CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome

Abstract

Study objective: To (1) replicate our prior result of low cerebrospinal fluid (CSF) histamine levels in human narcolepsy in a different sample population and to (2) evaluate if histamine contents are altered in other types of hypersomnia with and without hypocretin deficiency.

Design: Cross sectional studies.

Setting and patients: Sixty-seven narcolepsy subjects, 26 idiopathic hypersomnia (IHS) subjects, 16 obstructive sleep apnea syndrome (OSAS) subjects, and 73 neurological controls were included. All patients were Japanese. Diagnoses were made according to ICSD-2.

Results: We found significant reductions in CSF histamine levels in hypocretin deficient narcolepsy with cataplexy (mean +/- SEM; 176.0 +/- 25.8 pg/mL), hypocretin non-deficient narcolepsy with cataplexy (97.8 +/- 38.4 pg/mL), hypocretin non-deficient narcolepsy without cataplexy (113.6 +/- 16.4 pg/mL), and idiopathic hypersomnia (161.0 +/- 29.3 pg/ mL); the levels in OSAS (259.3 +/- 46.6 pg/mL) did not statistically differ from those in the controls (333.8 +/- 22.0 pg/mL). Low CSF histamine levels were mostly observed in non-medicated patients; significant reductions in histamine levels were evident in non-medicated patients with hypocretin deficient narcolepsy with cataplexy (112.1 +/- 16.3 pg/ mL) and idiopathic hypersomnia (143.3 +/- 28.8 pg/mL), while the levels in the medicated patients were in the normal range.

Conclusion: The study confirmed reduced CSF histamine levels in hypocretin-deficient narcolepsy with cataplexy. Similar degrees of reduction were also observed in hypocretin non-deficient narcolepsy and in idiopathic hypersomnia, while those in OSAS (non central nervous system hypersomnia) were not altered. The decrease in histamine in these subjects were more specifically observed in non-medicated subjects, suggesting CSF histamine is a biomarker reflecting the degree of hypersomnia of central origin.

Figure 1

CSF hypocretin-1 (Hcrt-1) and histamine values for each individual with sleep disorders. CSF Hcrt-1 (i: left panel) and histamine (ii: right panel) values for each individual are plotted. The patient groups are indicated as Group A to Group G from above (see Table 1 for the group definition). The results of the subjects with CNS stimulants (shadowed) and without CNS stimulants medication are presented separately in the figure. The vertical lines show mean values. The cut off value of CSF hypocretin-1 level ( ≤ 110 pg/mL) clearly segregated hypocretin deficiency from non-deficiency. None of the patients with idiopathic hypersomnia and OSAS showed hypocretin deficiency. We found significant reductions in CSF histamine levels in hypocretin deficient (B: 176.0 ± 25.8 pg/mL) and non-deficient narcolepsy with cataplexy (C: 97.8 ± 38.4 pg/mL), hypocretin non-deficient narcolepsy without cataplexy (E: 113.6 ± 16.4 pg/mL), and idiopathic hypersomnia (F: 161.0 ± 29.3 pg/mL); those with hypocretin deficient narcolepsy without cataplexy (D: 273.6 ± 105 pg/mL) and OSAS (G: 259.3 ± 46.6 pg/mL) were not statistically different from those in the control range (A: 333.8 ± 22.0 pg/mL). Low CSF histamine levels were mostly observed in non-medicated patients, and significant reductions in histamine levels were observed only in non-medicated patients with hypocretin deficient narcolepsy with cataplexy (B1: 112.1 ± 16.3 pg/mL) and idiopathic hypersomnia (F1: 143.3 ± 28.8 pg/mL). The levels in the medicated subjects are in the normal range (B2: 256.6 ± 51.7 pg/mL and F2: 259.5 ± 94.9 pg/mL). Non-medicated subjects had a low CSF histamine levels in hypocretin deficient narcolepsy without cataplexy (D1: 77.5 ± 11.5 pg/mL).