Pathogenesis, Causes, Symptoms, and Mechanism of Narcolepsy - Essay Example

?Narcolepsy is a neurological sleep disorder common man and canines. It affects one in every 2,000 humans and includes symptoms like daytime sleepiness, cataplexy, sleep paralysis, and hypogenic hallucinations (Black, 2005). There has been significant polemics in the beginning of 21st century over the incidence of Narcolepsy. For a long time, not a lot of effort was done to understand and find a cure for the disorder. However, the last decade has witnessed significant progress in identifying the causes and possible cure. This paper will evaluate the progress that has been made and make recommendations on what is the future direction of research on Narcolepsy. Narcoleptic experiments have been conducted on dogs and mice have all shown results pointing to an abnormality of a substance in the brain called hypocretin. This same result also showed up among humans. People that were diagnosed with Narcolepsy had low levels or no hypocretin cells at all and low levels or complete absence of hypocretin on cerebrospinal fluid (Black, 2005). Human leukocyte antigen or HLA is also being linked to the development of Narcolepsy on humans. HLAs are proteins found on the white blood cells that assist the body in fighting off external bacteria. There are evidences suggesting that the autoimmune system is attacking its own proteins. The result may lead to deficiency in the process of transmitting signals in the brain. However, this theory is yet to be proven. Compared to the past decades, these headways have been far more significant towards the understanding of Narcolepsy. However, the patterns and data being collected lack the consistency for any significant progress to be made preventing the development or curing an already developed narcolepsy. Narcolepsy has four common symptoms: excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations. This has been identified as a disorder in the 19th century but significant progress in research didn’t happen until the last decade (Nishino & Kanbayashi, 2005). For the longest time, researchers thought that ordinary sleep and narcoleptic sleep are the same, later studies have revealed that a Normal sleep is a cyclical process that alternates between periods of rapid-eye-movement (REM) and non­rapid-eye-movement (NREM) sleep. When one is under the NREM part, the whole body’s physical process slow down including pulse, metabolism, heartbeat, blood pressure, and brain wave activity. When the body goes into REM cycle begins, the brain becomes more active even when the whole body is still asleep. This was recorded using electroencephalograph (EEG). This is when people start dreaming. For healthy people, sleep actually begins in the NREM phase and it takes them an hour to go into the REM stage. After an hour or less, the body enters NREM and then REM, and so on (Chabas et al, 2003). During a narcoleptic sleep, the body doesn’t go into NREM. It goes straight into REM (Chabas et al, 2003) which makes the person sleep abruptly. Often, the person with the disease often don’t realise that they are about to sleep or they just fell asleep. Premature occurrence of REM is also related to cataplexy. Cataplexy is a type of paralysis or sudden weakness of muscles caused by extreme emotions such as anger, excitement or sadness. The person doesn’t exactly fall asleep but loses the ability to move. Some people find that only the limbs are affected but others actually lose the ability to movie their entire body. This stage can carry on for a couple of minutes (Black, 2005). This same symptom may happen when one just woke up. This is called Hypnagogic hallucinations. The paralysis happens before going to sleep or just as when a person is waking up. As the name indicates, the person experiences hallucinations including hearing sounds that were not even there. These episodes are vivid and it is not surprising for people to think the hallucinations are real (Chabas et al, 2003). Hypocretin Hypocretin, a.k.a. orexin, is a small protein or peptide that regulates the part of the brain controlling sleeping habits, appetite and general well-being. This part of the brain is called the hypothalamus. Hypocretin dictates whether a person is sleepy or awake and energetic. It is also the regulator of REM sleep. Apart from this, Hypocretin also influences one’s eating habits and the efficiency of the body’s motor function. Several autopsies revealed that patients with cataplexy had low levels of hypocretin almost to the point of absence (?110 pg/mL) in cerebrospinal fluid. Unfortunately, there is yet to be a conclusive study that will explain how the hypocretin dies and how it affects other central hypersomnia (Deloumeau et al, 2005).There are also other substances in the gene like dynorphon, neuronal activity-regulated pentraxin, and protein 3 (IGFBP3) that affects hypocretin (Ritchie, 2010). The increase of reports of sporadic narcolepsy as oppose to familial cases is proving that the death of hypocretin neurons is extremely affecting pathophysiological development of narcolepsy with cataplexy instead natural hypocretin deficiency (Ritchie, 2010). More studies have been made though and after the DNA of canine revealed that the Narcolepsy is indeed in the DNA, great progress have also been made on humans (Reily, 1999). Several experiments have already been conducted to know more about hypocretin neurons and one of the most progressive involved dogs. It was discovered that the changes in the gene prompted the brain on three different dog breeds. Hypocretin may also play a role in other sleeping disorders such as insomnia (Ritchie, 2010). Several experiments have already been conducted to know more about hypocretin neurons. One of these experiments involved dogs. It was discovered that the changes in the gene prompted the brain on three different dog breeds to change sleeping habits. This is what lead scientists to theorize that Hypocretin may also actually play a role in other sleeping disorders such as insomnia (Reily, 1999). Led by Dr. Emmanuel Mignot (1997), a team of researchers from the Stanford University Center for Narcolepsy in Palo Alto, California, the group manipulated the gene and injected it to a Dachshunds, Labrador retrievers and Doberman pinschers. Each dog breed showed different effects. Some showed sporadic day time sleepiness and some showed wakefulness. If these results are consistent with humans, genes may not be the only factor in Narcolepsy. The body make up will most likely dictate how the body will react to a specific stimulus such as hypocretin stimulus and how the body develops highly depend on diet and overall health (Ritchie et al, 2010). Researchers also believe that people may have less hypocretin neurons because the autoimmune system attacks the brain cells. What causes the attacks is also unknown. Autoimmune There also been a lot of indication that suggest Narcolepsy is connected to some irregularity in the autoimmune system. The autoimmune system is unable to identify its own proteins as an antigen. Antigen is a part or substance that does not naturally belong to the body. The autoimmune system of the body is programmed to attack any foreign object. Research determine that the attack happens against the brain peptide hypocretin. The death of hypocretin could trigger the development of narcolepsy. A subgroup of HLA called the DQB1-0602 is also present among Narcoleptic patients with cataplexy and sleep paralysis or the difficulty of moving limbs before or after sleep. As several studies have already established the strong connection of HLA and Narcolepsy. This is also being used as substantiation in indicating the connection between Narcolepsy and the autoimmune process. Researchers at the University of Lausanne, Switzerland, conducted one of the most definitive studies that linked auto-immune system or auto-antibodies to narcolepsy. The immune system usually is able to identify anything that is foreign and attacks it. It is the first line of defence of the body. When there is an abnormality in the autoimmune system, it is unable to identify what is foreign and what naturally belongs to the body (Deloumeau et al, 2010). The autoimmune system irregularity causes it to attack a natural protein called Trib2. This causes paralysis in the body which causes it to collapse or fall asleep abruptly. This theory seems to support peripubertal age of the development Narcolepsy to human beings. They are able to prove that certain people have an immunity system that specifically targets the hypocretin cells (Nishino et al, 2009). As mentioned, the body’s immune system is supposed to be able to identify anything foreign or organic in the body. What is unclear is how the immune system ends up unable to identify the hypocretin as a foreign substance in the body. It is when the immune system destroys too much hypocretin that Narcolepy starts developing (Black, 2005). There are currently no confirmed explanation and that may just be the biggest challenge of neurologists in relation to sleeping disorders especially because the immune system is one of the many functions of the body is that is highly dictated by external variable such as diet, body resistance and overall health. When the brain gets attacked, it is the hypocretin that gets destroyed. Any conclusive evidence that would affirm the autoimmune hypothesis of human narcolepsy would need direct connection of a specific autoantibody and a defined neural target (Black, 2005). Genes Narcolepsy is a genetic condition. Thus, it is highly probable for several Narcoleptic people to be in the same family circle. There is an estimate stating that of all Narcoleptic patients, eight to 10 percent is related to another Narcoleptic. There is a one to two percent average of a Narcoleptic patient to have a Narcoleptic parent or sibling. This is by no means an indication that genetics is the only factor in developing the disorder. The mere fact that there are people who develop Narcolepsy in adolescence and even much later in life could indicate that external factors could be playing a part. These factors include trauma, hormonal change, and even stress. Those who have the HLA-DR15 and HLA-DQ6 genes are most likely to be susceptible to external triggers. There have been many attempts to prove that Narcolepsy is genetically linked. Many studies suggest a genetic influence to narcolepsy. One of the strongest attempts made was back in the 1970s when Kessler found that out of 50 Narcoleptic people, a total of 9 Narcoleptic patients and 17 EDS patients with EDS were among first-degree relatives. Chabas and colleagues (2003) sampled 334 Narcoleptic patients. Out of this, 40% had at least one relative with daytime sleepiness but no formal diagnosis and six percent had diagnosed Narcolepsy. He furthered Narcolepsy with Cataplexy was present in in one to two percent among first degree blood relatives and four times that with other symptoms related to Narcolepsy. Black (2005) was able to link Narcolepsy with cataplexy to the human leukocyte antigen (HLA) subtypes DR2 (DRB1*1501) and DQ (DQB1*0602). A study concluded that at least one of the subtypes were discovered among Narcoleptic people. Most African American Narcoleptic patients had DQB1*0602. There are also some variations on the symptoms associated with Narcolepsy. Cataplexy, for example, had 85 percent to 95 percent DQB1*0602 presence. Those that didn’t show signs of cataplexy had less DQB1*0602 with 40 percent. The only problem is that it cannot be formally used as a diagnostic guideline because the general population had a prevalence of 26 percent (Maret & Tafti, 2005). This could indicate tendency. The development of this tendency would depend on other factor such as the environment (Chabas et al, 2003). HLA-DQ is not the only genetic sign that seeds Narcolepsy in the system of a person. Nakayama and colleagues (2000) also found that chromosome 4p13-q21, olymorphisms in the tumor necrosis factor (TNF) alpha and TNF receptor 2 genes have also been implicated. may be common among all Narcoleptic patients (Klein & Sato 2000). Environmental factors such as acquired diseases, head trauma, or even fluctuating health habits like diet, stress and sleep deprivation may contribute to developing Narcolepsy already present in the gene (Kroeger & Lecea, 2009). Conclusion The lack of vigilant interest to conclusively determine the causes of Narcolepsy is primarily due to the absence of life threatening effects. Aside from possible bumps or accidents a person with Narcolepsy might encounter during sleep attacks, no other reports remotely threatens the life of those who have it. However, the discovery on the connection between Narcolepsy and the autoimmune system might change this perspective (Black 2005). The antibodies are the first line of defence of the body. When it starts attacking what naturally belongs to the body. Future studies must be pursued to further understand whether the attacks are limited to Trib2 and what are the characteristics of Trib2 that makes the antibodies unable to identify it as an organic part of the body. There are children that are reported to have Narcolepsy but most cases happen between the ages of 15 and 25 (Chabas et al, 2003). Noticeably, it develops during the time when people have already been great affected by external stimulus such as food. This could further prove that the environment really play a big part in the development of Narcolepsy. Researchers believe, though, that even more cases go unreported, undiagnosed and untreated. There is also a need to explore the external stimulants that cause the body to develop Narcolepsy. Based on the studies, not everyone that has the Narcoleptic gene will develop Narcolepsy. Is it diet? General physical health? Certain environment triggers? Understanding what these factors are might be the key in preventing the disorder from fully developing. References Black , Logan III, J. (2005). Narcolepsy: A review of evidence for autoimmune diathesis. International Review of Psychiatry, 17(6), 461-469 Chabas, D., Taheri, S., Renier, C., & Mignot, E. (2003). THE GENETICS OF NARCOLEPSY. Annual Review of Genomics & Human Genetics, 4(1), 459-483 Deloumeau, A., Bayard, S., Coquerel, Q., Dechelotte, P., Bole-Feysot, C., Carlander, B., & Dauvilliers, Y. (2010). Increased immune complexes of hypocretin autoantibodies in narcolepsy. Plos One, 5(10), e13320 Klein, J., & Sato, A. (2000). The HLA system. First of two parts. The New England Journal Of Medicine, 343(10), 702-709. Kroeger, D., & de Lecea, L. (2009). The hypocretins and their role in narcolepsy. CNS & Neurological Disorders Drug Targets, 8(4), 271-280 Maret, S., & Tafti, M. (2005). Genetics of narcolepsy and other major sleep disorders. Swiss Medical Weekly, 135(45-46), 662-665. 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