Amyotrophic Lateral Sclerosis Treatment & Management

Updated: Jun 14, 2018
  • Author: Carmel Armon, MD, MSc, MHS; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Treatment

Approach Considerations

Treatment of amyotrophic lateral sclerosis (ALS) may be divided broadly into the following [19, 173, 174] :

  • Patient education

  • Mechanism-specific treatment

  • Adaptive or supportive treatment

Patient education can be enhanced by referral to multidisciplinary clinics staffed by specialists with special interest in ALS, by educational materials prepared for patients and families by national organizations in the United States [175, 176] and other countries or by individual experts, [19] and by patient participation in local support groups.

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Inpatient and Outpatient Care

Outpatient care

Most of the care of patients with ALS may be delivered in the outpatient setting. Often, guidance can be provided by a neurologist, physiatrist, or palliative care physician with special interest in the disease.

Multidisciplinary clinics can provide "one-stop shopping", allowing patients to receive all assessments and recommendations in the course of a single visit; most of these clinics provide a combination of on-site and off-site services. In the United States, Muscular Dystrophy Association/ALS centers and ALS Association certified centers have been established at several major medical centers, and in the United Kingdom, the Motor Neurone Disease Association has a network of 18 accredited Motor Neuron Disease Care and Research Centres.

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 of inadequate patient volume or, in some cases, insufficient philanthropic support. Some patients find full-day assessments exhausting; for them, more frequent, but shorter, visits are more acceptable.

In other models of care, the multidisciplinary team works in the community and visits the patient at home or care is provided through a local hospice team. Primary care providers have an important role and in some settings may be able to coordinate all of the care for a patient with ALS.

Inpatient care

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

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Pharmacologic Treatment

Riluzole

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 who have had the disease for less than 5 years and who have a forced vital capacity (FVC) of greater than 60%. [177]

Studies

This conclusion is based on 2 double-blinded, randomized, placebo-controlled clinical trials. [33, 34] A third clinical trial, in patients who were ineligible to participate in the second pivotal clinical trial, did not show efficacy, possibly due to low power (small number of patients included relative to the magnitude of the possible effect). [34, 178] A fourth clinical trial, conducted in Japan, did not show efficacy; details of the study’s results have not been published in the English literature. [179, 180]

A Cochrane review that pooled data from the first 3 clinical trials reported that the addition of data from the third trial, which included patients who were older and more seriously affected, reduced the overall treatment effect seen in the first 2 trials. [177] Nevertheless, evidence of benefit from riluzole remained statistically significant.

Subsequent reports have claimed greater efficacy for riluzole in clinical practice than in the clinical trial. However, the relevance of these claims has been challenged [181] because the reports pit class IV evidence against class I evidence, which is contrary to the usual evidence-based approach used to judge treatment efficacy.

Prognosis

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

Adverse effects

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

Cases of interstitial lung disease, some of them severe, have been reported in patients treated with riluzole; many of these cases have proved to be 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.

Aminotransferase

Some patients on riluzole develop abnormal liver function test results or neutropenia. Serum levels of aminotransferases, including alanine aminotransferase (ALT), should be measured before and during riluzole therapy, with ALT levels being 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 reach 5 times the upper limit of normal or higher or if clinical jaundice develops.

Edaravone

In May 2017, the pyrazolone free radical scavenger, edaravone (Radicava), was approved to slow the functional decline in patients with ALS. Although the precise mechanism by which edaravone works in ALS is unknown, it may lessen the effects of oxidative stress, which is thought to be a probable factor in ALS onset and progression.

FDA approval of edaravone was based on the pivotal Phase 3 study (MCI186-19), which evaluated 137 people with ALS. Data demonstrated patients who received edaravone for 6 months experienced significantly less decline in physical function (33% reduction or 2.49 ALSFRS-R points; p=0.001). [182]

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American Academy of Neurology Guideline

In October 2009, the American Academy of Neurology (AAN) published a 2-part, evidence-based Practice Parameter update about the care of patients with ALS. [2, 3] These publications updated the 1999 evidence-based practice parameter. [173]

NIV, PEG, and riluzole

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. [183]

Multidisciplinary care

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

Botulinum toxin

In patients with sialorrhea that is refractory to treatment with standard medications, botulinum toxin B injection of the salivary glands should be considered. Alternatively, low-dose radiation therapy to the salivary glands may be considered.

Botulinum toxin for ALS carries a manufacturer's warning regarding possible spread of the toxin to ventilatory muscles (leading to exacerbation of ventilatory failure) or bulbar muscles (exacerbating their weakness). The risk of these adverse effects tilts the balance in terms of safety toward salivary gland irradiation, except in patients with exceptional ventilatory and bulbar reserves.

Dextromethorphan and quinidine

Finally, the guideline recommends that dextromethorphan and quinidine be considered for pseudobulbar affect. A combination of these 2 agents (Nuedexta) is approved by the FDA for this indication.

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

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Treatment of Symptoms

Limb stiffness

Limb stiffness can be treated with the antispasticity agents baclofen (Lioresal) and tizanidine (Zanaflex). Baclofen can be started at 10 mg/day and titrated up to 10 mg 3 times per day. If adequate efficacy is not attained at a lower dose, baclofen can be titrated to double that dose, if tolerated. Tizanidine can be started at 1 mg 3 times daily and titrated upward, if tolerated, to as high as 8 mg 3 times daily.

The chief risks of both of these agents are that they induce drowsiness in some patients and that relief of spasticity may result in unpredictable loss of tone and falls. Starting at a low dose permits determination of the patient’s tolerance of the medication, before titration to an effective dose.

Intrathecal baclofen may be considered in slowly progressive, upper motor neuron (UMN) ̶ predominant patients with ALS or in patients with primary lateral sclerosis (PLS), who do not respond adequately to oral treatments.

Sialorrhea

Antisialorrhea treatments include the following:

  • Anticholinergics

  • Sympathomimetics

  • Botulinum toxin type B (potentially hazardous)

  • Salivary gland irradiation

Anticholinergics such as amitriptyline (25-50 mg at bedtime) and trihexyphenidyl (Artane; 0.5-2 mg as needed) 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 120-240 mg/day of the extended-release formulations may be used.

The efficacy of injections of botulinum toxin type B (2500 U) into the salivary glands has been reported in a small, double-blinded, placebo-controlled trial [184] , but there is a concern that the toxin could spread to bulbar or respiratory muscles, and there is a manufacturer’s warning to that effect. Salivary gland irradiation (7.5 Gy) was found to effective in a case series with a standardized outcome measure [185] and does not carry the same risk as botulinum toxin.

Thickened secretions

Mucolytics such as guaifenesin may be used to thin thickened secretions, although removal of secretions may require mechanical suction devices. Adequate hydration and humidification of room air may prove helpful and are recommended.

Depression and anxiety

For treatment of depression, selective serotonin reuptake inhibitors (SSRIs), such as citalopram 10-40 mg/day, work best. If the desired benefit is not achieved with one agent in this class, another may be tried.

For anxiety, lorazepam is commonly used (0.5-1 mg prn). Careful titration is required, as benzodiazepines have the potential to cause respiratory depression.

Pain

Pain may occur in patients with ALS as a secondary consequence of immobility, loss of muscle protection of joints, loss of muscle and fat padding of bony prominences, and overexerted muscles. Nonpharmacologic measures to protect bony prominences (cushions and appropriate bed padding) and support overexerted muscles (neck support, trunk support) should be pursued. Range-of-motion exercises should be employed to prevent frozen shoulders.

If pain develops, its causes need to be assessed and appropriate treatment initiated. Often, nonsteroidal anti-inflammatory drugs (NSAIDs) suffice. If needed, they should be prescribed on a regular schedule.

If stronger analgesics are required, tramadol (Ultram), ketorolac (Toradol), morphine (immediate or extended release), or a fentanyl patch may be considered. (Respiratory depression may occur with opiates.) Careful titration, starting with low doses, is needed. Patients must be assured that they will not be in pain as a result of the disease or its secondary consequences.

A combination of dextromethorphan and quinidine (Nuedexta) has shown efficacy in ameliorating involuntary laughter and crying (the expression of pseudobulbar affect). [186, 187] It has FDA approval for this indication.

Cramps

Cramps are difficult to treat. Quinine sulfate was used in the past; the recommended dose for nocturnal cramps was 200-300 or 324 mg at bedtime. However, quinine does not have FDA approval for this indication, its efficacy compared with placebo has not been well established, and there is a concern regarding its potential adverse cardiac effects. Quinine sulfate is contraindicated in patients with a prolonged QT segment, and has many interactions with other drugs. Its clearance is reduced in patients with renal failure.

Other agents that may be tried for treatment of cramps are benzodiazepines, antispasticity agents, and anticonvulsants (eg, gabapentin, carbamazepine, phenytoin). These agents have not been tested for this indication in controlled studies or approved for it, and their efficacy is uncertain.

Incontinence

Urinary urgency may be treated with tolderodine (Detrol). However, the effectiveness of this agent for incontinence may be limited when the incontinence is due to weakening of the muscles of the pelvic floor.

Sleeping problems

When patients complain of sleeping difficulties, the first step is to determine whether these are due to ventilatory failure; this can be accomplished through overnight polysomnography. In some cases the integrity of sleep can be restored just by introducing noninvasive ventilatory support, which usually consists of bilevel positive airway pressure (often with a backup rate). Adjunctive medications may be considered, but the clinician must bear in mind that some drugs may suppress the respiratory drive (hence the need to initiate noninvasive ventilatory support first).

Loss of appetite

Appetite tends to be reduced as ALS progresses. The following reasons have been imputed:

A full stomach makes it harder to breathe

Breakdown of muscle releases amino acids that produce a false sense of satiety

Metabolism of carbohydrates produces CO2, which requires breathing effort to clear

Reduced activity requires less energy intake

Appetite tends to be lost with reduced intake, creating a vicious circle

Nutritional consultation is advised. Frequent small meals, foods rich in fat and protein, and sometimes a feeding gastrostomy are needed. When initiating supplemental feedings in a patient who has not been nourished adequately, attention should be given to ventilatory support, as the patient may be too weak to blow off the extra CO2 or to breathe against a full stomach.

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Ventilatory Support

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 sleep disruption. 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 the following cases:

  • Patients who present with respiratory failure and who are otherwise largely neurologically intact

  • Patients who want to be kept alive using long-term invasive ventilatory support as their disease progresses

  • Patients in whom secretions cannot be managed, and who therefore cannot benefit from noninvasive ventilatory support (this occurs very rarely)

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Dietary Considerations

The patient’s appetite tends to decline as the disease progresses, and his/her ability to swallow may become impaired. Consultations with a dietician or nutritionist and with a speech therapist may be requested to help the patient compensate 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 as a result of swallowing difficulties and who have an FVC of greater than 50% of predicted. A gastrostomy can be placed even in patients with an FVC of less than 50% of predicted, but it requires extra care – usually anesthesiology presence. Consultation with a gastroenterologist or surgeon may be requested if PEG placement is being considered.

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Activity Restriction

Initially, no activity restriction is necessary. Indeed, early in the course of ALS, encourage patients to continue routine activities. 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. They need to realize, however, that their muscle reserve will diminish before overt sustained weakness appears, which means that in most cases they should avoid extreme endurance exercises (repetitions). Patients with slowly progressive disease will be able to tolerate exercise and benefit from it more than patients with rapidly progressive disease.

The chief goals of activity are as follows:

  • Maintenance of range of motion of all joints

  • Prevention of painful contractures

  • Maintenance of tone and strength of muscles not yet or minimally affected by the disease

  • Maintenance or improvement of cardiovascular health, mood, and energy level (this can be accomplished with low-impact exercise)

As the disease progresses, patients may become unstable and at risk of falls and may need to be counseled to use assistive devices or to not transfer without appropriate support. If they reach a point at which they cannot manage a vehicle safely, including in emergencies, they need to be counseled to stop driving or have modifications made to the car so that they are able to drive safely.

In the United States, some states require mandatory reporting by practitioners to the Department of Motor Vehicle Affairs, and some require disabled patients to pass a driving assessment if they have modifications made to their car (eg, hand controls). In the United Kingdom, any medical condition likely to last more than 3 months requires reporting to the Driver and Vehicle Licensing Agency by the patient.

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Alternative Therapies

Many patients with ALS elect to try alternative therapies. If not unsafe or exorbitantly priced, these treatments may be a reasonable approach to giving patients a sense of some control, may confer on them a feeling of calm, and may 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 World Federation of Neurology (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.

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Deterrence and Prevention

Smoking is the only established environmental risk factor for ALS. [54, 56] Smoking avoidance may result in a decrease in the age-specific incidence of the disease. However, this presumptive benefit may be attenuated if lower mortality from other smoking-related diseases (eg, cancer, cardiovascular diseases, stroke) results in more patients surviving to be at risk for ALS in each age bracket. As the population lives 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.

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Informing Patients of the Diagnosis

Doing this properly requires time, motivation, adequate staff, and preparation. The American Academy of Neurology (AAN) 1999 Practice Parameter [173] provided the following suggestions for breaking the news of a diagnosis of ALS to a patient, based on a review of literature pertaining to other diseases:

  • 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, as well as contact information for advocacy associations (providing a written summary or audiotape summarizing what has been discussed was suggested, but this author believes that 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

In this era of readily available information on the Internet, provision of the diagnosis will generate independent activity on the part of patients, families and friends to educate themselves about the disease. Thus, it is helpful if clinicians point patients and the families to those resources that they feel will serve this purpose best, to serve as the starting point (see Patient Education).

The 2009 AAN update to the 1999 practice parameter [2] refers to a 6-step protocol, described by the acronym SPIKES, that was designed for delivering bad news to patients with cancer. [188] The following is summarized from Appendix e-1 [2] :

  • Setting - Establish the appropriate setting

  • Perception - Determine the needs and the perception of the patient

  • Invitation - Request an invitation to give the news

  • Knowledge - Provide knowledge (information) to the patient

  • Explore/Empathic - Explore the patient’s feelings with empathic responses

  • Summarize/Strategy - Summarize and form a strategy with the patient with which to go forward

The SPIKES protocol has several advantages and may be further improved by the following 3 measures. First, it is important that relevant family members be present when the patient is informed about the diagnosis, so that the patient is not the one who has to inform them and answer their questions. They can support the patient, and the neurologist can inform and support them directly.

Second, 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 when the diagnosis was given. 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 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 discussing the next steps, including the follow-up visit.

Third, it is helpful to have a handout summarizing the information presented in the clinic. The handout should provide links to appropriate Web sites, as many patients will want to take an active role in educating themselves with the use of these resources.

The patient and his/her family may want to tarry a while after the visit. It is helpful to have a nonphysician staff member available to support them and to reinforce the immediate next steps.

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Patient Support and Advice

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.

Clinical trials

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, the Muscular Dystrophy Association (MDA), and ClinicalTrials.gov, which is a registry of federally and privately supported clinical trials conducted in the United States and around the world.

Off-label pharmaceuticals

Patients often request prescription of pharmaceuticals for off-label use in the hope of slowing disease progression. Since double-blinded, placebo-controlled studies to date have shown that all such pharmaceuticals either made patients worse or had no benefit, this practice should be avoided.

Government benefits

In the United States, 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. [189] 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 considerations

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 or national 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.

Resource access

For patients with limited access to home-based resources, social service professionals may be able to assist with placement. Local branches of advocacy organizations (the ALS Association of America and the Muscular Dystrophy Association) may be excellent sources of information on what resources are available locally.

Legal affairs

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 should be allowed to recover first from the initial shock of the diagnosis.

Loss of independence

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

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. In the United Kingdom, patients are obliged to inform the Driver and Vehicle Licensing Agency.

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Consultations

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, palliative care physicians, or physiatrists can provide directly. The following consultations may prove helpful:

  • 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 to 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 the 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; advises how to optimize it, particularly if intake is declining; and 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 healthcare aides) and 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

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

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Long-Term Monitoring

Patients are best cared for in a designated ALS center. Many mechanical aids can help them to overcome disabilities. A patient’s 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. [190]

The 2009 AAN practice parameter guideline reviewed available evidence to help maximize the care and quality of life of patients with ALS. [2, 3] The recommendations can be summarized as follows:

  • Riluzole should be offered to all patients with ALS to slow disease progression

  • Enteral nutrition via PEG should be considered to stabilize body weight in patients with impaired oral intake

  • PEG placement when FVC is still greater than 50% predicted minimizes the risk of insertion

  • PEG placement probably prolongs survival to some degree

  • NIV should be offered to treat respiratory insufficiency in order to prolong survival and slow the decline of FVC

  • NIV may be considered at the earliest sign of nocturnal hypoventilation or respiratory insufficiency

  • Mechanical insufflation/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

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