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Visual hallucinations and severe in the ICU after surgery Mina Boazak, MD, Ann C. Schwartz, MD, Raymond Young, MD, Frederick Boyer, DO, Andrea Boyer, MD, and Heather Greenspan, MD

After major surgery, Mr. B, age 42, has visual hallucinations How would you of someone placing a drug in his IV line, and develops handle this case? severe anxiety. What could be causing these symptoms? Answer the challenge questions at mdedge.com/ CurrentPsychiatry and see how your colleagues responded CASE Anxiety in the ICU e) akathisia Mr. B, age 42, an African American man, is f) all of the above admitted to the inpatient medical unit for surgical treatment of peritoneal carcinomato- sis with pelvic exenteration. He has a history The authors’ observations of metastatic rectal cancer, chronic pain, and Determining the cause of Mr. B’s anxiety is hypertension, but no psychiatric history. Mr. challenging because of his prolonged medi- B’s postsurgical hospital stay is complicated cal course, comorbidities, and exposure to by treatment-resistant tachycardia and hyper- multiple pharmacologic agents. The con- tension, and he requires a lengthy stay in the sulting psychiatric team should consider ICU. In the ICU, Mr. B reports having visual potential medical, psychiatric, and drug- hallucinations where he sees an individual related etiologies. placing a drug in his IV line. Additionally, he From a medical perspective, in a post- reports severe anxiety related to this experi- surgical patient treated in the ICU, the ence. His anxiety and visual hallucinations are treated with coadministration of IV loraz- Dr. Boazak is a PGY-3 resident, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, epam, , and . Atlanta, Georgia. Dr. Schwartz is Associate Professor of Psychiatry and These resolve the hallucinations, Behavioral Sciences, Director, Psychiatry Residency Education, and Director, Consultation-Liaison Service at Grady Memorial Hospital, but his anxiety worsens and he becomes Department of Psychiatry and Behavioral Sciences, Emory University restless. He receives additional doses of IV School of Medicine, Atlanta, Georgia. Dr. Young is Associate Professor of Psychiatry and Behavioral Sciences, Division Chief, Consultation- haloperidol administered in 5 mg increments Liaison Services at Emory Healthcare, and Director, Psychosomatic and reaching a cumulative 12-hour dose of Medicine Fellowship, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. Dr. 50 mg. Mr. B continues to report anxiety, so F. Boyer is Assistant Professor of Psychiatry and Behavioral Sciences, the psychiatry consultation-liaison (C-L) ser- and Emergency Department Psychiatry Attending Physician, Grady Memorial Hospital, Department of Psychiatry and Behavioral vice is called. Sciences, Emory University School of Medicine, Atlanta, Georgia. Dr. A. Boyer is a PGY-2 psychiatry resident, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, What should be part of the diagnostic Georgia. Dr. Greenspan is Assistant Professor of Psychiatry and consideration for Mr. B’s anxiety? Behavioral Sciences, and Consultation-Liaison Psychiatry Attending Physician, Department of Psychiatry and Behavioral Sciences, Emory a) delirium University School of Medicine, Atlanta, Georgia. b) generalized anxiety disorder Disclosures c) primary psychotic disorder The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers Current Psychiatry d) neuroleptic malignant syndrome (NMS) of competing products. Vol. 17, No. 4 e1 Cases That Test Your Skills

consulting practitioner must pay particu- ICU, patients are frequently managed on lar attention to delirium. ICU delirium multiple medications, which increase their is common—one report indicated that it risk of developing adverse effects and occurs in 32.3% of ICU patients1—and fre- adverse reactions.6 One potential conse- quently confused with psychiatric morbid- quence of polypharmacy is delirium, which ity.2 Identifying delirium as the cause of remains a relevant potential diagnosis for impairment is important because delirium Mr. B.7 Alternative consequences vary by has potentially modifiable underlying eti- and their respective pharma- ologies. Symptomatically, delirium presents codynamics. We take into consideration as impairment and fluctuation in attention, Mr. B’s exposure to high doses of the high- awareness, and at least one other cognitive potency agent, haloperidol. domain, with a clear indication that the Exposure to haloperidol can result in extra- Clinical Point impairment occurred over a short period of pyramidal symptoms, including akathi- time and represents a departure from base- sia,8,9,10 and the rare, but potentially fatal, In the case of akathisia, line.3 In Mr. B’s case, these symptoms have NMS.11 These reactions can often be distin- the clinician should not been excluded and should be considered guished by taking a thorough history and look for medication by the C-L psychiatrists. a physical evaluation. In the case of akathi- exposure, titration, or In addition to delirium, the C-L team sia, the clinician should look for medication taper must consider psychiatric comorbidity. Mr. B exposure, titration, or taper. Most com- has no psychiatric history and a sudden first monly, akathisia occurs secondary to anti- occurrence of hallucinations; therefore, it is psychotic exposure,12 followed by the onset unlikely that he has developed a primary of a combination of subjective symptoms, psychotic disorder. Because he reported his such as restlessness, anxiety, and irritabil- symptoms had been present only for sev- ity, and an objective symptom of increased eral days, he would not meet criteria for motor activity.3 NMS, on the other hand, is , which according to DSM-5 distinguished by symptoms that include criteria require at least 1 month of ≥2 symp- hyperthermia (>38ºC), diaphoresis, severe toms (including delusions, hallucinations, rigidity, urinary incontinence, vital insta- disorganized speech, disorganized behav- bility, alterations in mental health status, ior, or negative symptoms) and 6 months of and elevations in creatine kinase greater declining function.3 However, although it is than 4-fold the upper limit, usually in the improbable, the C-L team must consider a setting of treatment with antipsychot- primary psychotic illness, particularly given ics.3 Nearly all cases of NMS occur within the potential devastating consequence of the first 30 days of antipsychotic exposure.3 being misdiagnosed and mismanaged for an While, overtly, NMS may appear to be less alternative illness. Unlike psychotic disor- subtle than akathisia, clinicians should still ders, anxiety disorders are significantly more be weary to rule out this admittedly rare, prevalent in the U.S. general population than though potentially lethal diagnosis, espe- primary psychotic disorders.4 Furthermore, cially in an ICU patient, where the diagnosis the prevalence of anxiety disorders increases can be muddied by medical comorbidities Discuss this article at in the ICU setting; one study found that up that may mask the syndrome. www.facebook.com/ to 61% of ICU patients setting experience CurrentPsychiatry “anxiety features.”5 Therefore, anxiety disor- ders and stress disorders should be consid- EVALUATION Focus on akathisia ered in ICU patients who exhibit psychiatric On interview by the C-L team, Mr. B is visibly symptoms. restless, moving all 4 extremities. He reports Clinicians also should consider increased anxiety and irritability over the Current Psychiatry e2 April 2018 medication-induced adverse effects. In the past 2 to 3 days. Mr. B states that he is aware Cases That Test Your Skills

Table 1 Variations of akathisia and their characteristics Entity Description Medication-induced Presents as a combination of subjective anxiety/irritability and objective acute akathisia excessive movement (fidgeting, rocking, pacing) in the setting of the start, titration, or taper of medication (antipsychotic)3,16,17 Tardive akathisia The late presentation of akathisia symptoms during the course of treatment, despite there being no change in the suspected medication (antipsychotic). These symptoms may not improve upon medication discontinuation3,16,17 Chronic akathisia The chronic persistence of the symptoms of akathisia. Usually these symptoms tend to be objective, with subjective symptoms decreasing severity/remitting over time16,17 Withdrawal akathisia The new development of akathisia in the setting of antipsychotic withdrawal15 Pseudoakathisia The presence of objective akathisia symptoms, but not subjective symptoms, Clinical Point in the setting of treatment (most commonly antipsychotic). Usually these symptoms present late through the course of treatment. This diagnosis is NMS may appear to controversial because some feel that it can represent a various diagnoses, including tardive , tardive akathisia, or chronic akathisia14,16 be less subtle than Source: References 3,14-17 akathisia and clinicians should still be weary to rule out this of his increased motor movements and can , dexamethasone, haloperidol, diagnosis, especially in briefly suppress them. However, after sev- and olanzapine. an ICU patient eral seconds, he again begins spontaneously fidgeting, moving all 4 extremities and shift- What is the most likely diagnosis and cause of ing from side to side in bed, saying, “I just Mr. B’s symptoms? feel anxious.” He denies having visual hallu- a) akathisia secondary to haloperidol cinations, and says that the previous hallu- b) NMS secondary to haloperidol cinations had spontaneously presented and c) akathisia secondary to midazolam remitted after surgery. He denies the use of d) NMS secondary to midazolam psychotropics for mental illness, prior simi- lar symptoms to this presentation, a family history of mental illness, recent illicit sub- The authors’ observations stance use, or excessive alcohol use prior to We determined that the most likely diagno- presentation. This history is corroborated by sis for Mr. B’s symptoms was medication- collateral information from his brother, who induced akathisia secondary to haloperidol. was present in the ICU. On physical examina- Akathisia, coined by Haskovec in 1901,12,13 tion, Mr. B is afebrile and his vital signs are is from Greek, meaning an “inability to within normal limits. He does not have mus- sit.”12 DSM-5 describes 2 forms of akathisia: cular rigidity or neck . His labora- medication-induced acute akathisia, and tar- tory values, including complete blood count, dive akathisia.3 In the literature, others have electrolytes, liver function tests, and creatine described additional classifications, includ- phosphokinase, are within normal limits. ing chronic akathisia, withdrawal akathi- His medication administration record sia, and pseudoakathisia (Table 13,14-17). In includes 46 standing agents, 16 “as-needed” Mr. B’s case, given his sudden development agents, and 8 infusions. Several of the of symptoms and their direct chronologic standing agents had psychotropic prop- relationship to antipsychotic treatment, and erties; however, the most salient were his combined subjective and objective symp- Current Psychiatry several opioids, ketamine, midazolam, toms, we believed that Mr. B’s symptoms Vol. 17, No. 4 e3 Cases That Test Your Skills

were consistent with medication-induced risk factor for akathisia,18 although atypical acute akathisia (MIA). The identification , selective serotonin reuptake and treatment of this clinical entity is impor- inhibitors, and serotonin- tant for several reasons, including reducing reuptake inhibitors, have been linked to the patient morbidity and maximizing patient disorder.18,19 comfort. Additionally, because akathisia Regarding antipsychotics, risk factors has been associated with poor medication for akathisia include drug potency, dose, adherence, increased agitation/, and rapidity of titration.20 All of these fac- increased suicidality, and the eventual devel- tors were relevant in our patient’s case. opment of ,18 it is a relevant Risk across antipsychotic classes is not prognostic consideration when deciding to well understood; few head-to-head studies treat a patient with antipsychotics. have comparing antipsychotics. However, Clinical Point Pathophysiologically, we have yet to fully general estimates suggest a 15% to 40% shed light on the exact underpinnings of prevalence in patients exposed to typical High-potency akathisia. Much of our present knowledge antipsychotics, as compared with 0% to antipsychotics are stems from patient response to pharmaco- 12% exposed to atypical antipsychotics.8 believed to remain the logic agents. While blockade has The literature-reported difference in risk, as greatest risk factor for been linked to akathisia, the exact mecha- well as our patient’s comparative difference akathisia nism is not completely understood. Previous in exposure to large doses of haloperidol theories linking nigrostriatal pathways have (50 mg) as compared with 1 dose of olan- been expanded to include mesocortical and zapine (5 mg), led us to believe his akathisia mesolimbic considerations.12,17,18 Similarly developed primarily due to his exposure surmised from medication effects, the trans- to haloperidol. Conclusively linking his mitters y-aminobutyric acid, serotonin/ symptoms to haloperidol alone, however, is 5-hydroxytryptamine (5-HT), norepine­ not possible, and we did consider that olan- phrine, and acetylcholine also have been zapine may in fact have had some effect in linked to this syndrome, though as of yet, worsening Mr. B’s akathisia. exact gross pathophysiologic mechanisms have not been fully elucidated.12 More Which of the following is a treatment option recently, Stahl and Loonen19 described a for medication-induced akathisia? novel mechanism by which they link the a) shell of the nucleus accumbens to akathisia. b) benztropine In their report, they indicate that the poten- c) tial reduction in dopaminergic activity, sec- d) ondary to antipsychotic administration, can e) all of the above result in compensatory noradrenergic acti- vation of the locus coeruleus.19 The increased noradrenergic activity results in the down- The authors’ observations stream activation of the shell of the nucleus While there are reports on the efficacy of accumbens.19 The activation of the nucleus various agents in the treatment of akathisia, accumbens shell, which has been linked to the most commonly evaluated agents are unconditioned feeding and fear behavior, propranolol, , and benzodi- can then result in a cascade of effects that azepines.17, 21 would phenotypically present as the syn- Propranolol is a nonselective beta-adren- drome we recognize to be akathisia.19 ergic blocker with numerous indications.17 Numerous etiologies have been linked Despite a 2004 Cochrane Review indicat- to MIA. Of these, high-potency antipsy- ing that there is no evidence in support of Current Psychiatry e4 April 2018 chotics are believed to remain the greatest central acting beta-blockers for treating Cases That Test Your Skills

Table 2 Mr. B’s Barnes Akathisia Scale score before and after treatment with IV diphenhydramine 4 hours after first 2 hours after intervention (50 mg) and first intervention 2 hours after second Day 2 of Measure Pre-intervention (50 mg) intervention (25 mg) follow-up Objective 3 0 0 0 symptoms Awareness of 2 1 0 0 restlessness Distress related 3 1 0 0 to restlessness Summed 8 out of 9 2 out of 9 0 out of 9 0 out of 9 Clinical Point objective/ subjective When indicated, symptoms Global clinical 5 1 0 0 clinicians should assessment of lean toward using akathisia propranolol for treating akathisia akathisia,22 propranolol is not yet recog- patients with comorbid Parkinson’s dis- nized as an appropriate treatment.17 The ease. Despite these benefits, head-to-head reason for this discrepancy is likely due to trials seem to either point to the superiority the Cochrane Review’s restrictive inclu- of propranolol or to no difference between sion criteria, which prevented the analysis these agents for treating akathisia.28,29 In a of much of the literature.22 In fact, several review, we only found 1 trial demonstrat- reports cite evidence for the treatment effi- ing benztropine’s superiority over pro- cacy of propranolol17 and, to date, some pranolol,23 but this trial was constrained by reports continue to advocate for its use as a its small population (6 patients). Therefore, first-line agent in the treatment of akathisia. the data suggest that, when indicated, cli- Admittedly, besides the Cochrane Review,22 nicians should lean towards using pro- other reports have found propranolol to be pranolol for treating akathisia. ineffective for treating akathisia,23 although Diphenhydramine, a first-generation these tend to be limited by their population antihistamine with antimuscarinic proper- size and generalizability. ties, has been studied for its efficacy in treat- As with propranolol, a 2006 Cochrane ing -induced akathisia in Review found “no reliable evidence to the emergency setting.30 There are several support or refute” using reports on the efficacy of this agent, includ- agents in the treatment of akathisia.24 We ing a large randomized study involving suspect that the review’s findings were 281 patients that found it effective for pre- likely secondary to its strict inclusion crite- venting metoclopramide-induced akathi- ria.24 In fact, several reports support using sia.30 Another head-to-head trial reported anticholinergic agents for treating akathi- the benefit of the diphenhydramine vs sia.25 Here we focus on benztropine and midazolam.31 Both agents were effica- diphenhydramine. cious for treating akathisia; however, mid- Two reviews—Blaisdell26 (1994) and azolam had a more rapid onset. Despite Poyurovsky27 (2010)—suggest modest these positive reports, double-blind tri- Current Psychiatry benefits from benztropine, primarily in als have found diphenhydramine to be Vol. 17, No. 4 e5 Cases That Test Your Skills

prudent to utilize propranolol as a first-line Related Resources agent for treating akathisia. • Factor SA, Leffler JB, Murray CF. Drug-induced movement Finally, other reports have cited treat- disorders: a clinical review. Medscape. http://www.medscape. org/viewarticle/586881. ment efficacy linked to serotonin 2A recep- • Marder S, Stroup TS. Pharmacotherapy for schizophrenia: tor (5-HT2A) antagonists (mianserin, side effect management. UpToDate.https://www.uptodate mirtazapine, and ), clonidine, .com/contents/pharmacotherapy-for-schizophrenia-side- effect-management. gabapentin, amantadine, and other agents.17 Drug Brand Names If treatment with propranolol is ineffective Amantadine • Symmetrel Lorazepam • Ativan or contraindicated, clinicians should utilize Benztropine • Cogentin Metoclopramide • Reglan their clinical judgement in deciding on the Clonazepam • Klonopin Mianserin • Tolvon Clonidine • Catapres Midazolam • Versed use of one agent over another. Dexamethasone • Decadron Mirtazapine • Remeron Diazepam • Valium Olanzapine • Zyprexa Clinical Point Diphenhydramine • Benadryl Propranolol • Inderal Gabapentin • Neurontin Rivastigmine • Exelon OUTCOME Haloperidol • Haldol Trazodone • Oleptro Complete resolution have Ketamine • Ketalar Haloperidol is discontinued and diphen- also been found to be hydramine, 50 mg IV, is administered. efficacious for treating (Diphenhydramine was used instead of pro- akathisia pranolol due to immediacy of availability.) ineffective,17 which suggests propranolol Most of Mr. B’s resolve should be the first-line agent, assuming it on a repeat interview 3 hours later. He is not contraindicated. receives another dose of diphenhydramine, Benzodiazepines have also been found 25 mg IV, for persistent mild irritability. By to be efficacious for treating akathisia. A Day 2 of follow-up, his symptoms completely 1999 Cochrane Review included 2 random- resolve as measured on the Barnes Akathisia ized controlled trials that assessed the effi- Scale33 (Table 2, page e5). cacy of clonazepam vs placebo for treating akathisia.32 It found evidence of benefit References 1. Cavallazzi R, Saad M, Marik PE. Delirium in the ICU: an for clonazepam, but questioned the gen- overview. Ann Intensive Care. 2012;2:49. 32 eralizability of these studies. This review 2. Farrell KR, Ganzini L. Misdiagnosing delirium as did not include several other reports that depression in medically ill elderly patients. Arch Intern Med. 1995;155(22):2459-2464. suggest benefits of other benzodiazepines 3. Diagnostic and statistical manual of mental disorders, 5th for treating akathisia. Other than clonaze- ed. Washington, DC: American Psychiatric Association; 2013. pam, reports suggest benefit for diazepam, 4. National Alliance on Mental Illness. Mental health by the lorazepam, and midazolam for treating numbers. https://www.nami.org/learn-more/mental- health-by-the-numbers. Accessed March 4, 2018. akathisia.17 Despite this evidence and 5. Jacka MJ, Mitchell N, Perez-Parada J. Incidence and the findings from this Cochrane Review, prevalence of anxiety, depression, and post-traumatic stress disorder among critical care patients, families, and the literature does not appear to point to practitioners. J Anest & Inten Care Med. 2016;1(1):55555. doi: clear dominance of these agents over pro- 10.19080/JAICM.2016.01.555555. 6. Reis AM, Cassiani SH. Adverse drug events in an intensive pranolol. Given the safety concerns when care unit of a university hospital. Eur J Clin Pharmacol. prescribing benzodiazepines, it would be 2011;67(6):625-632. continued Bottom Line Akathisia is an elusive adverse effect of antipsychotics and can be misdiagnosed as anxiety. Close consideration should be given to potential medical, psychiatric, and drug-related etiologies in patients who have a prolonged medical course, Current Psychiatry e6 April 2018 comorbidities, and exposure to multiple pharmacologic agents. Cases That Test Your Skills

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Current Psychiatry Vol. 17, No. 4 e7