2025+PACTALS指南：肌萎缩侧索硬化的治疗

Research in context

# Evidence before this study

To date, there are no specific and rigorously graded guidelines to inform multidisciplinary care of ALS patients living in the Asia-Pacific region care. Amyotrophic lateral sclerosis is a relentlessly progressive neurodegenerative disease that disrupts motor, respiratory, nutritional and cognitive functions. Management demands seamless coordination across multiple specialties and must account for the region's wide ethnic, economic and health-system diversity.The Pan-Asian Consortium for Treatment and Research in ALS(PACTALS) management guidelines address this critical gap by applying Grading of Recommendations Assessment, Development, and Evaluation(GRADE)methodology to nine priority clinical questions. We synthesized data from Cochrane and other systematic reviews, meta-analyses, randomized controlled trials and,where necessary, regional expert consensus.

# Added value of this study

This is the first evidence-based ALS guideline tailored to the Asia-Pacific context. By pooling insights from 25 regional experts and systematically grading over relevant studies,

PACTALS delivers a clear, actionable recommendations across diagnostic pathways, disease-modifying therapies,dultisciplinary and palliative care models, as well as symptom-specific interventions that include respiratory support, nutrition, communication, cognitive/behaviour care and end-of-life planning. These guidelines will empower clinicians to harmonize care, strengthen advocacy for resources, and adapt swiftly as new therapies emerge.

# Implications of all the available evidence

Adoption of the PACTALS framework will(i) standardize diagnostic and referral pathways across diverse health systems,(ii) integrate multidisciplinary and palliative services from diagnosis onwards,(iii) enhance allocation of funding and training toward high-impact interventions that improve survival, functional independence and quality of life and(iv)provide a dynamic platform for guideline updates as novel management strategies and regional data become available.The PACTALS guidelines will reduce care variability, drive evidence-based policy, and ultimately transform ALS outcomes throughout the Asia-Pacific region making ALS a liveable disease.

Introduction

The Pan-Asian Consortium for Treatment and Research in Amyotrophic Lateral Sclerosis(PACTALS)was established in December 2014 to drive clinical and research initiatives across the region(Fig. 1).1 The PACTALS concept was based on existing regional Consortia, namely the United States-based North-East Amyotrophic Lateral Sclerosis(NEALS) and European Network for the Cure of ALS(ENCALS). PACTALS rep-resents the largest and most racially diverse patient pop-ulation cohort with active research groups across the Asia-Pacific region, representing ALS centres from mul-tiple countries. The mission of PACTALS remains(i) to develop a network of researchers and clinicians working with ALS,(ii) establish a patient registry within the

Asia-Pacific region that will facilitate the collation of clinical data, and(iii) initiate collaboration of centres across the Asia-Pacific region that will enable investigator-led clinical trials(https://pactals.org/) (Fig. 1).

In addition to research directed goals, the PACTALS collaborative represents an important vehicle for development of suitable management guidelines for patients living with ALS across the Asia-Pacific region.The European, United States and Japanese ALS patient management guidelines have been published,2-8 and relied on evidence-based data for those specific cohorts(systematic and Cochrane reviews, meta-analysis and randomized controlled trials) and on expert consensus opinion. Given the societal, economic, racial and reli-gious differences between Asia-Pacific and the North

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 Fig. 1: Countries comprising the Pan-Asian Consortium for Treatment and Research in ALS(PACTALS).

American and European regions, as well as within the PACTALS countries, specific management guidelines are clearly required.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both the upper and lower motor neuron systems and eventually results in generalized weakness and, ultimately, death due to respiratory failure, with a median survival of 3-5 years. 9-11 With the recent breakthroughs in compre-hending the pathogenic mechanisms of ALS, several crucial points have emerged: (1) The identification of novel causative genes has broadened our understand-ing of ALS, shifting it toward a motor neural network syndrome(ALS-Frontotemporal dementia continuum)or multisystem proteinopathy.(2) Recognizing noncell autonomous contributions to the pro-inflammatory neural system (CNS) milieu underlying mo-tor neuronal cell death underscores the importance of further investigating immune-inflammatory-metabolic modulation as a potential clinical therapeutic strategy for neurodegenerative diseases, including ALS. To date,only a few drugs have been approved by some or all of the agencies, including U.S Food and Drug Adminis-tration(FDA), the European Medicines Agency(EMA),the Korean Ministry of Food and Drug Safety(MFDS),the Pharmaceuticals and Medical Devices Agency(PMDA) and Therapeutic Goods Administration(TGA):riluzole, aravonever approved by EMA), tofersen,AMX0035(approved by FDA only, never approved by EMA recently withdrawn), and ultra-high dose

methylcobalamin(PMDA, Rozebalamin). However,these medications have exerted limited therapeutic benefits in ALS.18-18 Despite significant progress in linking clinical heterogeneity with genetic and patho-genic mechanisms of ALS, most clinical trials have not yielded successful outcomes.19,20 Failed trials, primarily based on single molecular targets, underscore the sig-nificance of incorporating multiple molecular targets within a broader therapeutic strategy.

Although ALS is characterised by muscle weakness and wasting, non-motor symptoms are frequent and result in significant morbidity.21 Specifically, cognitive and behavioural symptoms, as well as symptoms of malnutrition, respiratory dysfunction,sialrhea,pain,muscle cramps and spasticity, fatigue, pseudobulbar affect, thrombotic complications and constipation have an impact on the life quality and require appropriate and timely management.9,22-24 In the absence of curative therapies, supportive treatment strategies need consid-eration, although their availability to ALS patients living in the Asia-Pacific region remains variable.9,22-24

The diagnosis of ALS relies on identifying specific clinical features(upper and lower motor neuron signs),along with disease progression and exclusion of mimicking disorders.1,25 Clinical practices and technical skills are varied across the Asia-Pacific region, ultimately resulting in misdiagnosis and diagnostic uncertainty.

The development of region specific, PACTALS guidelines would provide guidance for health care professionals and patient advocacy groups to enhance

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the clinical management of ALS patients living in the Asia-Pacific countries, taking into consideration the diverse population of the region. As such, the present study describes the establishment of regional guide-lines in relation to diagnostic pathways, the use of currently available and emerging disease-modifying therapies, delivery of a multidisciplinary care model, as well as management of respiratory function and nutri-tional status, muscle weakness and cramps, spasticity,fatigue, sialorrhea, emotional lability, cognitive and behavioural symptoms, anxiety, depression, deep venous thrombosis prevention, musculoskeletal pain,non-motor symptoms, and communication. Psycho-logical support and advanced care directives, including voluntary assisted dying, are also addressed.

Methods

The PACTALS guidelines were developed in accor-dance with the Grading of Recommendation Assess-ment, Development, and Evaluation(GRADE)methodology,26 as per the recently published Euro-pean Academy of Neurology(EAN) guidelines.2 The guidelines are based on a series of nine major review questions that were divided into sections(see below),identifying key clinical areas for patient diagnosis and management. Analogous to the recently published EAN guidelines,2 the review questions were developed using a PICO(Patient, Intervention, Comparison,and Outcome) framework. The initial PICO frame-work was developed by three authors(SV, NS, and MCK), drawing on the EAN2 and NICE4 guidelines.The proposed questions were then circulated via email to the expert panel, comprising the current author group, and consensus was reached on the key areas to address. It was further agreed that the guidelines would be tailored specifically for the Asia-Pacific region. These discussions informed the eleven core sections that now structure the guidelines. The expert panel comprised thirty-one physicians from across the Asia-Pacific region who are recognised leaders in both research and the clinical management of patients living with ALS. All authors on this paper form part of the expert panel, are the clinical leads in ALS in their respective countries and represent key opinion leaders in the region, ensuring the guidelines reflect both the latest evidence and region-specific clinical expertise.

The GRADE-ADOLOPMENT approach was followed,27 and included the following principles:(i) adoption of existing recommendations from other criteria where possible;(ii) adaptation of existing recommendations to their own context; or(iii) de novo creation of recom-mendations. Monetary and non-monetary resources were considered, credibility of evidence, maximization of recommendation update and logical(consensus) argu-ments guided the process.

Search strategy and selection criteria

Initially, a mapping study of existing and compatible management guidelines was undertaken. Compatible guidelines included the American Academy of Neurology(AAN),3 EAN,2 and National Institute for Health and Care Excellence(NICE).7 Recommendations from existing guidelines were adapted to the PACTALS framework or were developed de novo. Cochrane re-views, systematic reviews and meta-analysis, as well as randomized controlled trials(RCT) were used where possible to develop guidelines. The following databases were searched: PubMed, Embase, MEDLINE, and Scopus. Additional search methods included checking reference lists, searching conference proceedings,screening trial registers, and reviewing all articles that cited papers included in specific reviews(“snow-balling"). The search strategy combined the following keywords and MeSH terms using in combination:“amyotrophic lateral sclerosis”,“Awaji criteria”,“behavioral”,“cognition;,”“constipation”,“cramps”,“El Escorial criteria”,“Gold Coast criteria”,“edaravone”,“lithium”“methylcobalamin”,“multidisciplinary care”,“models of care”,“motor neuron disorders”,“nutri-tion”,“pain”,“palliative care”,“primary lateral scle-rosis”,“progressive muscular atrophy”,“pseudobulbar affect”,“revised El Escorial(Airlie Beach) criteria”,“respiratory dysfunction”,“rilulose”,“sialrhea”,“spasticity”,“stem-cell”,“therapies”,“thrombosis”, and“tofersen”. In the setting of limited evidence consensus was sought. For consensus recommendations, the evi-dence to decision(EtD) framework was utilised.28 All available evidence was provided to the authors via email, and consensus was made after careful consider-ation of all evidence via email/electronic communication.

Results

The PACTALS management guidelines incorporate considerations developed by the EAN management guidelines, and where relevant, suggestions from the AAN,3 NICE-ALS and Japanese guidelines were also considered. In total, nine research sections were considered, encompassing diagnostic pathways, disease-modifying therapies, multidisciplinary clinical care,management of respiratory symptoms, nutrition,communication, symptoms impacting on the quality of life, cognitive and behavioural symptoms as well as end of life care and advanced care directives. Given the cul-tural, religious and societal heterogeneity of PACTALS countries, local service availability was considered when making the recommendations, consistent with regional roadmaps developed for neurodegenerative disease in the Western Pacific." Feedback was provided by mem-bers of the writing group representing each region,including resource-limited countries, who supported and agreed with this approach. As a general principle all authors agreed that primary recommendations should

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be based on best available evidence. The differential recommendations are intended as guidance, to support practical implementation in lower-resourced countries or in settings where specific resources may not yet be available. A summary of recommendations is provided in Table 1.

General remarks

● The availability of services and disease modifying therapies is different across the Asia-Pacific region.

● The legal framework, religious, societal and eco-nomic resourcing remains varied across the Asia-Pacific region.

● The term“ALS” was used instead of MND, Lou Gehrig's disease or the Maladie de Charcot, since ALS is the most widely used term across the Asia-Pacific region.

● Cognitive impairment will likely impact decision making in ALS patients, and the impact on patient management and their carers will vary across PACTALS countries depending on societal, cultural,religious and economic factors. Prior to instituting appropriate management plans, an assessment should be made by a neurologist and members of the multidisciplinary team(MDT) if available or physician with expertise in ALS. The patient's ability for decision making and provision of consent, as well as ability to accept and cope with MDT man-agement and pharmacological treatment should be determined.

● Video or telephone consultation, and remote care provision may be appropriate in most PACTALS regions, given the advances in communication technologies. Acceptance for remote care was con-textualised in the setting of cultural, religious, and social factors.

Interpretation and wording of recommendations

As outlined in Methods, recommendations are made in accordance with the GRADE methodology, reflecting the authors' confidence that the effect of an interven-tion outweighs either a lack of or an undesirable effect.The following wording for recommendations is used to facilitate understanding and interpretation.

● For strong recommendations we used the terms-“Offer” or“Don't offer”,“Do”, or“Don't do”.

● For weak recommendations we used terms-“Consider”or“Don’t consider”,“May do”,“May not do”.

● Strength of recommendations were also graded as follows, ${}^{26}$ :

○ Strong-High confidence that benefits clearly outweigh risks; applies to most patients; Moderate-Moderate confidence in balance of benefit over harm; may vary depending on circumstances;

Weak- Limited evidence or close balance between benefits and risks; should be tailored to individual cases; Not recommended: Evidence shows no benefit or potential harm outweighs benefit.

● Quality of evidence was graded as follows26:

High-Further research is very unlikely to change confidence in the estimate of effect; Moderate-Further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate. Low- Further research is very likely to have an important impact on the estimate and likely to change it; Very low- The estimate of effect is very uncertain.

Recommendations

Section 1. Diagnostic pathways in ALS

Background

The diagnostic pathways for ALS may be complex,relying on identification of concomitant upper and lower motor neuron signs within the same body region, or lower motor neuron signs in two body regions in the setting of a progressive motor syndrome. Given the clinical heterogeneity of ALS and the absence of a pathognomonic investigation, diagnostic criteria have been developed to provide certainty for patient manage-ment and recruitment into therapeutic trials. An important aspect of the diagnostic pathway pertains to the exclusion of mimicking disorders, with relevant in-vestigations encompassing nerve conduction studies(NCS), electromyography(EMG), transcranial magnetic stimulation(TMS), neuroimaging, neuromuscular ul-trasound, blood, and CSF-based laboratory investigations(see Fig. 2). The clinical availability of investigations varies between different PACTALS countries.

The original El Escorial criteria proposed four levels of diagnostic certainty, including definite, probable,possible, and suspected.30 Subsequently, the El Escorial criteria were modified(revised El Escorial or Airlie House) to increase the diagnostic sensitivity, whereby a“laboratory-supported probable ALS” was included which enabled the use of EMG data to substitute for clinical findings of lower motor neuron dysfunction and“suspected ALS” category was deleted.31 In 2008,the Awaji criteria were published to address concerns relating to consideration of ongoing changes(fibrilla-tion potentials and/or positive sharp waves) as an obligatory lower motor neuron sign, that were often absent in affected muscles.32 The Awaji criteria added the presence of fasciculations as a biomarker of lower motor neuron signs, that could substitute for ongoing changes, with evidence of chronic neurogenic changes and eliminated the category of laboratory-supported probable ALS', but maintained the definite, probable,and possible categories. ${}^{33}$

Two study level based meta-analysis reported increased overall sensitivity of the Awaji criteria,34,35

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|Section|Topic|Strength of evidence|Quality of evidence| |---|---|---|---| |1. Diagnostic pathways|Gold Coast criteria Transcranial magnetic stimulation (Identify upper motor neuron dysfunction) Neuromuscular ultrasound|Moderate Weak|Moderate Low-to-moderate| |2. Disease modifying therapies|Riluzole (Use as first line agent)|Strong|High| |2. Disease modifying therapies|Edaravone|Weak|Moderate| ||Ultrahigh-dose methylcobalamin|Weak Weak|Moderate| ||Tofersen°|Weak|Moderate| ||Cell-based therapies|Not recommended|Low-very low| ||Other therapies|Not recommended|Low-very low| |3. Multidisciplinary clinics|Integrated service (Consider resource limitations)|Strong|Moderate-high| |4. Management of respiratory insufficiency|Non-invasive ventilation|Strong|High| ||Diaphragmatic pacing|Not recommended|Low-very low| |4. Management of respiratory dysfunction|(i) Breathlessness: Palliative non-pharmacological Palliative pharmacological|Moderate Moderate to weak|Moderate to low| ||(ii) Cough management:|Moderate|Moderate| ||Cough augmentation Breath stacking|Moderate|Moderate| |5. Management of communication|Provide low- and high-level technologies|Moderate|Moderate| |5. Management of communication|Enteral feeding|Moderate|Moderate| |7. Management of symptoms impairing quality of life|(i) Sialorhea||| ||Anticholinergic medications|Moderate|Moderate| ||Glycopyrolate|Moderate|Moderate| ||Botulinum toxin|Moderate|Moderate| ||Irradiation of salivary glands|Weak|Low| ||(ii) Muscle weakness/Fatigue||| ||Physical therapy|Moderate|Low to moderate| ||(iii) Muscle cramps/spasticity||| ||Physical therapy|Moderate|Low to moderate| ||Sodium channel blocking medications|Weak|Low| ||Antispasmodic medications|Weak to moderate|Low to moderate| ||Botulinum toxin|Weak|Low to moderate| ||(iii) Pseudobulbar affect||| ||Dextromethorphan and quinidine|Moderate|Moderate| ||Antidepressant medications|Weak|Low| ||(v) Pain|Moderate|Low to moderate| ||Simple analgesia|Moderate|Low to moderate| ||Specific neuropathic pain medications|Weak|Low| ||Nonpharmacological strategies|Weak|Low| ||(vi) Thrombotic complications||| ||Identify risk factor|Strong|High| ||Nonpharmacological interventions (compression stacking/leg|Weak|Low| ||elevation)||| ||Prophylactic medications (low-molecular weight heparin)|Not recommended|Very low| ||(vii) Constipation||| ||Increase fluid and fibre intake/cease medications contributing to constipation/increase mobility|Weak|Low| ||Treat using laxatives|Moderate|Moderate| |8. Management of cognitive, behavioural and emotional symptoms|Functional assessment in MDT clinic|Strong|Moderate| ||Provide psychological support|Strong|Low to moderate| ||Anxiolytic agent for anxiety|Weak|Very low| ||Psychological therapy for depression|Moderate to strong|Moderate| ||Antidepressant medications for depression|Weak|Low to moderate| ||||(Table 1 continues on next page)|

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|Section|Topic|Strength of evidence|Quality of evidence| |---|---|---|---| |(Continued from previous page)|||| |9.Palliative care|Implementation of palliative care services. Integrate into MDT model|Moderate|Low| |10. Carers of ALS patients|of care to enhance symptom management.||| |10. Carers of ALS patients|Provision of education, information, psychological support, end-of-life weak and legal matters.|Weak|Low| |The designation of "weak" reflects the lack of a statistically significant difference in the primary endpoint between tofersen and placebo in the VALOR trial.|||| |Table 1: Executive summary of management guidelines, strength of evidence and quality of evidence recommendations as defined by the GRADE guidelines.||||

particularly in bulbar onset patients, ${}^{34}$ approximately 20% of ALS were downgraded to the"possible cate-gory".35 One individual patient data meta-analysis has reported higher sensitivity of the Awaji criteria, that was equally evident in bulbar- and limb-onset ALS patients.

The main limitations of the El Escorial and Awaji criteria relate to their complexity, resulting in low inter-rater reliability.37 Additionally, the diagnostic categories may not reflect the disease stage, with~22% of patients dying with the label of“possible ALS”.38 Consequently,a simplified Gold Coast criteria was proposed and subsequently endorsed by the World Federation of

Neurology and International Federation of Clinical Neurophysiology, with the following requirements25:

1. Progressive motor impairment documented by history or repeated clinical assessment, preceded by normal motor function, AND

2. Presence of upper and lower motor neuron dysfunction in at least 1 body region(with upper and lower motor neuron dysfunction noted in the same body region if only one body region is involved) or lower motor neuron dysfunction in at least 2 body regions, AND

3.Investigations excluding mimicking disorders.

 Fig. 2: Pathways for diagnosis of myatopionic lateral sclerosis(ALS). The Gold Coast criteria is recommended for diagnosis. Diagnostic categories of past criteria(E-Escorial(Awaj) are no longer necessary to avoid diagnostic delays. If there are uncertainties, it is recommended that investigations that support identifying upper motor neuron(UMN) and lower motor neuron(LMN) dysfunction be undertaken based on availability of these resources in the various PACTALS countries. At the outset, the possibility of mimic disorders should be considered given that of these are either treatable or have favourable prognosis.

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There have been no systematic reviews comparing the diagnostic utility between the Gold Coast, El Esco-rial and Awaji criteria. To date, seven cohort studies have been published comparing the diagnostic utility between the three criteria. In total, 9094 patients(ALS,8607; non-ALS, 487) have been recruited from Europe,39-41 North America42 and the Asia Pacific.39,43-45 The sensitivity of the Gold Coast criteria was reported to be higher, enabling an earlier diagnosis and expanding trial eligibility for ALS patients. The sensi-tivity was evident across different phenotypes, irre-spective of disease onset site, disease duration, or degree of functional disability. Additionally, patient presenting with a predominantly lower motor neuron phenotype(progressive muscular atrophy/flail arm variant) were diagnosed, while the primary lateral sclerosis phenotype was appropriately excluded.45 The Gold Coast criteria are increasingly used in clinical trials, given their simplicity and improved sensitivity compared to previous diagnostic criteria(El Escorial and Awaji). The increasing number of validation studies across various racial backgrounds throughout Asia, Europe and North America,39-55 will serve to has-ten bridging the gap towards broader adoption of the Gold Coast criteria as a diagnostic framework, with increasing alignment with regulatory requirements.Ultimately this will strengthen the clinical applicability and acceptance of the Gold Coast criteria.

PACTALS recommendations

The strength of recommendations is moderate; quality of evidence is moderate.

● Educate health-care workers to facilitate timely referral to neurologists with expertise in ALS Referral should occur as soon as an unexplained,progressive motor deficit is identified.

● Use the Gold Coast criteria for ALS diagnosis in all PACTALS countries due to greater simplicity and improved sensitivity.

● Investigations to exclude mimicking disorders may vary across the PACTALS region.

- Do NCS and EMG, neuroimaging(brain and spi-nal cord Magnetic Resonance Imaging), relevant blood and CSF examinations. These tests may be useful in selected cases where features suggest the presence of an ALS mimic disorder: basic biochemistry, haematology, vasculitis screen(antinuclear antibodies, extractable nuclear anti-bodies, antineutrophil cytoplasmic antibodies,angiotensin converting enzyme antibodies), para-neoplastic and limbic encephalitis(voltage gated K+ channels, IgLon5, NMDA receptor, CASPR2,LG11) antibodies, serology for myasthenia gravis,genetic testing for spinal muscular atrophy,infective serology(HIV, syphilis), Kennedy's dis-ease and/or whole exome sequencing

(neuromuscular panel) genetic tests, heavy metal screen(particularly lead), thyroid function test,parathyroid hormone and vitamin B12 levels.

Consider TMS for identifying upper motor neuron dysfunction, particularly in atypical phenotypes. At present, the evidence for diagnostic utility of TMS in ALS is limited, arising from one centre.

Consider neuromuscular ultrasound for identi-fying lower motor neuron dysfunction, particu-larly fasciculations in muscles where EMG may be difficult to perform such as the tongue. For patients with lower motor neuron syndrome, pe-ripheral nerve ultrasound may be used when available to determine whether there was thick-ening of peripheral nerves and to search for evi-dence of immune-related peripheral neuropathy.

The PACTALS recommendations will be reviewed as technologies evolve, including development of inex-pensive and rapid diagnostic methods which yield sensitive and specific diagnostic biomarkers.

Section 2. Disease modifying therapies

Riluzole

Background. Riluzole is an anti-glutamatergic com-pound which appears to block the presynaptic release of glutamate and partially and transiently(~ for 3 months)normalizes cortical hyperexcitability in ALS patients.There have been four randomized controlled trials(RCT) assessingriluzole efficacy in ALS. The first trial reported in 1994 reported a modest effect on survival with disproportionate effects in bulbar onset ALS patients.9A subsequent dose-ranging RCT disclosed similar modest effects of the intermediate(100 mg/day) and high(200 mg/day) doses ofriluzole.60 A third RCT undertaken on ALS patients with advanced disease(disease duration>5 years, Forced Vital Capacity<60%) or age>75 years did not disclose significant modulation of survival.61 An RCT conducted in Japanese ALS patients with multiple outcome measures that differed from the other three trials failed to demonstrate efficacy of iluzole.62

Metalysis of three RCTs, with data pooling, dis-closed a modest but significant increase in survival of 3 months in ALS patients treated by rhiluzole(100 mg/day).12 Riluzole therapy was associated with a 10% ab-solute increase in probability of surviving 12 months.Additionally, survival benefits were evident at 12 but not 18 months withriluzole therapy. While there were no significant effects ofriluzole on muscle strength, a modest significant effect was evident on bular and limb functional scores(Norris Scale).ALS patients receiving triluzole remained in mild and moderate health states for a longer period than those receiving placebo, while no significant prolongation was evident for the severe and terminal states.63 Variables including age, disease severity(as reflected by forced vital capacity) and disease duration did not impactriluzole efficacy in ALS.

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Riluzole is regarded as safe and is associated with milder side effects. The commonly reported adverse effects include nausea, asthenia, vomiting, diarrhoea,anorexia and dizziness, and elevation of serum alanine transferase.12 The main therapeutic concerns regarding riluzole include the modest effects on survival, lack of efficacy on secondary measures(such as muscle weakness) and high cost.12

PACTALS recommendations

Recommended triluzole dose should be 50 mg twice daily. Consider offering liquid/suspension formula-tions in patients with bulbar symptoms that impact swallowing. This will depend on availability of liquid riluzole. The strength of recommendations is strong,quality of evidence is high.

● Offer lifelong rhulizor therapy for all ALS patients at time of diagnosis.

● Consider compassionate access of rhiluzole for ALS patients at time of diagnosis in countries where it is not funded. Generic formulations of rhiluzole could be considered if rhiluzole is unfunded and unaf-fordable provided that generic formulations are available.

● Liquid or sublingual modes of rhiluzole administra-tion could also be used if available and preferred by patient.

If rilulose therapy is instituted, monitor for adverse effects(clinically and by liver function tests) and consider reducing dose and re-evaluate. Rilulose should be stopped in the setting of persistent adverse events, or terminal stage of disease(pallative) or when the patient has undergone a tracheostomy. If the patient reports financial difficulties and is unable to afford the treat-ment cost of rilulose, it is advisable to allocate the limited funds to patient care and nutritional support particularly in resource-limited countries.

Edaravone

Background. Edaravone(also known as MCI-186) is a free-radical scavenger of peroxy radicals and peroxyni-trite,64 which exerts modest therapeutic effects in ALS.65-67 Three RCT trials have assessed the therapeutic efficacy of intravenous edavone in ALS. The first RCT reported in 2014 did not find a significant effect of edaravone on functional decline(measured by the ALS functional rating score-revised[ALSFR-S], the primary endpoint), then post-hoc analysis of subpopulation suggested effect of edaravone on functional decline.65 In 2017, RCT with prespecified inclusion criteria recruit-ing ALS patients with early stage of disease, as defined by ALS grade 1 or 2 on the Japan ALS Severity Classi-fication(ambulant), scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of≥80%,definite or probable ALS according to revised El Escorial

criteria, and disease duration<2 years, reported effects in slowing ALSRS-R decline(33% reduction) at 6 months.66 Muscle strength(grip and pinch) and respi-ratory dysfunction were not significantly improved by intravenous edaravone at 6 months. Following the phase-III studies, open label extension study was un-dertaken with a follow-up period of up to 48 weeks.67,68 The survival benefit appeared to be modest, although formal statistical testing was not reported. Additionally,there were no significant long-term effects of intrave-nous edaravone on muscle strength, respiratory func-tion or life quality. Post-hoc analysis of Phase-III trial data disclosed a significant slowing of disease progres-sion in ALS patients with reduced forced vital capacity(FVC,<80%) along with continued preservation of motor function and maintenance of life quality,70 thereby implying ongoing clinical benefits. Long-term efficacy of edaravone, particularly effects on survival,should be undertaken in a real-world study.

Four systematic reviews(meta-analysis) have been conducted reporting on the efficacy of intravenous edaravone in ALS. The first systematic review(including 3RCTs and 367 participants) reported a modest effect of intravenous edaravone in reducing functional decline at 6 months.1 No significant effects were reported on muscle strength, respiratory function or quality of life.Subsequently, a systematic review including 5 RCTs and 566 patients reported modest effects of edaravone on reducing functional decline, as measured by the ALSFRS-R and the modified Norris Scale score, along with an increase in grip strength.7 There were no sig-nificant effects on pinger grip, respiratory function or quality of life. The incidence of adverse events, serious adverse events or death were not significantly increased in the edaravone treated patients.

Subsequently, a larger meta-analysis including 11 studies and 2845 patients(5RCTs reported again and 6 observational studies), reported a modest improvement in survival at 18, 24 and 30 months with intravenous edaravone treatment.73 There were no significant beneficial effects of edaravone on functional decline(measured by ALSFR-R and modified Norris scale),respiratory dysfunction, muscle strength or quality of life. Edaravone therapy was not associated with serious adverse events. A post-hoc analysis of the data through to week 48-which included a 24-week double-blind phase followed by 24 weeks of open-label edaravone suggested that edaravone may slow functional decline,as shown by a reduced rate of ALSFR-SR score deteri-oration, regardless of baseline FVC(<80%versus≥ 80%). In contrast, one real-world long-term studies of intravenous edaravone in ALS patients re-ported that while feasible and well tolerated, it was not associated with any disease-modifying benefit.18

The most recent meta-analysis included 16 studies(4 RCTs and 12 observation studies) with 4828 ALS patients. ${}^{74}$ The data from the 24-week open label

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extension study was not used in analysis. The data from pooled RCTs disclosed a modest slowing of functional decline at 3, 6, 9, 12, and 18 months, while data from pooled observation studies failed to disclose a signifi-cant effect on functional decline. While intravenous edaravone therapy was associated with improved sur-vival, the effects were not significant. Additionally,development of respiratory dysfunction was not pre-vented by edaravone therapy. GRADE assessment indicated that the evidence from RCTs was of moderate certainty, while the evidence from observational studies was of very low certainty.

While there is evidence for modest effects of intra-venous edaravone, a recent phase III trial(ADORE study,EudraCT 2020-003376-40/NCT05178810) reported that oral edaravone did not show significant benefit in reducing functional decline(assessed by ALSFRS-R) or long-term survival(assessed by Combined Assessment of Function and Survival score). A potential explanation for the discordant findings may relate to differences in the edaravone product(not from Mitsubishi Tanabe Pharma) and the less strict inclusion criteria used in the ADORE study. Separately, an oral suspension of edar-avone(105 mg/5 mL, RADICAVA ORS), approved by US-FDA in 2022 and marketed in Japan in 2023,exhibited bioequivalence to intravenous edaravone in a small phase-I study, with good tolerability during the 48-week treatment period and no new safety concerns.75

PACTALS recommendations

The dose of intravenous edaravone should be 60 mg/day for 14 days followed by 14 days of observation. For cycle one,administer edaravone for 14 consecutive days, while after cycle 2 administer for 10 out of 14-days. Edaravone therapy exerts modest effects on functional decline and survival. The strength of recommendation is weak;quality of evidence is moderate.

● Consider intravenous and oral suspension edar-avone therapy for a specific subgroup of ALS pa-tients(milder patients, see above inclusion criteria)at time of diagnosis if economically feasible and available. Resource allocation issues regarding method of administration need consideration.Should be preferably administered with ilruloz.

● Consider oral edaravone treatment in countries where available.

● Communicate with patients about the objective treatment effects and make an individualized trade-off between the impact of the time spent during the process of intravenous drug treatment on the quality of life and the benefits of the drug treatment.

Ultra-high- dose methylcobalamin

Background. Methylcobalamin, an active form of vitamin B12, has a therapeutic effect of repairing

impaired nerve tissue at low doses(0.5-1.5 mg/day)and is approved for the treatment of peripheral neu-ropathy in Japan.76.77 Ultrahigh-dose methylcobalamin has been shown to have neuroprotective effects against homocysteine toxicity, glutamate toxicity, and oxidative stress in vitro and in vivo.76,78-80 The first RCT of ALS patients within 3 years of onset reported in 2019 found that ultrahigh-dose methylcobalamin 25 mg or 50 mg was safe and well tolerated, although it did not show significant efficacy on the change from baseline in ALSFRS-R total score or survival time as the primary outcome.1 Nonetheless, post hoc analyses of patients who were enrolled within 1 year from symptom onset revealed dose-dependent efficacy of ultrahigh-dose methylcobalamin. Intramuscular injection of methyl-cobalamin 50 mg twice weekly prolonged the intervals to primary events(full ventilation support or death) by over 600 days compared to placebo. Additionally,ALSFR-S total score significantly differed between the two groups by 2.6 points at 16 weeks and by 5.3 points at 182 weeks, in favour of methylcobalamin. To confirm the efficacy and safety of ultrahigh-dose methyl-cobalamin in early stage ALS, a second RCT(the Japan Early-stage Trial of ultrahigh-dose methylcobalamin for ALS, JETALS) was conducted and data of the double-blind period was reported in 2022.15 The candidates of this trial were ambulatory patients aged, 20 years or older, who who were diagnosed with sporadic or familial ALS with definite, probable, or probable laboratory-supported categories using the updated Awaji criteria. They were within 1-year of symptom onset,were staged as ALS grade 1 or 2 on the Japan ALS Severity Classification, forced vital capacity of≥60%,and presented a 1- or 2-point decrease in the ALSFRS-R total score during the 12-week observation period.The patients were randomly assigned in a 1:1 ratio to receive the investigational drug(either methyl-cobalamin 50 mg or placebo). The least-squares mean changes in the ALSFR-SR total score at week 16 were-2.66±0.61 in the methylcobalamin group and-4.63±0.60 in the placebo group, and the dif-ference was 1.97 in favour of methylcobalamin.Among 90% of patients who concomitantly usedriluzole, the least-squares mean difference in ALSFRS-R score was 2.11 in favour of methylcobalamin,implying the combination of rhiluzole and methyl-cobalamin had a greater therapeutic effect than rilu-zole alone. The least-squares mean changes in%FVC,Norris scale total score, and manual muscle test total score did not show significant differences between the methylcobalamin and placebo groups. Adverse events were reported in 62% of patients in the methyl-cobalamin group and in 66% of patients in the placebo group and there were no adverse events leading to discontinuation. The survival is to be evaluated using data of an open label extended period.

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PACTALS recommendations. Ultrahigh-dose methyl-cobalamin is administered intramuscularly twice a week. The approved formulation contains 25 mg of methylcobalamin per vial. In each treatment, 25 mg of methylcobalamin, dissolved in 2.0 mL of saline, is administered to two sites, including the thigh, buttocks,and lateral surface of the upper arm. Methylcobalamin is susceptible to photolysis; therefore, it should be used immediately after opening and kept out of the light.Ultrahigh-doses methylcobalamin therapy exerts effects on functional decline. The safety and tolerability of ultrahigh-dose methylcobalamin are high, and there are no contraindications other than patients who are allergic to this drug. At present, ultrahigh-dose meth-ylcobalamin may not be available in many PACTALS countries. The strength of recommendation is weak;quality of evidence is moderate.

● Consider intramuscular ultrahigh-dose methyl-cobalamin therapy for a specific subgroup of ALS patients(milder patients, see the above inclusion criteria) at time of diagnosis for 48-weeks if available if economically feasible and if drug is available.Resource allocation issues regarding methods of administration need consideration. Should be pref-erably administered with rhulizole.

● At present, the efficacy of ultrahigh-dose methyl-cobalin in patients diagnosed with the disease more than one year after the onset of symptoms is yet to be established. The recommendation may be revised after the data for the open label extended period in the phase-III JETALS trial(NCT03548311)becomes available.

Genetic-based therapies

Background. Genetic research has revealed genetic variations in more than 40 genes to be associated with ALS. Hexanucleotide repeat expansions of the chro-mosome 9 open reading frame 72(C9orf72), variants in superoxide dismutase-1(SOD-1), TANK-binding kinase 1(TBK1), fused in sarcoma(FUS), and TAR DNA-binding protein 43(TARDBP) genes are the most prevalent mutations globally.82 A regional varia-tion in genetic etiology is prevalent, with the C9orf72 hexanucleotide repeat expansion affecting European and North American populations, while SOD1 muta-tions being the most prevalent genetic variations in many PACTALS countries(except Australia and New Zealand),1,83 likely influencing multiple steps of the disease cascade.84 The offer of genetic testing to all people newly diagnosed with ALS does not come without the need for reflection. Appropriate genetic counselling, ensuring an informed decision based on an evaluation of both risks and benefits, and consid-eration for challenging psychosocial scenarios, such as a variant identified in an individual with no previous family history, need to be addressed. Much like our

understanding of genetics in ALS and the advent of genetic therapies, this discussion is an evolution that anticipates a not-so-distant future when a therapy is approved.

Tofersen is an intratacheally administered antisense oligonucleotide(ASO) that was designed to reduce the synthesis of mutated messenger RNA and superoxide dismutase-1(SOD-1) protein.86,87 The mechanism by which tofersen exerts effects is by forming an RNA-DNA hybrid which subsequently becomes a substrate for degradation by inducing the enzyme Rnase H leading to targeted degradation of the SOD1 messenger RNA.88

One RCT(VALOR study) has been reported which assessed the efficacy of tofersen in SOD-1 associated ALS.89 At 28-week follow-up, the primary endpoint(change in ALSFRS-R score form baseline) was not significantly changed when compared to placebo. While there were no significant changes in clinical secondary endpoints(respiratory function, muscle strength and survival), cerebrospinal fluid SOD-1 protein(-40%) and plasma neurofilament light chain(-60%) levels were significantly reduced in treated patients.

An open label extension phase of the RCT was also undertaken whereby patients initially receiving placebo were switched to tofersen and compared to patients that were receiving tofersen from baseline. At 52-week follow-up, the latter group exhibited significantly higher functional scores(ALSFRS-R), respiratory func-tion(slow vital capacity) and muscle strength(handheld dynamometry) compared to the former group(initially receiving placebo). Based on findings in the VALOR study, tofersen received full approval by the FDA in 2023 for the treatment of SOD-1 ALS under the accel-erated approval pathway.

Tofersen therapy was associated with procedural pain(lumbar puncture), low-pressure headaches, pain in the arms, legs, and back, as well as falls. Myelitis,aseptic meningitis, lumbar radicopathy, raised intra-cranial pressure and papilledema were reported infre-quently. Asymptomatic elevation of CSF white cell count and protein levels were frequently evident,although these changes seemed to be clinically insignificant.

Real-world data from five independent studies have confirmed the findings of the VALOR trial.90-94 Across these studies,65 SOD1-ALS patients(35 males,30 fe-males) received to forseres for a median duration of 13 months(interquartile range: 8-38 months). Treatment was initiated at a median disease duration of 27.5 months(interquartile range: 26.2-42 months), with a median baseline ALSFRS-R(interquartile range:37-39), indicating a moderate level of functional deficit. Monthly to forsen injections resulted in a 68.3%(62.1-70) reduction in serum and 61.2%(53.3-68.6)reduction in CSF phosphorylated neurofilament heavy

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chain(pNfH) levels after a median of 13 months of treatment. The reduction in NfL levels was associated with stabilisation of disease progression, with the ALSFRS-R decline limited to a median of 3.1%(ranging from a 1%improvement to a 6.7% reduction). Tofersen was well tolerated, with no new adverse effects reported across the studies. These real-life studies have demonstrated the potential of tofersen to halt disease progression or even provide symptomatic improvement, representing a notable exception among approved medications for ALS treatment. Of relevance, tofersen has been approved by multiple regulatory agencies, including the U.S. FDA,European Medicines Agency's Committee for Medicinal Products for Human Use, and the UK's Medicines and Healthcare products Regulatory Agency.

PACTALS recommendations. Tofersen is administered intratecally, with a month 1 loading dose(day 0, 14 and 28), followed by monthly intrathecal injections. The approved dose is 100 mg in 15 mL bolus injection administered over 1-3 min. Tofersen may not be available in most of the PACTALS countries. The strength of recommendation is weak; quality of evi-dence is moderate.

● Consider tofersen in ALS patients due to SOD-1 mutation at time of diagnosis.

● If tofersen is not funded by government agencies in a specific country, consider tofersen in ALS patients due to SOD-1 mutation at time of diagnosis in these countries if available on a compassionate basis.

● At present, do not offer tofersen to asymptomatic SOD-1 mutation carriers until the results of the phase-III ATLAS trial(NCT04856982) becomes available.

Cell-based therapies

Cell-based therapies in an initial investigator-initiated trial were designed for the restoration of damaged mo-tor neurons. Given the neural system complexity and extensive degeneration from the motor cortex to the spinal cord, cell therapy focused on replacing injured cells and replacing degenerated motor neurons is chal-lenging. Furthermore, even if these new motor neu-rons are integrated into a diseased neural network, they may remain susceptible to the same pathological pro-cesses that destroy original motor neurons. Therefore,the therapeutic strategies using diverse types of mesen-chymal stem cells(MSCs) have been focused away from neuronal replacement or reconstruction, and toward creating an anti-inflammatory microenvironment. Be-sides direct effects, such as the release of neurotrophic factors and the stimulation of intrinsic neurogenesis,intrathecally administered MSCs have diverse immune inflammatory modulatory efficacy that can regulate the onset and progression of ALS by potentiating regulatory T cells and anti-inflammatory microglia in the CNS environment.97-100

To date, one systematic review and seven RCTs have reported on the efficacy of cell-based approaches in ALS.99,101-107 Strategies using infusion of mesenchymal stem cells, granulocyte colony-stimulating factor(G-CSF), or mesenchymal stem cell(MSC)-neurotrophic factor(NTF) cells have been undertaken in small ALS cohorts with limited evidence of clinical effects. The systematic review concluded that at this stage there was lack of high-certainty evidence to guide practice on the use of cell-based therapy to treat ALS.101 A recent study on long-term survival benefit of MSC treatment suggests that survival probability was higher in the bone-marrow derived MSC treated group compared to the external control group derived from the PROACT database.108

PACTALS recommendations.

● Based on the available evidence, the use of cell-based therapies outside clinical trials is not recom-mended for treatment of ALS patients. The strength of recommendation is not recommended or conditional use in clinical trials or research; quality of evidence is low-very low. A planned phase III trial(ALSUMMIT,NCT04745299) will further evaluate the clinical utility of intrathecal MSC treatment in ALS.

Other therapies

(i) AMXO035(sodium phenylbutyrate and taur-ursiololi), a compound that reduces neuronal degeneration by improving mitochondrial func-tion and mitigating endoplasmic reticulum stress was assessed, with modest effects reported on functional decline in ALS.14 While AMX0035 was approved by the US Food and Drug administra-tion Authority, the recent phase-3 PHOENIX clinical trial(NCT05021536) failed to meet pri-mary and secondary endpoints and the drug was withdrawn from the market.

(ii) Lithium carbonate therapy is being trialled in a subgroup of ALS patients with the UNC13A mu-tation(MAGNET trial).

PACTALS recommendations.

● Based on the available evidence, AMX0035 and lithium carbonate are not recommended for treat-ment of ALS patients. The strength of recommen-dation is not recommended or conditional use in clinical trials or research(lithium carbonate only);quality of evidence is low-very low.

●CNM-Au8 is a catalytically active gold nanocrystal neuroprotective agent that enhances intracellular energy metabolism and reduces oxidative stress.While a recent phase-2 study with open label exten-sion period(RESCUE-ALS) failed to meet the pri-mary endpoint(mean percent change in summed motor unit number index), a 60% reduction in mortality was reported at 12-months in ALS patients

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treated with CNM-Au8.109 Results of a larger Phase-2 study conducted by the HEALEY ALS platform trial(NCT04297683) are pending, although topline results reported a similar survival benefit to RESCUE-ALS.

PACTALS recommendations.

● Based on the available evidence, CNM-Au8 cannot be recommended for treatment of ALS patients.The strength of recommendation is not recommended or conditional use in clinical trials or research; quality of evidence is low-very low. The planned phase III trial(RESTORE-ALS) will provide further information of clinical utility of CNM-Au8 in ALS.

Section 3. Multidisciplinary clinical care

Background

A multidisciplinary approach to management of ALS patients has been advocated given the heterogeneity and rapid evolution of clinical features leading to requirement of health care professionals with a variety of skills. The American Academy and European ALS management guidelines have advocated for manage-ment of all ALS patients in a multidisciplinary clinic. ${ }^{2,3}$ Evidence supporting the clinical utility of multidisci-plinary clinics in the management of ALS has been provided by data derived from cross-sectional, pro-spective cohort and retrospective studies. ${ }^{110-119}$ Addi-tionally, three systematic reviews have been undertaken which provide support for efficacy of multidisciplinary clinics, ${ }^{120-122}$ although no RCTs have been performed.

<BeginOfPara>The "best evidence" to date suggests that manage-ment of ALS patients in a multidisciplinary clinic setting is associated with improved survival and enhanced quality of life.110-123 The survival outcomes were signifi-cantly better for ALS patients managed in a multidisci-plinary clinic compared to patients managed in a general neurology clinic. The improvement in survival was attributed to earlier diagnosis and thereby timely implementation of respiratory and nutritional supports(percutaneous gastrostomy feeding) as well as appro-priate referrals to allied health and palliative care ser-vices. Of interest, survival benefit seemed to be independent of age of disease onset, diagnostic delays,site of disease onset, or trilozule use. Quality of life improvement was driven by the mental health domain,while evidence for the effects of multidisciplinary care management on caregivers has not been addressed.While the quality of observational studies informing on clinical utility of multidisciplinary clinical care is modest,it would be difficult to undertake an RCT and is unlikely to negate the findings of prior observational studies. ${}^{124}$

PACTALS recommendations(Adopted from the EAN guidelines)

<BeginOfPara>The strength of recommendations is strong; quality of evidence is moderate to high. ${ }^{2}$

•Offer all ALS patients a multidisciplinary clinical care model where possible.

●The multidisciplinary clinic should be comprised of the following:

○ Healthcare professionals and allied health practi-tioners with expertise in ALS.

○ Clinical care should be integrated by a coordi-nator (specialist nurse or allied health practitioner).

o Assessments should be undertaken every 3-6 months to assess patients' symptoms and re-quirements, although this may vary across PAC-TALS countries.

$\bullet$ Health care practitioners should include neurology, rehabilitation, respiratory and pallia-tive care physicians.

o Access to gastroenterology or interventional radiology for insertion of percutaneous feeding tube.

○ Allied health practitioners should include where possible occupational therapist, physiotherapist, dietician, speech pathologist, and social care worker.

o Access to clinical psychology and neuropsychology

○ Access to trained orthotist for assessment and design of neck braces to manage neck weakness.

○ Provide supports in flail arm variants to prevent shoulder subluxation

○ Foot drop management with customised ankle foot orthotics

o Palliative care and allied health practitioner teams should have capability of assessing patients in their home.

● The multidisciplinary clinic task should assess,manage, and review the following areas:

o Respiratory function, requirements for ventilatory support, and cough effectiveness.

o Weight,diet, nutritional and fluid intake, feeding,and swallowing.

$\bullet$ Muscle weakness, atrophy, stiffness, cramps and pain.

$\circ$ Mobility, requirements for mobility aids, falls prevention strategies, assistive devices, home modifications, and ability to execute activities of daily living.

○ Ongoing home-based exercise program for strength and endurance training, expiratory strength training program.

o Speech and requirements for communication aids.

○ Orthotic intervention focusing on managing the symptoms, improving function and enhancing the quality of life. Upper limb orthotics to assist with hand function, provide support, manage-ment of spasticity and prevention of contractures.Functional wrist splines, restarting splints, and cus-tomised hand splints all play an important role in

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improving function and preventing secondary complications. Lower limb orthotics, such as ankle foot orthoses are effective in foot drop and can improve walking ability and safety, reduce fatigue, improve walking confidence and reducing falls.

Neck supports such as cervical collars or specif-ically designed braces such as Headmaster collar can be helpful in patients with head drop due to neck muscle weakness in providing stability,reduce pain, reduce discomfort, reduce postural sialorrhea, improve breathing, swallowing and posture.

Sialorrhea and other saliva related issues.

o Musculoskeletal pain and other pain syndromes.

o Gastrointestinal symptoms including con-stipation, nausea, diarrhoea.

o Mental health issues including anxiety, depres-sion and psychiatric symptoms.

o Cognitive and behavioural issues.

o Workplace adaptation to facilitate engagement in workforce.

o Occupational therapy for driving assessments in selected patients.

o Planned short-stay hospital admissions to facili-tate comprehensive assessment and manage-ment. Coordination with community based health care providers to ensure necessary services ae in place.

Functional assessment using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised[ALSFRS-R] score. Functional assessments should be undertaken longitudinally.

Social care requirements and management of caregiver issues. Provision of respite care.

End-of-life care needs and advanced care directives.

● The ability to undertake a multidisciplinary clinic model will vary across PACTALS countries. It is acknowledged that the implementation of a full MDT model of care is limited by resourcing. In limited-resource settings, provision of a full com-plement of services may not be possible, and a model with a clinical coordinator that has access to health and allied health practitioners should be considered. Adaptation of telemedicine and task shifting to local medical practitioners(such as gen-eral practitioners) may be appropriate. Integration of services should be provided by a dedicated co-ordinator where possible.

● Data collection would be important for phenotyping,monitoring effectiveness of management strategies and trial readiness. Data could be stored in complex multicentre registries, akin to that utilised by the MindAus registry,125 similar regional registries(Japanese Consortium for ALS, Korean Consortium

for ALS, China ALS registry), or could be simpler using freely available data software such as Redcap.

。Consider using national multicentre registries or a regional registry for data collection where feasible. Minimum data sets should be collected and include demographic details, disease dura-tion(months), site of disease onset, clinical phenotype as defined by Talman and colleges,126 muscle strength(using(Medical Research Coun-cil score), functional score(ALSFRS-R), respira-tory function(forced or slow vital capacity).

Section 4. Management of respiratory symptoms

Background

Respiratory dysfunction is a common cause of death in ALS patients resulting from weakness of the diaphragm and other ventilatory muscles. The development of res-piratory dysfunction is associated with an adverse prog-nosis.127 Non-invasive ventilation(NIV) was shown to improve survival, quality of life and sleep related symp-toms in ALS, although the benefits were not evident in patients with severe bulbar dysfunction.128-130 A subse-quent cohort study demonstrated effectiveness, as re-flected by prolonged survival with NIV treatment in bulbar-onset patients.131 Non-invasive ventilation was shown to relieve symptoms of breathlessness, reduce requirement for tracheostomy and intensive care hospitalisation, resulting in reduced health related expenditure.132,133 While NIV remains underutilised in management of ALS patients,134 a multidisciplinary service model of care is associated with increased frequency of institution of and adherence to NIV.135

The place(inpatient versus outpatient settings) and timing(early versus late disease stage) of NIV commencement, have only been addressed in small studies. The evidence suggests good adherence and efficacy of NIV irrespective of place of initiation.135 Early institution of NIV was associated with improved sur-vival when compared to standard NIV care(namely starting NIV when FVC<50%, presence of orthopnoea or daytime hypercapnia), although the differences were not statistically significant.131 Additionally, there was slowing of progressive decline in respiratory muscle strength as well as a reduction in the number and severity of respiratory events, while treatment adher-ence and tolerance were good without worsening of sleep or overall life quality.136,137 Delay in referral for NIV consideration may be associated with reduced compliance and suboptimal clinical outcomes.138 Opti-mization of NIV should be individualised considering a multitude of factors including; patient-related factors,social and caregiver factors, timing of NIV, machine and mask type, setting modes, management of secre-tions, monitoring efficacy, adjusting settings, service delivery, and discussion with patient and caregivers regarding withdrawal. ${}^{138}$

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Respiratory muscle strength was reported to exert modest benefits, mostly improving maximum expira-tory pressures, although the benefits need to be vali-dated in larger cohorts. In contrast, diaphragmatic pacing was associated with increased mortality and did not exert clinical benefits.140,141 The consensus evidence supporting tracehostomy invasive ventilation(TIV) re-mains limited, with variable utilization reported across countries and its impact on long-term prognosis and quality of life.121,142,143 An analysis from Japan indicates an increase in TIV usage,143 and the patient's decision to have TIV could potentially be driven by advancement in communication systems and assistive technologies which enable patients with ALS to maintain greater participation in daily life following tracheostomy.144 However, the decision to pursue TIV is complex,influenced by medical and care networks, cognitive status, societal, cultural, and ethical considerations.145 This decision may also arise in emergency settings without prior advance directives, highlighting the importance of timely discussions about end-of-life preferences with patients and their families.146

PACTALS recommendations

(A) Respiratory dysfunction

● Offer non-invasive pressure ventilation(NIV) for ALS patients with symptoms, signs, or laboratory investigations(respiratory function tests and/or polysomnography) that support the presence of respiratory insufficiency. The strength of recom-mendation is strong, quality of evidence is high. It is acknowledged that the ability to offer NIV de-pends on local service availability.

● Monitoring of efficacy(monitoring hypercap-nia) should be offered to or considered in all ALS patients, albeit may depend on local resourcing. The monitoring interval may be 3-months for ALSFRS-R and 6-months for supine vital capacity assessment.

● Consider early institution of NIV where appro-priate, depending on FVC values. Mouth Inrespiratory Pressure(MIP) and sniff nasal inspiratory pressure(SNIP) values may also be used as biomarkers for NIV institution. Future RCTs will be reviewed and recommendations may be upgraded.

● Respiratory muscle strength training cannot be recommended at this stage. Future RCTs will be reviewed, and recommendations may change.

● Diaphragmatic pacing is not recommended.

● Issues of invasive ventilation (tracheostomy)

○ Practices are varied across PACTALS coun-tries, depending on the degree of support provided by health care, ethnic and cultural background.

○ Discuss with patients and caregivers as part of advanced care planning.

o Expectations of patients and caregivers should be tempered and sensitives considered.

(B) Management of breathlessness

● In end stage disease or where breathlessness is refractory to NIV.

● Consider palliative non-pharmacological strategies such as reducing activity, chang-ing positions(sitting, lying down), distraction methods, and the use of breathing tech-niques(lip breathing, abdominal breathing,leaning forward, or putting the arms up),fresh air, moistening of lips, use of fans, cold temperature, and/or cognitive techniques.

Consider palliative pharmacological measures such as opioids. The strength of recommen-dation is moderate; quality of evidence is moderate.

Consider benzodiazepines for breathlessness related to anxiety. The strength of recom-mendation for management of breathlessness in isolation is weak; quality of evidence is low.

(C)Cough management(Adapted from EAN guidelines)2

The strength of recommendations is moderate quality of evidence is moderate. The following in-terventions are recommended:

●Cough augmentation techniques should be offered to ALS patients with weak cough. Peak cough flow meter reading of<270 L/min may be used as an objective measure of weak cough since values less than this are associated with increased secretion retention and risk of infection

•Manual assisted cough and unassisted breath stacking should be offered to ALS patients with weak cough.

● Assisted breath stacking should be considered if above technique is unsuccessful.

● Mechanical cough devices and suction should be considered for ALS patients with refractory weak cough.

● Educate patients with weak cough and dysphagia to avoid choking and teach caregiver the methods of dealing with choking to reduce the risk of asphyxiation.

(D) Management of laryngospasm and hoarseness

● Identify causes of laryngospasm, which may include:

● Dysphagia for solid and/or liquids

● Gastrosophagia refluxic range

● Postnasdnr or sialorhea

$\bullet$ Smoke(active or passive)

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● Pungent odours

● Cold and/or dry air

● Emotion

● Spicy foods

● Advise avoidance of triggers and consider speech pathology assessment.

● For people with laryngospasm, provide infor-mation about the clinical presentation and self-limiting character of the symptom to the patient and their family or carers.

● Advise the following manoeuvres:

● Treat underlying causes(sialorrhea, post-nasal drip)

- Treat GOR with medications. Consider pro-kinetic medications at night

● Swallow repetitively

● Breathing through nose. Use humidifiers in cold countries.

● Breathing with slow exhalation through lips

● Sleep or sit in an upright position of the body

● Consider sublingual or oral short-acting benzodiazepine medications in refractory symptoms or for crisis episodes.

(E) Management of insomnia

● In ALS patients reporting insomnia or sleep related symptoms, identify and treat the un-derlying cause. The strength of recommenda-tions is strong; quality of evidence is moderate.These may include:

● Respiratory insufficiency causing breathlessness

● Sleep apnoea or nocturnal hypoventiation

● Anxiety and depression

● Muscle cramps, pain and stiffness

● Poor mobility and loss of spontaneous movements

● Restless legs syndrome

● Nocturia

● Sialorrhea

● Sleep study to assess sleep architecture and identify cause(s) of insomnia. The sleep studies should be undertaken through a sleep clinic.

● Offer sleep studies depending on local service availability.

● Consider non-pharmacological interventions such as elevating head of bed, using medical beds, relaxation techniques.

● Consider pharmacological therapies(antide-pressants, benzodiazepines, or in severe cases antipsychotic medications and melatonin). The strength of recommendation is weak; quality of evidence is low.

Section 5. Management of communication

There have been systematic reviews or RCTs concerned with management of communication in ALS patients. ${}^{2}$ Given that bulbar dysfunction is a common presenting

feature of ALS and inevitably develops during ALS resulting in significant morbidity,44 managing communication related symptoms is important. Given the limited evidence to guide communication man-agement in ALS, the EAN guidelines were adapted,and recommendations have been formulated for PAC-TALS countries by consensus. The strength of recom-mendations is strong; quality of evidence is moderate.

● Assess communication related symptoms in a multidisciplinary clinic by a trained speech thera-pist. Assessment should be conducted in a face-to-face consultation and may be followed by using remote communication devices if in clinic appoint-ments are not possible.

● Provide appropriate equipment that meet the pa-tient communications requirements. The use of both low- and high-level technologies should be considered. Low-level technologies may include al-phabet, picture, or word boards. High-level tech-nologies may include computer or tablet-based devices with a voice output that are activated by tactile or visual inputs. Voice banking should be considered.

Regular review and reassessment of communication needs, including ongoing monitoring of communi-cation strategies and adaptation of augmentative and alternative communication(AAC) equipment as the disease progresses. The assessment should be performed by a speech therapist and may occur remotely or in-person to adapt interventions to the patient's ALS progression. Reassess and liaise with a specialised AAC hub if needed. The requirements should be tailored to patient's needs.

● Ensure integration of communication assistive de-vices with other technologies by involving other healthcare professionals, such as occupational therapists.

● Provide ongoing support and training for ALS pa-tients and their carers on using communication devices.

Section 6. Management of nutrition

Background

Weight loss in ALS patients is an adverse prognostic factor, with increased mortality by 30% per point loss of body mass index.148-153 The pathophysiological mecha-nisms underlying weight loss in ALS are multifactorial and related to muscle loss, poor oral intake and intrinsic hypermetabolism. Specifically, the resting en-ergy expenditure is increased by~10% in ALS patients above the reference population.154-157

When oral weight management becomes insuffi-cient, central feeding should be considered to maintain nutritional status and reduce the frequency of aspira-tion events.158 High-caloric fatty supplemental enteral

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feeding was shown to prolong survival in ALS with improvement in nutritional measures such as trans-ferrin, albumin, haemoglobin, and prealbumin.159 A separate RCT reported increased survival only in fast progressing ALS patients as measured by ALSFRS-R score decline.160 This was associated with a slower rate of functional decline, degree of neurodegeneration, and serum NfL levels.161 However, patients with more rapid disease progression and greater pre-baseline weight loss experienced less weight gain with enteral feeding.162 While weight gain was comparable between high-lipid and high-carbohydrate strategies, the latter was more often associated with early satiety and appe-tite loss.162 Hypercaloric enteral feeding was shown to be safe and well tolerated160,161,163, with systematic re-views supporting beneficial effects in ALS.121,159 How-ever, ALS patients with long-term ventilation show severe hypometabolism, and calorie restriction may be needed in the advanced stage.164,165

Given that body weight varies between Caucasian and Asian populations, formula have been proposed that estimate total energy expenditure, providing a guide for caloric requirements for enteral feeding. ${}^{155,156}$ In Japanese patients, the total energy expenditure(TEE) is higher and is predicted by the following formula ${}^{156}$ :

$$\text{ TEE}=(1.67\times\text{ RMR}-\text{ HB})+(11.8\times\text{ ALSFRS}-\text{ R)}-680$$

where RMR-HB refers to resting metabolic rate esti-mated by Harris-Benedict formula.

The timing of percutaneous endoscopic gastrostomy(PEG) tube insertion is critical and while there is limited evidence regarding timing of enteral feeding,consensus suggests placement of PEG when there is 10% reduction in body weight. Delayed placement of the PEG tube adversely affects disease progression 158,166 and increases the procedural risks, particularly when FVC<50%.121 NIV support has been suggested for PEG insertions in ALS patient with severe respiratory dysfunction(FVC<30%).167 Consequently, early dis-cussions about enteral feeding with patients and their families are essential to facilitate informed decision-making and avoid delays that could compromise safety and outcomes.

PACTALS recommendations

The strength of recommendations is moderate; quality of evidence is moderate.

● Identify the presence and rate of weight loss in ALS patients.

- Identify causes for weight loss in ALS:

$\circ$ Reduced oral intake due to dysphagia, loss of appetite, muscle wasting, depression, respiratory insufficient efficiency, saliva issues(Speech therapist assessment).

o Hypermetabolism(Dietician assessment).

○ Upper limb weakness leading to gross and fine motor impairment limiting use of eating utensils(Occupational therapy assessment)

o Implement strategies to increase oral intake

- Supplemental feeding

■ Addressing dysphagia, altering diet consis-tency, positioning.

■ Modify feeding utensils to enhance ability for independent feeding.

○ Oral hygiene and appetite management: Poor oral hygiene due to limb weakness can significantly impact appetite, which in turn affects nutritional status. Consider improving and maintaining oral hygiene by caregivers.

○ Encourage sufficient oral intake by providing adequate physical and psychological supports to overcome guilt imparted by the burden of requiring assistance

● Enteral feeding: Offer PEG feeding in line with local service availability.

o Discuss and explain PEG feeding to patients and caregivers.

o Explain the benefits of weight stabilisation/gain and prolonged survival.

$\circ$ In the absence of evidence for appropriate timing of PEG, recommend early placement of enteral feeding in the setting of rapid disease progression and weight loss. Monitor weight loss, respiratory dysfunction and rate of disease progression throughout the course of disease. Discuss poten-tial risks of a delay in commencement of enteral feeding.

o Encourage use of hypercaloric enteral feeding.

Introduce NIV prior to PEG insertion in setting of respiratory insufficiency

o Perform PEG while on NIV in ALS patients with severe respiratory insufficiency.

o PEG tubes should be inserted by gastroenterologist.

Consider radiologically guided feeding tube(RIG)insertion in cases if PEG tube insertion is not feasible. In some countries, where patients may be resistant to the idea of PEG tube insertion until more advanced disease, and radiologically inser-ted gastrostomy(RIG) tube insertion may be preferred with NIV support.

$\circ$ Consider nasogastric tube or parenteral feeding if percutaneous feeding not feasible or available.

Section 7. Management of symptoms affecting quality of life

Sialorrhea

Sialorrhea Sialorrhea for physiological phenomenon that disappears between 15 and 18 months after birth due the maturation of the orofacial motor function and coordination of swallow-ing. ${}^{168}$ The daily saliva production in adult humans is

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1500 mL, and comes from the submandibular(70-75%) and parotid(20-25%) glands.169 Sialorrhea is a common symptom of ALS(affecting~30% of pa-tients)170 and is caused by weakness of the oropharyn-geal and lingual musculature rather than increased production, leading to inefficient swallowing of saliva.171-173 Sialorrhea is a debilitating symptom, lead-ing to skin maceration, social embarrassment, psycho-logical burden and poor life quality.172 Additionally, the risk of aspiration pneumonia is increased, leading to increased hospitalisation, morbidity and mortality. ${}^{171,174}$ Adaptation and adherence to NIV may also be adversely affected by sialorrhea. ${}^{171}$ Consequently, the management of sialorrhea is important for reducing the risk of morbidity, mortality and improving life quality.

Historically, pharmacological treatment options for managing sialorrhea in patients with ALS have included anticholinergic drugs, such as atropine,scopolamine, glycopyrrolate, and amitrriptyline.175,176 However, there are limited RCT results in ALS,176 and dosing should be tailored to each patient to balance symptomatic improvement with minimizing side ef-fects. Mucolytic agents may also be beneficial, as they reduce mucus viscosity, facilitating clearance when there is sufficient cough flow.171 Non-pharmacological approaches such as tissue salts, as well as thorough assessment of saliva complexity(thick versus runny saliva) should also be considered.

Three small RCTs have reported on the efficacy of botulinum toxin injections of parotid and submandib-ular glands for the treatment of sialorrhea in ALS.17211tionally, irradiation of parotid and submandibular glands bilaterally(7-20 Gy) was shown to exhibit comparable efficacy as botulinum toxin treatment for reducing sialorrhea in ALS.179,180 The duration of botu-linum toxin effects is~3 months, while the effects of irradiation may vary from 4 to 7 months. Oral dextro-methorphan with quinidine(DMQ) exerted a mild benefit, while scopolamine patches did not exert sig-nificant effects.176 The limitation of all studies reporting on the treatment of sialorrhea in ALS relates to small sample sizes. The evidence is limited and larger RCTs would be required.121 Consequently, recent EAN guidelines were adapted from which recommendations have been formulated for PACTALS countries by consensus.

PACTALS recommendations

● Offer speech therapy for assessment of sialorhea(runny versus thick sialorhea) depending on service availability. While the management plan would ideally be guided by a speech therapy assessment, it is acknowledged that this may not always be possible.

Therefore, assessment by a speech pathologist is not a prerequisite for initiating treatment of sialorrhoea.

● Identify potential triggering factors, such as sugary foods.

● Consider anticholinergic medications as first line therapy such as amitrityline or sublingual atropine.The strength of recommendations is moderate quality of evidence is moderate.

● Consider glycopyrrolate or oxybutynin as second-line therapies in consultation with either palliative care physicians or physicians with expertise using these medications. DMQ may be considered,although dependent on availability in specific PAC-TALS countries. Scopolamine cannot be recom-mended due to absence of evidence for efficacy. The strength of recommendations is moderate; quality of evidence is moderate. A Phase II/III study is currently underway in Japan(jRCT2031240163) and will provide further information on the utility of scopolamine in ALS,175,176

● Consider botulinum toxin in ALS patients with se-vere sialorrhea, that have failed or are poorly toler-ating first-line pharmacotherapies. Consider offering before second-line pharmacotherapy agents if appropriate for the circumstances, although this will depend on availability of botulinum toxin in PACTALS countries. Additional challenge may be represented by ALS patients managed in the com-munity, where accessibility to botulinum toxin is limited. The strength of recommendation is moder-ate; quality of evidence is moderate.

● Irradiation could be offered as a last resort. This will depend on availability of salivary irradiation therapy in PACTALS countries. The strength of recom-mendations is weak; quality of evidence is low.

● Do not offer surgery for sialorrhea. This includes salivary gland excision, salivary gland duct ligation or rerouting, and interruption of the para-sympathetic innervation to the salivary glands(tymanic neurectomy).

● For thick mucus siorlhea consider the following for all countries:

o Review of all concomitant medications, particu-larly treatments for"runny" sialorrhea.

o Address issues of adequate hydration, reduce unnecessary suctioning, oral care and positioning.

Consider nebulisers, humidifiers, or mucolytics.

Muscle weakness and fatigue

Exercise therapy, including resistive and endurance exercises, was shown to improve spasticity and short-term functional decline(at 3 months).123,181,182 One meta-analysis reported no effects on muscle strength or quality of life,121 although a recent network meta-analysis reported a positive impact on muscle

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strength and quality of life.181 The impact of exercise intervention and physiotherapy was greater than nutritional intervention and NIV on muscle strength,while physiotherapy exerted greater benefits in reducing fatigue.181 A separate meta-analysis did not find significant benefits of exercise therapy on quality of life, muscle strength or function decline after excluding RCTs with high risk of bias.183 Given the contradictory evidence from meta-analysis and poor data quality,recommendations pertaining to management of mus-cle weakness and fatigue were adapted from the EAN guidelines and formulated for PACTALS countries by consensus.

PACTALS recommendations

● Review the impact of muscle weakness and fatigue on activities of daily living, gait, and propensity to fall in the multidisciplinary clinic or dedicated ALS clinic. The assessment should be performed by a physiotherapist and occupational therapist.

● Consider a suitable exercise programme for ALS patient to:

o Maintain joint function and prevent contracts.

o Reduce stiffness and pain.

o Optimise function, fatigue and quality of life as well as improving cardiovascular health.

● The exercise intervention may include resistance,endurance and passive exercise programmes, as well as aerobic exercise. Mild to moderate intensity exercise should be advised to induce a moderate level of within fatigue. The strength of recommen-dation is moderate; quality of evidence is low-moderate.

● Consider educating and including carers and family members in the exercise programme.

● Consider appropriate timing of instituting orthotics to aid mobility and prevent falls.

● Identify and treat underlying medical causes of fa-tigue. Specifically, address respiratory and sleep impairment(NIV/sleep apnoa, insomnia), comor-bidities(depression, anxiety, infections, drug side effects, anaemia, iron deficiency), sialorrhea, dehy-dration and malnutrition as well as pain and spasticity.

● Consider pausing or ceasing medications that may be exacerbating fatigue.

Muscle cramps and spasticity

Muscle cramps, fasciculations and spasticity are frequently reported and are debilitating symptoms in ALS. ${}^{9,22,184}$ The severity of symptoms varies from mild to severe with severe impacts on life quality. ${}^{185}$ Evi-dence pertaining to treatment of muscle cramps and spasticity in ALS is limited. One meta-analysis that included 20 RCTs did not find significant benefits of

vitamin E, backofen, irulizole, L-threonine, xaliproden,indinavir, memantine, creatine, gabapentin, dextro-methorphan, quinidine or lithium in treatment of muscle cramps in ALS.185 Moreover, orally adminis-tered tetrahydrocannabinol was shown to be ineffec-tive in treating muscle cramps in a small RCT. ${}^{186}$ Three small RCTs reported on efficacy of mexilitleine in significantly reducing the severity and frequency of muscle cramps, with an accompanying improvement in nerve excitability. ${}^{187-189}$ Mexiteline was well tolerated and safe.

Exercise programmes administered by physio-therapists, performed for 15 min twice daily for a period of 12 months, reduced spasticity for at least 6 months.182 Intrathecal baclofen infusions reduced spasticity and pain in a cohort of ALS patients with intractable symptoms.190 Combination of botulinum toxin and physiotherapy was effective at reducing spasticity in ALS patients failing oral antispasmodic medications.191 One RCT reported modest benefits of the cannabinoid nabibimol in reducing spasticity in ALS.192 While neuromodulation techniques(repetitive transcranial magnetic stimulation and transcranial direct current stimulation) were postulated to improve spasticity by exerting an effect on spinal and cortical circuits, there is limited evidence for clinical efficacy.193

The limitation of all studies reporting on the treat-ment of muscle cramps and spasticity in ALS is the small sample sizes. The evidence is limited and larger RCTs would be required.121 Consequently, recent EAN guidelines were adapted from which recommendations have been formulated for PACTALS countries by consensus. The recommendations will be reviewed pending updates in the literature.

PACTALS recommendations

● Consider physical therapy programmes for the treatment of spasticity. The strength of recommen-dation is moderate; quality of evidence is low-to-moderate.

o The programme should be tailored to the patients'needs and monitored by a physiotherapist.

o Engage caregivers in assisting with exercise programmes.

o Provide education to caregivers to maximise benefit and reduce risk of injury.

● Consider sodium channel modulating agents for treatment of muscle cramps when symptoms are debilitating or interfering with activities of daily living(for example, magnesium or mexitline). The strength of recommendations is weak; quality of evidence is low.

o Patient comorbidities should be considered to minimize side-effects.

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。The use of sodium channel blocking agents needs to be considered in the context of drug availability in PACTALS countries.

● Consider oral antispasmodic agents for the treat-ment of spasticity when symptoms are debilitating or interfering with activities of daily living(baclofen,tizanidine, pregabalin, or gabapentin). The strength of recommendation is weak-moderate; quality of evidence is low-moderate.

● Consider botulinum toxin and physical therapy for spasticity treatment if oral antisaspmodic medica-tions are inefficient. Cost may be prohibitive in middle- and low-income countries(limited-resource setting). In some PACTALS countries(such as Japan) botulinum toxin is contraindicated in ALS.The strength of recommendation is weak; quality of evidence is low-moderate.

● In some countries intrathecal baclofen infusion fusion may be considered in refractory cases failing above stra-tegies to improve symptoms although disease limits the utility of this approach. Cost may be prohibitive in limited-resource setting.

● Do not consider cannabinoid medications at this stage, although the recommendations will be reviewed when data from larger clinical trials be-comes available. The use of cannabis is pro-hibited in some PACTALS countries.

Pseudobulbar affect

Pseudobulbar affect(PBA) refers to emotional lability characterized by uncontrolled episodes of crying and laughing that have a disparity between emotional expe-rience and expression.194 Although frequently mis-identified as a mood disorder, such as depression or bipolar disorder, there are characteristic features that can be recognized clinically and validated scales, identifying PBA as a distinct entity requiring adequate manage-ment.194 While PBA is evident in a variety of neurode-generative disorders, it is especially prevalent in ALS particularly in patients with bulbar onset disease.196 The pathophysiological mechanism underlying PBA remains to be elucidated, although disruption of corticopontine-cerebellar pathways and/or the cerebellum appears to be important.197 Low-dose quinidine198 and combination of dextromethorphan hydrobromide/quinidine sulfate(AVP-923)199 were shown to reduce the frequency and severity of PBA symptoms and improve life quality.Additionally, the combination of dextromethorphan and quinidine improved bulbar function in ALS patients.There are no RCTs or meta-analysis supporting the use of other medications such as antidepressants.

PACTALS recommendations

● Differentiate PBA from frontotemporal dementia and mental health disorders(depression). Consider

using the Centre for Neurologic Study Lability Scale(CNS-LS) as a diagnostic aid for PBA.

● Consider the combination of dextromethorphan and quinidine for treatment of PBA. The strength of recommendation is moderate; quality of evidence is moderate. Consider potential comorbidities and drug availability in specific PACTALS country.

● If dextromethorphan and quinidine is unavailable,antidepressant medications(selective serotonin re-uptake inhibitors or serotonin-norepinephrine re-uptake inhibitors)194 may be trialled. The strength of recommendation is weak; quality of evidence is low.

● Consider referring to psychologist with experience in ALS if available.

#

Pain is a frequent and debilitating symptom of ALS,and includes muscle cramps, neuropathic and joint pain, as well as muscle, fibrous tissue and musculo-skeletal pain from intervertebral disc protrusion or spondylosis exacerbated by postural disturbance.201,202 Pooled prevalence of pain in ALS across studies in a recent meta-analysis was 60%(50-69%).202 Pain can adversely impact on the patient's quality of life across physical, psychological, social, and spiritual domains,and is important to manage.203,204 There is limited evi-dence to guide the treatment of pain in ALS. Conse-quently, recent EAN guidelines were adapted, and recommendations have been formulated for PACTALS countries by consensus. The recommendations will be reviewed pending updates in the literature.

PACTALS recommendations

● Assess and identify causes for the patents' pain. An assessment by a rehabilitation or palliative care specialist should be considered.

● Tailor management to specific causes of pain. Simple analgesia(paracetamol, non-steroidal anti-inflamma-tory agents, steroid injections) may be trialled initially. Early introduction of opioids in refractory pain should be considered with the aim of improving life quality.8 The strength of recommendation is moderate; quality of evidence is low-moderate.

● Consider specific agent for neuropathic pain(pre-gabalin, gabapentin, anti-depressant medications).Consider non-pharmacological interventions,including cognitive behavioural strategies and elec-trical stimulators in consultation with palliative care specialists. The strength of recommendation is weak; quality of evidence is low.

● Advise patients and their caregivers on preventive strategies.

o Refer to physiotherapy, exercise physiology, and occupational therapy for assessment and man-agement strategies.

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Thrombotic complications

The prevalence of venous thromboembolic complica-tions is increased in ALS patients.205 The risk factors for developing venous thromboembolic complications include immobility, decreased functional status, treat-ment with NIV and history of venous thrombosis.205 Pulmonary embolism may account in 2% of unex-pected deaths in ALS.206 Consequently, implementing strategies for reducing the risk of venous thromboem-bolic complications would reduce morbidity and mor-tality, particularly in immobile ALS patients.207 There is no robust evidence to guide management or prophyl-laxis of venous thromboembolic complications in ALS Consequently, recent EAN guidelines were adapted,and recommendations have been formulated for PAC-TALS countries by consensus.

PACTALS recommendations

● Identify and modulate risk factors that may contribute to development of thromboembolic complications.

● Advise ALS patients and caregivers on non-pharmacological interventions that may reduce risk of thromboembolic complications:

o Using compression stockings

o Limb elevation

$\mathcal{O}$ Physiotherapy with passive stretching

$\rho$ Optimising mobility

● The use of prophylactic anticoagulation, including low-dose heparin, cannot be recommended at this stage.

● In cases where thromboembolic complications develop, treatment with anticagulants should be started.

Contipation

Constipation is a debilitating symptom in ALS, nega-tively impacting life quality, contributing to patient discomfort and fatigue. The data is limited regarding management of constipation in ALS and EAN recom-mendations were adapted for PACTALS countries by consensus.

● Assess for the presence of constipation and identify potential causes(medications, dehydration, dietary issues,immobility, abdominal muscle weakness or presence of autonomic symptoms). Offer assess-ment by a dietician dependent on local service availability.

● Exclude underlying gastrointestinal morbidity.

● Offer advice on increasing fluid and fibre intake,ceasing medication that contribute to constipation(anticholinergics, opioids, and increase mobility. Use of gastrocolic reflex, whereby consumption of warm fluids with meals may stimulate the

gastrocolic reflex(increased peristalsis in the colon after food enters the stomach), thereby promoting better bowel function. The strength of recommen-dation is weak; quality of evidence is low.

● Consider laxatives in refractory cases. The strength of recommendation is moderate; quality of evidence is moderate.

● Ensure possibility of adequate toileting.

Section 8. Management of cognitive dysfunction,behaviour and emotional symptoms

Cognitive impairment and behavioural symptoms are common clinical features of ALS, being recognized in 35-50% of patients,208 and may develop in early stages of the disease.

Cognitive dysfunction may manifest as impairment of executive function and disturbance of normal speech,including poor working memory, loss of inhibition and fluency, with long-term memory and spatial domains remaining intact.14 Approximately 15% of ALS patients progress to develop frontoter temporal dementia.211 Behavioural symptoms include disinhibition, apathy,emotional disorders, stereotypies, and changes in eating habits. ${}^{9,184,212}$

The presence of cognitive and behavioural symp-toms adversely impacts the quality of life, patient management and prognosis.24,213 Separately, depression and anxiety are common emotional symptoms of ALS,particularly around the time of diagnosis,214 that nega-tively impact on life quality and treatment response. Consequently, incorporating the management of these non-motor symptoms is crucial for appropriate timing of vital decision making(such as end-of-life issues),improving quality of life, patient prognosis and reducing mortality.

PACTALS recommendations

● During the MDT clinic, consider assessing for the presence of cognitive dysfunction, behavioural and emotional symptoms(anxiety, depression, and emotional distress). Formal assessment using screening tools may be considered. The strength of recommendation is strong quality of evidence is moderate.

● Discuss psychological and emotional impacts of ALS and consider providing psychological support.The strength of recommendation is strong; quality of evidence is moderate.

● Consider the effects of cognitive, behavioural and emotional symptoms on the following:

o Impact on activities of daily living.

o Impact on personal relationship with family members and/or carers.

o Influence on family roles and dynamics.

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o Ability to understand and comprehend the gravity of diagnosis and prognosis.

o Capacity of adjusting to the new life circum-stances, perception of self, loss of autonomy, and economic impacts.

o Capability of operating equipment that will assist or enhance activities of daily living, such as voice assistive devices.

o Impact of sexuality and intimacy:

o Willingness and understanding of the need to accept assistance provided by caregivers.

● Managing cognitive impairment and behavioural symptoms. The strength of recommendations is strong, quality of evidence is moderate.

o Educate ALS patients and carers.

o Address underlying comorbidities contributing to symptoms, including insomnia, sleep disturbance nocturnal hypoventilation and polypharmacy.

Consider offering psychological and psychiatry(if needed) support.

Considering offering respite for carers.

● Managing anxiety

o Address comorbidities contributing to anxiety,such as fear of disease progression, fear of dying,or breathlessness.

Consider offering psychological and psychiatry(if needed) support. The strength of recommenda-tion is strong; quality of evidence is low-moderate.

Consider pharmacological therapies

o Anxiolytic medications(selective serotonin reuptake inhibitors, selective norepinephrine re-uptake inhibitors, tricyclic antidepressants, ben-zodyiazepines) for poorly controlled anxiety. The strength of recommendation is weak; quality of evidence is very low.

● Managing depression

o Address symptoms potentially contributing to depression such as insomnia, pain, sialorrhea, or constipation.

Consider offering psychological and psychiatry support. The strength of recommendation is moderate-strong; quality of evidence is moderate.

Consider pharmacological therapies

- These may include selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants. The strength of recommendation is weak; quality of evidence is low-moderate.

o If depression is refractory, consider non-invasive brain stimulation therapies. Likely only available in specific countries.

o Manage pseudobulbar affects(see above,section 7).

Integrate referrals to community or ALS support groups as part of a multidisciplinary care approach.

Section 9. Palliative care and end-of-life management in ALS

There is evidence to support the early integration of palliative care in the management of patients with ALS.216 This ensures effective communication and builds trust from the time of diagnosis. Although existing guidelines recommend the integration of palliative care in multidisciplinary teams(EAN/NICE/AAN), there are challenges in achieving these standards in practice.

In the Asia-Pacific region, there is a wide disparity in access to palliative care services. For instance, palliative care services are well-established in countries like Australia and Japan, but not in resource-limited set-tings.127 This leaves much of the delivery of palliative care services to neurologists or primary care physicians. There are differences in the delivery of palliative care services among the countries. These variations reflect the differ-ences in cultural background as well as access to services within the various healthcare systems. Historically, palli-ative care health care providers have focused on patients with terminal cancer diagnosis. Perceived barriers to specialist palliative management of patients with neuro-degenerative conditions include limited resources and lack of familiarity of providers with the disease trajectory of ALS. ${}^{218}$

Management of end-of-life care in ALS, including advanced directives, is typically delivered by specialist palliative care teams. The legal validity of advanced directives varies among countries in the Asia-Pacific re-gion varies. Cultural and religious sensitivities play a role in an individual's autonomy to choose their preferred care at the end of life. Discussions also require preserved cognitive function and clear insight into the disease,something that can be challenging to establish in resource-limited settings where access to psychological support is lacking. Advance care planning should be guided by ethical principles and adapted to the religious and cultural contexts of the Asia-Pacific region, including Confucian, Buddhist, Islamic, and secular perspectives.Differing norms relating to disclosure of prognosis and consideration of family decision-making hierarchies should also recognize variation in legal frameworks and healthcare system capacity. These contextual factors un-derscore the need for tailored guidance to support culturally sensitive palliative care recommendations.

PACTALS recommendations

Considering the wide disparities amongst PACTALS members, the following recommendations for ensuring the delivery of palliative care services, including end-of-life care, are suggested. Strength of recommendations are moderate; quality of evidence is low.

● Integrate palliative care services into the multidis-ciplinary care of patients with ALS at an early stage where possible.

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•Palliative care services should be delivered by a trained specialist, where possible.

● In settings where palliative care is not yet developed,the healthcare worker closely linked to the patient is best positioned to deliver this care and as such should be given access to necessary training.

● Palliative care can be delivered in either a hospital or community setting, depending on patients'preferences.

•Aspects of palliative care service include the following:

o Determining patients' preferences and concerns about their treatment options including initiation of respiratory support(both invasive and non-invasive ventilation), placements of feeding tube,pain control and other symptomatic relief.

$\circ$ The timing of these discussions should be tailored according to individual patients' prefer-ences and well as their functional and cognitive abilities.

o Offer the following activities surrounding the end-of-life, where possible:

■Identify a clinical lead who will coordinate end-of-life care including nursing, psychological and bereavement support.

■Advance care planning, namely decisions regarding "Not-For-Resuscitation", "Not-for-Treatment-Escalation" and consideration for timing of treatment withdrawal orders.

Depending on the countries legal framework,advance care directives can be implemented as well as discussions surrounding assisted sui-cide and euthanasia.

■Preference for place of death(home, commu-nity or hospital).

■Explanation to patient and carers of "What to expect", namely mode of death.

■ Access to medication that can relieve distress-ing symptoms, including pain and breathlessness.

■Bereavement support for the caregivers.

Section 10. Carers of ALS patients

The caregivers, whether family or friends, hold a pivotal role in supporting patients with ALS to ensure a good quality of life.219-221 Often, they are involved in the decision-making process. While caregiving can be pro-foundly fulfilling, strengthening bonds between loved ones, and instilling confidence in caregivers, its nega-tive effects often outweigh, making the experience both physically and emotionally challenging. 222,223 Caregiving for patients with long-term neurological diseases,including ALS, can result in caregiver stress and burden. ${}^{220,224-229}$

Patients with ALS face a constellation of symptoms that limit mobility and activities of daily living, as well as more complex issues like communication and

breathing dysfunction, which result in increasing de-pendency on their caregivers as the disease progresses.These clinical manifestations contribute to increasing patient dependency on caregivers, often requiring more assistance with daily tasks. In advanced stages, this may extend to the use of medical decisions and the need for critical medical decisions.

Beyond direct care, family caregivers also manage multiple roles, including financial responsibilities and household duties. These cumulative demands can strain caregivers' physical health, social re-lationships and negatively impact on emotional well-being, leading to feelings of isolation and over-whelming. ${}^{230}$ Previous research showed the level of pa-tients' behavioral and physical impairments had been associated with a higher caregiver burden and depression. ${}^{229}$ Not surprisingly, there is a correlation between a caregiver's well-being and the patient's quality of life. ${}^{231,232}$

The World Health Organization's Guidelines on Integrated Care for Older People psychological intervention, training, and support for family and caregivers, particularly but not exclusively in cases of complex care needs or high caregiver strain(The WHO Guidelines on Integrated Care for Older People(ICOPE), https://www.who.int/publications/i/item/9789241550109). The International Alliances of ALS/MND Associations emphasizes the fundamental rights of caregivers, advocating for respect, comprehensive support(emotional, social, and practical), time for self-care, access to financial and governmental support, and involvement in healthcare decisions(https://www.als-mnd.org/support-for-pals-cals/pals-and-cals-rights).

These rights underline the importance of creating a supportive environment for caregivers.

Studies have shown that there are four stages of caregiving once the diagnosis of ALS is made: post-diagnosis(stage 1), ongoing care(stage 2), end-stage care(stage 3) and bereavement(stage 4), with each stage requiring adjustments in the delivery of care.231,233 Therefore, it is crucial to ensure that caregivers have the necessary information and resources, which will also help alleviate frustrations and improve their prepared-ness for what is appropriate at each stage. When developing the framework of care for the individual living with ALS, it is important to consider a support mechanism for their caregivers as they navigate the complexity of the caregiving process at each stage of the disease, including safety considerations, symptom management, technology utilization, and emergency preparedness.222,234

Where possible, caregivers should have access to respite care and psychosocial support to avoid caregiver burnout. In many countries, there are patient advocacy groups that aim to provide community and support to people with lived experience, and early engagement is advisable. ${}^{235}$ In limited resource-settings, an emphasis

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on discussions relating to advance care plans will be important in managing care at the end of life where life-prolonging options are limited.

Living with ALS involves not only the patient but also their family.326 Caregivers of patients with ALS should be considered integral members of the health-care team and ensure that they receive the appropriate and targeted mental and physical health care and access to resources.237 By integrating caregiver support into ALS care frameworks, both patient and caregiver out-comes can be optimized.

PACTALS recommendations

● Strength of recommendations is weak; quality of evidence is low. Offer adequate education on ALS at time of diagnosis and throughout the disease trajectory.

● Offer information about community support group such as the ALS organization.

● Offer education and guidance on nursing care ac-cording to the different disease stages and the non-pharmacological management of ALS.

● Offer education and guidance on advance directives,end-of-life and legal matters to caregivers while maintaining patient's autonomy in patients without cognitive dysfunction.

● Offer psychosocial referral to at-risk caregivers.

● Consider reship/hospice care where necessary.

These recommendations should be implemented wherever possible, with adaptations based on the availability and capacity of local services. Service limi-tations should not preclude best-practice care where resources allow.

Section 11. Future vision: ALS as a liveable disease In collaboration with patients and their carers, the US National Academies of Sciences, Engineering, and Medicine(NASEM) has recently advocated for a concerted effort to transform ALS into a liveable dis-ease by accelerating therapeutic discoveries and developing personalised management approaches to enhance quality of life. ${}^{238}$ To achieve this goal, collab-oration at a local, national and international consortia level is required, combining expertise across multiple scientific and medical disciplines, as exemplified by PACTALS.

ALS remains a complex and clinically heterogenous neurodegenerative disorder mediated by a multi-step process, evident across different ALS phenotypes.A combination of genetic, environmental and epige-netic factors likely contributes to the development and progression of ALS.184 Current approaches using transgenic mouse and cell-based models do not faith-fully reproduce the complexity of disease evident in ALS patients, potentially accounting for inefficacy of

multiple clinical trials. ${}^{184}$ Investment into mechanism-driven research, utilising patient tissue samples and blood biomarkers, leading to a better understanding of pathophysiological process underlying ALS and iden-tifying novel therapeutic targets has been advocated.241-244

At a basic research level, consortia such as PAC-TALS must advocate interdisciplinary research imple-menting ofomics" technologies(genomics, proteomics,metabolomics, and exposome) for identifying novel pathogenic processes, linked to diagnosis and pheno-type.46.55 Fostering collaboration between medical research institutions, patient organizations, philan-thropy, government funding agencies and pharma-ceutical industries, as well as focussing on agents targeting multiple mechanisms and understanding limitations of non-clinical models is critical for devel-opment of new, more effective therapies.245 Given the variability in resources across PACTALS countries,targeted investment will be crucial to ensure equitable access to sophisticated technologies and scientific discoveries.

Investment into development of vital clinical trials infrastructure across the PACTALS region, including platform trial designs and biomarkers for patient stratification to facilitate a homogeneous recruited population, will be critical for enabling access to potentially lifesaving therapies across the re-gion.246,247 Building clinical and biorepositories,launching public awareness campaigns for improving patient recruitment and retention, as well as incorporating patient and carer perspectives into clinical research across the region is vital for devel-oping a roadmap for better management of ALS pa-tients living in PACTALS countries.125 Integration of clinical and biorepositories with currently available data collection systems, including Project MinE, New York Genome Center's ALS consortium, Answer ALS, Care-MND, Precision ALS, TRICALS and MiNDAUS will foster discoveries and provide access to research for ALS patients living in the PACTALS region. Similarly for basic research, targeted invest-ment would be crucial to ensure equitable access and development of required infrastructure across PAC-TALS countries.

Timely translation of scientific discoveries into effective therapies will lead to transformation of ALS into a chronic liveable disease and ultimately improve patient care. Ongoing investment along with continued multidisciplinary collaboration(scientists, clinicians, and stakeholders) will be critical for over-coming challenges that are faced across the PACTALS region and seize opportunities in ALS research.248 Continued collaboration will facilitate the develop-ment of effective therapies that will improve outcomes and bring hope to ALS patients, thereby making ALS a liveable disease.

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Conclusion

The PACTALS guidelines provide recommendations on the management of ALS patients living in the Asia-Pacific region, encapsulating the societal, religious,cultural and economic diversity. The recommenda-tions include advice on diagnostic pathways, the role of older and emerging disease modifying therapies, as well as delivery of multidisciplinary care models to address a variety of motor and non-motor symptoms that impact on the quality of life and prognosis in ALS.The landscape for ALS management will inevitably change over the next few years, with the development of more effective therapies. As such, further updates will be developed as new evidence becomes available,with granular detail supplied across the Asian Pacific region.

Contributors

Steve Vuc: Concept, methodology, literature search, synthesis of data,writing initial draft, figures, coordination.

Nortina Shahrizaila: Concept, methodology, literature, search, synthesis of data, writing initial draft, figures, coordination.

Osamu Kano: Concept, editing, literature review, methodology,expert panel.

Parvathi Menon: Concept, methodology, editing, expert panel.

Sheila Agustini: Concept, methodology, editing, expert panel.

Kongkiat Kulkantrakorn: Concept, methodology, editing, expert panel.Nalini Atchayaram: Concept, methodology, editing, expert panel.

Kay W.P.Ng: Concept, methodology, editing, expert panel.Jia B. Prado Jr.: Concept, methodology, editing, expert panel.Kay W.P.Ng: Concept, methodology, editing, expert panel.Jia B. Chai: Concept, methodology, editing, expert panel.

Hongon Tien Strongh Ngcon: Methodology, editing, expert panel.Palton Tabu: Concept, methodology, editing, expert panel.

Yuishin Izumi: Concept, methodology, editing, expert panel.Yuishin�: Concept, methodology, editing, expert panel.Riendu Xuii: Concept, methodology, editing, expert panel.

Mingsheng Liu: Concept, methodology, editing, expert panel.

Ohmohr: Kim. Concept, methodology, editing, expert panel.

Remli Rabani: Concept, methodology, editing, expert panel.

Yoon-Ho Hong: Concept, methodology, editing, expert panel.

Jung-Joon Sung: Concept, methodology, editing, expert panel.

Dongsheng Fan: Concept, methodology, editing, expert panel.

Vena Rayar: Concept, methodology, editing, expert panel.

Satoshi Kuwara: Concept, methodology, editing, expert panel.Seung Hyun Kim: Concept, methodology, editing, expert panel.Gen Soabor: Concept, methodology, editing, expert panel.Matthew C. Kiernan: Concept, methodology, literature search,synthesis of data, writing initial draft. figures.

Data sharing statement

This review is a summary of peer-reviewed, published reports and articles which readers may access as required.

Editor note

The Lancet Group takes a neutral position with respect to territorial claims in input maps and institution applications.

Dedaration of interests

Dr Nook Atais suncales regarding funding from Japan Agency for Medical Research and Development(Grant number) JP22ek0109538.

JP24mk0121294, JP24ak0101216, JP24wm0425009, JP24ek0109631),Grants-in-Aid for Scientific Research(Grant number: 22K07359,25K10781), consultant fees from Ono Pharma, Mitsubishi Tanabe Pharma: Pharma development America, Inc., and Biogen, honorarium for provided lectures by Mitsubishi Tanabe Pharma, Biogen, Eisai, Sumi-tomo Pharma Honorarium, and Alexion; Professor Gen Sobue reports grant funding from Japan Agency for Medical Research and Develop-ment(Grant Number JP24wn0425009h0004, JP24ak0101 216h0002 JP24ak1010222h0001), consulting fees from Nippon Boeh-ringer Ingelheim Co., Ltd, KinoPharma, Inc, NIHON PHARMACEU-TICAL CO., Ltd, personal fees Takumi Information Technology Inc.honorarium from Mitsubishi Tanabe Pharma Corporation, Takeda Co., Ltd, DAIICHI BANKYO, INC, Toray Industries Inc, and National Center for Global health and Medicine, payment for expert testimony from Mitsubishi Tanabe Pharma Corporation and Takeda Pharma-ceutical Company Limited; Dri-Yi-Chung Lee reports being principal investigator for the ION36-CS1 trial sponsored by IONIS and ALN-SOD-ALS-2351 trial sponsored by REGENERON, honorarium from Biogen Taiwan; Professor Matthew C. Kiernan has provided advice to members of the Therapeutic Goods Administration and the Pharma-ceutical Benefits Advisory Committee(Australia) concerning the man-agement of motor neuronide diseases, edited by the Motor Neurone Disease Handbook(2007) published by MJA Books, directed clinical trials as Principal Investigator on behalf of his employers, with funds admin-istered by these affiliated university and hospitals Professor Steve Vucic reports grant funding from National Health and Medical Research Council Australia, Medical Research Futve Fund, FightMND,MND research grant(NSW Health), honorarium for advisory board meeting Biogen Australia, co-inventor of medical device/test for diagnosis ALS(Mag(Xcite). Commercialised with international partner Soterix(USA),director in company that holds shares in Clene Inc, being principle investigator on VALOR study(sponsored by Biogen, Australia),RESQUE-ALS study(sponsored by Clene by Clne Inc, USA), RESTORE-ALS(sponsored by Clene Inc), ALCR study(funded by FightMND),TEALS study(funded by FightMND), and ALS-SOD-ALS-2351 trial(Funded by Regeneron, USA). While some authors have received honoraria or research support from industry partners(including Biogen and Mitsubishi Tanabe, and literature span overlapped with these declarations, all recommendations were developed through indepen-dent consensus, guided by the available evidence and the collective input of the full author group. Draft recommendations were reviewed collectively to ensure that individual conflicts did not influence guide-line content. Where therapies with industry ties were considered(e.g.,edavonear, discussions emphasised evidence appraisal and regional service availability. All conflicts of interest were declared and managed in accordance with the GRADE policy guidelines.

Acknowledgements

The manuscript did not receive funding.

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