Neuromuscular Notes: Amyotrophic Lateral Sclerosis Symptomatic Care

Amyotrophic lateral sclerosis (ALS) is a neuro-degenerative disease of cortical and spinal motor neurons that results in progressive weakness. The pathophysiology of ALS is incompletely understood but attributed to impaired RNA metabolism, protein aggregation, microglial activation, impaired axonal transport, and mitochondrial dysfunction of motor neurons.^1,2 The search for clinically useful biomarkers is ongoing, but diagnosis continues to be made by clinical history and neurologic examination with labs, electrodiagnostic studies, and imaging used to exclude alternative diagnoses.

Riluzole and edaravone are both approved for treatment of ALS by the US Food and Drug Administration (FDA), but only riluzole is approved by the European Medicines Agency (EMA). Riluzole inhibits glutaminergic neurotransmission and has been shown to prolong survival by approximately 3 months.³ Edaravone is an antioxidant shown to slow disease progression in a subpopulation of people with rapidly progressive ALS when given early in the disease course.⁴ There are several other treatment candidates under investigation, including genetic therapies targeting SOD1, C9orf72, FUS, and ATXN2.

Early use of noninvasive ventilation (NIV) and multidisciplinary clinical care have also been shown to prolong survival.^5,6 The survival benefits of disease-modifying therapy and these interventions are modest, however, with most people developing respiratory failure leading to death or ventilator-dependence within 2 to 5 years of symptom onset. The mainstay of treatment is supportive care—anticipating and addressing symptoms of ALS (Table).

Symptom Management

Neuromuscular Symptoms

Weakness is a direct result of motor neuron dysfunction, and strength cannot be regained once lost. Splints, braces, wheelchairs, and other adaptive equipment can help people maintain independence and mobility.

Cramps are a common symptom due to lower motor neuron hyperexcitability. Although evidence is limited, hydration, stretching, range-of-motion exercises, massage, and hydrotherapy are low-risk interventions that may be beneficial. Magnesium may decrease the severity in some people and is generally well tolerated, with diarrhea being the most common side effect. Baclofen, 5 to 20 mg given 3 to 4 times daily to a maximum of 80 mg/day, and gabapentin, 300 to 900 mg given 3 times daily, are also commonly used. The FDA has discouraged the use of quinine for cramps because of safety concerns regarding thrombocytopenia and QT prolongation, but tonic water contains a small amount of quinine (about 80 mg/L) and is helpful to some people. Mexiletine is an α-1 blocker that has been studied specifically in people with ALS and reduced cramp frequency and severity.⁷ A baseline electrocardiogram (ECG) is recommended to evaluate for underlying arrhythmias, but mexiletine is typically well tolerated at a dose of 150 mg given twice daily.

Spasticity is due to upper motor neuron involvement and present in varying degrees among people with ALS. Many of the same nonpharmacologic modalities used to treat cramps can be helpful. Much of the data used to inform treatment is from other populations including people with multiple sclerosis and cerebral palsy. Importantly, pharmacologic treatment of spasticity can unmask weakness such that mobility becomes more difficult. Baclofen or tizanidine can be titrated to the most effective dose tolerable. Side effects of baclofen and tizanidine include drowsiness (maximum dose of tizanidine is 4 mg given 3 times/day). Dantrolene can be titrated up to 100 mg given 3 times/day and requires monitoring of liver function. Benzodiazepines (eg, diazepam 5 mg given 2-3 times/day) are often beneficial. Botulinum toxin can be administered locally, but the extent of involvement (such as an entire limb) can quickly exceed the limits of this modality. Intrathecal baclofen pumps can be considered if side effects limit dosing of oral medications, although a person’s ability to tolerate and recover from an invasive procedure may preclude this option. Although use of cannabinoids remains limited by its regulatory status in the US (federally) and much of Europe, cannabinoids have been shown in 1 study to decrease spasticity in people with ALS.⁸

In addition to cramps and spasticity, people with ALS may have pain related to immobility (eg, frozen shoulder or pressure sores),⁹ which is best treated with interventions directed at the underlying cause (eg, range-of-motion exercise, slings or splints, and addressing seating or positioning). Pharmacologic options include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and muscle relaxants (eg, cyclobenzaprine). If neuropathic pain is present, standard treatment with gabapentin, pregabalin, tricyclic antidepressants, or selective norepinephrine reuptake inhibitors (SNRIs) is reasonable. Opioids can be considered, monitoring for side effects of constipation and drowsiness.

Oropharyngeal Symptoms

Communication impairment results from weakness of the oropharynx. In the absence of hand weakness, a person can use a text-to-voice device, such as a phone or tablet by typing their message. Predictive software can speed this process. With hand weakness, a person can use an eye gaze system to communicate.

Sialorrhea is excess saliva related to decreased clearance by a less frequent or less effective swallow. Many people choose to carry handkerchiefs or tissues. Oral suction devices may also be helpful but may not be practical for use throughout the day for people who are mobile. Anticholinergic agents are generally first-line pharmacologic measures: glycopyrrolate (≤2 mg given 3 times daily) or atropine ophthalmic solution (1-2 drops sublingual every 4-6 hours). Tricyclic antidepressants (TCAs) have the benefit of also treating mood disturbances, pain, or pseudobulbar affect, but they have potential side effects of dizziness, orthostatic hypotension, and constipation that need to be monitored, especially in the elderly. Botulinum toxin injections can be administered every 3 months directly into the salivary glands to decrease saliva production.¹⁰ Salivary gland irradiation is also effective but has not been shown superior to other modalities.¹⁰

Respiratory Symptoms

For some people with ALS, thick secretions are bothersome and can be treated by optimizing fluid intake and using humidifiers. Cough assist devices improve clearance of secretions and are typically used a couple times per day. Guaifenesin (200-400 mg every 4 hours as needed or 600 mg extended release twice daily) can increase the amount of secretions and decrease their viscosity, making them thinner and easier to clear.

Dyspnea is due to weakness of the diaphragm and other muscles of respiration. Lying supine and activity both tend to make dyspnea worse. In the supine position, elevating the head of the bed may relieve this symptom. Fans directed at a person’s face can also help. NIV provides pressure support and is often first used at night during sleep and then during the day as respiratory function declines. Invasive ventilation via tracheostomy can also relieve dyspnea but precludes verbal communication and any oral intake, and it has maintenance burdens. Opioids can be helpful at low doses (eg, morphine 7.5-15 mg or oxycodone 2.5-5 mg, given every 3-4 hours as needed). Benzodiazepines can also be used in low doses (eg, lorazepam 1 mg given 3 times daily).

Systemic Symptoms

Fatigue is a prominent symptom in many people with ALS. Counseling about energy conservation techniques is a mainstay of treatment, such as encouraging people to take strategic breaks throughout their day and use adaptive equipment to make tasks easier. Assistive ventilation can also be helpful when fatigue is due to hypoventilation. Stimulants such as methylphenidate and modafinil can be considered.

Weight loss occurs in many people with ALS related to dysphagia, arm weakness causing difficulty feeding, and increased metabolism.¹¹ Calorie-rich foods and nutritional supplements can help, as well as adapting the diet to textures that are easiest to swallow. Artificial nutrition via gastrostomy tube is generally offered but is not without risk and has not consistently been shown to stabilize weight, prolong life, or increase quality of life.¹²

Constipation in ALS may be caused by decreased fluid or fiber intake or decreased mobility. If fiber supplements and optimization of hydration are insufficient to address constipation, then laxatives such as polyethylene glycol and sennosides may be beneficial.

Edema results from decreased mobility and extremity muscle atrophy. Limb elevation is generally most helpful. Compression socks can also decrease edema but are usually difficult for people with ALS to put on and off. Diuretics simply exacerbate cramps and dehydration and should not be used.

Neuropsychiatric Symptoms

Pseudobulbar affect (PBA) is characterized by emotional expression (laughing or crying) out of proportion to what people are feeling. This emotional dysregulation is thought to be caused by involvement of the dorsolateral frontal regions and/or the brainstem.¹³ Education about the topic can help decrease the distress related to outbursts. TCAs and selective serotonin reuptake inhibitors (SSRIs) can be helpful modulating emotional responses. Dextromethorphan-quinidine is approved for the treatment of PBA in the US and has also been shown in 1 study to improve the bulbar functions of speech, swallowing, and salivation.¹⁴

Cognitive impairment is present in up to half of people with ALS,¹⁵ and even more so among those with C9orf72 repeat expansions. The pattern of impairment is most similar to frontotemporal dementia with disinhibition, apathy, lack of empathy or sympathy, perseverative or compulsive behaviors, and executive dysfunction with relatively spared memory. Management includes providing education and implementing protective measures, such as limited financial access or supervision.¹⁵ SSRIs and trazodone may improve behavioral symptoms, whereas acetylcholinesterase inhibitors may worsen symptoms.

Mood disorders (eg, depression and anxiety) may have increased prevalence among people with ALS. However, several compounding factors may coexist, including PBA, fatigue due to respiratory insufficiency, grief, and adjustment disorder. Addressing modifiable factors is recommended, as well as standard treatments for mood disorders including antidepressants, anxiolytics, and therapy.

Systems of Care

In addition to the support provided through medical clinics, people with ALS may benefit from support of in-home health care. In-home physical or occupational therapy evaluations can make specific recommendations regarding adaptive equipment such as grab bars. Homemaking or other nonmedical services can reduce burdens for people with ALS and their primary care partners. When prognosis is expected to be 6 months or less, hospice organizations can provide in-home support for symptom management and psychosocial support, although they tend not to provide advanced equipment such as NIV or power wheelchairs.

Conclusion

Although there are few interventions to date that significantly prolong survival for people with ALS, much can be done in the realm of symptom management to improve people’s experience and quality of life.