Amyotrophic Lateral Sclerosis

Treatment of amyotrophic lateral sclerosis (ALS) and motor neuron disease (MND) benefits greatly from a team-based approach in which neurologists, pulmonologists, nutritionists, and additional supportive staff collaborate to ensure an integrated care plan. The disease-modifying treatments for ALS provide limited benefit. Nonetheless, pulmonary, symptomatic, and other complementary therapies have significant impact on the survival and quality of life of patients. Here we review the standard of care for patients with ALS/MND and share our experience in implementing a multidisciplinary ALS center.

Characterized by dysfunction and death of corticospinal and spinal motor neurons,¹ ALS has incidence of approximately 2 in 100,000 per person-year. Prevalence in the US is approximately 20,000 per year. The average age of onset is between 55 and 65, and onset characteristics are variable with 70% of people affected having limb onset, 20% with onset in bulbar muscles, and less than 3% with onset in respiratory muscles. Most patients eventually die from respiratory failure or infection within 3 to 5 years of onset.¹

Most ALS treatments are based on expert opinion, but management is becoming more evidence based. The clinical practice parameters that most centers in the US follow were published in 2009, and although there are slight differences internationally, European guidelines roughly mirror the key treatment goals and strategies.^2-4 Although neuroprotective treatments such as riluzole or edaravone have limited benefit, many other aspects of ALS care have comparatively greater impact on survival and quality of life. The standard of care has evolved with multidisciplinary care centers coordinating pulmonary, nutritional, and symptomatic treatments.

ALS Centers and Multidisciplinary Care

There are many benefits to providing ALS care in a multidisciplinary setting. The prognosis is better with survival increasing by as much as 8 months in comparison with care from a general neurologist alone.⁵ By bringing all providers into a single setting, the most critical needs can be identified and acted on earlier. Individuals with limited mobility find travelling to a single clinic in which multiple providers can see them in a single visit can simplify the process of obtaining care. Some have significant commutes to ALS centers and nonneurologic medical problems that require more frequent care coordination. This makes formation of strong bonds with primary care physicians and other local providers essential (Figure). People with ALS also want to participate in clinical research, and having investigative staff in the clinic allows optimal access and coordination. Keeping all providers up to date and active in the care plan ensures critical issues are not missed and treatments are well integrated.

Neuroprotective Treatments

Neuroprotective and symptomatic treatments are summarized in the Table.

Riluzole is safe and provides survival benefit of 2 to 3 months or tracheostomy-free survival of 6 to 7 months.⁶ Riluzole is administered orally and generally well tolerated. Elevated transaminases are a side effect and monthly liver function testing is needed in the first 3 months and quarterly thereafter.

In a phase 3 clinical trial in Japan and South Korea, 137 participants with ALS were given either edaravone or placebo and followed for 24 weeks.⁷ Those treated with edaravone had a 33% reduction in the rate of progression of ALS Functional Rating Scale-Revised (ALSFRS-R) scores. The inclusion criteria were quite restrictive including a relatively homogenous population at a very early disease stage (within 3 years of onset, needing no assistance with activities of daily living [ADLs], and with a functional vital capacity [FVC] more than 80%). Optimism remains for edaravone, although long-term survival data in a heterogeneous group of participants is lacking.

Edaravone is administered as a daily hour-long intravenous infusion of 60 mg for 2 weeks followed by a 2-week rest period initially, followed by daily infusions for 10 days with 2-week rest periods in between. Most participants in both treatment and placebo arms of the landmark trial were also taking riluzole suggesting that individuals who take edaravone may have additional benefit from concurrent riluzole treatment. In clinical practice some people find the time commitment of administering edaravone challenging. Anecdotally, prescribing rates and individual preferences are variable, with some providers waiting for more long-term data and some patients finding the route/frequency of administration too difficult to tolerate.

Symptomatic Treatments

Cramps develop in a majority of people with ALS over the course of the disease. There is no evidence to support a particular treatment for ALS-associated cramps.⁸ Worldwide, quinine is the most commonly used therapy for cramps although in the US use is restricted because of arrythmogenic and hematologic complications. Some of the most widely used medications for the treatment of cramps include the antiseizure drugs gabapentin and levetiracetam, although the evidence to support use is limited. In a multicenter trial in 2018, mexiletine was found effective in reducing the frequency of cramps with favorable side-effect profile.⁹

Management of muscle spasticity can have significant benefit on quality of life, and especially for those with prominent upper motor neuron involvement, it can affect functioning. For example, swallowing, ambulation, and comfort are some of the symptoms that benefit the most. Evidence is predominantly expert opinion as randomized placebo-controlled trial data is limited.¹⁰ Our center has seen benefit with oral baclofen although we monitor individuals using baclofen carefully because as it can worsen muscle weakness and cause sedation. Several observational studies have seen benefit from intrathecal baclofen when oral baclofen has failed. Additional options include tizanidine and benzodiazepines, which can be used in patients who cannot tolerate baclofen.

As many as 75% of people with ALS report pain during their disease course, and nearly 25% feel their pain is inadequately treated.¹¹ Joint immobility, cramps, and pressure sores are just some causes. Often we use conservative treatment with physical therapy, stretching, and proactive management of pressure sores. Opioids are commonly used for pain relief in people with ALS. Although opiates have a side effect of respiratory depression at high doses, at lower doses they may decrease air hunger without much effect on overall lifespan.

Mood changes are widely reported in people with ALS. Anxiety is present in up to 33% of people and depression in up to 75%.¹² Evidence-based treatments for depression or anxiety in people with ALS specifically are lacking, and mood changes are treated with standard treatments including selective serotonin reuptake inhibitors (SSRIs). Tricyclic antidepressants (TCAs) are often also used, although anticholinergic side effects may be unfavorable in those with cognitive issues.

Approximately 25% to 50% of persons with ALS develop pseudobulbar affect, characterized by inappropriate emotionality, including bouts of laughter and crying that are often excessive, uncontrollable, and incongruent to the patient’s experienced emotion.¹³ A combination of quinidine and dextromethorphan is approved by the Food and Drug Administration (FDA) for treating pseudobulbar affect but can prolong the QT interval. increasing risk of cardiac arrhythmia. Monitoring of electrocardiogram (ECG) before initiation and during treatment is required. Alternative treatments include SSRIs or TCAs for those who cannot obtain or tolerate combined quinidine and dextromethorphan.

Approximately 10% to15% of people with ALS show signs of frontotemporal dementia (FTD) with most having the behavioral variant.¹⁴ Although not all patients meet criteria for FTD, only a small percentage of individuals reach the end-stage only of disease free of neuropsychologic impairment. Those with executive dysfunction have a worse prognosis, and behavioral changes negatively affect caregiver quality of life.¹⁵ Routine screening for cognitive dysfunction is recommended, although there are currently no evidence-based guidelines regarding the preferred test or management.³

Adaptive and Assistive Equipment

Many supportive devices are available from any pharmacy, but companies can provide custom fitted devices that many find to be more comfortable. For individuals with neck weakness, progressive neck kyphosis and musculoskeletal pain can significantly impact quality of life. A neck brace is a common and useful aid. Likewise, devices that facilitate dressing, eating, washing, and the use of computers help people independently interact with and manipulate their environments.

Screening for falls or mobility issues should be performed at every visit because the ability to move around the environment safely helps enhance independence and quality of life. In early stages of ALS, simple interventions such as ankle-foot orthoses (AFOs), canes, walkers, and rollators are sufficient. Many individuals eventually require devices such as motorized wheelchairs that are highly customizable with a variety of attachments to enhance functionality and comfort.

As people with ALS develop progressive dysarthria it becomes more challenging for them to explain their needs to caregivers. For those who enjoy writing for leisure or coping, it is an equally important challenge. Patients with intact speech but inability to type or write may use speech-to-text dictation software such as Dragon Dictate (https://www.nuance.com/dragon/dragon-anywhere.html). Alternatively, for those with difficult speech and functional limbs, writing boards or tablet-based text-to-speech apps may be useful. Some text-to-speech apps enable the patient to bank phrases of their own voice, which must be initiated early in the course of disease when the voice is still intelligible. If a person is without the use of limbs or voice, it is still possible for him or her to communicate with eye-gaze software that tracks eye movements to control a cursor and select text or phrases from customized menus.

Nutrition

With each 5% of bodyweight lost, ALS progresses approximately 30% faster.⁶ Conversely, overweight individuals have slower disease progression.¹⁶ The mechanism for this is multifactorial including intrinsic hypermetabolism, increased work of breathing, and inefficient movement/gait patterns. Weight loss is further complicated by poor food intake because of dysphagia, limb weakness, mealtime fatigue, and decreased appetite. Consequences of dysphagia exceed simple caloric deficit, as individuals with ALS are at risk for vitamin deficiencies (eg, thiamine deficiency that causes Wernicke’s encephalopathy).¹⁷

Nutritional interventions include quarterly assessments, behavioral adaptations, and enteral feeding. Bedside and videofluoroscopic assessments by speech therapists are important objective measures to confirm any concerns of subclinical dysphagia. Some noninvasive interventions include nutritional supplements, modification of food and/or liquid consistency, upright eating, and chin tuck maneuvers. Significant weight loss of approximately 10% or more should prompt intervention with enteral nutrition. A recent meta-analysis of 7 studies comparing methods of gastrostomy suggested that overall complication rates were similar but percutaneous endoscopic gastrostomy (PEG) caused less postprocedure pain and radiologically inserted gastrostomy (RIG) had superior success rates.¹⁸ Center and individual preference may help to guide decisions about whether to pursue PEG vs RIG.

The discussion about enteric nutrition should be started as early in the disease course as reasonably possible. Enteral nutrition may actually slow disease progression and improve survival.¹⁹ As respiratory function declines the sedation required for PEG tube insertion becomes more dangerous. Most guidelines support insertion of PEG tube before the decline in FVC is greater than 50%. If this does not occur, patients should be stabilized on noninvasive ventilation (NIV) and then have RIG. Importantly, individual attitudes toward invasive treatments may vary. Some individuals need more time than others to review their care goals with family and caregivers, and some ultimately decide against enteral nutrition.

Respiratory Management

Pulmonary care is the most effective intervention in terms of overall survival, and NIV can prolong survival by an average 7 months and slow the rate of decline in forced expiratory volume (FEV) by approximately 50%.²⁰ Furthermore, NIV may delay or preclude the need for tracheostomy and invasive ventilation.²¹ Symptoms of orthopnea or hypercapnia should be assessed at least every 3 months. Additional objective indicators that should prompt initiation of NIV include FVC less than 50% and maximal inspiratory pressure (MIP) less than −60 cm H₂O. Early in the disease, individuals may not complain of daytime dyspnea but have significant nocturnal hypoventilation, which makes nocturnal oximetry the most sensitive test. Nocturnal oxygen saturation of less than 90% for more than 1 minute is classified as abnormal.^2O

Early intervention, active pulmonologist support, and new technologies are making NIV easier to use. People often find certain types of masks uncomfortable, machines too loud and bulky, or settings intolerable. There are a tremendous number of options, however, for masks, slim-line and portable machines, and remote calibration so most individuals should be able to find comfortable and effective NIV equipment as they work in partnership with pulmonologists. Additional support can be obtained with sip ventilation or mask ventilation during the day. Devices such as ambubag therapy can be used to enhance lung recruitment and limit atelectasis.²² Cough can be enhanced with mechanical insufflation-exufflation (cough-assist) devices or vests that use high-frequency chest wall oscillations to help loosen respiratory secretions.

Secretion Management

Approximately half of people with ALS develop excessive oral secretions leading to drooling and the need for frequent oral suctioning.²³ Anticholinergic medications can improve comfort by decreasing secretions, and include tricyclic antidepressants, such as amitriptyline, that also improve pseudobulbar affect.²⁴ Alternatively scopolamine transdermal patches, glycopyrrolate, or sublingual atropine can be used. For those with sialorrhea refractory to treatment or who cannot tolerate first-line medications, intraglandular botulinum toxin is very effective. Some centers have also offered radiotherapy, which can be effective, although is not commonly used and has the risk of permanent dry mouth. With all treatments for excessive drooling, it is important to avoid overdrying oral secretions because this can also lead to thickened respiratory secretions. Proper respiratory hygiene with humidified air and mucolytics such as N-acetylcysteine can help to mitigate this risk.

Palliative and End-of-Life Care

The core goal of the ALS multidisciplinary center is to support the comfort of the individual with ALS at all stages of disease. Inevitably, this means care at the very end stages, during which respiratory dysfunction progresses to the need for ventilation not just at night but also for most of the day. Continuous ventilation makes individuals vulnerable to infection, which can lead to frequent hospitalizations. Eventually, the ability to maintain respiratory status using NIV alone is lost. Discussions regarding end-of-life goals and preferences should be approached as early as reasonable and revisited frequently to ensure that wishes are clear. Relevant topics include detailed clarification of advanced directives. Tracheostomy and invasive ventilations are options that few prefer for a variety of reasons. Invasive ventilation confers survival benefit in those under age 60, but patient and caregiver quality of life are a concern because individuals can become “locked-in” and invasive ventilation requires substantial caregiver support.²⁵

A family’s experience of their loved one’s passing will be remembered for a lifetime, which is why honest conversation and strong alliance is critical. Many people prefer to die at home with family and friends. Clarifying this goal is important because earlier introduction to palliative care and hospice may be appropriate for these patients to ensure that they can avoid hospitalization as death nears. Other important details include whether respiratory care and/ or medicines will be stopped in favor of comfort measures. In either case, people with ALS should be provided with adequate access treatment of air hunger with opiates and anxiety with drugs, such as benzodiazepines. An established and well-documented plan of care that the individual and her or his family fully understand will help to ease anxiety as all involved can be confident that comfort throughout the entire process is feasible.

Conclusions

Achieving the highest level of care for people with ALS benefits greatly from multidisciplinary care centers in which complex needs can be met in an integrated manner. Respiratory and nutritional interventions currently have the greatest benefit but there is great optimism about emerging neuroprotective therapies. Symptomatic treatments (eg, management of spasticity, pain, sialorrhea, and other symptoms) have a great impact on quality of life. Assistive devices for communication, mobility, and ADLs are also critical to improve autonomy, safety, and quality of life. A strong alliance between patients and physicians is very important as it enhances the discussion of challenging topics such as invasive ventilation, gastrostomy, and palliative medicine. Educating patients and families in a prompt, open, and honest way can help make navigating the challenging journey much easier.