Multidisciplinary collaborative consensus guidance statement on the assessment and treatment of neurologic sequelae in patients with post‐acute sequelae of <scp>SARS‐CoV</scp>‐2 infection (<scp>PASC</scp>)

Abstract

COVID-19 has been a transformative novel disease in modern health care. Unlike many other viral illnesses, COVID-19 not only causes multiorgan damage during the acute stage of the infection, but also has the potential to cause long-term sequelae, as part of post-acute sequelae of SARS-CoV-2 infection (PASC) or long-COVID syndrome. In a 2022 study released by the Centers for Disease Control and Prevention,1 electronic health record (EHR) data were examined from the time period of March 2020–November 2021 for persons in the United States aged ≥18 years to assess the incidence of 26 conditions often attributable to post-COVID-19. Among all patients, 38% of individuals experienced an incident condition compared with 16% of controls; conditions affected multiple systems and included cardiovascular, pulmonary, hematologic, renal, endocrine, gastrointestinal, musculoskeletal, neurologic, and psychiatric signs and symptoms.1 Neurological symptoms occur in approximately 80% of hospitalized patients during the acute phase of COVID-19 infection.2 The most prevalent PASC neurologic symptoms that remain after 3–4 weeks from the initial infection include “brain fog” (81%), headache (68%), numbness/tingling (60%), dysgeusia (59%), anosmia (55%), and myalgias (55%).3 Importantly, studies of post-acute COVID-19 neurologic outcomes across the care-setting spectrum of the acute phase of the disease (nonhospitalized, hospitalized, and admitted to intensive care) continue to emerge. Addressing this knowledge gap is important in helping guide PASC care strategies and health care system capacity planning. The U.S. Department of Veterans Affairs national health care databases were used to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls to estimate risks and burdens of incident neurologic disorders at 12 months following acute COVID-19. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Investigators found an increased risk of various neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (eg, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain–Barré syndrome (GBS), and encephalitis or encephalopathy.4 Importantly, up to 10% of critically ill COVID-19 patients have cranial nerve involvement.6 Sleep patterns can also be disturbed by these neurological sequelae, and in turn, exacerbate other PASC symptoms.7-10 Interestingly, the presence and severity of PASC symptoms do not fully correlate with initial COVID-19 symptoms.11 Another study of U.S. health care claims data involving 78,252 patients demonstrated that 75.8% of patients with persistent PASC symptoms (coded as U09.9 post COVID-19 condition) including anosmia, headache, altered mental status, stroke, and seizure, which significantly affected activities of daily living, experienced initial asymptomatic or mild COVID-19 and did not require hospitalization.12 This guidance statement focuses on the neurologic sequelae of PASC, including headaches, neuropathies and neuropathic pain, muscular pain/weakness and tremors, and cranial nerve conditions. Fatigue, autonomic dysfunction, and cognitive function changes are reviewed in separate American Academy of Physical Medicine and Rehabilitation (AAPM&R) guidance statements.8, 10, 13 In addition, an AAPM&R consensus document focused on mental health sequelae is currently in development. Despite the prevalence of neurological sequelae of COVID-19 infection and emerging data on longevity of symptoms, limited guidance exists regarding the assessment and treatment of neurologic sequelae in patients with PASC. The AAPM&R Multi-Disciplinary PASC Collaborative (PASC Collaborative), consisting of experts in PM&R, neurology, internal medicine, family practice, pediatric specialties, cardiology, physical therapy, occupational therapy, social work among other disciplines, was convened to address the pressing need for guidance in the care of patients with PASC. The PASC Collaborative is following an iterative, modified Delphi process to achieve consensus on assessment and treatment recommendations for a series of consensus guidance statements focused on the most prominent PASC symptoms. These recommendations and guidance are informed by experts from established PASC centers with experience in managing individuals across the spectrum of sequelae experienced by patients with PASC.8-10, 13, 14 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 been published previously.15 We acknowledge that the definition of PASC is evolving, and there are various factors that contribute to diagnosis and management. Literature available at the time of our consensus process suggested that PASC be defined as the persistence of symptoms beyond 4 weeks from the onset of acute infection.16 Alternative definitions of PASC include symptoms lasting longer than 3 months.17 The World Health Organization released a definition of “post-COVID condition,” including describing the timing as “usually 3 months from the onset of COVID-19” and lasting “for at least 2 months.”18 Based on patient feedback during our consensus process, we agree that earlier evaluation, diagnosis, and management can improve access to beneficial interventions. For the purposes of this guidance statement, we recommend expanded assessment if symptoms are not improving 1 month after acute symptom onset. At present, scientific evidence regarding effective assessment and treatment of PASC is limited, which prevents the creation of evidence-based clinical guidelines. This consensus guidance statement is intended to reflect current practice in patient assessment, testing, and treatments based on expert opinion from health care professionals who care for PASC patients regularly. It is intended as a resource and concise point of reference geared toward clinicians in different specialties caring for PASC patients. The recommendations 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. This guidance statement is structured to first outline initial evaluation components (Table 1: Initial Evaluation of Neurologic Sequelae in Patients with PASC) and initial treatment recommendations (Table 2: Initial Treatment Options for Patients with Neurologic Sequelae) for the neurologic sequelae of patients with PASC. These initial evaluation recommendations review both how to consider a wide differential of possible conditions and aspects to help further guide the diagnostic workup. There is also a section dedicated to “Red Flag” presentations that should prompt emergent escalation of care specific to neurologic features of PASC. Subsequent narrative sections review a series of common neurologic sequelae and how to best guide care. Clinicians should conduct a full patient history including a review of predisposing comorbidities, prior neurologic symptoms or disorders, relevant hospitalizations, time course and severity of COVID-19 infection(s), COVID-19 treatments, vaccines/boosters, pertinent family history, and social history. The patient history of present illness should address: For those patients identified with new or worsening focal neurologic deficits, an urgent/emergent referral to an emergency department for evaluation is warranted. (The section on Red Flags and corresponding table provides additional information). Determination of need for neuroimaging should be based on individual signs and symptoms. Consider consultation with a neurologist to guide imaging and further testing. Evaluate for medication and supplement use that may impact signs, symptoms, or assessment parameters with as review of and supplement use and of use that have or to impact on symptoms. patients with PASC often present on and that can contribute to neurologic symptoms. The following should be in new patients or for those a in the 3 months prior to the with including and function and and including evaluation for new may be based on the patient history, physical for conditions as in the relevant symptom that For patients who achieve a to daily consider physical as which may be effective in improving many neurologic symptoms and also contribute to Patients should be to escalation of physical and cognitive activities to syndrome by This is to symptoms do not and is neurologic symptoms are common in PASC, patients may present to care or PASC specific These clinicians must the of symptoms, of neurologic dysfunction, that referral to a or emergency department as may a neurologic (Table Red A neurologic assessment knowledge of a and cognitive symptoms, with to symptoms that require prompt for the of the of symptoms that may be to PASC condition history and physical is consider emergency department on time Consider capacity assessment and neuroimaging as consider or on time and neurologic signs and symptoms. Consider capacity assessment and neuroimaging as as or consider or on time and neurologic signs and symptoms. to or for for of timing following if changes or in to on time of and and review and cognition assessment, headache of with cause the or on time to headache section in this neurologic signs or symptoms that are new or if should be a sensory changes or cranial nerve may be of a focal or neurologic condition as stroke, or an acute syndrome. These should a referral which include imaging of the or additional testing. The presence of as or or or may be signs of the or these signs and symptoms are present at evaluation, clinicians should consider the differential diagnosis of stroke, and multiple diagnostic evaluation and treatment for patients with acute and neurologic symptoms can often and and peripheral nervous system has been to COVID-19, both and as part of evaluation of the peripheral nervous system and cranial sensory and and should be for is best by both of the patient for symptoms and by a clinical assessment of there is for autonomic dysfunction, if there is an in symptoms, to the PASC Collaborative consensus guidance statement on autonomic for assessment and treatment symptoms as with focal neurologic signs, and onset headache should be identified and of of may also a assessment and evaluation for an or nerve may require referral to for specific on the affected nerve to section and of acute ischemic as as or should be for symptoms of including and and cranial nerve involving or may as part of PASC, common conditions can also to and must first be For can also been in the of In addition, signs of increased should be with mental focal signs, as for clinicians should consider or onset of a or peripheral must be to a condition of increased as assess for other common Initial Treatment of and with for other common conditions as for that can Consider for and and and Consider referral to or Consider the following evaluation for that may exacerbate for other common Based on the prevalence of neurologic symptoms in patients with PASC, with multiorgan there is a need for care. The following sections focus on the most common neurologic sequelae by and clinicians patients with PASC and the symptom or system by to a assessment beyond the initial evaluation, of initial and to to or a care studies have demonstrated that COVID-19 infection to cranial neuropathies that may as persistent symptoms of of the studies cranial neuropathies in a cohort of patients hospitalized with COVID-19 found that 38% of patients cranial nerve with of the and many of the patients with multiple cranial The nerve was the most nerve to and nerve was the most compared to other cranial as of and and There was in of comorbidities, or intensive care in the that cranial neuropathies compared to as in a review of patients across the most affected cranial in patients with COVID-19 were and as or were often with or syndrome This study also found that patients often cranial nerve Evaluation and for cranial neuropathies are in patients multiple cranial should be with evaluation of toward a diagnosis of clinicians should have a of for cranial neuropathies and in patients, these may be cranial nerve can be present in PASC patients as cranial neuropathies often to and may be used to acute or Patients with further from and patients with cranial neuropathies have a with care compared to patients with multiple cranial neuropathies with who may achieve and experience longer symptom The of diagnosis of in acute COVID-19 is that these patients are at risk for PASC symptoms if not in the acute is a common symptom in both patients who were hospitalized with acute infection and in patients who did not require A found the prevalence of headache from to during the first months after SARS-CoV-2 have presentations that include those that may or may not have migraine features to be with the features and daily persistent have been to new daily persistent COVID-19 is also a risk for worsening headache disorders as The incidence of migraine in the United States is in and in studies have demonstrated an and migraine prevalence in the United headache can be even in those who did not experience headache in the acute COVID-19 can be or by other symptoms including memory and with PASC do not have a or specific clinical These require a clinical to if the headache is or The treatment of the headache should be by the Clinicians should be that patients with headache disorders may also headache We recommend the to of of the to for a A new daily persistent headache is a headache with a and onset with and present for 3 months and not for by of daily persistent headache is to additional evaluation and initial treatment for different of headache in patients with PASC. headache history including the features and symptoms to if the headache is to a headache migraine or or if is to a cause disorders, to to of or the a full medication review including and to if be to if headache is to Evaluate for with may be beneficial for those patients with or to for strategies headache is a headache that on or a month and as a of of acute headache for than 3 medication headache, is that or not be than a month for 3 months and that not be than month for 3 Sleep is an important for internal memory and of has on physical and mental In at Sleep a of the Sleep from the found that of patients at least and The study also that patients were than to have after from COVID-19 and that was with a incidence of In a of studies patients with COVID-19, was found that of patients have which were with and prevalence of and studies have also that in and cognitive including and which are of the most prevalent in patients with of a with to or factors and illnesses, as that with to for evaluation and initial treatment and to can be only all factors are and patients with have the phase of The first at this stage is cognitive for a and with the patient is to a by a and to on the only the for that with and time in and of increased and and as as as and has been as a therapy, as or have in a history to include review for other factors of medication can be by the presence of other symptoms. The following often have and should be used is not effective for all patients and is not to to of of or In a limited or course of is an if the patient is is during and to to the A can be a to or to a treatment is Sleep are or a A of to and and and or The to patients with than 1 is to identify potential and to address the if this or if is with use of medication is to help address with function and to including should be to individual patients and as in the and medication use and in or should be of health should also be regarding both diagnosis and For who in a and the may have with both and of to for other of how may neurologic PASC sequelae (Table Health and in Neurologic who identify as and from have been to have referral to neurologic than people as individuals with neurologic and as dysfunction, cognitive or should be for should occur in a should of will be most beneficial as as other factors as and should be to in health disparities and care for people who identify with have in neurologic symptoms and For (eg, are to both migraine and in A that were at a risk of symptoms as headache, and anosmia as symptoms of COVID-19 compared to The study also that were to be admitted to the intensive care and compared to the COVID-19 to evidence that severity and of COVID-19 is in than in be at increased risk of COVID-19 and of Another study found that were for both acute infection and PASC than is to in PASC. compared to individuals clinical including have in the of people across the and clinicians should be that care will the for studies to guide the care of and individuals may be to A study with controls in the of at least symptom lasting at least 2 months compared with the In addition, the or and or of compared to the A review in patients with 2 and PASC to The that in and contribute to and In addition, acute COVID-19 infection, and often cause onset of in COVID-19 COVID-19 infection may also contribute to new or worsening neurologic In patients with 2 of and other comorbidities, physical and and may be in and managing PASC individuals may have with following infection may than Clinicians should be new or worsening neurologic or with For individuals who have an may help to for may access to care for of conditions in is a that should be for individuals from that specific of and in an with COVID-19 prevalence were the and most of COVID-19 and This cohort study that was the most common of all symptoms and signs of acute COVID-19 infection, and factors with were than in a or living, stroke, and the studies in are evolving, is and should be at all to a PASC should be for symptoms continue and to pediatric pediatric and other there are neurologic symptoms and with conditions that cause and neurologic who are as that as a can a risk for PASC and neurologic individuals also for may not be for people with who have of to Addressing strategies can be system of care and in with and physical should be and consider as a should be to physical in this who are or access to health care States with the of the will have disparities in health outcomes among and worsening for those persons with There may be in to factors as and or as as social of health as a or to may be for health care access to individuals with with Clinicians should be of the of diagnostic and treatment interventions. Consider the of diagnostic to various conditions. Treatment as physical therapy, may be limited by the of and even in patients who have or may persons with of access to may care for for For individuals may have and new or a limited of available and to and and of the on the the and diagnostic for including and has expanded during the to use of these for these is is often and may improve function in neurologic conditions as as Patients with PASC may present with symptoms of peripheral as sensory and neuropathic In of patients in a neurologic COVID-19 In of patients numbness/tingling after studies have in patients with The presence of autonomic symptoms in patients with PASC should also of of help treatment with as which has to be beneficial in neuropathies as as illness may be present in patients who were hospitalized with In to and sensory patients may experience with movement that can cause limited and daily to for a of signs, symptoms, and additional evaluation and treatment for and neuropathic can be a symptom for patients with Patients with PASC often as or The symptoms are often at can help neuropathies from neuropathies are with of and with and can only in of and or evaluation but often the clinical can be Initial Treatment Evaluation for other common causes of as or or or In patients with persistent or and as and to and should also be as part of evaluation of studies can help for neuropathies acute or and which will need as or for of the with can nerve to nerve or can be used to the clinical and evaluation can be to neuropathies that can be with as We acknowledge these clinical may not be or in many care and PASC Patients with persistent symptoms should be for or and for For patients with sensory consider referral to a neurologist for and diagnosis, in the of or worsening Consider referral to a and the for an treatment to address neuropathic or peripheral Physical may include and and may include including and strategies for sensory and and can and strategies for neuropathic that or or may be to to help with to function and referral for physical and occupational is there remain in health equity for In a national individuals were significantly to than to persons continue to experience disparities in the and outcomes of are often included as symptoms in the These are of to care and In addition, studies have that muscular and may and illness has been in people with COVID-19 infection, with than and can contribute to PASC symptoms of and for weeks to months post In a study the impact of SARS-CoV-2 infection on prevalence and severity of long-term neurological individuals months after COVID-19 can and with can disease or (Table of of the and may need an of to these symptoms, as in patients with of on sensory with and can or Evaluation should include testing. the is than the of at or the patient need and nerve studies to for and nerve studies are of the with can help not at this is and the treatment of physical and evidence of at or evaluation by or with may be for diagnostic and Physical with of or can a These disorders are not with is in a patient with PASC, will and we consider to be part of symptoms of with and nerve or can help with diagnosis with referral to can be in the is not with and is present only with consider the is at or with of and consider neurological evaluation for the is only on consider For patients with muscular symptoms, as pain, tremors, or worsening consider referral to a neurologist for and to be a has that COVID-19 is a Importantly, the nervous system may be affected in patients with as cranial headaches, cognitive peripheral muscular symptoms, and The of neurological in PASC is not SARS-CoV-2 of the nervous other possible include persistent and of or of prior neurological and and It is that there is not but different that PASC in different patient further is in to the of PASC and and treatments and that are patient and symptoms not all the of PASC are at this is that clinicians continue to of new or worsening neurological symptoms in patients post COVID-19 infection and PASC Clinicians caring for patients with PASC who have neurological should diagnostic to clinical and treatment of new and peripheral nervous system The AAPM&R the need to access to care for individuals with PASC. The AAPM&R that access to care and patient access to in the health system that in access to care of or and care, including evaluation and of the PASC guidance statements were by a and of experts with patient an of health equity is beyond the of the PASC guidance health equity and to other and The has many different and focus on that is to achieve the of health and For the Centers for Disease Control and health equity as the for people to full health potential and that people should not be from potential of social or other The Centers for and the definition established in on 2021 that equity is and and treatment of all including individuals who to who have been as and and American and and other persons of of and persons with persons who in and persons affected by persistent or There are many causes for health of which the of include but are not limited to status, and access to and access to a In to for access to care for all persons with PASC, the AAPM&R of and that include is of and may be as a of a to of and a for and and for that of of and knowledge are and to that an and among various and different of the PASC guidance statements are to consider the recommendations the of health equity in to improve access to care for all individuals with PASC. The of this Multi-Disciplinary was in consultation with the AAPM&R PASC Multi-Disciplinary of PASC or of the PASC individuals in or from in the assessment and treatment of PASC to the of a series of consensus guidance The and by Collaborative are and do not reflect the of This consensus guidance statement a the clinical are in the first and This consensus guidance statement from patient and the the following and individuals for during the Collaborative the and and and The to acknowledge the of the PASC Collaborative and We also to acknowledge and a to and for in the of the PASC Collaborative and the aspects of this The work of the is by the American Academy of Physical Medicine and Rehabilitation were to with and other and have or from various to and for activities to PASC and areas of and have been reviewed and found to not be in to the work on this The only for this specific is who is to AAPM&R to the and of PASC Collaborative consensus guidance