Thank you to Emma for presenting a fascinating case of a middle aged man with SCC of the head and neck treated with a PD-1 inhibitor p/w hyponatremia found to have SIADH 2/2 hypothyroidism and central adrenal insufficiency (AI)!!!
Remember that replacement of thyroid hormone without replacement of glucocorticoids can precipitate acute adrenal insufficiency.
Nonthyroidal Illness (formerly known as Euthyroid Sick Syndrome) is a normal response to illness and is a relative hypothyroid state marked by elevated TSH and depression of Free T4 and T3.
NOTE: Thyroid function should not be assessed in seriously ill patients unless there is a strong suspicion of thyroid dysfunction (thanks Brad Monash!).
A standard stimulation test is 250 mcg of IV Cosyntropin which tests ability of ACTH -> increase cortisol (more details below)
Evaluation of Adrenal Insufficiency
The HPA Axis
A primary adrenal disorder resulting in deficiency of cortisol = 1° AI or Addison’s disease
A pituitary disorder resulting in deficiency of corticotropin (ACTH) secretion = 2° AI
A hypothalamic disorder resulting in deficiency of corticotropin-releasing hormone (CRH) and secondarily of ACTH = 3° AI
Evaluation of HPA Axis Response to ACTH
Early am cortisol < 3 is virtually diagnostic of primary OR secondary AI; >17 rules this out
If unclear (often the case) then go to stim testing!
Standard Stim test is 250 mcg of IV Cosyntropin
Measure cortisol before, 30 & 60 min after intravenous (IV) injection
If f/u cortisol is greater than 18, this indicates normal adrenal function
A inadequate response suggests EITHER primary or secondary AI
Authors: Elizabeth Yetter, MD (EM Resident Physician, Maimonides Medical Center, Brooklyn, NY), Lois Isaksen, MD (Attending, Maimonides Medical Center, Brooklyn, NY), and Laura Mulvey, MD (Attending, Maimonides Medical Center, Brooklyn, NY) // Edited by: Alex Koyfman, MD (@EMHighAK – EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Manpreet Singh, MD (@MPrizzleER – Assistant Professor of Emergency Medicine / Department of Emergency Medicine – Harbor-UCLA Medical Center)
A 70 year old male with a past medical history of uncontrolled diabetes presents with increasing left sided facial and ear pain over a month. He also reports drainage from his left ear as well as decreased hearing on the affected side. He noted that the left side of his face appeared swollen when he looked in the mirror this morning. When asked about his medication, he states he not taken his diabetes medications “in a long time.” The patient had recently emigrated from Pakistan.
T 101.9F, Pulse 91, RR 17, 141/51, 99%RA, Glc 378
On exam, the patient has notable facial asymmetry with his edematous left ear pushed forward by surrounding edema. There is erythema and induration overlying the tragus and lateral zygoma. The external auditory canal is swollen with foul-smelling purulent drainage. No vesicles are appreciated and the tympanic membrane is unable to be visualized due to swelling. The mastoid is inflamed and tender to palpation. The patient has a notable left-sided facial droop which spares the forehead. His hearing is significantly decreased on the left.
What should you be considering? What are your key steps to diagnosis and treatment?
Otitis externa, colloquially known as swimmers ear or tropical ear, is an infection of the external auditory canal (Figure 1). In the elderly, diabetics, AIDS patients, and the immunocompromised it may progress to Malignant Otitis Externa (MOE). Also known as Necrotizing External Otitis, it is an aggressive form of OE. Prognosis has improved with antibiotics but MOE still has a high rate of mortality1.
Other diagnoses on the differential may include Ramsay Hunt (although less likely in this patient considering no vesicles are seen), Otitis Externa, and Acute Otitis Media with ruptured tympanic membrane. Physical exam and imaging will help differentiate from these other pathologies.
External Otitis (EO) is inflammation of the external auditory canal; disruption of its lipid layer allows bacteria to enter. Possible causes of lipid layer violation include maceration by moisture, increased temperatures, high humidity, or local trauma2.
Once the bacteria crosses the interrupted lipid barrier in the canal, it spreads through the periauricular tissue and cartilaginous bony junction of the external auditory meatus. From there, it may spread via the Fissures of Santorini and the stylomastoid foramen to the base of the skull at the temporal bone, hence the term skull-base osteomyelitis.
Pseudomonas aeruginosa is the most common and main concern3. However, S. aureus, S. epidermidis, Proteus mirabilis, Klebsiella, Salmonella, or polymicrobial infections are possible. In patients who are immunocompromised or who have failed antibiotics, also consider fungal infections which can be primary or secondary causes. Cases of both aspergillosis4,5 and candida albicans6 have been reported. Anecdotally, these infections have been described as less painful but more pruritic.
Symptoms include otalgia, protrusion of the affected ear, and headache. Physical exam findings include otorrhea, granulation tissue in the external auditory canal, tenderness and swelling of the mastoid process, fever, and cranial nerve involvement.
The facial nerve, Cranial Nerve VII, may be involved and manifests as facial paralysis if the infection spreads to the stylomastoid foramen where CN VII exits the skull.
If the disease further extends to the jugular foramen, the glossopharyngeal, vagal, and spinal accessory nerves may be affected. There are also reports of hypoglossal, trigeminal, and abducens nerve involvement.
Complications from MOE include abscess, meningitis, encephalitis, and skull-base osteomyelitis.
Obtain blood cultures, otorrhea culture, and basic lab work to rule out DKA such as lactate, acetone, urine ketones, blood glucose, etc. if the patient is diabetic or may be an undiagnosed diabetic. ESR and CPR, while nonspecific, may help monitor the disease’s course3,7.
A small retrospective study found that ESR, CRP, duration of DM, and CT or MRI findings influenced prognosis of MOE; age, gender, mean glucose level, HbA1c, pathogen, comorbidity or cranial nerve involvement did not affect prognosis. Cranial nerve involvement’s role in prognosis is unclear as several studies have found that there is no correlation8 but a meta-analysis conducted by Chen found a statistically significant influence on prognosis of MOE.
CT head with no IV contrast will help to establish the diagnosis (Figure 2), although may be normal. MRI with Gadolinium, if available, will delineate the extent of the disease.
Once the diagnosis is made, antibiotics should be administered and ENT consulted. Blood glucose should also be controlled, particularly if the patient is presenting with DKA.
Several options are available but must cover pseudomonas.
Mild cases may use Ciprofloxacin 750mg po BID as ciprofloxacin has good bony penetrance. For moderate to severe cases, consider Cefepime 2GM (pediatric 50mg/kg) IV TID or Piperacillin/Tazobactam 4.5 GM (pediatric 100mg/kg) IV four times daily depending on your hospital’s antibiogram9.
If you are concerned for a fungal infection such as Aspergillus, consider antifungals such as Amphotericin B and/or Itraconazole although Voriconazole is now considered an alternative5,10. Keep in mind though that fungal causes are rare and pseudomonas is your first concern.
Historically, ENT would surgically intervene, but management is trending towards more medical therapy alone. Surgical management when required includes debridement of granulation tissue11.
Per a 2013 Cochrane review, no trials found that the addition of Hyperbaric Oxygen Therapy offered a better outcome than standard treatments alone12.
Take Home Points
Consider MOE if someone treated for Otitis Externa is not improving and/or they have fever and tenderness to palpation of the mastoid.
Pseudomonas is the most common etiology and coverage should be directed appropriately. However in rare cases fungal infections may also be the cause, such as in AIDS patients.
Obtain CT and/or MRI imaging of the mastoid.
References / Further Reading
Chandler JR. Malignant external otitis. 1968 Aug;78(8):1257–1294. DOI: 10.1288/00005537-196808000-00002
Roland PS & Stroman DW. The microbiology of acute otitis external. Laryngoscope 2002: 112(7) 1166-77. DOI: 10.1097/00005537-200207000-00005
Rubin Grandis J, Branstetter BF 4th, & Yu VL. The changing face of malignant (necrotising) external otitis: clinical, radiological, and anatomic correlations. Lancet Infect Dis. 2004; 4(1):34-9. DOI: http://dx.doi.org/10.1016/S1473-3099(03)00858-2
Weinroth SE, Schüssel D, & Tuazon CU.Malignant otitis externa in AIDS patients: case report and review of the literature. Ear Nose Throat Journal. 1994; 73(10): 772-4, 777-8.
Parize P et al. Antifungal therapy of Aspergillus invasive otitis externa: Efficacy of voriconazole and review. Antimicrobial agents and chemotherapy. 2009; 53(3): 1048-1053. doi: 10.1128/AAC.01220-08
Bhat V, Aziz A, Bhandary SK, Aroor R, Kamath P SD, & Saldanha M. Malignant Otitis Externa – A Retrospective Study of 15 Patients Treated in a Tertiary Healthcare Center. J Int Adv Otol. 2015;11(1):72-6. doi: 10.5152/iao.2015.430.
Phillips JS, Jones SEM. Hyperbaric oxygen as an adjuvant treatment for malignant otitis externa. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD004617. DOI: 10.1002/14651858.CD004617.pub3
Gray H. Figure 907 External and middle ear, opened from the front. Right side. Lewish WH, ed. Anatomy of the Human Body. 20th ed. com: Philadelphia and New York.
ImpediMed, a company with offices in California and Australia, is releasing its new SOZO bioimpedance spectroscopy system that performs advanced body composition analysis. The technology involves sending out electric current through the arms and legs and detecting how the body affects it as it passes through.
Though this technology has been in existence for a while, SOZO takes it up a notch by quickly scanning through 256 different frequencies between 3kHz and 1000 kHz, obtaining and interpreting significantly more data than your typical bioimpedance spectrosoper.
Lymphedema and other conditions that affect the fluid levels of the body will hopefully be diagnosed with greater ease using the SOZO and it may find itself not only in hospitals and clinics, but also in gyms, nursing homes, and other facilities full of people needing and wanting to be analyzed more closely.
It comes with tracking software to help keep eye on patients over time, helps to compare patients to similar population groups, and provides a bunch of data in the final results that individuals, and their health and fitness advisers, can make use of.