Acute Ischemic Stroke Patterns in Infective and Nonbacterial ...

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Acute Ischemic Stroke Patterns in Infective and
Nonbacterial Thrombotic Endocarditis
A Diffusion-Weighted Magnetic Resonance Imaging Study
Aneesh B. Singhal, MD; Mehmet A. Topcuoglu, MD; Ferdinando S. Buonanno, MD
Background and Purpose—Although infective endocarditis (IE) and nonbacterial thrombotic endocarditis (NBTE) are
associated with cardioembolic stroke, differences in the nature of these conditions may result in differences in associated
stroke patterns. We compared patterns of acute and recurrent ischemic stroke in IE and NBTE, using diffusion-weighted
Methods—Using ICD-9 diagnostic codes and medical record review, we identified 362 patients (387 episodes) with IE and
14 patients with NBTE. Thirty-five patients (with 27 episodes of IE, 9 NBTE) who underwent 36 initial and 29
follow-up DWI scans were selected for this study. DWI lesion size, number, and location were compared between
groups and correlated with stroke syndromes and endocarditis features.
Results—DWI was abnormal in all but 2 patients. Four acute stroke patterns were identified: (1) single lesion, (2) territorial
infarction, (3) disseminated punctate lesions, and (4) numerous small ( 10 mm) and medium (10 to 30 mm) or large
( 30 mm) lesions in multiple territories. All patients with NBTE exhibited pattern 4, whereas those with IE exhibited
patterns 1, 2, 3, and 4 (6, 2, 8 and 9 episodes, respectively). Seventy-five percent of patients with pattern 3 exhibited
the clinical syndrome of embolic encephalopathy. Vegetation size, valve, and organisms had no correlation with stroke
Conclusion—DWI has utility in differentiating between IE and NBTE. Patients with NBTE uniformly have multiple,
widely distributed, small and large strokes, whereas patients with IE exhibit a panoply of stroke patterns. (Stroke. 2002;

Key Words: brain infarction
magnetic resonance imaging
stroke, embolic
Ischemic stroke is the most common neurological compli- MRI.9–11 Using DWI, it is possible to detect ischemic lesions
cation of endocarditis.1–4 It occurs in approximately 20%
within minutes after symptom onset.12 DWI can detect very
of patients with infective endocarditis (IE) and in more than
small ischemic lesions because it has a high signal-to-noise
a third of patients with nonbacterial thrombotic endocarditis
ratio;13 it can be used to differentiate between acute and
(NBTE).1–4 Stroke is often one of the presenting symptoms of
chronic lesions because ischemic lesions appear hyperintense
endocarditis and can be the only manifestation. Brain MRI
within minutes after symptoms onset but lose their signal
findings in IE have been described and include multiple
intensity after a few days or weeks.14,15 Thus, DWI can
ischemic or hemorrhagic strokes, brain abscesses, and my-
provide knowledge of the temporal and spatial nature of
cotic aneurysms.5,6 We are aware of only 2 case reports of
stroke, and this ability is helpful in determining stroke
brain MRI findings in NBTE, including 1 from our institu-
subtype and pathophysiology.16–22 Patients with lacunar syn-
tion; both patients had multiple, widely distributed ischemic
dromes are considered likely to have small-vessel disease if
strokes.7,8 Patients with IE often undergo serial neuroimaging
DWI shows a single hyperintense lesion in the relevant
to assess for developing mycotic aneurysms, new strokes, and
location. Conversely, the presence of multiple lesions, in
hemorrhagic strokes and to evaluate the efficacy of antibiotic
more than 1 arterial territory, suggests emboli from a proxi-
treatment. Given the prevalence of endocarditis-associated
mal source like the heart or the aortic arch. At present, it is not
stroke, and the value of MRI in managing these patients,6 it is
known whether the topography of embolic stroke can be
important to determine the topography of acute and recurrent
influenced by the source of emboli or the nature of the
strokes associated with IE and NBTE.
underlying disease.
Diffusion-weighted MRI (DWI) is a relatively new imag-
In this study, we analyzed initial and subsequent DWI
ing technique that has several advantages over conventional
scans in patients with IE and NBTE. The purpose of the study
Received November 14, 2001; final revision received January 15, 2002; accepted January 30, 2002.
From the Stroke Service, Department of Neurology, Massachusetts General Hospital, and Harvard Medical School, Boston, Mass.
Correspondence to Aneesh B. Singhal, MD, VBK-802, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114. E-mail [email protected]
© 2002 American Heart Association, Inc.
Stroke is available at
DOI: 10.1161/01.STR.0000015029.91577.36

May 2002
was to compare the topography of acute and recurrent stroke
Patient Characteristics*
in 2 conditions known to cause cardioembolic stroke.
IE (n 27)
NBTE (n 9)
Subjects and Methods
Mean age (yr)
Using ICD-9 diagnostic codes 421 and 424.9, we identified 519
Male (%)
13 (48)
2 (22)
patients with 572 episodes of endocarditis admitted to the Massa-
Valve involved
chusetts General Hospital after 1993, the year DWI entered clinical
practice at this institution. We reviewed medical records and retro-
spectively confirmed the diagnosis of NBTE in 14 patients and IE in
362 patients who, in the aggregate, suffered 387 episodes of
endocarditis. A diagnosis of IE was confirmed if the patient had
14 (52)
5 (56)
pathologically verified IE or met Duke clinical criteria for “definite”
or “possible” endocarditis.23 A diagnosis of NBTE was confirmed if
3 (11)
3 (33)
the diagnosis was made on autopsy or if the patient had a triad of (1)
3 (11)
3 (33)
a disease process known to be associated with NBTE, (2) vegetations
2 (7)
3 (33)
on echocardiogram, and (3) the presence of embolic phenomena. The
medical history, neurological examination findings, and relevant
4 (15)
2 (22)
laboratory and radiological data were recorded for all patients.
16 (59)
6 (67)
Thirty-five patients who underwent DWI were selected for this
Peripheral embolism
2 (7)
2 (22)
study (26 with IE and 9 with NBTE). One patient underwent DWI
during each of 2 episodes of staphylococcal endocarditis; each
Stroke syndromes
episode was recorded separately for the purposes of this study and
12 (44)
4 (44)
thus a total of 27 episodes of IE were analyzed. Among patients with
2 (7)
1 (11)
NBTE, valvular vegetations were identified by transesophageal
echocardiogram in 5 patients, by transthoracic echocardiogram alone
1 (4)
0 (0)
in 3 patients, and by autopsy in 1 patient. Twenty-six of the 27
12 (44)
4 (44)
episodes of IE were evaluated by transesophageal echocardiogram,
In-hospital mortality
4 (15)
5 (56)‡
and vegetations were documented in 24 episodes.
Clinical syndromes were classified according to the Oxfordshire
IE indicates infective endocarditis; NBTE, nonbacterial thrombotic endocar-
Community Stroke Project criteria24 as total anterior circulation
ditis; PACS, partial anterior circulation syndrome; POCS, posterior circulation
syndrome (TACS), partial anterior circulation syndrome (PACS),
syndrome; LACS, lacunar syndrome; EE, embolic encephalopathy.
lacunar syndrome (LACS), and posterior circulation syndrome
*Numbers in parentheses indicate percentages.
(POCS). In addition, patients who had discrete focal neurological
†P 0.008.
deficits localized to both the anterior and posterior circulations were
‡P 0.015.
classified as “combined syndromes.” Patients with acute mental
status changes attributable to embolic stroke, but without docu-
mented focal neurological deficits, were classified as “embolic
established (P 0.079); approximately half of these patients
had no other endocarditis-related symptoms such as fever or
To study the topographical characteristics of the presenting stroke,
malaise. The distribution of atherosclerotic risk factors (hy-
we analyzed initial DWI films; to study patterns of recurrence and/or
pertension, diabetes, hypercholesterolemia, smoking) was
evolution of stroke, we reviewed subsequent DWI scans in all
patients in whom it was performed. The presence, size, number, and
similar between groups. Five patients with IE had a previous
location of all hyperintense lesions (ischemic strokes) were noted.
history of stroke, and 6 had atrial fibrillation. Demographic
Lesions were considered small if the largest axial diameter was
data and stroke characteristics are outlined in Table 1.
10 mm, medium if 10 to 30 mm, and large if
30 mm. Lesions
were considered multiple if they were noncontiguous on contiguous
Initial DWI
slices. We made note of the involved arterial territory (anterior
cerebral artery, middle cerebral artery [MCA], posterior cerebral
All patients underwent initial DWI within 1 week after the
artery [PCA], vertebrobasilar territory, borderzone) and arterial
onset of neurological symptoms, except for 1 patient with
circulation (unilateral carotid, bilateral carotid, vertebrobasilar,
NBTE and 3 with IE whose initial DWI were performed
between 1 and 2 weeks. The 2 most common indications were
evaluation of stroke and encephalopathy; other indications
Statistical Analysis
included evaluation of seizures and detection of asymptom-
Two-sample t tests and Fisher exact tests were used as appropriate.
A value of P 0.05 was considered statistically significant.
atic cerebral emboli or mycotic aneurysms (Table 2).
Initial DWI was normal in 2 episodes of IE (both were
associated with transient stroke-like symptoms). Initial DWI
DWI was performed in 9 patients with NBTE and in 26
in all other episodes showed hyperintense lesions, suggesting
patients with 27 episodes of IE. Based on Duke criteria, there
acute ischemic stroke. Single lesions (5 MCA, 1 PCA) were
were 26 episodes of “definite” and 1 episode of “possible”
present on 6 scans, all performed in patients with IE (Figure
endocarditis. Four patients had late-onset bioprosthetic valve
1). Multiple DWI lesions were present in all patients with
IE, including the patient with 2 episodes of endocarditis. All
NBTE (Figure 2) and in 19 (70%) episodes of IE (Figure 1).
patients with NBTE had adenocarcinomas (3 lung, 2 pan-
All patients with NBTE had at least 1 medium or large lesion
creas, 2 ovary, 1 liver, 1 colon). Seven patients with NBTE
and several smaller lesions, which were distributed in more
had metastatic cancer; however, none had brain metastases on
than 1 arterial territory. In general, patients with IE had fewer
MRI. Nine (35%) patients with IE and 6 (67%) with NBTE
and smaller-sized lesions. Seven of 9 patients with NBTE had
developed stroke before the diagnosis of endocarditis was
lesions in the anterior and posterior circulation; in contrast, all

Singhal et al
Stroke Patterns in Endocarditis
DWI Characteristics*
not correlate with DWI patterns. The size of the valvular
vegetations (recorded in 19 patients with IE and 6 with
IE (n 27)
NBTE (n 9)
NBTE) had no correlation to the size, number, or pattern of
Initial DWI
Because a difference in stroke patterns could provide clues
12 (44)
6 (67)
to distinguish between IE and NBTE in patients suspected to
11 (41)
2 (22)
have endocarditis, we separately analyzed the 6 patients with
1 (4)
1 (11)
NBTE and 9 with IE who developed stroke before they were
diagnosed with endocarditis. Again, all with NBTE had
Exclude silent lesions
3 (11)
0 (0)
pattern 4, whereas those with IE displayed a panoply of lesion
Lesion number/pattern
No lesion
2 (7)
0 (0)
Single lesion (pattern 1)
6 (22)
0 (0)
Follow-Up DWI Findings
Multiple lesions
Among patients with NBTE, 1 underwent a second DWI for
Pattern 2
2 (7)
0 (0)
evaluation of new hemiplegia after 6 days. The DWI showed
Pattern 3
8 (30)
0 (0)
new lesions (one large, multiple small) throughout the brain,
suggesting ongoing emboli (Table 2). Three patients with
Pattern 4
9 (33)
9 (100)†
NBTE had no new neurological symptoms but underwent 5
Follow-up DWI
follow-up scans to rule out additional, clinically silent strokes
within 1 month after the initial DWI. One of these scans
Evaluate new symptoms
4 (15)
1 (11)
showed a new stroke—a small cortical hyperintensity (Table
Exclude silent lesions
9 (33)
3 (33)
2). Because all patients with NBTE had pattern 4 at onset,
Scans with new lesions
these new lesions did not result in a change in the classifica-
3 (11)
1 (11)
tion of their stroke pattern.
2 (7)
1 (11)
In the IE group, 4 patients underwent repeat DWI for
evaluation of new neurological symptoms within 1 month
IE indicates infective endocarditis; NBTE, nonbacterial thrombotic endocar-
ditis; DWI, diffusion-weighted MRI.
after the initial DWI (Table 2). Three of these patients had
*Numbers in parentheses indicate percentages.
additional small lesions, resulting in a change in stroke
†P 0.017.
pattern in 2 (normal DWI changed to pattern 3, pattern 1
changed to pattern 2). Nine patients without new neurological
lesions were distributed exclusively in the anterior circulation
symptoms underwent 19 follow-up scans, of which 14 were
in the 14 episodes of IE associated with lesions on DWI
completed within 1 month after the initial DWI. Only 2
(P 0.054). The MCA territory was involved in all patients,
patients (DWI performed 3 days and 7 days after the initial
alone or in conjunction with other territories, except the 1
DWI) showed new lesions, which were small and did not
patient with IE who had a single large PCA stroke. Cerebellar
result in a change in the classification of the stroke pattern
lesions were frequent, being present in 67% of patients with
(Figure 3).
NBTE and 41% of patients with IE. In contrast, brain stem
lesions were uncommon, being present in only 3 patients who
had multiple additional strokes. Smaller lesions were often
DWI has become a useful imaging technique for the accurate
located in the arterial borderzones.
diagnosis and management of stroke. To our knowledge, ours
Five patients with IE and 2 with NBTE had hemorrhagic
is the first series in the literature to report the results of DWI
infarcts that manifested as punctate hypointensities (“stip-
in patients with NBTE or IE. We found that patients with
pling”) within the hyperintense ischemic lesions. In addition
NBTE uniformly had multiple, disseminated strokes of vary-
to ischemic strokes, 2 patients with IE (including 1 with a
ing sizes, with at least 1 medium or large lesion (pattern 4).
mycotic aneurysm) had intracranial hemorrhages in the MCA
Conversely, patients with IE had a variety of ischemic
territory, which appeared hypointense on DWI.
lesions, including single cortical, territorial, disseminated
We classified the DWI lesions into 4 patterns: (1) single
punctate, and disseminated small and large lesions (patterns 1
lesion, suggesting a solitary embolus; (2) multiple closely
to 4). These results are consistent with patterns of
spaced lesions in a single arterial territory—“territorial in-
endocarditis-associated stroke observed in previous studies.
farction”; (3) multiple punctate disseminated lesions; and (4)
A review of the literature shows that NBTE-associated
multiple small and medium or large disseminated lesions.
strokes are usually multiple, and the lesion size is heteroge-
Patterns 3 and 4 suggested multiple emboli occurring within
neous. Biller et al27 found that 31 of 33 patients with NBTE
a short time frame or fragmentation of a single embolus
had multiple small and large strokes on postmortem exami-
within the heart or aorta. All NBTE scans exhibited pattern 4
nation. Two recently reported patients with NBTE had
(Figure 2), which was present in 9 of 27 scans with IE
multiple strokes on brain MRI, compatible with pattern 4 in
(P 0.012). Patterns 1 (6 scans), 2 (2 scans), and 3 (8 scans)
this study.7,8 Two previous studies, using conventional MRI,
were observed only in IE patients (see Table 2). Six of 8
showed that IE-associated stroke can have a variety of
patients (75%) with pattern 3 exhibited “embolic encepha-
patterns, from single lesions to multiple small and large
lopathy” (P 0.013); however, other stroke syndromes did
lesions in multiple vascular territories.5,6 Our DWI study

May 2002
Figure 1. Schematic representation of stroke patterns on initial diffusion-weighted MRI (DWI) in patients with infective endocarditis.
Age, sex, and stroke syndromes are shown for each patient. TACS indicates total anterior circulation syndrome; PACS, partial anterior
circulation syndrome; LACS, lacunar syndrome; POCS, posterior circulation syndrome.

Singhal et al
Stroke Patterns in Endocarditis
of a T2 “shine-through” effect. Because of the retrospective
study design, we cannot definitively evaluate the incidence of
recurrent strokes. However, analysis of follow-up scans
suggests that recurrent strokes are not uncommon, can occur
days or weeks after initiation of treatment, and can be
clinically silent. Importantly, the only large recurrent stroke
occurred in a patient with NBTE. Among patients with IE,
recurrent strokes were small, few in number, and did not
result in a major change in the classification of stroke
In our series, all patients with NBTE had adenocarcinomas.
NBTE is associated with numerous other conditions,3 and it is
conceivable that these nonmalignant conditions do not cause
pattern 4 strokes. The large size and number of strokes in IE
and especially NBTE may be related to associated conditions
like sepsis, disseminated intravascular coagulation, hyperco-
agulable states and antiphospholipid antibodies.29,30 Although
we did not specifically measure lesion load, it seemed to be
higher in NBTE than in IE (compare Figures 1 and 2).
Because the timing of initial DWI was comparable, it is
unlikely that the higher lesion load in NBTE was an artifact
of later imaging. Differences in disease duration, vegetation
composition, and friability may account for the differences in
lesion load between NBTE and IE. Vegetations in NBTE may
fragment more easily and cause more widespread strokes
because they lack inflammatory reaction and have little
cellular organization.3 Previous studies have debated whether
larger vegetations are associated with a higher incidence of
embolic complications.4,31–35 Our study was not designed to
examine this relationship; however, it is important to note that
vegetation size did not have an effect on stroke number, size,
Figure 2. Schematic representation of stroke patterns on initial
or pattern.
DWI in patients with nonbacterial thrombotic endocarditis. Age,
Embolism is the most common mechanism of endocarditis-
sex, and stroke syndromes are shown for each patient. Abbrevi-
associated stroke, and nearly all our patients were docu-
ations as in Figure 1.
mented to have valvular vegetations. Thus, the topography of
ischemic lesions in our study probably reflects the general
extends previous observations; in addition, it adds knowledge
pattern of embolic stroke. Our results support several long-
about the topography of endocarditis-associated acute
standing concepts of cerebral embolism.28,36 Most patients
strokes, which cannot be easily distinguished from chronic
had multiple bihemispheric lesions, confirming that cardiac
strokes on other imaging techniques.
emboli are usually disseminated. The MCA territory was
In previously undiagnosed patients who present with
involved in all patients. Although most patients had wide-
stroke, and who prove to have cardiac vegetations, it is often
spread lesions, only 3 had brain stem lesions, and no patient
challenging to differentiate between IE and NBTE. Diagnos-
had multiple brain stem lesions. Importantly, no patient had
tic clues such as fever or Roth’s spots (which suggest IE) and
isolated brain stem strokes, suggesting that strokes restricted
metastatic tumors (which suggest marantic endocarditis) may
to the brain stem rarely result from cardioembolic disease.
be absent, and blood cultures may remain negative. Our
Although our patients presented with a single clinical event,
results suggest that DWI can provide additional diagnostic
most had several “clinically silent” lesions as has been
clues: patients with stroke pattern 1, 2, or 3 may be more
observed in previous studies of multiple acute strokes.16,18,21
likely to have IE, whereas patients with pattern 4 strokes can
Multiple acute strokes can occur in several conditions, and
have either IE or NBTE. The diagnosis of NBTE is most
several studies have attempted to correlate DWI patterns of
often made postmortem; however, DWI may have utility in
multiple infarctions with underlying causes and mecha-
making antemortem diagnosis because the presence of pattern
nisms.16,18 Patients with carotid stenosis can have multiple,
4 strokes on DWI should suggest a work-up for NBTE,
small and large, artery-to-artery emboli; however, strokes are
particularly if blood cultures are negative. Although our
distributed in the ipsilateral hemisphere,22 giving a pattern 2
patients had acute ischemic lesions, they may or may not have
appearance, quite unlike the widespread distribution of pat-
been simultaneous.28 However, it is likely that they occurred
tern 4 stroke described in this study. Patients with atrial
within a few days before or after the clinically relevant lesion.
myxoma and cerebral vasculitis commonly have multiple
We did not analyze apparent diffusion coefficient images,
strokes in more than 1 arterial circulation; however, in these
thus we cannot rule out that some of the lesions were a result
conditions, strokes are rarely as numerous or as large in size.

May 2002
Figure 3. A, Initial DWI in a patient with infective endocarditis shows disseminated punctate ischemic lesions (pattern 3). Note the inci-
dental ventricular hyperintensity (arrow), suggestive of ventriculitis. B, Follow-up DWI after 1 week shows additional punctate lesions
but no change in the stroke pattern. C, Initial DWI in a patient with nonbacterial thrombotic endocarditis shows multiple small and large
lesions (pattern 4).
Moreover, vasculitic strokes are usually located in deep rather
3. Lopez JA, Ross RS, Fishbein MC, Siegel RJ. Nonbacterial thrombotic
than cortical or borderzone arterial territories. Thus, the major
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