Dear Editor,
The third International Classification of Sleep Disorders (ICSD-3) defines narcolepsy
as patients with periods of sleep attacks or excessive daytime sleepiness. Neurophysiology
tests with unremarkable polysomnography and positive Multiple Sleep Latency Test scores
establish the diagnosis of narcolepsy[1].
The difficulties in the differential diagnosis include secondary causes of excessive
daytime sleepiness, narcolepsy, and other primary central hypersomnia disorders[1]. Usually, narcolepsy type 1 is differentiated by the presence of immunological pathophysiology
and the consequent lower levels of hypocretin-1[2].
Usually, narcolepsy type 1 patients have cataplexy and a CSF hypocretin-1 concentration
≤ 110 pg/mL or < 1/3 of mean values obtained in normal volunteers.[2] Interestingly, the ICSD-3 defines patients with excessive daytime sleepiness and
lower CSF hypocretin-1 levels as having type 1 narcolepsy, even without cataplexy.
In fact, measuring CSF levels of hypocretin-1 has been considered the best option
for the diagnosis of type 1 narcolepsy[1].
However, the normal levels of hypocretin-1 are higher than 200 pg/mL2. Indeed, there is a grey zone between 110 pg/mL and 200 pg/mL that is not discussed
in the literature.
We describe three patients with hypocretin-1 levels between 110 pg/mL and 200 pg/mL
([Table]). All had the presence of allele HLA-DQB1*0602, sleep hallucinations, and sleep
paralysis. Two patients had all the criteria for narcolepsy type 1, but one of them
did not have all the criteria for narcolepsy.
Table
Demographic, clinical, genetic, and hypocretin-1 characteristics.
|
Age
|
HLA-DQB1*0602
|
CSF-HCRT (pg/mL)
|
MSLT/Average latency/(min)
|
MSLT/SOREMP
|
Cataplexy
|
Sleep paralysis
|
Hallucinations
|
Automatic behavior
|
Disruptive sleep
|
|
49
|
Yes
|
135.4
|
1
|
4
|
Yes
|
Yes
|
Yes
|
No
|
Yes
|
|
23
|
Yes
|
139.49
|
4
|
1
|
No
|
Yes
|
Yes
|
No
|
No
|
|
40
|
Yes
|
140.65
|
5
|
4
|
Yes
|
Yes
|
Yes
|
No
|
Yes
|
CSF: cerebrospinal fluid; HCRT: hypocretin; MSLT: Multiple Sleep Latency Test; SOREMP:
sleep onset rapid eye moment period; min: minutes.
The hypocretin-1 threshold of 110 pg/mL has been identified by two studies[2]. Quality Receiver Operating Characteristic curve analysis indicates a threshold
of 200 pg/mL and 150 mg/mL for direct and extracted assays in volunteers, respectively[3],[4]. Although the biomarkers for identification of type 1 narcolepsy are very useful,
the identification of patients with narcolepsy type 2 is still a challenge in many
cases.
A paper written by Barateau et al. entitled Comorbidity between central disorders of hypersomnolence and immune-based disorders, expands this discussion.[5] They state that the prevalence of immune diseases, inflammatory disorders, and allergies
are not higher in narcolepsy type 1. Interestingly, autoimmune diseases were higher
in narcolepsy type 2 patients and inflammatory disorders were common in idiopathic
hypersomnolence.
Clinical and neurophysiology characteristics, genetics and hypocretin-1 levels are
not sufficient to define narcolepsy in all circumstances. Unfortunately, the description
of a few patients cannot characterize a pattern, especially in atypical cases. Further
efforts to study patients with hypocretin-1 between 110 pg/mL and 200 pg/mL should
help to classify them. It is possible that, in the future, biomarkers of inflammation
and immune responses will be useful for that.
