Altered Mental Status in an Elderly Woman with Concurrent Takotsubo Syndrome and Polymyalgia Rheumatica: A Case of Treatable Geriatric Delirium

Hien Nguyen, MD; Connie Le, MD; Hanh Nguyen, MD; Nam-Tran Nguyen

Winter 2012 - Volume 16 Number 1

Abstract

We present a unique case of a patient, aged 80 years, who presented with delirium and takotsubo syndrome. Also known as “broken heart syndrome” because it often originates following an emotional stress, takotsubo syndrome may be difficult to distinguish from myocardial infarction because of similar symptoms and demographics. However, the distinction of these opposing diagnoses is significant because takotsubo syndrome is associated with more favorable prognosis for complete recovery, especially with early diagnosis and expedient supportive therapy. To our knowledge, we present the first case of takotsubo syndrome in which the diagnosis was made in an elderly patient presenting with delirium and in the absence of the hallmark symptoms of chest pain and dyspnea. Finally, we describe this patient’s coexistent diagnosis of polymyalgia rheumatica and speculate on its possible theoretic relationship to takotsubo syndrome.

Introduction

Takotsubo syndrome has historically been considered quite rare but currently is suspected to be underdiagnosed, because the estimated incidence is approximately 1.7% to 2.2% of patients presenting with acute myocardial infarction (MI).1,2 It is important that physicians be familiar with this diagnosis because the elderly are rapidly becoming a large segment of the population. An enigmatic condition first described in 1990, takotsubo syndrome has the cardinal symptoms of angina and dyspnea, mimicking acute coronary syndrome.1,2 We present a case of rapidly reversible delirium heralded by the diagnosis of concurrent takotsubo syndrome and polymyalgia rheumatica (PMR).

Case Report

A black woman, age 80 years, with type 2 diabetes and hypertension was admitted to the hospital because of an acute change in sensorium evolving over two days, with abrupt aberrant sleep-wake cycles (agitated and awake at nighttime; sleeping in the daytime), fluctuating disorientation to family members, and refusal of food. At admission, it was found that her medications included mirtazapine, lisinopril, metformin, atenolol, simvastatin, and aspirin. A full review of organ systems revealed a five-pound weight loss, fatigue, myalgias, and low-grade fevers over the preceding month. The patient reported no chest pains, shortness of breath, headaches, abdominal pains, or falls at any time period before or during her acute decompensation. However, later during her hospital stay, a family member reported that the patient’s sister had recently died.

At admission, she was febrile, with a temperature of 100.3°F, and this continued intermittently throughout her hospitalization. Examination showed her blood pressure to be 73/49 mm Hg, her pulse to be 90 beats/minute, and her respiratory rate to be 22 breaths/minute. She had leukocytosis (30,000 cells/mm3), mild acute renal insufficiency (creatinine of 1.8 mg/dL), normal acid-base values, and slightly elevated liver enzyme levels. Her erythrocyte sedimentation rate was elevated, at 91 mm/h, and her C-reactive protein level was elevated, at 153 mg/L. Findings were normal on flow cytometry studies and on tests to evaluate for connective-tissue diseases, including antinuclear antibody, rheumatoid factor, anti-SSA, anti-SSB, cytoplasmic antineutrophil cytoplasmic antibodies, perinuclear antineutrophil cytoplasmic antibodies, hepatitis, cryoglobulins, and anticardiolipin antibody. Findings on blood cultures for infectious etiologies and on tests for mononucleosis, lyme disease, thyroid disease, syphilis, human immunodeficiency virus, tuberculosis, and Clostridium difficile infection were all normal. Neither whole-body computed tomography (CT) scanning of the chest, abdomen, and pelvis nor positron-emission tomography, indium white-blood-cell scanning, or gallium scanning revealed occult infection or malignancy.

An initial electrocardiogram revealed new acute deep T-wave inversions in all precordial leads, along with an old right bundle-branch block (Figures 1 and 2). Initial creatine kinase MB fractions and troponin levels were normal, as were follow-up serial cardiac enzyme levels. An initial echocardiogram demonstrated mild concentric left ventricular hypertrophy with a severely depressed ejection fraction of 20% and prominent apical ballooning (Figure 3). Complete restoration of cardiac ejection fraction was confirmed by echocardiography one week later (Figure 4). Cardiac CT scans demonstrated normal coronary vasculature, other than minimal coronary calcifications. Findings on a nuclear stress test were normal, with an ejection fraction of 58%. Thus, the consulting cardiologist recommended medical management. Initially, cardiac catheterization was contemplated, but it was not completed because cardiac function was rapidly reversible and because of benign findings on noninvasive evaluations. In the interim, the patient was treated with standard supportive therapy, including oxygen, acetylsalicylic acid, and intravenous hydration for hypotension.

Once infectious etiologies were excluded, a rheumatology consultant initiated corticosteroidal therapy at a dose of 20 mg of prednisone daily because of concern about the possibility of PMR, which was based on the patient’s clinical presentation and strikingly elevated levels of markers for inflammation. The patient’s cognition, laboratory-test findings, and functional status improved rapidly within less than one week, so she was transferred to subacute care with indefinite continuation of the prednisone dosage.

Discussion

Delirium

To the best of our knowledge, the case we present here is the first reported case of takotsubo syndrome in which delirium, in the absence of chest pain and shortness of breath, was the primary and unexpected manifestation. Our findings are in contrast with those of Malone et al,3 who reported that delirium may be the initial presentation for MI, the closest correlate of takotsubo syndrome. In that study of very old patients with acute MI, delirium developed in 28%; delirium was only rarely the initial presentation for MI.

Delirium involves acute global changes in cognition and consciousness. Its causes can be placed into four broad categories: metabolic, toxic, structural, and infectious.4 An alternative classification scheme is medical, chemical, surgical, or neurologic.4 However, delirium often has multiple causes, as was the situation with our patient, who had multiple preexisting medical comorbidities and presented with multisystemic disease. We believe that her delirium was primarily caused by metabolic derangements (hypotension, renal insufficiency, and transient heart failure). A frequent iatrogenic cause of delirium in the elderly is overmedication with, for example, tricyclic antidepressants and antiparkinsonian drugs. Elderly persons are especially at risk for delirium because of preexisting cognitive impairment, medical and psychiatric comorbidities, functional impairments, and polypharmacy.3,4

Takotsubo Syndrome

A diagnosis of takotsubo syndrome is based on four criteria developed by the Mayo Clinic: transient hypokinesis or akinesis of the left ventricle, sparing the apex; exclusion of obstructive coronary disease; electrocardiographic changes, including ST segment or T-wave inversions, and/or mild cardiac enzyme elevations; and exclusion of pheochromocytoma or myocarditis. The syndrome is sometimes called “broken heart syndrome” because of its high correlation with a stressful life event. Diagnosis is important because cardiogenic shock, pulmonary edema, dysrhythmia, left ventricular thrombus or free wall rupture, and death (mortality, 1.7%–2.3%). Takotsubo syndrome is also known as the broken heart syndrome because a stressful emotional stressor is often the trigger for the disease.5

In spite of the well-defined symptomatology of takotsubo syndrome, its diagnosis may be challenging because of ethnicity-, age-, and sex-related differences in presentations. Although 90% involve postmenopausal women older than 67 years, occurrences have been described in persons ranging in age from 2 to 80 years. In a recent case series in the US, 57% of patients were Asian, 40% were white, and 3% were of other ethinicity.1,2,5-7

Recently, Pezzo et al reported6 that blacks may present with dyspnea and without chest pain; our patient presented atypically with delirium and without angina or dyspnea. Other atypical presentations for takotsubo syndrome described in other case series include seizures, epigastric pain, or nausea and vomiting, but these patients also had concurrent chest pain and dyspnea.6

Therapy for takotsubo cardiomyopathy is generally supportive but may include aggressive treatment such as the use of inotropic agents or an intra-aortic balloon pump if there is severe or refractory hypotension. In most patients, the left ventricular ejection fraction normalizes within two months.6

Polymyalgia Rheumatica

PMR is characterized by fever, weight loss, fatigue, depression, proximal muscle pain and stiffness, and gel phenomenon and is seen more commonly in women older than age 50 years.8 Our patient’s elevated levels of inflammation markers and systemic symptoms strongly suggested a diagnosis of PMR concurrent with takotsubo syndrome, an association not previously reported.8 The diagnosis of PMR was strengthened when corticosteroids rapidly resolved her cognitive difficulties and aberrations on laboratory findings.

We speculate that there may be an association between takotsubo syndrome and PMR in the presence of a sympathetic nervous system dysfunction; this relationship is not unprecedented. There are two case reports in the medical literature describing reflex sympathetic dystrophy syndrome coexisting with PMR.9,10 Indeed, the most preeminent theory for the pathogenesis of takotsubo syndrome is a sympathetic hyperactivity, such as may occur from acute emotional or physical stress.9,10 However, it is entirely possible that the development of concurrent takotsubo syndrome and PMR was simply coincidental in this elderly patient, whose age group is associated with a higher incidence of both medical conditions independently.
A review of the literature illustrates two distinct cases of takotsubo syndrome associated with other acute conditions in which corticosteroids were interestingly prominent in the resolution of this cardiomyopathy, such as is illustrated in our case. Ukita et al reported resolution of takotsubo syndrome after corticosteroid therapy; the syndrome had developed during an acute adrenal crisis because of isolated adrenocorticotropin deficiency.11 Radhakrishnan and Granato reported resolution of this cardiomyopathy after corticosteroid therapy; it had developed during thyroid storm.12

PMR has not been previously described with delirium to our knowledge, and it is most closely related to temporal arteritis. Pascuzzi et al reported that a patient with temporal arteritis had a primary presentation of delirium—delusional thinking without concomitant headache or visual loss.13 We acknowledge, though, that our patient presented with other metabolic impairments that we believe contributed strongly to the development of delirium.

Conclusion

We presented the case of a patient with rapidly reversible delirium heralded by concurrent takotsubo syndrome and PMR. Both conditions are uncommon in general and even rarer when diagnosed concurrently in a single patient. Furthermore, our patient is black, a group that is not typically considered prone to PMR. Scandinavian people have been reported to have the highest rate of PMR, whereas black and Hispanic groups have the lowest rates.14 Less than 2% of patients diagnosed with takotsubo syndrome are black, with the majority being of Asian descent.7

Our case demonstrates valuable teaching points in the challenging management of delirium in an elderly patient. Delirium can have multiple etiologies, and atypical presentations for common medical conditions are commonplace in elderly patients presenting with delirium. Further research may be useful in searching for a possible relationship, based on sympathetic dysfunction, between takotsubo syndrome and PMR. This research will likely be facilitated by the rapid acceleration in the world’s geriatric population and an accompanying increase in the incidence of both of these medical conditions.

Disclosure Statement

The author(s) have no conflicts of interest to disclose.

Acknowledgment

Katharine O’Moore-Klopf, ELS, of KOK Edit provided editorial assistance.

References
1.    Satoh H, Tateishi H, Uchia T, et al. Stunned myocardium with specific (tsubo-type left ventriculographic configuration due to multivessel spasm. In: Kodama K, Haze K, Hori M, editors. Clinical aspects of myocardial injury: from ischemia to heart failure [In Japanese]. Tokyo: Kagakuhyouronsha; 1990. p 56–64.
2.    Bybee KA, Prasad A, Barsness GW, et al. Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am J Cardiol 2004 Aug 1;94(3):343–6.
3.    Malone ML, Rosen LB, Goodwin JS. Complications of acute myocardial infarction in patients > or = 90 years of age. Am J Cardiol 1998 Mar 1;81(15):638–41.
4.    Saxena S, Lawley D. Delirium in the elderly: a clinical review. Postgrad Med J 2009 Aug;85(1006):405–13.
5.    Kawai S, Kitabatake R, Tomoike H; Takotsubo Cardiomyopathy Group. Guidelines for diagnosis of takotsubo (ampulla) cardiomyopathy. Circ J 2007 Jun;71(6):990–2.
6.    Pezzo SP, Hartlage G, Edwards CM. Takotsubo cardiomyopathy presenting with dyspnea. J Hosp Med 2009 Mar;4(3):200–2.
7.    Jabara R, Gadesam R, Pendyala L, Chronos N, King SB, Chen JP. Comparison of the clinical characteristics of apical and non-apical variants of “broken heart” (takotsubo) syndrome in the United States. J Invasive Cardiol 2009 May;21(5):216–22.
8.    Subrahmanyan P, Dasgupta B. Polymyalgia rheumatica and giant cell arteritis. Br J Hosp Med (Lond) 2006 May;67(5):240–3. Erratum in: Br J Hosp Med (Lond) 2006 Jul;67(7):383.
9.    Wysenbeek AJ, Calabrese LH, Scherbel AL. Reflex sympathetic dystrophy syndrome complicating polymyalgia rheumatica. Arthritis Rheum 1981 Jun;24(6):863–4.
10.    Bordin G, Azteni F, Betatazzi L, Beyene NB, Carrabba M, Sarzi-Puttini P. Unilateral polymyalgia rheumatica with contralateral sympathetic dystrophy syndrome. A case of asymmetrical involvement due to pre-existing peripheral palsy. Rheumatology (Oxford) 2006 Dec;45(12):1578–80.
11.    Ukita C, Mivazaki H, Tovoda N, Kosaki A, Nishikawa M, Iwasaka T. Takotsubo cardiomyopathy during acute adrenal crisis due to isolated adrenocorticotropin deficiency. Intern Med 2009;48(5):347–52.
12.    Radhakrishnan A, Granato JE. An association between Takotsubo cardiomyopathy and thyroid storm. Postgrad Med 2009 May;121(3):126–30.
13.    Pascuzzi RM, Roos KL, Davis TE Jr. Mental status abnormalities in temporal arteritis: a treatable cause of dementia in the elderly. Arthritis Rheum 1989 Oct;32(10):1308–11.
14.    Labbe P, Hardouin P. Epidemiology and optimal management of polymyalgia rheumatica. Drugs Aging 1998 Aug;13(2):109–18.

More from this Journal section

Gastric Antral Vascular Ectasia (Watermelon Stomach)--An Enigmatic and Often-Overlooked Cause of Gastrointestinal Bleeding in the Elderly
Friday, 02 July 2010
Hien Nguyen, MD; Connie Le, MD; Hanh Nguyen, MD Fall 2009 - Volume 13 Number 4 Abstract Gastric antral vascular ectasia (GAVE) syndrome, also known as watermelon stomach is a significant cause of acute or chronic gastrointestinal blood loss in the elderly. is characterized endoscopically by “watermelon stripes.” Without cirrhosis, patients are 71% female, average age 73, presenting with occult blood loss leading to transfusion-dependent chronic iron-deficiency anemia, severe acute upper gastrointestinal bleeding, and nondescript abdominal pain. Introduction Gastric antral vascular ectasia (GAVE) syndrome, also known as watermelon stomach, is a rare but significant cause of severe acute or chronic gastrointestinal blood loss in the elderly.1–4 Although it is associated with heterogeneous medical conditions, including hepatic, renal, and cardiac diseases, its pathogenesis is unknown.1-3 The diagnosis of GAVE syndrome in patients with renal or hepatic disease is often problematic because there are more frequent causes of gastrointestinal bleeding in these diseases (vascular malformations, peptic ulcer disease, esophageal or gastric varices, and colonic and rectal ulcers) that overshadow GAVE syndrome. Furthermore, diagnosis may be challenging because gastrointestinal bleeding may be occult or overt, and the endoscopic appearance of GAVE syndrome resembles that in portal hypertensive gastropathy (PHG) or antral gastritis. However, differentiation of GAVE syndrome from these other causes is critical because of the vastly disparate therapies required for each. Building on a leading theory that mechanical stress is involved in the pathogenesis, we speculate that the diverse medical risk factors may be related to GAVE syndrome through an autonomic dysfunction.5,6 Case Report A woman, age 63 years, with a chronic hepatitis C infection, esophageal varices, and hemodialysis-dependent end-stage renal disease secondary to diabetes and hypertension presented at our institution and reported several weeks of intermittent generalized abdominal pain and vomiting and daily minimal stools that appeared blood-streaked on wiping but without hematemesis or melena. Laboratory findings showed a hemoglobin of 6.8 g/dL; a hematocrit of 20%; and normal hepatic function, platelet count, prothrombin time, and international normalized ratio. Although the anemia was consistent with iron deficiency, the low hemoglobin level invariably decreased to pretransfusion levels within days of blood transfusion. Contrast computed tomography scan of the abdomen revealed hepatomegaly but no other significant gastrointestinal pathology. Because our patient had had endoscopically proven portal esophageal varices and PHG two years before we examined her, which had been treated with sclerotherapy and propranolol, esophagogastroduodendoscopy was repeated in anticipation of further sclerotherapy for esophageal varices, PHG, or peptic ulcer disease. Instead, a repeat endoscopy revealed extensive vascular ectasias and patchy erythema in the distal antrum that were diagnostic of GAVE syndrome, but no esophageal or gastric varices. A colonoscopy showed hemorrhoids. It was thought that hemorrhoidal bleeding alone could not explain the severe and relapsing anemia, and GAVE syndrome was considered a more plausible cause of severe anemia from gastrointestinal blood loss. The endoscopist considered primary medical therapy with laser photocoagulation but because of the presence of diffuse and advanced vascular ectasias did not believe that this would be sufficient and would not produce long-lasting results. The patient was notified of the higher risks of definitive surgery in light of her multiple comorbidities and underwent an uncomplicated subtotal gastrectomy without a long-term need for blood transfusions. Discussion Although GAVE syndrome is a rare medical condition, it is a relevant possibility in older patients with severe acute or chronic gastrointestinal blood loss, because it accounts for up to 4% of nonvariceal upper gastrointestinal blood loss.1–4,7 The initial presentation may include occult blood loss leading to transfusion-dependent chronic iron-deficiency anemia, severe acute upper-gastrointestinal bleeding, nondescript abdominal pain, or even gastric outlet obstruction, as described in a prior case report. This disease entity was first described by Rider et al1 in a patient with severe chronic iron-deficiency anemia and gastroscopy showing “fiery red changes with marked hypertrophic mucosal changes, and scattered profuse bleeding.” A majority of patients without cirrhosis but with GAVE syndrome are female (71%) with median age of 73 years, whereas the majority of patients with both cirrhosis and GAVE syndrome are male (75%) with a mean age of 65 years.1,2 Associated medical conditions include heart, liver, and kidney diseases; diabetes; connective-tissue diseases; hypothyroidism; and status as a bone marrow transplant recipient.1–4 The epidemiologic features of GAVE syndrome are attributed to the age and sex distributions of the underlying medical conditions, of which connective-tissue diseases and cirrhosis are the most commonly related.1,2 The syndrome has the name watermelon stomach because of the pathognomonic endoscopic appearance (columns of red tortuous ectatic vessels along longitudinal folds of the antrum) that resembles watermelon stripes (Figure 1 and 2).1–5 Typical histologic changes include superficial hyperplastic antral mucosa, capillary ectasia with thrombosis, and fibromuscular hypertrophy of the lamina propria.1–4 GAVE syndrome is often misdiagnosed on endoscopy as PHG. Unlike watermelon stomach, PHG causes predominant changes in the fundus and corpus.1,2 GAVE syndrome does not respond to measures that decrease portal pressures in PHG, including transjugular intrahepatic shunt and β-blocker therapy.1,2,4,7 Therapy for GAVE syndrome can be separated into three categories: pharmacologic, endoluminal, and surgical approaches.1,2,7–9 Pharmacologic therapies have been described with the use of corticosteroids, estrogen–progesterone combinations, tranexamic acid (with a significant risk of ischemic events and pulmonary emboli), thalidomide, α-interferon, calcitonin, and cyproheptadine.1,2 However, the effectiveness of all these medications have been described only in reports of single cases or small case series.1,2,7,8 Endoluminal therapies are the mainstay of conservative management and include endoscopic band ligation, sclerotherapy, heater probe, and argon plasma coagulation, which is emerging as the preferred endoscopic therapy.1,2 Although multiple intraluminal treatment sessions may be required for cessation of transfusion dependence, the safety of endoscopic therapy is well documented, and there is only a single case report of a complication --gastric outlet obstruction secondary to argon plasma coagulation.8 Further, a recent case report described successful endoscopic mucosal resection of lesions in GAVE syndrome with resolution of anemia.9 There is a paucity of reports of controlled studies of GAVE syndrome in terms of medical versus surgical therapy. The consensus, however, is that primary surgical therapy is not advocated, because of reports of high morbidity and mortality from patients undergoing surgery with GAVE syndrome who often have multiple other serious medical comorbidities. However, Novitsky et al4 have argued for a somewhat more aggressive surgical approach as second-line therapy, especially in patients in whom a short trial of endoluminal treatment fails. They argue that antrectomy is the only reliable therapy with definitive and curative potential, especially for unresponsive or severe disease. Minimally invasive laparoscopic antrectomy has also been advocated as a novel approach to the therapy of GAVE syndrome.10 Furthermore, treatment of underlying medical conditions can lead to resolution of GAVE syndrome.1,2,4,7 For instance, liver transplantation has been reported to lead to complete resolution of GAVE syndrome.1,2 Our case presentation demonstrates the therapeutic dilemmas in this problematic disease, whereas reports of controlled studies comparing efficacy are lacking. Our patient possessed multiple medical comorbidities that placed her at higher surgical risk. Thus, she was initially referred to an endoscopist for the purpose of conservative intraluminal therapy with argon plasma coagulation. However, the endoscopist concluded that the patient’s particular mucosal lesions were so advanced and so diffuse that even intensive intraluminal therapy would be inadequate and would surely result in the need for multiple therapies that would produce questionable long-term control. This was significant because the patient had a history of lack of compliance, including regarding taking medications and keeping appointments for multiple medical evaluations across different specialties. The patient was advised about the risks and benefits of intraluminal versus surgical therapy, the latter of which the surgeon believed offered a more conclusive and definitive cure; the outcome was favorable. The pathogenesis of GAVE syndrome, principally considered an idiopathic disease, is unknown, and theories about it are controversial.1,2 An understanding of the pathophysiologic changes that lead to GAVE syndrome is lacking because most theories are based on single case reports or on reports of smaller series of fewer than 15 cases. However, a leading and plausible theory suggests antropyloric motility dysfunction.6 Quintero et al5 first conceptualized a theory of mechanical stress, where disordered peristaltic waves may cause partial prolapse of distal gastric mucosa through the pylorus, leading to formation of ectatic vessels.6 This disordered peristalsis and loss of gastric propulsive activity and motility may occur secondary to denervation of the digestive autonomic nervous system, which is primarily parasympathetic.6 The characteristic histologic finding of fibromuscular hyperplasia in GAVE syndrome further supports this hypothesis.1–6 We speculate that the altered gastric and antral motility in some patients with GAVE syndrome may be modulated by vagal denervation and sympathetic overactivity, which are already known to exist in many of the associated medical problems.5,6 Chronic liver disease is known to impair cardiovascular autonomic reflexes, whereas sympathetic overactivity is implicated in the pathogenesis and progression of renal diseases and heart failure.11–13 For several decades, it has been known that plasma norepinephrine levels are elevated in chronic renal failure, indicative of increased sympathetic nerve activity.12 Interestingly, recent research has hypothesized a role for the sympathetic nervous system in the modulation and expression of autoimmune lymphoproliferative and connective-tissue diseases such as systemic lupus erythematosus.14 Thus, these diverse medical conditions may share a common autonomic dysfunction with GAVE syndrome.12–14 In a retrospective chart review of our patient, we discovered that she had multiple symptoms suggestive of autonomic neuropathy and dysfunction, including neuropathy of the lower extremities, orthostatic hypotension, frequent hypoglycemia, and gastroparesis. Conclusion GAVE syndrome is an important diagnosis to consider in older patients with severe anemia and occult or profuse gastrointestinal bleeding, especially in the setting of heart, liver, or kidney diseases.1–4 The main inherent teaching point is that GAVE syndrome can be inadvertently overlooked as a remediable cause of gastrointestinal bleeding because there are more frequent causes of gastrointestinal bleeding (esophageal or gastric varices, PHG, and peptic ulcer disease) among patients with renal or hepatic diseases, which are the same medical conditions in which GAVE syndrome occurs. The endoscopic appearance of GAVE syndrome often mimics that of PHG or antral gastritis. Further, the case we reported here demonstrates that GAVE syndrome may be underdiagnosed because observational studies of screening gastroscopies in patients undergoing liver transplantation show that 1 in 40 patients has GAVE syndrome.1,2 Because this is a single-case report, we speculate that in larger case series, further studies of neurohormonal factors that may be involved in sympathetic nervous system dysfunction and disordered peristalsis in GAVE syndrome may provide more insight into the pathogenesis of this enigmatic disease.11–14 Disclosure Statement The author(s) have no conflicts of interest to disclose. Acknowledgments The authors would like to thank the Scleroderma Program, Division of Rheumatology, University of Michigan Medical Center for Figure 1 and the Pathology Department, University of Pittsburgh Medical Center for Figure 2. Katharine O’Moore-Klopf, ELS, of KOK Edit provided editorial assistance. References 1. Rider JA, Klotz AP, Kirshner JB. Gastritis with veno-capillary ectasia as a source of massive gastric hemorrhage. Gastroenterology 1953 May;24(1):118-23. 2. Selinger CP, Ang YS. Gastric antral vascular ectasia (GAVE): an update on clinical presentation, pathophysiology and treatment. Digestion 2008;77(2):131–7. 3. Stefandis I, Liakopoulos V, Kapsoritakis AN, et al. Gastric antral vascular ectasia (watermelon stomach) in patients with ESRD. Am J Kidney Dis 2006 Jun;47(6):e77–82. 4. Novitsky YW, Kercher KW, Czerniach DR, Litwin DE. Watermelon stomach: pathophysiology, diagnosis, and management. J Gastrointest Surg 2003 Jul–Aug;7(5):652–61. 5. Quintero E, Pique JM, Bombi JA, et al. Gastric mucosal vascular ectasias causing bleeding in cirrhosis. A distinct entity associated with hypergastrinemia and low serum levels of pepsinogen I. Gastroenterology 1987 Nov;93(5):1054–61. 6. Charneau J, Petit R, Calès P, Dauver A, Boyer J. Antral motility in patients with cirrhosis with or without gastric antral vascular ectasias. Gut 1995 Oct;37(4):488–92. 7. Dulai GS, Jensen DM, Kovacs TO, Gralnek IM, Jutabha R. Endoscopic treatment outcomes in watermelon stomach patients with and without portal hypertension. Endoscopy 2004 Jan;36(1):68–72. 8. Farooq FT, Wong RC, Yang P, Post AB. Gastric outlet obstruction as a complication of argon plasma coagulation for watermelon stomach. Gastrointest Endosc 2007 Jun;65(7):1090–2. 9. Kastsinelos P, Chatzimavroudis G, Katsinelos T, et al. Endoscopic mucosal resection for recurrent gastric antral vascular ectasia. Vasa 2008 Aug;37(3):289–92. 10. Sherman V, Klassen DR, Feldman LS, Jabbari M, Marcus V, Fried GM. Laparoscopic antrectomy: a novel approach to treating watermelon stomach. J Am Coll Surg 2003 Nov;197(5):864–7. 11. Stadlbauer V, Wright GA, Banaji M, et al. Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis. Gastroenterology 2008 Jan;134(1):111–19. Erratum in: Gastroenterology 2008 Mar;134(3):897. Stadlbauer V, Mookerjee RP. 12. Vonend O, Rump LC, Ritz E. Sympathetic overactivity--the Cinderella of cardiovascular risk factors in dialysis patients. Semin Dial 2008 Jul–Aug;21(4):326–30. 13. Goldsmith SR. Interactions between the sympathetic nervous system and the RAAS in heart failure. Curr Heart Fail Rep 2004 Jul;1(2):45–50. 14. del Rey A, Besedovsky HO. Sympathetic nervous system-immune interactions in autoimmune lymphoproliferative diseases. Neuroimmunomodulation 2008;15(1):29–36.
Echinococcus of the Liver Treated with Laparoscopic Hepatectomy
Thursday, 27 May 2010
Erina N Foster, MD; Gabor Hertz, MD Summer 2010 - Volume 14 Number 2 Abstract Echinococcosis or hydatid disease is endemic to many countries around the world where livestock, mainly sheep and cattle, are raised with dogs who act as the definitive hosts for the adult phase of the echinococcal tapeworm. We report a case of a man, age 22 years, who emigrated from Kyrgyzstan as a teenager, presenting with abdominal fullness and nausea and found to have a 9 cm echinococcal cyst of the liver which was successfully treated with laparoscopic hepatectomy because of a very favorable location. Case Presentation We report a case of a man, age 22 years, from Kyrgyzstan who presented with abdominal fullness and nausea. An ultrasound was performed and revealed a complex cystic liver mass. Computed tomography (CT) showed a large, mixed-density mass in the left lobe approximately 9 cm in size, with nondependent hypodense foci (Figure 1). His mother had mentioned another villager was diagnosed with a similar problem and was treated with surgery. Laboratory evaluation revealed no leukocytosis, normal blood count and liver enzymes. Echinococcal antibody was mildly elevated at 1.32 (positive over 1.2) and he was placed on albendazole 400mg bid preoperatively. Because of the advantageous location of the cystic mass, the patient was able to undergo laparoscopic segmental hepatectomy 4 weeks later (Figures 2 and 3). No postoperative complications were noted and the patient continued to do well 2 months after surgery. Discussion Echinococcosis or hydatid disease is endemic in the Mediterranean, Africa, Middle East, South America, Australia, Russia, and China where livestock, mainly sheep and cattle, are raised with dogs who act as the definitive hosts for the adult phase of the echinococcal tapeworm. Kyrgyzstan is a small, landlocked central Asian country, bordered by China, Kazakhstan, Uzbekistan, and Tajikistan with an estimated population of 5.4 million people. Kyrgyzstan has a predominantly agricultural economy, producing cotton, tobacco, wool, and meat.1 Livestock become infected when they eat food or water contaminated with dog feces which contain the larval form of the tapeworm. Infection leads to cysts in the liver in 75% of cases followed by lung, but can involve any part of the body.2 Mortality is estimated at 5% and sensitization can occur with systemic leakage of cysts into the bloodstream potentially leading to fatal anaphylaxis if a cyst ruptures.3 Most infections are caused by Echinococcus granulosus followed by Echinococcus multilocularis.3 Laboratory examination can rarely show a peripheral eosinophilia but usually the complete blood count is normal. Serologic testing is 84% sensitive but cannot definitively rule the diagnosis in or out.3 Imaging with ultrasound can show single or multiloculated cysts with a “snowflake or hail-storm” pattern and signs on CT include daughter cysts with a “wheel, rosette, or honeycomb-like” appearance.4 Treatment varies depending on the location, size of the cyst, and overall health of the patient. Surgical resection has been the treatment of choice but newer modalities through percutaneous aspiration called PAIR (puncture, aspiration, injection, and re-aspiration of scolicidal solutions) show promise. Patients treated with PAIR usually receive oral medication (albendazole or mebendazole) for 7 days before and 28 days after aspiration to help decrease the risk of recurrence.5 Surgical options include total pericystectomy, partial hepatectomy, and lobectomy, and can be complicated by bleeding, bile leak from the residual cavity, biliary fistula, or cholangitis. Endoscopic retrograde cholangiopancreatography (ERCP) is employed to mainly assist in postoperative management of these complications. Fortunately, the location of the cyst in our patient made it feasible to perform minimally invasive laparoscopic resection of his lesion. Disclosure Statement     The author(s) have no conflicts of interest to disclose. References     1.    The World Factbook: Central Asia: Kyrgyzstan [monograph on the Internet]. Washington, DC: Central Intelligence Agency; updated biweekly [cited 2010 Feb 1]. Available from: www.cia.gov/library/publications/the-world-factbook/geos/kg.html#.     2.    Voros D, Katsarelias D, Polymeneas G, et al. Treatment of hydatid liver disease. Surg Infect (Larchmt) 2007 Dec;8(6):621-7.     3.    Chrieki M. Echinococcosis–an emerging parasite in the immigrant population. Am Fam Physician 2002 Sep 1;66(5):817-20.     4.    Czermak BV, Akhan O, Hiemetzberger R, et al. Echinococcosis of the liver. Abdom Imaging 2008 Mar-Apr;33(2):133-43.     5.    Smego RA Jr, Sebanego P. Treatment options for hepatic cystic echinococcosis. Int J Infec Dis 2005 Mar;9(2):69-76.
Humanizing Patients through Narrative Approaches: The Case of Murphy, the “Motor-Mouth”
Tuesday, 08 June 2010
Michael Pickren Valenti, MA; Lewis Mehl-Madrona, MD, PhD, MPhil Summer 2010 - Volume 14 Number 2 Abstract Background: Some psychiatric patients are presented as hopeless, burned out, and devoid of social graces. Staff of mental health centers and hospitals are not encouraged to view these people differently. A narrative perspective allows anyone to emerge as a richly complex human being. Method: A course presented students with the opportunity to create narrative descriptions of patients presented by medical staff as hopeless. Results: One student’s narrative of “Murphy the Motor Mouth” is presented; it shows the validity and usefulness of the narrative approach in reconstructing a person to be avoided as an interesting, valuable, and richly complex human being. Conclusion: Murphy in story emerges as more interesting and worthy of knowing than the clinical Murphy constructed by medical staff. Narrative approaches offer a richness and intimacy that fosters a more therapeutic and effective relationship between patients and staff. Introduction In our contemporary psychiatric settings, patients are sometimes presented as hopeless, recalcitrant, and “burned out.” In this article we present the result of the interaction of a faculty and a student to change a “burned-out” patient into an interesting person through elicitation of his narrative. Narrative medicine has emerged as a new approach to humanize medicine,1 along with promoting empathy,2 and inculcating cultural competence.3 These approaches have not necessarily failed, but medicine still contains powerful dehumanizing influences.4 Methods As part of a course in narrative medicine, students were encouraged to find patients who had been dehumanized and to interview these patients to produce a narrative of interest about people who had been previously presented as uninteresting and burned out. The patient described herein was presented as a hopelessly recalcitrant “bipolar” with no redeeming social graces. We present an alternative narrative to show how narrative approaches can redeem the hopelessly lost, at least in the eyes of their caregivers, and foster more effective treatment. Results The story: Murphy, the “Motor-Mouth” was a special patient, but the staff at the hospital didn’t agree. His big presence, loud voice, and insatiable thirst for interaction were dramatic. He often laughed and made the sterile halls of the hospital come to life. But no one was laughing with him. I (MPV) was informed that Murphy was a Bipolar I substance abuser whose energy needed constant pharmaceutical correction. The staff hesitantly concurred that he was an interesting person, but tenaciously resisted the urge to know him. Yet, to me Murphy continued to stand out. The superficial level with which he had been conveyed became clear as I got to know him. Murphy presented as a tall, well-built male in his early fifties. His raspy voice projected from a large mouth with few teeth. He frequently asked, “How are you doing?” and cheerfully waved from across the room. Murphy loved to tell old stories, new stories, or retold stories. Once he got going, one could sit back and enjoy a fairly linear, often fast and disorganized, cascading monologue. Murphy was a Caucasian and Pacific Islander mixed male born in Provo, UT. He was raised in a large Mormon family with three brothers and five sisters. Murphy enjoyed a stable childhood with a family rooted in faith. He never experienced abuse or neglect. Murphy recalled fishing as a child and legendary moments in high school football. He boastfully shared many nicknames including “Kuntukinte,” “Dizzy D,” and “Baby Brain,” but could not recall their origin or meaning. After high school Murphy joined the military. He favorably recalled his time in Korea. Murphy loved the food and the people. He said “I felt love with the people” and “I ate kim chee.” His time in Korea also increased his appreciation for the US. He said, “People here are spoiled brats; they don’t know. They’re just used to having food every day.” He did not experience trauma in the service and was discharged after two years. A few years after his military service, Murphy experienced two traumatic events: witnessing the murders of his girlfriend and cousin. These events took place in his early thirties. Murphy appeared impenetrable to sadness until these memories emerged. They could silence a Murphy monologue above all else. Despite his high energy, Murphy’s ideology was easygoing. He was a person of the people, someone who did not strive for riches and power. Murphy often felt misunderstood and found refuge from judgment with his friends. Murphy claimed to “hang out with handicap people because they accept [him] for who [he is]” and said “[His] friends work at McDonalds.” Murphy experimented with drugs and alcohol at an early age. He was smoking cigarettes in the third grade and by the eighth grade using alcohol, marijuana, LSD, and cocaine. He used LSD every day in the summertime as a late adolescent. Despite his avid use, Murphy felt he was cautious. He “[found] out what [was] safe.” He did not blindly use any drug that came his way; Murphy did his homework. He read books and sought information before feeling comfortable with a substance. Murphy claimed drugs didn’t affect his mind and that they were “just an experience.” He was impenetrable to the effects of drugs. Murphy felt drugs played little part in his life path or current predicament. Despite his research and cautiousness, Murphy did experiment with some extremely dangerous substances. He used ice and sniffed paint, yet remained unscathed. Murphy was a proud marijuana smoker. He animatedly illustrated the joy of using marijuana in all its varieties. He felt it brought friends together and enhanced life. Murphy’s legal and psychiatric history were unclear. Murphy served five years in prison for robbing a bank. He said he was wrongly convicted, but wanted to serve the time and move on with his life. Murphy was diagnosed with Bipolar I disorder in his early thirties after “staying up for six days and six nights.” His first manic episode appeared to have followed the deaths of his cousin and girlfriend. However, because of Murphy’s often tangential, disorganized, and fast speech, he could not construct a coherent timeline. Murphy did not feel he had a mental illness; rather, a “motor mouth because doctors only give him a limited time to talk.” Doctors had not listened to him in the past and “[he knew] what it is like not to be heard.” Murphy loved to “talk story.” He was mostly interested in talking about life. When asked to talk about his experiences with pharmacologic agents, he often sidetracked. At the time of the class, he was taking lithium (600 mg twice daily), aripiprazole (30 mg daily), and benzotropine mesylate. He was first placed on lithium subsequent to his Bipolar I diagnosis. He felt very similar on or off drugs. When asked why he took medication, Murphy said, “Because I claim disability and my doctors think I am safe.” However, the medications gave him substantial digestive side effects. He recalled diarrhea so severe that “[he] kept wiping [himself], ….” Murphy told many stories of being unable to get to the bathroom fast enough and enduring this very tangible consequence. However, all the side effects disappeared when he took benzotropine mesylate. Murphy spoke highly of benztropine mesylate and treated it as a saving grace. He insisted on taking benzotropine mesylate while on any psychoactive medication. Without it, the side effects were unbearable. Benzotropine mesylate was Murphy’s favorite drug. He said it reduced his digestive symptoms. Benzotropine mesylate is known to cause euphoria and excitement. Murphy could have been enjoying the side effects rather than the drug’s primary mechanism. Passion can be expressed in many ways. Some endure years of practice and devote countless hours to perfect a craft. This brand of passion is most familiar to our modern day society. Yet, how many forms can passion take? Must it be hardworking? Murphy was a man of passion. He devoted himself to a lifestyle. From a young age he passionately sought an easy “feel-good sensation.” He walked a path of least resistance to a place of highest pleasure. Undoubtedly, this passion led to drug use. Drugs meet all Murphy’s criteria. To Murphy, his behavior was not a bad habit or pathology, it was him. In accordance with his philosophy, he didn’t resist physician’s orders. Rather, he took the prescribed drugs, added one for entertainment, and continued to live out his passion. Sparring with an opponent who rolls with every punch inevitably leads to the aggressor being unwilling to enter into the dance of the defendant. Murphy took the lead and all medicine could do was to avoid stepping on his toes. Conclusion “In a larger sense, the biological study of mind is more than a scientific inquiry of great promise; it is also an important humanistic endeavor. The biology of mind bridges the sciences—concerned with the natural world—and the humanities—concerned with the meaning of human experience. Insights that come from this new synthesis will not only improve our understanding of psychiatric and neurological disorders, but will also lead to a deeper understanding of ourselves.”     —Eric Kandel, MD5 Narratives give physicians the skills, methods, and texts to learn how to imbue the facts and objects of health and illness with their consequences and meanings for individual patients and physicians.1,6,7 The narrative about Murphy was more humanizing than the clinical story circulating among the medical staff.  In the above story, Murphy emerged as a competent, optimizing, goal-directed human being in stark distinction to the role cast by the medical staff as burned out, hopeless, uninteresting, and annoying. The shift of focus from clinical to narrative allows us to consider the impact of this change of focus. The patient comes to the clinician with a story to tell and wants someone else to hear this story and to reverence it.8 But the clinician's role is not simply to be the passive hearer, but to become a participant-observer and a listener. Our narratives carry important messages, both to ourselves and to whomever we are asking to listen. Murphy’s narrative carries a message of competence in contradistinction to the usual clinical narrative of incompetence in which he is usually presented. He maintains an aura of joy in a usual story of despair. A narrative perspective allows Murphy to be seen in all his complexity: his strengths, his joys, his weaknesses, and his despair. All of these operate for such a richly complex individual. A narrative perspective enriches ordinary clinical care and humanizes medicine to appreciate people as more than their diagnosis and symptoms. It exposes students to narrative ideas while studying standard clinical presentations and it allows students to appreciate the richness of human life over the reductionism of much of clinical science. For this reason, it should be encouraged within the clinical sciences. At the University of Hawaii, we are beginning to create a Narrative Medicine program to humanize the clinical sciences and to create bridges with the indigenous medicines of the Pacific Rim, which are decidedly based upon stories and the healing impact of “talking story.” Murphy is one of the many patients who would benefit from a narrative approach to psychiatry. Rita Charon, MD writes that “Narrative medicine has evolved as a means to honor the stories of illness, whether told by the patient, family member, doctor, or nurse. More sharply it has become a way to probe the narrativity of disease, of health, of healing, and of the relation between the sick person and the one who tries to help.”1 One’s story is more than “just” information. It is us giving to another a part of our soul: our essence. A person’s story is more than a case history of symptoms to be noted as part of a medical assessment; it is something to be prized and honored. Writing of time spent with her patients, Charon has this to say “Through the attention I donate and the authenticity he displays, we grow together in knowledge, in action and in grace, hoping for the best, making it out together …”1 This makes narrative into a shared experience where both clinician and patient can give to each other and learn from each other. Over the past five decades research has demonstrated the immense importance of therapeutic alliance, empathy, and collaboration. Successful treatment is reliably predicted by the presence of these three factors. The aforementioned variables were nonexistent between Murphy and the staff. Murphy was presented to Michael, the student from a distant and critical perspective in which the patient was receiving treatment. The staff offered little interest in Murphy’s perspective as his job was to take what he was given. This is not Murphy’s first stay at the hospital and it likely won’t be his last. Patients like Murphy are often regarded as “treatment failures.” Yet, in the absence of the three most crucial elements of effective treatment, it appears that he’s not failing treatment; treatment is failing him. Viewing patients through a narrative lens turns a clinical case into a person. When patients become people, collaboration and empathy exist more naturally and the patient enters into a bilateral relationship. The narrative approach is not simply a way to conceptualize, rather a catalyst for the implementation of more effective treatment of our mentally ill. Disclosure Statement The author(s) have no conflicts of interest to disclose. References     1.    Charon R. The patient-physician relationship. Narrative medicine: A model for empathy, reflection, profession, and trust. JAMA 2001 Oct 17;286(15):1897-902.     2.    DasGupta S, Charon R. Personal illness narratives: using reflective writing to teach empathy. Acad Med 2004 Apr;79(4):351-6.     3.    DasGupta S, Meyer D, Calero-BreckheimerA, Costley AW, Gullen S. Teaching cultural competency through narrative medicine: intersections of classroom and community. Teach Learn Med 2006 Winter;18(1):14-7.     4.    Coulehan J. Metaphor and medicine: narrative in clinical practice. Yale J Bio Med 2003;76(2):87-95.     5.    Kandel ER. Biology and the future of psychoanalysis: a new intellectual framework for psychiatry revisited. Am J Psychiatry 1999 Apr;156(4):505-24.     6.    Brody H. Stories of sickness. New Haven: Yale University Press; 1987.     7.    Kleinman A. The illness narratives: suffering, healing and the human condition. New York: Basic Books; 1998.     8.    Rudnytsky PL, Charon R. Psychoanalysis and narrative medicine (S U N Y series in psychoanalysis and culture). Albany, NY: State University of New York Press; 2008.
Peripartum Cardiomyopathy: Case Reports
Friday, 02 July 2010
Mary Wang, MD Fall 2009 - Volume 13 Number 4 Abstract Peripartum cardiomyopathy (PPCM) is a dilated cardiomyopathy defined as systolic cardiac heart failure in the last month of pregnancy or within five months of delivery. PPCM, which affects thousands of women each year in the US, was first described in the 1800s, yet its etiology is still unclear. Its diagnosis is often delayed because its symptoms closely resemble those within the normal spectrum of pregnancy and the postpartum period. When PPCM is misdiagnosed or its diagnosis is delayed, the consequences for patients are deadly: The disorder carries a high mortality rate. Introduction Peripartum cardiomyopathy (PPCM) is associated with one in every 3000 to 4000 live births, affecting thousands of women in the US each year.1 The definition of PPCM includes four criteria: 1) development of cardiac failure in the last month of pregnancy or within five months of delivery, 2) absence of an identifiable cause for the cardiac failure, 3) absence of recognizable heart disease before the last month of pregnancy, and 4) left ventricular (LV) dysfunction (ejection fraction of less than 45% or reduced shortening fraction).2,3 Risk factors include multiparity, black race, older maternal age, pre-eclampsia, and gestational hypertension.1,4 Symptoms of PPCM, which include fatigue, edema, and dyspnea, are similar to those for the normal spectrum of peripartum states and pregnancy comordities such as pulmonary emboli and eclampsia.5 Therefore, diagnosis is often delayed and the disorder is under recognized, with devastating consequences: Mortality is as high as 20% to 50%.5 The following two case reports illustrate a typical presentation and an atypical one. This article also reviews the etiology, clinical symptoms, treatment, and prognosis for PPCM, which must be understood to provide patients with the most efficient and appropriate care. Case 1 A white woman, age 29 years, presented to our urgent-care clinic five days after giving birth, reporting dyspnea and fatigue that had lasted two days. She said that because this was her first pregnancy, she thought her symptoms to be normal after delivery. However, when her husband insisted, she went to the clinic for evaluation. She was found to be dyspneic and hypoxic with saturation on room air in the low 80th percentile and was sent to the Emergency Department (ED) for further treatment. Her medical history included obesity, but the patient was in relatively good health until approximately her last month of pregnancy, when she developed gestational hypertension (without other significant pre-eclampsia signs and symptoms), dependent peripheral edema, as well as some symptoms of an upper respiratory infection. She was given labetalol, 200 mg orally, twice daily, for blood-pressure management. During examination in the ED, the patient was noted to be afebrile and had a blood pressure of 156/88 mm Hg, a pulse rate of 90 beats per minute, a respiratory rate of 20 breaths per minute, and an oxygen saturation of 95% while receiving oxygen through a 2-L nasal cannula. Her lungs were clear to auscultation and her heart rate was regular, with an S3 gallop. Her extremities were nonedematous, and she had no calf tenderness. Urinalysis results were negative for any proteins. Plasma levels of D-dimer and circulating levels of B-type natriuretic peptide (BNP) were 1981 pg/mL and 864 pg/mL, respectively. An electrocardiogram showed a normal sinus rhythm. Chest radiographs showed cardiomegaly with increased vascular congestion bilaterally. A computed tomography (CT) chest scan to evaluate for possible pulmonary emboli showed evidence of pleural effusion and cardiomegaly but no emboli. The patient was subsequently admitted to the hospital for new-onset PPCM and was given furosemide intravenously for diuresis. A transthoracic echocardiogram done at admission showed an LV ejection fraction of 35% to 40%, with trace aortic and mitral regurgitation. Her fatigue and dyspnea greatly decreased with diuresis; she was discharged from the hospital three days later and instructed to take lisinopril and labetalol. Follow-up examination at six months showed a stable cardiomyopathy and well-controlled hypertension, and a repeat echocardiogram at the same point showed an improved ejection fraction of 55% to 60%. Case 2 A white woman, age 25 years, presented at the ED with dyspnea six days after having given birth for the first time. She reported not having had any coughing, chest pain, or calf pain. Her medical history was significant for hypothyroidism, for which she was taking levothyroxine. Her pregnancy had been otherwise noneventful, except for flulike symptoms approximately one month before childbirth that included coughing, nausea, vomiting, and diarrhea. In the ED, the patient appeared to be slightly anxious. She had a blood pressure of 159/87 mm Hg, a pulse rate of 58 beats per minute, a respiratory rate of 20 breaths per minute, and an oxygen saturation of 100% on room air. Physical examination showed no jugular venous distention, S3 heart sound, edema, or hepatosplenomegaly. She was slightly tachypneic but not in any acute respiratory stress. Laboratory tests revealed no proteinuria and a BNP level of 272 pg/mL. Echocardiography showed a normal sinus rhythm at 46 beats per minute. Chest radiograph findings were noted to be normal, with no cardiomegaly or pulmonary congestion. A CT scan of the chest was negative for pulmonary emboli. The patient was discharged from the care of the ED physician with a diagnosis of dyspnea secondary to breast enlargement versus chest wall pain. She kept an appointment in our family medicine clinic four days later for a follow-up examination and still had the same symptoms. An echocardiogram ordered at that time showed left atrial and LV dilation, global LV hypokinesis, and an estimated ejection fraction of 25% to 30%. A cardiology consultation was done and the patient was given appropriate medications for heart failure, which alleviated her symptoms. Her follow-up echocardiogram three months later showed normalization of her ejection fraction to 60%. Discussion Approximately 60% to 70% of women experience a sensation of dyspnea during the course of normal pregnancy.6 Although historically PPCM risk factors occur in older women and in black women, contemporary trends show that there is an increasing incidence (24%–37%) in young primigravid and white patients.7–9 The details of the two cases reported here support this trend; the women are both young primigravidas and are white. Because dyspnea is a common finding in normal pregnancy and even in the initial postpartum state, PPCM is often missed, especially if the patient population does not fit the typical epidemiology. Etiology A possible relationship between pregnancy with dilated cardiomyopathy was recognized as early as the 1870s10 and was classified as a distinct clinical entity in the 1930s.11 Yet the cause of PPCM is still unknown. Most postulate that it is related to the cardiovascular stress of pregnancy (increased fluid load); others have suggested myocarditis. Felker et al12 found that 26 of 51 women with PPCM had histologic evidence of myocarditis on endomyocardial biopsy. Other researchers further postulate that PPCM may be an inflammatory response in pregnancy, citing an elevation of tumor necrosis factor-alpha and interleukin-6 levels.13,14 Some evidence also suggests that it may be a pathologic autoimmune response to fetal cells that lodge in the maternal circulation and cardiac tissue.3 There is also conflicting evidence whether nutritional deficiencies--more specifically, selenium deficiency--is a cause for PPCM.15,16 Clinical Features and Diagnosis Clinical features of PPCM include symptoms of congestive heart failure and chest pain. Signs can include tachycardia, tachypnea, pulmonary rales, an enlarged heart, and an S3 heart sound.4 Such signs and symptoms overlap with those of many other conditions, ranging from normal pregnancy to pulmonary emboli and upper respiratory infection (Table 1). Diagnosis of PPCM includes the four criteria described at the start of this report. There are no specific laboratory abnormalities for PPCM, although BNP is often elevated. However, other exclusionary laboratory studies should also be considered, including cardiac enzymes assessment and a pre-eclampsia workup. Imaging studies include electrocardiography, chest radiography, and echocardiography. Electrocardiographic findings are often normal but can include sinus tachycardia, nonspecific ST- and T-wave abnormalities, and voltage abnormalities.17 Chest radiographs can show signs of pulmonary congestion, cardiac enlargement, and even pleural effusions in some cases.9 Echocardiograms usually show decreased contractility and LV enlargement without hypertrophy.18 Treatment and Prognosis The treatment for PPCM is the same as for other forms of congestive heart failure (fluid and salt restriction, β-blocker, diuretic, and digoxin), except for angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, which are contraindicated in pregnancy.1 Hydralazine can be used during pregnancy to reduce afterload.4 Diuretics can be used cautiously during pregnancy to prevent dehydration and placental insufficiency. Patients with PPCM are also at high risk for thrombus formation;19 thus, anticoagulation should be considered especially for high-risk patients with severe LV dysfunction. In addition, physical activity should be encouraged according to patients’ tolerance of symptoms. The best time to discontinue these medications is unknown, but their use should be continued for at least one year.7 If medical treatments are not successful, heart transplantation is often the last resort. Fortunately, in recent years, the rate required transplantation has decreased to about 4% to 7%.20 Transplantation success rates are good with favorable long-term survival rates.21 In about 50% of patients, the ejection fraction normalizes. Regardless of recovery, however, a second pregnancy is usually not recommended for these patients because PPCM recurs in more than 30% of subsequent pregnancies, which puts both mother and baby at great risk.1 Conclusion The cases presented here demonstrate the variability of clinical presentation of PPCM. Case 1 illustrates a typical PPCM presentation, with gestational hypertension, S3 gallop, hypoxia, an elevated BNP level, cardiomegaly, and pulmonary congestion on chest radiographs. Case 2 illustrates an atypical PPCM presentation, with no abnormal findings on physical or imaging studies, yet with a lower ejection fraction shown by echocardiography. Thus, it is important that physicians be familiar with PPCM and therefore consider it when diagnosing dyspneic patients to expedite medical treatment for a potentially lethal condition. Disclosure Statement The author(s) have no conflicts of interest to disclose. Acknowledgment Katharine O’Moore-Klopf, ELS, of KOK Edit provided editorial assistance. References 1. Libby P, Bonow RO, Mann DL, Zipes DP, eds. Braunwald’s heart disease: a textbook of cardiovascular medicine. 8th ed. Philadelphia, PA: Saunders; 2007. p. xx–yy. 2. Demakis JG, Rahimtoola SH, Sutton GC, et al. Natural course of peripartum cardiomyopathy. Circulation 1971 Dec;44(6):1053–61. 3. Pearson GO, Veille JC, Rahimtoola S, et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. JAMA 2000 Mar 1;283(9):1183–8. 4. Marx JA, Hockberger RS, Walls RM, eds. Rosen’s emergency medicine: concepts and clinical practice. 6th ed. Philadelphia, PA: Elsevier Health Sciences; 2006. 5. Abboud J, Murad Y, Chen-Scarabelli C, Saravolatz L, Scarabelli TM. Peripartum cardiomyopathy: a comprehensive review. Int J Cardiol 2007 Jun 12;118(3):295–303. 6. Simon PM, Schwartzstein RM, Weiss JW, Fencl V, Teghtsoonian M, Weinberger SE. Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 1990 Nov;142(5):1009–14. 7. Sliwa K, Fett J, Elkayam U. Peripartum cardiomyopathy. Lancet 2006 Aug 19;368(9536):687–93. 8. Amos AM, Jaber WA, Russell S. Improved outcomes in peripartum cardiomyopathy with contemporary. Am Heart J 2006 Sep;152(3):509–13. 9. Bhakta P, Biswas B, Banerjee B. Peripartum cardiomyopathy: review of the literature. Yonsei Med J 2007 Oct 31;48(5):731–47. 10. Cunningham GF, Gant NF, Leveno KJ, Gilstrap III LC, Hauth JC, Wenstrom KD, eds. Williams Obstetrics. 21st ed. New York: McGraw-Hill; 2001. p 1141–514. 11. Hull E, Hafkesbring E. “Toxic” postpartal heart disease. New Orleans Med Surg J 1937;89:550-7. 12. Felker G, Thompson R, Hare J, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000 Apr 13;342(15):1077–84. 13. Sliwa K, Skudicky D, Bergemann A, Candy G, Puren A, Sareli P. Peripartum cardiomyopathy: analysis of clinical outcome, left ventricular function, plasma levels of cytokines and Fas/APO-1. J Am Coll Cardiol 2000 Mar 1;35(3):701–5. 14. Sliwa K, Förster O, Libhaber E, et al. Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in 100 prospectively studied patients. Eur Heart J 2006 Feb;27(4):411–6. 15. Cénac A, Simonoff M, Moretto P, Djibo A. A low plasma selenium is a risk factor for peripartum cardiomyopathy. A comparative study in Sahelian Africa. Int J Cardiol 1992 Jul;36(1):57–9. 16. Fett JD, Ansari AA, Sundstrom JB, Combs GF. Peripartum cardiomyopathy: a selenium disconnection and an autoimmune connection. Int J Cardiol 2002 Dec;86(2–3):311–6. 17. Davidson NM, Parry EH. The etiology of peripartum cardiac failure. Am Heart J 1979 Apr;97(4):535–6. 18. Lampert MB, Lang RM. Peripartum cardiomyopathy. Am Heart J 1995 Oct;130(4):860–70. 19. Walsh JJ, Burch GE, Black WC, Ferrans VJ, Hibbs RG. Idiopathic myocardiopathy of the puerperium (postpartal heart disease). Circulation 1965 Jul;32:19–31. 20. Felker G, Jaeger CJ, Klodas E, et al. Myocarditis and long-term survival in peripartum cardiomyopathy. Am Heart J 2000 Nov;140(5):785–91. 21. Rickenbacher PR, Rizeq MN, Hunt SA, Billingham ME, Fowler MB. Long-term outcome after heart transplantation of peripartum cardiomyopathy. Am Heart J 1994 May;127(5):1318–23.
Candida Mastitis: A Case Report
Monday, 28 February 2011
Louisa Hanna, MD, Stacie A Cruz, MD Winter 2011 - Volume 15 Number 1 Abstract Breastfeeding has been demonstrated to have many benefits for both mother and child. Nipple pain in the breastfeeding woman is a common complaint; it is the second most common cause of breastfeeding discontinuation in the first six months after childbirth. This case report addresses the characteristics of breast pain induced by Candida mastitis and the risk factors for and treatment of mastitis. Educating family physicians and other clinicians about how to recognize and treat this often difficult-to-eradicate infection will hopefully increase the percentage of mothers who breastfeed their infants through the first six months of life. Introduction The benefits of breastfeeding for both mother and child are extensive and have been well described. Breastfeeding has direct clinical benefits for the infant as well as potential long-term benefits that are realized after the breastfeeding period. The direct benefits of human milk include improvement in the infant’s gastrointestinal function and host defense and prevention of acute illnesses (eg, acute otitis media) during breastfeeding. There is increasing evidence of the potential long-term benefits of breast milk for the child after breastfeeding ceases, including possible reduction of the occurrence of acute illnesses, decreased risk of specific chronic conditions (eg, obesity, diabetes mellitus, cancer, cardiovascular disease, allergies, certain cancers), and improved neurodevelopmental outcomes compared with formula-fed infants.1 Benefits to the mother include more rapid postpartum uterine involution than in mothers who do not breastfeed, weight loss, and reduced psychological stress. In the long term, women who have breastfed their infants have a decreased risk of breast cancer, ovarian cancer, and cardiovascular disease.2–5 Despite these benefits, there is a high rate of breastfeeding discontinuation. Of children born in 2006 in the US, 73.9% were breastfed for at least some time, but by age six months, only 13.6% of that group were exclusively breastfed.6 Nipple pain is listed as the second most common reason for breastfeeding discontinuation, surpassed only by the maternal perception of insufficient milk supply.7 Of breastfeeding women in the US who experience nipple pain, it is estimated that about 18% have Candida mastitis.8 Although there are many causes of breast pain, Candida mastitis is likely an underdiagnosed and undertreated etiology. Case Report A woman, age 29 years, who has two previous pregnancies and two deliveries, underwent a cesarean section at term because of fetal intolerance to labor in her most recent pregnancy. Her immediate postpartum period was uneventful, and she was breastfeeding when she was discharged from the hospital. Two weeks later, she presented to urgent care, where she was found to have a surgical wound infection and was given cephalexin (Keflex). She returned two weeks later, reporting that her infant son had oral thrush and that his pediatrician had recommended that she seek treatment. She reported experiencing intermittent mild breast pain, and the skin surrounding the areolas were pink. She was prescribed clotrimazole 1% topical cream and instructed to apply it after every breastfeeding session. At her six-week postpartum visit, the patient reported continued painful breastfeeding. No breast examination was documented; the patient was prescribed topical nystatin and oral fluconazole, 150 mg to be taken orally each day for seven days. Two weeks later, the patient called her primary care physician (PCP) to say that she had finished all treatments as prescribed and that although her nipple pain decreased while she was taking fluconazole, it had now returned and was becoming unbearable. The patient was promptly referred to a lactation consultant. At her lactation appointment, the patient’s main concern was dry, itchy nipples. She said that she had no breast pain and was treated for dermatitis with Eucerin and with hydrocortisone cream as needed. Two weeks later, the patient was evaluated for painful intercourse and vaginal discharge. It was found that she had a history of recurrent vaginal yeast infections. Her current condition was diagnosed as a yeast infection and was treated with miconazole vaginal cream. One week later, the patient called her PCP to report that the skin around her areolas were still pink and that she still had stabbing breast pain during breastfeeding. She was instructed to take fluconazole orally for an additional seven days. On completion of the therapy, the patient’s symptoms recurred, and she was evaluated in a clinic. She had been using a vinegar wash on her breasts to prevent recurrence of the yeast on her skin. A physical examination revealed mild erythema of the superomedial area of the right breast and no nipple discharge. She was instructed to stop using the vinegar solution, because it could be irritating her skin, and was advised to return for possible antibiotic treatment if her symptoms did not resolve. The patient later called and informed her PCP that the pain was not decreasing and that she now experienced a stabbing pain in her breasts during feedings. She was instructed to continue using topical nystatin. At the most recent follow-up by phone, the patient reported that her son was nine months old and that she continued to breastfeed him in addition to giving him table foods. The patient reported that since her last office visit, she had sought the advice of additional lactation consultants and had stopped using the topical nystatin because it was not helping. She attributed the resolution of her symptoms to extensive changes in her diet that included a reduction in her intake of processed sugars and the addition of daily yogurt and probiotics. Discussion General This case illustrates several important points regarding Candida mastitis. Many clinicians are not aware of the characteristic presentation, risk factors, and recommended treatments for Candida mastitis. It also illustrates the difficulty of eradicating this infection. Several different Candida species may be found both in the oral cavities of infants and as part of breast skin flora. One study identified Candida species in the mouths of 34.55% of exclusively breastfed infants and in the mouths of 66.67% of strictly bottle-fed infants. Candida was found on the breasts of 34.55% of lactating women and on the breasts of 17.65% of nonlactating women. This information highlights the widespread colonization of Candida species both in infants’ oral cavities and on lactating mothers’ breasts. It also points to the use of artificial nipples (from either a pacifier or a bottle) as a risk factor for Candida colonization.9 Candida colonization of the lactating mother’s breast is often asymptomatic, but overgrowth may cause it to become symptomatic. Symptoms can be anywhere along a continuum from red sore nipples that do not heal to debilitating breast pain. Breast candidiasis may start as a superficial infection but may spread to the ductal system. Once a ductal infection is present, treatment may become more challenging, given the poor absorption of topical antifungals. Pain may be the only presenting symptom; it is typically described as a stabbing pain associated with feedings.10,11 Risk Factors Several maternal risk factors for the development of Candida mastitis have been identified, including intake of large amounts of dairy products, heavily sweetened foods, and artificial sweeteners, for which the evidence is mostly anecdotal and patient-reported. Other maternal risk factors include recent antibiotic use and a history of recurrent yeast infections (eg, vaginal yeast infections).12 The patient whose case is reported here had recently taken antibiotics and had a history of recurrent yeast infections. She also reported a reduction in her symptoms after reducing her intake of dairy products and processed sugar and adding yogurt and probiotics to her daily diet. Treatment The treatment of Candida mastitis initially consists of the application of topical antifungals such as nystatin, clotrimazole, ketoconazole, or miconazole by gentle massage into the mother’s nipples after every breastfeeding session, for 14 days, plus giving nystatin suspension to the infant. One study, a collaboration of lactation specialists and dermatologists, showed that nystatin cream may be less effective than clotrimazole, ketoconazole, or miconazole.13 Another study randomized 227 immunocompetent infants with oral thrush to either 25 mg of miconazole as an oral gel four times daily or 100,000 IU of nystatin suspension four times daily after meals. Miconazole gel was significantly superior to nystatin suspension with regard to efficacy, rapidity of achieving cure, and oropharyngeal yeast eradication. Relapses and adverse effects did not occur more frequently with miconazole than with nystatin.14 If the pain persists beyond the course of treatment, 500,000 U/day of oral nystatin (Mycostatin) or 200 mg/day of fluconazole for two to four weeks is recommended for the lactating mother. Clinicians often hesitate to prescribe oral fluconazole to breastfeeding mothers because of a concern that it will pass into breast milk; however, oral fluconazole has long been used in neonates and immunocompromised children. This makes its use less concerning, given that <5% of the recommended pediatric dose passes from the mother into her breast milk.15 Therefore, even if the mother is given oral fluconazole, the infant still must be treated for thrush, because the amount of medication that passes into the breast milk is insufficient to treat the infant. As evidenced by the high rates of Candida colonization in infants who use artificial nipples, eradication of the yeast on bottles, pacifiers, and breast pumps is an important part of treatment. It is commonly believed that this may be accomplished by boiling rubber nipples and by washing bras, bedding, and cloth diapers in hot water, possibly adding 1 cup (approximately 236.6 mL) of distilled vinegar to the rinse water.16 Conclusion Candida mastitis in lactating women is an underrecognized and undertreated cause of breast pain. Some of the sources cited in this article date back to 1986 because there is a paucity of evidence-based data on diagnosis, risk-factor management, and treatment for this condition. Even when appropriate treatment is initiated, it is an often difficult to eradicate infection. Because of this, clinicians who treat breastfeeding mothers must be alert to the possibility of Candida mastitis in patients with characteristic stabbing breast pain and erythematous or dry nipples. Being aware of the risk factors for the condition will lead to increased accuracy in diagnosis and treatment. The hope is that with an increased awareness of this infection, more mothers will be appropriately treated and will thus be more likely to continue breastfeeding. Disclosure Statement The author(s) have no conflicts of interest to disclose. Acknowledgment Katharine O’Moore-Klopf, ELS, of KOK Edit provided editorial assistance. References 1.    Ip S, Chung M, Raman G, et al. Breastfeeding and maternal and infant health outcomes in developed countries [monograph on the Internet]. Rockville, MD: Agency for Healthcare Research and Quality, US Department of Health and Human Services; 2007 Apr [cited 10 Nov 2010]. Available from: www.ahrq.gov/downloads/pub/evidence/pdf/brfout/brfout.pdf. 2.    Schwarz EB, Ray RM, Stuebe AM, et al. Duration of lactation and risk factors for maternal cardiovascular disease. Obstet Gynecol 2009 May;113(5):974–82. 3.    Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 2002 Jul 20;360(9328):187–95. 4.    Ness RB, Grisso JA, Cottreau C, et al. Factors related to inflammation of the ovarian epithelium and risk of ovarian cancer. Epidemiology 2000 Mar;11(2):111–7. 5.    Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992 Nov 15;136(10):1212–20. 6.    Percentage of children ever breastfed by age and exclusivity among children born in 2007 [chart on the Internet]. Menlo Park, CA: statehealthfacts.org: Henry J Kaiser Family Foundation; 2010 [cited 2010 Nov 9]. Available from: www.statehealthfacts.org/comparebar.jsp?ind=501&cat=10. 7.    Woolridge MW. Aetiology of sore nipples. Midwifery 1986 Dec;2(4):172–6. 8.    Amir LH, Garland SM, Dennerstein L, Farish SJ. Candida albicans: is it associated with nipple pain in lactating women? Gynecol Obstet Invest 1996;41(1):30–4. 9.    Zöllner MS, Jorge AO. Candida spp occurrence in oral cavities of breastfeeding infants and in their mothers’ mouths and breasts. Pesqui Odontol Bras 2003 Apr–Jun;17(2):151–5. 10.    Chetwynd E, Ives TJ, Payne PM, Edens-Bartholomew N. Fluconazole for postpartum candidal mastitis and infant thrush. J Hum Lact 2002 May;18(2):168–71. 11.    Tait P. Nipple pain in breastfeeding women: causes, treatment, and prevention strategies. J Midwifery Womens Health 2000 May–Jun;45(3):212–5. 12.    Mohrbacher N, Stock J. The breastfeeding answer book. 3rd revised ed. Schaumberg, IL: La Leche League International; 2003. 13.    Huggins KE, Billon SF. Twenty cases of persistent sore nipples: collaboration between lactation consultant and dermatologist. J Hum Lact 1993 Sep;9(3):155–60. 14.    Hoppe JE. Treatment of oropharyngeal candidiasis in immunocompetent infants: a randomized multicenter study of miconazole gel vs nystatin suspension. The Antifungals Study Group. Pediatr Infect Dis J 1997 Mar;16(3):288–93. 15.    Hale TW. Medications and mother’s milk: a manual of lactational pharmacology. 11th ed. Amarillo, TX: Pharmasoft Medical Publishing: 2004. 16.    Saunders S. Breast pain in the lactating mother. Midwives 1997;110(1308):8–9.
Acute Hypersensitivity Syndrome Caused by Valproic Acid: A Review of the Literature and a Case Report
Wednesday, 23 February 2011
Robert G Bota, MD, MSG; Allein P Ligasan, RN; Tom G Najdowski, LCSW; Andrei Novac, MD Spring 2011 - Volume 15 Number 2 Abstract Valproic acid (VPA) is an antiepileptic medication used in the treatment of bipolar disorder. Its toxicity profile is characterized by a very rare but well-documented complication—hepatotoxicity. The risk of acute hypersensitivity syndrome (AHS) caused by VPA is less well known. In the vast majority of reported cases of AHS, the syndrome is the result of aromatic anticonvulsants (AAs), such as carbamazepine or phenytoin. These compounds also have in-class cross-reactivity. We present the case of a 25-year-old woman with bipolar disorder who was unable to tolerate aripiprazole, ziprasidone, and lamotrigine. She was given extended-release VPA as a trial and developed AHS with a generalized rash, fever, liver and kidney involvement, and eosinophilia one week after the initiation of treatment. She recovered after one month of treatment, which included ten days of hospitalization. Our review of the literature focuses on AA and non-AA medications causing AHS. Introduction Hepatotoxicity is a rare adverse effect of valproic acid (VPA). The severity of hepatotoxicity can range from reversible hepatic dysfunction to irreversible liver failure.1 In an earlier review, Binek and colleagues2 reported a risk of 1:5000 to 1:10,000 of liver failure with VPA. Most of the reported cases involved boys younger than 10 years and with mental retardation. Major risk factors were being younger than 2 years and concomitant use of other anticonvulsant medication.3 Furthermore, 90% of patients developing hepatotoxicity were younger than 20 years.4 De Wolff et al5 reported that in 32 children with epilepsy, VPA did not affect γ-glutamyltranspeptidase activity, but it selectively enhanced d-glucaric acid excretion. Demircioğlu and colleagues6 looked at 38 children with epilepsy, 31 of whom were treated with carbamazepine and 7 of whom were treated with VPA. They reported that although there were no differences between the groups in serum lipid levels and liver-function test results, the total cholesterol levels, low-density lipoprotein levels, and total cholesterol/high-density lipoprotein levels were higher in the carbamazepine group during treatment. Aromatic anticonvulsants (AAs) such as carbamazepine and phenytoin can induce hypersensitivity syndrome (HS) at a rate of 1:10,000 in new patients and 1:1000 in patients already taking the treatment. Seitz et al7 suggested that there is a cross-reactivity between AAs and tricyclic antidepressants. Because cross-reactivity can be as high as 75%, they recommended that physicians be taught not to use these agents in such situations, but to instead use VPA, benzodiazepine, lamotrigine, and gabapentin.8,9 Alldredge et al10 reported that before the onset of symptoms, physicians for 3 of 4 patients with acute hypersensitivity syndrome (AHS) switched their medications to an anticonvulsant with an aromatic ring in the structure. They also reported that the symptoms subsided after the interruption of the medication and that all patients recovered. Three of these patients required continuation of antiepileptic drugs, and they tolerated VPA well. In an important study, Baba et al11 described 32 patients with AHS caused by AAs; 22 of them required continuation of anticonvulsive treatment, and they tolerated VPA well. AHS is a potentially life-threatening condition characterized by the triad of fever, rash (most of the body surface, ranging from mild exanthem to epidermal necrolysis), and multiorgan involvement (50% liver and 11% kidney), usually occurring in the first few weeks after the initiation of anticonvulsant treatment. Lymphadenopathy (70%) and eosinophilia (30%) are also frequent.8 Mortality from this condition has been reported to be up to 10%.12 Despite being reported to occur with AA treatments, AHS has rarely been reported in patients taking VPA. Roepke and colleagues13 reported details of a case involving a patient, age 48 years, with schizoaffective disorder whose medications were switched on the third day of hospitalization from haloperidol, fluphenazine, diazepam, clomethiazole, promethazine, biperiden, and vitamins B1 and B6 to long-acting VPA, lithium, amisulpride, and vitamins B1 and B6. Three weeks later, the patient developed lymphadenopathy, generalized maculopapular rash, and a fever (39.1°C), and his transaminase and creatinine levels were slightly elevated. VPA and vitamins B1 and B6 were discontinued, and the patient was instead given olanzapine and prednisolone (initially 80 mg/d). With this treatment, the patient recovered in one week. Another case report described a patient who, after resolution of symptoms caused by carbamazepine-induced AHS, was given VPA and immediately developed life-threatening AHS.14 In addition, Cogrel and colleagues15 reported an AHS-like condition with VPA treatment. The patient recovered after the VPA was discontinued. When the patient was again given carbamazepine as a medication challenge, the AHS reappeared and again resolved once the medication was discontinued. In a very recent case report, Dreesman and colleagues16 described another case of AHS induced by both lamotrigine and VPA. In another case report,17 two patients, one treated with carbamazepine alone and another treated with a combination of lamotrigine and VPA, developed AHS, which subsided immediately after the interruption of the causative agents and supportive treatment was begun. In a unique report, Chang et al18 described the case of a woman, age 48 years, with bipolar disorder who was treated with lamotrigine and VPA and then developed AHS because of the lamotrigine. The patient recovered after discontinuation of the anticonvulsant medication and initiation of supportive treatment. Karande et al19 discussed the case of a boy, age 2 years, treated with VPA and lamotrigine for epilepsy. The child developed AHS because of the lamotrigine, but went on to recover and was given VPA and discharged from the hospital. In addition, Rahman and Haider20 reported AHS in a patient treated with VPA after the addition of lamotrigine. Conilleau and colleagues21 described AHS secondary to both VPA and ethosuximide (patch test results were positive with both medications) in a Tunisian, age 6 years. After both medications were stopped and corticosteroid treatment was administered, the patient recovered. Fatal AHS has also been attributed to VPA. For example, Huang et al22 discussed a case of fatal AHS caused by VPA: The patient presented to the hospital with nonspecific polymorphous eruptions, fulminant hepatitis, and jaundice. Plantin et al23 and Picart and colleagues24 reported a case of AHS caused exclusively by VPA treatment. Case Report Ms A was 25 years old when we treated her. Three years earlier, her bipolar II disorder was diagnosed. Initial treatment with quetiapine helped control her symptoms. However, she grew concerned about the significant weight gain (>7% of her initial weight) and increase in total cholesterol level (299 mg/dL), triglyceride level (257 mg/dL), and low-density lipoprotein level (192 mg/dL) that she experienced. As a result, she was willing to explore other options. An initial trial of aripiprazole, at 5 mg/d, caused extrapyramidal symptoms (EPS), and thus the medication was stopped. Lamotrigine was then started at 25 mg/d and increased by 25 mg/wk. She bipolar disorder responded well to this medication. However, after one month, the medication was discontinued because the patient developed a nonspecific rash and had concerns about severe adverse effects. The third medication tried was ziprasidone, which was stopped because of EPS that were very similar to the adverse effects of aripiprazole. While taking ziprasidone, the patient also experienced nausea and vomiting. A few weeks later, Ms A agreed to a trial of extended-release divalproex. The results of liver-function tests at the start of her treatment were normal. The initial dose of divalproex was 500 mg orally at bedtime, which was increased after one week to 500 mg orally twice a day. The plan was to obtain results from new set of laboratory tests on day 10 of therapy. Unfortunately, 6 days later, she reported gastrointestinal symptoms and a low-grade fever. She went to the Emergency Department for evaluation, where her symptoms resulted in a diagnosis of gastroenteritis and she was given 2 antibiotics. Several days later, however, her symptoms had not subsided. Thus, we ordered the laboratory tests earlier than planned. The results were as follows: VPA level, was 60.4 μ/mL; alanine transaminase, 767 U/L; alkaline phosphatase, 681 U/L; bilirubin total, 10.2 mg/dL. The patient’s primary care physician was contacted, and she was admitted to the hospital. During her stay there, she was found to have VPA HS, with generalized rash, fever, liver and kidney involvement, and marked eosinophilia. Because of the involvement of multiple organs and the multiple possible causes for this clinical presentation, we obtained specialist consults. Possible etiologies for the syndrome at the time of admission included infection (viral or bacterial), medication (lamotrigine or VPA), and autoimmunity. A laboratory work-up for infectious diseases produced negative findings on blood and urine cultures, negative findings on chest radiographs, and negative results for acute hepatitis, Epstein-Barr virus, and human immunodeficiency virus tests. The patient had a monospot test, which produced positive findings for mononucleosis. Results of testing for autoimmune hepatitis, antinuclear antibodies, and antimitochondrial antibody were negative. Test results for serum antitrypsin and ceruloplasmin were also negative, as were tests for alcohol, acetaminophen, and salicylate levels. The gastroenterology consultant provided supportive treatment. The patient was given acetylcysteine (Mucomyst) for its antioxidant property and vitamin K for the coagulopathy that she presented with. The patient’s laboratory results improved during her hospital stay. Ms A also developed an erythematous rash on the body, which initially started on her lower legs and rapidly migrated to her trunk, chest, back, arms, and ultimately to the face and interfered with her ability to open her eyes. The rash did not involve palmar or plantar surfaces or the mucous membranes. Initially the rash was erythematous and slightly raised and patchy but confluent, but over the next few days, it became continuous with significant edema. A dermatologist treated the rash with topical corticosteroids and oral prednisone (Deltasone), starting with 80 mg/d for 10 days and then decreasing the dose by 20 mg every week. After taking 60 mg of prednisone for a week, the patient noticed a gradual exacerbation of her rash, this time including her palms, requiring an increase of the dose to the previous level and then a slower tapering off. After being discharged from the hospital, Ms A was monitored by the hospital’s ambulatory internal medicine service. The results of her liver-function tests improved to normal within the following three weeks. The generalized rash resolved after one month, and corticosteroid treatment was stopped. At the next few psychiatry visits, Ms A expressed concern at the idea of starting any new medications for her bipolar illness but expressed interest in and commitment to accepting any other interventions. Discussion Ms A was treated with lamotrigine one month before the initiation of treatment with VPA. Lamotrigine was stopped because of a rash that developed while she was taking the medication. Thus, we suggest that in patients in whom treatment with lamotrigine is discontinued because of the development of a rash, a more comprehensive review of symptoms should be performed to aid in the diagnosis of AHS. This is particularly important because of the future risk of AHS after initiation of a new antiepileptic medication. Specifically, as one case report described, a patient developed the AHS after the addition of lamotrigine, thus suggesting a possible cross-reactivity20 between lamotrigine and other antiepileptic medications. However, Krivoy et al25 suggested that there is no evidence of cross-reactivity between VPA and lamotrigine. In a recent retrospective study,26 carbamazepine was identified as the first cause of AHS, with phenytoin as the second cause and lamotrigine as the third. The authors concluded that VPA and benzodiazepine are safe alternatives to use in patients who present with AHS while taking the other medications. However, we identified four published reports of cases in which AHS was caused by VPA22–24 and another three in which it was caused by VPA and ethosuximide21 and by VPA and lamotrigene.16 In addition, most of reported AHS cases have involved patients treated for epilepsy, especially young boys. Apparently, being female and older than 20 years are protective factors against AHS. Cross-reactivity is a serious concern, especially in the AA class of medications. Our patient, Ms A, expressed serious concerns regarding starting a new medication to treat her bipolar disorder. In addition, AA medications, such as carbamazepine, are associated with a higher risk of AHS than non-AAs are. We could not identify any reports regarding patients who developed AHS in response to lamotrigine or VPA who subsequently were able to tolerate antiepileptic medications with an AA ring. Thus, it is logical to question whether this is a potential consideration. Our patient was unable to tolerate aripiprazole and ziprasidone because of EPS despite preventive treatment with hydroxyzine and lorazepam. The alternative of using other antipsychotic medications can be considered, but the risk of adverse effects is quite significant. Our patient will view any new intervention through the lens of her own recent challenging experiences. Not only was she hospitalized for ten days but also during that period, there were discussions about the possibility of liver transplantation, heightening our patient’s anxiety. In addition, Ms A’s concern about her own well-being was further intensified by the recent death of a family member. She wanted reassurance that any new medication regimen would be 100% effective and complication free. Unfortunately, no physician can make such a promise. Therefore, for now, any further treatment with anticonvulsants has been deferred. Thanks to her above-average intelligence, good self-insight, and a stable support system, she was more than willing to stay involved in psychiatric treatment, which consisted of monthly psychiatric follow-up visits and cognitive behavioral therapy and supportive psychotherapy. She also remained open to alternative treatment methods such as electroconvulsive therapy and hospitalization if needed. The patient was aware of the warning signs of depressive and manic relapses and had a history of reporting her symptoms at the earliest of times. After further discussions, she agreed to occasional benzodiazepine use for sleep and overt anxiety, as an additional preventive measure against further relapses. Conclusions Since the 1980s, it has been known that VPA can cause hepatotoxicity and liver failure,1,2 but only three cases of AHS had been reported before our report here. Overall, the previous reports showed that AAs induce AHS and that there is cross-reactivity between compounds of that class. Non-AA antiepileptic medications were presumed safe.7 Our case suggested that even though AA medications have a much lower likelihood of producing AHS, they do still pose a real, palpable risk for patients. In addition, medical professionals must remain alert regarding the potential of cross-reactivity between AA and non-AA medications. Additional studies and pharmacologic insight are needed to shed more light on this subject. Disclosure Statement The author(s) have no conflicts of interest to disclose. Acknowledgments We thank Daniela Alexandru, MD, and Bonita Jaros, PhD, for scientific review and critical suggestions. Dr Bota also thanks Carla Hix, PsyD, Linda DeSoucy, RN, and Soncerie Villegas, RN, for support. Katharine O’Moore-Klopf, ELS, of KOK Edit provided editorial assistance. References 1.    Cotariu D, Zaidman JL. Valproic acid and the liver. Clin Chem 1988 May;34(5):890–7. 2.    Binek J, Hany A, Egloff B, Heer M. [Acute fatal liver insufficiency due to valproic acid therapy]. [Article in German]. Schweiz Med Wochenschr 1991 Feb 16;121(7):228–33. 3.    Bell EA, Shaefer MS, Markin RS, et al. Treatment of valproic acid-associated hepatic failure with orthotopic liver transplantation. Ann Pharmacother 1992 Jan;26(1):18–21. 4.    Fisher RL, Sanuik JT, Nau H, Gandolfi AJ, Brendel K. Comparative toxicity of valproic acid and its metabolites in liver slices from adult rats, weanling rats and humans. Toxicol In Vitro 1994 Jun;8(3):371–9. 5.    de Wolff FA, Peters AC, van Kempen GM. The effects of valproic acid on liver function. Arch Toxicol Suppl 1983;6:369–73. 6.    Demircioğlu S, Soylu A, Dirik E. Carbamazepine and valproic acid: effects on the serum lipids and liver functions in children. Pediatr Neurol 2000 Aug;23(2):142–6. 7.    Seitz CS, Pfeuffer P, Raith P, Bröcker EB, Trautmann A. Anticonvulsant hypersensitivity syndrome: cross-reactivity with tricyclic antidepressant agents. Ann Allergy Asthma Immunol 2006 Nov;97(5):698–702. 8.    Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf 1999 Dec;21(6):489–501. 9.    Bohan KH, Mansuri TF, Wilson NM. Anticonvulsant hypersensitivity syndrome: implications for pharmaceutical care. Pharmacotherapy 2007 Oct;27(10):1425–39. 10.    Alldredge BK, Knutsen AP, Ferriero D. Antiepileptic drug hypersensitivity syndrome: in vitro and clinical observations. Pediatr Neurol 1994 Mar;10(2):169–71. 11.    Baba M, Karakaş M, Aksungur VL, et al. The anticonvulsant hypersensitivity syndrome. J Eur Acad Dermatol Venereol 2003 Jul;17(4):399–401. 12.    Papp Z, Török L. [Anticonvulsant hypersensitivity syndrome]. [Article in Hungarian]. Orv Hetil 2004 Aug 8;145(32):1665–8. 13.    Roepke S, Treudler R, Anghelescu I, Orfanos CE, Tebbe B. Valproic acid and hypersensitivity syndrome. Am J Psychiatry 2004 Mar;161(3):579. 14.    Arévalo-Lorido JC, Carretero-Gómez J, Bureo-Dacal JC, Montero-Leal C, Bureo-Dacal P. Antiepileptic drug hypersensitivity syndrome in a patient treated with valproate. Br J Clin Pharmacol 2003 Apr;55(4):415–6. 15.    Cogrel O, Beylot-Barry M, Vergier B, et al. Sodium valproate-induced cutaneous pseudolymphoma followed by recurrence with carbamazepine. Br J Dermatol 2001 Jun;144(6):1235–8. 16.    Dreesman A, Hoorens A, Hachimi-Idrissi S. Multiple organ dysfunction syndrome: infection or hypersensitivity reaction? Eur J Emerg Med 2010 Aug;17(4):228–9. 17.    Bin-Nakhi HA, Sadeq S, Pinto RG, Habeeb Y. Anticonvulsant hypersensitivity syndrome: report of 2 cases from Kuwait. Med Princ Pract 2003 Jul–Sep;12(3):197–9. 18.    Chang CC, Shiah IS, Yeh CB, Wang TS, Chang HA. Lamotrigine-associated anticonvulsant hypersensitivity syndrome in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2006 Jun;30(4):741–4. 19.    Karande S, Gogtay NJ, Kanchan S, Kshirsagar NA. Anticonvulsant hypersensitivity syndrome to lamotrigine confirmed by lymphocyte stimulation in vitro. Indian J Med Sci 2006 Feb;60(2):59–63. 20.    Rahman M, Haider N. Anticonvulsant hypersensitivity syndrome from addition of lamotrigine to divalproex. Am J Psychiatry 2005 May;162(5):1021. 21.    Conilleau V, Dompmartin A, Verneuil L, Michel M, Leroy D. Hypersensitivity syndrome due to 2 anticonvulsant drugs. Contact Dermatitis 1999 Sep;41(3):141–4. 22.    Huang YL, Hong HS, Wang ZW, Kuo TT. Fatal sodium valproate-induced hypersensitivity syndrome with lichenoid dermatitis and fulminant hepatitis. J Am Acad Dermatol 2003 Aug;49(2):316–9. 23.    Plantin P, Cartier H, Le Bihan G, Clouard P, Lellouche F, Leroy JP. [Drug hypersensitivity syndrome during treatment with valproic acid]. [Article in French]. Presse Med 1995 Nov 11;24(34):1624. 24.    Picart N, Périole B, Mazereeuw J, Bonafé JL. [Drug hypersensitivity syndrome to valproic acid]. [Article in French]. Presse Med 2000 Apr 1;29(12):648–50. 25.    Krivoy N, Taer M, Neuman MG. Antiepileptic drug-induced hypersensitivity syndrome reactions. Curr Drug Saf 2006 Aug;1(3):289–99. 26.    Mansur AT, Pekcan Yaşar S, Göktay F. Anticonvulsant hypersensitivity syndrome: clinical and laboratory features. Int J Dermatol 2008 Nov;47(11):1184–9.
Suppressed Wound Healing In a Patient with Rheumatoid Arthritis Taking Leflunomide (Arava)
Wednesday, 28 December 2011
D Miller Wise, MD Fall 2011 - Volume 15 Number 4 Abstract Although patients with rheumatoid arthritis taking disease-modifying antirheumatic drugs (DMARDs) are monitored for various medication adverse events, DMARDs, and leflunomide in particular, have effects that are not observed clinically, specifically adverse effects on wound healing. Introduction Patients with rheumatoid arthritis (RA), while taking newer disease-modifying antirheumatic drugs (DMARDs), are examined clinically for decreases in morning stiffness, in joint swelling or tenderness, and for medication adverse effects. Unfortunately, DMARDs have adverse effects not seen clinically. I believe that DMARDs, and leflunomide (LEF) in particular, have adverse effects on wound healing.1 When the patients with RA do not heal after surgery, a DMARD may be the cause. I report here the case of a patient with RA whose wound did not heal for three years, most likely because of LEF. Further study is needed to determine safe use of DMARDs for these patients when they undergo surgery.2 Case Report A white woman, age 60 years, with RA of the back, shoulders, knees, and hands had obtained no benefit from nonsteroidal anti-inflammatory drugs, sulfasalazine (Azulfidine), methotrexate, prednisone, or hydroxychloroquine (Plaquenil), alone or combined. LEF (Arava) provided improved control of her RA. A diagnosis of a large ovarian cyst in our patient led to a total abdominal hysterectomy by Pfannenstiel incision. The fascial repair would not heal, so a vacuum-assisted closure device was applied to her wound. However, an incisional hernia developed. During a period of 2 years, the hernia grew to 30 cm in diameter, and the fascia and skin wound would not heal, despite drainage procedures, mesh repair, mesh removal with repeated fascial repairs, or intermittent use of the vacuum device (Figure 1). During review of medications and a search of the literature on LEF, I found reports of patients taking LEF for RA or autoimmune vasculitis who developed leg ulcers, poor wound healing, and complications3–59 (Table 1). Furthermore, some patients’ ulcers healed after LEF washout with cholestyramine.4 A hypothesis grew: LEF is suppressing our patient’s healing; stop it, wash it out, and she may heal.4 Data for serum LEF level were not available locally; distant results take time. It seemed imprudent to wait for data on serum level after repeated washout procedures and after the patient had lived with an enlarging hernia for more than two years. The patient and I agreed that the benefits of washouts outweighed the risks of waiting to confirm serum LEF level. I did two washouts of LEF with oral cholestyramine, each during a one-week period as described in the literature, and I scheduled a hernia repair with abdominal-wall reconstruction.4-6 Within 10 days of the first washout, empiric evidence of healing appeared: The lower wound bled for the first time in 2 years, the granulation tissue was redder and thicker, and the lower epithelial wound border advanced 1 cm. At surgery, the chronic wound was peeled off the bowel, and then the hernia was reduced with no enterotomies. Poorly vascularized abdominal skin was removed. We placed a single-layer underlay of AlloDerm acellular dermal matrix, with the reticular dermal side up against the peritoneum and musculofascial layer.47–50 The AlloDerm was sutured under tension to the laterally pulling oblique muscles, taking tension off the midline closure. The rectus abdominis muscles and fascia were closed in the midline under mild tension, with no change in pulmonary compliance. Skin and subcutaneous tissue were closed without tension over suction drains. After surgery we observed no loss of pulmonary domain, no oxygen desaturation, no supplemental oxygen need, early ambulation, no infection, no dehiscence, and no ileus. Within six months, the patient remained healed until, after minor activity, she felt a tearing in the pubic area and presented with a new suprapubic hernia. Protein and iron stores, hemoglobin level, and hematocrit were all normal. Because LEF has been reported to leech out of bone and other tissues for up to two years after stopping the drug, and because of our empirical experience with healing during the first washouts, I elected to repeat cholestyramine washout two times, and then to repair the hernia. During surgery, I found that the first AlloDerm repair was intact and reperitonealized with no adhesions. The new tear was several inches caudal to the AlloDerm at the rectus origin from the symphysis pubis. The repopulated AlloDerm was stronger than the rectus origin from bone. I created an underlay of another piece of AlloDerm secured into the symphysis periosteum and caudal rectus fascia, and then closed the musculofascial layer over the AlloDerm. The patient healed rapidly and has remained healed for five years (Figure 2). Unfortunately, hydroxychloroquine, etanercept (Enbrel), and newer DMARDs are now used for her severe RA. Discussion LEF, a potent anti-inflammatory, antiproliferative, and antineoplastic drug, is one of a new generation of DMARDs for use in patients with severe RA, a group of drugs that includes etanercept, infliximab (Remicade), and adalimumab (Humira). Normal white blood cell (WBC) function and normal fibroblast function are necessary for a normal inflammatory response and wound healing. Multiple reports show that WBC and red blood cell precursor cell lines’ intra- and intercellular biochemical reactions are blocked by LEF. LEF is reported to suppress or block proliferation of multiple normal WBC lines: leukocyte phagocytic antigen-presenting cells,51 leukocyte dendritic cells,52,53 and lymphocyte T-cells54–57 (Figure 3). DMARDs should be considered immunosuppressive drugs, of a different class from corticosteroids. Pyrimidine synthesis, blocked by LEF, is a key process in synovial cell production and in fibroblast collagen production. LEF therefore affects proliferation and functions of normal cell lines. LEF alters fibroblast-like synovial cell proliferation, halting progression of RA; it appears in this case to affect true fibroblasts the same way, blocking wound fibrosis and healing. Milder adverse effects of LEF—that are not apparent clinically until the patient has a reported complication—may be treated by stopping and then restarting LEF once signs decrease.58 However, stopping LEF is not enough to prevent suppression of wound healing after surgery. LEF leaches out of tissues for up to 2 years.59 Surgeons should optimize conditions for wound healing, including cessation of smoking or harmful medications and the washout of suppressive DMARDs before surgery. Hernia recurrences increase with each hernia repair after the first. Recurrence is even higher in patients with associated comorbidities such as smoking or chronic obstructive pulmonary disease, massive obesity (a body mass index >35 kg/m2), and immunosuppression. This patient had no comorbidities other than RA treated with LEF. Her body mass index was 32 kg/m2, and she did not smoke or have chronic obstructive pulmonary disease. She was immunocompromised by LEF. Any patient taking DMARDs must be made aware of potentially fatal adverse effects, give informed consent, and then be closely monitored for hepatic, gastrointestinal, hematologic, infectious, pulmonary, dermatologic, and neurologic adverse effects.3–46 The 59th edition (2005) of the Physicians’ Desk Reference provided little information on the adverse effects of LEF.59 Serious adverse effects are typically learned from after-market reports3–59 (Table 1). In 2010, the US Food and Drug Administration added a black-box warning to LEF about hepatic injury and failure. Box warnings of all serious adverse effects belong on data sheets of all DMARDs, similar to after-market warnings added in the past for chloramphenicol (marrow suppression) and for oral contraceptives (thromboembolism). When a patient with RA needs surgery, how do the surgeon and rheumatologist manage medications to improve the likelihood of healing? The case I presented here is of a patient with RA whose lack of wound healing was most likely caused by the DMARD LEF. That hypothesis led to washout of LEF with cholestyramine. Clinical examination findings confirmed the effectiveness of LEF washout. Today, rapid local assays for serum LEF levels are available to confirm readiness for surgery.60 I believe that further studies are needed both to define the effects of DMARDs on WBC cell lines, fibroblasts, and wound healing and to help guide the prudent management of DMARDs—or their washout—in these patients with complex needs who must undergo surgery.2 Disclosure Statement The author(s) have no conflicts of interest to disclose. Acknowledgment Katharine O’Moore-Klopf, ELS, of KOK Edit provided editorial assistance. References 1.    Fuerst M, Möhl H, Baumgärtel K, Rüther W. Leflunomide increases the risk of early healing complications in patients with rheumatoid arthritis undergoing elective orthopedic surgery. 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