My father has been living with ALS for more than 15 years.
We have had to watch my dad lose functionality of his voluntary muscles until he became 100% disabled and dependent on a ventilator to breathe. He is still “all there” in his mind, but communication is difficult. My mom made a board with common commands on one side, and letters on the other so that he can let us know what he needs. We all pitch in to help when and where we can, but my mom does the bulk of the work. The beautiful thing is, they both still smile!
To learn more about ALS, please watch everything about ALS that I could cram into a 7 minute video:
(Watching is more interesting than reading about ALS)
WRITTEN OVERVIEW OF INFORMATIONAL VIDEO:
Amyotrophic Lateral Sclerosis as a Multiple System Neurodegenerative Disorder
Amyotrophic Lateral Sclerosis (ALS) is an adult onset neurological disorder characterized by the progressive and complete loss of voluntary muscle control due to upper and lower motor neuron death in the brain and spinal cord. There are other symptoms associated with ALS that receive less attention, perhaps because they don’t “fit” with the more obvious physical symptoms of ALS. An example is the narrow understanding of why motor neurons that supply the extraocular muscles with nerves are resistant to degeneration (Hideyama and Kwak, 2011). The rare ALS cases of sensory neuropathy in which the patient reports lack of feeling or odd feeling in limbs are another example.
Cognitive and behavioral symptoms, such as slower executive function and apathy, are also often-overlooked pieces of the ALS picture. Because ALS pathology ranges beyond the motor system and into frontotemporal dementia (FTD), Turner, Kiernan, Leigh, and Talbot (2009) were among those to assert the disease as a “multiple system neurodegenerative disorder”.
Unfortunately, even as knowledge is gained about this disease, not a lot of success has been made in the area of treatment for ALS patients. With only one medication approved in two decades, and a history of “failed” studies, the “big picture” of amyotrophic lateral sclerosis is still incomprehensible.
From a Greek origin, the words “amyotrophic lateral sclerosis” are broken down into: “a” means no, “myo” refers to muscles, “trophic” means nourishment (“no muscle nourishment”); “lateral” (toward the sides) is the area of the spine where the brain tells the muscles what to do; “sclerosis” is abnormal hardening of tissues. As the disease progresses, the lateral areas harden and the signals to the muscles stop. A person with ALS can still receive signals from affected areas of his or her body, as well as notice bodily urges, so the paralysis is most often (but not always) one way.
More than 90% of ALS cases are seemingly random (sporadic), whereas the remaining ALS cases have more than one other affected family member (familial). So far, 11 genes have been identified as associated with familial ALS, including the SOD1 gene that induces familial ALS in transgenic rodents (Almeida, 2012).
Hideyama et al. (2011) confirm reports that the death cascade of motor neurons are due to TDP-43 (DNA-binding protein) pathology. TDP-43 is identified as a major disease protein that does not only affect RNA regulation in the motor system, but multiple areas of the central nervous system. This may explain why symptoms are not strictly localized to motor neurons.
Physiological Basis of ALS
The physical symptoms of ALS usually begin with progressive hand or foot muscle weakness (limb onset; 75% of cases), or with weakness in the face and tongue muscles (bulbar onset). Other symptoms include sudden clumsiness (tripping and falling), chronic fatigue, muscle cramps, and visible twitching in arms, shoulders, or tongue. There are no tests that can diagnose ALS, so identification of the disease comes from ruling out everything else that may have common symptoms with ALS. It usually takes a year for this testing process (Witgert, Salamone, Strutt, Jawaid, Massman, Bradshaw, and Schulz, 2010), unfortunately by this time, substantial neuromuscular connectivity and muscle atrophy has occurred (limiting medication’s effectiveness).
As the disease progresses, it becomes increasingly difficult to swallow, breath normally, walk, or speak, and the use of aides become necessary. For example, canes, walkers, and wheelchairs are needed for mobility; caregivers must puree foods to avoid choking; and a non-invasive breathing apparatus worn at night helps by ensuring adequate oxygen intake; special eye-controlled computers facilitate communication since the muscles in the eyes are resistant to motor neuron degeneration. Eventually, more invasive procedures are needed, such as a feeding tube inserted into the stomach in order to allow for aspiration-free nutrition.
Oxygen levels drop as lung performance declines, and muscle fatigue (from oxygen deficiency) makes any movement extremely tiring, and possibly explains impairments in thinking and behavior. Without an invasive ventilator (requiring a tracheotomy), ALS is 100% fatal due to respiratory muscle failure within 2 to 4 years from diagnosis (Turner et al., 2009).
ALS obviously heavily effects motor nerves, but sensory nerves can show pathology as well (Isaacs, Dean, Shaw, Al-Chalabi, Mills, and Leigh, 2007). Isaacs et al.’s case study describes five patients found in their clinic’s database in which sensory nerve degeneration may be more evidence for the ALS multiple system disorder hypothesis. Isaacs et al. could not attribute the lack of feeling in the patient’s limbs to any cause other than sporadic ALS.
Behaviors Associated with ALS
Recent research is confirming the 100+ year old clinical observation that ALS has pathological processes that extend beyond the motor system and into at least some cognitive impairments seen in 40-60% of patients (Witgert et al., 2010; Turner et al., 2009).
Phukan and Hardiman (2007) found that the cognitive and behavioral symptoms found in ALS patients overlap clinically with frontotemporal dementia (FTP) radiologically, pathologically, and genetically. When ALS symptoms present with frontotemporal dementia (muscle atrophy with damaged or slow executive brain function), the patient receives a comorbid diagnosis of FTD-ALS (Merrilees, Klapper, Murphy, Lomen-Hoerth, & Miller, 2010).
Masellis, Zinman, and Black (2010) note that these symptoms include apathy, self-centeredness, indifference, perseveration (the repeating of a word, phrase, or gesture), irritability, emotional blunting, inflexibility, restlessness, obsessions, and repetitive/stereotyped behaviors. Phukan et al. (2007) would add personality change, poor insight, and pervasive deficits in frontal executive tests to the list of cognitive and behavioral symptoms found in ALS patients.
In upwards of 50% of the 241 sporadic ALS patients studied, at least some cognitive and behavioral symptoms had been observed at some time, but only 15% of these cases were severe enough to be diagnosed as dementia, and 24% labeled frontal-lobe mediated behavioral dysfunction (Witgert et al., 2010).
Apathy and executive dysfunction received the highest scores in a study conducted by Witgert et al. (2010), who took care to distinguish between apathy, depression, and fatigue (as they have common behavioral outputs). These cognitive and behavioral symptoms seem to exceed the natural and understandable responses one might exhibit upon being diagnosed and/or living with ALS, and like the physical symptoms, are progressively degenerative.
In those with FTD-ALS, the median survival is only 2 years and 4 months compared to the median of 3 years and 3 months in ALS patients without FTD (Merrilees et al., 2010), so patient/family-care planning is especially important in ALS cases that present with FTD.
Possible Treatments (Prolonging Life of ALS Patients)
Since 1995, there has only been one FDA approved medication for use in ALS patients. Riluzole has been reported to promote neuronal survival by inhibiting electrically evoked release of glutamate, acetylcholine, dopamine, and serotonin (Bellingham, 2011) as well as accelerating glutamate uptake. This medication has been shown to modestly, yet consistently extend life.
Research conducted by Hideyama et al. (2011) considers that excitotoxicity (and therefore motor neuron death) begins to occur when unhealthy motor neurons expressing unedited GluA2 (due to faulty TDP-43) overtake normally functioning motor neurons (those that express edited GluA2); therefore, forcing motor neurons to express only edited GluA2 may be a viable therapy for ALS.
Takeuchi, Mizoguchi, Doi, Jin, Noda, Liang, and Suzumura (2011) have focused on microgliosis, the accumulation of activated microglia, as the hallmark of ALS and various other neurological disorders. Microglia are small neuroglia that are activated by inflammation in the central nervous system, which may be triggered by neurological degenerative disorders. In this study, excitotoxicity via N-methyl-D-aspartate (NMDA) receptor signaling was induced by activated microglia releasing large amounts of glutamate. In an effort to block glutamate receptors without leading to severe adverse effects, Takeuchi et al. explored the gap junction hemichannels (the main avenue of excessive glutamate release) in transgenic rodent models. Rodents exposed to this therapy showed cessation of motor neuron death. This finding suggests that a blockade of gap junction hemichannels (with their novel blocker named INI-0602) may be an effective long-term treatment to counteract microglia-induced excitotoxicity in all neurodegenerative diseases.
There is no available treatment for the cognitive and behavioral challenges ALS patients face, and worse, these symptoms make complying with their doctor’s suggestions for care unlikely as decision making skills are impaired.
Patients and their care-givers can be better served with education on the multiple systems potentially affected by ALS in addition to the more common physical symptoms. Coping with the physical symptoms of this disease if often challenging enough, so caregivers need to understand their patient’s negative behaviors in order to not take the behaviors “personally”.
Researching scientists may be limiting their effectiveness by focusing on only on the physical aspect of this disease. There may be a chance that taking multiple symptoms into account will reap benefits from research conducted on other neurological disorders.
Further research should look for ways to take advantage of the less vulnerable motor neurons in the oculomotor nerves in ALS patients. I would also like to see more research done to exclude low oxygen/ high carbon dioxide levels from the cause of frontotemporal dementia seen in ALS patients.
Support of the community is monumental to the development of helpful services provided by the ALS Association. The ALS Association describes many research avenues on their website being pursued by Mayo clinic staff intent on halting the progression of the ALS pathology. One line of research includes adapting Antisense Technology (the development of drugs that bind to RNA instead of proteins). There are also stem cell trials, “transplantation of Autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors”. This trial uses the patient’s own body fat cells (cultured for 6-8) as neuron protective agents. These stem cells are injected into spinal fluid in hopes that they produce growth factors that help neurons to live longer. Neither of these trials have been released yet (as of 8/2015).
ALS Research Resources:
Almeida, J. M. (2012). Exercise and amyotrophic lateral sclerosis. Neurological Sciences, 33(1), 9-15.
Bellingham MC. (2011). A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? CNS Neuroscience & Therapeutics, 17(1), 4-31. doi:10.1111/j.1755-5949.2009.00116.x
Hideyama, T., & Kwak, S. (2011). When Does ALS Start? ADAR2–GluA2 Hypothesis for the Etiology of Sporadic ALS. Frontiers in Molecular Neuroscience, 4, 33. doi:10.3389/fnmol.2011.00033
Isaacs, J., Dean, A., Shaw, C., Al-Chalabi, A., Mills, K., & Leigh, P. Nigel (2007). Amyotrophic lateral sclerosis with sensory neuropathy: part of a multisystem disorder? BMJ Group. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2117693/
Masellis, M., Zinman, L., & Black, SE. (2010). More than just ‘frontal’: disentangling behavioural disturbances in amyotrophic lateral sclerosis. European Journal Of Neurology: The Official Journal Of The European Federation Of Neurological Societies, 17(1), 5-7. doi:10.1111/j.1468-1331.2009.02800.x
Merrilees, J., Klapper, J., Murphy, J., Lomen-Hoerth, C., & Miller, B. L. (2010). Cognitive and behavioral challenges in caring for patients with frontotemporal dementia and amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis, 11(3), 298-302. doi:10.3109/17482961003605788
Phukan J., Pender NP, & Hardiman O. (2007). Cognitive impairment in amyotrophic lateral sclerosis. The Lancet. Neurology, 6(11), 994-1003.
Takeuchi H, Mizoguchi H, Doi Y, Jin S, Noda M, Liang J, & Suzumura A. (2011). Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer’s disease. PloS One, 6(6), E21108. doi:10.1371/journal.pone.0021108
Turner MR, Kiernan MC, Leigh PN, & Talbot K. (2009). Biomarkers in amyotrophic lateral sclerosis. The Lancet. Neurology, 8(1), 94-109. doi:10.1016/S1474-4422(08)70293-X
Witgert, M., Salamone, A. R., Strutt, A. M., Jawaid, A., Massman, P. J., Bradshaw, M., & Schulz, P. E. (2010). Frontal-lobe mediated behavioral dysfunction in amyotrophic lateral sclerosis. European Journal Of Neurology, 17(1), 103-110.