Amyotrophic Lateral Sclerosis Management

Disease-Modifying Agents  

Riluzole  

Riluzole is a glutamate antagonist that inhibits presynaptic glutamate release and interferes with its postsynaptic effects. It is a neuroprotective drug for patients with amyotrophic lateral sclerosis. A daily dose of 100 mg of Riluzole has been shown to improve the 1-year survival rate by 15% and prolonged survival by approximately 3 months after 18 months of treatment. It is a glutamate antagonist that inhibits the presynaptic glutamate release and interferes with its postsynaptic effects. It is not a cure for amyotrophic lateral sclerosis but produces modest lengthening of survival. It may increase survival by 3 to 6 months. However, its efficacy has not been demonstrated in the late phase of the disease.
 
Increased survival rates have been shown after the administration of Riluzole in patients with the following clinical features:

• Definite or probable amyotrophic lateral sclerosis by World Federation of Neurology criteria
• Symptoms present for less than 5 years
• FVC >60% predicted
• No tracheostomy

Edaravone  

Edaravone is a potent free radical scavenger and antioxidant that can give neuroprotection against oxidative stress. It is not a cure, but studies show it may slow the decline of functional abilities in some patients with amyotrophic lateral sclerosis. It can be an adjunct to Riluzole in the early stage of amyotrophic lateral sclerosis. It is approved in Japan, Korea, and recently in the United States for treatment of amyotrophic lateral sclerosis. However, it is currently not recommended for use in amyotrophic lateral sclerosis by the European Academy of Neurology outside the context of a clinical trial.

Tofersen  

Tofersen is an intrathecal, antisense oligonucleotide that may be offered as first-line treatment for patients with progressive amyotrophic lateral sclerosis caused by pathogenic mutations in SOD1.
 
Symptomatic Management  

The goal of symptom management is to improve the quality of life for both the patient and the family.  

Sialorrhea  

Drugs that can be used for sialorrhea include Glycopyrrolate, Benztropine, Hyoscine, Trihexyphenidyl, and Atropine. These drugs have been used widely in amyotrophic lateral sclerosis patients to control sialorrhea in patients with other diseases where sialorrhea is a problem (eg cerebral palsy, developmentally disabled). Amitriptyline has been used widely in amyotrophic lateral sclerosis patients to control sialorrhea. It may be used to treat a combination of symptoms (eg depression, sialorrhea, pseudobulbar affect, nocturnal sedation and possible weight gain). Its side effects may limit usefulness. Botulinum toxin type B injection into salivary glands should be considered in amyotrophic lateral sclerosis patients with refractory sialorrhea. Radiotherapy may be considered if other treatments have failed. 

Bronchial Secretions  

Mucolytics like Guaifenesin and Acetylcysteine may be beneficial for thick mucus secretions. If the above measures are ineffective, nebulization with beta-agonists and/or anticholinergics bronchodilator and/or a mucolytic and/or Furosemide may be used in combination. It should only be used if there is sufficient cough flow.  

Dyspnea  

Morphine, given subcutaneously, may provide relief in amyotrophic lateral sclerosis patients with dyspnea at rest. Benzodiazepines (eg Midazolam, Diazepam, Lorazepam) may also be used.  

Pseudobulbar Affect  

Randomized controlled trial in multiple sclerosis (MS) patients supported the use of Amitriptyline in those with pseudobulbar affect. It may also be beneficial in patients with drooling. Satisfactory results were reported in a single study that included amyotrophic lateral sclerosis patients who used Fluvoxamine. Citalopram has been tested with good effects in other neurologic diseases. While Dextromethorphan with Quinidine have been shown to be effective in a class IA study but tests on long-term side effects and tolerability are still lacking.

Cramps and Spasticity  

Baclofen, Tizanidine, Memantine, Diazepam, Dantrolene, Eperisone, or Tolperisone may be given in amyotrophic lateral sclerosis patients with cramps and spasticity. However, they may cause weakness, sedation, and dizziness. Levetiracetam may be tried for cramps. If Levetiracetam is unsuccessful or if side effects occur, Quinine sulfate (200 mg twice daily) may be of benefit. Antispastic drugs such as Baclofen and Tizanadine may be tried as well. If spasticity is severe despite oral medications, intrathecal Baclofen may be helpful. In patients with focal spasticity, Botulinum toxin may be considered if other treatments are not effective, not tolerated or contraindicated. 

Pain  

Non-opioid analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) may be the initial treatment options for amyotrophic lateral sclerosis patients with pain. If non-opioid analgesics and NSAIDs fail, one may switch to opioid analgesics. Targeted steroid injections may be used to manage joint pain.
 
Anxiety, Depression and Emotional Distress  

Anxiety, depression, and emotional distress in amyotrophic lateral sclerosis is treated with an appropriate antidepressant (eg Amitriptyline, a selective serotonin reuptake inhibitor [SSRI], or Mirtazapine. It must be noted that SSRIs are preferred in the elderly or in cognitively impaired patients. Anxiety can be treated with Bupropion or benzodiazepines (eg Diazepam, Lorazepam). 

Insomnia and Fatigue  

Amitriptyline, Mirtazapine or appropriate hypnotics (eg Zolpidem) may be given to treat insomnia. Modafinil may be considered for debilitating fatigue.  

Venous Thrombosis  

Venous thrombosis should be treated with anticoagulants.

Constipation  

Laxatives may be considered if non-pharmacological interventions are insufficient.  

Laryngospasms  

If the occurrence of laryngospasms is frequent and non-pharmacological measures are ineffective, one may consider regular use of benzodiazepines. If the laryngospasms are due to gastroesophageal reflux disease (GERD), they are treated with antacid therapy.

Patient and Family Education  

Delivery of Diagnosis

It is important to ensure that the diagnosis is given in person in a quiet, comfortable, and private location. The patient’s support network should be present. The patient’s knowledge of amyotrophic lateral sclerosis is determined. It is important that questions are allowed, and that reassurance is given. Just as important, the cultural and social background of the patient is respected. Written information about the disease and support groups are provided, if available. One may refer to counselling or psychology services if needed. A second opinion is offered if the patient wants it.  

Reassurance  

It is important to explain that the complications of the disease are manageable. The patient is involved in the care decisions, and they are reassured that their treatment decisions will be respected.  

Sharing of Information  

Information needs to be provided to the patient and family in a timely manner which is appropriate for decision making. Needs are delivered well in advance of major management decision (eg mechanical ventilation).  

Genetic Counseling and Testing  

Genetic counseling and testing should only be offered in cases with a known familial history of amyotrophic lateral sclerosis. Testing should be done voluntarily and with informed consent.

Nutritional Management  

Patients with dysphagia are at risk for dehydration and nutritional deficiencies. Associated symptoms of dysphagia include drooling, choking on fluid or food, jaw weakness, and slow eating. Speech pathologists may be helpful in assisting patients who have swallowing problems. Safe swallowing techniques and a modified diet are highly recommended. The timing of percutaneous endoscopic gastrostomy/percutaneous radiological gastrostomy (PEG/PRG) is based on an individual approach taking into account bulbar symptoms, malnutrition (weight loss >10%), respiratory function, and the patient's general condition. Early insertion of a feeding tube is recommended; nasogastric tube feeding can be used while awaiting gastrostomy placement.

Percutaneous Endoscopic Gastrostomy (PEG)  

PEG should be considered as a supplemental or alternative nutritional route as dysphagia progresses. This ensures sufficient caloric and fluid intake. It is recommended that PEG be placed prior to forced vital capacity (FVC) falling <50% of the predicted. It should be offered to patients with substantial weight loss, even in the absence of dysphagia. The advantages of PEG include adequate nutrition intake, stabilization, and route of medication. In cases where PEG is not feasible, parenteral feeding may be considered.

Respiratory Management  

Respiratory failure indicates combined degeneration of the central respiratory centers and motor neurons contributing to the phrenic nerve. Respiratory insufficiency must be monitored, and serial pulmonary function measurements are recommended. Symptoms of respiratory insufficiency include dyspnea on minor exertion or talking, orthopnea, frequent nocturnal awakenings, excessive daytime sleepiness, daytime fatigue, morning headache, difficulty clearing secretions, apathy, poor appetite, poor concentration and/or memory.  

Signs of respiratory insufficiency are tachypnea, use of axillary respiratory muscles, paradoxical movement of the abdomen, decreased chest wall movement, weak cough, sweating, tachycardia, morning confusion, hallucinations, weight loss, and mouth dryness.  The American College of Chest Physicians recommends pulmonary function testing every 6 months for patients with neuromuscular disease to assist with management decisions (eg initiation on non-invasive ventilation [NIV]). If the FVC falls to <50% even in the absence of symptoms, planning for invasive or noninvasive ventilation needs to be discussed with the patient and family. The patient’s wish regarding the termination of ventilation needs to be discussed. NIV is usually preferred over invasive ventilation with tracheostomy. It offers clinical benefit to patients by improving symptoms of hypoventilation, and therefore the quality of life. Invasive ventilation may be more effective in increasing survival but is more expensive and requires more patient care. In patients who are unable to tolerate NIV or invasive ventilation, in those whom NIV is not successful or no longer adequate (end-stage disease), opioids can be used to relieve symptoms of breathlessness while benzodiazepines may help manage breathlessness exacerbated by anxiety. 

Communication  

The speaking rate of amyotrophic lateral sclerosis patients is a good indicator of overall bulbar deterioration. Dysarthria leads to communication difficulties. This should be regularly assessed and managed by a speech therapist. Appropriate communication supports systems are used from pointing boards with figures or words to computerized speech synthesizers. Family and caregivers should be educated.

Symptomatic Management  

Sialorrhea  

Sialorrhea or drooling may cause social stress and is associated with aspiration pneumonia. It tends to be due to poor handling of saliva. Suctioning secretions using a portable home suction device is recommended. It is also important to distinguish between thick mucus production and sialorrhea. Low-dose radiation therapy for medically refractory sialorrhea reduces salivary production, but may cause side effects (eg erythema, sore throat, nausea)  

Bronchial Secretions  

For bronchial secretions, a portable suction device and humidifier are provided. The patient and caregiver should be taught the technique of assisting expiratory movements using a manual-assisted cough. A mechanical cough-assisting device (insufflator-exsufflator) may also be used for acute respiratory infection. A suction device may be used in addition to the mechanical cough-assisting device. Cricopharyngeal myotomy may be done for frequent cricopharyngeal spasms and severe bronchial secretions.

Cramps and Spasticity  

Physical therapy, exercise, and hydrotherapy may help reduce cramps and spasticity.  

Pain (Musculoskeletal Pain, Skin Pressure Pain caused by Immobility)  

Pain in amyotrophic lateral sclerosis can be addressed by physiotherapy, repositioning and pressure area care, and pressure-relieving cushions and mattresses can be used.  

Anxiety, Depression and Emotional Distress  

Psychological support or psychotherapy is recommended. This may include discussing topics such as accepting and coping with the diagnosis and prognosis, ability to continue with current work and usual activities, adjusting to life changes and perception of self, and changes in relationships, familial roles and dynamics, sexuality and intimacy, and impact of disease on other family members and/or carers.

Venous Thrombosis  

Venous thrombosis may be prevented by physiotherapy, limb evaluation, and compression stockings.  

Weakness and Disability  

Physiotherapy and physical therapy may be used all throughout the course of the disease. An exercise program should be considered for patients with amyotrophic lateral sclerosis to maintain joint range of movement, prevent contractures, reduce stiffness and discomfort, optimize function and improve quality of life. Orthotics (eg ankle foot orthosis, neck collars) and adaptive aids (eg walking frame, wheelchair) can also be used.  

Cognitive Decline  

In all patients with frontal dysexecutive syndromes, care needs to be taken to ensure informed consent during decision-making; capacity issues may need to be considered. Carers and healthcare professionals should be informed of the symptoms of dysexecutive syndrome and trained in their management. 

Constipation  

Patients are advised on the importance of adequate fiber and fluid intake, regular toilet visits, and emphasis on the need for regular mobilization and physical therapy.  

Laryngospasm  

A multi-step maneuver involving a rapid change to upright position of the upper body, breathing through the nose, swallowing respectively, then breathing with slow exhalation through the lips may be used to relieve episode.

Palliative Care  

The goal of palliative care is to provide adequate relief from symptoms at the terminal stage; dyspnea, anxiety, and pain are treated as required. Shared decision-making between the physician and the patient is needed. Religious and cultural values need to be considered. Continued discussion throughout illness is important to understand and to follow the patient’s choices even if they change throughout their care. The goal is to provide adequate relief from symptoms at the terminal stage. Treating dyspnea, anxiety, and pain are also required. If available, hospice care is considered.