PRACTICE | CASES CPD

Eosinophilic myocarditis presenting with hypoactive delirium and cardioembolic stroke

Ka Hong Chan MD, Paul Gibson MD n Cite as: CMAJ 2019 October 21;191:E1159-63. doi: 10.1503/cmaj.190669

64-year-old woman with normal baseline functioning presented to hospital with an altered level of conscious- KEY POINTS ness. She had a history of hypertension (perindopril Hypereosinophilic syndrome is a rare condition manifested by 8 mg/d),A gout ( 200 mg/d) and anxiety (sertraline • hypereosinophilia with ensuing end-organ damage secondary 100 mg/d). She was brought to the hospital by her husband to tissue infiltration and by these cells; cardiac because of a 3-day history of being in a hypoactive state with uri- involvement from hypereosinophilic syndrome is known as nary and stool incontinence. Her husband reported no preceding eosinophilic myocarditis. infectious, allergic or constitutional symptoms. Family history • The pathophysiology of eosinophilic myocarditis is characterized and rheumatologic review of systems were noncontributory, and by 3 phases: acute necrosis (asymptomatic), thrombosis the patient had no recent history of rashes. There had been no (presents with secondary embolic phenomenon) and fibrosis (most common presentation; presents with cardiomyopathy). out-of-country travel in the preceding 2 years. Treatment of eosinophilic myocarditis relies on elucidating the On admission, the patient’s temperature was 36.3°C, she had a • underlying cause of eosinophilia, which can be broadly regular heart rate of 103 beats/min, her blood pressure was categorized as idiopathic, hypersensitivity, rheumatologic, 128/78 mm Hg and oxygen saturation was 95% on room air. Her neoplastic and infectious causes. glucose level was 5.7 (normal 3.3–11.0) mmol/L. The patient’s score • The cornerstone of eosinophilic myocarditis management on the Glasgow Coma Scale was 15/15, but she was inattentive and involves with or without anticoagulation, oriented to only her name. A neurologic examination was limited although evidence remains sparse. owing to lack of cooperation. The patient’s neck was supple. Pupils were equal and reactive, with no gaze preference or nystagmus. She was unable to squeeze her left hand, and had hypertonia of the potential infectious endocarditis or meningoencephalitis. An left lower extremity and a unilateral upgoing Babinski sign. On the extensive infectious workup was undertaken. Urinalysis was right side, she had antigravity strength. She was hyperreflexic clear. Blood, stool (including ova and parasites) and urine cul- (graded at 3/4) throughout. There were no features of heart failure. tures were negative. Cerebrospinal fluid (CSF) analysis showed a The examination was otherwise unremarkable. leukocyte count of 1 × 106/L and a CSF protein level of 0.47 (nor- Initial laboratory investigations showed a normal complete blood mal 0.15–0.45) g/L but was negative for culture and viral testing. count except for an elevated leukocyte count of 15.7 × 109/L owing to HIV testing was not performed owing to lack of risk factors and an count of 6.3 (normal < 0.7) × 109/L. The patient’s com- ability to consent. Transthoracic echocardiography did not show plete blood count had been normal 4 months earlier. Electrolytes, any left ventricular thrombus, effusions, valvular abnormalities creatinine, lipase, liver enzymes and vitamin B12 levels were within or abnormalities in systolic function. Telemetry for more than the normal ranges, and thyroid-stimulating hormone was minimally 96 hours showed no signs of arrhythmia. Electroencephalog­ elevated at 4.07 (normal 0.20–4.00) mIU/L. Importantly, her raphy showed only generalized slowing. C-reactive protein (CRP) level was substantially elevated at 110.3 Despite discontinuation of all her home medications, the (normal < 8) mg/L, and serial troponin levels ranged from 1620 to patient’s eosinophilia persisted for 7 days. Immunologic investi- 1780 (normal < 14) ng/L without any clear trend. Electrocardiography gations included negative testing for antinuclear antibodies, showed sinus tachycardia with nonspecific ST and T wave changes in extractable nuclear antigens, rheumatoid factor and antineutro- the inferolateral leads. Chest radiography and computed tomog­ phil cytoplasmic antibodies. Serum levels were raphy angiography of the head and neck were both normal. Magnetic normal at 19.9 (normal < 160.0) kIU/L, and peripheral blood flow resonance imaging (MRI), however, showed multiple foci of restricted cytometry showed no evidence of a B-cell neoplasm. Computed diffusion within the cerebral hemispheres, basal ganglia and pos­ tomography of the patient’s chest, abdomen and pelvis did not terior fossa, suggestive of cardioembolic phenomena (Figure 1). show any lymphadenopathy or occult . Cytogenetic The patient was initially given heparin for possible cardio­ investigations for platelet-derived receptor α and embolic stroke, and , vancomycin and acyclovir for mutations were also negative.

© 2019 Joule Inc. or its licensors CMAJ | OCTOBER 21, 2019 | VOLUME 191 | ISSUE 42 E1159 PRACTICE E1160 within theendocardium (hematoxylinandeosinstain, originalmagnification× 200). 400)andD)developmentofmuralthrombus ophils withdegranulationwithinthe myocardium(hematoxylinandeosinstain,originalmagnification × 400),C)eosin- B)presenceofeosinophilsinthemyocardium(hematoxylinand eosinstain,originalmagnification × stain, originalmagnification× 400), Figure 2:Pathologicfindingsofeosinophilic myocarditisshowingA)intravasculareosinophilsmigratingintothe myocardium (hematoxylinandeosin diffusion inthecerebralhemispheres(frontal,parietal,occipitalandtemporal),basalgangliaposteriorfossa,suggestiveofamultiterritorialstroke. Figure 1:Diffusion-weightedmagneticresonanceimagingina64-year-oldwomanwithalteredlevelofconsciousnessshowingmultiplefocirestricted patient wasunabletofollowcommandsforavalidstudy.The biopsy. CardiacMRIcouldnotbeconductedbecausethe workup, thepatientultimatelyunderwentanendomyocardial As therewasnocleardiagnosisdespiteanexhaustive

CMAJ | OCTOBER 21, 2019 | VOLUME 191 carditis (Figure ­formation, consistentwithadiagnosisofeosinophilicmyo ium, withassociatedmyocytedamageandmuralthrombi biopsy showedeosinophilicinfiltrationoftheendomyocard | ISSUE 42 2). Thepatientwassubsequentlystartedon

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PRACTICE ­ ­ E1161 – 34 36 13 9.5 5.0 Eosinophilic cardiac Eosinophilic cardiac 1,6 % in eosinophilic myocarditis % in eosinophilic 1–5 Although this multisystem condition condition Although this multisystem

1,3,6 /L or greater, has a wide differential diagnosis has a wide differential /L or greater, 9 ISSUE 42 ISSUE | × 10 Importantly, these cells can infiltrate tissues and cause Importantly, these cells 2 Hypereosinophilia, defined as an absolute eosinophilic an absolute eosinophilic defined as Hypereosinophilia, 1 most commonly involves the skin, gastrointestinal tract and the the skin, gastrointestinal tract and the most commonly involves syndrome can result in cardiac man lungs, hypereosinophilic 20%–50% of cases. ifestations in about Discussion in the cells that participate are a subtype of myeloid reac- and hypersensitivity response to parasites immunologic tions. end-organ damage, resulting in a rare condition known as hyper end-organ damage, resulting which has an estimated annual incidence eosinophilic syndrome, of 0.035 per 100 000. (Box 1). count of 1.5 VOLUME 191 VOLUME | - (e.g., eosinophilic granulomatosis with (e.g., eosinophilic granulomatosis

/L. Over the /L. Over the 9 ) OCTOBER 21, 2019 OCTOBER | CMAJ y (e.g., autosomal-dominant hyper-IgE syndrome) hyper-IgE y (e.g., autosomal-dominant tory (e.g., NSAIDs) s (e.g., gastrointestinal, lung and squamous epithelial ) s (e.g., gastrointestinal, ensives (e.g., hydrochlorothiazide, chlorthalidone and spironolactone) (e.g., hydrochlorothiazide, ensives tic (e.g., , and valproic acid) and valproic lamotrigine tic (e.g., phenytoin, tory bowel ophil cytoplasmic autoantibody–associated autoantibody–associated ophil cytoplasmic tics (e.g., and ) PDGFRA, PDGFRB, of the PDGFRA, with molecular abnormalities (e.g., mutations syndromes y hypereosinophilic terol emboli terol tomyositis elated disease elated onamides onic (e.g., polypoid) enal insufficiency temic erythematosus temic sclerosis temic coidosis al (e.g., HIV) vere rheumatoid vere ) (e.g., Dientamoeba otozoan adiation topy (e.g., and ) and allergic (e.g., asthma topy Schistosoma and Toxocara , Schistosoma (e.g., Strongyloides arasites osinophilic pulmonary pneumonia) (e.g., eosinophilic disorders osinophilic ransplant rejection or graft-versus-host disease or graft-versus-host rejection ransplant ungi (e.g., and aspergillosis) ungi (e.g., coccidioidomycosis ymphoma (e.g., B- and T-cell lymphoma, and Sézary syndrome) ymphoma (e.g., B- and T-cell Antineutr Chr A E Antihypert Sulf Antibio Antiepilep Anti-inflamma genes) PCM1 and JAK2 genes) FGFR1, Choles R Adr Immunodeficienc T Pr F Vir Solid tumour P polyangiitis and granulomatosis with polyangiitis) with and granulomatosis polyangiitis Primar E L IgG4-r Inflamma Sar Se Derma Sys Sys

Note: IgG4 = immunoglobulin G4, IgE = immunoglobulin E, NSAID = nonsteroidal antiinflammatory drug. antiinflammatory IgG4 = immunoglobulin G4, IgE = immunoglobulin E, NSAID = nonsteroidal Note: Rheumatologic and autoimmune Rheumatologic • Eosinophilic gastrointestinal disorders (e.g., ) disorders gastrointestinal Eosinophilic • • • • • • • Causes of eosinophilia Causes of Box 1: Causes of eosinophilia and prevalence in histologically proven eosinophilic myocarditis eosinophilic proven in histologically and prevalence eosinophilia 1: Causes of Box Idiopathic Hypersensitivity Medications • • • • • • Infectious • Others • • • • • • • • • • • • • Primary and neoplastic • course of a month, the patient’s CRP level returned to normal to normal CRP level returned a month, the patient’s course of to 50 ng/L. level decreased and her troponin her level Clinically, able and she was eventually slowly improved, of consciousness the Unfortunately, conversations. simple in participate to multifocal of her extent to the owing weak remained patient persistent cognitive dysfunction resulting and the stroke, - rehabilitation. For that reason, a bone mar severely limited her manage that felt was it as performed, never was biopsy row to be altered. The patient was discharged ment would not likely a long-term care facility.

methylprednisolone 1 gmethylprednisolone for 3 days intravenously followed by a taper starting at 1 mg/kg. day, her By the following to 0.1 × count completely normalized eosinophil 10 PRACTICE itis ischaracterizedby3 underlying pathophysiology.Historically,eosinophilicmyocard shows analternativepresentation,whichissupportedbythe E1162 bidity andmortalityinhypereosinophilicsyndrome. isamajorsourceofmor- carditis orfibroplasticendocarditis — also known as Loeffler endocarditis, eosinophilic myo- disease — stage of eosinophilic myocarditis, known as the thrombotic stage, stage ofeosinophilicmyocarditis,knownasthethromboticstage, ensuing damagetotheventricularwallresultsinsecond subsequent degranulationofeosinophilsinthemyocardium.The necrosis, typicallyasymptomatic,iscausedbyinfiltrationand ture havepresentedwithsymptomsofcardiacfailure. Biopsy Infectious Rheumatologic *Investigations shouldbeguidedby history andphysical examination for both causes andcomplications, inadditionto athorough reviewofallergic, drug andinfectious etiologies. Hematologic • Imaging andfunctional tests • General biochemistry Category Box 3:Recommended workup for hypereosinophilic syndrome Most cases of eosinophilic myocarditis described in the litera-

Fibrotic • Thrombotic • Acute necrosis Stage Box 2:The3pathologic andclinical stages of eosinophilic myocarditis phases (Box 2). • • • • • • • • • • • • • • • • • • • • • •

• • • • Vit Bone marr Biopsy ofaff HIV Ser S Urinalysis andurinecultur Blood cultur Rheuma Antineutr Antinucle Quantit Serum andurinepr Pulmonar Comput E C T Calcium Liv Comple Molecular s Flo P

failure Mos cardiomyopathy andrestrictive valvular movements andregurgitation (e.g.,mitral) Damag myocardial infarctions Can r the ventricles F pathologically U Infiltr roponin tool culture, andexamination for ova andparasites chocardiography, cardiac magnetic resonance imagingorboth eripheral bloodsmear -reactive protein ormation ofmural thrombi alongthedamaged endocardium, most characteristic at theapex of amin B sually asymptomatic, butmyocardial necrosis can potentially beseenbiochemically and er enzymes plusbilirubin,lactate dehydrogenase andalbumin w cytometry (bloodandmarrow)w cytometry ology for parasitesology orfungal infections (e.g.,Strongyloides) t commonly reported presentation ofeosinophilicmyocarditis withleft- orright-sided heart esult in secondary embolicphenomenoninabout10%ofcases,esult insecondary includingstrokes and ation ofeosinophilsto myocardium withsubsequentdegranulation oftoxic proteins ative immunoglobulins te bloodcount, electrolytes andcreatinine CMAJ ed tomography ofthechest, abdomenandpelvis(e.g.,lymphadenopathy andneoplasms) ed endocardium results inirreversible fibrosis andscarring, resulting inarestrictive 7 toid factor citrullinated andanti–cyclic peptide The first phase of acute Thefirstphaseofacute ophil cytoplasmic antibodies ar antibodyandextractable nuclear antigens 12 y function tests ow biopsy(especially intheabsence ofidentifiablecauses) andtryptase (elevated levels inmyeloid variants ofhypereosinophilic syndrome) tudies (e.g.,PDGFRA, FGFR1 andJAK2)ifeosinophiliccount isgreater than1.5 ×10 ected tissues es | OCTOBER 21, 2019 otein electrophoresis 4,6 6 Pathologic andclinical manifestations of stage Our case Ourcase e Investigations for hypereosinophilic syndrome ­ 2 * | VOLUME 191 chest painandcough. heart failuresecondarytorestrictivecardiomyopathy:dyspnea, eosinophilic myocarditis presentinthis phase with symptoms of final stageofeosinophilicmyocarditis.Mostreportedcases Replacement of the thrombus with fibrosis signals the third and our case,occurduringthisphaseinonly4%–12%ofcases. mic complications,suchasthemultifocalstrokesencounteredin Previousreviewshaveshownthatische endocardium (Figure 1). which ischaracterizedbythedevelopmentofthrombialong aware of the heterogeneity in the presentation of this condition. aware oftheheterogeneityinpresentationthiscondition. essentially normal.Thishighlightstheneedforclinicianstobe heart failureonpresentation,andherinitialechocardiogramwas | ISSUE 42 7 4,6,7 Interestingly, our patient had no signs of Interestingly,ourpatienthadnosignsof

9 /L 4,7 ­

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- - E1163 Am J Med J Am Long-term outcomes in outcomes in Long-term 4,7 Prim Care 2016;43:607-17.

MV, Adler ED, et al. Eosinophilic myocarditis: character- MV, Adler ED, et al. Eosinophilic ISSUE 42 ISSUE | auscher C, Freeman A. Drug-induced eosinophilia. Asthma Proc eosinophilia. Drug-induced A. C, Freeman auscher sinophilic syndromes. Immunol Allergy Clin North Am 2007;27:457-75. 2017;176:553-72. ment of eosinophilia. Br J Haematol 2017;92:1243-59. J Am Coll Cardiol 2017;70:2363-75. istics, treatment, and outcomes. Heart 2016;102:100-6. diagnosis and management. 2018;39:252-6. Cheung CC, Constantine M, Ahmadi A, et al. Eosinophilic myocarditis. Cheung CC, Constantine M, Sci 2017;354:486-92. et al. Guideline for the investigation and manage Butt NM, Lambert J, Ali S, — defined eosinophilic disorders: 2017 Gotlib J. World Health Organization stratification, and management. Am J Hematol update on diagnosis, risk Brambatti M, Matassini Kovalszki A, Weller PF. Eosinophilia. Mankad S. Hypereosinophilic syndrome: cardiac Mankad R, Bonnichsen C, of hypereo Ogbogu PU, Rosing DR, Horne MK. Cardiovascular manifestations R The section Cases presents brief case reports that convey clear, The section Cases presents brief case reports that convey clear, practical lessons. Preference is given to common presentations of important rare conditions, and important unusual presentations of common problems. Articles start with a case presentation (500 fol- a discussion of the underlying condition and words maximum), lows (1000 words maximum). Visual elements (e.g., tables of the dif- ferential diagnosis, clinical features or diagnostic approach) are atheir story is publication of encouraged. Consent from patients for necessity. See information for authors at www.cmaj.ca. Competing interests: None declared. This article has been peer reviewed. The authors have obtained patient consent. British Affiliations: Department of Medicine (Chan), University of (Gibson), CummingColumbia, Vancouver, BC; Department of Medicine Alta. School of Medicine, University of Calgary, Calgary, GibsonContributors: Ka Hong Chan drafted the manuscript, which Paul version to be pub- reviewed. Both authors gave final approval of the of the work.lished and agreed to be accountable for all aspects - Acknowledgement: The authors thank Dr. Yinong Wang for his sup port in obtaining the pictures of the biopsy. Correspondence to: Paul Gibson, [email protected]

these patients remain unknown. these patients 8. 3. 4. 5. 7. References 1. 2. 6. been studied for this indication. Congestive heart failure (from (from failure heart Congestive this indication. studied for been be treated myocarditis) should stage of eosinophilic the fibrotic involvement Valvular guidelines. failure heart on current based surgical interventions. may require VOLUME 191 VOLUME |

8 7 - Numer- 2 Conversely, Conversely, 3 7 OCTOBER 21, 2019 OCTOBER | CMAJ 4,6 More importantly, patients present- More importantly, patients Direct oral anticoagulants have not Direct oral anticoagulants have not 1,6 4,6,7 Second-line options include hydroxyurea and Second-line options include hydroxyurea and Monitoring with echocardiography or cardiac MRI Monitoring with echocardiography or cardiac MRI 1 . 1,2,6 Although the latter include angiotensin-converting Although the latter include angiotensin-converting 6,8 Management of eosinophilic myocarditis relies on removal of Management of eosinophilic myocarditis A diagnosis of eosinophilic myocarditis should also prompt a myocarditis should also prompt a A diagnosis of eosinophilic Cardiac MRI has emerged as a novel modality to help diag- novel modality to help has emerged as a Cardiac MRI econdary etiologies — econdary of expansion polyclonal in result which any precipitants (e.g., an allergic cause) and treatment of under- any precipitants (e.g., an allergic cause) and kinase inhibitors for lying causes, such as the use of tyrosine clonal disorders (e.g., PDGFRA positive). Corticosteroids, at 0.5– 1.0 mg/kg 2 weeks about for 2–3 months over tapered and a to 5–10 mg/d, of dose maintenance treat of cornerstone the are ment for idiopathic cases to decrease hypereosinophilia and the ment for idiopathic cases to decrease hypereosinophilia resulting end-organ damage, but evidence is limited to small case series. comprehensive investigation for potential underlying primary for potential underlying primary comprehensive investigation (Box 1,and secondary etiologies Box 3). Primary hypereosino- occurs in the setting of an underlying philic syndrome typically resulting in a monoclonal proliferation hematologic malignancy, subclassified (per the of eosinophils. These may then be further abnormalities, World Health Organization) based on molecular genes. such as mutations of the JAK2 or PDGFRA ous medications may cause eosinophilia, but they mostly include but they mostly ous medications may cause eosinophilia, and antihyper- antibiotics, anticonvulsants, anti-inflammatories tensives. interferon-α enzyme inhibitors, which our patient was taking (perindopril), taking (perindopril), enzyme inhibitors, which our patient was and enalapril. most reported cases are associated with captopril is indicated every 6 months in cases of sustained hypereosino- philia, and more frequently if cardiac disease is discovered.

A high be main- should involvement for cardiac suspicion index of and signs of hypereosinophilia patients present with tained when complications. dysfunction or ischemic end-organ in because of its superiority myocarditis nose eosinophilic and fibrosis. Unfortunately, inflammation, thrombi detecting of remain inconsistent in the early phases these imaging changes eosinophilic myocarditis. ­s Despite thorough investigation and removal of possible offend- Despite thorough investigation and removal myocarditis are idio- ing medications, most cases of eosinophilic pathic (as with our patient). Thrombotic complications should be managed with anticoagula- tion in the form of low-molecular-weight heparin or warfarin, but there is little guidance behind the recommended duration and their prophylactic use. ing with cognitive dysfunction may not be able to follow the may not be able to follow the ing with cognitive dysfunction effectively conduct an MRI examination. commands needed to standard remains the gold biopsy Therefore, endomyocardial eosinophilic myocarditis. diagnostic modality for eosinophils — include autoimmune and rheumatologic disorders medications. and exposures to parasites, allergens and