Amyotrophic lateral sclerosis (ALS) also known as “Lou Gehrig disease, is a neurodegenerative disorder of the motor neurons characterized by the progressive degeneration and eventual death of nerve cells (neurons) in the brain, brainstem, and spinal cord. ALS necessarily affects both upper and lower motor neurons with variable patterns of onset, most commonly beginning with signs of lower motor neuron degeneration within proximal limbs. The loss of upper and lower motor neurons in the motor cortex, the brain stem nuclei and the anterior horn of the spinal cord gives rise to progressive muscle weakness and wasting. 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, speak and swallow, support the neck and trunk, and 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.
Amyotrophic lateral sclerosis (a-my-o-TROE-fik LAT-ur-ul skluh-ROE-sis), or ALS, is a progressive nervous system disease that affects nerve cells in the brain and spinal cord and loss of the upper and lower motor neurons (LMNs) at the spinal or bulbar level, causing loss of muscle control. ALS is often called Lou Gehrig’s disease after the baseball player was diagnosed with it. These mechanisms include altered RNA processing leading to prion-like self-aggregation, superoxide dismutase type 1 SOD1 mutations leading to free radical toxicity, cascading inflammatory responses, and excessive concentrations of glutamate, among others.[rx][rx] The rarer entity of familial ALS has numerous genetic mechanisms, most frequently repeat expansion of the C9ORF72 gene and various mutations of the SOD1 gene.[rx] Mutated SOD1 protein misfolds and forms aggregates, leading to cellular injury and eventually apoptosis. Both genetic aberrations are inherited in a mainly autosomal dominant pattern.[rx] Ultimately, rather than a single unifying cause, ALS is an etiologically diverse clinical entity, which is the result of a multitude of separate potential preceding aberrations.[rx] ALS is also known as Charcot disease in honor of the first person to describe the disease, Jean-Martin Charcot, and motor neuron disease (MND) as it is one of the five MNDs that affect motor neurons. There are four other known MNDs: Primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), progressive bulbar palsy (PBP), and pseudobulbar palsy.
Symptoms
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. Symptoms/signs besides LMN and UMN disease, such as dementia (mostly frontotemporal), extrapyramidal, autonomic dysfunction, ocular motility disturbance, and/or sensory loss, these patients are considered to have ALS-plus syndrome.[rx]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 lead 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 the 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 three to five years, the individual will gradually lose the ability to stand or walk. In time, many patients will require mechanical assistance to breathe 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 the affected individuals. 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.
These symptoms may include dyspnea on exertion or talking, orthopnea, disturbed sleep, excessive daytime somnolence, morning headaches, fatigue, anorexia, depression, poor concentration, vivid nightmares, and nocturia.
Causes
The underlying cause of sporadic ALS is not known. It is thought that dysfunction in a variety of interconnected molecular mechanisms contributes 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 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.
At the genetic level, there is considerable disease heterogeneity as well, with more than 20 genes that have been associated with ALS. The five most common genetic causes are hexanucleotide expansions in chromosome 9 open reading frame 72 (C9orf72) and mutations in superoxide dismutase 1 (SOD1), TAR DNA‐binding protein 43 (TARDBP), fused in sarcoma (FUS), and TANK‐binding kinase 1 (TBK1). Together, they explain about 15% of all patients [rx, rx, rx].
Diagnosis
ALS is a clinical diagnosis. This means that no single test can reliably diagnose the disease. The diagnosis of ALS is therefore centered on 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 the transmission of nerve impulses to muscles and conduction of nerve impulses 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 World Federation of Neurology (WFN) has also set forth categories that aid in the description of ALS. Although the verbiage would seem to imply degrees of certainty, these categories instead reflect the degree of clinical involvement evident at the time of an examination. They are as follows:
- Clinically definite ALS: UMN and LMN signs in at least 3 body segments.
- Clinically probable ALS: UMN and LMN signs in at least 2 body segments with some UMN signs in a segment above the LMN signs.
- Clinically probable, laboratory-supported ALS: UMN and LMN signs in 1 segment or UMN signs in 1 region coupled with LMN signs by EMG in at least two limbs.
- Clinically possible ALS: UMN and LMN signs in 1 body segment, UMN signs alone in at least 2 segments, or LMN signs in segments above UMN signs.
- Clinically suspected ALS: Pure LMN syndrome with other causes of LMN disease adequately excluded.
Neither the El Escorial nor the Awaji criteria include specific radiologic findings in their diagnostic models. Therefore, while the role of radiology in the evaluation of ALS is mainly the exclusion of other possible etiologies of a patient’s clinical picture, a few subtle imaging findings have been associated with the upper motor disease found in ALS. Neuroimaging of ALS relies solely on magnetic resonance imaging (MRI). Studies have shown patients with ALS to demonstrate iron accumulation within the precentral gyrus.[rx] As a result, on susceptibility-weighted imaging, the decreased signal is visible across the precentral gyrus, which is known as the “motor band sign.”[rx] On conventional MRI, decreased signal intensity within the motor cortex on T2 weighted images has been associated with ALS and may be used to support the diagnosis. In addition, well-defined lesions of increased signal intensity can be visible within the corticospinal tracts on T2WI.
Findings indicative of upper motor neuronal disease have also been elucidated utilizing advanced MRI techniques such as spectroscopy and diffusion tensor imaging (DTI).[rx] MR spectroscopy can detect and quantify chemical concentrations, specifically of N-acetyl aspartate (NAA), choline, and creatine within imaged tissues. Multiple studies have demonstrated decreased absolute and relative quantities of NAA in patients with ALS.[rx][rx][rx]
Treatment
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.
Disease-modifying therapy
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
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 to pool 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.
Frequent and painful muscle spasms can be treated with mexiletine, which was well-tolerated and demonstrated good symptomatic response at a dose of 150 mg BID. in a small sample study.[rx][rx] Other options are levetiracetam and with less efficacy gabapentin, baclofen, and tizanidine.[rx] The latter two of which have shown efficacy in the management of spasticity. When oral therapy is not effective or well-tolerated, botulinum toxin injections into the spastic muscles can be useful. As weakness and functional decline inevitably progress, patients should be provided assistive devices (canes, orthoses, crutches, and eventually wheelchairs), removable headrests for those with neck weakness, specialized utensils, and holders, and eventually a pressure-relieving mattress with frequent repositioning to prevent pressure ulcers.[rx]
Sialorrhea is very common and can be treated with atropine (0.4 mg q4-6h), hyoscyamine, amitriptyline (10 to 150 mg QHS), and glycopyrrolate (1 mg TID), botulinum toxin injections into salivary glands, and even low-dose radiation therapy in those with refractory symptoms.[rx][rx][rx] Riluzole (50mg bid) is thought to reduce glutamate-induced excitotoxicity and is the only drug that has proven to improve overall survival
Edaravone is a free radical scavenger that is thought to reduce oxidative stress and has proven to be beneficial on a subset of patients with early stage and is administered in 60 mg daily infusions for 14 days followed by 14 days off for the first cycle, and then 60 mg/day for 10 days and 14 days off for the subsequent cycles. Edaravone should be used with caution in patients with asthma as it can cause serious asthmatic reactions in up to 5%.
Since Vitamin E or α-tocopherol functions as an antioxidant in neural cell membranes, there have been several studies testing its role in ALS. Vitamin A (beta-carotene) supplementation was investigated among ALS patients. Their results showed that beta-carotene neither has any neuroprotective effect on ALS patients nor helps with slowing down the progression of the disease. Dietary creatine supplementation did not have an impact on the survival rate of ALS patients or slowing disease progression.[rx]creatine intake may improve cellular glutamate transporter, an effect that would prevent glutamate excitotoxicity, a proposed mechanism of ALS.[rx] Pu-erh tea extract (PTE) can help in preventing the rapid advancement of ALS in patients.
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 for 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.
References
