Proefschrift Creemers

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

Huub Creemers

Op

timizin

g q

uality

of care

for p

atien

ts with

AL

S an

d th

eir fam

ily care

give

rsH

uu

b C

ree

me

rs

Voor het bijwonen van de openbare verdediging van het

proefschrift

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 CreemersSimonshavenstraat 191107 VA Amsterdam

[email protected]

Uitnodiging

Optimizing quality of care for patients with ALS

and their family caregivers

Paranimfen

Antoinette Vullings-CreemersFrancien Haex

door Huub Creemers

Op� mizing quality of care for pa� ents with ALS


Huub Creemers

Doctoral thesis, University of Amsterdam, The Netherlands

ISBN: 978-94-6233-182-2Copyright: ©2016 by Huub Creemers. All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system or transmi� ed in any form or by any means without the wri� en permission from the author or publishers of the included scien� fi c papers. Cover design: Rachel van Esschoten, DivingDuck Design (www.divingduckdesign.nl).Photo’s cover: iStock (Calgary, Alberta, Canada) and John from Ambient Photo (Wall, New Jersey, USA).Layout: Gildeprint − The Netherlands.Printed by: Gildeprint − The Netherlands.

Op� mizing quality of care for pa� ents with ALS


ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctoraan de Universiteit van Amsterdamop gezag van de Rector Magnifi cus

prof. dr. D.C. van den Boomten overstaan van een door het College voor Promo� es ingestelde commissie,

in het openbaar te verdedigen in de Agnietenkapelop woensdag 13 januari 2016, te 14.00 uur

door

Hubertus Wilhelmus Joseph Creemersgeboren te Venray

PROMOTIECOMMISSIE

Promotores: Prof. dr. F. Nollet Universiteit van Amsterdam Prof. dr. L.H. van den Berg Universiteit Utrecht

Co-promotores: Dr. J.A.J.M. Beelen Universiteit van Amsterdam Prof. dr. J.H Veldink Universiteit Utrecht

Overige leden: Prof. dr. A.J. Pols Universiteit van Amsterdam Prof. dr. M.A.G. Sprangers Universiteit van Amsterdam Prof. dr. S.C.C.M. Teunissen Universiteit Utrecht Prof. dr. J.M.A. Visser-Meily Universiteit Utrecht Prof. dr. M. de Visser Universiteit van Amsterdam Prof. dr. H.C.P.M. van Weert 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 AmsterdamThe department of Neurology, Rudolf Magnus Ins� tute of Neuroscience,University Medical Center Utrecht

The studies presented in this thesis were fi nancially supported by:The Netherlands Organisa� on for Health Research and Development (ZonMw)The Netherlands ALS Founda� onThe Netherlands ALS CenterDepartment 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.nlWellco Interna� onal BV / Fi] orm – www.fi ] orm.netQuo Vadis Nederland BV – www.qvn.nlPermobil 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 19 with ALS: a systema� c review

Chapter 3 The provision of assis� ve devices and home adapta� ons to pa� ents 51 with ALS in the Netherlands: Pa� ents’ perspec� ves Chapter 4 Cluster RCT of case management on pa� ents’ quality of life and 65 caregiver strain in ALS

Chapter 5 Need and value of case management in mul� disciplinary ALS care: 85 A qualita� ve study on the perspec� ves of pa� ents, spousal caregivers and professionals

Chapter 6 Factors related to caregiver strain in ALS 103

Chapter 7 General Discussion 119

Summary 141 Samenva ̀ ng 147 Dankwoord 153 Curriculum Vitae / Por] olio 155 List of publica� ons 161

1General introduc� on

Chapter 1

10

General introduc� on

11

11.1 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 profi le. 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 diffi cul� 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 aff ect voluntary muscle ac� vity, for example causing diffi cul� 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 classifi ed 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 caregiversIn 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 diff erent 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 diff erent

Chapter 1

12

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 diffi cult 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 careThe current evidence base for the management of ALS indicates that care in a mul� disciplinary se ̀ ng is most eff 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.


13

1From 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 benefi cial 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 modifi able factors associated with caregiver strain.

1.4 Aims of this thesisThe overall aim of this thesis is to op� mize mul� disciplinary ALS care through expanding our knowledge related to previously iden� fi ed 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.

Chapter 1

14

The specifi c aims of this thesis

• To summarize the available evidence based on the scien� fi c 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 eff ect 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 thesisChapter 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 eff ec� 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.


15

1Data, collected during the RCT case management, are applied to analyse which

(modifi 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 fi ndings, strengths and limita� ons of this thesis are described. Finally, the implica� ons of the study fi ndings for the care in ALS are discussed and future perspec� ves are considered.

Chapter 1

16

REFERENCES

1. Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and � me. Nat Rev Neurol. 2013 Nov;9(11):617-28.

2. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC. Amyotrophic lateral sclerosis. Lancet. 2011 Mar 12;377(9769):942-55.

3. Gauthier A, Vignola A, Calvo A, Cavallo E, Moglia C, Selli ̀ L, Mutani R, Chiò A. A longitudinal study on quality of life and depression in ALS pa� ent-caregiver couples. Neurology. 2007 Mar 20;68(12):923-6.

4. Hogden A. Op� mizing pa� ent autonomy in amyotrophic lateral sclerosis: inclusive decision-making in mul� disciplinary care. Neurodegener Dis Manag. 2014;4(1):1-3.

5. Tramon� F, Bongioanni P, Fanciullacci C, Rossi B. Balancing between autonomy and support: coping strategies by pa� ents with amyotrophic lateral sclerosis. J Neurol Sci. 2012 Sep 15;320(1-2):106-9.

6. Swinnen B, Robberecht W. The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol. 2014 Nov;10(11):661-70.

7. 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;82:1165-70.

8. Chiò A, Logroscino G, Traynor BJ, Collins J, Simeone JC, Goldstein LA, White LA. Global epidemiology of amyotrophic lateral sclerosis: a systema� c review of the published literature. Neuroepidemiology. 2013;41(2):118-30.

9. Francis K, Bach JR, DeLisa JA. Evalua� on and rehabilita� on of pa� ents with adult motor neuron disease. Arch Phys Med Rehabil. 1999 Aug;80(8):951-63.

10. Ng, L. L. L. The use of Interna� onal Classifi ca� on of Func� oning, Disability and Health in motor neurone disease rehabilita� on. Thesis Doctorate, Medicine, Den� stry & Health Sciences - Medicine (RMH & WH), The University of Melbourne. 2011. Persistent Link: h� p://hdl.handle.net/11343/36877

11. Bede P, Oliver D, Stodart J, et al. Pallia� ve care in amyotrophic lateral sclerosis: a review of current interna� onal guidelines and ini� a� ves. J Neurol Neurosurg Psychiatry 2011;82:413-8.

12. Turner MR, Kiernan MC. The standard of care in amyotrophic lateral sclerosis: a centralised mul� -disciplinary clinic encounter sets a new benchmark for a uniquely challenging neurodegenera� ve disorder. J Neurol Neurosurg Psychiatry. 2015 May;86(5):481-2.

13. 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;73:1227-33.

14. 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;19:360-75.

15. Van den Berg JP, de Groot IJ, Joha BC, van Haelst JM, van Gorcom P, Kalmijn S. Development and implementa� on of the Dutch protocol for rehabilita� ve management in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Dec;5(4):226-9.

16. Chiò A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, Traynor BG; Eurals Consor� um. Prognos� c factors in ALS: A cri� cal review. Amyotroph Lateral Scler. 2009 Oct-Dec;10(5-6):310-23.

17. Sco� on WJ, Sco� KM, Moore DH, Almedom L, Wijesekera LC, Janssen A, Nigro C, Sakel M, Leigh PN, Shaw C, Al-Chalabi A. Prognos� c categories for amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2012 Oct;13(6):502-8.


17

118. Turner MR, Kiernan MC, Leigh PN, Talbot K. Biomarkers in amyotrophic lateral sclerosis. Lancet

Neurol. 2009 Jan;8(1):94-109.19. Rooney J, Byrne S, Heverin M, Tobin K, Dick A, Donaghy C, Hardiman O. A mul� disciplinary clinic

approach improves survival in ALS: a compara� ve study of ALS in Ireland and Northern Ireland. J Neurol Neurosurg Psychiatry. 2015 May;86(5):496-501.

20. 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.

21. Van den Berg JP, Kalmijn S, Lindeman E, Veldink JH, de Visser M, Van der Graaff MM, Wokke JH, Van den Berg LH. Mul� disciplinary ALS care improves quality of life in pa� ents with ALS. Neurology. 2005 Oct 25;65(8):1264-7.

22. Foley G, Timonen V, Hardiman O. Pa� ents’ percep� ons of services and preferences for care in amyotrophic lateral sclerosis: a review. Amyotroph Lateral Scler. 2012 Jan;13(1):11-24.

23. Ng L, Talman P, Khan F. Motor neurone disease: disability profi le and service needs in an Australian cohort. Int J Rehabil Res. 2011 Jun;34(2):151-9.

24. Peters M, Fitzpatrick R, Doll H, Playford ED, Jenkinson C. The impact of perceived lack of support provided by health and social care services to caregivers of people with motor neuron disease. Amyotroph Lateral Scler. 2012 Feb;13(2):223-8.

25. Reagan P, Hurst R, Cook L, Zylicz Z, Otlowski M, Veldink JH, van den Berg LH, Wokke JH. Physician-assisted death: dying with dignity? Lancet Neurol. 2003 Oct;2(10):637-43. No abstract available

26. Hughes RA, Sinha A, Higginson I, Down K, Leigh PN. Living with motor neurone disease: lives, experiences of services and sugges� ons for change. Health Soc Care Community. 2005 Jan;13(1):64-74.

27. 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).

28. VSN onderzoeksverslag; Pallia� eve terminale zorg voor mensen met chronisch progressieve spierziekten (The Dutch Associa� on for Pa� ents with Neuromuscular Diseases research report; Pallia� ve terminal care for people with chronic progressive muscular diseases). March 2006 (Dutch).

29. Beisecker AE, Cobb AK, Ziegler DK. Pa� ents’ perspec� ves of the role of care providers in amyotrophic lateral sclerosis. Arch Neurol. 1988 May;45(5):553-6.

30. Long MJ. Case management model or case manager type? That is the ques� on. Health Care Manag (Frederick). 2002 Jun;20(4):53-65.

31. Coleman EA, Parry C, Chalmers S, Min SJ. The care transi� ons interven� on: results of a randomized controlled trial. Arch Intern Med. 2006 Sep 25;166(17):1822-8.

32. Parry C, Kramer HM, Coleman EA. A qualita� ve explora� on of a pa� ent-centered coaching interven� on to improve care transi� ons in chronically ill older adults. Home Health Care Serv Q. 2006;25(3-4):39-53.

33. Sargent P, Pickard S, Sheaff R, Boaden R. Pa� ent and carer percep� ons of case management for long-term condi� ons. Health Soc Care Community. 2007 Nov;15(6):511-9.

34. Sutherland D, Hayter M. Structured review: evalua� ng the eff ec� veness of nurse case managers in improving health outcomes in three major chronic diseases. J Clin Nurs. 2009 Nov;18(21):2978-92.

35. Peters-Klimm F, Campbell S, Hermann K, Kunz CU, Müller-Tasch T, Szecsenyi J; Competence Network Heart Failure. Case management for pa� ents with chronic systolic heart failure in primary care: the HICMan exploratory randomised controlled trial. Trials. 2010 May 17;11:56.

Chapter 1

18

36. O’Donnell M, Parker G, Proberts M, Ma� hews R, Fisher D, Johnson B, Hadzi-Pavlovic D. A study of client-focused case management and consumer advocacy: the Community and Consumer Service Project. Aust N Z J Psychiatry. 1999 Oct;33(5):684-93.

37. 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, Sufi 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.

2Prognos� c factors for the course of func� onal status of

pa� ents with ALS: a systema� c review

Huub Creemers Hepke GrupstraFrans NolletLeonard H. van den BergAnita Beelen

Journal of Neurology 2015. Jun;262(6):1407-23.

© Reprinted with permission from Springer

Chapter 2

20

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 insuffi cient 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.

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

21

2

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 diff erent 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, neuro-pallia� 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� onWe 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� fi ed 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 fi lter 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.

Chapter 2

22

Two reviewers (HC and AB) independently screened the abstracts iden� fi ed 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� fi ed by the computerized search.

An eligible study aimed to iden� fy prognos� c factors (sociodemographic, disease-specifi c, psychosocial and comorbid factors) on func� onal status assessed using (versions of) the ALSFRS in pa� ents with ALS who were classifi ed according to the El-Escorial diagnos� c criteria 1. This had to be designed as a longitudinal cohort study, with at least one follow-up 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� onOne 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 assessmentThere 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 fi ve 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 specifi c outcome based on a combina� on of several poten� al prognos� c factors. In advance, we determined the key characteris� cs specifi c 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.


23

2

Data synthesisDue to the expected heterogeneity of selected studies, we performed a qualita� ve best-evidence 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 eff ect 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.(Modifi ed from Huguet et al. 2013 16)

Ra� ng is modifi ed 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; diff erence in results are not clinically meaningful. Point of eff ect es� mates

are on either side of the line of no eff ect.

-Indirectness of evidence; the study sample does not fully represent the review ques� on defi ned 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� fi ca� 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 eff ect size within each

included study is reported 18.

Ra� ng is modifi ed upward:

-Moderate or large eff ect size. For meta-analysis: pooled eff ect is moderate or large. For narra� ve

summary; moderate or large similar eff ect is reported by most studies.

RESULTS

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

Chapter 2

24

Figure 1 Flowchart study selec� on.

�

��

�

��

��

��

�!�� "�

�#��$�� %��

�& ��'%(��

)�*�� (�

� �� +�� *�*��

�� +��

��

��

(��*�*�� +��'��

�, '��-��

�,��*�*��.��(�/��

�� 0��(�

�� 0�� (�

��

�� 0��0��

�� *��*�� (%�

�� (�

�� 12�*��%�

�,��*�*��.��/��

�� 0��

�� 0��%�

�� 0��0��

�� "�

�� 12�*��

��*�*�� +��1��

2�*��*�� +�� %�

2�� *�� +��

��*�*��

��-��

��

��

��

��


25

2

Study characteris� csThe 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 specifi 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 fi 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 — 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 factorsTable 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 pro-vided 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.

26

Tabl

e 1

Char

acte

ris�

cs

of th

e in

clud

ed s

tudi

es (n

= 1

3).

Aut

hor,

year

Stud

y de

sign

Sam

ple

size

(n),

stud

y po

pula

� on

Pa�

ents

’ cha

ract

eris

� cs

Trea

tmen

tO

utco

me

mea

sure

(s)

and

base

line

scor

e(s)

Loss

to

follo

w-u

p,

n (%

)

Follo

w-u

p du

ra�

on

(mo)

Prog

nos�

c fa

ctor

(s)

Gom

eni,

2013

[1

9]Pr

ospe

c� v

e m

ul� c

ente

r co

hort

338

PRO

-ACT

*

data

base

Age

(yrs

): m

ean

55.5

(SD

11.

6)M

ale:

65

%N

ot re

port

edA

LSFR

S-R;

mea

n 38

.7 (S

D 4

.9)

6 (2

)12

Ba

selin

e A

LSFR

S-R;

%Ch

ange

in

ALS

FRS-

R fr

om b

asel

ine

at w

eek

two;

%Ch

ange

in

ALS

FRS-

R fr

om b

asel

ine

at

wee

k fo

ur

Clav

elou

, 201

3 [2

0]Pr

ospe

c� v

e m

ul� c

ente

r co

hort

382

Sixt

een

outp

a� e

nt

univ

ersi

ty h

ospi

tals

Age

(yrs

): m

ean

61.0

(SD

12.

4)

Mal

e: 5

5 %

Bulb

ar o

nset

: 23.

3 %

Mea

n � m

e to

dia

gnos

is: 9

.6 m

o (S

D

8.1)

Tim

e si

nce

diag

nosi

s <

6 m

o

Rilu

zole

10

0 %

ALS

FRS;

mea

n 32

.82

(SD

4.6

6);

med

ian

34.0

;ra

nge

10 −

40

132

(35)

30

Site

of o

nset

(bul

bar,

low

er

limbs

, upp

er li

mbs

); G

ende

r

Elam

in,

2013

[21]

Pros

pec�

ve

coho

rt18

6Po

pula

� on-

base

d A

LS re

gist

er

Age

(yrs

): m

ean

63.4

(SD

10.

2)M

ale:

60

%Bu

lbar

ons

et: 3

6 %

Rilu

zole

82.8

%A

LSFR

S-R;

tota

l and

bul

bar

dom

ain

scor

es

med

ian

tota

l: 38

175

(94)

18

A

ge; G

ende

r; S

ite o

f ons

et

(bul

bar

vers

us s

pina

l);

Base

line

ALS

FRS-

R;

Fron

tote

mpo

ral s

yndr

ome

Körn

er,

2013

[22]

Retr

ospe

c� v

e co

hort

51

4A

LS o

utpa

� ent

cl

inic

Age

at d

iagn

osis

(yrs

): m

ean

58.8

Mal

e: 5

6 %

Bulb

ar o

nset

: 28

%

Not

repo

rted

A

LSFR

S-R;

base

line

scor

e no

t re

port

ed

0 (0

)>

6 Co

mor

bidi

� es;

Gen

der;

Age

at

dia

gnos

is; S

ite o

f ons

et

(bul

bar

vers

us s

pina

l); T

ime

to d

iagn

osis

Reic

h-Sl

otky

, 20

13 [2

3]Pr

ospe

c� v

e m

ul� c

ente

r co

hort

150

Nin

etee

n ou

tpa�

ent

cen

ters

Age

(yrs

): m

ean

57.0

(SD

10.

9)M

ale:

57

%Bu

lbar

ons

et: 1

6 %

BMI:

mea

n 26

.2FV

C%: m

ean

88

Rilu

zole

72%

Co

enzy

me

Q10

: 50%

ALS

FRS-

R;m

ean

35.4

4 (S

D 5

.22)

Non

e 9

BMI

27

2

Aut

hor,

year

Stud

y de

sign

Sam

ple

size

(n),

stud

y po

pula

� on

Pa�

ents

’ cha

ract

eris

� cs

Trea

tmen

tO

utco

me

mea

sure

(s)

and

base

line

scor

e(s)

Loss

to

follo

w-u

p,

n (%

)

Follo

w-u

p du

ra�

on

(mo)

Prog

nos�

c fa

ctor

(s)

Paga

noni

, 201

2 [2

4]Pr

ospe

c� v

e m

ul� c

ente

r co

hort

251

Thir

ty-s

even

ou

tpa�

ent

cen

ters

Age

(yrs

): m

ean

53.9

(SD

12.

5)M

ale:

63

%Bu

lbar

ons

et: 1

6 %

FVC%

: mea

n 87

.1

Tim

e si

nce

diag

nosi

s (d

ays)

: mea

n 29

4.9

Tim

e si

nce

onse

t (da

ys):

mea

n 67

2.1

BMI:

mea

n 26

.8

VC >

60

%D

isea

se d

ura�

on

< 5

yrs

Rilu

zole

59%

ALS

FRS-

R;m

ean

42.8

(SD

5.8

)10

3 (5

9)8

Uri

c ac

id le

vels

; BM

I

Gor

don,

201

0 [2

5]Pr

ospe

c� v

e co

hort

2,45

2O

ne o

utpa

� ent

ho

spita

l

Age

at d

iagn

osis

(yrs

): m

ean

59.7

(SD

13

.2)

Mal

e: 5

7 %

Bulb

ar o

nset

: 28

%

Not

repo

rted

ALS

FRS-

R; b

asel

ine

scor

e no

t rep

orte

d60

8 (2

5)M

ean

32

mo

(SD

36

)

Age

at o

nset

; Site

of o

nset

(b

ulba

r ve

rsus

lim

b);

Base

line

ALS

FRS-

R; T

ime

to

diag

nosi

s; G

ende

r; W

eigh

t at

the

fi rst

vis

it; H

eigh

t

Sora

rù,

2010

[26]

Retr

ospe

c� v

e co

hort

40 One

out

pa� e

nt

hosp

ital

UM

N-A

LS g

roup

(n =

20)

:A

ge a

t ons

et (y

rs):

mea

n 60

;M

ale:

50

%Bu

lbar

ons

et: 4

0 %

Tim

e to

dia

gnos

is (y

rs):

mea

n 2.

7 Ty

pica

l ALS

gro

up (n

= 2

0):

Age

at o

nset

(yrs

): m

ean

60;

Mal

e: 5

0 %

Bulb

ar o

nset

: 25

%Ti

me

to d

iagn

osis

(yrs

): m

ean

1.0

Not

repo

rted

ALS

FRS-

R, to

tal a

nd

dom

ain

scor

es

Base

line

tota

l sco

re:

UM

N-A

LS g

roup

: m

ean

35.5

; ran

ge

15−4

0Ty

pica

l ALS

gro

up:

mea

n 37

.7; r

ange

24

−45

8 (2

0)18

U

pper

Mot

or N

euro

n do

min

ance

Qur

eshi

, 200

8 [2

7]Pr

ospe

c� v

e m

ul� c

ente

r co

hort

795

Twen

ty-o

ne

outp

a� e

nt c

ente

rs

Age

(yrs

): m

ean

56.0

(SD

12.

2; n

=

596)

Mal

e: 6

4 %

Bulb

ar o

nset

: 19.

5 %

%VC

: mea

n 86

.3 (S

D 1

7.7)

Topi

ram

ate

57 %

Crea

� ne

58 %

Cele

coxi

b 67

%

ALS

FRS;

mea

n 31

.2 (S

D 5

.3)

294

(37)

6-12

(r

ange

)Ba

selin

e la

bora

tory

pa

ram

eter

s

28

Aut

hor,

year

Stud

y de

sign

Sam

ple

size

(n),

stud

y po

pula

� on

Pa�

ents

’ cha

ract

eris

� cs

Trea

tmen

tO

utco

me

mea

sure

(s)

and

base

line

scor

e(s)

Loss

to

follo

w-u

p,

n (%

)

Follo

w-u

p du

ra�

on

(mo)

Prog

nos�

c fa

ctor

(s)

Kram

pe, 2

008

[28]

Pros

pec�

ve

coho

rt31 O

ne o

utpa

� ent

cl

inic

Age

(yrs

): m

ean

60.3

(S

D 1

0.4)

A

ge a

t ons

et (y

rs):

mea

n 58

.4 (S

D

10.3

)M

ale:

61

%Bu

lbar

/mix

ed o

nset

: 19/

13 %

Tim

e to

dia

gnos

is (w

eeks

): m

ean

52.4

(S

D =

32.

3)FV

C%: m

ean

62.4

(SD

24.

5; n

= 2

0);

rang

e 13

−100

Tim

e fr

om o

nset

(yrs

): <

6yrs

Mel

aton

in

100

%Vi

tam

in E

74

%Ri

luzo

le 8

1 %

Am

itrip

tylin

e 48

%Ba

clof

en 2

6 %

Mg

52 %

Vit C

23

%Cr

ea� n

e 13

%

ALS

FRS;

mea

n 27

.0 (S

D 6

.6);

rang

e 12

−38

17 (5

5)12

G

ende

r; A

ge a

t ons

et;

Year

s of

edu

ca� o

n; T

ime

sinc

e on

set;

Tim

e fr

om

diag

nosi

s to

stu

dy in

clus

ion;

FV

C; P

erso

nalit

y fa

ctor

s (n

euro

� cis

m, e

xtra

vers

ion,

op

enne

ss, a

gree

able

ness

, co

nsci

en� o

us-n

ess)

; D

epre

ssio

n; F

TD a

nd

cogn

i� ve

per

form

ance

Rauc

hway

, 20

07 [2

9]Re

tros

pec�

ve

coho

rt50 O

ne

neur

ophy

siol

ogy

labo

rato

ry

Gro

up I

ALS

FRS

< 26

: n =

14

Age

at o

nset

(yrs

): m

edia

n 61

;Ti

me

sinc

e on

set (

mo)

: med

ian

4;

rang

e 2−

24G

roup

II: A

LSFR

S >2

6; n

=33

Age

at o

nset

(yrs

): m

edia

n 55

;Ti

me

sinc

e on

set (

mo)

: med

ian

10;

rang

e =

1−24

Not

repo

rted

ALS

FRS;

med

ian

(min

imum

-m

axim

um) G

roup

I;28

(13−

40) G

roup

II;

36 (2

8−40

)

3 (6

)10

(m

edia

n)Ti

me

from

ons

et o

f sy

mpt

oms

to in

i� al

ED

X st

udie

s

29

2

Aut

hor,

year

Stud

y de

sign

Sam

ple

size

(n),

stud

y po

pula

� on

Pa�

ents

’ cha

ract

eris

� cs

Trea

tmen

tO

utco

me

mea

sure

(s)

and

base

line

scor

e(s)

Loss

to

follo

w-u

p,

n (%

)

Follo

w-u

p du

ra�

on

(mo)

Prog

nos�

c fa

ctor

(s)

Qur

eshi

, 200

6 [3

0]Pr

ospe

c� v

e co

hort

95 One

out

pa� e

nt

hosp

ital

Age

(yrs

): m

ean

54.4

(SD

= 1

3.1)

Mal

e: 6

3.2

%Bu

lbar

ons

et: 2

4 %

Tim

e to

dia

gnos

is (y

rs):

mea

n 0.

9 (S

D

0.9)

Not

repo

rted

ALS

FRS;

mea

n 31

.9 (S

D 5

.7)

Non

e12

So

ciod

emog

raph

ic

char

acte

ris� c

s:A

ge; A

ge a

t ons

et; A

ge a

t di

agno

sis;

Gen

der;

Yea

rs o

f ed

uca�

on;

Mal

e ve

tera

ns;

Mar

ital s

tatu

s; R

ace

Clin

ical

exa

min

a� o

n ch

arac

teris

� cs:

El

Esc

oria

l cri

teri

a; S

ite o

f on

set (

bulb

ar/l

imb)

; Tim

e to

dia

gnos

is; B

asel

ine

FVC;

Ba

selin

e A

LSFR

S; H

eigh

t;

Wei

ght;

Fam

ilial

ALS

; His

tory

of

ALS

ALS

risk

fact

ors

(n =

12

fact

ors)

Com

orbi

dity

(n =

12

fact

ors)

De

Carv

alho

, 20

06 [3

1]Pr

ospe

c� v

e co

hort

57 One

out

pa� e

nt

cent

er

Age

(yrs

): m

ean

61.1

; ran

ge 3

2−78

Mal

e: 5

1 %

Bulb

ar o

nset

: 23

%Ti

me

sinc

e on

set (

mo)

: mea

n 16

.4;

rang

e 2−

63

Not

repo

rted

ALS

FRS;

Gro

up 1

: mea

n 34

.7

(SD

1.7

); ra

nge

32−3

7G

roup

2: m

ean

33.3

(S

D 4

.7);

rang

e 24

−39

24 (4

2)

6 A

> 8

.78%

redu

c� o

n in

A

LSFR

S sc

ore

at 3

mon

ths

PRO

-ACT

Poo

led

Reso

urce

Ope

n-A

cces

s A

LS C

linic

al T

rials

dat

abas

e (h

� ps

://n

ctu.

part

ners

.org

/Pro

ACT/

), m

o m

onth

s, y

rs y

ears

, SD

sta

ndar

d de

via�

on,

A

LSFR

S(-R

) Am

yotr

ophi

c La

tera

l Scl

eros

is(-

Revi

sed)

, BM

I Bod

y M

ass

Inde

x, F

VC%

per

cent

age

forc

ed v

ital c

apac

ity o

f pre

dict

ed n

orm

al v

alue

s, V

C vi

tal c

apac

ity,

UM

N u

pper

mot

or n

euro

n, M

g m

agne

sium

, Vit

vita

min

, FTD

fron

tote

mpo

ral d

emen

� a, E

DX

elec

trod

iagn

os� c

30

Tabl

e 2

Prog

nos�

c fa

ctor

s re

late

d to

out

com

e m

easu

res.

Pr

ogno

s� c

fact

orN

o. o

f stu

dies

(p

ar�

cipa

nts)

Sign

ifi ca

nt

asso

cia�

on

repo

rted

num

ber

of s

tudi

es

(par

� ci

pant

s)

Sta�

s�

cal a

naly

sis

Stre

ngth

of a

ssoc

ia�

onQ

ualit

y sc

ore

(bas

ed o

n G

RAD

E if

appl

icab

le)

Leve

l of e

vide

nce

Cons

ider

ed ju

dgm

ent

Out

com

e: D

eclin

e in

ALS

FRS

tota

l sco

re o

r A

LSFR

S-R

tota

l sco

reSo

ciod

emog

raph

ic c

hara

cter

is� c

sA

ge a

t ons

et4

[21]

, [25

], [2

8], [

30]

(n =

2,7

64)

1 [2

5](n

= 1

,844

)[2

1] M

ul� p

le li

near

re

gres

sion

[25]

, [28

], [3

0] M

ixed

eff

ect

s m

odel

[25]

ALS

FRS-

R =

−0.0

46 (S

E =

0.01

3) p

oint

s fo

r ev

ery

age

year

.

p <

0.00

1

[21]

, [28

], [3

0] N

ot s

igni

fi can

t

‘Low

’ evi

denc

eTh

ere

is ‘l

ow’ e

vide

nce

that

old

er

age

at o

nset

is a

ssoc

iate

d w

ith a

st

eepe

r fu

nc� o

nal d

eclin

e.

Age

at d

iagn

osis

2 [2

2], [

30]

(n =

609

)1

[22]

(n =

514

)[2

2] M

ul� p

le li

near

an

alys

is (o

nly

resu

lts

from

uni

vari

ate

anal

ysis

re

port

ed)

[30]

Mix

ed e

ff ect

s m

odel

[22]

Mea

n ra

� oa

= 1.

01 (9

5 %

CI =

1.0

0,

1.02

); Fo

r ev

ery

age

year

the

diff e

renc

e in

A

LSFR

S-R

decl

ine

is 1

%.

p =

0.01

5

[30]

Not

sig

nifi c

ant

‘Ver

y lo

w’

evid

ence

Ther

e is

‘ver

y lo

w’ e

vide

nce

that

ol

der

age

at d

iagn

osis

is a

ssoc

iate

d w

ith a

wor

se fu

nc� o

nal d

eclin

e.

Gen

der

6 [2

0], [

21],

[22]

, [25

], [2

8],

[30]

(n =

3,6

60)

0[2

0], [

25],

[28]

, [30

] M

ixed

eff e

cts

mod

el

[21]

Mul

� ple

line

ar

regr

essi

on

[22]

Mul

� ple

line

ar

anal

ysis

(onl

y re

sults

fr

om u

niva

riat

e an

alys

is

repo

rted

)

[20]

, [21

], [2

2], [

25],

[28]

, [30

] Not

si

gnifi

cant

‘Hig

h’ e

vide

nce

Ther

e is

‘hig

h’ e

vide

nce

that

ge

nder

is n

ot a

ssoc

iate

d w

ith a

st

eepe

r fu

nc� o

nal d

eclin

e.

Wei

ght

2 [2

5], [

30]

(n =

2,5

47)

0[2

5], [

30] M

ixed

eff e

cts

mod

el[2

5], [

30] N

ot s

igni

fi can

t‘M

oder

ate’

ev

iden

ceTh

ere

is ‘m

oder

ate’

evi

denc

e th

at w

eigh

t is

not a

ssoc

iate

d w

ith

func

� ona

l dec

line.

Hei

ght

2 [2

5], [

30]

(n =

2,5

47)

0[2

5], [

30] M

ixed

eff e

cts

mod

el[2

5], [

30] N

ot s

igni

fi can

t ‘M

oder

ate’

ev

iden

ceTh

ere

is ‘m

oder

ate’

evi

denc

e th

at h

eigh

t is

not a

ssoc

iate

d w

ith

func

� ona

l dec

line.

31

2

Prog

nos�

c fa

ctor

No.

of s

tudi

es

(par

� ci

pant

s)Si

gnifi

cant

as

soci

a� o

n re

port

ed n

umbe

r of

stu

dies

(p

ar�

cipa

nts)

Sta�

s�

cal a

naly

sis

Stre

ngth

of a

ssoc

ia�

onQ

ualit

y sc

ore

(bas

ed o

n G

RAD

E if

appl

icab

le)

Leve

l of e

vide

nce

Cons

ider

ed ju

dgm

ent

Year

s of

edu

ca� o

n2

[28]

, [30

](n

= 1

26)

0[2

8], [

30] M

ixed

eff e

cts

mod

el[2

8], [

30] N

ot s

igni

fi can

t‘L

ow’ e

vide

nce

Ther

e is

‘low

’ evi

denc

e th

at y

ears

of

edu

ca� o

n is

not

ass

ocia

ted

with

fu

nc� o

nal d

eclin

e.

Clin

ical

cha

ract

eris

� cs:

dis

ease

-rel

ated

and

func

� ona

l fac

tors

Site

of o

nset

5

[20]

, [21

], [2

2], [

25],

[30]

(n =

3,6

29)

3 [2

2], [

25],

[30]

(n =

3,0

61)

[20]

, [25

], [3

0] M

ixed

eff

ect

s m

odel

[21]

Mul

� ple

line

ar

regr

essi

on

[22]

Mul

� ple

line

ar

anal

ysis

(onl

y re

sults

fr

om u

niva

riat

e an

alys

is

repo

rted

)

[22]

Mea

n ra

� oa =

1.3

4 (9

5 %

CI =

1.0

7,

1.68

); Bu

lbar

ons

et re

sults

in a

diff

eren

ce in

A

LSFR

S-R

decl

ine

of 3

4% c

ompa

red

to s

pina

l on

set.

p =0

.012

[25]

Ste

eper

cha

nge

in A

LSFR

S-R

leg

onse

t ve

rsus

arm

ons

et.

Dat

a no

t rep

orte

d.

p =

0.02

[25]

Ste

eper

cha

nge

in A

LSFR

S-R

prox

imal

lim

b on

set v

ersu

s di

stal

lim

b-on

set.

Dat

a no

t rep

orte

d.

p =

0.00

4

[30]

The

mea

n ch

ange

in A

LSFR

S =

−0.0

2 (S

E =

+ 0.

01) p

oint

s/m

onth

of p

a� e

nts

with

bu

lbar

ons

et v

ersu

s lim

b on

set.

p =

0.02

[20]

, [21

] Bul

bar

vers

us li

mb

onse

t (A

LSFR

S an

d A

LSFR

S-R)

; not

sig

nifi c

ant.

‘Low

’ evi

denc

eTh

ere

is ‘l

ow’ e

vide

nce

that

bul

bar

onse

t of d

isea

se is

ass

ocia

ted

with

a w

orse

func

� ona

l dec

line

com

pare

d to

lim

b on

set.

Ther

e is

‘ver

y lo

w’ e

vide

nce

that

:- L

eg o

nset

is a

ssoc

iate

d w

ith a

st

eepe

r de

clin

e in

func

� ona

l sta

tus

com

pare

d to

arm

ons

et.

- Pro

xim

al li

mb

onse

t is

asso

ciat

ed

with

a s

teep

er d

eclin

e in

fu

nc� o

nal s

tatu

s co

mpa

red

to

dist

al li

mb

onse

t.

32

Prog

nos�

c fa

ctor

No.

of s

tudi

es

(par

� ci

pant

s)Si

gnifi

cant

as

soci

a� o

n re

port

ed n

umbe

r of

stu

dies

(p

ar�

cipa

nts)

Sta�

s�

cal a

naly

sis

Stre

ngth

of a

ssoc

ia�

onQ

ualit

y sc

ore

(bas

ed o

n G

RAD

E if

appl

icab

le)

Leve

l of e

vide

nce

Cons

ider

ed ju

dgm

ent

Tim

e fr

om

sym

ptom

ons

et to

di

agno

sis

3 [2

2], [

29],

[30]

(n =

3,1

11)

3 [2

2], [

29],

[30]

(n =

656

)[2

2] M

ul� p

le li

near

an

alys

is (o

nly

resu

lts

from

uni

vari

ate

anal

ysis

re

port

ed)

[29]

Man

n-W

hitn

ey

U-t

est

[30]

Mix

ed e

ff ect

s m

odel

[22]

Mea

n ra

� oa

= 0.

99 (9

5 %

CI =

0.9

8,

0.99

); Fo

r ev

ery

mon

th b

etw

een

sym

ptom

on

set t

o di

agno

sis

the

ALS

FRS-

R de

clin

e de

crea

ses

with

1 %

.

p <

0.00

1

[29]

A s

hort

er in

terv

al b

etw

een

sym

ptom

on

set a

nd d

iagn

osis

is a

ssoc

iate

d w

ith a

lo

wer

ALS

FRS

scor

e at

six

mon

ths

follo

w-u

p.

p =

0.02

[30]

For

eve

ry y

ear

that

ela

pses

bet

wee

n sy

mpt

om o

nset

and

dia

gnos

is, t

he s

lope

of

the

ALS

FRS

scor

e de

clin

es b

y 0.

12 p

oint

s (S

E =

0.03

6) p

er m

onth

.

p =

0.00

1

‘Low

’ evi

denc

e Th

ere

is ‘l

ow’ e

vide

nce

that

a

long

er �

me

betw

een

sym

ptom

on

set a

nd d

iagn

osis

is a

ssoc

iate

d w

ith a

mild

er fu

nc� o

nal d

eclin

e.

33

2

Prog

nos�

c fa

ctor

No.

of s

tudi

es

(par

� ci

pant

s)Si

gnifi

cant

as

soci

a� o

n re

port

ed n

umbe

r of

stu

dies

(p

ar�

cipa

nts)

Sta�

s�

cal a

naly

sis

Stre

ngth

of a

ssoc

ia�

onQ

ualit

y sc

ore

(bas

ed o

n G

RAD

E if

appl

icab

le)

Leve

l of e

vide

nce

Cons

ider

ed ju

dgm

ent

Ini�

al ra

te

of d

isea

se

prog

ress

ion

2 [1

9], [

31]

(n =

395

)2

[19]

, [31

](n

= 3

95)

[19]

Ste

pwis

e lo

gis�

c

regr

essi

on

[31]

Man

n-W

hitn

ey

U-t

est

[19]

%ch

ange

ALS

FRS-

R sc

ore

at w

eek

2 w

as

an in

depe

nden

t pro

gnos

� c fa

ctor

of s

low

di

seas

e pr

ogre

ssio

n at

6 m

onth

s [o

dds

ra� o

=

0.01

56 (9

5 %

CI =

0.0

057,

0.0

424)

, p <

0.

0001

] and

12

mon

ths

[odd

s ra

� o =

0.1

637

(95

% C

I = 0

.094

5, 0

.283

3), p

< 0

.000

1]

[19]

%ch

ange

ALS

FRS-

R sc

ore

at w

eek

4 w

as

an in

depe

nden

t pro

gnos

� c fa

ctor

of s

low

di

seas

e pr

ogre

ssio

n at

6 m

onth

s [o

dds

ra� o

=

0.07

97 (9

5 %

CI =

0.0

451,

0.1

406)

, p <

0.

0001

] and

12

mon

ths

[odd

s ra

� o =

0.3

073

(95

% C

I = 0

.229

0, 0

.412

3), p

< 0

.000

1]

[31]

A c

ut-o

ff p

oint

of 8

.78

% re

duc�

on

in A

LSFR

S sc

ore

in 3

mon

ths

(the

80t

h pe

rcen

� le

and

2 SD

’s a

bove

the

mea

n)

iden

� fi e

s pa

� ent

s w

ith a

rapi

d di

seas

e pr

ogre

ssio

n.

p <

0.01

‘Ver

y lo

w’

evid

ence

Ther

e is

‘ver

y lo

w’ e

vide

nce

that

a

high

er p

erce

ntag

e ch

ange

in

ALS

FRS(

-R) s

core

at d

iagn

osis

is

asso

ciat

ed w

ith a

fast

er fu

nc� o

nal

decl

ine.

Com

orbi

di� e

s2

[22]

, [30

](n

= 6

09)

1 [2

2](n

= 5

14)

[22]

Mul

� var

iate

an

alys

is (a

djus

ted

for

age

at d

iagn

osis

, reg

ion

of o

nset

, � m

e fr

om fi

rst

sym

ptom

to d

iagn

osis

)

[30]

Mix

ed e

ff ect

s m

odel

[22]

Par

kins

on’s

dis

ease

; mea

n ra

� oa =

0.4

6(9

5 %

CI =

0.2

2, 0

.98)

. Pa�

ent

s w

ith

sym

ptom

s of

Par

kins

on’s

dis

ease

hav

e a

mild

er A

LSFR

S-R

decl

ine

of 4

6 %

.

p =

0.04

[12}

Not

sig

nifi c

ant

‘Ver

y lo

w’

evid

ence

Ther

e is

‘ver

y lo

w’ e

vide

nce

that

‘c

omor

bidi

ty P

arki

nson

’s d

isea

se

ALS

’ is

asso

ciat

ed w

ith a

slo

wer

fu

nc� o

nal d

eclin

e co

mpa

red

to

ALS

with

no

com

orbi

dity

.

34

Prog

nos�

c fa

ctor

No.

of s

tudi

es

(par

� ci

pant

s)Si

gnifi

cant

as

soci

a� o

n re

port

ed n

umbe

r of

stu

dies

(p

ar�

cipa

nts)

Sta�

s�

cal a

naly

sis

Stre

ngth

of a

ssoc

ia�

onQ

ualit

y sc

ore

(bas

ed o

n G

RAD

E if

appl

icab

le)

Leve

l of e

vide

nce

Cons

ider

ed ju

dgm

ent

Resp

irato

ry s

tatu

s;

FVC

3 [2

3], [

28],

[30]

(n =

276

)

1 [2

3](n

= 1

50)

[23]

Uni

vari

ate

regr

essi

on

[28]

, [30

] Mix

ed e

ff ect

s m

odel

[23]

FVC

was

sig

nifi c

antly

ass

ocia

ted

with

th

e A

LSFR

S-R

decl

ine

(dat

a no

t rep

orte

d).

p =

0.01

[28]

, [30

] Not

sig

nifi c

ant

‘Ver

y lo

w’

evid

ence

Ther

e is

‘ver

y lo

w’ e

vide

nce

that

a

low

er F

VC is

ass

ocia

ted

with

a

wor

se fu

nc� o

nal d

eclin

e.

Nut

ri� o

nal s

tatu

s;

BMI

2 [2

3], [

24]

(n =

401

)1

[23]

(n =

150

)[2

3] M

ul� v

aria

te

regr

essi

on m

odel

(a

djus

ted

for

age

at

incl

usio

n an

d FV

C)

[24]

Mix

ed e

ff ect

s m

odel

[23]

BM

I was

sig

nifi c

antly

ass

ocia

ted

with

A

LSFR

S-R

redu

c� o

n ov

er �

me,

with

a

min

imal

ALS

FRS-

R sc

ore

decl

ine

at B

MI o

f 30

(dat

a no

t rep

orte

d).

p <

0.01

BMI<

30;

β =

−0.4

8 (S

E =

0.22

) poi

nts

ALS

FRS-

R

p =

0.03

BMI >

30 N

ot s

igni

fi can

t

[24]

Not

sig

nifi c

ant

‘Ver

y lo

w’

evid

ence

Ther

e is

‘ver

y lo

w’ e

vide

nce

that

a

BMI o

f 30

is a

ssoc

iate

d w

ith

a m

inim

al fu

nc� o

nal d

eclin

e co

mpa

red

to B

MI o

f <30

or

>30,

an

d th

at a

hig

her

BMI s

core

on

BMI o

f <30

is a

ssoc

iate

d w

ith

a sl

ower

func

� ona

l dec

line

com

pare

d to

a lo

wer

sco

re.

Base

line

ALS

FRS-

R sc

ore

4 [1

9], [

21],

[25]

, [30

](n

= 3

,071

)

2 [1

9], [

25]

(n =

2,1

76)

[19]

Ste

pwis

e lo

gis�

c

regr

essi

on

[21]

Mul

� ple

line

ar

regr

essi

on

[25]

, [30

] Mix

ed e

ff ect

s m

odel

[19]

Bas

elin

e A

LSFR

S-R

scor

e w

as a

n in

depe

nden

t pro

gnos

� c fa

ctor

of s

low

di

seas

e pr

ogre

ssio

n at

6 m

onth

s; o

dds

ra� o

=

1.11

6 (9

5 %

CI =

1.0

32, 1

.207

)

p =

0.00

47

[25]

β b

asel

ine

ALS

FRS-

R =

0.06

60 (S

E =

0.02

4) p

oint

s.

p <

0.00

1

[21]

, [30

] Not

sig

nifi c

ant

‘Low

’ evi

denc

eTh

ere

is ‘l

ow’ e

vide

nce

that

a

high

er b

asel

ine

ALS

FRS-

R to

tal

scor

e is

ass

ocia

ted

with

a s

low

er

func

� ona

l dec

line.


35

2

Prog

nos�

c fa

ctor

No.

of s

tudi

es

(par

� ci

pant

s)Si

gnifi

cant

as

soci

a� o

n re

port

ed n

umbe

r of

stu

dies

(p

ar�

cipa

nts)

Sta�

s�

cal a

naly

sis

Stre

ngth

of a

ssoc

ia�

onQ

ualit

y sc

ore

(bas

ed o

n G

RAD

E if

appl

icab

le)

Leve

l of e

vide

nce

Cons

ider

ed ju

dgm

ent

Fron

tote

mpo

ral

synd

rom

eb /

exte

nt o

f FTD

an

d co

gni�

ve

perf

orm

ance

2 [2

1], [

28]

(n =

217

)1

[21]

(n =

186

)[2

1] K

rusk

al-W

allis

test

(n =

98)

[21]

Mul

� ple

line

ar

regr

essi

on(n

= 1

86)

[28]

Mix

ed e

ff ect

s m

odel

[21]

Med

ian

ALS

FRS-

R de

clin

e at

12

mon

ths

is h

ighe

r in

pa�

ent

s w

ith a

fron

tote

mpo

ral

synd

rom

e. E

xecu

� ve

dysf

unc�

on,

−0.

76; n

o co

gni�

ve a

bnor

mal

ity 0

.42;

non

exec

u� v

e co

gni�

ve im

pair

men

t,

−0.6

6 po

ints

/mon

th.

p =

0.02

5

[21]

, [28

] Not

sig

nifi c

ant

‘Ver

y lo

w’

evid

ence

Ther

e is

‘ver

y lo

w’ e

vide

nce

that

th

e pr

esen

ce o

f a fr

onto

tem

pora

l sy

ndro

me

at b

asel

ine

is a

ssoc

iate

d w

ith a

wor

se fu

nc� o

nal d

eclin

e.

No.

num

ber,

GRA

DE

Gra

ding

of

Reco

mm

enda

� ons

Ass

essm

ent,

Dev

elop

men

t an

d Ev

alua

� on,

ALS

FRS

(-R)

am

yotr

ophi

c la

tera

l sc

lero

sis

func

� ona

l ra

� ng

scal

e (-

Revi

sed)

, CI c

onfi d

ence

inte

rval

, % p

erce

ntag

e, S

E st

anda

rd e

rror

, β b

eta;

reg

ress

ion

coeffi

cie

nt, F

VC fo

rced

vita

l cap

acity

, BM

I Bod

y M

ass

Inde

x, F

TD

fron

tote

mpo

ral d

emen

� a.

a M

ean

ra� o

; diff

eren

ce in

ALS

FRS-

R sc

ore

ra� o

. ALS

FRS-

R ra

� o=

the

dete

riora

� on

of th

e sc

ore

per m

onth

.b Fr

onto

tem

pora

l syn

drom

e= c

omor

bid

FTD

or e

xecu

� ve

dysf

unc�

on

in a

pa�

ent

with

out d

emen

� a.

Chapter 2

36

Methodological quality of included studiesThe 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 fi ve studies was judged as ‘high’, fi ve 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 classifi ed 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 classifi ed as ‘low’ risk of bias on all quality domains 23.

Synthesis of evidenceThe 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 diff er 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.

37

2

Tabl

e 3

Ada

pted

GRA

DE

tabl

e fo

r na

rra�

ve

syst

ema�

c re

view

s of

pro

gnos

� c

stud

ies.

Gra

de fa

ctor

sPo

ten�

al p

rogn

os�

c fa

ctor

s id

en�

fi ed

Par�

ci-

pant

s (n

)N

umbe

r of

st

udie

s U

ni-

vari

ate

+ 0

-

Mul

� -

vari

ate

+ 0

-

Phas

eSt

udy

limit

a� o

nsIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

ica�

on

bias

Mod

erat

e/

larg

e eff

ect

si

ze

Ove

rall

qual

ity

of

evid

ence

Age

at o

nset

2,

156

4 [2

1, 2

5, 2

8, 30

]

3

11

[21]

2 [2

5, 2

8, 3

0]

XX

�X

�X

‘Low

’

Age

at d

iagn

osis

609

2 [2

2, 3

0]1

1

1 [2

2]

2 [3

0]

XX

�X

XX

‘Ver

y lo

w’

Tim

e fr

om s

ympt

om

onse

t to

diag

nosi

s 65

63

[22,

29,

30]

2

11

[22,

29]

2 [30]

X�

�X

��

‘Low

’

Site

of o

nset

3,02

15

[20−

22, 2

5,

3

0]

1

2

2

1 [2

0−22

]

2 [2

5, 3

0]

XX

�X

�X

‘Low

’

Base

line

ALS

FRS(

-R)

scor

e2,

457

4 [1

9, 2

1, 2

5,

3

0]

1 2

1

1 [2

1]

2 [2

5, 3

0]

3 [1

9]

XX

�X

�X

‘Low

’

Ini�

al ra

te o

f dis

ease

pr

ogre

ssio

n38

92

[19,

31]

1

1

1 [3

1]

3 [1

9]

X�

XX

XX

‘Ver

y lo

w’

FTD

217

2 [2

1, 2

8]

1

21

[21]

2 [2

8]

XX

�X

XX

‘Ver

y lo

w’

FVC

276

3 [2

3, 2

8, 3

0]1

2

2 [2

3, 2

8, 3

0]X

X�

XX

X‘V

ery

low

’

Com

orbi

di� e

s60

92

[22,

30]

1

1

1 [2

2]

2 [3

0]

XX

�X

XX

‘Ver

y lo

w’

BMI

401

2 [2

3, 2

4]

1

12

[23,

24]

XX

�X

XX

‘Ver

y lo

w’

Phas

e, p

hase

of i

nves

� ga�

on:

pha

se 1

exp

lana

tory

stu

dy, i

den�

fyi

ng a

ssoc

ia� o

ns; p

hase

2 e

xpla

nato

ry s

tudy

, tes

� ng

inde

pend

ent

asso

cia�

ons

; pha

se 3

ex

plan

ator

y st

udy,

und

erst

andi

ng p

rogn

os� c

pat

hway

s.Fo

r un

i- an

d m

ul�

vari

ate

anal

yses

: +, n

umbe

r of

sig

nifi c

ant

eff e

cts

with

a p

osi�

ve v

alue

; 0, n

umbe

r of

non

-sig

nifi c

ant

eff e

cts;

-, n

umbe

r of

sig

nifi c

ant

eff e

cts

with

a n

ega�

ve

valu

e.Fo

r G

RAD

E fa

ctor

s: �

, no

serio

us li

mita

� ons

; X, s

erio

us li

mita

� ons

(or

not

pres

ent

for

mod

erat

e/la

rge

eff e

ct s

ize)

; unc

lear

, una

ble

to r

ate

item

bas

ed o

n av

aila

ble

info

rma�

on.

Fo

r ov

eral

l qua

lity

of e

vide

nce:

‘Ver

y lo

w’;

‘Low

’; ‘M

oder

ate’

; ‘H

igh’

.G

RAD

E G

radi

ng o

f Re

com

men

da� o

ns A

sses

smen

t, D

evel

opm

ent

and

Eval

ua� o

n, A

LSFR

S (-

R) A

myo

trop

hic

Late

ral

Scle

rosi

s Fu

nc� o

nal

Ra� n

g Sc

ale

(-Re

vise

d),

FTD

fro

ntot

empo

ral

synd

rom

e, F

VC f

orce

d vi

tal

capa

city

, BM

I Bo

dy M

ass

Inde

x, U

niva

riate

uni

varia

te a

naly

ses,

Mul

� var

iate

mul

� var

iate

an

alys

es.

Chapter 2

38

Time from symptom onset to diagnosisThe ‘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 signifi cant in one study 30. Another study presented a signifi cant 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 onsetFive 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-signifi cance 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 scoreWithin 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 fi ndings. Two studies with ‘low’ risk of bias, showed inconsistent results. One study demonstrated a signifi cant 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 signifi cant associa� on 21. We judged the other two studies to be ‘moderate’ quality or ‘low’ quality 19,30.

Age at onsetFour studies inves� gated the prognos� c value of age at onset for a decline in ALSFRS(-R) total score. Only one study presented a signifi cant, 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,


39

2

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 fi nding 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� fi ed 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� fi ed 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,

Chapter 2

40

the iden� fi ca� 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 diff ering 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 specifi c 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 diff erent 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 defi ned by the AALS; this increased with disease progression. Both scales, however, showed a signifi cant 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


41

2

heterogeneity will be iden� fi ed in the years to come. This might enable the development of predic� on tools stra� fi ed 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 insuffi cient 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� fi ed by gene� cally defi ned subtypes of ALS.

Chapter 2

42

REFERENCES

1. Brooks BR, Miller RG, Swash M, Munsat TL, World Federa� on of Neurology Research Group on Motor Neuron Diseases (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293-299

2. Turner MR, Hardiman O, Benatar M, Brooks BR, Chiò A, de Carvalho M, Ince PG, Lin C, Miller RG, Mitsumoto H, Nicholson G, Ravits J, Shaw PJ, Swash M, Talbot K, Traynor BJ, Van den Berg LH, Veldink JH, Vucic S, Kiernan MC (2013) Controversies and priori� es in amyotrophic lateral sclerosis. Lancet Neurol 12:310-322. doi:10.1016/S1474-4422(13)70036-X

3. Goldstein LH, Abrahams S (2013) Changes in cogni� on and behaviour in amyotrophic lateral sclerosis: nature of impairment and implica� ons for assessment. Lancet Neurol 12:368-380. doi:10.1016/S1474-4422(13)70026-7

4. Ng L, Khan F, Mathers S (2009) Mul� disciplinary care for adults with amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database Syst Rev 4:CD007425. doi: 10.1002/14651858

5. Sco� on WJ, Sco� KM, Moore DH, Almedom L, Wijesekera LC, Janssen A, Nigro C, Sakel M, Leigh PN, Shaw C, Al-Chalabi A (2012) Prognos� c categories for amyotrophic lateral sclerosis. Amyotroph Lateral Scler 13:502-508. doi:10.3109/17482968.2012.679281

6. Turner MR, Kiernan MC, Leigh PN, Talbot K (2009) Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol 2009 8:94-109. doi:10.1016/S1474-4422(08)70293-X

7. Altman DG (2001) Systema� c reviews of evalua� ons of prognos� c variables. BMJ 323:224-2288. Hogden A, Greenfi eld D, Nugus P, Kiernan MC (2013) Development of a model to guide decision

making in amyotrophic lateral sclerosis mul� disciplinary care. Health Expect 23:1-14. doi:10.1111/hex.12169

9. The ALS CNTF treatment study (ACTS) phase I-II Study Group. [No authors listed] (1996) The Amyotrophic Lateral Sclerosis Func� onal Ra� ng Scale. Assessment of ac� vi� es of daily living in pa� ents with amyotrophic lateral sclerosis. Arch Neurol 53:141-147

10. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A (1999) The ALSFRS-R: A revised ALS func� onal ra� ng scale that incorporates assessments of respiratory func� on. J Neurol Sci 169:13-21

11. Gordon PH, Miller RG, Moore DH (2004) ALSFRS-R. Amyotroph Lateral Scler Other Motor Neuron Disord 5 Suppl 1:90-93

12. Kollewe K, Mauss U, Krampfl K, Petri S, Dengler R, Mohammadi B (2008) ALSFRS-R score and its ra� o: a useful predictor for ALS-progression. J Neurol Sci 275:69-73. doi: 10.1016/j.jns.2008.07.016

13. Hayden JA, Côté P, Bombardier C (2006) Evalua� on of the quality of prognosis studies in systema� c reviews. Ann Intern Med 144:427-437

14. Hayden JA, van der Windt DA, Cartwright JL, Côté P, Bombardier C (2013) Assessing bias in studies of prognos� c factors. Ann Intern Med 158:280-286. doi:10.7326/0003-4819-158-4-201302190-00009

15. Guya� GH, Oxman AD, Schünemann HJ, Tugwell P, Kno� nerus A (2011) GRADE guidelines: a new series of ar� cles in the Journal of Clinical Epidemiology. J Clin Epidemiol 64:380-382. doi:10.1016/j.jclinepi.2010.09.011

16. Huguet A, Hayden JA, S� nson J, McGrath PJ, Chambers CT, Tougas ME, Wozney L (2013) Judging the quality of evidence in reviews of prognos� c factor research: adap� ng the GRADE framework. Syst Rev 2:71. doi:10.1186/2046-4053-2-71

17. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Y� er Y, Meerpohl J, Norris S, Guya� GH (2011) GRADE guidelines: 3. Ra� ng the quality of evidence. J Clin Epidemiol 64:401-406. doi:10.1016/j.jclinepi.2010.07.015


43

2

18. Centre for Reviews and Dissemina� on York (2008) Systema� c Reviews. CRD’s Guidance for Undertaking Reviews in Health Care. Systema� c reviews of clinical tests;109-156. Available at h� p://www.york.ac.uk/inst/crd/pdf/Systema� c_Reviews.pdf

19. Gomeni R, Fava M; Pooled Resource Open-Access ALS Clinical Trials Consor� um (2014) Amyotrophic lateral sclerosis disease progression model. Amyotroph Lateral Scler Frontotemporal Degener 15:119-129. doi:10.3109/21678421.2013.838970

20. Clavelou P, Blanquet M, Peyrol F, Ouchchane L, Gerbaud L (2013) Rates of progression of weight and forced vital capacity as relevant measurement to adapt amyotrophic lateral sclerosis management for pa� ent Result of a French mul� centre cohort survey. J Neurol Sci 331:126-131. doi:10.1016/j.jns.2013.06.002

21. Elamin M, Bede P, Byrne S, Jordan N, Gallagher L, Wynne B, O’Brien C, Phukan J, Lynch C, Pender N, Hardiman O (2013) Cogni� ve changes predict func� onal decline in ALS: a popula� on-based longitudinal study. Neurology 80:1590-1597. doi:10.1212/WNL.0b013e31828f18ac

22. Körner S, Kollewe K, Ilsemann J, Müller-Heine A, Dengler R, Krampfl K, Petri S (2013) Prevalence and prognos� c impact of comorbidi� es in amyotrophic lateral sclerosis. Eur J Neurol 20:647-654. doi:10.1111/ene.12015

23. Reich-Slotky R, Andrews J, Cheng B, Buchsbaum R, Levy D, Kaufmann P, Thompson JL (2013) Body mass index (BMI) as predictor of ALSFRS-R score decline in ALS pa� ents. Amyotroph Lateral Scler Frontotemporal Degener 14:212-216. doi:10.3109/21678421.2013.77028

24. Paganoni S, Zhang M, Quiroz Zárate A, Jaff a M, Yu H, Cudkowicz ME, Wills AM (2012) Uric acid levels predict survival in men with amyotrophic lateral sclerosis. J Neurol 259:1923-1928. doi:10.1007/s00415-012-6440-7

25. Gordon PH, Cheng B, Salachas F, Pradat PF, Bruneteau G, Corcia P, Lacomblez L, Meininger V (2010) Progression in ALS is not linear but is curvilinear. J Neurol 257:1713-1717. doi:10.1007/s00415-010-5609-1

26. Sorarù G, Ermani M, Logroscino G, Palmieri A, D’ Ascenzo C, Orse ̀ V, Volpe M, Cima V, Zara G, Pegoraro E, Angelini C (2010) Natural history of upper motor neuron-dominant ALS. Amyotroph Lateral Scler 11:424-429. doi:10.3109/17482960903300867

27. Qureshi M, Shui A, Dibernardo AB, Brown RH Jr, Schoenfeld DA, Cudkowicz ME (2008) Medica� ons and laboratory parameters as prognos� c factors in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 9:369-374. doi:10.1080/17482960802163614

28. Krampe H, Bartels C, Victorson D, Enders CK, Beaumont J, Cella D, Ehrenreich H (2008) The infl uence of personality factors on disease progression and health-related quality of life in people with ALS. Amyotroph Lateral Scler 9:99-107. doi:10.1080/17482960701875805

29. Rauchway AC, Kaiboriboon K, Bansal SK, Kulkantrakorn K, Guo X, Parks BJ, Hayat GR (2007) A role for func� onal classifi ca� on in the early iden� fi ca� on of prognos� c factors in ALS. Amyotroph Lateral Scler 8:214-216

30. Qureshi MM, Hayden D, Urbinelli L, Ferrante K, Newhall K, Myers D, Hilgenberg S, Smart R, Brown RH, Cudkowicz ME (2006) Analysis of factors that modify suscep� bility and rate of progression in amyotrophic lateral sclerosis (ALS). Amyotroph Lateral Scler 7:173-182

31. De Carvalho M, Swash M (2006) Can selec� on of rapidly progressing pa� ents shorten clinical trials in amyotrophic lateral sclerosis? Arch Neurol 63:557-560

32. Chiò A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, Traynor BG; Eurals Consor� um (2009) Prognos� c factors in ALS: A cri� cal review. Amyotroph Lateral Scler 10:310-323. doi:10.3109/17482960802566824

Chapter 2

44

33. Franchignoni F, Mora G, Giordano A, Volan� P, Chiò A (2013) Evidence of mul� dimensionality in the ALSFRS-R Scale: a cri� cal appraisal on its measurement proper� es using Rasch analysis. J Neurol Neurosurg Psychiatry 84:1340-1345. doi:10.1136/jnnp-2012-304701

34. Grimby G, Tennant A, Tesio L. The use of raw scores from ordinal scales: � me to end malprac� ce? (2012) J Rehabil Med 44:97-98. doi:10.2340/16501977-0938

35. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC (2011) Amyotrophic lateral sclerosis. Lancet 377:942-955. doi:10.1016/S0140-6736(10)61156-7

36. Ravits JM, La Spada AR (2009) ALS motor phenotype heterogeneity, focality, and spread: deconstruc� ng motor neuron degenera� on. Neurology 8;73:805-811. doi:10.1212/WNL.0b013e3181b6bbbd

37. Su XW, Broach JR, Connor JR, Gerhard GS, Simmons Z (2014) Gene� c heterogeneity of amyotrophic lateral sclerosis: Implica� ons for clinical prac� ce and research. Muscle Nerve 49:786-803. doi:10.1002/mus.24198

38. Ganesalingam J, Stahl D, Wijesekera L, Galtrey C, Shaw CE, Leigh PN, Al-Chalabi A (2009) Latent cluster analysis of ALS phenotypes iden� fi es prognos� cally diff ering groups. PLoS One 4(9):e7107. doi:10.1371/journal.pone.0007107

39. Talman P, Forbes A, Mathers S (2009) Clinical phenotypes and natural progression for motor neuron disease: analysis from an Australian database. Amyotroph Lateral Scler 10:79-84. doi:10.1080/17482960802195871

40. Chiò A, Calvo A, Moglia C, Mazzini L, Mora G; PARALS study group (2011) Phenotypic heterogeneity of amyotrophic lateral sclerosis: a popula� on based study. J Neurol Neurosurg Psychiatry 82:740-746. doi:10.1136/jnnp.2010.235952

41. Sabatelli M, Zollino M, Luige ̀ M, Grande AD, La� ante S, Marangi G, Monaco ML, Madia F, Meleo E, Bisogni G, Conte A (2011) Uncovering amyotrophic lateral sclerosis phenotypes: clinical features and long-term follow-up of upper motor neuron-dominant ALS. Amyotroph Lateral Scler 12:278-282. doi:10.3109/17482968.2011.580849

42. Roche JC, Rojas-Garcia R, Sco� KM, Sco� on W, Ellis CE, Burman R, Wijesekera L, Turner MR, Leigh PN, Shaw CE, Al-Chalabi A (2012) A proposed staging system for amyotrophic lateral sclerosis. Brain 135(Pt 3):847-852. doi:10.1093/brain/awr351

43. Bedlack RS (2013) The Importance of Func� onal Assessment in Amyotrophic Lateral Sclerosis: a Clinical Review. Neurology reviews [Supplement];S1-S4. URL: h� p://www.neurologyreviews.com/fi leadmin/qhi_archive/Ar� clePDF/NR/0210100S1.pdf

44. Egger M, Zellweger-Zahner T, Schneider M, Junker C, Lengeler C, Antes G (1997) Language bias in randomised controlled trials published in English and German. Lancet 350:326-329

45. Moher D, For� n P, Jadad AR, Jüni P, Klassen T, Le Lorier J, Libera� A, Linde K, Penna A (1996) Completeness of repor� ng of trials published in languages other than English: implica� ons for conduct and repor� ng of systema� c reviews. Lancet 347:363-366

46. Vous� aniouk A, Seidel G, Panchal J, Sivak M, Czaplinski A, Yen A, Appel SH, Lange DJ (2008) ALSFRS and appel ALS scores: discordance with disease progression. Muscle Nerve 37:668-672. doi:10.1002/mus.20977

47. Riley RD, Hayden JA, Steyerberg EW, Moons KG, Abrams K, Kyzas PA, Malats N, Briggs A, Schroter S, Altman DG, Hemingway H; PROGRESS Group (2013) Prognosis Research Strategy (PROGRESS) 2: prognos� c factor research. PLoS Med 10:e1001380. doi:10.1371/journal.pmed.1001380


45

2

Appendix 1 Prognos� c factors related to outcome measures analysed in one study.

Prognos� c factor No. of par� cipants

Sta� s� cal analysis

Strength of associa� on Quality score

Level of evidenceConsidered judgement

Outcome: Decline in ALSFRS total score or ALSFRS-R total scoreSociodemographic characteris� csAge > 40 years 1 [30]

(n = 95)Mixed eff ects model

Not signifi cant ‘Very low’ evidence

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

Age at symptom onset < 54.9 years

1 [30](n = 95)

Mixed eff ects model


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

Race (Caucasian) 1 [30](n = 95)



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

Male veterans and male veterans performing ac� ve duty

1 [30](n = 95)


Male veterans and male veterans of ac� ve duty correlated signifi cantly with disease progression; mean (SD) changes in ALSFRS/month; -0.02 (+ 0.01) points. p=0.03

Not signifi cant

‘Very low’ evidence

There is ‘very low’ evidence that male veterans and male veterans of ac� ve duty is associated with a less worse func� onal decline.

Marital status 1 [30](n = 95)



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

Environmental factors ALS risk factors# 1 [30]

(n = 95)Mixed eff ects model


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

Chapter 2

46





Clinical characteris� cs: disease-related factors and func� onal factorsUMN-dominant ALS

1 [26](n = 40)

Friedman test

Addi� onal decline in ALSFRS-R 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


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

El Escorial criteria 1 [30](n = 95)



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

Familial ALS 1 [30](n = 95)



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

Family history of ALS

1 [30](n = 95)



There is ‘very low’ evidence that a family history of ALS is associated with a worse func� onal decline.

%change ALSFRS-R score from baseline at week 2

1 [19](n = 338)

Stepwise logis� c regression

%change ALSFRS-R score at week 2 was an independent 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.


1 [19](n = 338)


%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]




47

2





Change in ALSFRS in 3 month

1 [31](n = 57)

Mann-Whitney U-test

A cut-off point of 8.78% reduc� on in ALSFRS score (the 80th percen� le and 2 SD’s above the mean) iden� fi es 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.

Ini� al rate of disease progression

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

[19] Stepwise logis� c regression

[31] Mann-Whitney U-test

[19] %change ALSFRS-R score at week 2 was an independent 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]

[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� fi es pa� ents with a rapid disease progression,p<0.01


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

Biological markers of disease progressionUric acid levels 1 [24]

(n = 251)Mixed eff ects model (including BMI as a covariate)


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

Serum chloride level

1 [27](n = 795)


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


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

Chapter 2

48





Psychosocial factorsPersonality factors: neuro� cism, extraversion, openness, agreeableness, conscien� ousness (NEO-A)

1 [28](n = 31)


Lower baseline scores on agreeableness is associated with slower rate of disease progression.Time:β = -0.90 (SE = 0.12) points/month ALSFRS.p<0.001Agreeableness;β = -6.79 (SE = 3.17) points/month ALSFRS.p=0.045AgreeablenessXTime;β = -0.83 (SE = 0.31) points/month ALSFRS.p=0.016

Other personality factors (neuro� cism, openness, conscien� ousness, extraversion) not signifi cant.


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

Depression 1 [28](n = 31)



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

Clinical characteris� cs: func� onal factors%change ALSFRS-R score from baseline at week 2

1 [19](n = 338)


%change ALSFRS-R score at week 2 was an independent 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]




1 [19](n = 338)


%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]




49

2





Change in ALSFRS in 3 month

1 [31](n = 57)

Mann-Whitney U-test

A cut-off point of 8.78% reduc� on in ALSFRS score (the 80th percen� le and 2 SD’s above the mean) iden� fi es 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.

Outcome: Decline in ALSFRS-R domain scoreClinical characteris� cs: disease related factorsSite of onset 1 [21]

(n = 186)Mul� ple linear regression

Bulbar onset of disease predicts a more rapid decline in ALSFRS-R bulbar score;β = 0.156 (95% CI = 0.055 - 0.258) points/month.p=0.0003


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

Frontotemporal syndrome##

1 [21](n = 186 )

Mul� ple linear regression(n = 186)

Kruskal-Wallis test (n = 98)

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

Median change in bulbar 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


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 fi sh 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� cism-extroversion-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 coeffi cient, CI confi dence interval, FTD frontotemporal demen� a.

Chapter 2

50

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

First author Study par� cipa� on

Study a� ri� on

Prognos� c factor measurement

Outcome measurement

Sta� s� cal analysis and repor� ng

Overall quality

Reich-Slotky [23] Low Low Low Low Low +Clavelou [20] Low Moderate Low Low Low +Elamin [21] Low Moderate Low Low Low +Gordon [25] Low Moderate Low Low Low +Qureshi [27] Low Moderate Low Low Low +Gomeni [19] Moderate Moderate Low Low Low +/-Sorarù [26] Low Low Low Low High +/-Paganoni [24] Low High Low Low Moderate +/-Krampe [28] High Moderate Low Low Low +/-Rauchway [29] Low High Low Low Moderate +/-De Carvalho [31] Moderate Moderate Low Low High -Körner [22] Moderate High Moderate Low Moderate -Qureshi [30] Moderate High Moderate Low Moderate -

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

3The provision of assis� ve devices and home

adapta� ons to pa� ents with ALS in the Netherlands:

Pa� ents’ perspec� ves

Huub CreemersAnita BeelenHepke GrupstraFrans NolletLeonard H. van den Berg

Amyotrophic Lateral Sclerosis and Frontotemporal Degenera� on 2014. Sep;15(5-6):420-5.

© Reprinted with permission from Taylor & Francis Group

Chapter 3

52

ABSTRACT

Objec� veThe � 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.

MethodsWe 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.

ResultsOne hundred fi { 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� es’ lack of disease knowledge (24%). Pa� ents viewed these issues as the most prominent requiring improvement.

ConclusionThe 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.

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

53

3

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 fi 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 diff 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.

Chapter 3

54

MATERIALS AND METHODS

Pa� entsIn 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� onnaireOur self-administered ques� onnaire, specifi cally designed for this study, addressed diff erent 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 fi rst 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 offi ces (Excep� onal Medical Expenses Act). These authori� es judge the applica� on, take care of the fi nancing of the ADHA and commission suppliers to deliver the ADHA. The complexity of the procurement procedures may diff er 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 off er 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 specifi c 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.


55

3

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

fi nally receiving it (<1; 1–3; >3 months).• Whether the � me-span between the moment of applica� on for the ADHA and the

fi nal 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 fi nal 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 fi rst.

Data collec� on and analysisFor 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 fi rst 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 diff erences 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.

Chapter 3

56

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

Respondents(n=179)

Mean age (SD) years 62.6 (11.5)Male (%) 60Limb onset (%) 67Median ALSFRS-R [Q1-Q3] 36 [26−41]Median � me to diagnosis [Q1-Q3], months 12.0 [8.3−20.5]Median � me since diagnosis [Q1-Q3], months 17.3 [10.3−39.1]Specialized ALS care versus general ALS care (%) 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: fi rst quar� le to third quar� le.

Table 2 Use of ADHA.

ICF a code Assis� ve devices and home adapta� ons n (%) b

e1 Products and technology e115 Products and technology for personal use in daily livinge1151 Bathroom adapta� ons 118 (66)e1151 Electric li{ recliner chair 88 (49)e1151 Electrically operated bed 75 (42)e1151 Shower, toilet and commode chair 59 (33)e1151 Shower chair 57 (32)e1151 Pressure-relieving ma� ress and pressure-relieving cushion 52 (29)e1151 Toilet chair 20 (11)e1151 Mobile arm support device 16 (9)e1151 Elbow crutches 14 (8)e1151 Mechanical page turner 13 (7)e1151 Mul� -adjustable table 11 (6)e120 Products and technology for personal indoor and outdoor mobility and

transporta� one1201 Rollator walker 116 (65)e1201 Electric wheelchair 73 (41)e1201 Modular system chair with castors 66 (33)e1201 Electric pa� ent li{ 50 (28)e1201 Mobility scooter 43 (24)e1201 Stair li{ system 43 (24)e125 Products and technology for communica� one1251 Communica� on devices 54 (30)e1251 Computer so{ - and hard-ware 30 (17)e5 Services, systems and policiese540 Transporta� on services, systems and policiese5400 Disabled parking permit 111 (62)e575 General social support services, systems and policiese5750 Home care services 116 (65)

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


57

3

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 insuffi cient 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 ADHAb

Time-span< 1 monthc

Time-span1 - 3 monthsc

Time-span≥ 3 monthsc

Time-span not acceptablec

Insuffi cient quality of the procurement processd

n (%) n (%) n (%) n (%) n (%) n (%) n (%)

Bathroom adapta� ons

118 (66) 111 (94) 20 (18) 30 (27) 60 (54) 33 (30) 18 (16)

Manual wheelchair

116 (65) 114 (98) 51 (45) 49 (43) 14 (12) 14 (12) 7 (6)

Home care services

116 (65) 109 (94) 62 (57) 32 (29) 15 (14) 16 (14) 23 (20)

Disabled Parking Permit

111 (62) 103 (93) 58 (56) 32 (31) 11 (10) 15 (14) 22 (20)

Stair li{ 37 (21) 25 (68) 5 (20) 7 (28) 13 (52) 2 (8) 2 (8)

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 fi nal delivery.d n (%) of pa� ents who judged the en� re procurement process as insuffi cient 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 specifi c needs for ADHA to be burdensome. The most frequent diffi cul� 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 offi ce reported that they were subjected to repeated medical examina� ons.

Chapter 3

58

Table 4 Themes of problem areas pa� ents with ALS perceived in obtaining ADHA.

n (%)a

The long dura� on of the process of applica� on and provision 39 (42)Authori� es’ lack of knowledge about disease characteris� cs of ALS/MND 22 (24)The bureaucracy and paperwork 15 (16)Lack of clarity of the legal procedures and informa� on 15 (16)Errors by the suppliers /wrong confi gura� on /malfunc� on 13 (14)Dependency /refusal /no opportunity to comment 13 (14)Home care services /needs assessment 6 (6)Financial problems 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 offi ces). 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 offi ces. This can be explained by the fact that these agencies manage a stock of assis� ve devices which can be provided immediately upon request.


59

3

Figure 1 Comparison of problems indicated by pa� ents with ALS in obtaining ADHA from municipali� es.

3

��

��

��

��

"��

��

��

��*�� 4�� *��

5�0�� *�� **��)�*��6��&��5��-��-�1��0�

a and from health insurance companies b. a % 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.

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� ent’s part in ini� a� ng the requests cannot be ruled out.

A remarkable fi nding was the rela� vely low propor� on of pa� ents who perceived the � me-span for the fi ve selected ADHA as not acceptable – 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 fi 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 fi ve ADHA to be suffi 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.

Chapter 3

60

Delay is confi rmed 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. Diff erences exist in the authori� es’ judgement as to whether or not a pa� ent meets the criteria for a permit or, more specifi cally, if the approving authority is willing to take the progressive nature of the disease into considera� on.

A striking diff erence with other studies is our fi nding that problems related to the fi nancing 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 fi nanced by health insurers and municipali� es and − within certain fi nancial limits − pa� ents receive these ADHA free of charge. For some of the ADHA, however, e.g., architectural home adapta� ons, a fi nancial 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 diff er 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 diff er 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 aff ected 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 eff ect of the quality of communica� on between clinics and systems on pa� ents’ experiences.

Clinical implica� ons and future studiesTimely 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


61

3

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 fi ndings 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 eff ec� 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.

Chapter 3

62

REFERENCES

1. Turner-Stokes L, Sykes N, Silber E. Long-term neurological condi� ons: management at the interface between neurology, rehabilita� on and pallia� ve care. Clin Med 2008 Apr;8(2):186-191.

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

3. Brownlee A, Palovcak M. The role of augmenta� ve communica� on devices in the medical management of ALS. NeuroRehabilita� on 2007;22(6):445-450.

4. Davies A, De Souza LH, Frank AO. Changes in the quality of life in severely disabled people following provision of powered indoor/outdoor chairs. Disabil Rehabil 2003 Mar 18;25(6):286-290.

5. Souza A, Kelleher A, Cooper R, Cooper RA, Iezzoni LI, Collins DM. Mul� ple sclerosis and mobility-related assis� ve technology: systema� c review of literature. J Rehabil Res Dev 2010;47(3):213-223.

6. Van Teijlingen ER, Friend E, Kamal AD. Service use and needs of people with motor neurone disease and their carers in Scotland. Health Soc Care Community 2001 Nov;9(6):397-403.

7. Henschke C. Provision and fi nancing of assis� ve technology devices in Germany: a bureaucra� c odyssey? The case of amyotrophic lateral sclerosis and Duchenne muscular dystrophy. Health Policy 2012 May;105(2-3):176-184.

8. Van den Berg JP, Kalmijn S, Lindeman E, Wokke JH, van den Berg LH. Rehabilita� on care for pa� ents with ALS in The Netherlands. Amyotroph Lateral Scler Other Motor Neuron Disord 2003 Sep;4(3):186-190.

9. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, et al. The ALSFRS-R: a revised ALS func� onal ra� ng scale that incorporates assessments of respiratory func� on. BDNF ALS Study Group (Phase III). J Neurol Sci 1999 Oct 31;169(1-2):13-21.

10. Chio A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, et al. Prognos� c factors in ALS: A cri� cal review. Amyotroph Lateral Scler 2009 Oct;10(5-6):310-323.

11. Wessels RD, De Wi� e LP, Jedeloo S, van den Heuvel WP, van den Heuvel WJ. Eff ec� veness of provision of outdoor mobility services and devices in The Netherlands. Clin Rehabil 2004 Jun;18(4):371-378.

12. Jedeloo S, De Wi� e LP, Linssen BA, Schrijvers AJ, Jedeloo S, De Wi� e LP, et al. Client sa� sfac� on with service delivery of assis� ve technology for outdoor mobility. Disabil Rehabil 2002 Jul;24(10):550-557.

13. O’Brien MR, Whitehead B, Murphy PN, Mitchell JD, Jack BA. Social services homecare for people with motor neurone disease/amyotrophic lateral sclerosis: Why are such services used or refused? Palliat Med 2012 Mar;26(2):123-131.

14. Rolfe J. Planning wheelchair service provision in motor neurone disease: implica� ons for service delivery and commissioning. Bri� sh Journal of Occupa� onal Therapy 2012 May; 75(5):217-222.

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

16. 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.

17. 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.

18. 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.


63

3

19. 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.

20. 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.

21. 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.

22. 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.

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

4Cluster RCT of case management on pa� ents’ quality

of life and caregiver strain in ALS

Huub CreemersJan H. VeldinkHepke GrupstraFrans NolletAnita BeelenLeonard H. van den Berg.

Neurology 2014. Jan;82(1):23-31.

© Reprinted with permission from Wolters Kluwer Health

Chapter 4

66

ABSTRACT

Objec� vesTo study the eff ect 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.

MethodsWe 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.

ResultsCase 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 signifi cantly (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 signifi cantly during follow-up.

ConclusionWithin the context of mul� disciplinary ALS care teams, case management appears to confer no benefi t for pa� ents with ALS or their caregivers.

Classifi ca� on of EvidenceThis study provides Class III evidence that case management in addi� on to mul� disciplinary ALS care does not signifi cantly improve health-related quality of life of pa� ents with ALS.

Eff ec� veness of case management in ALS

67

4

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 designWe performed a cluster randomized controlled trial (RCT) with the mul� disciplinary ALS team as the unit of randomiza� on (fi gure 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 aff ect 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.

Chapter 4

68

Standard Protocol Approvals, Registra� ons, and Pa� ent ConsentsThe 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.

ClustersWe 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 aff ect 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� fi ed 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� cipantsThe 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 insuffi cient mastery of the Dutch language, and ins� tu� onaliza� on. The exclusion criterion for caregivers was insuffi cient mastery of the Dutch language.

BlindingIn 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� onsUsual careUsual 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.


69

4

Case managementWe 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 fi rst 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 (client-centered 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.

Chapter 4

70

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 measuresThe 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 fi ve 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 fi ve 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-specifi c measure to assess func� on 23; a lower score indicates more disability.

Data analysisA 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 diff erence 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 coeffi cient (� me interval 4 months) of 0.75 at a signifi cance level of 0.05 (one-sided) 24. We calculated the sample size without taking into account the intracluster correla� on coeffi cient, 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 non-par� 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 diff erences in outcomes between the interven� on and control group over � me and to adjust for the clustering of the data 25. In case of signifi cant diff erences in baseline characteris� cs of pa� ents and caregivers between the interven� on and control group, we adjusted for these variables.


71

4

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 coeffi cients for the eff ects 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 eff ects 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.

RESULTS

Cluster randomiza� onThirty-one mul� disciplinary ALS teams (72%) agreed to par� cipate in the study (fi gure 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� cipantsFrom 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 (fi gure 1). Baseline sociodemographic and clinical characteris� cs of pa� ents and caregivers did not diff er 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 diff er signifi cantly 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.

Chapter 4

72

Figure 1 Flow of clusters and individual par� cipants.

ALS teams

invited to participate the study

n=44

Randomization of ALS teams

n=31

No consent

n=13

Completed the trial:

Patients n=43 Caregivers n=41

Death: n=23 Patient’s death: n=22

Stop: n=5 Stop: n=3

Number of evaluations of:

Patients n=173

Caregivers n=164

Intervention:

case management + usual care

Enrolment:

Patients n=71

Caregivers n=66

Enrollment of ALS teams

Control:

usual care

Enrolment:

Patients n=61

Caregivers n=60

Completed the trial:

Patients n=36 Caregivers n=35

Death: n=15 Patient’s death: n=15

Stop: n=10 Stop: n=10

Number of evaluations of:

Patients n=152

Caregivers n=142

Analysis

Intervention teams n=16

Patients n=155

ALS patients

No consent

n=166

Baseline

Control teams n=15

Patients n=143

Allocation of ALS teams

ALS = amyotrophic lateral sclerosis.


73

4

Table 1 Baseline characteris� cs of study par� cipants.

Pa� ent variables Interven� on (n=71)

Control (n=61)

p Value

Mean age (SD), y 63 (11) 62 (11) 0.680Male 57 64 0.786Married 83 84 0.789Primary caregiver is partner 82 84 0.474Caucasian ethnicity 100 97 0.307College or university degree 42 31 0.190Employed 7 15 0.168Limb onset 73 79 0.466Median � me since onset (Q1-Q3), y 1.8 (1.2 – 3.5) 2.2 (1.2 – 3.9) 0.600Median � me since diagnosis (Q1-Q3), y 0.9 (0.3 – 1.7) 0.9 (0.4 – 2.3) 0.277Mean predicted FVC % (SD) 86 (23) 83 (24) 0.627PEG 14 21 0.275NIV/IV 17 18 0.864Riluzole 91 95 0.398Mean ALSFRS-R (SD) 32 (8) 32 (9) 0.685Mean ALSAQ-40 Emo� onal Func� oning (SD) 21 (18) 19 (17) 0.524Mean ALSAQ-40 sum score (SD) 37 (17) 37 (18) 0.919Mean quality of care ra� ng score (SD) 8.2 (0.8) 8.3 (0.8) 0.803Caregiver variables Interven� on

(n=66)Control (n=60)

p Value

Mean age (SD), y 59 (14) 57 (15) 0.922Female 70 62 0.342Married 94 90 0.463Caucasian ethnicity 97 95 0.463College or university degree 37 27 0.197Employed 23 32 0.305Mean CSI (SD) 6 (3) 5 (3) 0.184Mean quality of care score “care for the pa� ent” (SD) 8.0 (0.9) 8.2 (1.1) 0.298Mean quality of care score “care for the caregiver” (SD) 7.6 (1.4) 7.8 (1.6) 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 = fi rst quar� le to third quar� le; SD = standard devia� on; y = years.Values are percentages unless otherwise indicated.

Case managementThe 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 diff ered 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

Chapter 4

74

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.

Eff ec� veness of case managementDespite signifi cant disease progression, emo� onal well-being as refl ected by ALSAQ-40 EF did not change over � me. No signifi cant diff erence in ALSAQ-40 EF score was detected between the interven� on group and the usual care group (table 2 and fi gure 2).

Caregiver strain (CSI) increased signifi cantly during the study period in both groups, without diff erences 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 signifi cantly aff ect the QOC ra� ng score.


75

4

Table 2 Eff ects of case management and usual care at baseline and 4, 8, and 12 months.

Outcome measures

Case managementa

Mean (SD), nUsual carea

Mean (SD), nLinear Mixed Modelβ (SE); p-value

1. ALSAQ-40 Emo� onal Func� oning (0 – 100)b

Baseline4 months8 months12 months

21.3 (18.2), 7019.8 (14.6), 4321.5 (13.5), 2822.8 (16.4), 30

19.3 (17.0), 6119.4 (16.6), 3920.0 (16.1), 2219.1 (14.7), 27

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

2. CSI (0-13)b


5.8 (3.4), 667.1 (3.4), 427.0 (3.6), 257.9 (2.9), 29

5.0 (2.9), 596.4 (3.1), 377.4 (3.5), 207.3 (3.2), 24

Time: 0.60 (0.11)p < 0.0001c

Time x Group: -0.08 (0.15)p = 0.59

3. QOC report mark pa� ents with ALS (1 – 10)d


8.2 (0.8), 658.2 (0.9), 438.1 (1.0), 287.9 (0.9), 30

8.3 (0.8), 558.0 (0.7), 378.0 (1.1), 238.0 (0.7), 25

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

4. QOC report mark caregivers: pa� ent care (1 – 10)d


8.0 (0.9), 638.3 (0.8), 408.0 (0.9), 267.9 (0.7), 27

8.2 (1.1), 598.2 (0.8), 378.1 (0.8), 187.9 (0.9), 24

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

5. QOC report mark caregivers: caregiver care (1 – 10)d


7.6 (1.4), 567.7 (1.0), 387.3 (1.6), 257.3 (1.3), 25

7.8 (1.6), 497.7 (1.2), 337.6 (1.0), 167.1 (1.0), 22

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

Disease progression: ALSFRS-R (0 – 48)d


32.1 (7.9), 7129.9 (7.0), 4327.4 (7.1), 2724.0 (9.3), 28

31.6 (8.8), 6127.6 (10.2), 3727.8 (11.0), 2025.1 (11.5), 25

Time: -2.64 (0.40)p < 0.0001c

Time x Group: -0.26 (0.54)p = 0.63

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 coeffi cient for the eff ect 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 diff erent for both groups.a Intracluster correla� on coeffi cient (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.

Chapter 4

76

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 signifi cant benefi 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


77

4

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 eff ect of case management models in ALS, future studies must be conducted in other health care systems.

In other diseases, eff ec� veness of case management on pa� ents’ QOL has been demonstrated 28,29, although the evidence is limited due to inconsistent fi ndings 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� fi ed 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 infl uence 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-specifi c health-related QOL measure to evaluate the eff ect 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 eff ect on those measures. However, the lack of eff ect does not seem to be due to the scales used as we did not fi nd an eff ect on any other outcome measure.

In addi� on to the lack of eff ec� 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 fi nding 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 fi nding of an increasing burden for caregivers indicates the need for a more prominent role of interven� ons targe� ng caregivers in future studies.

Chapter 4

78

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 eff ect on the power of the study considering the size of the mul� level regression interac� on coeffi cient for the eff ect 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 eff ect” 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 eff ect of diff erent 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.


79

4

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.

Chapter 4

80

REFERENCES

1. Van den Berg JP, Kalmijn S, Lindeman E, et al. Mul� disciplinary ALS care improves quality of life in pa� ents with ALS. Neurology 2005 Oct 25;65(8):1264-1267.

2. Turner-Stokes L, Sykes N, Silber E. Long-term neurological condi� ons: management at the interface between neurology, rehabilita� on and pallia� ve care. Clin Med 2008 Apr;8(2):186-191.

3. 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 Mar;19(3):360-375.

4. Miller RG, Jackson CE, Kasarskis EJ, et al. Prac� ce parameter update: the care of the pa� ent with amyotrophic lateral sclerosis: drug, nutri� onal, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommi� ee of the American Academy of Neurology. Neurology 2009 Oct 13;73(15):1218-1226.

5. 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.

6. Ng L, Talman P, Khan F. Motor neurone disease: disability profi le and service needs in an Australian cohort. Int J Rehabil Res 2011 Jun;34(2):151-159.

7. Reagan P, Hurst R, Cook L, et al. Physician-assisted death: dying with dignity? Lancet Neurol 2003 Oct;2(10):637-643.

8. Long MJ. Case management model or case manager type? That is the ques� on. Health Care Manag 2002 Jun;20(4):53-65.

9. Wynia K, Annema C, Nissen H, De KJ, Middel B. Design of a Randomised Controlled Trial (RCT) on the eff ec� veness of a Dutch pa� ent advocacy case management interven� on among severely disabled Mul� ple Sclerosis pa� ents. BMC Health Serv Res May 27; 2010;10:142.

10. Meier DE, Thar W, Jordan A, Goldhirsch SL, Siu A, Morrison RS. Integra� ng case management and pallia� ve care. J Palliat Med 2004 Feb;7(1):119-134.

11. Van den Berg JP, Kalmijn S, Lindeman E, Wokke JH, van den Berg LH. Rehabilita� on care for pa� ents with ALS in The Netherlands. Amyotroph Lateral Scler Other Motor Neuron Disord 2003 Sep;4(3):186-190.

12. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A prac� cal method for grading the cogni� ve state of pa� ents for the clinician. J Psychiatr Res 1975 Nov;12(3):189-198.

13. Van den Berg JP, de Groot IJ, Joha BC, van Haelst JM, van Gorcom P, Kalmijn S. Development and implementa� on of the Dutch protocol for rehabilita� ve management in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2004 Dec;5(4):226-229.

14. Averill AJ, Kasarskis EJ, Segerstrom SC. Psychological health in pa� ents with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2007 Aug;8(4):243-254.

15. Oeseburg B, Wynia K, Middel B, Reijneveld SA. Eff ects of case management for frail older people or those with chronic illness: a systema� c review. Nurs Res 2009 May;58(3):201-210.

16. Rheaume A, Frisch S, Smith A, Kennedy C. Case management and nursing prac� ce. J Nurs Adm 1994 Mar;24(3):30-36.

17. Client-centred prac� ce: what does it mean and does it make a diff erence?18. Law M, Bap� ste S, Mills J. Can J Occup Ther. 1995 Dec;62(5):250-257.19. Epton J, Harris R, Jenkinson C. Quality of life in amyotrophic lateral sclerosis/motor neuron disease: a

structured review. Amyotroph Lateral Scler 2009 Feb;10(1):15-26.


81

4

20. Jenkinson C, Fitzpatrick R, Brennan C, Bromberg M, Swash M. Development and valida� on of a short measure of health status for individuals with amyotrophic lateral sclerosis/motor neurone disease: the ALSAQ-40. J Neurol 1999 Nov;246 Suppl 3:III16-III21.

21. 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 fi ve-item version (ALSAQ-5) in a longitudinal survey. Clin Rehabil 2007 Mar;21(3):266-272.

22. 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.

23. Robinson BC. Valida� on of a Caregiver Strain Index. J Gerontol 1983 May;38(3):344-348.24. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS func� onal ra� ng scale that

incorporates assessments of respiratory func� on. BDNF ALS Study Group (Phase III). J Neurol Sci 1999 Oct 31;169(1-2):13-21.

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

26. Twisk JWR. Applied Mul� level Analysis. A Prac� cal Guide. 1st ed. Cambridge University Press; 2006.27. Foley G, O’Mahony P, Hardiman O. Percep� ons of quality of life in people with ALS: eff ects of coping

and health care. Amyotroph Lateral Scler 2007 Jun;8(3):164-169.28. 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.

29. Aiken LS, Butner J, Lockhart CA, Volk-Cra{ BE, Hamilton G, Williams FG. Outcome evalua� on of a randomized trial of the PhoenixCare interven� on: program of case management and coordinated care for the seriously chronically ill. J Palliat Med 2006 Feb;9(1):111-126.

30. Moore S, Corner J, Haviland J, Wells M, Salmon E, Normand C, et al. Nurse led follow up and conven� onal medical follow up in management of pa� ents with lung cancer: randomised trial. BMJ 2002 Nov 16;325(7373):1145.

31. 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: 10.1186/1472-6963-8-227.:227-228.

32. Fegg MJ, Kögler M, Brandstä� er M, Jox R, Anneser J, Haarmann-Doetko� e S, et al. Meaning in life in pa� ents with amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010 Oct;11(5):469-474.

33. Clarke S, Hickey A, O’Boyle C, Hardiman O. Assessing individual quality of life in amyotrophic lateral sclerosis. Qual Life Res. 2001;10(2):149-158.

34. Mus] a N, Walsh E, Bryant V, et al. The eff ect of noninvasive ven� la� on on ALS pa� ents and their caregivers. Neurology 2006 Apr 25;66(8):1211-1217.

35. Gauthier A, Vignola A, Calvo A, et al. A longitudinal study on quality of life and depression in ALS pa� ent-caregiver couples. Neurology 2007 Mar 20;68(12):923-926.

36. Messina P, Beghi E. Modeling drop-outs in amyotrophic lateral sclerosis. Contemp Clin Trials 2012 Jan;33(1):218-222.

37. Jenkinson C, Harris R, Fitzpatrick R. The Amyotrophic Lateral Sclerosis Assessment Ques� onnaire (ALSAQ-40): evidence for a method of impu� ng missing data. Amyotroph Lateral Scler 2007 Apr;8(2):90-95.

38. Renders CM, Valk GD, de Sonnaville JJ, et al. Quality of care for pa� ents with Type 2 diabetes mellitus--a long-term comparison of two quality improvement programmes in the Netherlands. Diabet Med 2003 Oct;20(10):846-852.

Chapter 4

82

39. Howgego IM, Yellowlees P, Owen C, Meldrum L, Dark F. The therapeu� c alliance: the key to eff ec� ve pa� ent outcome? A descrip� ve review of the evidence in community mental health case management. Aust N Z J Psychiatry 2003 Apr;37(2):169-183.

40. Yamashita M, Forchuk C, Mound B. Nurse case management: nego� a� ng care together within a developing rela� onship. Perspect Psychiatr Care 2005 Apr;41(2):62-70.


83

4

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 62.9 (11.2) 63.4 (11.7) 0.702Male 65 57 0.151Married 83 77 0.375Primary caregiver is partner 83 67 0.312Caucasian ethnicity 99 96 0.326College or university degree 42 30 0.190Limb onset 76 70 0.233Median � me since onset (Q1-Q3), years 2.1 (0.3 - 12.6) 2.3 (0.1 - 22.7) 0.372Median � me since diagnosis (Q1-Q3), years 0.9 (0.05 - 12.1) 1.1 (0.01 - 22.2) 0.446Mean predicted FVC % (SD) 85 (22) 81 (21) 0.325PEG use 17 19 0.680NIV/IV use 17 13 0.273Riluzole 93 90 0.326Median ALSFRS-R (Q1-Q3) 33 (26 – 39) 32 (26 – 40) 0.868

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 = fi rst 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.

2

3

5

7

7

9

10

10

12

13

19

19

31

35

37

38

39

Social services / voluntary work

Supporting children

Respite care

Durable power of attorney

Work

Respiratory care / NIV

Advance directives / end of life decisions

Transportation services

Domestic life services

Nutrition / PEG

Finances

Personal care services

Palliative care provision

Psychosocial

Symptoms

Activities and participation

Provision of assistive products and technology

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

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

5Need 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 BakkerHuub CreemersKaren SchipperAnita BeelenHepke F. GrupstraFrans Nollet

Tineke A. Abma

Amyotrophic Lateral Sclerosis and Frontotemporal Degenera� on 2015. Jun;16(3-4):180-6.

© Reprinted with permission from Taylor & Francis Group

Chapter 5

86

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� fi 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.

Need and value of case management in ALS

87

5

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 eff ect of case management, provided in addi� on to usual care and tailored to pa� ents’ needs, was performed. Case management started by off ering 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 benefi ts 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 benefi ts 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� fi es 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 designIn 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 specifi cally, we aimed to iden� fy factors that might infl uence how and why people with ALS and their carers engage with case management care 9.

Data collec� on processUsing 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

Chapter 5

88

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

Par� cipants: interviewsWe 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 (defi ned 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 benefi t from case management (judged by the case manager). Also, we enrolled pa� ents from diff erent ALS teams, because the care delivered by the ALS teams may diff er.

Par� cipants: focus groupWe recruited par� cipants for the focus group via purposive selec� on to create a diverse group with equal numerical representa� on of the diff erent groups of stakeholders. The aim of the focus group was to enhance the credibility of the fi ndings, 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 diff erent disciplinary backgrounds of the professionals.

Data collec� onTo 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 aff ected 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


89

5

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 analysisFor this study we used induc� ve content analysis 13. This approach moves from the specifi c 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 fi nal 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.

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

Table I. Quality procedures.

Procedure Explana� on and reasonMember check 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 Diff erent inves� gators were involved in the analysis process. The inves� gators arrived at the same conclusions, which heightened our confi dence 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 diff erent 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� fi ed indica� ng that satura� on was reached 25.

Chapter 5

90

Ethics considera� onsThe 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. Confi den� 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 infl uence 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).


91

5

Table II. Quota� ons about the func� oning of the mul� disciplinary ALS care.

1. “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)

2. “The case manager fi lled the gaps of the regular care of the ALS team. (…) The regular care consists of separate “isles”.” (R7, male pa� ent, 57 , medium progression)

3. “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 infl uence 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. “In case of rapid progression, people are more in need of support, to try to get everything organized in � me.” (R24, case manager)

2. “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)

3. “I think my need for support will increase as he will suff er 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 infl uenced by the personal factors of pa� ents. Some couples were independent, self-suffi cient and wanted to organize the care themselves (Table IV, quote 1). Other couples were less self-asser� ve or less self-suffi cient, 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 infl uenced 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).

Chapter 5

92

Table IV. Quota� ons about the personal factors.

1. “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)

2. “We already have a lot of experience, because of our son (who has Duchenne, eds). Back then, it felt very diff erent, 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)

3. “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 infl uenced the need for case management. Professionals recognised a diff erence 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 infl uenced 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. “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)

2. “The kids take care of a whole bunch of things.” (R15, female caregiver, 74, slow progression)

3. “The prac� cal help (is important, eds), for example that people are willing to mow the lawn. That kind of prac� cal support defi nitely 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.


93

5

Table VI. Quota� ons about house calls.

1. “A{ er a short term, he made house calls. That was very nice!” (R1, female pa� ent, 55, rapid progression)

2. “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 diff erent from having a conversa� on at the coff ee 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. “I think it’s much easier this way, because the case manager sits here at the coff ee table in my own house, not restrained by the idea that he has another appointment. That is very diff erent 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 fi nish the session even if we were not fi nished 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)

2. “As soon as I walk into a hospital (…) I have the feeling that the � me is limited.” (R12, male caregiver, 55, rapid progression)

3. “I think the fact that the case manager makes house calls and has ample � me is the most important.” (R33, rehabilita� on medicine consultant)

4. “The next couple of years, the possibili� es will only decrease instead of increase.” (professional)

5. “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).

Chapter 5

94

Table VIII. Quota� ons about proac� ve care.

1. “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)

2. “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 refl ec� 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. “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)

2. “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)

3. “The consulta� ons with the case manager helped me to refl ect on the situa� on.” (R2, male pa� ent, 51, medium progression)

4. “It gives you the possibility to tell your story again. That makes it more bearable” (R18, female caregiver, 51, medium progression)

DISCUSSION

Principle fi ndingsThis 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 aff ect 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 managementThe RCT on case management showed no signifi cant benefi t to pa� ents’ QOL, caregiver strain, or increased sa� sfac� on with care of pa� ents and caregivers when added to the


95

5

usual mul� disciplinary ALS care 3. Our fi ndings 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-suffi ciency, adequate coping and a suppor� ve social network.

Comparison with other studiesExperiences with case management in the context of ALS care have, to our knowledge, not to date been inves� gated. Relevant studies in other fi elds 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 diff erent 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� onsThe 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 fi nancing and reimbursement are well organized 2. Responsiveness to case management might be infl uenced by this specifi c context. Readers can assess whether fi ndings 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 diff erent from those men� oned in the current data. Further research is required to explore the impact of other medical, interpersonal and fi nancial factors on care needs.

Clinical implica� onsExperiences with case management can be used to improve the usual ALS care. Our results suggest that in specifi c circumstances aspects of case management can be of added value to the mul� disciplinary ALS care. Therefore, it is important to iden� fy the specifi c circumstances of individual pa� ents and their caregivers. These specifi c 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.

Chapter 5

96

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 off 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.


97

5

REFERENCES

1. Mitsumoto H, Del Bene M. Improving the quality of life for people with ALS: the challenge ahead. Amyotroph Lateral Scler 2000;1:329-36.

2. Van den Berg JP, Kalmijn S, Lindeman E, Veldink JH, de Visser M, van der Graaff MM, et al. Mul� disciplinary ALS care improves quality of life in pa� ents with ALS. Neurology 2005;65(8):1264-7.

3. 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.

4. Turner-Stokes L, Sykes N, Silber E. Long-term neurological condi� ons: management at the interface between neurology, rehabilita� on an pallia� ve care. Clin Med 2008 Apr;8(2):186-91.

5. Ng L, Talman P, Kahn F. Motor neurone disease: disability profi le and service needs in an Australian cohort. Int J Rehabil Res 2011;34(2):151-9.

6. Reagan P, Hurst R, Cook L. Physician-assisted death: dying with dignity? Lancet Neurology 2003;2(10):637-43.

7. Long MJ. Case management model or case manager type? That is the ques� on. Health Care Manag 2002;20(4):53-65.

8. Lincoln YS, Guba EG. Naturalis� c Inquiry. Beverly Hills: Sage Publica� ons; 1985.9. Guba EG, Lincoln YS. Fourth Genera� on Evalua� on. Beverly Hills: Sage Publica� ons; 1989.10. Baur VE, Abma TA, Widdershoven GAM. Par� cipa� on of marginalized groups in evalua� on: mission

impossible? Eval Program Plann 2010;33(3):238-45.11. Kollewe K, Mauss U, Krampfl K, Petri S, Dengler R, Mohammadi B. ALSFRS-R score and its ra� o: a

useful predictor for ALS-progression. J Neruol Sci 2008;275:69-73.12. Lambert SD, Loiselle CG. Combining individual interviews and focus groups to enhance data richness.

J Adv Nurs 2008;62(2):228-37.13. Charmaz K. Grounded theory in the 21st century. Applica� ons for advancing social jus� ce studies.

In: Denzin NK, Lincoln YS, editors. The Sage Handbook of Qualita� ve Research.Thousand Oaks: Sage Publica� ons; 2005.

14. Elo S, Kyngäs H. The qualita� ve content analysis process. J Adv Nurs 2008;62(1):107-15.15. Mays N. Qualita� ve research in health care. Assessing quality in qualita� ve research. BMJ

2000;320(7226):50-2.16. Warren J, Garthwaite K, Bambra C. ‘It was just nice to be able to talk to somebody’: long-term

incapacity benefi t recipients’ experiences of a case management interven� on. J Public Health (Oxf) 2013;35(4):518-24.

17. 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.

18. Brown JB. User, carer, and professional experiences of care in motor neuron disease. Prim Health Care Res Dev 2003;4:207-17.

19. Herbert RS, Lacomis D, Easer C, Frick V, Shear MK. Grief support for informal caregivers of pa� ents with ALS: A na� onal survey. Neurology 2005;64:137-8.

20. Foley G, Timonen V, Hardiman O. Pa� ents’s percep� ons of services and preferences for care in amyotorphic lateral sclerosis: A review. Amyotroph Lateral Scler 2012;13:11-24.

21. Goldstein LH, Atkins L, Leigh PN. Correlates of Quality of Life in people with motor neuron disease (MND). Amyotroph Lateral Scler 2002;3(3):123-9.

22. Beisecker AE, Cobb AK, Ziegler DK. Pa� ents’ perspec� ves of the role of care providers in amyotrohpic lateral sclerosis. Arch Neurol 1988;45(5):553-6.

Chapter 5

98

23. Abma TA, Stake RE. Stake’s responsive evalua� on: Core ideas and evolu� on. New direc� ons for evalua� on 2001;92:7-22.

24. Guion LA. Triangula� on: establishing the validity of qualita� ve studies. Florida Ins� tute of Food and Agricultural Services . 2002. h� p://edis.ifas.ufl .edu/fy394. 20-1-2014.

25. Meadows LM, Morse JM. Construc� n Evidence Within The Qualita� ve Project. In: Morse JM, Swanson JM, Kuzel AJ, editors. The Nature of Qualita� ve Evidence.Thousand Oaks: Sage Publica� ons; 2001.

26. Brown J, Addington-Hall J. How people with motor neurone disease talk about living with their illness: a narra� ve study. J Adv Nurs 2008;62(2):200-8.

27. Fegg MJ, Brandstä� er M, Jox R, Anneser J, Haarmann-Doetko� e S, Wasner M, et al. Meaning in life in pa� ents with Amyotrophic Lateral Sclerosis. Amyotroph Lateral Scler 2010;11(5):469-74.

28. Nelson ND, Trail M, Van JN, Appel SH, Lai EC. Quality of life in pa� ents with Amyotrophic Lateral Sclerosis: percep� ons, coping resources, and illness characteris� cs. J Palliat Med 2003;6(3):417-24.


99

5

Appendix 1. Study phases.

Phase Ac� vi� es GoalExplora� on Reading literature and stories

of pa� ents.Ge ̀ ng insight into living with ALS and ge ̀ ng input for the topic list.

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.

Consulta� on Recrui� ng par� cipants. Making contact by telephone, sending the informa� on le� er about the content of the study.

Semi-structured interviews (n=30).

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.

Collabora� on Thema� c content analyses of the interviews.

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

Mee� ng of the research team.

Valida� ng and deepening the analyses of the interviews.

One focus-group (n=20) 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� ents’ and caregivers’ 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.

Chapter 5

100

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 infl uence 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 fi nal 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

• 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?


101

5

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?

The period a er case management

• How did you feel about fi nishing 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

Chapter 5

102

• Member check possible?

• Explain that the respondents will receive a copy of the fi nal report

Personal details

• Educa� on

• Experience with ALS care

• Age

• Gender

Experiences with the case manager

• What did the case manager off er in your opinion?

• What do you think the case manager could off er (poten� ally)?

• What do you think of the exis� ng ALS care? Are there any gaps? Who should fi ll 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 fi nished (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

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

• Thank you for your � me

• Explana� on about the report

6Factors related to caregiver strain in ALS:

a longitudinal study

Huub Creemers Sandra de MoréeJan H. VeldinkFrans NolletLeonard H. van den BergAnita Beelen

Journal of Neurology, Neurosurgery & Psychiatry, Online First, published on September 4, 2015 as 10.1136/jnnp-2015-311651.

© Reprinted with permission from BMJ Publishing Group Ltd.

Chapter 6

104

ABSTRACT

Objec� veTo examine the longitudinal associa� ons between caregiver strain and pa� ents’ clinical andpsychosocial characteris� cs as well as caregivers’ psychosocial characteris� cs.

MethodsAt 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 eff ec� 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.

ResultsCaregiver strain increased signifi cantly during the study period (β=0.315 points/months, p<0.001) and was signifi cantly 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).

ConclusionOur study has iden� fi ed 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 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.

Factors related to caregiver strain in ALS

105

6

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 signifi cant amount of � me, a� en� on and eff ort 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 signifi cantly 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 refl ec� 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� fi ed 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 modifi able, 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 specifi c pa� ent and caregiver modifi able 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� onThis quan� ta� ve longitudinal cohort study was part of a cluster randomized controlled trial (RCT) that evaluated the eff ec� veness of case management in 132 pa� ents with ALS

Chapter 6

106

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 insuffi cient mastery of the Dutch language.

Standard protocol approvals, registra� ons, and pa� ent consentsThe 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� onDuring 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.

MeasurementsCaregiver 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 eff ort 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 fl oor eff ects 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-specifi c measure to assess func� on, and consists of four domains: fi ne 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-specifi c health status measure, containing 40 items incorporated in fi ve 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


107

6

items), and emo� onal func� oning (10 items). Each of the fi ve 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 four-point 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 diff erent 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, off ensive 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 analysisNormality of the data was checked by plo ̀ ng histograms and by means of a Kolmogorov-Smirnov test. We measured baseline correla� ons between pa� ents’ and caregivers’ variables and the CSI total score using Pearson’s correla� on coeffi cients.

The longitudinal course of caregiver strain and its associa� on with pa� ents’ and caregivers’ variables were analysed with random coeffi cient 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 signifi cantly associated with caregiver strain, and another model in which we included

Chapter 6

108

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 signifi cant 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 fi t (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 fi nal 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 coeffi cient 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 fl ow-chart of par� cipants (fi gure 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 fi ve 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.


109

6

Table 1 Baseline characteris� cs of study par� cipants.

Caregivers n=126 Pa� ents n=126Caregivers and pa� ents Female n (%) 83 (66) 41 (33) Age, years mean (SD) 58.8 (12.5) 62.7 (11.4) College or university degree n (%) 41 (33) 45 (37) Caucasian n (%) 121 (97) 124 (98) Employed n (%) 34 (27) 21 (17) QOC report mark ‘care for the pa� ent’ mean (SD) (Score range 1-10)

8.1 (1.0) 8.2 (0.8)

UCL ac� ve approach mean (SD) (Score range 7-28)

18.5 (4.0) 17.8 (4.7)

UCL passive reac� on mean (SD) (Score range 7-28)

10.7 (2.7) 10.2 (2.3)

HADS anxiety mean (SD) (Score range 0-21)

6.4 (3.9) 3.9 (3.2)

HADS depression mean (SD) (Score range 0-21)

5.3 (4.1) 4.4 (3.5)

Caregivers CSI mean (SD) (Score range 0-13)

5.4 (3.2)

Partner is caregiver n (%) 107 (85) Daughter or son is caregiver n (%) 10 (8) QOC report mark “care for the caregiver” mean (SD) (Score range 1-10)

7.7 (1.5)

Pa� ents Median � me since onset (Q1 – Q3), years 2.1 (1.2 - 3.5) ALSFRS-R mean (SD) (Score range 0-48)

31.8 (8.2)

Bulbar onset n (%) 30 (24) ALSAQ-40 emo� onal func� oning mean (SD) (Score range 0-100)

20.2 (17.5)

ALSAQ-40 sum score mean (SD) (Score range 0-100)

36.8 (17.8)

Predicted FVC% mean (SD) 85 (22) PEG n (%) 23 (18) NIV/IV n (%) 22 (18) Riluzole n (%) 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, fi rst quar� le to third quar� le; QOC, Quality of Care; SD, standard devia� on; UCL, Utrecht Coping List.

Chapter 6

110

Figure 1 Flowchart par� cipants.


111

6

Table 2 CSI scores and scores of par� cipants’ � me-dependent variables at the four assessments.

Baselinemean (SD)n

4 monthsmean (SD)n

8 monthsmean (SD)n

12 monthsmean (SD)n

β (95% CI)

CSI total score(Score range 0-13)

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)Time-dependent caregiver variablesQOC - for the pa� ent(Score range 1-10)

8.1 (1.0)122

8.3 (0.8)77

8.0 (0.9)44

7.9 (0.8)51

-0.012(-0.026 to 0.002)

QOC - for the caregiver(Score range 1-10)

7.7 (1.5)105

7.7 (1.1)71

7.4 (1.4)41

7.2 (1.2)47

-0.025(-0.003 to -0.047) *

UCL subscale ac� ve approach(Score range 7-28)

18.5 (4.0)124

18.6 (3.8)79

17.7 (3.7)47

18.6 (4.1)52

-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)

6.4 (3.9)124

5.5 (3.6)78

6.0 (3.8)47

6.6 (4.2)51

0.022(-0.023 to 0.067)

HADS depression(Score range 0-21)

5.3 (4.1)124

4.2 (3.3)78

5.4 (4.0)47

5.7 (4.1)51

0.029(-0.022 to 0.080)

Time-dependent pa� ent variables

ALSFRS-R sum score(Score range 0-48)

31.8 (8.2)126

28.9 (8.7)79

27.3 (8.8)46

24.5 (10.4) 52

-0.710(-0.843 to -0.578) **

ALSAQ-40 emo� onal func� oning(Score range 0-100)

20.2 (17.5)125

19.6 (15.6) 81

20.6 (14.3) 48

21.1 (15.7) 56

0.180 (-0.018 to 0.378)

QOC for the pa� ent(Score range 1-10)

8.2 (0.8)116

8.1 (0.8)79

8.0 (1.0)49

7.9 (0.8)54

-0.017(-0.031 to -0.003) *

UCL subscale ac� ve approach(Score range 7-28)

17.8 (4.7)124

18.9 (4.0)81

18.1 (4.5)49

19.4 (4.0)58

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)

3.9 (3.2)124

2.1 (2.7)81

2.2 (2.3)49

2.3 (2.3)58

-0.079(-0.118 to -0.040) **

HADS depression(Score range 0-21)

4.4 (3.5)124

4.1 (2.8)81

4.0 (2.8)49

4.2 (2.4)58

0.011(-0.030 to 0.052)

*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 coeffi cient which is an es� ma� on of the longitudinal chance of the variable.

Chapter 6

112

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

Independent variable N β (SE) 95% CIPa� 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)

126126126126126126126126126

126

122

124

124

122

124

124

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)

-0.173 (0.018)

0.039 (0.012)

0.097 (0.044)

0.145 (0.081)

-0.413 (0.207)

-0.011 (0.062)

0.128 (0.060)

-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

-0.208 to -0.138 ****

0.015 to 0.063 ***

0.011 to 0.183 **

-0.014 to 0.304 *

-0.819 to -0.007 **

-0.133 to 0.111

0.010 to 0.246 **

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)

126126126126126126

124

124

124

124

117

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

0.287 (0.048)

0.296 (0.045)

0.030 (0.055)

0.315 (0.070)

-0.708 (0.141)

-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

0.193 to 0.381 ****

0.208 to 0.384 ****

-0.078 to 0.138

0.178 to 0.452 ****

-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 coeffi cient which is an es� ma� on of the longitudinal rela� onship between the independent variable and caregiver strain.


113

6

Mul� level analyses showed that caregiver strain increased signifi cantly during the study period. Time and � me squared were signifi cant, 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 coeffi cient analyses for the associa� ons between caregiver strain (CSI) and independent caregiver and pa� ent variables (N=116).

Independent variable Dependent; CSIβ (95% CI)

Time, months 0.205 (0.105 to 0.305) **

Time2 -0.008 (-0.004 to -0.012) **

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

0.186 (0.086 to 0.286) **

-0.452 (-0.672 to -0.232) **

0.152 (0.015 to 0.289) *

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

-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 coeffi cient 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 diff erences (univariate vs mul� variate associa� ons).

Chapter 6

114

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 fi rst to reveal evidence for this associa� on. We believe that this fi nding 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 fi nding 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 fi nding eff ec� ve (ac� ve) coping strategies may lead to manageable strain.

The current study supports previous fi ndings 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 specifi c evidence-based interven� ons to guide the family caregivers 11. Caregiver strain should be recognised by the care professionals and tailor-made 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 diff erent (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 off er � 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.


115

6

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 coeffi cients 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 specifi c 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 diff erent � 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 diff er as diff erences in cultural, spiritual and religious beliefs could aff ect 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

Chapter 6

116

caregiving 40. It is important to consider both posi� ve and the nega� ve aspects when off ering caregiver support. The currently available ALS-specifi c 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 fi ndings 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 modifi able 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.


117

6

REFERENCES

1. Chiò A, Gauthier A, Vignola A, et al. Caregiver � me use in ALS. Neurology 2006;67:902-4.2. Gauthier A, Vignola A, Calvo A, et al. A longitudinal study on quality of life and depression in ALS

pa� ent-caregiver couples. Neurology 2007;68:923-6.3. Goldstein LH, Atkins L, Landau S, et al. Predictors of psychological distress in carers of people with

amyotrophic lateral sclerosis: a longitudinal study. Psychol Med 2006;36:865-75.4. Creemers H, Veldink JH, Grupstra H, et al. Cluster RCT of case management on pa� ents’ quality of life

and caregiver strain in ALS. Neurology 2014;82:23-31. 5. Roach AR, Averill AJ, Segerstrom SC, et al. The dynamics of quality of life in ALS pa� ents and caregivers.

Ann Behav Med 2009;37:197-206. 6. Levine C, Zuckerman C. The trouble with families: toward an ethic of accommoda� on. Ann Intern Med

1999;130:148-52.7. Campbell P, Wright J, Oyebode J, et al. Determinants of burden in those who care for someone with

demen� a. Int J Geriatr Psychiatry 2008;23:1078-85.8. Boerner K, Mock SE. Impact of pa� ent suff ering on caregiver well-being: the case of amyotrophic

lateral sclerosis pa� ents and their caregivers. Psychol Health Med 2012;17:457-66.9. Chiò A, Gauthier A, Calvo A, et al. Caregiver burden and pa� ents’ percep� on of being a burden in ALS.

Neurology 2005;64:1780-2.10. 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;73:1227-33.

11. 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;19:360-75.

12. Aoun SM, Bentley B, Funk L, et al. A 10-year literature review of family caregiving for motor neurone disease: moving from caregiver burden studies to pallia� ve care interven� ons. Palliat Med 2013;27:437-46.

13. Ng L, Talman P, Khan F. Motor neurone disease: disability profi le and service needs in an Australian cohort. Int J Rehabil Res 2011;34:151-9.

14. Peters M, Fitzpatrick R, Doll H, et al. The impact of perceived lack of support provided by health and social care services to caregivers of people with motor neuron disease. Amyotroph Lateral Scler 2012;13:223-8.

15. Lillo P, Mioshi E, Hodges JR. Caregiver burden in amyotrophic lateral sclerosis is more dependent on pa� ents’ behavioral changes than physical disability: a compara� ve study. BMC Neurol 2012;12:156.

16. Pagnini F, Rossi G, Lune� a C, et al. Burden, depression, and anxiety in caregivers of people with amyotrophic lateral sclerosis. Psychol Health Med 2010;15:685-93.

17. Qutub K, Lacomis D, Albert SM, et al. Life factors aff ec� ng depression and burden in amyotrophic lateral sclerosis caregivers. Amyotroph Lateral Scler Frontotemporal Degener 2014;15:292-7.

18. Tramon� F, Barsan� I, Bongioanni P, et al. A permanent emergency: a longitudinal study on families coping with amyotrophic lateral sclerosis. Fam Syst Health 2014;32:271-9.

19. Brule ̀ G, Comini L, Scalvini S, et al. A two-year longitudinal study on strain and needs in caregivers of advanced ALS pa� ents. Amyotroph Lateral Scler Frontotemporal Degener 2015;16:187-95.

20. Kaub-Wi� emer D, Steinbüchel Nv, Wasner M, et al. Quality of life and psychosocial issues in ven� lated pa� ents with amyotrophic lateral sclerosis and their caregivers. J Pain Symptom Manage 2003;26:890-6.

Chapter 6

118

21. Chiò A, Vignola A, Mastro E, et al. Neurobehavioral symptoms in ALS are nega� vely related to caregivers’ burden and quality of life. Eur J Neurol 2010;17:1298-303.

22. Robinson BC. Valida� on of a Caregiver Strain Index. J Gerontol 1983;38:344-8.23. Jenkinson C, Fitzpatrick R, Swash M, et al. The ALS Health Profi le Study: quality of life of amyotrophic

lateral sclerosis pa� ents and carers in Europe. J Neurol 2000;247:835-40.24. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS func� onal ra� ng scale that

incorporates assessments of respiratory func� on. BDNF ALS Study Group (Phase III). J Neurol Sci 1999;169:13-21.

25. Jenkinson C, Fitzpatrick R, Brennan C, et al. Evidence for the validity and reliability of the ALS assessment ques� onnaire: the ALSAQ-40. Amyotroph Lateral Scler Other Motor Neuron Disord 1999;1:33-40.

26. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361-70.

27. Schreurs PJG, van de Willege G, Brosschot JF, et al. The Utrecht Coping List: UCL. Coping with problems and events. Utrecht: Swets en Zeitlinger; 1993 (Dutch).

28. Skinner EA, Edge K, Altman J, et al. Searching for the structure of coping: a review and cri� que of category systems for classifying ways of coping. Psychol Bull 2003;129:216-69.

29. Schaufeli W, Van Dierendonck D. The reliability and validity of the Utrecht Coping List. A longitudinal study of school-leavers. Gedrag en Gezondheid 1992;1:38-45 (Dutch).

30. Guerriere D, Husain A, Zagorski B, et al. Predictors of caregiver burden across the home-based pallia� ve care trajectory in Ontario, Canada. Health Soc Care Community 2015 Mar 25.

31. Weisser FB, Bristowe K, Jackson D. Experiences of burden, needs, rewards and resilience in family caregivers of people living with Motor Neurone Disease/Amyotrophic Lateral Sclerosis: A secondary thema� c analysis of qualita� ve interviews. Palliat Med 2015; 29(8):737-45.

32. Bakker M, Creemers H, Schipper K, et al. 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. Amyotroph Lateral Scler Frontotemporal Degener 2015;16:180-6.

33. Olsson Ozanne A, Graneheim UH, Persson L, et al. Factors that facilitate and hinder the manageability of living with amyotrophic lateral sclerosis in both pa� ents and next of kin. J Clin Nurs 2012;21:1364-73.

34. Oyebode JR, Smith HJ, Morrison K. The personal experience of partners of individuals with motor neuron disease. Amyotroph Lateral Scler Frontotemporal Degener 2013;14:39-43.

35. Adelman RD, Tmanova LL, Delgado D, et al. Caregiver burden: a clinical review. JAMA 2014;311:1052-60.

36. 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;82:1165-70.

37. Morano CL, King D. Religiosity as a mediator of caregiver well-being: does ethnicity make a diff erence? J Gerontol Soc Work 2005;45:69-84.

38. Houseman G, Walsh S, Brothers A, et al. Frontotemporal degenera� on in the pa� ent with amyotrophic lateral sclerosis: helping the caregiver cope. J Neurosci Nurs 2013;45:96-100.

39. Schoenmakers B, Bun� nx F, DeLepeleire J. Suppor� ng the demen� a family caregiver: the eff ect of home care interven� on on general well-being. Aging Ment Health 2010;14:44-56.

40. Williams MT, Donnelly JP, Holmlund T, et al. ALS: Family caregiver needs and quality of life. Amyotroph Lateral Scler 2008;9:279-86.

7General Discussion

Chapter 7

120

General Discussion

121

7

The overall aim of this thesis is to op� mize mul� disciplinary ALS care through expanding our knowledge on previously iden� fi ed 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 eff ec� 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 fi ndings of the previous chapters are discussed and issues concerning the methodology are cri� cally reviewed. The implica� ons of the fi ndings for clinical prac� ce are considered and, fi nally, 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 insuffi cient 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 confi rmed part of the prognos� c factors we derived and iden� fi ed addi� onal prognos� c factors 3-6. The studies of Hothorn (2014), Atassi (2014) and Küff ner (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-signifi cant 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 fi ndings did not result in an upgrade of the overall quality of evidence, mainly due to the quality factors inconsistency and imprecision.

Chapter 7

122

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 confl ic� ng fi ndings were reported by Wolf et al. (2015) who found male gender related to worse prognosis 11.

Küff ner 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 misclassifi ed 35 percent of the pa� ents, so it seems that the model might off er 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. Signifi cant 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 fi rst 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 signifi cant 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� fi ca� on by site of onset or type of motor neuron dominance. Turner et al. (2013) suggested stra� fi ca� on by 1) rate of disease progression, defi ned as the � me to spread to a new region, and 2) degree of cogni� ve impairment 14. Possibly these stra� fi ca� ons might well be be� er alterna� ves in ALS clinical prac� ce as they seem to be� er fi t 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

General Discussion

123

7

the problems during the process of procuring ADHA within the context of the Dutch health care system and based on earlier literature fi ndings, 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 fi ndings 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 fi ll the aforemen� oned gaps in ALS care, we hypothesized that case management might be eff ec� ve to improve quality of care (QOC). Our cluster RCT on case management in mul� disciplinary ALS care demonstrated no signifi cant benefi t 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 infl uence 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 eff ect of the interven� on within the Dutch ALS care se ̀ ng.

Pa� ents and caregivers diff ered 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 confi rmed by the fi ndings 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

Chapter 7

124

(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 specifi c situa� ons. Factors that emerged from the interviews and the focus group and appeared to infl uence 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-suffi ciency 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 insuffi cient 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 diff erent 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 signifi cantly 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� fi c 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� onThe 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 confi dent 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.

General Discussion

125

7

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 diff erence, although not signifi cant, 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 confi dent that this did not result in a bias of treatment eff ect 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 diff er. The baseline CSI scores of their caregivers was signifi cantly 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 eff ect on caregiver strain. However, controlling for this baseline diff erence in our mul� level analysis would have contributed to an even larger nega� ve value of the mul� level regression coeffi cient for the eff ect 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 infl uenced 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 clarifi es that there was no diff erence in the willingness of poten� al pa� ents and their caregivers to par� cipate in the RCT.

Study designThe 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 confi rmed 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

Chapter 7

126

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 managementWithin the RCT the contrast between usual care and usual care plus intensive case management was not strong enough to demonstrate an interven� on eff ect. 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 diff ering 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 off ered 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 fi nding confi rms the importance of � ming of disease management with respect to off ering 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 diff erent study result due to the above men� oned interpreta� on.

Outcome measuresThe 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 diff ering RCT outcome as we did not fi nd an eff ect on any other outcome measure.

At baseline, we expected diff erences 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

General Discussion

127

7

its en� rety during the past month. We did not assess specifi c 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 diff erent 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 specifi c 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 diff erences 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 benefi ts 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 specifi c 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 specifi c 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 specifi c 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 aff ect caregivers’ health 40. The authors indicated that an increase of the MNDCQ score suggests a higher level of caregiver

Chapter 7

128

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 specifi c caregiver strain assessment tool including both posi� ve and nega� ve aspects of caregiving as well as an ALS specifi c caregiver needs instrument 41,42.

GeneralizabilityOutcomes of case management interven� ons are reported within other diseases, but comparing these study results is diffi cult due to diff erences 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 diff er 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 diff erences in (the quality of and accessibility of) health care systems, treatments availability, se ̀ ngs, religions and ethnici� es across the diff erent countries, causes that we cannot extrapolate our fi ndings to the en� re ALS popula� on.

CLINICAL IMPLICATIONS

Case managementThe fi ndings 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 fi ts 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 refl ec� 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 off er 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

General Discussion

129

7

support is advisable: an insuffi cient 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-suffi cient, 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 off er opportuni� es to adjust care to their needs.

Prognos� ca� onThe 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.

Chapter 7

130

ADHABased on our results we suggest diff erent 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 ice-bucket 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/amyotrofi sche-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

General Discussion

131

7

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 strainThe 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 fi t 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-specifi c caregiver strain inventory, to survey the above-men� 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 off ering 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 diff er 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 diff erence 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 diff erent ALS health care systems, we might get more insight in the eff ec� veness of the diff erent systems and the diff erences 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.,

Chapter 7

132

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 specifi c 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 eff ec� 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/amyotrofi sche-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 specifi c 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) off ers opportuni� es to come to signifi cant improvements in measuring func� onal decline and prognos� ca� on of func� onal milestones.

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

General Discussion

133

7

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 off er 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 eff ec� 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 fi nd an adequate, evidence based approach to support these caregivers in their roles and thereby contribu� ng to the pa� ents’ well-being. The eff ect 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� fi ed 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 insuffi cient 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 benefi t 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� fi ed 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

Chapter 7

134

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 fi t 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-suffi cient.

• 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 specifi c 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 effi cient 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 specifi c 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 diff erences 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 fi ndings 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.

General Discussion

135

7

REFERENCES

1. 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;73:1227-33. doi:10.1212/WNL.0b013e3181bc01a4.

2. 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;19:360-75. doi:10.1111/j.1468-1331.2011.03501.x. [published Online First: 14 September 2011].

3. Hothorn T, Jung HH. RandomForest4Life: a Random Forest for predic� ng ALS disease progression. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Sep;15(5-6):444-52. doi:10.3109/21678421.2014.893361.

4. Atassi N, Berry J, Shui A, Zach N, Sherman A, Sinani E, Walker J, Katsovskiy I, Schoenfeld D, Cudkowicz M, Leitner M. The PRO-ACT database: design, ini� al analyses, and predic� ve features. Neurology. 2014 Nov 4;83(19):1719-25. doi:10.1212/WNL.0000000000000951. Epub 2014 Oct 8.

5. Küff ner R, Zach N, Norel R, Hawe J, Schoenfeld D, Wang L, Li G, Fang L, Mackey L, Hardiman O, Cudkowicz M, Sherman A, Ertaylan G ,Grosse-Wentrup M, Hothorn T, van Ligtenberg J, Macke JH, Meyer T, Schölkopf B, Tran L, Vaughan R, Stolovitzky G, Leitner ML. Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression. Nat Biotechnol. 2015 Jan;33(1):51-7. doi:10.1038/nbt.3051. Epub 2014 Nov 2.

6. Watanabe H, Atsuta N, Nakamura R, Hirakawa A, Watanabe H, Ito M, Senda J, Katsuno M, Izumi Y, Morita M, Tomiyama H, Taniguchi A, Aiba I, Abe K,Mizoguchi K, Oda M, Kano O, Okamoto K, Kuwabara S, Hasegawa K, Imai T, Aoki M, Tsuji S, Nakano I, Kaji R, Sobue G. Factors aff ec� ng longitudinal func� onal decline and survival in amyotrophic lateral sclerosis pa� ents. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec 30:1. [Epub ahead of print].

7. Chiò A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, Traynor BG; Eurals Consor� um (2009) Prognos� c factors in ALS: A cri� cal review. Amyotroph Lateral Scler 10:310-323. doi:10.3109/17482960802566824.

8. Pupillo E, Messina P, Logroscino G, Beghi E; SLALOM Group. Long-term survival in amyotrophic lateral sclerosis: a popula� on-based study. Ann Neurol. 2014 Feb;75(2):287-97. doi:10.1002/ana.24096. Epub 2014 Feb 24.

9. Jordan H, Fagliano J, Rechtman L, Le¬ owitz D, Kaye W. Eff ects of demographic factors on survival � me a{ er a diagnosis of amyotrophic lateral sclerosis. Neuroepidemiology. 2015;44(2):114-20. doi:10.1159/000380855. Epub 2015 Mar 17.

10. Elamin M, Bede P, Montuschi A, Pender N, Chio A, Hardiman O. Predic� ng prognosis in amyotrophic lateral sclerosis: a simple algorithm. J Neurol. 2015 Jun;262(6):1447-54. doi:10.1007/s00415-015-7731-6. Epub 2015 Apr 11.

11. Wolf J, Safer A, Wöhrle JC, Palm F, Nix WA, Maschke M, Grau AJ. Factors Predic� ng Survival in ALS Pa� ents - Data from a Popula� on-Based Registry in Rhineland-Pala� nate, Germany. Neuroepidemiology. 2015 Apr 21;44(3):149-155. [Epub ahead of print].

12. Turner MR, Bakker M, Sham P, Shaw CE, Leigh PN, Al-Chalabi A. Prognos� c modelling of therapeu� c interven� ons in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2002 Mar;3(1):15-21.

13. Sco� on WJ, Sco� KM, Moore DH, Almedom L, Wijesekera LC, Janssen A, Nigro C, Sakel M, Leigh PN, Shaw C, Al-Chalabi A (2012) Prognos� c categories for amyotrophic lateral sclerosis. Amyotroph Lateral Scler 13:502-508. doi:10.3109/17482968.2012.679281.

Chapter 7

136

14. Turner MR, Hardiman O, Benatar M, Brooks BR, Chio A, de Carvalho M, Ince PG, Lin C, Miller RG, Mitsumoto H, Nicholson G, Ravits J, Shaw PJ, Swash M,Talbot K, Traynor BJ, Van den Berg LH, Veldink JH, Vucic S, Kiernan MC. Controversies and priori� es in amyotrophic lateral sclerosis. Lancet Neurol. 2013 Mar;12(3):310-22. doi:10.1016/S1474-4422(13)70036-X.

15. Van Teijlingen ER, Friend E, Kamal AD. Service use and needs of people with motor neurone disease and their carers in Scotland. Health Soc Care Community. 2001 Nov;9(6):397-403.

16. 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.

17. Pagnini F, Simmons Z, Corbo M, Molinari E. Amyotrophic lateral sclerosis: � me for research on psychological interven� on? Amyotroph Lateral Scler. 2012 Sep;13(5):416-7. doi: 10.3109/17482968.2011.653572. Epub 2012 Feb 13.

18. Pagnini F, Di Credico C, Ga� o R, Fabiani V, Rossi G, Lune� a C, Marconi A, Fossa� F, Castelnuovo G, Tagliaferri A, Banfi P, Corbo M, Sansone V, Molinari E,Amadei G. Medita� on training for people with amyotrophic lateral sclerosis and their caregivers. J Altern Complement Med. 2014 Apr;20(4):272-5. doi: 10.1089/acm.2013.0268. Epub 2013 Dec 11.

19. Joanna Briggs Ins� tute. Caregiver burden of terminally-ill adults in the home se ̀ ng. Nurs Health Sci. 2012 Dec;14(4):435-7. doi:10.1111/nhs.12013.

20. Larsson BJ, Fröjd C, Nordin K, Nygren I. Rela� ves of pa� ents with amyotrophic lateral sclerosis: Their experience of care and support. Palliat Support Care. 2015 Mar 16:1-8. [Epub ahead of print].

21. 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.

22. Köpke S, McCleery J. Systema� c reviews of case management: too complex to manage? Editorial. Cochrane Database Syst Rev. 2015 Jan 13;1:ED000096. doi:10.1002/14651858.ED000096.

23. Weisser FB, Bristowe K, Jackson D. Experiences of burden, needs, rewards and resilience in family caregivers of people living with Motor Neurone Disease/Amyotrophic Lateral Sclerosis: A secondary thema� c analysis of qualita� ve interviews. Palliat Med 2015;Mar 11. pii:0269216315575851.

24. Simmons Z. Pa� ent-Perceived Outcomes and Quality of Life in ALS. Neurotherapeu� cs. 2015 Apr;12(2):394-402. doi:10.1007/s13311-014-0322-x.

25. Fegg MJ, Kögler M, Brandstä� er M, Jox R, Anneser J, Haarmann-Doetko� e S, Wasner M, Borasio GD. Meaning in life in pa� ents with amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010 Oct;11(5):469-74. doi:10.3109/17482961003692604.

26. Clarke S, Hickey A, O’Boyle C, Hardiman O. Assessing individual quality of life in amyotrophic lateral sclerosis. Qual Life Res. 2001;10(2):149-58.

27. Cohen SR, Mount BM, Bruera E, Provost M, Rowe J, Tong K. Validity of the McGill Quality of Life Ques� onnaire in the pallia� ve care se ̀ ng: a mul� -centre Canadian study demonstra� ng the importance of the existen� al domain. Palliat Med. 1997 Jan;11(1):3-20.

28. Rademakers J, Delnoij D, de Boer D. Structure, process or outcome: which contributes most to pa� ents’ overall assessment of healthcare quality? BMJ Qual Saf. 2011 Apr;20(4):326-31. doi:10.1136/bmjqs.2010.042358. Epub 2011 Feb 21.

29. Foley G, Timonen V, Hardiman O. Experience of services as a key outcome in amyotrophic lateral sclerosis (ALS) care: the case for a be� er understanding of pa� ent experiences. Am J Hosp Palliat Care. 2012 Aug;29(5):362-7. doi: 10.1177/1049909111423774. Epub 2011 Oct 13.

General Discussion

137

7

30. Stephens HE, Felgoise S, Young J, Simmons Z. Mul� disciplinary ALS clinics in the USA: A comparison of those who a� end and those who do not. Amyotroph Lateral Scler Frontotemporal Degener. 2015 Jun;16(3-4):196-201. doi:10.3109/21678421.2014.994530. Epub 2015 Jan 20.

31. Claessen SJ, Francke AL, Sixma HJ, de Veer AJ, Deliens L. Measuring pa� ents’ experiences with pallia� ve care: the Consumer Quality Index Pallia� ve Care. BMJ Support Palliat Care. 2012 Dec;2(4):367-72. doi: 10.1136/bmjspcare-2011-000055. Epub 2012 Sep 21.

32. Claessen SJ, Francke AL, Sixma HJ, de Veer AJ, Deliens L. Measuring rela� ves’ perspec� ves on the quality of pallia� ve care: the Consumer Quality IndexPallia� ve Care. J Pain Symptom Manage. 2013 May;45(5):875-84. doi: 10.1016/j.jpainsymman.2012.05.007. Epub 2012 Sep 25.

33. Franchignoni F, Mora G, Giordano A, Volan� P, Chiò A. Evidence of mul� dimensionality in the ALSFRS-R Scale: a cri� cal appraisal on its measurement proper� es using Rasch analysis. J Neurol Neurosurg Psychiatry. 2013 Dec;84(12):1340-5. doi:10.1136/jnnp-2012-304701. Epub 2013 Mar 20.

34. Franchignoni F, Mandrioli J, Giordano A, Ferro S; ERRALS Group. A further Rasch study confi rms that ALSFRS-R does not conform to fundamental measurement requirements. Amyotroph Lateral Scler Frontotemporal Degener. 2015 Apr 27:1-7. [Epub ahead of print].

35. Grimby G, Tennant A, Tesio L. The use of raw scores from ordinal scales: � me to end malprac� ce? J Rehabil Med. 2012 Feb;44(2):97-8. doi:10.2340/16501977-0938. No abstract available.

36. Gordon PH, Cheng B, Salachas F, Pradat PF, Bruneteau G, Corcia P, Lacomblez L, Meininger V. Progression in ALS is not linear but is curvilinear. J Neurol. 2010 Oct;257(10):1713-7. doi:10.1007/s00415-010-5609-1. Epub 2010 Jun 8.

37. Gomeni R, Fava M; Pooled Resource Open-Access ALS Clinical Trials Consor� um. Amyotrophic lateral sclerosis disease progression model. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Mar;15(1-2):119-29. doi:10.3109/21678421.2013.838970. Epub 2013 Sep 26.

38. Streiner DL, Norman GR. Health Measurement Scales, Third Edi� on. Oxford University Press; 2006.39. Robinson BC. Valida� on of a Caregiver Strain Index. J Gerontol 1983 May;38(3):344-8.40. Mockford C, Jenkinson C, Fitzpatrick R. Development of the Motor Neuron Disease Carer Ques� onnaire.

Amyotroph Lateral Scler. 2009 Oct-Dec;10(5-6):463-9. doi:10.3109/17482960802455408.41. Al-Janabi H, Frew E, Brouwer W, Rappange D, Van Exel J. The inclusion of posi� ve aspects of caring

in the Caregiver Strain Index: tests of feasibility and validity. Int J Nurs Stud. 2010 Aug;47(8):984-93. doi:10.1016/j.ijnurstu.2009.12.015. Epub 2010 Jan 29.

42. Ewing G, Brundle C, Payne S, Grande G; Na� onal Associa� on for Hospice at Home. The Carer Support Needs Assessment Tool (CSNAT) for use in pallia� ve and end-of-life care at home: a valida� on study. J Pain Symptom Manage. 2013 Sep;46(3):395-405. doi:10.1016/j.jpainsymman.2012.09.008. Epub 2012 Dec 12.

43. Zach N, Ennist DL, Taylor AA, Alon H, Sherman A, Kueff ner R, Walker J, Sinani E, Katsovskiy I, Cudkowicz M, Leitner ML. Being PRO-ACTive: What can a Clinical Trial Database Reveal About ALS? Neurotherapeu� cs. 2015 Apr;12(2):417-23. doi:10.1007/s13311-015-0336-z.

44. Byrne S, Elamin M, Bede P, Shatunov A, Walsh C, Corr B, Heverin M, Jordan N, Kenna K, Lynch C, McLaughlin RL, Iyer PM, O’Brien C, Phukan J, Wynne B,Bokde AL, Bradley DG, Pender N, Al-Chalabi A, Hardiman O. Cogni� ve and clinical characteris� cs of pa� ents with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a popula� on-based cohort study. Lancet Neurol. 2012 Mar;11(3):232-40. doi:10.1016/S1474-4422(12)70014-5. Epub 2012 Feb 3.

45. Wicks P. The ALS ice bucket challenge - can a splash of water reinvigorate a fi eld? Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7-8):479-80. doi:10.3109/21678421.2014.984725.

46. Holmström I, Röing M. The rela� on between pa� ent-centeredness and pa� ent empowerment: a discussion on concepts. Pa� ent Educ Couns. 2010 May;79(2):167-72. doi:10.1016/j.pec.2009.08.008. Epub 2009 Sep 11.

Chapter 7

138

47. van Berkel JJ, Lambooij MS, Hegger I. Empowerment of pa� ents in online discussions about medicine use. BMC Med Inform Decis Mak. 2015 Apr 8;15:24. doi:10.1186/s12911-015-0146-6.

48. Jedeloo S, De Wi� e LP, Linssen BA, Schrijvers AJ. Client sa� sfac� on with service delivery of assis� ve technology for outdoor mobility. Disabil Rehabil. 2002 Jul 10;24(10):550-7.

49. Hughes RA, Sinha A, Higginson I, Down K, Leigh PN. Living with motor neurone disease: lives, experiences of services and sugges� ons for change. Health Soc Care Community. 2005 Jan;13(1):64-74.

50. Ozanne AO, Graneheim UH, Strang S. Finding meaning despite anxiety over life and death in amyotrophic lateral sclerosis pa� ents. J Clin Nurs. 2013 Aug;22(15-16):2141-9. doi: 10.1111/jocn.12071. Epub 2013 Feb 7.

51. Breitbart W, Poppito S, Rosenfeld B, Vickers AJ, Li Y, Abbey J, Olden M, Pessin H, Lichtenthal W, Sjoberg D, Cassileth BR. Pilot randomized controlled trial of individual meaning-centered psychotherapy for pa� ents with advanced cancer. J Clin Oncol. 2012 Apr 20;30(12):1304-9. doi: 10.1200/JCO.2011.36.2517. Epub 2012 Feb 27.

52. Leow M, Chan S, Chan M. A pilot randomized, controlled trial of the eff ec� veness of a psycho-educa� onal interven� on on family caregivers of pa� ents with advanced cancer. Oncol Nurs Forum. 2015 Mar;42(2):E63-72. doi:10.1188/15.ONF.E63-E72.

53. Aoun SM, Bentley B, Funk L, Toye C, Grande G, Stajduhar KJ. A 10-year literature review of family caregiving for motor neurone disease: moving from caregiver burden studies to pallia� ve care interven� ons. Palliat Med. 2013 May;27(5):437-46. doi:10.1177/0269216312455729. Epub 2012 Aug 20.

Summary

Samenva ̀ ng

Dankwoord

Curriculum Vitae / Por] olio

List of publica� ons

Summary

140

Summary

141

S

SUMMARY

In the absence of an eff ec� 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 suffi cient evidence for those care issues that have been iden� fi ed 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 off er 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, disease-specifi c, psychosocial, and comorbid factors) for the rate of func� onal decline in pa� ents with ALS. Within fi ve 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 insuffi cient to develop a reliable predic� on model, suitable for daily clinical prac� ce.

Summary

142

‘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, simplifi ed 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 eff ect 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 eff ect 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 signifi cant benefi t 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 fi ndings of an increasing

Summary

143

S

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 diff erent health care systems is a cer� fi ed profession and contributes to ALS care, our research design might facilitate future research projects in other countries.

During the RCT, pa� ents and caregivers diff ered in their need for informa� on, support, treatment, resources and care. Some par� cipants did report case management benefi ts 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 infl uence 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-suffi cient, 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 specifi c 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 fi ts the individual care needs of pa� ents and their informal caregivers.

Caregiver strain increased signifi cantly during the case management study, which fi ndings 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

Summary

144

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 fi ndings 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 fi ndings , strengths and limita� ons of this thesis are described. Finally, the implica� ons of the study fi ndings 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 diffi cult 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 insuffi cient 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 fi t 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-suffi cient.

• 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.

Summary

145

S

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 specifi c 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 specifi c 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 eff ect 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.

Samenva� ng

146

Samenva� ng

147

S

SAMENVATTING

Momenteel is er nog geen eff ec� eve behandeling om Amyotrofi sche 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� fi ceerd: 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 (sociodemografi sche, ziekte-specifi eke, psychosociale en comorbide factoren) voor de func� onele achteruitgang bij pa� ënten met ALS. Binnen vijf bibliografi sche 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.

Samenva� ng

148

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 eff ecten 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 eff ect 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.

Samenva� ng

149

S

Honderdtweeënder� g pa� ënten en 126 mantelzorgers deden mee aan het onderzoek. De resultaten lieten geen signifi cant 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 profi jt 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 ona ankelijk zijn, minder asser� ef zijn, en terughoudendheid zijn in het vragen om hulp.

Samenva� ng

150

Deze kwalita� eve studie hee{ ons inzicht in de specifi eke 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, signifi cant 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 (sociodemografi sche 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

Samenva� ng

151

S

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 ALS-specifi ek 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-specifi eke 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 eff ect 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

Samenva� ng

152

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.

Dankwoord

153

D

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.

Curriculum Vitae / Por� olio

154


155

CV/P

CURRICULUM VITAE / PORT FOLIO

Curriculum VitaeHuub 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.


156

Por olioPhD student: Huub CreemersPhD period: January 2008 – December 2015PhD supervisors: Prof. dr. F. Nollet Prof. dr. L.H. van den Berg

1. PHD TRAININGYear Workload

(Hours / ECTS)GENERAL COURSESBasic course Prac� cal Biosta� s� cs. AMC Graduate School for Medical Sciences, UVA Amsterdam

2011 34 / 1.2

Scien� fi c Wri� ng in English for Publica� on. AMC Graduate School for Medical Sciences, UVA Amsterdam

2011 42 / 1.5

Basic Course in Legisla� on and Organiza� on for Clinical Researchers. AMC Graduate School for Medical Sciences, UVA Amsterdam

2011 31 / 1.1

Basic Course Qualita� ve Health Research. AMC Graduate School for Medical Sciences, UVA Amsterdam

2011 54 / 1.9

Oral Presenta� on in English. AMC Graduate School for Medical Sciences, UVA Amsterdam

2011 24 / 0.9

Advanced Topics in Biosta� s� cs. AMC Graduate School for Medical Sciences, UVA Amsterdam

2012 60 / 2.1

SPECIFIC COURSES‘AL(le)S uit de kast’. Landelijk Mul� disciplinair Symposium ALS Centrum Nederland. Ede

2010 8 / 0.2

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

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

2013 8 / 0.2

Congress ‘Recent developments in policy, fi eld and research on Dutch Health care legisla� on’. Julius Center UMC Utrecht

2013 6 / 0.2

Workshops Mo� va� onal Interviewing. Amsterdam School of Health Professions. Amsterdam

2014 16 / 0.6

PRESENTATIONS‘The eff ec� 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]

2008 14 / 0.5

‘Onderzoek ALS Hulpmiddelen’. ALS Centrum Nederland. UMC Utrecht [oral]

2008 14 / 0.5


157

CV/P

‘De meerwaarde van intensieve zorg coaching in de behandeling en begeleiding van pa� ënten met Amyotrofi sche Laterale Sclerose (ALS)’. Projectleidersbijeenkomst Programma Pallia� eve Zorg ZonMw. Den Haag. [oral]

2008 14 / 0.5

‘Een zorgcoach voor mensen met ALS’. Landelijke Wetenschappelijke bijeenkomst ALS Centrum Nederland. UMC Utrecht. [oral]

2008 14 / 0.5

‘Zorgcoach onderzoek’ Revalida� e Advies Centra Neuromusculaire Aandoeningen Spierziekten Nederland. Baarn. [oral]

2008 14 / 0.5

‘De meerwaarde van intensieve zorg coaching in de behandeling en begeleiding van pa� ënten met Amyotrofi sche Laterale Sclerose (ALS)’. 2e Na� onaal Congres Pallia� eve Zorg. ZonMw sessie Programma Pallia� eve Zorg. Lunteren. [oral]

2008 14 / 0.5

‘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

‘Zorgcoach onderzoek’. Research bespreking Afdeling Revalida� e. AMC Amsterdam. [oral]

2008 14 / 0.5

‘De ALS Zorgcoach; een meerwaarde in de ALS zorg?’. Regionale Refereerbijeenkomsten Revalida� eafdelingen regio Noord-Holland. AMC Amsterdam. [oral]

2009 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 Neurologie UMCG. UMC Groningen. [oral]

2009 14 / 0.5

‘Zorgcoach onderzoek’. Research bespreking Afdeling Revalida� e. AMC Amsterdam. [oral]

2010 14 / 0.5

‘De meerwaarde van intensieve zorg coaching van pa� ënten met Amyotrofi sche Laterale Sclerose (ALS)’. Projectleidersbijeenkomst Pallia� eve Zorg ZonMw. Den Haag. [oral]

2010 14 / 0.5

‘De meerwaarde van intensieve zorg coaching van pa� ënten met Amyotrofi sche Laterale Sclerose (ALS)’. 3e Na� onaal congres Pallia� eve Zorg. ZonMw sessie Programma Pallia� eve Zorg. Lunteren. [oral]

2010 14 / 0.5

‘Zorgcoach onderzoek’. Revalida� e Advies Centra Neuromusculaire Aandoeningen Spierziekten Nederland. Baarn. [oral]

2011 14 / 0.5

‘Het zorgcoach onderzoek’. Landelijke Wetenschappelijke bijeenkomst ALS Centrum Nederland. RadboudUMC. Nijmegen. [oral]

2011 14 / 0.5

‘Het zorgcoach onderzoek’. Research bespreking Afdeling Revalida� e AMC. Amsterdam. [oral]

2011 14 / 0.5

‘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

‘A Randomized Controlled Trial on the Eff ect of Case Management on Pa� ents’ Quality of Life and Caregiver burden in ALS’. 22nd Interna� onal Symposium on ALS/MND in Sydney, Australia. [poster]

2011 14 / 0.5

‘De meerwaarde van intensieve zorg coaching in de behandeling en begeleiding van pa� ënten met Amyotrofi sche Laterale Sclerose (ALS)’. Projectleidersbijeenkomst Programma Pallia� eve Zorg ZonMw. Utrecht. [oral]

2012 14 / 0.5


158

‘De meerwaarde van intensieve zorg coaching in de behandeling en begeleiding van pa� ënten met Amyotrofi sche 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]

2012 14 / 0.5

‘Het zorgcoach onderzoek’. Research bespreking Afdeling Revalida� e AMC Amsterdam. [oral]

2012 14 / 0.5

‘De meerwaarde van intensieve zorg coaching in de behandeling en begeleiding van pa� ënten met Amyotrofi sche Laterale Sclerose (ALS)’. Spierziektecongres door Spierziekten Nederland en het Beatrix Spierfonds. Veldhoven. [poster]

2012 14 / 0.5

‘Zorgcoaching; ervaringen van pa� ënten met ALS en hun mantelzorgers’. Spierziektecongres door Spierziekten Nederland en het Beatrix Spierfonds. Veldhoven. [poster]

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]

2012 14 / 0.5

‘Case management as an adjunct to mul� disciplinary care for ALS pa� ents and their primary caregivers in the Netherlands: no eff ect on quality of life or caregiver strain’. 23rd Interna� onal Symposium on ALS/MND Symposium in Chicago, USA. [oral]

2012 14 / 0.5

‘Mul� disciplinaire ALS Zorg; kan het beter?’. Landelijk mul� disciplinair symposium ALS Centrum Nederland. Utrecht. [oral]

2013 14 / 0.5

‘Ervaringen van mensen met ALS, hun naasten en professionals met de zorgcoach’. Spierziektecongres door Spierziekten Nederland en het Beatrix Spierfond. Veldhoven. [poster]

2013 14 / 0.5

‘Zorgcoaching bij ALS’ Regionale Refereeravonden Revalida� egeneeskunde. AMC Amsterdam. [oral]

2013 14 / 0.5

‘Overbelas� ng van mantelzorgers van mensen met ALS’. Spierziektecongres door Spierziekten Nederland en het Beatrix Spierfonds. Veldhoven. [poster]

2014 14 / 0.5

‘Prognos� c factors for the course of func� onal status of pa� ents with ALS: a systema� c review’. 25th Interna� onal Symposium on ALS/MND in Brussels, Belgium. [poster]

2014 14 / 0.5

‘Factors related to caregiver strain in ALS’. Research bespreking Afdeling Revalida� e AMC Amsterdam. [oral]

2015 14 / 0.5

‘Overbelas� ng van mantelzorgers met ALS’. Major Donor Dag ALS Centrum Nederland en S� ch� ng ALS Centrum Nederland. UMC Utrecht. [oral]

2015 14 / 0.5

‘Overbelas� ng van mantelzorgers met ALS’. Open Dag ALS Centrum Nederland. UMC Utrecht. [oral]

2015 4 / 0.1

(INTER-)NATIONAL CONFERENCES19th Interna� onal Symposium on ALS/MND in Birmingham, United Kingdom.

2008 24 / 0.9


159

CV/P

6st Annual Allied Professionals Forum on ALS/MND in Birmingham, United Kingdom.

2008 8 / 0.2

21st Interna� onal Symposium on ALS/MND in Orlando, USA. 2010 24/ 0.98th Annual Allied Professionals Forum on ALS/MND in Orlando, USA. 2010 8 / 0.222nd Interna� onal Symposium on ALS/MND in Sydney, Australia. 2011 24 / 0.99th Annual Allied Professionals Forum on ALS/MND in Sydney, Australia. 2011 8 / 0.223rd Interna� onal Symposium on ALS/MND in Chicago, USA. 2012 24 / 0.910th Annual Allied Professionals Forum on ALS/MND in Chicago, USA. 2012 8 / 0.225th Interna� onal Symposium on ALS/MND in Brussels, Belgium. 2014 24 / 0.912th Annual Allied Professionals Forum on ALS/MND in Brussels, Belgium.

2014 8 / 0.2

2nd European polio conference, June 25–27, 2014, Amsterdam, the Netherlands.

2014 24 / 0.9

OTHERDeelname ZonMw project ‘De pa� ënt als informa� edrager’. Spierziekten Nederland. Baarn.

2008 8 / 0.2

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]

2011 20 / 0.7

Deelname ALS Kennispla] orm ALS Centrum Nederland en S� ch� ng ALS Centrum Nederland. UMC Utrecht.

2012 4 / 0.1

De ervaringen met mantelzorg � jdens het zorgcoach onderzoek. Bijdrage Contact op Maat t.b.v. leden met ALS/HSP/PSMA/PLS van Spierziekten Nederland.

2013 16 / 0.5

Project zorgcoach bij ALS. Bijdrage Contact op Maat t.b.v. leden met ALS/HSP/PSMA/PLS van Spierziekten Nederland.

2013 16 / 0.5

Deelname Onderzoek Netwerk Ergotherapie voor de regio Amsterdam (ONE-Amsterdam) periode 2011-2014. Amsterdam.

2011-2014 16 / 0.5

‘Pa� ents’, caregivers’ and professionals’ perspec� ves on case management in ALS’. 24th Interna� onal Symposium on ALS/MND in Milan, Italy. [poster]

2013 10 / 0.3

‘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 door Spierziekten Nederland en het Beatrix Spierfonds, september 2015. Veldhoven. [poster]

2015 8 / 0.2


160


161

L

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):420-5.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 fi nal publica� on is available at the Taylor & Francis Group via h� p://dx.doi.org/10.3109/21678421.2014.920031

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 fi nal 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 fi nal publica� on is available at the Taylor & Francis Group via h� p://dx.doi.org/10.3109/21678421.2014.971811

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 fi nal publica� on is available at Springer via h� p://dx.doi.org/10.1007/s00415-014-7564-8

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 fi nal publica� on is available at the BMJ Publishing Group Ltd via h� p://jnnp.bmj.com/content/early/2015/09/04/jnnp-2015-311651

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

Huub Creemers

Op

timizin

g q

uality

of care

for p

atien

ts with

AL

S an

d th

eir fam

ily care

give

rsH

uu

b C

ree

me

rs

Voor het bijwonen van de openbare verdediging van het

proefschrift

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 CreemersSimonshavenstraat 191107 VA Amsterdam

[email protected]

Uitnodiging

Optimizing quality of care for patients with ALS


Paranimfen

Antoinette Vullings-CreemersFrancien Haex

door Huub Creemers

Proefschrift Creemers

Documents

Transcript of Proefschrift Creemers