Hypersomnia consists of conditions characterized by chronic or recurrent excessive daytime sleepiness and excess sleep. Hypersomnia is considered "secondary" if it is caused by an inability to get enough sleep, or by other medical problems or disease that result in sleepiness. The International Classification of Sleep Disorders divides primary hypersomnias between chronic forms, such as narcolepsy and Idiopathic Hypersomnia, and recurrent forms, such as Kleine-Levin Syndrome. Recent research suggests that Idiopathic Hypersomnia and Narcolepsy Type 2 may share a common pathological mechanism in which an endogenous peptide or small protein acting as a GABA agonist increases neuronal inhibition, resulting in sedation and sleepiness.
Idiopathic Hypersomnia (IH)
IH is a rare, incurable chronic neurological disorder characterized by pervasive daytime sleepiness despite adequate or extraordinary sleep amounts. IH is recognized under the International Classification of Sleep Disorders with established diagnostic criteria. According to these criteria, a person with IH (i) experiences excessive daytime sleepiness daily for at least three continuous months, (ii) exhibits objective evidence of a shortened sleep latency or prolonged sleep time, (iii) experiences neither cataplexy nor multiple periods of sleep onset rapid eye movement and (iv) the hypersomnia is not due to insufficient sleep syndrome, another sleep disorder, a medical or psychiatric disorder, medication use or substance use.
A notable feature occurring in many individuals with IH is prolonged, severe sleep inertia also known as sleep drunkenness. Sleep drunkenness consists of extreme difficulty awakening with repeated returns to sleep, irritability, automatic behavior and confusion. This is true despite a characteristically high level of sleep efficiency during night time sleep. People with IH are difficult to arouse from sleep and often resort to using special devices or procedures in an attempt overcome this difficulty. In addition to experiencing sleep drunkenness, many people with IH complain of a sense of impaired alertness, which they may refer to as brain fog and others complain of memory loss, mental fatigue and other cognitive difficulties. IH profoundly affects work, education and quality of life. Patients are often too sleepy to work or attend school regularly, and they are predisposed to develop serious performance decrements in multiple areas of function as well as to experience potentially life-threatening domestic, work-related and driving accidents. IH symptoms generally persist throughout life at a relatively stable level of severity. There are no approved treatments for IH.
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Narcolepsy is an incurable chronic neurological disorder of sleep-wake control characterized by disrupted nocturnal sleep and excessive daytime sleepiness. The classic four narcoleptic symptoms consist of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis, though only a minority of patients experience all of these symptoms. Excessive daytime sleepiness is chronic and severe and is typically manifested by sudden, irresistible bouts of sleep that can last a few seconds to several minutes and are referred to as sleep attacks. Many people with narcolepsy complain of a sense of impaired alertness, which they may refer to as brain fog, and others complain of memory loss, mental fatigue and other cognitive difficulties.
Two forms of narcolepsy are described in the International Classifications of Sleep Disorders: narcolepsy with cataplexy, or Narcolepsy Type 1 (Na-1), and narcolepsy without cataplexy, or Narcolepsy Type 2 (Na-2). Cataplexy is a sudden loss of voluntary muscle tone triggered by emotions and ranges in severity from a barely perceptible weakness in a limited set of muscles to severe bilateral paralysis where speech and movement are temporarily impossible. Na-1 is caused by loss or degeneration of hypocretin-secreting neurons, which leads to inappropriate intrusions of sleep into wakefulness and vice versa. Na-2 patients do not have cataplexy and have normal to mildly decreased levels of cerebrospinal fluid hypocretin. The predominant symptom in Na-2 is excessive daytime sleepiness.
Narcolepsy can have a significant negative impact on educational, occupational and interpersonal performance and function. There continues to be significant unmet medical needs in narcolepsy. A recent survey of over 1,000 people with narcolepsy was conducted by the FDA and 95% of responders reported treatment with at least one FDA-approved medication. Despite this, 74% complained of narcolepsy symptoms and 84% described impaired school or work performance and characterized their condition as moderate or severe.
Down syndrome (DS) is the most common form of intellectual disability with an incidence rate of about 1 in 700 births and a prevalence of more than 400,000 in the U.S. and just under 6 million worldwide. It is a genetic condition also called Trisomy 21 because people with DS have 3 copies of chromosome 21 rather than 2. People with DS share characteristic physical features and have a higher risk for congenital heart defects, gastroesophageal reflux disease, recurrent ear infections, obstructive sleep apnea, thyroid dysfunctions, and impaired vision and hearing.
Children with DS display a decline in IQ starting in the first year of life and trail cognitive development of their peer group throughout childhood. By adulthood, people with DS have IQs in the mild to moderately delayed (35–80) range. Impaired short term and long term memory which may result from hippocampal-mediated dysfunction is a hallmark for this population. Pronounced speech and language deficits are common and thought to be driven by significant deficits in verbal short term memory.
Though improvements in the treatment and management of physical complications have extended the projected life span of persons with DS from 12 years in 1949 to 60 years and beyond today (median of 49), there have been very few research and development efforts to address the cognitive disability in this population. Accordingly, this has been and remains a neglected and much underserved area of drug development. There are currently no pharmacological options to address the cognitive deficits in DS.
Today most people with DS require supervision and assistance from family or public agencies their entire lives. It is likely that even 10-20% improvements in cognition would have major benefits in learning, language and executive function and enable persons with DS to live more independently and to be more fully integrated in their communities. Furthermore, enhanced cognition could reduce the cost of care and burden to society, and significantly improve the quality of life for both people with DS and their families.