To diagnose narcolepsy type 1 after a negative multiple sleep latency test: the contribution of systematic hypocretin...

We evaluated the diagnostic potential of detecting narcolepsy type 1 (NT1) by systematically measuring cerebrospinal fluid hypocretin-1 (CSF-HCRT1) in patients with suspected central disorder of hypersomnolence (CDH), after the multiple sleep latency test (MSLT) was negative for narcolepsy criteria.

Consecutive untreated patients with suspected CDH were hospitalized at the Bologna Narcolepsy Center (Italy) from 2013 to 2024. They underwent a standardized protocol of 2-day continuous polysomnography (PSG), MSLT, and systematic CSF-HCRT1 measurement. Our focus was the identification of additional NT1 cases through the detection of low CSF-HCRT1 < 110 pg/mL among those with negative PSG-MSLT for narcolepsy (i.e. mean sleep latency>8 min or sleep onset REM periods-SOREMPs<2). Features of patients with CSF-HCRT1 < 110 pg/mL and negative PSG-MSLT were explored.

Out of 870 patients with suspected CDH (all with CSF-HCRT1 assay, 52% males, 30.1% pediatric), 342 had PSG-MSLT criteria consistent with narcolepsy with cataplexy (NT1). Sixty-four had PSG-MSLT criteria consistent with narcolepsy but did not have cataplexy (31.3% with CSF-HCRT1 deficiency). In the remaining 464 cases with a PSG-MSLT negative for narcolepsy, CSF-HCRT1 < 110 was detected in 34 (five without cataplexy), increasing NT1 diagnoses by 9.9% and re-classifying 7.3% of MSLT negative cases (p < 0.001 vs. PSG-MSLT+cataplexy). Among the 378 cases with CSF-HCRT1 < 110, the 34 patients with negative PSG-MSLT carried HLA-DQB1*0602 less often (88.2% vs. 96.5%, p = 0.046), had fewer SOREMPs, and higher CSF-HCRT1 values in comparison to the 344 positive at the first PSG-MSLT.

In suspected CDH, systematically measuring CSF-HCRT1 in the presence of a negative PSG-MSLT identifies about 10% additional NT1 cases (of which 15% without cataplexy), otherwise possibly misdiagnosed. Statement of Significance In clinical practice, cerebrospinal fluid hypocretin-1 measurement (diagnostic for narcolepsy type 1 if below 110 pg/mL) is not routinely performed in patients with suspected central disorders of hypersomnolence when the multiple sleep latency test (MSLT) is negative. Therefore, in this large consecutive cohort of adults and children with suspected hypersomnolence, we systematically performed hypocretin-1 assay after MSLT negative for narcolepsy, significantly improving the diagnostic yield by correctly identifying narcolepsy type 1 in cases unrecognized by MSLT alone. These patients have subtle phenotypical differences from those with MSLT positive for narcolepsy. We also provided some highly sensitive markers that can suggest the presence of narcolepsy type 1 despite a negative MSLT, guiding the physician to second-line assessments, to reduce misdiagnosis.