Sleep Disorders

What are your symptoms?
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Highlighting some of the symptoms of sleep disorders [15]

It is difficult to define sleep disorders but they can viewed as disturbances in our normal sleep patterns. According
to the updated version of International Classification of Sleep Disorders (ICSD-2), there are approximately 81 sleep disorders that can be characterized into 8 categories[13]. These disorders have been shown to have an affect on an individual's sleep, their cognition, ability to function properly during their daily lives and in some studies it has also been shown certain sleep disorders have been associated with causing major diseases or have been identified to be the precursors of other diseases. As a result, the significance of unwrapping the mysteries around these sleep disorders has become even more important as they have shown to drastically change a person’s life. As an example, a recent study reported in the journal Movement Disorder has made an association between Restless leg syndrome (RLS) and Parkinson’s disease (PD), where some individuals with RLS compared to those without RLS were more likely to develop PD[14]. Although this may not be a direct correlation and the fact it also requires much more research before such associations can be confirmed, this highlights the significance of examining symptoms, etiology and pathophysiology of sleep disorders to determine their treatments[13]. For this reason, this page will be examining the three common sleep disorders and the research associated with them: Narcolepsy, Cataplexy and Restless leg syndrome.

1. Narcolepsy

1.1 Overview

Narcolepsy with cataplexy
Showing the dreadful effects of narcolepsy with cataplexy [16]

Narcolepsy is a chronic sleep disorder found in 0.05% of the world population. According to the International classification of sleep disorders (ICSD-2) narcolepsy can be characterized into three categories: narcolepsy with cataplexy, narcolepsy without cataplexy, and secondary narcolepsy which is often associated with a medical condition [1]. Patients with Narcolepsy are often seen experiencing cataplexy (muscle atonia), hypnagogic hallucinations (occurs before sleep involving sensory events), sleep paralysis (inability in movement) and more severe is excessive daytime sleepiness (EDS) [2] . Excessive daytime sleepiness is characterized by the inability to control sleep/wake cycles. It can occur during a conversation, during play, while driving, hiking, eating; in other words, it can occur anytime. As a result of EDS, patients often describe being fatigue, show minimal energy and sometimes show symptoms of depression. Patients sometimes experience an automatic behavior as well where they describe having no recollection of task they performed due to an episode of micro-sleep [3]. Although this will be further discussed, it has been shown patients that suffer from narcolepsy have low production of orexin A and B neuropeptides that function to mediate sleep wake cycles, feeding and arousals [4].

1.2 Diagnosis: Sporadic and HLADQB1*0602

Narcolepsy has been identified to have both a genetic and an environmental factor. Patients are 10-40 times more likely to have narcolepsy if a member of their family has been diagnosed. Additionally, environmental factors such as a head injury, stroke, heavy metal and sometimes H1N1 vaccination have been linked to producing narcolepsy [1]. It can be diagnosed either through a polysomnogram (PSG) that measures disruptions in sleep, or through a multiple sleep latency test (MSLT) that measures the time it takes for an individual to sleep. However, although it may not be a reliable diagnosis, but an observation for the human leukocyte antigen (HLA) can be assessed by looking at the allele HLA DQB1*0602, which is found on chromosome 6 [1,3]. 85% of patients who have narcolepsy with cataplexy have this specific allele, while only 50% of the patients have this allele that have narcolepsy without cataplexy. One of the reasons it is bad diagnosis is because 12-13% of the normal individuals have also found to have this allele [1].

1.3 Histaminergic Network

Histamine is a neurotransmitter that is synthesized by the enzyme histidine decarboxylase (HDC) in the Tuberomammillary nucleus (TMN) of the posterior hypothalamus. It is said to play a pivotal role in the regulation of sleep/wakefulness. As a result many researchers started to examine the histaminergic pathway. The neurons of TMN project their axons to many different parts of the brain, in which these axons are also said to mediate HCRT (orexin) signaling. The study by Anaclet et al. looked at the distinct role of both histamine (HDC) and orexin (HCRT) through a knock-out. As expected, the cortex showed histamine deficiency when HDC was knocked-out and orexin deficiency when HCRT was knocked-out. However, one of the key things her experiment concluded was HDC promoted wakefulness in the cortex and HCRT promoted wakefulness that have found be a location dependent; in other words showing that both HCRT and HDC have a distinct role in promoting wakefulness but they work parallel [5-6]. Additionally, when brains of narcoleptic patients were observed, they saw low CSF histamine levels [5]. This makes sense because if both histamine (HDC) and orexin (HCRT) promote wakefulness, and if both histamine and orexin levels were low in narcoleptic patients, that would mean low wakefulness, and more EDS as seen in narcolepsy. Likewise Lin et al was the first research group to show good effects of H3R receptor antagonist as a treatment for EDS in narcoleptic patients, since H3R receptor not only play a role in sleep/wakefulness but also in the synthesizes and release of histamine [5-6]. However, more research is needed to prescribe histamine-related drugs as histamine has a very short life and takes long time to reach CSF [5].

1.4 Orexin: Orexin A and B Distinction (Kohlmeier KA et al)

As mentioned earlier, it has been found patients who suffer from narcolepsy have lower concentration of orexin neuropeptides in their brain. Orexin A and B/Orexin 1 and 2 are found to play an important role not only in sleep/wake cycles but also in feeding and arousals [1,4]. Orexin A and B act on their specific A and B G-protein coupled receptors that are often also the targets for other disorders beside sleep. These include obesity, stress and addictions. As an example, dual orexin receptor antagonists (DORAs) are used as therapeutic treatments for patients with insomnia. Studies around these receptors has also led researchers to try to find specific single orexin receptor antagonists (SORAs). A recent discovery led by kohlmeiers et al has found specific distinct functions of Orexin 1 and 2 through knock-out that may lead to researchers in the future to better find specific therapeutic SORAs for those suffering from narcolepsy. Kohlmeirers group decided to look at the brainstem mesopontine cholinergic [lacterodorsal segmental nucleus (LDT)] and monoaminergic [ dorsal raphe(DR) and locus coeruleus (LC)] neurons as orexin 1 and 2 are found to signal through these specific pathways. His group through whole cell recordings wanted to see if OX2 by knocking out OX1 receptor would depolarize and whether their would be the influx of Ca2+ through the L-type Ca2+ channels in LDT, DR, and LC neurons. Their data showed OX2 receptor was unable to depolarize LDT and LC neurons but did observe depolarization in the DR neurons. They still observed the influx of Ca2+ ions through the three neurons. They followed the same procedure for OX2 knock out and the results showed depolarization and increase Ca2+ influx in all three neurons suggesting regardless of what receptor KO, Ca2+ influx would still cause transcriptional signaling in LDT, LC and DR neurons. Despite specific limitations outlined in their article, this was the first experiment to show the distinction between each orexin receptors and through future research, one can possible develop better SORAs for narcoleptic patients [4]

2. Cataplexy

2.1 Overview

Although cataplexy is symptom of narcolepsy, it can examined as a separate sleep disorder that affects our population. Cataplexy can be described as muscle weakness/ loss of muscle tone where the individual is unable to move after collapsing to the ground (7-8). It has a major impact on an individuals life, since it is triggered by an emotional stimuli such as laughing, excitement, embarrassment, anger..etc [7-8]. Cataplexy can be characterized as either severe or mild. An individual who has experienced severe cataplexy, although not very common, will tend to lose muscle tone in its entire body and as a result will collapse to the ground. It is interesting to note, during a severe cataplexy attack the diaphragm/ocular muscles are the only muscles that don’t show any muscle weakness/ loss of muscle tone [7]. However, a mild cataplexy attack will affect the neck, arms or face. These attacks can last from one to two min, but if sustained for a longer period of time the individual will fall asleep. During muscle weakness/loss of muscle tone an individual is fully aware of its surroundings, however they are just unable to move [7-8].

2.2 Hypocretin (HLA DQB1*0602)

Since cataplexy is a symptom of narcolepsy, patients who suffer from these cataplectic attack also experience increased HLA DQB1*0602 and also suggest autoimmune destruction of orexin/hypocretin neurons [2,7,8]. Axons of these neurons travel from the lateral hypothalamus to many different parts of the brainstem nuclei, particularly referring to the mesopontine cholinergic and monoaminergic neurons [4,7]. It is believed hypocretin neuropeptides play a role in increasing muscle tone by releasing noradrenaline and serotonin from the locus coeruleus and the raphe nuclei. For this reason, they appear to be at its peak during the time of wakefulness. However, during the transition from wakefulness to sleep, these neurons from the locus coeruleus and the raphe nuclei are inhibited during REM sleep by the GABAb acting on its specific GABA receptors; thus inhibiting the hypocretin/orexin neuropeptides and resulting in muscle atonia. Researchers as a result have started examining GABA antagonist for the treatment of cataplexy as it has been shown, the muscle atonia that people experience during REM sleep is the same muscle atonia experienced during cataplexy [7].

2.3 Treatment: Antidepressants and GHB

Tricyclic antidepressants(TCAs) were the first drugs that showed positive effects on treating cataplexy by alleviating REM sleep. This was done by blocking the pre-synaptic re-uptake of catecholamines and serotonin as they are shown to be responsible with muscle/blood circulation and sleep. These are released by the adrenal medulla and locus coeruleus/raphe nuclei resulting in a higher post-synaptic depolarization [7]. However, over the years TCAs such as clomipramine and imipramine have been less used due to their side effects. More frequently, serotonin-norepinephrine reuptake inhibitors (SNRIs) and serotonin reuptake inhibitors (SSRIs) are being used [2]. In 2002 a new drug called sodium oxybate (family member of the gamma-hydroxybutyrate (GHB) famliy) was approved by the FDA when a double-blind placebo controlled study conducted on 254 patients alleviated cataplexy attacks by 69% over a 4 weeks study [7]. Since the discovery, more research was done on sodium oxybate and showed that it reduced not cataplexy but also EDS and narcolepsy with cataplexy. Despite its half life of thirty minutes and duration of the effect for up to two-four hours, it is still one of the most effective drugs [2]. As more is learned about the mechanisms of positive emotions and pathopshysiology of cataplexy, more efficient and better drugs will be produced to target maybe specific receptors in specific brain areas.

2.4 Medial Prefrontal Cortex (Oishi et al)

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Figure 1: Displaying the effects of positive emotion (triggered by chocolate)
in both wild type (A) and in Orexin KO mice (B) [8]

A recent article by Oishi et al are the first research group to record the involvement of medial prefrontal cortex (mPFC) in cataplexy through their study on orexin KO mice. They started their research by examining a stimulus that would show the cataplectic effects in mice that were observed through EEG and EMG activity. During cataplexy, mice experience high theta and low delta frequency in an EEG and low skeletal muscle activity in an EMG. As a result they decided to look at different foods that would produce the affects of cataplexy, since mice were shown to experience positive emotions when food was given as a reward stimuli. One of the foods Oishi’s group decided to test was chocolate. After conducting the study Oishi’s group concluded chocolate was the stimulus in orexin KO mice that produced similar EEG and EMG activity, which was earlier observed in cataleptic mice. Subsequently, they used Fos immunostaining technique to see how many brain regions were activated in those orexin KO mice after they fed them chocolate. They saw an increased fos expression in 27 different brain regions and hypothesized mPFC to be the vital region as early research by Ishikawar et al, Damasio et al…etc demonstrates mPFC is activated during positive emotions. Oishi’s group specifically looked at the anterior cingulate cortex (ACC) and the prelimbic cortex (PLC) as they are connected and part of the mPFC. In other words, the neurons that were activated in those orexin KO mice during their cataplexy attack after they fed the mice chocolate were those of the ACC/PLC neurons. As a result, next thing they wanted to see was the relationship between ACC/PLC neurons and cataplexy after feeding chocolate to those orexin KO mice. To do so, Oishi’s group injected an adeno-assoicated virus (AAV) containing modified GluCl channels + fos expression stain (fos immunostaining technique) into the ACC/PLC, where they discovered after injecting those KO mice with IVM, an anti-parasitic reversible inhibition drug for GluCl channels, fos expression (that meant cataplexy activity) in mPFC was reduced drastically. IVM was used because of its minimal effects on neurons in the brain lacking GluCl channels. Therefore further illustrating the involvement of ACC/PLC neurons who's cataplectic activity was reduced following the reversible inhibition of IVM. Further analyzing the ACC/PLC pathways, oishi’s group also concluded BLA, and MCH neurons may also be involved in producing cataplexy. However, there were also few limitations with the experiment as highlighted by Oishi’s group; BUT more research done on oishi’s statements may contribute drastically to the finding a cure for cataplexy [8].

3. Restless Legs Syndrome

3.1 Overview

This video gives a general understanding of RLS [17]

Restless leg syndrome (RLS) is a neurological sleep disorder that affects 2-3% of world population. Patients who suffer from RLS describe an odd sensation down their leg and to alleviate that sensation they start moving their leg; in other words, it is described as the inability to control leg movement either during sleep (PLMS) or during wakefulness (PLMW) [9-11]. Restless leg syndrome can be characterized into two categories: primary RLS and secondary RLS. Patients whose cause is unknown are described as suffering from primary restless leg syndrome [10]. They often have a genetic component to their syndrome where researchers have discovered 5 genes and 10 possible alleles: PTPRD, TOX3, MEIS1 are some examples of those alleles [9-10]. On the contrary, patients suffering from secondary RLS do not have a genetic aspect rather their condition is caused by a pre-existing condition/or disease. Unlike primary RLS, the syndrome does not worsen over time [10]. Additionally, it seems to affect more women than men and tends to occur every five to ninety seconds lasting between one or half a second [9]. However, these numbers can vary depending on the severity of RLS, wether it is severe or mild in patients. For this reason, it has a drastic effect on the patients sleep and their regular activities through the day [9-10]. Researchers have observed patients that are suffering from RLS appear to be sleeping on an average of less than 5.5 hours a day and despite reoccurring sleep loss there have been no abnormalities seen in the frontal lobe that is responsible for recalling long term memories, motor functioning and much more [12]. When researchers started to examine different parts of the brain, they observed a reoccurring pattern of low iron in the substantia nigra (SNc) [10].

3.2 Iron Deficiency

Iron deficiency seems to be the key diagnosis for those patients suffering from RLS. Using autopsy and MRI techniques, iron deficiency was found in both the substantia nigra (SNc) and also in the cerebrospinal fluid (CSF). Additionally, low levels of ferritin, a protein that stores and releases iron in the body were also found in the cerebrospinal fluid. Many studies have verified these findings but with additional research of Connor’s group we have also discovered dopamine metabolism, neuromelanin cells (NM) and transferrin receptors are also affected as a result of iron deficiency [10]. Therefore, oral iron supplements of 50-60mg can be prescribed to patients to alleviate some of their symptoms of RLS [9]. Although, we know oral iron has shown positive effects on RLS, a lot of mystery still surrounds around the mechanisms of low iron in restless leg syndrome disorder.

3.3 Treatment: Dopamine agonists, Non-pharmacological, Placebo

Other than oral iron supplements, dopamine agonists are also prescribed to patients with RLS. Currently approved by the FDA: Rotigotine, Ropinirole, and Pramipexole are non-ergoline dopamine agonists. The discovery of Levodopa and benserazide in 1982 by akpinar were the first ergoline dopamine agonists prescribed to patients, however were quickly discarded due to the its severe side effects and the recurrence of the symptoms coming back with long term usage. These discoveries eventually led to the current FDA approved agonists. Ropinirole was approved in 2005 where it has been shown to act directly on dopamine D3 receptors and drastically help to reduce PLMS during sleep, but not sleep/wake arousals. Dopamine appears to play a role in alleviating some symptoms of RLS. The effects of ropinirole were examined over a 66 week period on 404 patients where during the first 26 weeks, the pharmacological agent had lost its affect on 13% of the patients. Subsequently, during the next 40 weeks, the pharmacological agent had lost its affect on 16% of the 269 patients studied. A similar study was done on the effects of pramixpexole and of its placebo in a 26 week period where the affects had gotten worse in 9.2% of patients and 6% in those given placebo. Surprisingly, 56% of these patients had also developed EDS and 10% had developed other impulsive disorders. These studies illustrate the limitations of these drugs and calls upon more research to be done to establish specific pharmacological agents that are incapable of such loss of effects or the side effects. As mentioned before, placebo effects have also shown to be beneficial in treating RLS where meta-analysis from 36 studies done by Fulda et al, Fernandez et al, and Diederich et al have shown 1/3 of the patients showed some reduction in their RLS symptoms. However, these placebos had very minimal effects on treating PLMS during sleep. Subsequently, non-pharmacological studies were also done where 28 patients were put on a 12 week intensive physical leg program that also showed some improvements in reducing the severity movements in their legs. All these different approaches in treating RLS are still incomplete, however, a recent study done Allen et al’s group may shed some light in treating RLS [9]

3.4 Thalamic glutamate/glutamine in RLS (Allen et al)

Allen et al’s group focused their study specifically on the glutamatergic neurons because earlier studies have shown increased activity in the thalamus affects sleep. According to the statement by Allen’s group, they are the first group that confirms the overactivity of glutamatergic neurons found in patients suffering from RLS. In other words, they have shown an association with amount of glutamate/glutamine present and the amount of sleep disturbances experienced by the individuals with RLS. Their results further showed: PLMS during sleep and sleep disturbances, two symptoms of RLS act independently of each other suggesting that the effects patients experience are due to dopamine and glutamate/glutamine abnormalities. This phenomena can be observed through a pharmacological glutamate/glutamine drug, alpha-2-delta anticonvulsants gabapentin. This drug has been shown to play a positive effect in treating sleep disturbances in RLS; however, has shown minimal effects on treating PLMS during sleep. Similarity, dopamine agonists have been shown to play a pivotal role in PLMS comparing its minimal effects on treating sleep disturbances. Prior studies by Hornyak et al and Saletu et al have shown patients with RLS experience sleep disturbances usually around stage 2 of sleep. Data collected by Allen’s group shows increased glutamatergic activity during stage 2 of sleep. According to Allen’s group more research is still required to show whether increased glutamatergic activity affects sleep disturbances or increased sleep disturbances affects the increased glutamatergic activity. Therefore, although there are few limitations with their study as stated by Allen et al (i.e. need a bigger sample group), this study on RLS could potentially open many new doors in treating RLS [12]

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