JOURNAL OF PALLIATIVE MEDICINE Volume 23, Number 11, 2020 Special Report 2020 Mary Ann Liebert, Inc. ª 2020 European Academy of Neurology and European Association of Palliative Care DOI: 10.1089/jpm.2020.0220 EAN Guideline on Palliative Care of People with Severe, Progressive Multiple Sclerosis Alessandra Solari, MD,1 Andrea Giordano, MSc,1,2 Jaume Sastre-Garriga, MD, PhD,3 Sascha Köpke, PhD,4,5 Anne C. Rahn, PhD,5 Ingo Kleiter, MD,6 Katina Aleksovska, MD,7 Mario A. Battaglia, MD, PhD,8 Jette Bay,9 Massimiliano Copetti, PhD,10 Jelena Drulovic, MD, PhD,11 Liesbeth Kooij, MSc,12 John Mens, MD,12 Edwin R. Meza Murillo, MD,3 Ivan Milanov, MD, PhD, DSc,13 Ron Milo, MD,14,15 Tatiana Pekmezovic, PhD,16 Janine Vosburgh,17 Eli Silber, MD,18 Simone Veronese, MD, PhD,19 Francesco Patti, MD,20 Raymond Voltz, MD, PhD,21,22 and David J. Oliver, MD, FRCP23; on behalf of the Guideline Task Force* Abstract Background and Purpose: Patients with severe, progressive multiple sclerosis (MS) have complex physical and psychosocial needs, typically over several years. Few treatment options are available to prevent or delay further clinical worsening in this population. The objective was to develop an evidence-based clinical practice guideline for the palliative care of patients with severe, progressive MS. Methods: This guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Formulation of the clinical questions was performed in the Patients–Intervention– Comparator–Outcome format, involving patients, carers and healthcare professionals (HPs). No uniform definition of severe MS exists: in this guideline, constant bilateral support required to walk 20 m without resting (Expanded Disability Status Scale score >6.0) or higher disability is referred to. When evidence was lacking for this population, recommendations were formulated using indirect evidence or good practice statements were devised. 1 Unit of Neuroepidemiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 2 Department of Psychology, University of Turin, Turin, Italy. 3 Department of Neurology/Neuroimmunology, Multiple Sclerosis Centre of Catalonia (Cemcat), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain, Germany. 4 Institute of Clinical Nursing Science, University of Cologne, Cologne, Germany. 5 Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 6 Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany. 7 European Academy of Neurology, Vienna, Austria. 8 Department of Life Sciences, University of Siena, Siena, Italy. 9 Multiple Sclerosis International Federation, People with MS Advisory Committee, Copenhagen, Denmark. 10 Unit of Biostatistics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. 11 Clinic of Neurology, CCS, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. 12 Nieuw Unicum, Zandvoort, The Netherlands. 13 Medical University of Sofia, Sofia, Bulgaria. 14 Department of Neurology, Barzilai Medical Center, Ashkelon, Israel. 15 Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. 16 Faculty of Medicine, University of Belgrade, Belgrade, Serbia. 17 Israel Multiple Sclerosis Society, Tel-Aviv, Israel. 18 Department of Neurology, King’s College Hospital NHS Foundation Trust, London, United Kingdom. 19 FARO Charitable Foundation, Turin, Italy. 20 Neurology Clinic, Multiple Sclerosis Centre, University Hospital Policlinico Vittorio Emanuele, Catania, Italy. 21 Department of Palliative Medicine, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany. 22 Center for Health Services Research (ZVFK), Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany. 23 The Tizard Centre, University of Kent, Canterbury, United Kingdom. *See the Guideline Task Force in Appendix S1. This article is co-published by the European Journal of Neurology and the Journal of Palliative Medicine.  Alessandra Solari et al., 2020; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits any non- commercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. 1426 EAN GUIDELINE PALLIATIVE CARE IN MULTIPLE SCLEROSIS 1427 Results: Ten clinical questions were formulated. They encompassed general and specialist palliative care, advance care planning, discussing with HPs the patient’s wish to hasten death, symptom management, multi- disciplinary rehabilitation, interventions for caregivers and interventions for HPs. A total of 34 recommenda- tions (33 weak, 1 strong) and seven good practice statements were devised. Conclusions: The provision of home-based palliative care (either general or specialist) is recommended with weak strength for patients with severe, progressive MS. Further research on the integration of palliative care and MS care is needed. Areas that currently lack evidence of efficacy in this population include advance care planning, the management of symptoms such as fatigue and mood problems, and interventions for caregivers and HPs. Keywords: clinical practice guideline; GRADE assessment; multiple sclerosis; palliative care Introduction Methods M ultiple sclerosis (MS) is a chronic neurological disease affecting 2.3 million people worldwide. It has a variety of clinical presentations, an unpredictable disease The Grading of Recommendations Assessment, Devel- opment and Evaluation (GRADE) methodology and the updated EAN recommendations were followed.14 A TF of course, and is the most common cause of neurological dis- 21 members from nine European countries and three disci- ability in young adults in many western countries.1 Around plines (neurology, PC, rehabilitation) was assembled, with 15% of MS patients have a progressive course from the outset invitations from the chair (AS) on the basis of expertise in (primary progressive MS); a further 40% develop progres- MS care. JD, IM, RM, RV and DO were appointed by the sive disease after 15 years with relapsing–remitting disease EAN; SV, RV and DO by the EAPC; MAB, JD and JSG by (secondary progressive MS).2 No uniform definition of se- the RIMS, and JSG and RV by the ECTRIMS (Appendix S1). vere MS exists: in this guideline, patients needing constant bilateral support (cane, crutch or braces) to walk 20 m with- The clinical questions out resting [i.e. Expanded Disability Status Scale (EDSS) score >6.0]3 or higher disability are referred to. A significant Ten clinical questions were formulated by the TF in Patients– proportion of such patients need assistive devices4 and they Intervention–Comparator–Outcome (PICO) format (Appendix are at risk of death from aspiration pneumonia, urinary tract S2). The formulation was guided by literature search, MS expert infections, complications of falls and fractures, and sepsis survey (47 participants), MS patients and caregivers online secondary to pressure ulcers.5,6 Nevertheless, some patients survey (1119 participants) and five focus group meetings (three with severe, progressive MS (hereafter, severe MS) live for of MS patients, two of caregivers; overall 35 participants). The many years, and most die in hospital rather than at home.7,8 TF, originally organized into a Guideline Working Panel and a The provision of palliative care (PC) has been proposed to Methodological Panel, added a Client Consultation Panel to help respond to the complex and varying bio-psychosocial help with this phase, which took place between April 2017 and needs of patients with severe MS, for whom few treatment February 2018 and is detailed in a dedicated paper.13 In October options are currently available to delay or prevent further 2018, TF members independently rated the importance of the clinical worsening.9–12 outcomes identified for each clinical question on a 9-point scale15 (Fig. 1): all outcomes were considered as critical (score range 7–9) or important but not critical (score range 4–6). Scope This guideline was devised by an international task force Literature search (TF) appointed by the European Academy of Neurology Seven electronic databases were searched from inception to (EAN) in partnership with the European Association for October 2018: MEDLINE (OVID), PubMed, Embase, Psy- PC (EAPC) and the European Network for Best Practice and cINFO, CINAHL, Cochrane Central Register of Controlled Research in MS Rehabilitation (RIMS). TF members were Trials and Cochrane Database of Systematic Reviews. The also appointed by the MS International Federation (MSIF) search strategies were developed in collaboration with two in- and by the European Committee for Treatment and Research formation specialists. The full MEDLINE search strategies are in MS (ECTRIMS). This collaborative, multiple stakeholder provided in Appendix S3. The search was expanded by looking approach was adopted to reflect practice across a variety of at the references in the studies selected and at citations in the healthcare systems in Europe. Web of Science Citation Index; by hand search of the online The aim was to focus on outcomes that are important for pa- material available for major PC and MS journals; and by search tients and useful for caregivers and healthcare professionals on clinical trials registries and guideline (www.guidelines.gov) (HPs). To ensure this, the clinical questions were formulated via and health technology assessment (www.inahta.org) websites. direct engagement of MS patients and caregivers.13 The primary intended audience is clinicians working in MS care, PC, emer- Study selection and data extraction gency medicine, nursing, rehabilitation and related disciplines. In addition, policy-makers, charities and other stakeholders may Between July and December 2018, two TF members in- find this guideline useful for informing and planning policies. dependently reviewed the titles and abstracts identified and A pertinent document to the guideline is the EAN con- discarded the clearly irrelevant ones and those that did not sensus review on PC for patients with chronic and progres- meet the inclusion criteria. Any discrepancy at this stage was sive neurological diseases.10 resolved by consensus. Full text of the selected studies was 1428 SOLARI ET AL. FIG. 1. Outcomes identified as important (score range 4–6; blue bars) or critical (score range 7–9; red bars) by the task force for each clinical question on a 9-point scale.15 ADL, activities of daily living; HP, healthcare professional; MS, multiple sclerosis; QOL, quality of life; SDM, shared decision-making. then reviewed independently by the two reviewers. Any the weighted score difference between PC and usual care disagreement regarding inclusion of individual studies was groups, controlling for study, baseline EDSS score and resolved by consensus; if agreement was not obtained, the baseline domain score. The one-stage approach was selected full-text study was sent to a third independent reviewer for as it provides a more exact likelihood in the case of small adjudication. Full details of the literature selection results studies.21 Our primary IPDMA analysis was intention-to- for each clinical question are presented in Appendix S4. treat, with multiple imputations of the missing data via Data from each included study were extracted by one TF logistic regression models.22 A per-protocol analysis was member using an electronic form. A second member checked also performed. Further, a sensitivity analysis was performed the data and disagreement was resolved by consensus; if after exclusion of the PeNSAMI trial,20 to check whether consensus was not obtained, a third TF member was invol- the results obtained from all three studies (clinical questions ved. Two TF members assessed the quality of evidence of 1 and 2) were consistent with those of the two studies on the included studies using the Cochrane tool for risk of specialist PC (clinical question 2). bias (randomized controlled trials, RCTs)16 and the CASP It was not possible to perform a quantitative synthesis on 10-item tool (qualitative studies, http://www.casp-uk.net/ the other clinical questions, except for nabiximols for spas- #!casp-tools-checklists/c18f8). Any disagreement was re- ticity (clinical question 5) where a random-effects model solved by consensus; if consensus was not obtained, a third meta-analysis was used. The effect on spasticity (patient- TF member was involved. reported numerical rating scale, NRS) and caregiver-reported global impression of change (CGIC) scores were considered as they were used in all three included studies.23–25 The mean Data synthesis NRS differences between end of study and baseline reported For general and specialist PC (clinical questions 1 and 2), in each study and, for CGIC, the odds ratios of nabiximols an individual participant data meta-analysis (IPDMA)17 was versus placebo were estimated. Between-study heterogeneity used to estimate the overall effect of the three RCTs currently was assessed by Higgins I2 statistic with 95% confidence available,18–20 one of which enrolled a mixed population of intervals (CIs). The meta-analyses were performed by an participants with neurodegenerative disorders, including MS independent statistician (MC) and an EAN methodologist (18/ 49, 37%).19 The baseline scores (T0) and the end-of- (KA). The preliminary and final results of the IPDMA were study scores (T1, at 12 weeks for the UK,18 16 weeks for the shared with the authors of the included studies. The IPDMAs NE-PAL trial19 and 24 weeks for the PeNSAMI trial20) were were performed using STATA 16 (STATA College Station, considered. Domains that were assessed by all the studies TX, USA) and meta-analyses using RevMan 5.3 (The Nordic were identified. For each domain, multivariate linear re- Cochrane Centre, The Cochrane Collaboration, Copenhagen, gression models were used to estimate the variability of Denmark). EAN GUIDELINE PALLIATIVE CARE IN MULTIPLE SCLEROSIS 1429 Formulation of recommendations retained: the study and the baseline domain score (results Two TF members from the methodological panel formu- with the baseline EDSS score included were similar; data lated the preliminary wording and grading for each recom- not shown). A statistically significant effect in favour of mendation. Agreement upon the direction (‘for’ or ‘against’) PC was found on pain (regression coefficient —17.36; 95% and the strength (‘strong’ or ‘weak’) of each recommendation CI —31.54 to —3.18) and sleeping problems (regression was obtained via teleconferences and electronic discussions, coefficient —14.15; 95% CI —26.93 to —1.36), whilst there using a modified Delphi method.26 Agreement was reached was no effect on the remaining five symptoms and on care- after one clinical round for recommendations pertaining to giver burden (Fig. 3; Table 3). clinical questions 7–10, after two rounds for recommendations The per-protocol analysis was consistent with intention-to- pertaining to clinical questions 1–4 and 6, and after two to three treat findings except for a significant reduction in caregiver rounds for recommendations pertaining to clinical question 5. burden (mean coefficient —7.07; 95% CI —12.88 to —1.26) in the sensitivity analysis. In conclusion, three RCTs reporting on the effectiveness of Ethics statement PC services compared to usual care were found. Two studies The guideline protocol was approved by the ethics com- assessed home-based specialist PC18,19 and one study home- mittee of the Fondazione IRCCS Istituto Neurologico Carlo based general PC.20 Studies differed in length of follow-up Besta, Milan, Italy (ref. no. 34, 2016). (12–24 weeks) but were considered sufficiently homogene- ous for a quantitative synthesis. Overall, there is low certainty Results in our findings, mostly due to risk of bias and imprecision. Also, publication bias cannot be ruled out. General and specialist palliative care (clinical A statistically significant effect in favour of PC was found questions 1 and 2) for two of the eight domains considered, pain and sleep- PC seeks to improve the quality of life of patients and their ing problems. A per-protocol analysis additionally found a families facing a life-threatening illness, through the pre- reduction in caregiver burden, for specialist PC only. There vention and relief of suffering by means of early identifica- is no evidence of effects on quality of life and on the tion and impeccable assessment and treatment of pain and other outcomes. No studies were found on inpatient or out- other problems, physical, psychosocial and spiritual.27 The patient PC. PC provided by HPs who specialize in this discipline is known as specialist PC. Special PC services are characterized Recommendation. It is suggested that home-based PC by a multiprofessional team approach and interdisciplinary is offered to patients with severe MS, either by HPs with good mode of work.28 General PC can be provided by primary and basic PC skills and knowledge (general PC) or by multi- specialist HPs who have attained PC competences but do not professional teams of PC specialists (specialist PC) (weak provide PC as the main focus of their work. recommendation, low certainty evidence). Ten publications on PC interventions were found: two de- scribed a qualitative study assessing the experiences of nine Good practice statement. It is suggested that inpatient MS patients participating in a PC daycare programme29,30 and or outpatient PC is offered to patients with severe MS. Patient eight described three RCTs.18–20,31–35 The characteristics of preference, living conditions and availability of PC services the RCTs, and participants, are reported in Table 1. should be taken into account. The UK trial18,32,33 and NE-PAL19 were single-centre Recommendations pertaining to clinical questions 3–10 RCTs comparing home-based specialist PC to usual care (1:1 are reported below. A full report which also contains the ratio). PeNSAMI20,34 was a multicentre RCT comparing references of the included studies for these questions is home-based general PC to usual care (2:1 ratio). The inter- available in Appendix S5. vention lasted 12 weeks in the UK trial, 16 weeks in the NE- PAL trial and 24 weeks (with a 12-week assessment) in the Advance care planning (clinical question 3) PeNSAMI study. The risk of bias was low overall except for performance bias (all studies) and detection bias (UK and According to the EAPC, advance care planning (ACP) is a NE-PAL). UK trial participants were slightly younger (mean process that enables individuals who have decisional capacity age 53 years), less severely affected (median EDSS 7.5) and to identify their values, to reflect upon the meanings and predominantly women (68%) compared to participants in the consequences of serious illness scenarios, to define goals and other two studies (Table 1). Each patient had a caregiver who preferences for future medical treatment and care, and to participated in the trial (in most instances a woman, and discuss these with family and HPs. ACP addresses individ- patient spouse or partner). uals’ concerns across the physical, psychological, social, and Eight domains were assessed by all the studies (Table 2): spiritual domains. It encourages individuals to identify a pain, shortness of breath, bladder problems, bowel problems, personal representative and to record and regularly review anxiety, depression, sleeping problems and caregiver burden. any preferences, so that their preferences can be taken into Figure 2 illustrates the mean changes in these domains by account should they, at some point, be unable to make their study arm across the three studies. own decisions.36 Individual participant data meta-analysis results are re- Of 617 records screened, seven were assessed as full text ported in Fig. 3 and Table 3, which provide data for the and excluded from the final selection (Appendix S5). From a intention-to-treat and per-protocol analyses considering both systematic review,37 there is no evidence of the effects of the full dataset and the sensitivity analyses. Besides the in- ACP for people with neurological diseases, including MS. tervention, in each regression model two covariates were However, there is some evidence from other progressive Table 1. Characteristics of the Trials on General/Specialist Palliative Care (Clinical Questions 1 and 2) and of Trial Participants Study MS patients (%) Carers (%) Country No. of Length Risk of bias Intervention (name) centres (weeks) (low/high) No. Age3 Women EDSSb No. Agea Women Relation c Specialist PC UK - 1 12 Selection (low) 52 53.0 (33–75) 36 (69) 7.5 (5.5–9.5) 43 - - Partner/spouse 29 (67) home- Selection (low)d Son/daughter 7 (16) based Performance (high) Parent 4 (10) Detection (high) Other relative 3 ( 7) Attrition (low) Paid carer 0(0) Reporting (low) Other (low) Specialist PC Italy 1 16 Selection (low)c 18 54.2 (40–71) 10 (56) 8.5 7.0–9.5) 18 - 14 (78) Partner/spouse 11 (61) home- (NE-PAL) Selection (low)d Son/daughter 1 ( 5) 1430 based Performance (high) Parent 2 (10) Detection (high) Other relative 1 ( 5) Attrition (low) Paid carer 3 (17) Reporting (low) Other (low) General PC Italy 3 24 Selection (low)c 76 59.2 (41–80) 43 (57) 8.5 (8.0–9.5) 76 60.3 47 (62) Partner/spouse 40 (53) home- (PeNSAMI) Selection (low)d (23– Son/daughter 8(11) based Performance (high) 84) Parent 12 (16) Detection (low) Other relative 13 (17) Attrition (low) Paid carer 3(4) Reporting (low) Other (low) EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; PC, palliative care. aMean (range). bMedian (range). cRandom sequence generation. dAllocation concealment. EAN GUIDELINE PALLIATIVE CARE IN MULTIPLE SCLEROSIS 1431 Table 2. Summary of Findings for General/Specialist) Participants Certainty of the PC/UC evidence Outcomes Description (studies) (GRADE) Symptom burden Of seven symptoms assessed by all three RCTs using 143 44.. LOWb,c (Edmonds et al., different measures (MS-POS-5S, Core-POS, 86/57 2010,18 Veronese POS-S-MS, POS-8, VAS) there was a significant (3 RCTs) et al., 2017,19 Solari improvement in the PC group but not in the UC group et al., 201820) over follow-up for pain and sleeping problems, whilst there was no difference between groups for shortness of breath, bladder problems, bowel problems, anxiety and depression Quality of life SEIQOL-DW was used in both RCTs. No differences 71 44.. LOWb,c (Veronese et al., were found on mean change in SEIQOL-DW total 43/28 2017,19 Solari et al., score over 16/24 weeks between the PC group and the (2 RCTs) 201820) UC group in both RCTs (P = 0.13/P = 0.88) Unplanned In Veronese et al.19 there was one unplanned 94 444. hospitalizations hospitalization (UC group) versus none in the PC 60/34 MODERATEc (Veronese et al., group over 16 weeks. In Solari et al.20 there were (2 RCTs) 2017,19 Solari et al., 12 (24%) unplanned hospitalizations in the PC group 201820) versus seven (27%) in the UC group (P = 0.78) over 24 weeks Hospital deaths There were five deaths overall: two in Edmonds et al., 143 44.. LOWb,c (Edmonds et al., 201018 (one in the PC group, at the patient’s home; one 86/57 2010,18 Veronese in the UC group, place not specified); none in (3 RCTs) et al., 2017,19 Solari Veronese et al., 201719; three in Solari et al., 201820 et al., 201820) (three in the PC group: two in hospital and one at the patient’s home) Quality of death/dying Not reported Not reported Statistically significant mean 52 44.. LOWb,c Complicated total cost saving per patient over 12 weeks of £1789 25/21 bereavement Costs for PC versus UC (including inpatient and informal (1 RCT) (Higginson et al., caregiver savings). No statistical differences were 200933) found for PC (versus UC) in community costs per patient and in costs to informal caregivers; the saving appeared to be mainly due to a lower use of primary and acute hospital services Caregiver quality of life There was no effect of PC (versus UC) on both SF-36 76 50/26 44.. LOWb,c (Solari et al., 201820) PCS score (P = 0.87) and MCS score (P = 0.96) (1 RCT) Caregiver mood (Solari There was no effect of PC (versus UC) on both HADS 76 50/26 44.. LOWb,c et al., 201820) anxiety score (P = 0.50) and HADS depression score (1 RCT) (P = 0.45) Caregiver burden The three studies used different measures (CBI, ZBI-12, 124 4... (Edmonds et al., ZBI-22) and there was no effect of PC (versus UC) 73/51 VERY LOWa,c 2010,18 Veronese in the combined analysis (P = 0.46). For specialist PC (3 RCTs) et al., 2017,19 Solari data (2 RCTs), there was a reduction in caregiver et al., 201820) burden versus no change in UC (ITT analysis only; P = 0.019) Patient or population: patients with severe multiple sclerosis. Setting: home-based patient care. Intervention: palliative care (PC). Comparison: usual care (UC). GRADE Working Group grades of evidence. High certainty: there is great confidence that the true effect lies close to that of the estimate of the effect. Moderate certainty: there is moderate confidence in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: there is very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of the effect. CBI, Caregiver Burden Index; Core-POS, Core Palliative Outcome Scale; HADS, Hospital Anxiety and Depression Scale; ITT, intention to treat; MCS, Mental Composite Scale; MS- POS-5S, Multiple Sclerosis Palliative Outcome Scale 5 Symptoms; PCS, Physical Composite Scale; POS-8, Eight-item Palliative outcome Scale; POS-S-MS, Palliative Outcome Scale Symptoms Multiple Sclerosis; RCT, randomized controlled trial; SEIQOL-DW, Schedule for the Evaluation of Individual Quality of Life Direct Weight; SF-36, 36-item Short Form Health Survey; VAS, Visual Analogue Scale; ZBI-12, 12- item Zarit Burden Index; ZBI-22, 22-item Zarit Burden Index. aVery serious risk of bias. bSerious risk of bias. cImprecision. and life-threatening illnesses that ACP decreases the use of discussions.38,39 Often professionals leave discussions until life-sustaining treatment, increases hospice/PC, reduces the later stages of progression in MS.40 Patients react in hospitalizations and increases compliance with patients’ end- different ways on discussion of future planning: a small study of-life wishes.37 showed that some MS patients made clear decisions, some Concerning MS, there is evidence that patients and care- undertake some planning but without a clear advance direc- givers often would like to discuss the issues of death and tive and some were still ‘hoping for a cure’ and did not wish dying and HPs should acknowledge and encourage these to look ahead.41 However, caregivers may be left having 1432 SOLARI ET AL. FIG. 2. Boxplots of the 0/100 transformed score changes in each of the eight domains, by arm and across the three studies (per-protocol data). The top and bottom of each box are the 25th and 75th percentiles; the horizontal line inside the box is the median; the whiskers are the upper and lower adjacent values; the dots are outlier values. difficult decisions if no planning has taken place and this is Good practice statements. stressful for caregivers.42 1. Patients should be encouraged to discuss their wishes about future care, including the restriction of treatment Good practice statements. and interventions and the wish for hastened death. 1. It is suggested that early discussion of the future with 2. Healthcare professionals should be aware of the risk ACP is offered to patients with severe MS. factors for the wish for hastened death – including 2. It is suggested that regular communication about the depression, isolation, restricted abilities – and encour- future progression of MS is undertaken with patients age the discussion of these issues and the appropriate and families/caregivers. management. Patient discussion with HPs of their wish to hasten death (clinical question 4) Symptom management (clinical question 5) Healthcare professionals’ acknowledgment of, and open This patient population is characterized by the presence discussion about, the patient’s wish to hasten death and re- of multiple symptoms, in variable combinations between lated issues emerged as key from both TF members (chiefly patients and in the same patient over time (Table 4). The PC physicians) and MS patients.13 Of 491 records screened, management of pain and other symptoms is at the core of seven were assessed as full text and excluded from the final PC. Nevertheless, some symptoms (e.g. spasticity, fatigue) selection (Appendix S5). Berkman et al.43 reported that 33% typically affect MS patients and were not addressed in clin- of MS patients considered suicide or assisted dying. In ical questions 1 and 2. Patients with severe MS should be more recent studies, 22% of MS patients had suicidal in- carefully and regularly assessed in order to proactively detect tention,44 and 7% would consider suicide and 65% assisted their bio-psychosocial symptoms. Whenever necessary (e.g. dying if they had unbearable pain.45 Suicidal ideation or in patients with severe cognitive compromise or communi- consideration of assisted dying was related to depression, cation problems), interviews with patient caregivers and the hopelessness, MS affecting leisure time and feeling socially use of proxy versions of symptom scales should be added isolated.11,46 Access to PC expertise has been recommended to patient assessment. for individuals requesting euthanasia or physician-assisted Of 7195 records screened, 530 were assessed as full text suicide as further assessment and management of symptoms, and 44 (43 trials) were included. Ten publications addressed psychosocial or spiritual distress.47 more than one symptom. The symptom with the highest EAN GUIDELINE PALLIATIVE CARE IN MULTIPLE SCLEROSIS 1433 FIG. 3. Individual participant data meta-analysis results. Intention-to-treat results are reported in black, and per-protocol results are reported in grey. In each model the dependent variable is the 0/100 transformed score change on the domain; the independent variables are the intervention, the study and the 0/100 transformed baseline score. PC, palliative care; UC, usual care. number of publications was spasticity, followed by fatigue trials (84%) addressed drugs (baclofen, benzodiazepines, and pain (Table 4). cannabinoids, GABAergics, tizanidine and botulinum tox- Considering the type of intervention, 32/43 trials (75%) in) and five trials addressed nonpharmacological treatments were on pharmacological interventions, 10 (23%) on non- (exercise, radial shock wave therapy and transcutaneous pharmacological approaches and one (2%) was a trial electrical nerve stimulation). A meta-analysis was per- assessing a combination of botulinum toxin A and physio- formed for nabiximols: all the three RCTs23–25 shared the therapy. No studies on interventions targeted to the man- patient-reported NRS for spasticity and CGIC ‘ease of agement of 10/19 pre-specified symptoms were found in transfer’ (Table 5). Mean NRS spasticity difference fa- our literature search (Table 4). Further, the included studies voured nabiximols (—0.51; 95% CI —0.96 to —0.07); and reported on few of our predefined outcomes. Recommen- the odds ratio for CGIC ‘ease of transfer’ improvement was dations on four symptoms (spasticity, fatigue, pain and 1.99 (95% CI 1.17–3.38) for nabiximols versus placebo bladder problems) were produced. For each symptom, a full (Fig. 4). report is available in Appendix S5 and summary of findings tables in Appendix S6. Recommendations. 1. Nabiximols are recommended to reduce spastic- Spasticity ity in patients with severe MS. Drug availability, The majority of the included publications (32/44, 73%; the presence of other symptoms and possible ad- 31 trials) addressed spasticity as an outcome. Of these, 26 verse events should be considered in treatment FIG. 3. (Continued). 1434 FIG. 3. (Continued). 1435 1436 SOLARI ET AL. Table 3. Individual Participant Data Meta-Analysis Results, with Data Adjusted for Study and Baseline Score Full dataset (clinical questions 1 and 2) Sensitivity analysis (clinical question 2) Domain Coefficient SE P value 95% CI Coefficient SE P value 95% CI Intention to treat Pain 9.81 4.52 0.032 -18.76 to -0.85 -17.36 7.09 0.017 -31.54 to -3.18 Shortness of breath -2.57 3.67 0.485 -9.83 to 4.69 -6.41 4.89 0.195 -16.20 to 3.37 Bladder problems 8.11 4.16 0.054 -0.15 to 16.37 11.06 6.84 0.111 -2.62 to 24.74 Bowel problems -1.52 5.12 0.768 -11.65 to 8.62 10.39 7.06 0.146 -3.73 to 24.51 Anxiety -9.38 5.19 0.073 -19.65 to 0.88 -9.56 8.22 0.249 -26.03 to 6.90 Depression 1.54 3.99 0.700 -6.37 to 9.44 -1.74 6.79 0.798 -15.38 to 11.89 Sleeping problems -9.88 4.01 0.015 -17.81 to -1.94 -14.15 6.39 0.031 -26.93 to -1.36 Caregiver burden -2.61 3.53 0.465 -9.78 to 4.56 -5.80 5.76 0.325 -17.72 to 6.12 Service satisfactiona 9.81 9.50 0.307 -9.26 to 28.88 Per protocol Pain -8.98 4.49 0.048 -17.87 to -0.10 -16.83 7.03 0.020 -30.89 to -2.77 Shortness of breath -3.00 3.70 0.420 -10.31 to 4.32 -6.94 4.97 0.168 -16.89 to 3.01 Bladder problems -1.94 5.49 0.724 -12.81 to 8.93 11.09 7.96 0.170 -4.89 to 27.06 Bowel problems -9.50 5.20 0.070 -19.79 to 0.79 -10.02 8.24 0.229 -26.50 to 6.47 Anxiety 7.42 4.30 0.087 -1.11 to 15.95 8.39 7.26 0.253 -6.17 to 22.95 Depression 1.57 4.01 0.697 -6.37 to 9.52 1.61 6.72 0.811 -15.09 to 11.86 Sleeping problems -8.22 3.90 0.037 -15.92 to -0.51 -10.50 6.16 0.093 -22.82 to 1.82 Caregiver burden -1.92 1.91 0.318 -5.72 to 1.87 -7.07 2.84 0.019 -12.88 to -1.26 Service satisfactiona 13.68 9.92 0.174 -6.22 to 33.59 Statistically significant values are reported in bold; CI, confidence interval. aNot assessed in the PeNSAMI study. decision-making (strong recommendation/moderate symptoms and possible adverse events should be certainty evidence). considered in treatment decision-making. 2. Oral baclofen is suggested to reduce spasticity in 3. Intrathecal baclofen is suggested to reduce spasticity patients with severe MS (weak recommendation/ in patients with severe MS (weak recommendation/ very low certainty evidence). Presence of other very low certainty evidence). The presence of other symptoms and possible adverse events (related to Table 4. Publications Found for Each Specified the drug and to pump and catheter placement/ Symptom (10 Out of 43 Trials Addressed More Than One Symptom) replacement) should be considered in treatment decision-making. Publication year 4. Tizanidine is suggested to reduce spasticity in pa- Symptom Publications Trials (min–max) tients with severe MS (weak recommendation/ low certainty evidence). The presence of other symptoms Spasticity 32 31 1975–2017 and possible adverse events should be considered in Fatigue 10 9 2001–2017 treatment decision-making. Paina 7 6 2003–2017 Sleeping problemsa 6 5 2003–2017 5. GABAergic drugs are suggested to reduce spasticity Bladder problemsa 6 4 1996–2006 in patients with severe MS (weak recommendation/ Mobility/transfer 5 5 1996–2017 low or very low certainty evidence). The presence of Tremor 4 3 2003–2009 other symptoms and possible adverse events should Balance 1 1 2015 be considered in treatment decisionmaking. Arm function 1 1 2018 6. Other cannabinoids (D9-tetrahydrocannabinol Swallowing 0 - - or cannabis sativa plant extract) are suggested to (e.g. dysphagia) reduce spasticity in patients with severe MS (weak Bowel problemsa 0 - - recommendation/moderate certainty evidence). Drug Communication 0 - – availability, the presence of other symptoms and (e.g. dysarthria) Depressed mooda 0 – – possible adverse events should be considered in Cognitive problems 0 – – treatment decision-making. Sexual problems 0 – – 7. Botulinum toxin A is suggested to reduce hip adductor Shortness of breath/ 0 – – spasticity in patients with severe MS (weak recom- dyspnoeaa mendation/low certainty evidence). The presence of Nausea, vomiting 0 – – other symptoms and possible adverse events should be Poor appetite/ 0 – – considered in treatment decision-making. anorexia 8. Exercise is suggested to reduce spasticity in patients Mouth problems 0 – – with severe MS (weak recommendation/ very low a Also addressed in clinical questions 1 and 2 (general and certainty evidence), considering patient preferences specialist palliative care). and resource availability. Table 5. Summary of Findings for Nabiximols to Treat Spasticity (Clinical Question 5) No. of participants Certainty of the IG/CG evidence Outcomes Description (studies) (GRADE) Symptom burden (meta-analysis) The meta-analysis showed a significant difference 614 444. (Collin et al., 2010,23 Novotna between groups for spasticity NRS (mean 309/305 MODERATEa et al., 2011,24 Notcutt et al., difference -0.51, 95% CI -0.96 to -0.07) (3 RCTs) 201225) Symptom burden (MAS) (Collin There were no significant differences between 614 309/305 444. et al., 2010,23 Novotna et al., groups in the MAS scores (3 RCTs) MODERATEa 2011,24 Notcutt et al., 201225) Symptom burden (SGIC) There were significant differences between groups 277 142/135 444. (Novotna et al., 2011,24 favouring nabiximols (2 RCTs) MODERATEa Notcutt et al., 201225) ADL (Collin et al., 2010,23 There was a significant difference between groups 578 44.. LOWa,b Novotna et al., 201124) in Novotna et al. favouring nabiximols, but not 291/287 in Collin et al. (2 RCTs) QOL (Collin et al., 2010,23 There was no difference between groups in Collin 578 291/287 444. Novotna et al., 201124) et al. (EQ-5D, MSQOL-54) and Novotna et al. (2 RCTs) MODERATEa (EQ-5D, SF-36) CGIC (ease of transfer, meta- The meta-analysis of CGIC showed a significant 614 309/305 444. analysis) (Collin et al., 2010,23 difference between groups (OR 1.99, 95% CI (3 RCTs) MODERATEa Novotna et al., 2011,24 1.17–3.38) Notcutt et al., 201225) Adverse events (Collin et al., Collin et al.: A total of 55 patients (16%) 614 444. 2010,23 Novotna et al., discontinued treatment early; 35 (21%) in the 309/305 MODERATEa 2011,24 Notcutt et al., 201225) nabiximols group and 20 (12%) in the placebo (3 RCTs) group. Of these 55 patients, 32 (58%) withdrew from the study. The primary reason given for withdrawal was AE occurrence: nine patients (5%) on nabiximols and five (3%) on placebo. The following AEs were reported more frequently in the nabiximols group compared to placebo: dizziness [53/167 (32%) vs. 17/170 (10%)], fatigue [42/167 (25%) vs. 32/170 (19%)], somnolence [24/167 (14%) vs. 7/170 (4%)], nausea [53/ 167 (32%) vs. 17/170 (10%)], asthenia [26/167 (16%) vs. 11/170 (6%)] and vertigo [19/167 (11%) vs. 7/170 (4%)]. Two subjects died from cancer during the study: neither death was considered to be related to the (active) study medication Notcutt et al.: There was one SAE (pain in hip and thigh and lumbar spinal stenosis) in a patient on nabiximols, which was considered unrelated to study medication. The only AE reported in association with abnormal laboratory values was a mild increase in gamma- glutamyl transferase in one patient on nabiximols. Novotna et al.: 17 patients discontinued the treatment early (7%); 15 were on nabiximols (four due to AEs, 11 due to withdrawal of consent). AEs were overall few and similar between nabiximols and placebo, with no single event occurring at a rate >10% in either group; the most common AEs were vertigo (6% nabiximols vs. 1% placebo) and fatigue (5% vs. 1%) Patient or population: people with severe multiple sclerosis (and spasticity). Setting: research hospitals, outpatients. Intervention: nabiximols (2.7 mg D9-tetrahydrocannabinol and 2.5 mg cannabidiol, up to 24 sprays in 24 h) for 4–15 weeks. Comparison: placebo. GRADE Working Group grades of evidence. High certainty: there is great confidence that the true effect lies close to that of the estimate of the effect. Moderate certainty: there is moderate confidence in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: there is very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of the effect. ADL, activities of daily living; AE, adverse event; CG, control group; CGIC, carer global impression of change; CI, confidence interval; EQ-5D, EuroQol-5 Dimensions; IG, intervention group; MAS, modified Ashworth scale; MSQOL-54, Multiple Sclerosis Quality of Life 54 items; NRS, numerical rating scale; OR, odds ratio; QOL, quality of life; RCT, randomized controlled trial; SAE, serious adverse event; SF-36, 36-item Short Form Health Survey; SGIC, subjective global impression of change. aSevere risk of bias. bInconsistency. 1437 1438 SOLARI ET AL. FIG. 4. Efficacy of nabiximols (versus placebo) to treat spasticity: forest plots of patient and caregiver assessments. CI, confidence interval; df, degree of freedom; IV, instrumental variable. 9. Transcutaneous electrical nerve stimulation is sug- evidence). Patient preferences and the setting and gested to reduce spasticity in patients with severe availability of the apparatus should be considered in MS (weak recommendation/very low certainty evi- decision-making. dence), considering patient preferences and resource 3. It is suggested that nabiximols are not used to availability. treat fatigue in patients with severe MS (weak 10. It is suggested that benzodiazepines are not used recommendation/low certainty evidence). to reduce spasticity in patients with severe MS due to insufficient evidence for efficacy and frequent ad- verse events (weak recommendation/very low cer- Additional recommendations based on indirect tainty evidence). evidence (weak recommendations/very low certainty evidence). Fatigue 1. It is suggested that amantadine is used to treat fatigue in patients with severe MS. In total, 10/44 publications (nine trials) addressed fa- 2. Mindfulness-based training, cognitive behavioural tigue as an outcome. Five of these publications (four trials) therapy, fatigue management programmes or other ex- considered drugs (cannabinoids and 4-aminopyridine) and ercise training is suggested to treat fatigue in patients five publications considered exercise (Appendices S5, S6). with severe MS. Patient preferences and the setting Because of the limited direct evidence on the efficacy of and availability of the programme should be consid- interventions for fatigue in this population, the TF decided ered in decision-making. to include indirect evidence available from the National Institute for Health and Care Excellence (NICE) guidance on the management of MS in primary and secondary care48 and Pain the Cochrane review on exercise therapy for fatigue in MS.49 Seven full-text publications (six trials) addressed pain as an outcome: five were on drugs (cannabinoids) and two Recommendations. on non-pharmacological treatments (Appendices S5, S6). 1. D9-tetrahydrocannabinol or cannabis plant extract Because of the limited direct evidence on the efficacy of (weak recommendation/low certainty evidence) or interventions for pain in this population, the TF decided 4-aminopyridine (weak recommendation/very low cer- to include indirect evidence available from pertinent EAN tainty evidence) is suggested to treat fatigue in and NICE guidelines.50–52 patients with severe MS. Drug availability, the pres- ence of other symptoms and possible adverse events Recommendations. should be considered in treatment decision-making. 2. Exercise training is suggested to treat fatigue in pa- 1. Any of the three different cannabinoid preparations tients with severe MS. This includes robot-assisted (D9-tetrahydrocannabinol, cannabis sativa plant ex- gait training, inspiratory muscle training, upper body tract or nabiximols) are suggested to reduce pain in endurance training and manual wheelchair propulsion patients with severe MS (weak recommendation/low training (weak recommendation/ very low certainty certainty evidence). Drug availability, the presence of EAN GUIDELINE PALLIATIVE CARE IN MULTIPLE SCLEROSIS 1439 other symptoms and possible adverse events should be when deciding on the most suitable preparation, dose considered in treatment decision-making. and route of administration. 2. Radial shock wave therapy (weak recommendation/ 2. D9-tetrahydrocannabinol or cannabis extract is sug- low certainty evidence) or transcutaneous electrical gested to improve urinary continence in patients nerve stimulation (preferably 8-h application time; with severe MS (weak recommendation/low certainty weak recommendation/very low certainty evidence) evidence). Drug availability, the presence of other are suggested to reduce pain in patients with severe symptoms and possible adverse events should be MS. Patient preferences and treatment availability considered in decisionmaking. should be considered in treatment decision-making. 3. Desmopressin intranasal spray is suggested for nocturia in patients with severe MS (weak recom- mendation/very low certainty evidence). The drug Additional recommendations based on indirect should not be offered to patients with uncontrolled evidence (weak recommendations/very low certainty hypertension, cardiovascular and/or renal diseases. evidence). Possible adverse events should be considered in decision-making. 1. Gabapentin, pregabalin, amitriptyline, duloxetine or 4. It is suggested that nabiximols are not used to improve lamotrigine is suggested to reduce pain in patients urinary continence in patients with severe MS due to with severe MS. The presence of other symptoms and insufficient evidence for efficacy (weak recommen- possible adverse events should be considered in dation/low certainty evidence). treatment decision-making. 2. Opioids might be considered if long-term pain treat- ment is not an issue. Additional recommendations based on indirect 3. Carbamazepine or oxcarbazepine is suggested for pa- evidence (weak recommendations/very low certainty tients with severe MS and trigeminal neuralgia. Sec- evidence). ond choice drugs might be lamotrigine, gabapentin, 1. Behavioural management programmes (e.g. timed botulinum toxin type A, pregabalin, baclofen and voiding, bladder retraining or habit retraining) are phenytoin, used either alone or as add-on therapy. suggested to improve urinary continence in patients Surgery might be offered if medical treatment is not with severe MS. effective or is poorly tolerated. 2. Pelvic floor muscle training – alone or in combination with biofeedback and/or electrical stimulation of the pelvic floor – is suggested to improve urinary conti- Bladder problems nence in patients with severe MS. Bladder symptoms are present in over 90% of patients 3. It is suggested that patients with severe MS with with progressive MS. Difficulty with storage control (urinary a persistent residual volume >100 ml are offered frequency, urgency and incontinence) is the most common the opportunity to learn clean intermittent self- symptom, caused by neurogenic detrusor overactivity. Ap- catheterization. If self-catheterization is not possi- proximately half of the patients have coexistent voiding ble, a patient carer can be trained to catheterize the difficulty due to detrusorsphincter-dyssynergia.53 patient. Six of the 44 included publications (four trials) addressed 4. If clean intermittent (self-)catheterization is no longer drugs to improve urinary continence in severely affected MS possible, a long-term indwelling catheter (preferably patients (Table 4). Two studies were crossover RCTs: one suprapubic) might be offered. compared antimuscarinics for urinary incontinence and one 5. Patients with severe MS in whom antimuscarinic desmopressin intranasal spray to placebo for nocturia. Two drugs have proved to be ineffective or poorly tolerated studies were RCTs on cannabinoids which included urinary might be offered intradetrusor injections of botulinum symptoms as secondary outcomes. These drugs are generally toxin A. used in combination with (self-)catheterization. A range of other drugs (e.g. new antimus-carinics, mirabegron) and Multidisciplinary rehabilitation (clinical question 6) neurostimulation/ neuromodulation approaches are now available, which need to be proved effective in this popu- According to Wade55 rehabilitation is a problem-solving lation (Appendices S5, S6). Because of the limited direct educational process aimed at reducing symptoms and evidence on the efficacy of interventions for bladder symp- limitations at the level of activity and participation. Multi- toms in this population, the TF decided to include indirect disciplinary rehabilitation encompasses different interven- evidence available from the NICE guideline on urinary tions applied by a number of different (health) professionals, incontinence in neurological disease.54 including physiotherapists, physicians, nurses, occupational therapists, psychologists. It is frequently delivered in reha- bilitation clinics on an inpatient or outpatient basis and Recommendations. sometimes at community centres or the patients’ home. Khan 1. Antimuscarinic drugs are suggested to improve uri- et al.56 defined multidisciplinary (also called interdisci- nary continence in patients with severe MS (weak plinary) rehabilitation as ‘an inpatient, outpatient, home or recommendation/very low certainty evidence). The community-based coordinated intervention, delivered by presence of other symptoms (e.g. cognitive problems) two or more disciplines in conjunction with physician con- and possible adverse events should be considered sultation (neurologist or rehabilitation medicine physician), 1440 SOLARI ET AL. which aims to limit patient symptoms, and enhance func- selection; Appendix S5). There is increasing discussion of tional independence and maximize participation, as defined the need for close collaboration between PC and neurology, by ICF [International Classification of Functioning, Dis- and for neurologists to receive training in basic PC princi- ability and Health].’57 ples.59–62 It has been recommended that neurologists should Eleven publications were found reporting on nine trials have familiarity and comfort with communicating bad news, (eight RCTs and one controlled clinical trial) that differed engaging in end-of-life conversations and ACP, caregiver in terms of setting, intervention (components, duration and assessment and other PC skills. On the other hand, PC teams intensity), outcomes and length of follow-up. Therefore it may also need specialized training for managing MS patients. was not possible to perform meta-analyses, and results were The required competences can be achieved through enhanced summarized descriptively (Appendices S5, S6). joint training within the two specialties.62 Despite efforts to improve the PC training of neurology residents,63 there is Recommendations. no evidence available as to its use or effectiveness and rec- ommendations can only be made by consensus using the 1. It is suggested that multidisciplinary rehabilitation is evidence from the literature.10 offered to patients with severe MS (weak recom- mendation/very low or low certainty evidence). 2. Multidisciplinary rehabilitation might be offered Good practice statements. either as inpatient, outpatient or home-based rehabil- 1. It is suggested that the principles of PC are included in itation or as a combination (weak recommendation/ the training and continuing education of neurologists very low or low certainty evidence). Patients’ pref- and other HPs involved in MS care. erence and other circumstances (transport, situation 2. It is suggested that the principles of the management at home and resources) should be taken into account of MS patients are included within the training and when deciding on the setting. continuing education of specialist PC professionals. Interventions for caregivers (clinical questions Discussion 7 and 8) Recognizing significant variation in the PC of patients with Two clinical questions concerned interventions for care- severe MS across Europe, the EAN assembled a TF to givers, in terms of structured education and training pro- summarize the existing evidence and develop a clinical grammes on caregiving, and of structured, practical and/or practice guideline. To ensure client involvement the TF in- emotional support programmes (Appendix S2). One RCT58 cluded a person with MS who participated in all aspects of the comparing a 2-year, community-based, comprehensive care development of the guideline; in addition, MS patients and programme for MS patients and caregiver units to usual care caregivers were involved via an international online survey were included. The trial (also included in clinical question 6 and focus group meetings in the formulation of the 10 clinical on multidisciplinary rehabilitation) addressed both clinical questions.13 questions 7 and 8, as the programme included education For four clinical questions (1, 2, 5 and 6) the TF produced as well as practical and emotional support for caregivers 34 recommendations (one of which was a strong recom- (Appendix S5). mendation) and one good practice statement. For interven- tions for caregivers (clinical questions 7 and 8) only one Recommendations. study was found. No research evidence was found for four 1. It is suggested that caregivers of patients with severe clinical questions: ACP (3), discuss with HPs the wish to MS are offered education and training programmes on hasten death (4), and interventions for HPs (9, 10). For these caregiving (weak recommendation/ very low certainty four clinical questions, the TF produced six good practice evidence). Caregivers’ preferences and habits should statements. Thus, there is currently a knowledge gap on be taken into account when deciding on the setting many questions in this population, and on several outcomes of the programme, e.g. hospital based, home based or considered as important by stakeholders (Fig. 1). online. Two pertinent studies have been published since the search 2. It is suggested that caregivers of patients with severe was closed. One was a Cochrane review on PC in MS pa- MS are offered practical and emotional support (weak tients, which included the same RCTs as in our IPDMA.64 It recommendation/very low certainty evidence). Care- should be noted, however, that in this systematic review pain givers’ preferences and habits should be taken into and sleeping problems were considered as PC adverse events account when deciding on the setting of the support and the pre-specified secondary outcome measures included programme. relapse-free survival, progression-free survival, neuropsy- chological assessment and the EDSS.64 The other study was a pragmatic RCT from the UK, which demonstrated that a Interventions for HPs (clinical questions 9 and 10) standing frame programme significantly increased motor Finally, two clinical questions concerned education and function in people with severe MS and was cost-effective in training for HPs: one concerned training in PC/ specialist PC comparison to standard care.65 for MS HPs, and one training in MS for PC HPs (Appendix The limited evidence on PC in MS (and in other neuro- S2). No evidence was found regarding the effectiveness of logical conditions) contrasts with the situation in oncology.10 any of these training programmes (of 37 records screened, The TF agreed on the formulation of good practice statements two were assessed as full text and excluded from the final (instead of abstaining from any recommendation) in response EAN GUIDELINE PALLIATIVE CARE IN MULTIPLE SCLEROSIS 1441 to clinical questions where evidence was lacking. This was Medis; grants from the Ministry of Education, Science, and the case for ACP where, besides the all-important differ- Technical Development, Republic of Serbia, outside the ences in clinical features, commonalities may exist in the submitted work. Dr Milo reports personal fees from Actelion, psychosocial and spiritual needs across patient popula- Biogen and Medison Pharma; grants, personal fees and other tions. Whilst emphasizing the need to produce evidence in from Merck Serono and Teva; personal fees and other from MS, consensus documents on ACP and interventions cur- Novartis, Roche; other from TG Therapeutics and MAPI- rently available for other conditions can inspire MS cli- Pharma, outside the submitted work. Dr Pekmezovic reports nicians to have effective conversations with their patients grants from the Ministry of Education, Science and Tech- and patient significant others and stimulate research in this nological Development of the Republic of Serbia; personal area.37,66,67 fees from Teva Actavis, Merck and Roche, outside the sub- mitted work. Dr Patti reports personal fees from Almirall, Conclusion Bayer, Celgene, Roche, Novartis, Sanofi and TEVA; grants and personal fees from Biogen and Merck; grants from This clinical practice guideline provides evidence-based Reload Onlus, FISM and MIUR, outside the submitted work. recommendations of PC in severely affected MS patients. Dr Voltz reports personal fees from Prostrakan, Pfizer, Areas that currently lack evidence of efficacy include ACP, MSD Sharp&-Dome and AOK; grants from TEVA/ the management of symptoms such as fatigue and mood EffenDys, Otsuka, and DMSG/Hertie Stiftung, outside the problems in this population, and interventions for caregivers submitted work. All the other authors have nothing to and HPs. Further research on the integration of PC and MS declare. care is needed, including consideration of the various models of PC provision. Supplementary Material Acknowledgments Supplementary Appendix S1 This is a joint initiative of the EAN (approval date: Supplementary Appendix S2 February 27, 2020), the EAPC RIMS(approval date: Supplementary Appendix S3 February 22, 2020) and the RIMS (approval date: February Supplementary Appendix S4 24, 2020), and has been endorsed by the ECTRIMS and by Supplementary Appendix S5 the MSIF. 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