Central hypersomnia and chronic insomnia: expanding the spectrum of sleep disorders in long COVID syndrome – a prospective cohort study

Abstract:

Introduction: Long-onset COVID syndrome has been described in patients with COVID-19 infection with persistence of symptoms or development of sequelae beyond 4 weeks after the onset of acute symptoms, a medium- and long-term consequence of COVID-19. This syndrome can affect up to 32% of affected individuals, with symptoms of fatigue, dyspnea, chest pain, cognitive disorders, insomnia, and psychiatric disorders. The present study aimed to characterize and evaluate the prevalence of sleep symptoms in patients with long COVID syndrome.

Methodology: A total of 207 patients with post-COVID symptoms were evaluated through clinical evaluation with a neurologist and specific exams in the subgroup complaining of excessive sleepiness.

Results: Among 189 patients included in the long COVID sample, 48 (25.3%) had sleep-related symptoms. Insomnia was reported by 42 patients (22.2%), and excessive sleepiness (ES) was reported by 6 patients (3.17%). Four patients with ES were evaluated with polysomnography and test, multiple sleep latencies test, and actigraphic data. Two patients had a diagnosis of central hypersomnia, and one had narcolepsy. A history of steroid use was related to sleep complaints (insomnia and excessive sleepiness), whereas depression was related to excessive sleepiness. We observed a high prevalence of cognitive complaints in these patients.

Conclusion: Complaints related to sleep, such as insomnia and excessive sleepiness, seem to be part of the clinical post-acute syndrome (long COVID syndrome), composing part of its clinical spectrum, relating to some clinical data.

Source: Moura AEF, Oliveira DN, Torres DM, Tavares-Júnior JWL, Nóbrega PR, Braga-Neto P, Sobreira-Neto MA. Central hypersomnia and chronic insomnia: expanding the spectrum of sleep disorders in long COVID syndrome – a prospective cohort study. BMC Neurol. 2022 Nov 9;22(1):417. doi: 10.1186/s12883-022-02940-7. PMID: 36352367; PMCID: PMC9643986. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9643986/ (Full text)

Systemic exertion intolerance disease/chronic fatigue syndrome is common in sleep centre patients with hypersomnolence: A retrospective pilot study

Abstract:

Symptoms of the central disorders of hypersomnolence extend beyond excessive daytime sleepiness to include non-restorative sleep, fatigue and cognitive dysfunction. They share much in common with myalgic encephalomyelitis/chronic fatigue syndrome, recently renamed systemic exertion intolerance disease, whose additional features include post-exertional malaise and orthostatic intolerance. We sought to determine the frequency and correlates of systemic exertion intolerance disease in a hypersomnolent population.

One-hundred and eighty-seven hypersomnolent patients completed questionnaires regarding sleepiness and fatigue; questionnaires and clinical records were used to assess for systemic exertion intolerance disease. Sleep studies, hypocretin and cataplexy were additionally used to assign diagnoses of hypersomnolence disorders or sleep apnea. Included diagnoses were idiopathic hypersomnia (n = 63), narcolepsy type 2 (n = 25), persistent sleepiness after obstructive sleep apnea treatment (n = 25), short habitual sleep duration (n = 41), and sleepiness with normal sleep study (n = 33). Twenty-one percent met systemic exertion intolerance disease criteria, and the frequency of systemic exertion intolerance disease was not different across sleep diagnoses (p = .37).

Patients with systemic exertion intolerance disease were no different from those without this diagnosis by gender, age, Epworth Sleepiness Scale, depressive symptoms, or sleep study parameters. The whole cohort reported substantial fatigue on questionnaires, but the systemic exertion intolerance disease group exhibited more profound fatigue and was less likely to respond to traditional wake-promoting agents (88.6% versus 67.7%, p = .01). Systemic exertion intolerance disease appears to be a common co-morbidity in patients with hypersomnolence, which is not specific to hypersomnolence subtype but may portend a poorer prognosis for treatment response.

Source: Maness C, Saini P, Bliwise DL, Olvera V, Rye DB, Trotti LM. Systemic exertion intolerance disease/chronic fatigue syndrome is common in sleep centre patients with hypersomnolence: A retrospective pilot study. J Sleep Res. 2018 Apr 6:e12689. doi: 10.1111/jsr.12689. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29624767

A retrospective review of the sleep characteristics in patients with chronic fatigue syndrome and fibromyalgia

Abstract:

This study characterizes findings on sleep testing and Human Leukocyte Antigen (HLA) markers in a group of patients with fibromyalgia (FM) and chronic fatigue syndrome (CFS). One hundred eighteen patients seen in a general neurology practice over 5 years meeting standard clinical criteria for FM or CFS were analyzed retrospectively. Cases of untreated sleep apnea or restless legs syndrome were excluded prior to inclusion in this study.

Ninety-two patients had multiple sleep latency testing (MSLT). Seventy-three (80%) were abnormal by standard criteria. Of 57 females having positive MSLTs, 22 (39%) had one or more periods of sleep onset rapid eye movement (SOREM), and 5 of 16 (31%) males with positive MSLTs had one or more SOREM. Highly fragmented sleep, as previously described in FM, was seen but not analyzed quantitatively. HLA DQB1*0602 was obtained in 74 patients, and positive in 32 (43%), P < 0.0001 compared with published values in 228 populations.

In our patients, who presented with neuromuscular fatigue or generalized pain, we found a sleep disorder characterized by objective hypersomnia. Some patients had characteristics of narcolepsy. Objective assessment by sleep studies can assist the diagnostic process, aid future research, and provide rationale for treatment.

 

Source: Spitzer AR, Broadman M. A retrospective review of the sleep characteristics in patients with chronic fatigue syndrome and fibromyalgia. Pain Pract. 2010 Jul-Aug;10(4):294-300. doi: 10.1111/j.1533-2500.2009.00352.x. Epub 2010 Mar 2. https://www.ncbi.nlm.nih.gov/pubmed/20230458

 

Actigraphic assessment of sleep disorders in children with chronic fatigue syndrome

Abstract:

Children with chronic fatigue syndrome (CFS) often suffer from sleep disorders, which cause many physiological and psychological problems. Understanding sleep characteristics in children with CFS is important for establishing a therapeutic strategy. We conducted an actigraphic study to clarify the problems in sleep/wake rhythm and physical activity in children with CFS.

METHODS: Actigraphic recordings were performed for 1-2 weeks in 12 CFS children. The obtained data were compared with those of healthy age-matched children used as the control.

RESULTS: Sleep patterns were divided into two groups based on subjects’ sleep logs: irregular sleep type and delayed sleep phase type. Compared to the control group, total sleep time was longer and physical activity was lower in both groups of CFS. Continuous sleep for more than 10h was not uncommon in CFS. In the irregular sleep type, impaired daily sleep/wake rhythms and disrupted sleep were observed.

CONCLUSION: Using actigraphy, we could identify several characteristics of the sleep patterns in CFS children. Actigraphic analysis proved to be useful in detecting sleep/wake problems in children with CFS.

 

Source: Ohinata J, Suzuki N, Araki A, Takahashi S, Fujieda K, Tanaka H. Actigraphic assessment of sleep disorders in children with chronic fatigue syndrome. Brain Dev. 2008 May;30(5):329-33. Epub 2007 Nov 26. https://www.ncbi.nlm.nih.gov/pubmed/18031961

 

Antinuclear antibodies in patients with chronic fatigue syndrome

Abstract:

Significance of antinuclear antibodies (ANA) in the patients with chronic fatigue syndrome (CFS) was reviewed. When indirect immunofluorescence with the HEp-2 cells as the substrates was used, prevalence of the positive ANA was reportedly 15-25%. The ANA titers were low and the immunofluorescent staining patterns were heterogeneous.

One group in the USA reported that ‘nuclear envelope staining pattern’ was found in more than 50% of the patients with CFS. This results, however, have not been confirmed by any other research groups. Clinical significance of the positive ANA in the CFS patients resides in differential diagnoses of systemic lupus erythematosus and other diffuse connective tissue diseases. Recently, several ANAs specific to CFS have been described.

We reported anti-68/48kD protein antibodies utilizing SDS-PAGE/ immunoblot method. These autoantibodies were found in 13% of 114 CFS patients and 0% in healthy subjects (p < 0.05). Hypersomnia and difficulty in concentration were found more frequently in the CFS patients with this specific autoantibody.

 

Source: Nishikai M. Antinuclear antibodies in patients with chronic fatigue syndrome. Nihon Rinsho. 2007 Jun;65(6):1067-70. [Article in Japanese] https://www.ncbi.nlm.nih.gov/pubmed/17561698

 

Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders

Abstract:

OBJECTIVE: To identify antinuclear antibodies (ANA) specific for chronic fatigue syndrome (CFS), and in related conditions such as fibromyalgia (FM) or psychiatric disorders.

METHODS: One hundred and fourteen CFS patients and 125 primary and secondary FM patients were selected based on criteria advocated by the Centers for Disease Control and Prevention and by the American College of Rheumatology, respectively. As controls, healthy subjects and patients with either various psychiatric disorders or diffuse connective tissue diseases were included. Autoantibodies were examined by immunoblot utilizing HeLa cell extracts as the antigen.

RESULTS: Autoantibodies to a 68/48 kDa protein were present in 13.2 and 15.6% of patients with CFS and primary FM, respectively. In addition, autoantibodies to a 45 kDa protein were found in 37.1 and 21.6% of the patients with secondary FM and psychiatric disorders, respectively. Meanwhile, these two autoantibodies were not found at all in connective tissue disease patients without FM, nor in healthy subjects (P<0.05). As a group, the anti-68/48 kDa-positive CFS patients presented more frequently with hypersomnia (P<0.005), short-term amnesia (P<0.07) or difficulty in concentration (P<0.05) than those CFS patients without the antibodies.

CONCLUSIONS: The presence of the anti-68/48 kDa protein antibodies in a portion of both CFS and primary FM patients suggests the existence of a common immunological background. These antibodies may find utility as possible markers for a clinicoserological subset of CFS/FM patients with hypersomnia and cognitive complaints.

 

Source: Nishikai M, Tomomatsu S, Hankins RW, Takagi S, Miyachi K, Kosaka S, Akiya K. Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders. Rheumatology (Oxford). 2001 Jul;40(7):806-10. http://rheumatology.oxfordjournals.org/content/40/7/806.long (Full article)

 

Chronic fatigue syndrome and seasonal affective disorder: comorbidity, diagnostic overlap, and implications for treatment

Abstract:

This study aimed to determine symptom patterns in patients with chronic fatigue syndrome (CFS), in summer and winter. Comparison data for patients with seasonal affective disorder (SAD) were used to evaluate seasonal variation in mood and behavior, atypical neurovegetative symptoms characteristic of SAD, and somatic symptoms characteristic of CFS.

Rating scale questionnaires were mailed to patients previously diagnosed with CFS. Instruments included the Personal Inventory for Depression and SAD (PIDS) and the Systematic Assessment for Treatment Emergent Effects (SAFTEE), which catalogs the current severity of a wide range of somatic, behavioral, and affective symptoms. Data sets from 110 CFS patients matched across seasons were entered into the analysis. Symptoms that conform with the Centers for Disease Control and Prevention (CDC) case definition of CFS were rated as moderate to very severe during the winter months by varying proportions of patients (from 43% for lymph node pain or enlargement, to 79% for muscle, joint, or bone pain).

Fatigue was reported by 92%. Prominent affective symptoms included irritability (55%), depressed mood (52%), and anxiety (51%). Retrospective monthly ratings of mood, social activity, energy, sleep duration, amount eaten, and weight change showed a coherent pattern of winter worsening.

Of patients with consistent summer and winter ratings (n = 73), 37% showed high global seasonality scores (GSS) > or = 10. About half this group reported symptoms indicative of major depressive disorder, which was strongly associated with high seasonality.

Hierarchical cluster analysis of wintertime symptoms revealed 2 distinct clinical profiles among CFS patients: (a) those with high seasonality, for whom depressed mood clustered with atypical neurovegetative symptoms of hypersomnia and hyperphagia, as is seen in SAD; and (b) those with low seasonality, who showed a primary clustering of classic CFS symptoms (fatigue, aches, cognitive disturbance), with depressed mood most closely associated with irritability, insomnia, and anxiety.

It appears that a subgroup of patients with CFS shows seasonal variation in symptoms resembling those of SAD, with winter exacerbation. Light therapy may provide patients with CFS an effective treatment alternative or adjunct to antidepressant drugs.

 

Source: Terman M, Levine SM, Terman JS, Doherty S. Chronic fatigue syndrome and seasonal affective disorder: comorbidity, diagnostic overlap, and implications for treatment. Am J Med. 1998 Sep 28;105(3A):115S-124S. http://www.ncbi.nlm.nih.gov/pubmed/9790493

 

Sleep disorders in patients with chronic fatigue

Abstract:

This prospective, cohort study examined the prevalence of sleep disorders among highly selected patients with chronic fatigue. On the basis of responses suggestive of sleep pathology on a screening questionnaire, 59 patients from a university-based clinic for chronic fatigue who had undergone a medical and psychiatric evaluation underwent polysomnography.

Criteria for chronic fatigue syndrome (CFS) were met by 64% of patients and those for a current psychiatric disorder were met by 41%. Overall, 41% of patients had abnormal results for a multiple sleep latency test and 81% had at least one sleep disorder, most frequently sleep apnea (44%) and idiopathic hypersomnia (12%).

In comparing patients who did and did not meet CFS criteria, no significant differences were found in individual sleep symptoms or sleep disorders. Likewise, symptoms and sleep disorders were unrelated to psychiatric diagnoses. In conclusion, chronically fatigued patients with suggestive symptoms may have potentially treatable coexisting sleep disorders that are not associated with meeting criteria for CFS or a current psychiatric disorder.

 

Source: Buchwald D, Pascualy R, Bombardier C, Kith P. Clin Infect Dis. 1994 Jan;18 Suppl 1:S68-72. http://www.ncbi.nlm.nih.gov/pubmed/8148456

 

Treatment of the chronic fatigue syndrome. A review and practical guide

Abstract:

The chronic fatigue syndrome (CFS) was formally defined in 1988 to describe a syndrome of severe and disabling fatigue of uncertain aetiology associated with a variable number of somatic and/or psychological symptoms. CFS has been reported in most industrialised countries and is most prevalent in women aged between 20 and 50 years.

Despite occasional claims to the contrary, the aetiology of CFS remains elusive. Although abnormalities in tests of immune function and cerebral imaging have been described in variable numbers of CFS patients, such findings have been inconsistent and cannot be relied upon, either to establish or exclude the diagnosis. Thus, diagnosis rests on fulfillment of the Centers for Disease Control case definition which was revised in 1992. This case definition remains somewhat controversial, largely due to its subjectiveness.

The mainstay of treatment is establishing the diagnosis and educating the patient about the illness. An empathetic clinician can stop further consultations elsewhere (‘doctor shopping’) and subsequent excessive investigations, which frequently occur in such patients.

Most patients should undertake a trial of antidepressant therapy, even if major depression is not present. The choice of antidepressant drug should tailor the tolerability profile to relief of particular CFS symptoms, such as insomnia or hypersomnia. Failure to improve within 12 weeks warrants an alternative antidepressant agent of another class. Many other drugs have been reported anecdotally to be beneficial, but no therapy has been demonstrated to be reproducibly useful in double-blind, placebo-controlled clinical trials with an adequate duration of follow-up.

 

Source: Blondel-Hill E, Shafran SD. Treatment of the chronic fatigue syndrome. A review and practical guide. Drugs. 1993 Oct;46(4):639-51. http://www.ncbi.nlm.nih.gov/pubmed/7506650

 

Abnormalities of sleep in patients with the chronic fatigue syndrome

Abstract:

OBJECTIVE: To determine whether patients with the chronic fatigue syndrome have abnormalities of sleep which may contribute to daytime fatigue.

DESIGN: A case-control study of the sleep of patients with the chronic fatigue syndrome and that of healthy volunteers.

SETTING: An infectious disease outpatient clinic and subjects’ homes.

SUBJECTS: 12 patients who met research criteria for the chronic fatigue syndrome but not for major depressive disorder and 12 healthy controls matched for age, sex, and weight.

MAIN OUTCOME MEASURES: Subjective reports of sleep from patients’ diaries and measurement of sleep patterns by polysomnography. Subjects’ anxiety, depression, and functional impairment were assessed by interview.

RESULTS: Patients with the chronic fatigue syndrome spent more time in bed than controls (544 min v 465 min, p < 0.001) but slept less efficiently (90% v 96%, p < 0.05) and spent more time awake after initially going to sleep (31.9 min v 16.6 min, p < 0.05). Seven patients with the chronic fatigue syndrome had a sleep disorder (four had difficulty maintaining sleep, one had difficulty getting to sleep, one had difficulty in both initiating and maintaining sleep, and one had hypersomnia) compared with none of the controls (p = 0.003). Those with sleep disorders showed greater functional impairment than the remaining five patients (score on general health survey 50.4% v 70.4%, p < 0.05), but their psychiatric scores were not significantly different.

CONCLUSIONS: Most patients with the chronic fatigue syndrome had sleep disorders, which are likely to contribute to daytime fatigue. Sleep disorders may be important in the aetiology of the syndrome.

 

Source: Morriss R, Sharpe M, Sharpley AL, Cowen PJ, Hawton K, Morris J. Abnormalities of sleep in patients with the chronic fatigue syndrome. BMJ. 1993 May 1;306(6886):1161-4. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1677618/ (Full article)