Narcolepsy
BACKGROUND
The prevalence of Narcolepsy in the United States is approximately one in every 2000, which makes it comparable to other Neurologic disorders including Multiple Sclerosis, and more common than other better known conditions such as Cystic Fibrosis.
SYMPTOMS
Cataplexy – Sudden paralysis while awake, these can be dramatic such as falling to the ground during an emotional moment or subtle such as dropping something or even just the drooping of an eyelid.
Excessive Daytime Sleepiness – Sleep attacks can be profound and can intrude significantly with daytime functioning, work, and relationships.
Hypnogogic Hallucinations – Dreams during transitions to and from sleep. Many patients with Narcolepsy can have very vivid experiences during their daytime lives as well, which are commonly mistaken for psychiatric illness.
Sleep Paralysis - Occasionally people with Narcolepsy are unable to move upon awakening, sometimes for several minutes. This can also rarely occur in people without Narcolepsy.
Sleep Disruption – though not considered one of the four classic or cardinal manifestations of Narcolepsy, it is now well appreciated that patients with Narcolepsy have problems with maintaining normal and consolidated sleep at night. One of the most effective medications for Narcolepsy is actually a Sleep Medication, Sodium Oxybate which is FDA approved for both Excessive Daytime Sleepiness as well as Cataplexy associated with Narcolepsy.
DIAGNOSIS
Diagnosing Narcolespy can sometimes be tricky because patients may not understand that many of their symptoms are all related to the disease. Likewise many physicians are not trained to screen for the condition. Somewhat surprisingly, it may be over 10 years before a Narcoleptic finally receives a diagnosis, and this is even if they are seeking medical attention. The reasons for this are complex and some are stated above. When patients undergo testing for Narcolepsy, other sleep problems may be discovered which may require treatment such as Insomnia or Sleep Apnea. Once treatment is initiated for these other problems, circling back around to thinking about Narcolepsy may only come about if patients have persistent complaints that justify further testing.
TESTING
Confirmation of Narcolepsy can be done on clinical grounds are requires documentation of Narcolepsy. However, usually patients undergo a Nocturnal Polysomnogram (PSG) and a Multiple Sleep Latency Test (MSLT), though they must have a normal preceeding night PSG. A MSLT is a series of 4 or 5 naps for up to 15 minutes that are spaced 2 hours apart. We will look for 2 or more Sleep Onset REM Periods (SOREMS) as well as a very short Mean Sleep Onset Latencies (usually less than 3 min each).
PATHOPHYSIOLOGY
We are learning more and more about Narcolepsy all the time. We know that there is markedly decreased or absent levels of hypocretin in the CSF, usually 90% absence or more. Marked reduction in or absence of hypocretin-containing neurons. CSF levels may have diagnostic role in future, though I do not perform spinal taps as part of routine diagnosis and testing currently. Idiopathic Hypersomnolence is a related disorder where patients have some of the symptoms of Narcolepsy but not all, or they may not have all the typical findings on their MSLT. In this disorder there is typically a 50% hypcretin knockout. Hypocretin is a neuropeptide produced in the Hypothalamus and is thought to be a regulator of sleep and wake systems.
Newer evidence has linked high levels of antibodies to Streptococcus, or ASO titers, to Narcolepsy. Hence, we are beginning to think of Narcolepsy as more of an autoimmune syndrome, or caused by an immune reaction from or to a bacterial infection. There is also a very high correlation of Narcolepsy is strongly associated with HLA-DQB1*0602 genotype, HLA-DR2 and HLA-DQ1. The human leukocyte antigen system (HLA) is the name of the major histocompatibility complex (MHC) in humans. The superlocus contains a large number of genes related to immune system function in humans. This group of genes reside on chromosome 6, and encode cell-surface antigen-presenting proteins and many other genes.
TREATMENT
Treatment is tailored to the individual, based on symptoms and therapeutic response. The time required to achieve optimal control of symptoms is highly variable, and may take several months or longer. Medication adjustments are also frequently necessary, and complete control of symptoms is seldom possible. While oral medications are the mainstay of formal narcolepsy treatment, lifestyle changes are also important. The main treatment of excessive daytime sleepiness in narcolepsy is with central nervous system stimulant drugs such as methylphenidate, racemic - amphetamine, dextroamphetamine, and methamphetamine, or modafinil (Provigil), a new stimulant with a different pharmacologic mechanism, and more recently, armodafinil (Nuvigil). In Fall 2007 an alert for severe adverse skin reactions to modafinil was issued by the FDA. In many cases, planned regular short naps can reduce the need for pharmacological treatment of the EDS to a low or non-existent level.
Cataplexy and other REM-sleep symptoms are frequently treated with tricyclic antidepressants such as clomipramine, imipramine, or protriptyline, as well as other drugs that suppress REM sleep. Venlafaxine (branded as Effexor XR by Wyeth Pharmaceuticals), an antidepressant which blocks the reuptake of serotonin and norepinephrine, has shown usefulness in managing symptoms of cataplexy, however, it has notable side-effects including sleep disruption.
Gamma-hydroxybutyrate (GHB), more commonly known on the pharmaceutical market as Sodium Oxybate, or Xyrem (branded by Jazz Pharmaceuticals), is the only medication specifically indicated and approved for narcolepsy and cataplexy. Gamma-hydroxybutyrate has been shown to reduce symptoms of EDS associated with narcolepsy. While the exact mechanism of action is unknown, GHB is thought to improve the quality of nocturnal sleep by increasing the prevalence of slow wave (delta) sleep (as this is the time when the brain is least active and therefore most at rest and able to rebuild and repair itself physiologically). GHB appears to help sufferers much more effectively than the hypnotic class of medications typically used for insomnia (hypnotics tend to obstruct delta wave sleep), so it can be vital to be properly diagnosed as narcoleptic rather than insomniac. GHB was previously available on the open market as a dietary supplement but was reclassified a controlled substance in the United States due to pressure associated with the abuse of the chemical (it is infamously known as the date rape drug). It can currently only be legally acquired through prescription, after very specific diagnoses (typically for narcolepsy itself).
In addition to drug therapy, an important part of treatment is scheduling short naps (10 to 15 minutes) two to three times per day to help control excessive daytime sleepiness and help the person stay as alert as possible. Daytime naps are not a replacement for nighttime sleep, especially if a person's body is natively inclined towards a nocturnal life cycle. Ongoing communication between the health care provider, patient, and the patient's family members is important for optimal management of narcolepsy. Finally, a recent study reported that transplantation of hypocretin neurons into the pontine reticular formation in rats is feasible, indicating the development of alternative therapeutic strategies in addition to pharmacological interventions.
