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case records of themassachusetts general hospital

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

n engl j med 360;11 nejm.org march 12, 20091126

Founded by Richard C. CabotNancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor

Jo-Anne O. Shepard, m.d.,Associate Editor Alice M. Cort, m.d.,Associate EditorSally H. Ebeling,Assistant Editor Christine C. Peters, Assistant Editor

From the Department of Neurology(A.B.S.), Partners Neurology ResidencyProgram (W.T.K.), and the Departmentsof Radiology (P.W.S.) and Pathology(E.T.H.-W.), Massachusetts General Hos-pital; and the Departments of Neurology(A.B.S., W.T.K.), Radiology (P.W.S.), andPathology (E.T.H.-W.), Harvard MedicalSchool.

N Engl J Med 2009;360:1126-37.Copyright 2009 Massachusetts Medical Society.

Presentation of Case

Dr. W. Taylor Kimberly: A 36-year-old woman was admitted to the hospital because ofheadaches, hypertension, and seizures.

Nineteen days before the current admission, she delivered healthy twins at 35.6weeks of gestation by cesarean section (for breech presentation) at another hospital.She was discharged on the fifth day. Nine days before the current admission, shebegan to have intermittent, throbbing, bifrontal headaches, and 2 days later she sawher gynecologist. She rated the pain as 8 (on a scale of 0 to 10, with 10 being themost severe pain). The blood pressure was 150/72 mm Hg. She was referred to aninternist the same day, but she did not see the internist because the headache re-solved while she was in the waiting room, and she returned home. Headacherecurred that evening, and she went to the emergency department of a secondhospital, where the blood pressure was 190/80 mm Hg. Computed tomography(CT) and magnetic resonance imaging (MRI) of the brain and the results of labo-ratory tests were reportedly normal. Oxycodoneacetaminophen was given for pain;the blood pressure decreased to 168/70 mm Hg, and she was sent home.

Four days before admission, the patient saw the internist. She reported thatthe headaches were sudden in onset and were usually worse in the early morn-ing, when they awakened her from sleep, and in the late afternoon. She describedher current headache as dull and rated the severity of the pain as 2 out of 10.

The blood pressure was 142/78 mm Hg; trace peripheral edema was present. Theremainder of the examination was normal. Furosemide and potassium chloridewere prescribed.

Two days before admission, a severe headache (10 out of 10 in severity) oc-curred, with nausea and photophobia. The patient returned to the emergency roomof the second hospital; the blood pressure was 204/96 mm Hg. The hematocrit was34.7%; the results of the remainder of the complete blood count were normal, aswere the results of other laboratory tests, including measurements of serum elec-trolytes, magnesium, calcium, and phosphorus and tests of renal and liver func-tion. A urinalysis revealed that the specific gravity was 1.020, the pH 6.0, and the

Case 8-2009: A 36-Year-Old Womanwith Headache, Hypertension, and Seizure

2 Weeks Post PartumAneesh B. Singhal, M.D., W. Taylor Kimberly, M.D., Ph.D., Pamela W. Schaefer, M.D.,

and E. Tessa Hedley-Whyte, M.D.

The New England Journal of Medicine

Downloaded from nejm.org on September 27, 2011. For personal use only. No other uses without permission.

Copyright 2009 Massachusetts Medical Society. All rights reserved.


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case records of the massachusetts general hospital

n engl j med 360;11 nejm.org march 12, 2009 1127

protein 30 mg per deciliter, with 5 to 10 red cellsper high-power field. Hydromorphone was ad-ministered intravenously. Shortly thereafter, ageneralized tonicclonic seizure occurred, withurinary incontinence and loss of consciousnessfor 2 minutes. A CT scan of the head was nor-mal. Examination of the cerebrospinal fluid

(CSF) revealed no cells, a protein level of 64 mgper deciliter (reference range, 15 to 45), and aglucose level of 54 mg per deciliter (3.0 mmolper liter) (reference range, 47 to 70 mg per deci-liter [2.6 to 3.9 mmol per liter]); Grams stainingand culture were negative. Metoclopramide,lorazepam, and fentanyl were given intrave-nously, and oxycodone and methyldopa orally;the systolic blood pressure ranged between 140and 160 mm Hg, and a frontal headache (4 out of10 in severity) persisted. Magnesium sulfate andhydralazine were administered by continuous in-

travenous infusion, and the patient was admittedto the intensive care unit (ICU).

The next day, MRI with magnetic resonanceangiography (MRA) and venography revealed pos-terior white-matter changes on T2-weighted se-quences and multifocal narrowing and dilatationof all the intracranial arteries. On the morningof the third hospital day, the patient appearedconfused. A 5-minute episode of difficulties inword-finding and pronunciation and right hemi-paresis occurred. Aspirin was administered. A CTscan of the head showed no evidence of acuteinfarction or hemorrhage. The patient was trans-ferred by ambulance to this hospital, arriving4 hours after the episode of aphasia.

She had given birth to a healthy child 2 yearsearlier, after a full-term pregnancy, without com-plications. She had not had hypertension or head-aches before or during her pregnancies, and rou-tine prenatal screening was normal. She livedwith her husband and children and did notsmoke, drink alcohol, or use illicit drugs or oralcontraceptives. Her mother had hypertension and

her father had cardiovascular disease; there wasno family history of eclampsia. Medications be-fore admission included furosemide, iron, multi-vitamins, and oxycodoneacetaminophen. Therewere no known drug allergies.

On examination, the patient was alert andoriented, with a normal affect. The temperaturewas 36.8C, the blood pressure 136/91 mm Hg,the pulse 95 beats per minute, the respiratory rate24 breaths per minute, and the oxygen satura-

tion 98% while she was breathing ambient air.There was 1+ peripheral edema. The remainderof the general physical examination was normal.Speech was fluent and clear, but responses wereslow. The first cranial nerve was not tested;other cranial nerves were normal. Strength wasgraded as 4 out of 5 on the right and normal on

the left. There was ataxia on tests of rapid alter-nating movements and finger-to-nose and heelkneeshin testing; she was not able to touch hernose with her right forefinger. Gait was not test-ed. The remainder of the neurologic examina-tion was normal. The d-dimer level was 1975 ngper milliliter (normal level,


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on command, withdrew arms and legs on stimu-lation, and occasionally answered questions. Attimes she was unresponsive, with her eyes open.

A diagnostic procedure was performed.

Differential Diagnosis

Dr. Aneesh B. Singhal: May we review the brain im-aging studies?

Dr. Pamela W. Schaefer: MRI of the brain andMRA of the circle of Willis on postpartum day11 were normal. Brain MRI performed the daybefore admission to this hospital, on postpartum

day 18 (Fig. 1A), revealed hyperintense regionsinvolving the posterior parietaloccipital lobes,the left frontal cortex, and the subcortical whitematter. These regions had elevated diffusion,

which was consistent with vasogenic edema.MRA of the circle of Willis (Fig. 1B) revealedmultifocal stenoses in the proximal anterior,middle, and posterior cerebral arteries. Brain MRIperformed 1 day later, on admission to this hos-pital, revealed extension of the previously identi-fied hyperintense regions (Fig. 1C), with newrestricted diffusion (Fig. 1D), a finding that wasconsistent with cytotoxic edema secondary to

l

A B C

E FD

Figure 1. MRI Studies of the Brain.

A fluid-attenuated inversion recovery (FLAIR) image obtained on postpartum day 18 (Panel A) shows hyperintense

regions in both parietaloccipital lobes (arrows) that had elevated diffusion (not shown), findings that are consis-tent with vasogenic edema. MRA of the circle of Willis (Panel B) shows multifocal stenoses in the proximal anterior,middle, and posterior cerebral arteries. A FLAIR image from MRI performed on admission to this hospital (postpar-

tum day 19) shows a hyperintense lesion (Panel C) in the left frontal lobe (arrow). The lesion is hyperintense on dif-fusion-weighted images (Panel D, arrow), a finding consistent with ischemia. MRA (Panel E) shows worsening of

the multifocal cerebral arterial stenoses. A FLAIR image from MRI performed on hospital day 6 (Panel F) shows bi-lateral cerebral infarction with edema and hemorrhage.





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ischemia. MRA of the circle of Willis (Fig. 1E)revealed worsening of the previously identifiedmultifocal anterior, middle, and posterior cere-bral-artery stenoses.

Dr. Singhal: I am aware of the diagnosis in thiscase. Recurrent headaches with hypertension de-veloped in this 36-year-old woman 10 days after

an unremarkable cesarean delivery of twins,which followed an uncomplicated pregnancy.Head CT, brain MRI and MRA, and the resultsof routine laboratory tests were initially normal.I shall begin by considering the differential diag-nosis at this stage of her illness.

Primary Headache Disorders

The incidence of postpartum headaches (Table 1)is nearly 40% in the f irst week,1,2 with migraineand tension-type headaches accounting for morethan 75% of cases. This patients headaches were

severe and reached peak intensity within min-utes, which is atypical for migraine and is consis-tent with thunderclap headaches, as defined bythe International Headache Society.3 Thunder-clap headaches can be primary or secondary4;virtually every condition listed in Table 1 hasbeen associated with thunderclap headache. Pri-mary thunderclap headaches are associated withcoughing, strenuous exertion, sexual activity,and even bathing. They can be diagnosed onlyafter secondary causes are ruled out by diagnos-tic testing that includes brain imaging and CSFexamination.

Subarachnoid hemorrhage

The initial diagnostic evaluation of thunderclapheadache should focus on subarachnoid hemor-rhage from a ruptured brain aneurysm, which isfound in approximately 25% of patients withthunderclap headache; 75% of patients with an-eurysmal subarachnoid hemorrhage present witha thunderclap headache.5 Aneurysmal ruptureseems unlikely as a cause of this patients head-

aches, because the imaging studies were initiallynormal, the CSF examination showed no redcells, and the thunderclap headaches recurred,which is distinctly uncommon for aneurysmalcerebral hemorrhage. The normal brain imaging,the results of CSF examination, and the absenceof fever and nuchal rigidity also help rule out manyother causes of secondary postpartum headache(Table 1).

Cerebral-Artery Dissections and Venous

Sinus Thrombosis

The estimated incidence of cerebral venous sinusthrombosis is 12 cases in 100,000 deliveries, withcesarean delivery and pregnancy-related hyperten-sion being important risk factors.6 Thunderclapheadache develops in approximately 15% of pa-tients with cerebral venous sinus thrombosis,7 and20% of all patients with cerebral-artery dissec-tions present with thunderclap headache.8 Thispatients magnetic resonance venogram showed noevidence of cerebral venous sinus thrombosis. Al-though the initial head MRA study was unremark-able, the neck arteries were not imaged, so thepossibility of dissection remains.

Postdural puncture headache

Approximately 5% of postpartum headaches arepostdural puncture headaches. They result fromintracranial hypotension due to a persistent CSF

leak after the administration of a spinal anes-thetic or inadvertent dural puncture during theadministration of an epidural anesthetic. Theseheadaches are usually persistent and have a pos-tural component, although they can be manifestedas thunderclap headache.9 As is often the case, wedo not have knowledge of the CSF opening pres-sure in this patient, which would be diagnostic.It is conceivable that changes in CSF pressure in

Table 1. Types and Causes of Postpartum Headache.

Primary headache disorders

Migraine

Tension-type headache

Primary thunderclap headache

Causes of secondary headaches

Postdural puncture headache

Embolic stroke

Carotid- or vertebral-artery dissection

Aneurysmal subarachnoid hemorrhage

Parenchymal brain hemorrhage

Cerebral venous sinus thrombosis

Meningitis, encephalitis

Pituitary disorders (e.g., pituitary apoplexy or the Sheehan syndrome)

Postpartum preeclampsia and eclampsia

Reversible posterior encephalopathy syndrome

Postpartum angiopathy (a reversible cerebral vasoconstriction syndrome)

Coincidental conditions (e.g., cerebral vasculitis or brain tumor)





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some way contributed to the patients headachesand subsequent angiographic abnormalities.

Delayed Postpartum Eclampsia

In the second week after the onset of symptoms,the patient continued to have thunderclap head-aches, which were associated with hypertension,

pedal edema, and a generalized seizure. Repeat-ed brain MRI showed bilateral lesions at thejunction of the cortex and subcortex, which weresuggestive of vasogenic edema. This imaging pat-tern is observed in several conditions, includingeclampsia, and in the appropriate clinical settingis recognized as the reversible posterior leukoen-cephalopathy syndrome.10,11 The time course ofthis patients symptoms and the clinical and im-aging features are consistent with delayed post-partum eclampsia.12,13

Eclamptic convulsions can occur before, dur-

ing, or after delivery. Postpartum eclampsia oc-curs in 10 to 45% of women with eclampsia.12,13About half of the cases of postpartum eclampsiaoccur within 48 hours after delivery, and theremainder occur between 2 days and 4 weeksafter delivery (delayed postpartum eclampsia), asin this case. The symptoms are identical to thoseof antepartum eclampsia and include occipitalor frontal headaches such as thunderclap head-aches, blurred vision, scotomas, photophobia, al-tered mental status, shortness of breath, and up-per abdominal pain.

Magnesium sulfate is indicated to prevent fur-ther seizures in women with eclampsia and wasadministered in this case. Magnesium has cere-bral vasodilatory effects, alters the expression ofendothelin-1 receptors, and reduces the perme-ability of the bloodbrain barrier. These actionsare relevant, since regional vasoconstriction, al-tered cerebral autoregulation with cerebral hyper-perfusion, endothelial dysfunction, and break-down of the bloodbrain barrier are central tothe pathophysiology of vasogenic edema in pa-

tients with eclampsia.10

Pregnancy-related stroke

Confusion, transient aphasia, right hemiparesis,ataxia, and visual deficits developed in this pa-tient, and repeated MRI showed ischemic strokes.Pregnancy-related stroke has an incidence of 34.2cases per 100,000 deliveries.14 Risk factors, whichare relevant to this patient, include an age of more

than 35 years, multiple gestation, increased par-ity, and preeclampsia.14 The greatest period of riskis during the 6 weeks after delivery. Although preg-nancy-related stroke can result from thrombophil-ia, embolism, cerebral venous sinus thrombosis,and other causes, in this case the repeated MRAshowed progressive multifocal vasoconstriction.

This raises specific diagnostic considerations.

Primary Angiitis of the Central Nervous

System

Primary angiitis of the central nervous system isan inflammatory condition characterized by in-sidious headaches with multifocal neurologicdeficits and elevated white-cell count and proteinlevels in the CSF.15,16 The initial brain MRI isvirtually always abnormal,16 with scattered small-vessel infarcts, often with diffuse white-matterchanges. Cerebral angiography can be normal,

since this disease affects small arteries beyondthe resolution of conventional angiography. How-ever, many patients have ectasia and narrowingof the medium-size arteries, as seen in this pa-tient. Primary angiitis of the central nervous sys-tem is a progressive disorder requiring promptimmunosuppressive therapy. Serologic evaluationfor the disorder in this patient was negative; how-ever, serologic and imaging tests have limiteduse for this diagnosis.17 Nonetheless, in this pa-tient, the dramatic clinical presentation with re-current thunderclap headaches, the absence ofCSF pleocytosis, and the initially normal MRIand MRA make primary angiitis of the centralnervous system unlikely. The rapid changes onMRA also argue against intracranial atheroscle-rosis, infectious arteritis, fibromuscular dyspla-sia, and other pathological entities associatedwith angiographic beading.

Reversible Cerebral Vasoconstriction

Syndrome (Postpartum Angiopathy)

This patients recurrent thunderclap headaches,

benign CSF results, rapidly progressive brainedema, strokes, and dynamic arterial changes arehighly suggestive of postpartum cerebral angiop-athy, a reversible cerebral vasoconstriction syn-drome.18

Reversible cerebral arterial narrowing has beenreported since the 1960s, with variable nomen-clature (eclamptic vasospasm, migraine angiitis,and central nervous system pseudovasculitis) that





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reflected the clinical setting or the presumedcause. In the past 20 years, a syndrome of cere-bral vasoconstriction associated with diverse con-ditions (Table 2) but with similar clinical, imag-ing, and prognostic features,19 some cases ofwhich had previously been thought to be pri-mary angiitis of the central nervous system,15,20has been recognized. This syndrome, now knownas reversible cerebral vasoconstriction syndrome,nonetheless remained underrecognized until thepublication of review articles and reports onlarge case series that have helped to define andcharacterize it.18,21-25

The reversible cerebral vasoconstriction syn-drome typically affects relatively young persons(20 to 60 years of age), occurs twice as often inwomen as in men, and is characterized by recur-rent thunderclap headaches and reversible seg-mental arterial vasoconstriction on serial brainimaging all features of this case with nohistologic evidence of inflammation. Brain im-aging is normal in approximately 70% of pa-tients with the reversible cerebral vasoconstric-

tion syndrome, and the rest have border-zoneischemic strokes, parenchymal hemorrhage, vaso-genic edema, and nonaneurysmal subarachnoidhemorrhage overlying the cortical surface.18,24,26The reversible cerebral vasoconstriction syndromehas many features in common with both isolatedthunderclap headache and the leukoencephalopa-thy syndrome,26,27 which suggests that these enti-ties may belong to the same spectrum of disor-

ders. The angiographic abnormalities in reversiblecerebral vasoconstriction syndrome, as in thispatient, are dynamic and often subtle and typi-cally resolve within 3 months.18,24,25 Most patientsrecover completely, although neurologic impair-ment (and even death) from progressive vasocon-striction, stroke, and brain edema has beenreported.28,29 To prevent this progression, treat-ment with calcium-channel antagonists, cortico-steroids, and blood-pressuremodulating agentsis initiated, as it was in this patient.

Clinical Di agnosis

Delayed postpartum eclampsia with postpartumangiopathy (the reversible cerebral vasoconstric-tion syndrome) complicated by brain edema andischemic and hemorrhagic strokes.

Pathological Discussion

Dr. Kimberly: The first diagnostic procedure wasCT angiography of the brain.

Dr. Schaefer: CT angiographic examination (Fig.2A and 2B) on the second hospital day (postpar-tum day 20) confirmed the presence of multifo-cal severe proximal stenoses of the anterior,middle, and posterior cerebral arteries.

Dr. Kimberly: These results supported the diag-nosis of the reversible cerebral vasoconstrictionsyndrome. On the third hospital day, further neu-rologic deterioration occurred, with unrespon-

Table 2. Factors Associated with the Reversible Cerebral Vasoconstriction Syndrome.

Idiopathic

No identifiable precipitating factor

Headache disorders (migraine, primary thunderclap headache, benign exertional headache, benign sexual headache,and primary cough headache)

Pregnancy and puerperium

Early puerperium, late pregnancy, preeclampsia, eclampsia, delayed postpartum eclampsia

Drugs and blood products

Phenylpropanolamine, pseudoephedrine, ergotamine tartrate, methylergonovine, bromocriptine, lisuride, selectiveserotonin-reuptake inhibitors, sumatriptan, isometheptene, cocaine, ecstasy, amphetamine derivatives, marijuana,lysergic acid diethylamide, tacrolimus, cyclophosphamide, erythropoietin, intravenous immune globulin, and red-cell transfusions

Miscellaneous

Hypercalcemia, porphyria, pheochromocytoma, bronchial carcinoid tumor, unruptured saccular cerebral aneurysm,head trauma, spinal subdural hematoma, postcarotid endarterectomy, postdural puncture, open neurosurgicalprocedures





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siveness, continuous lip smacking and chewingmovements, and spasticity and hyperreflexia inall limbs, with extensor plantar responses. Anexternal ventricular drain was placed to monitorintracranial pressure; the trachea was intubated,and cerebral angiography was performed whilethe patient was under general anesthesia.

Dr. Schaefer: A digital-subtraction angiogramobtained on the third hospital day showed severe

segmental narrowing and dilatation of multipleintracranial arteries in the anterior, middle, andposterior vascular territories (Fig. 2C).

Dr. Kimberly: Nicardipine was injected into theleft vertebral and right and left internal carotidarteries, resulting in nearly complete resolutionof the arterial narrowing. However, on the fourthday, head CT scans and CT angiographic imagesshowed recurrent severe narrowing of the distal

A B

DC

l

Figure 2. CT Angiography and Digital-Subtraction Angiography of the Brain.

A CT angiogram obtained on the second hospital day (postpartum day 20) (Panel A) shows multifocal stenoses in

the proximal anterior cerebral arteries (arrows). There is also stenosis of the middle cerebral arteries (Panel B, ar-

rowheads) and posterior cerebral arteries (Panel B, arrows). A magnified lateral view from a digital-subtraction an-giogram obtained on hospital day 3 (Panel C) shows multifocal areas of vasoconstriction (arrows) in the branches of

the right middle cerebral artery. A CT angiogram obtained on hospital day 4 after the injection of nicardipine (PanelD) shows nearly complete resolution of previously seen vasoconstriction in the territories of the anterior, middle,

and posterior cerebral arteries.





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branches of the left middle cerebral artery andboth posterior cerebral arteries, with increasedmean transit times of blood through both pos-terior and distal territories of the middle cere-bral artery. A transcranial Doppler study showedincreased blood-flow velocities consistent withthe presence of severe right and mild left vaso-

spasm. Nimodipine was administered. Repeatedcerebral angiography with the administration ofintraarterial and intravenous nicardipine again re-sulted in improvement of the arterial narrowing.Treatment with intrathecal nicardipine, insulinon a sliding scale, cefazolin, nafcillin, propofol(titrated to intracranial pressure) and milrinonewas begun.

During the next 24 hours, intravenous phen-ylephrine, fludrocortisone, and intravenous nor-epinephrine were administered in an effort toraise systemic blood pressure and improve cere-

bral perfusion. Transcranial Doppler studiesshowed continuing vasospasm. A head CT scanrevealed progressive watershed-territory infarc-tions with extensive cerebral edema. Hypertonictherapy, mannitol, pentobarbital, acetylcysteine,and hypothermia were administered, but the pa-tients condition did not improve. On the seventhhospital day, the pupils were dilated and did notreact to light. Brain imaging showed extensiveischemia and edema in both cerebral hemi-spheres. After discussion with the patients fam-ily, supportive care was withdrawn, and the pa-tient died on the eighth hospital day. An autopsywas performed.

Dr. Schaefer: After treatment with intraarterialnicardipine, both digital-subtraction and CT an-giograms (Fig. 2D) revealed nearly completeresolution of the previously identified vasocon-striction. Multiple head CT and brain MRI scansobtained during the patients hospital courseshowed the continued development of new is-chemic regions and brain swelling. The finalbrain MRI scan on hospital day 6 (postpartum

day 25) (Fig. 1F) showed infarctions in the brainstem, bilateral thalami, and bilateral frontal,parietal, and occipital lobes, with hemorrhagictransformation in some regions of ischemia, dif-fuse brain swelling with effacement of the basi-lar cisterns, and transtentorial herniation.

Dr. E. Tessa Hedley-Whyte: Postmortem exami-nation was restricted to the brain, which wasswollen and soft and weighed 1504 g (normal

range, 1250 to 1400). The vessels of the circle ofWillis were normal in diameter and wall thick-ness. Coronal sectioning revealed a dusky cutsurface with a blurred junction of gray and whitematter, particularly in the border-zone areas(Fig. 3A and 3B). A hemorrhage in the rightfrontal and parietal lobes, related to the ventricu-

lar drain track, extended across the midline intothe left frontal lobe. The lateral ventricles weremildly dilated and contained blood clot. On mi-croscopical examination, there was widespreadrecent infarction, approximately 48 to 72 hoursold, with foci of hemorrhage consistent withreperfusion (Fig. 3C). There was diffuse neuronalnecrosis secondary to hypoxicischemic injury(Fig. 3D). The small blood vessels in the whitematter had scattered hemosiderin-laden macro-phages in their adventitia, a feature suggestive ofearly hypertensive vascular changes. The arteries

of the circle of Willis were normal, apart fromone patch of subendothelial thickening in theposterior cerebral artery (Fig. 3E and 3F). Nospecific morphologic abnormalities have beendescribed that correlate with the phenomenon ofdiffuse vascular spasm.

Dr. Kimberly: Because this patient had featuresshared by postpartum angiopathy and antepar-tum eclampsia, we investigated this relationshipfurther. Blood levels of placental growth factor(PlGF) and a soluble PlGF receptor (sFlt-1)30,31(members of the vascular endothelial growthfactor [VEGF] pathway) and a soluble form ofthe transforming growth factor 1 receptor (sol-uble endoglin)32 correlate with the presence ofantepartum eclampsia and also predict its devel-opment. Plasma from the patient was analyzedin the laboratory of Dr. Ravi Thadhani at thishospital. We compared the results in this patientwith the mean values reported in the literaturefor antepartum and postpartum patients30-35 (Ta-ble 3). This patient had a slightly elevated sFlt-1level (121 pg per milliliter) but virtually no PlGF

(


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A B

DC

FE

l





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proximately 32 in patients with antepartum pre-eclampsia. These data suggest that a functionallylow PlGF state, similar to that seen in antepartumpreeclampsia, may have played a role in this pa-tients disease process.

Dr. Nancy Lee Harris(Pathology): In a woman whois more than 2 weeks post partum, do you expectto find any PlGF in the serum?

Dr. Kimberly: Yes. Although it was first discov-ered in human placenta, PlGF is also produced byseveral other cell types, most notably endothelialcells, which release PlGF,37 resulting in a meanPlGF level in nonpregnant women of 11.5 pg permilliliter.38

Dr. Harris: Dr. Greene, would you like to com-ment?

Dr. Michael F. Greene(Obstetrics and Gynecology):I am not sure whether abnormalities in sFlt-1 andPlGF levels are a cause or a result of preeclampsiaand eclampsia.

Dr. Kimberly: There is evidence that these pro-

teins are causative. Administration of sFlt-1 in apregnant-rat model produces both clinical andpathological changes of preeclampsia,39 and co-administration of sFlt-1 with soluble endoglincauses a HELLP-like syndrome (hemolysis, elevat-ed liver-enzyme levels, and a low platelet count).40In humans, inhibition of the VEGF pathway withbevacizumab (which is functionally analogousto excess sFlt-1) can cause symptoms similar tothose of preeclampsia.41,42

Dr. Singhal: Progression to death is uncommonin the reversible cerebral vasoconstriction syn-

drome. Unfortunately, this case illustrates thatpharmacologic blood-pressure modulation, cal-cium-channel antagonists, and direct interven-tions such as balloon angioplasty or injection ofvasodilators may not be effective in preventingdisease progression. Opening the artery may ex-pose the brain to the risks of reperfusion injury.Nevertheless, the prompt but transient relief ofvasoconstriction with the use of a vasodilatorsupports vasospasm as the underlying mechanism.Further research should focus on uncovering pre-cise mechanisms43 for the various conditionsincluded in the reversible cerebral vasocon-striction syndrome in order to develop specifictherapies.

Figure 3 (facing page). Postmortem Examinationof the Brain.

Coronal sections of the left (Panel A) and right (Panel B)cerebral hemispheres show hemorrhage, originating

around the drain tract, that extends across the corpus

callosum into the left hemisphere. The gray matterwhite matter junctions are indistinct, and overall, the

brain has a dusky appearance consistent with diffuseischemic damage. A section of parietal cortex (hema-

toxylin and eosin) shows an acute infarction with neu-trophils and axonal retraction balls (Panel C, arrow)

and neurons (Panel D) with eosinophilic cytoplasmcharacterized by loss of Nissl substance, which indi-

cates neuronal death (arrows). A section of the rightposterior cerebral artery (Panel E, hematoxylin and eosin)

shows normal elastica and mild endothelial thickening.An Epon-embedded section of the distal middle cerebral

artery (Panel F, toluidine blue) shows normal arterial-

wall structures. The internal elastic lamina has a nor-mal appearance. Electron-microscopical examination

of the arteries showed no abnormalities.

Table 3. Angiogenic and Antiangiogenic Serum Proteins in the Patient As Compared with Those in Control Patients

and Patients with Antepartum Preeclampsia.*

Variable Antepartum Postpartum

Control PatientsPatients withPreeclampsia Control Patients This Patient

Soluble endoglin (ng/ml) 5.9 31 NA 4.7

sFlt-1 (pg/ml) 1643 4382 45 121

PlGF (pg/ml) 669 137 Approximately 50 5

sFlt-1:PlGF ratio 2.5 31.9 0.9 24.2

* NA denotes not available, PlGF placental growth factor, and sFlt-1 soluble vascular endothelial growth factor receptor 1.Values for antepartum and postpartum control samples represent mean levels reported in the literature for antepartumand postpartum patients.30-35 Antepartum samples (control and preeclampsia) were obtained during the third trimes-ter. Postpartum control samples were obtained between 3 and 7 days after delivery. This patients samples were mea-sured from blood obtained on hospital day 1 (postpartum day 19).





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ANATOMICAL DIAGNOSES

Multiple bilateral acute cerebral infarcts with largeright intracerebral hemorrhage arising in a sub-acute infarct (secondary to arterial spasm).

Diffuse cortical neuronal necrosis (due to isch-emia).

Hypertensive small-vessel changes, mild.Cerebral edema.(Reversible cerebral vasoconstriction syndrome.)

Dr. Hedley-Whyte reports having equity ownership in BectonDickinson. No other potential conflict of interest relevant to thisarticle was reported.

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