Intravenous Immunoglobulin Therapy in Pediatric Narcolepsy: A Nonrandomized, Open-Label, Controlled, Longitudinal Observational Study

Abstract

Study Objectives: Previous case reports of intravenous immunoglobulins (IVIg) in pediatric narcolepsy have shown contradictory results. Methods: This was a nonrandomized, open-label, controlled, longitudinal observational study of IVIg use in pediatric narcolepsy with retrospective data collection from medical files obtained from a single pediatric national reference center for the treatment of narcolepsy in France. Of 56 consecutively referred patients with narcolepsy, 24 received IVIg (3 infusions administered at 1-mo intervals) in addition to standard care (psychostimulants and/or anticataplectic agents), and 32 continued on standard care alone (controls). Results: For two patients in each group, medical files were unavailable. Of the 22 IVIg patients, all had cerebrospinal fluid (CSF) hypocretin ≤ 110 pg/mL and were HLA-DQB1*06:02 positive. Of the 30 control patients, 29 were HLA-DQB1*06:02 positive and of those with available CSF measurements, all 12 had hypocretin ≤ 110 pg/mL. Compared with control patients, IVIg patients had shorter disease duration, shorter latency to sleep onset, and more had received H1N1 vaccination. Mean (standard deviation) follow-up length was 2.4 (1.1) y in the IVIg group and 3.9 (1.7) y in controls. In multivariate-adjusted linear mixed-effects analyses of change from baseline in Ullanlinna Narcolepsy Scale (UNS) scores, high baseline UNS, but not IVIg treatment, was associated with a reduction in narcolepsy symptoms. On time-to-event analysis, among patients with high baseline UNS scores, control patients achieved a UNS score < 14 (indicating remission) less rapidly than IVIg patients (adjusted hazard ratio 0.18; 95% confidence interval: 95% confidence interval: 0.03, 0.95; p = 0.043). Shorter or longer disease duration did not influence treatment response in any analysis. Conclusions: Overall, narcolepsy symptoms were not significantly reduced by IVIg. However, in patients with high baseline symptoms, a subset of IVIgtreated patients achieved remission more rapidly than control patients. I NTRO DUCTI O NNarcolepsy is a debilitating and currently an incurable neurological condition with a characteristic constellation of symptoms, including excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep.Until recently, and at the time patients in this study were treated, the disorder was categorized into narcolepsy with cataplexy and narcolepsy without cataplexy according to the revised second edition of the International Classification of Sleep Disorders (ICSD).1 ICSD-2-revised has now been replaced by ICSD-3, which classifies narcolepsy into type 1 and type 2 narcolepsy. 2The majority of patients with type 1 narcolepsy have hypocretin deficiency (cerebrospinal fluid [CSF] hypocretin-1 level ≤ 110 pg/ mL), which is considered to result from an autoimmune-mediated loss of hypocretin-secreting neurons in those who are genetically predisposed (most commonly those with human leucocyte antigen [HLA] DQB1*06:02 haplotype). The...

Narcolepsy treatment: pharmacological and behavioral strategies in adults and children

“…Several pieces of evidence support an autoimmune mechanism underlying the onset of NT1, offering a rationale for the use of immunomodulation therapy with intravenous immunoglobulin G (IVIG) close to disease onset. Only a few investigators [39,[90][91][92] have tried IVIG in early-onset narcoleptic patients to understand its therapeutic efficacy, but the results are controversial due to the small sample size, openlabel design, and self-report observations. The results suggest a potential improvement in frequency and severity of cataplexy and ameliorated daytime sleepiness, data further confirmed by new evidence [93].…”

Narcolepsy Associated with Pandemrix Vaccine

“…We have reported a patient with a dramatic, but again unfortunately temporary, improvement of symptoms after treatment with rituximab [74]. The largest study so far on the immunomodulatory treatment in pediatric narcolepsy is a non-randomized controlled open-label trial in France [75]. In this study, a subset of patients with the highest scores in the narcolepsy screening questionnaire Ullanlinna Narcolepsy Scale (UNS) had remission of symptoms sooner than those who were not treated with IVIg.…”

The case for narcolepsy as an autoimmune disease

“…It has been shown that the loss of HCRT is still ongoing close to symptom onset in some patients [19], and there is thus a great clinical need for immunomodulatory treatment options. Therapies such as corticoids and intravenous immunoglobulins have however shown mostly a disappointing lack of efficacy [20][21][22]. Such therapies mainly target the humoral immune system.…”