Multi‐disciplinary collaborative consensus guidance statement on the assessment and treatment of cognitive symptoms in patients with post‐acute sequelae of SARS‐CoV‐2 infection (PASC)

Abstract

The emergence of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought with it a plethora of new challenges. In the beginning of the pandemic, efforts were focused on pathogenesis and acute treatment; however, over time, understanding and managing post-COVID sequelae have become the new frontier.1, 2 Generally, the majority of individuals show symptom resolution within 3–4 weeks of COVID-19, but a substantial number of people continue to experience lingering effects and develop protracted illness, regardless of initial symptom severity. Although still being defined, these effects can be collectively referred to as postacute sequelae of SARS-CoV-2 infection (PASC),3 which is the term used in this report. Notably, there are a number of other terms that are found in the literature (eg, long COVID, postacute COVID-19 syndrome, long-haul COVID, chronic COVID). At the time of development, much of the literature focused on patients who were not vaccinated, and the incidence and trajectory of PASC in vaccinated patients with “breakthrough” cases (including but not limited to current and emerging variants of the virus) are evolving. The PASC Collaborative took this into account during the development process and these guidance statements generally apply to individuals who develop PASC regardless of their vaccination status. This guidance statement has a specific focus on the cognitive-related symptoms of PASC that can occur in people who have been diagnosed with acute COVID-19 infection or presumed to have had the infection and initially experienced mild to severe symptoms. Some patients required hospital acute care, whereas many others were managed in nonhospitalized community settings. This consensus guidance statement is one in a series extending across the breadth of the most prevalent or recognized PASC sequelae. Published and in-process guidance statements from this collaborative include the assessment and management of PASC associated fatigue, breathing and respiratory sequelae, cardiovascular complications, autonomic dysfunction, mental health, and neurologic sequelae. These statements are intended to provide consensus-driven practice guidance to clinicians in the assessment and treatment of individuals presenting with PASC. At the time of this report, approximately 5.2 million people worldwide have died from COVID-19 and 235 million people have “recovered;”4 however, the absolute percentage of individuals who have completely recovered remains evasive. Fatigue, dyspnea, cough, anosmia, cognitive symptoms (“brain fog”), and dysgeusia are the most common symptoms encountered in PASC.2 Numerous studies have demonstrated disproportionately high infection or morbidity and mortality rates in certain populations including, but not limited to, racial/ethnic minority groups and people who live or work in prisons and other detention centers. Some studies suggest that women may be at higher risk for developing PASC-related symptoms.5 It is widely acknowledged that systematic study of PASC is needed to develop an evidence-based approach for caring for individuals with PASC. At present, there is a dearth of rigorous scientific evidence regarding effective assessment and treatment of PASC that prevents the creation of evidence-based clinical guidelines. However, the U.S. health care system is seeing an increase in the number of patients presenting with PASC and there is an urgent need for clinical guidance in treating these patients. As these Consensus Guidance Statements on PASC are published they will be available via https://onlinelibrary.wiley.com/. The American Academy of Physical Medicine and Rehabilitation (AAPM&R) Multi-Disciplinary PASC Collaborative (PASC Collaborative) was created, in part, to develop expert recommendations and guidance from established PASC centers with extensive experience in managing patients with PASC. The PASC Collaborative is following an iterative, development approach to achieve consensus on assessment and treatment recommendations for a series of Consensus Guidance Statements focused on the most prominent PASC symptoms. These statements were developed by a diverse team of experts, with input from patient representatives with a history of PASC. These statements integrate evolving experience and expertise with available evidence to provide tools to clinicians treating patients. There is an intentional focus on health equity as disparities in care and outcomes are critically important to address. Beyond patient care, the hope is that a broadened understanding of current patient care practices will help identify areas of future research. A full description of the methodology has also been published.6 We acknowledge that the definition of PASC is evolving, and there are various factors that contribute to both diagnosis and treatment. For example, previous literature has suggested that PASC be defined as the continuation of symptoms beyond 3 or 4 weeks from the onset of acute infection.7 Other definitions of PASC include symptoms lasting longer than 3 months.8 Based on feedback from clinicians and patient representatives that earlier evaluation, diagnosis, and management can improve access to beneficial interventions, for the purpose of this Consensus Guidance Statement, we recommend expanded PASC assessment if symptoms are not improving 1 month after acute symptom onset. These Consensus Guidance Statements are intended to reflect current practice in patient assessment, testing, and treatments. They should not preclude clinical judgment and must be applied in the context of the specific patient, with adjustments for patient preferences, comorbidities, and other factors. Prominent neurological and behavioral symptoms have been reported in the growing PASC literature. Common neurological and neuropsychiatric symptoms in individuals with PASC include fatigue, myalgia, headaches, sleep disturbance, anxiety, depression, dizziness, anosmia, dysgeusia, and cognitive symptoms, often called a “brain fog.” It is important for clinicians to recognize that disease severity may not be a predictor of PASC symptoms as many patients presenting to outpatient COVID recovery centers experienced only mild initial SARS-CoV-2 infection. Primary cognitive symptoms include deficits in reasoning, problem solving, spatial planning, working memory, difficulty with word retrieval, and poor attention.9-12 In addition, small studies in patients recovering from COVID-19 who develop postural orthostatic tachycardia syndrome (POTS) have shown worsening executive function and attention in the standing position.13 Assessment and treatment of cognitive symptoms in patients with PASC is the focus of this review. The physiologic effects of SARS-CoV-2 infection on the central nervous system (CNS) are incompletely understood. Neurons express surface angiotensin-converting enzyme-2 (ACE-2) receptors, although at a lesser density than respiratory or gastrointestinal epithelium. Prior human coronaviruses (SARS-CoV-1, Middle East respiratory syndrome) infections have demonstrated neurotrophism, invading the CNS via ACE-2 receptor binding and migration along motor and sensory pathways. Experimental intranasal SARS-CoV-1 in mice has demonstrated transmission along the olfactory bulb, with subsequent transmission to limbic structures, and progression to brainstem and spinal cord.14 Reporting to date is not convincing that SARS-CoV-2 infection in humans typically involves CNS infection, even in cases of severe respiratory infection. Studies have included cerebral spinal fluid sampling, brain imaging, and brain examination at autopsy and have demonstrated SARS-CoV-2 within vessels and cerebral support structures but no evidence of intrathecal viral replication.15 SARS-CoV-2 infection related ischemic and hemorrhagic stroke, postinfectious encephalitis, acute necrotizing encephalopathy, and endotheliitis have been described but are infrequent.16 Microthrombi in cerebral microvasculature, central venous thrombosis, and patterns of hypoxic ischemic injury have also been demonstrated. Generalized, focal, and subclinical seizures have been observed.16 Neurological conditions associated with SARS-CoV-2 infection will be addressed in a future AAPM&R PASC Consensus Guidance Statement. Neurological symptoms are present in more than 80% of hospitalized patients during the acute phase of the infection. The most frequent neurologic symptoms persisting after the acute onset of the infection were: “brain fog” (81%), headache (68%), numbness/tingling (60%), dysgeusia (59%), anosmia (55%), and myalgias (55%).17 Acute toxic metabolic encephalopathy is the most common neurological complication among acutely hospitalized patients with COVID-19 and its etiology is multifactorial including potential contributions from sepsis, hypoxia, hypercarbia, hypernatremia, hyponatremia, uremia, multiorgan system failure, and hyperinflammatory state. Neurologic impairment is more prominent in severe COVID-19 infection. Hospitalized patients with encephalopathy demonstrated significantly increased 30-day mortality.16, 18 Proposed mechanisms of SARS-CoV-2 related CNS pathophysiology include (1) inflammation-mediated increased permeability of blood brain barrier (including thinning of the basal lamina) with activation of CNS immune mediators and glia; (2) an associated activation of metabolic pathways to induce synaptic pruning and neuronal loss; (3) excessive glutamate/N-methyl-D-aspartate excitotoxicity and neurotransmitter depletion; (4) subsequent diaschisis effects; (5) unmasking of previous subclinical neurological and neuropsychiatric impairments; and less likely (6) direct SARS-CoV-2 infection.19 The aggregate clinical presentation of PASC has features similar to other postinfectious syndromes, including Epstein-Barr, Lyme, Zika, and clinical conditions such as myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia syndrome, postintensive care syndrome, and POTS. The many similarities of these conditions including cognitive symptoms, fatigue, headaches, sleep disturbance, and mood disorders may represent a final common pathway for a phenotype of postinfectious immune and neuronal dysregulation. The established literature for these conditions, as well as references for the management of mild acquired brain injury, may be helpful in implementing approaches to treatment and patient education. An important group of SARS-CoV-2 infected patients to consider are older individuals as there are a number of cognitive-related concerns in this population. (See Appendix: Health Equity Considerations and Examples in Post-Acute Sequelae of SARS-CoV-2 Infection [PASC]: Cognitive Symptoms.) One report noted that healthy older individuals as well as those with mild cognitive symptoms and dementia have been among the most affected with acute COVID-19 infections, and both direct and indirect cognitive-related issues have been described.20 The report also highlighted that both the patient and the patient's caregiver may experience SARS-CoV-2 related cognitive decline and that this population may have more challenges with virtual care. Worsening conditions, particularly cancer, time-dependent diseases, and degenerative conditions were also noted to be a concern as older individuals who may not have received the routine care they needed during the pandemic. In all age groups, mental health conditions and substance use (e.g., alcohol, recreational drug use) have increased during the pandemic and may additionally contribute to cognitive dysfunction.21 Preexisting static conditions such as cerebral palsy, stroke, and traumatic brain injury as well as progressive neurologic illnesses such as multiple sclerosis and dementia are important to consider. In female adults, pregnancy and the postpartum period are well documented to cause fatigue and cognitive symptoms and in a subset of patients postpartum depression, which can make the PASC-related diagnosis more challenging. Overlapping fatigue, nonrestorative sleep, dysautonomia, the psychosocial impact of surviving life-threatening illness, and personal losses due to COVID-19, compounded by multifaceted impacts of pandemic-related social isolation, may further exacerbate cognitive deficits. It is also important to consider preexisting conditions and symptoms to avoid clinical attribution errors. As noted in the AAPM&R Multi-Disciplinary PASC Consensus Guidance Statement methodology,6 the recommendations that follow (Table 1: Cognitive Symptom Assessment Recommendations for Individuals with PASC) are based on expert consensus. Specific guidance recommendations that have been approved by consensus will be noted in the tables and recommendations will be followed by additional discussion. Patients should be evaluated for conditions that may exacerbate cognitive symptoms and warrant further testing and potential subspecialty referral (see Table 3). Particular areas include: Note: Patients often report dissatisfaction with their care because of their persistent symptoms being attributed to factors. It is important to that mood disorders may be to persistent conditions or one of many factors to cognitive symptoms. The following should be to for factors to cognitive symptoms. The initial in new patients or those in the 3 to including blood function metabolic function In one may consider and human Other may be based on the of these or if there is specific concern for conditions as in Table should a full patient history with of preexisting conditions and and for those that may contribute to cognitive symptoms. patients with PASC often present on and that can contribute to cognitive symptoms. cognitive the for initial used include the Cognitive and the of These are defined in Table 2 and can be by a of clinical including care. in Table are specific to those in testing and As there are no evidence or statements on to cognitive symptoms during the SARS-CoV-2 acute or after symptom resolution in as SARS-CoV-2 related cognitive symptoms may have and may or be present from the acute infection of the of PASC and often a of symptoms, of additional studies and referral for common is It should be noted that cognitive are not a for more cognitive testing, and on not warrant a cognitive on their Table 3 and common related to PASC cognitive symptoms, including additional testing and referral cognitive or dysfunction, or cognitive fatigue, dizziness, of poor excessive poor risk factors for (eg, and or and in of on anxiety, depression, fatigue, mood in that limited sleep to to sleep on frequent at during the failure, mood metabolic As in acquired brain injury, new may be present, may induce or disease consider on the patient one may and and disease are other less common activation syndrome for behavioral health conditions to conditions from and may include of anxiety, and and Health for the and attention is not sleep can be the or sleep study with to for or central sleep of and Individuals PASC may present with a of cognitive and symptoms. It is for clinicians to by cognitive and consider cognitive assessment tools (see Table and to a treatment It is also important to consider testing which can be with such as the of and to of and symptoms the patient of and in this context are described as of symptom assessment including should be only by clinicians such as who in the of Cognitive has been in groups of and there are for in study populations to of testing and treatment testing and treatment may be or for people who identify with and groups or other or groups because of a of issues such as not as a not for in or and (See Appendix: Health Equity Considerations and Examples in Post-Acute Sequelae of SARS-CoV-2 Infection [PASC]: Cognitive word use word with to various such as word of for all that are based on with available may the and severity of of and to and in to and Examples of of for on a or at the of such as or to or of for and including use of or or on a and or to of for such as from to to for (eg, use of system the PASC patient concerns on referral to or may be for more and specific a expertise in an with cognitive that should be referred to a with expertise in for further and treatment. These may by community but are typically and or It is important to or fatigue from mental or cognitive fatigue is defined as a progressive in cognitive over time in cognitive attention and executive of deficits from sleep or neurological examination is typically for most patients with PASC. The neurologic should include assessment of mental motor sensory and and of and a expertise in neurological is an with neurological that patient should be referred to brain injury or for further In patients with is typically although studies have in and patients with PASC have had brain A study of patients presenting to a found the most common brain was of these patients were found to have of headache or worsening neurological or cognitive including headache warrant brain The can be used as a in patients with to identify the of that warrant for a Although most are evaluated and managed by care consider referral to a if there is regarding the diagnosis or management of a patient with metabolic can contribute to cognitive symptoms. include: metabolic including blood and and and mediators may or in of postacute infection, including blood with and can be with and For patients with current symptoms or patients with issues during acute infection (e.g., or additional assessment may include and brain function and may be in patients with and Although these recommendations in on the American Academy of recommendations for this not that COVID-19 to dementia that PASC is a progressive neurological It is important for clinicians to recognize patient symptom widely and it is that treatment earlier will in earlier resolution of symptoms. The absolute of PASC-related cognitive symptoms should not management symptom and clinical preexisting and COVID-19 comorbidities, and impacts on function and of should an and approach (Table As with treatment clinicians treating patients with PASC are to the of PASC and as well as the and of Patients have reported symptom after following a and to The is to to of to and is a management approach for many patients. A team approach for patients with cognitive issues and fatigue can be with and such as a longer into small with For and of established used for patients with or traumatic brain injury a or to and Other include time, sleep managing and Based on brain injury cognitive is an effective treatment for cognitive symptoms and should be to the should a of direct and use of (eg, Table 4 by cognitive The impact of poor sleep on is well The of sleep is to approaches include behavioral and and referral to sleep should be sleep include time, to of sleep with the need to in and a potential sleep and referral for sleep study are as effective sleep treatment can including memory, and executive Cognitive behavioral for is as a evidence-based of treatment for chronic in may have as sleep can be by the use of and There is no that or are beneficial for of may be include receptor receptor receptor and receptor such as or with effects should be and for of time as they may particularly in older patients. The of to improve sleep should be with this potential risk of cognitive may be by if the patient not have a to These may include such as or effects (eg, It is important to that of these was consensus process and should be on a must be to potential effects and and with patient these should not be used in to clinical judgment and patient care. the of the to must be specific for the may be beneficial for individuals with PASC-related cognitive symptoms. in patients with mild cognitive and has been for the It is important to that use of and across PASC or should be on a the limited scientific there should be of the of the risk of of and of and It is important to those social associated with the COVID-19 pandemic, including social and with or who are that may mental health, which can individuals with PASC should be for mental health disorders such as anxiety, and acute or to and mental health conditions can also cognitive function and need to be with PASC who have been and in with a of should be acknowledged for their in of their health has also shown that individuals with social and sleep and more in of the of treatment Patients with PASC should be to social and on support during this which may include patient In the context of it is important to focus on health health and social of health are to the Table Health Equity Considerations and Examples in Post-Acute Sequelae of SARS-CoV-2 Infection Cognitive for guidance the of health equity with the and treatment of individuals with PASC. In addition, the Multi-Disciplinary Collaborative Consensus Guidance Statement on the Assessment and of in Post-Acute Sequelae of SARS-CoV-2 Infection an extensive of health equity on PASC and health disparities are and are related to have and will continue to during the The of that support the health of all individuals in the is also populations PASC may have or no health and may have less limited in their and to and health including and virtual may be helpful for also additional for caregiver which can be particularly for a patient with cognitive symptoms, because the patient and caregiver not need to be in the The of this PASC Collaborative Guidance Statement is to a and systematic approach to the and treatment of patients presenting with PASC-related cognitive symptoms. The recommendations represent a consensus of a collaborative of centers focused on the treatment of individuals with PASC. The recommendations are based on the most current available from evidence in similar conditions, and the clinical experience of treating of patients with PASC-related cognitive symptoms. It is important to recognize emerging and of cognitive symptoms as a of The PASC Collaborative patients with PASC typically present with a of symptoms that multiple and focus in this statement only the surface of the emerging The and recovery of the PASC-related have to be and post-COVID patients will experience Beyond cognitive symptoms, studies provide evidence that patients with COVID-19 can develop a of neurological including those from stroke, syndrome, and PASC Collaborative Consensus Guidance Statements will further and guidance on mental health and symptoms in patients with PASC. The work of the is by the American Academy of Physical Medicine and Rehabilitation (AAPM&R) were required to with and other The of this Multi-Disciplinary Consensus Guidance Statement was developed in with the PASC Multi-Disciplinary of PASC who to the development of the consensus statements via individuals working in their or from their expertise in the assessment and treatment of PASC in their expert The and by collaborative are their and not reflect the of This statement a group the clinical is as the and group and not reflect or The acknowledge the contributions of the PASC Collaborative and We also acknowledge and a to and for their and efforts to and in the PASC Collaborative work and is a by AAPM&R for and a from of Health and for Rehabilitation to the present to this by the and is a at minority groups who identify as (including and individuals who live in that to various of who have in or mental health, or social cognitive or and and other the SARS-CoV-2 pandemic, people with cognitive may from their to recommendations regarding health social practices and their personal with and PASC-related cognitive are to by The of a chronic with PASC-related cognitive symptoms may have an additional impact on function and community individuals with chronic or deficits may on for memory, problem solving, and Individuals with PASC-related cognitive symptoms may report more difficulty with their Recommendations should be to the specific and who identify with a in is or who have from in to live in the