The Clinical Management of Amyotrophic Lateral Sclerosis

March 1, 2007

Amyotrophic lateral sclerosis (ALS) is a progressive, debilitating, fatal disease that involves degeneration of upper and lower motor neurons. Patients often initially present with limb or bulbar weakness, atrophy, and spasticity, followed by progressive loss of ambulation and, ultimately, respiratory failure, which is the most common cause of death.

Amyotrophic lateral sclerosis (ALS) is a progressive, debilitating, fatal disease that involves degeneration of upper and lowermotor neurons. Patients often initially present with limb or bulbar weakness, atrophy, and spasticity, followed by progressive loss of ambulation and, ultimately, respiratory failure, which is the most common cause of death.

Despite numerous investigations into the pathogenesis of ALS, the mechanism for neuron loss is not known, and drug therapies have yet to prolong life expectancy for more than a few months.1 Treatment is largely supportive and symptomatic. Evidence-based guidelines have been generated to address the multidisciplinary approach to treatment. Points reviewed here include the following:

1. How to convey the diagnosis.
2. Symptomatic treatment.
3. Management of nutritional needs and use of enteral feeding.
4. Management of respiratory weakness and use of artificial ventilation.
5. End-of-life planning.

DELIVERING THE DIAGNOSIS
Informing a patient of a terminal diagnosis is a difficult task. Information should be delivered in a way that considers the anxiety faced by the patient and that communicates the physician's commitment to continued patient care, with particular attention to amelioration of distressing symptoms that develop in the course of ALS. Some hope of preserving quality of life (QOL) should be offered without providing false hope. In many cases, patients have already been told that ALS is a possibility and might suspect the diagnosis.

When the diagnosis is electromyographically confirmed and testing has ruled out other possible causes for signs and symptoms, it is important for the physician caring for the patient to deliver the diagnosis. It should always be performed in a face-to-face interview and never by telephone. The physician should clearly state that the diagnosis is ALS-or Lou Gehrig disease-without referring to similar terms (such as anterior horn cell disease or motor neuron disease) that may have no meaning for medically untrained patients.

Patients should be told that there is no definitive cure for ALS and that there are no treatments that significantly alter its clinical course. A specific time frame for life expectancy should be avoided because life expectancy is very difficult to predict in any given patient.2,3 A rough estimate can be made if the patient or family insists on it in regard to long-term planning.

Ideally, the SPIKES (setting, perception, invitation, knowledge, exploration, and strategy or summary) criteria should be fulfilled.4,5 This requires a private place and setting aside sufficient time for questions and explanations and for providing information about appropriate resources. Patients often report that physicians do not allow enough time for discussion and do not provide adequate information about the disease or about resources such as specialty clinics and organizations such as the Amyotrophic Lateral Sclerosis Association (ALSA) and the Muscular Dystrophy Association (MDA). Physicians spending less than 20 minutes with patients were consistently rated poorly in their ability to deliver bad news.2

Patients also should be made aware of clinical trials of treatments for ALS. Many patients appreciate the opportunity to potentially benefit from these treatments and are grateful to participate in research that may help others with ALS.

A follow-up soon after the delivery of the diagnosis should be arranged during which other important aspects of ALS care should be discussed. The patient should be informed that decisions about the use of feeding tubes and invasive ventilation and about code status will need to be made in the future and that caregivers and family members should participate in such decision making. It is usually preferable (unless clinical circumstances dictate that immediate decisions be made) to avoid in-depth discussions about ventilation and feeding options at the time of diagnosis. The physician should encourage the patient to provide updates about symptoms and should regularly follow up with patients to address new symptoms and to remind patients that many of the symptoms can be managed.

PHARMACOTHERAPY
Riluzole (Rilutek), a glutamate antagonist, is currently the only medication approved by the FDA for the treatment of ALS. Clinical studies demonstrated a modest improvement in life expectancy in those patients taking the drug for 18 months.6 Riluzole appears to be most helpful when administered early in the disease course.1 Riluzole can cause a transitory rise in liver transaminase levels and, rarely, neutropenia.7 Although there is much debate on the cost-effectiveness and efficacy of riluzole, most physicians prescribe it for patients with ALS, and approximately 70% of these patients take it.

Patients with ALS often ask questions about experimental therapies. More than 30 clinical studies sponsored by the NIH are now enrolling patients with ALS. Six of these studies are for new disease-modifying therapies. Patients often seek out ALS centers to participate in research studies. Web sites such as that of the ALSA (www.alsa.org) and www.clinicaltrials.gov are helpful to patients because they provide descriptions, locations, and contact numbers of study centers. Many centers, however, will not enroll patients living at a great distance because of the inherent difficulties in managing complications that may arise.

Many patients have either tried or read about alternative or experimental therapies.8 Bone marrow transplantations for patients with ALS are offered at sites outside the United States. Nutritional supplements and colonic cleansing and detoxification programs are publicized widely on the Internet. Many of these programs have little or no literature to support their effectiveness and safety. The costs of these regimens can be prohibitive-some cost more than $10,000 per treatment.

Discussing alternative and experimental treatments with patients and pointing out the lack of scientific evidence supporting them helps patients avoid dangerous treatments and causes them to give more thought to whether they should spend large sums of money on such endeavors.

It is important not to be dismissive of all treatments; alienation of the patient will negatively impact the doctor-patient relationship, and the patient will be less likely to speak about the alternative regimens he or she may be using.9

SYMPTOM MANAGEMENT
Patients with ALS experience a broad range of symptoms. Patients commonly have physical therapy needs and require interventions for spasticity, sialorrhea, pseudobulbar affect (PBA), slurred speech, fatigue and sleep disorders, and depression (and possibly suicidality). At diagnosis, many patients may not require specific symptomatic treatment, but nearly all benefit from an evaluation with physical, occupational, and speech therapists early in the illness.

Depending on the specific limitations of a patient, physical, occupational, and speech therapies can help maximize function and independence. Devices that aid gait and activities of daily living (ADL) can be recommended, and guidance about swallowing techniques can be provided as well as assistive technology for speech impairment and communication needs.

Spasticity. Spasticity is a common complaint in ALS. Upper motor neuron signs are a prerequisite to making the diagnosis, and many patients have spasticity as their predominant complaint. A few controlled studies have reported on effective treatments for spasticity, specifically in ALS.10,11 The most commonly used medications include baclofen, tizanidine, and occasionally diazepam.9,12 Adverse effects may make implantable baclofen pumps a better option than oral medications. As in other disorders, botulinum toxin type A or B (Botox and Myobloc, respectively) can be helpful for focal areas of spasticity causing pain or difficulty with ADL.13,14 The wearing of splints at night is often helpful for preventing contractures.

Sialorrhea. Sialorrhea in ALS is a result of weakness of the oropharyngeal musculature and ineffective clearance of secretions. Saliva production is actually decreased in patients with ALS. Drooling is associated with significant anxiety and social embarrassment, but several treatments are available.

Most pharmacological treatments reduce saliva production by augmenting anticholinergic effects. Examples are tricyclic antidepressants (eg, amitriptyline, nortriptyline), glycopyrrolate (Robinul), trihexyphenidyl, benztropine, transdermal scopolamine (Transderm Scop Transdermal Therapeutic System), and atropine. Few controlled studies have evaluated these medications, but in uncontrolled studies and clinical experience, they are often effective.3,12

Thick mucus secretions arise from sites other than the salivary glands because nasal and pulmonary secretions that are not swallowed remain in the oral cavity. These may respond to b-adrenergic antagonists such as propanolol or to increased hydration.15 Other treatments for sialorrhea include suction devices, cough-assist devices, botulinum toxin A injections, and external beam irradiation to the parotid glands.

Botulinum toxin A injections have been shown to qualitatively decrease sialorrhea and improve QOL.16,17 Effects may last from 2 to 5 months. Anticipated adverse effects include worsening of dysarthria and dysphagia, but these symptoms were not observed in the studies showing improved QOL.16,17 As for radiation to the parotid gland, one study showed benefit using a single dose of 7 to 8 Gy bilaterally.18

PBA. PBA, a condition in which patients have a pathological inability to control laughter or crying, can be a debilitating symptom of ALS. Physicians often must ask about this problem because patients and families often fail to recognize it as a medical symptom that can be treated. Amitriptyline and selective serotonin reuptake inhibitors have been shown to have some effectiveness in treating PBA in patients with multiple sclerosis and stroke.19-21 More recently, the combination of dextromethorphan 30 mg/quinidine sulfate 30 mg twice daily has been shown to be effective in relieving these symptoms.22

Slurred speech. Communication is a problem for many patients with ALS because of bulbar weakness. The mixture of flaccid and spastic dysarthria is almost pathognomonic for ALS. Multiple devices can be used to augment communication.23-25 Occasionally, sur- gical procedures such as palatal lift and palatal augmentation prostheses can improve dysarthria and intelligibility for prolonged periods.26

Addressing communication challenges early is important because effective preventive and rehabilitative training takes time and patients' needs change as the disease progresses. Lack of communication is cited by many patients as a significant concern, and it is frequently associated with depression.27 Physicians are encouraged to refer patients to a speech therapist or to recommend assistive technology early in the course of the disease. Many national groups such as the MDA and ALSA can assist patients in obtaining otherwise expensive communication devices.

Fatigue. Fatigue in ALS may mimic depression but has been shown to reflect general and physical fatigue, rather than mental fatigue.28 Treatment with amantadine or modafinil (Provigil) may be helpful in relieving fatigue and in improving sleep.

Depression. Depression in ALS is associated with bulbar symptoms and respiratory difficulty.27,29,30 Prevalence ranges from "notable absence"31 to 26%29,32 depending on the definition or the psychological symptom inventory used. Depression was shown to be most common soon after diagnosis, without increasing as the disease progressed.29,32

Treatment of depression in ALS should first address the contributing circumstances-particularly the perceived quality of social support33-and impact of caregiver burden. Support groups, hospice and respite care, and counseling play important roles in treatment, in addition to standard pharmacological treatment. Tricyclic antidepressants are often used for their duel effect of also addressing sialorrhea and improving sleep.12

Suicidality. The wish to die is present in some patients with ALS. In one study, 12% of hospice-eligible patients with ALS expressed a wish to end their lives.34 These patients tended to be older and male and lived alone. There was less use of percutaneous endoscopic gastrostomy (PEG) tube placement and noninvasive positive pressure ventilation (NIPPV). Nearly all had contemplated suicide, and 30% appeared to hasten their deaths. These patients reported more insomnia, discomfort, and unacceptability with their level of disability. In contrast, patients who chose long-term mechanical ventilation (LTMV) had less depression, and many retained optimism as LTMV continued.35

NUTRITION
The majority of patients with ALS are affected by dysphagia at some time during the disease course.36 Even when able to eat normally, many patients have evidence of altered food bolus transport and bolus stasis in the pharynx.37

Dysphagia is often recognized at the same time as other bulbar symptoms, such as dysarthria and tongue fasciculations, and it progresses at a variable pace. Patients will often present with symptoms of coughing, choking, and chewing fatigue during meals. Typical testing for dysphagia includes bedside swallowing evaluation, video fluoroscopy, and fiberoptic endoscopic evaluation of swallowing.

Treatment of dysphagia initially can be achieved by instructing patients in the chin tuck maneuver and by changing food consistency.9,38 Most patients eventually require enteral feeding, which can be performed safely using a PEG tube or percutaneous radiological gastrostomy (PRG).39-51

Critical issues in decisions about enteral feeding include the patient's religious and cultural beliefs, degree of malnutrition, and the patient's respiratory status. PEG tube placement is safer when performed before forced vital capacity (FVC) falls below 50% of predicted.3 A PRG tube may be placed safely at this time, or noninvasive ventilation may be used to aid PEG tube placement when FVC is below 50%.42-44

It is important to stress to patients that enteral feeding does not significantly prolong survival.45,52 Enteral feeding is important, however, in treating malnutrition, which negatively impacts survival in ALS.47 There is an ongoing discussion on whether ALS causes a hyperbolic state, which predisposes patients to malnutrition, or whether early dysphagia and other complications of ALS prevent patients from receiving adequate calories.48-50 Current guidelines promote enteral feeding by PEG or other means and frequent reassessment of caloric needs to maintain weight (Table 1).3,38

 Table 1 - Nutritional maintenance
Nutritional status 
At each visit: 
Measure weight and body mass index 
Indications for PEG 
Weight loss 
Other tools for nutritional maintenance 
Calorie supplements 
PEG, percutaneous enteral gastrostomy; FVC, forced vital capacity.

RESPIRATORY SUPPORT
Respiratory muscle weakness and subsequent respiratory failure are the most common problems that limit life expectancy in patients with ALS. It is critical to address options about ventilator support early in the course of the disease and to allow the patient time to reflect on the implications and make informed decisions well before the clinical need for the intervention arises. Respiratory failure in a patient with ALS who has not decided whether he wants mechanical ventilation can be challenging for the patient, family, and physician.

Although patients with ALS (fewer than 10%) can present in respiratory failure, most will have some abnormal pulmonary function at the time of diagnosis. Typical findings include decreased vital capacity, but in one study, few- er than one quarter of those with abnormal pulmonary function test (PFT) results had respiratory symptoms.51 As the disease progresses, patients typically have a linear decrease in vital capacity and negative inspiratory force, until respiratory failure develops.51,52

FVC is a parameter often used to evaluate the progression of respiratory weakness; values of less than 50% of predicted indicate poor prognosis-typically less than 6 months' survival.53,54 Sniff nasal inspiratory force, which has the advantage of being independent of bulbar weakness, may have better sensitivity in identifying patients with less than 6 months' survival; however, this is not commonly performed in the United States.55 The recommended practice is to evaluate with PFTs at diagnosis and every 3 months, with repeated neurological examinations as well.52,56

Respiratory symptoms include dyspnea, orthopnea, subjective feelings of suffocation, nocturnal or daytime cough, morning headache, and daytime sleepiness and fatigue, the last being a result of sleep apnea or hypopnea and carbon dioxide retention. Even when none of these symptoms is present, patients with ALS may experience nocturnal hypoventilation as a result of respiratory weakness or bulbar weakness causing upper airway obstruction.

In addition to PFTs, nocturnal pulse oximetry or polysomnography are useful tests for evaluating the possibility of nocturnal hypopnea.3,52 Even when tests fail to show a specific threshold of weakness, NIPPV is recommended for the treatment of these respiratory symptoms. In the absence of these symptoms, when respiratory surveillance demonstrates a decline in FVC of less than 50%, PaCO2 of greater than 45 mm Hg, or nocturnal desaturations of less than 88% sustained over 5 minutes, NIPPV should be started (Table 2).57

 Table 2 - Managing respiratory weakness
After diagnosis: 
Schedule pulmonary function tests every 3 months 
As respiratory capacity decreases: 
Discuss options and direct advance planning for NIPPV, code status, and LTMV 
Indications for NIPPV 
FVC < 50% 
Management of persistent symptoms after NIPPV 
Mechanical insufflation/exsufflation 
NIPPV, noninvasive positive pressure ventilation; LTMV, long-term mechanical ventilation; FVC, forced vital capacity; SpO

NIPPV is most commonly delivered through an oral or nasal mask with bi-level positive pressure. This can be used nocturnally, as needed during the day, or nearly continuously. Some patients with ALS-particularly those with advanced bulbar weakness-cannot tolerate masks58; however, recent studies have shown that tolerance of NIPPV predicts improved survival-to a median 10 to 12 months.59,60 NIPPV also improves QOL after 1 month of use, which is maintained for more than 1 year.61,62

Other methods of augmenting respiratory function include chest percussion, manual cough assist, and a mechanical insufflator/exsufflator (MIE). The MIE works with a mouthpiece that provides abrupt decrements in expiratory pressure, mimicking a cough. This technique may be useful in patients-including those who cannot voluntarily cough-to generate clinically effective cough flow rates,63 improving secretion clearance. High-frequency chest wall oscillation, which uses a vest with inflated sections that pulsate at frequencies of 5 to 20 Hz, may slow the decline of FVC.64-66

When other options for noninvasive pulmonary assistance fail, the last remaining treatment for patients in impending respiratory failure is LTMV through tracheotomy. Patients seldom choose this option; however, those who do tend to be younger and to have young children, increased income, increased education, and increased optimism.35

If a patient chooses LTMV, it should be undertaken when pulmonary symptoms are declining with upcoming respiratory failure. Waiting for actual respiratory failure adds unnecessary morbidity and risk of complication to the transition. Nonetheless, many patients do not decide to undertake LTMV until a respiratory emergency occurs.52

Patients can sometimes live nearly 3 years after starting LTMV, although many experience severe progressive systemic weakness mimicking a locked-in state. Despite this, the large majority of patients were glad that they chose this care option, and it has been noted that depression is remarkably absent in this group.35

LTMV requires 24-hour supervision and care, which can be provided at a skilled nursing facility or at home. Patients with LTMV who live at home require at least 2 full-time caregivers so that one may be with the patient at all times to address any problems that develop with the ventilator and other technical needs.

END-OF-LIFE CARE
ALS has heightened public awareness and increased public policy debates about end-of-life issues more than most other terminal illnesses. Physician-assisted suicide is practiced in ALS more than in other terminal illnesses in Oregon, where the procedure is legal,67 and in a 60 Minutes broadcast on November 24, 1998, millions of persons observed Jack Kevorkian, MD, euthanize a patient with ALS. In the Netherlands, 35% of patients with ALS plan to die by euthanasia and another 4% by physician-assisted suicide.68

Many physicians are uncertain about their legal and ethical duties regarding end-of-life issues.69 An important component of ALS care is discussion of end-of-life issues such as code status and advance directives about respiratory and feeding decisions. Because patients are often reluctant to consider these issues, it is important that the physician or nurse caring for the patient proactively address them. It is also important for physicians to discuss their ethical and legal obligations to the patient in regard to end-of-life care.

A living will, durable power of attorney, and other documents are needed to dictate patients' wishes about care to be received or withheld.70,71 Because advance directives do not ensure appropriate care, it is important that the patient discuss the directives with the physician and family.13,14,72,73 The article "Empowering the individual with ALS at the end-of-life: disease-specific advance care planning" by Benditt and colleagues,70 which appeared in the December 2001 issue of Muscle & Nerve, includes an ALS-specific directive that patients may find useful.

Home care is often inadequate and results in a large burden on caregivers.74 In contrast, hospice services often allow patients to die in their own homes with less suffering.75,76 Hospice care has been shown to be helpful in reducing symptoms of pain, sialorrhea, and dyspnea.77 Its use should be discussed early with patients.78,79

Significant symptoms in terminal phases of ALS include choking, breathing difficulties, pain, and fear.76,80 Pain in particular-which despite popular misconceptions is common and can be severe at any stage of ALS-is most often described in the last month of life, with prevalence ranging from 34% to 88%.81-83 Pain can be managed with narcotic and nonnarcotic analgesics. Stretching and range of motion exercises are also helpful both in prevention and treatment of pain.3

Notably, most caregivers report that patients with ALS die with dignity and in a peaceful manner.

CONCLUSION
Although curative treatments are not yet an option in the care of patients with ALS, management of symptoms and complications improves QOL. A multidisciplinary approach involving respiratory, physical, and occupational therapists; social workers; and counselors is helpful in the care of these patients. A proactive approach to discussing and planning for future disease progression is helpful in avoiding unnecessary complications, maximizing QOL, and providing patients with a sense of control.

Acknowledgment
The authors wish to thank Peter Donofrio, MD, director of the Vanderbilt ALS Clinic and MDA Clinic and division chief of Neuromuscular Disorders at Vanderbilt University in Nashville, Tennessee, for his helpful editorial comments on the manuscript.

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CHRISTOPHER LEE, MD, is a residentand AMANDA C. PELTIER, MD, MS, isassistant professor of neurology, Departmentof Neurology, Vanderbilt University MedicalCenter, Nashville, Tennessee.