Facial swelling: Etiologies, Presentations, Evaluation, and Management

Author: Winford Ko, MD (Emergency Medicine Resident, UT Southwestern/Parkland Memorial Hospital, Dallas, TX) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit) 

Case

It’s a relatively slow day during the beginning of your shift in the critical care pod. Suddenly, a tech quickly brings a new patient in a wheelchair. Your new patient is a 60-year-old female, with history of HTN, who presents with facial swelling. As you go to see her, you see a woman in distress: she has significant angioedema of the tongue/lips, tripoding, tachypneic, drooling with stridorous respirations. Your nurses quickly hook the patient up to the monitor, and she is noted to have an oxygen saturation in the 80’s. She tries to tell you more history, but given her significant swelling and respiratory distress, you are unable to understand her. She did bring a list of her medications, and of note, was recently started on Lisinopril for her HTN.

Background

Facial Swelling is a complaint with a wide differential. The etiologies of facial swelling can vary from a dental infection, to a decompensated Ludwig’s angina that is compromising the airway. As emergency clinicians, it is important to distinguish the life-threatening causes of facial swelling from the less emergent causes.

We can separate the differential of facial swelling into categories based on the location of the swelling. While the causes are expansive in nature, here are some of the important ones to consider. The bolded differentials are considered “can’t miss” diagnoses to always consider given immediate life threat.

• Orbital/Periorbital space
  • Cavernous Venous Thrombosis
  • Orbital Cellulitis
  • Myxedema Coma
• Subcutaneous
  • Facial Cellulitis
• Submandibular Space
  • Ludwig’s Angina
  • Salivary Gland pathology
• Intra-oral
  • Angioedema
  • Odontogenic infection
• Miscellaneous causes
  • Trauma
  • Superior Vena Cava Syndrome
  • Malignancy

Immediate life-threatening causes of Facial Swelling

Angioedema

Angioedema is one of the most important “can’t miss” cause of facial swelling. Angioedema is defined as subcutaneous swelling resulting from fluid extravasation into interstitial tissue. This will usually present rapidly, with initial onset within minutes. While there are numerous causes and etiologies of facial angioedema, for emergency physicians, three important causes of angioedema to consider are:

• Angioedema secondary to anaphylaxis
• Angiotensin Converting Enzyme (ACE) inhibitor-induced Angioedema
• C1 inhibitor deficiency (Hereditary Angioedema)

Angioedema secondary to anaphylaxis occurs via an IgE-mediated immune response, which activates mast cells and releases numerous inflammatory compounds, increasing vascular permeability and causing the resultant angioedema [1]. In both ACE inhibitor-induced angioedema and Hereditary Angioedema, the etiology is due to a disruption in bradykinin pathway (inhibition of bradykinin degradation from ACE inhibition, or increased production of bradykinin from C1 inhibitor deficiency) [2].

There are subtle differences in presentation among the 3 categories above. In most cases, angioedema will present with a rapid onset of swelling to the face, lips, larynx, and/or bowel. When facial swelling occurs, it will usually be swollen in the lips, tongue, and uvula. These symptoms are most prominent in ACE inhibitor-induced Angioedema [3]. It is important to try to identify the etiology of the angioedema, as this can affect the treatment. Reviewing the patient’s medications is key, specifically regarding ACE inhibitor use.

The diagnosis is usually clinical. Patients can have varying degrees of facial angioedema of the lips, tongue, uvula or larynx. In patients with anaphylaxis induced angioedema, you may also other signs including urticaria, flushing of the skin, bronchospasm, or pruritus [4].

While in the majority of cases the course of angioedema will be benign, if there is significant swelling of the tongue, upper airway, or larynx causing upper airway obstruction, this can be life threatening. Consider intubation in patient that develop any sign of airway compromise. Depending on the degree of angioedema, fiberoptic nasal intubation may be required if there is significant tongue swelling. Given the expected difficulty of the intubation, always prepare for surgical cricothyrotomy as backup if your first line techniques fail.

Aside from airway evaluation/management, treatment of angioedema is dependent on the etiology. For patients with angioedema due to anaphylaxis, immediately administer epinephrine 0.3 mg IM (for adults). You may have to repeat the dose depending on the severity of the symptoms. Consider glucocorticosteroids and antihistamines, but epinephrine is the mainstay of treatment.

Treatment of ACE inhibitor induced angioedema is to discontinue the offending agent in the long term. There are multiple therapies that can be considered, including Icatibant (which works as a bradykinin receptor inhibitor, blocking the action of bradykinin), C1 inhibitor concentrate (which will decrease Kallikrein, and in effect decrease bradykinin production), and Fresh Frozen Plasma (FFP); however, the effect of therapies is controversial. Studies show that early administration is important for the therapies to be effective [5-7]. In most cases, discontinuation of the ACE inhibitor medication and airway management will be the primary treatments. The angioedema associated with ACE inhibitors usually resolve within 1-3 days [8].

For patients that have Hereditary Angioedema, aside from airway management, primary treatment options include C1 inhibitor concentrate, Icatibant, Ecallantide (Kallikrein inhibitor). Unlike in ACE inhibitor induced Angioedema, these therapies are much more effective in treating hereditary angioedema.

Submandibular Space Infection (Ludwig’s Angina)

Submandibular space infection, otherwise known as Ludwig’s Angina, is an infection that is present in the floor of the mouth. This is a rapidly spreading infection with a high potential for decompensation and death. While mortality used to be upwards of 50%, with early directed antibiotic therapies, it has decreased dramatically to 0-4% [9]. About 2/3 of patients with Ludwig’s Angina are odontogenic in nature, usually involving the second/third mandibular molar [10]. Once present, infection can rapidly spread, causing significant swelling of the tongue and the submandibular space, and even potentially spreading to the epiglottis.

Diagnosis is usually made with history and physical, with support from imaging. Patients will usually present with fever, chills, and mouth pain. As the infection spreads, patients can develop stiffness of the neck, difficulty talking, drooling, and stridor. On exam, there is symmetric swelling and tenderness in the submandibular area, occasionally with palpable crepitus, and the tongue may protrude. The imaging of choice to evaluate for Ludwig’s angina is CT, which allows for evaluation for infection within the submandibular space and can also localize the infection in case surgery and drainage is required [11,12]. This may not be possible to obtain in the patient’s airway is in jeopardy.

The goals for treatment of Ludwig’s Angina is airway management and early antibiotic treatment. While most cases may not need an emergent airway, it is important to keep a low threshold for early intervention. It is important to obtain airway control before the onset of airway compromise (stridor, hypoxia, asphyxia) occur. Nasal fiberoptic intubation is the modality of choice if feasible, but video laryngoscopy can be considered as well, depending on a case by case basis [13]. Consider consulting anesthesia if they are in house for assistance with the airway if you feel it is necessary.

Once the airway has been evaluated and/or controlled, it is important to administer antibiotics. The choice of antibiotics is dependent on patient’s immune status. If they are otherwise healthy, it is recommended to start the following regiments summarized below [14]:

• Ampicillin-Sulbactam (3 grams IV every 6 hours) or
• Penicillin G (2 to 4 MU IV every 4-6 hours) + Metronidazole (500 mg IV every 6-8 hours) or
• Clindamycin (600 mg IV every 6-8 hours)

If there is a history of immunocompromise, they will usually require broader coverage, with the regiment below:

• Cefepime (2 g IV every 12 hours), + Metronidazole (500 mg IV every 6-8 hours) or
• Imipenem (500 mg IV every 6 hours) or
• Meropenem (1 g IV every 8 hours) or
• Piperacillin-Tazobactam (4.5 g IV every hours) or

While surgical intervention may not be needed initially, it is important to consult your otolaryngologist (ENT) colleagues early. They may consider early operative I&D versus observation for IV antibiotics. They can also assist with back-up surgical cricothyrotomy if neccessary. Depending on the severity of the infection, patient’s may need ICU management, specifically for airway monitoring. While steroids have been postulated to decrease swelling and inflammation, potentially decreasing the need for a surgical airway, there have not been any randomized control trials to demonstrate the effectiveness of steroids [15].

Decompensated Hypothyroidism/Myxedema Coma

While facial swelling is often not the main symptom associated with myxedema coma, it is important to consider, especially in a patient who has a history hypothyroidism and other signs and symptoms of hypothyroidism. This is because the mortality of myxedema coma is high, even with proper treatment.

Myxedema coma is defined as severe hypothyroidism, leading to decreased mental status and hypothermia, and other symptoms related to hypothyroidism, including bradycardia, hypotension, and hypoglycemia [16]. It can be caused by severe uncontrolled hypothyroidism or be trigged by other events such as myocardial infarction (MI), sepsis, and drugs [17].

In patients in myxedema coma, the facial swelling is noted with “puffiness” of the face diffusely. Bilateral periorbital edema and swelling of the lip and/or tongue may be present. The swelling is due to abnormal deposits of proteins and mucopolysaccharides, resulting in non-pitting edema.

Diagnosis is usually made clinically with supporting lab values. The T4 level is often very low. The TSH level can be high or low depending on the etiology [19]. However, if you have a high suspicion for myxedema coma, do not wait for lab values to initiate treatment. Treatment is thyroid hormone supplementation, usually given intravenously. Adrenal insufficiency should also be considered as well in conjunction with the hypothyroidism, with hydrocortisone.

As mentioned before, the mortality of myxedema coma is high (30%) [20]. Therefore, keep a high index of suspicion for patients that come in with facial swelling and other signs of myxedema. Death in myxedema coma is usually due to multi-organ failure.

Cavernous Sinus Thrombosis (CST)

While not a common etiology, for patients with periorbital facial swelling, cavernous sinus thrombosis (CST) is an important life-threatening diagnosis to not miss. If untreated, the mortality of CST is high [21].Prior to antibiotics the mortality rate was as high as 100%. With proper management, it is now less than 30%.

CST occurs when a thrombus forms inside of a cavernous sinus, which is the most centrally located dural sinuses, just lateral to the sphenoid sinus. The cavernous sinuses receive blood from multiple sites including the facial vein, as well as the middle cerebral vein and sphenoid veins, which then eventually empties into the internal jugular veins. Due to these sinuses not containing any valves to control the direction of blood flow, infection of the face or sinuses is usually a common etiology of CST, with the most common infection due to Staph aureus.

Initial signs and symptoms can be highly variable. Most patients will complain of a headache initially, which usually localizes to CN V (Trigeminal Nerve). They may also develop a fever, eye pain, and vision changes. As the severity increases, they can develop confusion, somnolence, and a coma. On exam, patients can have chemosis, ptosis, proptosis, and ophthalmoplegia (given the proximity of cranial nerves III, IV, and VI to the cavernous sinuses) [22].

While a non-contrasted CT head scan is usually the initial test obtained, it can be normal in 30% of cases [23]. Abnormal findings on a CT head include filling defects in the cavernous sinus as well as dilation of the superior ophthalmic vein.

However, CT is usually utilized first given faster imaging technique and rapidly available. The most accurate imaging modality to obtain an MRI with venogram (MRV), which will show decreased to no flow in the affected cavernous sinus [24]. Sensitivity of MRI with MRV can be as high as 100% [25].

Immediate treatment in the ED includes early antibiotics. While CST is usually due to S aureus, it can also be polymicrobial in nature, including gram positive, gram negative, and anaerobic bacteria. Empiric antibiotic choice should include a penicillinase-resistant penicillin and a 3^rd-4^thgeneration cephalosporin. If there is any concern for MRSA, vancomycin should be administered. Anticoagulation in the treatment of CST is controversial. Given limited data in CST due the low prevalence of the condition, anticoagulation has not been properly studied. Current data suggest with heparin or Low Molecular Weight Heparin (LMWH) such as enoxaparin to prevent the thrombus from worsening is safe [26]. Corticosteroids can be considered as well as an additional therapy to help reduce inflammation and edema, but antibiotics remain the mainstay of treatment. Patients with CST will need to be admitted to the ICU for observation and additional treatment given high mortality and morbidity.

Orbital Cellulitis

When facial swelling is localized primarily to the orbital/periorbital space, orbital cellulitis is an important diagnosis to consider. Untreated orbital cellulitis can lead to severe complications such as permanent vision loss, abscesses, cavernous venous thrombophlebitis, and even death [27]. Orbital cellulitis is an infection that involves the components of the orbit. This contrasts with periorbital cellulitis, which is an infection of the eyelid. It is vital to distinguish between the two conditions since orbital cellulitis can cause significant complications as mentioned above.

Orbital cellulitis usually affects young children but can affect adults as well. Rhinosinusitis is the most common cause of orbital cellulitis [28]. Other potential causes include recent eye surgery, trauma, and dental infections. The most common organism that causes orbital cellulitis is Staphylococcus aureus and Streptococci. Uncommon causes of orbital cellulitis include anaerobic bacteria, Pseudomonas Aeruginosa, Hemophilus Influenza, and fungal infections (mucormycosis in patients in diabetic ketoacidosis) [29].

On clinical presentation, patients will complain of eye pain, eyelid swelling, and double vision. On exam they will have pain with eye movements, proptosis, and ophthalmoplegia due to inflammation and swelling to the extraocular muscles (EOM). This is different from patients who only have periorbital cellulitis, who should not have pain with EOM or ophthalmoplegia [30].

The diagnosis is usually made with a combination of clinical judgement and imaging. CT scan is a reasonable first line imaging modality to evaluate the orbits. inflammation of extraocular muscles, fat stranding, and anterior displacement of the globe are common CT findings [31].

Most patients with orbital cellulitis can be treated with antibiotics. The empiric antibiotics of choice are list below:

• Vancomycin: 15 mg – 20 mg/kg IV daily every 8-12 hours AND
  • Ceftriaxone: 2 g IV every 24 hours OR
  • Cefotaxime: 2 g IV every 24 hours OR
  • Ampicillin-Sulbactam: 3 g IV every 6 hours OR
  • Piperacillin-Tazobactam: 4.5 g IV every 6 hours

While most cases will not require surgery, it is important to consult an Ophthalmologist and Otolaryngologist for further management, as patients with orbital cellulitis will require close monitoring for worsening of infection.

Other differentials of facial swelling to consider

Dental Infections

Dental infections comprise a large percentage of patients who present with facial swelling. Roughly 65 million of Americans greater than the age of 30 suffer from periodontal disease [32].

While isolated odontogenic infections are rarely life-threatening with antibiotics, untreated infections can potentially spread to other locations and result in dangerous conditions such as Ludwig’s Angina. Dental infections develop from colonization of bacteria onto the surface of the tooth, known as plaque. The spread of the infection is dependent on the location of the plaques. Plaques that are present above the gingival margin can lead to dental caries, which can spread to the pulp of the tooth, and potentially to the alveolar bone, causing periapical abscesses [33]. Plaques below the gingival margin can cause gingivitis and periodontal infections, which can eventually spread to the deeper fascial spaces of the face and neck [34]. Odontogenic infections may also spread towards the jaw, resulting in osteomyelitis.

Most patients below the age of 35 who present with odontogenic infections have dental caries, which is the localized destruction of dental structures from the plaque bacteria. The main causative organisms are the streptococcus species (Streptococcus mutans) [35]. As the caries worsens, it may result in further exposure of the dental pulp, leading to pulpitis and periapical abscesses as it travels towards the root of the tooth.

For patients above 35 years old, the rate of periodontal infections increases [36]. While the destructive process of the infection is often slow, rapidly spreading periodontitis can occur, resulting in periodontal abscesses, as well as deep fascial infections.

When examining patients to evaluate for odontogenic infections, be thorough. While evaluating the overall dentition, examine around the root of the tooth to look for periapical abscesses, as well the gingivae for periodontal abscesses. Given the possibility of odontogenic infections spreading to deep fascial spaces, be sure to evaluate the submandibular space for signs of Ludwig’s angina.

While imaging is often not necessary in the ED for uncomplicated odontogenic infections, CT can be useful for evaluating the bony structures for osteomyelitis, as well as evaluate the deep fascial planes for signs of spread of the infection [37].

The treatment of dental infections depends on the severity of the symptoms. Dental caries typically does not need further management in the ED and can be referred to a dentist. Uncomplicated gingivitis rarely requires systemic antibiotics, and chlorhexidine 0.12 % oral rinse can be used, which has anti-bacterial properties [38].

In more severe cases or if there is a presence of an abscess, systemic antibiotics can be prescribed:

• Amoxicillin 500 mg PO every 8 hours or
• Amoxicillin-Clavulanate 875 mg PO every 12 hours or
• Clindamycin 450 mg PO every 6 to 8 hours

Simple abscesses may be drained in the ED and referred to a dentist for further management, while more complex abscesses may require a specialist for surgical drainage, especially when spreading to other fascial planes.

Facial Cellulitis

Facial cellulitis can present with facial swelling due to the infection spreading to the dermis and subcutaneous tissue. Most infections are due to Streptococcus pyogenes and Staphylococcus species, including MRSA [39]. Often times there will be overlying erythema and warmth. It is important to distinguish between simple facial cellulitis versus more complex infections such as orbital cellulitis, or deep space infections such as Ludwig’s Angina, as those can be life-threatening. Imaging is rarely required unless you have a concern for a more severe infection include deep space infection, or orbital cellulitis, in which a CT would be recommended. Treatment involves antibiotics tailored to the suspected organisms.

Superior Vena Cava Syndrome (SVC syndrome)

Superior vena cava syndrome (SVC syndrome) is an important cause of facial swelling to identify. SVC syndrome is a constellation of symptoms that results from blood flow obstruction from the superior vena cava. The majority of cases are due to underlying malignancy, with non-small cell lung cancer (NSCLC) being the most common malignancy [40].

Obstruction of the SVC from malignancy is due to external compression of the vessel or invasion of the malignancy into the vessel. Other causes of SVC syndrome include thromboses (especially with the presence of indwelling intravascular devices), infection, or radiation therapy. Clinical presentation of SVC syndrome consists of dyspnea, facial swelling, or head fullness [41]. Patients may also have arm swelling, cough, and chest pain. The severity of the symptoms depend on how fast the SVC obstruction develops. On exam, facial edema will often be evident, along with venous distention of the neck and chest. If severe, patients can also develop stridor due to acute compression.

Chest X-ray may show a mediastinal mass but is nonspecific. A CT chest with IV contrast is usually the preferred imaging modality, which can define the vascular anatomy and determine the location of the blockage, as well as the etiology [42].

Treatment is usually supportive, as well as treating the etiology of the SVC syndrome. The head of the bed should be elevated. IM injections of the upper extremities should be avoided due to the obstructed venous system delaying drug absorption. Corticosteroids and diuretics can be considered, though their effectiveness is controversial [43] [44]. For patients that develop SVC syndrome secondary to malignancy, radiation therapy is often indicated. Anticoagulation for SVC syndrome secondary to thrombus is recommended.

Malignancy

Malignancies of the head and neck are the 6^th most common malignancy, with the most common squamous cell carcinoma (SCC) [45]. Malignancies can involve a variety of structures including the oral cavity, pharynx, soft tissue, bone, and larynx. Malignancies of the face are usually a chronic cause of unilateral facial swelling [46]. Patients will usually present with a slow growing mass on the face. Advance imaging including CT and/or MRI is often necessary to evaluate the anatomy and the extent of the malignancy. It is important to rule out any other etiologies that may be contributing, such as cellulitis, as well as evaluate for airway involvement.

Trauma

Be sure not to miss any facial trauma when evaluating a patient, especially if history is limited. The face is complex, including multiple structures: bones, nerves, vasculature, glands, muscles, and muscles, and when injured, may cause complications with breathing, vision, talking, and with the central nervous system. The majority of facial trauma is due to blunt trauma, from violence or motor vehicle collisions (MVC’s) [47].  Facial trauma secondary to gunshot wounds (GSW) often possess a higher mortality rate.

As with all traumas, focus on the initial primary survey, and identify any life-threatening injuries. With severe facial trauma, be sure to identify injuries that may impair breathing or that affects the airway.

Once the primary survey is completed, a secondary survey can then be performed. Be sure to perform a thorough exam to evaluate for any abnormalities. While we won’t go into too much of the specifics regarding facial trauma, here are some quick pearls:

• For ocular trauma, examine the pupils for reactivity and size, as well as extra-ocular movements and visual acuity. If there are signs of any orbital trauma, evaluate for proptosis and signs of retrobulbar hematoma/open globe injuries. These are ophthalmologic surgical emergencies and can’t be missed!
• Any lacerations near the medial aspect of the eye/eyelid should raise your suspicion for a nasolacrimal duct injury, which will usually need to be repaired by a specialist.
• The bedside halo test to evaluate for CSF leak is sensitive, but does not differentiate between CSF or any other clear liquids (saline, saliva, sweat, etc.) [48].
• Facial fractures that warrant urgent evaluation by a specialist and admission include the following
  • LeFort fractures of the midface
  • Facial fractures in patients with multi-organ trauma
  • Zygomatic arch fractures associated with trismus (airway monitoring)
  • Nasoethmoid fractures, to evaluate for CSF leaks

Salivary gland pathology

Though rarely life-threatening, salivary gland pathology (stones or infection), can also cause facial swelling. Salivary gland stones, or sialolithiasis, can be common. Once the gland becomes inflamed, it causes sialoadenitis, either from a primary infection, or from a secondary infection. Examples of sialoadenitis include viral parotitis secondary to mumps, bacteria sialoadenitis, or from a secondary cause such as an obstructed sialolithiasis causing stasis [49].

Sialolithiasis is more common in men than women, and the majority of cases are present in patients greater than 30 years old. Risk factors include trauma, smoking, diuretics, anticholinergic medications, and dehydration [50].

The three major salivary glands are the parotid gland, submandibular gland, and submental gland. The majority occur in the submandibular gland (up to 90%) [51].

Patients will usually present with pain and swelling localized to the gland, worsened by eating or salivating. On exam, patients with sialolithiasis may have a palpable stone within the ductal system. When inflamed, the gland itself may be tender and externally erythematous [52].

While imaging may not be required for diagnosis, it can help determine the location of the stone, and if any underlying complications are present, including tumors or abscesses. Imaging modalities that can be used to diagnose sialolithiasis include ultrasound and CT. Ultrasound will detect 90% of stones > 2 mm. CT is another modality, with a high sensitivity for stone detection, up to 98% sensitivity and 88 % specificity [53].

Treatment in the Emergency Department is usually conservative. This involves instructing patients to stay hydrated, massage the gland/duct. Lemon drops or other agents that can increase salivary flow may be helpful as well. If there are any signs of secondary infection, antibiotics may be indicated.

Conclusion

Going back to our original case presentation, our patient came in with signs of ACE-inhibitor induced angioedema, causing signs of airway obstruction. The patient was emergently intubated via fiberoptic intubation without any complications. She was admitted to the MICU for further management. Eventually the angioedema resolved after 3 days, and the patient was extubated and discharged home the next day. Lisinopril and ACE inhibitors were placed on the patient’s allergies list.

Take home points

• While most causes of facial swelling are usually benign, there are certain etiologies of facial swelling that can be acutely life threatening. It is important to consider these “can’t miss” diagnoses!
  • Angioedema
  • Submandibular Space Infection/Ludwig’s Angina
  • Decompensated Hypothyroidism/Myxedema coma
  • Cavernous Sinus Thrombosis (CST)
  • Orbital Cellulitis
• The location of the swelling can help you narrow down the various etiologies of facial swelling.
• Complete a thorough exam to evaluate the location and extent of the swelling, with a focus on the airway and any pathology that could result in airway compromise.
• If there is any concern for airway compromise, TAKE CONTROL OF THE AIRWAY. The earlier, the better.
• Have an algorithm for airway management for patients with significant facial swelling. Be comfortable with multiple techniques for intubation, including Video Laryngoscopy, Fiberoptic Intubation, and Cricothyrotomy.
• For sick patients with significant facial swelling in which you are concerned for an infectious etiology, start antibiotics as soon as possible.

References/Further Reading

1. Bernstein A, Cremonesi P, Hoffmann TK, et al. Angioedema in the emergency department: a practical guide to differential diagnosis and management. International Journal of Emergency Medicine. 2017;10:15.
2. Bas M, Adams V, Suvorava T, et al. Nonallergic angioedema: role of bradykinin. Allergy. 2007 Aug. 62(8):842-56.
3. Alcoceba E, Gonzalez M, Gaig P, et al. Edema of the uvula: etiology, risk factors, diagnosis, and treatment. J Investig Allergol Clin Immunol 2010; 20:80.
4. Greaves MW, Sabroe RA. ABC of allergies. Allergy and the skin. I–Urticaria. BMJ 1998; 316:1147.
5. Baş M, Greve J, Stelter K, et al. A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med 2015; 372:418.
6. Straka BT, Ramirez CE, Byrd JB, et al. Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema. J Allergy Clin Immunol 2017; 140:242.
7. Sinert R, Levy P, Bernstein JA, et al. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema. J Allergy Clin Immunol Pract 2017; 5:1402.
8. Banerji A, Clark S, Blanda M, et al. Multicenter study of patients with angiotensin-converting enzyme inhibitor-induced angioedema who present to the emergency department. Ann Allergy Asthma Immunol 2008; 100:327.
9. Furst IM, Ersil P, Caminiti M. A rare complication of tooth abscess–Ludwig’s angina and mediastinitis. J Can Dent Assoc 2001; 67:324.
10. Boscolo-Rizzo P, Da Mosto MC. Submandibular space infection: a potentially lethal infection. Int J Infect Dis 2009; 13:327.
11. Hurley MC, Heran MK. Imaging studies for head and neck infections. Infect Dis Clin North Am 2007; 21:305.
12. Kulkarni AH, Pai SD, Bhattarai B, et al. Ludwig’s angina and airway considerations: a case report. Cases Journal. 2008;1:19.
13. Ovassapian A, Tuncbilek M, Weitzel EK, et al. Airway management in adult patients with deep neck infections: a case series and review of the literature. Anesth Analg 2005; 100:585.
14. Brook I. Microbiology and principles of antimicrobial therapy for head and neck infections. Infect Dis Clin North Am 2007; 21:355.
15. Hasan W, Leonard D, Russell J, “Ludwig’s Angina—A Controversial Surgical Emergency: How We Do It,” International Journal of Otolaryngology, vol. 2011, Article ID 231816, 4 pages, 2011
16. Kwaku MP, Burman KD. Myxedema coma. J Intensive Care Med 2007; 22:224.
17. Ono Y, Ono S, Yasunaga H, et al. Clinical characteristics and outcomes of myxedema coma: Analysis of a national inpatient database in Japan. J Epidemiol 2017; 27:117.
18. Berger T, James WD, Elston D. Andrews’ Diseases of the skin: clinical dermatology (11th ed.)
19. Garber J, Cobin R, Gharib H, et al. Clinical Practice Guidelines for Hypothyroidism in Adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocrine Practice: November 2012, Vol. 18, No. 6, pp. 988-1028.
20. Ono Y, Ono S, Yasunaga H, et al. Clinical characteristics and outcomes of myxedema coma: Analysis of a national inpatient database in Japan. J Epidemiol 2017; 27:117.
21. Laupland KB. Vascular and parameningeal infections of the head and neck. Infect Dis Clin North Am. 2007 Jun. 21(2):577-90, viii.
22. Duong DK, Leo MM, Mitchell EL. Neuro-ophthalmology. Emerg Med Clin North Am. 2008 Feb. 26(1):137-80, vii.
23. Bousser MG, Russell RR. Cerebral venous thrombosis. In: Major Problems in Neurology, Warlow CP, Van Gijn J (Eds), WB Saunders, London 1997. p.27, 104.
24. Coutinho JM, Ferro JM, Canhão P, et al. Unfractionated or low-molecular weight heparin for the treatment of cerebral venous thrombosis. Stroke. 2010 Nov. 41(11):2575-80
25. Sadigh G, Mullins M, Saindane A, Diagnostic Performance Of MRI Sequences For Evaluation Of Dural Venous Sinus Thrombosis. American Journal of Roentgenology2016 206:6, 1298-1306
26. Durand, ML. Periocular infections. In: Principles and Practice of Infectious Diseases, 7th ed, Mandell, GL, Bennett, JE, Dolin, R (Eds), Churchill Livingstone Elsevier, Philadelphia 2010. p.1569.
27. Sobol SE, Marchand J, Tewfik TL, et al. Orbital complications of sinusitis in children. J Otolaryngol 2002; 31:131.
28. McKinley SH, Yen MT, Miller AM, et al. Microbiology of pediatric orbital cellulitis. Am J Ophthalmol 2007; 144:497.
29. Seltz LB, Smith J, Durairaj VD, et al. Microbiology and antibiotic management of orbital cellulitis. Pediatrics 2011; 127:e566.
30. Botting AM, McIntosh D, Mahadevan M. Paediatric pre- and post-septal peri-orbital infections are different diseases. A retrospective review of 262 cases. Int J Pediatr Otorhinolaryngol 2008; 72:377.
31. Eustis HS, Mafee MF, Walton C, et al. MR imaging and CT of orbital infections and complications in acute rhinosinusitis. Radiol Clin North Am 1998; 36:1165.
32. Eke PI, Dye BA, Wei L, et al. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res 2012; 91:914.
33. Selwitz RH, Ismail AI, Pitts NB. Dental caries. Lancet 2007; 369:51.
34. Loesche W. Dental caries and periodontitis: contrasting two infections that have medical implications. Infect Dis Clin North Am 2007; 21:471.
35. Chow AW. Infections of the oral cavity, neck and head. In: Principles and Practice of Infectious Diseases, 6th ed, Mandell GL, Bennett JE, Dolin R (Eds), Churchill Livingstone, Philadelphia 2005. p.787.
36. Albandar JM, Brunelle JA, Kingman A. Destructive periodontal disease in adults 30 years of age and older in the United States, 1988-1994. J Periodontol 1999; 70:13.
37. Hurley MC, Heran MK. Imaging studies for head and neck infections. Infect Dis Clin North Am 2007; 21:305.
38. Krayer JW, Leite RS, Kirkwood KL. Non-surgical chemotherapeutic treatment strategies for the management of periodontal diseases. Dent Clin North Am 2010; 54:13.
39. Rath E, Skrede S, Mylvaganam H, et al. Aetiology and clinical features of facial cellulitis: a prospective study,Infectious Diseases, 2018; 50:1, 27-34.
40. Rice TW, Rodriguez RM, Light RW. The superior vena cava syndrome: clinical characteristics and evolving etiology. Medicine (Baltimore) 2006; 85:37.
41. Markman M. Diagnosis and management of superior vena cava syndrome. Cleve Clin J Med 1999; 66:59.
42. Kim HJ, Kim HS, Chung SH. CT diagnosis of superior vena cava syndrome: importance of collateral vessels. AJR Am J Roentgenol 1993; 161:539.
43. Rowell NP, Gleeson FV. Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: a systematic review. Clin Oncol (R Coll Radiol) 2002; 14:338.
44. Wilson LD, Detterbeck FC, Yahalom J. Clinical practice. Superior vena cava syndrome with malignant causes. N Engl J Med 2007; 356:1862.
45. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017; 67:7.
46. Farhood AI, Hajdu SI, Shiu MH, et al. Soft tissue sarcomas of the head and neck in adults. Am J Surg 1990; 160:365.
47. Erdmann D, Follmar KE, Debruijn M, et al. A retrospective analysis of facial fracture etiologies. Ann Plast Surg 2008; 60:398.
48. Dula DJ, Fales W. The ‘ring sign’: is it a reliable indicator for cerebral spinal fluid? Ann Emerg Med 1993; 22:718.
49. Huoh KC, Eisele DW. Etiologic factors in sialolithiasis. Otolaryngol Head Neck Surg 2011; 145:935.
50. Williams MF. Sialolithiasis. Otolaryngol Clin North Am 1999; 32:819.
51. Mandel L. Salivary gland disorders. Med Clin North Am 2014; 98:1407.
52. Paterson JR, Murphy MJ. Bones, groans, moans… and salivary stones? J Clin Pathol 2001; 54:412.
53. Thomas WW, Douglas JE, Rassekh CH. Accuracy of Ultrasonography and Computed Tomography in the Evaluation of Patients Undergoing Sialendoscopy for Sialolithiasis. Otolaryngol Head Neck Surg 2017; 156:834.