key: cord-311316-j79nmq0j
authors: Tony, Abeer Abdelhady; Tony, Effat Abdelhady; Ali, Shazly B.; Ezzeldin, Azza M.; Mahmoud, Amal A.
title: COVID-19-associated sleep disorders: A case report
date: 2020-09-12
journal: Neurobiol Sleep Circadian Rhythms
DOI: 10.1016/j.nbscr.2020.100057
sha: 
doc_id: 311316
cord_uid: j79nmq0j

PURPOSE: We reported one patient infected with acute respiratory syndrome coronavirus-2 (SARS-CoV-2) presented with sleep disorders; insomnia and restless leg syndrome. METHODS: Patient data were obtained from medical records from Al-Raghy Isolation Hospital in Assuit University. RESULTS: A 49-year-old female patient presented with insomnia and restless leg syndrome associated with anosmia, ageusia. Three days before, she had developed a cough, malaise and athenia, headache, arthralgia, myalgia affecting mainly upper limbs, diarrhea and a fever followed by tachypnea. The naso-oropharyngeal swab test for coronavirus disease 2019 (COVID-19) by qualitative real-time reverse-transcriptase–polymerase-chain-reaction assay was positive. The patient was treated with Oseltamivir 75mg and clarithromycin 500 mg (12 hourly for each respectively) for 10 days with paracetamol. Two weeks later, the patient made a complete neurological and respiratory recovery. CONCLUSION: Our case highlighted the rare occurrence of restless leg syndrome and insomnia during the COVID-19 pandemic. The era of sleep disorders spectrum in patients with COVID-19 remains to be characterized suggesting a frightening scientific association between COVID-19 and neuropsychiatric illness.

The coronavirus disease 2019 (COVID-19) is critically affecting not only the physical health but also mental health globally [1] [2] [3] . The spectrum of the coronavirus disease 2019 (COVID-19) ranges from asymptomatic infection to severe respiratory failure. Gastrointestinal (e.g., diarrhea) or even neurological manifestations (e.g., headache) have also been reported as other features of COVID-19. In addition, other neurological symptoms such as anosmia and ageusia are presented by many patients [4] . There is a scarcity of evidence on the magnitude of sleep disorders among individuals affected by this pandemic. In humans infected with influenza virus, sleep duration decreases during incubation and increases during the symptomatic phase . A recent review of randomized control trials of oseltamivir versus placebo in adults and adolescents with influenza showed a significantly faster return to baseline sleep durations with treatment, supporting the notion that it was the virus that caused increased sleep [5] . Interestingly, We describe a case of COVID-19-associated sleep disorders as presenting symptoms .

On 12th May 2020, a 49-year-old healthcare worker woman known to have hypertension, diabetes mellitus and ischemic heart disease with paroxysmal atrial fibrillation (AF); was admitted to isolation emergency department of Assuit University Hospitals for fever, dry cough, tachypnoea, watery diarrhea, lassitude , arthralgia and myalgia. One week before, while the patient was in Aswan Univerity Hospitals developed fever ( 38.5-39 °C), dry cough with burning sensation in the nasopharynx and sore throat.

This was associated with severe agonizing pain allover the body especially joints and muscles of upper J o u r n a l P r e -p r o o f limbs. At this time , she was treated with antibiotic, antipyretic and antitussive medications. Within 2 days, she developed bleeding per nose, infrequent blood tinged sputum, severe anorexia and loss of taste and smell. Meanwhile, she experienced sleep disturbances; insomnia, poor sleep quality, and abnormal events that occur during sleep as strong urge to move her legs over the nigh that improved somewhat by moving them (restless leg syndrome). Therefore, the patient was transferred to Assuit University Hospitals for admission by her will. On admission at Al-Raghy isolation Hospital of Assuit University 

J o u r n a l P r e -p r o o f To our knowledge, the interaction between sleep disorders and COVID-19 pandemic is not yet elucidated.

In this study, we expressed a case with PCR confirmed COVID-19 infection presented with sleep disorders. Sleep is a fundamental CNS phenomenon that is regulated by complex interactions between neurotransmitters, immunologically active peptides, and hormones [6] .

In our PCR positive COVID-19 case, the main presenting sleep disorders were insomnia and restless leg syndrome. This could be directly related to the infection per se or related to hypoxia. Notably, Sleep and the immune system are bidirectionally related. However, the mechanisms of these changes have not been determined entirely. This hypothesis was in agreement with Ibarra-Coronado et al. [7] who suggested that altered sleep during infection is a component of the acute phase response, promoting recovery during illness, likely through mechanisms that involve cytokines and interleukins and their receptors, as well as receptors of the innate immune system. The consequent secretion of these immunological mediators is accompanied by responses by the endocrine and nervous systems, such as the secretion of cortisol and epinephrine. These substances can cross the blood-brain barrier to reach their receptors in various neural structures or may have a vagal input to modulate the responses that maintain homeostasis.

Moreover, Das et al., [5] stated that no single cytokine is consistently associated with sleep, and this may explain why different infections are associated with different patterns of sleep disruption. Cytokine storm, which is a well known immune reaction of this particular viral infection, may lead to inflammation and injury of the central nervous system tissue. Furthermore, Wan et al., [8] stated that interleukin (IL)-6, an important member of the cytokine storm, was associated with the severity of COVID-19 symptoms.

Interestingly, Lasselin et al., [9] reported that poor sleep quality and longer sleep latency which are central symptoms in insomnia, were observed during acute respiratory infection, suggested that immune processes could possibly contribute to pathological states of sleep disturbances. Moreover, respiratory infections affected both objective and subjective sleep in a number of ways: when sick, people spent objectively longer time in bed and slept longer, but also suffered from more awakenings, at least during the first days when symptoms were high. During sickness, people also reported having worse sleep quality, increased difficulties falling asleep, more restless sleep and less deep sleep. Asif, [10] reported that Sleep and stress are also associated. While sleep inhibits the activity of the hypothalamic-pituitaryadrenal gland (HPA) axis, which mediates several facets of the response to most stressors, several stressors inhibit sleep and increase waking time and brain cortical arousal.

Our patient had restless leg syndrome ( RLS) .This could be attributed by COVID19-induced cytokine storm syndrome which led to cytokine IL-6 production that can stimulate up-regulation of hepcidin production in the choroid plexus. This hepcidin bound to choroid plexus-associated ferroportin, leading to decrease availability of iron for the CNS in RLS. Moreover, the microcytic hypo chromic anemia due to low serum iron level in our case could be considered as another factor behind the occurrence of RLS.

These findings were in consistent with Weinstock et al., [11] who stated that Inflammation can lead to systemic iron deficiency that could trigger CNS iron deficiency and subsequent RLS symptoms . Another explanation for the occurrence of RLS is that our patient had known to be diabetic and so, she could had a subclinical, otherwise asymptomatic diabetic peripheral neuropathy which exacerbate with viral infection. Interestingly Ishaqui et al., [14] reported that the combination therapy of oseltamivir and azithromycin, like in our case, significantly reduced numerous proinflammatory cytokines and there was a trend towards faster symptoms resolution compared with oseltamivir alone.

We recognize that the main limitations of the case were the absence of electroencephalography and polysomnography studies as well as magnetic resonance imaging of brain. The reason for this was the extreme circumstances in our hospitals at the peak of this pandemic.

In conclusion, we described a patient with confirmed PCR COVID-19 infection who presented by fever, asthenia, insomnia and restless leg syndrome with good outcome. Neurological manifestations might occur because of an aberrant immune response to COVID-19. At present, the full clinical spectrum of patients with COVID-19 with sleep disorders remains to be characterized. Further studies would be urgently needed for a comprehensive understanding of the neurological pathology of COVID-19 and its effects on the nervous system. Improving our understanding of the neurobiology of corona viruses could augment our knowledge of sleep disorders with potential viral association.

Mental Health Outcomes of Quarantine and Isolation for Infection Prevention: A Systematic Umbrella Review of the Global Evidence

COVID-19 and mental health: A review of the existing literature

Burnout Among Healthcare Providers During COVID-19 Pandemic : Challenges and Evidence-based Interventions

Miller Fisher Syndrome and polyneuritis cranialis in COVID-19

Neurological Insights of COVID-19 Pandemic

The Sleep-Immune Crosstalk in Health and Disease

The bidirectional relationship between sleep and immunity against infections

Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with

Sleep during naturally occurring respiratory infections: A pilot study

Human immune system during sleep

Restless legs syndrome -Theoretical roles

The authors declare that they have no competing interests Funding Non declared.

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