Brain fog in central disorders of hypersomnolence: a review

Abstract

Brain fog is an undefined term describing a cluster of symptoms related to fatigue and impaired memory, attention, and concentration. Brain fog or brain fog–like symptoms have been reported in central disorders of hypersomnolence and in a range of seemingly unrelated disorders, including coronavirus disease 2019, major depressive disorder, multiple sclerosis, lupus, and celiac disease. This narrative review summarizes current evidence and proposes a consensus definition for brain fog. Brain fog is prevalent in narcolepsy and idiopathic hypersomnia, with more than three-quarters of patients with either disorder reporting this symptom in a registry study; it has also been reported as particularly difficult to treat in idiopathic hypersomnia. Studies directly evaluating brain fog are rare; tools for evaluating this symptom cluster typically are patient reports, with few objective measures validated in any disorder. Evaluating brain fog is further complicated by confounding symptoms, such as excessive daytime sleepiness, which is a hallmark of hypersomnolence disorders. No treatments specifically address brain fog. The paucity of literature, assessment tools, and medications for brain fog highlights the need for research leading to better disambiguation and treatment. Until a clear consensus definition is established, we propose brain fog in hypersomnia disorders be defined as a cognitive dysfunction that may or may not be linked with excessive sleepiness, related to an underlying neuronal dysfunction, which reduces concentration and impairs information processing, leading to a complaint of lack of clarity of mental thinking and awareness.

Citation:

Rosenberg R, Thorpy MJ, Doghramji K, Morse AM. Brain fog in central disorders of hypersomnolence: a review. J Clin Sleep Med. 2024;20(4):643–651.

INTRODUCTION

Brain fog has yet to be formally defined; rather, it is a colloquial cognitive complaint that describes a cluster of symptoms that may include fatigue and impaired memory, attention, and concentration.^1–5 A recent study of the use of “brain fog” on social media (Reddit) identified 717 posts describing experiences with brain fog. Of these, 141 first-person phenomenological accounts included descriptions of forgetfulness, difficulty concentrating, dissociative phenomena, cognitive “slowness” and excessive effort, communication difficulties, “fuzziness,” “grogginess” or pressure in the head, and fatigue.⁶ Brain fog has recently received increased attention as a common, persistent symptom of coronavirus disease 2019 (COVID-19) infection.⁷ Brain fog, or a similar symptom cluster, has been reported not only in the hypersomnolence disorders narcolepsy and idiopathic hypersomnia⁸ but also in a broad range of immune or inflammatory disorders associated with fatigue, such as multiple sclerosis,^9,10 systemic lupus erythematosus (lupus),^11,12 and celiac disease (CD).¹³

Studies assessing brain fog are rare and generally lack consistency, regardless of the underlying condition. Further, owing to a lack of a formal definition and validated assessment tools, a high degree of variability in self-reported responses can be expected. These factors may complicate comparisons among studies for several reasons: (1) researchers are reliant on study participants’ interpretation of brain fog or its definition or inability to articulate their symptoms, (2) brain fog may manifest differently across each disorder, and (3) brain fog symptoms could be confounded or influenced by the primary or comorbid symptoms of each disorder.

Given the ambiguity surrounding the nature of brain fog in sleep disorders, this review summarizes the literature to date describing the symptoms, measurement tools, prevalence, and proposed pathophysiological links of brain fog in central hypersomnolence disorders; attempts to distinguish brain fog from other types of cognitive dysfunction or fatigue; and identifies the key areas of research needed to recognize and address brain fog in patients with hypersomnolence.

METHODS

Search methodology

For this narrative review, no formal search strategy or inclusion and exclusion criteria were developed. Broadly, PubMed was searched for journal articles detailing human studies published in the past 10 years with the following keywords: (“brain fog”[Title/Abstract]) AND (2012:2022[pdat]). Additional searches were conducted for “(fog) AND (narcolepsy),” “(fog) AND (idiopathic hypersomnia),” and “(“mental fatigue” OR “cognitive dysfunction”) AND (narcolepsy OR hypersomnolence).” Due to the low number of relevant hits, PubMed searches were supplemented with further literature cited within the manuscripts identified.

RESULTS

Clinical presentation

Central disorders of hypersomnolence associated with brain fog

Brain fog is difficult to define and identify, possibly because patients may conflate sleepiness, mental fatigue, and cognitive dysfunction with brain fog. However, there are some studies in several sleep and other disorders in which brain fog or similar symptoms have been reported. Notably, while brain fog is not listed as a symptom for any disorder in the American Academy of Sleep Medicine’s International Classification of Sleep Disorders, third edition, text revision,¹⁴ it has been reported as a common symptom in the hypersomnolence disorders narcolepsy and idiopathic hypersomnia.^8,15

Narcolepsy

Narcolepsy is a chronic neurologic condition characterized by a pentad of symptoms: excessive daytime sleepiness (EDS), disrupted nighttime sleep, sleep paralysis, hypnagogic or hypnopompic hallucinations, and cataplexy.¹⁴ The pathophysiology of narcolepsy type 1 (NT1) may be linked to hypocretin deficiency in most patients.¹⁴ In narcolepsy type 2 (NT2), cataplexy is absent and cerebrospinal fluid hypocretin concentrations are intermediate to normal.¹⁴ Narcolepsy is associated with functional impairment in various domains, including academic, professional, and social, as well as a reduced quality of life.^16–18 Narcolepsy is also associated with substantial medical and psychiatric comorbidities, including disorders with overlapping symptoms (eg, other sleep disorders and depression).^19–22

A recent systematic literature review identified 48 studies of cognitive function in NT1, NT2, and/or idiopathic hypersomnia conducted over the past two decades.²³ Attentional deficits were consistently found in studies of NT1, NT2, and idiopathic hypersomnia. Interestingly, despite common complaints of memory troubles, performance by patients with NT1 was comparable to controls in tests for memory span, declarative and visuospatial memory, and verbal learning. More directly, in a study of symptoms experienced by patients in the Hypersomnia Foundation Registry, which included participants with narcolepsy, 86.0% and 74.4% of people with NT1 and NT2, respectively, indicated that they experienced brain fog.⁸ Fewer participants reported “difficulty remembering things” (78.0% and 62.8% for NT1 and NT2, respectively), demonstrating some difference between these symptoms and/or patient vocabulary.

Idiopathic hypersomnia

Idiopathic hypersomnia is a chronic central disorder of hypersomnolence characterized by EDS, sleep inertia, and long and unrefreshing naps, with some patients experiencing prolonged nighttime sleep.^24,25 In 2005, the International Classification of Sleep Disorders, second edition described two clinical phenotypes of idiopathic hypersomnia: with long sleep time (≥ 10 hours) and without (< 10 hours).²⁶ The third edition of the International Classification of Sleep Disorders (2014) included both phenotypes under one definition (mean sleep latency ≤ 8 minutes or total sleep time ≥ 11 hours)²⁵; this combined phenotype was retained in the most recent text revision (International Classification of Sleep Disorders, third edition, text revision, 2023).¹⁴ Concurrent psychiatric disorders, especially depression, have been reported, along with symptoms suggestive of autonomic dysfunction.^27–33 Idiopathic hypersomnia is also associated with an increased risk of driving impairment and accidents,^34,35 decreased health-related quality of life,^36,37 and impairment in work functioning and productivity.³⁸ Although several theories regarding the cause of idiopathic hypersomnia have been proposed, the pathophysiology of this disorder is still unknown.³⁹

Either brain fog or cognitive dysfunction is commonly reported by patients with idiopathic hypersomnia,²⁴ and cognitive performance was identified as an outcome of interest for idiopathic hypersomnia uniquely during the drafting of the most recent American Academy of Sleep Medicine guidelines for the treatment of central disorders of hypersomnolence.⁴⁰ In a study of symptoms experienced by participants in the Hypersomnia Foundation Registry, 82.6% of participants with idiopathic hypersomnia (86.9% vs 78.1% for idiopathic hypersomnia with vs without long sleep time) indicated that they experienced brain fog as a symptom.⁸ As with narcolepsy, fewer participants reported “difficulty remembering things” in the same study (71.8% overall). In another recent survey (n = 75), 17.3% of participants with idiopathic hypersomnia (13.5% vs 21.1% with vs without long sleep time, respectively) identified brain fog as the most difficult to treat symptom.⁴¹

Differentiating brain fog from EDS and other cognitive symptoms in central disorders of hypersomnolence

It is not well understood whether brain fog in disorders of hypersomnolence reflects an impairment of vigilance due to sleepiness itself or is a discrete symptom independent of sleepiness. Brain fog in hypersomnolence disorders has been defined as “being unable to think clearly or concentrate at any time throughout the day” in a symptomatology study from the Hypersomnia Foundation Registry, which included participants with NT1 (narcolepsy with cataplexy), NT2 (narcolepsy without cataplexy), and idiopathic hypersomnia.⁸ However, brain fog may also appear and feel similar to other cognitive difficulties, such as mental fatigue (exhaustion from constant/extended periods of mental exertion) and cognitive dysfunction (an absolute deficit). Based on the Hypersomnia Foundation description, brain fog appears to represent slow/sluggish thinking, which in comparison to mental fatigue is variable and may be present at any time, independent of extended periods of exertion.

Across the disorders in which brain fog has been identified, a wide range of symptoms have been described (Table 1). In addition to the prolonged sensation of being unable to think clearly or concentrate described for narcolepsy and idiopathic hypersomnia, repeated reference across disorders was made to forgetfulness,^4,5,42,43 confusion,^4,43 word-finding difficulties,^4,5,42 and attentional deficits.^3,4 Such common descriptors may be helpful in establishing a more formalized definition of brain fog.

Table 1.

Commonly used descriptors for brain fog symptoms.

Population/Disorder	Symptoms Assessed/Characterized as “Brain Fog”
Idiopathic hypersomnia8,64,65	Mental fog/fogginess; being unable to think clearly or concentrate at any time throughout the day
Narcolepsy8	Being unable to think clearly or concentrate at any time throughout the day
Celiac disease4	Difficulty concentrating; problems with attentiveness; lapses in short-term memory; word-finding difficulties; temporary loss in mental acuity and creativity; confusion and disorientation
COVID-191,7,47	Lack of concentration; cognitive symptoms; problems with multitasking, answering questions in an understandable/unambiguous manner, communication of thoughts, and recalling new information
ME/CFS50	Reduced processing speed; impaired verbal and sustained attention; deficits in memory, attention, word-finding, and reasoning; “thinking/focusing difficulty”
Menopause51	Memory and attention difficulties involving difficulty encoding and recalling words, names, stories, or numbers; difficulty maintaining a train of thought; distractibility; forgetting intentions (reason for coming into a specific room); difficulty switching between tasks
Fibromyalgia/chronic pain53,55	Fluctuating states of cognitive dysfunction that could have implications in the functional application of cognitive skills in people’s participation in daily activities; reduced psychomotor speed, executive function, and attention
Lupus43	Periods of forgetfulness and confusion that are related to impaired cognition
POTS42	Forgetful, difficulty thinking, difficulty focusing, cloudy, difficulty finding the right words/communicating, mental fatigue, slow, “mind went blank,” spacey, difficulty processing what others say, exhausted, easily distracted, difficulty processing words read, confusion, annoying, sleepy, lost, detached, thoughts moving too quickly
Thyroid disorders5	Fatigue, depressed mood, cognitive difficulties, problems with memory and word finding, low energy, forgetfulness, feeling sleepy, difficulty focusing
Miscellaneousa,6	Forgetfulness, difficulty concentrating, dissociative phenomena, cognitive “slowness” and excessive effort, communication difficulties, “fuzziness,” “grogginess,” pressure in the head, fatigue

^a Based on a social media analysis of users describing “brain fog” as a symptom or experience. ME/CFS = myalgic encephalomyelitis/chronic fatigue syndrome, POTS = postural orthostatic tachycardia syndrome.

Other disorders associated with brain fog

In addition to its prevalence in central disorders of hypersomnolence, brain fog has also been associated with a diverse range of disorders and medical treatments. These include CD, COVID-19, lupus, postural orthostatic tachycardia syndrome, and hypothyroidism.^{7,12,13,42,44,45} Understanding the presentation and etiology of brain fog in these disorders may help clarify brain fog as it presents in narcolepsy and idiopathic hypersomnia.

Celiac disease

CD is an autoimmune condition triggered by gluten ingestion.⁴⁶ Few studies have directly measured brain fog in CD; however, it is a common anecdotal complaint. Indeed, in a large survey-based study, 89% of participants with CD (self-reporting a diagnosis by small intestine biopsy and/or serology) reported neurocognitive impairment, or brain fog. Over half of study participants with CD reported onset of symptoms, including difficulty concentrating, mental confusion, forgetfulness, grogginess, or feeling detached, within 2 hours of ingesting gluten.¹³ Further, in a study of patients with CD, brain fog (assessed using a battery of cognitive tests) was found to improve when patients adhered to a gluten-free diet, suggesting a link between inflammation and brain fog symptoms.⁴

COVID-19

Brain fog is a common complaint of people who have active COVID-19 infection or postinfectious long COVID-19.^7,44 Self-reported brain fog in long COVID-19 is a recognizable symptom cluster that is primarily characterized by fatigue, dizziness, myalgia, word-finding difficulties, and memory impairment; it is also associated with adverse psychological and psychomotor correlates.² One study found that 85% of participants endorsed brain fog (or lack of concentration) as a symptom related to COVID-19, second in prevalence only to memory difficulties.⁷ Similarly, brain fog was endorsed as the second most common symptom following COVID-19 infection (behind fatigue) in a separate study of COVID-19 survivors.⁴⁴ A recent study employing a questionnaire that was developed in consultation with neurologists who had experienced COVID-19 infection demonstrated strong positive correlations between quality of life at work and difficulties relating to multitasking, answering questions in an understandable and unambiguous manner, communicating one’s thoughts, and recalling new information.⁴⁷ A meta-analysis of 18 studies comprising 10,530 adults with post-COVID-19 syndrome reported on the prevalence (95% confidence interval) of brain fog (32.2% [10.3%, 54.0%]), memory issues (28.4% [21.5%, 35.4%]), and attention disorder (21.8% [7.3%, 36.4%]).⁴⁸ Another recent review and meta-analysis synthesized 74 studies to determine the pooled prevalence of cognitive impairment among patients with post-COVID-19 syndrome to be 22% (95% confidence interval 17%, 28%; n = 13,232).⁴⁹ Despite its prevalence, the biological basis of brain fog in COVID-19 has yet to be established.

Myalgic encephalomyelitis/chronic fatigue syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder characterized by intolerance to physical exertion, fatigue, cognitive problems, and dysautonomia.⁵⁰ Within the cognitive domain, the most prevalent problems are lower processing speed and impaired verbal and sustained attention; deficits in memory and attention, word-finding, and reasoning are also pronounced.⁵⁰ In this context, brain fog has been described as a “thinking/focusing difficulty.” In light of the similarities in cognitive and physical deficits observed in ME/CFS and COVID-19, a recent study compared the severity of symptoms in patients (n = 115) with ME/CFS (n = 42) and post-COVID-19 infection (n = 73).⁵⁰ Impairments in sustained attention (83.3% ME/CFS; 56.2% post-COVID-19) and processing speed (52.4% ME/CFS; 41.4% post-COVID-19) were prevalent.⁵⁰

Menopause

Brain fog is also a common complaint among peri- and postmenopausal women and has been defined as “the constellation of cognitive symptoms experienced by women around the menopause, which most frequently manifests in memory and attention difficulties and involves such symptoms as difficulty encoding and recalling words, names, stories, or numbers, difficulty maintaining a train of thought, distractibility, forgetting intentions (reason for coming into a specific room), and difficulty switching between tasks.”⁵¹ In a survey of 947 perimenopausal women age 40 years or older, 68.3% reported experiencing brain fog; further, difficulty concentrating (63.9%) and poor memory (56.6%) were common.⁵²

Fibromyalgia/chronic pain

Although somewhat less common than in other disorders described herein, brain fog is known to affect patients with chronic pain disorders such as fibromyalgia.⁵³ Brain fog occurs in approximately 15% to 40% of patients with chronic pain,⁵³ although one large study found that brain fog, memory loss, and cognitive impairment were reported in < 5% of patients with fibromyalgia.⁵⁴ A study in pediatric patients with fibromyalgia (n = 31) found deficits in psychomotor speed (23%), executive function (23%), and attention (3%).⁵⁵ In chronic pain disorders, brain fog might be defined as “fluctuating states of cognitive dysfunction that could have implications in the functional application of cognitive skills in people’s participation in daily activities,”⁵³ similar to brain fog in other disorders.

Lupus

Lupus is an autoimmune condition resulting in multisystemic inflammation due to formation and deposition of autoantibodies and immune complexes, leading to eventual organ damage.⁵⁶ Patients experience periodic flares varying in severity. Cognitive dysfunction is a commonly reported symptom in lupus (in up to 90% of patients) and can significantly affect quality of life.^11,57 Specifically, brain fog in lupus is termed “lupus fog”; there is no formal definition but patient descriptions refer to confusion, difficulty planning, loss of concentration, difficulty articulating thoughts, and memory impairment. A study of patients with lupus using question 28 (dissociative fog) of the Dissociative Experience Scale-II to define the presence of fog found a prevalence of 13%.¹² The American Psychiatric Association defines dissociation as a disruption of and/or discontinuity in the normal integration of one or more aspects of psychological functioning⁵⁸; this characterization seems to diverge from the symptoms reported in other disorders discussed here but is self-reported and may nevertheless be applicable to brain fog.

Autoimmune encephalitis

Autoimmune encephalitis is a collection of disorders wherein an immune response against self-antigens produces a wide variety of neurologic or psychiatric symptoms, possibly including brain fog.^59,60 In a cohort of patients with antigamma-aminobutyric acid B receptor encephalitis, 79% (n = 11/14) had impaired short-term memory and slow response times.⁶¹ Although cognitive deficits at onset of autoimmune encephalitis are typically more severe and affect multiple cognitive domains,⁶² milder forms of memory and cognitive impairment have been reported in some cases. For example, one case report detailed the development of “mental fog” and memory deficits in a 15-year-old boy 3 months after presenting with antiglutamic acid decarboxylase 65 encephalitis.⁶³ Another case report detailed progressive brain fog and cognitive dysfunction associated with an anti-N-methyl d-aspartate receptor response in a 32-year-old woman, which deteriorated from neuropsychiatric manifestations to neurologic dysfunction.⁵⁹

Postural orthostatic tachycardia syndrome

Brain fog was found to be highly prevalent in a study of participants with postural orthostatic tachycardia syndrome (n = 138) using an open-ended questionnaire developed to evaluate brain fog.⁴² In total, 96% of participants experienced brain fog overall, with 67% experiencing brain fog daily. Most participants indicated that brain fog impaired daily activities, including schoolwork (86%; 96 of 111 participants), work productivity (80%; 66 of 82 participants), and social activities (67%; 92 of 138 participants).⁴² Of 19 brain fog descriptors evaluated, ≥ 75% of participants agreed with 13. The terms with margins of agreement (agree minus disagree) > 75% among the participants were “forgetful” (90%), “difficulty thinking” (88%), “difficulty focusing” (86%), “cloudy” (85%), “difficulty finding the right words/communicating” (85%), “mental fatigue” (84%), “slow” (84%), “mind went blank” (81%), “spacey” (79%), and “difficulty processing what others say” (76%).⁴² These descriptors with substantial agreement among patients may be helpful in defining brain fog in other populations.

Thyroid disorders

Many patients with hypothyroidism experience brain fog.⁴⁵ Their symptoms include fatigue, depressed mood, and difficulty with cognition relating to memory and executive function.⁵ Specifically, in a 2021 study of patients with hypothyroidism with brain fog, 79% indicated they experienced brain fog “frequently” or “all the time,” with over 95% indicating they felt low energy/fatigue, forgetfulness, sleepiness, and trouble focusing.⁴⁵

Other disorders

Finally, there are a number of other disorders in which brain fog is not a formally recognized feature but that are associated with impairments resembling brain fog (Table 2).

Table 2.

Disorders and treatments associated with brain fog–like symptoms.

Domain	Characteristics
Disorder associated
Major depressive disorder88	Difficulty concentrating
Multiple sclerosis9	Cognitive impairment, including processing speed, complex attention, working memory, visuospatial ability, and executive function
Sluggish cognitive tempo89,90	Slowed behavior and information processing; mental confusion, absent-mindedness, hypoactivity, deficiencies in perceptual processes, attentional selection, and orienting of attention
Treatment associated
Antidepressants with/without antipsychotics91	“Feeling foggy or detached”
Chemotherapy92	Deficiencies in neurocognitive tests, which can persist after withdrawal from treatment

Assessments and diagnosis

Patient-reported outcome surveys are well positioned to capture loosely defined symptoms like brain fog but ideally would be paired with an objective performance-based test.⁵ Although little work has been done to date to validate assessments of brain fog in patients with sleep disorders, complementary efforts have been made to define measurements in other disorders.

Self-reported measures of brain fog

The Idiopathic Hypersomnia Symptom Diary, based on concept elicitation interviews with patients with idiopathic hypersomnia and used in the IH202 trial assessing an oral gamma-aminobutyric acid antagonist (BTD-001), contains a “Mental Fog” scale.^64,65 This scale is described as assessing “worst severity of mental fogginess/brain fog”; however, this questionnaire has not yet been validated or published in full.^64,65

Two scales, both named the Brain Fog Scale, were recently developed in Polish⁶⁶ and Turkish⁶⁷ populations. The (Polish) Brain Fog Scale is a self-reported scale that was developed and validated in Polish university students.⁶⁶ This 23-item scale, which was determined to have good psychometric properties, revealed that students who had tested positive for COVID-19 infection had significantly greater mental fatigue, impaired cognitive acuity, and confusion compared with matched controls who had not tested positive for COVID-19 infection.⁶⁶ Items on the (Turkish) Brain Fog Scale, recently developed in a Turkish population for use in participants with COVID-19 infection, were based on a literature review and expert feedback.⁶⁷ After validity and reliability analyses, 30 items scored on a 5-point Likert-type scale were determined to reliably measure the level of brain fog over the preceding 30 days.⁶⁷ However, use of these scales has not been validated in participants with central hypersomnolence disorders.

In one study, a 38-item questionnaire to assess brain fog in a group of adolescents and adults with postural orthostatic tachycardia syndrome was assessed in a study modeled after the Nausea Profile.^42,68 Open-ended questions were posed to a focus group of patients (n = 25); the most popular answers were then used to generate terms for the final 38-item questionnaire. The first 19 items of the final questionnaire asked for demographic and diagnostic information; the remaining 19 were scaled questions regarding the frequency, severity, descriptors, triggers, and treatments of brain fog.⁴²

The Wood Mental Fatigue Inventory, a questionnaire that asks participants to rate the frequency of nine mental fatigue syndromes and has been validated in chronic fatigue syndrome and orthostatic intolerance, was also used to assess potential brain fog in adolescents and adults with postural orthostatic tachycardia syndrome.⁴² There was a significant positive correlation between Wood Mental Fatigue Inventory score and brain fog severity as ranked by patients on a 0- to 100-point scale (ρ = 0.512; P < .0001). Higher numbers indicate greater severity on both assessments. This finding reinforces that there is a fatigue component in brain fog, although the moderate correlation implies that other factors may be involved.⁴²

A survey to assess brain fog in participants with thyroid disease has been adapted from the validated Thyroid-Specific Patient-Reported Outcome survey, which captures a range of symptoms in thyroid disease.^5,45 Participants were asked to indicate the onset, frequency, and daily duration of brain fog, as well as to describe the frequency and impact of individual symptoms they associated with brain fog.

Although not designed for use in central disorders of hypersomnolence, many of these scales may be repurposed to evaluate brain fog in people with sleep disorders.

Objective measures of brain fog

There are currently no established objective measures of brain fog. Therefore, researchers wishing to objectively assess this symptom must rely on instruments developed to measure other constructs. For example, a longitudinal study in newly diagnosed participants with CD employed a battery of cognitive tests in an attempt to identify measurable differences in brain fog symptoms.⁴ Tests included were the Subtle Cognitive Impairment Test, Trail Making Test, Rey-Osterrieth Complex Figure, Controlled Oral Word Association Task, and Rey Auditory Verbal Learning Task. To the best of our knowledge, these tests are not widely used at present to assess cognition in central disorders of hypersomnolence. The Trail Making Test has been used in studies of narcolepsy,⁶⁹ Kleine–Levin syndrome,⁷⁰ and ME/CFS and COVID-19,⁵⁰ and in some cases where sleep disturbances were evaluated as a comorbidity. A battery to assess neurocognitive function in pediatric patients with fibromyalgia included the Children and Adolescent Memory Profile, Digit Span subtest, Conners Continuous Performance Test, Delis-Kaplan Executive Function System, Trail Making Test, Color-Word Interference Test, and Grooved Pegboard Test.⁵⁵ Similar batteries could be used to assess brain fog in central disorders of hypersomnolence or other disorders; alternatively, they may need to be adapted for use in central disorders of hypersomnolence, or the development of new tools may be appropriate. Further research will be needed to develop and validate objective measures of brain fog once consensus on the symptom has been reached.

Pathophysiology

Much like the symptomatology, the pathophysiology of brain fog is not well understood; however, many of the diseases with which it is commonly associated (including narcolepsy, autoimmune encephalitis, COVID-19, and lupus) have autoimmune and/or inflammatory components.^59,71–73

Narcolepsy and idiopathic hypersomnia

Although the pathophysiology of narcolepsy and idiopathic hypersomnia are incompletely understood, autoimmune destruction of hypocretin-producing neurons is a leading hypothesis for the cause of NT1.⁷⁴ The link between inflammation and NT2 or idiopathic hypersomnia is less clear, but, compared with healthy controls, patients with NT2 more frequently experience comorbid autoimmune disorders and patients with idiopathic hypersomnia more frequently experience comorbid inflammatory disorders.

COVID-19

COVID-19 affects nearly every organ system, including the brain. Pathological changes that have been documented in the COVID brain include hippocampal and cortical atrophy or hypoxic injury and hypometabolism in the cingulate cortex, which could be one explanation for the memory, attention, and processing deficits characteristic of brain fog.^75,76 In a recent meta-analysis,⁴⁹ a total of 14 studies that examined inflammatory markers were identified, with 13 reporting elevations in ≥ 1 proinflammatory marker. Among the 14 studies, 9 reported persistent fatigue and/or cognitive impairment that coincided with elevated proinflammatory markers.⁴⁹ Further studies aiming to associate brain abnormalities with common brain fog symptoms will help to establish an understanding of the underlying pathology in COVID-19, which may then be extrapolated to sleep and other disorders.

Autoimmune encephalitis

Most patients with autoimmune encephalitis have antibodies in their cerebrospinal fluid, which may be triggered systemically and reactivated in the central nervous system.^77,78 Patients with autoimmune encephalitis may have lesions indicated by hyperintensities visible on T2/fluid-attenuated inversion recovery magnetic resonance imaging.^59,63,78 First-line treatment for patients with autoimmune encephalitis is immunotherapy.^78,79

Lupus

Central nervous system manifestations of lupus are not widely understood and have been attributed to a variety of mechanisms, such as disruption of the blood-brain barrier, autoantibody production (antineuronal and antiphospholipid antibodies), and the production of proinflammatory mediators.⁵⁷ This leads to injury of the cerebral vessels and the disturbance of neuronal function, which can present as cognitive dysfunction or “brain fog.”

Celiac disease

The cerebellum is frequently the target of autoimmune dysfunction in patients with CD; the accumulation of antigliadin antibodies in the cerebellum is commonly associated with apparently idiopathic ataxia.⁸⁰ As the cerebellum has been recognized to have a role in cognitive function (eg, cerebellar cognitive affective syndrome), it follows then that gluten sensitivity is one possible explanation for cognitive deficits in this population.⁴⁶

Treatment

Although no medications have been developed or studied specifically to manage brain fog, drugs that target the cluster of symptoms comprising brain fog or its pathophysiology could have beneficial effects. In central disorders of hypersomnolence, medications that improve sleepiness may, by proxy, improve symptoms of brain fog. However, brain fog has been shown to persist despite treatment in some patients with hypersomnolence disorders. In fact, 50.0%, 26.3%, and 54.3% of people with NT1, NT2, and idiopathic hypersomnia, respectively, indicated persistence of brain fog with treatment (off-label for those with idiopathic hypersomnia).⁸ In that survey, participants with idiopathic hypersomnia reported current use of amphetamine-dextroamphetamine (31.7%), methylphenidate (21.8%), modafinil or armodafinil (38.0%), melatonin (12.1%), flumazenil (5.7%), clarithromycin (5.0%), or sodium oxybate (2.7%); some participants were taking more than one off-label idiopathic hypersomnia medication.⁸ These results suggest that, though therapeutics that alleviate EDS can reduce brain fog for some patients with sleep disorders, a substantial proportion continue to experience brain fog despite these treatments.

A phase 3 study of low-sodium oxybate (LXB) for idiopathic hypersomnia found that Idiopathic Hypersomnia Severity Scale item 11 scores (hypersomnolence impact on intellectual functioning) improved with open-label LXB treatment.^81–86 Participants who were randomized to placebo during a double-blind randomized withdrawal period had nominally significant worsening on item 11 of the Idiopathic Hypersomnia Severity Scale compared with those who continued LXB.⁸¹ Among participants randomized to placebo during the double-blind randomized withdrawal period, the percentage of participants who selected the best score on item 11 of the Idiopathic Hypersomnia Severity Scale increased while they were taking LXB during an open-label extension period.⁸⁶ Although not a direct assessment of brain fog, item 11 of the Idiopathic Hypersomnia Severity Scale refers to problems with concentration and memory and may thus capture important brain fog symptoms.⁸⁷ Thus, the self-reported improvement in intellectual functioning observed with LXB treatment supports the use of LXB in patients with idiopathic hypersomnia who have brain fog–like symptoms.

Overall, as the term “brain fog” covers an array of symptoms across a multitude of conditions, it has not definitively been measured as an outcome in clinical studies. More research is necessary to measure, validate, and understand the effect of pharmacotherapy on brain fog.

DISCUSSION

Future directions

Given the paucity of studies that specifically assess brain fog in disorders of hypersomnolence, there is a pressing need for a formal consensus definition in addition to validated tools to assess the presence and severity of brain fog. Until a clear consensus definition of brain fog is established, we propose that brain fog in hypersomnia disorders be defined as a cognitive dysfunction that may or may not be linked with excessive sleepiness, related to an underlying neuronal dysfunction, which reduces concentration and impairs information processing, leading to a complaint of lack of clarity of mental thinking and awareness. There are insufficient data to speculate on etiology, but most disorders in which brain fog has been reported have an inflammatory component. Further investigation is necessary to understand its pathophysiology and develop treatments.

Clinicians and researchers might look to already-existing tools used and validated in other disease states in their efforts to study brain fog. These will need validation in sleep disorders like idiopathic hypersomnia and narcolepsy. An important factor to consider is the confounding effect of EDS, which is a central component to both disorders. Additionally, there is a need for better understanding around the underlying cause of brain fog and how this may differ between disease states. Once defined and operationalized, better measures that distinguish brain fog from other types of cognitive dysfunction are needed.

CONCLUSIONS

Based on the literature reviewed here, brain fog should be used to refer to symptoms including but not limited to fatigue and impaired memory, attention, and concentration.^1–5 Brain fog, or a similar symptom profile, is prevalent across patients with the central hypersomnolence disorders narcolepsy and idiopathic hypersomnia, as well as a multitude of neurologic, psychiatric, autoimmune, infectious, hormonal, and medication-associated disorders. Additionally, brain fog is often self-reported, may manifest differently and has varying pathologies within each disorder, and could be influenced by comorbid symptoms of primary disorders (such as EDS); these factors complicate comparisons between studies and make it difficult to identify, define, measure, and quantify. Studies that evaluated symptom clusters similar to brain fog demonstrated that medications used to treat sleepiness can have a positive effect on intellectual functioning in populations with sleep disorders, though their use in these populations will need to be further studied.

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. This study was sponsored by Jazz Pharmaceuticals. Under the direction of the authors, Benjamin M. Hiller, PhD, and Sean Anderson, PhD, of Peloton Advantage, LLC, an OPEN Health company, provided medical writing and editorial support. Jazz Pharmaceuticals provided funding to Peloton Advantage for medical writing and editorial support. Russell Rosenberg received consultancy fees from Eisai; received research funding from Jazz Pharmaceuticals, Eisai, and Philips Respironics; and served on speakers’ bureaus for Harmony Biosciences and Jazz Pharmaceuticals and as an advisory board member for Jazz Pharmaceuticals and Avadel. Michael J. Thorpy has received research/grant support and consultancy fees from Axsome, Balance Therapeutics, Flamel/Avadel, Harmony Biosciences, LLC, Jazz Pharmaceuticals plc, Suven Life Sciences Ltd., Takeda Pharmaceutical Co., Ltd, NLS Pharmaceuticals, XW Pharma, Idorsia Pharmaceuticals, and Eisai Pharmaceuticals. Karl Doghramji has received consultancy fees from Jazz Pharmaceuticals, Axsome, Harmony, Idorsia, Purdue, Eisai, Imbrium, Inspire, and Janssen; has received research support from Inspire, Harmony, Sommetrics, and Nyxoah; and owns stock in Merck. Anne Marie Morse has received research/grant support and consultancy fees from Flamel/Avadel, Takeda, Harmony Biosciences, LLC, Jazz Pharmaceuticals plc, National Institutes of Health, and Geisinger Health Plan.

ABBREVIATIONS

CD

celiac disease

COVID-19

coronavirus disease 2019

EDS

excessive daytime sleepiness

LXB

low-sodium oxybate

ME/CFS

myalgic encephalitis/chronic fatigue syndrome

NT1

narcolepsy type 1

NT2

narcolepsy type 2