Pfizer/BioNTech SARS-CoV-2 vaccine as a potential trigger for the development of narcolepsy: a case report

Abstract

Narcolepsy is a rare condition in Israel. Currently, the incidence of narcolepsy following SARS-CoV-2 vaccination in Israel is unknown. We are reporting a case report of a 51-year-old woman of Ashkenazi Jewish descent who was evaluated for complaints of excessive daytime sleepiness and relative functional decline that immediately followed receipt of the Pfizer/BioNTech SARS-CoV-2 vaccination. Evaluation of patient-reported data with polysomnography and multiple sleep latency test was consistent with narcolepsy with cataplexy, meeting the criteria for a diagnosis of type 1 narcolepsy. Further investigation included human leukocyte antigen testing. Prior studies have demonstrated genetic, immunological, and environmental factors associated with narcolepsy following other vaccinations. This case is a valuable contribution to the literature as there are no prior reports of type 1 narcolepsy following SARS-CoV-2 vaccination in the State of Israel.

Citation:

Mahamid A, Bornstein RJ, Amir H. Pfizer/BioNTech SARS-CoV-2 vaccine as a potential trigger for the development of narcolepsy: a case report. J Clin Sleep Med. 2022;18(10):2503–2506.

INTRODUCTION

During the COVID-19 pandemic, numerous large-scale studies have been published documenting chronic neurological sequelae related to both vaccinations and COVID-19 infection. Disturbances of sleep, primarily the development of hypersomnia, have been documented extensively in the literature. In a multinational cohort study published in 2021, narcolepsy was identified as 1 of the primary complications of interest following SARS-CoV-2 vaccination. One United States study identified the incidence of narcolepsy following any vaccine for SARS-CoV-2 as 31–38 cases per 100,000 person years among those aged 25–64 years.¹ Prior studies on other vaccinations have yielded associations with neurological sequelae including narcolepsy. We are presenting a case report of a 51-year-old Ashkenazi Jewish woman who developed narcolepsy following Pfizer/BioNTech SARS-CoV-2 vaccination. The prevalence of narcolepsy in the United States and Europe has been estimated at 19–56 per 100,000 people.² In contrast, the estimated prevalence of narcolepsy in Israel is very low at 0.14–0.21 per 100,000.³ In a 1988 case control study by Wilner et al,⁴ all 7 cases of type 1 narcolepsy among Israeli Jews were associated with the human leukocyte antigen (HLA)-DR2 Dw2 haplotype, which has a very low frequency in this population, ∼9%. In a later genetic study in Israel, 11 cases of narcolepsy also reported the presence of HLA-DR2 in addition to concordant alleles including DRB1*1501, DQA1*0102, and, most significantly, the DQB1*0602 allele associated with the majority of cases of type 1 narcolepsy.⁵

REPORT OF CASE

We are presenting a case report of a patient with a premorbid subclinical sleep disturbance that developed a clinically severe case of narcolepsy following inoculation with the Pfizer/BioNTech SARS-CoV-2 vaccine. The patient was evaluated to the Institute of Sleep Medicine at Loewenstein Hospital Rehabilitation center in Raanana, Israel.

Our patient is a 51-year-old woman, separated with 3 children, right hand dominant, native of Argentina, immigrated to Israel in 1988, currently lives with her family in the central part of Israel in a private residence, and works as a clinical psychologist. She is independent in all basic and instrumental activities of daily living. Past medical history was significant for a history of attention deficit hyperactivity disorder from childhood, originally treated with Ritalin (Novartis, Basel, Switzerland), which was later discontinued. Currently, she is on treatment with Attent (TEVA PHARMACEUTICAL INDUSTRIES LTD, Kfar Saba, ISRAEL) (mixed amphetamine salts) 30 mg daily. She also has a history of obesity treated by sleeve gastrectomy in August of 2014. In December 2020, the patient began to experience repeated episodes of vomiting and underwent a gastroenterological work-up with no significant findings.

Past health history was significant for a documented sleep disturbance, primarily chronic insomnia throughout her early life. At the age of 21 years, she was treated with cognitive behavioral therapy and melatonin followed by marked improvement of symptoms. In February 2020, the patient was involved in a series of domestic incidents with no reported physical trauma that resulted in significant emotional stress and progressive worsening of chronic insomnia. During this period, the patient remained independent and continued to work as usual. On January 9, 2021, the patient received the first dose of the Pfizer/BioNTech SARS-CoV-2 vaccine. Immediately following vaccination, she reported severe fatigue, persistent nausea, and numbness and tingling in all 4 extremities. She also reported elevated levels of stress and difficulties with her memory. Additionally, she noted alternating episodes of loss of bodily control upon awakening. She was then referred for neurological consultation. The neurologist recommended a work-up for polyneuropathy, including laboratory testing and electrodiagnostic studies. Laboratory testing was unremarkable. Evidence of bilateral carpal tunnel syndrome was found on electromyography without evidence of polyneuropathy. On February 4, 2021, the patient received the second dose of the Pfizer/BioNTech vaccination. The week following vaccination, the patient reported severe fatigue and was unable to work. She described long abnormal episodes of sleep throughout the week. Following the first week, she experienced alternating episodes of generalized muscle paralysis upon awakening that were more pronounced as compared to those experienced following receipt of the first dose. During this time, she reported excessive daytime sleepiness, with episodes of sleep at inappropriate times and settings, along with involuntary eye closing during stimulating activities such as laughing. A psychiatrist was consulted who recommended treatment for suspected depression and anxiety with olanzapine (Teva Pharmaceutical Works Private Limited Company, Debrecen, Hungary); however, the patient denied symptoms of depression and refused treatment with antidepressant or antipsychotic medications. The psychiatrist was alarmed by the patient’s reports of memory impairment and referred her to the emergency room at Sheba Medical Center. There head computed tomography was performed with no evidence of hemorrhage and no additional abnormalities noted on exam. Follow-up brain magnetic resonance imaging and electroencephalogram were recommended. On July 6, 2021, electroencephalogram was performed and demonstrated no abnormal activity. On June 27, 2021, brain magnetic resonance imaging noted that at the subcortical right frontal vertex there was an isolated 2.5 mm enhancing lesion of unknown significance. No additional abnormalities were noted on exam. Follow-up magnetic resonance imaging was performed on August 11, 2021, and found no change in the isolated subcortical enhancing lesion. Vascular work-up was initiated with an ultrasound duplex of the carotid arteries with no abnormal findings. Transthoracic echocardiogram was performed along with Holter electrocardiogram that were also normal. At this time, the patient demonstrated progressive deterioration in function compared with baseline. Excessive daytime sleepiness prevented the patient from driving, and at this time, she found significant difficulty in continuing her work as a psychologist. On September 1, 2022, polysomnography (PSG) and a multiple sleep latency test (MSLT) were performed at the Institute of Sleep Disorders at Loewenstein Rehabilitation Center. The Epworth Sleepiness Scale (ESS) questionnaire was administered. Prior to receipt of the vaccine, the patient scored a 3 on the ESS scale. At the time of evaluation at our clinic, an ESS score of 16 was recorded. Accordingly, the change in the ESS scores reflect the acute onset and severity of self-reported daytime sleepiness. During PSG, there were no clinically significant episodes of sleep-disordered breathing, with an apnea-hypopnea index of 0.8 events/h and no clinically apparent snoring. No abnormal activity was noted on electroencephalogram, and electrocardiogram was within normal limits with no disturbances of rate or rhythm. There were no recorded episodes of periodic limb movement. On MSLT, the average sleep latency was 3.3 minutes. The patient entered sleep stages in 4 out of 4 nap intervals, with rapid eye movement sleep present in 3 of 4. Findings in both PSG and MSLT were consistent with a diagnosis of narcolepsy. As per the International Classification of Sleep Disorders, third edition, both self-reported and objective assessments in this case were diagnostic for type 1 narcolepsy.

Following the patient history, diagnostic work-up, and evaluation of associated exposures, it was necessary to determine the patient’s baseline risk for the development of narcolepsy with HLA-typing by sequence-specific priming and sequence-specific oligonucleotide probe hybridization. According to the literature, there is a low prevalence of HLA DR2 and HLA DQB1 06:02 in Israel. It has been suggested that the low prevalence of this HLA type is related to the low incidence of narcolepsy in this population. Alternatively, in the 2 studies examining HLA and narcolepsy in Israel, all cases carried both HLA DR2 and HLA DQB1 06:02. HLA testing in our patient was negative for HLA DQB1 06:02 as well as all known HLA types that are associated with narcolepsy. In a 2014 retrospective case-control study, the authors found that the primary genetic determinant of both narcolepsy risk and protection in their European sample was the DQB1 locus.⁶ Our patient was positive for HLA DQB1 06:03, which in the same 2014 study carried an odds ratio of 0.17 for developing narcolepsy, conferring a reduced odds of disease compared to the general population. We can therefore define this case as the development of narcolepsy following vaccination in the absence of HLA alleles associated with narcolepsy.

DISCUSSION

During the SARS-CoV-2 pandemic, chronic neurologic complications have been noted in the literature following both vaccination and disease. In cases of infection, it is known that some coronaviruses result in viral spread from peripheral nerves and cross the blood-brain barrier by way of ACE2 receptors. Schirinzi et al⁷ describe a proposed mechanism of neuropathogenicity in an article. Neuronal infection, olfactory pathway tropism, blood-brain barrier disruption, systemic inflammation, lymphocyte imbalance, and intestinal colonization result in a central nervous system inflammation, neurodegeneration, and demyelination that may trigger the development of chronic neurological disorders such as parkinsonism, multiple sclerosis, and narcolepsy. The literature on narcolepsy documents potential triggers that include certain vaccines.

Vaccine-associated narcolepsy has been observed specifically following influenza.⁸ In a 2015 article published by Ahmed and Steinman,⁹ it was found that antibodies to influenza nucleoprotein cross-react with human hypocretin receptor. Decreased cerebrospinal fluid hypocretin (< 110 pg/mL) has been associated with the development of excessive daytime sleepiness. In a 2017 systematic review and meta-analysis, the H1N1 Pandemrix vaccine demonstrated a 2-to-7-fold risk of narcolepsy developing among vaccinated adults in 2009–2010 across Finland, France, Ireland, Netherlands, Norway, Sweden, and the United Kingdom. In a 2015 study by Saariaho et al,¹⁰ the Pandemrix vaccine induced the formation of antiganglioside GM3 antibodies, which were associated with the HLA-DQB1*0602. Additionally, anti-GM3 antibodies demonstrated a significant association with the development of narcolepsy-cataplexy. Most studies have demonstrated multiple autoantibody targets, suggesting a multifactorial process.

The Pfizer/BioNTech SARS-CoV-2 vaccine is an mRNA vaccine. It is formulated in lipid particles that deliver mRNA into host cells that subsequently express the S-antigen, causing an immune response.¹¹ A US study identified the incidence of narcolepsy following any vaccine for SARS-CoV-2 as 31–38 cases per 100,000 person years among persons aged 25–64 years.¹

Additional studies have identified specific immune mechanisms associated with the development of narcolepsy. Specifically, a 2018 study by Lippert et al¹² observed a process of primarily CD4 T-cell mediated damage in disorders of hypersomnia. As noted above, studies have elaborated on pathologic immune activity associated with the development of narcolepsy following the specific vaccines that are documented in the literature. Further research may elucidate the underlying mechanisms involved in such disease in support of similar conclusions regarding vaccination against SARS-CoV-2 or, specifically, the Pfizer/BioNTech vaccine.

The patient reported data that included (patient interview and use of ESS) and objective measures (PSG and MSLT), with results that strongly support the diagnosis of type 1 narcolepsy. The onset of symptoms occurred directly after vaccination and were not related to any other known factors, including additional exposures, changes in medications, and recent significant life events. An extensive medical work-up including imaging studies demonstrated no evidence of alternative etiology.

The prior history of chronic insomnia is notable, although we believe that it is most likely related to attention deficit hyperactivity disorder with respect to onset and subsequent response to cognitive behavioral therapy. In addition, the patient reported no symptoms of narcolepsy prior to receipt of the vaccine. The family reported no witnessed episodes of sleep attacks or sudden loss of muscle tone. The patient reported that PSG was performed; however, the results could not be obtained and therefore sleep apnea cannot be ruled out as a contributing factor given the history of obesity. A 2015 cross-sectional study performed in France reported that children with narcolepsy demonstrated clinically significant symptoms of attention deficit disorder (either inattentive or hyperactive).¹³ Increasing severity of attention deficit hyperactivity disorder symptoms were associated with increased levels of sleepiness, fatigue, and insomnia. Among study participants, a high percentage were found to carry HLA DQB1-06:02 in both cases of narcolepsy with or without cataplexy. Sleep disturbance, specifically chronic insomnia, is a well-documented comorbid condition that presents with attention deficit hyperactivity disorder. Cognitive behavioral therapy has demonstrated effectiveness for chronic insomnia among both children and adults with attention deficit disorder.¹⁴ The patient’s response to cognitive behavioral therapy is also consistent with a premorbid history of chronic insomnia.

Following vaccination, the patient reported symptoms of excessive daytime sleepiness, hypersomnia, and episodes of general muscle paralysis upon awakening. She described acute attacks of sleep during inappropriate times. Consequently, the patient experienced a significant functional decline compared to baseline, being unable to perform daily activities at home and at work, which caused a marked decrease in her quality of life. The ESS was administered to compare prevaccination and postvaccination symptoms and severity and, additionally, to establish a baseline for monitoring response to therapy. PSG and MSLT were performed with findings consistent with the diagnostic criteria for type I narcolepsy.

Treatment was recommended with Pitolisant (Bioprojet Pharma, Paris, France), a novel therapeutic agent that acts as a histamine H3-receptor specific antagonist and inverse agonist that was approved by the US Food and Drug Administration for treatment of patients with excessive daytime sleepiness associated with type 1 narcolepsy (narcolepsy-cataplexy).¹⁵ The patient is continuing follow-up to assess response to therapy with intermittent sleep studies as needed.

Narcolepsy is exceedingly rare in Israel compared to other developed countries. Cases of vaccine-induced narcolepsy have been observed in the past associated with Pandemrix and more recently as an adverse event of interest following SARS-CoV-2 vaccinations.^1,8 The incidence data regarding SARS-CoV-2 vaccination and type 1 narcolepsy support the need for further studies to establish and define such an association. This case report is notable and may implicate vaccination against SARS-CoV-2 as a trigger for the development of narcolepsy in certain individuals with predisposing factors.

DISCLOSURE STATEMENT

All authors have seen and approved this manuscript. Work for this study was performed at the Loewenstein Rehabilitation Center. The opinions and assertions in this case report are those of the authors and do not necessarily represent those of the Clalit, The Ministry of Health, or any other government agency in the State of Israel. The authors report no conflicts of interest.

ABBREVIATIONS

ESS

Epworth Sleepiness Scale

HLA

human leukocyte antigen

MSLT

Multiple Sleep Latency Test

PSG

polysomnography