Abstract
According to the International Classification of Sleep Disorders, third edition guidelines, the diagnosis of narcolepsy type 1 is based on the association of excessive daytime sleepiness plus either cataplexy and electrophysiological criteria, or a cerebrospinal fluid hypocretin-1 concentration below 110 pg/mL. This threshold remains debated, and recent works have proposed alternative values in the intermediate (110 to 200 pg/mL) zone. We report the case of a patient who presented with typical clinical symptoms of narcolepsy type 1 developing over six years but in whom initial polysomnography and multiple sleep latency test were negative and cerebrospinal fluid hypocretin-1 was intermediate (132 pg/mL). Cerebrospinal fluid hypocretin-1 reassessment four years later found a dramatic decrease, < 50 pg/mL, and the multiple sleep latency test proved to be abnormal, eventually allowing to confirm the diagnosis. This case highlights the importance of reassessing patients with intermediate hypocretin-1 values and contributes to the debate on the determination of alternative cerebrospinal fluid hypocretin1 thresholds for narcolepsy type 1 diagnosis.
Citation:
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.
Keywords: narcolepsy, orexin, multiple sleep latency test, cataplexy
INTRODUCTION
According to the International Classification of Sleep Disorders, third edition (ICSD-3) guidelines1 the diagnosis of narcolepsy type 1 (NT1) relies on the association of excessive daytime sleepiness occurring for at least three months with (1) either cataplexy (ie, sudden loss of muscle tone elicited by emotions) plus mean sleep latency ≤8 minutes and ≥2 sleep onset rapid eye movement periods [rapid eye movement sleep within 15 minutes of sleep onset (SOREMp)] on a Multiple Sleep Latency Test (MSLT) (2) or low cerebrospinal fluid (CSF) hypocretin-1 concentration ≤ 110 pg/mL.
Hypocretin-1/orexin A level is highly specific and sensitive for the diagnosis of NT1. It is particularly useful in cases of associated sleep disorders such as sleep deprivation or circadian disturbances, difficulties to perform MSLT, or when psychoactive medications prone to influence rapid eye movement sleep latency cannot be discontinued.2 The pathological threshold for hypocretin-1 levels is 110 pg/ml, with values above 200 pg/mL considered as normal, when using a Stanford reference sample.2 Recently, several works have investigated clinical and electrophysiological features in patients with intermediate CSF hypocretin-1 values (110 to 200 pg/mL) and reported heterogeneous phenotypes regarding cataplexy, nocturnal sleep disruption, hallucinations, and MSLT results.3–5 A 150 pg/ml threshold was proposed to be the most predictive of the presence of typical cataplexy and/or positive polysomnography and MSLT findings.4 However, the dynamics of clinical symptoms over time and the prognosis of the disease in case of intermediate CSF hypocretin-1 values remain poorly understood. Thus, efforts to phenotype patients in this category and to provide longitudinal follow-up are highly needed.3–5 Here we report the case of a patient with typical cataplexy but normal mean sleep latency on MSLT and intermediate hypocretin-1 values, with later progression to typical narcolepsy, suggesting parallel clinical, electrophysiological, and biological evolution.
REPORT OF CASE
A 26-year-old man presented to the Sleep Medicine Center of Lyon University Hospital in February 2021 for symptoms suggestive of narcolepsy. He was a student in a business school. He had no medical or surgical history and reported regular tobacco consumption (five to six cigarettes per day), as well as occasional cannabis use. Sleepiness was present since he was 20 years old. Typical cataplexy elicited by emotions, sleep paralysis, and disrupted nighttime sleep had developed by the age of 16. He had been vaccinated with H1N1 vaccine when he was 15. The Narcolepsy Severity Scale6 scored at 25/57 (Table 1) and Epworth Sleepiness Scale at 17/24, with typical partial cataplexy occurring on a weekly base and total cataplexy on a monthly base (Figure 1).
Table 1.
Evolution of the total and item-per-item score at the NSS.
| Nov. 2016, Age 21 | Feb. 2021, Age 26 | Aug. 2021, Age 26 | |
|---|---|---|---|
| NSS Total Score | 17 | 25 | 36 |
| Irresistible need to sleep during the day (Item 1) | Per month (3) | Per week (4) | Per day (5) |
| Worried about falling asleep during the day (Item 2) | Not worried at all (0) | Worried (2) | Not very Worried (1) |
| Disruption of work/activities caused by daytime sleep attacks (Item 3) | Not important at all (0) | Moderately important (1) | Moderately important (1) |
| Disruption of social and family life by daytime sleep attacks (Item 4) | Not important at all (0) | Moderately important (1) | Moderately important (1) |
| Feeling after one of such daytime sleep attacks (Item 5) | Tired (1) | Tired (1) | Tired (1) |
| Time passed before the next episode of daytime sleep attack (Item 6) | No irresistible sleep attack (0) | No irresistible sleep attack (0) | Less than 1 hour (4) |
| Impact of daytime sleep episodes on the ability to drive a car (Item 7) | Not at all (0) | Not too much (1) | Not too much (1) |
| Frequency of generalized cataplexy episodes (Item 8) | Per month (3) | Per month (3) | Per day (5) |
| Frequency of partial cataplexy episodes (Item 9) | Per month (3) | Per week (4) | Per day (5) |
| Impact of cataplexy episodes on work, social or family life (Item 10) | Much (2) | Much (2) | Very much (3) |
| Frequency of hallucinations when falling asleep/waking up (Item 11) | Per month (3) | Not at all (0) | Per year (2) |
| Hallucination bothering (Item 12) | Not very bothered (1) | Not bothered at all (0) | Not bothered at all (0) |
| Frequency of sleep paralysis when falling asleep/waking up (Item 13) | Not at all (0) | Per week (4) | Per week (4) |
| Sleep paralysis bothering (Item 14) | Not bothered at all (0) | Not bothered at all (0) | Not very bothered (1) |
| Nighttime sleep disturbance (Item 15) | Not too much (1) | Much (2) | Much (2) |
NSS = Narcolepsy Severity Scale.
Figure 1. Evolution of clinical symptoms, electrophysiological data, and cerebrospinal hypocretin-1 levels over time.
The diagnosis of narcolepsy had already been suggested following a first assessment carried out in another hospital in Lyon at the age of 21 in 2016. The Narcolepsy Severity Scale was 17/56 (Table 1). A SOREMp was found during the first overnight polysomnography, but mean sleep latency was normal (10 min) on MSLT with a single SOREMp. The Human Leukocyte Antigen DQB1*06:02 allele was positive. Hypocretin-1 CSF level was determined at the Lyon University Hospital Biology Center using an in-house radioimmunoassay. Briefly, duplicate CSF samples were incubated with rabbit polyclonal antibody (Orexin A) and orexin labeled with I125. The calibration curve was obtained with Orexin A from Phoenix Pharmaceuticals. The interassay coefficient of variation was 11.4% at levels 88 ng/L and 6.5% at 380 ng/L. The quantification limit was < 50 ng/L. Intermediate levels of hypocretin were found, with a value of 132 pg/ml. Modafinil was first proposed at that time but stopped due to weight loss (11 pounds). Pitolisant was then prescribed but was also discontinued because of insufficient efficacy. The patient eventually decided not to take any medication and had been coping with his sleepiness by taking short refreshing naps for 3 years when he was first seen at our center.
During the first visit at Lyon Sleep Center in 2021, we first proposed to reintroduce modafinil, and a full reassessment was scheduled, after discontinuation of treatment. In August 2021, this second exploration was performed including a full polysomnography night followed by a MSLT. Mean sleep latency was 2 min 15 s and 3 SOREMp were recorded. Another SOREMp was observed on the night polysomnography. CSF hypocretin-1 was reassessed in the same center (Lyon University Hospital Biology Center); the level turned out to be < 50 ng/l. Intriguingly, the patient was initially satisfied with the reintroduction of only 100 mg modafinil per day, but after several months he noticed significant increase in partial and generalized cataplexies, which had become daily. The Narcolepsy Severity Scale was 36/57 (Table 1) in August 2021. An anticataplectic treatment with venlafaxine was then proposed and proved to be effective at the dose of 37.5 mg per day.
DISCUSSION
We report the case of a patient presenting with typical narcolepsy clinical symptoms (ie, sleepiness and typical cataplexy7) but nontypical MSLT findings (mean sleep latency > 8 min), with an intermediate CSF hypocretin-1 value in the 110 to 200 pg/ml range at first evaluation. The patient’s clinical (increased sleepiness, cataplexy burden, and sleep paralysis) and electrophysiological deterioration was associated with a dramatic decrease in CSF hypocretin-1 levels (< 50 pg/ml) over more than 4 years. Currently, NT1 diagnosis is accepted for patients with intermediate hypocretin-1 range only if they have typical cataplexy and electrophysiological criteria.1,5 Thus, our patient did not meet criteria for NT1 at the first evaluation yet performed 6 years after symptoms onset (including typical cataplexy). Of note, the cataplexy had occurred before the sleepiness, which is not typical as sleepiness is commonly the first symptom of NT1.7 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.
Few cases of patients with typical cataplexy and a progressive decline of CSF hypocretin-1 have been reported, mostly in patients with recent disease onset fewer than 2 years or initially associated with mean sleep latency test < 8 min.8 In our case, the initial evaluation was performed 6 years after disease onset, suggesting that slower evolution can be observed.9
The hypocretin-1 cutoff value (below 110 pg/ml) was established by Mignot et al with a specificity of 98% and a sensitivity of 60% for the diagnosis of ICSD-2–defined narcolepsy.2 Of note, in this prospective study, the best sensitivity/specificity ratio was 200 pg/ml for healthy controls (n = 296) vs patients with sleep disorder (n = 274). An “intermediate” CSF-hypocretin range was thus proposed.2,5 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.4 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 interassay variability associated with hypocretin-1 level.4,10 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. Interestingly, in our case, such criteria would have allowed the diagnosis of NT1 at the time of the first CSF hypocretin-1 assessment despite nontypical findings on polysomnography. Given the current ICSD-3 criteria, it was only confirmed 4 years later.
As a conclusion, our case report supports the need of CSF hypocretin-1 reassessment in case of intermediate level and emphasizes the need to interpret hypocretin-1 values within clinical context.
DISCLOSURE STATEMENT
All authors have seen and approved the manuscript. This work was performed in the Center for Sleep Medicine and Respiratory Diseases, Croix-Rousse Hospital, Lyon Academic Hospital, Lyon 1 University, 69004 Lyon, France. The authors report no conflicts of interest.
ABBREVIATIONS
- CSF
cerebrospinal fluid
- MSLT
Multiple Sleep Latency Test
- NT1
narcolepsy type 1
- SOREMp
sleep onset rapid eye movement period
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