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Amyotrophic Lateral Sclerosis: Diagnosis and Causes
Thesis statement
Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrigs disease refers to the common neurological disease that is caused by progressive and unabated degeneration of the motor neurons located in the spinal cord (particularly the ventral horn) and cortical neurons. The effect of the disease is to cause; weakness in the patients muscles (atrophy), impairment of speech and swallowing (dysarthria and dysphagia), fasciculations, and eventually a weakened respiratory system which is the most common cause of death for ALS patients. The disease is fatal and survival duration is placed at three to five years. This paper shall look at the nature of the disease and the huge psychological burden that it causes on the patient and his/her family. I shall also argue that the recent inroads made in genetics particularly in stem-cell research stand the greatest chance of finding a cure for the disease.
Introduction
The usage of the term Amyotrophic Lateral Sclerosis has been used in the medical world two refer to two overlapping conditions. Among some doctors, the term refers to several conditions that lead to degeneration of neurons. However, other doctors e.g., in the US attribute the term to the particular neurological condition that produces both upper and lower motor neuron signs. Generally, where only upper signs are evident, the condition is referred to as primary lateral sclerosis. On the other hand, lower signs only indicate progressive spinal muscular atrophy. ALS is thus present where both are evident.
The word Amyotrophic in itself represents the signs of fasciculation, weakness and atrophy in muscles which as stated above, are all lower motor neuron signs. The term lateral sclerosis refers to the palpation or hardening of the lateral part of the spinal cord and is mainly observed during autopsy. However, in reported cases, the two signs make up less than 10 percent of all motor neuron diseases (MNDs). The most reported signs of ALS are weaknesses in hands and legs, problems in speech, twitching (fasciculation), stiffness and emotional liability (exaggeration of emotions such as crying, laughing and smiling among others due to a degeneration of the bulbar upper motor neurons).
Diagnosis
Lewis et al (2001) report that 95% of clinical diagnoses in the US are usually correct. This does not however take away the fact that there is no special diagnostic test for ALS and it can be mistaken for other neurotic diseases such as X-linked spinal-bulbar muscular atrophy and Kennedys disease. The criterion used in clinical trials is often restrictive and there are some patients who succumb to ALS without being tested therapeutically. Trials for ALS have also yielded conflicting diagnoses with cervical spondylotic myelopathy and myasthenia gravis.
Another disorder that somehow masquerades as ALS is multifocal motor neuropathy (MMN) that closely resembles ALS symptoms by attacking lower motor neurons (Lewis et al, 2001). However, MMN is responsive to treatment especially intravenous immune globulin and cyclophosphamide. Nevertheless, electromyography can help in discerning between the two since it will most likely show the damage occasioned to upper motor neurons by ALS. Through magnetic resonance imaging (MRI), it is possible to investigate conduction in the corticospinal tracts. Through spectroscopy, the physician can accurately measure the remaining neurons in the motor cortex to gauge the extent of damage occasioned by ALS.
Causes
Genetic Causes
Generally, the causes of ALS are presently unknown. However, this is the cause in all MNDs. Nevertheless, 5% to 10% of ALS cases are hereditary in nature. Lewis et al state that about 20 percent of all familial ALS cases are brought about by a mutation in the gene encoding superoxide dismutase 1 (SOD1) p.1683 . The reason for the hereditary factor is the dominant nature of the SOD1 mutation. Lewis et al (2001) also find that the number of syndromes attributed to SOD1 mutations usually vary according to penetrance. However, the common characteristics of SOD1-related ALS are a younger age of susceptibility (40 or less years), varied survival range (maybe from 1 to 20 years) and clinical manifestation in bulbar rather than spinal areas.
Apart from SOD1 mutations, another cause of genetic ALS has been a dominant gene mutation in chromosome 9q21-22. This kind of mutation brings about early ALS (before 25 years). Researchers have also found that some families are naturally susceptible to neurotic disorders. They have found that those with high genetic susceptibility to ALS were also highly likely to develop Parkinsons disease and Dementia. Other conditions such as primary hyperthyroidism have also been found to occur within the same gene type (Jackson et al, 1998).
Environmental Causes
The high incidence of ALS in certain areas or in certain groups of people has led researchers to assert that there is an environmental link to ALS. A good example of this phenomenon is the prevalence of Dementia, ALS and Parkinsons disease during the Second World War in Guam. Celebrated neuropathologist and author, Harry Zimmerman observed that the prevalence in Guam alone was 50 times higher than anywhere else (Lewis et al, 2001). This is the situation to this day. A hereditary cause was disqualified owing to the fact that in many cases, both spouses were affected that meant that the cause was more environmental than hereditary.
Another group that has been observed to have a huge incidence of ALS is that of Italian soccer players. Initially, this was thought to be caused by the head injuries and concussions that players got in the normal cause of playing. However, the damage to both the upper and lower neurons in almost all cases meant that concussions were not a likely cause. Another discrediting factor was the fact that there have been no other reports of prevalent ALS outside Italy except for a few isolated cases. This meant that the environment has more to do with ALS prevalence than injuries sustained during a game. However, neurologists have accepted that repeated concussions may cause damage to the brain that may mimic MNDs.
Exposure to Heavy Metals
Another belief among neurologists about the cause of non-familial ALS is high exposure to heavy metals. In actual fact, neurologists have consistently tested the blood and urine of many ALS patients for arsenic, mercury and lead with intent to confirm this fact. However, there has been no correlation between high incidence of mercury and arsenic and ALS. The closest neurologists have come to connecting the two was a reported case of lead exposure leading to both lower and upper motor neuron signs. However, intensive research yielded no evident correlation between lead and ALS. Nevertheless, neurologists have not give up hope that there is a link between heavy metals and ALS and research is still ongoing.
Viral Infection and Prion Disease as Causes
There have been various isolated cases linking ALS to persistent viral infections. Enterovirus RNA was once reported in the spinal cord of an ALS patient but no other cases came up to confirm the connection between enteroviruses such as the poliovirus and ALS. There have also been reported MNDs in some HIV/AIDS patients but interestingly, anti-HIV therapy especially the use of ARVs have led to a reversal of these diseases. In another report, a severe case of Lyme disease was found to have shown both upper and lower signs but there was no other similarity to typical ALS.
Other viral diseases that have had a close connection to ALS include CreutzfeldtJakob disease and prion disease. Before 1983, neurologists had assumed that CreutzfeldtJakob disease had an amyotrophic form but researchers later found that the disease could not be transmitted to monkeys except in 2 cases where atypical features were exhibited by the patients. In prion disease, 50 observed cases showed that only lower motor neurons were affected thus ruling out ALS.
Other theories
The most common of alternative theories is the autoimmunity theory. Pathologists believe that the evidence of T cells and microglia in spinal cords of ALS patients especially those with IgG antibodies can link autoimmunity to ALS. Alternatively, it has been microscopically observed that where patients develop sporadic ALS, antibodies against voltage-gated calcium channels may interfere with the regulation of intracellular calcium, leading to the degeneration of motor neurons (Lewis et al, 2001, p. 1690) . However, autoimmune causes have been rejected due to the fact that immunotherapy has generally failed even with the administration of intravenous immune globulin, corticosteroids, plasmapheresis, full-body radiation and cyclophosphamide (Whitaker, 2001).
Despite the setback of the autoimmunity theory, there are still unanswered questions as to why ALS occurs concurrently with autoimmune disorders. There has been a high incidence of ALS occurring together with lymphoproliferative diseases. Hodgkins lymphoma, myeloma and macroglobulinemia have been found in a majority of patients with ALS (Younger, 1991). There has also been a close link between monoclonal gammopathy and ALS though no scientific explanation has been given for this. However, in almost all cases of ALS occurring together with another condition, the patient dies of the ALS and not the other disease (Jackson et al, 1998). This has given fodder to critics of the autoimmune theory to show that the occurrence is not proof of association.
Prognosis
With the progression of ALS, patients report having difficulty in standing, walking, getting out of bed, using limbs and communicating. The atrophy in the muscles also takes away the patients ability to perform activities requiring fine movement such as turning a knob, using a key and brushing teeth. Upon progression of the disease, atrophy occurs in the muscles of the respiratory system causing the patient to have difficulties in breathing. Ventilation measures taken at this stage assist in prolonging life but further atrophy eventually leads to a collapse of the system. This is why most ALS patients die of respiratory failure after 3-5 years from the initial reported symptoms. In their study on ALS prevalence, Lewis et al found that the median time for survival is 20 to 48 months though close to 20% of patients survive for periods longer than 10 years.
Treatment
Pharmacotherapy
The, Food and Drug Administration (FDA) has only licensed the use of one drug ALS treatment. This drug is known as Riluzole and it is a glutamate antagonist. Noh et al (2000) performed a therapeutic trial of Riluzole and found that the drug prolonged survival for close to six months. Alternatively, they found that in 124 cases, the drug actually slowed the pace of muscle atrophy in limbs. While the efficacy of glutamate points to a possible excitotoxic-glutamate cause in ALS pathogenesis, the non-responsiveness of the disease to other glutamate-antagonists such as dextromethorphan and lamotrigine have thrown proponents of the glutamate theory into a state of confusion.
Another drug that raised interest in the medical world was gabapentin, which like Riluzole, increased survival in transgenic mice that had mutant SOD1. However, the drug failed to prevent the onset of the disease. Vitamin E on the other hand has been shown to prevent the onset of ALS but eventually failed to prolong survival (Sato et al, 1997). However, both drugs failed to have a similar effect on ALS patients.
Other agents that researchers are working on that may produce positive effective control of ALS include; creatine, xaliproden, orally administered brain-derived neurotrophic factor, cyclooxygenase-2 and caspase inhibitors, intrathetically administered brain-derived neurotrophic factor and other high-throughput drugs.
Mechanical Ventilatory Support
Another option for ALS patients is to undergo mechanical ventilation procedures such as a tracheotomy. However, very few patients opt for this method due to its effects of immobility and huge cost. Alternatives are available in the form of non-invasive ventilation measures. Ventilation prolongs life by ensuring that the patient does not succumb to respiratory failure as is common in almost all ALS cases. It relieves pressure on the thoracic region and prevents pressure on the lungs.
Treatment for Depression
Sedatives and anti-depressants are usually administered to counter the depression that comes with an ALS diagnosis. This is because of the general assumption that all ALS patients end up becoming depressed yet it has only been found in about 11% of all patients in studies. Other ways to reduce depression are spiritual and psychological factors and physical therapy. Some cannabis proponents have suggested that the drug could be used to ease the psychological pressure on the patient.
Proposed Treatments
In the US, effective treatment for ALS had been hard to come by and patients had to lobby government and pharmaceutical companies to fund therapeutic trials in what Lewis et al (2001) refer to as guerilla science . The suggested treatments from the research are gene therapy and direct delivery of the gene for EAAT2 contained in a viral vector through an intraparenchymal injection so as to lower glutamate levels.
The greatest hope for the research has been to use stem-cell therapy to replace dysfunctional cells and reverse ALS effects. Perhaps the biggest setback to the success of stem therapy is the complexity and inter-connectivity of the human motor systems. However, even this cannot take away the protective value that stem-cell therapy has by preventing further damage to the motor neurons. The breakthroughs in stem-cell research have given ALS patients a second lease of life-literally.
The Effects of ALS on Self and Family
Mitsumoto and Munsat (2001) state that a diagnosis of ALS is usually traumatizing to the patient. The fact that the disease guarantees one a slow, painful death is hard to take for any person and most patients usually suffer from depression especially in the initial stages. Others consider assisted suicide or euthanasia as an option after considering the toll the disease will likely take on themselves and their families. Most patients usually have to hire a private nurse or get into a hospice or a similar program.
The stigma that comes with the disease also compounds the patients problems. Mitsumoto and Munsat (2001) explain that due to the weaknesses in muscles, the patient may usually suffer from a dropped gait, slurred speech, drooling, urinating on oneself, and staggering among others all that may be mistaken as drunkenness. Additionally, emotional liability causes the patients emotions to become overextended and they may laugh or cry unusually.
ALS is also a very expensive disease to maintain and available treatments such as new stem-cell therapy are classified under experimental treatments and are thus not covered by insurance. The family has to undergo emotional stress as well as a physical burden where the patients muscles fail him/her and he/she has to be assisted even for simple activities like taking a bath and walking about.
Restatement of thesis and conclusion
ALS is a very devastating disease due to the weakness and pain that it causes its patients. The disease can however be maintained through the administration of Riluzole which extends life and new treatment methods in the form of stem-cell therapy. The latter seeks to bring an end to the degeneration of the motor neuron and thus prevent the advancement of the disease. This means that early diagnosis can help the patient greatly in controlling the debilitating effects of the disease. This, in addition to continuing research in other medical frontiers, promises to eliminate ALS from the list of incurable diseases.
References
Jackson, C.E., Amato, A.A., Bryan W.W., Wolfe G.I. Sakhaee K., Barohn R.J. (1998). Primary Hyperparathyroidism and ALS: Is There a Relation? Neurology, 50, 1795-1799.
Lewis, P., Rowland, M.D., and Neil, A. S. (2001). Amyotrophic Lateral Sclerosis. New England Journal of Medicine, 344 (1), 1688-1700.
Mitsumoto, H., and Munsat, T.L. (2001). Amyotrophic Lateral Sclerosis: A Guide for Patients and Families. New York: Demos Medical Publishing.
Noh, K.M., Hwang J.Y., Shin H.C., Koh J.Y. (2000). A Novel Neuroprotective Mechanism of Riluzole: Direct Inhibition of Protein Kinase C . Neurobiological Disorders, 7 (4), 375383.
Sato Y, Honda Y, Asoh T, Kikuyama M, Oizumi K. (1997). Hypovitaminosis D and Decreased Bone Mineral Density in Amyotrophic Lateral Sclerosis. European Neurology, 37, 225-229.
Whitaker, C.H., Malchoff, C.D., and Felice K.J. (2001). Treatable Lower Motor Neuron Disease Due To Vitamin D Deficiency and Secondary Hyperparathyroidism. Amyotrophic Lateral Sclerosis Other Motor Neuron Disorders, 1, 283-286.
Younger, D. S., Rowland L. P., Latov, N., Hays A. P., Lang D.J., Sherman W., Inghirami G., Pesce M. A., Knowles D.M., Powers J., Miller J.R., Fetell M.R., and Lovelace R.E. (1991). Lymphoma, Motor Neuron Disease and Amyotrophic Lateral Sclerosis. Annual Neurology, 29, 78-86.
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