Daniel Thomas Ginat MD, MS Department of Radiology , University of Chicago Juan Small MD

1. Imaging of Non-Neoplastic Effects of Drugs and Pharmaceuticals in the Head and Neck Daniel Thomas Ginat MD, MS Department of Radiology, University of Chicago Juan Small MD Department of Radiology, Lahey Clinic Pamela W Schaefer MD Department of Radiology, MGH ID: eEdE-94-3044

2. Disclosures The authors have published a textbook related to this topic.

3. Introduction • The purpose of this exhibit is to review the variety of conditions that may result from the use of drugs and pharmaceuticals as they appear on head and neck imaging. • This review should help radiologists identify expected consequences of drug and pharmaceutical use and their potential complications.

4. ACE Inhibitors: Angioedema Axial contrast-enhanced CT image shows circumferential mucosal pharyngeal swelling (arrows) and diffuse stranding of the parapharyngeal and subcutaneous fat bilaterally. Sagittal T1, axial and coronal T2, and coronal post-contrast T1 MR images show diffusely massive tongue edema (arrows). Courtesy of Jason Johnson.

5. ACE Inhibitors: Angioedema • Indication: Treatment of hypertension and congestive heart failure. • Mechanism: ACE inhibitors are believed to result in angioedema through increased bradykinin activity, which causes transient vasodilation and extravasation of fluid into the extracellular space, resulting in edema. • The use of ACE inhibitors is believed to be the most common cause of angioedema, comprising approximately 35% of all cases of angioedema. • ACE inhibitor–induced angioedema is primarily localized in the head and neck, especially in the face, mouth, tongue, lips, and larynx. • The distribution of involvement tends to be diffuse and bilateral, although focal or unilateral lingual and peritonsillar edema have been reported.

6. Alcohol: Madelung Disease The patient is a middle-aged male with progressive increase in size of the neck and a history of abundant alcohol consumption. Axial and sagittal CT images show extensive fat attenuation deposits within the bilateral superficial and deep compartments of the neck in a symmetric distribution.

7. Alcohol: Madelung Disease • Originally called 'fat neck' (Fetthals) by Madelung in 1888. • The disorder is characterized by painless symmetrical diffuse hypertrophy of brown adipose tissue. • The etiology is believed to be an abnormality in the synthesis of intracellular cyclic adenosine monophosphate (cAMP) induced by the stimulation of noradrenaline. The defect in adrenergic-stimulation lipolysis generates the autonomy of fat cells in bilateral symmetric lipomatosis. • CT can demonstrate non-encapsulated bilateral fat-attenuation masses in multiple compartments of the neck bilaterally, including the supraclavicular regions, subcutaneous tissues, and anterior and posterior triangle of the neck. • Alcohol cessation may halt the progression of bilateral symmetric lipomatosis, but the condition does not regress.

8. Alcohol: Sialosis Axial CT image show homogeneous diffuse enlargement of the bilateral parotid glands.

9. Alcohol: Sialosis • Sialosisis a disorder of altered secretory and parenchymal function of the salivary glands, most commonly the parotid. • Caused by autonomic neuropathy. • On histology, there is adipose infiltration and periacinal edema. • The condition presents as an indolent, bilateral, non-inflammatory, non-neoplastic, soft, symmetrical, painless and persistent enlargement of the salivary glands. • On imaging, there is bilateral diffuse homogenous enlargement of the affected salivary glands with soft tissue or fat attenuation or signal characteristics. • Imaging may be obtained in order to exclude the presence of a tumor. 

10. Betel Nut: Inflammatory Lymphadenitis Axial PET-CT fusion image shows a hypermetaboliclower lip squamous cell carcinoma (arrowheads) and bilateral level 1B hypermetabolic lymph nodes (arrows) that did not contain malignant cells on histology. Courtesy of Grayson Hooper.

11. Betel Nut: Inflammatory Lymphadenitis • Areca nut (Areca catechu) is an ancient cultural and pharmacologic staple that is commonly chewed with the betel leaf (Piper betle) and is thus often referred to as the betel nut. • Betel nut and its myriad preparations are a known cause of oral squamous cell carcinoma. • In the case of oral squamous cell carcinoma there is a betel nut dose-dependent relationship and a synergistic relationship with alcohol and tobacco usage. • Betel nut-associated oral squamous cell carcinomas generally appear as heterogeneous, diffusely-enhancing masses on CT. • There is often discordance between the FDG-PET-CT features of the cervical lymph nodes and their pathologic specimens due to an inflammatory reaction related to betel nut use.

12. Bisphosphonates: Osteonecrosis Bisphosphonate-induced osteonecrosis of the mandible. Axial CT image shows a mixed sclerotic and lucent lesion within the left mandibular body that has a bone-within-a-bone appearance (arrow). Bisphosphonate-induced osteonecrosis of the maxilla. Coronal CT image shows a defect in the left maxillary sinus wall and alveolus with associated oroantral fistula (arrow). Courtesy of Christine Glastonbury.

13. Bisphosphonates: Osteonecrosis • Indication: Primarily used for treatment of osteoporosis and osteopenia, as well as some less common metabolic bone disorders including Paget’s disease of bone, osteogenesisimperfecta, and fibrous dysplasia.   • Mechanism: Bisphosphonates are inorganic pyrophosphate analogs that inhibit osteoclast activity, thereby suppressing bone remodeling and resorption. • Bisphosphonate-related osteonecrosis of the jaw presents as painful or painless bone exposure in the mandible, maxilla, or both, often preceded by tooth extraction or infection. • CT is often obtained to delineate the area of necrosis, which appears as osteosclerotic and osteolytic lesions. • MRI can be used to further delineate involvement of the surrounding soft tissues and bone marrow edema.

14. Bromocriptine: Pituitary Hemorrhage MR images obtained shortly after starting treatment shows hemorrhage within a left pituitary microadenoma with a fluid-fluid level (arrows). Follow up MRI obtained several months later show resolution of the hemorrhage with overall slight interval decrease in size of the lesion.

15. Bromocriptine: Pituitary Hemorrhage • Indication: Treatment of patients with idiopathic hyperprolactinemia and prolactinomas. • Mechanism: Ergot derivative, which is a dopamine receptor agonist and inhibitor of prolactin secretion. • Bromocriptinesignificantly increases the incidence of intratumoral hemorrhage, mainly in tumors with high initial serum prolactin levels. • This condition can manifest as T1 hyperintensity and fluid-fluid levels within the tumor on MRI. • Patients with intratumoral hemorrhage are generally asymptomatic, but some patients may experience headaches and visual field defects.

16. Cannabis: Barotrauma Axial and sagittal CT image show extensive air-attenuation within the spinal canal, deep spaces of the neck, and upper mediastinum. Courtesy of AlaaJaly, Chris Coutinho, and SachinMathur.

17. Cannabis: Barotrauma • Smoking of marijuana using devices such as a narrow outlet bong can result in barotrauma associated with repeated deep inspiration with airflow resistance that equivalent to performing Müller's maneuver. • Successive inhalation through resistance could have resulted in extreme negative intrathoracic pressure, which would have caused a transmural pressure gradient inducing barotrauma and release of extra respiratory air. • Air can enter multiple compartments, including the epidural space of the spine, deep neck spaces, subcutaneous tissues, and mediastinum, which can be readily depicted on CT.

18. Cocaine: Sinonasal Erosion Coronal CT image show nasal septal perforation as well as destruction of the right middle turbinate, nasal antral wall, and hard palate.

19. Cocaine: Sinonasal Erosion • Nasal septal perforation is a complication of snorting cocaine, which results from a combination of chemical irritation, ischemic necrosis from intense vasoconstriction, and direct trauma. • Nasal septal perforation is preceded by mucosal atrophy and followed by chronic osteolysis that can also affect the hard palate. • The sinonasal destructive changes that result from cocaine use can lead to oronasal fistulas, dacryocystitis, and orbital cellulitis. • Other related complications include enamel erosion, gingival erosion, and midline granuloma.

20. Cocaine: Dacryocystitis Coronal post-contrast CT image shows enlargement of the right lacrimal sac with surrounding inflammatory changes (arrow).

21. Cocaine: Dacryocystitis • The sinonasal destructive changes that result from cocaine use can also lead to dacryocystitis and orbital cellulitis. • Diagnostic imaging is useful for evaluating the orbital complications related to cocaine use, which may manifest as dacryocystitis. • On imaging, dacrocytitis appears as enlargement of the lacrimal sac and orbital cellulitis as stranding of the orbital fat, with or without abscess formation.

22. Crack: Thermal Pharyngitis The patient present with a sore throat after accidentally ingesting a crack pipe Brillo pad filter. Axial CT image shows edema of the right arytenoid (arrow). Frontal radiograph shows a metallic structure that represents the Brillopad (arrow).

23. Crack: Thermal Pharyngitis • Crack cocaine is commonly smoked in a pipe with a metallic filter made from a steel wool scouring pad, such as Brillo. • Occasionally, smokers can accidentally aspirate and ingest the filter, which can result in a burn injury to the hypopharynx. • Imaging may be obtained in order to assess the degree of burn injury, which can manifest as edema in hypopharynx, and to localize the foreign body, which is radiopaque.

24. Dilantin: Cranial Hyperostosis Axial CT images obtained at initial presentation and after over a decade of anti-epileptic treatment show development of substantial diffuse calvarial thickening.

25. Dilantin: Cranial Hyperostosis • Indication: Phenytoin is an anticonvulsant used for the treatment and prevention of generalized tonic-clonic seizures, complex partial seizures and seizures related to neurosurgical procedures. • Mechanism: Although the mechanism of action of phenytoin has not been completely elucidated, it appears to act primarily in the motor cortex by intervening with neuronal sodium channels. • The incidence of calvarial thickening in epileptic patients treated with phenytoin is approximately 33%. On imaging, progressive diffuse, smooth intramedullary expansion can be observed.

26. Ipilimumab: Hypophysitis Sagittal post-contrast T1-weighted MR images obtained before and after Ipilimumab show interval diffuse enlargement and enhancement of the pituitary gland and stalk.

27. Ipilimumab: Hypophysitis • Indication: Ipilimumab consists of monoclonal antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4) used in the setting of metastatic or unresectable melanoma. • Mechanism: The inflammatory reaction is secondary to specific human monoclonal antibodies that antagonize cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4 mAbs), thereby inducing unrestrained T-cell activation. • Ipilimumab-induced hypophysitis occurs in up to 17% of patients. • The hypophysitis can manifest as variable degrees of diffuse enlargement of the pituitary gland and infundibulum. • The enhancement pattern is usually homogeneous. • Loss of the hyperintenseT1 signal in the posterior pituitary can also be observed.

28. Nasal Decongestatants: Rhinitis Medicamentosa Axial and coronal CT images show marked mucosal thickening of the bilateral inferior turbinates, with resultant nasal airway obstruction.

29. Nasal Decongestatants: Rhinitis Medicamentosa • Indication: Widely used for the management of acute, and in certain cases chronic, rhinosinusitis. Specific agents include ephedrine, phenylephrine, and phenylpropanolamine. • Mechanism: Nasal decongestant agents contain substances that have sympathomimetic effects by acting upon epinephrine, norepinephrine, or alpha-adrenergic receptors, which results in vasoconstriction. • However, overuse of these nasal decongestant agents can result in rebound congestion, nasal hyperreactivity, tolerance, and histologic changes of the nasal mucosa, which is a phenomenon known as rhinitis medicamentosa. • Rhinitis medicamentosa is characterized by nasociliary loss, squamous cell metaplasia, epithelial edema, epithelial cell denudation, goblet cell hyperplasia, and inflammatory cell infiltration. • On imaging, these changes manifest as diffuse swelling of the nasal mucosa, particularly the turbinates.

30. Prostaglandin: Periorbitopathy The patient has a history of left eye only Lumigan use for a number of years and had left enophthalmos along with superior sulcus deformity due to loss of orbital fat. Sagittal T1-weighted MRI shows enophthalmoswith a deep superior sulcus (arrow) due to diffusely diminished orbital and periorbital fat. The patient’s unaffected contralateral orbit is shown on the sagittal T1-weighted image for comparison.

31. Prostaglandin: Periorbitopathy • Indication : Potent agents for reducing intraocular pressure associated with glaucoma. • Mechanism: Prostaglandin receptors and associated mRNAs are present in the trabecular meshwork, ciliary muscle, and sclera. Prostaglandin analogues result in a considerable increase in uveoscleral outflow and may also improve trabecular outflow and stimulate of aqueous flow. • Chronic topical prostaglandin has been associated with the development of periorbitopathy, which consists of enophthalmos associated with the atrophy of orbital and periorbital fat. • CT or MRI can be used to demonstrate the diffusely decreased orbital and periorbital fat volume.

32. Thorotrast: Thorotrastoma The patient is an 82-year-old female with right vocal cord paralysis and a history of Thorotrast extravasation during an angiogram performed in the 1950's. Axial and coronal CT images show hyperattenuatingmaterial in the deep spaces of the neck.

33. Thorotrast: Thorotrastoma • Indication: Radioactive contrast agent introduced in 1928 and mainly used for cerebral angiography until the 1950s. • Mechanism: Thorotrast granules can be phagocytized by macrophages and cause extensive surrounding fibrosis. • Although obsolete, patients may still present with the sequelaof Thorotrast exposure. • ExtravasatedThorotrast can be retained for many years along the carotid sheath if a transcervical approach was used for the injection. • The extravastedThorotrast can form granulomas (thorotrastomas), which can be complicated by persistent open draining neck wounds. • Thorotrastis extremely hyperattenuating.

34. Tobacco: Lymphoid Hyperplasia This is a 40 year old smoker with obstructive symptoms. Axial and sagittal post contrast CT images show diffuse marked enlargement of the adenoids (arrows).

35. Tobacco: Lymphoid Hyperplasia • Heavy tobacco smoking has been linked to the development of nasopharyngeal lymphoid hyperplasia, which is characterized by the presence of cytotoxic lymphocytes mucosa. • The adenoids may be obstructive in up to 30% of heavy smokers. • On imaging, there is diffuse symmetric enlargement of the adenoidal tissues. • Nevertheless, it is important to exclude other conditions, such as nasopharyngeal carcinoma.

36. Warfarin: Nasal Hypoplasia Axial and non-contrast bone window CT images of the brain and a 3D surface rendered image of the face in an infant demonstrating dramatic midface and nasal hypoplasia (arrows) in the setting of warfarin use in the first trimester. Courtesy of Caroline Robson.

37. Warfarin: Nasal Hypoplasia • Indication: Anticoagulation therapy for stroke risk prevention, treatment of deep venous thrombosis, and pulmonary embolism.   • Mechanism: Selective inhibition of vitamin K epoxide reductase enzyme resulting in diminished stores of vitamin K available to the tissues. • Several findings are associated with fetal warfarin syndrome, including epiphyseal stippling, nasal hypoplasia, nasal cartilage calcification, scoliosis, and brachydactyly. • Warfarin use later in pregnancy imparts a lower risk of birth defects.

38. Intravenous Drug Use in General: Abscess and Thrombophlebitis Axial post-contrast fat-suppressed image shows a rim-enhancing fluid collection in the right supraclavicular fossa (arrow) with surrounding inflammatory changes. Axial post-contrast CT image shows thrombosis of the right external jugular vein branch (arrow) with associated surrounding cellulitis and myositis.

39. Intravenous Drug Use in General: Abscess and Thrombophlebitis • The intravenous administration of illicit drugs (IVDU) in unsanitary conditions and perhaps in individuals with underlying immunosuppressed states predisposes to associated blood borne infections. • Neck abscess, septic thrombophelibitis of the jugular veins, and associated cellulitis and myositis are possible manifestations of IVDU. • Both CT and MRI with contrast are suitable modalities for evaluating infectious complications of IVDU, although these patients often present to the emergency department, where CT is generally more readily available.

40. Conclusion