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)

Field: Medicine (Health Sciences)

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 psychological factors. It is important to note that mood disorders may be secondary to persistent medical conditions or one of many factors leading to cognitive symptoms. The following basic lab workup should be considered to screen for reversible factors contributing to cognitive symptoms. The initial lab workup in new patients or those without lab workup in the 3 months prior to visit including complete blood count, vitamin B12, thiamine, folate, homocysteine, 1,25-dihydroxy vitamin D, magnesium, liver function tests, comprehensive metabolic panel thyroid function tests (thyroid stimulating hormone, free T3, free T4). In high-risk patients, one may consider syphilis rapid plasma regain and human immunodeficiency virus testing. Other laboratory tests may be considered based on the results of these tests or if there is specific concern for comorbid conditions as outlined in Table 3. Clinicians should conduct a full patient history with review of preexisting conditions and comprehensive medication and supplement review for those that may contribute to cognitive symptoms. Of note, patients with PASC often present on antihistamine, anticholinergic, and antidepressant/anxiolytic medications that can contribute to cognitive symptoms. Standardized general cognitive screening assessments form the foundation for initial neurocognitive assessment. Commonly used instruments include the Mini Mental Status Examination, Montreal Cognitive Assessment, Saint Louis Missouri Mental Status Exam, Mini-Cog, and the Short Test of Mental Status. These screening instruments are defined in Table 2 and can be administered by a variety of clinical professionals, including primary care. Subsequent formal neurocognitive tools, outlined in Table 4, are specific to those trained in neurocognitive testing and interpretation. As noted, there are no consistent evidence or guideline statements on when to diagnose cognitive symptoms during the SARS-CoV-2 acute course, or after primary symptom resolution in PASC, as SARS-CoV-2 related cognitive symptoms may have delayed onset, and may fluctuate or be continually present from the acute infection phase. Because of the varying presentations of PASC and often a constellation of overlapping symptoms, consideration of additional studies and referral options for common manifestations is warranted. It should be noted that cognitive screening measures are not a substitute for more in-depth cognitive testing, and abnormal scoring on screening measures does not warrant a cognitive disorder on their own. Table 3 describes diagnostic categories and common findings related to PASC cognitive symptoms, including additional testing and referral options. Symptoms: headache, weakness, numbness, cognitive or communication dysfunction, difficult walking, bowel or bladder dysfunction Signs: focal weakness, abnormal cognitive screening, ataxia, hyperreflexia, aphasia, aprosody Symptoms: palpitations, fatigue, dizziness, weight gain/loss, sense of chills/fever, irregular menstrual cycle, poor diabetic control, excessive thirst/urination Signs: tachycardia, poor activity tolerance, weight gain/loss, low/elevated temperature, elevated finger-stick/urine glucose, ketotic (fruity) breath, bone pain, risk factors for malnutrition (eg, "tea and toast" diet or alcohol abuse) Symptoms: rash, joint/ muscle pain and stiffness, fever, mouth sores/ ulcers, cold/ pale/blue/red fingers, sharp chest pain, numbness/ tingling/ burning in fingers/toes, blurry/ decreased vision Signs: rash, arthropathy/ swelling/warmth, decreased range of motion, myopathy/ tenderness/ weakness, fever, Raynaud's phenomena, pleuritic pain on deep breathing, altered sensation, decreased visual acuity Symptoms: anxiety, irritability, chest tightness, low frustration tolerance, depression, fatigue, mood swings, palpitations, change in memory/recall Signs: flat affect/low mood, emotional lability that is, crying/laughing inappropriately, limited impulse control, psychosis Symptoms: Poor sleep - hard to get to sleep/wakes frequently/wakes early, nonrestorative/refreshing sleep - "tired" on waking, snoring, frequent urination at night, bad dreams/nightmares, falls asleep during the day Signs: snoring, restless legs, observed apneic episodes, hypertension, arrhythmias, narcolepsy, congestive heart failure, impaired cognition, poorly controlled mood disorder, metabolic dysfunction: glucose intolerance Thyroid stimulating hormone (TSH)/free T4 (thyroxine), cortisol levels, growth hormone, luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (men), estradiol (women) As in acquired brain injury, new neuroendocrine dysfunction may be present, assess serum cortisol, growth hormone (IGF-I), testosterone, estradiol, prolactin. Cytokine storming may induce or unmask autoimmune disease so consider ANA, RF, cyclic citrullinated peptide antibody, HLA B-27 antigen, antithyroid peroxidase antibodies, antiphospholipid antibodies Depending on the patient history, one may add HIV and syphilis (RPR) screening. HSV, EBV, Lyme disease, and Whipple's disease are other less common causes.54 Consider mast cell activation syndrome assessment. Screening assessments for behavioral health conditions assist to disentangle psychiatric conditions from cognition impairments and may include assessments of anxiety, depression and posttraumatic stress disorder (PTSD): Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory (BDI) fast screen; Geriatric Depression Scale (GDS); Patient Health Questionnaire for depression (PHQ-2/9), (or PHQ-8 removing the suicidal thoughts question when immediate review and attention is not available); Generalized Anxiety Disorder 7 (GAD-7); PTSD Checklist-5 Restorative sleep can be assessed using the Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale, PROMIS Sleep, or Sleep Scale Survey, Insomnia Severity Index screen Sleep apnea evaluation: STOP-BANG questionnaire; overnight sleep study with oximetry to assess for obstructive or central sleep apnea, benefit of CPAP/BIPAP, and oral appliances Individuals experiencing PASC may present with a broad constellation of cognitive and neurobehavioral symptoms. It is useful for trained clinicians to sort subjective impairments by cognitive domain and consider appropriate formal cognitive assessment tools (see Table 4) and intervention options to form a reasoned treatment plan. It is also important to consider effort testing which can be formally assessed with performance validity measures such as the Test of Memory Malingering, Rey-15, and Advanced Clinical Solutions Word Choice. Such tests aim to detect signs (patterns of test performance) and symptoms (verbal reports - what the patient says), indicative of deliberate distortion and in this context are described as tests of symptom validity. Neurocognitive assessment including performance validity tests should be administered only by trained clinicians such as who in the of neurocognitive 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 variety of issues such as not as a primary 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 impaired based on consistent with available may the and severity of of using 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 visual for visual such as from to to for (eg, use of system the PASC patient reports primary concerns subjective cognition performance on screening referral to neurocognitive or may be appropriate for more formal and specific a without expertise in cognition an with cognitive that should be referred to a with expertise in cognition for further and treatment. These may by community but are typically and or It is important to general or fatigue Severity Scale, Scale, from mental or cognitive Mental fatigue is defined as a progressive in cognitive over time when 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 deep sensory and and of and a without expertise in neurological is an with neurological that patient should be referred to brain injury or for further In patients with PASC, is typically although studies assessments 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 screening in patients with to identify the of that warrant for a secondary Although most are evaluated and managed by primary care consider referral to a if there is regarding the diagnosis or management of a patient with metabolic can contribute to cognitive symptoms. laboratory tests include: comprehensive metabolic panel including blood serum and liver and and vitamin mediators may or in of postacute infection, including complete blood with and chest can be assessed with and For patients with current symptoms or patients with issues during acute infection (e.g., heart or additional assessment may include and brain Thyroid function antibody, and may be appropriate in patients with and Although these recommendations in on the American Academy of recommendations for reversible this does 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 intervention 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 considered with and such as a longer into small with For and of established used for patients with or traumatic brain injury using a or to and Other include screen 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 intervention options by cognitive The impact of poor sleep on cognition is well The of sleep is 7 to approaches include behavioral and and referral to sleep should be sleep include screen time, to of sleep with the need to in and a consistent potential sleep apnea and referral for formal sleep study are as effective sleep apnea treatment can including memory, and executive Cognitive behavioral for is as a evidence-based form of treatment for chronic in may have benefit as subjective sleep can be by the use of and There is no that magnesium, or are beneficial for of may be include receptor receptor receptor and receptor such as