Differentiation of Narcolepsy TYPE I, TYPE II, and Idiopathic Hypersomnia
Narcolepsy Type I (Formerly Narcolepsy with Cataplexy)
The diagnosis of Narcolepsy can be challenging. It is firmly established that most cases of Narcolepsy Type I are caused by deficiencies in hypocretin (also known as “orexin”) signaling due to loss of hypothalamic hypocretin producing neurons. A vast majority of patients (90 – 95%) with type I Narcolepsy have undetectable, or low (<110pg/ml) levels of hypocretin in CSF fluid. Patients without cataplexy may also have low hypocretin levels but with lower frequency.
Excessive daytime sleepiness is the cardinal symptom of both types of narcolepsy and idiopathic hypersomnia, and often the most disabling. Patients with Type I narcolepsy experience repeated daily episodes of extreme sleepiness. Most patients awaken from these episodes refreshed, however, this is only for a short time. In some instances sleepiness may manifest as sudden irresistible urges to sleep (sleep attacks) that occur in unusual situations such as while walking, eating or talking to another person. Even when seemingly awake many narcoleptics express automatic behavior such as writing gibberish or interrupting a normal conversation with a completely different topic.
Cataplexy is the defining characteristic of narcolepsy with cataplexy. It is defined as “More than one episode of generally brief (<2 min.), of sudden loss of muscle tone with retained consciousness”. Episodes may be precipitated by strong emotions such as laughter or anger. Cataplexy differs greatly between patients and ranges from sporadic, partial episodes to complete attacks of collapse.
In addition to sleepiness and cataplexy, patients with narcolepsy type I often report disruption of nighttime sleep, sleep onset is rarely a problem, however, inability to maintain continuous sleep is very common. Hypnogogic hallucinations, defined as “ vivid dreamlike experiences occurring at the transition from wake to sleep” are present in 30 – 80% of patients. Hypnogogic hallucinations may be accompanied by visual, auditory or tactile phenomena. Sleep paralysis describes the disturbing temporary inability to move voluntary muscles at sleep to wake transitions. Other symptoms may include ptosis, blurred vision and diplopia. Other studies have shown that obesity is a common symptom of narcolepsy and occurs more than twice as often in narcoleptic patients than in the general population. An increased frequency of other sleep abnormalities have been described in narcolepsy, including sleep talking, periodic limb movements, sleep apnea and REM behavior disorder. Panic, anxiety and depression are also common manifestations in patients with narcolepsy.
At the genetic level, Type I narcolepsy is closely associated with the human leukocyte antigen (HLA) DQB1*0602. Almost all patients with cataplexy are positive for DQB1*0602, compared with 12 – 38% of the general population. There is a low prevalence of familial cases ; the risk of narcolepsy type I in first degree relatives is approximately 1 -2%. Families with more than two affected members are uncommon.
Onset and Course:
Onset typically occurs between the ages of 10 and 25. Typically two peaks are noted at around 15 years old and again around age 35. Sleepiness is usually the first symptom, cataplexy often occurs within a year of onset. Hypnogogic hallucinations, sleep paralysis and disturbed sleep often show up later in disease progression. In most cases symptoms develop over the course of several years. Cataplexy may lessen with age, or occasionally increase in frequency and severity.
Children will present different clinically than adults. Sleepiness may be difficult to assess, and may be expressed simply as a long nights sleep, or the recurrence of previously discontinued daytime napping. Children may present with hyperactive behavior, inattentiveness, behavioral problems or difficulty in school. The combination of lack of energy, insomnia, hallucinations or sleep paralysis often leads to a psychiatric misdiagnosis of depression or schizophrenia. The difficulties in assessment, differences in PSG and MSLT and their interpretation makes the CSF hypocretin values of particular value.
Diagnosis of Narcolepsy and Testing:
The overnight polysomnogram (PSG) and Multiple sleep latency test (MSLT) are still the “gold standards” for diagnosing narcolepsy. The PSG/MSLT should be preceded by at least one week of actigraphic recording or a sleep log. Patients must be free of sleep influencing medications and all stimulants for at least two weeks. A urine drug screen should be completed, and the sleep wake schedule standardized as much as possible.
PSG in narcolepsy will reveal the following: rapid sleep onset, rapid REM onset, fragmented sleep, frequent awakenings, frequent unexplained arousals, an increase in stage I sleep and REM without atonia.
MSLT in narcolepsy will reveal the following: A mean sleep onset latency of less than 8 minutes, typically in less than 5 min. over the course of 5 naps. The presence of two sleep onset REM periods (SOREMPS) or alternatively, One SOREMP on MSLT and one SOREMP that occurs in <15min on the preceding night PSG.
If testing is negative, yet a high index of suspicion remains for narcolepsy the testing may need repeated or consider HLA typing or Lumbar puncture.
In the absence of cataplexy, narcolepsy type I can be diagnosed based on the presence of hypersomnolence and low CSF hypocretin 1 levels. When cataplexy is absent and CSF hypocretin 1 levels are normal, or unknown, Narcolepsy type II should be diagnosed. Cataplexy should be differentiated from hypotension, transient ischemic attack, drop attacks, akinetic seizures, neuromuscular disorders, vestibular disorders, psychological or psychiatric disorders and sleep paralysis. Clear improvement of symptoms with antidepressant medications may favor a diagnosis of cataplexy in difficult cases.
Sleepiness may be secondary to. Obstructive sleep apnea, insufficient sleep syndrome, shift work sleep disorder and effects of substances or medication.
Idiopathic Hypersomnia is differentiated from narcolepsy type I by the absence of cataplexy and the lack of two or more SOREMP’s on MSLT. Patients with idiopathic hypersomnia generally have a high sleep efficiency, sleep drunkenness and long non refreshing naps.
Insufficient sleep syndrome is not associated with cataplexy and normalizing sleep time eliminates the daytime sleepiness. Chronic fatigue syndrome and depression may mimic narcolepsy but do not show the typical MSLT findings.
For diagnosis a high degree of suspicion must be maintained. An adequate history and physical exam is of utmost importance. The PSG/MSLT must be performed by technicians familiar with the administration and testing process. Interpretation of results must be by a physician experienced with a narcolepsy diagnosis.
NARCOLEPSY TYPE II (formerly narcolepsy without cataplexy)
The exact prevalence of narcolepsy type II is unknown but it is postulated that 15 – 24% of the narcoleptic population are diagnosed with type II. Approximately 24% of patients who have Type II narcolepsy will have low hypocretin CSF levels and will be positive for HLA DQB1* 0602 antigen. These patients are now reclassified reclassified as having Type I narcolepsy, regardless of whether cataplexy is present.
Onset typically occurs in adolescence. In about 10% of these patients, cataplexy will develop later in the course of the disease, necessitating a change in the diagnosis. There is a subgroup of Narcolepsy Type II patients who will have hypocretin deficiency, presumably from loss of neurons. These patients cannot be accurately separated clinically or diagnostically from the majority of patients without cataplexy other than by CSF hypocretin levels. When left untreated narcolepsy type II is socially disabling and isolating.
In children symptoms are extremely similar to type I narcolepsy, however, children with type II narcolepsy should be considered in an evolving disorder.
Recommendations for PSG/MSLT remain the same as for Type I Narcolepsy.
To diagnose Type II narcolepsy the following conditions must be met:
Daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for atleast 3 months.
A mean sleep latency of < 8 min. and 2 or more sleep onset REM periods on MSLT. A SOREMP (within 15 min. of sleep onset) on preceding nocturnal polysomnogram may replace one of the SOREMP’s on the MSLT
Cataplexy is absent
The hypersomnolence or MSLT findings are not better explained by other causes such as insufficient sleep, Obstructive sleep apnea, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal.Either CSF hypocretin has not been measured or the concentration is 110pg/ml or greater.
The hypersomnolence or MSLT findings are not better explained by other causes such as insufficient sleep, Obstructive sleep apnea, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal.
IDIOPATHIC NARCOLEPSY (Secondary Narcolepsy)
Patients with narcolepsy generally have a normal neurological exam and no definite pathology on brain imaging. Secondary narcolepsy is defined as “manifestations of the narcolepsy syndrome associated with specific brain pathology.” This generally secondary to tumors found in the hypothalamic area, but can rarely occur from arteriovenous malformation or following a stroke. Other reported associations of cerebral disease and narcolepsy include Multiple Sclerosis, and Niemann Pick type C disease.
Idiopathic hypersomnia is a diagnosis of exclusion. It is actually less common than Narcolepsy. Some patients given the diagnosis of IH were later found to have upper airway resistance syndrome or mild obstructive sleep apnea when monitored utilizing esophageal pressure monitoring.
Atypical depression, insufficient sleep syndrome, medication side effects, narcolepsy with delayed cataplexy and neurological disease must be excluded.
Symptoms may include excessive sleepiness, long nocturnal sleep period, sleep drunkenness (confused, slow awakenings), and typically long non refreshing naps.
IH patients may also have neurovegetative symptoms of orthostatic hypotension, syncope, Raynauds Phenomenon or frequent headaches. Sleep paralysis and hypnogogic hallucinations are common. Cataplexy is absent. Patients typically do not easily awaken to alarm clocks and frequently use special devices or procedures to wake up. Naps are long (>60 min) and non refreshing, 30% of patients report sleep times greater than 12 hours.
Total sleep time is normal or increased, REM latency is normal as is time in REM sleep. The MSLT shows excessive sleepiness (mean sleep latency <10 min,). Less than 2 SOREMP’s in 5 naps. Daytime sleepiness does not respond to an increase in nocturnal sleep time.
To diagnose Idiopathic Hypersomnia the following criteria must be met:
Daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least three months.
Cataplexy is absent
MSLT shows fewer than 2 SOREMP’s
MSLT shows a mean sleep latency less than 8 minutes
The 24 hr sleep time is greater than 12 – 14 hours (For the long sleep duration variant)
Insufficient sleep syndrome is ruled out
The hypersomnolence or MSLT findings are not better explained by another sleep disorder, medical or psychiatric disorder or the use of drugs or medications.