Case-29

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n engl j med 373;12 nejm.org September 17, 20151154

T h e n e w e n g l a n d j o u r n a l o f medicine

Presentation of Case

Dr. Blair Wylie (Obstetrics and Gynecology): A 38-year-old pregnant woman (gravida 2,para 0) was admitted to this hospital at 33 weeks 3 days of gestation because ofheadache and visual symptoms.

The patient had been in her usual health until 2 weeks before admission, whenneck pain developed. Eleven days before admission, she was seen in the emer-gency department and the labor and delivery unit because of neck and back pain,occipital headache, vomiting, and a self-reported temperature of 38.9°C. On exami-nation, the back was tender; the vital signs and remainder of the examination werenormal. Laboratory test results are shown in Table 1. Urinalysis revealed yellow,cloudy urine, with trace ketones, 1+ albumin, and 2+ urobilinogen; urine sedimentshowed a few squamous cells per high-power field and mucin. Hydromorphoneand cyclobenzaprine were administered, with some improvement. The patient wasdischarged home. A urine culture grew abundant mixed bacteria, with smallamounts of two potential pathogens. The headache improved spontaneously after3 days.

On the day of presentation, the patient felt the onset of a panic attack followedby tunnel vision; she began to hyperventilate and her vision went black from theperiphery to the center. The symptoms lasted for approximately 2 minutes and werefollowed by spots in her visual fields, headache, neck pain that radiated to herarms, nausea, and dizziness (both unsteadiness and vertigo). The capillary glucose

level, which was obtained by the patient, was 122 mg per deciliter (6.8 mmol perliter). She called her caregivers and was advised to go to the labor and delivery unit.On presentation, the patient reported normal fetal movement and no fever,

diarrhea, abdominal pain, vaginal bleeding, leaking fluid, or contractions. She hadreceived prenatal care, including screenings for syphilis, human immunodefi-ciency virus, gonorrhea, and chlamydia (all of which were negative) and routineultrasound examinations. During the third trimester, a glucose-tolerance test waspositive. She had intermittent atypical chest pain that had lasted for several years;2.5 months before admission, an evaluation of the pain included electrocardiogra-phy (ECG), which revealed nonspecif ic ST-segment and T-wave changes, and trans-thoracic echocardiography, which was normal. At 17 years of age, she had presented

From the Department of Neurology,Brigham and Women’s Hospital (S.K.F.);the Divisions of Infectious Diseases (M.G.)and Cardiology (D.M.D.) and the Depart-ments of Radiology (R.G.G.) and Pathol-ogy (A.E.K.), Massachusetts General Hos-pital; and the Departments of Neurology(S.K.F.), Medicine (M.G., D.M.D.), Radi-ology (R.G.G.), and Pathology (A.E.K.),Harvard Medical School — all in Boston.

N Engl J Med 2015;373:1154-64.

DOI:

10.1056/NEJMcpc1404335

Copyright © 2015 Massachusetts Medical Society.

Founded by Richard C. CabotEric S. Rosenberg, M.D., Editor Nancy Lee Harris, M.D., Editor Jo-Anne O. Shepard, M.D., Associate Editor Alice M. Cort, M.D., Associate Editor Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor

Case 29-2015: A 38-Year-Old PregnantWoman with Headache and Visual Symptoms

Steven K. Feske, M.D., Marcia Goldberg, M.D., David M. Dudzinski, M.D.,Ramon Gilberto Gonzalez, M.D., and Alexandra E. Kovach, M.D.

Case Records of the Massachusetts General Hospital

The New England Journal of Medicine

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n engl j med 373;12 nejm.org September 17, 2015 1155


VariableReference

Range, Adults†6 Mo before Admission

11 Days before Admission

On

AdmissionHospital Day 3

Hematocrit (%) 36.0–46.0 31.0(women)

31.8 33.3 29.6

Hemoglobin (g/dl) 12.0–16.0 10.4

(women)

10.3 10.6 9.5

White-cell count (per mm3) 4500–11,000 7500 10,300 10,500 9800

Differential count (%)

Neutrophils 40–70 58 65 48

Lymphocytes 22–44 37 15 15

Monocytes 4–11 4 3 3

Eosinophils 0–8 1 16 33

Basophils 0–3 0 1 1

Platelet count (per mm3) 150,000–400,000 295,000 237,000 184,000 187,000

Mean corpuscular volume (µm3) 80–100 76 79 78 78

Erythrocyte count (per mm3) 4,000,000–

5,200,000

4,100,000 4,040,000 4,270,000 3,800,000

Erythrocyte sedimentation rate (mm/hr) 0–20 91

Sodium (mmol/liter) 135–145 137 134 134

Potassium (mmol/liter) 3.4–4.8 3.4 3.2 4.0

Chloride (mmol/liter) 100–108 104 103 104

Carbon dioxide (mmol/liter) 23.0–31.9 24.5 18.0 20.4

Glucose (mg/dl) 70–110 91 120 125

Albumin (g/dl) 3.3–5.0 4.0 2.7

Urea nitrogen (mg/dl) 8–25 9 4 6

Creatinine (mg/dl) 0.60–1.50 0.65 0.49 0.51

Estimated glomerular filtration rate

(ml/min/1.73 m2

)

≥60 >60 >60 >60

Alkaline phosphatase (U/liter) 30–100 133 337 355

Aspartate aminotransferase (U/liter) 9–32 19 38 41

Alanine aminotransferase (U/liter) 7–30 23 38 43

Lactate dehydrogenase (U/liter) 110–210 327 549

C-reactive protein (mg/liter) <8.0 45.1

Fibrinogen (mg/dl) 150–400 818

Triglycerides (mg/dl) 40–150 296

Cholesterol (mg/dl) <200 (desirable) 209

High-density lipoprotein (mg/dl) 35–100 27

Low-density lipoprotein (mg/dl) <130 (desirable) 123

Cardiac risk ratio ≤5.0 7.7

Functional protein S (%) 70–140 41

Free protein S antigen (%) 70–140 42

* To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for urea nitrogen tomillimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To con-vert the values for triglycerides to millimoles per liter, multiply by 0.01129. To convert the values for cholesterol to milli-moles per liter, multiply by 0.02586.

† Reference values are affected by many variables, including the patient population and the laboratory methods used. Theranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditionsthat could affect the results. They may therefore not be appropriate for all patients. For normal ranges in pregnancy,see Cunningham.1

Table 1. Laboratory Data.*




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at 20 weeks of gestation with sepsis and a still-born fetus; dilation and evacuation had beenperformed. She also had anemia (Table 1) (witha history of iron deficiency), bipolar disorder,panic attacks associated with syncope and tin-gling on the left side, recurrent pelvic pain withpelvic adhesions, benign ovarian cysts, asthma,

and seasonal allergic rhinitis; she had had a posi-tive purified protein derivative skin test with anormal chest radiograph, which had been treat-ed with isoniazid and vitamin B

6 for 9 months.

She had undergone multiple laparoscopies, includ-ing cholecystectomy for cholelithiasis, lysis of ad-hesions, and ovarian cystectomies. Medicationsincluded a prenatal multivitamin and ferrous sul-fate; antidepressants were discontinued by thepatient at the start of the current pregnancy. She was allergic to loperamide, morphine (whichcaused chest discomfort), meperidine hydrochlo-ride (which caused hives), and contrast material(which caused a rash). She did not smoke, drinkalcohol, or use illicit drugs. She was born inGuatemala, had immigrated to the United States15 years earlier, and had last visited Guatemala3 years earlier. She lived with her boyfriend. Shehad worked in an office but was currently receiv-ing disability benefits because of her bipolar dis-order. Her mother had had breast cancer anddied in her 50s.

On examination, the temperature was 35.9°C,

the blood pressure 117/68 mm Hg, the pulse104 beats per minute, and the respiratory rate18 breaths per minute. Her abdomen was gravid,soft, and nontender, with active fetal movements.The fetal heart-rate tracing was reassuring. There was no peripheral edema or abdominal tender-ness. Reflexes were normal, as were the remain-ing general and neurologic examinations.

The capillary glucose level was 111 mg perdeciliter (6.2 mmol per liter). Blood levels of uricacid, magnesium, calcium, phosphorus, total pro-tein, globulin, and total and direct bilirubin were

normal; other test results are shown in Table 1.Intravenous fluids, acetaminophen, and butal-bital–acetaminophen–caffeine were administered,followed by prochlorperazine, oxycodone–acet-aminophen, and diphenhydramine; the patient’scondition partially improved. Magnetic resonanceimaging (MRI) of the head could not be per-formed because of the patient’s anxiety; prelimi-nary magnetic resonance venography showed noevidence of sinus thrombosis.

After 24 hours of observation in the labor and

delivery unit, the patient’s symptoms had notresolved, and she was admitted to the hospital.She reported occipital headache, which she ratedat 9 on a scale of 0 to 10 (with 10 indicating themost severe pain).

Dr. Ramon Gilberto Gonzalez: Later that day, MRIof the head was performed without the adminis-

tration of contrast material (Fig. 1A and 1B).Diffusion-weighted images showed multiple (atleast eight) small hyperintense lesions scatteredthroughout both cerebral hemispheres, in whiteand gray matter; the largest lesion (7 mm inmaximal diameter) was located in the left cen-trum semiovale, with no evidence of associatedintracranial mass or hemorrhage. The lesions were thought to reflect infarcts that had occurredat least 6 hours earlier. Results of magnetic reso-nance angiography and venography were normal.

Dr. Wylie: Ultrasonography of the legs revealedno evidence of deep venous thrombosis. ECGshowed sinus tachycardia at a rate of 108 beatsper minute and nonspecific ST-segment andT-wave changes. Holter monitoring did not re- veal an arrhythmia. A lumbar puncture was un-successful; the patient declined further attempts.Aspirin (81 mg daily), metoclopramide, and pre-natal vitamins were administered.

On the third day, the prothrombin time,prothrombin-time international normalized ratio,and activated partial-thromboplastin time were

normal, as were results of tests for factor VIII,partial-thromboplastin time–lupus anticoagulant,anticardiolipin IgG and IgM antibodies, func-tional antithrombin III, functional protein C,activated protein C resistance, and prothrombingene mutation; other test results are shown inTable 1. Betamethasone was administered (in two12-mg intramusclar doses 24 hours apart) to pro-mote fetal lung maturity. An active, well-grownfetus was seen on ultrasound examination. Thepatient’s headache resolved. The next day, onevaluation by ophthalmology consultants, she

reported no acute change in vision, eye pain, oreye redness, but she did have floaters, which shedescribed as “worms.” On examination, there was binocular horizontal diplopia (which couldbe relieved with the use of corrective lenses) anda pterygium on the left side, with no evidence ofpapilledema, embolic phenomena, or vasculitison funduscopic examination. Testing revealedantibodies to hepatitis A virus; screening forhepatitis B and C viruses was negative.

Dr. Gonzalez: Repeat MRI of the head (Fig. 1C)




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revealed multiple foci of restricted diffusion, in-cluding a few that were new in the bilateral fron-tal and right occipital lobes. These findings werethought to be consistent with multiple smallacute infarcts.

Dr. David M. Dudzinski: On the fifth day, trans-thoracic echocardiography (Fig. 2; and Videos 1,2, and 3, available with the full text of this article

at NEJM.org) revealed a hyperkinetic left ventri-cle without wall-motion abnormalities and withobliteration of the left ventricular cavity duringsystole. The right ventricular apex was akineticand aneurysmal. In both ventricles, there wasprominent accumulation of sessile, smooth-bor-dered endocardial material with an echodensitythat was distinctly different from that of themyocardium; this finding was not present onthe previous echocardiogram. Thrombus in theleft ventricle would be unlikely in this case giventhe diffuse accumulation of endocardial material

and the absence of global or regional dysfunc-tion. Apical hypertrophic cardiomyopathy couldproduce a hyperkinetic ventricle with obliterationof the left ventricular cavity during systole butnot one in which the wall has an echodensitythat is different from that of the myocardium.Thus, the findings were suggestive of endocar-dial deposits. There was no patent foramen ovaleor clinically significant valvulopathy (specificallyno valvular thickening, vegetations, tethering, ormalcoaptation) and only trace mitral and tricuspid

regurgitation. Tissue Doppler echocardiography,Doppler assessment of the transmitral flow veloc-ity and pulmonary-vein flow velocity, and assess-ment of the color M-mode propagation velocityrevealed that the left ventricular diastolic func-tion was normal.

Dr. Wylie: Consultations with the infectiousdiseases, hematology, and rheumatology services

were requested. The level of lipoprotein(a) wasnormal, and testing was negative for antibodiesto β

2-glycoprotein 1, SSA (Ro), SSB (La), Sm, and

RNP and for IgG antibodies to cyclic citrullinatedpeptides. A continuous intravenous infusion ofheparin was initiated. Additional diagnostic tests were performed.

Differential Diagnosis

Dr. Steven K. Feske: This woman, who was in thethird trimester of pregnancy, presented with

multiple neurologic symptoms and had lesionson MRI that were suggestive of multiple strokes.I will begin by reviewing the neurologic presenta-tion and the questions it raises. Eleven days beforeadmission, she was evaluated for neck pain andsubjective fever. On the day of admission, she hada 2-minute spell that was suggestive of a panicattack, to which she is predisposed, with hyperventilation, dimming of peripheral vision, head-ache, neck pain, and dizziness that was speci-fied as both unsteadiness and vertigo.

Videos showingtransthoracicechocardiography

are available atNEJM.org

Figure 1. Axial MRI Scans of the Head.

Images were obtained at the level of the centrum semiovale. A diffusion-weighted image (Panel A) shows multiple

small hyperintensities that are indicative of acute infarcts. A few of the lesions seen on the diffusion-weighted image(Panel A, arrow) had corresponding hyperintensities on a fluid-attenuated inverted recovery image (Panel B, arrow),

but most did not (Panel A, arrowhead); these findings indicate that the infarcts had occurred at different times.

A diffusion-weighted image that was obtained 2 days later (Panel C) shows two new punctate foci of diffusion restriction

that are indicative of new acute infarctions (arrowhead).

A B C




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Headache in Pregnancy

Although the majority of headaches are benign,the combination of headache, neck pain, andfever raises the question of infection or inflam-mation of the central nervous system. Duringlate pregnancy, one must consider preeclampsiaand eclampsia with hypertensive encephalopa-

thy, cerebral venous sinus thrombosis, and hem-orrhage as possible causes of headache. Respira-tory alkalosis and hypocapnia that are due tohyperventilation may cause light-headedness and visual symptoms. Although visual loss may alsobe caused by dysfunction in any of the structuresin the visual pathways from the retina to the visual cortex, the transient symptoms in thiscase are nonspecific and cannot be distinguishedfrom the effect of hyperventilation. Dizziness andunsteadiness may be due to dysfunction of cere-bellar and vestibular pathways but are also non-specific. Therefore, neurologic localization basedon the transient symptoms is not at all precise.The symptoms suggest transient dysfunction inthe brain stem and cerebellum and possibly in theposterior hemispheres, which may have beendue to transient ischemic attacks or smallstrokes. However, the absence of specificity fortransient ischemic attacks or stroke allows forother possible interpretations.

The patient’s temperature and blood pressure were normal. MRI of the head showed multiple

lesions typical of recent acute ischemic strokes, with no evidence of posterior reversible encepha-lopathy, hemorrhage, or other lesions. Magneticresonance angiography revealed no flow abnor-malities suggestive of reversible cerebral vasocon-striction or vasculitis, and magnetic resonance venography revealed no evidence of cerebral ve-nous sinus thrombosis. Laboratory evaluationshowed microcytic anemia, with a normal plate-let count and striking elevation of the eosinophilcount. Mild hyponatremia and a decreased levelof carbon dioxide are normal in late pregnancy.

Levels of alkaline phosphatase, lactate dehydro-genase, and fibrinogen may all be elevated in latepregnancy, but the levels in this case are slightlyhigher than normal reported values. The eryth-rocyte sedimentation rate and C-reactive proteinlevel are also typically elevated in pregnancy, butnot to the degree that was seen in this case;these findings are suggestive of an inflamma-tory disorder.1

Figure 2. Transthoracic Echocardiograms.

A still image obtained in the apical four-chamber view

near end systole (Panel A) shows thickening of the mid-ventricular and apical left ventricular walls, with oblit-

eration of the cavity. A still image obtained in the para-

sternal short-axis view, below the level of the papillarymuscles, in diastole (Panel B) shows marked thicken-

ing of the left ventricular walls due to an accumulatedsessile material that has an echodensity that is dis-

tinctly different from that of the myocardium. A stillimage obtained in the subcostal four-chamber view

in diastole (Panel C) shows aneurysmal dilatation ofthe right ventricle and sessile, echodense deposits in

the apex.

A

B

C




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Ischemic Stroke in Pregnancy

Are the strokes related to the patient’s pregnancy?Ischemic stroke is uncommon during pregnancy,although there is a high relative increase afterdelivery (relative risk, 8.7).2,3 The rate of bothischemic and hemorrhagic strokes during preg-nancy may be increasing,4 perhaps because of

increased rates of hypertension and heart dis-ease. Normal pregnancy leads to changes inhemodynamic function, vascular-wall structureand integrity, endothelial function, and the levelsand function of procoagulant and anticoagulantproteins that are factors associated with an in-creased risk of stroke.

The most common causes of pregnancy-asso-ciated ischemic stroke are cardioembolism, pre-eclampsia and eclampsia, and cerebral venoussinus thrombosis. Acquired or inherited underly-ing hypercoagulability may exacerbate the phys-iologic prothrombotic state that occurs duringpregnancy. Atherosclerosis may also contributeto the risk of stroke in patients with risk factorsfor early-onset disease. The primary causes ofstroke in young patients in general are cardio-embolism, arterial dissection, and drug abuse.Many of these considerations have been ruledout by the clinical presentation and laboratoryand imaging studies in this case. There is no evi-dence of eclamptic encephalopathy, cerebral venous sinus thrombosis, arterial dissection, or

drug abuse. The low levels of functional protein Sand free protein S antigen are expected duringpregnancy and contribute to physiologic hyper-coagulability, but they do not distinguish thispatient from other pregnant women. The multi-focal strokes in the posterior and anterior circula-tions are suggestive of embolism from the heartor from another proximal source or of multifo-cal small-vessel disease. Cerebral vasculitis mosttypically causes small, deep infarcts, whereas thepresence of wedge-shaped infarcts that reach thecortex is suggestive of embolism. The small in-

farcts seen on MRI in this case could result fromeither of these causes of stroke. The echocardio-gram offers critical information, but before ad-dressing this, I will turn my attention to theeosinophilia.

Eosinophilia

Eosinophilia can be caused by the primary hyper-eosinophilic syndromes or by secondary causes,

including parasitic and viral infections, drug-induced and other allergic causes, and lymphomaand other tumors. Current criteria for a diagnosisof the primary hypereosinophilic syndrome in-clude eosinophilia (>1500 cells per cubic milli-meter) that has persisted for 6 months, the ab-sence of secondary causes of eosinophilia, and

end-organ involvement.5,6 This patient does not yet meet criteria for a primary hypereosinophilicsyndrome, since the eosinophilia has not beenpresent for 6 months and secondary causes havenot been ruled out. Damage to the heart due toeither primary or secondary hypereosinophiliacan be manifested by eosinophilic endocarditis(Löffler’s endocarditis)7 or endomyocardial fibro-sis (Davies’ disease).8

The echocardiographic findings in this caseare typical of Löff ler’s endocarditis, which is char-acterized by arteritis that causes severe endocar-dial scarring, with negligible fibroelastosis andcommonly with thromboembolism. It may occur with either primary or secondary hypereosino-philia. Many cases of helminthic infections —including schistosomiasis, trichinosis, and filari-asis — have been associated with either ischemicstrokes or endocarditis.9-14 The findings on MRIsuggest embolism as a likely mechanism of stroke.

Churg–Strauss eosinophilic vasculitis is an-other consideration. However, it is not supportedby the absence of lung, skin, and peripheral-

nerve involvement or by the results of magneticresonance angiography.In summary, I think that this patient has Löff-

ler’s endocarditis as a result of either primary orsecondary hypereosinophilia. Might this diagno-sis be related to her pregnancy, her origin inGuatemala, or both?

Eosinophilia in Pregnancy

I will consider three possible connections ofeosinophilia to pregnancy: pregnancy-induceddysregulation of eosinophils, pregnancy-related

immunosuppression with reactivation of latentinfection, and pregnancy-related geophagia (thehabit of eating clay or earth) as a potentialsource of a new helminthic infection.

Eosinophils play a major role in the normalphysiological processes of pregnancy — includ-ing, for example, a controlled cytotoxic effectcontributing to remodeling of the uterus — andthere has been speculation that eosinophilic




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dysregulation may play a role in postpartum car-diomyopathy.15 However, I am aware of no casesof severe blood eosinophilia that have been in-duced by pregnancy alone.

The immune status of pregnant women iscomplex.16 Some reactivation infections, such asherpes zoster, are more likely to occur during

pregnancy, and some immune-mediated diseases,such as multiple sclerosis, tend to remit duringpregnancy. However, pregnancy does not typical-ly increase susceptibility to infections. Althoughthere is some evidence of reactivation of proto-zoan and helminthic infections during preg-nancy, this topic has not been studied adequate-ly, and I will not consider it further.17

Helminthic Infection

I strongly favor the possibility that a new hel-minthic infection developed in this patient. Shehad chronic microcytic anemia (probably due toiron deficiency), which is a cause of pica (a crav-ing to eat nonfood substances, such as soil, clay,or cornstarch). The history indicates that shehad no eosinophilia 6 months before admissionand that she had not traveled to Guatemala for3 years. These facts favor local exposure.

Most helminthic infections — including thosecaused by hookworms, whipworms, and thread- worms — are common in Latin America, andrisk of exposure reaches into the southern United

States. Furthermore, Toxocara canis and T. cati in-fect dogs and cats throughout the United States.Could this patient have contracted toxocariasisthrough geophagia? Could her recurrent visualsymptoms have, in fact, been cyclic manifesta-tions of visceral larva migrans resulting fromtoxocara infection? Might there still be a con-nection to Guatemala?

Guatemala is the “hot spot” in the Americasfor nematode infections. I can think of two pos-sible connections to Guatemala, one indirect andone direct. The indirect one is cultural. Geopha-

gia is practiced in Guatemala and even encour-aged during pregnancy as a desired nutritionalsupplement. According to a tourist brochurefrom the Christian shrine in Esquipulas, Guate-mala, “In Guatemala, eating clay tablets com-bines healing, devotional reminders, blessingsfrom Our Lord of Esquipulas, good fortune, andpregnancy nutrition.” Therefore, the patient mayhave been encouraged to consume soil at home.Furthermore, “In Esquipulas, Guatemala, homeof the St. Esquipulas shrine, 5.7 million holy clay

tablets are produced annually! The evolution ofthe Christian shrine here may have ‘Christian-ized’ clay consumption. The Roman CatholicChurch has indeed blessed medicinal clay tabletssince the earliest days of Christianity.” Could a well-meaning grandmother have sent the patientclay tablets from the shrine of St. Esquipulas?

In summary, I believe this patient had a para-sitic infection, most likely acquired through pica,that caused hypereosinophilia, Löffler’s endo-carditis, and embolic strokes. The diagnostictests that I would perform would be a stool ex-amination for ova and parasites, serologic test-ing for toxocara and strongyloides, and possiblyan endomyocardial biopsy.

Dr. Nancy Lee Harris (Pathology): Dr. Wylie, would you tell us the thinking of the clinical team?

Dr. Wylie: Our working diagnosis was endo-carditis due to the hypereosinophilic syndrome.A number of services were consulted to considerpossible underlying causes.

Dr. Marcia Goldberg: We also thought that aparasitic cause of the eosinophilia was mostlikely. We ordered a stool examination for ovaand parasites, serologic testing for parasitic in-fection, and a bone marrow biopsy to rule out aprimary hypereosinophilic syndrome.

Clinical Diagnosis

Embolic strokes due to Löffler’s endocarditis, which was possibly caused by parasitic infectionor, less likely, by a neoplastic process.

Dr. Ste ven K. Fesk e’s Diagnosis

Embolic strokes due to Löffler’s endocarditis, which was most likely caused by helminthic in-fection (toxocariasis), with secondary hypereo-sinophilic syndrome.

Pathological Discussion

Dr. Alexandra E. Kovach: Examination of the bonemarrow–biopsy specimen revealed approximately60% overall cellularity, which is normal for thepatient’s age and inconsistent with the hyper-cellularity that is typical of myeloproliferativeneoplasms. There was maturing trilineage hema-topoiesis (Fig. 3A). The only abnormalities werea slight increase in the eosinophil count in theperipheral blood (13%) and a slight increase inpolyclonal plasma-cell count (3%); these are




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common, nonspecific findings that are associat-ed with a variety of reactive conditions (Fig. 3B).No iron was present on an iron stain. Results ofconventional karyotype analysis, f luorescence insitu hybridization for the FIP1L1-PDGRFA rearrange-ment (which is seen in myeloproliferative neo-plasms with eosinophilia), B-cell and T-cell

clonality testing by means of polymerase-chain-reaction assay for an occult lymphoma, andquantitative BCR-ABL testing for chronic myeloidleukemia were all normal.

A panel of serologic tests for parasites wasperformed. Enzyme-linked immunosorbent as-says (ELISAs) were positive for antibodies againsttrichinella (qualitative assay) and weakly positivefor antibodies against toxocara (quantitative as-say); antibodies against strongyloides and taenia(cysticercus) species were not detected. A singlestool examination for ova and parasites wasnegative; examination of a single specimen, ascompared with multiple specimens, has a report-ed sensitivity of 91% in the microbiology labora-tory of this hospital.18 Serum was also sent tothe Centers for Disease Control and Prevention(CDC); serologic testing was positive for toxo-cara at a dilution of 1:64 (positive, >1:32), andELISA was positive for trichinella at 1.46 arbi-trary units per milliliter (normal, <0.40).

The pathological diagnosis is hypereosino-philia, most likely due to parasitic infection. The

weakly positive result for toxocara may representcross-reactivity of trichinella antibodies with thetoxocara assay (or vice versa), and clinical cor-relation is required.

Discussion of Management

Obstetrical Management

Dr. Wylie: In view of the likelihood that the hyper-eosinophilic syndrome was caused by a parasiticinfection, prophylactic ivermectin was adminis-tered to prevent strongyloides hyperinfection.

Therapy with high-dose intravenous glucocorti-coids was then begun, and insulin was adminis-tered to maintain euglycemia.

Initially, delivery was deferred to avoid a pre-term birth and to allow time for treatment toimprove the patient’s cardiac and neurologicfunction and reduce the clot burden in the left ventricle. Despite an improvement in her eosino-philia, severe headache recurred and paresthe-sias developed. Repeat MRI revealed new foci ofischemia, and the patient was transferred to the

intensive care unit. Laboratory tests revealedaminotransferase levels that were almost 10times as high as the normal levels. We wereconcerned that such endothelial dysfunction andsystemic involvement would confer both mater-nal and fetal risks of the HELLP syndrome (he-molysis, elevated liver-enzyme levels, and a low

platelet count). At this point, the patient was at34 weeks of gestation, and the decision wasmade to proceed with delivery.

Because the patient had right ventricular dys-function, femoral arterial and venous catheters were surgically placed in case extracorporealmembrane oxygenation was required. A cesare-an delivery was performed in the main operatingroom with the patient receiving an epidural an-esthetic. A viable male infant was delivered, witha weight of 2960 g and Apgar scores of 7 and 8at 1 and 5 minutes, respectively.

Figure 3. Biopsy Specimen and Aspirate of Bone Marrow.

A bone marrow–biopsy specimen (Panel A, hematoxy-lin and eosin) shows overall normal cellularity and com-

position, with conspicuous eosinophils. A smear of thebone marrow aspirate (Panel B, Wright–Giemsa) shows

a slight increase in the proportions of mature eosino-phils (arrows) and plasma cells (arrowhead).

A

B




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Consideration of Infections

Dr. Goldberg: The positive serologic tests stronglysuggested that a parasitic infection was thecause of the patient’s illness. Considerations in-cluded infection with toxocara, trichinella, orStrongyloides stercoralis or a combined infection.

Hookworm, which is present in New England,

is usually acquired through penetration of theskin by larvae from contaminated soil but canalso be acquired through ingestion (Table 2).Adult worms cause a chronic intestinal infectionthat is accompanied by low-level eosinophilia(500 to 700 cells per microliter); the level ofeosinophilia observed in this patient was higherthan would be expected with this condition.Adult worms damage intestinal capillaries andconsume 0.03 to 0.20 ml of blood per day, causingiron-deficiency anemia.19 Diagnosis is determinedby means of stool examination for ova and para-sites, with a single examination reportedly hav-ing approximately 80% sensitivity.20 Given thepatient’s iron-deficiency anemia, the relativelylow sensitivity of a single stool examination, andthe normal eosinophil count that had been ob-tained 6 months earlier, we considered thathookworm infection of less than 6 months’ dura-tion may have contributed to her illness.

Although strongyloides is not endemic in NewEngland and the patient had not traveled to Guate-mala recently, we were concerned about strongy-

loides infection. In a patient who is receivingglucocorticoid treatment, strongyloides can causea potentially fatal hyperinfection syndrome, in which larvae penetrate the bowel wall and dis-seminate, causing bacterial sepsis, colitis, pneu-monia, meningitis, or a combination of theseconditions. Because this patient was receivingglucocorticoids, we empirically administered iver-mectin to prevent this potential complication. Anegative stool examination is only 30% sensitivefor strongyloides infection.20 An initial serologictest for strongyloides was negative, but a repeat

serologic test that was performed 18 monthsafter admission was positive, raising the pos-sibility that the patient could have had acutestrongyloidiasis at the time of admission.

Serologic testing was positive for both trichi-nella and toxocara. Serologic tests for helminthscan have cross-reactivity, which makes the inter-pretation of low-level positive results difficult.Trichinella infection, which is acquired throughthe ingestion of encysted larvae in meat, results

in the presence of encysted larvae in striatedmuscle, which typically causes fever, muscle pain,periorbital edema, eosinophilia, and an elevatedlevel of creatine kinase. In this case, the absenceof an elevated level of creatine kinase madetrichinella infection unlikely. The serologic testresult for trichinella was most likely false positive.

Toxocara species are acquired through theingestion of contaminated soil or infected meat;these organisms are present in New England.Larvae hatch in the human intestine and migratethrough the bloodstream to multiple organs,including the liver, spleen, lungs, and eye. Symp-toms commonly include wheezing, fever, hepa-tomegaly, and eosinophilia and occasionally in-clude cough, urticaria, pruritus, pneumonia, andanemia. In this case, the patient presented withfever, anemia, and eosinophilia and later reportedgeneralized pruritus, but she did not have wheez-ing or other findings. Serologic testing waspositive at both our laboratory and the CDC,making toxocara infection a potential cause ofthe patient’s illness.

After the serologic test results were known,the patient reported that she had ingested soilfrom a yard near her home during her preg-nancy. The details that were reported to variouscaregivers differed, without a specific answer tothe question of whether soil or clay had beensent to her from Guatemala. Nonetheless, this

exposure provided a potential source for inges-tion of toxocara eggs, hookworm larvae, or both.We considered it likely that pica led to toxo-

cara infection and thereby caused hypereosino-philia. The patient may have also had subacutehookworm infection that contributed to her severe iron-deficiency anemia, thus predisposingher to pica.21-23

The treatment of choice for both toxocara andhookworm infection is albendazole, which thepatient received. It also covers trichinella infec-tion. Treatment of toxocara infection may also

include glucocorticoids. In this case, there weremultiple reasons to administer glucocorticoids,including maturation of the fetal lungs, the hyper-eosinophilic syndrome, and potential toxocarainfection.

Albendazole and ivermectin are pregnancycategory C drugs (i.e., studies in animals sug-gest adverse fetal effects, but there are no well-controlled studies involving humans). Albenda-zole was administered only after the baby was




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T a b l e 2 . P o t e n t i a l P a r a s i t i c C a u s

e s o f H y p e r e o s i n o p h i l i a i n t h i s P a t i e n t .

P a r a s i t e

G e n e r a l F e a t u r e s

F e a t u r e s o f T h i s C a s e

C o m m o n S o u r c e

R e l e v a n t A s p e c t s

o f P r e s e n t a t i o n

D i a g n o s

t i c T e s t s

R e c o m m e n d e d

T r e a t m e n t

P o t e n t i a l S

o u r c e

R e l e v a n t A s p e c t s

o f P r e s e n t a t i o n

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T r e a t m e n t

T o x o c a r a c a n i s ,

T . c a t i

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t a m

i n a t e d s o i l

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m e

a t

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v a r i o u s o r g a n s

S e r o l o

g i c t e s t

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f o r 5 d a y s ) ,

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r

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m o n a r y l a r v a l

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( s t a r t e d o n


1 0 , a f t e r

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T r i c h i n e l l a s p i r a l i s

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e d

p o r k , b o a r ,

h o r s e , o r b e a r

M y o s i t i s

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t e s t

A l b e n d a z o l e * ( 7 . 5

m g / k g t w i c e

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m e b e n d a z o l e

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t w i c e d a i l y f o r

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g l u c o c o r t i c o i d s

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e d c r e a t i n e

k i n a s e l e v e l

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t e s t

( p o s i t i v e )


( s t a r t e d o n


1 0 , a f t e r d e l i v -

e r y ) a n d g l u -

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s t e r c o r a l i s

P e n e t r

a t i o n o f s k i n

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l a r v a e f r o m

c o n t a m i n a t e d

s o i l

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a p a t i e n t r e -

c e i v i n g g l u c o -

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d a i l y f o r

2 d a y s )

U n c e r t a i n

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t e s t s ( i n i t i a l l y

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p o s i t i v e 1 8

m o

a f t e r a d m i s -

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i n a -

t i o n f o r o v a

a n d p a r a s i t e s

( n e g a t i v e )

I v e r m e c t i n ( o n

h o s p i t a l d a y s

5 a n d 6 )

* T h i s i s a p r e g n a n c y c a t e g o r y C d

r u g ( i . e . , s t u d i e s i n a n i m a l s s u g g e s t a d v e r s e f e t a l e f f e c t s , b u t t h e r e a r e n o w e l l - c o n t r o

l l e d s t u d i e s i n v o l v i n g h u m a n s ) a n d i s e x c r

e t e d i n b r e a s t m i l k .




7/17/2019 Case-29




delivered. We thought that the administration ofivermectin could not wait until after deliverybecause of the potential risk of disseminatedstrongyloides. Since albendazole is excreted inbreast milk, with uncertain consequences inbreast-fed babies, the patient was advised notto breast-feed while she was receiving albenda-

zole. She was discharged on the 14th hospitalday; she took a planned 3-week course of alben-dazole and a tapering course of glucocorticoids.

Warfarin was given for 6 months, and oraland parenteral iron were administered for iron-deficiency anemia. The eosinophilia had resolvedby the time of discharge and did not recur. Theechocardiographic abnormalities had resolved al-most completely within 6 weeks after discharge,

and more than 3 years later, the patient remains well. Her child is healthy.

Pathological Diagnoses

The hypereosinophilic syndrome due to para-sitic infection (most likely toxocariasis) acquired

through pica, with Löffler’s syndrome and car-dioembolic strokes.

Iron-deficiency anemia.This case was presented at Obstetrics and Gynecology Grand

Rounds.No potential conflict of interest relevant to this article was

reported.Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.We thank Drs. Michael Greene (Obstetrics and Gynecology) and

Thomas Byrne (Neurology) for help with organizing the conference.

References

1. Cunningham FG. Appendix B: labora-

tory values in normal pregnancy. In:Queenam JT, Hobbins JC, Spong CY, eds.Protocols for high-risk pregnancies. Phil-adelphia: Blackwell Science, 2010:587-95.2. Kittner SJ, Stern BJ, Feeser BR, et al.Pregnancy and the risk of stroke. N Engl JMed 1996;335:768-74.3. Feske S, Klein AM. Clinical risk fac-tors predict pregnancy-associated strokes.Stroke 2009;40(4):e183-e184.4. Grear KE, Bushnell CD. Stroke andpregnancy: clinical presentation, evalua-tion, treatment, and epidemiology. ClinObstet Gynecol 2013;56:350-9.5. Chusid MJ, Dale DC, West BC, Wolff SM.The hypereosinophilic syndrome: analysis

of fourteen cases with review of the litera-ture. Medicine (Baltimore) 1975;54:1-27.6. Simon HU, Rothenberg ME, BochnerBS, et al. Refining the definition of hype-reosinophilic syndrome. J Allergy ClinImmunol 2010;126:45-9.7. Löffler WL. Endocarditis parietal fi-broplastica with eosinophilia: a strangedisease. Schweiz Med Wochenschr 1936;66:817-20. (In German.)8. Davies JN. Some considerations regard-ing obscure diseases affecting the muralendocardium. Am Heart J 1960;59:600-31.9. Barbosa MM, Lamounier JA, OliveiraEC, Souza MV, Marques DS, Lambertucci

JR. Short report: endomyocardial f ibrosis

and cardiomyopathy in an area endemic

for schistosomiasis. Am J Trop Med Hyg1998;58:26-7.10. Ellrodt A, Halfon P, Le Bras P, et al.Multifocal central nervous system lesionsin three patients with trichinosis. ArchNeurol 1987;44:432-4.11. Fourestie V, Douceron H, BrugieresP, Ancelle T, Lejonc JL, Gherardi RK.Neurotrichinosis. A cerebrovascular dis-ease associated with myocardial injuryand hypereosinophilia. Brain 1993;116:603-16.12. Rashwan MA, Ayman M, Ashour S,Hassanin MM, Zeina AA. Endomyocardi-al fibrosis in Egypt: an illustrated review.Br Heart J 1995;73:284-9.13. Sarazin M, Caumes E, Cohen A, Ama-renco P. Multiple microembolic border-zone brain infarctions and endomyocardi-al fibrosis in idiopathic hypereosinophilicsyndrome and in Schistosoma mansoniinfestation. J Neurol Neurosurg Psychia-try 2004;75:305-7.14. Seshadri S, Narula J, Chopra P. Asymp-tomatic eosinophilic myocarditis: 2 + 2 =4 or 5! Int J Cardiol 1991;31:348-9.15. Borczuk AC, van Hoeven KH, FactorSM. Review and hypothesis: the eosino-phil and peripartum heart disease (myo-carditis and coronary artery dissection)— coincidence or pathogenetic signifi-

cance? Cardiovasc Res 1997;33:527-32.

16. Mor G, Cardenas I. The immune sys-

tem in pregnancy: a unique complexity.Am J Reprod Immunol 2010;63:425-33.17. Brabin BJ. Epidemiology of infection inpregnancy. Rev Infect Dis 1985;7:579-603.18. Branda JA, Lin TY, Rosenberg ES,Halpern EF, Ferraro MJ. A rational ap-proach to the stool ova and parasite ex-amination. Clin Infect Dis 2006;42:972-8.19. Roche M, Layrisse M. The nature andcauses of “hookworm anemia.” Am J TropMed Hyg 1966;15:1029-102.20. Goka AK, Rolston DD, Mathan VI,Farthing MJ. Diagnosis of Strongyloidesand hookworm infections: comparison offaecal and duodenal fluid microscopy.Trans R Soc Trop Med Hyg 1990;84:829-31.21. Barton JC, Barton JC, Bertoli LF. Picaassociated with iron deficiency or deple-tion: clinical and laboratory correlates in262 non-pregnant adult outpatients. BMCBlood Disord 2010;10:9.22. López LB, Marigual M, Martín N, et al.Characteristics of pica practice during preg-nancy in a sample of Argentine women. J Obstet Gynaecol 2012;32:150-3.23. Thihalolipavan S, Candalla BM, Ehr-lich J. Examining pica in NYC pregnant women with elevated blood lead levels.Matern Child Health J 2013;17:49-55.Copyright © 2015 Massachusetts Medical Society.

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