Amyotrophic Lateral Sclerosis from Bench to Bedside
Posted 05/13/2008
Catherine Lomen-Hoerth, M.D., Ph.D.
Author Information
Abstract and Introduction
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive disease for which there are currently no significant treatments to alter the fatal outcome. The cause of the disease is still elusive, except in familial cases where significant advances have been made in identifying new genetic causes. ALS is a relatively rare disease affecting ~1 in 100,000 people equally across geographic and ethnic distributions. It is a difficult disease to diagnose, and there are many mimics of ALS. Overlap with dementia may provide new clues to the etiology and treatment. There have been many advances in symptomatic treatments and improvements in the quality of life for ALS patients due to technological advancements.
Introduction
Amyotrophic lateral sclerosis (ALS) was first described in the late 1800s in France. It is a progressive, fatal disease causing weakness of the voluntary muscles. It starts most typically in the limbs and spreads contiguously. Bulbar onset is less common, and respiratory onset is very rare. Death occurs on average 3 to 5 years after the first symptoms from respiratory failure, but the range is very broad with some people dying 2 months after their first symptoms, whereas others are still walking 10 to 15 years after their first symptoms. There is, unfortunately, still no cure for this disease or medication to significantly slow disease progression. The general public became aware of ALS in the 1930s when Lou Gehrig, the famous New York Yankees baseball player, developed the disease and rapidly declined over the course of 2 years. ALS has an incidence of 1 to 3 cases per 100,000 without any geographic or ethnic preferences. It occurs somewhat more in men and has an average onset age of 56 years, with onset ranging from 20 to 80 years. ALS is usually a sporadic disease, but 10% of the time it is familial, typically with autosomal-dominant inheritance.[1]
Clinical Features
Amyotrophic lateral sclerosis is clinically diagnosed with a combination of upper and lower motor neuron findings. Upper motor neuron findings include slow speech, brisk gag and jaw jerk, brisk reflexes, spasticity, and Hoffman's or Babinski's signs. Lower motor neuron findings include atrophy, fasciculations, and weakness. Patients may present to the clinic with findings in just one region (e.g., cervical), making it difficult to make a definitive diagnosis. They may also have a pure upper motor neuron syndrome, typically termed primary lateral sclerosis (PLS), in the setting of a normal electromyelogram (EMG) and symptoms for over 3 years. A pure lower motor neuron syndrome, typically termed progressive muscular atrophy (PMA), is a variant of ALS. Both conditions may evolve over time to ALS, and there is no guarantee that these variants will necessarily progress more slowly than typical ALS.
It is important to exclude mimics of ALS. Upper motor neuron mimics include brain tumors, multiple sclerosis, and vitamin B12 deficiency. Lower motor neuron mimics include multifocal motor neuropathy, paraneoplastic syndromes, monoclonal gammopathies, lead toxicity, and polio. Spine disease is perhaps the only condition that could cause a combination of upper and lower motor neuron findings if there is spinal stenosis compressing the cord and foraminal narrowing compressing nerve roots. A brainstem tumor could also cause both upper and lower motor neuron findings, depending on where it is located. Because spine disease and brain tumors are much more common than ALS, a magnetic resonance imaging (MRI) scan of the spine and/or the brain is often the first study in an evaluation of a potential ALS patient, depending on the clinical examination findings. Blood work typically includes a complete blood count (CBC), platelets, electrolytes, blood urea nitrogen (BUN), creatinine, calcium, creatine phosphokinase (CPK), liver function tests, magnesium, B12, serum protein electrophoresis, immunofixation, urine protein electrophoresis, blood lead level, and thyroid-stimulating hormone (TSH).
In a pure lower motor neuron syndrome, it may also be useful to look for anti-GM1 antibodies for multifocal motor neuropathy, trinucleotide repeats in the androgen receptor for Kennedy's disease, and Lyme enzyme-linked immunoabsorbent assay (ELISA) if in a Lyme-endemic area. Signs of Kennedy's disease include family history, gynecomastia, testicular atrophy, and, in some cases, sensory abnormalities in the feet and absent ankle jerks. Signs of multifocal motor neuropathy include weakness in a peripheral nerve distribution without sensory abnormalities. Lyme disease may have other associated symptoms such as a history of a tick bite or rash and cranial neuropathies. For a young person, HIV and hexosaminidase A would also be appropriate to consider. A spinal tap is typically not indicated, but it can be useful in a pure upper motor neuron syndrome for human T-cell leukemia virus (HTLV) I or II and multiple sclerosis, or in a pure lower motor neuron syndrome for lymphoma with a large volume of cerebrospinal fluid (CSF) sent for cytology. In ALS, typically all these tests are normal; however, anti-GM1 antibodies may be mildly elevated.
An EMG is another part of the critical pathway toward a diagnosis, particularly in pure lower motor neuron syndrome. Nerve conduction studies with proximal stimulation can help identify conduction block, which is typical of multifocal motor neuropathy, a disease usually easily treated with intravenous immunoglobulin (IVIg) therapy, although there are cases without conduction block that still respond to IVIg therapy. Kennedy's disease may have absent or low amplitude sensory nerve action potentials. Bulbar onset cases may be confused with myasthenia gravis, and repetitive nerve stimulation may aid in the diagnosis along with testing acetylcholine receptor (AChR) antibodies. Myopathies are evident on the needle part of the EMG study, showing the opposite findings of a neurogenic process with short duration motor unit action potentials and early recruitment. Even in clear cut cases of ALS with diffuse upper and lower motor neuron findings, the EMG is useful in helping with prognosis based on the degree of denervation present and in determining subclinical disease in areas not yet obviously affected clinically.
Pathogenesis
The cause of ALS is still unknown; however, there have been great advances in our understanding of the disease, particularly in relation to genetics ( Table 1 ). The cause of most cases of familial ALS is unknown; however, a variety of genes have recently been identified. ALS types 1-8 have been defined based on the chromosomal loci containing mutations. Most are rare with unique phenotypes, except for ALS 1, which is caused by a mutation in superoxide dismutase. This gene causes ALS in 10 to 20% of familial ALS cases and is the only commercially available gene that can be tested at this time. The mechanism of action of superoxide dismutase 1 (SOD-1) in causing disease remains ambiguous. The animal model of ALS used in screening drugs to treat ALS is created with SOD-1 gene mutations. Other genes or gene loci have been identified that cause ALS, frontotemporal dementia and ALS, and frontotemporal dementia and Parkinson's disease.
The mechanisms of motor neuron degeneration proposed are many and are outlined in Figure 1.[2] Excitotoxicity is one theory, and excess glutamate has been found in the CSF of patients with ALS. Riluzole is a glutamate antagonist and is the one drug approved by the U.S. Food and Drug Administration (FDA) to treat ALS. Growth factor deficiency is another theory, but despite dramatic results in ALS mice treated with growth factor, the human trials in ALS have been disappointing. Activation of caspases and damage to the mitochondria are other possibilities, and drug trials are ongoing to test these possibilities. In recent years, more attention is being paid to the supporting cells such as astrocytes, microglia, and macrophages as potential causes for the disease and targets for therapy.[3]
/ Figure 1. (click image to zoom)Proposed mechanisms of motor neuron degeneration. EAAT2, excitatory amino acid transporter 2; VEGF, vascular endothelial growth factor; IGF, insulinlike growth factor. (From Bruijn LI, Miller TM, Cleveland DW. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci 2004;27:723-749.)
Classification
In addition to classic ALS, there are variants of ALS that have additional features, traditionally termed ALS Plus.[4] More recently, attempts to refine this classification, particularly with regard to cognitive and behavioral abnormalities, were reviewed and are summarized in Table 2 .[5] Cognitive and behavioral changes are now recognized as a feature of ALS in some patients. The percentage of patients affected has been reported to range from 3% to more than 50% depending on the study and the extent of psychological testing. The severity of dementia lies on a spectrum of frontotemporal abnormality with patients possessing a range of behavioral and cognitive disorders.[5] These cognitive and behavioral disorders can significantly affect survival due to their impact on compliance with recommendations for treatment.[6] Recently, transactive response (TAR)-DNA-binding protein 43 (TDP-43) was discovered as a protein found in the neuronal inclusions of both ALS and ALS-frontotemporal dementia patients, suggesting potentially a common mechanism underlying these diseases.[7] In addition, TDP-43 may be a means of distinguishing between SOD-1 and non-SOD-1 cases of ALS.[8] This has important implications because all drug development to date has been based on the SOD-1 mouse model, which may not be the appropriate model for all ALS patients. TDP-43 may offer a new target for drug development.
Diagnostic Approach
Amyotrophic lateral sclerosis is a diagnosis of exclusion. There are many mimics of ALS (discussed previously) that need to be ruled out before ALS is even listed in the differential to the patient. Because of the wealth of information available on the Internet, breaking the news to the patient needs to be performed only when the diagnosis is certain. Specific guidelines for breaking the news have been determined and are listed in Table 3 .[9] It is critical that the news be told in a calm, compassionate manner with information presented in written form for the patient and family to digest later. It is most important that the patient not feel abandoned by the diagnosis, understand there are many advances in treatment for disease symptoms, and know there are ongoing clinical research trials in which he or she may participate. The patient needs to leave the office feeling a sense of hope in the midst of receiving this devastating diagnosis. Hope is possible to instill by assuring the patient that he or she will have strong support throughout the process, offering phone numbers to reach the physician and nurse for further questions, talking about advances in symptomatic management, and discussing opportunities to participate in clinical research.
Treatment
Treatment for ALS focuses on the following main areas: slowing disease progression, treating symptoms, multidisciplinary care, and end of life issues. There is only one medication approved by the FDA to treat ALS-riluzole (Rilutek). The drug prolongs survival by 10% and delays disease progression modestly. It is very expensive, approximately $1000 per month, sometimes causing a hardship for patients, especially patients who are on Medicare without supplemental prescription coverage. It is usually fairly well tolerated, however, and ~50% of ALS patients typically take the drug. Other treatments that may slow disease progression are coenzyme Q10, currently being tested in ALS clinical trials, and antioxidants such as vitamins C and E, beta-carotene, and α lipoic acid. Their effect has not yet been proved through human clinical studies. There are many trials ongoing for ALS, and patients are usually referred to the ALS association at or the Muscular Dystrophy Association at for updated information about current clinical trials and ALS research.
Treating ALS symptoms is critical for maintaining both quality and quantity of life in ALS, and caring for patients in a multidisciplinary clinic with a team of professionals makes that much easier. Good nutrition is critical because even overweight patients can easily become malnourished and lose muscle mass if they are not able to take in enough calories, either from difficulty swallowing or difficulty eating due to arm weakness. In addition to difficulty eating, metabolism is increased due to the increased work of breathing and moving. A high-protein, high-calorie diet is recommended with modifications of food consistency as needed for swallowing safety, and ultimately a feeding tube in many cases to maintain adequate nutrition and hydration.
Maintaining good breathing is necessary; oxygen needs to be avoided because it can trigger CO2 retention and even cause coma. Noninvasive positive pressure ventilation is recommended in cases where the forced vital capacity (FVC) is less than 50% or when the maximum inspiratory force (MIF) is low or there are significant nocturnal desaturations. The symptoms of nocturnal desaturation are often subtle-including cognitive problems, restless sleep, and fatigue-but they are easily reversible with noninvasive ventilation. Eventually the diaphragm strength weakens to the point that noninvasive ventilation is no longer effective; unless the patient chooses tracheostomy and mechanical ventilation, he or she will ultimately die of respiratory failure. Approximately 1% of patients in North America decide on long-term ventilation, usually younger patients with small children or more affluent patients who can afford the care required. In other countries when mechanical ventilation is strongly recommended by physicians and there is strong social support for families, such as in Japan, ~50% of patients with ALS are maintained on long-term ventilation, making the prevalence of ALS in Japan as high as Parkinson's disease.
Other symptoms that can be treated in ALS include pseudobulbar affect, cramps, excess saliva, spasticity, urinary urgency, sleep, depression, agitation, and constipation ( Table 4 ). Wide variations in how clinicians treat these symptoms exist, but there are some general trends.[10] Pseudobulbar affect is typically treated with low-dose amitriptyline (Elavil). A combination of dextromethorphan and quinidine is being tested in clinical trials and is quite promising for controlling this symptom. Cramps were typically managed with quinine until it was pulled from the market, so now patients have the option of drinking tonic water, which contains quinine, or taking qualaquin, which is the new formulation of quinine sulfate that is nongeneric. Tegretol is also effective for cramps, but the side effects make it less desirable. Baclofen, which is also prescribed for spasticity, also may have some benefit for cramps. Excessive saliva is typically managed with atropine drops or pills, glycopyrrolate (e.g., Robinul), or a scopolamine patch. Typically patients start at 1 mg every 4 hours of Robinul and gradually increase up to 2 mg every 4 hours as their saliva increases. If this fails, adding 0.04 mg atropine pills or 1% drops every few hours may help. When these treatments become ineffective as saliva increases, undergoing radiation treatments to the salivary glands or injecting botulinum toxin injections into the salivary glands is often very effective. To thin saliva, guaifenesin (over-the-counter Robitussin) is very effective and now comes in a pill form (Mucous Relief). Patients should be instructed to take up to a maximum of 400 mg every 4 hours to help thin saliva. Both of these treatments are available over the counter and are quite affordable. If patients have trouble with the taste of Robitussin, there is a prescription form of guaifenesin available that may be more easily tolerated.
Spasticity is a very disabling problem in ALS, and there is often a balance between relief of spasticity and loosening the legs too much to cause difficulty walking. Valium at night is often effective at doses of 10 to 20 mg. Baclofen in doses up to 100 mg per day is effective, but the titration upwards or downwards needs to be very slow, at a rate of no more than one half of a pill per day. Zanaflex is sometimes effective when used in combination with baclofen or alone, and, again, slow titration upwards and downwards is important. When medications are at their maximum tolerated doses and spasticity is still a significant problem, a baclofen pump may be effective. A trial is often performed first in the hospital with gradually increasing doses administered until a bell-shaped curve of response is produced, indicating a dose-dependent effect. A pump is then implanted and the dose started where peak efficacy was identified. This therapy often allows patients to completely come off of their oral medication. Urinary urgency can be managed with medications such as Detrol or Ditropan, and for men a condom catheter is often useful when traveling long distances.
Sleep is often difficult in ALS due to difficulty breathing and difficulty turning in bed. Solving mechanical problems with a turning bed or an air mattress is often effective. A nocturnal oximetry study done in the home can quickly evaluate if nocturnal desaturations are the problem with sleep, and, if so, starting bilevel positive airway pressure (BiPAP) can relieve the problem and provide more energy during the day as well. If these problems are solved and sleep is still difficult, sleep aids such as Ambien are often effective, as are sedating antidepressants such as Remeron and Trazodone, which have the added benefit of improving mood. Depression is rare in ALS; however, when it does occur, it is usually easily managed with antidepressants.[11,12] Anxiety is more difficult to manage and often a combination of medication and behavioral approaches are needed, particularly when anxiety is due to comorbid frontotemporal dementia or executive dysfunction.[6,11] Constipation can be a problem due to mobility problems and lack of fluid intake. Preventative treatment with adequate fluid intake, stool softeners, and fiber is often effective, but stronger measures such as lactulose are often needed to prevent constipation. One symptom that is uncomfortable and unresponsive to most treatments is fasciculations. They can be somewhat alleviated by benzodiazepines, but at doses that tend to cause drowsiness.