Amyotrophic Lateral Sclerosis (ALS) Treatment & Management

Treatment of amyotrophic lateral sclerosis (ALS) may be divided broadly into patient education, mechanism-specific treatment, and adaptive or supportive treatment.^{[8, 96]} Patient education can be enhanced by referral to multidisciplinary clinics staffed by specialists with special interest in ALS, by reading educational materials prepared for patients and families by national organizations in the US^{[97, 98]} and other countries or by individual experts^[8] , and by participating in local support groups.

Most of the care of patients with ALS may be delivered in the outpatient setting, and often guidance can be provided by a neurologist or physiatrist with special interest in the disease. Multidisciplinary clinics can provide "one-stop shopping" for patients, where patients can receive all assessments and recommendations in the course of a single visit. Most multidisciplinary clinics provide a combination of on-site and off-site services. Muscular Dystrophy Association/ALS Centers have been established at some major medical centers.

While multidisciplinary clinics are a highly effective method of delivering care to patients with ALS, this approach may not be available in all venues because adequate patient volume and, usually, some nonclinical (ie, philanthropic) support, is required to sustain it. Some patients find full-day assessments exhausting, and for them more frequent, but shorter, visits are more acceptable. The patients’ primary care providers have an important role in the care of patients with ALS, and in some settings may be able to coordinate all the patients’ care.

The glutamate pathway antagonist riluzole (Rilutek) is the only medication that has shown efficacy in extending life in ALS. Compared with placebo, riluzole may prolong median tracheostomy-free survival by 2-3 months in patients younger than 75 years with definite or probable ALS with disease duration under 5 years who have a forced vital capacity (FVC) of greater than 60%.^[99]

This conclusion is based on 2 double-blinded, randomized, placebo-controlled clinical trials.^{[29, 30]} A third clinical trial^[100] in patients who were ineligible to participate in the second pivotal clinical trial^[30] did not show efficacy, possibly due to low power (small number of patients included relative to the magnitude of the possible effect). A fourth clinical trial conducted in Japan^[101] did not show efficacy,^[102] and the details have not been published in the English literature.

A Cochrane review pooled the data from the first three clinical trials,^{[29, 30, 100]} but not the fourth.^[101] The statistical significance of the data for efficacy, using the pooled data from the first 3 trials is P=0.056. Subsequent reports have claimed greater efficacy for riluzole in clinical practice than in the clinical trials.

The relevance of these claims has been challenged.^[103] They pit class IV evidence against class I evidence, which is contrary to the usual evidence-based approach to judge treatment efficacy.

Patients with ALS who have depression, frontotemporal dementia, or a milder level of frontal impairment are now recognized as less likely to accept treatment recommendations and have a poorer prognosis. Failure to accept riluzole treatment is a marker for a risk factor for poor survival, not its cause. Furthermore, registries in place since before the introduction of riluzole show no overall extension of survival of patients with ALS.

The principal clinical side effects some patients with riluzole may experience are stomach upset and asthenia (lack of energy). These effects resolve if the medication is discontinued.

Cases of interstitial lung disease have been reported in patients treated with riluzole, some of them severe; upon further investigation, many of these cases were hypersensitivity pneumonitis. If respiratory symptoms such as dry cough and/or dyspnea develop, chest radiography should be performed, and if findings suggest interstitial lung disease or hypersensitivity pneumonitis (eg, bilateral diffuse lung opacities), riluzole should be discontinued immediately.

In most reported cases, respiratory symptoms resolved after drug discontinuation and symptomatic treatment.

Some patients on riluzole develop abnormal liver function test results or neutropenia. Serum aminotransferases, including alanine aminotransferase (ALT) levels, should be measured before and during riluzole therapy. Serum ALT levels should be evaluated every month during the first 3 months of treatment, every 3 months during the remainder of the first year, and periodically thereafter.

Serum ALT levels should be evaluated more frequently in patients who develop elevations. Treatment should be discontinued if ALT levels are 5 times the upper limit of normal or higher or if clinical jaundice develops.

Inpatient care may be needed temporarily for patients with ALS who decompensate in the outpatient setting, for example due to pneumonia, or those who reach critical ventilatory failure without having appropriate ventilatory support in place and without having made end-of-life decisions (advance directives) declining such ventilatory support and electing comfort measures instead.

In October 2009, the American Academy of Neurology (AAN) published a 2-part evidence-based Practice Parameter update about the care of the patient with ALS^{[104, 105]} , updating the previous evidence-based practice parameter published in 1999.^[96]

The chief findings of the practice parameter are that for extending life or slowing disease progression, the evidence is best for use of noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole. The authors comment that these treatments are often underutilized and recommend that they should be offered to patients, in the case of riluzole, or considered by the physician, in the case of NIV and PEG.

The median extension of life by riluzole in placebo-controlled studies was 2-3 months. The median extension of life by NIV or PEG may be approximately 6 months, provided the treatments are applied early and adhered to. The efficacy of NIV is supported by a randomized controlled trial.^[106]

The parameter authors also recommend that referral to a multidisciplinary clinic should be considered for managing patients with ALS to optimize health care delivery, prolong survival, and enhance quality of life.

The parameter authors recommend that botulinum toxin B should be considered for the treatment of refractory sialorrhea and that low-dose radiation therapy to the salivary glands may be considered.

Medication treatments for sialorrhea are typically tried first. Patients who gain insufficient relief with medications are considered refractory. The use of botulinum toxin in patients with ALS carries a manufacturer's warning due to concern of spread of the toxin to ventilatory muscles (leading to exacerbation of ventilatory failure) or bulbar muscles (exacerbating their weakness). In the opinion of the author of this article, this may tilt the balance in terms of safety toward salivary gland irradiation, except in patients with exceptional ventilatory and bulbar reserves.

Finally, the parameter authors recommend that dextromethorphan and quinidine should be considered for pseudobulbar affect (now approved by the US Food and Drug Administration). For patients who develop fatigue while taking riluzole, withholding the drug may be considered.

Clinician and patient summaries are available on the AAN website, as follows:

• Clinical Summary, Part 1
• Clinical Summary, Part 2
• Patient Summary, Part 1
• Patient Summary, Part 2

Antispasticity agents may be used to treat limb stiffness.

Antisialorrhea treatments include anticholinergics, sympathomimetics, botulinum toxin type B, and salivary gland irradiation. Anticholinergics such as amitriptyline (25-50 mg qhs) or trihexyphenidyl (Artane) (0.5-2.0 mg prn) may be administered as tolerated. A scopolamine patch may work in patients who have not attained adequate relief from oral anticholinergics. Sympathomimetics such as pseudoephedrine may be tried if tolerated; 30-60 mg may be administered as needed or in the extended release formulations, 120-240 mg/d may be used.

The efficacy of injections of botulinum toxin type B (2500 units) into the salivary glands has been reported in a double-blinded, placebo-controlled trial.^[107] Salivary gland irradiation (7.5 Gy) has been found effective in a case series with standardized outcome measure.^[108] .

Mucolytics such as guaifenesin may be used to thin thickened secretions. Adequate hydration and humidification of room air may prove helpful and are recommended. Mechanical suction devices may be needed to remove secretions.

For treatment of depression, selective serotonin reuptake inhibitors work best (eg, citalopram 10-40 mg/d). If the desired benefit is not achieved with one agent, another may be tried.

For anxiety, lorazepam is commonly used (0.5-1.0 mg as needed). Careful titration is needed, as benzodiazepines have the potential to cause respiratory depression.

If analgesics are needed, tramadol (Ultram), ketorolac (Toradol), morphine (immediate or extended release), or a fentanyl patch may be considered. Respiratory depression with opiates may occur. Careful titration, starting with low doses, is needed.

A combination of dextromethorphan and quinidine (Nuedexta) has shown efficacy in ameliorating involuntary laughter and crying (the expression of pseudobulbar affect).^{[109, 110]} It has FDA approval for this indication.

Noninvasive ventilatory support has been shown to improve patients’ quality of life and to extend life when applied as patients begin to experience the early effects of ventilatory failure, including disruption of sleep. Noninvasive ventilatory support is probably more effective than all other treatments for prolonging life in ALS patients.

Overnight polysomnography may identify disruption of the contiguity of sleep, one of the early consequences of ventilatory failure that may precede frank apneas, hypopneas, or nocturnal oxygen desaturation.

Invasive ventilatory support, requiring tracheostomy, may be considered in patients who present with respiratory failure and who are otherwise largely neurologically intact; in patients who want to be kept alive using long-term invasive ventilatory support as their disease progresses; or in very rare patients in whom secretions cannot be managed, and therefore cannot benefit from noninvasive ventilatory support.

Patients’ appetite tends to decline as the disease progresses, and their ability to swallow may become impaired. Consultations with a dietician or nutritionist and a speech therapist may be requested to assist the patient in compensating for these losses. Dietary supplements may be used to assure adequate caloric intake.

Placement of a feeding gastrostomy may be considered in patients who cannot maintain adequate caloric intake due to swallowing difficulties. Consultation with a gastroenterologist or surgeon may be requested if percutaneous endoscopic gastrostomy (PEG) placement is being considered.

Initially, no activity restriction is necessary. However, patients should not overexert themselves to the point of fatigue or pain. Patients should maintain a regular exercise regimen if their degree of weakness allows. Patients need to realize that their muscle reserve will diminish before overt sustained weakness will appear, and in most cases they should avoid endurance exercises (repetitions).

The chief goals of activity are maintenance of range of motion of all joints, prevention of painful contractures, and maintenance of tone and strength of muscles not yet or minimally affected by the disease.

As the disease progresses, patients may become unstable and at risk of falls and may need to be counseled to use assistive devices or not transfer without appropriate support. If they reach a point when they cannot manage a vehicle safely, including in emergencies, they need to be counseled to stop driving. Some states require mandatory reporting by practitioners.

Smoking is the only established risk factor for ALS.^{[31, 33]} Smoking avoidance may result in a decrease in the age-specific incidence of ALS. However, if more patients at risk for developing the disease survive to each age bracket due to reduced mortality from other smoking-related diseases, such as cancer, cardiovascular diseases, and stroke, this presumptive benefit of smoking cessation may not be realized fully. As the population survives to older ages (in which age-specific incidence of ALS is higher), the crude incidence of ALS may increase.

Individuals with a gene for familial ALS may benefit from genetic counseling if they wish to minimize the risk of transmitting the gene to the next generation.

Support groups are available to patients in many communities. Burnout of the primary caregiver needs to be anticipated and avoided by assuring that the primary caregiver is not the only caregiver.

Patients with ALS may wish to help with the search for treatments for the disease through participation in clinical trials. They should be encouraged to focus on trials that have been listed with the ALS Association and with ClinicalTrials.gov, a registry of federally and privately supported clinical trials conducted in the United States and around the world.

Patients often request prescription of available pharmaceuticals for off-label use in the hope of slowing disease progression. Since all such pharmaceuticals, so far, have either made patients worse when tested in double-blinded placebo-controlled studies or have had no benefit, this practice cannot be recommended.

Patients are eligible for Social Security and Medicare benefits once they are diagnosed with ALS, without the waiting period required of other patients with chronic diseases. Patients should be advised to apply early.

Since September 2008, ALS has been considered a service-connected condition for US Veterans, and they are eligible for care and benefits.^[111] Eligible patients should be advised to apply early. Volunteers from local branches of veterans’ organizations may be able to assist in preparing the application and moving it rapidly through the approval process.

End-of-life issues may be discussed and clarified early. However, this may not work well for some patients. The physician should be aware of the individual state laws that regulate these issues, encourage, if appropriate for the patient, completion of advance directives, and document the patient’s preferences in the medical records, whether or not formal advance directives have been written.

For patients with limited access to home-based resources, social service professionals may be able to assist with placement. Local branches of advocacy organizations (ALSA and MDA) may be excellent resources to inform patients of what is available to them locally.

Patients will have decreasing ability to sign documents or to mobilize themselves for taking care of personal affairs. Some may benefit from legal advice. The earlier they do so the better, but they may need to recover from the initial shock of the diagnosis.

All patients will become at risk for falls as the disease progresses: they should be informed and cautioned gently. Most patients tend to sustain several falls before they relinquish the independent activities that led to the falls.

All patients will become unable to drive as their disease progresses. They need to be alerted when this draws close. Most are gracious about quitting before their driving results in injury. Some states require mandatory reporting by practitioners to the Department of Motor Vehicle Affairs.

Informing the patient

The American Academy of Neurology 1999 Practice Parameter^[96] provided the following suggestions for breaking the news of a diagnosis of ALS to a patient, based on a review of the literature in other diseases available at the time:

• Give the diagnosis to the patient and discuss its implications; respect the cultural and social background of the patient in the communication process by asking whether the patient wishes to receive information or prefers that the information be communicated to a family member
• Always give the diagnosis in person, never by telephone
• Provide printed materials about the disease and contact information for advocacy associations. Providing a written summary or audiotape summarizing what has been discussed was suggested, but this author believes this option needs to be exercised primarily in the absence of adequate printed material
• Avoid withholding the diagnosis, providing insufficient information, delivering information callously, or taking away or failing to provide hope

The 2009 AAN update^[104] made reference to SPIKES, A 6-step protocol for delivering bad news to patients with cancer.^[112] The following is summarized from Appendix e-1^[104] :

• S etting - Establish the appropriate setting
• P erception - Determine the needs and the perception of the patient
• I nvitation - Request an invitation to give the news
• K nowledge - Provide knowledge (information) to the patient
• E  xplore/ E mphathic - Explore the patient’s feelings with empathic responses
• S  ummarize/ S trategy - Summarize and form a strategy with the patient with which to go forward

This author concurs with these suggestions, and wishes to add the following suggestions, based on his experience:

• It is important that relevant family members be present when the patient is informed about the diagnosis (1) so that the patient is not the one who needs to inform them and answer their questions, (2) so that they can support the patient, and (3) so that the neurologist can inform and support them directly.
• It is very helpful to schedule an early follow-up visit to answer questions that will arise and inform/update family members who were not present.
• Many patients and families will not remember most of what they are told when they hear the diagnosis for the first time, as they will be in shock. The shock may be a little less if they have anticipated the bad news, but it cannot be avoided completely. The greater the perceived shock, the more the focus should be on support and next steps, including the follow-up visit.
• Patient and family may want to tarry a while after the visit. It is helpful to have a nonphysician staff member to be there to support them and to reinforce the immediate next steps.
• Doing this well requires time, motivation, adequate staff, and preparation.

Consultants are best used within the multidisciplinary model based on patients’ preferences and need to complement the range of services that the patients’ primary care providers and primary neurologists or physiatrists can provide directly.

Physical and occupational therapists help the patient adapt to loss of function, provide exercises to maximize existing function and ameliorate spasticity, identify safety concerns and advise how to address them, and help patients select and learn to use assistive devices, including, as the disease advances, a customized wheelchair.

A speech therapist can advise on adaptation to swallowing difficulties, and, as speech fails, on use of communication devices.

A respiratory therapist can assist with learning to use noninvasive ventilation support and, if needed, advise on secretion management, suctioning equipment, and selection of a cough assistive device.

A dietician or nutritionist evaluates caloric intake and advises how to optimize it, particularly if intake is declining. They may be able to provide guidance regarding nutritional supplementation.

A pulmonologist, if needed, assesses for tracheostomy and manages the ventilator, tracheostomy, and complications (such as infections) if this treatment is selected.

A gastroenterologist or general surgeon advises and performs PEG placement and advises on its care and maintenance.

Visiting nurses assess patients’ in-home needs and help quantify the need for and time the introduction of personal care assistants (home health care aides) and other home-based therapies.

Hospice service provides the framework for in-home end-of-life care, or helps with alternative arrangements.

Spiritual (religious) services, if elected by patients, usually connect with the resource of their choice.

Alternative therapies (frequently elected by patients), if not unsafe or exorbitantly priced, may be a reasonable approach to giving patients a sense of some control, may confer on them a feeling of calm, and thus be of benefit, in subjective terms. Since most, if not all, alternative therapies have not been tested against placebo controls, physicians cannot provide blanket recommendations but may be able to be supportive, if circumstances permit, of specific patient choices.

When alternative therapies impose a great burden on patients, in terms of cost or time commitment, they should be avoided. Since 2009, the ALS Untangled group of investigators, who are members of the North American ALS Research Group or the WFN ALS Research Group has evaluated several claims of efficacy of specific alternative therapies (to slow the course of ALS) and shown them to lack adequate foundation.

While many patients and families might benefit from referral to a psychiatrist, psychologist, or counselor, patients may be most likely to use these resources if they had already done so prior to disease onset, or if they have these options offered within the multidisciplinary model of care.

Early in the treatment course of ALS, encourage patients to continue routine activities.

Patients are best cared for in a designated ALS center. Many mechanical aids can help overcome disabilities.

Patients' length of survival and quality of life are enhanced by night-time breathing assistance early in the course of the disease and by aggressive application of alternate feeding options to ensure good nutrition once swallowing becomes difficult.^[113]

The 2009 American Academy of Neurology practice parameter guidelines reviewed available evidence to help neurologists maximize the care and quality of life of patients with ALS.^{[104, 105]} The recommendations are summarized below:

• Riluzole should be offered to all patients with ALS to slow disease progression
• Enteral nutrition via percutaneous endoscopic gastrostomy (PEG) should be considered to stabilize body weight in patients with impaired oral intake
• PEG placement when forced vital capacity (FVC) is still >50% predicted minimizes risk of insertion
• PEG placement probably prolongs survival to some degree
• Noninvasive ventilation (NIV) should be offered to treat respiratory insufficiency to prolong survival and slow the decline of FVC
• NIV may be considered at the earliest sign of nocturnal hypoventilation or respiratory insufficiency
• Mechanical insufflations/exsufflation may be considered to clear secretions in patients with reduced peak cough flow, particularly during an acute lower respiratory infection
• Creatine and high-dose vitamin E should not be used