Amyotrophic lateral sclerosis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

all patients

1st line – riluzole + supportive care

Back

1st line –

riluzole + supportive care

All patients are started on riluzole at the time of diagnosis.[35][64][65] Riluzole prolongs survival in patients with ALS, with potential advantage in patients with bulbar onset.[11][64][66] Annual survival benefit with riluzole is approximately 9%.[11]

Liver function tests and complete blood counts should be monitored monthly for the first 3 months, then every 3 months thereafter; neutropenia can also occur but is rare.[64][67] Nausea and lethargy are possible adverse effects.[59]

Care of patients with ALS is best provided in a multidisciplinary ALS clinic, with a team comprising a respiratory therapist, physical and occupational therapists, a dietitian, a speech and swallowing specialist, a social worker, and other specialists as needed. This approach allows for optimization of care, and has been shown to be associated with improved survival, fewer hospital admissions, increased use of adaptive equipment, and better quality of life.[11][58][59][60][61]

Patients living with ALS should be supported using the principles of palliative care and, in particular, the use of a holistic approach to support patients and their families throughout the course of their illness. Key components of palliative care in ALS are goals-of-care discussions, advance directive planning, symptom management, and end-of-life support.[11][35][62][63] There are several models of palliative care that can be followed, including integration of palliative care into the multidisciplinary ALS clinic, separate involvement of a palliative care specialty team, home-based palliative care, telemedicine-supported care, and hospice care.

Advance directives and wishes for end-of-life care should be discussed with the patient and family/caregivers as early as possible, long before hospice care is needed, and should be an ongoing conversation.[62][104]

Revisiting advance directives should precede discussions about starting hospice care and end-of-life management.[11][59][80] End-of-life management should focus on the patient's comfort and dignity.

Primary options

riluzole: 50 mg orally twice daily

Consider – edaravone

Back

Consider –

edaravone

Treatment recommended for SOME patients in selected patient group

Edaravone is approved in the US and some other countries (but not in Europe) for treating ALS. Although one phase 3 randomized controlled trial did not show an overall benefit of intravenous edaravone in slowing ALS progression, a benefit has been demonstrated in a subgroup of patients.[68][69] The effect of edaravone on survival was not evaluated in the study; one real-world analysis reported that intravenous edaravone was associated with prolonged overall survival in a large predominantly riluzole-treated US cohort.[70] However, one cohort study reported that although intravenous edaravone therapy for approximately 1 year was feasible and mainly well tolerated, no disease-modifying benefit was observed compared with standard therapy alone (riluzole).[71] It may be used in addition to riluzole and sodium phenylbutyrate/taurursodiol.

Primary options

edaravone: 60 mg intravenously once daily for 14 days followed by 14 days off for the initial treatment cycle, then 60 mg once daily for 10 days within a 14-day period followed by 14 days off for subsequent treatment cycles; 105 mg orally once daily for 14 days followed by 14 days off for the initial treatment cycle, then 105 mg once daily for 10 days within a 14-day period followed by 14 days off for subsequent treatment cycles

Consider – sodium phenylbutyrate/taurursodiol

Back

Consider –

sodium phenylbutyrate/taurursodiol

Treatment recommended for SOME patients in selected patient group

Sodium phenylbutyrate/taurursodiol is a combination of the salt of an aromatic fatty acid and a bile acid. The mechanism of action in patients with ALS is unclear. The combination was demonstrated in one clinical trial to modestly slow progression of ALS over a 6-month period in patients with definite ALS (as defined by the revised El Escorial criteria) who had onset of symptoms within the previous 18 months. The magnitude of effect was similar to the effect size of edaravone over a 6-month period.[56] A larger confirmatory trial with expanded inclusion criteria is ongoing, with results expected in 2024. The combination drug received Food and Drug Administration (FDA) approval in 2022 and has conditional approval in Canada, but is not yet approved in Europe. It may be used in addition to riluzole and edaravone.

Primary options

sodium phenylbutyrate/taurursodiol: 3 g (sodium phenylbutyrate)/1 g (taurursodiol) orally once daily for 3 weeks initially, followed by 3 g (sodium phenylbutyrate)/1 g (taurursodiol) twice daily

with respiratory symptoms

Plus – noninvasive ventilation (NIV) or chronic invasive ventilation or palliative care

Back

Plus –

noninvasive ventilation (NIV) or chronic invasive ventilation or palliative care

Treatment recommended for ALL patients in selected patient group

Patients with mild or moderate respiratory dysfunction may be entirely asymptomatic, or may have symptoms that are either nocturnal or exercise-related. Monitoring of respiratory function every 3 months is recommended by screening for subjective symptoms of respiratory insufficiency and objective signs of respiratory insufficiency.

Symptoms of respiratory insufficiency may be shortness of breath on exertion or at rest, orthopnea, frequent awakenings at night, early morning headaches or confusion (due to nocturnal hypercapnia), poor vocal projection, and poor cough efficacy.

Options for objectively monitoring respiratory function include forced vital capacity (FVC), slow vital capacity (SVC), and sniff nasal inspiratory pressure (SNIP).[11][72] As supine FVC correlates well with symptoms of nocturnal hypoventilation, monitoring may be considered, along with erect FVC.[65] SNIP may be particularly useful in patients with bulbar weakness who might not be able to form a complete seal around the mouthpiece for obtaining FVC.[73] SNIP <40 cm H₂O has been found to be related to nocturnal hypoxia and has demonstrated a higher sensitivity for predicting 6-month mortality when compared with FVC <50%. In addition, nocturnal oximetry and/or sleep study can provide data regarding nocturnal hypoxia.[65][72]

NIV is recommended for patients with FVC of less than 50% to 65% of predicted value, or maximal SNIP <40 cm H₂O, or abnormal nocturnal oximetry.[35][36][58][72] Historic guidelines have used a threshold for asymptomatic patients of FVC <50% of predicted for initiation of NIV. More recent expert-based best practice recommendations have suggested earlier initiation of NIV in asymptomatic patients, with a threshold of FVC <65% of predicted, because of evidence suggesting that NIV initiation at FVC around 50% is better than at FVC below 50%.[11][72][74] All guidelines suggest NIV initiation for symptomatic patients, even if they have FVC >65%.

When NIV is prescribed, modification in pressure settings to ensure maximum comfort is often required, as is individual determination of the most appropriate interface (contact between ventilator and patient). Anxiolytic medication, such as lorazepam, may help with the process of adjustment to this type of treatment.

NIV is usually used initially at night, but with symptom progression it can be used up to 24 hours per day. Patients usually need uptitration of NIV pressures as their respiratory function declines. Also, patients often require different interfaces for day use and night use as they increase their NIV usage to avoid constant pressure points with a single mask and to allow for better integration with activities.[72] For example, some patients with ALS will still be able to speak if supported by a nasal-only interface for NIV during the day. Successful NIV has been shown to have a positive impact on quality of life and survival.[65][75]

Chronic invasive ventilation is an option for patients with severe respiratory insufficiency not sufficiently treated with NIV. For those who would consider long-term invasive ventilation, tracheostomy and permanent positive pressure ventilation can be life-prolonging.[65][72][78]

Consideration of treatment should be preceded by revisiting advance directives and a thorough discussion regarding the type of care that is needed for patients with invasive ventilation. This discussion should take place well in advance of respiratory failure.[11][62][72] As caring for a patient on permanent mechanical ventilation requires a high level of skill and 24-hour support for management of the ventilator and deep suctioning, most often patients cannot be supported in a home environment and placement in a chronic hospital environment is required. Less than 10% of patients with ALS consider invasive ventilation.

With permanent ventilation in place, patients may survive a variable number of years. Invasive ventilation can be withdrawn any time at the patient's request, although it is recognized that this may become a difficult decision, particularly if the patient has developed cognitive impairment or has progressed to a locked-in state, with no means left to express their wishes.[11][79]

For patients with severe respiratory insufficiency who would not consider long-term invasive ventilation, care becomes palliative.[11][62] Palliative care focuses on comfort, with special emphasis on symptomatic treatment of shortness of breath with opioids and/or benzodiazepines and consideration of concurrent support via NIV. Increased airflow in the room via an open window or fan can also be considered.[59][80][81]

with difficulty expelling mucus secretions

Plus – supportive respiratory management

Back

Plus –

supportive respiratory management

Treatment recommended for ALL patients in selected patient group

Mechanical cough assist devices may be very helpful, particularly if peak cough flow is reduced.[11][65][72] Carbocysteine is a mucolytic that can break down mucus, making it easier to clear, but it is not available in the US.[92] Other mucolytics such as nebulized acetylcysteine or oral guaifenesin can be tried. Ensuring sufficient hydration and reduction in anticholinergics can potentially help with management of thick secretions. Occasionally, patients may elect to undergo tracheostomy to allow for more complete suctioning of airways, but this is uncommon.

with dysphagia and weight loss

Plus – diet modification or feeding tube

Back

Plus –

diet modification or feeding tube

Treatment recommended for ALL patients in selected patient group

Frequently reported symptoms include choking, prolongation of meal times, and changes in diet due to decreased ability to swallow.

For mild weight loss, dietary modification with high-calorie supplements under the care of a dietitian or nutritionist can stabilize the patient's weight for a variable period of time.[82]

For management of dysphagia, texture modification of food can be suggested by a speech-language pathologist or occupational therapist trained in dysphagia assessment. Early intervention may include avoiding dry and particulate food. As dysphagia worsens, the swallowing assessor may suggest progression to pureed food and thickening of liquids.

For patients who are unable to maintain a stable weight, percutaneous endoscopic gastrostomy (PEG) or radiologically inserted gastrostomy (RIG) tube placement should be suggested. Feeding tube placement should be discussed as part of the decision-making related to long-term care. Nutrition by feeding tube allows for weight stabilization, and overall might have a beneficial impact on survival.[11][35][65][83] It has an uncertain impact on patient quality of life.[65][83][84]

Gastrostomy surgery should be considered before forced vital capacity (FVC) decreases below 50% of its predicted value, to reduce the risks of perioperative morbidity associated with respiratory dysfunction, even if the patient does not have significant dysphagia at that time.[65][85] If a feeding tube is placed presymptomatically, patients are encouraged to maintain the oral intake as tolerated, while the tube is only flushed with normal saline daily to maintain patency. Even with tube feeding, the aspiration precautions should be maintained.

There is insufficient evidence on whether PEG or RIG tube feeding is better in terms of safety and clinical outcomes.[11][86] RIG allows placement in patients with more advanced respiratory failure, but RIG tubes have been found to have a high rate of blocking, leaking, and needing to be replaced in the months after insertion.[86]

with dysarthria

Plus – alternative communication methods

Back

Plus –

alternative communication methods

Treatment recommended for ALL patients in selected patient group

Speech therapy is usually not effective, so the most effective intervention consists of finding appropriate communication strategies to substitute for normal speech. This may include writing, as well as use of a variety of augmentative and alternative communication systems that can be activated with hand movements, facial movements, eye gaze, or whatever movement a given patient is able to perform.[11][59][87][88] As the patient's mobility is progressively changing, close monitoring and regular reassessment is necessary to enable them to maintain effective communication ability.

with drooling (sialorrhea)

Plus – pharmacotherapy or radiation therapy

Back

Plus –

pharmacotherapy or radiation therapy

Treatment recommended for ALL patients in selected patient group

Pharmacologic options include anticholinergics or rimabotulinumtoxinB (formerly known as botulinum toxin type B).[72]

Anticholinergics decrease pharyngeal secretions and should be titrated to provide comfort.

For patients with refractory sialorrhea, rimabotulinumtoxinB may be considered.[11][59][72][89] If injected into each parotid and submandibular gland, it can interrupt saliva release; however, localization for injections is variable and the response is also variable. Uncommonly, adverse effects may include worsening dysphagia, neck pain, and speech disturbance. More severe adverse effects include dyspnea with respiratory compromise.[105] When effective, repeat injections are usually required at approximately 3-month intervals. Maximum benefit is usually experienced at 4 weeks.[90]

Low-dose radiation therapy to the salivary glands (e.g., a single dose of 7 Gy to 12.5 Gy) is possibly effective in patients with medically refractory sialorrhea, although evidence is uncertain.[11][59][72][89] It may decrease saliva secretion for up to 6 months.[59][90][91] Adverse effects may include sore throat, nausea, erythema, and persistent xerostomia.[59][90]

Primary options

hyoscyamine: (0.125 mg/5 mL) 0.125 to 0.25 mg orally every 4-6 hours when required, maximum 1.5 mg/day

amitriptyline: 10 mg orally once daily at bedtime initially, increase gradually according to response, maximum 75 mg/day

atropine: 0.4 mg orally every 4-6 hours when required

glycopyrrolate: 1-2 mg orally twice or three times daily

Secondary options

rimabotulinumtoxinB: consult specialist for guidance on dose

with muscle weakness

Plus – physical therapy and occupational therapy or palliative treatment

Back

Plus –

physical therapy and occupational therapy or palliative treatment

Treatment recommended for ALL patients in selected patient group

Physical therapy is for maintenance of muscle elasticity and joint range of motion to prevent contractures, and to determine the level of appropriate bracing and the need for ambulation devices. Such devices include ankle foot orthoses, cervical collars (neck weakness), canes, walkers, and wheelchairs. In each case, a range of devices is available, and the choice must be made by an experienced professional, taking into account the patient's needs and preferences.[61]

Individualized exercise programs of moderate intensity are considered safe and beneficial for patients with early disease.[11][94][95] These should be home-based and monitored by physical therapists, using telemedicine approaches if necessary.[61]

The goal of occupational therapy is to assess the needs of a patient in order to support their independence in performing activities of daily living and to assist with the care for patients with advanced disease. Examples include devices to assist with transfer from and to a wheelchair (e.g., bed rails, Hoyer-lift) and adapting the environment (e.g., ramps, shower chair, commode, powered hospital-type bed, modifying keyboards, adaptive utensils, accessible clothing).

Serial evaluations by both physical and occupational therapists will be necessary as the disease progresses, in order to define the patient's needs at different points in time.[11][36]

In patients with severe generalized weakness, treatment goals relate to maintaining skin integrity and comfort. Motorized beds and water and air mattresses can reduce pressure and vary sites of skin contact, preventing pressure ulcers and aiding in providing adequate pain control.[36][96]

with spasticity

Plus – pharmacotherapy + physical therapy

Back

Plus –

pharmacotherapy + physical therapy

Treatment recommended for ALL patients in selected patient group

Muscle spasms are usually a reflection of spasticity, and are treated with exercises and antispasticity medication (e.g., baclofen, tizanidine, botulinum toxin, benzodiazepines, and cannabinoids).[11][59][97][98][106] Baclofen, tizanidine, and botulinum toxin (e.g., onabotulinumtoxinA) are approved in the US for the treatment of spasticity. Antispasticity medications can sometimes worsen ambulation or transfer ability due to the emergence of underlying muscle weakness when limb tone is reduced, and benzodiazepines bring a risk of respiratory suppression.

Physical therapy for spasticity aims to reduce muscle tone, maintain range of motion and mobility, and improve comfort. Modalities include strengthening, stretching, and positioning exercises. Individualized exercise programs of moderate intensity are considered safe for patients with early disease.[94][95] Therapy to actively or passively perform range-of-motion movements will reduce tone as effectively as pharmacologic therapy, but is time-consuming and often requires family members or therapists to provide passive movements.

Primary options

baclofen: 5 mg orally three times daily initially, increase by 5 mg/dose increments every 3 days according to response, maximum 80 mg/day

tizanidine: 4 mg orally initially, increase by 2-4 mg/dose increments every 6-8 hours according to response, maximum 24 mg/day

onabotulinumtoxinA: consult specialist for guidance on dose

with depression and/or anxiety

Plus – pharmacotherapy and/or psychological therapy

Back

Plus –

pharmacotherapy and/or psychological therapy

Treatment recommended for ALL patients in selected patient group

Symptoms of depression and anxiety should be sought for at every patient visit. The incidence of depression in patients with ALS is not well studied, but may be higher than in the general population, especially in those with advanced disease.[99]

Depression is often well treated pharmacologically with a selective serotonin-reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).[11][59] Because most patients with ALS eventually develop dysphagia, it is appropriate to consider initiating treatment with an antidepressant that can be safely crushed (by avoiding capsules or coated medications).

Evidence for psychological interventions for patients with ALS is limited, but there is some evidence of effectiveness for mindfulness and cognitive behavioral therapy for treating depression and anxiety.[100][101]

with insomnia

Plus – treatment of underlying cause and/or pharmacotherapy

Back

Plus –

treatment of underlying cause and/or pharmacotherapy

Treatment recommended for ALL patients in selected patient group

If insomnia is a problem, it is important to determine the cause so that appropriate treatment can be started. If insomnia is related to respiratory insufficiency, nocturnal noninvasive ventilation (NIV) may be an effective treatment. Other possible causes of insomnia include mood disorders and pain.[11]

Treatment of insomnia with benzodiazepines should generally be avoided in patients with ALS due to the risk of respiratory suppression. Non-benzodiazepine sleep medication such as melatonin or zopiclone can be considered.

with pseudobulbar affect

Plus – reassurance ± pharmacotherapy

Back

Plus –

reassurance ± pharmacotherapy

Treatment recommended for ALL patients in selected patient group

Occasionally patients with significant bulbar upper motor neuron signs will also display pseudobulbar affect, manifested by excessive or inappropriate laughing or crying. Most often, explanation of the etiology of these symptoms and reassurance are sufficient to allow patients to deal with this symptom.

If treatment is needed, the combination of dextromethorphan/quinidine has been found to be efficacious in controlling the pseudobulbar affect and is well tolerated.[11][59][93] Amitriptyline may be considered for treating sleep problems and pseudobulbar affect.

A selective serotonin-reuptake inhibitor (SSRI) may also be used to treat depression and pseudobulbar affect; because most patients with ALS eventually develop dysphagia, it is appropriate to consider initiating treatment with an SSRI that can be safely crushed (by avoiding capsules or coated medications).[11]

Primary options

dextromethorphan/quinidine: 20 mg/10 mg orally once daily for 7 days, followed by 20 mg/10 mg twice daily thereafter

amitriptyline: 10 mg orally once daily at bedtime initially, titrate dose until symptomatic relief, maximum 75 mg/day

Use of this content is subject to our disclaimer

Amyotrophic lateral sclerosis

Treatment algorithm

all patients

riluzole + supportive care

Primary options

edaravone

Primary options

sodium phenylbutyrate/taurursodiol

Primary options

noninvasive ventilation (NIV) or chronic invasive ventilation or palliative care

supportive respiratory management

diet modification or feeding tube

alternative communication methods

pharmacotherapy or radiation therapy

Primary options

Secondary options

physical therapy and occupational therapy or palliative treatment

pharmacotherapy + physical therapy

Primary options

pharmacotherapy and/or psychological therapy

treatment of underlying cause and/or pharmacotherapy

reassurance ± pharmacotherapy

Primary options