NORD gratefully acknowledges Etienne Leveille, MD, Yale School of Medicine and Christina Fournier, MD, MSc, Associate Professor of Neurology, Interim Director, Neuromuscular Division, Emory University Department of Neurology, for assistance in the preparation of this report.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive degeneration and eventual death of nerve cells (neurons) in the brain, brainstem and spinal cord. The neurons involved in ALS facilitate communication between the nervous system and voluntary muscles of the body (motor neurons). Normally, motor neurons in the brain (upper motor neurons) send messages to motor neurons in the spinal cord and brainstem (lower motor neurons), which then relay the message to various muscles. ALS affects both the upper and lower motor neurons so that the transmission of messages is interrupted and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. ALS affects the muscles needed to move the arms and legs, to speak and swallow, to support the neck and trunk, and to breathe. The symptoms of ALS progress over time and, ultimately, the disease leads to ventilatory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. Although two therapies are approved to slow the progression of the disease by a small amount (disease-modifying therapy) in the United States, the mainstay of therapy for ALS is centered on symptom control and supportive care.
ALS causes a combination of upper and lower motor neuron disease, and the symptoms vary depending on the muscle controlled by the affected neurons and whether upper or lower motor neurons are predominantly affected. The main manifestations of upper motor neuron disease are muscle weakness, increased muscle tone and stiffness (spasticity), increased reflexes (hyperreflexia), and abnormal speech and swallowing. Lower motor neuron disease causes muscle weakness and wasting (atrophy), decreased muscle tone, decreased reflexes (hyporeflexia), twitching of muscle fibers (fasciculations), muscle cramps, and abnormalities of speech, swallowing, and breathing. When ALS affects the limb and trunk muscles, it leads to symptoms such as difficulty walking or falls and difficulty performing activities of daily living. When ALS affects nerves of the head and neck (cranial nerves), it can leads to bulbar symptoms, which include difficulty swallowing (dysphagia) or speaking (dysarthria) and weakness of the muscles of the face or tongue. Dysphagia can lead to complications such as difficulty feeding, choking, excess saliva or drooling, and weight loss. Dysphagia can also lead to pneumonia because of aspiration of food contents (aspiration pneumonia), when food or liquids enter the airway due to dysfunctional swallowing. Bulbar symptoms can also include emotional lability characterized by episodes of sudden, uncontrollable, and inappropriate laughing or crying (pseudobulbar affect).
Although the symptoms of ALS can begin at any time in adulthood, they most commonly manifest in individuals between 55 and 75 years old. Genetic forms of ALS with childhood onset are very rare. Early in the disease, patients can present with either or both upper and lower motor neuron symptoms. Symptoms most commonly begin in the extremities (spinal-onset ALS). Symptoms that develop in the limbs can affect either or both the upper and lower extremities and are typically more pronounced on one side (asymmetric) initially. Early on, the symptoms of ALS can be subtle and include slight muscle weakness, clumsy hand movements, and/or difficulty performing tasks that require delicate movements of the fingers and/or hands. Muscle weakness in the legs may cause tripping and falling. About a third of patients initially present with predominant bulbar symptoms (bulbar-onset ALS). More rarely, patients might initially present with breathing symptoms such as shortness of breath (dyspnea) because of weakness of the ventilatory muscles. ALS is a neurodegenerative disease, so the symptoms progress and become worse over time; muscles become more severely affected and additional muscles become involved. The disease may progress quickly or slowly. As ALS progresses, typically over the course of three to five years, the individual will gradually lose the ability to stand or walk. In time, many patients will require mechanical assistance to breath and are at increased risk for ventilatory failure. A small percentage of people with ALS experience a gradual stabilization of symptoms and may maintain that level (plateau) for a few months or rarely years.
Although ALS is predominantly seen as a disease affecting motor neurons, non-motor symptoms can be observed in up to half of affected individuals. In fact, about 10% of patients are concurrently affected by a disease known as behavioral variant frontotemporal dementia (bvFTD) and can develop cognitive impairment and behavioral symptoms such as disinhibition, overeating and compulsive or inappropriate behavior (for more information on this disorder, choose “frontotemporal degeneration” as your search term in the Rare Disease Database). Other non-motor symptoms that can be seen in ALS include cognitive impairment and behavioral changes that are typically less marked than in patients with FTD, mood alterations such as depression and pseudobulbar affect (as described above). In addition, patients with ALS might be at an increased risk of developing blood clots due to decreased mobility.
The underlying cause of sporadic ALS is not known. It is thought that dysfunction in a variety of interconnected molecular mechanisms contribute to the disease. These mechanisms include dysfunction of protein balance, folding and transport, excessive neuron stimulation (excitotoxicity), oxidative stress, neuroinflammation and dysfunction of mitochondria (the “powerhouse of the cell”). Ultimately, these anomalies lead to damage and death of motor neurons, hence leading to the symptoms of ALS. Only age and family history are clearly established risk factors for ALS.
Approximately 10 percent of all cases of ALS are familial (hereditary). More than 25 genes have been associated with the disease. Most familial cases follow a dominant pattern of inheritance, although recessive or X-linked patterns of inheritance are also possible. However, some individuals with a disease-causing (pathogenic) genetic mutation will not develop the disease (incomplete penetrance). Age of onset and disease characteristics often cannot be precisely predicted based on the presence of a known genetic mutation.
Familial ALS is most commonly caused by mutations in the C9ORF72 gene. This mutation can cause ALS, frontotemporal dementia (FTD), or both. The second most common cause of familial ALS is due to mutations in the SOD1 gene. Almost half of familial ALS cases are caused by mutations in SOD1 and C9ORF72 genes, and another 20% are caused by mutations in genes known as TARDBP and FUS. Mutations in these genes are all associated with dominant forms of familial ALS.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
ALS is a rare disorder that develops in 1.5 to 3 per 100,000 people every year in North American and European populations. Approximately 30,000 people are affected in the United States, with an estimated 5,000 new cases diagnosed each year. ALS affects more males than females, as about 60% of affected individuals are males. Further research on the epidemiology of ALS needs to be done, as the vast majority of epidemiologic research is centered on North American and European populations.
ALS is a clinical diagnosis. This means that no single test can reliably diagnose the disease. The diagnosis of ALS is therefore centered on a careful patient history and neurologic examination. Laboratory and imaging tests may be helpful to exclude other conditions depending on the clinical presentation. The diagnosis of ALS requires a history of progressive muscle weakness spreading to one or more anatomical regions and clinical evidence of upper and lower motor neuron disease, although only one type of motor neuron dysfunction might be predominant early in the disease course (see the Signs & Symptoms section above for more details on the clinical manifestations of upper and lower motor neuron disease). Electrodiagnostic studies such as electromyography (EMG) and nerve conduction studies (NCS), which evaluate transmission of nerve impulse to muscles and conduction of nerve impulse across neurons, can complement the physical examination and show further evidence of motor neuron dysfunction. Brain imaging, such as magnetic resonance imaging (MRI), is often performed in patients with suspected ALS. Although some level of brain atrophy can be seen in ALS, imaging is mostly performed to rule out other causes of motor neuron disease. Genetic testing is particularly helpful in cases of suspected familial ALS. Diagnostic delay is a common problem with ALS, with an average diagnostic delay of 1 year from symptom onset.
The treatment of ALS generally requires a multidisciplinary team approach and should notably include neurologists, physical therapists, speech pathologists, pulmonologists, pulmonary therapists, medical social workers, nutritionists, psychologists and specialized nurses. Multidisciplinary care for ALS is associated with improved survival and patient satisfaction.
There are two main components to ALS treatment: therapy that slows the progression of the disease (disease-modifying therapy) and therapy that helps manage symptoms and improve quality of life (supportive therapy). Unfortunately, there is no cure for ALS.
The drug riluzole (Rilutek) was the first drug to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of ALS. In clinical trials, riluzole was shown to prolong survival by an average of three to five months, although it did not substantially delay muscle deterioration. The other FDA approved disease-modifying therapy for ALS is edaravone (Radicava). It was shown to slow the rate of functional decline in certain patients with ALS. The benefits seem to be more pronounced in those with early ALS.
Symptomatic therapy of ALS has two main components: medications and non-pharmacological management.
Several drugs may be used to help alleviate the symptoms of ALS. Muscle spasticity and fasciculations can be managed with muscle relaxants such as baclofen, tizanidine or diazepam. In some patients with severe and disabling spasticity, baclofen might be administered directly into the spinal canal (intrathecal administration) with a device known as an intrathecal pump. Some individuals with spasticity might also benefit from treatment with cannabinoids. Muscle cramps, which may be painful, can be treated with medications such as quinine sulfate, levetiracetam or mexiletine. Some patients with ALS might develop hypersalivation (sialorrhea) and be unable to manage pooling of secretions; this can be managed with medications such as atropine, scopolamine, amitriptyline, glycopyrrolate, or botulinum toxin injections. Oral suction devices can also be of benefit. Mood alterations such as depression or behavioral symptoms related to frontotemporal dementia can be managed with antidepressants such as selective serotonin reuptake inhibitors (SSRIs). Some patients with ALS may experience pain for different reasons, which can be managed with several medications depending on the type of pain.
Physical and occupational therapy is very important and should consist of daily range-of- motion exercises. These exercises can help maintain the flexibility of affected joints and prevent the fixation of muscles (contractures). It is also essential that people with ALS maintain proper nutrition. Weight loss is an independent predictor of poor prognosis in ALS. Soft foods should be carefully chosen for patients who have dysphagia. When adequate nutrition and fluids cannot be maintained because of dysphagia, a gastric feeding tube can be considered. Speech therapy and augmentative communication devices can be useful for individuals with dysarthria.
Once individuals develop ventilatory muscle weakness, non-invasive positive pressure ventilation (NIPPV) is beneficial to assist breathing. Cough assist devices are also useful to clear secretions. Eventually, ventilatory weakness progresses to the point where patients cannot breathe on their own and some patients will choose to pursue tracheostomy and permanent mechanical ventilation. For patients who decide against mechanical ventilation, home hospice services can provide supportive care and assist with comfort measures.
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