Jeff: Welcome back to EMplify, the podcast corollary to EB Medicine’s Emergency Medicine Practice. I’m Jeff Nusbaum, and I’m back with my co-host, Nachi Gupta. This month, we’re tackling an incredibly important topic – evaluation and management of life threatening headaches in the Emergency Department.
Nachi: Fear not, this will not simply be “who needs a head CT episode”; we’ll cover much more than that. Listen closely as this is an important topic, with huge consequences for mismanagement.
Jeff: Absolutely. As some quick background – headaches account for 3% of all ED visits in the US, with 90% being benign primary headaches and less than 10% being secondary to other causes like vascular, infectious, or traumatic etiologies. It’s within these later 10% that we are looking for the red flag signs to identify the potentially life-threatening headaches.
Nachi: And to do so, Dr. David Zodda and Dr. Amit Gupta, PD and APD at Hackensack University Medical and Trauma Center, and their colleague Dr. Gabrielle Procopio, a PharmD, have done a fantastic job parsing through the literature, which included over 500 abstracts, 89 full text articles, guidelines from ACEP and the American Academy of Neurology, as well as canadian and european neurology guidelines, to summarize the best evidence based recommendations for you all.
Jeff: We would be remiss to not also mention Dr. Mert Erogul of Maimonides Medical Center and Dr. Steven Godwin, Chair of Emergency Medicine at the University of Florida College of Medicine.
Nachi: Alright, so let’s get started with some definitions and pathophysiology. The international classification of headache disorders 3, or ICHD-3, classifies headaches into primary, secondary, and cranial neuropathies.
Jeff: Primary headache disorders include migraine, tension, and cluster headaches. Secondary headaches include those secondary to vascular disorders, traumatic disorders, and disorders in hemostasis. These are the potentially life threatening headaches that can have a mortality has high as 50%.
Nachi: And the final category includes cranial neuropathies, such as trigeminal neuralgia.
Jeff: And I think we can safely say that that wraps up our discussion in this episode on cranial neuropathies, moving on….
Nachi: Headaches result from traction to or irritation of the meninges and blood vessels, which are the only innervated central nervous system structures. Activation of specific nerve ganglion complexes by neuropeptides like — substance P and calcitonin gene-related peptide — are thought to contribute to head pain.
Jeff: It is important to note that all headache pain shares common pain pathways, thus response to pain medications does not exclude potential life threatening secondary causes of headache. This led to the ACEP guideline which states just that..
Nachi: I feel like that deserves ding sound as it’s a critically important point. To repeat, just because a pain medication relieves a headache, that does not exclude dangerous secondary causes!
Jeff: And what are the life threatening headaches? Life-threatening headaches include subarachnoid hemorrhage, cervical Artery Dissection, which includes both vertebral Artery Dissection and carotid artery dissection, cerebral Venous Thrombosis, idiopathic intracranial hypertension, giant cell arteritis, and posterior reversible encephalopathy syndrome, or PRES.
Nachi: Slow down for a second and let’s not skip over your favorite section.. Let’s talk pre hospital care for headache patients.
Jeff: Good call! Pre-hospital care is fairly straightforward and includes a primary survey, conducting a focused neurologic exam, and assessing for red flag signs, which include focal neurologic deficits, sudden onset headache, new headache in those over 50, neck pain or stiffness, changes in visual Acuity, fever or immunocompromised State, history of malignancy, pregnancy or postpartum status, syncope, and seizure. That’s quite a list. For a visual reference, see Table 3 in the print issue.
Nachi: And patients with neurologic deficits or severe sudden-onset headaches, should be transported immediately to the nearest available stroke center. Tylenol should be offered for pain management. Avoid opioids and nsaids.
Jeff: Upon arrival to the emergency department, history and physical should include your standard vitals, testing neurologic function, cranial nerve testing, head and neck exam, as well as a fundoscopic exam. As was the case for your pre-hospital colleagues, you should also assess for red flag signs for life-threatening headaches. Check out tables 2, 3, and 4 for more details here.
Nachi: With respect to Vital Signs, in the setting of an acute headache, severe hypertension should prompt a search for signs of end-organ damage such as hypertensive encephalopathy, intracranial Hemorrhage, PRES, and preeclampsia in pregnant women. Additionally, fever, and especially fever and neck stiffness, should raise concern for CNS infection.
Jeff: For your neurologic examination, make sure to include assessments of motor strength, coordination, reflexes, sensory function, and gait. Don’t forget that lesions involving the anterior circulation, such as dysarthria, cognitive impairment, and Horner syndrome may be indicative of a carotid artery dissection, whereas dizziness, vision changes, and limb weakness may be due to a vertebral Artery Dissection.
Nachi: And for cranial nerve testing – pay particular attention to cranial nerves 2, 3 and 6. For cranial nerve 2 – look out for an afferent pupillary defect, or a marcus-gunn pupil, which is seen in optic neuritis, giant cell artertitis, and central retinal artery occlusion. For CN3, oculomotor nerve palsies raise concern for a posterior communicating aneurysm and SAH. And lastly, CN6 palsies, which often presents with diplopia on lateral gaze , are often seen with intracranial idiopathic hypertension and cerebral venous thrombosis, in addition to impaired visual acuity, visual field defects, and tunnel vision.
Jeff: For the head and neck exam, remember that a partial horner syndrome, with miosis and ptosis without anhidrosis, may be indicative of a cervical artery dissection. Unfortunately, if the patient presents acutely, their only complaint may be pain, as the neurologic sequelae may take days to develop.
Nachi: Additionally, with respect to the head and neck exam, evaluate the patient for tenderness and beading along the temporal artery.
Jeff: One review noted that temporal artery beading actually had the highest likelihood ratio for GCA, 4.6, whereas temporal artery tenderness only had a LR of 2.6
Nachi: And the last physical exam maneuver you should ideally perform is a fundoscopic exam for papilledema, which is often seen in IIH, malignant hypertension, and CVT.
Jeff: Perfect so that rounds out the physical, next we have diagnostic studies. Most importantly, routine lab testing is typically of low utility in aiding in the diagnosis of headache.
Nachi: Even ESR and CRP in the setting of possible giant cell arteritis have poor sensitivity and specificity to diagnose it. So even if the ESR and CRP are negative, if the suspicion for GCA is high enough, it should be treated and you should get a biopsy.
Jeff: Do consider adding on a venous or arterial carboxyhemoglobin in the right clinical scenario, as CO poisoning represents an important cause of headache you wouldn’t want to miss. This is especially important at this time of year when heating systems are working overtime here in the states.
Nachi: And hopefully you have a co-oximeter, so you can even check this non-invasively.
Jeff: Interestingly, there may be a unique role for a d-dimer here as well. Several small studies have used the d-dimer to risk stratify patients with possible CVT. In one study a d-dimer level < 500 mcg/L had a 97% sensitivity and a negative predictive value of 99% – not bad!
Nachi: Pretty impressive performance characteristics. I think that about wraps up lab work. Let’s talk radiology.
Jeff: Though low yield, CT utilization is estimated at 2.5-10% of non-traumatic headaches. A non-con CT should be reserved for those with suspicion for an intracranial hemorrhage, while a contrast CT would be required in those in whom there is concern for an infectious process or space occupying lesion.
Nachi: CT angio or MRI should be used in cases of possible cervical artery dissection. MRI also is the neuroimaging of choice for PRES, which is more sensitive for cerebral edema than CT.
Jeff: Similarly, MRV is recommended in those with a concerning story for CVT.
Nachi: To help guide your emergent neuroimaging utilization, ACEP suggests imaging in those with headache and an abnormal finding on neuro exam, those with new and sudden-onset severe headache, HIV positive patients with new headache, and those over 50 with a new headache.
Jeff: With that in mind, let’s dive a bit deeper into the use of CT for SAH, a topic which doesn’t get a ding sound, but is certainly critically important. Recent literature have found that a CT within 6 hours of symptom onset has a sensitivity and specificity and negative predictive value of 100%. In addition, one 2016 study demonstrated a LR of 0.01 in those with a negative HCT within 6 hours. These are really important results because that means SAH is essentially ruled out with a negative study.
Nachi: Unfortunately, the 2008 ACEP guideline and 2012 AHA guidelines still recommend a lumbar puncture in those being worked up for SAH. Luckily the ACEP guideline is currently being revised so your decision to forego the LP with a negative HCT in the first 6 hours will likely also be backed by ACEP in the near future.
Jeff: That’s a nice transition into our next test – the LP. Since LP carries a risk of herniation, in those with signs of increased ICP, make sure to get appropriate neuroimaging before attempting the puncture. In those without signs of increased ICP, no imaging is necessary.
Nachi: While the position in which the LP is performed doesn’t matter as much when ruling out infection or SAH, in those with suspected IIH, make sure to obtain an opening pressure with the patient lying in the lateral decubitus position. An opening pressure of greater than 25 is often seen in IIH.
Jeff: And the LP in the setting of IIH is not only diagnostic but also potentially therapeutic, as the removal of 1 ml of CSF can lower the pressure by 1 cm of H20 and potentially relieve the patient’s symptoms.
Nachi: Always rewarding to diagnose and treat simultaneously…
Jeff: Absolutely. But back to the LP for SAH for a second or two. When evaluating for a subarachnoid hemorrhage, you’ll often note an opening pressure of greater than 20 with persistent RBC in all tubes.
Nachi: While there are no RBC cutoffs, one study found no patients with a SAH with less than 100 RBC in the final tube. In contrast, greater than 10,000 RBC increased the odds by a factor of 6. In addition, one 2015 study found that patients without xanthrochromia and less than 2000 RBC were effectively ruled out of having a SAH with a combined sensitivity of 100%
Jeff: Lots of 100% sensitivities and specificities being thrown around today, which is definitely not the norm. No complaints here, I’ll take it. Anyway, the last test to discuss is our good friend the ultrasound, specifically the ocular ultrasound.
Nachi: Examining the optic nerve sheath 3 mm posterior to the globe, an optic nerve sheath diameter of 5 mm or greater is predictive of an ICP greater than 20.
Jeff: Keep in mind that this may expedite the work up, though a normal diameter does not rule out increased ICP, so a head CT may still be indicated.
Nachi: Alright, so we’ve talked a lot about testing, both lab and imaging, and we’ve mentioned a bunch of pathologies, but let’s spend a few minutes going over the specifics of each.
Jeff: Let’s start with SAH. SAH account for 1% of all headache visits to the ED. Most nontraumatic SAH are caused by aneurysm rupture. A missed diagnosis of SAH can have a case-fatality rate as high as 50%
Nachi: Although 75% of SAH patients report an abrupt onset, objective neck stiffness has the highest likelihood ratio of 6.6. Other important features include LOC, neurologic deficit, subjective neck stiffness, photophobia, and onset during exertion or intercourse.
Jeff: Additionally, approximately 20% of patients with a SAH have warning signs of a sentinel bleed including headaches, cranial nerve palsies, neck pain, or nausea and vomiting.
Nachi: In order to aid you in diagnosing a SAH, you should consider the ottawa SAH Rule which has a 100% sensitivity and a 15% specificity. To use this rule you must be between 15 and 40 with a GCS of 15 and present with a headache with maximal intensity within 1 hour of onset. If you meet those inclusion criteria, and you have no neurologic deficits, no neck pain or stiffness, no witnessed LOC, no onset during exertion, no limitation of neck flexion, and no thunderclap onset, you can essentially rule out a SAH.
Jeff: While the ottawa SAH rule has been prospectively validated, know that this study has been challenged for its interobserver variability, but in any case it still provides helpful red flags to consider. If your patient is found to have a SAH, a CT angiogram and neurosurgical consultation should be considered immediately.
Nachi: In addition to monitoring ABCs, early care involves the administration of analgesics and anti-emetics. Also consider elevating the head of the bed to 30 deg, which may also improve venous drainage and decrease ICP.
Jeff: In terms of BP management, guidelines from the american stroke association recommend targeting a SBP of 160 with a titratable agent like nicardipine or clevidipine.
Nachi: In addition, nimodipine, 60 mg q4h, should be given to those with aneurysmal SAH to improve outcomes.
Jeff: and any role for anti-epileptics?
Nachi: That’s controversial and the authors state it may be considered in the immediate post-hemorrhagic period and should be limited to a 3-7 day course with longer courses required in special populations.
Jeff: The next pathology to discuss is cervical artery dissections, which account for 2% of all strokes and nearly 20% of strokes in those 50 and under. cervical artery dissections are most commonly due to trauma, but can occur spontaneously.
Nachi: Risk factors include Ehlers-Danlos syndrome, osteogenesis imperfecta, and Marfan syndrome.
Jeff: Regardless of the etiology, the management of cervical artery dissections is primarily medical with IV heparin followed by warfarin or a direct oral anticoagulant in those with extracranial dissections, and antiplatelet therapy like aspirin or clopidogrel in those with intracranial dissections.
Nachi: Thanks to the CADISP study, we know there is no difference in mortality or neurologic outcome when choosing between antiplatelet therapy and anticoagulation.
Jeff: Next we have cerebral venous thrombosis. This typically presents with a gradual onset headache. Though it can happen to anybody, cerebral venous thrombosis typically results from thrombotic disease.
Nachi: Important risk factors include oral contraceptive use, pregnancy and postpartum states, Factor V Leiden deficiency, and lupus.
Jeff: Treatment for CVT is controversial due to a high risk of hemorrhage and hemorrhagic transformation. According to the best available evidence, anticoagulation is the standard therapy with full dose anticoagulation of low-molecular weight heparin or heparin as a bridge to warfarin.
Nachi: Yeah, it’s really a tough spot to be in as one third end up having some form of hemorrhage too….
Jeff: Perhaps yet another good place for shared decision making?
Nachi: Honestly, it’s a good thought, but anticoagulation is the guideline recommendation, so I think that is likely the best route in this case.
Jeff: Great point. Next we have idiopathic intracranial hypertension. This is typically associated with obese women of childbearing age. It may also be due to hypervitaminosis A from excessive dietary intake and even drugs like the retinoids used in treating dermatologic conditions and cancers.
Nachi: idiopathic intracranial hypertension can be diagnosed by the modified dandy criteria which are found in table 8 on page 11. Let’s just run through the criteria.
Jeff: The modified Dandy criteria for idiopathic intracranial hypertension include: signs and symptoms of increased ICP, no other neurologic abnormalities or altered level of consciousness, ICP > 20 on LP with normal CSF composition, neuroimaging without another etiology for intracranial hypertension, and lastly no other identified cause of intracranial hypertension.
Nachi: And as we mentioned a few minutes ago, an LP can be both diagnostic and therapeutic, though the relief is likely temporary
Jeff: For more permanent treatment, weight loss is the key. Acetazolamide, 250 mg to 500 BID is the first line pharmacotherapy. Combined with weight loss, acetazolamide and a low sodium diet has been shown to improve visual field function.
Nachi: And if this fails, topiramate, furosemide, and in the worst case surgical options like CSF shunting, venous sinus stenting, and optic sheath fenestration are all options.
Jeff: I imagine taking a diuretic for a headache could be a real hindrance on quality of life, though I suppose it’s better than risking vision loss or having a significant neurosurgery.
Nachi: Agreed. Next we have giant cell arteritis. GCA is rare, with a prevalence of <1%. It is 3x more likely in women and is really a disease of those older than 50.
Jeff: Common features include fever, fatigue, myalgias, headache, jaw claudication, and visual symptoms like diplopia and amaurosis fugax. Treatment should be started in anyone in whom you are highly suspicious.
Nachi: And the treatment of choice is high-dose methylprednisolone 15 mg/kg/day for 1-3 days followed by prednisone 40 mg/day. Of course, don’t wait the biopsy to begin treatment if concerned.
Jeff: That’s quite a bit of steroids….
Nachi: It is! But again, better than the alternatives. Next up we have PRES. PRES is a form of hypertensive emergency in which severe hypertension leads to cerebral autoregulatory failure, vasodilation, interstitial extravasation of fluid, and brain vasogenic edema.
Jeff: PRES is commonly associated with hypertensive encephalopathy, eclampsia, and using immunosuppressive agents.
Nachi: PRES usually manifests with an acute onset headache in the setting of elevated BP and altered level of consciousness. Seizures are very common as well.
Jeff: PRES should be treated with blood pressure control with your agent of choice, though nicardipine is often preferred, with the goal of reducing the MAP by 25% within the first hour. If it were caused by a medication such as an immunosuppressive, medication cessation will also be imperative.
Nachi: While we’re on the topic of BP control, I should also mention two trials, INTERACT-2 and ATACH-2. Results from these trials showed that BP control didn’t appear to impact rates of death or disability, but it was associated with improved functional outcomes. Therefore, current guidelines recommend lowering SBP to 140 in the setting of an ICH.
Jeff: We’ve mentioned quite a few BP goals here, but if you can’t remember, start nicardipine to begin lowering the MAP in a controlled and titratable manner.
Nachi: The next pathology we haven’t talked about yet, but it certainly is worth discussing – acute angle closure glaucoma.
Jeff: Most commonly found in the elderly or hyperoptic patients, acute angle closure glaucoma presents with headache, pain, redness, tearing, photophobia, nausea and vomiting, blurred vision, and seeing halos in the setting of a rapid rise in intraocular pressure above the normal 10-21.
Nachi: If untreated, this can lead to fairly rapid vision loss, so initiating treatment with timolol, pilocarpine, and apraclonidine is imperative..
Jeff: And the last pathology to discuss is pre-eclampsia.
Nachi: Preeclampsia is defined as hypertension with a systolic bp greater than 140 or a diastolic greater than 90 for 2 readings 4 hours apart, or a systolic greater than 160 or a diastolic greater than 110 for one reading with either proteinuria, thrombocytopenia, liver impairment, renal insufficiency, pulmonary edema and a new-onset headache in a woman who is greater than 20 weeks gestation to 4 weeks postpartum.
Jeff: Treat severe preeclampsia, that is preeclampsia with thrombocytopenia, liver impairment, renal insufficiency, pulmonary edema, or new headache with IV magnesium, a 4-6 grams load over 15-20 minutes followed by an infusion of 1-2 g/h. If the patient simply has hypertension and proteinuria, you may skip the magnesium and only use anti-hypertensives, such has labetalol, hydralazine, or nifedipine. And with that, I think we’ve covered all the big secondary causes of headache. Let’s talk disposition.
Nachi: Pretty straight forward. Nearly all patients diagnosed with a severe, life-threatening headache will require admission or transfer to a facility with access to a 24-hour neurology critical care team.
Jeff: Often such patients will end up in the ICU, so make sure to get the ball rolling early as delays have been shown to increase rates of morbidity and mortality.
Nachi: Let’s wrap up this episode with a quick review of key points and clinical pearls.
- 1. Headaches account for 3% of all ED visits, with 90% being benign primary headaches.
- 2. The most common life-threatening causes of headaches are subarachnoid hemorrhage (SAH), cervical artery dissection (CAD), cerebral venous thrombosis (CVT), idiopathic intracranial hypertension (IIH), giant cell arteritis (GCA), and posterior reversible encephalopathy syndrome (PRES).
- 3. SAH accounts for 1% of all headaches and is commonly caused by aneurysm rupture. 75% present with abrupt onset. Nimodipine should be administered to those with aneurysmal SAH to improve outcomes. The use of prophylactic antiepileptic drugs is controversial.
- 4. CAD accounts for 2% of all strokes and is commonly associated with trauma and connective tissue disorders. Treat with IV heparin followed by warfarin or a direct oral anticoagulant in those with extracranial dissections, and treat with aspirin or clopidogrel in those with intracranial dissections
- 5. CVT presents as a gradual-onset headache which is often the result of thrombotic disease and spreading facial infections. Current recommendations for the treatment of CVT include low-molecular weight heparin or heparin as a bridge to warfarin. Consider broad-spectrum antibiotics if an infectious etiology is suspected.
- 6. IIH is associated with obese women of childbearing age as well as hypervitaminosis A. Lumbar puncture is both diagnostic and therapeutic for IIH. The LP should be performed in the lateral decubitus position to measure opening pressures, which will be greater than or equal to 25. Acetazolamide is a first-line pharmacotherapy.
- 7. GCA is more common in woman and is almost exclusively found in patients older than 50. Common features include fever, fatigue, myalgias, jaw claudication, and visual symptoms. Polymyalgia rheumatica is present in more than half of all cases. Treat with steroids.
- 8. PRES is a form of hypertensive emergency due to cerebral autoregulatory failure, vasodilatation, interstitial extravasation of fluid, and vasogenic brain edema. PRES is treated with blood pressure control, typically with nicardipine or labetalol.
- 9. When treating hypertensive emergencies, aim for a 25% reduction in MAP in the first hour.
- 10. Based on data from the INTERACT-2 and ATACH-2 trials, for patients with ICH, lowering SBP to <140 is safe. This, however, does not impact death or disability, but it is associated with improved functional outcomes.
- 11. For patients with an aneurysmal SAH, target an SBP of 160 using nicardipine or clevidipine.
- 12. Pre-eclampsia is defined as elevated blood pressure with proteinuria or other severe symptoms after 20 weeks’ gestation. Treat with 4-6 g of magnesium as a loading dose, followed by 1-2g/h as maintenance in addition to antihypertensives.
- 13. Acute angle closure glaucoma is found most commonly in the elderly. It presents with headache, pain, redness, tearing, photophobia, nausea, blurred vision, and vision loss. Treat with timolol, pilocarpine, and apraclonidine while awaiting an ophthalmology consult.
- 1. Routine laboratory testing in the setting of a headache is generally of low utility. ESR and CRP are poor screening tests for GCA. Biopsies should be obtained in those with high suspicion for GCA after treatment has already begun.
- 2. Consider a d-dimer in low risk patients to exclude CVT.
- 3. Non-contrast and contrast head CT should be reserved for those suspected of having acute intracranial hemorrhage and space occupying lesions. MRV is the test of choice for concern of CVT.
- 4. A non-contrast head CT performed within 6 hours of onset of headache is adequate to rule out SAH. A lumbar puncture looking at RBC and xanthochromia will be required if outside of this window. Utilize shared decision making to determine an appropriate testing and treatment plan.
- 5. Ocular ultrasound can expedite the diagnosis and management of ocular emergencies and rapidly diagnose ICP by measuring optic sheath diameter. Optic nerve sheath diameter greater than 5 mm is predictive of an intracranial pressure > 20.
Jeff: So that wraps up episode 25 – Evaluation and Management of Life-Threatening Headaches in the Emergency Department .
Nachi: Additional materials are available on our website for Emergency Medicine Practice subscribers. If you’re not a subscriber, consider joining today. You can find out more at www.ebmedicine.net/subscribe. Subscribers get in-depth articles on hundreds of emergency medicine topics, concise summaries of the articles, calculators and risk scores, and CME credit. You’ll also get enhanced access to the podcast, including the images and tables mentioned. You can find everything you need to know at ebmedicine.net/subscribe.
Jeff: It’s also worth mentioning for current subscribers that the website has just undergone a major rehaul and update. The new site is easier to use on mobile browsers, has better search functionality, mobile-friendly CME testing, and quick access to the digest and podcast.
Nachi: And the address for this month’s credit is ebmedicine.net/E0219, so head over there to get your CME credit. As always, the you heard throughout the episode corresponds to the answers to the CME questions. Lastly, be sure to find us on iTunes and rate us or leave comments there. You can also email us directly at EMplify@ebmedicine.net with any comments or suggestions. Talk to you next month!
Most Important References
1.* Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1- 211. (Clinical guideline)
7.* Edlow JA, Panagos PD, Godwin SA, et al. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute headache. Ann Emerg Med. 2008;52(4):407-436. (Clinical policy)
15.* Carpenter CR, Hussain AM, Ward MJ, et al. Spontaneous subarachnoid hemorrhage: a systematic review and meta-analysis describing the diagnostic accuracy of history, physical examination, imaging, and lumbar puncture with an exploration of test thresholds. Acad Emerg Med. 2016;23(9):963-1003. (Meta-analysis; 22 studies)
54.* Perry JJ, Stiell IG, Sivilotti ML, et al. Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid hemorrhage: prospective cohort study. BMJ. 2011;343:d4277. (Prospective; 3132 patients)
65.* Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368(25):2355-2365. (Prospective; 2794 patients)
87.* ACOG Task Force on Hypertension and Pregnancy. Hypertension in pregnancy. American College of Obstetricians and Gynecologists. Available at:www.acog.org/~/media/Task%20Force%20and%20Work%20Group%20Reports/public/HypertensioninPregnancy.pdf. Accessed January 10, 2019. (Expert/guideline recommendations)
Last Updated on April 29, 2022