Rare Case Study Challenges Hypocretin-1 Thresholds for Narcolepsy Diagnosis

Laure Peter-Derex, MD, PhD

In a recent case report, a 26-year-old old man with symptoms of narcolepsy type 1 had tested negative for the condition using standard tests; however, 4 years later had a dramatic decrease in cerebrospinal fluid (CSF) hypocretin-1, eventually leading allowing to confirm the diagnosis.1 This report highlights the importance of reevaluating patients with intermediate hypocretin-1 values, and further contributed to the ongoing debate on alternative thresholds for diagnosing narcolepsy type 1 (NT1).

According to the International Classificiation of Sleep Disorders, the diagnosis of NT1 is based on the association of excessive daytime sleepiness plus either cataplexy and electrophysiological criteria, or a CSF hypocretin-1 concentration below 110 pg/mL.² Upon presenting, the patient reported intermediate levels (132 pg/mL) of hypocretin-1 along with negative results on polysomnography and multiple sleep latency test.

In the reassessment, the patient’s clinical increase in sleepiness, cataplexy burden, and sleep paralysis as well electrophysiological worsening was associated with a considerable reduction in CSF hypocretin-1 levels, which were below 50 pg/mL. At the same time, the patient demonstrated a mean sleep latency of 2min and 15s and had 3 sleep onset rapid-eye moment periods (SOREMp) with another SOREMp observed on the night of a polysomnography.

“Currently, NT1 diagnosis is accepted for patients with intermediate hypocretin-1 range only if they have typical cataplexy and electrophysiological criteria. Thus, our patient did not meet criteria for NT1 at the first evaluation yet performed 6 years after symptoms onset (including typical cataplexy),” senior author Laure Peter-Derex, MD, PhD, neurologist at the Center for Sleep Medicine and Respiratory Diseases, Croix-Rousse Hospital, in Lyon, France, and colleagues wrote.¹

The patient presented to the Sleep Medicine Center of Lyon University Hospital in February 2021 for suggestive symptoms of narcolepsy. He attended business school as a student, had no medical or surgical history, and reported being a regular consumer of tobacco as well as occasional use of cannabis. At the age of 16 years, the patient experienced typical cataplexy symptoms including emotions, sleep paralysis, and disrupted nighttime sleep, and by the age of 20 years old, sleepiness was reported.

“Of note, the cataplexy had occurred before the sleepiness, which is not typical as sleepiness is commonly the first symptom of NT1.It may be hypothesized that sleepiness was ‘trivialized’ in the context of the changes in sleep schedules associated with adolescence or that the patient adapted to it by optimal use of naps, to the extent that it became less disabling for him,” Peter-Derex et al noted.¹

Further results showed that on the Narcolepsy Severity Scale,the patient scored a 25 out of 57 and a 17 out of 24 on the Epworth Sleepiness Scale, indicating typical partial cataplexy occasionally on a weekly basis and total cataplexy on a monthly basis. Following the first assessment in 2016, a diagnosis of narcolepsy was suggested with the patient at the age of 21 years old. During the first overnight polysomnography, a SOREMp was observed, yet mean sleep latency test (MSLT) results remained normal. At first, modafinil and then pitolisant (Wakix) was recommended at that time but the patient discontinued treatments because of weight loss up to 11 pounds and insufficient efficacy. Eventually, the patient coped with sleepiness by taking naps for 3 years instead of taking any prescribed medication for the condition.

During the first visit at the Lyon Sleep Center, investigators recommended a reintroduction of modafinil, in which a full reassessment was scheduled following the discontinuation of the treatment. In August 2021, the second investigation was conducted with a full polysomnography night and then a MSLT. At this time, the patient scored 36 out of 57 on the Narcolepsy Severity Scale. Although the patient was reportedly satisfied with modafinil treatment at only 100 mg per day, he reported a significant increase in partial and generalized cataplexies that had become a daily occurrence several months later. Following that, an anticataplectic treatment with venlafaxine was recommended and also proved effective at the dosage of 37.5mg per day.

“Recently a CSF hypocretin-1 cutoff of 150 pg/ml was found to best predict the presence of typical cataplexy and/or positive electrophysiological findings.It was proposed to combine biological (hypocretin-1 level) and clinical (typical cataplexy) features in diagnosis criteria for NT1, keeping in mind issues related to the intraassay variability associated with hypocretin-1 level. This approach has the merit of improving the sensitivity of the assay by compensating for the associated loss of specificity through the addition clinical and paraclinical criteria,” Peter-Derex et al noted.¹

REFERENCES
1. Ricordeau F, Bridoux A, Raverot V, Peter-Derex L. Progressive narcolepsy: how to deal with intermediate hypocretin-1 values?. J Clin Sleep Med. 2023;19(7):1375-1378. doi:10.5664/jcsm.10576
2. Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014;146(5):1387-1394. doi:10.1378/chest.14-0970