Exploring Post-COVID Central Hypersomnia: Insights from Clinical Observations


The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has reverberated globally, disrupting lives and altering societal norms. Since its emergence, the world has grappled with over 623 million confirmed cases and mourned the loss of approximately 6.5 million lives as of October 2022 [1].

As nations implemented stringent measures to curb transmission, such as social distancing, lockdowns, and remote work arrangements, the pandemic’s ramifications transcended mere health concerns, seeping into various aspects of daily life, including sleep patterns and daytime functioning [2-7].

Research has meticulously documented the pandemic’s profound impact on sleep quality, insomnia, dream content, and mental health, highlighting a surge in symptoms of anxiety and depression alongside disrupted sleep patterns [6-9]. However, limited attention has been directed towards understanding the pandemic’s direct and indirect influence on daytime functioning attributable to sleep disturbances [4,9]. Yet, the significance of addressing sleep-related impairments, including hypersomnolence, fatigue, and excessive sleep duration, has been increasingly underscored in public health discourse [10-12].

Hypersomnolence, characterized by excessive daytime sleepiness (EDS) or an increased need for sleep leading to daytime impairment, presents a multifaceted challenge [11,13]. While diagnostic delineation can be intricate, encompassing variations in frequency, severity, and underlying causes, the prevalence of EDS spans from 2.5% to 33% in the general population, with an observed escalation of 16% amid the COVID-19 pandemic [4,11].

Contributing factors to this rise remain elusive, with behavioral, physiological, and psychosocial determinants potentially intertwining [11]. Excessive quantity of sleep (EQS), defined as nocturnal sleep exceeding 9 hours and associated with impaired daytime functioning, further compounds the issue, affecting 8.4% of individuals [14]. EQS correlates with a spectrum of health adversities, including depression, obesity, and obstructive sleep apnea, underlining its clinical significance [14,17].

The International COVID-19 Sleep Study (ICOSS) emerged as a pivotal endeavor, aiming to delineate the pandemic’s repercussions on sleep and circadian rhythms worldwide [4,16]. Preliminary findings from ICOSS underscored heightened sleep problems, fatigue, and EDS during the pandemic’s initial phase, elucidating the urgent need for comprehensive investigations [4,16]. Consequently, the study’s overarching objective was to ascertain the prevalence, dynamics, and determinants of EDS, EQS, and fatigue preceding and during the COVID-19 pandemic across diverse geographical contexts.

By examining sleep patterns and daytime functioning across multiple nations, ICOSS aimed to offer insights into the pandemic’s broader ramifications on public health. Through meticulous scrutiny of sleep-related parameters, including EDS and EQS, the study sought to unravel the intricate interplay between the pandemic and individuals’ physiological and psychological well-being. Such endeavors are critical not only for understanding the acute effects of the pandemic but also for devising targeted interventions to mitigate its enduring impact on global health.

In a recent study examining patients with Persistent COVID-19 Symptoms (PCC), a striking discovery emerged: the identification of central hypersomnia in a subset of individuals. Central hypersomnia, characterized by excessive daytime sleepiness and disruptions in wakefulness regulation, is a condition rarely encountered in the general population. However, within this cohort of 530 PCC patients, four cases of objective central hypersomnia were documented, shedding light on a potentially overlooked aspect of post-COVID neurological sequelae.

The study delineates the clinical characteristics and management strategies for these cases of post-COVID central hypersomnia. Three of the four patients met the International Classification of Sleep Disorders, Third Edition (ICSD-3) criteria for idiopathic hypersomnia, while one presented with type II narcolepsy. The temporal association between the onset of symptoms and SARS-CoV-2 infection, coupled with the exclusion of alternative etiologies, strongly suggests a causal relationship between the viral infection and central hypersomnia in these individuals. Consequently, the term “post-COVID central hypersomnia” is proposed to encapsulate this phenomenon.

Therapeutically, methylphenidate was prescribed for three of the patients, yielding notable improvements in excessive daytime sleepiness and functional impairment. While modafinil is typically recommended as a first-line treatment for idiopathic hypersomnia, reimbursement constraints in Switzerland necessitated the use of methylphenidate as the primary pharmacological intervention. Moreover, the broad pharmacological profile of methylphenidate, encompassing both dopaminergic and adrenergic effects, posits its utility in ameliorating cognitive dysfunctions associated with Long COVID beyond mere wakefulness regulation.

TABLE 1 – Methylphenidate and Hypersomnia: Pathophysiology, Pharmacology, and Clinical Considerations

Hypersomnia is a neurological disorder characterized by excessive daytime sleepiness (EDS), leading to significant impairment in daytime functioning. Within the spectrum of hypersomnia, central hypersomnia stands out as a distinct entity, involving dysregulation of the brain’s sleep-wake cycle. This article aims to provide a comprehensive analysis of hypersomnia, particularly central hypersomnia, in conjunction with an in-depth exploration of methylphenidate, a pharmacological agent commonly used in its management.

Hypersomnia: Pathophysiology and Clinical Features

Pathophysiology: Hypersomnia encompasses a range of conditions characterized by disturbances in sleep-wake regulation. Central hypersomnia, in particular, involves dysfunction within the brain’s arousal systems, leading to excessive daytime sleepiness. – Neurotransmitter Imbalance: Dysregulation of neurotransmitters, including dopamine, serotonin, and norepinephrine, is implicated in the pathophysiology of hypersomnia. – Structural Abnormalities: Brainstem nuclei involved in sleep-wake regulation, such as the hypothalamus and brainstem reticular formation, may exhibit structural abnormalities in individuals with hypersomnia.

Clinical Features:

  • Excessive Daytime Sleepiness (EDS): Persistent and uncontrollable urges to sleep during waking hours, often leading to impaired daytime functioning.
  • Cognitive Impairment: Individuals with hypersomnia may experience deficits in attention, memory, and cognitive flexibility, further impacting daily activities.
  • Psychosocial Impact: Hypersomnia can significantly impair quality of life, leading to social and occupational dysfunction.

Methylphenidate: Pharmacology and Mechanism of Action

Chemical Composition: Methylphenidate, chemically known as (RS)-2-methyl-2-phenylpiperidin-2-yl acetate, is a central nervous system (CNS) stimulant.

Pharmacodynamics: – Dopaminergic Activity: Methylphenidate primarily acts by blocking the reuptake of dopamine and norepinephrine, leading to increased synaptic concentrations of these neurotransmitters. – Noradrenergic Activity: Additionally, methylphenidate exerts noradrenergic effects, enhancing arousal and cognitive function.

Pharmacokinetics: – Absorption: Methylphenidate is rapidly absorbed after oral administration, with peak plasma concentrations reached within 1-2 hours. – Metabolism: Hepatic metabolism via carboxylesterase enzymes converts methylphenidate into inactive metabolites. – Elimination: The majority of methylphenidate and its metabolites are excreted renally, with a half-life of approximately 2-4 hours in adults.

Clinical Applications:

  • Attention-Deficit/Hyperactivity Disorder (ADHD): Methylphenidate is widely used as a first-line treatment for ADHD, improving attention, impulse control, and hyperactivity.
  • Narcolepsy and Hypersomnia: In individuals with narcolepsy and hypersomnia, methylphenidate is prescribed to alleviate excessive daytime sleepiness and improve wakefulness.

Management of Central Hypersomnia with Methylphenidate

Clinical Considerations:

  • Treatment Approach: Methylphenidate is utilized as a second-line therapy for central hypersomnia, particularly in cases where modafinil is ineffective or contraindicated. – Dosage and Titration: Initiation of methylphenidate therapy typically involves low doses, gradually titrated to achieve optimal symptom control while minimizing adverse effects.
  • Monitoring and Adverse Effects: Regular monitoring of clinical response and adverse effects, including insomnia, appetite suppression, and cardiovascular effects, is essential during methylphenidate therapy.
  • Efficacy and Outcomes: – Clinical Studies: Several clinical studies have demonstrated the efficacy of methylphenidate in reducing excessive daytime sleepiness and improving cognitive function in individuals with central hypersomnia.
  • Long-Term Management: Long-term use of methylphenidate may be necessary to maintain symptom control and optimize functional outcomes in patients with chronic central hypersomnia.

In summary, central hypersomnia represents a complex neurological disorder characterized by excessive daytime sleepiness and impaired wakefulness regulation. Methylphenidate, with its potent dopaminergic and noradrenergic effects, emerges as a valuable pharmacological agent in the management of central hypersomnia, offering symptom relief and improving daytime functioning. However, further research is warranted to elucidate the long-term efficacy, safety profile, and optimal dosing strategies of methylphenidate in this patient population.

Despite these significant findings, the study acknowledges several limitations. Firstly, the absence of a definitive diagnostic test for post-COVID central hypersomnia underscores the challenge of establishing a causal link between SARS-CoV-2 infection and hypersomnia. Furthermore, the prevalence of this condition remains elusive, with the study’s design precluding accurate estimations due to inherent biases. Additionally, the observational nature of the study, coupled with the small sample size, constrains comprehensive insights into the natural history and treatment outcomes of post-COVID central hypersomnia.

The study posits several mechanistic explanations for the observed association between SARS-CoV-2 infection and central hypersomnia. These include neurological damage, immune dysregulation, autonomic nervous system dysfunction, and persistent viral presence, collectively contributing to dysfunction within brainstem nuclei governing sleep-wakefulness regulation. Importantly, the study situates post-COVID central hypersomnia within the broader landscape of neurological complications associated with Persistent COVID-19 Symptoms, emphasizing the need for further elucidation of its pathophysiology and management strategies.

Drawing parallels with other viral infections, such as SARS-CoV-1 and Epstein Barr virus, which have been implicated in idiopathic hypersomnia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), respectively, the study underscores the potential immunological mechanisms underlying central hypersomnia. Additionally, documented cases of narcolepsy exacerbation post-SARS-CoV-2 vaccination further underscore the interplay between viral exposure and sleep-wakefulness dysregulation.

While acknowledging the clinical and biological similarities between Long COVID and ME/CFS, the study delineates central hypersomnia as a distinct entity, characterized by its atypical presentation within the context of ME/CFS symptomatology. Despite these distinctions, the study underscores the importance of comprehensive differential diagnosis in individuals presenting with post-COVID neurological sequelae.

In conclusion, the emergence of post-COVID central hypersomnia underscores the complex interplay between viral infection and neurological dysfunction. While offering preliminary insights into its clinical characteristics and management, further research is imperative to unravel the mechanistic underpinnings, natural history, and optimal therapeutic approaches for this intriguing manifestation of Long COVID.

reference link :

  • https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1349486/full
  • [] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10163923/


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