All posts by Drew A. Long

Thunderclap Headache – Pearls and Pitfalls

Authors: Drew A. Long, BS (@drewlong2232, Vanderbilt University School of Medicine) and Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

You are working in the ED and see that your next patient is a 38 y/o female complaining of headache.  As soon as you enter the room, you notice the patient appears to be in pain, holding her hand to her left temple and wincing.  She states she was going on a run about an hour earlier when she experienced a 10/10 intensity headache.  When you ask about the onset of the headache, she states “One moment I was running, and suddenly I was bent over in pain.”  She also complains of dizziness, nausea, and tingling and numbness of her left hand and foot.  The patient has no history of headaches and no pertinent past medical history.  She recently gave birth 6 weeks prior via spontaneous vaginal delivery.  Her vitals include HR 110, RR 16, BP 173/100, oxygen saturation of 98%, and a normal temperature.  As you gather the rest of the history and move to the physical examination, what must you consider in this patient?

What is a thunderclap headache?

A thunderclap headache (TCH) has been defined as a “headache that reaches 7 (out of 10) or more in intensity within less than one minute.”1 TCH is often unexpected and not preceded by any warning signs or symptoms.  While the duration and location of the headache are important parts of the history, they do not have a role in defining TCH and are nonspecific for TCH.1 When evaluating a patient with a headache, it is vital the Emergency Physician (EP) determine both the intensity and time it took the headache to reach maximum severity.  The EP must keep in mind that a normal neurological exam and absence of any associated symptoms does not exclude a serious cause in a patient with a TCH, and the patient still requires a diagnostic workup for potentially deadly pathologic conditions.1 Additionally, pain relief with treatment does not exclude a serious cause.2-4

The classic teaching in medical school is that a “thunderclap” headache is pathognomonic for subarachnoid hemorrhage (SAH) from a ruptured intracranial aneurysm.  However, only 11-25% of TCHs are due to SAH.5,6 What else should the EP think of when a patient presents with a TCH?

Differential Diagnosis

Table 1 depicts conditions that may manifest as a TCH.1,7,8

Subarachnoid Hemorrhage
Cerebral Venous Thrombosis
Cervical Artery Dissection
Acute Hypertensive Crisis/

Posterior Reversible Encephalopathy Syndrome

Ischemic Stroke
Intracranial Hypotension
Pituitary Apoplexy
Retroclival Hematoma
Third Ventricle Colloid Cyst
Temporal Arteritis
Reversible Cerebral Vasoconstriction Syndrome

Subarachnoid Hemorrhage

Most cases of SAH occur from a ruptured cerebral aneurysm (about 85% of cases), which occur most commonly at branch points in the Circle of Willis.9 The typical presentation of SAH is a sudden, severe headache that the patient describes as “the worst headache of my life.”  A headache will be the primary symptom of SAH in 70% of patients, of which 50% will present with a TCH.6,10-12 The headache usually lasts for several days and very rarely resolves within a few hours.13 Accompanying signs and symptoms include loss of consciousness (one third of patients), seizures (6-9%), delirium (16%), stroke, visual disturbances, N/V, dizziness, neck stiffness, and photophobia.14-16

As TCH is a common presentation of a SAH, any patient that presents with TCH must be evaluated for SAH due to high morbidity and mortality.  According to literature, the average fatality rate of SAH is 51%.17 About 10% of patients with aneurysmal SAH die prior to hospital arrival, 25% die within the first 24 hours of SAH onset, and 45% die within 30 days.18

In evaluating for SAH it is helpful to consider a sentinel headache.  A sentinel headache is a headache that occurs days or weeks prior to a ruptured cerebral aneurysm.  This is thought to arise from a small leak of blood into the subarachnoid space.8 About 10-43% of patients with aneurysmal SAH report a prior similar warning headache.19 Importantly, signs often accompanying SAH, such as a stiff neck, altered mental status, and focal neurological deficits, are usually absent in a sentinel headache.7 However, even if these signs are absent the patient still requires evaluation for a SAH.  For more on evaluation of SAH, see

Cerebral Venous Thrombosis

A headache occurs in 75-95% of patients with cerebral venous thrombosis (CVT).20,21 While the onset of headache in CVT is usually gradual, about 2-13% of patients experience a TCH as the primary symptom.22 Additionally, patients may experience accompanying neurological symptoms from several vascular territories.  Other signs and symptoms include seizures (more commonly focal), papilledema, altered mental status, and focal neurological deficits.7,8 The symptoms can be associated with thrombus location.23,24 Importantly, patients with CVT presenting with TCH as their main symptom are clinically indistinguishable from patients with SAH presenting with TCH.7

While CVT is a relatively rare disorder, 80% of patients with CVT are younger than 50.23,25,26 CVT is more common in women, especially in the peripartum period and in patients with recent surgery.27 CVT is also associated with hypercoagulable states including the use of oral contraceptives, hematologic disorders, factor V Leiden, protein C or S deficiency, and anti-thrombin III deficiency.25,28

For more information about CVT, check out a previous post here:

Cervical Artery Dissection

A cervical artery dissection can result in an ischemic stroke, transient ischemic attack, or more rarely a SAH.8 Carotid or vertebral artery dissections are an especially important cause of strokes to consider in young and middle aged patients.29-32 A significant risk factor is a history of neck trauma, which can be minor (e.g. manipulation therapy of the neck or sports-related trauma).33 Other risk factors include connective tissue disease, large vessel arteriopathies, hypertension, and a history of migraines.34-36

Headaches are reported in 60-95% of patients with carotid artery dissections and 70% of patients with vertebral artery dissections.36 While headache onset is typically gradual, TCH occurs in about 20% of patients with a cervical artery dissection.38,39 According to the International Headache Society’s diagnostic criteria, headaches from cervical artery dissection must be ipsilateral to the dissected artery.40 The typical first symptom of a cervical artery dissection is unilateral headache (68%), neck pain (39%), or facial pain (10%).41 The headache from a carotid artery dissection is found most commonly in the frontotemporal region.42 Additionally, about 25% of patients will experience a partial Horner’s syndrome (miosis and ptosis).43 A vertebral artery dissection presents with neck pain (66%) and headache (65%), which can be unilateral or bilateral.44 The headache is more commonly posterior in location.  Many other symptoms may be present, including facial paresthesia, dizziness, vertigo, nausea/vomiting, visual disturbances (such as diplopia), ataxia, limb weakness or numbness, dysarthria, and hearing loss.42

Acute Hypertensive Crisis/Posterior Reversible Encephalopathy Syndrome

Two case reports describe patients who presented with TCH from either a hypertensive crisis or posterior reversible encephalopathy syndrome (PRES).45,46 In a hypertensive emergency, while the diastolic pressure is often ≥ 120 mmHg, there is no specific threshold, as different patients will manifest signs of end-organ damage at varying blood pressures.47 While about 20% of patients with hypertensive crises have associated headaches, most of these are not a TCH but rather a throbbing headache.48 Additionally, a hypertensive crisis may present with symptoms in addition to headache consistent with end-organ damage.  These may include dizziness, dyspnea, vision change, chest pain, psychomotor agitation, change in urine output, fluid overload state, or focal neurological deficits.8

Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome with radiographic findings that presents with headache, seizures, and visual loss often with extreme hypertension.49 Other symptoms include nausea/vomiting, focal neurological signs, or altered mental status.49,50 Specific radiographic findings are necessary for the diagnosis, most commonly symmetric white matter edema in the posterior cerebral hemispheres.51 The headache associated with PRES generally has an acute onset.7 PRES may occur in conjunction with other disorders including eclampsia, thrombotic thrombocytopenic purpura or hemolytic uremic syndrome, and immunosuppressive therapy.52

It is important to determine whether a patient with TCH is hypertensive due to a stress response to the severe headache or if the TCH is the result of the hypertension.  In patients with TCH and extreme hypertension, it is vital to evaluate for signs of end-organ damage suggesting an acute hypertensive crisis and to consider PRES in patients presenting with headache, seizures, and visual loss.

Ischemic Stroke

About 25-34% of patients with stroke develop an associated headache.53,54 In 50% of these patients, the headache precedes any other neurological signs or symptoms.54 Typically, the headache is throbbing and ipsilateral to the side of the stroke.54  TCH associated with stroke is rare, but several case reports document patients presenting with TCH due to stroke.5,55,56

Spontaneous Intracranial Hypotension

The most common cause of spontaneous intracranial hypotension is CSF leakage from spinal meningeal defects or dural tears.57 This most commonly occurs after lumbar puncture, but can occur from minor trauma such as falls, lifting, coughing, or sports.1,7 Most commonly intracranial hypotension presents with a positional headache that improves after lying down and worsens when upright.58 However, 15% of patients will present with TCH.59,60  Other symptoms associated with spontaneous intracranial hypotension are nausea/vomiting, dizziness, auditory changes, diplopia, visual blurring, interscapular pain, or upper extremity pain.7,8


Meningitis can very rarely present with TCH.  A prospective study of patients presenting with TCH found 2.7% to have an infectious etiology.6 Consider meningitis if the patient is febrile, at increased risk for infection (immunocompromised), or has features of meningitis (e.g. stiff neck).

Pituitary Apoplexy

Pituitary apoplexy occurs with hemorrhage or infarction of the pituitary gland.1,7,8 This most commonly occurs in the setting of a pituitary adenoma, but may occur in association with pregnancy, general anesthesia, bromocriptine therapy, or pituitary irradiation.61 Pituitary apoplexy usually presents with a combination of acute headache, ophthalmoplegia, decreased visual acuity, reduction in visual fields, and altered mental status.62 The headache is usually sudden and severe.62

Retroclival hematoma

A retroclival hematoma is usually seen as a rare manifestation of severe head and neck injuries in which there is atlantoaxial dislocation.63,64 Patients with retroclival hematomas may present with TCH, which has been described in several patients.65,66

Third Ventricle Colloid Cyst

A colloid cyst of the third ventricle can impede the flow of CSF leading to obstructive hydrocephalus.  Third ventricle colloid cysts account for 0.5% of intracranial tumors and are most commonly diagnosed between the third and fifth decades of life.67 The most common symptom is headache, which occurs in 68-100% of patients.68 The headache of a third ventricle colloid cyst usually begins abruptly, lasts for seconds up to one day, and resolves quickly.69 The headache may be relieved with a supine position. Additionally, 50% of patients have associated nausea/vomiting.  They can also experience loss of consciousness, altered mental status, seizures, coma, or death.68

Temporal Arteritis

Temporal arteritis is a very rare cause of TCH.  Temporal arteritis should be suspected in older patients (>50) complaining of a new onset headache, temporal pain, visual symptoms, or jaw claudication.  It is also associated with polymyalgia rheumatica, which occurs in 40-50 percent of patients with temporal arteritis.70 For more information on temporal arteritis, check out this previous post:

Reversible Cerebral Vasoconstriction Syndrome

Reversible Cerebral Vasoconstriction Syndrome (RCVS) includes conditions associated with TCH and diffuse, segmental, reversible vasospasm.71,72 RCVS is thought to account for most cases of TCH that are termed “benign,” or unexplained.1 Risk factors for RCSV include the postpartum period, history of migraine, and use of pharmacologic agents including ergotamine, triptans, SSRIs, pseudoephedrine, cocaine, amphetamines, ecstasy, cannabis, and bromocriptine.73-81 Half of RCVS cases occur during the postpartum period or after exposure to serotoninergic agents, adrenergic agents, or cannabis.81-83

The hallmark of RCVS is multiple thunderclap headaches that recur every day or every few days.  These headache recurrences can occur for up to four weeks.72,81 Other symptoms include altered mental status, motor or sensory deficits, seizures, visual changes, ataxia, speech abnormalities, and N/V.7

While RCVS is usually self-limiting, it is not always benign.  A minority of patients can experience residual effects including seizures or strokes.72,82,84

Other causes of TCH

Other conditions that have been reported in association with TCH include complicated sinusitis; cluster headache; primary cough, exertional, and sexual headaches; and primary TCH.1,7,8


What is the workup of TCH?

Every patient with TCH must be assumed to have a life-threatening intracranial condition.  Management of patients presenting with TCH starts with the ABCs.  Once the patient is stabilized, diagnostic evaluation is initiated beginning with specific evaluation for SAH.  Schwedt, Matharu, and Dodick proposed an algorithm for TCH evaluation in 2005, beginning with head CT:7


Figure 1.  Diagnostic Evaluation of TCH.7 (CVST:  cerebral venous sinus thrombosis; SIH:  spontaneous intracranial hypotension; PRES:  posterior reversible encephalopathy syndrome; RCVS:  reversible cerebral vasoconstriction syndrome)

The initial imaging modality is a noncontrast head CT.  CT scan has a high sensitivity and specificity for SAH.  When conducted within 6 hours of onset of TCH, CT has a specificity of 98% and sensitivity nearing 100%.11 As time from headache onset increases, the sensitivity of CT for SAH declines:  86% on day two, 76% after two days, and 58% after five days.85 However, these numbers are based on head CTs interpreted by neuroradiologists, and the scanners utilized were at least third generation.

Unfortunately, CT can miss many causes of TCH including SAH (especially if after 12 hours), CVT, CVA dissection, acute hypertensive crisis/PRES, intracranial hypotension, meningitis, pituitary apoplexy, and retroclival hematoma.  For CVT, the initial CT may be normal in up to 25-30% of patients.86 In a patient with CVA dissection without an ischemic stroke, head CT is usually normal.1,7 Similarly, CT is typically unrevealing in patients with acute hypertensive crisis, intracranial hypotension, meningitis, pituitary apoplexy, and retroclival hematoma.1,7,8 For patients with an acute hypertensive crisis or PRES, while neuroradiographic changes may be apparent on CT, they are best visualized on MRI.87,88

Some authors recommend always performing a CTA or MRA after negative CT noncontrast.1,7,72,89 If the patient has a SAH, a CTA can detect a ruptured aneurysm.  One method is for the TCH patient to receive a CT and CTA, as CTA will additionally further evaluate for SAH or an aneurysm, CVA dissection, stroke, and RCVS.

An LP with opening pressure can aid in diagnosis.  LP is the gold standard for the diagnosis of SAH, especially if the patient presents after 12 hours of headache onset.11,89,90 CSF studies including glucose, protein, white cells, and differential are used for diagnosing viral and bacterial meningitis.  Additionally, opening pressure can be utilized to detect increased or decreased pressures.  CVT may be associated with an elevated opening pressure, while intracranial hypotension is associated with a low opening pressure.1,22 Finally, the CSF should be visually inspected for xanthochromia.

The majority of evidence states that conventional angiography is not necessary in patients with a normal head CT and LP.91 Angiography has a small risk of transient and permanent neurological complications.92 In evaluating patients with TCH and normal head CT and LPs, prospective studies have found no subsequent development of SAH or sudden death in patients with normal head CT and normal LP, supporting the viewpoint that conventional angiography may be more harmful than helpful.93-96

The role of MRI for imaging of the brain and cerebral vasculature has not yet been defined in patients with TCH, especially in the setting of the Emergency Department.  Schwedt, Matharu, and Dodick in 2005 recommended that patients presenting with TCH and a normal head CT and LP receive further evaluation with MRI.7 An MRI can help further evaluate for CVT, pituitary apoplexy, PRES, or intracranial hypotension.7 If MRI is normal, Schwedt et al. recommends evaluation with either an MRA or MRV.  Ducros and Bousser in 2012 have similar recommendations and state that all patients with TCH and a normal head CT and LP should receive a CTA or MRA.1 If these are normal, they recommend a brain MRI for further evaluation.

Even with a thorough workup, studies estimate that a diagnosis is made in only 27-71% of patients with TCH.5,6,10,95 The most common diagnosed cause of TCH is SAH.5,6,10,95 Other vascular causes are the second most common diagnosed cause, which includes cervical artery dissection, CVT, and RCVS.1,97

In determining workup of patients with TCH, the patient history is essential in determining the necessary diagnostic evaluation.  Table 2 provides several suspicious features associated with TCH that may help an Emergency Physician suspect a specific diagnosis.  While the physical exam is useful, patients with TCH and a normal exam (specifically a neurological exam) may still have a deadly intracranial condition.  The decision to pursue further measures beyond a head CT and/or LP should be made in conjunction with a neurologist, so early consultation is warranted. Neurosurgery may also need to be on board.  The ideal mechanism of imaging for each potential condition is shown in Table 3.

Table 2.  Features of TCH that aid with diagnostic evaluation1,7,8,42

Diagnosis Suspect with…
Subarachnoid Hemorrhage Any patient with TCH; also a/w neck stiffness, transient loss of consciousness, and focal neurological symptoms
Cerebral Venous Thrombosis Nonanatomic neurologic deficits, women in peripartum period, recent surgical history, clotting disorders, use of OCPs
Cervical Artery Dissection Young/middle-age patient presenting with stroke S/S, neck trauma
Acute Hypertensive Crisis/

Posterior Reversible Encephalopathy Syndrome

-Hypertensive Crisis:  extreme HTN with S/S of end-organ damage

-PRES:  extreme HTN with headache, seizures, and visual loss

Ischemic Stroke Patients with risk factors for stroke with focal neurological S/S in anatomic distribution
Intracranial Hypotension S/P lumbar puncture or mild trauma with orthostatic headache
Infectious Patient with fever, immunocompromise, or S/S of meningitis
Pituitary Apoplexy Patient with hx of pituitary adenoma, or currently pregnant, with headache, visual S/S, and AMS
Retroclival Hematoma Severe head and neck injury
Third Ventricle Colloid Cyst TCH that resolves quickly, pain often relieved with supine position
Temporal Arteritis Older patient with HA, pain in temporal distribution, visual sx, or jaw claudication.  A/w PMR
Reversible Cerebral Vasoconstriction Syndrome Recurrent TCH over several weeks; history of migraine; postpartum; or use of ergotamine, triptans, SSRIs, pseudoephedrine, cocaine, amphetamines, ecstasy, cannabis, or bromocriptine

Table 3.  Gold-Standard Diagnostic Modality for Conditions resulting in TCH1,7,8,42

Diagnosis Gold-standard diagnosing modality
Subarachnoid Hemorrhage Head CT and Lumbar Puncture
Cerebral Venous Thrombosis MR Venography
Cervical Artery Dissection Brain MRI with MRA or head CT with CTA
Acute Hypertensive Crisis/

Posterior Reversible Encephalopathy Syndrome

Brain MRI
Ischemic Stroke Brain MRI
Intracranial Hypotension Brain MRI
Infectious LP
Pituitary Apoplexy Brain MRI
Retroclival Hematoma MRI
Third Ventricle Colloid Cyst CT or brain MRI
Temporal Arteritis Temporal Artery Biopsy
Reversible Cerebral Vasoconstriction Syndrome CTA or MRA

Case Conclusion

Upon further questioning, the patient remembers that she was in a minor car accident several days prior.  She states she was not injured other than minor neck pain from “whiplash.”  However, the pain had been decreasing over the past several days and was barely noticeable prior to today.  When asked about neck pain, she admits she is experiencing left sided neck pain, but not nearly as severe as her headache.  Now suspicious for a CVA dissection, you order a head CT and CTA.  CTA demonstrates a left sided vertebral artery dissection, revealing the cause of this patient’s thunderclap headache.


A thunderclap headache (TCH) is a headache that reaches 7 (out of 10) or more in intensity within less than one minute.  Every patient presenting with TCH must be assumed to have a life-threatening intracranial condition.  As many conditions can present with TCH (most commonly SAH or RCVS), a thorough history is essential in evaluating for risk factors for other conditions.  The Emergency Physician must keep in mind that the absence of associated symptoms and a normal physical and neurological exam does not exclude a serious cause in a patient with a TCH; the patient still requires a diagnostic workup.  Due to the high morbidity and mortality of subarachnoid hemorrhage, any patient that presents with TCH must be evaluated for SAH.  A noncontrast head CT has a sensitivity for SAH nearing 100% if performed within 6 hours of headache onset.  We recommend TCH patients to receive a CTA with the initial head CT, as this will further evaluate for an aneurysm, cervical artery dissection, stroke, or RCVS.  Decisions on further imaging and diagnostic evaluation should be made in conjunction with neurology and possibly neurosurgery.


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  59. Schievink WI, Wijdicks EF, Meyer FB, et al. Spontaneous intracranial hypotension mimicking aneurysmal subarachnoid hemorrhage.  Neurosurgery 2001;48:513-7.
  60. Ferrante E, Savino A. Thunderclap headache caused by spontaneous intracranial hypotension.  Neurol Sci 2005;26:S155-57.
  61. Mohr G, Hardy J. Hemorrhage, necrosis, and apoplexy in pituitary adenomas.  Surg Neurol 1982;18:181-189.
  62. Randeva HS, Schoebel J, Byrne J, et al. Classical pituitary apoplexy:  clinical features, management and outcome.  Clin Endocrinol (Oxf) 1999;51:181-88.
  63. Kuroso A, Amano K, Kubo O, et al. Clivus epidural hematoma.  J Neurosurg 1990;72:660-62.
  64. Orrison WW, Rogde S, Kinard RE, et al. Clivus epidural hematoma:  a case report.  Neurosurgery 1986;18:194-6.
  65. Tomaras C, Horowitz BL, Harper RL. Spontaneous clivus hematoma:  case report and literature review.  Neurosurgery 1995;37:123-24.
  66. Schievink WI, Thompson RC, Loh CT, Maya MM. Spontaneous retroclival hematoma presenting as thunderclap headache.  J Neurosurg 2001;95:522-24.
  67. Spears RC. Colloid cyst headache.  Curr Pain Headache Rep 2004;8:297-300.
  68. Young WB, Silberstein SD. Paroxysmal headache caused by colloid cyst of the third ventricle:  case report and review of the literature.  Headache 1997;37:15-20.
  69. Kelly R. Colloid cysts of the third ventricle; analysis of twenty-nine cases.  Brain 1951;74:23-65.
  70. Gonzalez-Gay MA, Barros S, Lopez-Diaz MJ, Garcia-Porrua C, Sanchez-Andrade A, Llorca J.  Giant cell arteritis:  disease patterns of clinical presentation in a series of 240 patients.  Medicine (Baltimore) 2005;84(5):269.
  71. Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB. Narrative review:  reversible cerebral vasoconstriction syndromes.  Ann Intern med 2007;146(1):34.
  72. Ducros A. Reversible cerebral vasoconstriction syndrome.  Lancet Neurol 2012 Oct;11(10):906-17.
  73. Schluter A, Kissig B. MR angiography in migrainous vasospasm.  Neurology 2002;59(11):1772.
  74. Farine D, Andreyko J, Lysikiewicz A, Simha S, Addison A. Isolated angiitis of brain in pregnancy and puerperium.  Obstet Gynecol 1984;63(4):586.
  75. Janssens E, Hommel M, Mounier-Vehier F, Leclerc X, Guerin du Masgenet B, Leys D. Postpartum cerebral angiopathy possibly due to bromocriptine therapy.  Stroke 1995;26(1):128.
  76. Henry PY, Larre P, Aupy M, Lafforgue JL, Orgogozo JM. Reversible cerebral arteriopathy associated with the administration of ergot derivatives.  Cephalalgia 1984;4(3):171.
  77. Meschia JF, Malkoff MD, Biller J. Reversible segmental cerebral arterial vasospasm and cerebral infarction:  possible association with excessive use of sumatriptan and Midrin.  Arch Neurol 1998;55(5):712.
  78. Singhal AB, Caviness VS, Begleiter AF, Mark EJ, Rordorf G, Koroshetz WJ. Cerebral vasoconstriction and stroke after use of serotonergic drugs.  Neurology 2002;58(1):130.
  79. Levine SR, Washington JM, Jefferson MF, Kieran SN, Moen M, Feit H, Welch KM. “Crack” cocaine-associated stroke.  Neurology 1987;37(12):1849.
  80. Reneman L, Habraken JB, Majoie CB, Booij J, den Heeten GJ. MDMA (“ecstasy”) and its association with cerebrovascular accidents:  preliminary findings.  AJNR Am J Neuroradiol 2000;21(6):1001.
  81. Ducros A, Boukobza M, Porcher R, Sarov M, Valade D, Bousser MG. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome.  A prospective series of 67 patients.  Brain 2007;130(Pt 12):3091.
  82. Singhal AB, Hajj-Ali RA, Topcuoglu MA, Fok J, Bena J, Tang D, et al. Reversible cerebral vasoconstriction syndrome:  analysis of 139 cases.  Arch Neurol 2011;68:1005-12.
  83. Fugate JE, Ameriso SF, Ortiz G, Schottlaender LV, Wijdicks EF, Flemming KD, et al. Variable presentations of postpartum angiopathy.  Stroke 2012;43:670-6.
  84. Ducros A, Fiedler U, Porcher R, Boukobza M, Stapf C, Bousser MG. Hemorrhagic manifestations of reversible cerebral vasoconstriction syndrome.  Frequency, features, and risk factors.  Stroke 2010;41:2505-11.
  85. van Gijn J, van Dongen KJ. The time course of aneurysmal haemorrhage on computed tomograms.  Neuroradiology 1982;23(3):153.
  86. Rao KC, Knipp HC, Wagner EJ. Computed tomographic findings in cerebral sinus and venous thrombosis.  Radiology 1981;140(2):391.
  87. Oppenheim C, Logak M, Dormont D, Lehericy S, Manai R, Samson Y, Marsault C, Rancurel G. Diagnosis of acute ischemic stroke with fluid-attenuated inversion recovery and diffusion-weighted sequences.  Neuroradiology 2000;42(8):602.
  88. Schwartz RB, Jones KM, Kalina P, Bajakian RL, Mantello MT, Garada B, Holman BL. Hypertensive encephalopathy:  findings on CT, MR imaging, and SPECT imaging in 14 cases.  AJR Am J Roentgenol 1992;159(2):379.
  89. Moussouttas M, Mayer SA. Thunderclap headache with normal CT and lumbar puncture:  further investigations are unnecessary:    Stroke 2008;39:1394-5.
  90. Savitz SI, Edlow J. Thunderclap headache with normal CT and lumbar puncture:  further investigations are unnecessary:    Stroke 2008;39:1392-3.
  91. Savitz SI, Levitan EB, Wears R, Edlow JA. Pooled analysis of patients with thunderclap headache evaluated by CT and LP:  is angiography necessary in patients with negative evaluations?  J Neurol Sci 2009 Jan;276(1-2):123-5.
  92. Warnock NG, Gandhi MR, Bergvall U, Powell T. Complications of intraarterial digital subtraction angiography in patients investigated for cerebral vascular disease.  Br J Radiol 1993;66(790):855.
  93. Markus HS. A prospective follow up of thunderclap headache mimicking subarachnoid hemorrhage.  J Neurol Neurosurg Psychiatry 1991;54(12):1117.
  94. Linn FJ, Rinkel GJ, Algra A, van Gijn J. Follow-up of idiopathic thunderclap headache in general practice.  J Neurol 1999;246(10):946.
  95. Harling DW, Peatfield RC, Van Hile PT, Abbott RJ. Thunderclap headache:  is it a migraine?  Cephalalgia 1989;9(2):87.
  96. Landtblom AM, Boivie J, Fridriksson S, et al. Thunderclap headache:  final results form a prospective study of consecutive cases.  Acta Neurol Scand 1996;167(Suppl 94):23.
  97. Schwedt TJ. Clinical spectrum of thunderclap headache.  Expert Rev Neurother 2007 Sep;7(9):1135-44.

Drug Withdrawal: Pearls and Pitfalls

Authors: Drew A. Long, BS (@drewlong2232, Vanderbilt University School of Medicine, US Army) and Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC, USAF) // Edited by: Courtney Cassella, MD (@Corablacas, EM Resident Physician, Icahn SoM at Mount Sinai) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Case 1: A 45-year-old male presents to the ED with one day of myalgias, sweating, and anxiety. He is tachycardic and appears uncomfortable.  On examination, you notice lacrimation, excessive yawning, and a significant tremor.  He denies any illicit drug use, but he does have a history of chronic back pain for which he uses oxycodone. However, he ran out of oxycodone three days ago.

 Case 2: A 33-year-old female presents to the ED feeling depressed.  She has also been sleeping 16 hours per day and experiencing extreme hunger. She is trying to stop meth, for which her boyfriend was recently incarcerated.  Her examination and vital signs are normal, but she wants to know if she needs to be concerned about her symptoms, and more importantly, what she can do to feel better.


This is the second of a two-part series covering withdrawal states. Our first post evaluated the diagnosis and management of alcohol withdrawal. This second discussion will not be all encompassing, but it will cover the more commonly abused agents.



The incidence of opioid abuse has risen drastically in the United States.  Worldwide, between 26.4 million and 36 million people abuse opioids.1 In 2012, an estimated 2.1 million people in the United States had prescription opioid substance use disorders.2 The number of prescription opioids has escalated from an estimated 76 million people in 1991 to 207 million in 2013.3 Specifically, the number of heroin users has increased from 373,000 in 2007 to 681,000 in 2013.4 Along with this increase in opioid prescriptions and opioid abuse, the number of people dependent on opioids and number of opioid overdoses have also increased.

screen-shot-2016-09-10-at-12-11-58-amOpioids are most commonly used for pain management.  Opioids act on transmembrane neurotransmitter receptors (mu, kappa, delta) coupled to G proteins.  These receptors are located in both the central and peripheral nervous systems.  When these receptors are stimulated by opioids, the signal transduction pathway leads to the effects of analgesia in addition to triggering the reward center.5

Opioid withdrawal occurs when a person who is physiologically dependent on opioids either reduces or abruptly stops using opioids.  The diagnosis of opioid withdrawal is made by the history and physical exam.  The signs and symptoms of opioid withdrawal are often vague and nonspecific.  While opioid withdrawal may be uncomfortable, it is rarely life-threatening.  Broad categories of manifestations include gastrointestinal distress, flu-like symptoms, and sympathetic nervous system arousal, which are categorized in Table 1.6


Other common symptoms of opioid withdrawal include yawning, sneezing, dizziness, myalgias, arthralgias, and leg cramps.  While not always present, yawning and lacrimation are helpful due to high specificity for opioid withdrawal.7

The course of opioid withdrawal greatly depends upon which opioid the patient was using.  An opioid must be consumed daily for 3 weeks or more for the patient to become physiologically dependent.  The withdrawal period typically lasts two to three times the half-life of the opioid.6 Characteristics of commonly abused opioids are shown in Table 2. screen-shot-2016-09-10-at-12-15-48-am

A thorough history and physical is vital when assessing a patient suspected of undergoing opioid withdrawal.  Concomitant substance use disorders, mental disorders, and other disorders are common in patients with opioid use disorder.  Nicotine use has been associated with up to 85% of patients undergoing opioid withdrawal.  Mental disorders may be found in up to 70% of patients undergoing opioid withdrawal.  These include major depression, panic disorder, general anxiety disorder, and post traumatic stress disorder.9-11 A systemic review found a prevalence of co-occurring depressive disorders to be 27% and co-occurring anxiety disorders to be 29%.12 It is important to consider that opioid withdrawal may exacerbate co-occurring mental disorders.  Other disorders to consider include comorbid alcohol and benzodiazepine withdrawal, comorbid cocaine and methamphetamine withdrawal, or personality disorders.

Mimics of opioid withdrawal include other intoxication or withdrawal syndromes.  As opioid users usually have insight into their addiction, the history is often enough to establish a diagnosis.  Several other withdrawal syndromes, specifically ethanol and sedative-hypnotic withdrawal, may appear similar to opioid withdrawal.  However, these are much more likely to cause significant tachycardia and hypertension compared to opioid withdrawal.  Additionally, these syndromes may produce seizures and/or hyperthermia.  Another syndrome that may mimic opioid withdrawal is sympathomimetic intoxication.  However, similar to ethanol and sedative-hypnotic withdrawal, this syndrome produces much more severe findings (mydriasis, agitation, tachycardia, hypertension) than opioid withdrawal.7

Opioid withdrawal is not life-threatening, and the mainstay of treatment is management of symptoms.  Patients suffering from opioid withdrawal can undergo medically supervised opioid withdrawal (detoxification).  Symptoms from withdrawal can be managed with multiple agents, including opioids and non-opioids.  Popular agents utilized for managing opioids withdrawal include methadone and buprenorphine.  Methadone is a long-acting opioid, while buprenorphine is a partial opioid agonist.7  Methadone, which may be used in a psychiatric setting, is not an option for ED providers due to inability for patient follow up in the ED setting and risk of overdose.  Buprenorphine is a partial opioid receptor agonist with high affinity. These properties provide a lower risk of respiratory depression which, along with its long duration of action, make it an effective and safe therapy for opioid withdrawal. However, its use is also controversial. This medication is a synthetic agent with less abuse potential and dependence, acting as a partial agonist. If a patient is opioid dependent and given this medication, withdrawal will occur, as buprenorphine has higher receptor affinity and less activity than other opioids.  It is approved in the U.S. for outpatient treatment of opioid dependence, given once daily. Providers are required to have a special waiver from the DEA to prescribe this medication.



Benzodiazepines (BZDs) are sedative-hypnotic agents used for sedation and treatment of anxiety, seizures, withdrawal states, and insomnia.  BZDs act via modulation of the gamma-aminobutyric acid A (GABA-A) receptor, which is the main inhibitory neurotransmitter of the central nervous system.13


BZD withdrawal occurs when any chronic user abruptly decreases or ceases BZD consumption.  Rapid recognition and management of BZD withdrawal is vital as it can be life-threatening.  The signs and symptoms of BZD withdrawal are similar to those associated with withdrawal from other sedative-hypnotics (barbiturates, alcohol, etc.).  Milder symptoms of BZD withdrawal can include headache, nausea, vomiting, tremors, insomnia, agitation, and anxiety.  More severe symptoms may include hallucinations, psychotic behavior, altered mental status, and seizures.  Seizures, while uncommon, are a feared complication of benzodiazepine withdrawal.13,14

Like opioids, the timing of symptoms varies according to the half-life of the BZD involved.  Table 3 depicts the half-life of commonly abused BZDs.  In patients abusing BZDs with shorter half-lives (such as Xanax, Ativan, and Versed) withdrawal symptoms may occur in 1-2 days, while withdrawal symptoms from BZDs with longer half-lives may occur up to two weeks after cessation.15,16


Management of BZD withdrawal depends first on accurate diagnosis by history and characteristic signs and symptoms described above. After identifying withdrawal, treatment should be initiated with a BZD that has a prolonged clinical effect, such as diazepam.18-20 This BZD should be administered intravenously with a goal of eliminating symptoms of withdrawal without causing excessive sedation.  Patients undergoing withdrawal experiencing milder symptoms may be treated with a long-acting oral BZD.  While other agents have been used to treat BZD withdrawal (such as beta blockers, antipsychotics, SSRIs, and antihistamines), they have all been shown to be inferior with standard treatment.18,20 Valproic acid and carbamazepine have not shown any additional benefit and have not been extensively studied to be included in the standard management of BZD withdrawal.21,22

There are several scales for monitoring BZD withdrawal.  The Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) and Clinical Institute Withdrawal Assessment Scale-Benzodiazepines (CIWA-B) are two of the more commonly utilized scales.  The BWSQ is a 20-item self-report, validated questionnaire, while the CIWA-B uses 22-items to assess and monitor the severity of symptoms from withdrawal.  While these scales are helpful, they should not be solely relied upon to monitor complicated withdrawal.  Monitoring of withdrawal should always include careful observation and evaluation of the patient in addition to the Emergency Physician’s clinical judgment.23



Cocaine is a stimulant associated with many life-threatening complications, including seizure, stroke, and myocardial infarction.  Cocaine exerts its effect by enhancing monoamine neurotransmitters in the brain (dopamine, norepinephrine, and serotonin) via blockade of presynaptic reuptake of these neurotransmitters, both in the central and peripheral nervous systems.24


Withdrawal from cocaine, while uncomfortable, is not life-threatening.  The cocaine withdrawal syndrome is highlighted by prominent psychological features.  These include depression, anxiety, fatigue, difficulty concentrating, anhedonia, increased appetite, increased sleep, increased dreaming, and increased craving for cocaine.25,26  Intense symptoms at the beginning of the withdrawal period (the crash) may occur, which may include psychomotor retardation and severe depression with suicidal ideation.  Signs of cocaine withdrawal are typically minor and include musculoskeletal pain, tremors, chills, and involuntary motor movement.27Another potential complication of withdrawal includes myocardial ischemia, which is most commonly seen in the first week of withdrawal.28

Treatment for cocaine withdrawal is mainly supportive, including encouraging the patient to sleep and eat as necessary (especially if the patient is experiencing hypersomnia and increased appetite).29 No drugs have been shown to be beneficial in treating cocaine withdrawal.  For patients with severe agitation or insomnia, a short acting benzodiazepine may be helpful.  Patients with depression lasting several weeks or suicidal ideation may require admission to a psychiatric unit and treatment with antidepressants.29,30 As the relapse risk is high during the early withdrawal period, patients should be referred to an addiction treatment program for further support in abstaining from cocaine use.  Discharge from the ED is appropriate if the patient is stable with no other psychiatric concerns (severe depression, suicidal thoughts, etc.).



Similar to cocaine, methamphetamine is a stimulant that causes the release of monoamine neurotransmitters, while also blocking reuptake.  Amphetamine-type stimulants are the fastest rising drug of abuse worldwide and the second most widely used class of illicit drugs worldwide.31-33 Individuals with chronic amphetamine use have a high incidence of comorbid psychiatric disorders, including primary psychotic disorder, mood disorder, anxiety disorders, and ADHD.34 Depressive symptoms also commonly occur with methamphetamine use.35


Opposed to the euphoric effect of methamphetamine intoxication, withdrawal is marked by a dysphoric state, which is highlighted by depressive symptoms.  These include anhedonia, depression, anxiety, and social inhibition.26 Watson et al. reported that depression peaked at 2-3 days and persisted for 4 days following amphetamine cessation.36 Based on the initial dysphoric state, methamphetamine withdrawal can mimic major depressive disorder.  Other symptoms include irritability, poor concentration, hyperphagia, insomnia or hypersomnia, and psychomotor agitation or retardation.  These symptoms typically last 5 days to two weeks.37

Similar to the management of cocaine withdrawal, the mainstay of amphetamine withdrawal is supportive therapy.  No available treatment has shown to be effective in treatment of amphetamine withdrawal.  Similar to cocaine withdrawal, the patient must be evaluated for severity of depressive symptoms and suicidal ideation and receive in-patient psychiatric treatment if necessary.  If the patient is not actively suicidal nor is suffering from major depressive symptoms, they can be discharged home with warning to return if depressive symptoms worsen.  Importantly, they should be referred to an addiction support and treatment program to help in cessation of amphetamine abuse.38



Caffeinated beverages are the most consumed stimulants in the world.  About 90% of adults in the world consume caffeine on a daily basis.39 Consumption of up to 400 mg of caffeine on a daily basis is safe for most adults.40 Table 3 lists the caffeine content of various beverages.  The most common caffeinated beverages include coffee, tea, and soft drinks.  Caffeine is an antagonist of central and peripheral nervous system adenosine receptors, stimulating the release of excitatory neurotransmitters.41


Caffeine withdrawal, while uncomfortable, is not associated with any adverse medical consequences.  Withdrawal symptoms include headache, fatigue, decreased energy, decreased attentiveness, sleepiness, decreased sense of wellbeing, depressed mood, difficulty concentrating, and irritability.  Of these, headache is the most common symptom experienced.  It is estimated that only about 50 percent of chronic caffeine users experience withdrawal symptoms.  Symptoms typically begin to occur 12-24 hours after ceasing caffeine intake, peak at one to two days, and resolve within one week.43

Management of caffeine withdrawal is supportive.  Patients should be reassured that caffeine withdrawal is not associated with any adverse events or complications.  If the patient’s headache is severe, an anti-inflammatory agent such as ibuprofen can be utilized.  The patient can also be offered caffeine (any caffeinated beverage or soft drink), as re-administration of caffeine reverses the withdrawal symptoms.

Case Resolution

Case 1:  This 45-year-old male was diagnosed with opioid withdrawal from the history and physical.  On further evaluation, he denied any other substance abuse and had no psychiatric history or comorbidities.  As the patient requested detoxification, he was provided information for detoxification centers.

Case 2:  This 33-year-old female was concerned about cessation of methamphetamine.  On further evaluation, she stated she had been feeling down lately but denied any anhedonia or suicidal ideation.  On further evaluation, she admitted to intermittent alcohol use but denied any other substance abuse.  You reassure her that though these symptoms may last for up to two weeks, they are not life-threatening and will improve.  She expresses interest in cessation of methamphetamine abuse, and you refer her to an amphetamine addiction support group and counseling center.


  • The signs and symptoms of opioid withdrawal are often vague and nonspecific, and include gastrointestinal distress, flu-like symptoms, and sympathetic nervous system arousal. Yawning and lacrimation are specific for opioid withdrawal.
  • Alcohol withdrawal and stimulant intoxication can mimic opioid withdrawal. However, these are much more likely to cause significant tachycardia and hypertension compared to opioid withdrawal.
  • Quick recognition of benzodiazepine withdrawal is essential, as this syndrome can be life-threatening.
  • The onset and duration of symptoms of BZD withdrawal depends on the half-life of the BZD.
  • The mainstay of therapy for BZD withdrawal is a BZD with a prolonged clinical effect, with the goal of alleviating symptoms.
  • Both cocaine and amphetamine withdrawal can manifest with depressive symptoms. Patients should be evaluated for suicidal ideation and hospitalized if necessary.
  • Treatment for both cocaine and amphetamine withdrawal is supportive, in addition to consideration and care for any psychological symptoms.
  • Caffeine withdrawal is not associated with any adverse complications. If patients are requesting treatment for withdrawal symptoms, ibuprofen or a caffeinated beverage can provide timely relief.


References/Further Readin

  1. “World Drug Report 2012.”   United Nations Office on Drugs and Crime.
  2. “Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings.” NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013.
  3. “America’s Addiction to Opioids: Heroin and Prescription Drug Abuse.” National Institute on Drug Abuse.
  4. Jones CM, Logan J, Gladden RM, Bohm MK. Vital Signs: Demographic and Substance Use Trends Among Heroin Users-United States, 2002-2013. MMWR Morb Mortal Wkly Rep. 2015 Jul;64(26):719-25.
  5. Strain E. Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis. UpToDate. May 2016.
  6. Sevarino K. Opioid withdrawal: Clinical manifestations, course, assessment, and diagnosis. UpToDate. May 2016.
  7. Stolbach A, Hoffman RS. Opioid withdrawal in the emergency setting. UpToDate. May 2016.
  8. Choo C. Medications Used in Opioid Maintenance Treatment. US Pharm. 2009;34(11):40-53.
  9. Teoh BGJ, Yee A, Habil MH. Psychiatric comorbidity among patients on methadone maintenance therapy and its influence on quality of life. Am J Addict. 2016 Jan;25(1): 49-55. Epub 2015 Dec 21.
  10. Fareed A, Eilender P, Haber M, Bremner J, Whitfield N, Drexler K. Comorbid posttraumatic stress disorder and opiate addiction: a literature review. J Addict Dis. 2013;32(2):168-79.
  11. Rosen D, Smith ML, Reynolds CF. The prevalence of mental and physical health disorders among older methadone patients. Am J Geriatr Psychiatry. 2008 Jun;16(6):488-97.
  12. Goldner EM, Lusted A, Roerecke M, Rehm J, Fischer B. Prevalence of Axis-1 psychiatric (with focus on depression and anxiety) disorder and symptomatology among non-medical prescription opioid users in substance use treatment: systematic review and meta-analysis. Addict Behav. 2014 Mar;39(3):520-31. Epub 2013 Dec 2.
  13. Greller H, Gupta A. Benzodiazepine poisoning and withdrawal. UpToDate. May 2016.
  14. Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl). 2004;176(1):1.
  15. Hood HM, Metten P, Crabbe JC, Buck KJ. Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11. Genes Brain Behav. 2006;5(1):1.
  16. Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, et al. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr. 2009 Nov;67(6):408-13. Epub 2009 Sep 18.
  17. Gussow L, Carlson A. Rosen’s Emergency Medicine, 8th Ed., Chapter 165, 2076-2083.e1. Philadelphia PA: Saunders, 2014.
  18. Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;23(1):19.
  19. Voshaar RC, Couvee JE, van Balkom AJ, Mulder PG, Zitman FG. Strategies for discontinuing long-term benzodiazepine use: meta-analysis. Br J Psychiatry. 2006 Sep;189:213-20.
  20. Parr JM, Kavanagh DJ, Cahill L, Mitchell G, McD Young R. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction. 2009 Jan;104(1):13-24. Epub 2008 Oct 31.
  21. Lum E, Gorman SK, Slavik RS. Valproic acid management of acute alcohol withdrawal. Ann Pharmacother. 2006;40(3):441.
  22. Schweizer E, Rickels K, Case WG, Greenblatt DJ. Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Effects on withdrawal severity and outcome. Arch Gen Psychiatry. 1991;48(5):448.
  23. Alvanzo A. Management of Substance Withdrawal in Acutely Ill Medical Patients: Opioids, Alcohol, and Benzodiazepines. Society of General Internal Medicine 36th Annual Meeting. 27 April 2013.
  24. Gorelick DA. Cocaine use disorder in adults: Epidemiology, pharmacology, clinical manifestations, medical consequences, and diagnosis. UpToDate. May 2016.
  25. Coffey SF, Dansky BS, Carrigan MH, Brady KT. Acute and protracted cocaine abstinence in an outpatient population: a prospective study of mood, sleep and withdrawal symptoms. Drug Alcohol Depend. 2000;59(3):277.
  26. Lago JA, Kosten TR. Stimulant withdrawal. Addiction. 1994;89(11):1477.
  27. Khantzian EJ, McKenna GJ. Acute toxic and withdrawal reactions associated with drug use and abuse. Ann Intern Med. 1979;90(3):361.
  28. Nademanee K, Gorelick DA, Josephson MA, Ryan MA, Wilkins JN, Robertson HA, et al. Myocardial ischemia during cocaine withdrawal. Ann Intern Med. 1989;111(11):876.
  29. Schuckit MA. Drug and Alcohol Abuse. A Clinical Guide to Diagnosis and Treatment, 6th ed, Springer, New York 2007.
  30. Weiss RD, Greenfield SF, Mirin SM. Intoxication and withdrawal syndromes. In: Manual of Psychiatric Emergencies, Hyman, SE, (Ed), Little, Brown & Co, Boston, MA 1994. p. 279-93.
  31. Degenhardt L, Mathers B, Guarinieri M, Panda S, Phillips B, Strathdee SA, et al. Meth/amphetamine use and associated HIV: Implications for global policy and public health. Int J Drug Policy. 2010 Sep;21(5):347-58. Epub 2010 Feb 1.
  32. World Drug Report 2010, United Nations Publication, Vienna 2010.
  33. UNODC. World Drug Report 2012, Contract No: E.12.XI.1, United Nations Publication, New York 2012.
  34. Salo R, Flower K, Kielstein A, Leamon MH, Nordahl TE, Galloway GP. Psychiatric comorbidity in methamphetamine dependence. Psychiatry Res. 2011 Apr;186(2-3):356-61. Epub 2010 Nov 4.
  35. Zorick T, Sugar CA, Hellemann G, Shoptaw S, London ED. Poor response to sertraline in methamphetamine dependence is associated with sustained craving for methamphetamine. Drug Alcohol Depend. 2011 Nov;118(2-3):500-3. Epub 2011 May 17.
  36. Watson R, Hartmann E, Schildkraut JJ. Amphetamine withdrawal: affective state, sleep patterns, and MHPG excretion. Am J Psychiatry. 1972 Sep;129(3):263-9.
  37. McGregor C, Srisurapanont M, Jittiwutikarn J, Laobhripatr S, Wongtan T, White JM. The nature, time course and severity of methamphetamine withdrawal. Addiction. 2005 Sep;100(9):1320-9.
  38. Srisurapanont M, Jarusuraisin N, Kittirattanapaiboon P. Treatment for amphetamine withdrawal. Cochrane Library. 23 October 2001.
  39. Medicines in my Home: Caffeine and Your Body. Food and Drug Administration.
  40. Heckman MA, Weil J, Gonzalez de Mejia E. Caffeine (1,3,7-trimethylxanthine) in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters. J Food Sci. 2010 Apr;75(3):R77-87.
  41. Freholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 1999;51(1):83.
  42. Bordeaux B, Lieberman HR. Benefits and risks of caffeine and caffeinated beverages. UpToDate. May 2016.
  43. Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl). 2004;176(1):1.

Alcohol Withdrawal: Pearls and Pitfalls

Authors: Drew Long, BS (Vanderbilt University School of Medicine, US Army) and Brit Long, MD (@long_brit) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) & Justin Bright, MD (@JBright2021)


A 33 y/o man is brought in by EMS after a witnessed tonic-clonic seizure.  His vitals are notable for a HR of 124 and BP of 178/86.  The patient states he is trying to cut down on his alcohol consumption due to pressure from his wife and hasn’t had a drink in over 24 hours.  He is a social drinker and normally consumes “somewhere around 3-4 beers” each day in addition to “a little bit of vodka every now and then.”  He appears anxious, has a severe tremor, and is unable to hold a glass of water without spilling its contents.  The rest of the physical exam is unremarkable.  What is the initial workup and management of this patient?  Is he in alcohol withdrawal?  What other conditions must be ruled out?


Alcohol use is extremely widespread throughout developed countries.  It is estimated that 8 million people in the US are alcohol dependent.1 Approximately 20% of men and 10% of women will at some point in their lives have an alcohol-use disorder.2 About half of people with alcohol-use disorders will have symptoms of withdrawal when they cut down or stop their alcohol consumption.3 Extreme complications, including seizures and/or delirium tremens, will occur in 3-5% of these people.3


Alcohol is a CNS depressant: it potentiates GABA receptors to enhance inhibitory tone in the brain and antagonizes the NMDA receptor to inhibit excitatory tone.1,4 Chronic alcohol exposure leads to brain adaptation to the effects of alcohol through changes in receptors.  Chronic ethanol use leads to down-regulation and conformational changes of the GABA receptor.  Additionally, in chronic alcoholics, NMDA receptors undergo conformational changes and up-regulation.  These changes lead to an increased tolerance to ethanol, requiring higher blood alcohol levels to achieve the similar effects of intoxication.1,5-7

The underlying pathophysiology of acute alcohol withdrawal is CNS hyperexcitation.6 After the chronic alcoholic ceases alcohol consumption, they lose the GABA inhibitory effect and have a potentiation of NMDA excitatory effects.  These effects lead to CNS hyperstimulation.

Differential Diagnosis and Evaluation

First and foremost, alcohol withdrawal syndrome (AWS) is a clinical diagnosis (cannot be confirmed by any laboratory tests) and a diagnosis of exclusion.  Even in the withdrawing chronic alcoholic, the Emergency Physician must evaluate for an underlying process resulting in the patient’s presentation.  It is vital to consider and rule out other pathologies that can mimic alcohol withdrawal syndrome (Table 1), while keeping in mind that chronic alcoholics are prone to malnutrition, trauma, and electrolyte abnormalities.  At the same time, the Emergency Physician must strive to recognize AWS early to prevent progression of minor symptoms to life-threatening complications.

Table 1.  Differential Diagnosis of Alcohol Withdrawal Syndrome6








Alcohol intoxication

Sympathomimetic intoxication

Anticholinergic syndrome

Sedative-hypnotic withdrawal

Serotonin syndrome

Neuroleptic malignant syndrome











Myocardial ischemia



Acute psychosis


Head trauma

Hepatic failure

GI bleed

Sepsis and septic shock



The diagnosis of AWS is driven by the history and physical.  The patient’s history of alcohol abuse, including amount of alcohol consumed per day in addition to number of years of alcohol use, must be quantified.  The Emergency Physician should keep in mind that patients with alcohol use disorder commonly minimize their alcohol consumption.  Furthermore, it is very important to recognize that a patient can have alcohol in their system and still be withdrawing.  For example, if a patient typically has a basal alcohol level of 0.30 g/dL, then a serum level of 0.15 g/dL would be a significant reduction for this patient.  The patient should also be asked why they decided to cease consumption of alcoholA quick and easy method of screening a patient with a positive history of alcohol use is the CAGE questionnaire (  The Emergency Physician should also inquire about illicit drug use.

In approaching the patient with alcohol withdrawal, the Emergency Physician should additionally consider underlying pathologies, such as pancreatitis or severe gastritis.  In tachycardic patients, further evaluation for PE, MI, sepsis, or dehydration may be warranted.6

Testing in patients with suspected alcohol withdrawal syndrome should be driven by the differential diagnosis, in which the Emergency Physician should rule out mimicking or potential coexisting conditions.  Helpful laboratory and imaging evaluations are shown in Table 2.

Table 2.  Tests in AWS6
Serum pH and osmolality
CMP (evaluate for alcoholic hepatitis)
Serum salicylate and APAP levels
Ethanol level (controversial)
Head CT
Coagulation panel (PT/INR, PTT)


A CBC may show pernicious anemia from vitamin B12 deficiency.  The CMP may show hypokalemia, hypomagnesemia, hyponatremia, and/or elevated liver enzymes.  Chronic alcoholics are prone to electrolyte abnormalities due to malnutrition and dehydration.  In regards to LFTs, remember that in alcoholic hepatitis, AST is elevated to a greater degree than ALT. Especially if the patient is altered, a rapid glucose is necessary to evaluate for and if necessary correct hypoglycemia.  If concerned with another ingestion, it is helpful to order serum salicylate and APAP levels.  An ECG can assist in evaluating for ischemia or other toxic ingestions. If fever or hypoxia is present, a CXR is useful in ruling out pulmonary pathologies (most likely pneumonia).  A head CT is warranted if there is a concern for any type of trauma or the patient is altered.  Coagulation studies may reveal elevated INR.5,6

Stages of Withdrawal

Reductions in the concentration of alcohol in the blood lead to symptoms that are generally the opposite of the acute effects of alcohol intoxication.  Symptoms from alcohol withdrawal usually start within 6-8 hours (after the blood alcohol level decreases), peak at 72 hours, and diminish by days 5 to 7 of abstinence.1,7 Broad withdrawal symptoms from alcohol include insomnia, anxiety, GI upset (nausea/vomiting), tremulousness, headache, diaphoresis, palpitations, increased body temperature, heart rate, and blood pressure.1,3  Of note, patients taking beta blockers or alpha-2 agonists may have blunted autonomic hyperactivity.5  If the patient’s withdrawal does not progress, these withdrawal symptoms will often resolve within 24 to 48 hours.8

Alcohol hallucinations generally occur 12-24 hours after the patient’s last drink.9 Alcoholic hallucinations occur in 7-8% of patients with AWS.10 These hallucinations are most commonly tactile but may also be visual.  Importantly, alcoholic hallucinations can be differentiated from delirium tremens in that patients with alcoholic hallucinations will have an otherwise normal sensorium.

Withdrawal seizures generally occur 12-48 hours after the patient’s last drink.11 These seizures, while generalized tonic-clonic, are typically minor (isolated, short in duration, little post-ictal period).  In the seizing alcoholic patient, alternative causes of seizures must be considered (i.e. infection, subdural hematoma, or metabolic abnormalities).6 Of note, AWS patients who have withdrawal seizures have a higher likelihood of progressing to delirium tremens, as 1/3 of patients with withdrawal seizures progress to DT.11

Delirium tremens (DT) is a rapid-onset, fluctuating disturbance of attention and cognition (sometimes with hallucinations) plus alcohol withdrawal symptoms and autonomic instability.5 DT occur in 3-5% of patients who are hospitalized for alcohol withdrawal.7,12,13 DT usually begins 3 days after the appearance of withdrawal symptoms and lasts for 1 to 8 days.7,14,15 The mortality of hospitalized patients with DT is currently estimated to be 1-4%.7,13-15 DT can be predicted by the following factors:16-18

  • History of previous DT
  • History of sustained drinking
  • CIWA scores > 15
  • Patients with SBP > 150, or patients with HR greater than 100
  • Recent withdrawal seizures
  • Prior withdrawal delirium or seizures
  • Older age
  • Recent misuse of other depressants
  • Concomitant medical problems


Like every patient presenting to the ED, the initial management for any patient with suspected alcohol withdrawal is the ABCs (airway, breathing, circulation).  The mainstay of treatment of mild, moderate, and severe alcohol withdrawal is benzodiazepines.7,14,19 Benzodiazepines act as central GABAA agonists, addressing the underlying problem being alcohol withdrawal (CNS hyperexcitation).  Benzodiazepines treat the psychomotor agitation experienced by withdrawing alcoholics in addition to preventing progression to more serious withdrawal symptoms.   While benzodiazepines are the optimal treatment for AWS, there is debate regarding which benzodiazepine is best.  No single benzodiazepine has been shown to be superior. 

Four benzodiazepines to be aware of in the management of AWS are Valium (diazepam), Ativan (lorazepam), Versed (midazolam), and Librium (chlordiazepoxide). For acute symptom control, most clinicians prefer diazepam or lorazepam.  Diazepam has a faster onset of action (1-5 minutes) compared to lorazepam (5-20 minutes), which may allow for easier titration and avoidance of dose stacking.20 Diazepam also has active metabolites, nordazepam and oxazepam, which extend the duration of sedating effects. On the other hand, lorazepam has a short half-life and no active metabolites, which may help prevent prolonged effects of oversedation.  Another benzodiazepine to consider is chlordiazepoxide, which is available in only oral format.  Chlordiazepoxide has a slow onset of action and relatively long half-life, making it ideal for an outpatient setting.  These properties also provide chlordiazepoxide with a lower potential for abuse. Table 3 compares various benzodiazepines in the treatment of AWS.

Table 3.  Benzodiazepines for AWS6

Drug Lipid solubility Time to onset Active metabolites? Initial Dose
Diazepam ++++ 1-5 min IV Yes 10-20 mg IV

10-20 mg PO

Lorazepam +++ 5-20 min IV No 2-4 mg IV

2-4 mg PO

Midazolam +++ 2-5 min IM/IV Yes 2-4 mg IM/IV
Chlordiazepoxide +++ 2-3 hrs PO Yes 50-100 mg PO


The decision to give benzodiazepines is often based on symptom-triggered therapy, as evaluated by the Clinical Institute Withdrawal Assessment for Alcohol (CIWA) scale.  Symptom-triggered therapy was validated by Saitz et al in 1994.  This study was a randomized double-blind controlled trial comparing patients receiving chlordiazepoxide for AWS with either a fixed schedule or symptom-triggered therapy.  This study found patients in the symptom-triggered therapy group required less medication (median 100 vs. 425 mg) and a shorter treatment period (median 9 vs. 68 hours).21 The maximum score of the CIWA scale is 67.  A mild score is 15 or less, moderate is 16-20, and severe withdrawal is a score greater than 20.  For CIWA monitoring, evaluations as frequent as every 10-15 minutes may be appropriate for patients with severe AWS receiving treatment with benzodiazepines.  Once symptoms are under control, hourly reassessment with CIWA is effective.22

For patients with severe AWS, repeating escalating doses of IV diazepam (20, 40, 80 mg) or lorazepam (2, 4, 8, 16 mg) are recommended.  An escalating dose of diazepam can be given every 10-15 minutes as required, while an escalating dose of lorazepam can be given every 15-20 minutes as required.  The clinician should utilize this regimen of escalating doses based on the patient’s vital signs and clinical appearanceFor severe withdrawal, titrating benzodiazepines to achieve a state of somnolence with arousal to minimal stimulation is a reasonable goal.   This method of escalating benzodiazepines dosing and front-loading has been shown to reduce seizures, DT, and the need for mechanical ventilation in patients with severe AWS.6,23,24

A pitfall to avoid in the management of AWS is attributing complications from AWS to another condition and administering the incorrect treatment.  For example, in alcoholic hallucinosis, the management is benzodiazepines, with limited data showing that antipsychotics are actually detrimental in acute AWS.25 For withdrawal seizures, there is no role for antiepileptic medications, and benzodiazepines are again the treatment of choice.26

A small subgroup of patients may have benzodiazepine-resistant alcohol withdrawal and DT.  Early aggressive treatment of these patients is warranted, including fast escalation of doses of benzodiazepines.24 A reasonable choice in these patients not responding to benzodiazepines is a barbiturate such as phenobarbital, which has been associated with a decrease in ICU admissions when utilized early in the course of management of AWS.27 Additionally, intubation should be at the forefront of patients with severe AWS not responding to benzodiazepines, with propofol being ideal as an induction agent due to its GABA agonist and NMDA antagonist effects.28,29  Some preliminary evidence also supports the use of dexmedetomidine in these patients

Other therapies to consider in patients with AWS include re-orienting the patient to time, place, and date.  The patient should be placed in a well-lit room, provided reassurance, receive frequent monitoring of vitals, and receive adequate volume resuscitation.  Severe alcohol withdrawal has an important impact on a patient’s fluid and electrolyte status, and almost all patients with AWS are hypovolemic.  In addition, thiamine and multivitamins should be given to the chronic alcoholic.  Any electrolyte abnormalities should be corrected.


Disposition of the AWS patient depends on accurate identification of the patient’s degree of withdrawal.  Patients who have a very mild CIWA score and are not currently intoxicated may be considered for discharge.  On the other end of the spectrum, patients with severe AWS and/or medical comorbidities will need ICU admission.  Table 4 outlines aspects to consider in the disposition of patients with AWS.

Table 4.  Disposition for AWS6





Discharge with detoxification referral31


-CIWA Score <8

-Patient not currently intoxicated (alcohol or other drugs)

-No history of complicated AWS (seizures, hallucinosis, DT)

-No significant medical or psychiatric comorbidities







Inpatient detoxification or medical unit


-No underlying medical or surgical condition requiring ICU-level care

Normalization or near-normalization of vitals in ED

Clear sensorium

-Responsive to 10-20 mg diazepam

Tolerates 2-4 hours between benzodiazepine doses

-Presence of medical or psychiatric condition requiring inpatient admission








Intensive Care Unit


-Underlying medical or surgical condition requiring ICU-level care

-Patient requires >100-200 mg of diazepam to control symptoms in ED

-Requires benzodiazepines more frequently than every 2 hours

-Requires phenobarbital or other adjunctive therapy to control AWS

-Hyperthermia present

-Altered sensorium or recurrent seizures present



Case Resolution

After your encounter with this patient, you remember that while he is likely going through alcohol withdrawal, this is a diagnosis of exclusion.  You evaluate the patient for other etiologies of his seizure (including infection, subdural hemorrhage, and metabolic abnormalities).  While considering other conditions, you place this patient on the CIWA scale, for which he scores 23.  A head CT is negative for any abnormalities, and his laboratory analysis is remarkable for an AST of 92, ALT of 41, and Tbili of 5.  His UDS comes back positive for cocaine and methamphetamine.

Due to his severe withdrawal as graded by the CIWA score, requirement for frequent monitoring and administration of benzodiazepines, he is admitted to the ICU for further management of his alcohol withdrawal.


  • The underlying pathophysiology of AWS is CNS hyperexcitation.
  • AWS is a diagnosis of exclusion; it is vital to rule out other mimicking conditions (including other toxins, head trauma, and sepsis).
  • AWS must be recognized early based on the presentation and history of alcohol use and cessation of alcohol consumption.
  • Patients can withdraw from alcohol even if they still have alcohol in their system
  • Stages of withdrawal include withdrawal symptoms, hallucinations, seizures, and delirium tremens.
  • Delirium tremens is a rapid-onset fluctuating disturbance of attention and cognition (sometimes with hallucinations) plus alcohol withdrawal symptoms and often autonomic instability. It usually begins about 3 days after the appearance of symptoms and can last anywhere from 1-8 days.
  • The mainstay of treatment for all stages of AWS is benzodiazepines.
  • Symptom-triggered therapy is recommended for dosing and administration of benzodiazepines.


  • Even in AWS patients who develop DT, early symptoms may be mild.
  • In the tachycardic alcoholic patient, be sure to consider PE, myocardial infarction, sepsis, dehydration, and other potential diagnoses other than AWS.
  • Alcoholics commonly present with a range of metabolic abnormalities, some of which can be life-threatening. Be sure to check for these abnormalities and correct as appropriate.
  • The presence of confusion or altered mentation in a patient with AWS may be due to DT and warrants admission to a higher level of care such as an ICU.
  • AWS is a diagnosis of exclusion: consider structural CNS pathology, metabolic abnormalities, infection, other toxicologic causes, and other conditions before diagnosing AWS.
  • A seizure in a patient with AWS who has never had a previous seizure warrants a complete neurological work-up and cranial imaging.
  • Patients with alcohol use disorder commonly minimize their alcohol consumption, often understating the true degree of how much alcohol they consume on a daily basis.
  • Benzodiazepines are always your first line treatment for alcohol withdrawal syndromes.

References/Further Reading

  1. Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal.  N Engl J Med.  2003 May 1;348(18):1786-95.
  2. Schuckit MA. Alcohol-use disorders.  Lancet.  2009;373:492-501.
  3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders.  5th  DSM-5.  Washington, DC:  American Psychiatric Publishing, 2013.
  4. Schuckit MA. Ethanol and methanol.  In:  Brunton LL, Chabner BA, Knollmann BC, eds.  Goodman and Gilman’s the pharmacologic basis of therapeutics.  12th  New York:  McGraw-Hill, 2011:629-47.
  5. Schuckit MA. Recognition and management of withdrawal delirium (delirium tremens).  N Engl J Med.  2014 November 371;22:2109-2113.
  6. Yanta JH, Swartzentruber GS, Pizon AF. Alcohol withdrawal syndrome:  Improving outcomes through early identification and aggressive treatment strategies.  EB Medicine.  2015 June 17;6:1-20.
  7. Mainerova B, Prasko J, Latalova K, et al. Alcohol withdrawal delirium—diagnosis, course and treatment.  Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2013;157:1-9.
  8. Etherington JM. Emergency management of acute alcohol problems.   Part 1:  Uncomplicated withdrawal.  Can Fam Physician. 1996;42:2186.
  9. Victor M, Adams RD. The effect of alcohol on the nervous system.  Res Publ Assoc Res Nerv Ment Dis.  1953;32:526.
  10. Tsuang JW, Irwin MR, Smith TL, et al. Characteristics of men with alcoholic hallucinosis.    1994;89(1):73-78.
  11. Victor M, Brausch C. The role of abstinence in the genesis of alcoholic epilepsy.    1967;8(1):1.
  12. Eyer F, Schuster T, Felgenhauer N, et al. Risk assessment of moderate to severe alcohol withdrawal—predictors for seizures and delirium tremens in the course of withdrawal.  Alcohol Alcohol.  201146:427-33.
  13. Berggren U, Fahlke C, Berglund KJ, Blennow K, Zetterberg H, Balldin J. Thrombocytopenia in early alcohol withdrawal is associated with development of delirium tremens or seizures.  Alcohol Alcohol.  2009;44:382-6.
  14. Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium:  an evidence-based practice guideline.  Arch Intern Med.  2004;164:1405-12.
  15. Hjermo I, Anderson JE, Fink-Jensen A, Allerup P, Ulrichsen J. Phenobarbital versus diazepam for delirium tremens—a retrospective study.  Dan Med Bull.  2010;57:A4169.
  16. Ferguson JA, Suelzer CJ, Eckert GJ, Zhou XH, Dittus RS. Risk factors for delirium tremens development.  J Gen Intern Med.  1996;11(7):410.
  17. Cushman P Jr. Delirium tremens.  Update on an old disorder.  Postgrad Med.  1987;82(5):117.
  18. Schuckit MA, Tipp JE, Reich T, Hesselbrock VM, Bucholz KK. The histories of withdrawal convulsions and delirium tremens in 1648 alcohol dependent subjects.    1995;90(10):1335.
  19. Amato L, Minozzi S, Vecchi S, Davoli M. Benzodiazepines for alcohol withdrawal.  Cochrane Database Syst Rev.  2010;3:CD005063.
  20. Stehman CR, Mycyk MB. A rational approach to the treatment of alcohol withdrawal in the ED.  Am J Emerg Med.  2013;31(4):734-742.
  21. Saitz R, Mayo-Smith MF, Roberts MS, Redmond HA, Bernard DR, Calkins DR. Individualized treatment for alcohol withdrawal.  A randomized double-blind controlled trial.  JAMA.  1994;272(7):519.
  22. Hoffman RS, Weinhouse GL. Management of moderate and severe alcohol withdrawal syndromes.  UpToDate.  12 November 2015.
  23. Muzyk AJ, Leung JG, Nelson S, et al. The role of diazepam loading for the treatment of alcohol withdrawal syndrome in hospitalized patients. Am J Addict. 2013 Mar-Apr;22(2):113-8.
  24. Gold JA, Rimal B, Nolan A, et al. A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens.  Crit Care Med.  2007;35(3):724-730.
  25. Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal state:  a comparison of four drugs.  Am J Psychiatry.  1969;125(12):1640-1646.
  26. D’Onofrio G, Rathlev NK, Ulrich AS, et al. Lorazepam for the prevention of recurrent seizures related to alcohol.  N Engl J Med.  1999;340(12):915-919.
  27. Rosenson J, Clements C, Simon B, et al. Phenobarbital for acute alcohol withdrawal:  a prospective randomized double-blind placebo-controlled study.  J Emerg Med.  2013;44(3):592-598.
  28. Hans P, Bonhomme V, Collette J, et al. Propofol protects cultured rat hippocampal neurons against N-methyl-D-aspartate receptor-mediated glutamate toxicity.  J Neurosurg Anesthesiol.  1994;6(4):249-253.
  29. Irifune M, Takarada T, Shumizu Y, et al. Propofol-induced anesthesia in mice is mediated by gamma-aminobutyric acid-A and excitatory amino acid receptors.  Anesth Analg.  2003;97(2):424-429.
  30. Tolonen J, Rossinen J, Alho H, Harjola VP.  Dexmedetomidine in addition to benzodiazepine-based sedation in patients with alcohol withdrawal delirium.  Eur J Emerg Med.  2013 Dec;20(6):425-7.
  31. Asplund CA, Aaronson JW, Aaronson HE. 3 regimens for alcohol withdrawal and detoxification.  J Fam Pract.  2004;53(7):545-554.
  32. Arendt RM, Greenblatt DJ, deJong RH, et al. In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamics action and peripheral distribution.  J Pharmacol Exp Ther.  1983;227(1):98-106.

Pneumonia Mimics: Pearls and Pitfalls

Authors: Drew A. Long, BS (@drew2232, Vanderbilt University School of Medicine, US Army) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) & Justin Bright, MD (@JBright2021, Senior Staff Physician, Henry Ford Hospital)

It’s a busy day in the ED. You have a full waiting room and multiple patients who have been roomed but not seen. You force your exhaustion to the back of your mind as you see your next patient: a 52-year-old male with cough and shortness of breath for three days. He states he has felt warm at home, but he denies chest pain, abdominal pain, vomiting, and diarrhea. He has experienced several episodes of nausea.  His past medical history includes hypertension and hyperlipidemia.

His vital signs include HR 103, RR 24, BP 128/72, T 99.8, and SpO2 95% on room air. He has some crackles in the lower lung bases, but has an otherwise normal physical exam. You order a chest x-ray, which demonstrates a right lower lobe infiltrate. As you write the diagnosis of “pneumonia” on the discharge form and write a prescription for antibiotics, you pause. Is there something else you could be missing? Are there other diagnoses you should consider?


Pneumonia is defined as an acute infection of the pulmonary alveoli.  Pneumonia can be life-threatening, most commonly in older patients with comorbidities or immunocompromised patients.  It is the 7th leading cause of death in the U.S. and the number one cause of death from infectious disease in the U.S.1   The annual incidence of community acquired pneumonia (CAP) ranges from 2 to 4 million, resulting in an estimated annual 500,000 hospitalizations.1  Pneumonia is broken into several categories: community-acquired (CAP), hospital-acquired, healthcare-associated (HCAP), and ventilator-associated (VAP) (Table 1).

Table 1.  Classification of Pneumonia (Adapted from Maloney G, Anderson E, Yealy DM.  Tintinalli’s Emergency Medicine:  A Comprehensive Study Guide.  Chapter 65:  Pneumonia and Pulmonary Infiltrates.  McGraw Hill Professional 2016.  8th ed.)



Community-acquired pneumonia



Acute pulmonary infection in a patient who is not hospitalized or residing in a long-term care facility 14 or more days before presentation



Hospital-acquired pneumonia


New infection occurring 48 hours or more after hospital admission




Healthcare-associated pneumonia


Patients hospitalized ≥ 2 days within past 90 days

Nursing home/long-term care residents

Patients receiving home IV therapy

Dialysis patients

Patients receiving chronic wound care

Patients receiving chemotherapy

Immunocompromised patients



Pneumonia can be caused by bacteria, viruses, or fungi.  However, it is often challenging to differentiate between these in the ED, and many patients will not have an etiologic agent identified even after inpatient evaluation.   It is estimated that a microbial agent cannot be identified in nearly half of cases of CAP.1 The “typical” pathogens in patients hospitalized with pneumonia include S. pneumoniae and H. influenza, with S. pneumoniae being the most common.  The “typical” pathogens are thought to account for about half of cases.1 “Atypical” pathogens include Legionella, Mycoplasma, and Chlamydia.  The most common identified viral causes of pneumonia are influenza and parainfluenza viruses.  Fungal pneumonia is often associated with patients who are immunocompromised or possess other risk factors.1,2

History and Physical Examination

The classic presentation of pneumonia is a cough productive of purulent sputum, shortness of breath, and fever.  The most common signs of pneumonia include cough (79%-91%), fever (up to 75%), increased sputum (up to 65%), pleuritic chest pain (up to 50%), and dyspnea (approximately 70%).3 There are many patterns of presentation with a variety of these symptoms and physical findings, making the diagnosis at times difficult. Elderly or debilitated patients in particular can present with non-specific complaints, such as altered mental status without the classic symptoms.1,2 In addition, pneumonia may cause lightheadedness, malaise, weakness, headache, nausea/vomiting, joint pain, and rash.  The examination may reveal bronchial or decreased breath sounds, dullness on percussion, rales, rhonchi, or wheezing. This wide variation in symptoms and presentation provides potential for misdiagnosis, especially if other conditions are not considered.

The chest x-ray in patients with pneumonia can vary greatly.  Radiologic findings in pneumonia are used in conjunction with the physical exam to identify any area of consolidation.  The most common cause of pneumonia, S. pneumoniae, classically presents with a lobar infiltrate visualized on chest x-ray.  Other organisms, such as Staphylococcus aureus pneumonia can be seen on chest x-ray as extensive infiltration and effusion or empyema.  Klebsiella may present with diffuse, patchy infiltrates.  Other findings on chest x-ray found in various organisms include pleural effusions, basilar infiltrates, interstitial infiltrates, or abscesses.1,2,4 However, each agent can present multiple ways on chest x-ray, and many patients may not demonstrate the classic radiographic findings, especially elderly and immunocompromised patients with weakened immune systems.

PA chest radiograph showing left upper lobe pneumonia.  (Image from Marx JA.  Rosen’s Emergency Medicine:  Concepts and Clinical Practice.  Saunders 2014.  8th ed.)

 While it is tempting to diagnose pneumonia in a patient with a classic presentation (fever, cough, shortness of breath) and a supportive chest x-ray, what else should be considered?  As Table 2 shows, many conditions can be confused for pneumonia based on the history, physical exam, and radiographic findings.

Table 2.  Mimics of Pneumonia (Adapted from Marx JA.  Rosen’s Emergency Medicine:  Concepts and Clinical Practice and Maloney G, Anderson E, Yealy DM.  Tintinalli’s Emergency Medicine:  A Comprehensive Study Guide.  Chapter 65:  Pneumonia and Pulmonary Infiltrates.)

Pulmonary Embolism
Septic Emboli
Congestive Heart Failure
Cancer and leukemic infiltrates
Acute Respiratory Distress Syndrome
Bronchiolitis obliterans organizing pneumonia
Granulomatous disease
Drug induced pulmonary disease
Pulmonary fibrosis
Eosinophilic pneumonia
Allergic/hypersensitivity pneumonitis
Radiation pneumonitis
Foreign body obstruction


Unfortunately, many of these diagnoses are not even considered in a patient with a classic presentation for pneumonia until the patient fails to improve with initial antibiotic management.  Of the diagnoses listed in Table 2, several of these carry high potential for morbidity and mortality.  These include pulmonary embolism, endocarditis, vasculitis, acute decompensated heart failure, tuberculosis, primary lung cancer, and acute respiratory distress syndrome.  The remainder of this discussion will focus on differentiating each of these from pneumonia.

*Bonus: What can potentially assist providers? Ultrasound (US)!

US has demonstrated tremendous utility differentiating pneumonia from other conditions. X-ray has a sensitivity of 46-77% in diagnosing pneumonia. US findings with pneumonia include air bronchograms, b-lines, consolidations, pleural line abnormalities, and pleural effusions. Dynamic air bronchograms (those that move) are considered pathognomonic for pneumonia.  Positive likelihood ratios (LR) for these findings range from 15.6 to 16.8, with negative LR’s of 0.03 to 0.07.5,6  Please see a prior post on the use of US in pneumonia:

Air bronchograms in pneumonia (From

Pulmonary Embolism

Pulmonary embolism (PE) occurs when a thrombus, most commonly from the venous system, embolizes to the pulmonary vasculature.7,8 Like pneumonia, the clinical presentation of a PE can vary greatly, ranging from an asymptomatic patient to an ill-appearing, dyspneic patient.  PE can be easily confused with pneumonia, as the most common presenting symptom is dyspnea followed by pleuritic chest pain and cough.8,9 Fever can also be present in pulmonary embolism. The most common symptoms and their frequency are shown in Table 3.

Table 3.  Signs and Symptoms Of Pulmonary Embolism (adapted from Stein PD, Beemath A, Matta F, et al.  Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med. 2007;120(10):871.)

Sign/Symptom Frequency
Dyspnea 73%
Tachypnea 70%
Pleuritic Chest Pain 66%
Rales 51%
Cough 37%
Tachycardia 30%
S4 heart sound 24%
Accentuated P2 23%
Hemoptysis 13%
Circulatory collapse 8%


A PE most commonly has non-specific chest x-ray findings (atelectasis, pleural effusion, peripheral infarct/consolidation, elevated hemidiaphragm) or is normal.2  That being said, while a normal chest x-ray is helpful in distinguishing PE from pneumonia, a normal chest x-ray does not definitively exclude pneumonia or pulmonary embolism.  Hampton’s Hump (peripheral wedge-shaped opacity with base against pleural surface) and Westermark’s Sign (focus of oligemia and vessel collapse distal to the PE) are classic findings in the PE radiograph, but they lack sensitivity.

The important aspect of not missing PE is first considering it. As the presentation of PE is nonspecific, clinical gestalt and risk stratification are useful. Evaluate the patient for signs/symptoms of PE including shortness of breath with pleuritic chest pain, tachypnea, and leg swelling in the setting of risk factors such as recent travel history, prior history of thrombosis, family history of thrombosis, or history of cancer.  If signs and/or symptoms are present and concerning, do not hesitate to begin the workup for PE.

In PE, US may reveal RV strain with dilated RV and free wall hypokinesis and normal RV apical contractility (McConnell Sign). On short axis view, the LV will appear “D” shaped, with RV bowing into the LV due to elevated right-sided pressures.10-12

Enlarged RV when compared to LV in setting of acute PE (from


Endocarditis is most commonly caused by a bacterial agent, with a one-year mortality of 40%.13 The most common symptoms are intermittent fever (85%) and malaise (80%).1  Additionally, endocarditis can present with dyspnea, chest pain, cough, headache, weakness, and myalgias.  Infective endocarditis (IE) can easily be confused with pneumonia in a patient presenting with fever and dyspnea or chest pain.  Risk factors for IE are shown below in Table 4.  Diagnosis includes the Duke Criteria. A patient with flu-like symptoms (cough, myalgias, etc.) with the risk factors shown in Table 4, warrants further evaluation for IE. 13-17

Table 4.  Risk factors for IE

Age ≥ 60 (over half of cases occur in this population)
History of IV drug use
Poor dentition or dental infection
Structural heart disease (e.g. valvular or congenital)
Presence of prosthetic valve
Presence of intravascular device
Chronic hemodialysis


One of the most important aspects to not miss is the patient with multiple infiltrates on chest x-ray, as a dreaded complication of IE is septic emboli.  This has been described in 13 to 44% of patients with IE.18,19 Septic emboli can lead to damage in the systemic or pulmonary artery circulation, depending on left vs. right-sided disease.  Specifically, embolization can lead to stroke, paralysis, blindness, ischemia of the extremities, splenic or renal infarction, pulmonary emboli, or an acute myocardial infarction.18 In particular, septic emboli from the right heart to the pulmonary arteries can lead to a toxic-appearing patient with fever and shortness of breath.  Again, the chest x-ray may demonstrate multiple infarcts or consolidations. This patient may originally be worked up for pneumonia.  In the patient with IE risk factors described above and multiple consolidations/infarcts on chest x-ray, strongly consider IE and obtain multiple blood cultures and echocardiogram.  US may reveal valvular vegetation(s) and/or regurgitation.

Multiple emboli with consolidations from R sided IE (From
Valvular Regurgitation with Vegetation in Endocarditis (From Journal of Medicine Cases,

Vasculitis (Systemic Lupus Erythematosus)

A vasculitis that often manifests with pulmonary involvement is systemic lupus erythematosus (SLE).  SLE is an autoimmune disorder that leads to inflammation of multiple organ systems.  Pulmonary involvement is common and has been observed in up to 93% of patients with SLE.20,21 Lung involvement in SLE often manifests as pleurisy, coughing, and/or dyspnea.21-23 The most common respiratory condition among patients with SLE is pleuritis, thought to be due to autoantibodies damaging the pleura itself.1 Pneumonitis may also occur in the setting of SLE. Patients with acute lupus pneumonitis present with a rapid onset of fever, cough, and dyspnea, with elevation of serum antinuclear antibodies and anti-DNA antibodies.22,23

Patients with SLE (either diagnosed or undiagnosed) and lung involvement should be worked up for infection.  Since patients with SLE are often immunosuppressed due to immunomodulatory therapy and the disease itself, they are at a much higher risk of infection with both typical and opportunistic agents.  The patient with extrapulmonary features of SLE (e.g. malar rash, oral ulcers, polyserositis, renal insufficiency, cytopenia, thrombophilia, lymphadenopathy, splenomegaly, or arthritis) and signs of lung involvement warrants treatment for infection and worsening vasculitis. Consultation with rheumatology and the ICU is recommended due to the potential for rapid decompensation.

Diffuse alveolar hemorrhage (DAH) is one of the most life-threatening conditions in SLE. Diffuse alveolar damage is a more common presentation in patients who already have a documented history of lupus and rarely presents as the initial manifestation of lupus.  These patients present with severe shortness of breath, hemoptysis, and diffuse patchy infiltrates on chest x-ray. Patients often require intubation, ICU admission, and high dose steroids.24-26

Heart Failure Exacerbation

A patient with heart failure exacerbation can present similarly to a patient with pneumonia, particularly if a patient has undiagnosed heart failure.  Patients with acute decompensated heart failure most commonly present with cough, shortness of breath, fatigue, and/or peripheral edema.  The history and physical exam may be enough to differentiate a heart failure exacerbation from pneumonia.  A history of orthopnea and/or paroxysmal nocturnal dyspnea leading up to the patient’s presentation is sensitive and specific for heart failure.  Furthermore, many of these patients will have a cardiac history, history of cardiac procedures, and comorbid conditions for CHF (such as diabetes, hypertension, hyperlipidemia, or a history of smoking).  Physical exam may reveal an S3 or S4 heart sound, elevated jugular venous pressures, lower extremity edema, and crackles indicating interstitial pulmonary edema on auscultation of the lungs.  These patients often have nonspecific EKGs showing left-ventricular hypertrophy, bundle branch block, or signs of a previous MI such as prominent Q waves or T wave inversions.  BNP will more likely be elevated in CHF exacerbations, though sepsis from pneumonia can also increase BNP.1,27

The chest x-ray findings in CHF may include prominent interstitial markings, cardiomegaly, and pleural effusions.2

CXR in a patient with CHF depicting cardiomegaly, alveolar, and interstitial edema (From

US in the setting of CHF will reveal b-lines in 3 or more lung fields bilaterally, which has a +LR of 20. The IVC will often reveal significant distension, with 2-2.5cm in size and < 50% collapse. Echocardiogram may reveal depressed contractility if systolic dysfunction is present.28

Multiple b-lines in the setting of acute CHF (From,


Tuberculosis (TB) is currently the world’s second leading infectious cause of death.1 The lungs are the major site for infection with Mycobacterium tuberculosis.  TB can occur in multiple forms, including primary TB, reactivation TB, laryngeal TB, endobronchial TB, lower lung field TB infection, and tuberculoma.29 As TB affects the lungs and can present with fever, cough, or dyspnea, it is often misdiagnosed as viral or bacteria pneumonia.  There are a wide array of nonspecific signs and symptoms associated with the multiple forms of TB, shown in Table 5.30

Table 5.  Symptoms and Signs of Tuberculosis (Adapted from Barnes PF, et al:  Chest roentgenogram in pulmonary TB: new data on an old test. Chest. 94:316, 1988.)

Symptom or Sign Frequency
Cough 78%
Weight loss 74%
Fatigue 68%
Tactile fever 60%
Night sweats 55%
Chills 51%
Anorexia 46%
Chest pain 40%
Dyspnea 37%
Hemoptysis 28%


In differentiating TB from pneumonia, it is important to assess the patient for risk factors for TB.  The most commonly reported behavioral risk factor among patients with TB in the U.S. is substance abuse (including drugs, tobacco, and alcohol).31 Other risk factors include malnutrition, systemic disease (silicosis, malignancy, diabetes, renal disease, celiac disease, or liver disease), or patients who are immunocompromised or homeless.32  Additionally, TB should be considered when a patient has a history of recent travel to an area where TB is endemic (Africa, the Middle East, Southeast and East Asia, and Central and South America).33

 As TB has many forms, the chest x-ray in TB can vary and may not be all that helpful in differentiating TB from pneumonia.  In summary, TB should be suspected in a patient with vague symptoms who possesses risk factors for TB, particularly in patients who are homeless, immunosuppressed, have a history of drug use, or have recently traveled to a TB endemic area.

Primary Lung cancer

In 2012, lung cancer worldwide was the most common cancer in men and the third most common cancer in women.34 In the U.S., lung cancer occurs in an estimated 225,000 patients every year and is responsible for over 160,000 deaths.35 There are many risk factors for cancer, the most notorious of which is smoking.

A patient with a primary lung cancer can easily be confused with pneumonia due to the similarity of symptoms (Table 6).  What is key in primary lung cancer is these symptoms have a more insidious onset than the relatively more acute onset of symptoms in pneumonia. Furthermore, these symptoms will progress over time and may include symptoms less commonly seen in pneumonia (weight loss, bone pain, or voice hoarseness).

Table 6.  Symptoms of lung cancer at presentation.  (Modified from: Hyde, L, Hyde, CI. Chest 1974; 65:299-306 and Chute CG, et al. Cancer 1985; 56:2107-2111).

Symptom Percent of Patients Affected
Cough 45-74%
Weight Loss 46-68%
Dyspnea 37-58%
Chest pain 27-49%
Hemoptysis 27-29%
Bone pain 20-21%
Hoarseness 8-18%


The chest x-ray in patients with lung cancer varies depending on the type and stage of cancer.  The chest x-ray in patients with a primary lung cancer may display a solitary nodule, an interstitial infiltrate, or may be normal.2

Non-small cell lung cancer.  (Image from

 If considering a primary lung malignancy in a patient whose presentation is consistent with pneumonia, more definitive imaging including CT of the chest may be warranted. Discussion with the oncology service is advised.

Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome (ARDS) is acute, diffuse, inflammatory lung injury that carries high rates of morbidity, ranging from 26 to 58%.35,36 ARDS stems from diffuse alveolar damage and lung capillary endothelial injury, leading to increased capillary permeability and pulmonary edema.1 This disease manifests with respiratory distress, with patients often displaying tachycardia, tachypnea, hypoxemia, and dyspnea.37 Arterial blood gas analysis shows hypoxemia in addition to acute respiratory alkalosis and increased alveolar-arterial oxygen gradient (though ABG is usually not required in the ED).  A chest radiograph will typically reveal bilateral alveolar infiltrates, and classically, no cardiomegaly is seen.2

Chest radiograph depicting bilateral lung opacities in a patient with ARDS.  (Image from

When considering ARDS, several factors come into play.  The diagnosis of ARDS is complicated, as the most common cause or ARDS is sepsis. Thus, ARDS may result from a prior pneumonia leading to sepsis. The patient with ARDS will appear sick and will likely require high levels of FiO2 or positive pressure ventilation if not intubated, while the severity of pneumonia varies greatly based on the patient and infectious microbe.  Risk factors such as sepsis, aspiration, and multiple transfusions are commonly seen with ARDS.38 Other risk factors for ARDS include alcohol abuse, trauma, and smoke inhalation.  On physical exam, patients with ARDS often have diffuse crackles on auscultation of the lungs.  The chest x-ray shows more diffuse involvement than would be expected in a patient with pneumonia.2 US will reveal b-lines in multiple lung fields.  If concerned for ARDS, be ready to intubate the patient for clinical course/oxygenation and admit to the ICU.

Case resolution

As you return to this 52-year-old gentleman’s room with his prescription for antibiotics, you notice that he remains tachycardic, tachypneic, and hypoxic (HR 105, RR 24, SpO2 93%).  You perform a more complete review of systems and find out this gentleman has been experiencing pain in his right calf over the past week after returning from an overseas business trip.  On exam, you notice that his right lower extremity is slightly edematous compared to the left.  In addition to pneumonia, you decide to begin to work up this gentleman for a possible deep venous thrombosis and pulmonary embolism.  A chest CT reveals a large right-sided segmental PE.


Many potentially deadly conditions can be confused for pneumonia.  Unfortunately, many of these conditions are not considered until the patient fails to improve after treatment with antibiotics.  The following should be considered in a patient presenting with signs of pneumonia:

  • Pulmonary embolism: suspect when a patient has signs/symptoms of PE including shortness of breath with pleuritic chest pain, tachypnea, and leg swelling in the setting of risk factors for DVT/PE.
  • Endocarditis/septic emboli: consider in febrile patients with risk factors including history of IV drug use, poor dentition, structural heart disease, or the presence of a prosthetic valve. Septic emboli leading to pulmonary infarction can present with multiple infiltrates on chest x-ray.
  • Systemic Lupus Erythematosus: pulmonary involvement is very common in lupus. Patients with SLE and lung involvement must always be evaluated for infection, and diffuse alveolar hemorrhage is a life-threatening complication.
  • Heart Failure exacerbation: suspect in a patient with cardiac history and signs/symptoms of heart failure (orthopnea, PND, peripheral edema, elevated jugular venous distension, etc.).
  • Tuberculosis: suspect in patients with risk factors for TB including substance abuse, malnutrition, systemic diseases, immunocompromise, or recent foreign travel.
  • Lung cancer: suspect in patients with insidious onset of symptoms and in patients complaining of constitutional symptoms such as weight loss or fatigue.
  • Acute Respiratory Distress Syndrome: suspect in toxic-appearing patients with white-out on chest x-ray who require high levels of FiO2 or positive pressure ventilation.


References/Further Reading

  1. Marx JA. Rosen’s Emergency Medicine:  Concepts and Clinical Practice.  Saunders 2014.  8th
  2. Maloney G, Anderson E, Yealy DM. Tintinalli’s Emergency Medicine:  A Comprehensive Study Guide.  Chapter 65:  Pneumonia and Pulmonary Infiltrates.  McGraw Hill Professional 2016.   8th
  3. Fine MJ, Stone RA, Singer DE et al. Processes and outcomes of care for patients with community-acquired pneumonia:  results from the Pneumonia Patient Outcomes Research Team (PORT) cohort study.  Arch Intern Med 159:  970, 1999.
  4. Bartlett JG. Diagnostic approach to community-acquired pneumonia in adults.  UpToDate.  Jan 2016.
  5. Hu QJ, Shen YC, Jia LQ, et al. Diagnostic performance of lung ultrasound in the diagnosis of pneumonia: a bivariate meta-analysis. Int J Clin Exp Med. 2014;7(1):115-21. [pubmed]
  6. Chavez MA, Shams N, Ellington LE, et al. Lung ultrasound for the diagnosis of pneumonia in adults: a systematic review and meta-analysis. Respir Res. 2014;15:50. [pubmed]
  7. Thompson BT. Overview of acute pulmonary embolism in adults.  UpToDate.  Jan 2016.
  8. Thompson BT. Clinical presentation, evaluation, and diagnosis of the adult with suspected acute pulmonary embolism.  UpToDate.  Jan 2016.
  9. Stein PD, Beemath A, Matta F, et al. Clinical characteristics of patients with acute pulmonary embolism:  data from PIOPED II.  Am J Med.  2007;120(10):871.
  10. Perera, T. Mailhot, D. Riley, and D. Mandavia, “The RUSH exam: rapid ultrasound in Shock in the evaluation of the critically ill,” Emergency Medicine Clinics of North America, vol. 28, no. 1, pp. 29–56, 2010.
  11. P. Borloz, W. J. Frohna, C. A. Phillips, and M. S. Antonis, “Emergency department focused bedside echocardiography in massive pulmonary embolism,” Journal of Emergency Medicine, vol. 41, no. 6, pp. 658–660, 2011.
  12. Madan and C. Schwartz, “Echocardiographic visualization of acute pulmonary embolus and thrombolysis in the ED,” American Journal of Emergency Medicine, vol. 22, no. 4, pp. 294–300, 2004.
  13. Murdoch DR, Corey GR, Hoen B. Clinical Presentation, Etiology and Outcome of Infective Endocarditis in the 21st Century:  The International Collaboration on Endocarditis-Prospective Cohort Study.  Arch Intern Med.  2009 Mar 9;169(5):463-473.
  14. Sexton DJ. Epidemiology, risk factors, and microbiology of infective endocarditis.  UpToDate.  Jan 2016.
  15. Hill EE, Herijgers P, Claus P. Infective endocarditis:  changing epidemiology and predictors of 6-month mortality:  a prospective cohort study.  Eur Heart J.  2007;28(2):196.
  16. Cantrell M, Yoshikawa TT. Infective endocarditis in the aging patient.  Gerontology.  1984;30(5):316.
  17. Castillo FJ, Anguita M, Castillo JC, et al. Changes in the Clinical Profile, Epidemiology and Prognosis of Left-sided Native-valve Infective Endocarditis Without Predisposing Heart Conditions.  Rev Esp Cardiol (Engl Ed).  2015 May;68(5):445-8.  Epub 2015 Mar 16.
  18. Spelman D, Sexton DJ. Complications and outcome of infective endocarditis.  UpToDate.  Jan 2016.
  19. Steckelberg JM, Murphy JG, Ballard D, et al. Emboli in infective endocarditis:  the prognostic value of echocardiography.  Ann Intern Med.  1991;114(8):635.
  20. Dellaripa PF, Danoff Sonye. Pulmonary manifestations of systemic lupus erythematosus in adults.  UpToDate.  Jan 2016.
  21. King Jr. TE, Kim EJ, Kinder BW. Connective tissue diseases:  In:  Interstitial Lung Disease, 5th, Schwartz MI, King TE Jr. (Eds), People’s Medical Publishing House-USA, Shelton, CT 2011.
  22. Matthay RA, Schwarz MI, Petty TL, et al. Pulmonary manifestations of systemic lupus erythematosus:  review of twelve cases of acute lupus pneumonitis.  Medicine (Baltimore).  1975;54(5):397.
  23. Wiedemann HP, Matthay RA. Pulmonary manifestations of systemic lupus erythematosus.  J Thorac Imaging.  1992;7(2):1.
  24. Zamora MR, Warner ML, Tuder R, Schwarz MI. Diffuse alveolar hemorrhage and systemic lupus erythematosus.  Clinical presentation, histology, survival, and outcome.  Medicine (Baltimore).  1997;76(3):192. 
  25. Andrade C, Mendonca T, Farinha F, et al. Alveolar hemorrhage in systemic lupus erythematosus:  a cohort review.  Lupus.  2016 Jan;25(1):75-85.  Epub 2015 Sep 18.
  26. Collard HR, Schwarz MI. Diffuse alveolar hemorrhage. Clin Chest Med 2004;25:583–592, vii.
  27. Borlaug BA. Clinical manifestations and diagnosis of heart failure with preserved ejection fraction.  UpToDate.  Jan 2016.
  28. Ang S-H, Andrus P. Lung Ultrasound in the Management of Acute Decompensated Heart Failure. Current Cardiology Reviews. 2012;8(2):123-136.
  29. Pozniak A. Clinical manifestations and complications of pulmonary tuberculosis.  UpToDate.  Jan 2016.
  30. Barnes PF, et al: Chest roentgenogram in pulmonary TB:  new data on an old test.  94:316, 1988.
  31. Oeltmann JE, Kammerer JS, Pevzner ES, Moonan PK. Tuberculosis and substance abuse in the United States, 1997-2006.  Arch Intern Med.  2009;169(2):189.
  32. Horsburgh CR. Epidemiology of tuberculosis.  UpToDate.  Jan 2016.
  33. World Health Organization. Global Tuberculosis Report 2014.
  34. World Cancer Research Fund International. Worldwide Data.
  35. MacCallum NS, Evans TW. Epidemiology of acute lung injury.  Curr Opin Crit Care.  2005;11(1):43.
  36. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury.  N Engl J Med.  2005;353(16):1685.
  37. Hansen-Flaschen J, Siegel MD. Acute respiratory distress syndrome:  Clinical features and diagnosis in adults.  UpToDate.  Jan 2016.
  38. Siegel MD. Acute respiratory distress syndrome:  Epidemiology, pathophysiology, pathology, and etiology in adults.  UpToDate.  Jan 2016.

Bell’s Palsy: Pearls and Pitfalls in Evaluation and Management

Authors: Drew A. Long BS (@drewlong2232, Vanderbilt University School of Medicine, US Army) and Brit Long MD (@long_brit, EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Stephen Alerhand, MD (@SAlerhand)

A 32 year-old man presents to the Emergency Department complaining of facial drooping. He states that over the past two days, he has had increasing difficulty moving the right side of his face. He first noticed his mouth drooping on the right side along with difficulty closing his right eye. He has no history of any previous episode like this, no past medical history, and no history of trauma. His vitals are normal. Physical exam reveals complete paralysis of the right side of his facial muscles, though the rest of the neurologic exam is normal. What conditions are important to rule out? How do you treat this patient? What do you tell him when he asks if and how soon he will regain normal function?
BP face
32 year-old male presenting to E.D. with facial weakness


Bell’s palsy (BP) is a unilateral facial paralysis resulting from lower motor neuron involvement of Cranial Nerve VII.1 While the exact pathogenesis is unclear, BP is thought to occur from inflammation and swelling of the facial nerve at the geniculate ganglion, which can cause compression and ischemia or demyelination of the nerve.2,3 The exact etiology of BP is controversial; reactivated herpes simplex virus is thought to be the most probable cause followed by herpes zoster virus.3,4 It affects about 40,000 people in the U.S. every day,5 affects men and women equally, and has a median age of onset of 40.2 BP is more common in diabetics and pregnant women, with diabetics making up 5-10% of patients.6,7 The risk of developing BP increases threefold during pregnancy, especially the third trimester, which is thought to occur due to swelling of the facial nerve.8

How does BP present? The presentation can be linked to its involvement with the facial nerve. The facial nerve is a mixed nerve and has motor, sensory, and parasympathetic components. It has four major functions:3

  1. Voluntary facial movement (motor fibers)
  2. Lacrimal, submandibular, and sublingual gland secretions (parasympathetic fibers)
  3. Taste of anterior two-thirds of tongue (afferent fibers from taste receptors)
  4. Sensation of external auditory canal and pinna (somatic afferent fibers)

The classic presentation of BP is a patient with partial or complete weakness of the muscles on one half of the face. This results in an inability to raise eyebrows, wrinkle the forehead, or close the eyelid. Furthermore, the nasolabial fold is lost and the mouth will droop. These deficits all result from involvement of the motor component of the facial nerve. Involvement of the parasympathetic fibers leads to decreased tear production and salivation. Involvement of the afferent fibers from taste receptors leads to alterations and lack of taste sensation. Lastly, hyperacusis or ear pain may occur due to involvement of the somatic afferent fibers to the external auditory canal and pinna.1-4

Several factors set the presentation of BP apart from other conditions that can affect the facial nerve. The onset is acute, often occurring overnight.5 While acute, BP does not develop over a matter of minutes but instead progresses over hours, usually peaking within 72 hours.1 Additionally, a patient with BP should not complain of any facial pain and should not have any cranial nerve involvement other than the facial nerve. BP is usually unilateral, and bilateral facial palsy suggests a diagnosis other than BP.1-5

An important distinction to make during the exam is involvement of the forehead. The innervation of the upper facial muscles is bilateral and that of the lower facial muscles unilateral. If the patient has weakness of the lower half of his/her face but not the upper half, an intracranial process should be suspected.3,9 Thus a patient who has a drooping mouth but is able to wrinkle his/her forehead must be worked up immediately, with stroke at the forefront of consideration. Unfortunately, despite what we are taught, complete unilateral facial paralysis does not exclude an intracranial process, and if the history or presentation is concerning for an upper motor neuron process the patient should receive further evaluation.

BP innervation
Innervation of the upper and lower facial muscles


The differential for facial nerve palsy is broad. The main diagnoses to consider when a patient’s presentation is suspicious for BP can be grouped into infectious, inflammatory, neoplastic, and cerebrovascular categories.1 This grouping is shown in Table 1. Additionally, trauma can result in facial nerve palsy; this can be gathered from the history and will likely also be evident on exam. Ultimately, what every physician is worried about missing is stroke or an intracranial process.

Table 1. Differential Diagnosis of Bell’s Palsy.1,3

Infectious Ramsay-Hunt Syndrome, Otitis Media, Lyme Disease, HIV


Inflammatory Guillain-Barré syndrome, Sarcoidosis, Sjögren syndrome 
 Neoplastic  Tumor
 Cerebrovascular  Ischemic or Hemorrhagic Stroke


When considering the differential for BP, the history and physical will often be enough to exclude most of these conditions. A history of hypertension, diabetes, smoking, dyslipidemia, or cardiovascular disease calls for close evaluation of other deficits. Likewise, risk factors for HIV, such as IV drug use or risky sexual behavior, necessitates HIV testing. Any history of a prior cancer or of facial palsy that progresses over weeks or months is concerning for either brain metastasis or expansion of an intracranial tumor. The physical exam will be enough to rule out Ramsay-Hunt Syndrome (which will present with an erythematous vascular rash in the ear) and otitis media (facial paralysis is a potential complication). Facial nerve palsy is the most common cranial neuropathy associated with Lyme disease, and was found to occur in up to 63% of patients with Lyme meningitis in one study.10 However, Lyme disease often presents with other symptoms preceding the facial paralysis, such as erythema migrans, heart block, or arthritis.3 Unfortunately, patients often do not recall exposure to a tick. While Guillain-Barré syndrome can present with facial weakness in up to 50% of patients,11,12 it is most commonly bilateral and occurs with symmetric muscle weakness and absent or decreased deep tendon reflexes. Neurosarcoidosis can frequently result in cranial neuropathy including facial nerve palsy and should be considered in a patient with a history of sarcoidosis.3 While Sjogren’s syndrome can cause facial nerve palsy, it is uncommon to occur without other cranial neuropathies or skin, eye, and/or mouth dryness.13

When considering BP, a provider must evaluate for several red flags. These are detailed in Table 2. Presence of any of the factors warrants an evaluation for an underlying cause other than BP.

Table 2. Red Flags of Facial Nerve Palsy 1,2,9
Cranial Nerve involvement other than CN VII
Bilateral facial palsy
Step-wise progression of facial palsy or slowly progressive beyond 72 hrs
Recurrent facial palsy
Prolonged facial palsy (>4 months)
Sudden-onset complete facial palsy
Weakness or numbness of arms or legs
Unaffected upper facial muscles (forehead)
Headache, visual deficits, nausea or vomiting
History of travel through woods or tick bite
Ulceration or blisters near ear



Bell’s palsy is a clinical diagnosis, which depends on the presentation and not clinical studies. It is based on the following criteria:3

  • Diffuse involvement of the facial nerve, as seen by unilateral facial weakness, with or without loss of taste of the anterior two-thirds of the tongue or altered secretion from the salivary and/or lacrimal glands.
  • Acute onset, usually over a day or two; recovery occurs in less than 6 months.

The diagnosis depends on the history and physical exam. For BP, no other CN involvement, altered mental status, or signs of stroke/intracranial process should be present.1-5,9 The presence of any red flags in the history and physical (see Table 2) warrants additional diagnostic evaluation. If a red flag is present, further testing including a complete blood count with differential, sedimentation rate, Lyme titer, thyroid function studies, and electrolytes is warranted.4 Intracranial imaging with CT noncontrast of the head should be obtained. The best test for evaluation of intracranial processes is MRI, but this is often difficult to obtain in the ED.14

Perhaps the most worrisome mimic of BP is stroke. The possibility of stroke in a patient presenting with what looks like BP must be considered and ruled out immediately. Ischemic stroke is the second leading cause of unilateral facial paralysis, behind BP.15 As previously stated, a common rule of thumb is that upper motor neuron lesions spare the forehead, which receives bilateral upper motor neuron innervation. On the other hand, lesions that affect the facial nerve after it exits the brainstem (such as BP) result in weakness of the entire ipsilateral face. However, this rule does not always hold true, as rarely ipsilateral pontine pathology (such as ischemia or mass) can lead to a lower motor neuron pattern of facial weakness. In this case, dysfunction of the ipsilateral abducens nerve (resulting in lateral gaze palsy) will also be present, helping to differentiate a stroke of the ipsilateral pons from BP.1 In summary, when evaluating for stroke, take into account the overall clinical picture of the patient. Speak to the patient, perform a neuro exam, and look for any associated signs/symptoms, and if the possibility of a stroke is still a valid possibility, rule it out.16 CN involvement other than VII requires immediate imaging.  


Medical treatment for BP in the past has revolved around two medications: antivirals and steroids. Recent literature favors the use of steroids and not antivirals. Sullivan et al. in 2007 examined the treatment options for BP in a randomized control trial across 17 sites in Scotland. At three months, 83% of patients in the prednisolone group versus 63.6% of patients in the non-prednisolone group fully recovered while 71.2% in the acyclovir versus 75.7% in the non-acyclovir group fully recovered. Furthermore, recovery rates were lower in the group receiving prednisolone and acyclovir compared to the group receiving prednisolone alone.17 A meta-analysis in 2009 examining use of corticosteroids alone vs. antivirals alone found that treatment with steroids was associated with a reduced risk of unfavorable recovery, while treatment with antivirals alone was not.18 A second meta-analysis in 2009 determined there was no significant benefit of combined antiviral and steroid treatment compared to steroids alone.19 Currently, the recommended treatment regiment for BP is prednisone, 60 to 80 mg per day, for one week.20

In addition to medical treatment, eye care in BP patients is imperative. Severe BP can result in inability to completely close the eye in addition to decreased lacrimal secretions, leading to drying and/or tearing of the cornea. These patients should be given lubricating eye drops for use during the day in addition to a corneal lubricant to use at night.4 Furthermore, patches or taping the eyelid closed can be used at night. The patient should be referred to an ophthalmologist if they experience ocular pain or develop any ocular complications.

The prognosis of BP is good even without treatment. About 85% of patients without treatment will show signs of recovery within 3 weeks, with the other 15% recovering between 3-6 months later.21 The prognosis depends on the severity of the lesion, with less severe lesions recovering faster.20 If no facial function has returned within three to four months, the diagnosis of BP is doubtful and further investigations are warranted. Unfortunately, the recurrence rate of BP is estimated to be between 7%-15% of patients.22-25


Bell’s palsy is an idiopathic paralysis of the facial nerve and is the most common cause of lower motor neuron facial palsy. It is unilateral and acute in onset, progressing over a period of hours and reaching maximal intensity within several days. The signs and symptoms can be traced to the various functions of the facial nerve. Involvement of the forehead can be used as a baseline in differentiating lower versus upper motor neuron involvement. When evaluating BP, any features concerning for an intracranial process such as a tumor or stroke warrant further consideration. There are no tests for diagnosing BP, and the diagnosis is one of exclusion. Careful history and examination are paramount. Treatment consists of prednisone 60-80 mg per day for one week. In addition, eye care in patients with BP must be a priority. The prognosis of BP is excellent, with 85% of patients regaining function within three weeks.


References / Further Reading
  1. Eviston TJ, Croxson GR, Kennedy PGE, et al. Bell’s palsy: aetiology, clinical features, and multidisciplinary care. J Neurol Neurosurg Psychiatry. 2015;86:1356-1361.
  2. Fahimi J, Navi BB, Kamel H. Potential Misdiagnoses of Bell’s Palsy in the Emergency Department. Ann Emerg Med. 2014;63:428.
  3. Ronthal M. Bell’s palsy: pathogenesis, clinical features, and diagnosis in adult. UpToDate. October 2015.
  4. Billue JS. Bell’s Palsy: An Update on Idiopathic Facial Paralysis. Nurse Pract. 1997;22(8):88,97-100.
  5. Herbert M, Swadron S, Mallon B, Lex J. Bell’s Palsy: That was then, this is now. EMRAP. 2015;15:3-4.
  6. Mountain RE, Murray JA, Quaba A, Maynard C. The Edinburgh facial palsy clinic: a review of three years’ activity. J R Coll Surg Edinb. 1994;39(5):275.
  7. Adour KK, Byl FM, Hilsinger RL Jr, Zahn ZM, Sheldon MI. The true nature of Bell’s palsy: analysis of 1,000 consecutive patients. Laryngoscope. 1978;88(5)787.
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