Providers face challenges in teasing out narcolepsy symptoms from those of comorbid disorders, but it is important to diagnose comorbidities appropriately for treatments to be more effective.
On September 24, 2013, patients with narcolepsy and others indirectly affected by the disorder gathered in Silver Spring, Md, on the campus of the Food and Drug Administration (FDA) to speak directly to regulators concerning the impact of the sleep disorder on daily life and issues concerning its available therapies and drug development.1 This meeting, the Patient-focused Drug Development Initiative, was the first session dedicated to this rare disease. To prepare patients, family, and caregivers for this meeting, Wake Up Narcolepsy Inc—a nonprofit organization dedicated to improving the diagnosis of narcolepsy and helping to find a cure—posted on its site a comprehensive survey about narcolepsy. More than 1,350 respondents answered the survey anonymously, and the information from their responses was presented at the FDA meeting. The survey revealed a high rate of certain conditions that were comorbid with narcolepsy, which corroborated the findings of several research investigations.1
Nearly all people with narcolepsy struggle with excessive sleepiness. Approximately 70% of people with narcolepsy suffer from cataplexy.2 Sudden muscle weakness during a cataplexy episode can affect a few muscles (for example, facial muscles) or all skeletal muscles at once. The latter can result in a fall to the floor as if fainting; however, the person remains alert throughout the episode.
Cataplexy was initially used to divide narcolepsy into two subtypes: “narcolepsy with cataplexy” and “narcolepsy without cataplexy.” As new findings have emerged about the disorder, scientists have begun revising the features of the subtypes of narcolepsy. Now the subtypes are “narcolepsy type 1” and “narcolepsy type 2.”3 (Learn more about the subtypes in “Narcolepsy’s New Names,” published in the May 2014 issue of Sleep Review.)
The Wake Up Narcolepsy Survey found that two-thirds of respondents had one or more medical conditions in addition to narcolepsy. The most frequent comorbid conditions reported were anxiety, sleep apnea, migraines, and fibromyalgia or other chronic pain conditions. The Wake Up Narcolepsy Survey was an informal investigation. More formal investigations into narcolepsy and comorbid conditions also reveal an association between narcolepsy and some of these same conditions, as well as other comorbid conditions.
Researchers Birgit Frauscher et al reviewed the polysomnographic records and medical charts of 100 narcoleptic patients to determine which comorbid conditions existed. The review showed the patients had the following comorbid conditions: rapid eye movement (REM) sleep without atonia (90%); periodic leg movements (75%); sleep fragmentation (68%); sleep-related movement disorders such as bruxism and restless legs syndrome (55%); high-frequency leg movements such as hypnagogic foot tremor and alternating leg muscle activation during sleep (35%); parasomnias such as REM sleep-behavior disorder (RBD) and non-REM parasomnias (34%); insomnia (28%); restless leg syndrome (24%); sleep-related breathing disorders such as obstructive sleep apnea, mixed sleep apnea, or central sleep apnea (24%); and excessive fragmentary myoclonus (22%).4
Psychiatric comorbidities were major depression (2%), bipolar disorder (2%), substance abuse disorder (2%), anxiety disorder (1%), and the first manic episode with psychotic symptoms (eg, acoustic hallucinations with a religious content) (1%). Based on these findings, Frauscher suggests that REM sleep without atonia, a periodic leg movement index greater than five movements per hour, and sleep fragmentation could be polysomnographic features of narcolepsy. Frauscher further suggests that narcolepsy may need to be considered in people with a complaint of insomnia.
Maurice Ohayon interviewed narcoleptic patients using Sleep-EVAL and found that the five most common diseases among people with narcolepsy were (in decreasing order) digestive system diseases, upper respiratory tract diseases, heart disease, hypercholesterolemia, and hypertension.5 The most frequent psychiatric disorders were major depressive disorder and social anxiety disorder, both of which affected nearly 20% of narcoleptic individuals. Based on these findings, Ohayon encourages clinicians to address these comorbidities when developing a treatment plan.
Many people with narcolepsy have struggled with symptoms for up to 15 years, on average, before finally receiving a correct diagnosis.6 They are often diagnosed or misdiagnosed with other disorders first. For example, Poul Jennum and colleagues examined conditions people tended to be diagnosed with 3 years before a narcolepsy diagnosis and 3 years after the diagnosis.7 Before a diagnosis of narcolepsy, people were often treated for sleep apnea and central hypersomnias. After diagnosis, the most significant diagnoses were (in decreasing order) other sleep disorders, sleep apnea, obesity, neurological diseases, chronic obstructive pulmonary disease, low back pain, osteoarthritis, diabetes, and other diseases.
A misdiagnosis can delay appropriate treatment for narcolepsy. For example, excessive daytime sleepiness may be misdiagnosed as depression, cataplexy may be misdiagnosed as epilepsy, and arousals from sleep may be misdiagnosed as insomnia.
Part of the reason for a misdiagnosis is because clinicians are often unaware of narcolepsy symptoms. Clinical psychologist Shelby Harris, PsyD, CBSM, director of the Behavioral Sleep Program at Montefiore Medical Center in New York, tells me via personal correspondence, “Any clinician who is confronted with a patient that reports excessive daytime sleepiness should have narcolepsy in their mind as a possible diagnosis. Sure, there’s lots of diagnoses that have EDS [excessive daytime sleepiness] as a symptom or red flag (eg, sleep apnea), but too often clinicians don’t even think of narcolepsy as a possibility. Far too frequently I encounter clinicians who have never heard of cataplexy and don’t know some simple questions to assess for it. Although it is getting better, the average time to accurate diagnosis for a patient with narcolepsy has been 15 years—this is unacceptable.”
Once a person is diagnosed with narcolepsy, a comorbid condition could make treating narcolepsy difficult. Harris says, “I do see a lot of patients who have narcolepsy along with depression, and at times it can be tough to tease apart what is due to narcolepsy and what is due to depression. Honestly, in many cases it is both.”
This distinction between whether narcolepsy or a comorbid illness or both are primarily responsible for a symptom can be important for treatment. For example, treating obstructive sleep apnea in a person with narcolepsy may provide a substantial reduction in sleepiness. However, if the person were treated for narcolepsy but not obstructive sleep apnea, an excessive level of sleepiness could remain, despite appropriate treatment for narcolepsy.
It is also possible that a drug treatment for a comorbid illness in a person with narcolepsy could conflict with the treatment goals for narcolepsy. For example, treating a person with narcolepsy and heart disease can be difficult because stimulants that are used to increase alertness in people with narcolepsy have adverse effects on the cardiovascular system.
To what extent narcolepsy may contribute to comorbid conditions is unclear and continues to be investigated. For example, many people with narcolepsy are also obese or overweight. Scientists suspect the increased adiposity may be related to the loss of hypocretin-producing neurons in the brain of people with narcolepsy.8,9 Hypocretin is a hormone that is involved in alertness and in appetite. When these cells are destroyed (possibly as an autoimmune destruction), the consequences are impaired wakefulness and impaired energy balance, which leads to weight gain.
Improved efforts to educate patients, caregivers, and medical professionals about the increased prevalence of certain conditions in people with narcolepsy may reduce the time it takes for a person to receive a proper diagnosis of narcolepsy. With this awareness, medical professionals will more quickly send a person to a sleep center to be assessed for narcolepsy and patients may be more willing to undergo a sleep study for what appears to be a problem unrelated to their presenting complaint. Research investigations, patient input to governmental organizations, and support organizations for people with narcolepsy are just a few of the avenues through which this educational goal can be accomplished.
1. Wake Up Narcolepsy Inc. Patient-focused narcolepsy survey: interim analysis. 2013. http://www.unitenarcolepsy.org/wp-content/uploads/Interim-Survey-Analysis-v1.pdf. Accessed April 25, 2015.
2. US Department of Health, Public Health Service, National Institutes of Health. Narcolepsy. 2013. http://www.ninds.nih.gov/disorders/narcolepsy/narcolepsy_fs.pdf. Accessed May 10, 2015.
3. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, Ill: American Academy of Sleep Medicine; 2014.
4. Frauscher B, Ehrmann L, Mitterling T, et al. Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the Innsbruck Narcolepsy Cohort. J Clin Sleep Med. 2013;9:805-812.
5. Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 2013;14:488-492.
6. Thorpy MJ, Krieger AC. Delayed diagnosis of narcolepsy: characterization and impact. Sleep Med. 2014;15:502-507.
7. Jennum P, Ibsen R, Knudsen S, et al. Comorbidity and mortality of narcolepsy: a controlled retro- and prospective national study. Sleep. 2013;36:835-840.
8. Nakamura M, Kanbayashi T, Sugiura T, et al. Relationship between clinical characteristics of narcolepsy and CSF orexin-A levels. J Sleep Res. 2011;20(1 Pt 1):45-49.
9. Sonka K, Kemlink D, Buskova J, et al. Obesity accompanies narcolepsy with cataplexy but not narcolepsy without cataplexy. Neuro Endocrinol Lett. 2010;31:631-634.