Approach

Currently there is no cure for ALS, so the focus of medical care is to provide symptomatic management for all patients. Disease-modifying pharmacologic therapies to treat ALS include riluzole, edaravone, and sodium phenylbutyrate/taurursodiol.[11][56]​​ There is no evidence for a differential response to treatment between patients with familial versus sporadic ALS.[57]

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]

Immunizations, including pneumococcal vaccination, COVID-19 vaccination, and annual seasonal influenza vaccination, are recommended in patients with ALS, given the underlying chronic pulmonary dysfunction.

Informing patients and their families about the diagnosis, and ongoing counseling regarding prognosis, treatments, and end-of-life issues, with special emphasis on advance directives, are extremely important aspects of the patient-physician relationship.[11][35]​​[62][63]​​​

Pharmacologic therapy

Riluzole

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]

Significant hepatic toxicity and neutropenia are associated with riluzole use, but are rare.[67] Liver function tests and complete blood count should be monitored monthly for the first 3 months, then every 3 months thereafter.[64]​​​ Nausea and lethargy are possible adverse effects of riluzole.[59]

Edaravone

Edaravone is a free radical scavenger that exerts neuroprotective effects by reducing oxidative stress in motor neurons. It 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]

The treatment regimen for edaravone is very intensive, with treatment needed for 14 days initially, followed by treatment for a further 10 consecutive days a month as maintenance therapy. Edaravone is available in intravenous and oral formulations.

Sodium phenylbutyrate/taurursodiol

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. This combination therapy 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.

Symptomatic management

ALS is a progressive disease of the motor system and, as such, produces symptoms primarily relating to the location and degree of weakness. The exact treatment needs vary between patients, and will change with time for individual patients.[11][35][36][59][65][72]​​​​

  • Respiratory and nutritional support is critical, with the actual intervention required dependent on the status of the patient.

  • Patients with significant weakness of bulbar musculature may require interventions for dysphagia, sialorrhea, and communication difficulties.

  • Patients with weakness in the extremities may require support aimed at maintaining mobility, therapy for spasticity, or devices aimed at maintaining upper extremity function.

  • Mental status changes that may require treatment include depression, anxiety, and pseudobulbar affect. Cognitive and behavioral changes associated with frontotemporal impairment may also require interventions.

General principles of respiratory dysfunction management

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]

Symptomatic patients or asymptomatic patients with at least one of: FVC values of less than 50% to 65% of predicted value, or SNIP <40 cm H₂O, or abnormal nocturnal oximetry

Noninvasive ventilation (NIV) is indicated for these patients.​[35]​​​[36][58][72]​​​​ Historic guidelines have used a threshold for asymptomatic patients of FVC <50% of predicted value 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, might help with the process of adjustment to this type of treatment.

NIV is usually used initially at night, but with symptom progression 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 use has been shown to have a positive impact on quality of life and survival.[65][75]

Diaphragm pacing should not be used for patients with ALS because it is ineffective and may be harmful.[11][76][77]

Severe respiratory insufficiency not sufficiently treated with NIV

For patients 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 who would not consider long-term invasive ventilation and who have progressed to this degree of severity of respiratory dysfunction, 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]

Mild to moderate symptomatic dysphagia with mild weight loss (<10%)

For weight loss, the first step is diet modification. A dietitian should be involved to suggest nutritionally adequate substitutions. Diet modification with high-calorie supplements is usually effective in maintaining weight for a variable period of time, after which other options must be discussed.[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.

Moderate symptomatic dysphagia with significant weight loss (>10%)

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 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, 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]

Dysarthria

Most (but not all) patients with ALS experience significant dysarthria progressing to anarthria. 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.

Sialorrhea

Patients with dysphagia often experience drooling because of inability to swallow saliva. Symptomatic treatments usually consist of anticholinergic drugs such as hyoscyamine hydrobromide, amitriptyline, atropine, or glycopyrrolate.[11][72]

For patients with refractory sialorrhea, rimabotulinumtoxinB (formerly known as botulinum toxin type B) 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. 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 is also 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]

Difficulty with mucus secretions

Reduced cough volume and strength may result in inability to expel pulmonary secretions. 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.[11] 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.

Pseudobulbar affect

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 and quinidine has been found to be efficacious in controlling the pseudobulbar affect and is well tolerated.[11][59][93]​​​ Alternatively, amitriptyline may be considered for treating sleep problems and pseudobulbar affect, or a selective serotonin-reuptake inhibitor (SSRI) may be used to treat depression and pseudobulbar affect.[11]

Physical therapy for muscle weakness

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]​ Functional decline is an inevitable feature of ALS, so serial evaluations by physical therapists will be necessary throughout the course of the illness.

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]

Occupational therapy for muscle weakness

The goal 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 occupational therapists will be required as the disease progresses, in order to define the patient's needs at different points in time.[11][36]

Therapy for fully paralyzed patients

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.[96]

Muscle spasms and spasticity

Muscle spasms are usually a reflection of spasticity, and are treated with exercises and antispasticity medication. Medications that may be considered include baclofen, tizanidine, botulinum toxin, benzodiazepines, and cannabinoids.[11][59]​​​[97][98]​​ 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 and beneficial 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.

Depression and anxiety

Symptoms of depression and anxiety should be sought 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 an 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]

Insomnia

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 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.

Cognitive and behavioral impairment

Up to 45% of patients with ALS have associated cognitive and behavioral impairment, and in approximately 14% of patients these deficits are severe enough to meet criteria for frontotemporal dementia.[102]​ Symptoms may precede the onset of motor neuron disease symptoms, or may become evident late in the disease course.[4][103]​​​​ Screening for behavioral, cognitive, and language dysfunction should be carried out for patients with ALS.​​[11][59]​​ Interventions are generally supportive, as there is no evidence for effectiveness of pharmacologic therapies.

Palliative care

ALS does not have a cure, and weakness and functional deficits will progress throughout the disease course. 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][62]​ 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.

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