Case Presentation

A previously healthy 9-year-old girl was referred due to new-onset narcolepsy type 1 following SARS-CoV-2 infection. In May 2023, about 4 months before presentation, she had experienced SARS-CoV-2 infection with fever. She was infected during the period when almost everyone was infected, as all coronavirus restrictions were lifted in China following the COVID-19 outbreak. Her oropharyngeal specimen tested positive. In addition to fever, the patient also experienced a cough, sore throat, and body aches. While the COVID symptoms lasted for about 2 weeks and then subsided, the sleepiness persisted. Subsequently, she began to experience additional narcoleptic symptoms, including cataplexy, characterized by a sudden loss of muscle tone, which was triggered by positive emotions such as laughter, while consciousness remained unaffected. She also began to experience nightmares and violent behaviors during her nocturnal sleep, which were not present before her SARS-CoV-2 infection. At the same time, she developed obesity and exhibited psychiatric symptoms such as agitation, anxiety, and aggression. Cataplexy and sleepiness were so extreme that they impeded the ability to carry out normal daily activities, leading to a significant decline in academic performance. The Epworth Sleepiness Scale (ESS) scores were 24 upon admission. Prior to admission, her medical history was insignificant.

Neurological examination and brain MRI showed no remarkable findings. Polysomnography (PSG) followed by a daytime multiple sleep latency test (MSLT) was under taken. MSLT showed a mean sleep latency of 2.7 min, and five times sleep onset REM periods.

A lumbar puncture was conducted shortly after her initial admission, revealing unremarkable cerebrospinal fluid (CSF) results. Comprehensive screening for neuronal autoantibodies yielded negative results in both serum and CSF samples. We assessed the CSF hypocretin-1 concentration utilizing the RIA kit from Phoenix Pharmaceuticals Inc. The CSF orexin-A level was pathologically low at 34.06 pg/mL, and she tested positive for HLA-DQB1*06:02. Consequently, a diagnosis of narcolepsy type 1 was confirmed.

Initially, she was prescribed sertraline, which demonstrated a temporary therapeutic effect. However, within a month, she exhibited signs of resistance to the medication. After a careful discussion with the parents, we decided to try ofatumumab, a fully humanized anti-CD20 monoclonal antibody expressed in B lymphocytes.

The girl was administered ofatumumab at a dosage of 20 mg. CD19⁺ and total B-cell population were measured before and after ofatumumab treatment. The measurements showed a significant reduction from 11% and 296 cells per microliter to 0.56% and 11 cells per microliter, signifying the B cell-depleting efficacy of ofatumumab.

Within a week following ofatumumab therapy, there was a marked improvement in both excessive daytime sleepiness and cataplexy. The ESS score was 8 after treatment. She could normally attend school. At the 6-month follow-up, the CD19⁺ B cell and total B cell counts were re-evaluated, yielding results of 7% and 119 cells per microliter, respectively (Table 1). A repeat lumbar puncture was conducted to reassess CSF orexin-A levels, which were found to be with a similar level with the initial measurement at 33.21 pg/mL. Both samples were measured using the same RIA assay. A follow-up MSLT was conducted 9 months after treatment with ofatumumab. The results were similar to the initial assessment, with a shorter mean sleep latency of 3.1 min and four times sleep onset REM periods. Her cataplexy was nearly resolved, with only occasional episodes triggered by intense emotional stimuli, such as roaring with laughter, observed during the nearly 9-month follow-up period. Her condition remained stable throughout the follow-up period. No other treatment was offered during the past 9 months' follow-up.

Discussion

It is widely recognized that influenza and other respiratory infections can act as potent triggers for the onset of narcolepsy type 1 in individuals with a genetic predisposition.^{1, 2} The specific mechanisms underlying the rapid induction of narcolepsy type 1 by SARS-CoV-2 infection remain to be elucidated. Narcolepsy with cataplexy is considered to be an autoimmune disorder involving T cells.¹ Nonetheless, empirical evidence definitively linking a primary role for T cells in neuronal destruction is currently absent. Previous studies have observed a significant increase in the frequency of circulating B cells in narcolepsy patients compared to healthy controls. This investigation further contributes novel insights, suggesting a potential role for T cell-dependent B cell responses in the pathogenesis of narcolepsy type 1.³ Therefore, we hypothesize that a B cell-mediated autoimmune attack, induced by SARS-CoV-2 infection, results in the destruction of orexinergic neurons and the development of narcolepsy type 1.

Over the past few years, new generations of anti-CD20 monoclonal antibodies (mAbs) have demonstrated efficacy in treating numerous autoimmune diseases. Moreover, these advanced mAbs have exhibited promising outcomes in patients with narcolepsy.^{4, 5} Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody that selectively depletes B cells, has been used in the treatment of autoimmune diseases. The remarkable response to ofatumumab in our narcolepsy patient suggests the potential for an ongoing B cell-mediated autoimmune response contributing to the symptoms of narcolepsy. Although treatment with ofatumumab did not increase CSF orexin-A levels, there was a significant improvement in clinical symptoms. Notably, her cataplexy was almost resolved following ofatumumab therapy, with only occasional episodes triggered by very intense emotional stimuli, such as roaring with laughter, observed during the nearly 9-month follow-up period. Her condition remained stable throughout the 9-month follow-up period. The follow-up of this patient is still going on. The efficacy of ofatumumab in this case provides further evidence supporting the role of B cells in the pathophysiology of cataplexy. The occurrence of cataplexy may be mediated by cellular cytotoxicity, with B cells potentially playing a significant role.

The CSF concentration of orexin-A remained similar before and after ofatumumab treatment. Our findings align with a previous study showing that narcolepsy patients treated with rituximab did not exhibit increased levels of CSF orexin-A.⁵ This suggests that the process of orexin neuronal cell death is likely irreversible. Animal experiments indicate that only 5% of orexin neurons remain when cataplexy occurs, suggesting that a small fraction of orexinergic neurons are viable at the onset of treatment.⁶ The destruction of hypothalamic orexin-producing neurons might be cell-mediated through cytotoxicity without the involvement of B cells. Consequently, the depletion of B cells following ofatumumab treatment would not be expected to affect orexin-A levels.⁵ Moreover, several studies have revealed a link between viral infections and cataplexy, suggesting that the loss of orexin neurons may have an autoimmune origin.^{2, 7} However, the precise mechanisms underlying the pathophysiology of cataplexy remain unclear, and the onset of cataplexy is a complex process that likely involves the interplay of multiple factors and mechanisms, which require further research to elucidate.

Determining whether the therapeutic effect of ofatumumab in this patient is long-lasting or temporary requires a longer follow-up. Previous study has revealed that the therapeutic effect of IVIG was not long-lasting and did not persist during follow-up.⁸ A large case–control study revealed that IVIG has no effect on narcolepsy symptoms.⁹ The natural course of narcolepsy is likely erratic, and the complexity of its pathogenesis is not well understood. Therefore, elucidating the complexity of narcolepsy's pathogenesis requires large, controlled studies. We will extend this treatment strategy to other narcolepsy type 1 patients to form exploratory case series or clinical research.

In summary, the efficacy of ofatumumab in this case provides additional support for an autoimmune etiology in narcolepsy with cataplexy, highlighting the potential involvement of B cells in its pathophysiology. Elucidation of the pathogenesis of narcolepsy type 1 may pave the way for significant new research into the underlying immunological mechanisms. This understanding will aid in the development of specific immunotherapeutic strategies for early implementation upon disease onset.

Author Contributions

Xiaoli Wang: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. Xinbo Zhang: major role in the acquisition of data; analysis or interpretation of data. Na Yuan: major role in the acquisition of data; analysis or interpretation of data. Yonghong Liu: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data.

Funding Information

National Key Research and Development Program of China (Grant No.2022YFC2503806).

Conflicts of Interest

The authors report no relevant disclosures.