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)
2021; Wiley; Volume: 14; Issue: 1 Linguagem: Inglês
10.1002/pmrj.12745
ISSN1934-1563
AutoresJeffrey S. Fine, Anne Felicia Ambrose, Nyaz Didehbani, Talya K. Fleming, Lissette Glashan, Michele Longo, Alexandra Merlino, Rowena Ng, Gerald J. Nora, Summer Rolin, Julie K. Silver, Carmen M. Terzic, Monica Verduzco–Gutierrez, Sarah Sampsel,
Tópico(s)Psychosomatic Disorders and Their Treatments
ResumoThe 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 neuropsychologists who specialize in the administration of neurocognitive tests.22 Cognitive neuroscience has primarily been conducted in homogenous groups of individuals, and there are calls for greater diversity in study populations to ensure reliability of testing and treatment interventions.23 Both testing and treatment may be biased or inaccurate for people who identify with racial and ethnic groups or other socially or historically marginalized groups because of a variety of issues such as not having English as a primary language, hearing impairments, not properly accounting for variations in dialect or education level, and stereotype threat. (See Appendix: Health Equity Considerations and Examples in Post-Acute Sequelae of SARS-CoV-2 Infection [PASC]: Cognitive Symptoms.)24 Semantic feature analysis, word finding strategies, use word associations, convergent/divergent naming tasks, anagrams. Structured tasks with speech-language pathology (SLP) to address various domains, such as comprehension, recall, word finding, thought organization, identification of strategies for all domains that are impaired based on assessments. Energy Envelope Theory: maintaining expended energy levels consistent with available energy levels may reduce the frequency and severity of symptoms.56 Mindfulness-Based Stress Reduction (MBSR): method of using meditation and yoga to cultivate awareness and reduce stress.57 Training in metacognitive strategies to promote self-awareness and self-monitoring. Examples of metacognitive strategies: Goal-Plan-Do-Review, self-talk, Goal Management Training (Stop- Think - Plan), Predict-Perform Technique. Use of organizational aids (calendar, filing system, daily checklist for chores/tasks, etc.), alarms/reminders on a phone or smartwatch, creating routines, placing items at the same place. Use of language-mediated strategies such as self-talk or verbalization to solve problems or remember information. Application of compensatory strategies/aids for writing and organization, including use of graph or lined paper, limiting problems or text on a page, and highlighting key words or text to remember. Use of visual cancellation tasks, strategies for visual organization such as scanning from left to right, top to bottom for symbols, shapes, numbers, etc. Verbalize maps (eg, use of global positioning system [GPS]). If the PASC patient reports primary concerns affecting subjective cognition despite normal performance on screening instruments, referral to neurocognitive rehabilitation specialists or neuropsychologists may be appropriate for more formal and specific assessments. When a clinician without expertise in cognition diagnoses an individual with cognitive impairment, that individual should be referred to a specialist with expertise in cognition for further evaluation and treatment. These practitioners may vary by community but are typically neuropsychologists, speech and language pathologists, or occupational therapists. It is important to distinguish general or exertional fatigue (Fatigue Severity Scale, Modified Fatigue Impact Scale, Patient-Reported Outcomes Measurement Information System Fatigue) from mental or cognitive fatigue. Mental fatigue is defined as a progressive decrease in cognitive resources over time when participating in cognitive tasks requiring sustained attention and executive function, independent of deficits from diminished sleep hygiene (daytime sleepiness) or motivation.25 Routine neurological physical examination is typically nonfocal for most patients with PASC. The neurologic exam should include assessment of mental status, cranial nerves, motor function, deep tendon reflexes, sensory and coordination function, and evaluation of balance and gait. When a clinician without expertise in neurological diagnoses is evaluating an individual with neurological impairment, that patient should be referred to brain injury medicine physiatry or neurology for further evaluation. In patients with PASC, head computed tomography is typically unrevealing, although contrast studies rarely demonstrate leptomeningeal enhancement.26 Research-based positron emission tomography scan assessments have revealed hypometabolism in frontal, temporal, and cerebellar regions.27 Most patients with PASC have had normal brain magnetic resonance imaging (MRI). A study of 48 patients presenting to a neuro-COVID clinic found the most common brain MRI abnormality was nonspecific white matter changes. None of these patients were found to have abnormalities of magnetic resonance (MR) vessel wall imaging.17 Persistent headache (duration >4 hours, daily, upon wakening)28 or worsening neurological or cognitive deficits, including headache progression, warrant brain imaging. The SNOOP10 mnemonic can be used as a screening tool in patients with headaches to identify the presence of red flags that would warrant investigation for a secondary cause.29 Although most headaches are evaluated and managed by primary care providers, consider referral to a specialist if there is uncertainty regarding the diagnosis or management of a patient with headaches. Ongoing metabolic abnormalities can contribute to cognitive symptoms. Preliminary laboratory tests include: comprehensive metabolic panel including blood urea nitrogen, serum creatinine and liver function, and folate and vitamin B12 levels. Inflammatory mediators may smolder or reactivate in setting of postacute opportunistic infection, warranting reassessment including complete blood count with differential, erythrocyte sedimentation rate, C-reactive protein, ferritin, procalcitonin, urinalysis, and chest x-ray. Inflammatory coagulopathy can be assessed with D-dimer, fibrinogen, and international normalized ratio. For patients with current cardiac symptoms or patients with cardiac issues during acute infection (e.g., myocarditis, heart failure or demand ischemia), additional assessment may include troponins and brain natriuretic peptide. Thyroid function studies, antinuclear antibody, and creatinine kinase may be appropriate in patients with weakness and myalgias. Although these recommendations draw in part on the American Academy of Neurology's recommendations for reversible dementia,30 this does not imply that COVID-19 leads to dementia nor that PASC is a progressive neurological condition. It is important for clinicians to recognize individual patient symptom timelines vary widely and it is possible that initiating treatment earlier will result in earlier resolution of symptoms. The absolute duration of PASC-related cognitive symptoms should not dictate management approach. Alternatively, individual symptom and clinical presentation, preexisting and COVID-19 exacerbated comorbidities, and impacts on function and quality of life should guide an identification and intervention approach (Table 5). As with any treatment plan, clinicians treating patients with PASC are encouraged to discuss the unknowns of PASC treatments and prognosis, as well as the pros and cons of any therapeutic approach. Patients have reported symptom improvement after following a structured and titrated return to activity.17 The long-term goal is to progress to resumption of exercise, return to work, and avocational interests. Energy conservation is a key management approach for many patients. A rehabilitation team approach for patients with cognitive issues and fatigue can be considered with pacing and energy conservation strategies, such as dividing up a longer task into small increments with judicious breaks. For memory and organization issues, application of established techniques used for patients with concussion or traumatic brain injury includes taking notes, using a planner or phone app to record information, and setting electronic reminders. Other tactics include reducing screen time, proper sleep maintenance, managing stress, and increasing physical activity.31-33 Based on brain injury research, cognitive rehabilitation is an effective treatment for cognitive symptoms and should be tailored to the individual patient.34 Interventions should involve a combination of remediation through direct training, metacognitive strategy instruction, and use of compensatory techniques (eg, memory notebooks, alarms, smartphone apps, calendars). Table 4 offers intervention options sorted by cognitive domain. The detrimental impact of poor sleep on cognition is well established. The ideal duration of total sleep is 7 to 8 hours per night.35 Treatment approaches include behavioral (nonpharmacologic) and pharmacological and referral to sleep specialists should be considered. Behavioral sleep hygiene strategies include avoiding caffeine, avoiding screen time, avoiding liquids before bed to prevent interruption of sleep with the need to urinate, engaging in relaxation activities, and maintaining a consistent sleep/wake schedule.36 Treating potential sleep apnea and referral for formal monitored sleep study are recommended as effective sleep apnea treatment can enhance cognition,37 including attention, processing speed, memory, and executive functioning.38 Cognitive behavioral therapy for insomnia is recommended as a therapeutic, evidence-based form of treatment for chronic insomnia in adults.39 Nutritional supplements may have benefit as subjective sleep quality can be improved by the use of amino acids, melatonin, and Vitamin D.40-42 There is no indication that magnesium, zinc, resveratrol, or nitrate supplementation are beneficial for restoration of normal sleep.43 Should conservative interventions produce incomplete effect, then pharmacological interventions may be indicated. Medications include benzodiazepine receptor agonists, histamine receptor antagonists, melatonin receptor agonists, and dual orexin receptor antagonists. Medications such as benzodiazepines
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