Grey zone between narcolepsy type 1 and type 2

Zona cinzenta entre narcolepsia tipo 1 e tipo 2

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 narcolepsy¹.

The difficulties in the differential diagnosis include secondary causes of excessive daytime sleepiness, narcolepsy, and other primary central hypersomnia disorders¹. Usually, narcolepsy type 1 is differentiated by the presence of immunological pathophysiology and the consequent lower levels of hypocretin-1².

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 narcolepsy¹.

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 studies². Quality Receiver Operating Characteristic curve analysis indicates a threshold of 200 pg/mL and 150 mg/mL for direct and extracted assays in volunteers, respectively³,⁴. 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.

References

• ¹
  Ruoff C, Rye D. The ICSD-3 and DSM-5 guidelines for diagnosing narcolepsy: clinical relevance and practicality. Curr Med Res Opin. 2016: 1-12.
• ²
  Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59(10):1553-62. https://doi.org/10.1001/archneur.59.10.1553
  » https://doi.org/10.1001/archneur.59.10.1553
• ³
  Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000;355(9197):39-40. https://doi.org/10.1016/S0140-6736(99)05582-8
  » https://doi.org/10.1016/S0140-6736(99)05582-8
• ⁴
  Nishino S, Ripley B, Overeem S, Nevsimalova S, Lammers GJ, Vankova J et al. Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy Ann Neurol. 2001;50(3):381-8. https://doi.org/10.1002/ana.1130
  » https://doi.org/10.1002/ana.1130
• ⁵
  Barateau L, Lopez R, Arnulf I, Lecendreux M, Franco P, Drouot X et al. Comorbidity between central disorders of hypersomnolence and immune-based disorders. Neurology. 2017;88(1):93-100. https://doi.org/10.1212/WNL.0000000000003432
  » https://doi.org/10.1212/WNL.0000000000003432

Publication Dates

• Publication in this collection
  Sept 2017

History

• Received
  07 Mar 2017
• Accepted
  31 Mar 2017