ents or between health care systems, we present the prognos c value for each factor separately. We did not conduct sensi vity analyses because of the small number of studies for each prognos c factor.

The evidence according to the GRADE approach for the prognos c value of me from symptom onset to diagnosis, site of onset, ALSFRS-R score at diagnosis, and age at onset is summarized below.

36

37

2 [21, 28]

217

276

609

401

FTD

FVC

Comorbidi es

BMI

2 [23, 24]

1 [22] 2 [30]

2 [23, 28, 30]

1 [21] 2 [28]

1 [31] 3 [19]

1 [21] 2 [25, 30] 3 [19]

1 [20−22] 2 [25, 30]

1 [22, 29] 2 [30]

1 [22] 2 [30]

1 [21] 2 [25, 28, 30]

Phase

X

X

X

X

X

X

X

X

X

X

X X

X

X

X

X

X

X

X X X X X

X

X

X

X

X

X

X

X

X

X

X

X

‘Low’ ‘Very low’ ‘Low’ ‘Low’ ‘Low’

‘Very low’ ‘Very low’ ‘Very low’ ‘Very low’ ‘Very low’

X X

X X

X X X X X

Grade factors Study Inconsistency Indirectness Imprecision Publica on Moderate/ Overall limita ons bias large effect quality of size evidence

Phase, phase of inves ga on: phase 1 explanatory study, iden fying associa ons; phase 2 explanatory study, tes ng independent associa ons; phase 3 explanatory study, understanding prognos c pathways.

For uni- and mul variate analyses: +, number of significant effects with a posi ve value; 0, number of non-significant effects; -, number of significant effects with a nega ve value.

For GRADE factors: , no serious limita ons; X, serious limita ons (or not present for moderate/large effect size); unclear, unable to rate item based on available informa on.

For overall quality of evidence: ‘Very low’; ‘Low’; ‘Moderate’; ‘High’.

GRADE Grading of Recommenda ons Assessment, Development and Evalua on, ALSFRS (-R) Amyotrophic Lateral Sclerosis Func onal Ra ng Scale (-Revised), FTD frontotemporal syndrome, FVC forced vital capacity, BMI Body Mass Index, Univariate univariate analyses, Mul variate mul variate analyses.

1 1

2 [23, 24]

2 1 1

1

2

1

1 2 1

2 2

1

2 [22, 30]

3 [23, 28, 30]

2 [19, 31]

Ini al rate of disease 389 progression

30]

4 [19, 21, 25,

1

2,457

Baseline ALSFRS(-R) score 1

1

5 [20−22, 25,

3,021

Site of onset 30]

2

1

1

2 [22, 30] 3 [22, 29, 30]

609

Age at diagnosis

3 1

Mul variate + 0 -

4 [21, 25, 28, 30]

Univariate + 0 -

Time from symptom 656 onset to diagnosis

2,156

Age at onset

Poten al prognos c Par ciNumber of factors iden fied pants (n) studies

Table 3 Adapted GRADE table for narra ve systema c reviews of prognos c studies.

2

Chapter 2

Time from symptom onset to diagnosis The ‘low’ quality of evidence according to the GRADE approach for the prognos c value of me from symptom onset to diagnosis was based on three studies. The independent associa on between longer me from symptom onset to diagnosis and a slower func onal decline turned out to be significant in one study 30. Another study presented a significant associa on in a univariate analysis 22. The third study did not present the strength of the associa on and uncertainty es ma on 29. Imprecision and moderate to ‘high’ risk of bias within studies forced the quality of evidence to be downgraded to ‘low’.

Site of onset Five studies inves gated the prognos c value of site of onset for decline in ALSFRS(-R) total score. Prognos c value of bulbar onset versus limb onset was reported in four studies.

Inconsistency due to non-significance in two of these four studies and imprecision of results, resulted in ‘low’ quality of evidence for greater decline in ALSFRS(-R) total score in bulbar onset ALS. Baseline ALSFRS-R score Within the four studies presen ng baseline ALSFRS-R score as prognos c factor, we summarized the overall quality of evidence according to the GRADE approach as ‘low’ mainly due to inconsistent and imprecise findings. Two studies with ‘low’ risk of bias, showed inconsistent results. One study demonstrated a significant associa on between a higher baseline ALSFRS-R total score and a slower func onal decline 25. The mul ple linear regression model in the other study, using the total ALSFRS-R slope as dependent variable, showed no sta s cally significant associa on 21. We judged the other two studies to be ‘moderate’ quality or ‘low’ quality 19,30.

Age at onset Four studies inves gated the prognos c value of age at onset for a decline in ALSFRS(-R) total score. Only one study presented a significant, independent associa on between older age at onset and greater decline in ALSFRS-R total score 25. Inconsistency and imprecision in results, taking into account the small number of studies, resulted in an overall ‘low’ quality of evidence according to the GRADE approach.

DISCUSSION Our systema c review summarizes the evidence on prognos c factors for the rate of decline in func onal status of (recently) diagnosed pa ents with ALS. The qualita ve synthesis according to the GRADE approach resulted in ‘low’ evidence for age at onset,

38

Prognos c factors for the func onal course in ALS

site of onset, me from symptom onset to diagnosis, and baseline ALSFRS(-R) score. We graded the evidence for age at diagnosis, ini al rate of disease progression, FVC, FTD, BMI and comorbidity as ‘very low’, mainly due to the heterogeneity, the limited number and methodological quality of the selected studies.

In contrast to the limited number of studies repor ng prognos c factors predic ve for the pa ents’ func oning, a larger number of publica ons on prognos c factors for survival of pa ents with ALS are available. In their cri cal review, Chiò et al. (2009) 32 summarized the evidence on prognos c factors related to survival. Although several ALS outcome studies are based on register methodology (longitudinal cohorts, prospec ve popula on-based registers), the appraisal of the methodological quality of these studies was not conducted.

In view of the strong correla on between rate of progression of ALSFRS-R and survival, certain prognos c factors for survival also have prognos c value for func onal decline: age at onset, site of onset, diagnos c delay, FVC, BMI, and baseline ALSFRS(-R) 32. This finding strengthens the relevance of the prognos c factors we found, contrary to our overall quality of evidence judgment of these factors based on the GRADE approach. Nevertheless, it seems reasonable to assume that other prognos c factors for survival will also be associated with func onal decline, but these (e.g., El Escorial diagnos c categories, nutri onal status, and cogni ve func ons) have either not yet been studied, or we found no evidence in the iden fied studies about their prognos c value for the func onal course.

We selected the ALSFRS(-R) represen ng func onal status in ALS as the most widely used outcome marker of disease progression in clinical prac ce and research. Recently, Franchignoni et al. (2013) 33 ques oned the metric quality of the subjec ve ALSFRS-R and demonstrated that the scale as a single (total)score lacks unidimensionality. Trea ng an ordinal summed ra ng scale as an interval measure, assuming equal intervals, and subjec ng such scale to parametric sta s cs (as regression analyses) will likely lead to invalid results 23. This may well be one of the reasons for the low level of evidence we found for the prognos c factors, even for those that are o{en used by professionals in individual prognos ca on. Furthermore, most sta s cal models used in prognos c studies assume a linear decline in func oning during the en re disease trajectory; this assump on is not met for the total raw score of the ALSFRS(-R) in ALS 19,25. In contrast to the heterogeneity of the ALSFRS(-R) total score, the domains of the ALSFRS(-R) (bulbar, motor, and respiratory func ons) appear unidimensional, and adequately represent the respec ve constructs 34.

It is surprising that only one study was iden fied that inves gated prognos c factors for ALSFRS-R domains, and even this was limited to one domain (bulbar). It may well be that stronger associa ons can be found between poten al prognos c factors and decline in bulbar, motor or respiratory func ons.

Most likely, ALS disease heterogeneity complicates the development of prognos c models. More knowledge about the gene c and molecular pathophysiological mechanisms is required to allow development of more accurate predic on models 35. In this context,

39

2

Chapter 2

the iden fica on of gene c subtypes in ALS might be of vital importance. The phenotypic heterogeneity in ALS is evident in view of the clinical manifesta on of the region of symptom onset and disease course in ALS 22,37–39. Although studies showed differing average rates of disease progression across ALS phenotypes, there was also a clear varia on within these phenotypes 39,40. Within each subgroup, pa ents might have a rela vely slow or fast disease course. Consequently, predic on of func onal deteriora on on the basis of the specific phenotype encompasses major uncertainty. Furthermore, there are no clear boundaries between phenotypes 41. Future analysis of large numbers of pa ents within phenotypes might elucidate the within-phenotype varia on and could iden fy phenotypes with consistent prognos c pa erns 2.

Previous studies made use of prognos c categories for survival in ALS by applying prognos c models or staging systems 5,42. As far as we know, there are no studies about the validity and applicability of comparable models and systems for func onal status. Further research is warranted to assess the validity of such models and systems and their clinical applicability in individual pa ent management 43.

This review has strengths and limita ons. The robust search in 5 relevant databases, the use of the QUIPS tool for the appraisal of study quality and the GRADE framework for the quality of prognos c evidence are strengths of our study. It is possible that we have missed studies that are not indexed for these databases, but by checking references of included studies, we presume that no relevant ar cles were missed. Earlier studies reported nega ve consequences due to our selec on criteria ‘published in English’. We conclude, based on the available English abstracts of the non-included, non-English ar cles, that it is unlikely that our results are biased because of language restric ons 44,45.

As we selected studies with the ALSFRS (-R) as outcome measure for func onal status, we may have missed prognos c studies with different outcome measures. One study suggested that the examina on-based AALSS (Appel ALS Score) provides a be er es mate of disease severity in ALS compared to the ques onnaire-based ALSFRS 46. Based on normalized scores of both scales, the ALSFRS underes mated disease severity defined by the AALS; this increased with disease progression. Both scales, however, showed a significant change with disease progression. We do not expect that including other outcome measures for func onal status in the present review would lead to higher levels of evidence for prognos c factors as the ALSFRS(-R) is the most frequently used clinical measure for disability progression in ALS. The ability to predict the decline in func onal status of the individual pa ent with ALS remains uncertain. This review has highlighted a gap in the current literature about prognos c value of clinical variables for func onal decline. Comprehensive data collec on – na onal and interna onal standardized measurements of pa ent, disease, and interven on variables recorded in daily clinical prac ce and entered into large electronic databases – might enhance the possibility of iden fying prognos c factors. Furthermore, it is likely that the gene c varia on in ALS will be unravelled and gene c subtypes with less clinical

40

Prognos c factors for the func onal course in ALS

heterogeneity will be iden fied in the years to come. This might enable the development of predic on tools stra fied by ALS subtypes with be er prognos c performance in individual pa ents.

Our results endorse the need for well-conducted prospec ve cohort studies on prognos c factors for the course of the func onal status of pa ents with ALS. These studies should not only focus on sociodemographic and clinical prognos c factors, but also inves gate the prognos c importance of psychosocial factors, cogni on and comorbidity. Future prognos c studies preferably use an op mal design including selec on of incep on cohort, mul variate sta s cal models, registering reliable informa on about the (mul disciplinary) treatment given and all poten al prognos c variables 47.

In conclusion, the current strength of evidence on prognos c factors for func onal decline in ALS is insufficient to allow the development of a clinical predic on tool that can support the professionals’ judgement of the func onal course. Methods for standardized assessment and registra on of pa ents’ sociodemographic, clinical and psychosocial characteris cs, symptom treatment, and outcome measures preferably may be agreed interna onally; data sharing may enable more reliable evidence synthesis of prognos c factors for func onal decline in ALS. With the future prospect of improved understanding of ALS gene cs, more accurate prognos ca on may be achieved through the development of predic on tools stra fied by gene cally defined subtypes of ALS.

41

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Chapter 2

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Prognos c factors for the func onal course in ALS Appendix 1 Prognos c factors related to outcome measures analysed in one study.

Prognos c factor

No. of Sta s cal Strength of associa on par cipants analysis

Outcome: Decline in ALSFRS total score or ALSFRS-R total score Sociodemographic characteris cs Age > 40 years 1 [30] Mixed Not significant (n = 95) effects model

Age at symptom 1 [30] onset < 54.9 years (n = 95)

Mixed effects model

Not significant

Race (Caucasian)

1 [30] (n = 95)

Mixed effects model

Not significant

1 [30] Male veterans and male veterans (n = 95) performing ac ve duty

Mixed effects model

Quality score

Level of evidence Considered judgement

‘Very low’ There is ‘very low’ evidence evidence that age > 40 years is associated with a worse func onal decline.

‘Very low’ There is ‘very low’ evidence evidence that age at symptom onset < 54.9 years is associated with a worse func onal decline.

‘Very low’ There is ‘very low’ evidence evidence that Caucasian race is associated with a less worse func onal decline.

‘Very low’ There is ‘very low’ Male veterans and male evidence evidence that male veterans of ac ve duty veterans and male correlated significantly with veterans of ac ve disease progression; mean (SD) duty is associated changes in ALSFRS/month; -0.02 with a less worse (+ 0.01) points. func onal decline. p=0.03 Not significant

Marital status

1 [30] (n = 95)

Environmental factors ALS risk factors# 1 [30] (n = 95)

Mixed effects model

Not significant

‘Very low’ There is ‘very low’ evidence evidence that marital status is associated with a less worse func onal decline.

Mixed effects model

Not significant

‘Very low’ There is ‘very low’ evidence evidence that ALS risk factors are associated with a worse func onal decline.

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Chapter 2 Prognos c factor

No. of Sta s cal Strength of associa on par cipants analysis

Clinical characteris cs: disease-related factors and func onal factors UMN-dominant 1 [26] Friedman Addi onal decline in ALSFRS-R ALS (n = 40) test total score from baseline to 6 months and sub-scores (bulbar, spinal, respiratory) from baseline to twelve months is steeper in pa ents with typical ALS compared to UMN-dominant ALS (data not reported). p<0.02 El Escorial criteria

1 [30] (n = 95)

Mixed effects model

Not significant

Familial ALS

1 [30] (n = 95)

Mixed effects model

Not significant

Family history of ALS

1 [30] (n = 95)

%change ALSFRS-R 1 [19] score from (n = 338) baseline at week 2

%change ALSFRS-R 1 [19] score from (n = 338) baseline at week 4

46

Quality score

Level of evidence Considered judgement

‘Very low’ There is ‘very low’ evidence evidence that upper motor neuron dominant ALS is associated with a slower func onal decline compared to classical ALS.

‘Very low’ There is ‘very evidence low’ evidence that one of the El Escorial categories is associated with a less or worse func onal decline.

‘Very low’ There is ‘very low’ evidence evidence that familial ALS is associated with a worse func onal decline.

Mixed Not significant ‘Very low’ There is ‘very low’ effects evidence evidence that a model family history of ALS is associated with a worse func onal decline.

‘Very low’ There is ‘very low’ Stepwise %change ALSFRS-R score at evidence evidence that a logis c week 2 was an independent higher %change regression prognos c factor of slow disease ALSFRS-R score from progression at 6 months [odds baseline at week 2 ra o = 0.0156 (95% CI = 0.0057, is associated with 0.0424), p<0.0001] and 12 a faster func onal months [odds ra o = 0.1637 decline at 6 months (95% CI = 0.0945, 0.2833), and at 12 months. p<0.0001] ‘Very low’ Stepwise %change ALSFRS-R score at evidence logis c week 4 was an independent regression prognos c factor of slow disease progression at 6 months [odds ra o = 0.0797 (95% CI = 0.0451, 0.1406), p<0.0001] and 12 months [odds ra o = 0.3073 (95% CI = 0.2290, 0.4123), p<0.0001]

There is ‘very low’ evidence that a higher %change ALSFRS-R score from baseline at week 4 is associated with a faster func onal decline at 6 months and at 12 months.

Prognos c factors for the func onal course in ALS Prognos c factor

No. of Sta s cal Strength of associa on par cipants analysis

Change in ALSFRS in 3 month

1 [31] (n = 57)

Ini al rate of disease progression

2 [19], [31] (n = 395)

Quality score

Level of evidence Considered judgement

MannWhitney U-test

‘Very low’ A cut-off point of 8.78% reduc on in ALSFRS score (the evidence 80th percen le and 2 SD’s above the mean) iden fies pa ents with a rapid disease progression, p<0.01

There is ‘very low’ evidence that a pa ent with a > 8.78% reduc on in ALSFRS score at 3 months is associated with a faster func onal decline compared to a pa ent with a < 8.78% reduc on.

[19] Stepwise logis c regression

‘Very low’ [19] %change ALSFRS-R score at week 2 was an independent evidence prognos c factor of slow disease progression at 6 months [odds ra o = 0.0156 (95% CI = 0.0057, 0.0424), p<0.0001] and 12 months [odds ra o = 0.1637 (95% CI = 0.0945, 0.2833), p<0.0001]

There is ‘very low’ evidence that a higher percentage change in ALSFRS(-R) score at diagnosis is associated with a faster func onal decline.

[31] MannWhitney U-test

[19] %change ALSFRS-R score at week 4 was an independent prognos c factor of slow disease progression at 6 months [odds ra o = 0.0797 (95% CI = 0.0451, 0.1406), p<0.0001] and 12 months [odds ra o = 0.3073 (95% CI = 0.2290, 0.4123), p<0.0001] [31] A cut-off point of 8.78% reduc on in ALSFRS score (the 80th percen le and 2 SD’s above the mean) iden fies pa ents with a rapid disease progression, p<0.01 Biological markers of disease progression Not significant Uric acid levels 1 [24] Mixed (n = 251) effects model (including BMI as a covariate)

Serum chloride level

1 [27] (n = 795)

Mixed effects model

For each unit decrease in baseline serum chloride level, the slope of ALSFRS decreased by 0.14 (SE = 0.04) points. p=0.0002

‘Very low’ There is ‘very low’ evidence evidence that higher baseline uric acid levels tend to be associated with a slower deteriora on in the total func onal decline.

‘Very low’ There is ‘very low’ evidence evidence that a lower chloride level is associated with a faster rate of decline in func onal status.

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No. of Sta s cal Strength of associa on par cipants analysis

Psychosocial factors Personality factors: 1 [28] (n = 31) neuro cism, extraversion, openness, agreeableness, conscien ousness (NEO-A)

Mixed effects model

Lower baseline scores on agreeableness is associated with slower rate of disease progression.

Time: β = -0.90 (SE = 0.12) points/ month ALSFRS. p<0.001 Agreeableness; β = -6.79 (SE = 3.17) points/ month ALSFRS. p=0.045 AgreeablenessXTime; β = -0.83 (SE = 0.31) points/ month ALSFRS. p=0.016

Quality score

Level of evidence Considered judgement

‘Very low’ There is ‘very low’ evidence evidence that a lower baseline agreeableness score is associated with a slower rate of decline in func onal status.

Other personality factors (neuro cism, openness, conscien ousness, extraversion) not significant.

Depression

1 [28] (n = 31)

Mixed effects model

Not significant

‘Very low’ There is ‘very low’ evidence evidence that a lower score on depression is associated with a slower decline in func onal status.

Clinical characteris cs: func onal factors ‘Very low’ %change ALSFRS-R 1 [19] Stepwise %change ALSFRS-R score at evidence score from (n = 338) logis c week 2 was an independent baseline at week 2 regression prognos c factor of slow disease progression at 6 months [odds ra o = 0.0156 (95% CI = 0.0057, 0.0424), p<0.0001] and 12 months [odds ra o = 0.1637 (95% CI = 0.0945, 0.2833), p<0.0001]

There is ‘very low’ evidence that a higher %change ALSFRS-R score from baseline at week 2 is associated with a faster func onal decline at 6 months and at 12 months.

‘Very low’ Stepwise %change ALSFRS-R score at evidence logis c week 4 was an independent regression prognos c factor of slow disease progression at 6 months [odds ra o = 0.0797 (95% CI = 0.0451, 0.1406), p<0.0001] and 12 months [odds ra o = 0.3073 (95% CI = 0.2290, 0.4123), p<0.0001]

There is ‘very low’ evidence that a higher %change ALSFRS-R score from baseline at week 4 is associated with a faster func onal decline at 6 months and at 12 months.

%change ALSFRS-R 1 [19] score from (n = 338) baseline at week 4

48

Prognos c factors for the func onal course in ALS Prognos c factor

No. of Sta s cal Strength of associa on par cipants analysis

Change in ALSFRS in 3 month

1 [31] (n = 57)

MannWhitney U-test

Quality score

‘Very low’ A cut-off point of 8.78% reduc on in ALSFRS score (the evidence 80th percen le and 2 SD’s above the mean) iden fies pa ents with a rapid disease progression, p<0.01

Outcome: Decline in ALSFRS-R domain score Clinical characteris cs: disease related factors Site of onset 1 [21] Mul ple Bulbar onset of disease predicts ‘Very low’ (n = 186) linear a more rapid decline in ALSFRS-R evidence regression bulbar score; β = 0.156 (95% CI = 0.055 0.258) points/month. p=0.0003 Frontotemporal syndrome##

1 [21] (n = 186 )

Mul ple linear regression (n = 186)

A frontotemporal syndrome at ‘Very low’ baseline predicts a more rapid evidence decline in ALSFRS-R bulbar score; β = 0.13 (95% CI = 0.012 0.250) points/months. p=0.032

KruskalWallis test Median change in bulbar (n = 98) ALSFRS-R sub scores at 6 months is higher in pa ents with a frontotemporal syndrome.

FTD, -0.20; execu ve dysfunc on, -0.20; no frontotemporal syndrome, 0.00 points/months. p=0.026

Level of evidence Considered judgement There is ‘very low’ evidence that a pa ent with a > 8.78% reduc on in ALSFRS score at 3 months is associated with a faster func onal decline compared to a pa ent with a < 8.78% reduc on.

There is ‘very low’ evidence that bulbar disease onset is associated with a worse func onal decline (bulbar domain score).

There is ‘very low’ evidence that the presence of a frontotemporal syndrome at baseline is associated with a worse func onal decline (bulbar score).

#

Pet ownership, welding as occupa on, consump on cigare e smoking, number of cigare e packs per day, no fish consump on, high milk consump on, smoking quit age, smoking start age, geographical area, mean hours of ac vity, number of ac vi es. ## Frontotemporal syndrome= comorbid FTD or execu ve dysfunc on in a pa ent without demen a.

No. number, GRADE Grading of Recommenda ons Assessment, Development and Evalua on, ALSFRS (-R) amyotrophic lateral sclerosis func onal ra ng scale (-Revised), SD standard devia on, BMI, Body Mass Index, UMN, upper motor neuron, SE standard error, % percentage, FVC forced vital capacity, NEO-A neuro cismextroversion-openness-agreeableness inventory. This subscale of the NEO Five Factor Inventory consists of 12 items. A higher score indicates more agreeable nature. Β beta; regression coefficient, CI confidence interval, FTD frontotemporal demen a.

49

2

Chapter 2 Appendix 2 Risk of bias of the included studies (n=13).

First author

Study Study par cipa on a ri on

Prognos c Outcome Sta s cal Overall factor measurement analysis and quality measurement repor ng

Reich-Slotky [23] Clavelou [20] Elamin [21] Gordon [25] Qureshi [27] Gomeni [19] SorarĂš [26] Paganoni [24] Krampe [28] Rauchway [29] De Carvalho [31] KĂśrner [22] Qureshi [30]

Low Low Low Low Low Moderate Low Low High Low Moderate Moderate Moderate

Low Low Low Low Low Low Low Low Low Low Low Moderate Moderate

Low Moderate Moderate Moderate Moderate Moderate Low High Moderate High Moderate High High

Low Low Low Low Low Low Low Low Low Low Low Low Low

Low Low Low Low Low Low High Moderate Low Moderate High Moderate Moderate

Low = Low risk of bias; Moderate = Moderate risk of bias; High = High risk of bias Overall methodological quality: + = high; +/- = moderate; - = low

50

+ + + + + +/+/+/+/+/-

3 The provision of assis ve devices and home adapta ons to pa ents with ALS in the Netherlands: Pa entsâ&#x20AC;&#x2122; perspec ves Huub Creemers Anita Beelen Hepke Grupstra Frans Nollet Leonard H. van den Berg

Amyotrophic Lateral Sclerosis and Frontotemporal Degenera on 2014. Sep;15(5-6):420-5. Š Reprinted with permission from Taylor & Francis Group

Chapter 3

ABSTRACT Objec ve The mely provision of assis ve devices and home adapta ons (ADHA) is crucial in the management of pa ents with Amyotrophic Lateral Sclerosis (ALS) in order to maintain their independence and relieve their caregivers. Our objec ve was to study the experiences of pa ents with ALS during the process of procuring ADHA. Methods We sent a cross-sec onal ques onnaire survey addressing issues concerning the applica on for and provision process of ADHA to 239 pa ents with ALS registered at one of the three ter ary academic diagnos c centers within the Netherlands ALS Center.

Results One hundred ďŹ {y-nine (89%) of the 179 responding pa ents (response rate 75%) had experience with the procurement process and ninety-three (58%) of them indicated problems in obtaining ADHA. The most reported problems were delay (42%) and the authori esâ&#x20AC;&#x2122; lack of disease knowledge (24%). Pa ents viewed these issues as the most prominent requiring improvement.

Conclusion The main problems perceived by pa ents indicate that increasing awareness of ALS and promo ng a proac ve a`tude among professional caregivers towards the applica on for ADHA may contribute posi vely to the quality of ALS care.

52

The provision of assis ve devices and home adapta ons in ALS

INTRODUCTION The mainstay in the management of pa ents with ALS and their caregivers is proac ve neuropallia ve rehabilita on consis ng of symptoma c treatment, preven on of complica ons, reduc on of caregiver strain and maintenance of op mal func on and quality of life 1,2. Assis ve devices and home adapta ons (ADHA) cons tute one of the important healthcare interven ons to support ALS pa ents and their caregivers 3-5. Due to the rapid rate of disease progression, and as a consequence the changing requirements of pa ents with ALS, adequate and mely provision of ADHA is needed. From pa ent quality of care evalua ons and daily clinical prac ce it appeared that the procurement process of ADHA can be problema c for pa ents and their informal caregivers 6.

Literature on this topic is scarce. Earlier research reported the discrepancy between the progressive disease condi on and the usual me-span in which health care provision procedures take place 3. Recently a study suggested that availability and ďŹ nancing of assis ve technology devices are common problems among pa ents with ALS 7. The long approval processes and serious bureaucra c burden, inducing inadequate provision of assis ve technology devices, is perceived as problema c by ALS pa ents in Germany 7. As health care systems and health care resources diďŹ&#x20AC;er in European countries, we do not know the scale of the problem in other countries, nor what aspects of the procurement process are most problema c from the point of view of pa ents with ALS. Insight into the barriers that pa ents encounter in the applica on and provision process will enable us to design targeted strategies to improve the provision of ADHA and thereby help improve the quality of ALS care.

Through a na onwide survey, we sought to explore the experiences of pa ents with ALS during the applica on and provision process of ADHA, and par cularly to determine the problems they perceived during this procurement process.

53

3

Chapter 3

MATERIALS AND METHODS Pa ents In our cross-sec onal study, we sent a ques onnaire with informa on on background and objec ve to all pa ents with ALS, who in August 2007 were registered at one of the three ter ary academic diagnos c centers which collaborate within the Netherlands ALS Centre.

Directly a{er the diagnosis, the referral op on to one of the specialized mul disciplinary ALS care teams in their district of residence is proposed to the pa ent. Actual referral explicitly incorporates the pa ents’ own preferences. Even a{er receiving specialized ALS care, pa ents may withdraw from this specialized care at a later stage of disease.

We collected sociodemographic and clinical characteris cs of these pa ents from the popula on-based register of the Netherlands ALS Centre: age, gender, site of disease onset, date of diagnosis, me to diagnosis, me since diagnosis, ALSFRS-R score and whether the pa ent received specialized mul disciplinary ALS care or general ALS care 8-10. The procedures we followed were in accordance with the ethical standards of the Medical Ethics Commi ee of the three centers involved. All pa ents took part on a voluntary basis.

Ques onnaire Our self-administered ques onnaire, specifically designed for this study, addressed different issues of the applica on and provision process of ADHA in the Netherlands. A copy of the ques onnaire is available upon request. The ques onnaire consisted of three sec ons.

In the first sec on, pa ents were asked which of 22 ADHA they use. In the Netherlands, three competent authori es provide most of the ADHA in the home: health insurers (Health Insurance Act), municipali es (Social Support Act) and health care administra on offices (Excep onal Medical Expenses Act). These authori es judge the applica on, take care of the financing of the ADHA and commission suppliers to deliver the ADHA. The complexity of the procurement procedures may differ depending on the type of ADHA. Prescrip on of ADHA can come from any level of care – ter ary care, secondary care and primary or community care. In the Dutch health care system, pa ents with ALS ini ate the process of procurement for ADHA themselves. Health care professionals from any level of care offer support to pa ents during the procurement for ADHA. For some of the ADHA that are covered by health insurance, authoriza on from a medical professional (trea ng physician) is required.

The second sec on of the ques onnaire addressed pa ents’ experiences with the procurement process of 5 specific ADHA: home care services, bathroom adapta ons, a stair li{ system, a manual wheelchair, and a disabled parking permit. These 5 ADHA were selected because they are frequently prescribed for pa ents with ALS and represent the diversity of procedures in the Dutch health care system when applying for ADHA. Our aim was to collect quan ta ve informa on about pa ents’ experiences.

54

The provision of assis ve devices and home adapta ons in ALS

For each of these 5 ADHA, we asked the par cipa ng pa ents: • Whether they applied for the ADHA. • To indicate the me-span between the moment of applying for the ADHA and finally receiving it (<1; 1–3; >3 months).

• Whether the me-span between the moment of applica on for the ADHA and the final provision was considered acceptable (yes/no).

• To judge the quality of the en re procurement process from applica on for to provision of the ADHA (including the contacts with the funding authori es and suppliers) on an ordinal scale from 1 to 10 (1=poor quality, 10=excellent quality).

The third sec on of the ques onnaire consisted of two open ques ons, providing qualita ve data on the procurement process. We asked pa ents, when thinking back to the procurement process of one or more ADHA, to report the major problems perceived during the en re process, if appropriate. And in a final ques on, we asked pa ents to report two priority problems during the applica on and provision process that in their opinion needed to be solved first.

Data collec on and analysis For the descrip ve analysis of the sociodemographic and clinical characteris cs of the responding pa ents with ALS, we compiled a frequency table. We reported data from the first sec on, indica ng pa ents’ experiences with the procurement process of 22 ADHA, using descrip ve sta s cs. By pu`ng data from the second sec on of the ques onnaire into another frequency table, we produced a descrip ve analysis of the pa ents’ experiences with the procurement process of 5 ADHA. We merged the pa ents’ qualita ve responses to the open ques ons of the third sec on into limited themes, indica ng the problem areas.

RESULTS One hundred and seventy-nine pa ents with ALS returned the ques onnaire (response rate 75%). Table 1 presents the characteris cs of the respondents. We found no relevant differences in baseline sociodemographic or clinical characteris cs between respondents and non-respondents. Eighty-nine percent (n=159) of the pa ents had experience with the process of applica on for and provision of the previously selected 22 ADHA. Table 2 shows the number and propor on of pa ents who had experience with the procurement process of each of the 22 ADHA.

55

3

Chapter 3 Table 1 Sociodemographic and clinical characteris cs of responding pa ents with ALS (n=179).

Mean age (SD) years Male (%) Limb onset (%) Median ALSFRS-R [Q1-Q3] Median me to diagnosis [Q1-Q3], months Median me since diagnosis [Q1-Q3], months Specialized ALS care versus general ALS care (%)

Respondents (n=179) 62.6 (11.5) 60 67 36 [26−41] 12.0 [8.3−20.5] 17.3 [10.3−39.1] 71/29

ALS: amyotrophic lateral sclerosis; n: number; SD: standard devia on; %: percentage; ALSFRS-R: amyotrophic lateral sclerosis func onal ra ng scale-revised; Q1-Q3: first quar le to third quar le.

Table 2 Use of ADHA. ICF a code Assis ve devices and home adapta ons e1 Products and technology e115 Products and technology for personal use in daily living e1151 Bathroom adapta ons e1151 Electric li{ recliner chair e1151 Electrically operated bed e1151 Shower, toilet and commode chair e1151 Shower chair e1151 Pressure-relieving ma ress and pressure-relieving cushion e1151 Toilet chair e1151 Mobile arm support device e1151 Elbow crutches e1151 Mechanical page turner e1151 Mul -adjustable table e120 Products and technology for personal indoor and outdoor mobility and transporta on e1201 Rollator walker e1201 Electric wheelchair e1201 Modular system chair with castors e1201 Electric pa ent li{ e1201 Mobility scooter e1201 Stair li{ system e125 Products and technology for communica on e1251 Communica on devices e1251 Computer so{- and hard-ware e5 Services, systems and policies e540 Transporta on services, systems and policies e5400 Disabled parking permit e575 General social support services, systems and policies e5750 Home care services

n (%) b

118 (66) 88 (49) 75 (42) 59 (33) 57 (32) 52 (29) 20 (11) 16 (9) 14 (8) 13 (7) 11 (6)

116 (65) 73 (41) 66 (33) 50 (28) 43 (24) 43 (24) 54 (30) 30 (17)

111 (62) 116 (65)

ADHA: assis ve devices and home adapta ons; ALS: amyotrophic lateral sclerosis; ICF: Interna onal Classifica on of Func oning, Disability and Health; n: number; %: percentage. a Assis ve devices and home adapta ons classified according to the Interna onal Classifica on of Func oning, Disability and Health 23. b n (%) of respondents (n = 179).

56

The provision of assis ve devices and home adapta ons in ALS

In Table 3, the pa ents’ experiences regarding me-span and quality of the procurement process of the 5 selected ADHA are listed. The propor on of pa ents who rated the dura on of the process as unacceptable, was highest for bathroom adapta ons (30%). The propor on of pa ents who judged the en re method of assignment and delivery to be of insufficient quality, ranged from 6 to 20%.

Table 3 Self-reported me-span and appraisal of procurement process for 5 ADHA. ADHA Applica on

Pa entsa Obtained Time-span Time-span Time-span Time-span Insufficient ADHAb < 1 monthc 1 - 3 ≥3 not quality of the monthsc monthsc acceptablec procurement processd n (%) n (%) n (%) n (%) n (%) n (%) n (%)

Bathroom adapta ons Manual wheelchair Home care services Disabled Parking Permit Stair li{

118 (66) 111 (94)

20 (18)

30 (27)

60 (54)

33 (30)

18 (16)

116 (65) 114 (98)

51 (45)

49 (43)

14 (12)

14 (12)

7 (6)

116 (65) 109 (94)

62 (57)

32 (29)

15 (14)

16 (14)

23 (20)

111 (62) 103 (93)

58 (56)

32 (31)

11 (10)

15 (14)

22 (20)

37 (21)

5 (20)

7 (28)

13 (52)

2 (8)

2 (8)

25 (68)

ADHA: assis ve devices and home adapta ons; ALS: amyotrophic lateral sclerosis; n: number; %: percentage. a n (%) of pa ents with ALS (n = 179) who applied for the evaluated ADHA. b n (%) of pa ents with ALS to whom the ADHA was assigned. c Time-span, reported by pa ents with ALS, between the moment of applica on for the ADHA and the final delivery. d n (%) of pa ents who judged the en re procurement process as insufficient quality (scores ≤ 5).

Table 4 shows the themes of problem areas we derived from the perceived major problems. Ninety-three pa ents (58%) reported at least one priority problem. The most frequently stated problem was the long dura on of assent and delivery. Pa ents also reported problems in the quality of the procurement process due to lack of knowledge about the disease of par es involved, failures in delivery and technical errors. Furthermore, pa ents reported that they felt inhibited because of unfamiliarity with the applica on process and powerless in the case of rejec on as they perceived the reason to be arbitrary.

Pa ents found the need to repeatedly explain the disease, its impact on func oning, and their specific needs for ADHA to be burdensome. The most frequent difficul es perceived by pa ents involved the procurement of an electric wheelchair and home adapta ons. Sixteen percent of pa ents (n=19) who applied for bathroom adapta ons at the municipal office reported that they were subjected to repeated medical examina ons.

57

3

Chapter 3 Table 4 Themes of problem areas pa ents with ALS perceived in obtaining ADHA. The long dura on of the process of applica on and provision Authori es’ lack of knowledge about disease characteris cs of ALS/MND The bureaucracy and paperwork Lack of clarity of the legal procedures and informa on Errors by the suppliers /wrong configura on /malfunc on Dependency /refusal /no opportunity to comment Home care services /needs assessment Financial problems

n (%)a 39 (42) 22 (24) 15 (16) 15 (16) 13 (14) 13 (14) 6 (6) 5 (5)

ADHA: assis ve devices and home adapta ons; ALS: amyotrophic lateral sclerosis; MND: motor neuron disease. a n (%) responding pa ents with ALS (n=93) who experienced problems in obtaining ADHA.

Regardless the level of care (ter ary to community) or se`ng (specialized ALS-teams/ non-specialized teams) pa ents must pass through one of the three systems (procurement procedures of health insurers, municipali es and health care administra on offices).

We compared the experienced problems between two of the systems (health insurance procedure and municipali es procedure) and the results showed a similar trend (Figure 1), although the long wai ng me and errors by the suppliers were experienced more frequently in the ‘municipality’ procedure, and lack of disease knowledge more frequently in the ‘health insurance’ procedure. None of the par cipants reported problems with the health care administra on offices. This can be explained by the fact that these agencies manage a stock of assis ve devices which can be provided immediately upon request.

58

The provision of assis ve devices and home adapta ons in ALS Figure 1 Comparison of problems indicated by pa ents with ALS in obtaining ADHA from municipali es.

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(UURUV RI WKH VXSSOLHUV

'HSHQGHQF\ UHIXVDO 7KH EXUHDXFUDF\

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0XQLFLSDOLWLHV

+HDOWK LQVXUDQFH FRPSDQLHV

a

and from health insurance companies b. % of pa ents with ALS who obtained ADHA from their municipality (n=124) and perceived problems (n=38). b % of pa ents with ALS who obtained ADHA from their health insurance company (n=147) and perceived problems (n=28).

ALS: amyotrophic lateral sclerosis; ADHA: assis ve devices and home adapta ons; %: percentage. a

DISCUSSION About half of the pa ents with ALS experienced problems during the procurement process.

The most common problems men oned are delay and lack of knowledge about ALS by service funders and ADHA suppliers. These were indicated to be the most urgent problems to be solved in order to improve services. Bureaucracy, complexity of procedures, long delivery mes, lack of disease knowledge, failures in the procedures, and technical errors all contribute to delay. However, since the process of procurement is ini ated by the pa ents themselves, a delay on the pa entâ&#x20AC;&#x2122;s part in ini a ng the requests cannot be ruled out.

A remarkable ďŹ nding was the rela vely low propor on of pa ents who perceived the me-span for the ďŹ ve selected ADHA as not acceptable â&#x20AC;&#x201C; a discrepancy compared with the propor on of 42% who reported long dura on as problema c. This may be because the selec on of the ďŹ ve ADHA does not fully represent the overall experiences of pa ents. That a majority of pa ents indicated the quality of the process for the ďŹ ve ADHA to be suďŹ&#x192;cient shows that the process o{en runs sa sfactorily. However, op mizing these procedures is important due to the progressive nature of the disease.

59

3

Chapter 3

Delay is confirmed by other studies, resul ng in an increase in disease symptoms, func onal limita ons, pa ent distress, and caregiver strain 7,11,12. Ignorance about ALS on the part of service funders and suppliers may lead to unnecessary bureaucracy, incorrect indica ons and selec ons of ADHA, resul ng in delay 13,14. In the Netherlands, for example, the process of gran ng a parking permit can be completed within the me-span of a few weeks. Differences exist in the authori es’ judgement as to whether or not a pa ent meets the criteria for a permit or, more specifically, if the approving authority is willing to take the progressive nature of the disease into considera on.

A striking difference with other studies is our finding that problems related to the financing of ADHA were uncommon, probably because of the way funding resources in the Netherlands are organized and available. Most of the ADHA for Dutch pa ents are financed by health insurers and municipali es and − within certain financial limits − pa ents receive these ADHA free of charge. For some of the ADHA, however, e.g., architectural home adapta ons, a financial contribu on from the users themselves may be required which for some pa ents can be a problem.

Our study had a high response rate and relevant characteris cs of our sample (age, gender, site of onset and me to diagnosis) did not differ from those of the 1128 incident pa ents in the popula on based register in the Netherlands, thereby enhancing the generalizability of the study results 15.

Although we inves gated pa ents’ experiences with the procurement process of only the most frequently provided ADHA, it is probable that these experiences do not differ from those with non-surveyed ADHA since the procedures and stakeholders involved are the same.

Since procurement for ADHA is formally ini ated by the pa ent, regardless of the type of clinic pa ents followed up and the level of care, it is unlikely that the type of clinic or the level of care affected pa ents’ experiences with the procurement process. Both the ALS-special and non-special clinics may have direct communica on with one or more of the three systems. Clinical prac ce shows that through rigorous communica on many problems during the procurement process can be avoided or solved, but we did not inves gate the effect of the quality of communica on between clinics and systems on pa ents’ experiences.

Clinical implica ons and future studies Timely provision of ADHA requires a proac ve approach by all stakeholders. Pa ents and caregivers have to be informed by the mul disciplinary ALS care team about the threat of delay, especially in complex ADHA procedures such as home adapta ons. Tailored educa on by the ALS care team about ALS, ADHA, and the procurement procedures should empower pa ents and caregivers in their procurement process. Disease monitoring and adequate prognos ca on support the ming of proac ve applica on for ADHA. Nevertheless, the available evidence on prognos c factors for the course of the func onal status of pa ents

60

The provision of assis ve devices and home adapta ons in ALS

with ALS is limited 16-18. ALS care teams should consider con nuous evalua on of the procurement process so that they can undertake ac on when structural problems are recognised 19-21. Agreement by all stakeholders with regard to an emergency procedure for indica on and delivery of ADHA is the next challenge in improving quality of ALS care.

The findings of our study can form a star ng point for stakeholders to jointly develop informa on packages on the procurement processes of ADHA in ALS. The pa ent can act as a source of informa on and provide all those concerned in the procedure with appropriate details (e.g., disease symptoms, func onal limita ons, proac ve indica ons) that may improve the procurement process 22.

For future studies on the quality of the provision of ADHA in ALS we recommend conduc ng longitudinal studies, quan ta ve as well as qualita ve. The roles of the caregivers in the procurement process of ADHA as well as outcomes of ADHA are relevant topics, about which limited informa on is available. With the increased public awareness about ALS as a result of an intensive ALS publicity campaign, and the implementa on of an ALS informa on package about the applica on for home care services in the Netherlands, it would be of interest to repeat our study in order to evaluate the effec veness of these measures.

We conclude that the problems in the procurement process of ADHA perceived by pa ents with ALS are frequent and require increased awareness of the impact of the disease on pa ents’ func oning and the nega ve consequences of delay in the provision of ADHA. This might help authori es, suppliers, care professionals and policy-makers to arrange the procurement process in a more demand-oriented, proac ve and me-saving manner.

ACKNOWLEDGEMENT The authors wish to thank the individuals with ALS for par cipa ng in this research survey.

We are grateful to L.G. Grosze Nipper and K. Grosze Nipper for their ini a ve which resulted in this survey and L.G. Grosze Nipper and A. Boutkan for funding and for collec ng the data.

This study was supported by a grant from L.G. Grosze Nipper and A. Boutkan.

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Chapter 3

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4.

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18.

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Albert SM, Murphy PL, Del Bene ML, Rowland LP. Prospec ve study of pallia ve care in ALS: choice, ming, outcomes. J Neurol Sci 1999 Oct 31;169(1-2):108-113.

Beghi E, Millul A, Logroscino G, Vitelli E, Micheli A. Outcome measures and prognos c indicators in pa ents with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2008 Jun;9(3):163-167.

Bromberg MB, Brownell AA, Forshew DA, Swenson M. A meline for predic ng durable medical equipment needs and interven ons for amyotrophic lateral sclerosis pa ents. Amyotroph Lateral Scler 2010;11(1-2):110-115.

The provision of assis ve devices and home adapta ons in ALS 19.

20.

21.

22.

23.

Demers L, Wessels R, Weiss-Lambrou R, Ska B, De Wi e LP. Key dimensions of client sa sfac on with assis ve technology: a cross-valida on of a Canadian measure in The Netherlands. J Rehabil Med 2001 Jul;33(4):187-191.

Demers L, Mone e M, Lapierre Y, Arnold DL, Wolfson C. Reliability, validity, and applicability of the Quebec User Evalua on of Sa sfac on with assis ve Technology (QUEST 2.0) for adults with mul ple sclerosis. Disabil Rehabil 2002 Jan 10;24(1-3):21-30.

Wessels RD, De Wi e LP. Reliability and validity of the Dutch version of QUEST 2.0 with users of various types of assis ve devices. Disabil Rehabil 2003 Mar 18;25(6):267-272.

Nierse CJ, Abma TA, Horemans AM, van Engelen BG. Research priori es of pa ents with neuromuscular disease. Disabil Rehabil 2013 Mar;35(5):405-412.

WHO ICF 2013. www3.who.int/icf/ic{emplate.cfm.

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4 Cluster RCT of case management on pa entsâ&#x20AC;&#x2122; quality of life and caregiver strain in ALS Huub Creemers Jan H. Veldink Hepke Grupstra Frans Nollet Anita Beelen Leonard H. van den Berg.

Neurology 2014. Jan;82(1):23-31. Š Reprinted with permission from Wolters Kluwer Health

Chapter 4

ABSTRACT Objec ves To study the effect of case management on quality of life (QOL), caregivers’ strain, and perceived quality of care (QOC) in pa ents with amyotrophic lateral sclerosis (ALS) and their caregivers.

Methods We conducted a mul center cluster randomized controlled trial, with the mul disciplinary ALS care team as the unit of randomiza on. During 12 months, pa ents with ALS and their caregivers received case management plus usual care, or usual care alone. Outcome measures were the 40-item ALS Assessment Ques onnaire (ALSAQ-40), Emo onal Func oning domain (EF); the Caregiver Strain Index (CSI); and the QOC score. These measures were assessed at baseline and at 4, 8, and 12 months.

Results Case management resulted in no changes in ALSAQ-40 EF, CSI, or QOC from baseline to 12 months. ALSAQ-40 EF scores in both groups were similar at baseline and did not change over me (p = 0.331). CSI scores in both groups increased significantly (p < 0.0001). Pa ents with ALS from both groups rated their perceived QOC at baseline with a median score of 8, which did not change significantly during follow-up.

Conclusion Within the context of mul disciplinary ALS care teams, case management appears to confer no benefit for pa ents with ALS or their caregivers.

Classifica on of Evidence This study provides Class III evidence that case management in addi on to mul disciplinary ALS care does not significantly improve health-related quality of life of pa ents with ALS.

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INTRODUCTION There is no cure for amyotrophic lateral sclerosis (ALS); treatment is limited to op mal neuropallia ve care, an cipa ng the relentless progression of muscle weakness and its consequences to daily ac vi es and par cipa on 1,2. In the Netherlands, in accordance with interna onal guidelines,3-5 most pa ents with ALS are supported by one of the 43 ALS teams that provide proac ve mul disciplinary ALS care. Neuropallia ve care is diverse and complex. We know from clinical prac ce and from QOC evalua ons from pa ents and caregivers that ALS care does not always adequately address the needs of pa ents and their caregivers 6,7.

Case management has been suggested as an innova ve strategy to op mize complex care, thereby improving pa ent sa sfac on, caregiver sa sfac on, and quality of life (QOL) 8. In case management, an individual supports the pa ent and caregiver through the complex naviga on of available resources to manage the consequences of ALS, with the aim of stabilizing QOL 9. Case management programs are o{en directed at pa ents with serious and life-threatening illness and increasingly incorporate pallia ve care assessment and interven ons 10.

In this study we inves gated the added value of case management to mul disciplinary ALS care. We hypothesized that case management in addi on to usual care would improve QOL of pa ents with ALS, caregivers’ burden, and perceived QOC of pa ents with ALS and their informal caregivers.

METHODS Study design We performed a cluster randomized controlled trial (RCT) with the mul disciplinary ALS team as the unit of randomiza on (figure 1). Teams as a whole were randomized, instead of individual pa ents, to avoid readjustment of each team’s treatment procedures during the study period owing to their experiences with case management. The full details of our trial protocol are available upon request from the correspondence address.

The primary research ques on for this study was to determine whether case management in addi on to usual mul disciplinary ALS care would improve the QOL of pa ents. The secondary research ques ons were if supplemental case management would affect caregivers’ strain and the QOC of pa ents and their primary informal caregivers compared with mul disciplinary ALS care alone.

This study design provided Class III evidence for case management in addi on to mul disciplinary care on health related QOL for pa ents with ALS, on caregiver burden and on QOC for pa ents and their caregivers.

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Standard Protocol Approvals, Registra ons, and Pa ent Consents The Medical Ethics Commi ee of the Academic Medical Center in Amsterdam waived the need for ethical approval. Our RCT was registered at the Netherlands Trial Register, number NTR1270. Informed consent was obtained from all par cipa ng pa ents and all caregivers.

Clusters We invited all 43 Dutch mul disciplinary ALS teams (clusters) to par cipate. Pairs of teams were formed that were matched on three factors that may affect the QOC: the number of pa ents with ALS the team supports during one year (≤10; 11−20; >20); the type of center the team is working in (outpa ent department of a hospital or rehabilita on center); and whether or not the team is cer fied by the Dutch Associa on for Pa ents with Neuromuscular Disease as a “Neuromuscular Rehabilita on Center” 11. Finally, a researcher (HC) performed computer generated randomiza on of the teams. Alloca on concealment was at the cluster level.

Par cipants The rehabilita on medicine consultant of each par cipa ng ALS team introduced the study to the eligible pa ents and their most important informal caregiver. Pa ents were not eligible for trial entry if they met one or more of the exclusion criteria: cogni ve dysfunc on (Mini Mental State Examina on <20, 12 insufficient mastery of the Dutch language, and ins tu onaliza on. The exclusion criterion for caregivers was insufficient mastery of the Dutch language.

Blinding In the interven on and control groups, the case manager administered the outcome assessment ques onnaires during baseline home visits; assessments were unblinded for group assignment. Two independent researchers who were blinded to group assignments performed outcome assessments during follow-up at 4, 8, and 12 months.

Interven ons Usual care Usual care in the Netherlands is neuropallia ve care by mul disciplinary, secondary care teams. Such teams consist of a rehabilita on medicine consultant, an occupa onal therapist, physical therapist, speech pathologist, die cian, social worker, psychologist and consultant physicians (in neurology, respiratory and gastroenterology). Community and social services also play an important role in care for pa ents with ALS and their caregivers.

General prac oners, district nurses, home care services, paramedics, social workers, and voluntary workers par cipate in these services.

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Effec veness of case management in ALS

Case management We performed the interven on “case management” at the individual par cipant level. The predominant focus of the pa ent advocacy case management model is more comprehensive coordina on of services across the con nuum of care, viewed from the pa ent perspec ve 8,13-16 .

During the 12-month interven on period, case management was provided by 2 experienced occupa onal therapists, specialized in ALS care and trained in client-centered prac ce, who used a client-centered approach to guide the par cipants 17. The case manager had an independent posi on outside, but in close contact with, the ALS team. The case manager’s role was to be a en ve to the needs of the par cipants. The case manager provided par cipants all of the informa on needed to allow individual choices about how their needs would be met.

The case manager started the interven on by visi ng par cipants at home at study entry and subsequently every three months. Between visits, contact was possible by telephone, e-mail, or in wri ng. At the first visit, the case manager provided par cipants with addi onal oral and wri en informa on about the procedures and objec ves of the case management interven on. The posi on, tasks, and responsibili es of the case manager in rela on to the par cipants’ usual care system were also elucidated.

The star ng point for the case management interven on was any soma c, psychosocial, environmental, or care issue raised by the par cipants. On the basis of the issue, the case manager discussed the aims to achieve and the steps necessary for achievement (clientcentered approach). In response to the issues raised, the case manager undertook one or more of the following steps: • Inform par cipants’ mul disciplinary ALS team and other professional caregivers involved.

• Provide par cipants with wri en and oral informa on and advice.

• Give emo onal support to par cipants.

• Refer par cipants to health care providers and agencies.

• Mediate if problems arose between par cipants and health care providers or agencies.

• Support par cipants during their contact with agencies and suppliers.

• Evaluate the handling of the issues raised by par cipants.

During the quarterly home visits, the case manager monitored the par cipants’ disease process with the aim to iden fy symptoms or problems related to ALS progression or caregiver burden. For that purpose, a symptom checklist was used to monitor disease progression and to register changes in disease symptoms. When the case manager no ced QOC problems or observed an increase in symptom burden, psychosocial problems, or caregiver burden, the issue was discussed with the par cipants. Subsequently, steps toward solu ons of the relevant issues were discussed and put into ac on, if desired by the par cipants.

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A{er randomiza on, the case manager and the rehabilita on medicine consultant (as coordinator of the team) agreed upon lines of communica on with the ALS team during the study. The case manager visited the ALS team before ini a on of the study to meet the team upon request. The case manager reported any ques ons of the par cipants, and ac ons or issues no ced by the case manager to the rehabilita on medicine consultant.

Outcome measures The primary outcome was each pa ent’s health-related QOL assessed with the 40-item ALS Assessment Ques onnaire (ALSAQ-40), Emo onal Func oning domain (EF). The ALSAQ-40 contains 40 items incorporated in five dis nct areas of health: Physical Mobility, Ac vi es of Daily Living/Independence, Ea ng and Drinking, Communica on, and Emo onal Func oning. Each of the five scales is transformed into a scale of 0 to 100 (100 indica ng worst health) 18-21.

Secondary outcomes were caregiver strain assessed with the Caregiver Strain Index (CSI) 22 and Quality of Care (QOC). To score QOC, we asked pa ents rate the total care provided on a 10-point scale, with 1 as very poor QOC and 10 as excellent QOC. Caregivers were asked to give two ra ngs, one for the care provided to the pa ent, and one for the care provided to the caregiver.

We monitored disease progression with the ALS Func onal Ra ng Scale-Revised (ALSFRS-R). The ALSFRS-R is a 48-point validated disease-specific measure to assess func on 23 ; a lower score indicates more disability.

Data analysis A sample size of 65 pa ents with ALS and their caregiver in each treatment group was planned. This group size has 80% power to detect a treatment difference of 11.9 points (SD: 26.25) in QOL scores on the ALSAQ-40 EF between the groups 20. This calcula on is based on 4 repeated measurements with a within-person correla on coefficient ( me interval 4 months) of 0.75 at a significance level of 0.05 (one-sided) 24. We calculated the sample size without taking into account the intracluster correla on coefficient, as the number of par cipants per mul disciplinary ALS team is rela vely small.

We compared sociodemographic characteris cs of the pa ents and their caregivers, as well as the clinical characteris cs of the pa ents in both groups (par cipa ng vs nonpar cipa ng and interven on vs control) with 2-tailed independent t tests (for con nuous variables) and chi-squared tests (for dichotomous and categorical variables).

We used linear mixed models with an unstructured covariance type (mul level analysis) to analyse differences in outcomes between the interven on and control group over me and to adjust for the clustering of the data 25. In case of significant differences in baseline characteris cs of pa ents and caregivers between the interven on and control group, we adjusted for these variables.

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Effec veness of case management in ALS

A linear mixed model does not require complete follow-up data from all par cipants.

We expected incomplete follow-up owing to decease or withdrawal. Sta s cal analysis was carried out on an inten on to treat basis and data of all included pa ents and caregivers, including those with incomplete sets of data were analysed. We calculated regression coefficients for the effects of case management compared with usual care as β values and standard errors (SE). Because outcomes are measured at the individual pa ent level, the analysis must be adjusted for poten al clustering in the data. The analysis yields maximum likelihood es mates for the effects of me, treatment group, and the me treatment group interac on. All hypotheses were tested 2-sided, with a cri cal value of <0.05.

4

RESULTS Cluster randomiza on Thirty-one mul disciplinary ALS teams (72%) agreed to par cipate in the study (figure 1).

We evaluated 16 interven on teams and 15 control teams. No teams dropped out during the interven on period. Par cipa ng teams were representa ve of all Dutch ALS teams, and their service areas cover all parts of the country. The median cluster size was 4 pa ents for the interven on teams (range 0−10 pa ents) and 2 pa ents for the control team (range 0−17 pa ents).

Par cipants From March 2009 to July 2011, 132 pa ents and 126 of their caregivers par cipated: 71 in the interven on group and 61 in the control group (figure 1). Baseline sociodemographic and clinical characteris cs of pa ents and caregivers did not differ between the case management and control group (table 1) or between par cipants and non-par cipants (supplementary table e-1). Most caregivers were partners (n=112).

During follow-up, the propor on of missing assessments did not differ significantly between the interven on group (pa ents 111/284, caregivers 100/264) and the control group (pa ents 92/244, caregivers 98/240). Reasons for missing outcome data were pa ent death, pa ent withdrawal, and pa ent request to skip an assessment. The required number of pa ents according to the study protocol (n=130) was reached.

71

Chapter 4 Figure 1 Flow of clusters and individual par cipants.

Enrollment of ALS teams

ALS teams invited to participate the study n=44 No consent n=13

Allocation of ALS teams Randomization of ALS teams n=31

Intervention teams n=16

Control teams n=15

Patients n=155

Patients n=143

ALS patients No consent n=166 Control: usual care

Intervention: case management + usual care Enrolment: Patients n=71 Caregivers n=66

Baseline

Enrolment: Patients n=61 Caregivers n=60

Completed the trial:

Completed the trial:

Patients n=43 Death: n=23 Stop: n=5

Patients n=36 Death: n=15 Stop: n=10

Caregivers n=41 Patientâ&#x20AC;&#x2122;s death: n=22 Stop: n=3

Number of evaluations of: Patients n=173 Caregivers n=164

ALS = amyotrophic lateral sclerosis.

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Analysis

Caregivers n=35 Patientâ&#x20AC;&#x2122;s death: n=15 Stop: n=10

Number of evaluations of: Patients n=152 Caregivers n=142

Effec veness of case management in ALS Table 1 Baseline characteris cs of study par cipants.

Pa ent variables Mean age (SD), y Male Married Primary caregiver is partner Caucasian ethnicity College or university degree Employed Limb onset Median me since onset (Q1-Q3), y Median me since diagnosis (Q1-Q3), y Mean predicted FVC % (SD) PEG NIV/IV Riluzole Mean ALSFRS-R (SD) Mean ALSAQ-40 Emo onal Func oning (SD) Mean ALSAQ-40 sum score (SD) Mean quality of care ra ng score (SD) Caregiver variables Mean age (SD), y Female Married Caucasian ethnicity College or university degree Employed Mean CSI (SD) Mean quality of care score “care for the pa ent” (SD) Mean quality of care score “care for the caregiver” (SD)

Interven on (n=71) 63 (11) 57 83 82 100 42 7 73 1.8 (1.2 – 3.5) 0.9 (0.3 – 1.7) 86 (23) 14 17 91 32 (8) 21 (18) 37 (17) 8.2 (0.8) Interven on (n=66) 59 (14) 70 94 97 37 23 6 (3) 8.0 (0.9) 7.6 (1.4)

Control (n=61) 62 (11) 64 84 84 97 31 15 79 2.2 (1.2 – 3.9) 0.9 (0.4 – 2.3) 83 (24) 21 18 95 32 (9) 19 (17) 37 (18) 8.3 (0.8) Control (n=60) 57 (15) 62 90 95 27 32 5 (3) 8.2 (1.1) 7.8 (1.6)

p Value 0.680 0.786 0.789 0.474 0.307 0.190 0.168 0.466 0.600 0.277 0.627 0.275 0.864 0.398 0.685 0.524 0.919 0.803 p Value 0.922 0.342 0.463 0.463 0.197 0.305 0.184 0.298 0.436

Abbrevia ons: ALSAQ-40 = 40-item Amyotrophic Lateral Sclerosis Assessment Ques onnaire; ALSFRS-R = Amyotrophic Lateral Sclerosis Func onal Ra ng Scale-Revised; CSI = Caregiver Strain Index; FVC% = percentage of the predicted value of forced vital capacity; IV = invasive ven la on; NIV = noninvasive ven la on; PEG = percutaneous endoscopic gastrostomy; Q1-Q3 = first quar le to third quar le; SD = standard devia on; y = years.

Values are percentages unless otherwise indicated.

Case management The dura on of home visits ranged from 60 to 180 minutes. The extent to which pa ents and their caregivers relied on case management varied widely. Par cipants differed in their need for informa on, support, treatment, resources, and care (Supplementary Figure e-1).

Seventeen pa ents (24%) and their caregivers did not raise any ques ons for the case

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manager. Twenty-nine par cipants contacted the case manager at least once during the interval between visits. Thirty-one caregivers and 48 pa ents raised at least one issue during the interven on period.

Ac ons by the case manager were mostly related to emo onal well-being (coping with loss, emo ons, dependence and changes, caregiver strain, and private life) and consisted of providing a listening ear for par cipants, discussing the impact of having ALS and the impact of symptoms on daily func oning. Prac cal ac ons included providing oral and wri en informa on, reference to health care providers, and contac ng/informing health care providers.

Effec veness of case management Despite significant disease progression, emo onal well-being as reflected by ALSAQ-40 EF did not change over me. No significant difference in ALSAQ-40 EF score was detected between the interven on group and the usual care group (table 2 and figure 2).

Caregiver strain (CSI) increased significantly during the study period in both groups, without differences between the groups.

At baseline, pa ents as well as caregivers rated the QOC as high (table 2). The QOC scores did not change over me, and the interven on did not significantly affect the QOC ra ng score.

74

Effec veness of case management in ALS Table 2 Effects of case management and usual care at baseline and 4, 8, and 12 months.

Outcome measures

Case managementa Mean (SD), n

Usual carea Mean (SD), n

Linear Mixed Model β (SE); p-value

1. ALSAQ-40 Emo onal Func oning (0 – 100)b Baseline 4 months 8 months 12 months

21.3 (18.2), 70 19.8 (14.6), 43 21.5 (13.5), 28 22.8 (16.4), 30

19.3 (17.0), 61 19.4 (16.6), 39 20.0 (16.1), 22 19.1 (14.7), 27

Time: 0.54 (0.58) p = 0.35 Time x Group: 0.33 (0.79) p = 0.68

5.8 (3.4), 66 7.1 (3.4), 42 7.0 (3.6), 25 7.9 (2.9), 29

5.0 (2.9), 59 6.4 (3.1), 37 7.4 (3.5), 20 7.3 (3.2), 24

Time: 0.60 (0.11) p < 0.0001c Time x Group: -0.08 (0.15) p = 0.59

2. CSI (0-13)b Baseline 4 months 8 months 12 months

4

3. QOC report mark pa ents with ALS (1 – 10)d Baseline 4 months 8 months 12 months

8.2 (0.8), 65 8.2 (0.9), 43 8.1 (1.0), 28 7.9 (0.9), 30

8.3 (0.8), 55 8.0 (0.7), 37 8.0 (1.1), 23 8.0 (0.7), 25

Time: -0.06 (0.04) p = 0.13 Time x Group: -0.02 (0.05) p = 0.69

4. QOC report mark caregivers: pa ent care (1 – 10)d Baseline 4 months 8 months 12 months

8.0 (0.9), 63 8.3 (0.8), 40 8.0 (0.9), 26 7.9 (0.7), 27

8.2 (1.1), 59 8.2 (0.8), 37 8.1 (0.8), 18 7.9 (0.9), 24

Time: -0.05 (0.04) p = 0.21 Time x Group: 0.02 (0.06) p = 0.21

5. QOC report mark caregivers: caregiver care (1 – 10)d Baseline 4 months 8 months 12 months

7.6 (1.4), 56 7.7 (1.0), 38 7.3 (1.6), 25 7.3 (1.3), 25

7.8 (1.6), 49 7.7 (1.2), 33 7.6 (1.0), 16 7.1 (1.0), 22

Time: -0.10 (0.06) p = 0.12 Time x Group: 0.004 (0.08) p = 0.96

31.6 (8.8), 61 27.6 (10.2), 37 27.8 (11.0), 20 25.1 (11.5), 25

Time: -2.64 (0.40) p < 0.0001c Time x Group: -0.26 (0.54) p = 0.63

Disease progression: ALSFRS-R (0 – 48)d Baseline 4 months 8 months 12 months

32.1 (7.9), 71 29.9 (7.0), 43 27.4 (7.1), 27 24.0 (9.3), 28

Abbrevia ons: ALSFRS-R = Amyotrophic Lateral Sclerosis Func onal Ra ng Scale Revised; ALSAQ-40 = ALS Assessment Ques onnaire-40 items; CSI = Caregiver Strain Index; QOC = Quality Of Care; SD = standard devia on; SE = standard error. β = mul level regression coefficient for the effect of case management compared with usual care, and is an es ma on of the longitudinal rela onship between the parameter and the outcome.

Time = change over me (4 months) in outcome for both groups; Time x treatment group interac on term = change over me (4 months) in outcome different for both groups. a Intracluster correla on coefficient (ICC): All ICC values were less than zero. b Score range; lower scores indicate a be er situa on. c p < 0.05. d Score range; higher scores indicate a be er situa on.

75

Chapter 4 Figure 2 Trajectories of ALSAQ EF score for pa ents in the usual care group and interven on group.

The lighter lines denote individual trajectories (i.e., individual pa ents); the thick line represents the es mated course during 12 months. ALS-AQ EF = 40-item Amyotrophic Lateral Sclerosis Assessment Ques onnaire, Emo onal Func oning domain.

DISCUSSION This cluster randomized clinical trial on case management in mul disciplinary ALS care demonstrated no signiďŹ cant beneďŹ t of case management to the emo onal func oning of pa ents, the level of strain experienced by the caregiver, or the level of sa sfac on of pa ents and caregivers when added to standard mul disciplinary care compared with

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Effec veness of case management in ALS

standard care alone. The design and results of our study must be viewed in the context of the Dutch ALS care se`ng. Par cipants were recruited from ALS teams, and all received standard mul disciplinary ALS care. Previous studies demonstrated that mul disciplinary ALS care results in a be er QOL and sa sfac on with QOC than non-specialized general care 1,4,5,26. We es mate that at least 80% of pa ents with ALS are presently being referred to a mul disciplinary ALS team in the Netherlands 27. To further explore the effect of case management models in ALS, future studies must be conducted in other health care systems.

In other diseases, effec veness of case management on pa ents’ QOL has been demonstrated 28,29, although the evidence is limited due to inconsistent findings 30.

The present study aimed to improve any shortcomings in the needs of pa ents with ALS and their caregivers. Judging from the frequency of ques ons and issues raised during the interven on period, the interven on did not result in an intensive use of case management by the par cipants. The high scores on mental QOL and sa sfac on with care and the modest number of issues raised by pa ents and their caregivers suggest that problems in Dutch mul disciplinary ALS care, as iden fied in daily prac ce, are incidental, with rela vely low impact on mental QOL and overall sa sfac on with ALS care.

In our study design, we deliberately chose a case manager who was not a member of the mul disciplinary ALS team. Pa ents and caregivers in this way had the opportunity to consult the independent case manager for a second opinion or when the ALS team did not adequately address the needs of pa ents/caregivers. Regular contacts between the case manager and the team were assured to avoid overlap. The case managers’ professional background in our opinion did not influence our study results: their broad overview of the Dutch ALS care and their extensive experience in ALS care were appropriate for their signaling, suppor ve and advisory func on.

We chose an ALS-specific health-related QOL measure to evaluate the effect of case management. SMiLE 31 and SEIQOL 32 measure non-health-related factors of QOL and are more focused on psychological, existen al and support factors. We cannot exclude an effect on those measures. However, the lack of effect does not seem to be due to the scales used as we did not find an effect on any other outcome measure.

In addi on to the lack of effec veness for pa ents with ALS, we were unable to demonstrate any improvement in caregivers’ burden. The increased caregiver burden over me has been described earlier 33,34. This finding may result from the fact that most issues raised during the interven on period were directly aimed at pa ents and were less o{en issues concerning caregiver strain. This possibility is illustrated by the content of the issues raised, which was mostly related to the provision of assis ve products and technology, restric ons in ac vi es and par cipa on, symptom treatment, psychosocial problems, and provision of pallia ve care, illustra ng that the focus was more on the pa ent than the caregiver. Our finding of an increasing burden for caregivers indicates the need for a more prominent role of interven ons targe ng caregivers in future studies.

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The strengths of this study are its randomized controlled design and the large sample size of pa ents with ALS, which is representa ve for the Dutch ALS popula on as we compare pa ent characteris cs (with respect to age at disease onset, sex, me to diagnosis, and site of onset) with those of a recently described popula on-based epidemiology study 27. In addi on, we applied mul level analysis to account for various poten al confounding factors.

The number of missing data could be considered a limita on of the study, but is inherent to longitudinal studies of pa ents with ALS 35,36. Loss to follow-up is not expected to have a substan al effect on the power of the study considering the size of the mul level regression interac on coefficient for the effect of case management. Irrespec ve of the number of observa ons per par cipant, every par cipant was included in the mul level analyses, and these analyses deal appropriately with the varying numbers of observa ons 25,37 . Another possible limita on of this study is the limited dura on of the interven on period (12 months). Wynia et al. 9 (2010) stated that although there is no evidence, it seems reasonable to assume that an “investment effect” is applicable for outcome variables such as QOL. However, 12 months is rela vely long considering that ALS care is intensive during a rela vely short disease period compared with other progressive diseases (e.g., mul ple sclerosis). It is credible that the quarterly home visits, combined with the possibility of contact by telephone and e-mail between visits, allowed for our interven on period to be long enough to build trust and stability in the case manager/par cipant rela onship 38,39.

Our data do not support the implementa on of case management as part of ALS care.

Because health care systems vary considerably between countries and regions, as does the rate of implementa on of mul disciplinary ALS care, our research design facilitates future case management research projects in other countries, as well as outside the context of specialized ALS teams. Such studies will decisively determine the effect of different case management models in ALS care.

ACKNOWLEDGEMENT The authors thank the pa ents; their caregivers; the referring rehabilita on medicine consultants; Marije Bolt (Academic Medical Center Amsterdam), who was one of the case managers; Maud Maessen, PhD (University Medical Center Utrecht), who contributed to conceptualiza on of the trial; Gerda Valk, research nurse (University Medical Center Utrecht) and Kim Bibbe, psychology student (University Medical Center Utrecht), who conducted the outcome assessments; and Tim Zandbelt (University Medical Center Utrecht) and Hermieneke Vergunst (University Medical Center Utrecht), who conducted data entry.

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STUDY FUNDING Funded by ZonMw, the Netherlands Organiza on for Health Research and Development, within the Programme Pallia ve Care grant agreement no. 1150.0008, and the Netherlands ALS Founda on.

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Miller RG, Jackson CE, Kasarskis EJ, et al. Prac ce parameter update: the care of the pa ent with amyotrophic lateral sclerosis: mul disciplinary care, symptom management, and cogni ve/ behavioral impairment (an evidence-based review): report of the Quality Standards Subcommi ee of the American Academy of Neurology. Neurology 2009 Oct 13;73(15):1227-1233.

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Client-centred prac ce: what does it mean and does it make a difference?

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Jenkinson C, Fitzpatrick R, Swash M, Jones G. Comparison of the 40-item Amyotrophic Lateral Sclerosis Assessment Ques onnaire (ALSAQ-40) with a short-form five-item version (ALSAQ-5) in a longitudinal survey. Clin Rehabil 2007 Mar;21(3):266-272.

Maessen M, Post MW, Maille R, et al. Validity of the Dutch version of the Amyotrophic Lateral Sclerosis Assessment Ques onnaire, ALSAQ-40, ALSAQ-5. Amyotroph Lateral Scler 2007 Apr;8(2):96-100.

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Twisk JWR. Applied longitudinal data analyses for epidemiology; a Prac cal Guide. 1st ed. Cambridge University Press; 2003.

Twisk JWR. Applied Mul level Analysis. A Prac cal Guide. 1st ed. Cambridge University Press; 2006.

Foley G, O’Mahony P, Hardiman O. Percep ons of quality of life in people with ALS: effects of coping and health care. Amyotroph Lateral Scler 2007 Jun;8(3):164-169.

Huisman MH, de Jong SW, van Doormaal PT, et al. Popula on based epidemiology of amyotrophic lateral sclerosis using capture-recapture methodology. J Neurol Neurosurg Psychiatry 2011 Oct;82(10):1165-1170.

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Wulff CN, Thygesen M, Sondergaard J, Vedsted P. Case management used to op mize cancer care pathways: a systema c review. BMC Health Serv Res 2008 Nov 6;8:227. doi: 10.1186/1472-6963-8227.:227-228.

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Effec veness of case management in ALS Supplementary Table e-1 Baseline characteris cs of study par cipants versus non-par cipants.

Variables

Par cipants (n=132)

Non-par cipants (n=166)

p Value

Mean age (SD), years Male Married Primary caregiver is partner Caucasian ethnicity College or university degree Limb onset Median me since onset (Q1-Q3), years Median me since diagnosis (Q1-Q3), years Mean predicted FVC % (SD) PEG use NIV/IV use Riluzole Median ALSFRS-R (Q1-Q3)

62.9 (11.2) 65 83 83 99 42 76 2.1 (0.3 - 12.6) 0.9 (0.05 - 12.1) 85 (22) 17 17 93 33 (26 – 39)

63.4 (11.7) 57 77 67 96 30 70 2.3 (0.1 - 22.7) 1.1 (0.01 - 22.2) 81 (21) 19 13 90 32 (26 – 40)

0.702 0.151 0.375 0.312 0.326 0.190 0.233 0.372 0.446 0.325 0.680 0.273 0.326 0.868

4

Abbrevia ons: ALSFRS-R = Amyotrophic Lateral Sclerosis Func onal Ra ng Scale-Revised; FVC% = percentage of the predicted value of forced vital capacity; IV = invasive ven la on; NIV = noninvasive ven la on; PEG = percutaneous endoscopic gastrostomy; Q1-Q3 = first quar le to third quar le; SD = standard devia on.

Values are percentages unless otherwise indicated.

Supplementary Figure e-1 Themes of issues about which par cipants raised ques ons.

39

Provision of assistive products and technology

38

Activities and participation

37

Symptoms

35

Psychosocial

31

Palliative care provision

19

Personal care services

19

Finances

13

Nutrition / PEG

12

Domestic life services

10

Transportation services

10

Advance directives / end of life decisions

9

Respiratory care / NIV

7

Work

7

Durable power of attorney

5

Respite care

3

Supporting children Social services / voluntary work

2 Number of ALS patients and/or caregivers who raised the issue

Abbrevia ons: PEG, percutaneous endoscopic gastrostomy; NIV, non-invasive ven la on.

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5 Need and value of case management in mul disciplinary ALS care: A qualita ve study on the perspec ves of pa ents, spousal caregivers and professionals Minne Bakker Huub Creemers Karen Schipper Anita Beelen Hepke F. Grupstra Frans Nollet Tineke A. Abma Amyotrophic Lateral Sclerosis and Frontotemporal Degenera on 2015. Jun;16(3-4):180-6. Š Reprinted with permission from Taylor & Francis Group

Chapter 5

ABSTRACT Our objec ve was to explore the needs and value of case management according to pa ents with amyotrophic lateral sclerosis (ALS), their spousal caregivers, and health care professionals in the context of mul disciplinary ALS care. We undertook semi-structured interviews with 10 pa ents with ALS, their caregivers (n=10) and their ALS health care professionals (n=10), and held a focus group (n=20). We transcribed the audio-taped interviews and we analysed all data thema cally. Par cipants indicated that in certain circumstances case management can have an added value. They iden ďŹ ed factors for recep veness to case management: adequacy of usual care, rate of disease progression, and degree of social network support and personal factors of pa ents and spousal caregivers. Par cipants valued the me for consulta on, house calls and the proac ve approach of the case manager. Pa ents with ALS and caregivers appreciated emo onal support, whereas professionals did not men on the importance of emo onal support by the case manager.

In conclusion, ALS teams can consider implementa on of valued aspects of case management (accessibility, ample me, proac ve approach, emo onal support) in the usual mul disciplinary ALS care. Addi onal support might be provided to pa ents with rapidly progressive disease course, passive coping style and small social network.

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INTRODUCTION Pa ents with ALS require neuropallia ve care because this disease has no cure 1-4.

Shortcomings in ALS care have been described, revealing subop mal collabora on in complex mul disciplinary care, delays in service requests, untreated symptoms, and lack of support for informal caregivers 3,5,6. The concept of case management has been suggested as a strategy to op mize mul disciplinary care 3,7. The aim of case management is to improve the pa ents’ quality of life (QOL) and reduce caregiver strain 3,7.

Recently, a randomized controlled trial (RCT) on the effect of case management, provided in addi on to usual care and tailored to pa ents’ needs, was performed. Case management started by offering a comprehensive coordina on of services across the con nuum of care as viewed from the pa ent’s perspec ve. Using a client-centered approach, the case manager provided addi onal support for soma c, psychosocial, and environmental problems. The study found no benefits for pa ents’ QOL and caregiver strain compared to the usual Dutch ALS care, which is provided by mul disciplinary secondary care teams 3. However, some pa ents did report benefits during the RCT. Therefore, this qualita ve study explores pa ents’ care needs and the experiences of pa ents, spousal caregivers and professionals with case management coupled with mul disciplinary ALS care. The ar cle also iden fies what aspects of case management may have addi onal value to the usual mul disciplinary ALS care and factors for recep veness to case management.

METHODS Study design In this study, we were interested in the subjec ve experiences of pa ents, caregivers and professionals with case management interven on. We used qualita ve methods as these are preferred for gaining an understanding of the experiences and life-world context of people 8. We explored percep ons of case management in ALS care among relevant stakeholders (pa ents, caregivers, healthcare professionals). More specifically, we aimed to iden fy factors that might influence how and why people with ALS and their carers engage with case management care 9.

Data collec on process Using the responsive evalua on approach, the study consisted of four phases (see Supplementary Appendix 1) 10. Data collec on consisted of interviews and a focus group.

The process of data collec on and analysis was itera ve, as the process alternated during the research; we analysed interviews during the process of data collec on. In this way, the

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emerging themes could be further explored and validated in the following interviews and focus group un l satura on was reached.

Par cipants: interviews We recruited pa ents and caregivers from the RCT cohort. Professionals were rehabilita on medicine consultants (RMCs) and the case managers involved in the RCT. We used purposive selec on to capture diversity in some characteris cs of the pa ents. Characteris cs such as age, gender, rate of progression (defined as change score in ALSFRS-R: slow progression = < 6 points/year, medium progression = 6−12 points/year and rapid progression = >12 points/year) 11, and current stage of ALS were taken into account. In addi on, to make sure that posi ve and nega ve experiences were included, we examined both varia on in the extent to which pa ents and caregivers made an appeal to case management and perceived benefit from case management (judged by the case manager). Also, we enrolled pa ents from different ALS teams, because the care delivered by the ALS teams may differ.

Par cipants: focus group We recruited par cipants for the focus group via purposive selec on to create a diverse group with equal numerical representa on of the different groups of stakeholders. The aim of the focus group was to enhance the credibility of the findings, by checking whether the care needs men oned in the interviews were recognised by a wider group of pa ents and caregivers 12. Furthermore, pa ents, caregivers and professionals discussed whether appreciated aspects of case management could be incorporated in the usual ALS care, with or without case management. Par cipants formulated sugges ons for ALS care improvements to meet pa ents’ and caregivers’ needs. We chose pa ents, caregivers and professionals familiar with ALS care (not necessarily involved in the RCT). In addi on, we selected par cipants according to age, gender, a variety in ALS teams and different disciplinary backgrounds of the professionals.

Data collec on To explore the needs and experiences with case management, interviews with pa ents, caregivers, and professionals were conducted. During the interviews we used an interview guide (see Supplementary Appendix 2). The guide contained topics about experiences with the usual ALS care, case management and the case manager.

Interviews with pa ents and caregivers took place in their homes, for privacy and comfort. If possible, interviews with pa ents were held separately from the interview with their caregiver. During some interviews the caregiver a ended the interview with the pa ent for prac cal reasons such as assis ng in the communica on with bulbar affected pa ents.

The interviews with professionals took place at their work space. A{er permission, we audio-recorded the interviews and transcribed them verba m. Interviews were conducted

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between October 2010 and July 2011. Subsequently, a focus group was organized. The focus group session was audio-taped and transcribed verba m a{er permission.

Data analysis For this study we used induc ve content analysis 13. This approach moves from the specific to the general, so that par cular instances are observed and then combined into a larger whole or general statement 14. Individual research team members read all transcripts and cross-case analysed them with constant comparison. All emerging themes in the transcripts were marked, labelled and compared within the team to increase dependability and to reach consensus on the discussed themes 15. The themes of all transcripts were grouped together. This created a list of recurring themes. The corresponding quotes were compared and the most suitable were selected for the final report.

We added informa on about the par cipants’ background in the Results sec on (Tables II-IX). Addi onally, we provided informa on about age, gender and rate of progression in cases where the quota on is from a pa ent or caregiver. Quota ons from the focus group do not contain this la er informa on, because par cipants were not given a respondent number.

Specific quality procedures used to improve dependability and credibility of our research are described in Table I. Table I. Quality procedures.

Procedure Member check

Explana on and reason To enhance credibility, all par cipants received an interpreta on of their interview or focus group and were asked if they recognised the analysis 15.

Inves gator triangula on

Different inves gators were involved in the analysis process. The inves gators arrived at the same conclusions, which heightened our confidence 24.

Methodological triangula on We used interviews as well as a focus group for data collec on in order to increase the credibility of the study 24.

Data triangula on

We interviewed different sources (pa ents, partners, professionals) in order to increase the credibility of the study 15.

Satura on

Satura on in data collec on is when no new or relevant informa on emerges and data collec on stops. In order to verify whether we reached the satura on point, we conducted the analysis during the process of data collec on. A{er 10 cases in each group (pa ents, caregivers and professionals) no new codes emerged and therefore satura on was reached. During the focus group no new care needs were iden fied indica ng that satura on was reached 25.

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Ethics considera ons The followed procedures were in accordance with the ethics standards of the Medical Ethics Commi ee of the VU Medical Centre and Academic Medical Centre. All par cipants voluntarily took part. Confiden ality was maintained using restricted, secure access to the data, destruc on of audio tapes following transcrip on and de-iden fying the transcripts.

RESULTS We conducted interviews with pa ents (n=10), caregivers (n=10) and professionals (eight RMCs and two case managers). The group of pa ents comprised three females and seven males, ranging in age from 51 to 74 years (mean age 61 years), with a disease dura on of 0.6 to 66 months (mean, 28.5 months). Rate of progression was slow in four cases, medium in four cases and rapid in two cases 11. All were married and had children. We held a focus group with six pa ents, four caregivers, one RMC, one speech therapist, two psychologists, two physical therapists, two occupa onal therapists and two social workers. Similar themes and issues arose in the interviews and the focus group. Pa ents and caregivers who par cipated in the focus group recognized the care needs that emerged from the interviews. We derived two main themes from the interviews and focus group: ‘needs for and recep veness to case management’ and ‘appreciated aspects of case management’.

Case management: needs and recep veness Four factors emerged from the data that appear to influence pa ents’ and caregivers’ needs for and recep veness to case management.

Func oning of the mul disciplinary ALS team. The need for case management was determined by the par cipants’ percep on of the ALS team func oning. Some pa ents and caregivers perceived the level of func oning of the ALS team as subop mal and reported surplus value of case management for op mizing ALS care (Table II, quote 1, 2). Professionals also recognized that case management can be of surplus value in the case of subop mal func oning of the ALS team (Table II, quote 3).

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Need and value of case management in ALS Table II. Quota ons about the func oning of the mul disciplinary ALS care.

1.

2.

3.

“The case manager was the constant factor in the ALS care. Our ALS team had a large turnover and some team members were not very experienced.” (R16, female caregiver, 58, medium progression) “The case manager filled the gaps of the regular care of the ALS team. (…) The regular care consists of separate “isles”.” (R7, male pa ent, 57 , medium progression) “I’ve seen it very o{en in the interven on group, that if everything in the ALS team func ons well, that means that the primary care, the general prac oner, maybe paramedical support, the home care, if everything func ons well and the contact is sa sfactory, then I have very li le to add as a case manager. Maybe even nothing.” (R21, case manager)

Rate of progression. Mostly professionals recognised the influence of the disease process as relevant for the recep veness to case management among pa ents and caregivers (Table III, quote 1). With a slow rate of progression, the need for assis ve devices, home care services, and other forms of support was o{en less acute and therefore easier to an cipate by pa ents and caregivers themselves. In the case of more rapid progression, an cipa on was harder and the help from a case manager was o{en welcomed (Table III, quotes 2, 3).

Table III. Quota ons about the rate of progression.

1.

2.

3.

“In case of rapid progression, people are more in need of support, to try to get everything organized in me.” (R24, case manager) “If the disease progresses rapidly, you might start to panic. Then you need someone who can arrange things for you.” (R14, female caregiver, 65, slow progression) “I think my need for support will increase as he will suffer from more dysfunc ons that we have to deal with. I think he [the case manager, eds] could have meant more for me in the future, because the situa on will get harder.” (R17, female caregiver, 51, medium progression)

Personal factors. The degree to which pa ents and caregivers experienced a need for case management was also influenced by the personal factors of pa ents. Some couples were independent, self-sufficient and wanted to organize the care themselves (Table IV, quote 1). Other couples were less self-asser ve or less self-sufficient, and welcomed support with applica ons for assis ve devices and home adapta ons (Table IV, quote 2). The coping style of those involved also influenced the need for case management. The case manager reported the need to support pa ents and caregivers who could not adequately cope with the situa on by informing them about the future disease course and the impacts on daily func oning (Table IV, quote 3).

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Chapter 5 Table IV. Quota ons about the personal factors.

1.

2.

3.

“If something needs to be organized, we’ll do it ourselves. We don’t need a case manager for that.” (R15, female caregiver, 74, slow progression) “We already have a lot of experience, because of our son (who has Duchenne, eds). Back then, it felt very different, we s ll had to learn everything. Now, I was able to arrange things myself, but people who don’t have this experience are not going to arrange things, because they don’t know what the possibili es are.” (R3, female pa ent, 58, rapid progression) “You should advise people who bury their head in the sand and pretend the problem does not exist. You need to make sure that they won’t be taken by surprise. And people who tend to keep on going, need to be slowed down, to make sure they have some energy le{ for the long term.” (R27, rehabilita on medicine consultant)

Social network support. The extent to which pa ents with ALS and caregivers relied on their social network also influenced the need for case management. Professionals recognised a difference in need between pa ents with and without a partner (Table V, quote 1).

Also, the quan ty and quality of the social network support influenced the need for case management. Pa ents with an extended social network showed less need than those with a small network. A small network with enough support also led to a lower demand for case management. For example, in some cases, children supported the pa ent with the necessary applica ons and gave prac cal and emo onal support which decreased the need for case management (Table V, quotes 2, 3).

Table V. Quota ons about the social network.

1.

2.

3.

“I can imagine that maybe people without a partner might need a case manager, to think along with them or to organize things with them.” (R31, rehabilita on medicine consultant) “The kids take care of a whole bunch of things.” (R15, female caregiver, 74, slow progression) “The prac cal help (is important, eds), for example that people are willing to mow the lawn. That kind of prac cal support definitely helps this couple to handle the situa on.”

(R22, case manager)

Case management: appreciated aspects Most par cipants appreciated the house calls, ample me for consulta on, proac ve consulta on and emo onal support of the case manager.

House calls. House calls were highly appreciated by all stakeholder groups (Table VI, quote 1). The informal and accessible style of case management was perceived as complementary to the usual ALS care (Table VI, quote 2). Although most ALS teams have professionals who visit the pa ent at home, the combina on of the house calls and the me the case manager had for these visits was of added value for most pa ents and caregivers.

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Need and value of case management in ALS Table VI. Quota ons about house calls.

1.

2.

“A{er a short term, he made house calls. That was very nice!” (R1, female pa ent, 55, rapid progression) “The case manager makes house calls, that is very convenient for the pa ent, and he was easily accessible. She [the pa ent, eds] can call us, of course, but that is s ll different from having a conversa on at the coffee table.” (R31, rehabilita on medicine consultant)

Time. All par cipants experienced the me the case manager had for the pa ents as a great advantage (Table VII, quotes 1-3). The case manager had ample me to talk with the pa ent and caregiver. The dura on of the visits by the case manager ranged from one to three hours, depending on the needs of the pa ent and caregiver. This contrasts with the strict me-limits of the ALS team consulta ons where people work on a much ghter schedule.

The combina on of me and home visits made it possible for the case manager to provide person-centred care.

A downside of this type of care is that it is rela vely expensive; the case manager cannot visit more than one or two pa ents a day (Table VII, quote 4). A concern expressed by the pa ents was that, even though case managers did not work on a ght schedule, they visited pa ents on prearranged days and were not available upon immediate request (Table VII, quote 5).

Table VII. Quota ons about me.

1.

2.

3.

4.

5.

“I think it’s much easier this way, because the case manager sits here at the coffee table in my own house, not restrained by the idea that he has another appointment. That is very different from an occupa onal therapist or physical therapist and all that kind of care. They work by the hour, and whether they like it or not, at a certain point the next pa ent is standing at their door and then he has to finish the session even if we were not finished yet. So the fact that the case manager has ample me makes it very useful for me. The case manager some mes stayed here for hours.” (R9, male pa ent, 59, medium progression) “As soon as I walk into a hospital (…) I have the feeling that the me is limited.” (R12, male caregiver, 55, rapid progression) “I think the fact that the case manager makes house calls and has ample me is the most important.” (R33, rehabilita on medicine consultant) “The next couple of years, the possibili es will only decrease instead of increase.” (professional) “You can’t always plan every conversa on in advance.” (pa ent)

Proac ve care. Pa ents and caregivers appreciated the proac ve approach of the case manager. Using a proac ve approach, case managers felt they were able to adequately list the care needs of pa ents (Table VIII, quote 1). Most pa ents felt reluctant to an cipate new care needs beforehand. The case manager prompted them to think about future care needs and informed them about the procedures. Pa ents felt grateful that the case manager had raised these topics during an early stage (Table VIII, quote 2).

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Chapter 5 Table VIII. Quota ons about proac ve care.

1.

2.

“I felt the care of the ALS team was quite distant. The occupa onal therapist had a very “wait and see” a`tude and waited for the couple to take the ini a ve. But this was not a couple that asked a lot of ques ons. They some mes had concerns that I could alleviate quite easily.” (R25, case manager) “I tend to think “we’ll see…”, but then you are really too late. The case manager a ends to me about things and helps with it.” (R7, male pa ent, 57, medium progression)

Emo onal support. Emo onal support of the case manager was valued by most pa ents and caregivers. Pa ents reported the case manager enhanced feelings of safety (Table IX , quotes 1, 2), and assisted in coping with their situa on through reflec ons (Table IX, quote 3) and sharing emo ons (Table IX, quote 4). Professionals mainly appreciated the prac cal support, such as gathering informa on or assis ng with the applica on of a medical device.

Professionals did not men on the poten al added value of emo onal support.

Table IX. Quota ons about emo onal support.

1.

2.

3.

4.

“It is a nice feeling that there is someone there for you. Even if you don’t have any ques ons, it is nice to know that you could ask him if you wanted to.” (R14, female caregiver, 65, slow progression) “I felt calmer with a case manager than without. I felt reassured that everything was taken good care of.” (R16, female caregiver 58, , medium progression) “The consulta ons with the case manager helped me to reflect on the situa on.” (R2, male pa ent, 51, medium progression) “It gives you the possibility to tell your story again. That makes it more bearable” (R18, female caregiver, 51, medium progression)

DISCUSSION Principle findings This study revealed insight into the experiences of pa ents, their spousal caregivers and professionals with case management in addi on to the usual mul disciplinary ALS care.

Appreciated aspects of case management interven on included house calls, with ample me for consulta on, and the proac ve approach by the case manager. Pa ents and caregivers appreciated the emo onal support while professionals did not men on this. Data revealed factors that may affect the poten al need of case management support: perceived quality of the usual ALS care as subop mal, a more rapid rate of disease progression, passive coping styles and poor social network support.

Comparison with RCT on case management The RCT on case management showed no significant benefit to pa ents’ QOL, caregiver strain, or increased sa sfac on with care of pa ents and caregivers when added to the

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usual mul disciplinary ALS care 3. Our findings describe why not all pa ents and caregivers experienced a need for case management. Responsiveness to ALS case management is lower when there is sa sfac on with the usual ALS care, low or medium rate of progression, independence and self-sufficiency, adequate coping and a suppor ve social network.

Comparison with other studies Experiences with case management in the context of ALS care have, to our knowledge, not to date been inves gated. Relevant studies in other fields corroborate the appreciated aspects of case management found in our study, including accessibility, me, and personal contact 16,17.

Studies concerning the emo onal support by professional caregivers in ALS care show that pa ents and caregivers feel that their need for emo onal support is not always met 18,19 . This is remarkable, as different studies describe that emo onal support is one of the primary expecta ons of service users in ALS care 19-22. The results of our study point in the same direc on, revealing that the need for emo onal support is men oned by the pa ents and caregivers, but not by the professionals.

Study limita ons The results of our study must be viewed in the context of the Dutch ALS care se`ng in which specialized ALS teams provide mul disciplinary care according to interna onal guidelines 2.

The Dutch ALS care, its financing and reimbursement are well organized 2. Responsiveness to case management might be influenced by this specific context. Readers can assess whether findings can be transferred to their situa on 23. Another limita on was the limited variety of the pa ent group. We did not capture the full diversity of the syndrome of ALS, and our sample did not include pa ents with cogni ve and behavioural dysfunc on (as this was among the exclusion criteria for the RCT). Furthermore, pa ents with young families, single pa ents and caregivers with health problems were not included. Those pa ents and caregivers might have care needs different from those men oned in the current data.

Further research is required to explore the impact of other medical, interpersonal and financial factors on care needs.

Clinical implica ons Experiences with case management can be used to improve the usual ALS care. Our results suggest that in specific circumstances aspects of case management can be of added value to the mul disciplinary ALS care. Therefore, it is important to iden fy the specific circumstances of individual pa ents and their caregivers. These specific circumstances — perceived subop mal quality of ALS care, a progressive disease course, personal factors, e.g., inability to ask for support, a passive coping style, and poor social network support — could be used as a decision guide to tailor care to the needs of pa ents and caregivers.

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Addi onal support can be drawn from the ALS care team, with one of the team members providing extra support.

CONCLUSIONS This qualita ve study has increased our understanding of the par cular care needs of pa ents with ALS and their caregivers. ALS teams might consider implementa on of valued aspects of case management (accessibility, ample me, proac ve approach, emo onal support) in the usual ALS care. Because not all pa ents experienced a need for case management, addi onal support especially might be oďŹ&#x20AC;ered to vulnerable pa ents with a rapidly progressive disease course, passive coping style and restricted social network.

ACKNOWLEDGEMENT We thank the pa ents, their caregivers and the professionals for sharing their stories and experiences with us. We also thank H. van den Oever and R. Janssens for their contribu on to data collec on and analysis.

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Creemers H, Velding JH, Grupstra H, Nollet F, Beelen A, van den Berg LH. A cluster RCT of case management on pa ents’ quality of life and caregiver strain in ALS. Neurology 2014;82(1):23-31.

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Gensichen J, Guethlin C, Sarmand N, Sivakumaran D, Jäger C, Mergenthal K, et al. Pa ents’ perspec ves on depression case management in general prac ce - A qualita ve study. Pa ent Educ Couns 2012;86(1):114-9.

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Need and value of case management in ALS Appendix 1. Study phases.

Phase Explora on

Consulta on

Ac vi es Reading literature and stories of pa ents.

Ge`ng insight into living with ALS and ge`ng input for the topic list.

Goal Ge`ng insight into living with ALS and ge`ng input for the topic list.

A topic list is used in order to check if all relevant topics are discussed during an interview.

Selec on of pa ents from the list of the interven on group of the RCT on case management.

To arrive at a selec on of pa ents who are going to be contacted and informed about the study.

To get maximal varia on, to get as many perspec ves as possible and to learn as much as possible.

Recrui ng par cipants.

Making contact by telephone, sending the informa on le er about the content of the study.

Ge`ng informa on about the experiences with the case manager and the care needs of the pa ents with ALS and their caregivers and what possibly should improve. The conversa ons were furthermore aimed at ge`ng informa on on how physicians in PMR experienced case management.

Semi-structured interviews (n=30).

5

Collabora on

Thema c content analyses of the interviews.

Mee ng of the research team.

One focus-group (n=20)

Obtaining a ďŹ rst insight into relevant themes. To use the informa on as input for the following interviews.

Valida ng and deepening the analyses of the interviews.

Valida ng and deepening the informa on from the interviews and clustering the data from the interviews leading to an overview of factors (personal and environmental) that support and are associated with pa entsâ&#x20AC;&#x2122; and caregiversâ&#x20AC;&#x2122; needs and improvements of ALS care.

Integra on

A mee ng of the research team.

Formula on of methods and ac ons that may lead to the availability of case management for pa ents with ALS and their caregivers.

Wri ng the research report.

Describing the project and results in order to disseminate knowledge, in order to improve the care for pa ents with ALS and their caregivers.

A mee ng of the research team.

Ge`ng feedback on research report and ge`ng ideas for implementa on of results and needed ac ons in order to improve the care for pa ents with ALS and their caregivers.

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Chapter 5 Appendix 2. Interview guides.

The topic guides are based on professionals’ experiences with ALS care and on literature providing insight in pa ents’ experiences with living with ALS

26,27

and on aspects that might influence the

experiences of pa ents with case management, i.e. disease dura on 28.

Interview guide for pa ents and caregivers General informa on about the interview •

Personal introduc on

•

Brief explana on about the project

•

Aim of the interview

•

An cipated dura on of the interview

•

Informed consent to record the interview

•

Informa on about anonymising the interview

•

Member check possible?

•

Explain that the respondents will receive a copy of the final report

Personal details •

Diagnosis

•

Date of diagnosis

•

Age

•

Gender

•

Educa on

•

Marital status

•

Formal or informal health care (or both)

•

Job (before and a{er the diagnosis)

•

Most important limita ons (complaints, quality of life, limita ons)

Life with ALS •

Period prior to the diagnosis (i.e. complaints, emo ons, doubts, consulta ons)

•

Period during the diagnosis and shortly a{er the diagnosis

•

Life with ALS since the diagnosis un l now (outlook on life, a`tude towards the illness, approach to managing changing circumstances, orienta on to me)

Formal and informal care prior to and during the case manager project

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•

Did you receive formal or informal support before the case manager started?

•

If yes, what kind of support?

•

How have you experienced this support?

•

Was there anything lacking in the support/counselling?

•

If yes, what?

Need and value of case management in ALS Mo ves and expecta ons •

For what reason did you sign up for the case manager?

•

What were your expecta ons beforehand regarding the case manager support?

•

What needs did you have beforehand regarding the case manager support?

Experiences with the case manager •

What kind of support did you receive from the case manager (prac cal as well as emo onal)?

•

How did you experience the ac ons of the case manager?

•

What is your opinion on the exper se of and support from the case manager? (exper se, treatment, communica on)

•

Did it yield anything for you? Why?

•

Did it meet your expecta ons?

•

Did you receive other forms of support besides the case manager?

•

Could someone else have given you the support the case manager provided? If yes, who?

5 The period a er case management •

How did you feel about finishing case management (i.e. is anything missing, is someone else giving addi onal support)?

•

Do you think case management has changed something for the foreseeable future? What?

•

What kind of support/counselling do you receive? From whom?

Advice •

What could be improved?

•

What should be preserved?

•

Would you advise peers to get a case manager? Why (not)?

Conclusion •

Is there anything you would like to add to this interview?

•

Thank you for your me

•

Explana on about the report

Interview guide for professionals General informa on about the interview •

Personal introduc on

•

Brief explana on about the project

•

Aim of the interview

•

An cipated dura on of the interview

•

Informed consent to record the interview

•

Informa on about anonymising the interview

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Chapter 5 •

Member check possible?

•

Explain that the respondents will receive a copy of the final report

Personal details •

Educa on

•

Experience with ALS care

•

Age

•

Gender

Experiences with the case manager •

What did the case manager offer in your opinion?

•

What do you think the case manager could offer (poten ally)?

•

What do you think of the exis ng ALS care? Are there any gaps? Who should fill them?

•

Could someone else have given the support the case manager provided? If yes, who?

The period a er case management •

What is the ALS care like now, a{er the case manager finished (is there anything missing, is someone else giving more support now etc.)?

Advice about this form of support •

What could be improved?

•

What should be preserved?

•

Would you advise other pa ents to get a case manager? Why (not)?

Conclusion

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•

Is there anything you would like to add to this interview?

•

Thank you for your me

•

Explana on about the report

6 Factors related to caregiver strain in ALS: a longitudinal study Huub Creemers Sandra de MorĂŠe Jan H. Veldink Frans Nollet Leonard H. van den Berg Anita Beelen

Journal of Neurology, Neurosurgery & Psychiatry, Online First, published on September 4, 2015 as 10.1136/jnnp-2015-311651. Š Reprinted with permission from BMJ Publishing Group Ltd.

Chapter 6

ABSTRACT Objec ve To examine the longitudinal associa ons between caregiver strain and pa ents’ clinical and psychosocial characteris cs as well as caregivers’ psychosocial characteris cs.

Methods At 4-monthly intervals during the 12 months study period, longitudinal data on caregiver strain and pa ent and caregiver factors poten ally associated with caregiver strain were collected from 126 couples, who par cipated in a randomized controlled trial on the effec veness of case management in ALS. Caregiver strain was assessed with the Caregiver Strain Index (CSI). Pa ent and caregiver factors included sociodemographic characteris cs, distress, coping style and perceived quality of care, as well as the pa ent’s func onal status and emo onal func oning. Mul level regression analyses were performed.

Results Caregiver strain increased significantly during the study period (β=0.315 points/months, p<0.001) and was significantly associated with pa ent me-dependent factors func onal status (β=-0.131 points/months, p<0.001) and emo onal func oning (β=0.022 points/ months, p=0.03), and caregiver me-dependent factors passive coping style (β=0.152 points/months, p=0.03), symptoms of anxiety (β=0.186 points/months, p<0.001) and perceived quality of care for the caregiver (β=-0.452 points/months, p<0.001).

Conclusion Our study has iden fied that apart from the pa ent’s physical disability and emo onal wellbeing, a passive coping style of the caregiver, increased symptoms of anxiety and feeling less supported by the ALS-team impact on caregiver strain. The mul disciplinary teams involved with the care of pa ents with ALS need to be aware of these factors and increase their a en on for the caregiver. This will help guide the development of evidence based suppor ve interven ons that focus on caregiver’s coping style and avoiding distress.

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INTRODUCTION Owing to the progression of muscle weakness and the associated disease symptoms over the full course of the disease, pa ents with amyotrophic lateral sclerosis (ALS) become increasingly dependent on the support and care of their partner, family members and other rela ves. Generally, the partner or one of the pa ents’ closest family members is the most important informal caregiver 1. During informal caregiving, a significant amount of me, a en on and effort is devoted to the pa ent with ALS 1.

As the disease progresses, strain on and psychological distress of informal caregivers of pa ents with ALS increase significantly 2-4, while caregivers’ quality of life worsens 5. Role strain due to many demands because of managing care, providing care, suppor ng the pa ent in decision-making, pa ent advoca ng and ordinary daily live responsibili es may have an impact on caregiver strain 6,7.

Reducing the strain of informal caregivers should be a high priority in ALS care. Op mizing the caregivers’ well-being is cri cal, not only for themselves but also for the pa ents 8,9 Knowledge about interven ons which relieve caregiver strain is, however, s ll limited. ALS treatment guidelines and ALS literature lack evidence for interven ons aimed at reducing caregivers’ adverse experiences and caregiver strain 10,11. In their literature review, Aoun et al. (2012) highlighted the absence of interven ons to improve care for family caregivers 12.

From the results of cross-sec onal surveys it appeared that caregivers reported shortcomings in ALS management as a reflec on of caregiver strain 13,14.

Insight into factors associated with caregiver strain may help to iden fy those at risk for high levels of strain and may guide the development of suppor ve interven ons. Earlier cross-sec onal studies iden fied various determinants of ALS caregiver strain, 9,15-18 but fewer studies have reported longitudinal data 3,19. Some of the explored pa ent-related and caregiver-related variables might be modifiable, for example, pa ent’s emo onal lability and mental health and caregiver’s distress (depression and anxiety) 20,21. By acquiring more knowledge about specific pa ent and caregiver modifiable factors related to caregiver strain and the way it increases over me, we will be able to apply this to tailoring ALS care to the needs of the caregiver.

The aim of our cohort study was to iden fy pa ent and caregiver disease-related and psychosocial-related factors associated with caregiver strain over me in ALS.

METHODS Study design and popula on This quan ta ve longitudinal cohort study was part of a cluster randomized controlled trial (RCT) that evaluated the effec veness of case management in 132 pa ents with ALS

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and their most important informal caregiver (n=126) 4. Pa ents were not eligible for trial entry if they had cogni ve dysfunc on. Pa ents and caregivers were excluded if they had insufficient mastery of the Dutch language.

Standard protocol approvals, registra ons, and pa ent consents The Medical Ethics Commi ee of the Academic Medical Centre in Amsterdam waived the need for ethical approval. The RCT was registered at the Netherlands Trial Register, number NTR1270. Informed consent for processing their research data was obtained from all par cipa ng pa ents and all caregivers 4.

Data collec on During the 12-month study period, we assessed baseline sociodemographic characteris cs of the pa ents and their caregivers (e.g., gender, age, educa on). Baseline informa on on ALS clinical characteris cs (e.g., site of onset, me since onset, forced vital capacity, percutaneous endoscopic gastrostomy use and non-invasive/invasive ven la on (NIV/IV) use) was provided by the trea ng rehabilita on medicine consultant from the mul disciplinary ALS care team of the pa ent-caregiver couple. Baseline and 4-month assessments of the measurements were carried out in the homes of the par cipants. Baseline assessments were performed by two experienced occupa onal therapists and 4-monthly assessments by two experienced research assistants 4.

Measurements Caregiver strain was measured with the generic 13-item Caregiver Strain Index (CSI), widely used in health care research and clinical prac ce 22. Caregiver strain refers to the percep on of stress and fa gue caused by the sustained effort required in caring for the pa ent 22. The CSI is a concise instrument with dichotomous yes/no answers to proposi ons, to assess par cipants’ nega ve caregiving experiences. The instrument measures both the objec ve impact of care (e.g., “There have been changes in personal plans”) and subjec ve impact (e.g., “Feeling completely overwhelmed”). The CSI showed no ceiling or floor effects and a high internal reliability 23.

We monitored disease progression with the ALS Func onal Ra ng Scale-Revised (ALSFRS-R). The ALSFRS-R is a 48-point validated disease-specific measure to assess func on, and consists of four domains: fine motor func on, gross motor func on, bulbar func on and respiratory func on. A lower total score indicates greater disability 24.

We assessed emo onal aspects of the pa ent’s health-related quality of life (QOL) with the Dutch version of the 40-item ALS Assessment Ques onnaire (ALSAQ-40), domain emo onal func oning. The ALSAQ-40 is a disease-specific health status measure, containing 40 items incorporated in five dis nct areas of health: physical mobility (10 items), ac vi es of daily living/independence (10 items), ea ng and drinking (3 items), communica on (7

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Factors related to caregiver strain in ALS

items), and emo onal func oning (10 items). Each of the five scales is transformed into a scale of 0-100 (100 indica ng poorest health) 25.

Perceived quality of care (QOC) of the total ALS care provided, was rated by pa ents and their caregivers on a 10-point numerical ra ng scale; 1 represen ng very poor QOC and 10 as excellent QOC. Caregivers were asked to give two ra ngs: one for the care provided to the pa ent, and one for the care provided to themselves.

As indicator for emo onal distress, we used the Hospital Anxiety and Depression Scale (HADS) 26. The HADS is a pa ent-reported outcome measure, developed as a screening instrument for use in hospital outpa ent departments and has been validated for use with primary care pa ents and the general popula on. The HADS comprises 14 items divided equally between the two mood states (anxiety and depression). Par cipants were asked to rate items on anxiety and depressive symptoms during the previous week on a fourpoint scale (0-3), rendering a maximum score of 21 points for each subscale. A higher score indicates more distress.

Coping strategy was assessed with the Utrecht Coping List (UCL) 27. The UCL consists of seven subscales, each represen ng a different coping strategy: ac ve approach, pallia ve response, avoidance, seeking social support, passive reac on, expression of emo ons and reassuring thoughts. We used the subscales ac ve approach and passive reac on, as these represent the conceptualisa on of adap ve and maladap ve coping styles 28,29. An ac ve approach coping style is an ac ve, offensive strategy to handle experienced problems and is considered as an adap ve coping style, whereas a passive reac on coping style is considered as a defensive, reac ve coping strategy that is regarded as maladap ve 29. Both subscales consist of seven items scored on a four-point scale (1-4). We used the sum scores of these subscales in the analyses. Higher scores on the scale indicate that the par cular coping strategy is used more o{en. The UCL showed moderate to good internal consistency (Cronbach’s α 0.43−0.89) and test-retest reliability (r=0.37−0.85) 27.

Sta s cal analysis Normality of the data was checked by plo`ng histograms and by means of a KolmogorovSmirnov test. We measured baseline correla ons between pa ents’ and caregivers’ variables and the CSI total score using Pearson’s correla on coefficients.

The longitudinal course of caregiver strain and its associa on with pa ents’ and caregivers’ variables were analysed with random coefficient analysis. This analysis technique does not require complete follow-up data from all par cipants. Consequently, data of all par cipants, including those with incomplete sets, were analysed. First, we inves gated me-independent and me-dependent factors for their bivariate associa on with caregiver strain.

Second, we built a mul variate model in which we included pa ents’ variables significantly associated with caregiver strain, and another model in which we included

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caregivers’ variables. Each model included me (as a con nuous variable in months) and me squared to capture linear and non-linear course. Furthermore, within each model we explored whether the ALSFRS-R sum score was sta s cally significant in terms of the associa on with caregiver strain over me. In order to account for individual trajectories of caregiver strain, we used a random intercept (and slope). A random slope was only included if this improved the model fit (based on the likelihood ra o test). We employed a backward selec on on the variables (based on the Wald test) to exclude all variables with a p value greater than 0.1.

Third, the remaining pa ent and caregiver variables together with me (linear and quadra c) were combined in a final associa on model. Variables with a p value greater than 0.05 were eliminated, resul ng in the best model for pa ents’ and caregivers’ determinants associated with caregiver strain.

For the descrip ve sta s cs we used SPSS 22.0 so{ware and for the random coefficient analyses MLwiN (MLwiN V.2.32, Centre for Mul level Modelling, University of Bristol, UK).

RESULTS Table 1 presents baseline descrip ve sta s cs of the sociodemographic and clinical characteris cs of the 126 informal caregivers and pa ents with ALS who par cipated in our study. One hundred and seven caregivers were spouses of the pa ents with ALS, ten caregivers were sons or daughters, and 66 percent of the caregivers were female. The flowchart of par cipants (figure 1) shows the number of assessments and the reason why data were missing at each me point.

Scores of par cipants’ me-dependent variables at the four assessments are presented in table 2. Analyses of the me-independent and me-dependent factors associated (univariate and bivariate, respec vely) with caregiver strain resulted in five caregiver variables: age at inclusion; HADS anxiety and depression; QOC care for the caregiver; UCL passive reac on, and seven pa ent variables: age at inclusion; ALSAQ-40 domain emo onal func oning; ALSFRS-R sum score; QOC care for the pa ent; HADS depression; UCL ac ve approach and passive reac on. Table 3 presents the longitudinal associa on with CSI total score for each independent variable separately.

108

Factors related to caregiver strain in ALS Table 1 Baseline characteris cs of study par cipants.

Caregivers and pa ents Female n (%) Age, years mean (SD) College or university degree n (%) Caucasian n (%) Employed n (%) QOC report mark ‘care for the pa ent’ mean (SD) (Score range 1-10) UCL ac ve approach mean (SD) (Score range 7-28) UCL passive reac on mean (SD) (Score range 7-28) HADS anxiety mean (SD) (Score range 0-21) HADS depression mean (SD) (Score range 0-21) Caregivers CSI mean (SD) (Score range 0-13) Partner is caregiver n (%) Daughter or son is caregiver n (%) QOC report mark “care for the caregiver” mean (SD) (Score range 1-10) Pa ents Median me since onset (Q1 – Q3), years ALSFRS-R mean (SD) (Score range 0-48) Bulbar onset n (%) ALSAQ-40 emo onal func oning mean (SD) (Score range 0-100) ALSAQ-40 sum score mean (SD) (Score range 0-100) Predicted FVC% mean (SD) PEG n (%) NIV/IV n (%) Riluzole n (%)

Caregivers n=126

Pa ents n=126

83 (66) 58.8 (12.5) 41 (33) 121 (97) 34 (27) 8.1 (1.0)

41 (33) 62.7 (11.4) 45 (37) 124 (98) 21 (17) 8.2 (0.8)

18.5 (4.0)

17.8 (4.7)

10.7 (2.7)

10.2 (2.3)

6.4 (3.9)

3.9 (3.2)

5.3 (4.1)

4.4 (3.5)

5.4 (3.2)

6

107 (85) 10 (8) 7.7 (1.5)

2.1 (1.2 - 3.5) 31.8 (8.2) 30 (24) 20.2 (17.5) 36.8 (17.8) 85 (22) 23 (18) 22 (18) 115 (94)

%, percentage; ALSAQ-40, Amyotrophic Lateral Sclerosis Assessment Ques onnaire-40 items; ALSFRS-R, Amyotrophic Lateral Sclerosis Func onal Ra ng Scale-Revised; CSI, Caregiver Strain Index; FVC%, percentage of the predicted value of forced vital capacity; HADS, Hospital Anxiety and Depression Scale; IV, invasive ven la on; n, number; S NIV, non-invasive ven la on; PEG, percutaneous endoscopic gastrostomy; Q1-Q3, first quar le to third quar le; QOC, Quality of Care; SD, standard devia on; UCL, Utrecht Coping List.

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Chapter 6 Figure 1 Flowchart par cipants.

110

Factors related to caregiver strain in ALS Table 2 CSI scores and scores of par cipants’ me-dependent variables at the four assessments.

Baseline 4 months mean (SD) mean (SD) n n

8 months mean (SD) n

12 months β mean (SD) (95% CI) n

5.4 (3.2) 125

6.8 (3.3) 79

7.2 (3.5) 45

7.6 (3.0) 53

0.315 (0.221 to 0.409) ** Time (linear) -0.010 (-0.014 to -0.006) ** Time2 (quadra c)

8.1 (1.0) 122 7.7 (1.5) 105 18.5 (4.0) 124

8.3 (0.8) 77 7.7 (1.1) 71 18.6 (3.8) 79

8.0 (0.9) 44 7.4 (1.4) 41 17.7 (3.7) 47

7.9 (0.8) 51 7.2 (1.2) 47 18.6 (4.1) 52

-0.012 (-0.026 to 0.002) -0.025 (-0.003 to -0.047) * -0.007 (-0.044 to 0.030)

UCL subscale passive reac on (Score range 7-28)

10.7 (2.7) 124

10.2 (2.6) 79

10.6 (3.2) 47

10.7 (3.3) 52

0.317 (-0.047 to 0.021)

HADS anxiety (Score range 0-21) HADS depression (Score range 0-21) Time-dependent pa ent variables ALSFRS-R sum score (Score range 0-48) ALSAQ-40 emo onal func oning (Score range 0-100)

6.4 (3.9) 124 5.3 (4.1) 124

5.5 (3.6) 78 4.2 (3.3) 78

6.0 (3.8) 47 5.4 (4.0) 47

6.6 (4.2) 51 5.7 (4.1) 51

0.022 (-0.023 to 0.067) 0.029 (-0.022 to 0.080)

31.8 (8.2) 126 20.2 (17.5) 125

28.9 (8.7) 79 19.6 (15.6) 81

27.3 (8.8) 46 20.6 (14.3) 48

24.5 (10.4) 52 21.1 (15.7) 56

-0.710 (-0.843 to -0.578) ** 0.180 (-0.018 to 0.378)

QOC for the pa ent (Score range 1-10) UCL subscale ac ve approach (Score range 7-28)

8.2 (0.8) 116 17.8 (4.7) 124

8.1 (0.8) 79 18.9 (4.0) 81

8.0 (1.0) 49 18.1 (4.5) 49

7.9 (0.8) 54 19.4 (4.0) 58

-0.017 (-0.031 to -0.003) * 0.062 (0.115 to 0.009) *

UCL subscale passive reac on (Score range 7-28)

10.2 (2.3) 124

9.5 (2.1) 81

9.5 (2.2) 49

9.4 (1.8) 58

-0.028 (-0.057 to 0.001)

HADS anxiety (Score range 0-21) HADS depression (Score range 0-21)

3.9 (3.2) 124 4.4 (3.5) 124

2.1 (2.7) 81 4.1 (2.8) 81

2.2 (2.3) 49 4.0 (2.8) 49

2.3 (2.3) 58 4.2 (2.4) 58

-0.079 (-0.118 to -0.040) ** 0.011 (-0.030 to 0.052)

CSI total score (Score range 0-13)

Time-dependent caregiver variables QOC - for the pa ent (Score range 1-10) QOC - for the caregiver (Score range 1-10) UCL subscale ac ve approach (Score range 7-28)

*p<0.05; **p<0.001.

ALSAQ-40, Amyotrophic Lateral Sclerosis Assessment Ques onnaire-40 items; ALSFRS-R, Amyotrophic Lateral Sclerosis Func onal Ra ng Scale-Revised; CSI, Caregiver Strain Index; HADS, Hospital Anxiety and Depression Scale; n, number; QOC, Quality of Care; SD, standard devia on; Time2, me squared; UCL, Utrecht Coping List; β, βeta, a regression coefficient which is an es ma on of the longitudinal chance of the variable.

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Chapter 6 Table 3 Longitudinal associa on with CSI total score for each independent variable separately.

Independent variable Pa ents – me-independent Educa onal level (college or university) Site of onset (limb onset) Time since onset (years) Gender (Male) Age at inclusion (years) Ethnicity (Caucasian) NIPPV/IV at baseline (yes/no) PEG at baseline (yes/no) FVC% at baseline Pa ents – me-dependent ALSFRS-R sum score (Score range 0-28) ALSAQ-40 emo onal func oning (Score range 0-100) UCL ac ve approach (Score range 7-28) UCL passive reac on (Score range 7-28) QOC - for the pa ent (Score range 1-10) HADS anxiety (Score range 0-21) HADS depression (Score range 0-21) Caregivers – me-independent Partner is caregiver Gender (female) Age at inclusion (years) Ethnicity (Caucasian) Employment (yes/no) Educa onal level (college or university) Caregivers – me-dependent HADS anxiety (Score range 0-21) HADS depression (Score range 0-21) UCL ac ve approach (Score range 7-28) UCL passive reac on (Score range 7-28) QOC - for the caregiver (Score range 1-10)

N

β (SE)

95% CI

126 126 126 126 126 126 126 126 126

0.504 (0.550) 0.109 (0.623) 0.129 (0.109) 0.343 (0.559) -0.055 (0.023) -2.236 (2.919) -0.440 (0.686) -0.117 (0.682) -0.011 (0.014)

-0.574 to 1.582 -1.112 to 1.330 -0.085 to 0.343 -0.753 to 1.439 -0.100 to -0.010 *** -7.957 to 3.485 -1.785 to 0.905 -1.454 to 1.220 -0.038 to 0.016

126

-0.173 (0.018)

-0.208 to -0.138 ****

122

0.039 (0.012)

0.015 to 0.063 ***

124

0.097 (0.044)

0.011 to 0.183 **

124

0.145 (0.081)

-0.014 to 0.304 *

122

-0.413 (0.207)

-0.819 to -0.007 **

124

-0.011 (0.062)

-0.133 to 0.111

124

0.128 (0.060)

0.010 to 0.246 **

126 126 126 126 126 126

0.801 (0.737) 0.943 (0.551) -0.051 (0.021) -0.423 (1.893) 0.163 (0.587) 0.285 (0.558)

-0.644 to 2.246 -0.137 to 1.023 -0.092 to -0.010 ** -4.133 to 3.287 -0.988 to 1.314 -0.809 to 1.379

124

0.287 (0.048)

0.193 to 0.381 ****

124

0.296 (0.045)

0.208 to 0.384 ****

124

0.030 (0.055)

-0.078 to 0.138

124

0.315 (0.070)

0.178 to 0.452 ****

117

-0.708 (0.141)

-0.984 to -0.432 ****

*p<0.1; **p<0.05; ***p<0.01; ****p<0.001.

ALSAQ-40, Amyotrophic Lateral Sclerosis Assessment Ques onnaire-40 items; ALSFRS-R, Amyotrophic Lateral Sclerosis Func onal Ra ng Scale-Revised; CSI, Caregiver Strain Index; FVC%, percentage of the predicted value of forced vital capacity; HADS, Hospital Anxiety and Depression Scale; N, number of subjects included in the analysis; NIPPV/IV, non-invasive posi ve pressure ven la on/invasive ven la on; PEG, percutaneous endoscopic gastrostomy; QOC, Quality of Care; UCL, Utrecht Coping List; β, βeta, a mul level regression coefficient which is an es ma on of the longitudinal rela onship between the independent variable and caregiver strain.

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Mul level analyses showed that caregiver strain increased significantly during the study period. Time and me squared were significant, although the size of the βeta for the quadra c me trend was very small compared to that for the linear term (βeta -0.008 (SE 0.002) versus 0.299 (SE 0.053)) indica ng only a slight devia on from a linear trend. Increase in caregiver strain was associated with the pa ents’ me-dependent variables ‘disease severity’ and ‘ emo onal func oning’, and with the caregivers’ me-dependent variables ‘anxiety’, ‘perceived quality of care for themselves’, and ’passive coping style’ (Table 4).

Table 4 Results of the random coefficient analyses for the associa ons between caregiver strain (CSI) and independent caregiver and pa ent variables (N=116).

Independent variable

Dependent; CSI β (95% CI)

Time, months Time2 Caregiver variables HADS anxiety (Score range 0-21) QOC−for the caregiver (Score range 1-10) UCL passive reac on (Score range 7-28)

0.205 (0.105 to 0.305) ** -0.008 (-0.004 to -0.012) **

Pa ent variables ALSFRS-R sum score (Score range 0-48) ALSAQ-40 emo onal func oning (Score range 0-100)

0.186 (0.086 to 0.286) ** -0.452 (-0.672 to -0.232) ** 0.152 (0.015 to 0.289) *

6 -0.131 (-0.170 to -0.092) ** 0.022 (0.002 to 0.042) *

*p<0.05; **p<0.001.

ALSAQ-40, Amyotrophic Lateral Sclerosis Assessment Ques onnaire-40 items; ALSFRS-R, Amyotrophic Lateral Sclerosis Func onal Ra ng Scale-Revised; CSI, Caregiver Strain Index; HADS, Hospital Anxiety and Depression Scale; N, number of subjects included in the analysis; NIPPV/IV, non-invasive posi ve pressure ven la on/invasive ven la on; Quality of Care; Time2, me squared; UCL, Utrecht Coping List; β, βeta, a mul level regression coefficient which is an es ma on of the longitudinal rela onship between the independent variable and caregiver strain.

DISCUSSION Our longitudinal study has shown that apart from factors rela ng to the pa ent’s physical disability and emo onal func oning, caregiver’s coping behaviour, anxiety and perceived quality of care for the caregiver have an impact on caregiver strain in ALS. The posi ve associa on we found between caregiver burden and the pa ent’s physical limita ons is in agreement with previous ALS studies 2,9,16, as well as with studies in other progressive neurological disorders 30. Some studies could not, however, corroborate the impact of physical limita ons on caregiver strain 15,17,19. This inconsistency might be explained by methodological differences (univariate vs mul variate associa ons).

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We found that caregivers of pa ents with be er emo onal func oning perceived less strain. As far as we could ascertain, our study is the first to reveal evidence for this associa on. We believe that this finding is of importance for improving mul disciplinary ALS care with respect to QOL of the pa ent and caregiver strain 11. Therefore, interven ons targe ng pa ent’s emo onal problems aimed at op mizing QOL is a real challenge for the mul disciplinary care team and community care professionals, the development of support programmes should be priori zed.

This study showed that caregivers who used more passive coping strategies experienced higher levels of strain, a finding in line with results of Weisser et al’s 31 longitudinal study, in which caregivers described becoming (pro)ac ve in dealing with the situa on as ‘helpful’.

We suggest that interven ons aimed at providing insight into how caregivers cope with the nega ve changes in their situa on and at finding effec ve (ac ve) coping strategies may lead to manageable strain.

The current study supports previous findings that lower QOC for the caregiver is associated with higher strain, which indicates the importance of high quality ALS care for the caregiver during the disease stages. All par cipa ng pa ents and caregivers received support from a mul disciplinary ALS care team in accordance with the gold standard treatment for pa ents with ALS. Within our cohort, both pa ents and caregivers rated the overall quality of ALS care as moderate to good. Nevertheless, caregivers experienced lower QOC for themselves compared to QOC for the pa ents. Bakker et al. 32 in their qualita ve study reported that some pa ents and caregivers perceived the QOC of their ALS team to be subop mal. Other studies showed that family members of pa ents with ALS search for prac cal and emo onal support from their health care professionals 13,14,33. Caregivers who experienced the specialist ALS clinic as being suppor ve, men oned that this helped them to cope with the situa on 34. For ALS care professionals, a shortcoming in mul disciplinary ALS care is the availability of specific evidence-based interven ons to guide the family caregivers 11. Caregiver strain should be recognised by the care professionals and tailormade interven ons to prevent or reduce strain, fi`ng the needs of the caregivers, should be developed, validated and implemented.

Reduced caregiver distress contributes to managing the caregiver’s situa on and thus decreasing strain 33. In line with these caregiver experiences, our study showed that higher levels of caregiver anxiety were associated with higher levels of caregiver strain. Previous cross-sec onal studies also reported a posi ve rela on of caregiver anxiety with caregiver strain 15,16. The caregivers’ anxiety scores in these studies were comparable to our results, although all studies used different (types of) anxiety ques onnaires. During the pa ent’s disease trajectory, par cular a en on to the caregiver’s symptoms of distress is needed to offer mely interven ons to alleviate caregiver strain. Previous interven on studies within demen a and cancer showed improvements in distressing caregiver symptoms like mood and coping associated with strain 35.

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The strengths of our study include the large sample of pa ents and their caregivers, the data collec on over a one-year follow-up period and the random coefficients model for data analysis.

The results of our study must be viewed in the context of the Dutch ALS care se`ng − all pa ents and caregivers were supported by a mul disciplinary ALS care team and by their primary healthcare professionals. In the Netherlands clinical prac ce guidelines do not provide specific suppor ve interven ons for caregivers in ALS but emo onal and psychological support is available within the Dutch ALS care se`ng. We did not monitor the content and frequency of psychological or emo onal support par cipants received within the mul disciplinary or primary care se`ng, but emo onal func oning of the pa ent par cipants was rated as almost uncomplicated and did not worsen over me. In addi on, the rela vely low to moderate levels of caregiver strain and pa ents’ and caregivers’ anxiety and depression suggest that in general the Dutch mul disciplinary ALS care is for pa ents as well as caregivers of a high standard.

Neither this nor previous longitudinal studies concerning caregiver strain inves gated an incep on cohort, with the disadvantage of limita ons in the comparability of the results due to the different me points in the disease trajectory of the pa ents. Our study was representa ve with respect to pa ents’ baseline characteris cs (age, bulbar onset, me to diagnosis, gender) for the total ALS popula on in the Netherlands 36. Furthermore, the sociodemographic characteris cs of the caregivers studied were comparable to those of previous prospec ve ALS studies 2,19. The propor on of non-Caucasian par cipants might not be representa ve for the total ALS popula on. The strain experienced by non-Caucasian caregivers of pa ents with ALS has not been the subject of previous studies. The results within this subgroup might differ as differences in cultural, spiritual and religious beliefs could affect coping styles, experienced distress and care needs 37.

This study was conducted alongside the RCT on case management for pa ents with ALS and their most important caregivers 4. Pa ents with neurobehavioural symptoms were excluded from par cipa on in the case management study. We did not assess our pa ents’ neurobehavioural symptoms during the study period and hence did not inves gate the associa on with caregiver burden. Previous ALS studies showed an associa on of caregiver strain with neurobehavioural changes in the pa ent 15,21. Caregiver interven on, aimed at improving the way neurobehavioural changes are dealt with might reduce caregiver strain, but requires further study 38. Studies reviewing interven ons in caregivers of pa ents with demen a that require an ac ve par cipa on of caregivers, such as psycho-educa on, counselling, cogni ve behavioural therapy and mutual support groups, showed a reduc on in caregiver stress or burden, and caregivers highly appreciated suppor ng interven ons 39.

Our study focused on aspects of caregiver strain and ignored the posi ve aspects of caregiving 32. Taking care of a loved-one can apparently give the caregiver the feeling of doing a good job which in turn contributes posi vely to coping with the demands of

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caregiving 40. It is important to consider both posi ve and the nega ve aspects when offering caregiver support. The currently available ALS-specific and generic caregiver strain measurement instruments should be validated for the ALS caregiver popula on, to quan fy this phenomenon and to use this new knowledge in ALS caregiver studies.

CONCLUSIONS AND CLINICAL IMPLICATIONS Our findings demonstrate that apart from the pa ent’s physical disability and perceived emo onal func oning, caregiver’s coping behaviour, psychological distress, and perceived quality of care for the caregiver is related to their perceived strain. In addi on to a en on and support for the caregiver, care professionals should be aware of the modifiable factors that are poten ally amenable to interven ons to help caregivers ac vely cope with their changing role and their impending overload, thus contribu ng to a higher QOC. The strong associa on between strain on and perceived QOC for the caregiver indicates the importance of the quality of ALS care during the disease stages. Psychoeduca onal interven ons are required to provide caregivers with insight into their (poten al) mental imbalance related to strain and anxiety, and stress-management strategies should be implemented to help them deal with their tasks and responsibili es. Also in the interest of the caregiver, future studies might focus on tailor-made support with respect to the emo onal well-being of the pa ent with ALS.

ACKNOWLEDGEMENT The authors thank the par cipa ng pa ents and their caregivers; the recrui ng rehabilita on medicine consultants; the par cipa ng rehabilita on medicine consultants, Gerda Valk, research nurse (University Medical Centre Utrecht) and Kim Bibbe, psychology student (University Medical Centre Utrecht), who conducted the outcome assessments; and Tim Zandbelt (University Medical Centre Utrecht) and Hermieneke Vergunst (University Medical Center Utrecht), who conducted data entry.

STUDY FUNDING The research leading to these results has received funding from the Netherlands Organiza on for Health Research and Development (ZonMw), support grant No 1150.0008, and the Netherlands ALS Founda on.

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7 General Discussion

Chapter 7

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General Discussion

The overall aim of this thesis is to op mize mul disciplinary ALS care through expanding our knowledge on previously iden fied bo lenecks in complex ALS care – prognos ca on, the provision of aids and adapta ons, and caregiver strain − and to inves gate the added value of case management in a mixed methods research project.

In the absence of a cure for ALS or effec ve interven ons to slow down or stop the progression of muscle weakness, the quality of ALS care requires con nuous a en on.

Exis ng guidelines lack conclusive evidence on aspects of ALS care, indicated by pa ents and/ or caregivers as shortcomings e.g., symptom treatment, caregiver strain, care coordina on, communica on between health professionals, provision of aids and adapta ons 1,2. This thesis focussed on pa ents with ALS as well as their caregivers and included the following topics: 1) prognos ca on of the rate of func onal decline as a consequence of the disease, 2) the procurement of assis ve devices and home adapta ons (ADHA), 3) client-centered suppor ve care for pa ents and their caregivers, and 4) caregiver strain.

In this chapter the main findings of the previous chapters are discussed and issues concerning the methodology are cri cally reviewed. The implica ons of the findings for clinical prac ce are considered and, finally, recommenda ons for further research are made.

MAIN FINDINGS The systema c review revealed that the current evidence on prognos c factors for func onal decline in ALS is insufficient to allow the development of a predic on tool that can support clinical decisions (chapter 2). Due to the limited data and inconsistency of results in the small number of studies included, the quality of evidence for the prognos c value of age at onset, site of onset, me from symptom onset to diagnosis, and ALSFRS-Revised baseline score was low. The prognos c value of ini al rate of disease progression, age at diagnosis, forced vital capacity, frontotemporal demen a, body mass index, and comorbidity remains unclear.

Recent literature confirmed part of the prognos c factors we derived and iden fied addi onal prognos c factors 3-6. The studies of Hothorn (2014), Atassi (2014) and Küffner (2015) were based on the same data from the PRO-ACT database (www.ALSDatabase. org) 3-5. In our literature search, we found only one study for uric acid as a non-significant prognos c variable for disease progression. However, the Atassi study (2015; n=4,838) showed that higher uric acid levels at baseline were predic ve for a slower drop in ALSFRS-R (p=0.01). Therefore, we upgraded the overall quality of evidence (in accordance with our GRADE approach) for uric acid from ‘no’ into ‘very low’ evidence. The weighing of the other prognos c variables within these recent studies in addi on to our findings did not result in an upgrade of the overall quality of evidence, mainly due to the quality factors inconsistency and imprecision.

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The relevance of the prognos c factors we found was strengthened by previous reported prognos c factors for survival in the cri cal review of Chio et al. (2009) and in later conducted prognosis studies 6-11. Partly conflic ng findings were reported by Wolf et al.

(2015) who found male gender related to worse prognosis 11.

Küffner and colleagues (2015) presented the results of a crowdsourcing compe on for predic on models of disease progression 5. The best predic ng model of disease progression adequately dis nguished between pa ents with a slow and fast disease progression.

Compared to this predic on model, clinicians misclassified 35 percent of the pa ents, so it seems that the model might offer added value to the physician in pa ent counseling. The authors announced that the u lity of the best models of the compe on will be tested in a clinical se`ng 5. However, the studied models resulted in a predic on of the slope of func onal decline, and lack the predic on of func onal milestones during the disease, like loss of ambula on, ADL independency, and verbal communica on. Clinical prac ce shows that besides informa on on disease dura on and rate of decline, pa ents also want to be informed about the nature and sequence of the progressive func onal limita ons.

Previous studies have a empted to build predic on models for survival 12,13. Although these models can be valuable for research purposes, they lack reliability for use as a credible algorithm in individual pa ent care. Significant uncertainty remains around es ma ng individual survival me. Recently Elamin et al. (2015) 10 validated a prognos c index for survival and Wolf et al. (Neuroepidemiology, 2015) 11 presented a model to predict the survival probability at the me of diagnosis for an individual pa ent. Within these studies, prognos c factors easily available at the first clinic visit, were used. Most pa ents also want to be informed about the nature and sequence of the progressive func onal limita ons, and physicians want reliable, predic ve informa on about the func onal course for accurate symptom management. The model of Elamin (2015) 10 included execu ve dysfunc on which showed to be a significant prognos c factor for shorter survival and Wolf’s model (2015) 11 included early cogni ve decline independently related to shorter survival. The informa on generated from survival studies might be useful for the development of prognos c models for the rate of func onal decline, as corresponding factors for func onal decline and survival enhance predic on reliability. In literature, there is a debate about the usefulness of the generally used disease stra fica on by site of onset or type of motor neuron dominance.

Turner et al. (2013) suggested stra fica on by 1) rate of disease progression, defined as the me to spread to a new region, and 2) degree of cogni ve impairment 14. Possibly these stra fica ons might well be be er alterna ves in ALS clinical prac ce as they seem to be er fit the func onal limita ons pa ents are confronted with. The model of Elamin (2015) is promising and provides clues for further development of a reliable prognos c model for the func onal decline of the individual pa ent 10.

One of the prac cal issues of disease management in ALS in which prognos ca on plays a fundamental role are assis ve devices and home adapta ons (ADHA). Confronted with

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the problems during the process of procuring ADHA within the context of the Dutch health care system and based on earlier literature findings, we performed a na onwide survey in 2007 to gain insight in the experiences and problems from the viewpoint of pa ents with ALS. The results of our cross-sec onal study described in chapter 3 underscored our clinical experiences and the earlier findings with respect to problems during the ADHA procurement process despite mul disciplinary support 15,16. Seventy-one percent of the surveyed pa ents were supported by specialized mul disciplinary ALS care teams. Fi{y-eight percent of the pa ents reported problems in obtaining ADHA. Pa ents with ALS viewed me delay and the authori es’ lack of disease knowledge as the most prominent requiring improvement in the procurement process.

Quick and easy (=minimal bureaucracy) procurement procedures, increased awareness of all stakeholders involved, reliable prognos ca on and empowerment of the pa ents and their caregivers in the applica on process might enhance pa ent and caregiver sa sfac on with the service delivery systems and outcomes.

To fill the aforemen oned gaps in ALS care, we hypothesized that case management might be effec ve to improve quality of care (QOC). Our cluster RCT on case management in mul disciplinary ALS care demonstrated no significant benefit of case management to the pa ents’ QOL, caregivers’ strain and pa ents’ and caregivers’ QOC when added to standard mul disciplinary care compared with standard care alone (chapter 4). Most striking was that pa ents as well as caregivers rated the overall quality of ALS care for the pa ent as good.

Caregivers rated the care for themselves to a slightly lesser extent as good. An explana on for the earlier reported gaps in Dutch ALS care might be that a non-recurring nega ve experience does not have a profound influence on how pa ents and caregivers rate the overall QOC we asked them to weigh. The ‘low’ scores on the ALSAQ-40 domain Emo onal Func oning, the primary outcome, indica ng a rela vely low impact of the disease on the pa ent’s well-being, are remarkable. These ‘low’ scores on QOL, indica ng a be er emo onal func oning, and the rela vely high scores on QOC imply that there was li le room for improvement through intensive case management, and might be an explana on for the lack of effect of the interven on within the Dutch ALS care se`ng.

Pa ents and caregivers differed in their need for case management. One quarter of the pa ents and their caregivers made no appeal to the case manager. But on the other hand, 31 caregivers and 48 pa ents raised at least one issue during the 12 months interven on period. The ac ons undertaken by the case manager during the interven on, were aimed at improving quality of care (e.g., symptom treatment, care coordina on, ADHA realiza on), providing emo onal support and reducing caregiver strain. This was confirmed by the findings of our qualita ve study on the perspec ves and service needs of pa ents with ALS, their spousal caregivers and healthcare professionals on case management in addi on to the usual mul disciplinary ALS care (chapter 5). Both pa ents and caregivers being interviewed appreciated the prac cal and emo onal support of the case manager. Professionals

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(rehabilita on medicine consultants and case managers) did not men on the added value of emo onal support by the case manager. Pa ents, caregivers and healthcare professionals indicated that case management can have surplus value in specific situa ons. Factors that emerged from the interviews and the focus group and appeared to influence pa ents’ and caregivers’ needs for and recep veness to case management are less func oning of the ALS care team, a rapid disease progression, personal factors (e.g., maladap ve coping styles, less self-asser ve, less self-sufficiency and reluctant to ask for support) and inadequate support from the social network of pa ents and caregivers. Par cipants valued the house calls, ample me to talk with pa ents and caregivers and proac ve approach of the case manager.

These aspects of the case management interven on might be usable as addi onal support for vulnerable pa ents and caregivers. We conclude that there is insufficient evidence to implement our case management model in the Dutch ALS care se`ng. The interviews with par cipants and the focus group discussion resulted in a greater understanding of the ALS care needs from the different perspec ves.

As highlighted in chapter 4, the case management interven on did not reduce caregiver strain. More than that, in both study groups caregiver strain increased significantly during the interven on period. This stressed the need for more insight in factors related to (increase of) caregiver strain and a more prominent role of ALS care interven ons targe ng caregiver strain. The data from longitudinal assessments within our RCT showed that apart from the amount of func onal limita ons and condi on of emo onal well-being of the pa ent, a passive (avoidant) coping style of the caregiver, increased feelings of anxiety, and feeling less supported by the ALS team impact on the strain of ALS caregivers (chapter 6). In order to regulate caregiver strain and to tailor mul disciplinary ALS care to the caregivers’ needs, ALS care teams should increase their support for the caregiver and implement caregiver interven on programs that focus on caregiver’s coping style and distress. Evidence in scien fic literature for interven ons targe ng caregiver strain in ALS lacks 17,18. Care support for informal caregivers should be based on individual needs and on two-sided aspects: the caregiver in the care for the pa ent and in the care for themselves 19,20.

METHODOLOGICAL CONSIDERATIONS Study popula on The large sample sizes within our longitudinal studies strengthened the reliability of our results. Together with the comparability of our study par cipants with those of a Dutch popula on-based epidemiology study, we are confident that the conclusions we made hold for the Dutch ALS popula on 21. Inherent to longitudinal studies of pa ents with ALS is the high missing rate due to death during the study or because par cipa ng the study becomes too burdensome.

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The numbers of dropout par cipants and intermi ent missing data within both study groups of the case management RCT resulted in an equal propor on of evalua ons within both groups. We found a difference, although not significant, between both groups in the number of pa ents who died (interven on n=23, control n=15) and who stopped (interven on n=5, control n=10) during the study period. Pa ents who died had older age, lower FVC predicted and lower ALSFRS-R total score at baseline compared to pa ents who stopped. We are confident that this did not result in a bias of treatment effect es mate on QOL or QOC since the baseline scores of the pa ents who died or stopped on the outcome measures QOL and QOC did not differ. The baseline CSI scores of their caregivers was significantly higher in pa ents who died compared to those who stopped (mean (SD): 7.0 (2.7) versus 4.7 (3.1); p=0.03), possibly resul ng in a distor on of the interven on effect on caregiver strain. However, controlling for this baseline difference in our mul level analysis would have contributed to an even larger nega ve value of the mul level regression coefficient for the effect of the case management interven on on caregiver strain we found (β= -0.08; p=0.15).

A strength of the mul level analyses of the longitudinal data we conducted is that these analyses use all available data in the es ma on of the model parameters.

Due to the randomiza on of the mul disciplinary ALS care teams instead of the par cipants, poten al RCT par cipants knew in advance which study group they would be assigned to par cipate. Considering par cipa ng the study or not might be influenced by that. However, forty-six percent par cipa on willingness of the pa ents from the interven on teams and forty-three percent of the control teams clarifies that there was no difference in the willingness of poten al pa ents and their caregivers to par cipate in the RCT. Study design The mixed methods approach – RCT and qualita ve study case management − allowed us to be er understand the interven on outcomes and the meaning and relevance of the interven on for the par cipants. Köpke and McCLeery (2015) in their editorial on systema c reviews of case management for pa ents with demen a and their caregivers stated that the inclusion of non-RCT evidence like qualita ve studies might contribute to disentangle the complex care interven on case management, which was confirmed by our mixed methods approach 22.

By inves ga ng determinants of caregiver strain using data captured in the randomized controlled trial on case management, relevant determinants of strain may have been missed. We did not ask our par cipants which pa ent and caregiver factors, according to their opinion, contribute to caregiver strain. An addi onal qualita ve study probably might have resulted in more insight in pa ent and caregiver factors associated with caregiver strain as experienced by par cipants. However, semi-structured interviews with purposive selected par cipants (pa ents, caregivers, physicians) of the RCT case management

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showed that informal caregiver care needs are related to subop mal care provided by the mul disciplinary ALS team, a rapid disease progression, personal factors of pa ents and caregivers and a poor social network. Assuming an associa on between caregiver strain and content of care these results indicate the surplus value of addi onal qualita ve research 23.

The interven on case management Within the RCT the contrast between usual care and usual care plus intensive case management was not strong enough to demonstrate an interven on effect. Pa ents and caregivers experienced usual care of a very high quality so that addi onal case management had no added value. Our qualita ve analysis showed that the range of tasks of the case manager fi ed the needs of the par cipants and any shortcoming in ALS care. We assume that within the Dutch ALS care se`ng a differing case management model likewise would show comparable results.

Par cipants of our qualita ve study indicated that the ming of the case management interven on was not op mal. Either case management was offered too late − par cipants already put things into ac on by themselves – or par cipants regre ed that the interven on had to stop a{er 12 months. This finding confirms the importance of ming of disease management with respect to offering support for pa ents with ALS and their caregivers.

The use of an incep on cohort and an extended interven on dura on in our opinion would not have resulted in a different study result due to the above men oned interpreta on.

Outcome measures The primary outcome in the RCT on case management was the pa ents’ health-related QOL assessed with the 40-item ALS Assessment Ques onnaire (ALSAQ-40), domain Emo onal Func oning (EF). The EF domain addresses various emo onal problems, for example, feeling lonely, feeling hopeless about the future, and feeling embarrassment in social situa ons.

Possibly not all aspects of emo onal well-being are covered with the 10 items of EF. Other, in ALS research sparingly used generic global QOL measures (e.g., SEIQOL, SEIQOL-DW, SMiLE, McGillQOL) are more focused on domains of QOL such as the existen al domain (meaning in life, percep on of purpose, spirituality, religion) or on those life areas which are important to the individual pa ent’s QOL (e.g., family, household, work, speech) 24-27. Given the content of our interven on, the choice of one of these QOL outcome measures in our opinion would not have led to a differing RCT outcome as we did not find an effect on any other outcome measure.

At baseline, we expected differences in processes, structures and outcomes of care provided by the single ALS care teams and the judgement of this care by the par cipants.

As a result of the randomiza on, the quality of care was equally rated in both RCT study groups. We used a 10-point scale to assess perceived QOC by asking par cipants to indicate with a report mark (1=very poor QOC, 10=excellent QOC) their opinion about the ALS care in

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its en rety during the past month. We did not assess specific domains or items of QOC and did not make dis nc on in structures, processes and outcomes of care 28. Consequently, we did not know how par cipants weighted different aspects of ALS care, such as professional exper se, accessibility, client-centeredness, availability of ADHA, symptom management and the frequencies of the team contacts. ALS specific QOC measurements are not yet available and in literature sugges ons are made to develop an ALS QOC instrument which includes the domains of sa sfac on with care for pa ents with ALS 29. Stephens et al.

(2015) concluded no differences in QOC outcomes between pa ents a ending and not a ending mul disciplinary clinics, and indicated that other QOC instruments are needed to demonstrate the benefits of mul disciplinary care 30. Today in Dutch clinical prac ce other methods are used to assess the experienced quality of ALS care, such as self-administered or generic QOC ques onnaires, mirror mee ngs and a{er-death evalua ons with informal caregivers 31,32. In our opinion, the development of an ALS specific QOC instrument for pa ent and caregiver care could be a valuable addi on to ALS care and research.

We used versions of the ALSFRS(-R) as outcome measure for func onal decline.

Franchignoni et al. (2013 and 2015) demonstrated that the ALSFRS-R lacks unidimensionality 33,34 . In contrast to the heterogeneity of the ALSFRS(-R) total score, the domains of the ALSFRS(-R) (bulbar, motor, and respiratory func ons) appear unidimensional, and adequately represent the respec ve constructs 33,35. Grimby and colleagues (2012) reported that trea ng an ordinal summed ra ng scale as an interval measure assuming equal intervals, and subjec ng such scale to parametric sta s cs, will likely lead to invalid results 35 . This might be an explana on for the low level of evidence for the prognos c factors we found in our review. Grimby et al. (2012) consider it of importance to use Rasch analysis and Rasch derived instruments to allow a valid interpre ng of data derived from ordinal ra ng scales 35. In line with Grimby’s study (2012) 35, we suggest to use modern test theory in the development and evalua on of ALS specific instruments.

In addi on, results from earlier studies on the ALSFRS(-R) total score showed that this score does not meet the assump on of a linear decline for sta s cal models in prognos c studies 36,37. We suggest that a thorough revision of the ALSFRS-R through the item response theory paradigm (IRT) or the development of an ALS specific composite measure with biomarkers for disease progression (e.g., uric acid, crea nine, blood pressure) might contribute to a more reliable clinical reproduc on of func onal decline during the en re disease course 38. Un l the availability of such a measure, we recommend to u lize the ALSFRS-R domain scores in daily prac ce and clinical research.

To measure caregiver strain in ALS, we chose the generic Caregiver Strain Index (CSI) as it is widely used in clinical prac ce and health care research 39. Mockford et al. (2009) developed and validated the on carer report based MND Carer Ques onnaire (MNDCQ), measuring the extent to which dimensions of caring affect caregivers’ health 40. The authors indicated that an increase of the MNDCQ score suggests a higher level of caregiver

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burden and that the instrument may be used to iden fy the individual caregiver needs.

In con nua on of the Mockford study, which is based on the UK’s health care system, we suggest to develop a combined qualita ve and quan ta ve ALS specific caregiver strain assessment tool including both posi ve and nega ve aspects of caregiving as well as an ALS specific caregiver needs instrument 41,42.

Generalizability Outcomes of case management interven ons are reported within other diseases, but comparing these study results is difficult due to differences in outcome measures and case management models used. Relevant characteris cs of our studied samples (age, gender, site of onset and me to diagnosis) within the ADHA study, the RCT case management study and the caregiver strain study did not differ from those of the 1128 incident pa ents in the popula on based register in the Netherlands 21. As pa ents characteris cs within the study of Huisman et al. (2011) were comparable with other na onal popula on based studies, we conclude that our results can be generalized across popula ons 21. However, we have to remark that pa ents with cogni ve or behavioural impairments were excluded from par cipa ng our RCT study, which poten ally limits the generalizability of our RCT and caregiver strain study. In addi on, the possible differences in (the quality of and accessibility of) health care systems, treatments availability, se`ngs, religions and ethnici es across the different countries, causes that we cannot extrapolate our findings to the en re ALS popula on.

CLINICAL IMPLICATIONS Case management The findings of our RCT on case management do not support the implementa on of this case management model as part of ALS care in the Netherlands. However, aspects of case management might be a valuable contribu on to mul disciplinary ALS care: house calls, ample me for consulta on, emo onal support and proac ve care. Tailored care is the key to ALS care that best fits the personal care needs of pa ents with ALS and their informal caregivers. Health care professionals should prompt pa ents and caregivers, if suscep ble, to think about (near) future topics and care needs. Through reflec ons and sharing emo ons pa ents and caregivers might feel supported in coping with their situa on. Structural monitoring of and discussing ALS care with pa ents and their caregivers contributes to mely discovery of bo lenecks in care. To offer a central contact person (e.g., one of the members of the ALS team), easily accessible, might be the link between mul disciplinary care and the individual care needs of the pa ent and caregiver. A en veness of the mul disciplinary care team for factors that might play a part in the pa ent’s or caregiver’s need for addi onal

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support is advisable: an insufficient social network and lack of social support, shortcomings in the usual care, a rapid disease progression rate, the disease stage, and personal factors of pa ents and caregivers (e.g., passive coping styles, limited resilience, less asser ve, less self-sufficient, reluctant to ask for support). Possibly a quick scan of these factors during the RMC consulta ons could help.

ALS care teams should be con nuously alert on the quality of care the teams provide to the pa ents and their informal caregivers. Periodic quality of care evalua ons should be a standard within ALS care and monitoring as well as discussing the quality of ALS care with pa ents and their caregivers offer opportuni es to adjust care to their needs.

Prognos ca on The available knowledge concerning the prognos c factors we found in our systema c review and on reported prognos c factors for survival might help physicians when considering the pa ent’s disease course (slow, moderate or rapid disease progression) 6-11. Based on our results we recommend ini al quan ta ve assessment of the following prognos c factors at the pa ent’s baseline visit at the RMC: age at onset, site of onset, me from symptom onset to diagnosis, baseline ALSFRS(-R) score, ini al rate of disease progression, FVC, FTD, BMI, and comorbidity. This assessment might help the clinician to make a prognos c es mate at baseline. In informing pa ents about their prognosis, the clinician should acknowledge their likely inaccuracies, and discuss possible scenarios for the disease course. By monitoring disease progression (ALSFRS-R, FVC, BMI) during follow-up visits, prognosis can be adjusted if necessary.

To iden fy clinical ALS phenotypes with consistent prognos c pa erns, popula on based data are needed 14. It is of great importance to assess the clinical development of ALS – the display of clinical phenotyping and disease heterogeneity within pa ents – in order to achieve reliable prognos ca on of pa ents with ALS 5. Comprehensive longitudinal data collec on, with interna onal standardized measurements of pa ent, disease, and interven on variables recorded in daily clinical prac ce and entered into large electronic databases, might enhance the possibility of iden fying reliable prognos c factors 43. These data preferably are based on incep on cohorts. It’s the challenge for ALS care teams to inform pa ents with ALS about the importance of this type of research so pa ents are mo vated to par cipate.

Given current advances in knowledge about the role of gene cs in ALS, it is likely that the gene c varia on in ALS will be unravelled to clinically more homogeneous subtypes in the future. This new knowledge might contribute to the development of predic on tools 44.

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ADHA Based on our results we suggest different approaches for improvement of the procurement process: - A proac ve approach by all stakeholders − authori es, agencies and suppliers − to a ain mely realiza on of the needed ADHA through increasing awareness of ALS and the impact on pa ents’ func oning. An online training for service providers related to this issue may contribute to achieve care improvement. (h p://www.mndcare.net.au/ overview/online-training-for-service-providers/mnd-aware) In 2011, the Netherlands ALS Founda on started an ALS awareness campaign to inform the Dutch public about this incurable disease and the impact on the pa ent’s daily life. (h p://www.als.nl/ s ch ng-als/reclamecampagnes/ik-ben-inmiddels-overleden/) The interna onal icebucket challenge hype in 2014 resulted in an unprecedented media a en on for ALS and contributed to an immense increase of familiarity with ALS within the public worldwide (h p://www.alsa.org/about-us/ice-bucket-challenge faq.html?referrer=h ps://www. google.nl/) 45.

- The pa ent as informa on carrier to transfer (wri en) knowledge to all relevant par es about the disease, the consequences for independence and autonomy, the func onal prognosis and the ALS care network might be the key to increased ALS awareness of all those involved. The ALS care teams, ALS pa ent associa ons, ALS knowledge centers and ALS funding agencies possibly may want to contribute to the prepara on of an up-to-date package. As an example, the Dutch neuromuscular pa ent organisa on (Spierziekten Nederland) developed informa on brochures for primary care physicians, for home care services and personal care assessors. (h ps://www.spierziekten.nl/ overzicht/amyotrofische-laterale-sclerose/voor-hulpverleners-over-als/) - Empowerment of pa ents and their caregivers by the mul disciplinary ALS care team through tailored psycho-educa on about ALS, ADHA, and the procurement procedures, so pa ents and caregivers learn to enter into dialogue with authori es, agencies and providers 46,47. Lack of clarity of the legal procedures and lack of informa on on what pa ents can expect from authori es, agencies and providers might be tackled through revision of the quality of current pa ent informa on 48,49.

- An emergency procedure for a demand-oriented indica on and realisa on process of ADHA for pa ents with ALS, endorsed by all stakeholders. Experiences within regional projects in the Netherlands so far showed that bureaucracy can be reduced and fast delivery is feasible. These projects might serve as best prac ce models for improving na onal quality of ALS care related to ADHA. Due to the variability in how the na onal health care systems organize their ADHA provision, the implementa on of improvements will have to be tailor-made to these systems.

- Suppor ng the ming of proac ve applica on of ADHA by monitoring the disease course and adequate prognos ca on. A task for the mul disciplinary ALS care team to

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inform those pa ents who are ready to discuss this topic in order to mely start up the procurement process. However, as stated before, the current knowledge on prognos c factors to inform the individual pa ent about the course and me-span of the disease, hampers health care professionals in prescient recommenda ons. Improvements in predic ng the rate and nature of func onal impairments will contribute to decrease the me-span wherein AHDA applica ons are realized.

Monitoring and registra on of the me points and outcomes of the en re procurement process of ADHA of each pa ent should be standard within ALS care to gain insight in the me phases of the process and to provide authori es and agencies with reliable feedback if problems arise. Empowerment of the pa ent and the caregiver by the ALS care team in their role during the procurement process might contribute to increased sa sfac on with the process.

Caregiver strain The vital role of informal caregivers in suppor ng pa ents with ALS is well recognized but caregivers are o{en vulnerable and overlooked by health care professionals. Health care professionals should increase their a en on for the caregiver to fit their support to the needs of the caregiver. There are several methods to structure this a en on: frequently asking the caregivers about their experiences with the changing situa on and their workload, recurrent use of a valid disease-specific caregiver strain inventory, to survey the abovemen oned pa ent and caregiver factors, to formulate the aims of support for the caregiver within the ALS care plan and through regularly checks for addi onal support needs. For the la er, a caregiver needs ques onnaire could be used. The ming of offering informa on and support facili es, and the realiza on of needed support is essen al during the en re disease process. Finally, health care professionals should inform the informal caregiver about the availability of support a{er bereavement by the ALS care team or community care professionals.

RECOMMENDATIONS FOR RESEARCH / FUTURE PROSPECTS It would seem that QOL and QOC of pa ents with ALS differ among countries. When we compare the QOL scores (ALSAQ-40 domain EF) within the RCT case management with scores in other countries, there is a striking difference in favour of the Dutch ALS popula on.

Studies of pa ents’ and caregivers’ percep ons on QOC are scarce. By comparing data on QOL and QOC of pa ents and caregivers and on outcomes of QOC within different ALS health care systems, we might get more insight in the effec veness of the different systems and the differences in QOL and QOC, which will contribute to the improvement of ALS care. Furthermore, more insight is needed in the associa on between QOL (e.g.,

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mood, physical limita ons, communica on, fa gue) and QOC to know which QOC indicators (e.g., falls, respiratory status, nutri onal status, survival, pain, saliva on, caregiver burden, accessibility, client-centeredness, professional exper se) should be manipulated in order to maintain a sa sfactory level of QOL for pa ents with ALS and their caregivers. In addi on, it is suggested to conduct more qualita ve studies to inves gate aspects of quality of ALS care, as expecta ons and experiences of pa ents, caregivers and health care professionals might contribute to gain insight in structures, processes and outcomes of ALS care. Interna onal collabora on between ALS knowledge centres will facilitate this type of research. An ALS specific instrument for measuring pa ent and caregiver sa sfac on with care, needs to be developed in consulta on with pa ents and caregivers.

In con nua on of our cross-sec onal study, a longitudinal study, quan ta ve as well as qualita ve, is needed to further inves gate the experiences of incident pa ents and caregivers in the en re procurement process and the outcomes of ADHA. Within the Dutch ALS care se`ng it would be of interest to repeat our study to evaluate the effec veness of the ALS awareness campaign and the implementa on of ALS informa on packages for home care workers and personal care assessors (h ps://www.spierziekten.nl/overzicht/ amyotrofische-laterale-sclerose/voor-hulpverleners-over-als/). Registering data on ADHA in daily prac ce, available for pa ent management and research purposes and without extra burdening for pa ents and their caregivers, might help to improve ALS care.

It is proposed to conduct prospec ve comprehensive interna onally data collec on within incep on cohorts, with standardized measurements of pa ent, disease and interven on variables to iden fy prognos c factors that have predic ve value for a decline in ALSFRS-R domain scores and related func onal milestones. Aim is to come to more reliable evidence synthesis of prognos c factors for func onal decline in individual pa ents. The psychometric proper es of the ALSFRS-R should be thoroughly revised and validated through Rasch analysis. It needs to be sorted out if an ALS specific composite measure with biomarkers for disease progression (e.g., uric acid, crea nine, blood pressure) might contribute to a more reliable clinical reproduc on of func onal decline during the en re disease course. The in January 2014 started ALS-CarE research project (h p://www.neurodegenera onresearch. eu/fileadmin/Project_Fact_Sheets/PDFs/Healthcare_Evaluation/ALS-Care_Fact_Sheet_ Template.pdf) offers opportuni es to come to significant improvements in measuring func onal decline and prognos ca on of func onal milestones.

Our findings contributed to more insight in caregiver strain in ALS. The currently available caregiver strain ques onnaires should be reviewed and an ALS specific ques onnaire including posi ve and nega ve aspects of caregiving should be validated for the ALS caregiver popula on. The effect of the pa ents’ cogni ve and behaviour deficits on the strain of their informal caregivers needs further study and interven ons to support informal caregivers confronted with those deficits, should be developed and implemented.

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Behavioural and/or psychological interven ons (e.g., meaning centered psychotherapy) targe ng the pa ent’s emo onal well-being should be developed 50,51. The development of a psycho-educa onal interven on to offer caregivers the opportunity to get insight in their mental imbalance related to strain and anxiety, and the implementa on of stress managing strategies to enable caregivers to deal with their tasks and responsibili es should also be subject to further research. Longitudinal studies to assess ALS caregivers’ needs, to develop ALS caregiver behavioural (e.g., cogni ve behaviour therapy) and/or psychological interven ons (e.g., psycho-educa on) and to determine the effec veness of caregiver interven ons in ALS are needed 52,53. Recently, the Netherlands ALS Center started a research project on informal caregivers of pa ents with ALS. (h p://www.als-centrum. nl/kennisbank/project-mantelzorgers/) Aim of this project is to find an adequate, evidence based approach to support these caregivers in their roles and thereby contribu ng to the pa ents’ well-being. The effect on the caregivers’ and pa ents’ QOL will also be examined.

GENERAL CONCLUSION The overall aim of this thesis was to op mize mul disciplinary ALS care through expanding our knowledge related to previously iden fied bo lenecks in complex ALS care. The systema c review revealed that the current evidence on prognos c factors for func onal decline in pa ents with ALS is insufficient to allow the development of a predic on tool that can support clinical decisions. The na onwide survey to explore the experiences of pa ents with ALS during the procurement of ADHA indicated that pa ents viewed me delay and the authori es’ lack of disease knowledge as the most prominent requiring improvement in the procurement process. The RCT on case management showed that pa ents with ALS and their informal caregivers in general rate the quality of the Dutch ALS care as good.

The interven on case management in addi on to usual ALS care showed no benefit with respect to the pa ents’ QOL, caregivers’ strain and the QOC for the pa ents and their caregivers. Based on the interviews and focus group within the qualita ve study of the case management project we concluded that ALS teams can consider implementa on of valued aspects of case management (accessibility, home visits and ample me, proac ve approach, emo onal support) in usual mul disciplinary care. Addi onal support might be provided to pa ents with rapidly progressive disease course, passive coping style and small social network. Finally, the longitudinal study on factors associated with caregiver strain over me iden fied that apart from the pa ent’s physical disability and emo onal well-being, a passive coping style of the caregiver, increased symptoms of anxiety and feeling less supported by the ALS-team impact on the strain of ALS caregivers. The mul disciplinary teams involved with the care of pa ents with ALS need to be aware of these factors and increase their a en on for the caregiver. We conclude improvements in knowledge and insight into the

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bo le necks determined at an earlier stage, but also into clues for advances in ALS care and further research. Our recommenda ons for improvements in mul disciplinary ALS care to fit the individual care needs of pa ents and their caregivers are: • Provide tailor made, proac ve care to the pa ent and the informal caregiver.

• Discuss the quality of ALS care with the pa ent and informal caregiver.

• In the interest of both the pa ent as the caregiver; take care for the caregiver.

• Stay alert for vulnerable pa ents and caregivers: a rapidly progressive disease course, an inadequate coping style, a less suppor ve or an inadequate social network and being less self-asser ve or less self-sufficient.

• ALS health care professionals should be easy accessible.

• Consider to appoint a central contact person within the mul disciplinary ALS care team.

• Empower the pa ent and caregiver in the procurement process of ADHA. An ALS specific instrument for measuring pa ent and caregiver sa sfac on with care should be developed in consulta on with pa ents and caregivers.

It is proposed that increased knowledge on prognos ca on might contribute to a more efficient procurement process of ADHA, improvements in care planning and ming of symptom management. More interna onal collabora ve research on prognos c factors for the func onal decline in ALS is suggested. It is recommended to develop an ALS specific composite measure including biomarkers for disease progression (e.g., uric acid, crea nine, blood pressure) for reliable measurement of func onal decline during the en re disease course.

Decrease of me-delay and increase of disease knowledge are indicated priori es to improve the procurement process of ADHA. Points for improvement are suggested to achieve a be er ra ng for the en re procurement process. In addi on, a survey of methods used within the ALS care teams to op mize the procurement process might lead to best prac ces, as there are differences in structures, processes, care networks, and care provision between the ALS teams.

The informal caregiver’s well-being is in the interest of both the pa ent as the caregiver.

Therefore, appropriate tailor made support for the caregiver should be one of the aims of the mul disciplinary ALS teams. Our study findings provide clues for caregiver and pa ent support and, with the involvement of caregivers and pa ents, for further development of evidence-based suppor ve interven ons. An ALS caregiver needs assessment tool for clinical purpose might be the next step towards improved care for caregivers.

The establishment of a na onal ALS Care and Research Network within the Netherlands ALS Centre will be an organiza onal founda on for the further development of excellent quality of care and care research in ALS and for intensive interna onal collabora on within the studied care topics.

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Summary Samenva`ng Dankwoord Curriculum Vitae / Por]olio List of publica ons

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SUMMARY In the absence of an effec ve treatment to cure or stop Amyotrophic Lateral Sclerosis (ALS) the mul disciplinary care is aimed at relieving symptoms and maintaining quality of life.

The complex care for pa ents with ALS and their informal caregivers demands con nuous a en on. Current evidence based guidelines for the management of ALS lack sufficient evidence for those care issues that have been iden fied as bo lenecks in previous studies and clinical prac ce: the provision of assis ve devices and home adapta ons (ADHA), the management of disease symptoms, the coordina on of the mul disciplinary care, and the strain of the informal caregiver. This research project was designed to contribute to the improvement of the quality of mul disciplinary ALS care (Chapter 1). The overall aim was to increase our knowledge related to the aforemen oned bo lenecks and offer sugges ons for improvements in ALS care. This research project focuses on both pa ents with ALS and their most important informal caregivers in rela on to the following topics: 1) prognos c factors for the func onal course of the disease, 2) the process of applica on and provision of ADHA, 3) client-centered suppor ve care for pa ents and informal caregivers, and 4) caregiver strain.

ALS is a progressive motor neurone disease characterised by loss of func on of both upper and lower motor neurons, causing muscle weakness of voluntary muscles in the whole body. Pa ents with ALS show a large variability in the rate of progression and the pa ern of muscle weakness within one body region and the progression to other body regions.

In addi on, cogni ve impairments and behavioural changes may precede loss of muscle func on or can occur during the course of the disease. The variability of the disease course hampers a reliable prognos ca on of the rate of disease progression and the consequences of decreased muscle func on for daily life. Consequently, healthcare professionals are also hindered in their ming of the various interven ons related to the occurring disease symptoms, like home adapta ons, assis ve devices (e.g., for speech, mobility), respiratory support, nutri on management and professional home care. Chapter 2 describes the results of a systema c literature search on prognos c factors (sociodemographic, diseasespecific, psychosocial, and comorbid factors) for the rate of func onal decline in pa ents with ALS. Within five bibliographic databases we found thirteen cohort studies inves ga ng prognos c factors for the decline in ALSFRS(-R) in pa ents with an established diagnosis of ALS. The quality of evidence for the associa on of ‘older age at onset’, ‘bulbar site of onset’, ‘a shorter me from symptom onset to diagnosis’ and ‘a lower ALSFRS-Revised baseline score’ with a greater decline in func onal status was low, mainly due to the limited data and inconsistency of results in the small number of studies included.

The current evidence for prognos c factors for the func onal decline in pa ents with ALS is insufficient to develop a reliable predic on model, suitable for daily clinical prac ce.

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‘Data sharing’, jointly gathering and u lizing interna onal clinical and research data, and the future prospect of improved understanding of ALS gene cs, will most probably enable a more reliable prognos ca on of the pa ent’s func onal decline in the near future.

In Chapter 3 we present the results of a na onwide survey to explore experiences of 179 pa ents with ALS with the applica on and provision process of ADHA, and par cularly to iden fy problems during this procurement process. Eighty-nine percent (n=159) of the par cipa ng pa ents indicated experiences with the procurement process and 58 percent of these pa ents reported problems during this process. The most frequently reported problems were delay (42%) and the authori es’ lack of knowledge and understanding of the disease and the consequences for daily func oning (24%). Par cipants indicated these problems as the most urgent to be solved in order to improve services. We conclude that increased awareness of the disease and the consequences of the progression of muscle weakness for the pa ent’s func oning in daily life, less bureaucracy, simplified procedures, less failures and errors in the delivery, empowerment of the pa ents and their caregivers and a proac ve approach by all stakeholders will contribute to an improved realiza on of ADHA. Improvements in prognos ca on of func onal milestones will op mize the ming of proac ve applica on and provision of ADHA. Chapter 4 and 5 present the results from a mixed-methods approach to evaluate the effect of case management in pa ents with ALS and their most important informal caregiver.

In Chapter 4 the results of the cluster randomized controlled trial (RCT) on case management in pa ents with ALS and their most important informal caregiver are presented. We studied the effect of 12 month intensive case management in addi on to usual mul disciplinary ALS care on the pa ents’ QOL, the caregivers’ strain and the QOC for the pa ents and for their caregivers. Par cipa ng mul disciplinary ALS care teams (n=31 clusters) were randomized to interven on or control team. The star ng point for the case management interven on was the ques ons raised by the pa ent and/or the caregiver. The role of the case manager was to provide emo onal support, prac cal support, oral and wri en informa on and advice, to refer par cipants to health care professionals and agencies and to mediate if problems arose between par cipants and health care professionals, agencies or authori es.

One-hundred and thirty-two pa ents and 126 caregivers par cipated the study.

The study demonstrated no significant benefit of case management to the emo onal func oning domain of QOL (pa ent), caregiver strain and QOC (pa ent and caregiver) when added to standard mul disciplinary care compared with standard mul disciplinary care alone. The results of the cluster RCT must be seen within the context of the Dutch ALS care se`ng. Pa ents’ high level of emo onal well-being and the high level of pa ents’ and caregivers’ sa sfac on with ALS care might explain these results. We conclude no na onwide implementa on of our case management model. Our findings of an increasing

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strain for caregivers during the disease course indicates the need for a more prominent role of interven ons targe ng caregivers in future studies. As case management in some other countries with different health care systems is a cer fied profession and contributes to ALS care, our research design might facilitate future research projects in other countries.

During the RCT, pa ents and caregivers differed in their need for informa on, support, treatment, resources and care. Some par cipants did report case management benefits during the trial. Therefore, we explored the pa ents’ care needs and the experiences of pa ents, informal caregivers and health care professionals with case management in a qualita ve study (Chapter 5). This knowledge might contribute to implement improvements in ALS care for pa ents and their caregivers. In this part of our case management study we conducted semi-structured interviews with 10 pa ents, 10 caregivers, 8 rehabilita on medicine consultants and 2 case managers. Subsequently, a focus group (n=20) with pa ents, caregivers and health care professionals who did not par cipate in the RCT was organized. Aim of the focus group was supplementary data collec on to validate the care needs men oned in the interviews by a wider group of pa ents and caregivers and to formulate sugges ons for ALS care improvements.

We derived two main themes from the interviews and focus group: 1) needs for and recep veness to case management and 2) appreciated aspects of case management.

Appreciated aspects of case management were the house calls and ample me for consulta on, proac ve consulta on and emo onal support of the case manager. Four factors appear to influence the need of pa ents and caregivers for and recep veness to case management: subop mal func oning of the ALS care team, a more rapid disease progression, a less suppor ve social network and personal factors (e.g., a passive coping style, less self-sufficient, less self-asser ve, reluctant in asking for help).

This qualita ve study has increased our understanding of the par cular care needs of pa ents with ALS and their caregivers. We conclude that in specific circumstances aspects of case management can be of addi onal value for pa ents and caregivers. ALS teams can consider implementa on of valued aspects of case management (accessibility, ample me, proac ve approach, emo onal support) in the usual mul disciplinary ALS care. Addi onal support might be provided to pa ents with a rapidly progressive disease course, a passive coping style and a poor social network. Tailor made client-centered care is ALS care that best fits the individual care needs of pa ents and their informal caregivers.

Caregiver strain increased significantly during the case management study, which findings were in agreement with earlier studies on caregivers in ALS. Reducing the strain of informal caregivers is in the interest of both caregivers and pa ents. To develop suppor ve interven ons, insight into factors associated with caregiver strain is needed. In Chapter 6 we describe the results of our longitudinal study that aimed to examine the longitudinal

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associa ons between caregiver strain and pa ent’s clinical and psychosocial characteris cs as well as caregiver’s psychosocial characteris cs. Caregiver strain was assessed with the Caregiver Strain Index (CSI) ques onnaire. Poten al pa ent and caregiver factors associated with caregiver strain were sociodemographic factors, anxiety and depression, coping style and quality of care, and pa ent factors emo onal well-being, disease characteris cs and func onal status. Mul level regression analyses showed that caregiver strain was associated with pa ent me-dependent factors physical disability and emo onal well-being and with caregiver me-dependent factors coping style, symptoms of anxiety and experienced quality of ALS care. The mul disciplinary teams involved with the care of pa ents with ALS should be aware of these factors and increase their a en on for the caregiver. Our findings will help guide the development of evidence based suppor ve interven ons that focus on caregiver’s coping style, avoiding distress and on emo onal well-being of the pa ent with ALS. In the General Discussion (Chapter 7), the main findings , strengths and limita ons of this thesis are described. Finally, the implica ons of the study findings for improvements in ALS care are discussed and recommenda ons for future research are given.

As ALS is a heterogeneous disease with a wide variability in disease course, it is difficult to improve the quality of complex mul disciplinary ALS care when it comes to providing the op mal care at the right me for pa ents with ALS and their informal caregivers. Therefore, accurate predic on of the rate of loss of muscle strength and the consequences for daily func oning contributes to op mal care management. Improvements in prognos ca on of the pa ent’s func onal status will also op mize the mely realiza on of ADHA. In spite of the current knowledge on prognos c factors for func onal decline in ALS, at this moment the evidence is insufficient to develop a reliable predic on tool that can support clinical decision making.

From the studies presented in this thesis the following recommenda ons for mul disciplinary ALS care can be made to fit the individual care needs of pa ents and their caregivers: • Provide tailor made, proac ve care to the pa ent and the informal caregiver.

• Discuss the quality of ALS care with the pa ent and informal caregiver.

• In the interest of both the pa ent as the caregiver; take care for the caregiver.

• Stay alert for vulnerable pa ents and caregivers: a rapidly progressive disease course, an inadequate coping style, a less suppor ve or an inadequate social network and being less self-asser ve or less self-sufficient.

• ALS health care professionals should be easy accessible.

• Consider to appoint a central contact person within the mul disciplinary ALS care team.

• Empower the pa ent and caregiver in the procurement process of ADHA.

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Recommenda ons for future research include the development of a reliable model for accurately predic on of the func onal decline to support health care professionals in daily prac ce. The development of an ALS specific composite measure including biomarkers for disease progression (e.g., uric acid, crea nine, blood pressure) for reliable measurement of func onal decline during the en re disease course is needed. An ALS specific instrument for measuring pa ent and caregiver care needs and sa sfac on with care should be developed in consulta on with pa ents and caregivers. Further inves ga on into the development of evidence based suppor ve interven ons that focus on the caregiver’s coping style and controlling distress is needed. In addi on, psychological interven ons targe ng the pa ent’s well-being should be subject to future research. It is suggested to repeat the ADHA study in a mixed methods design to longitudinally examine the effect of the ALS awareness campaign and the implementa on of an ALS informa on package. The implementa on of emergency procedures for indica on and delivery of ADHA is necessary to achieve mely delivery of ADHA. Future (inter-)na onal collabora ve research is needed to come to evidence-based improvements in mul disciplinary care. The current development of establishing a na onal ALS Care and Research Network within the Netherlands ALS Center will be an organiza onal founda on for the further development of excellent quality of care and care research in ALS and for intensive (inter-)na onal collabora on within the studied care topics.

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SAMENVATTING Momenteel is er nog geen effec eve behandeling om Amyotrofische Laterale Sclerose (ALS) te genezen of om de ziekte te stoppen. Daarom vraagt de complexe zorg voor pa ënten met ALS en hun mantelzorgers con nue aandacht.

In de huidige behandelrichtlijnen voor ALS ontbreekt het aan voldoende bewijs voor die aspecten van de ALS zorg die in eerdere studies en in de klinische prak jk als knelpunten zijn geïden ficeerd: de verstrekking van hulpmiddelen en woningaanpassingen (H&WA), de behandeling van symptomen van de ziekte, de coördina e van de mul disciplinaire zorg, en de overbelas ng van de mantelzorger. Het doel van dit proefschri{ was om onze kennis over de bovengenoemde knelpunten te vergroten en om van hieruit aanbevelingen te kunnen doen voor verbeteringen in de ALS zorg. Het onderzoek bij pa ënten met ALS en hun belangrijkste mantelzorgers richt zich op de volgende thema’s: 1) prognos sche factoren voor het func onele verloop van de ziekte, 2) het proces van de aanvraag en de verstrekking van H&WA, 3) cliënt gecentreerde, ondersteunende zorg voor pa ënten en mantelzorgers, en 4) de overbelas ng van de mantelzorger.

ALS is een progressieve motorneuron ziekte, gekenmerkt door verlies van func e van zowel het centrale motor neuron als het perifere motor neuron, met als gevolg spierzwakte van willekeurige spieren in het hele lichaam. Pa ënten met ALS tonen een grote varia e in de mate van progressie en in het patroon van de spierzwakte binnen één lichaamsregio en in de uitbreiding van de spierzwakte naar de andere lichaamsdelen. Naast verlies van spierfunc e kunnen ook cogni eve stoornissen en gedragsveranderingen optreden. De grote varia e in het ziektebeloop maakt het las g een betrouwbare voorspelling te doen van de snelheid van de progressie en van de gevolgen van de verminderde spierfunc e voor het dagelijks leven. Voor een adequate ming van het inze en van maatregelen en voorzieningen, zoals woningaanpassingen, hulpmiddelen (bijvoorbeeld voor de spraak of de mobiliteit), ademhalingsondersteuning, voedingsmaatregelen en professionele thuiszorg, is inzage nodig in de factoren die samenhangen met de ziekteprogressie. Hoofdstuk 2 beschrij{ de resultaten van een systema sch literatuuronderzoek naar prognos sche factoren (sociodemografische, ziekte-specifieke, psychosociale en comorbide factoren) voor de func onele achteruitgang bij pa ënten met ALS. Binnen vijf bibliografische databanken vonden we der en cohort studies naar prognos sche factoren voor de daling van de ALSFRS(Revised) score bij pa ënten met een vastgestelde diagnose ALS. De kwaliteit van het bewijs voor de associa e van ‘een hogere lee{ijd bij aanvang van de ziekte’, ‘een bulbair begin van de ziekte’, ‘een kortere jd tussen aanvang van de symptomen en de diagnose’ en ‘een lagere ALSFRS-Revised beginscore’ met een sterkere afname van de func onele status was laag, met name als gevolg van de beperkte gegevens en de inconsisten e van de resultaten in het kleine aantal geïncludeerde studies.

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Het huidige bewijs voor prognos sche factoren voor de func onele achteruitgang bij pa ënten met ALS is onvoldoende om een betrouwbaar voorspellingsmodel, geschikt voor de dagelijkse klinische prak jk, te ontwikkelen. ‘Data sharing’, het delen van (inter-) na onale klinische- en onderzoeksgegevens, en de vooruitzichten van een beter begrip van de gene sche aspecten van ALS, zullen waarschijnlijk in de nabije toekomst een meer betrouwbare voorspelling van de func onele achteruitgang van de pa ënt mogelijk maken.

In Hoofdstuk 3 beschrijven we de resultaten van een landelijk onderzoek naar de ervaringen van 179 pa ënten met ALS met de aanvraag en verstrekking van H&WA, en in het bijzonder naar de ervaren problemen jdens de aanvraag. Negenentach g procent (n = 159) van de deelnemende pa ënten hee{ aangegeven een aanvraag voor H&WA te hebben gedaan en 58 procent van deze pa ënten gaf aan problemen te hebben ervaren jdens het aanvraag proces. De meest frequent gemelde problemen waren de lange jdsduur (42%) en het gebrek aan kennis van de ziekte en de gevolgen voor het dagelijks func oneren bij de autoriteiten (24%). De deelnemers gaven aan dat deze twee problemen beslist opgelost moeten worden om de dienstverlening te verbeteren. We concluderen dat de toegenomen bewustwording van de ziekte en de gevolgen van de progressie van de spierzwakte voor het func oneren van de pa ënt in het dagelijks leven, minder bureaucra e, vereenvoudigde procedures, minder missers en fouten bij de levering, empowerment van de pa ënten en hun mantelzorgers en een proac eve aanpak door alle belanghebbenden zullen bijdragen aan een verbeterde verstrekking van H&WA. Verbeteringen in de voorspelling van de func onele mijlpalen zal de ming van de proac eve aanvraag en verstrekking van H&WA op maliseren.

Hoofdstuk 4 en 5 beschrijven de resultaten van een “mixed methods” aanpak om effecten van zorg coaching (case management) bij pa ënten met ALS en hun belangrijkste mantelzorger te evalueren. In hoofdstuk 4 worden de resultaten van de cluster gerandomiseerde en gecontroleerde studie (cluster RCT) naar zorg coaching bij pa ënten met ALS en hun belangrijkste mantelzorger gepresenteerd. We bestudeerden het effect van 12 maanden intensieve zorg coaching toegevoegd aan de gebruikelijke mul disciplinaire ALS zorg op de kwaliteit van leven (KvL) van pa ënten, de zorglast van de mantelzorgers en de kwaliteit van zorg (KvZ) voor de pa ënten en voor hun mantelzorgers. Deelnemende mul disciplinaire ALS behandelteams (n = 31) werden gerandomiseerd naar interven e of controle team. Het uitgangspunt voor de zorgcoach interven e waren de vragen van de pa ënt en/of de mantelzorger. De rol van de zorgcoach was het geven van emo onele ondersteuning, prak sche ondersteuning, het verstrekken van mondelinge en schri{elijke informa e en advies, de deelnemers verwijzen naar zorg professionals, organisa es en instan es, en bemiddelen als er problemen zouden ontstaan tussen deelnemers en zorg professionals, organisa es of instan es.

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Honderdtweeënder g pa ënten en 126 mantelzorgers deden mee aan het onderzoek.

De resultaten lieten geen significant voordeel zien van zorg coaching, toegevoegd aan standaard mul disciplinaire ALS zorg, op het KvL domein emo oneel func oneren (pa ënt), de zorglast van de mantelzorger en de KvZ (pa ënt en mantelzorger) in vergelijking met alleen standaard mul disciplinaire ALS zorg. Deze bevindingen moeten worden gezien in de context van de Nederlandse ALS zorg. De rela ef lage scores (=betere KvL) op het KvL domein emo oneel func oneren en de hoge mate van tevredenheid van de pa ënten en de mantelzorgers met de ALS zorg kunnen een verklaring zijn voor deze resultaten. We concluderen hieruit dat landelijke implementa e van ons case management model niet gewenst is. Onze bevindingen van een toenemende zorglast van mantelzorgers jdens het ziekteverloop wijst op de noodzaak voor een prominentere rol van interven es gericht op mantelzorgers in toekoms g onderzoek. Aangezien case management, de interna onale term voor zorg coaching, in een aantal andere landen met verschillende gezondheidszorg systemen is ingevoerd in de ALS zorg, kan ons onderzoek mogelijk toekoms ge onderzoeksprojecten in andere landen bevorderen.

Tijdens de RCT bleek dat de pa ënten en mantelzorgers verschillende behoe{en hadden aan informa e, ondersteuning, behandeling, hulpbronnen en zorg. Sommige deelnemers gaven aan profijt te hebben van zorg coaching. Om inzicht te krijgen in de zorgbehoe{en van pa ënten en in de ervaringen van de pa ënten, mantelzorgers en zorg professionals met zorg coaching hebben we een kwalita eve studie uitgevoerd (Hoofdstuk 5). Deze informa e kan bijdragen aan de implementa e van verbeteringen in de ALS zorg voor pa ënten en mantelzorgers. In dit deel van ons zorgcoach onderzoek hebben we semi-gestructureerde interviews gehouden met 10 pa ënten, 10 mantelzorgers, 8 revalida eartsen en 2 zorgcoaches. Vervolgens werd een focusgroep (n=20) georganiseerd met pa ënten, mantelzorgers en zorg professionals die niet deelnamen aan de RCT. Doel van de focusgroep was aanvullende gegevens verzamelen om de zorgbehoe{en die genoemd waren in de interviews te valideren door een bredere groep pa ënten en mantelzorgers en om sugges es voor verbeteringen in de ALS zorg te formuleren.

Uit de interviews en de focusgroep hebben we twee hoofdthema’s afgeleid: 1) gewaardeerde aspecten van zorg coaching en 2) behoe{e aan en ontvankelijkheid voor zorg coaching. Gewaardeerde aspecten van zorg coaching waren de huisbezoeken en voldoende jd voor overleg, proac ef adviseren en emo onele ondersteuning door de zorg coach. Vier factoren lijken van invloed op de behoe{e aan en de ontvankelijkheid voor zorg coaching van pa ënten en mantelzorgers: subop maal func oneren van het ALS behandelteam, een snellere progressie van de ziekte, een minder ondersteunend sociaal netwerk, en persoonlijke factoren zoals een passieve coping s jl, minder ona­ankelijk zijn, minder asser ef zijn, en terughoudendheid zijn in het vragen om hulp.

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Deze kwalita eve studie hee{ ons inzicht in de specifieke zorgbehoe{en van pa ënten met ALS en hun mantelzorgers vergroot. We concluderen dat in bepaalde omstandigheden aspecten van zorg coaching van toegevoegde waarde voor pa ënten en mantelzorgers kunnen zijn. ALS teams kunnen overwegen om gewaardeerde aspecten van zorg coaching (bereikbaarheid, voldoende jd, proac eve aanpak, emo onele ondersteuning) in de gebruikelijke mul disciplinaire ALS zorg te implementeren. Extra ondersteuning zou aangeboden kunnen worden aan pa ënten met een snel progressief ziekte verloop, een passieve coping s jl en een beperkt sociaal netwerk. Cliënt gecentreerde zorg is ALS zorg die het beste past bij de individuele zorgbehoe{e van pa ënten en hun mantelzorgers.

Het zorgcoach onderzoek liet zien dat de zorglast van mantelzorgers over het jaar waarin de deelnemers gevolgd werden, significant toenam. Een bevinding in overeenstemming met eerdere onderzoeken bij mantelzorgers van pa ënten met ALS. Het verminderen van de zorglast van de mantelzorgers is in het belang van zowel de mantelzorgers als van de pa ënten. Om ondersteunende interven es te kunnen ontwikkelen is inzicht nodig in factoren die samenhangen met de zorglast van mantelzorgers. In hoofdstuk 6 beschrijven we de resultaten van onze longitudinale studie die als doel had om de longitudinale associa es tussen de zorglast van de mantelzorger en klinische en psychosociale kenmerken van de pa ënt alsmede psychosociale kenmerken van de mantelzorger te onderzoeken. De zorglast van de mantelzorger werd gemeten met de Caregiver Strain Index (CSI) vragenlijst. Pa ënt en mantelzorger factoren (sociodemografische factoren, angst en depressie, coping s jl en ervaren kwaliteit van zorg van zowel pa ënt als mantelzorger, naast de pa ënt factoren emo oneel welbevinden, ziekte kenmerken en func onele status) werden onderzocht op samenhang met de zorglast van de mantelzorger. Mul level regressie analyses toonden aan dat de zorglast van de mantelzorger was geassocieerd met de pa ënt factoren ‘fysieke beperkingen’ en ‘emo oneel welbevinden’ en met de mantelzorg factoren ‘coping s jl’, ‘symptomen van angst’ en ‘ervaren kwaliteit van ALS zorg’. De mul disciplinaire teams, betrokken bij de zorg voor pa ënten met ALS, zouden zich bewust moeten zijn van deze factoren en zouden hun aandacht voor de mantelzorger moeten vergroten. Onze bevindingen kunnen bijdragen aan de ontwikkeling van ondersteunende interven es gericht op de coping s jl van de mantelzorger, het verminderen van angst bij de mantelzorger en op het emo oneel welbevinden van de pa ënt met ALS. In de algemene discussie (hoofdstuk 7) zijn de belangrijkste bevindingen, de sterke punten en de beperkingen van dit proefschri{ beschreven. Tot slot worden de implica es van de onderzoeksbevindingen voor verbeteringen in de ALS zorg besproken en worden aanbevelingen voor toekoms g onderzoek gedaan.

Aangezien ALS een heterogene aandoening is met grote varia e in het ziekteverloop, blij{ het op het juiste moment aanbieden van op male zorg voor pa ënten met ALS en

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hun mantelzorgers een grote uitdaging voor professionals in de ALS zorg. Derhalve zal een nauwkeurige voorspelling van het verlies van spierkracht en de gevolgen voor het dagelijks func oneren bijdragen bij aan op maal zorgmanagement. Verbeteringen in de voorspelling van de func onele status van de pa ënt zal ook het jdig realiseren van H&WA op maliseren.

Ondanks de huidige kennis over prognos sche factoren voor de func onele achteruitgang bij pa ënten met ALS is er op dit moment onvoldoende bewijs om een betrouwbaar voorspellingsmodel te ontwikkelen dat kan ondersteunen bij de klinische besluitvorming.

Vanuit de onderzoeken die in dit proefschri{ gepresenteerd worden kunnen de volgende aanbevelingen voor de mul disciplinaire ALS zorg, passend bij de individuele zorgbehoe{e van de pa ënten en hun mantelzorgers, worden gedaan: • Biedt de pa ënt en de mantelzorger proac eve zorg op maat.

• Bespreek de kwaliteit van de ALS zorg met de pa ënt en de mantelzorger.

• In het belang van zowel de pa ënt als de mantelzorger; zorg voor de mantelzorger.

• Blijf alert op kwetsbare pa ënten en mantelzorgers: een snel progressief ziekteverloop, een inadequate coping s jl, een minder ondersteunend of een ontoereikend sociaal netwerk en minder asser eve of minder zelfvoorzienende pa ënten en mantelzorgers.

• ALS zorg professionals moeten gemakkelijk toegankelijk en bereikbaar zijn.

• Overweeg om een centraal aanspreekpunt binnen het mul disciplinaire ALS behandelteam te benoemen.

• Empower de pa ënt en de mantelzorger in het aanvraagproces van H&WA. Aanbevelingen voor toekoms g onderzoek zijn de ontwikkeling van een betrouwbaar model voor het nauwkeurig voorspellen van de func onele achteruitgang van de pa ënt met ALS om zorgprofessionals in de dagelijkse prak jk te ondersteunen. De ontwikkeling van een ALSspecifiek samengesteld mee nstrument met inbegrip van biomarkers voor ziekteprogressie (bijvoorbeeld: urinezuur, crea nine, bloeddruk) voor een betrouwbare me ng van de func onele achteruitgang gedurende het gehele ziekteverloop is nodig. ALS-specifieke vragenlijsten voor het meten van de zorgbehoe{e van de pa ënt en de mantelzorger en de tevredenheid van de pa ënt en de mantelzorger met de zorg zouden ontwikkeld moeten worden in overleg met pa ënten en mantelzorgers. Nader onderzoek naar de ontwikkeling van evidence-based ondersteunende interven es die zich richten op de coping-s jl van de mantelzorger en het verminderen van angstklachten bij de mantelzorger is nodig.

Daarnaast behoeven psychologische interven es gericht op het emo oneel welbevinden van de pa ënt in toekoms g onderzoek te worden onderzocht. Voorgesteld wordt om het H&WA onderzoek in een ‘mixed methods’ onderzoeksproject te herhalen om longitudinaal het effect van de ALS bewustzijn en bekendheid campagne en de implementa e van een ALS informa epakket te onderzoeken. De implementa e van spoedprocedures voor de aanvraag en levering van H&WA is nodig om jdige verstrekking van H&WA te realiseren.

Toekoms g (inter-)na onaal gezamenlijk onderzoek is nodig om tot evidence-based verbeteringen in de mul disciplinaire ALS zorg te komen. De huidige ontwikkeling van de

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oprich ng van een na onaal ALS Zorg en Onderzoek Netwerk binnen het ALS Centrum Nederland vormt een organisatorische basis voor de verdere ontwikkeling van ALS zorg onderzoek en excellente kwaliteit van ALS zorg en voor intensieve (inter-)na onale samenwerking binnen de onderzochte zorg onderwerpen.

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DANKWOORD Dit proefschri{ is tot stand gekomen dankzij de inspanningen en ondersteuning van AMC, VUmc en UMCU collega’s. Allen daarvoor heel erg bedankt.

Dit onderzoeksproject is opgezet voor pa ënten met ALS en hun belangrijkste mantelzorgers. Alle pa ënten en mantelzorgers die deelnamen aan de onderzoeken bedank ik voor de jd en energie die ze hebben besteed aan het invullen van de vragenlijsten en de gesprekken met de onderzoekers en de zorgcoaches.

Leonard van den Berg bedank ik voor het verkrijgen van de subsidie in het kader van het ZonMw project Pallia eve zorg, waardoor het zorgcoach onderzoek mogelijk werd. Frans Nollet en Leonard van den Berg boden mij de kans om dit onderzoekstraject te doorlopen, hartelijk dank daarvoor. Leonard van den Berg, Frans Nollet, Jan Veldink en Anita Beelen als projectgroep leden bedank ik voor hun essen ële bijdrage aan de opzet en de uitwerking van de onderzoeken. Tineke Abma, Minne Bakker en Karin Schipper bedank ik voor de uitvoering van het kwalita eve onderzoek. De wetenschappelijke publica es waren niet tot stand gekomen zonder de construc eve, inhoudelijke bijdrage van alle mede auteurs: Frans Nollet, Leonard van den Berg, Jan Veldink, Anita Beelen, Hepke Grupstra, Tineke Abma, Minne Bakker, Karen Schipper en Sandra de Morée. Speciaal bedank ik Anita Beelen voor haar s mulerende, opbouwende, al jd posi eve en waar nodig ook vermanende commentaar op alles wat in de afgelopen jaren op mijn onderzoekspad kwam.

Tot slot bedank ik Jeanne, Jort, Thomas, Ludo en Leandra, die me kri sch en soms verbaasd bleven volgen, een s mulans voor mij waren en, indien nodig, ervoor zorgden dat ik weer even rela veerde.

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Curriculum Vitae / Por olio

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CURRICULUM VITAE / PORT FOLIO Curriculum Vitae Huub Creemers was born in Venray, the Netherlands, on the 23rd of November, 1956. In 1975 Huub graduated from secondary school (VWO−Atheneum) at the Boschveld College in Venray.

In 1980 Huub started his bachelor study on Occupa onal Therapy at the Occupa onal Therapy College in Weesp, the Netherlands. A{er gradua ng as an occupa onal therapist in 1984 Huub worked as an occupa onal therapist in a rehabilita on center, a public hospital and the Academic Medical Center (AMC) in Amsterdam. Between 1994 and 2003 Huub worked as a rehabilita on advisor for several rehabilita on consul ng and sales companies.

Since February 2003 Huub is employed as occupa onal therapist at the Department of Rehabilita on of the AMC where he par cipates in the mul disciplinary rehabilita on team that supports pa ents with ALS. In 2005 Huub started his master study ‘Evidence Based Prac ce’ at the University of Amsterdam. A{er gradua on in 2008 Huub started his PhD project on op mizing quality of care for pa ents with Amyotrophic Lateral Sclerosis (ALS) and their informal caregivers.

Besides patent care and research, Huub performs substan ve suppor ve ac vi es for the Netherlands ALS Center that was established in November 2003. The Netherlands ALS Center is a center of exper se for care, research and educa on on ALS, PSMA and PLS. It is a collabora on between the Departments of Neurology and Rehabilita on of the University Medical Center Utrecht (UMCU) and the AMC Amsterdam.

Huub lives with Jeanne Arts, together they are parents of Jort, Thomas, Ludo and Leandra.

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Curriculum Vitae / Por olio

Por olio PhD student: PhD period: PhD supervisors:

Huub Creemers January 2008 – December 2015 Prof. dr. F. Nollet Prof. dr. L.H. van den Berg

1. PHD TRAINING Year

Workload (Hours / ECTS)

2011

34 / 1.2

2011

42 / 1.5

2011

31 / 1.1

2011

54 / 1.9

2011

24 / 0.9

2012

60 / 2.1

2010

8 / 0.2

2011

4 / 0.1

‘The future today’. Symposium on technology innova ons in the care for pa ents with neuromuscular diseases. The Dutch Neuromuscular Disease Organisa on. Veldhoven

2012

4 / 0.1

‘10 jaar ALS Centrum; van na onaal naar mondiaal’. Landelijk Mul disciplinair Symposium ALS Centrum Nederland. Utrecht Congress ‘Recent developments in policy, field and research on Dutch Health care legisla on’. Julius Center UMC Utrecht Workshops Mo va onal Interviewing. Amsterdam School of Health Professions. Amsterdam PRESENTATIONS ‘The effec veness of case management in the treatment of pa ents with Amyotrophic Lateral Sclerosis (ALS) and their caregivers’.

Revalida e Advies Centra Neuromusculaire Aandoeningen Spierziekten Nederland. Baarn. [oral] ‘Onderzoek ALS Hulpmiddelen’. ALS Centrum Nederland. UMC Utrecht [oral]

2013

8 / 0.2

2013

6 / 0.2

2014

16 / 0.6

2008

14 / 0.5

2008

14 / 0.5

GENERAL COURSES Basic course Prac cal Biosta s cs. AMC Graduate School for Medical Sciences, UVA Amsterdam Scien fic Wri ng in English for Publica on. AMC Graduate School for Medical Sciences, UVA Amsterdam Basic Course in Legisla on and Organiza on for Clinical Researchers.

AMC Graduate School for Medical Sciences, UVA Amsterdam Basic Course Qualita ve Health Research. AMC Graduate School for Medical Sciences, UVA Amsterdam Oral Presenta on in English. AMC Graduate School for Medical Sciences, UVA Amsterdam Advanced Topics in Biosta s cs. AMC Graduate School for Medical Sciences, UVA Amsterdam SPECIFIC COURSES ‘AL(le)S uit de kast’. Landelijk Mul disciplinair Symposium ALS Centrum Nederland. Ede AMC Spinoza Master Class Gordon Gya . ‘Meaningful change in quality of life scores: can it be assessed in pa ents with amyotrophic lateral sclerosis?’ Department of Medical Psychology, AMC Amsterdam

156

Curriculum Vitae / Por olio ‘De meerwaarde van intensieve zorg coaching in de behandeling en begeleiding van pa ënten met Amyotrofische Laterale Sclerose (ALS)’.

Projectleidersbijeenkomst Programma Pallia eve Zorg ZonMw. Den Haag. [oral] ‘Een zorgcoach voor mensen met ALS’. Landelijke Wetenschappelijke bijeenkomst ALS Centrum Nederland. UMC Utrecht. [oral] ‘Zorgcoach onderzoek’ Revalida e Advies Centra Neuromusculaire Aandoeningen Spierziekten Nederland. Baarn. [oral] ‘De meerwaarde van intensieve zorg coaching in de behandeling en begeleiding van pa ënten met Amyotrofische Laterale Sclerose (ALS)’.

2e Na onaal Congres Pallia eve Zorg. ZonMw sessie Programma Pallia eve Zorg. Lunteren. [oral] ‘To improve living with ALS/MND: the provision of assis ve devices and environmental adapta ons’. 19th Interna onal Symposium on ALS/ MND. Birmingham, United Kingdom. [poster]

2008

14 / 0.5

2008

14 / 0.5

2008

14 / 0.5

2008

14 / 0.5

2008

14 / 0.5

‘Zorgcoach onderzoek’. Research bespreking Afdeling Revalida e. AMC 2008 Amsterdam. [oral] ‘De ALS Zorgcoach; een meerwaarde in de ALS zorg?’. Regionale 2009 Refereerbijeenkomsten Revalida eafdelingen regio Noord-Holland.

AMC Amsterdam. [oral]

14 / 0.5

‘De ALS Zorgcoach; een meerwaarde in de ALS zorg?’. S ch ng Revalida e Ziekenhuizen Noord-Holland. Medisch Centrum Alkmaar. [oral]

2009

14 / 0.5

‘De ALS Zorgcoach; een meerwaarde in de ALS zorg?’. Afdeling 2009 Neurologie UMCG. UMC Groningen. [oral] ‘Zorgcoach onderzoek’. Research bespreking Afdeling Revalida e. AMC 2010 Amsterdam. [oral] ‘De meerwaarde van intensieve zorg coaching van pa ënten met 2010 Amyotrofische Laterale Sclerose (ALS)’. Projectleidersbijeenkomst Pallia eve Zorg ZonMw. Den Haag. [oral]

14 / 0.5

‘De meerwaarde van intensieve zorg coaching van pa ënten met 2010 Amyotrofische Laterale Sclerose (ALS)’. 3e Na onaal congres Pallia eve Zorg. ZonMw sessie Programma Pallia eve Zorg. Lunteren. [oral]

14 / 0.5

‘Zorgcoach onderzoek’. Revalida e Advies Centra Neuromusculaire Aandoeningen Spierziekten Nederland. Baarn. [oral] ‘Het zorgcoach onderzoek’. Landelijke Wetenschappelijke bijeenkomst ALS Centrum Nederland. RadboudUMC. Nijmegen. [oral] ‘Het zorgcoach onderzoek’. Research bespreking Afdeling Revalida e AMC. Amsterdam. [oral] ‘Pa ents’ and Caregivers’ Perspec ve on Case Management in ALS Care’. 22nd Interna onal Symposium on ALS/MND in Sydney, Australia. [poster]

2011

14 / 0.5

2011

14 / 0.5

2011

14 / 0.5

2011

14 / 0.5

‘A Randomized Controlled Trial on the Effect of Case Management on 2011 Pa ents’ Quality of Life and Caregiver burden in ALS’. 22nd Interna onal Symposium on ALS/MND in Sydney, Australia. [poster]

14 / 0.5

‘De meerwaarde van intensieve zorg coaching in de behandeling en 2012 begeleiding van pa ënten met Amyotrofische Laterale Sclerose (ALS)’.

Projectleidersbijeenkomst Programma Pallia eve Zorg ZonMw. Utrecht. [oral]

14 / 0.5

14 / 0.5

14 / 0.5 14 / 0.5

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157

Curriculum Vitae / Por olio ‘De meerwaarde van intensieve zorg coaching in de behandeling en begeleiding van pa ënten met Amyotrofische Laterale Sclerose (ALS)’.

Presenta e eindrapportage ZonMw. Utrecht. [oral]

2012

14 / 0.5

‘Does case management improve quality of ALS care in the Netherlands?’. Annual Congress 2012 of the Netherlands Society of Physical and Rehabilita on Medicine in Noordwijkerhout, the Netherlands. [oral] ‘Het zorgcoach onderzoek’. Research bespreking Afdeling Revalida e AMC Amsterdam. [oral] ‘De meerwaarde van intensieve zorg coaching in de behandeling en begeleiding van pa ënten met Amyotrofische Laterale Sclerose (ALS)’. Spierziektecongres door Spierziekten Nederland en het Beatrix Spierfonds. Veldhoven. [poster] ‘Zorgcoaching; ervaringen van pa ënten met ALS en hun mantelzorgers’. Spierziektecongres door Spierziekten Nederland en het Beatrix Spierfonds. Veldhoven. [poster]

2012

14 / 0.5

2012

14 / 0.5

2012

14 / 0.5

2012

14 / 0.5

‘Case management as an adjunct to mul disciplinary ALS care in the Netherlands; a mixed methods approach’. Wetenschappelijke bijeenkomst ALS Centrum Nederland, AMC Amsterdam. [oral]

2012

14 / 0.5

‘Het zorgcoach onderzoek’ Bijeenkomst Landelijke Werkgroep nurse prac oners NMA, UMC Utrecht. [oral] ‘Case management as an adjunct to mul disciplinary care for ALS pa ents and their primary caregivers in the Netherlands: no effect on quality of life or caregiver strain’. 23rd Interna onal Symposium on ALS/ MND Symposium in Chicago, USA. [oral] ‘Mul disciplinaire ALS Zorg; kan het beter?’. Landelijk mul disciplinair symposium ALS Centrum Nederland. Utrecht. [oral] ‘Ervaringen van mensen met ALS, hun naasten en professionals met de zorgcoach’. Spierziektecongres door Spierziekten Nederland en het Beatrix Spierfond. Veldhoven. [poster]

2012

14 / 0.5

2012

14 / 0.5

2013

14 / 0.5

2013

14 / 0.5

‘Zorgcoaching bij ALS’ Regionale Refereeravonden Revalida egeneeskunde. AMC Amsterdam. [oral] ‘Overbelas ng van mantelzorgers van mensen met ALS’.

Spierziektecongres door Spierziekten Nederland en het Beatrix Spierfonds. Veldhoven. [poster]

2013

14 / 0.5

2014

14 / 0.5

‘Prognos c factors for the course of func onal status of pa ents with 2014 ALS: a systema c review’. 25th Interna onal Symposium on ALS/MND in Brussels, Belgium. [poster]

14 / 0.5

‘Factors related to caregiver strain in ALS’. Research bespreking Afdeling 2015 Revalida e AMC Amsterdam. [oral] ‘Overbelas ng van mantelzorgers met ALS’. Major Donor Dag ALS 2015 Centrum Nederland en S ch ng ALS Centrum Nederland. UMC Utrecht. [oral]

14 / 0.5

‘Overbelas ng van mantelzorgers met ALS’. Open Dag ALS Centrum Nederland. UMC Utrecht. [oral] (INTER-)NATIONAL CONFERENCES 19th Interna onal Symposium on ALS/MND in Birmingham, United Kingdom.

2015

4 / 0.1

2008

24 / 0.9

158

14 / 0.5

Curriculum Vitae / Por olio 6st Annual Allied Professionals Forum on ALS/MND in Birmingham, United Kingdom.

21st Interna onal Symposium on ALS/MND in Orlando, USA. 8th Annual Allied Professionals Forum on ALS/MND in Orlando, USA. 22nd Interna onal Symposium on ALS/MND in Sydney, Australia.

9th Annual Allied Professionals Forum on ALS/MND in Sydney, Australia.

23rd Interna onal Symposium on ALS/MND in Chicago, USA. 10th Annual Allied Professionals Forum on ALS/MND in Chicago, USA. 25th Interna onal Symposium on ALS/MND in Brussels, Belgium.

12th Annual Allied Professionals Forum on ALS/MND in Brussels, Belgium.

2nd European polio conference, June 25–27, 2014, Amsterdam, the Netherlands.

OTHER Deelname ZonMw project ‘De pa ënt als informa edrager’.

Spierziekten Nederland. Baarn.

AMC Spinoza Master Class Gordon Gya . ‘Meaningful change in quality of life scores: can it be assessed in pa ents with amyotrophic lateral sclerosis?’ Department of Medical Psychology, AMC Amsterdam. [oral]

2008

8 / 0.2

2010 2010 2011 2011 2012 2012 2014 2014

24/ 0.9 8 / 0.2 24 / 0.9 8 / 0.2 24 / 0.9 8 / 0.2 24 / 0.9 8 / 0.2

2014

24 / 0.9

2008

8 / 0.2

2011

20 / 0.7

Deelname ALS Kennispla]orm ALS Centrum Nederland en S ch ng ALS 2012 Centrum Nederland. UMC Utrecht.

De ervaringen met mantelzorg jdens het zorgcoach onderzoek.

2013 Bijdrage Contact op Maat t.b.v. leden met ALS/HSP/PSMA/PLS van Spierziekten Nederland.

4 / 0.1 16 / 0.5

Project zorgcoach bij ALS. Bijdrage Contact op Maat t.b.v. leden met 2013 16 / 0.5 ALS/HSP/PSMA/PLS van Spierziekten Nederland.

Deelname Onderzoek Netwerk Ergotherapie voor de regio Amsterdam 2011-2014 16 / 0.5 (ONE-Amsterdam) periode 2011-2014. Amsterdam.

‘Pa ents’, caregivers’ and professionals’ perspec ves on case 2013 10 / 0.3 management in ALS’. 24th Interna onal Symposium on ALS/MND in Milan, Italy. [poster] ‘Factors related to strain experienced by caregivers of pa ents with ALS’. 9th World congress of the Interna onal Society of Physical and Rehabilita on Medicine. June 2015. Berlin, Germany. [poster]

2015

8 / 0.2

‘Belas ng van mantelzorgers van mensen met ALS’. Spierziektecongres 2015 door Spierziekten Nederland en het Beatrix Spierfonds, september 2015. Veldhoven. [poster]

8 / 0.2

CV /P

159

List of publica ons

160

List of publica ons

LIST OF PUBLICATIONS / PEER REVIEWED JOURNALS 1.

The provision of assis ve devices and home adapta ons to pa ents with ALS in the Netherlands: pa ents’ perspec ves. Creemers H, Beelen A, Grupstra H, Nollet F, van den Berg LH. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Sep;15(5-6):4205.

This is the authors accepted manuscript of an ar cle published as the version of record in Amyotrophic Lateral Sclerosis and Frontotemporal Degenera on 2014. The final publica on is available at the Taylor & Francis Group via h p://dx.doi.org/10.3109/21 678421.2014.920031

2.

Cluster RCT of case management on pa ents’ quality of life and caregiver strain in ALS. Creemers H, Veldink JH, Grupstra H, Nollet F, Beelen A, van den Berg LH. Neurology.

2014 Jan 7;82(1):23-31.

The final publica on is available at Wolters Kluwer Health via h p://www.neurology. org/content/82/1/23.full.pdf+html

3.

Need and value of case management in mul disciplinary ALS care: A qualita ve study on the perspec ves of pa ents, spousal caregivers and professionals. Bakker M, Creemers H, Schipper K, Beelen A, Grupstra H, Nollet F, Abma T. Amyotroph Lateral Scler Frontotemporal Degener. 2015 Jun;16(3-4):180-6.

This is the authors accepted manuscript of an ar cle published as the version of record in Amyotrophic Lateral Sclerosis and Frontotemporal Degenera on 2015. The final publica on is available at the Taylor & Francis Group via h p://dx.doi.org/10.3109/21 678421.2014.971811

4.

Prognos c factors for the course of func onal status of pa ents with ALS: a systema c review. Creemers H, Grupstra H, Nollet F, van den Berg LH, Beelen A. Prognos c factors for the course of func onal status of pa ents with ALS: a systema c review. J Neurol.

2015 Jun;262(6):1407-23.

The final publica on is available at Springer via h p://dx.doi.org/10.1007/s00415-0147564-8

5.

Factors related to caregiver strain in ALS: a longitudinal study. Creemers H, de Morée S, Veldink JH, Nollet N, van den Berg LH, Anita Beelen. J Neurol Neurosurg Psychiatry. 2015 Sep 4. doi: 10.1136/jnnp-2015-311651. [Epub ahead of print] The final publica on is available at the BMJ Publishing Group Ltd via h p://jnnp.bmj. com/content/early/2015/09/04/jnnp-2015-311651

161

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Huub Creemers

Optimizing quality of care for patients with ALS and their family caregivers

Uitnodiging Voor het bijwonen van de openbare verdediging van het proefschrift

Optimizing quality of care for patients with ALS and their family caregivers

Optimizing quality of care for patients with ALS and their family caregivers door Huub Creemers

op woensdag 13 januari 2016 om 14.00 uur in de Agnietenkapel Oudezijds Voorburgwal 231 te Amsterdam Na afloop bent u van harte welkom op de receptie aldaar Huub Creemers Simonshavenstraat 19 1107 VA Amsterdam huub.creemers@planet.nl

Paranimfen Antoinette Vullings-Creemers Francien Haex

Huub Creemers