As more pharmaceuticals are introduced to treat a variety of infectiousprocesses, as well as benign and malignant neoplastic disorders, more medicalproblems are noted to complicate the clinical courses of children followingtreatment. These complications are varied, affect all organ systems, andfrequently are associated with significant morbidity and mortality. While someof these disease processes can be suggested on physical examination or byabnormal laboratory values, most are effectively diagnosed only by radiologicevaluation. This article presents a spectrum of radiologic and imaging findingsin pediatric patients being treated for infections, benign and malignantneoplasms, hematologic disorders, seizures, and congenital heart disease, whosubsequently developed serious and often life-threatening complications as aresult of pharmacologic therapy.

The term "iatrogenic" comes from the Greek "iatros"(physician) and "gennan" (to produce). We have come to understandiatrogenic disease as any additional problem or complication that results fromtreatment by a physician. As the administration of pharmaceuticals is a wellestablished treatment used by physicians for a wide range of disorders, itfollows that, unfortunately, certain unanticipated or undesirable problems maycomplicate drug therapy. Some of the radiologic manifestations of thesecomplications are listed in table 1, and are discussed below.

Cyclosporine immunosuppression and the development oflymphoproliferative disorders

Cyclosporine, a hydrophobic fungal endecapeptide, was first used as animmunosuppressive agent for kidney transplantation by Calne in 19791 and worksprimarily through its potent anti-T cell action. Use of this immunosuppressiveagent has been shown to result in the development of lymphoma, which is relatedto the duration of treatment, dosage, and number of agents used simultaneously.In the general population, most lymphomas involve the lymph nodes. However, intransplant recipients, 70% involve extra-nodal sites (figure 1), with astrikingly high incidence of CNS involvement. Morphologically, the most commontypes are large-cell lymphomas; immunologically, 86% are of B-cell origin.2

Cyclophosphamide and hemorrhagic cystitis

Cyclophosphamide has been used in cancer chemotherapy since 1958; it is alsoused as an immunosuppressant in systemic lupus erythematosus. Hemorrhagiccystitis, defined as acute or insidious diffuse vesical bleeding, wasrecognized as a complication of cyclophosphamide therapy as early as 1959;3 itsincidence varies from 2% to 40%. Histologically, bladder wall edema andhyperemia are observed within 4 hours of cyclophosphamide administration.Damage may progress for up to 36 hours after one dose.3 Often, diagnosis can bemade with sonography, which reveals echogenic material adherent to the bladderwall, consistent with clot (figure 2). Patients with hemorrhagic cystitis thatis unresponsive to irrigation with chemical cauterizing agents are treated withselective embolization of the anterior branches of the hypogastric arteries(figure 3). A variety of materials have been used for embolization includingmuscle tissue, reinforced autologous clot, gelatin foam, dura, occlusion coils,polyvinyl alcohol (Ivalon) and isobutyl 1-2 cyanoacrylate.

Androgen- related primary hepatic tumors

An association between androgen therapy and the development of primaryhepatic tumors was first reported in 1965.4 The spectrum of androgen-inducedhepatic tumors includes hepatic adenoma, hepatocellular carcinoma, hepaticangiosarcoma, and cholangiocarcinoma. Hepatic adenoma (figure 4) is a benignepithelial tumor that has a potential for malignant degeneration. It is a welldefined, encapsulated tumor without a central scar, composed entirely ofhepatocytes and devoid of Kupffer cells or bile ducts. A relatively rare lesionin the pediatric age group, hepatic adenoma occurs most often in children withglycogen storage disease type I or VI, familial diabetes mellitus,galactosemia, androgen-treated aplastic anemia, and Fanconi's anemia. Themean duration of androgenic steroid therapy for development of hepatic tumorsis significantly shorter in patients with Fanconi's anemia than that fornon-Fanconi patients. Hepatic adenomas, though benign, can cause significantmorbidity, and sometimes mortality, due to rupture and the resultanthemoperitoneum. The size of adenoma may remain stable, or it may diminishfollowing discontinuation of anabolic steroids. Patients on anabolic steroidsshould be routinely followed by serial ultrasound examinations at 6-to 12-monthintervals.

Antibiotic-associated pseudomembranous colitis

Pseudomembranous colitis (PMC) is so named because the dominant pathologicalfinding often is a pseudomembrane that is adherent to the colonic mucosa; thisentity has been recognized for over a century. Evidence for a bacterialenterotoxin as the cause of antibiotic associated colitis was first put forwardby Larson in 1977.5 PMC may occur in a variety of clinical settings includingantibiotic-associated colitis, ischemic colitis, uremic colitis, and colitiscomplicating obstruction and infection. Diarrhea is the most prominent clinicalsymptom; its onset generally occurrs during antibiotic therapy, though it maybegin as late as 2 months after therapy is complete. Stool cultures and assaysfor Clostridium difficile are positive in over 95% of patients with PMC and in25% of patients with antibiotic-associated diarrhea without recognizablecolitis or pseudomembrane. A positive correlation between toxin titers and thepresence of pseudomembrane has been reported. Several drugs have beenimplicated in the development of PMC (table 2), with more cases associated withoral, rather than parenteral, administration of the drug.

When PMC is mild, plain films of the abdomen will be normal.6 In severecases, however, a characteristic plain film appearance of colon dilatation andreplacement of interhaustral folds with wide, transverse bands and/or"thumb-printing" often will be present (figure 5). These changesgenerally involve most or all of the large bowel. Diagnosis ofantibiotic-associated PMC can be established either by assay of the stool forC. difficile or cytotoxin, or by endoscopy at which discrete, yellowish plaquesor a confluent pseudomembrane is seen. Barium enema is contraindicated in theseverely ill patient. PMC is now the most frequent cause of toxic megacolon,replacing ulcerative colitis. Treatment includes withdrawal of the offendingantibiotic and administration of a course of metronidazole or vancomycin.

Stevens-Johnson syndrome causing epiglottitis andesophageal stricture

Erythema multiforme is clinically characterized by its minor and majorforms. The major form, known as Stevens-Johnson syndrome (SJS), was describedin 19227 in two cases that were characterized by generalized eruption, fever,inflamed buccal mucosa, and severe purulent conjunctivitis. At least 40 drugshave been implicated in

SJS (table 3), including sulfonamides (including co-trimoxazole),penicillin, phenylbutazone, tetracycline, isoniazid, carbamazepine, aspirin,furosemide, barbiturates, and hydantoin. Because Stevens-Johnson syndromeinvolves mucous membranes, involvement of the epiglottis (figure 6) andesophagus can be anticipated.8 A lateral neck film

will show any epiglottal enlargement. Esophagitis can be severe, leading tostricture formation. In these cases, barium swallow studies may be helpful forevaluation.

Complications of phenytoin therapy

In cases of maternal epilepsy, an association between anticonvulsant drugusage and an increased incidence of congenital abnormalities has been suspectedfor at least 25 years. In 1975, Harrison and Smith described the clinicalfeatures of birth abnormalities that are associated with hydantoin (Dilantin)therapy, known as the fetal hydantoin syndrome.9 These consist of craniofacialanomalies (microcephaly, large anterior and posterior fontanelles, depressednasal bridge, mild hypertelorism, ptosis of the eyelids, low-set ears,prominent lips, and cleft lip and/or palate), short neck, prenatal andpostnatal growth deficiency, psychomotor development retardation, limb defects(hypoplasia of the nails, finger-like thumb, hypoplasia of the distal phalangesof the hand and feet, pes cavus, clubfoot, polydactyly, congenital hipdislocation), and scoliosis.

Cardiovascular anomalies include atrial septal defect, ventricular septaldefect, pulmonary stenosis (figure 7), and coarctation of the aorta, all ofwhich are typically delineated on echocardiogram. Other reported anomaliesinclude medullary sponge kidney, diaphragmatic hernia, hypospadias, andumbilical and inguinal hernias. The risk that an infant exposed to hydantoin inutero will have a clinical phenotype of the full-blown fetal hydantoin syndromeis approximately 10%.10

In addition to the above mentioned anomalies, Dilantin also has beendescribed to cause hypophosphatemic rickets (figure 8). Plain film of the wristor knee will demonstrate the changes characteristic of rickets.

Cerebrovascular complications ofL-asparaginase

L-asparaginase, an enzyme derived and purified from Escherichia coli B, hasbeen a drug of choice in the treatment of acute lymphoblastic leukemia sincethe 1960s. One of the toxic side effects of L-asparaginase is coagulopathy,first described by Priest in 1980.11 Hemorrhagic (figure 9) and thromboticneurologic complications include cortical infarction, capsular infarction,intracerebral hemorrhage, hemorrhagic infarction, and cerebral venous and duralsinus thrombosis. Complications occur in 1 to 2% of patients receivingL-asparaginase therapy.

Complications of prolonged systemic corticosteroidtherapy

Corticosteroids have assumed a major role in the management of a widevariety of inflammatory and immunologically mediated diseases in the last 30years. Corticosteroid-induced pancreatitis, first described in 1955,12 canoccur as a consequence of inflammation and obstruction to outflow of pancreaticsecretions (figure 10).

Steroid-induced osteoporosis involves the entire skeleton, but tends to bemore severe in areas rich in trabecular bone (figure 11). Avascular necrosis ofbone secondary to steroids usually involves the femoral head, but also mayoccur in the knee and humeral head (figure 12). The exact mechanism for thisinsult is unknown, but fat emboli have been implicated.

Fatty infiltration of the liver (figure 13) is another process which can besteroid-induced and is easily appreciated on cross-sectional CT images of theabdomen. Gastrointestinal complications of steroids include esophageal ulcer,peptic ulcer (figure 14), hemorrhage, and perforation of the bowel.

Prostaglandin-induced cortical hyperostosis

Prostaglandin E1 (PGE 1) is an arachidonic acid derivative routinely used innewborns with ductal dependent congenital heart disease.11 The first reports ofcortical hyperostosis occurring as a side effect of prostaglandin therapy werepublished in 1980.13 Bone changes usually take 30 to 40 days to develop, butperiosteal elevation has been described as early as 9 days after therapy(figure 15). After cessation of prostaglandin administration, the new bone iscompletely incorporated into underlying bone, and remodeling ensues.14

Recently, gastric outlet obstruction secondary to antral mucosal hyperplasiahas been described in neonates receiving prostaglandin therapy for more than120 hours.

Nephrocalcinosis and nephrolithiasis secondary tofurosemide therapy

Nephrocalcinosis and nephrolithiasis have been well documented in prematureinfants treated with furosemide (figure 16). Renal calcification in very lowbirth weight infants treated with furosemide was first described by Hufnagle in1982.15 The exact mechanism by which furosemide causes nephrocalcinosis is notcertain, but it appears to be multifactorial; hypercalciuria withouthypercalcemia, the long furosemide half life, and reduced glomerular filtrationin premature infants all may play a role in the development ofnephrocalcinosis. Deposits of calcium oxalate and calcium phosphate crystalsare seen in the papillary interstitium and collecting tubules. Replacement offurosemide with a thiazide diuretic can reverse nephrocalcinosis.AR

Drugs associated with pseudomembranous colitis

Dr. Narla, Dr. Spottswood, and Dr. Hingsbergen are in the Departmentof Radiology at the Medical College of Virginia, Hospitals of VirginiaCommonwealth University in Richmond, VA.

References

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