Efficacy of pitolisant in treatment resistant narcolepsy with cataplexy: a clinical case report

Introduction

Narcolepsy is a chronic sleep–wake disorder characterised by excessive daytime sleepiness and, in some patients, cataplexy, resulting from dysfunction of orexinergic and downstream arousal networks. Reduced orexin signalling destabilises wake-promoting circuits including histaminergic neurons in the tuberomammillary nucleus. Pitolisant is a histamine H3 receptor inverse agonist that enhances central histamine release and promotes wakefulness. Randomised controlled trials have demonstrated efficacy in reducing excessive daytime sleepiness and cataplexy [1],[2]. However treatment-resistant cases remain challenging especially when psychosocial stressors and circadian disruption are present. Additionally circadian misalignment and occupational shift work may exacerbate symptom severity and reduce adaptive sleep-wake regulation. These factors contribute to marked heterogeneity in clinical presentation and often complicate pharmacological management strategies in routine practice particularly in adults requiring multimodal care approaches included assessment.

Aims

To describe the clinical efficacy of pitolisant in a treatment-resistant case of narcolepsy with cataplexy and evaluate its impact on daytime sleepiness and cataplexy frequency in real-world clinical practice.

Methods

This case report describes a 34-year-old male with long-standing excessive daytime sleepiness, hypnagogic hallucinations, and episodes suggestive of cataplexy since adolescence. Diagnosis was confirmed by polysomnography and multiple sleep latency testing with mean sleep latency of 3.2 minutes across five naps and comorbid moderate to severe restless legs syndrome. Previous pharmacological treatments included venlafaxine, clonazepam, pregabalin, modafinil, methylphenidate and lisdexamfetamine with limited response. Pitolisant was initiated at 4.5 mg/day and titrated to 18 mg/day. Outcomes included Epworth Sleepiness Scale score and weekly cataplexy frequency with descriptive longitudinal analysis over seven months. Behavioural and occupational history suggested significant psychosocial burden and circadian disruption contributing to symptom persistence despite pharmacological escalation. Treatment response was assessed clinically without inferential statistical testing due to single-case design constraints.

Results

Following initiation of pitolisant the patient showed clinically meaningful improvement. Epworth Sleepiness Scale score decreased from 20 at baseline to 11 after 4 weeks and remained stable at seven-month follow-up. Cataplexy episodes previously occurring approximately twice weekly resolved completely after treatment initiation. Improvement was progressive during the first month and stabilised thereafter. Residual symptoms included need for daily nap although functional capacity emotional regulation and occupational safety improved markedly. No adverse effects were reported during follow-up and tolerability was favourable. Subjectively the patient also reported improved emotional stability and reduced anticipatory anxiety related to work performance and safety concerns. These changes were accompanied by improved social functioning and reduced interpersonal conflict within the family environment as reported by patient self-report.

Conclusions

This case supports effectiveness of pitolisant in treatment-resistant narcolepsy with cataplexy demonstrating substantial reduction in excessive daytime sleepiness and cataplexy frequency consistent with previous studies[1],[2]. Findings reinforce role of histaminergic modulation within orexin-related arousal networks as a therapeutic target. Nevertheless partial persistence of symptoms highlights complexity of narcolepsy and need for individualised multimodal management strategies integrating pharmacological and behavioural approaches. Further research is warranted to clarify long-term outcomes predictors of response and real-world applicability. From a neurobiological perspective these findings further support modulation of histamine H3 receptor mediated pathways as viable downstream strategy in orexin-deficient states. This case highlights real-world applicability.

References

1. Dauvilliers, Y., Arnulf, I., Szakacs, Z., Leu-Semenescu, S., Lecomte, J.M., Scart-Gres, C., Schwartz, J.C., 2013. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 12 (11), 1068–1075.
2. Thorpy, M.J., Shapiro, C., Mayer, G., Corser, B., Emsellem, H., Plazzi, G., Bogan, R., 2019. A randomized study of pitolisant for excessive daytime sleepiness in narcolepsy. Sleep Med. 56, 37–44.