New ALS treatment guidelines from the European Academy of Neurology

The European Academy of Neurology (EAN) recently published its first guideline on the management of amyotrophic lateral sclerosis (ALS), in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).¹

The guideline is an update on the European Federation of Neurological Societies (EFNS) guideline published in 2012, and it provides new recommendations on the clinical use of disease-modifying therapies, of which there are several novel options. It also provides recommendations on aspects of support and care for people with ALS, including nutritional, respiratory, and psychological and emotional support.

Methodology
The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used for the development of the EAN guideline. Some of the guidelines for nutritional support, respiratory insufficiency, and end-of-life care and support are adapted from National Institute for Health and Care Excellence (NICE) guidelines. Of the twenty-six research questions when devising these guidelines, evidence for eight could be adapted from NICE guidelines. The remaining guidelines used evidence from existing systematic reviews or required de novo reviews.

In many of the areas researched, there were no randomized controlled trials of sufficient quality available to guide the management. It is emphasized that regional differences in the organization of the care should be taken into consideration when using these guidelines to treat patients with ALS.

“The scope of this guideline is comprehensive, encompassing not only disease-modifying therapies but also multidisciplinary care, symptomatic treatments, and end-of-life care. It notably incorporates emerging therapies not yet available in Europe but approved by the FDA. While offering recommendations on therapies in development presented challenges, we relied on the available evidence, recognising the need for ongoing updates in the future.” -Philip Van Damme, University Hospitals Leuven,Leuven, Belgium, guideline development lead.⁴

Disease-modifying treatments
The new guideline maintains the recommendation that patients should be offered lifelong riluzole, with a dosage of 50mg twice daily, at diagnosis. It additionally recommends that tofersen be offered as a first-line treatment for patients with progressive ALS caused by pathogenic mutations in superoxide dismutase 1 (SOD1). Tofersen is an antisense oligonucleotide that targets the production of SOD1 and was approved for use in the EU in May 2024 based on the results of the Phase 3 VALOR study (NCT02623699). Potential serious adverse effects, treatment burden, and the balance of potential benefits and harms of tofersen should, however, be discussed with the patient prior to use.

Based on the available evidence, the panel does not recommend the use of edaravone, cell-based therapies, or AMX0035 as disease-modifying therapies, but these interim recommendations will be updated once results from ongoing trials are available.

Nutritional support
The EAN guideline generally recommends that healthcare providers identify causes for weight loss and reduced food and fluid intake, which can include physical issues like swallowing problems, respiratory insufficiency, and upper limb weakness, as well as depression and loss of appetite. In case of weight loss or swallowing difficulties, a dietitian, speech therapist, and/or occupational therapist should be contacted for advice. This can include advice on food composition, consistency, and meal frequency; use of utensils; and positioning and seating.

With the patient’s preferences, as well as issues like ability to swallow, weight loss, and respiratory function taken into account, gastrostomy should be discussed at an early stage and at regular intervals, and also discussed with the patient’s family and/or carers. The benefits of an early gastrostomy and possible risks of a late one (e.g. low critical body mass, respiratory complications, risk of dehydration) should be explained. If there is respiratory insufficiency, gastrostomy should be performed with the patients established on non-invasive ventilation (NIV). When gastrostomy is not feasible, parenteral feeding can be considered.

Respiratory insufficiency
It is recommended that NIV be offered to all patients with either symptoms, signs, or laboratory investigations showing respiratory insufficiency. Utmost effort must be made to allow the use of NIV, as opposed to invasive ventilation (IV), independent of the patient’s bulbar function.

Invasive ventilation should be part of advance care planning, with physicians advised to be sensitive about the timing of the discussions. This should take into account the patient’s clinical status and their emotional ability to cope with the conversation, as well as that of their carer. Emergency invasive ventilation should be avoided. Diaphragmatic pacing is not recommended for the treatment of ALS.

For patients who are not or are no longer suitable for NIV or IV, for various reasons, or are in end-stage disease, pharmacological intervention can be considered. Opioids can be an option to relieve symptoms of breathlessness, and benzodiazepines can manage breathlessness that is exacerbated by anxiety.

Because of the nature of the pathology, patients with ALS experience a diverse range of symptoms. The EAN panel provides further recommendations for the management of many of these, including muscle weakness, muscle cramps, sialorrhea, constipation, pain, and insomnia.

Psychological and emotional support
Topics to discuss with patients relating to the psychological and emotional impact of ALS and their potential psychological care needs include their ability to continue with current work and usual activities, changes in relationships and family dynamics, and accepting and coping with the diagnosis and prognosis, including concerns about dying. Specific guidance is also provided on the treatment of anxiety, depression, and emotional distress.

At diagnosis, and at other trigger points like a change in respiratory function or the use of interventions such as gastrostomy or NIV, patients with ALS should be given the opportunity to discuss end-of-life care. This should be approached carefully, with the timing and contents of the discussion taking into account the person’s communication ability, cognitive status and mental capacity, and coping ability. Care providers should also prepare to discuss end-of-life issues whenever the patient wishes to do so. Topics discussed may include advance care planning (including advance decisions to refuse treatment, do-not-resuscitate orders, and lasting power of attorney), invasive ventilation, and euthanasia and assisted suicide.

Additional support should be provided as the end-of-life approaches, including additional psychological, social, or nursing care. Informal carers and family should be enabled to reduce their carer responsibilities and spend time with the patient. Access to methods of communication that meet the patient’s needs (e.g. an Augmentative and Alternative Communication system), specialist palliative care, necessary equipment, and anticipatory medicines should be provided promptly towards the end of life.

These guidelines are a valuable resource for clinicians, ensuring consistent, high-quality care can be provided based on the most recent and most relevant clinical evidence and contributions from a wide range of stakeholders. However, further evidence is needed on the efficacy and safety of new disease-modifying therapies for these to be included in these guidelines.

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Written by Niru Varma

Reviewed by Henry Shippey & Juliet Lawrence

References:

1. Van Damme P, Al-Chalabi A, Andersen PM, et al. European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD). Eur J Neurol. Jun 2024;31(6):e16264.