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Acute Headache

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Last Update: July 26, 2023.

Continuing Education Activity

Headache is a nearly universal complaint. Most headaches are benign, and most patients can be safely treated and discharged with minimal workup. However, many serious and life-threatening conditions may present with headaches. Recognition, evaluation, and appropriate management of these dangerous secondary headaches are critical to preventing long-term disability or death. This activity describes the assessment and medical management of headaches in the emergency department and highlights the role of the interprofessional team in assessing and appropriately treating patients with this chief complaint, with specific emphasis on differentiating benign from concerning presentations.

Objectives:

  • Review the etiology of common causes of headaches.
  • Outline the important exam findings of headaches.
  • Describe a management strategy for the treatment of headaches in the emergency department.
  • Summarize interprofessional team strategies for the identification of life-threatening versus benign causes of headaches to improve patient outcomes.
Access free multiple choice questions on this topic.

Introduction

Headache, or pain in any part of the head, is a nearly universal ailment. Headaches comprise 3% of emergency department chief complaints.[1] While most headaches are benign (96%), recognizing less common, emergent causes of headaches is critical, as a timely intervention may be life-saving.[2] The primary role of the emergency provider (EP) is to carefully analyze specific aspects of the history and physical exam to determine which patients are at risk for serious underlying pathology. The emergency provider must decide which patients require immediate further testing, such as laboratory studies and imaging, to confirm the diagnosis and direct management. In addition to diagnosing and managing life-threatening causes of headaches, the EP must be well versed in treating common primary headache disorders, as proper management of the natural course of the disease may improve patient outcomes.

Etiology

Headaches are broadly classified as primary or secondary. Primary headaches are those with no identifiable underlying cause. Secondary headaches are the result of other underlying pathology.[3]

The International Classification of Headache Disorders (ICHD-III) classifies headaches.[4] These categories are:

  • Primary headache, including tension, migraine, and cluster
  • Secondary headache, including potentially life-threatening etiologies such as traumatic brain injury and vascular disorders
  • Cranial neuropathies, such as trigeminal neuralgia 

Headache can be a symptom of many underlying pathologies, some of which can lead to severe disability and mortality.[2] The emergency clinician should be especially familiar with the following conditions:

  • Hypertensive emergencies
  • Idiopathic intracranial hypertension
  • Carotid or vertebrobasilar dissection
  • Space occupying lesions (tumors, abscesses, cysts)
  • Acute hydrocephalus
  • Dural sinus thrombosis
  • Intracranial hemorrhage
  • Giant cell (temporal) arteritis
  • Cerebrovascular accident or stroke
  • Meningitis and encephalitis
  • Carbon monoxide poisoning
  • Toxin exposure or withdrawal
  • Acute angle-closure glaucoma
  • Medication overuse headache

Epidemiology

The burden of headaches is considered to be underestimated and undertreated by the medical community.[5] Unlike most chronic diseases, much of the morbidity associated with headache disorders is focused on otherwise young, healthy people. The prevalence of headaches tends to peak between the ages of 25 to 40 and decreases with age in both sexes. In the United States, the prevalence of having experienced a headache of any type in one's lifetime is estimated to be 96%.[6] Women tend to suffer more than men from active headache disorders. For example, the prevalence of severe headaches or migraines is 20.7% in women and 9.7% in men.[1] 

It remains unclear whether regional differences in headache prevalence exist. Differences in international data collection methods, diagnostic criteria, and cultural characterization of headaches can impact this data.[7]

Pathophysiology

The brain parenchyma does not have nociceptors. Thus, headache is typically the result of pain originating in surrounding structures, such as blood vessels, meninges, muscle fibers, facial structures, and cranial or spinal nerves. Stretching, dilatation, constriction, or any nociceptor stimulation within these structures can result in the perception of headache.[8] However, primary headache pathophysiology is not fully understood. Many studies have attempted to correlate certain anatomical and physiological derangements to specific types of primary headaches. Still, it is unlikely that a single mechanism underlies all primary headaches. The pathophysiology of secondary headaches depends on the underlying process.

History and Physical

Very often, in patients with headaches, the diagnosis can be established by careful history taking and physical examination. Primary headaches are not life-threatening and do not require imaging in the emergency department. Many types of secondary headaches (e.g., TMJ, uncomplicated otitis media, hangover headache) are similarly benign and require little or no additional workup beyond a thorough history and physical. Though less common, more serious etiologies of secondary headache must be considered before establishing a primary headache diagnosis.[9]

History should be geared toward obtaining a detailed account of the current headache, a full review of systems, and a description of any prior headache disorder or headache history. In addition, specific questions relating to any possible life-threatening causes of secondary headache should be asked, as the answers and any examination findings will direct additional testing or emergent therapy. 

As with any chief complaint of pain, the history should begin with the following questions:

  • Where is the pain located?
  • When did the pain begin?
  • What was the patient doing when the pain began?
  • How has the pain progressed? Is it improving, worsening, or constant?
  • What is the quality of the pain?
  • What is the severity of the pain?
  • Does anything make the pain better or worse?
  • Does the pain radiate?
  • Has the patient experienced pain like this in the past?

Important additional questions to ask are:

  • What is the patient's medical history?
  • Does the patient take new medications, or have they recently changed them?
  • Does the patient take "blood thinners"?
  • Is this the worst headache the patient has ever experienced?
  • Was the pain maximal at the onset?
  • Has the patient had any difficulty moving or speaking normally?
  • Did the patient have nausea or vomiting?
  • Does the patient have a fever?
  • Does the patient have any changes in vision or hearing?
  • Does the patient have eye pain?
  • Does the patient have any neck or facial pain?
  • Did the patient have a seizure?
  • Does the patient have dizziness?
  • Does the patient have any sensitivity to light?
  • Does the patient feel generally weak?
  • Is there a weakness in a specific area of their body?
  • Has the patient traveled recently?
  • Has the patient been around sick contacts?
  • Is the patient less than six weeks postpartum?
  • Does the patient have a history of immunosuppression or take immunosuppressive medication?

 A thorough physical examination is important in all patients presenting with headaches. Although the neurologic exam is the most obvious imperative, it is also crucial to perform a complete HEENT exam, which may uncover findings suggestive of either benign (sinusitis, otitis, odontogenic headache) or serious conditions (e.g., papilledema suggesting intracranial pressure, temporal artery tenderness suggesting giant cell arteritis). 

Certain clinical features suggest that a patient is very unlikely to have a serious etiology of headaches.[10][11] Conversely, screening mnemonics such as SNOOP (see below) can be useful to elicit clinical clues for life-threatening diagnoses.[12] If a patient has all of the low-risk features and no red flags, further history and exam can be directed toward determining the type of primary headache or the benign secondary cause. Additional workup is mandated if high-risk features are present, and patients typically require emergent neurological imaging. 

Low-risk features include:

  • Age under 50 years
  • Features typical of primary headaches
  • History of similar headache
  • Normal neurologic exam
  • No change in the usual headache pattern
  • No high-risk comorbidities
  • No new or concerning findings on history or physical 

SNOOP: Red flags for dangerous underlying conditions

  • S: Systemic illness (fever, cancer, pregnancy, HIV)
  • N: Neurologic signs or symptoms (confusion, focal neurologic signs, seizures, papilledema)
  • O: Onset is new or sudden (especially if age over 50)
  • O: Other associated features (head trauma, drugs or toxins, headache awakens from sleep or worse with Valsalva, precipitated by coughing or exertion)
  • P: Previous headache history with progression or change in characteristics

History and physical are usually sufficient to diagnose primary headaches, provided no high-risk features are present. For primary headaches, physicians must be able to differentiate the type of primary headache to initiate proper therapy.

Clinical features of primary headache subtypes:

Table Icon

Table

Table 1. Characteristics of migraine, tension-type, and cluster headache syndromes.

Conversely, if patients have high-risk features or a history and physical not compatible with primary headache, the etiology of secondary headache must be investigated. As is often the case in clinical medicine, pattern recognition is useful. The following are several of the most important critical diagnoses of secondary headaches to consider and their key clinical features: 

  •  Subarachnoid Hemorrhage
    • "Thunderclap" headache that is sudden, with maximal pain at onset, and often described as the "worst headache of my life."[14]
    • The headaches are associated with nausea or vomiting, neck pain and/or stiffness, and focal neurological deficits.
    • History may include age greater than 50, loss of consciousness, known vascular aneurysms, connective tissue diseases, polycystic kidney disease, family members with SAH, or a history of poorly controlled hypertension.[15]
    • Physical exam findings may include hemotympanum, focal neurological deficits, or nuchal rigidity.[16]
  •  Cervical artery dissection
    • Symptoms include headache, neck pain, dizziness or unsteadiness, double vision, focal weakness, confusion, and stroke-like symptoms in a younger patient.[16]
    • History may include trauma to the head or neck.
    • Physical exam findings may include carotid bruit, cerebellar deficits, visual field deficits, bulbar deficits, and asymmetric strength or motor findings.
  • Meningitis and encephalitis
    • Symptoms may include fever, headache, nuchal rigidity, altered mental status, non-specific flu-like prodrome, nausea, vomiting, focal neurological deficits, photophobia, and seizures.
    • History may include non-vaccination, immunocompromised state, close-quarter living, recent travel, tick or mosquito bite,  and sick contacts.
    • Physical exam findings may include Kernig sign (painful knee extension on hip flexion), Brudzinski sign (passive hip flexion on active neck flexion), papilledema, or petechial rash.
  •  Dural sinus thrombosis
    • Symptoms include headache, blurry vision or visual field deficits, nausea, and vomiting. The history may include infection, head trauma, inherited or acquired hypercoagulable disorders of the patient or family members, or other causes of hypercoagulability such as systemic lupus erythematosus (SLE), sickle cell anemia, OCP use, cancer, pregnancy, estrogen use, previous thromboembolic events, antiphospholipid syndrome, and dehydration.[17]
    • The physical exam may reveal papilledema and focal neurological and/or cranial nerve deficits.
  •  Ischemic or hemorrhagic stroke/cerebrovascular accident
    • Symptoms correspond to the anatomic area of the brain affected. Focal neurological deficits are the most common and specific findings. Other symptoms may include headache, nausea, vomiting, vertigo, aphasia, confusion, and visual deficits.[18]
    • History may include previous ischemic or hemorrhagic events, tobacco use, diabetes, hyperlipidemia,  hypertension, and other vascular risk factors.
    • The physical exam may include neurological deficits, altered mental status, and facial droop.
  •  Carbon monoxide poisoning
    • Symptoms may include headache, dizziness, ataxia, confusion, nausea, and vomiting.
    • History may include the use of indoor heaters, house fires, and exposure to car exhaust.
    • The physical exam may reveal pink-tinged skin, wheezing, hyperventilation, singed nares, and an edematous oropharynx.
  •  Acute angle-closure glaucoma
    • Symptoms may include unilateral or bilateral eye pain, photophobia, changes in or loss of vision, and sudden onset of headache.
    • The history may include older age, exacerbation of symptoms in a dark room, and family history.
    • Physical exam findings may include decreased visual acuity, conjunctival injection, increased intraocular pressure (60 to 90 mmHg is diagnostic), a shallow anterior chamber, and a fixed and mid-dilated pupil.[16]
  •  Idiopathic intracranial hypertension
    • Symptoms may include headaches not responding to analgesia, changes in vision, nausea, vomiting, and the headache worse when supine.
    • History may include female gender, childbearing age, obesity, and new medication use. Specific medications implicated in IIH include oral contraceptives and tetracycline antibiotics, as well as lithium and vitamin A.[19]
    • Physical exam findings may include papilledema, bradycardia, and visual field deficits.[20]
  •  Hypertensive emergencies
    • Symptoms include headache, changes in vision, nausea and vomiting, confusion, seizure, and oliguria or anuria.
    • History may include pregnancy (preeclampsia/eclampsia), history of hypertension, medication noncompliance, and autonomic dysregulation syndromes, including those secondary to stroke, pheochromocytoma, and neuromuscular diseases.[21]
    • Physical exam findings may include altered mental status, symptoms of heart failure, bradycardia, papilledema, jaundice, and a renal vein bruit.
  • Temporal (giant cell) arteritis
    • Symptoms may include unilateral headache, painless monocular vision loss, jaw claudication, and proximal muscle weakness.
    • History may include older age (greater than 65), polymyalgia rheumatica, and female gender.
    • Physical exam findings may include tenderness along the temporal bone, papilledema, and decreased strength of proximal muscle groups.

Evaluation

When permitted, evaluation of headaches in the emergency department should begin with a thorough history and physical exam. Most headaches can be attributed to primary benign headache subtypes deduced through the primary survey; however, sometimes, further evaluation will be warranted.[22] No single algorithm or clinical decision rule applies to all emergency department patients with headaches. Thus, determining the necessary evaluation requires a sophisticated clinical approach that is evidence-based and hypothesis-driven. 

Laboratory Studies

Routine laboratory testing is typically not helpful in headache diagnosis. However, if a life-threatening cause of headache is suspected, specific tests may be helpful. Female patients with headaches and elevated blood pressure should be screened for pregnancy. Patients with headaches, altered mental status, or focal neurologic deficits require a serum glucose level. A carboxyhemoglobin level should be obtained if there is suspicion of carbon monoxide poisoning.

If there is suspicion of giant cell arteritis (GCA), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) should be obtained. However, if normal and suspicion remain high, patients should be treated for GCA pending temporal artery biopsy results.[23][24][25]

Coagulation studies may be abnormal in patients with suspected cerebral venous thrombosis (CVT). D-dimer may be useful to exclude CVT in low-risk patients (defined as patients with a normal neurologic exam, normal head CT, and absence of risk factors such as current or recent pregnancy), but high-risk patients should proceed to MRV regardless of level.[26][27]

Abnormalities in white blood cell (WBC) levels are associated with infective or inflammatory etiologies but are non-specific.

Radiographic Imaging

The 2019 ACEP clinical policy on headache recommends neuro-imaging in patients with headaches and any new neurologic deficits, new and sudden-onset severe headaches, HIV-positive patients with a new type of headache, and patients greater than 50 with a new headache. This policy is helpful but does not include every scenario where imaging is warranted. Generally, the positive predictive value of pathology on neuroimaging increases with specific parameters.[23] These include:

  • Age greater than 50
  • Recent head trauma
  • Altered mental status
  • Nausea and vomiting
  • Headache is sudden and maximal at onset
  • Papilledema
  • Immunocompromised state
  • Focal neurological deficits
  • Headache is worse in the morning or wakes the patient up from sleep. 

In the subset of patients suspected of an emergent headache, non-contrast head CT is the screening test of choice. However, alternative and/or additional imaging choices should be directed toward the specific emergent diagnosis in question. For example, cerebral CT angiography (CTA) can be useful in identifying nontraumatic subarachnoid hemorrhage, arterial dissections, dural sinus thrombosis, and posterior circulation pathologies.[23] Although dural sinus thrombosis may be seen on non-contrast CT and CTA, the test of choice is MRI and MR venography (MRV) or CT with CT venography if MRI is unavailable.[28] 

Lumbar puncture (LP) and cerebrospinal fluid studies should be considered in some patients with headaches. Indications include fever with altered mental status, meningeal signs, focal neurological deficits, and a history of HIV or another immunocompromised state. Additionally, LP is indicated in a patient whose history and physical exam are suspicious for idiopathic intracranial hypertension, as elevated opening pressure would be diagnostic. Of note, CT is estimated to be negative in up to 5% of patients with subarachnoid hemorrhage; thus, CSF examination for red blood cells or xanthochromia can be useful if the index of suspicion for hemorrhage is high.[23] 

More recent studies have suggested that in patients who arrive within 6 hours of headache onset, CT (without LP) is sufficient to rule out subarachnoid hemorrhage.[29] In suspected increased intracranial pressure, LP should not be performed before CT imaging to rule out asymmetric space-occupying lesions, as reduction of pressure from LP can result in fatal herniation. LP should also not delay antibiotics if suspicious of an infectious process.

Often clinicians will pursue these modalities to avoid missing potentially fatal or debilitating conditions. It is not uncommon for these exams to reveal no abnormalities. Clinicians should use these modalities as tools, along with clinical judgment, to decide if the patient should be further observed and examined or if the next step is to follow up with primary care for possible primary headache syndromes.

Treatment / Management

Treatment of primary headaches in the emergency department should be focused on reducing symptoms and providing supportive care. Often, primary headaches are recurrent, and follow-up with a neurologist or primary care physician should be recommended for preventive and abortive management options. The goal of medical management of headaches centers on achieving fast and long-lasting analgesia with little to no side effects. Headaches are frequently associated with nausea and vomiting, so medications should be administered parenterally when possible. Treatment should also include managing patient expectations. Headache recurrence is common, and patients should understand both what to do for a headache that recurs at home and when to return to the emergency department. 

Medication options with favorable outcomes include:

  • Fluid rehydration
    • IV fluids have not been shown to provide pain relief; however, rehydration is essential in patients with nausea and vomiting who may not be able to tolerate oral intake.[30]
  • Antidopaminergic agents such as prochlorperazine, chlorpromazine, promethazine, and metoclopramide
    • These medications provide both analgesic and antiemetic effects. Extrapyramidal symptoms are a possible side effect of these medications; this can be treated with diphenhydramine, which is often given contemporaneously to metoclopramide.[31]
  • Acetaminophen
    • This medication has been shown to provide good short-term relief, but recurrence rates remain high.[30]
  • NSAIDs such as ibuprofen, ketorolac, naproxen, and diclofenac
    • Excellent analgesic effect. Generally well-tolerated, but caution is necessary for patients at risk of bleeding. These agents inhibit cyclooxygenase, thus reducing platelet function, which could exacerbate bleeding. Side effects of these medications include GI irritation and nephrotoxicity when used over time. 
  • Triptans such as sumatriptan
    • These medications have been shown to provide good long-term relief and are often used to prevent and abort migraine headaches, but their side effect profile causes them to be prescribed primarily in the outpatient setting, where follow-up is more easily facilitated. Side effects of triptans are primarily vascular, including chest pain, shortness of breath, and flushing.[31] Triptans have poor bioavailability when administered enterally; hence IV or subcutaneous administration is preferred. 
  • Corticosteroids such as dexamethasone
    • Steroids have been shown to decrease headache recurrence, particularly for migraines, which have lasted more than 72 hours.[32][33] Steroids may also give some adjunctive analgesia when given with metoclopramide, though they are inadequate when given alone.[34] 

Cluster headaches benefit from high flow oxygen administration.[35][30]

Opiates should be avoided, as they increase ED visit frequency, decrease the efficacy of other medications, and carry a high addiction burden.[31] If a patient specifically requests opiates, abuse and dependence may be a consideration. These patients should have access to counseling and interventions aimed at addressing opiate abuse and addiction. 

Another treatment modality increasingly utilized in the ED is administering a noninvasive intranasal sphenopalatine ganglion nerve block, in which topical local anesthetic is applied intranasally via a long cotton-tipped applicator. In a 2015 trial by Schaffer et al., it was found that patients with an acute headache not attributable to secondary pathology reported at least a 50% reduction in headache severity with the administration of 0.3 mL 0.5% bupivacaine solution compared with placebo.[36] In another trial by Binfalah et al., it was found that 70.9% of patients receiving 2 mL 2% lidocaine solution reported being headache-free after 15 minutes.[37] The emergence of the sphenopalatine nerve block method of analgesia is still somewhat new and controversial. Yet, it appears to be a relatively safe and effective treatment for primary headache conditions as well as facial pain syndromes such as trigeminal neuralgia.

Treatment of a secondary headache depends on identifying and treating the underlying pathology.

Differential Diagnosis

The differential diagnosis for headaches is broad. Additional conditions that can be accompanied by headaches not yet discussed include:

  • Acute sinusitis
  • Otitis media or externa
  • Hydrocephalus
  • Temporomandibular joint syndrome
  • Wisdom tooth impaction
  • Dental cavities
  • Cervical and paraspinal radiculopathies
  • Medication overuse headache
  • Withdrawal
  • Brain malignancy
  • Post-lumbar puncture headache
  • Post-concussive syndrome
  • Viral infection
  • Toxins
  • Vascular malformations
  • Pituitary tumors

Treatment Planning

Table Icon

Table

Table 2. Acute therapy for migraine.

*Adverse effects in this section pertain to all the triptans unless specified

Table Icon

Table

Table 3. Short-term preventive therapy for episodic cluster therapy.

Prognosis

The prognosis of primary headaches is variable and depends on the sub-type. Primary headaches are often recurrent and thus create a heavy medical burden on both emergency medicine and primary care. The prognosis is favorable, as primary headaches do not cause death or permanent disability. Recurrent headaches, however, may be distressing enough to cause temporary disability for some sufferers. A specialist should medically manage such headaches. Remission from chronic headache is possible, and predictors often include withdrawal from analgesic medications, compliance with preventative medications, physical exercise, and stress reduction.[56] 

The prognosis of secondary headaches depends on the underlying pathology. Many causes of secondary headaches are chronic conditions that demand ongoing medical management to reduce symptoms. Some causes of secondary headaches are severely debilitating or even fatal. Medical management in these cases should be aimed at rapid resuscitation, minimizing systemic effects, and maximizing patient comfort to achieve the best outcomes.

Complications

Complications of primary headaches are most often secondary to the temporary loss of normal function that they pose and can include loss of workdays and productivity. One complication of treating chronic primary headaches is medication overuse headache, also known as a rebound headache. This phenomenon occurs when tolerance develops to headache analgesia. In this instance, the headache is no longer responsive to treatment and worsens precipitously when the analgesic is abruptly stopped.[57]

Complications of secondary headache range from mild, temporary disability and discomfort to severe neurologic disability and even death. It is critical for clinicians to consider secondary causes of headaches through a comprehensive primary and secondary survey to ensure that the underlying pathology of a patient’s headache is correctly managed, minimizing complications of late treatment.

Deterrence and Patient Education

For primary headaches, patients should be educated about the benign nature of their condition. Knowing that despite the discomfort, their headache poses no long-term sequelae is often enough to mitigate some of the debilitating effects of the headache. Patients should also be urged to follow up with a specialist if they suffer from recurrent headaches. Such follow-up can offer appropriate preventative or abortive medication options. Further, patients should be encouraged to keep track of their headaches and be mindful of potential triggers, as avoidance of those triggers can ultimately reduce headache burden and improve the quality of life. For some patients, simple lifestyle interventions such as getting adequate sleep and avoiding excessive caffeine may improve chronic headaches.[58][59][60] Patients should also be educated on rebound medication overuse headaches, how they occur, how to avoid them, and how to otherwise manage their headache burden. 

Patients with secondary headaches should be educated about the underlying pathology and how to optimize management to minimize their symptom burden. Further, if a headache is secondary to medical intervention or trauma, patients should know which activities to avoid and for how long, as well as possible "red flags" that should prompt them to seek immediate medical care.

Enhancing Healthcare Team Outcomes

Headache is a common chief complaint in the emergency room. Though the vast majority of cases will require only analgesia and reassurance, the emergency medical team must always be vigilant about identifying the more severe cases. Managing these critical secondary causes of headaches requires an interdisciplinary team of clinicians, nurses, pharmacists, and ancillary staff. The professionals involved will vary depending on the underlying pathology, but most commonly, medical teams will include emergency physicians, neurologists, radiologists, pharmacists, critical care specialists, and neurosurgeons. Communication between nurses and physicians is critical; to monitor response to treatment and immediately note any clinical deterioration. Often, the management of these patients does not end in the emergency department. Effective communication during the handoff between emergency and inpatient teams is essential. Planning and coordination between teams of professionals involved in patient care are essential for favorable healthcare outcomes.[61] [Level 1] 

While clinicians will manage the case both in the ED and after that, nursing will provide support in performing examinations, patient counseling, and serving as coordinators for the interprofessional team. Pharmacists will perform medication reconciliation, verify appropriate dosing, and counsel patients on potential adverse reactions. Any interprofessional team member who notes a change in status or anything that causes concern for the patient's condition or progress must be able to contact other team members as appropriate to ensure the proper interventions or changes can be implemented. This coordinated, interprofessional team approach will optimize outcomes for patients with headaches. [Level 5]

This research was supported in part by HCA Healthcare and/or an HCA Healthcare-affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.

Review Questions

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Disclosure: Leeran Baraness declares no relevant financial relationships with ineligible companies.

Disclosure: Annalee Baker declares no relevant financial relationships with ineligible companies.

Copyright © 2024, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Bookshelf ID: NBK554510PMID: 32119397

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