OBSERVATION

Postpartum Angiopathy With Reversible
Posterior Leukoencephalopathy
Aneesh B. Singhal, MD

Background: Postpartum angiopathy (PPA) is a cerebral
vasoconstriction syndrome of uncertain cause that affects
large and medium-sized cerebral arteries. Postpartum angiopathy is frequently complicated by ischemic stroke. The
reversible posterior leukoencephalopathy syndrome (RPLS)
is a distinct clinical-radiological entity characterized by transient vasogenic edema on brain imaging. The pathophysiological features of RPLS are related to small-vessel dysfunction and breakdown of the blood-brain barrier.
Objectives: To report the coexistence of PPA and RPLS
in 4 patients and to discuss possible interrelationships
between these 2 entities.

Results: Four women developed a clinical-radiological

syndrome overlapping PPA and eclampsia shortly after
an uncomplicated pregnancy. All had acute severe (“thunderclap”) headaches and hypertension. Three developed seizures. All patients had reversible angiographic
narrowing of large and medium-sized cerebral arteries.
Serial magnetic resonance imaging showed transient
nonischemic brain lesions, resembling the lesions described in patients with RPLS. The results of extensive
tests for cerebral vasculitis were negative.
Conclusion: These cases, and the literature, suggest an
interrelationship between RPLS and cerebral vasoconstriction syndromes such as PPA.

Design: Four case reports and a review of the litera-

ture.

Arch Neurol. 2004;61:411-416

T

From the Stroke Service,
Department of Neurology,
Massachusetts General Hospital
and Harvard Medical School,
Boston.

HE REVERSIBLE CEREBRAL

segmental vasoconstriction syndrome (RCV) is a
clinical-angiographic syndrome characterized by
the abrupt onset of severe headaches, seizures, focal neurological deficits, and
segmental narrowing and dilatation of
large and medium-sized cerebral arteries,
typically in women aged 20 to 50 years.
The vasoconstriction can be idiopathic
or associated with conditions like
migraine, vasoactive drug use, and pregnancy or puerperium (postpartum angiopathy [PPA]).1
The reversible posterior leukoencephalopathy syndrome (RPLS) is characterized by reversible posteriorpredominant white and gray matter
lesions (vasogenic edema) on brain magnetic resonance imaging (MRI), in
patients with conditions like eclampsia,
hypertensive encephalopathy, and uremia. 2 Acute headaches, seizures, and
visual deficits are typical clinical features. The pathophysiological features of
RPLS have been related to small-vessel

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411

dysfunction and breakdown of the
blood-brain barrier, usually in the face of
severe hypertension.
Described herein are 4 patients with
clinical and angiographic features of PPA,
whose neuroimaging findings were consistent with RPLS (Table).
REPORT OF CASES

PATIENT 1
On days 4 and 13 after an elective cesarean section, a 37-year-old woman developed sudden-onset severe occipital headaches. She had no history of migraines.
On hospital admission (day 13), her
blood pressure was 150/78 mm Hg and
she had no neurological deficits. Blood
cell counts, electrolyte levels, and urinalysis results were normal. The results
of extensive tests for vasculitis were
negative, including tests for antinuclear
and anti–double-stranded DNA antibodies, rheumatoid factor, anti–neutrophil
cytoplasm antibodies, antibodies to proteinase 3 and myeloperoxidase, and anti-

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Patient Characteristics
Patient No.
Characteristic

1

2

3

4

Age, y
History of migraine
Postpartum day of onset
Clinical features

37
−
4
Thunderclap headaches

Admission BP, mm Hg
Brain MRI findings

150/78
Reversible posterior
bihemispheric lesions

23
+
12
Thunderclap headaches
and seizures
200/100
Reversible bihemispheric
and cerebellar lesions

31
−
4
Thunderclap headaches
and seizures
200/100
Reversible posterior
bihemispheric lesions

Arteries involved

ICA, MCA, and PCA

21
+
7
Thunderclap headaches and
seizures
180/108
Reversible bihemispheric
and cerebellar lesions and
SAH
PCA, VA, and basilar artery

ACA and MCA

ICA, ACA, MCA, and PCA

Abbreviations: ACA, anterior cerebral artery; BP, blood pressure; ICA, internal carotid artery; MCA, middle cerebral artery; MRI, magnetic resonance imaging;
PCA, posterior cerebral artery; SAH, subarachnoid hemorrhage; VA, vertebral artery; −, absent; +, present.

Ro, anti-La, anti–Scl-70, and anti–Jo-1 antibodies, and
serological tests for syphilis and Lyme disease. A cerebrospinal fluid examination showed 0 red blood cells
per microliter, 2 white blood cells per microliter, and
protein level of 0.044 g/dL. Transcranial Doppler studies showed elevated blood flow velocities in all circle of
Willis arteries. A brain MRI (on day 13) showed multiple lesions, hyperintense on T2-weighted and fluidattenuated inversion recovery (FLAIR) sequences
(Figure 1A), without restricted diffusion on apparent
diffusion coefficient (ADC) maps. The results of MR
venography were normal. Her hospital course was
notable for frequent headache exacerbations with blood
pressure elevations up to 190/100 mm Hg. Twentyfour–hour urine metanephrine and vanillylmandelic
acid levels were normal. On day 17, a second brain MRI
showed resolution of most previously noted parenchymal lesions, and the results of MR angiography (MRA)
of the head and neck vessels were normal. She had an
acute headache exacerbation on day 20. A repeat brain
MRI was normal; however, MRA showed segmental
vasoconstriction of the bilateral distal internal carotid
arteries, middle cerebral arteries (MCAs), and posterior
cerebral arteries (Figure 2A). She was treated with
intravenous magnesium sulfate and antihypertensive
agents. Head computed tomographic (CT) angiography
on day 22 showed complete resolution of proximal
MCA and posterior cerebral artery vasoconstriction
(Figure 2B); however, segmental narrowing was still
present in some MCA branches. Her headaches resolved
over 10 days, and she was discharged from the hospital.
PATIENT 2
One week after an uncomplicated vaginal delivery, a
21-year-old woman developed a sudden severe headache followed by generalized seizures. She had a history
of common migraine headaches and depression, treated
with fluoxetine for 3 months. On hospital admission,
her blood pressure was 180/108 mm Hg and she had
hyperreflexia but no focal neurological deficits. A cerebrospinal fluid examination showed 1070 red blood
cells per microliter, 0 white blood cells per microliter,
and protein level of 0.051 g/dL. Brain MRI showed mul(REPRINTED) ARCH NEUROL / VOL 61, MAR 2004
412

tiple lesions, all hyperintense on T2-weighted and
FLAIR sequences, without restricted diffusion on ADC
maps. In addition, there was a minor subarachnoid
hemorrhage overlying the right frontal cortex (Figure
1B). Transfemoral cerebral angiography and CT angiography (Figure 2C) showed narrowing of the left posterior cerebral artery, but no cerebral aneurysm. She was
treated with intravenous magnesium, labetalol hydrochloride, and phenytoin. The following day, she developed another sudden severe headache. Repeat CT/CT
angiography showed new vertebral and basilar artery
narrowing (Figure 2D); however, the previously noted
subarachnoid blood was no longer visualized. Severe
headaches recurred, but with decreasing intensity and
frequency. Brain MRIs on puerperal days 9 and 11
showed gradual resolution of the previously noted
abnormalities. Transfemoral cerebral angiography,
repeated after 1 month, showed complete resolution of
vasoconstriction.
PATIENT 3
A 23-year-old woman with a history of common migraine developed mild headaches and dyspnea 12 days
after an uncomplicated vaginal delivery. On day 15, she
developed a sudden severe headache that was different
from her prior migraine headaches, followed by generalized seizures and severe hypertension (blood pressure, 200/100 mm Hg). The result of head CT was normal, and there was no subarachnoid hemorrhage. Brain
MRI showed multiple lesions (Figure 1C) that were hyperintense on T2-weighted and FLAIR sequences, without restricted diffusion on ADC maps. Head MRA showed
vasoconstriction in the right anterior cerebral artery and
MCA (Figure 2E). Transcranial Doppler studies showed
diffusely elevated blood flow velocities with an abnormal spectral configuration, suggesting cerebral vasoconstriction. Blood cell counts, electrolyte levels, urinalysis
results, serum and urine toxicology screen results, and
24-hour urine metanephrine and vanillylmandelic acid
levels were normal. The workup for dyspnea included
chest CT angiography (normal results) and cardiac ultrasonography, which showed diffuse hypokinesia and
a low ejection fraction. She was diagnosed as having
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A

B

C

D

Figure 1. Brain magnetic resonance imaging (MRI) fluid-attenuated inversion recovery sequences. A, Patient 1. The MRI findings on postpartum day 13 show
subcortical white matter lesions in the right posterior temporal and parietal regions and the forceps major. B, Patient 2. The MRI findings on day 7 show multiple
cortical and subcortical hyperintense lesions in bilateral temporal and parietal regions. In addition, a small amount of subarachnoid blood is present in the right
frontal region (arrow). C, Patient 3. The MRI findings on day 15 show hyperintense lesions in the left cerebellar hemisphere and in the bilateral temporal, parietal
cortical, and subcortical regions. D, Patient 4. The MRI findings on day 6 show subcortical hyperintense lesions in the posterior regions of both cerebral
hemispheres.

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A

B

C

D

E

F

Figure 2. Angiographic findings. A, Patient 1. Magnetic resonance angiographic (MRA) findings on postpartum day 20 show segmental vasoconstriction in the
bilateral posterior cerebral arteries and basilar artery. B, Patient 1. Computed tomographic angiographic (CTA) findings on day 22 show complete resolution of the
vasoconstriction. C, Patient 2. The CTA findings on day 7 show vasoconstriction of the proximal left posterior cerebral artery. D, Patient 2. The findings of a repeat
CTA on day 8, performed to investigate severe headache exacerbation, show new vasoconstriction in the basilar and bilateral intracranial vertebral arteries.
E, Patient 3. The MRA findings on day 15 show segmental vasoconstriction (arrows) of the right middle cerebral artery and left anterior cerebral artery branches.
F, Patient 4. The MRA findings on day 17 show severe narrowing (arrows) of the left internal carotid and anterior, middle, and posterior cerebral arteries.

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peripartum dilated cardiomyopathy, and treated with intravenous magnesium and captopril. After 1 week, a second brain MRI showed complete resolution of the previously noted abnormalities. The results of follow-up
transcranial Doppler studies were normal. The cardiomyopathy resolved within 10 days. She had no further headaches or seizures, and was discharged from the hospital.
PATIENT 4
Four days after an uncomplicated vaginal delivery, a 31year-old woman developed a sudden excruciating headache. On hospital admission, her blood pressure was 200/
100 mm Hg and she had hyperreflexia but no focal
neurological deficits. The result of head CT was normal. The headache and hypertension improved after intravenous magnesium and labetalol treatment. On day
6, the headache suddenly increased in intensity; her blood
pressure measured 148/77 mm Hg. Brain MRI showed
multiple lesions, all hyperintense on T2-weighted and
FLAIR sequences (Figure 1D), without restricted diffusion on ADC maps. The result of MR venography was
normal. Headaches recurred frequently, and on day 10,
she developed generalized seizures. Serial brain MRIs on
days 14, 17, and 19 showed initial progression and then
resolution of the RPLS-like lesions. Magnetic resonance
angiography on days 17 and 19 showed severe left internal carotid artery, anterior cerebral artery, MCA, and
posterior cerebral artery narrowing (Figure 2F). In addition, there was incidental dissection of the extracranial left internal carotid artery. Carotid ultrasonography on day 22 showed normal blood flow velocities in
both carotid arteries. Her clinical status improved gradually over 10 days, and she was discharged from the hospital. Repeat MRA at 6 months showed resolution of all
arterial abnormalities.
COMMENT

All patients developed “thunderclap” headaches and hypertension in the postpartum period, 3 developed seizures, and all had angiographic segmental cerebral arterial vasoconstriction. Brain MRI showed posteriorpredominant subcortical and cortical lesions that were
hyperintense on FLAIR, T2-weighted, and ADC images,
similar to the lesions described in patients with RPLS.
Clinical features and imaging abnormalities resolved spontaneously within days to weeks. The results of extensive
tests for cerebral vasculitis were negative. In patient 2,
the sudden-onset basilar artery vasoconstriction was probably unrelated to the minor nonaneurysmal subarachnoid hemorrhage overlying the frontal cortex. Nonaneurysmal subarachnoid hemorrhages can occur in patients
with pregnancy-induced hypertension and eclampsia, possibly due to the rupture of pial vessels in the face of sudden hypertension and impaired autoregulation.3 This patient was exposed to fluoxetine, a serotonin-enhancing
drug that might have contributed to the reversible cerebral vasoconstriction.4
Classification of these patients is a challenge. Features such as acute headaches, seizures, hypertension, and
reversible vasoconstriction are consistent with the diag(REPRINTED) ARCH NEUROL / VOL 61, MAR 2004
415

nosis of PPA. However, brain MRI showed lesions consistent with RPLS and not ischemic stroke, which is the
usual lesion associated with PPA. Headaches, seizures,
hypertension, and RPLS occurring more than 48 hours
after delivery raise the possibility of postpartum eclampsia; however, none of the patients had proteinuria. Postpartum patients with segmental cerebral vasoconstriction who do not meet the criteria for eclampsia are usually
classified as having PPA.5 The constellation of clinical and
imaging features in these patients is similar to those of
previously published cases, and supports the view that
PPA and eclampsia are interrelated conditions with similar pathophysiological features.5,6
The literature7-11 suggests that a similar relationship exists between RPLS and RCV in patients with
conditions other than pregnancy. Clinical features such
as abrupt onset, severe (thunderclap) headaches, confusion, seizures, and visual deficits are common in
patients with RPLS and RCV. While patients with RCV
have large-artery (proximal) cerebral vasoconstriction
and stroke, the pathophysiological features of RPLS
have been related to endothelial dysfunction and failure
of cerebral autoregulation involving distal arterioles and
capillaries. The brain lesions of RPLS probably reflect
fluid and protein extravasation (vasogenic edema) due
to passive vasodilatation in the face of severe hypertension. Nevertheless, numerous reports7-12 of decreased
cerebral blood flow, cytotoxic edema, ischemic stroke,
and angiographic vasoconstriction, in hypertensive and
nonhypertensive patients with RPLS, suggest an important role for cerebral vasoconstriction in RPLS. In retrospect, one previously described patient with sumatriptan succinate–associated cerebral vasoconstriction
probably had brain lesions consistent with RPLS. 4
Finally, the topographic features of ischemic strokes
that occasionally complicate RPLS are similar to those
of strokes associated with RCV—“watershed” distribution strokes that often spare the cortex while involving
the subcortical regions.13
These data indicate that large and medium-sized cerebral vasoconstriction occurs in patients with RPLS, and
that vasogenic edema can occur in patients with largeartery vasoconstriction syndromes such as PPA. Central
to the pathophysiological features might be disturbances in the regulation of cerebral arterial tone (due to
either intrinsic factors like endothelin or serotonin or extrinsic factors like vasoactive drugs), with regional variations determining whether the patient manifests with RCV,
RPLS, or an overlapping syndrome, as in these 4 patients. For example, coexisting vascular changes in the
distal arterial bed might lead to the development of vasogenic edema in patients with angiographic (proximal) arterial vasoconstriction.
Most patients with RPLS have normal cerebral angiogram results. Mild or medium-sized arterial narrowing might escape detection with newer imaging modalities, such as CT or MRA. Timing of the vascular imaging
study might be another factor: vasoconstriction is not always present at the onset of symptoms, can begin abruptly,
can fluctuate, and can resolve within days. In patients 1
and 2, the initial angiographic studies showed no significant vasoconstriction. However, repeat studies perWWW.ARCHNEUROL.COM

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formed soon after acute headache exacerbations showed
severe reversible vasoconstriction (Figure 2B). Further
study is needed to fully understand the pathophysiological features, causes, and interrelationships of these conditions.
Accepted for publication August 8, 2003.
I thank Anne-Marie Wills, MD, Elizabeth Finger, MD,
and Anand Viswanathan, MD, PhD, for referring patients
2 and 4.
Corresponding author and reprints: Aneesh B.
Singhal, MD, Stroke Service, Massachusetts General Hospital, Room VBK-802, Boston, MA 02114 (e-mail:
asinghal@partners.org).
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