Narcolepsy, CDH and rare sleep disorders

Excessive daytime sleepiness

Excessive Daytime sleepiness (EDS), i.e. the inability to stay awake and alert during the major episodes of wakefulness during the day, resulting in periods of incoercible sleep or involuntary bouts of drowsiness or sleep, is the primary complaint in the disorders included in this group. In all cases, daytime sleepiness should not be caused by disturbed nocturnal sleep or disordered circadian rhythms and, when other sleep disorders are present, they need to be treated adequately before a diagnosis in this category can be established.

The term ‘hypersomnolence’ refers to the symptom of excessive sleepiness, whereas hypersomnia indicates specific disorders, such as idiopathic hypersomnia.

Sleep deprivation (and/or reduced sleep quantity) is the most common cause of hypersomnolence at all ages, followed by sleep fragmentation (reduced sleep quality).

EDS is reported by 10 to 25 percent of the general population. The causes of EDS are numerous, and multiple factors may contribute in any one patient. Some of the most common causes of EDS are insufficient sleep, depression, medications, and comorbid medical and psychiatric disorders. Obstructive sleep apnea (OSA) is a common and treatable cause of EDS.

In some forms of hypersomnolence, sleepiness is associated with large increases in total daily amount of sleep without any genuine feeling of restoration. In others, sleepiness can be alleviated temporarily by naps but reoccurs shortly thereafter.

Differential diagnosis of EDS:

1. Insufficient sleep syndrome: chronic sleep insufficiency is due to volitional partial sleep loss or insufficient opportunity to sleep. Sleep-deprived individuals will rapidly fall asleep if given the opportunity, whereas individuals with insomnia are unable to fall asleep, even though they feel fatigued during the day
2. Sleep disorders (such as obstructive sleep apnea or circadian rhythm sleep-wake disorders, restless legs syndrome and periodic limb movement disorder
3. Other neurologic disorders: Neurodegenerative disease, structural lesions or brain tumors affecting thalamus, hypothalamus, or brainstem, traumatic brain injury, encephalitis lethargica , cerebral trypanosomiasis
4. Medical disorders: Hypothyroidism, obesity, end-stage renal disease, adrenal insufficiency, hepatic encephalopathy, diabetes
5. Genetic disorders: daytime sleepiness may be a symptom of different chromosomal abnormalities and microdeletion syndromes like Smith-Magenis, Prader-Willi, fragile X, or Moebius syndrome. EDS and predominantly cataplexy can be a symptom of neurometabolic disorders such as Niemann-Pick type C disease. Myotonic dystrophy as an example of neuromuscular diseases with triplete genetic component and increased daytime sleepiness
6. Psychiatric disorders: Depression, anxiety, substance abuse (alcohol, narcotics, prescription opioid abuse, stimulant withdrawal), psychogenic sleepiness
7. Medications: Benzodiazepines, nonbenzodiazepine sedatives, antipsychotics, opioid analgesics, beta-blockers (lipophilic), barbiturates, antihistamines, anticonvulsants, sedative antidepressants

Diagnostic criteria for insufficient sleep syndrome

1. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep or, in the case of prepubertal children, there is a complaint of behavioral abnormalities attributable to sleepiness.
2. The patient’s sleep time, established by personal or collateral history, sleep logs, or actigraphy, is usually shorter than expected for age.
3. The curtailed sleep pattern is present most days for at least three months.
4. The patient curtails sleep time by such measures as an alarm clock or being awakened by another person and generally sleeps longer when such measures are not used, such as on weekends or vacations.
5. Extension of total sleep time results in resolution of the symptoms of sleepiness.
6. The symptoms are not better explained by another untreated sleep disorder, the effects of medications or drugs, or other medical, neurologic, or mental disorders.

Central disorders of hypersomnolence 

Disorders that increase sleep drive (hypersomnias of central origin) are relatively rare causes of EDS.

Most of these diseases start usually in adolescence and have a chronic course with a great impact on physical and mental health from childhood until adulthood. Narcolepsy and Kleine-Levin syndrome start/occur during the first two decades. The Kleine-Levin syndrome is a rare disorder with unknown prevalence. The prevalence of narcolepsy is also low but it is increasing in the last decades. Narcolepsy with cataplexy occurs in 0.02% to 0.18% of the United States and western European populations. A lower prevalence has been reported in Israel, whereas narcolepsy with cataplexy may be slightly more common in Japan (0.16% to 0.18%). Both sexes are affected, with a slight preponderance of males. However, the narcolepsy prevalence, for not clarified reasons, is increasing in the last decade. A clear risk factor was the vaccination against H1N1 flu virus with Pandemrix, due to the adjuvant used (AS03)  HLA-DQB1 *06:02 positivity is a risk factor for narcolepsy. Recently, an association between narcolepsy and allergic diseases has been observed but there are differences between patients with and without cataplexy since the frequency of allergic conditions, particularly asthma and allergic rhinitis, was markedly lower in narcolepsy with cataplexy (58/275) when compared with patients without cataplexy.

According to the International Classification of Sleep Disorders (ICSD-3) Central disorders of hypersomnolence are classified as follows:

1. Narcolepsy type 1 or 2
2. Kleine-Levin syndrome
3. Idiopathic hypersomnia
4. Long sleepers, isolated symptom or normal variants

Narcolepsy Type 1

The following diagnostic criteria must be met:

1. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months.
2. The presence of one or both of the following:
   1. Cataplexy and a mean sleep latency of ≤8 min and two or more sleep-onset REM periods (SOREMPs) on an MSLT. A SOREMP (within 15 min of sleep onset) on the preceding nocturnal polysomnogram may replace one of the SOREMP on the MSLT.
   2. Cerebrospinal fluid (CSF) hypocretin-1 (hcrt-1) concentration, measured by immunoreactivity, is either ≤110 pg/mL or <1/3 of mean values obtained in normal subjects with the same standardized assay.

In young children, narcolepsy may sometimes present as excessively long night sleep or as resumption of previously discontinued daytime napping In some cases, the diagnosis of narcolepsy type 1 can be difficult. Increased daytime sleepiness may sometimes be the only clinical feature for years; the sleep episodes become increasingly long, lasting up to hours; confusional arousals with features of sleep drunkenness may be present. Cataplexy may develop with a delay. In addition, lumbar puncture necessary for hcrt-1 estimation is invasive procedure, and to obtain

parent’s consent cannot be easy in some cases.

Narcolepsy Type 2

The following diagnostic criteria must be met:

1. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months.
2. A mean sleep latency of ≤8 min and two or more sleep-onset REM periods (SOREMPs) are found on an MSLT. A SOREMP (within 15 min of sleep onset) on the preceding nocturnal polysomnogram may replace one of the SOREMP on the MSLT.
3. Cataplexy is absent.
4. Either CSF hcrt-1 concentration has not been measured or CSF hcrt-1 concentration measured by immunoreactivity is either >110 pg/mL or >1/3 of mean values obtained in normal subjects with the same standardized assay.
5. The hypersomnolence and/or MSLT findings are not better explained by other causes such as insuffi cient sleep, obstructive sleep apnea, delayed sleep phase disorder, or effect of medication or substances or their withdrawal.

If cataplexy develops later, or if CSF hcrt-1 concentration is below the recommended level, then the disorder should be reclassified as narcolepsy type 1. In all cases, the possibility of future development of cataplexy should be considered.
With the exception of cataplexy, all associated features such as hypnagogic/hypnopompic hallucination and sleep paralysis can be present similarly as in narcolepsy type 1.
In comparison with normal population, the frequency of HLA- DQB1*06:02 haplotype is increased; almost one half of narcolepsy type 2 patients are HLA- DQB1*06:02 positive.