Acta Neurol Scand 2009: 119: 1–16 DOI: 10.1111/j.1600-0404.2008.01059.
x Copyright  2008 The Authors
Review Article
Stroke and cancer: a review
Grisold W, Oberndorfer S, Struhal W. Stroke and cancer: a review.
Acta Neurol Scand 2009: 119: 1–16.
 2008 The Authors Journal compilation  2008 Blackwell Munksgaard.
Stroke is a disabling disease and can add to the burden of patients
already suffering from cancer. Several major mechanisms of stroke
exist in cancer patients, which can be directly tumour related, because
of coagulation disorders, infections, and therapy related. Stroke can
also occur as the first sign of cancer, or lead to its detection. The
classical literature suggests that stroke occurs more frequently in
cancer patients than in the average population. More recent studies
report a very similar incidence between cancer and non-cancer patients.
However, there are several cancer-specific types and causes of stroke in
cancer patients, which need to be considered in each patient. This
review classifies stroke into ischaemic, haemorrhagic, cerebral venous
thrombosis and other rarer types of cerebrovascular disease. Its aim is
to identify the types of stroke most frequently associated with cancer,
and give a practical view on the most common and most specific types
of stroke. The diagnosis of the cause of stroke in cancer patients is
crucial for treatment and prevention. Management of different stroke
types will be briefly discussed.
Introduction
Cancer is a global expression for describing malig-
nant disease, which usually is classified by histo-
logical and biological criteria. For this review, a
distinction between Ôsolid tumoursÕ and Ôhaemato-
logical malignanciesÕ (leukaemia and lymphoma)
was made. The impression is that solid tumours
and haematological malignancies have different
causes leading to stroke.
Clinicians often consider focal deficits in cancer
patients to be a sign of cerebral metastasis,
associated with poor prognosis. In accordance
with the natural history of the cancer type, the
likelihood of the cause of the brain lesion can be
assumed. For example, lung cancer has a high
probability for cerebral metastasis vs prostate
cancer where this is extremely rare. Moreover,
patients with lung cancer develop brain metastases
in the early course of the disease, while this occurs
late in breast cancer patients. However, clear
discernment demands imaging, such as computed
tomography (CT) and magnetic resonance imaging
(MRI), or even brain biopsy.
Cerebrovascular disorders are the most frequent
neurological diseases and neoplastic disease
Journal compilation  2008 Blackwell Munksgaard
ACTA NEUROLOGICA
SCANDINAVICA
W. Grisold, S. Oberndorfer,
W. Struhal
LBI NeuroOncology, KFJ Hospital, Vienna, Austria
Key words: stroke; cancer; haemorrhage; ischaemic
cerebrovascular disease; cerebral venous thrombosis
Stefan Oberndorfer, LBI NeuroOncology, KFJ Hospital,
Vienna, Austria
Tel.: +00431601912008
Fax: +00431601912009
e-mail: oberndorfer.stefan@chello.at or
stefan.oberndorfer@wienkav.at
Accepted for publication April 21, 2008
(cancer and haematological malignancies) is the
second most frequent cause of death in the
industrial world. From the neurologistÕs point of
view, however, stroke is a less frequent neurolog-
ical complication in cancer patients, compared to
metastases or neurotoxicity from anticancer treat-
ment (1). The aim of this review was to evaluate the
types of stroke occurring in cancer patients, and its
different mechanisms (Fig. 1).
The association between cancer and stroke can
be approached from two standpoints:
1 Is cerebrovascular disease increased in the cancer
population in general?
2 Are there any specific causes or subtypes of
cerebrovascular disease related to the biology of
cancer, or cancer treatment?
There are several ÔkeyÕ papers on this issue: the
older literature, which is based on autopsy results
from large series of oncological patients, quoted
stroke as a common neurological complication in
cancer patients (2–4). Graus et al. found in 15% of
cancer patients pathological evidence of cerebro-
vascular disease, and about half of them had
clinical symptoms of stroke (2). This was a
1
Grisold et al.
retrospective autopsy study of a large cohort of
cancer patients. They found that classical risk
factors were not as important as factors attributed
to the cancer, such as direct tumour effects,
coagulation disorders, infection, therapeutic and
diagnostic procedures. In haematological malig-
nancies, cerebral haemorrhages were seen more
often (in leukaemia 72% of strokes, and in
lymphoma 36% of strokes) with different causes,
such as septic thrombi and intravascular coagula-
tion. Rogers stated that cerebrovascular disorders
are common in patients with cancer and found
similar results concerning ischaemic and haemor-
rhagic strokes, as well as regarding causes of stroke
in solid and haematological malignancies (5). In a
large cohort of stroke patients Lindvig et al. (4)
found increased risk for cancer, which is also
summarized by Posner (3). However, in another
retrospective single-centre clinical study by Cha-
turvedi et al., only 3.5% of their cancer population
experienced strokes, and arteriosclerosis and coag-
ulation disorders were the most relevant patho-
physiology (6). In this study, the risk of recurrent
ischaemic events was also similar to that of the
non-cancer population.
Recent articles compare cancer patients with a
non-cancer population by means of image-based
classifications and common risk factors for stroke
(7–11). Concerning the studies, they all suffer from
referral bias, which is less marked in general
hospitals than in cancer centres. Two larger clinical
retrospective studies by Cestari et al. (7) (non-
haemorrhagic strokes) and by Zhang et al. (11)
(haemorrhagic and non-haemorrhagic strokes)
found no significant differences with respect to
Figure 1. Vascular problems in cancer patients: (A) Metastatic subdural haematoma. (B) Haemorrhage into a metastasis. (C)
Intravascular lymphoma. (D) Sinus venous thrombosis. (E) Embolic (territorial infarct). (F) Intraparenchymal micro bleeds:
coagulation disorder, DIC. (G) Intraparenchymatose patchy haemorrhage in leukaemia, diffuse and irregular borders towards brain
parenchyma. (H) Neoplastic ⁄ oncotic ⁄ mycotic aneurysm (tumour embolus, infection). (I) Pituitary apoplexy. Art by: J. Schulz and
W. Grisold.
2
vascular risk profile for cancer patients compared
with a large series of stroke patients. In the study
by Zhang et al., there was an increased risk for
haemorrhagic strokes in the cancer population,
which was attributed to several factors, such as
chemotherapy-induced thrombocytopenia, dissem-
inated intravascular coagulopathy, and the fact
that haematological malignancies do have a higher
risk for intracranial haemorrhages compared with
the non-cancer population. Moreover, these clini-
cal studies conclude that the prognosis may be
worse in patients with cancer and stroke, due to
reduced general health, a point which presently
lacks evidence. Despite the trend towards similar
incidence and risk for both groups, several cancer-
specific aspects need to be considered. These are
tumour-related effects, coagulation disorders,
infection, therapy-related effects and paraneoplas-
tic causes. Paraneoplastic causes deserve a defini-
tion, as in recent years Ôparaneoplastic diseaseÕ has
been linked to autoimmune causes. Whereas in the
context of stroke, rather a cancer-dependent, non-
neoplastic relation is meant. In the types ÔclassicalÕ
paraneoplastic syndromes, stroke is not included
(12).
We classify the conditions as ischaemic, haem-
orrhagic, cerebral venous thrombosis (CVT) and
miscellaneous types of cerebrovascular disorders.
Within this classification, we distinguish several
specific conditions, listed below, which are impor-
tant not so much in terms of frequency as in their
specific cause and effect relationship with cancer
such as (i) tumour-related, (ii) coagulation, (iii)
infections, (iv) therapy-related and (v) paraneo-
plastic.
 Stroke and cancer

Table 1 Occurrence of frequent and rare stroke conditions in cancer patients Table 2 Patient characteristics in cancer (n = 69) vs non-cancer stroke patients
(n = 69)
Stroke and cancer Most frequent Specific causes
Cancer Non-cancer P
Ischaemic stroke Ischaemic and embolic stroke: Tumour related
incidence and risk factors Coagulation disorders Age (mean) 77 77
similar to that in the Infection Male ⁄ female 47 ⁄ 22 47 ⁄ 22
non-cancer population Therapy related Ischaemic stroke 56 (81) 64 (93) 0.057
Paraneoplastic Haemorrhagic stroke 13 (19) 5 (7) 0.057
Haemorrhagic stroke Haemorrhage into metastasis Venous occlusion
Vascular risk factor
or primary brain tumour. Subdural haematomas
Hypertension 49 (71) 48 (70) NS
Haemorrhage due to Coagulation disorders
Ex and current smoking 35 (51) 28 (41) NS
coagulation disorder in Therapy related
Ischaemic heart disease 33 (48) 33 (48) NS
leukaemias
Hypercholesterinaemia 26 (38) 35 (51) NS
Cerebral venous Sinus venous thrombosis Infection
Atrial fibrillation 19 (28) 27 (39) NS
thrombosis (compression or coagulation Treatment related
Diabetes mellitus 11 (16) 17 (25) NS
disorder) Paraneoplastic
Alcohol abuse 6 (9) 3 (4) NS
Other conditions Pituitary apoplexy
Family history of stroke 0 3 (4) NS
Mycotic aneurysm
Vasculitis Previous thrombotic episode
Stroke 20 (29) 19 (28) NS
Myocardial infarction 19 (28) 10 (15) NS
Table 1 provides an overview concerning the Deep vein thrombosis 8 (12) 1 (1) 0.039
occurrence of frequent and rare stroke conditions in Pulmonary embolism 6 (9) 2 (3) NS
cancer patients. This heterogeneity, and also the Treatment for cancer
sparsity of some of the described entities, makes Chemotherapy 11 (16) NA NA
recommendations for specific diagnostic and ther- Head or neck dissection 3 (4) NA NA
Radiotherapy to head or neck 4 (6) NA NA
apeutic guidelines difficult. However, short man- Hormone therapy 9 (13) NA NA
agement suggestions are provided representing the
most common approaches. Values are expressed as n (%) unless otherwise stated. NA, not applicable. NS,
statistically not significant.
Adapted with permission from Zhang et al. (11).
Ischaemic cerebrovascular disease
Cerebrovascular ischaemic infarcts in cancer
Tumour related
patients occur in a fairly large number (15%)
based on an autopsy study (2). The clinical Direct tumour effect – Tumour embolism can be
significance of these findings is not clear, as the considered as a direct effect of cancer causing
range includes silent infarcts, diffuse vascular stroke. Myxoma or other heart tumours (14–17) as
encephalopathies and vascular events with focal well as lung tumours can be the source of embolism
deficits. Evaluations based on stroke criteria (Trial into the brain (18–20). The occlusion of a cerebral
of ORG10172 in Acute Stroke Treatment vessel can either cause an ischaemic stroke or give
ÔTOASTÕ) (13), and common risk factors [hyper- rise to arterial neoplastic aneurysms (21, 22).
tension, diabetes mellitus, hyperlipidaemia, cardiac In leptomeningeal metastases strokes can result
disease (e.g. cardiac fibrillation), smoking, and from infiltration of vessel walls (23). Parasellar
large vessel disease], suggest a similar profile tumours can cause stroke by direct vessel com-
between cancer and non-cancer-related strokes pression (24). Extracranial tumours compress or
(6, 7, 10, 11) (Table 2). invade a large artery causing cerebral infarction
The issue of embolic stroke vs non-embolic (Fig. 2), however strokes in this context are rarely
ischaemic stroke resulting from atherosclerotic reported (3, 25).
changes is a subject of discussion. Cestari et al. In clinical practice, direct tumour-related stroke
(7) identified 54% embolic and 46% non-embolic is rare and also difficult to identify. Neoplastic
strokes. The relatively high proportion of embolic aneurysms seem to occur more frequently in
strokes was probably due to the retrospective choriocarcinoma (26).
character of the investigation, as well as a not
uniform diagnostic assessment regarding stroke Intravascular lymphoma – Intravascular large B-cell
aetiology. In the study of Zhang et al., embolic (or less commonly T-cell) lymphoma or malignant
strokes were found in 27% and non-embolic (large angioendotheliosis bears several synonyma: Tap-
and small vessel disease) in 41%, with no signif- peinerÕs disease, intravascular lymphomatosis, and
icant differences when compared with the non- angiotropic large-cell lymphoma and ⁄ or neoplastic
cancer population (11). angioendotheliosis. It is a rare type of intravascular

3
Grisold et al.

A B

Figure 2. Neck metastasis adherent to the internal carotid artery usually indicates advanced tumour disease. Arrows indicate the
tumour mass surrounding the carotid artery. The asterisk (*) indicates the carotid artery lumen. Surgical treatment is risky;
radiotherapy bears the risk of additional therapy-related damage.

lymphoma, with a predilection for cerebral vessels,

A
although other organ manifestations (in particular
skin) have been reported (27). Patients often
present with diffuse encephalopathy or multifocal
cerebral infarcts. The diagnosis, even with MRI
techniques, is difficult and in most cases is only
revealed at autopsy (28–30) (Fig. 3). Some cases
have been successfully treated with plasmapheresis
(31) and chemotherapy, but this remains excep-
tional, as well as with regard to diagnosis and
successful therapy (32).

Haematological malignancies – Hyperviscous obstruc-

tions of arterial vessels by neoplastic cells can occur
(35). Examples are polycythemia vera (33, 34).
B
Hyperleukocytic syndrome occurs in acute mye-
logenous leukaemia (cell count >100,000 mm3) or
chronic lymphatic leukaemia (cell count
>250,000 mm3) (36, 37), but usually results in
intracranial haemorrhage. In patients with multiple
myeloma, hyperviscosity syndrome due to elevated
protein can cause ischaemic stroke (38, 40). The
ÔNeel Bing syndromeÕ results in diffuse encephal-
opathies (39). In leukaemia, haematologists are
aware of these complications, and reduce the cell
count and blood viscosity in order to avoid
cerebral infarction.
Figure 3. Intravascular lymphoma: (A) Macroscopic appear-
ance of the brain at autopsy resembles microbleeds, vasculitis
Coagulation disorders or encephalitis. (B) Histologically two types of pathology can
be seen: (B1) intravascular lymphoma with tumour cells, (B2)
Cancer is one of the major acquired prothrombotic adjacent intraparenchymatose micro-bleeds.
states associated with increased risk for stroke (41).
Haematological disorders and haemostatic defects
have an increased risk for stroke (34). The impor- syndrome (47–49) seem to be more common in
tance and significance of coagulation disorders for cancer patients with solid tumours. Disseminated
stroke in patients with solid tumours is less clear. intravascular coagulation (DIC) is more frequent
Cerebral venous thrombosis (42, 46), venous in haematological malignancies and metastatic
thromboembolism (43–45) and the rare Trousseau cancer. Although specific markers for DIC are

4

generally lacking, D-dimer is often elevated (7).
Several other changes in coagulation laboratory
parameters have been described, which will be
subsequently discussed. Two main conditions can
be identified: DIC and non-bacterial thrombotic
endocarditis (NBTE), which seem to occur more
often in the cancer population compared with the
non-cancer population.
Disseminated intravascular coagulation – In DIC, the
balance between thrombus formation and throm-
bolysis is disturbed. The activation of coagulation
causes widespread dissemination of microthrombi
with subsequent thrombotic occlusion of small
vessels. At the same time depletion of platelets and
coagulation proteins results in diffuse haemor-
rhage. For these reasons DIC in cancer patients
can be associated with thrombotic stroke, as well
as intracerebral haemorrhage (36, 50–52). The
acute type of DIC occurs more frequently in
myelogenous leukaemia and also in lymphoma.
Thrombosis (e.g. deep venous thrombosis) is asso-
ciated with haemorrhages in the central nervous
system (CNS), which are often fatal. They are
mostly located in the brain parenchyma or the
subdural compartment. The chronic type is
observed in the clinical setting of thrombosis,
rather than in patients with haemorrhages.
Laboratory markers such as prothrombin time
and partial thromboplastin time can be normal or
only slightly altered. Consumption may decrease
fibrinogen levels, as may declining platelet counts
(53, 54).
Non-bacterial thrombotic endocarditis – Non-bacte-
rial thrombotic endocarditis has been assumed to
be one of the most common types of ischaemic
stroke in cancer patients (9). In a large autopsy
series of 171 cases, 59% of patients with NBTE
suffered from malignancy (55). It can be associated
with any type of cancer, but seems to be more
common in adenocarcinoma, particularly pancre-
atic carcinoma (56–58).
In NBTE, sterile vegetations located on the
cardiac valves cause embolization into the arterial
system and brain (Fig. 4). NBTE can occur in
association with DIC. Laboratory parameters are
only slightly abnormal and must be interpreted
cautiously. The diagnosis is made by echocardiog-
raphy, preferably by transoesophageal echography.
Blood cultures are sterile. Imaging studies often
show multiple cerebral infarcts (59), sometimes
with a haemorrhagic component. Although NBTE
has been described in association with stroke in
many reports, the incidence in cancer patients is
unknown.
Stroke and cancer
A
B
Figure 4. Cancer-associated non-bacterial endocarditis (NBTE)
demonstrating the verruca-like valvular deposits.
Other associations – Several laboratory parameters
in cancer patients have been reported to be
associated with stroke. Apart from D-dimer eleva-
tion (60), there are reports of acquired protein S
deficiency (41), protein C deficiency (61), activated
protein C resistance (62), antiphospholipid anti-
bodies (63), catastrophic antiphospholipid syn-
drome (64, 65), hyperfibrinogenaemia (66), CA
125 tumour marker evaluation (60, 67) and
thrombocytosis. The practical relevance of these
ancillary findings is not clear. Thrombocytosis may
be a nonspecific sign in cancer patients, in partic-
ular in patients with osteomyelofibrosis (68).
Thrombotic microangiopathy can occur as a
complication of cancer in breast, lung, gastric
cancer, lymphoma and myeloma after transplan-
tation (69) because of cancer therapy (mitomycin,
5-flouorouracil, carboplatinum and cisplatin) (70–
72) and can also appear after cancer has apparently
been cured (3). It is characterized by thrombotic
microangiopathy, haemolytic anaemia and throm-
bocytopenia. Clinically it presents with encepha-
lopathy and multifocal neurological deficits. It
resembles microangiopathic haemolytic anaemia
and haemolytic uremic syndrome.
The association of primary brain tumours and
ischaemic strokes has been described (73, 74).
Ischaemic lesions have been observed in a postop-
erative study of patients with high-grade gliomas,
5
Grisold et al.
where adjacent ischaemic lesions were assessed by
means of MRI in about 70% of patients (75). The
pathophysiology is unclear.
Infection
In cancer patients with stroke-like presentations of
neurological symptoms, infection of the brain must
be also taken into account as a differential diag-
nosis. Cancer patients and patients with haemato-
logical malignancies are often immunologically
compromised. Further, radiotherapy (RT), treat-
ment with anti-cancer drugs, results in additional
immune suppression. Opportunistic infections such
as the JC 40 virus, which can induce progressive
multifocal leucoencephalopathy (80), can be mis-
taken for a cerebrovascular lesion. Also, opportu-
nistic infections with fungi (aspergillus, candida or
other types) often occur as a result (76). Cerebral
aspergillus infections typically originate from the
lungs, whereas candida infections typically stem
from gastrointestinal or genitourinary tract infec-
tions (77). Reactivation of Varicella-Zoster infec-
tion is common and can be complicated by
encephalitis (78,79).
Sepsis can occur and may be associated with
DIC. Sepsis and bacterial endocarditis can cause
septic cerebral infarction.
Therapy-related
Therapy-related stroke can occur in three para-
digms:
• In association with surgery
• RT-induced vasculopathy
• In association with chemotherapy
In association with surgery the risk for embolic
stroke is generally increased. Surgery may promote
the release of emboli (81–84). In particular in pulmo-
nary interventions, such as bronchoscopic biopsies
and lung surgery, strokes have been described to
occur perioperatively and postoperatively.
Radiotherapy – Post-radiation vasculopathy can
affect intracranial and extracranial vessels. Vascul-
opathy of medium- and large-sized vessels is the
most common complication. The frequency of
internal carotid stenosis following external radia-
tion of the neck ranged from 12% to 60% (85),
although there is some controversy (86). Routine
ultrasound surveillance of carotid arteries follow-
ing neck radiation has been suggested to prevent
stroke (87). Surgical revascularization in a reradi-
ated field has been reported to be safe (88). In
6
children, whole brain RT may result in the
development of Moyamoya disease (89). ÔStroke-
likeÕ migraine attacks after radiation therapy
(SMART), which may last several days, have a
good prognosis (90). Following RT of the neck
pseudo-aneurysms and ruptures of the carotid
artery have also been characterized as the Ôcarotid
blow out syndromeÕ (91).
Chemotherapy – Some chemotherapies are consi-
dered to pose a potential risk for stroke (88, 92).
An extensive analysis of ischaemic stroke after
chemotherapy, in a series of 10,963 patients (93),
concluded that the risk for stroke was predicted by
the use of cisplatin-based chemotherapy and not by
the histological type of cancer. Other studies did
not reach this conclusion (18). Generally, the risk
of chemotherapy-induced stroke seems low (94),
but no systematic, drug-specific conclusion can be
drawn up till now.
Systemic chemotherapy with cyclophosphamide,
5 FU, taxol and paclitaxel has been reported in
several papers to be associated with stroke, but the
literature search is confined to case observations.
The association seems to be higher in cisplatin,
methotrexate (MTX) and in particular l-aspara-
ginase and warrants comment (61, 95, 96).
Cisplatin – Cerebrovascular events have been
observed with cisplatin therapy. A study of patients
with non-small cell lung cancer treated with cisplatin
and gemcitabine (97) came to the conclusion that
chemotherapy is a powerful risk factor for cerebro-
vascular events. At present, however, the patho-
mechanism, the types of stroke potentially caused
by chemotherapy and the therapeutic implications
are not entirely clear. Circulating endothelial-
derived and platelet-derived microparticles occur-
ring during the third or fourth infusion might
contribute to cisplatin-induced stroke (98). From
the clinical point of view, platinum compounds seem
to bear the highest risk for stroke, although the
incidence and quantitative relevance remain open.
MTX – Intrathecal administration might be asso-
ciated with stroke-like events (96) or stroke (99).
Silent lacunes have been described in children after
treatment (including RT) for primary brain
tumours (100). Long-term survivors from the
paediatric group are 40 times more likely to
develop stroke than their sibling controls (101).
l-asparaginase – l-asparaginase is often used in
combination therapies for haematological malig-
nancies (e.g. acute lymphoblastic leukaemia) (102).
Cerebrovascular side effects occur either as cerebral

thrombosis (4.2%) or haemorrhage (2.1%) (103).
Patients receiving l-asparaginase need to be moni-
tored closely and the therapy interrupted, in case the
patient suffers cerebrovascular events (104).
Estramustine phosphate – An increased risk of
venous thrombosis has been suspected in prostate
cancer patients treated with estramustine, but the
related studies were unable to sustain the suspicion.
Moreover, the risk of stroke does not seem to be
increased (105).
Intra-arterial chemotherapy – In primary brain
tumours, nitrosureas, cisplatin and carboplatin,
etoposide and MTX have been used by intra-arte-
rial application (112). Vascular and neurological
toxicity is characterized by stroke and leucoence-
phalopathy.
Miscellaneous
Tamoxifen – Tamoxifen is a hormonal treatment
used in breast cancer (106). The data are contro-
versial as to whether tamoxifen treatment can
increase the risk of stroke (107) or implies a small
risk (108), or whether the only risk factor is
chemotherapy (109) and not the use of tamoxifen.
Colony-stimulating factors (CSF) – Erythropoietin,
granulocyte-CSF and other CSF are considered to
be beneficial in stroke treatment. However, a
Cochrane review reported that it was too early to
know whether functional outcome can be
improved in stroke on the basis of currently
available data (110). However, they do not seem
to imply an increased risk for stroke.
Other drugs, such as all-trans retinoic acid,
corticosteroids, thalidomide and arsenic trioxide,
which are also used in association with cancer, are
reported to have a thrombogenic potential in
general (111). This may be also true for stroke.
The influence on stroke of the new ÔbiologicalÕ
cancer treatments such as antibodies and kinase
inhibitors has not been studied systematically up
till now.
Thrombocytopenia can have several causes, such
as haematological disease and bone marrow infil-
tration in solid tumours. It can be therapy related
and be the result of extensive radiation (e.g. RT of
the neuraxis), chemotherapy or polychemotherapy
(3, 8, 66).
Paraneoplastic
The relevant question for the clinician is whether
a first-ever stroke in a tumour naive patient can
Stroke and cancer
be an indicator of cancer, and thus be a
ÔparaneoplasticÕ cause. Generally, this does not
seem to be the case, and stroke has not been
included among the ÔclassicalÕ immune-mediated
paraneoplastic syndromes (12). The literature
discloses a number of case reports (113), which
describe an ill-defined hypercoagulable state.
Although laboratory tests are lacking, increased
risk for venous thrombosis, increased DVD and
the TrousseauÕs syndrome seem to indicate this
(48, 49).
Management
Stroke in cancer patients is a problem, with
different aetiologies. Several Ôstroke mimicsÕ have
been described such as a primary brain tumour
(114) (Fig. 5).
Routine examinations in stroke patients include
blood and heart investigations, ultrasound of the
extracranial arteries and imaging methods, such
as CT and ⁄ or MRI of the brain. Compared to
CT, MRI techniques are superior in distinguish-
ing vascular from possible neoplastic processes.
The typical pattern of an ischaemic lesion
according to the vascular territory, which can
be easily detected with both MRI and CT, points
towards a vascular aetiology. Diffusion weighted
imaging including apparent diffusion coefficient
has a high specificity with respect to acute
vascular lesions. Moreover contrast enhancement
as well as brain oedema is generally absent.
However, in the subacute phase it becomes
increasingly difficult to distinguish ischemia from
possible neoplastic processes by means of imag-
ing. For the future, MR-spectroscopy might
become a powerful tool in the discrimination of
different brain pathologies, including neoplastic
and vascular lesions.
Stroke from direct tumour involvement such as
tumour emboli or neoplastic aneurysms is extre-
mely rare, so is the intravascular lymphoma.
Management depends on the individual case.
Although several types of coagulopathies have
been described, except D-dimer, no practical
recommendations for the laboratory inves-
tigation of possible cancer related coagulopathies
causing stroke can be given. DIC and
NBTE have been reported to appear cancer
related, but can also occur in other conditions.
Treatment approaches are based on anticoagula-
tion, but no established treatment is available. It
is especially controversial in patients with acute
DIC. In patients with NBTE, also valvular
surgery may be considered in some individual
cases (115).
7
Grisold et al.

A B

Figure 5. Stroke mimick: A 50-year-old previously healthy woman presented with focal seizures of her leg. (A) MRI T1-weighted
image including contrast media shows mild uncharacteristic enhancement. (B) MRI T2-weighted image resembled an anterior
cerebral artery lesion. Diffusion-weighted imaging was not carried out in the initial studies, which delayed diagnosis. Biopsy
confirmed an astrocytoma. (A), with infarction of the vermis of the cerebellum (B). Autopsy revealed multiple systemic metastasis of
an adenocarcinoma, the primary tumour could not be detected.

Intracranial haemorrhage Haemorrhages and venous occlusion – Cerebral

venous occlusion presents as sinus thrombosis,
Intracranial haemorrhages appear more often in
thrombosis of inner cerebral veins or superficial
leukaemia, but may also occur in lymphoma and
venous thrombosis (42). Localized parenchymal
multiple myeloma. In solid tumours, haemor-
lesions occur in about half of the patients, and are
rhage into a metastasis occurs and can also be
characterized by oedema, infarction with or with-
misdiagnosed for a primary intracerebral haem-
out haemorrhage. Other features suggesting
orrhage, if the cancer is unknown. Cancer-related
venous thrombosis are distribution and the fre-
intracranial haemorrhages can be characterized
quent haemorrhagic transformations. The causes
by types of intracranial haemorrhage, and aeti-
will be discussed under CVT.
ological subclassification of cerebral haemor-
rhage.
Haemorrhage into primary brain tumour or metasta-
sis – Primary brain tumours, in particular astrocy-
Types of intracranial haemorrhage tomas grade WHO 3 and 4, sometimes present with
haemorrhage into the brain, or haemorrhages
Intracranial haemorrhages can be observed in a
appear later in the course of the tumour. As the
number of circumstances in cancer patients
intratumoural haemorrhage can be the presenting
(Fig. 6). They can be caused by intraparenchymal
sign, it may obscure the diagnosis of a brain
bleeding (e.g. hyperleucocytosis, coagulation dis-
tumour (117). Meningioma may also cause severe
orders), secondary to venous occlusion, haemor-
intracerebral haemorrhage (118).
rhage into a primary brain tumour or a metastasis,
Cancer metastases with haemorrhage can be
by a ruptured neoplastic aneurysm or manifest in a
mistaken for a primary intracerebral haemorrhage
subdural haematoma.
(114, 119–121). Potentially, brain metastases from
Intraparenchymatous haemorrhages appear to
any cancer can cause haemorrhage. Lung cancer,
present more often in haematological malignan-
melanoma and germ cell tumours are most fre-
cies, particularly acute myelogenous leukaemia,
quently quoted for their tendency to haemorrhage
and in particular in acute promyelocytic leukaemia
(2, 120, 122).
(2) and in other conditions with deficient coagula-
The differential diagnosis of cerebral haemor-
tion (22). Intracerebral haemorrhage can develop
rhage from metastasis can be difficult. Indicators
in lymphoma and multiple myeloma due to
are an atypical location, a non-haemorrhagic tissue
thrombocytopenia, hyperviscosity and several
within the haemorrhage, and an uneven distribu-
other causes (3, 116). In solid tumours thrombo-
tion of density within the haemorrhage. Oedema at
cytopenia due to various factors (toxic or bone
the presentation of the haemorrhage can be an
marrow infiltration) is often the cause, although
indicator of preexistent cerebral metastasis.
this is rarer than in leukaemia (3).

8

A agulant therapy and coagulopathies resulting from
B rysm formation and subsequent rupture, resulting
C primary fibrinolysis (66), hyperleucocytic syn-
Figure 6. Several types of intraparenchymatose haemorrhage
in leukaemia: (A) large intracranial haemorrhage into the
cerebellum in a fairly classic shape. (B) Large, terminal
polygonal haemorrhage into the brainstem. Diffuse and irreg-
ular haemorrhagic invasion of adjacent brain parenchyma. (C)
Diffuse and spot-like haemorrhages resulting from coagulop-
athy in leukaemia.
Additional sites of enhancement can indicate
multiple metastases and give a clue to cancer as
the cause of the haemorrhage.
Subdural haematomas – Leukaemia, lymphoma and
cancer (e.g. prostate and breast cancer) can
metastasize into the subdural space and cause
local bleeding. MRI scan usually shows the
haematoma and thickened dura, suggesting metas-
tasis (Fig. 7).
Subdural haematomas are more likely to occur
due to coagulopathies (123). Trauma, and antico-
Stroke and cancer
either cancer (bone marrow infiltration) or cancer
treatment (thrombocytopenia) need to be consid-
ered. In addition, subdural haematoma has been
reported in acute myeloic leukaemia, and in some
cases following lumbar puncture (124).
Aetiological subclassification of intracranial
haemorrhages
Direct tumour involvement
Neoplastic infiltration of arteries can cause aneu-
in subarachnoid or intraparenchymatous haemor-
rhage. Aneurysms are located in distal arterial
branches. Tumour emboli can invade the vessel
walls. The invasion of vessels by adjacent brain
metastasis is rare. Cardiac myxomas, choriocarci-
noma and lung cancer are malignancies that have
been described (21, 26).
Coagulation disorder
Several coagulation disorders such as DIC,
drome (125), thrombocytopenia (116), vitamin K
deficiency (due to poor diet or antibiotic treatment
with iatrogenic sterilization of the gut) and protein
synthesis deficiency due to liver damage, can cause
haemorrhages (116).
Thrombocytopenia is most frequently caused
either by deficient bone marrow due to tumour
infiltration or treatment toxicity, in tumour-asso-
ciated hypersplenism, immune-mediated platelet
destruction (52), and thrombotic thrombocytope-
nic purpura. In DIC, hypercoagulability and
haemorrhagic diatheses with bleeding can coexist.
Infection and haemorrhage
Infections by micro-organisms, such as by fungi
(e.g. aspergillus, candida) can cause vasculitis or
mycotic aneurysms, which can be the source of
intracranial haemorrhage (126).
Therapy-related haemorrhage
Intraparenchymatose and extraparenchymatose
cerebral haemorrhage can be caused by neurosur-
gical and ear nose and throat procedures affecting
the adjacent cerebral vessels.
Cerebral haemorrhage is rarely caused by RT,
e.g. gamma knife (127). The haemorrhage can be
on the site of the radiation necrosis (128). Indi-
rectly systemic RT can result in thrombocytopenia,
9
Grisold et al.

A B

C D E

Figure 7. Dural metastasis in prostate cancer causing subdural haematoma (A, B). Nodular lumps (*) are suspicious for cancer
involvement. CSF analysis showed elevated protein, but no tumour cells. Before radiotherapy a dural biopsy confirmed the dural
metastasis. (C) Dural biopsy with HE staining. (D) PSA staining. (E) Racemase staining.

which may underlie delayed intracerebral haemor-
rhage (129).
Management
Despite modern imaging techniques, the distinction
from a primary cerebral haemorrhage or a metas-
tasis with secondary haemorrhage can be difficult,
and may require several imaging studies within the
course of the disease. Even contrast media applied
with both CT and MRI techniques can be mislead-
ing. Oedema surrounding the haemorrhage, which
is already present in the acute diagnostic setting, is
suspicious for an underlying neoplasm. Also,
multiple haemorrhages into brain parenchyma, or
atypical location of the haemorrhage, especially in
patients with known cancer, such as melanoma and
lung cancer, are highly suspect for metastasis.
Intracerebral haemorrhage is a severe event in
cancer patients that warrants acute attention.
Further treatment decision is based on the strategic
site of the lesion, the general oncological condition
of the patient, and must also include a neurosur-
gical consideration.
Cerebral venous thrombosis
Cerebral venous thrombosis, either of superficial
cerebral veins, inner cerebral veins or sinus veins,
can occur in association with cancer. It is specu-
lated that CVT could be more frequent in cancer
patients, in particular in patients with haemato-
logical malignancies. Due to its diffuse and possi-
bly misleading clinical symptoms, CVT might be
overlooked.
In one report, cancer and tumours accounted for
7.4% of all CVT. Of these, 2.2% were associated
with CNS malignancy, 3.2% with solid tumours
outside the CNS and 2.9% with haematological
disorders (42).

10

Direct tumour effect
The cerebral sinus can be mechanically affected
by compression or invasion of the cerebral
sinuses from dural ⁄ calvarial metastasis (130)
or lymphoma (131). Local metastasis compress-
ing the sinus can cause a pseudo tumour
cerebri-like syndrome (132). Venous occlusions
have also been reported in haematological disease
(133).
Coagulation disorder
Coagulation abnormalities, usually termed the
hypercoagulable state, are hypothesized to be the
cause (7, 94).
Infection
Local infections and septicaemia can cause CVT. A
specific association of infection in patients with
cancer (or haematological malignancies) and CVT
could not be described.
Therapy-related
l-asparaginase treatment has been described to
cause SVT (130, 131). Other therapies have also
been suspected, such as tamoxifen (134), thalido-
mide (135), intrathecal MTX (136) and medroxy-
progesterone acetate (137).
Paraneoplastic
The occurrence of paraneoplastic SVT has been
discussed in several case reports (138). It is mostly
related to observational reports.
Management
Cerebral venous thrombosis is a rare event. In a
cancer-naive patient, CVT does not necessarily
pinpoint to an occult malignancy. Imaging,
such as CT scans, MRI angiography, performed
with and without contrast media, or conventional
angiography can demonstrate impaired
venous flow (e.g. empty delta sign) or flow
obstruction. The pattern and distribution of
cerebral involvement, often with secondary
haemorrhages, is characteristic of the diagnosis
(139).
The treatment strategies are similar to other
causes of CVT (42). If a local tumour obstructing
the sinus can be identified, local therapy – either
surgical or by radiation or chemotherapy – may be
an option.
Stroke and cancer
Summary and future aspects
This review is based on several ÔstandardÕ and key
papers which have been published over the past
decades. The practical analysis of the present
knowledge has several aspects.
Quantity of stroke and cancer
Recent studies (7, 11) found no striking difference
between stroke incidence and Ôrisk factorsÕ in
cancer and non-cancer patients. However, Zhang
et al. came to the conclusion that cancer patients
with stroke have a more dismal prognosis, prob-
ably due to their general state and the concurrence
of two severe diseases (10, 11).
Specificity of stroke and cancer
Contrary to this practical general view, we found a
number of cancer-specific associations in ischaemic
and hemorrhagic stroke, CVT and some other rare
cerebrovascular events. These causes can be grouped
into cancer-related, coagulopathies, infections and
therapy-related causes. Most of these observations
are based on case reports, which bear little evidence
and do not permit general statements. However, the
biological activities of the cancer, such as associated
coagulopathy, increased viscosity, tendency to
haemorrhage, site of metastasis, permit improve-
ment of the diagnosis and treatment in cancer
patients with cerebrovascular disease.
Additional therapeutic aspects
Stroke is a disabling disease, in non-cancer as well
as in cancer patients. Large studies on recombinant
tissue plasminogen activator (rTPA) have excluded
patients with malignancy for the acute treatment of
stroke. This criterion should be reconsidered in
future studies, identifying tumour entities where
rTPA lysis could be applied safely.
Neurorehabilitation is an increasingly powerful
tool for improving the fate of stroke patients. Until
recently, many patients with malignancy were not
admitted to rehabilitation units. Improved man-
agement and care of both stroke and cancer have
improved the chances of patients affected with
both diseases, and it is hoped that the fate of
patients with both diseases will also be positively
influenced.
Future directions of research
The evidence from the literature has two major
obstacles: (i) the older studies are based almost
11
Grisold et al.
entirely on neuropathological findings, whereas (ii)
newer studies are based on clinical data, analysis of
risk factors, and imaging findings, but yet contain
too few patients to provide absolute statements.
Two goals for future research should be: (i)
identification of risk factors in cancer related
stroke patients compared to stroke patients with-
out cancer, (ii) the identification of cancer types
which have a specific propensity to cause stroke.
The latter would be helpful in stroke prevention.
Although coagulopathies, in particular the
hypercoagulable state, have been considered to be
increased in cancer patients, presently no practical
and universally applicable coagulation test identi-
fying stroke or haemorrhage inclination in cancer
patients is available. The detection of a laboratory
ÔmarkerÕ for cancer patients with increased risk for
stroke would be helpful.
Imaging has become the main tool for the
diagnosis of stroke. An improvement of ultra-
sound, CT, MRI and nuclear medicine techniques
in identifying cancer related strokes will be neces-
sary. Examples are a possible early distinction
between primary intracerebral haemorrhages and
haemorrhages from cerebral metastases.
One of the main future needs will be directed to
the identification of potentially neurotoxic effects
of therapy, resulting in a cerebrovascular disease.
Several chemotherapeutic drugs have neurotoxic
vascular effects, which may cause stroke and need
to be prevented.
Search strategies and selection criteria
In our search we differentiated between ÔcancerÕ,
lymphoma and leukaemia. The search strategy was
designed accordingly. References for this review
were identified by searches in PubMed from 1975
until March 2007, with terms Ôcancer and strokeÕ,
Ôcerebral ischaemia and cancerÕ, Ôleukaemia and
strokeÕ, Ôlymphoma and strokeÕ, Ôintracerebral haem-
orrhageÕ for Ôcancer, lymphoma, and leukaemiaÕ,
and Ôsubarachnoidal haemorrhageÕ, for Ôcancer lym-
phoma and leukaemiaÕ, as well as Ôcerebral venous
thrombosisÕ for Ôcancer, leukaemia and lymphomaÕ.
Articles were also identified through searches of
authorsÕ own files. From approximately 500
selected references the authors selected 142 relevant
papers, which appear in the reference list. Gener-
ally the references were published in English,
except five articles, which were published in differ-
ent languages but PubMed abstracts are available.
Conflict of interest statement
All authors have nothing to declare.
12
Acknowledgements
This work was supported by funding from the European
Commission contract no. LSSM-CT-2005–518174, and by the
Ludwig Boltzmann Institute of Neurooncology, Vienna. We
acknowledge the work of our collaborators, who helped
immensely with this work: Barabara Horvarth-Mechtler (Insti-
tute of Radiology, KFJ-Hospital, Vienna) who provided
images, Joann Flemming and Claudia Steffek who contributed
to editing and our neuropathology group, in particular
J. Feichtinger and K. Jellinger.
References
1. Clouston PD, DeAngelis LM, Posner JB. The spectrum of
neurological disease in patients with systemic cancer. Ann
Neurol 2006;31:268–73.
2. Graus F, Rogers LR, Posner JB. Cerebrovascular com-
plications in patients with cancer. Medicine (Baltimore)
1985;64:16–35.
3. Posner JB (ed.). Vascular disorders. In: Neurologic com-
plications of cancer. Philadelphia, PA: FA Davies Comp,
1995;199–299.
4. Lindvig K, Moller H, Mosbech J, Jensen OM. The pattern
of cancer in a large cohort of stroke patients. Int J Epi-
demiol 1990;19:498–504.
5. Rogers LR. Cerebrovascular complications in cancer
patients. Oncology (Williston Park) 1994;8:23–30.
6. Chaturvedi S, Ansell J, Recht L. Should cerebral ischae-
mic events in cancer patients be considered a manifesta-
tion of hypercoagulability? Stroke 1994;25:1215–8.
7. Cestari DM, Weine DM, Panageas KS, Segal AZ,
DeAngelis LM. Stroke in patients with cancer: incidence
and aetiology. Neurology 2004;64:2025–30.
8. Nguyen T, DeAngelis LM. Stroke in cancer patients. Curr
Neurol Neurosci Rep 2006;6:187–92.
9. Rogers LR. Cerebrovascular complications in cancer
patients. Neurol Clin 2003;21:167–92.
10. Zhang YY, Cordato D, Shen Q, Sheng AZ, Hung WT,
Chan DK. Risk factor, pattern, etiology and outcome in
ischemic stroke patients with cancer: a nested case–
control study. Cerebrovasc Dis 2006;23:181–7.
11. Zhang YY, Chan DKY, Cordato D, Sheng AZ. Stroke risk
factor, pattern and outcome in patients with cancer. Acta
Neurol Scand 2006;114:378–83.
12. Graus F, Delattre JY, Antoine JC et al. Recommended
diagnostic criteria for paraneoplastic neurological syn-
dromes. J Neurol Neurosurg Psychiatry 2004;75:1135–
40.
13. Low molecular weight heparinoid, ORG 10172 (danapa-
roid), and outcome after acute ischemic stroke: a ran-
domized controlled trial. The Publications Committee for
the Trial of ORG 10172 in Acute Stroke Treatment
(TOAST) Investigators. JAMA 1998;279:1265–72.
14. Dehnee AE, Brizendine S, Herrera CJ. Recurrent strokes
in a young patient with papillary fibroelastoma: a case
report and literature review. Echocardiography 2006;
23:592–5.
15. Perez de Colosia Rama V, Boveda Alvarez FJ, Zabala Y
Morales MS, Lucini Pelayo G. Ischemic stroke and car-
diac myxomas. Findings in cranial magnetic resonance
imaging. Neurologia 2006;21:260–4.
16. Yeh HH, Yang CC, Tung WF, Wang HF, Tung JN.
Young stroke, cardiac myxoma, and multiple emboli: a
case report and literature review. Acta Neurol Taiwan
2006;15:201–5.

17. Mendes S, Nobre A, Brito D, Costa E Silva A, Gallego J,
Cravino J. Cardiac papillary fibroelastoma. Rev Port Cir
Cardiotorac Vasc 2006;13:145–9.
18. Behrendt CE, Ruiz RB. Cerebral ischemic events in
patients with advanced lung or prostate cancer. Neuro-
epidemiology 2005;24:230–6.
19. Imaizumi K, Murate T, Ohno J, Shimokata K. Cerebral
infarction due to a spontaneous tumor embolus from lung
cancer. Respiration 1995;62:155–6.
20. Lefkovitz NW, Roessmann U, Kori SH. Major cere-
bral infarction from tumor embolus. Stroke 1986;
17:555–7.
21. Gliemroth J, Nowak G, Kehler U et al. Neoplastic cere-
bral aneurysm from metastatic lung adenocarcinoma
associated with cerebral thrombosis and recurrent sub-
arachnoid haemorrhage. J Neurol Neurosurg Psychiatry
1999;66:246–7.
22. Glass J. Neurologic complications of lymphoma and
leukemia. Semin Oncol 2006;33:342–7.
23. Klein P, Haley EC, Wooten GF, VandenBerg SR. Focal
cerebral infarctions associated with perivascular tumor
infiltrates in carcinomatous leptomeningeal metastases.
Arch Neurol 1989;46:1149–52.
24. Civit T, Pinelli C, Lescure JP, Anxionnat R, Auque J,
Hepner H. Stroke related to a dermoid cyst: case report.
Neurosurgery 1997;41:1396–9.
25. Matsuo R, Kamouchi M, Inoue T, Okada Y, Ibayashi S.
Cerebral infarction due to carotid occlusion caused by
cervical vagal neurilemmoma: report of a case. Stroke
2002;33:1428–31.
26. Kalafut M, Vinuela F, Saver JL et al. Multiple cerebral
pseudoaneurysms and hemorrhages: the expanding spec-
trum of cerebral choriocarcinoma. J Neuroimaging
1998;8:44–7.
27. Terasaki M, Abe T, Tajima Y, Fukushima S, Hirohata M,
Shigemori M. Primary choroid plexus T-cell lymphoma
and multiple aneurysms in the CNS. Leuk Lymphoma
2006;47:1680–2.
28. Liszka U, Drlicek M, Hitzenberger P et al. Intravascular
lymphomatosis: a clinicopathological study of three cases.
J Cancer Res Clin Oncol 1994;120:164–8.
29. Imamura K, Awaki E, Aoyama Y et al. Intravascular large
B-cell lymphoma following a relapsing stroke with tem-
porary fever: a brain biopsy case. Intern Med 2006;
45:693–5.
30. Baehring JM, Henchcliffe C, Ledezma CJ, Fulbright R,
Hochberg FH. Intravascular lymphoma: magnetic reso-
nance imaging correlates of disease dynamics within the
central nervous system. J Neurol Neurosurg Psychiatry
2005;76:540–4.
31. Harris CP, Sigman JD, Jaeckle KA. Intravascular
malignant lymphomatosis: amelioration of neurolo-
gical symptoms with plasmapheresis. Ann Neurol 1994;
35:357–9.
32. Baehring JM, Longtine J, Hochberg FH. A new approach
to the diagnosis and treatment of intravascular lym-
phoma. J Neurooncol 2003;61:237–48.
33. Beckers EA, Gonzalez Garcia FN, Vrielink H, Sanquin B.
Brain infarction due to polycythemia as first indication of
renal cell carcinoma. Ned Tijdschr Geneeskd 2006;
150:1642.
34. Matijevic N, Wu KK. Hypercoagulable states and strokes.
Curr Atheroscler Rep 2006;8:324–9.
35. Gonthier A, Bogousslavsky J. Cerebral infarction of
arterial origin and haematological causation: the Lau-
sanne stroke experience and a review of the literature. Rev
Neurol (Paris) 2004;160:1029–39.
Stroke and cancer
36. Dabrow MB, Wilkins JC. Management of hyperleukocy-
totic syndrome, DIC and thrombotic, thrombocytopenic
purpura. Postgrad Med 1993;5:193–202.
37. Novontny JR, Muller-Beissenhirtz H, Herget-Rosenthal S
et al. Grading of symptoms in hyperleukocytic leukae-
mia: a clinical model for the role of different blast types
and promyelocytes in the development of leukostasis
syndrome. Eur J Haematol 2005;74:501–10.
38. Park MS, Kim BC, Kim IK et al. Cerebral infarction in
IgG multiple myeloma with hyperviscosity. J Korean Med
Sci 2005;20:699–701.
39. Civit T, Coulbois S, Baylac F, Taillandier L, Auque J.
WaldenstromÕs macroglobulinemia and cerebral lym-
phoplasmocytic proliferation: Bing and Neel syndrome.
Apropos of a new case. Neurochirurgie 1997;43:
245–9.
40. Donix M, Beuthien-Baumann B, von Kummer R, Gahn G,
Thomas F, Holthoff V. Nonfluent aphasia in a patient
with WaldenstromÕs macroglobulinemia. J Clin Neurosci
2007;14:601–3.
41. Hiatt BK, Lentz SR. Prothrombotic states that predispose
to stroke. Curr Treat Options Neurol 2002;4:417–25.
42. Ferro JM, Canhao P, Stam J et al. Prognosis of cerebral
vein and dural sinus thrombosis: results of the Interna-
tional Study on Cerebral Vein and Dural Sinus Throm-
bosis (ISCVT). Stroke 2004;35:664–70.
43. Isaacs C. Venous thromboembolic disease and stroke in
women taking tamoxifen for breast cancer chemopre-
vention. Clin Adv Hematol Oncol 2005;3:913–4.
44. Luyendyk JP, Tilley RE, Mackman N. Genetic
susceptibility to thrombosis. Curr Atheroscler Rep 2006;
8:193–7.
45. Prandoni P. Acquired risk factors for venous thrombo-
embolism in medical patients. Hematology Am Soc
Hematol Educ Program 2005;458–61.
46. Sagduyu A, Sirin H, Mulayim S et al. Cerebral cortical
and deep venous thrombosis without sinus thrombosis:
clinical MRI correlates. Acta Neurol Scand 2006;114:
254–60.
47. Andreescu AC, Cushman M, Hammond JM, Wood ME.
TrousseauÕs syndrome treated with long-term subcutane-
ous lepirudin (case report and review of the literature).
J Thromb Thrombolysis 2001;11:33–7.
48. Liu PG, Jacobs JB, Reede D. TrousseauÕs syndrome in the
head and neck. Am J Otolaryngol 1985;6:405–8.
49. Varki A. TrousseauÕs Syndrome: multiple definitions and
multiple mechanisms. Blood 2007;13:487–92.
50. Gordon Sg, Franks JJ, Lewis B. Cancer procoagulant A: a
factor X activating procoagulant from malignant tissue.
Thromb Res 1975;6:127–37.
51. Iversen N, Lindahl AK, Abildgaard U. Elevated plasma
levels of the factor Xa-TFPI complex in cancer patients.
Thromb Res 2006;105:33–6.
52. Rosen PJ. Bleeding problems in the cancer patient.
Hematol Oncol Clin North Am 1992;6:1315–28.
53. Wada H, Gabazza EC, Asakura H et al. Comparison of
diagnostic criteria for disseminated intravascular coagu-
lation (DIC): diagnostic criteria of the International
Society of Thrombosis and Hemostasis and of the Japa-
nese Ministry of Health and Welfare for overt DIC. Am J
Hematol 2003;74:17–22.
54. Claes F, Verhagen CV, Verhagen WI, Schaafsma E,
Rongen RJ. Acute isodense intracerebral haematoma due
to coagulopathy associated with prostate cancer. Clin
Neurol Neurosurg 2007;109:520–2.
55. Steiner I. Nonbacterial thrombotic endocarditis – a study
of 171 case reports. Cesk Patol 1993;29:58–60.
13
Grisold et al.
56. Gonzalez Quintela A, Candela MJ, Vidal C et al. Non-
bacterial thrombotic endocarditis in cancer patients. Acta
Cardiol 1991;46:1–9.
57. Herrera de Pablo P, Esteban Esteban E, Gimenez Soler JV,
Pareja Martinez A, Moscoso del Prado J. Nonbacterial
thrombotic endocarditis as initial event of lung cancer. An
Med Interna 2004;21:495–7.
58. Ojeda VJ, Frost F, Mastaglia FL. Non-bacterial throm-
botic endocarditis associated with malignant disease: a
clinicopathological study of 16 cases. Med J Aust 1985;
142:629–31.
59. Singhal AB, Topcuoglu MA, Buonanno FS. Acute ischemic
stroke patterns in infective and nonbacterial thrombotic
endocarditis: a diffusion-weighted magnetic resonance
imaging study. Stroke 2002;33:1267–73.
60. Elikowski W, Maka K, Bol K, Jedlinski I, Kubaszewska M.
Multifocal ischaemic stroke and myocardial infarction in
a woman with occult lung cancer complicated with
chronic DIC and thrombotic endocarditis. Neurol Neu-
rochir Pol 2006;40:530–5.
61. Ohashi S, Yazumi S, Nishio A et al. Acute cerebral
infarction during combination chemotherapy with s-1 and
cisplatin for a young patient with a mucin-producing
adenocarcinoma of the stomach. Intern Med 2006;
45:1049–53.
62. De Lucia D, De Francesco F, Marotta R et al. Pheno-
typic APC resistance as a marker of hypercoagulability
in primitive cerebral lymphoma. Exp Oncol 2005;27:159–
61.
63. Langer F, Eifrig B, Marx G et al. Exacerbation of anti-
phospholipid antibody syndrome after treatment of
localized cancer: a report of two cases. Ann Hematol
2002;81:727–31.
64. Katsuoka H, Mimori Y, Kohriyama T et al. An autopsy
case of catastrophic antiphospholipid syndrome present-
ing with recurrent multiple cerebral infarction associated
with lung cancer. No To Shinkei 2000;52:64–9.
65. Ideguchi H, Ohno S, Ueda A, Ishigatsubo Y. Catastrophic
antiphospholipid syndrome associated with malignancies
(case report and review of the literature). Lupus
2007;16:59–64.
66. Leary MC, Saver JL. Cerebrovascular complications of
cancer. In: Schiff D, Wen PY, eds. Cancer neurology in
clinical practice. Totowa, NJ: Humana Press, 2003;137–
57.
67. Tovin TG, Boosupalli V, Zivkovic SA et al. High titers of
CA-125 may be associated with recurrent ischemic strokes
in patients with cancer. Neurology 2005;64:1944–5.
68. Brodmann S, Passweg JR, Gratwohl A, Tichelli A, Skoda
RC. Myeloproliferative disorders: complications, survival
and causes of death. Ann Hematol 2000;79:312–8.
69. Guerrero AL, Perez-Simon JA, Cunado A, Cacho J,
Vidriales B. Fulminant angiopathy caused by allogenic
transplantation of bone marrow with cerebral involve-
ment: clinico-pathologic correlation. An Med Interna
1998;15:545–7.
70. Zakarija A, Bennett C. Drug-induced thrombotic micro-
angiopathy. Semin Thromb Hemost 2005;31:681–90.
71. Venat-Bouvet L, Ly K, Szelag JC et al. Thrombotic
microangiopathy and digital necrosis: two unrecognized
toxicities of gemcitabine. Anticancer Drugs 2003;14:829–
32.
72. Nadir Y, Hoffman R, Brenner B. Drug-related thrombosis
in hematologic malignancies. Rev Clin Exp Hematol
2004;8:E4.
73. Wick W, Kaufmann A. Glioblastoma: whatÕs ischemia got
to do with it? Neurology 2006;67:1540–1.
14
74. RojasMarcos I, Martin-Duverneuil N, Laigle-Donadey F
et al. Ischemic stroke in patients with glioblastoma
multiforme. J Neurol 2006;252:488–9.
75. Ulmer S, Braga TA, Barker FG, Lev MH, Gonzalez RG,
Henson JW. Clinical and radiographic features of peritu-
moral infarction following resection of glioblastoma.
Neurology 2006;67:1668–70.
76. Kawanami T, Kurita K, Yamakawa M, Omoto E, Kato T.
Cerebrovascular disease in acute leukemia: a clinico-
pathological study of 14 patients. Intern Med 2002;
41:1130–4.
77. Pruitt AA. Nervous system infections in patients with
cancer. Neurol Clin 2003;21:193–219.
78. Kleinschmidt-DeMasters BK, Gilden DH. Varicella-
Zoster virus infections of the nervous system: clinical and
pathologic correlates. Arch Pathol Lab Med 2001; 125:
770–80.
79. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ,
Mahalingam R, Cohrs RJ. Neurologic complications of
the reactivation of varicella-zoster virus. N Engl J Med
2000;342:635–45.
80. Subsai K, Kanoksri S, Siwaporn C, Helen L, Kanokporn O,
Wantana P. Neurological complications in AIDS patients
receiving HAART: a 2-year retrospective study. Eur
J Neurol 2006;13:233–9.
81. Apostolakis E, Koletsis EN, Panagopoulos N et al. Fatal
stroke after completion pneumonectomy for torsion of
left upper lobe following left lower lobectomy. J Cardio-
thorac Surg 2007;1:25. doi: 10.1186/1749-8090-1-25.
82. Brown DV, Faber LP, Tuman KJ. Perioperative stroke
caused by arterial tumor embolism. Anesth Analg
2004;98:806–9.
83. Brisman MH, Sen C, Catalano P. Results of surgery for
head and neck tumors that involve the carotid artery at
the skull base. J Neurosurg 1997;86:787–92.
84. Bejjani GK, Sekhar LN, Yost AM, Bank WO, Wright DC.
Vasospasm after cranial base tumor resection: pathogen-
esis, diagnosis, and therapy. Surg Neurol 1999;52:577–83.
85. Cheng SW, Wu LL, Ting AC, Lau H, Lam LK, Wei WI.
Irradiation-induced extracranial carotid stenosis in
patients with head and neck malignancies. Am J Surg
1999;178:323–8.
86. Marcel M, Leys D, Mounier-Vehier F et al. Clinical out-
come in patients with high-grade internal carotid artery
stenosis after irradiation. Neurology 2005;65:959–61.
87. Carmody BJ, Arora S, Avena R et al. Accelerated carotid
artery disease after high-dose head and neck radiother-
apy: is there a role for routine carotid duplex surveillance?
J Vasc Surg 1999;30:1045–51.
88. Leseche G, Castier Y, Chataigner O et al. Carotid artery
revascularization through a radiated field. J Vasc Surg
2003;38:244–50.
89. Desai SS, Paulino AC, May WY et al. Radiation-induced
moyamoya syndrome. Int J Radiat Oncol Biol Phys
2006;65:1222–7.
90. Black DF, Bartleson JD, Bell ML et al. SMART:
stroke-like migraine attacks after radiation therapy.
Cephalalgia 2006;26:1137–42.
91. Broomfield SJ, Bruce IA, Luff DA, Birzgalis AR, Ash-
leigh RJ. Endovascular management of the carotid
blowout syndrome. J Laryngol Otol 2006;120:694–7.
92. El Amrani M, Aidi S, Amarenco P. Cerebral ischemic
events and anti-cancer therapy. Rev Neurol (Paris) 2003;
159:371–80.
93. Li SH, Chen WH, Tang Y et al. Incidence of ischemic
stroke post-chemotherapy: a retrospective review of
10,963 patients. Clin Neurol Neurosurg 2006;108:150–6.

94. Rogers LR. Cerebrovascular complications in patients
with cancer. Semin Neurol 2004;24:453–60.
95. Chan AT, Leung WT, Johnson PJ. Cerebrovascular event
following taxol infusion. Clin Oncol (R Coll Radiol)
1994;6:202–3.
96. Rollins N, Winick N, Bash R et al. Acute methotrexate
neurotoxicity: findings on diffusion-weighted imaging and
correlation with clinical outcome. AJNR Am J Neuro-
radiol 2004;25:1688–96.
97. Numico G, Garrone O, Dongiovanni V et al. Prospective
evaluation of major vascular events in patients with
nonsmall cell lung carcinoma treated with cisplatin and
gemcitabine. Cancer 2005;103:994–9.
98. Periard D, Boulanger CM, Eyer S et al. Are circulating
endothelial-derived and platelet-derived microparticles a
pathogenic factor in the cisplatin-induced stroke? Stroke
2007;38:1636–8.
99. Henderson RD, Rajah T, Nicol AJ, Read SJ. Posterior
leukoencephalopathy following intrathecal chemotherapy
with MRA-documented vasospasm. Neurology 2003;
60:326–8.
100. Fouladi M, Langston J, Mulhern R et al. Silent lacunar
lesions detected by magnetic resonance imaging of chil-
dren with brain tumors: a late sequela of therapy. J Clin
Oncol 2000;18:824–31.
101. Anderson NE. Late complications in childhood central
nervous system tumour survivors. Curr Opin Neurol
2003;16:677–83.
102. Kieslich M, Porto L, Lanfermann H, Jacobi G, Schwabe D,
Bohles H. Cerebrovascular complications of l-aspara-
ginase in the therapy of acute lymphoblastic leukemia.
J Pediatr Hematol Oncol 2003;25:484–7.
103. Fleischhack G, Solymosi L, Reiter A, Bender-Gotze C,
Eberl W, Bode U. Imaging methods in diagnosis of
cerebrovascular complications with l-asparaginase ther-
apy. Klin Padiatr 1994;206:334–41.
104. Feinberg WM, Swenson MR. Cerebrovascular complica-
tions of l-asparaginase therapy. Neurology 1988;38:127–
33.
105. Lubiniecki GM, Berlin JA, Weinstein RB, Vaughn DJ.
Thromboembolic events with estramustine phosphate-
based chemotherapy in patients with hormone-refractory
prostate carcinoma: results of a meta-analysis. Cancer
2004;101:2755–9.
106. Nilsson G, Holmberg L, Garmo H, Terent A, Blomqvist C.
Increased incidence of stroke in women with breast can-
cer. Eur J Cancer 2005;41:423–9.
107. Braithwaite RS, Chlebowski RT, Lau J, George S, Hess R,
Col NF. Meta-analysis of vascular and neoplastic events
associated with tamoxifen. J Gen Intern Med 2003;18:
937–47.
108. Bushnell CD, Goldstein LB. Risk of ischemic stroke with
tamoxifen treatment for breast cancer: a meta-analysis.
Neurology 2004;63:1230–3.
109. Geiger AM, Fischberg GM, Chen W, Bernstein L. Stroke
risk and tamoxifen therapy for breast cancer. J Natl
Cancer Inst 2004;96:1528–36.
110. Bath PM, Sprigg N. Colony stimulating factors (including
erythropoietin, granulocyte colony stimulating factor and
analogues) for stroke. Cochrane Database Syst Rev
2006;3:CD005207.
111. Tallman MS, Kwaan HC. Intravascular clotting activa-
tion and bleeding in patients with hematologic malig-
nancies. Rev Clin Exp Hematol 2004;8:E1.
112. Newton HB. Intra-arterial chemotherapy of primary brain
tumors. Curr Treat Options Oncol 2005;6:519–30.
Stroke and cancer
113. Cornuz J, Bogousslavsky J, Schapira M, Regli F,
Camenzind E. Ischemic stroke as the presenting manifes-
tation of localized systemic cancer. Schweiz Arch Neurol
Psychiatr 1988;139:5–11.
114. Omuro AM, Leite CC, Mokhtari K, Delattre JY. Pitfalls
in the diagnosis of brain tumours. Lancet Neurol
2006;5:937–48.
115. Royter V, Cohen SN. Recurrent embolic strokes and
cardiac valvular disease in a patient with non-small
cell adenocarcinoma of lung. J Neurol Sci 2006;241:99–
101.
116. Quinones-Hinojosa A, Gulati M, Singh V et al. Sponta-
neous intracerebral hemorrhage due to coagulation dis-
orders. Neurosurg Focus 2003;15:E3.
117. Huff JS. Stroke mimics and chameleons. Emerg Med Clin
North Am 2002;20:583–95.
118. Sakowitz OW, Harting I, Kohlhof P, Unterberg AW,
Steiner HH. Acute haemorrhage into a microcystic
meningioma leading to cerebral herniation. Br J Neuro-
surg 2005;19:260–4.
119. Jouary T, Delaunay M, Taieb A. Hematoma-like metas-
tases. J Am Acad Dermatol 2006;55:1106–7.
120. Mandybur TI. Intracranial hemorrhage caused by meta-
static tumors. Neurology 1977;27:650–5.
121. Park SK, Lee JK, Joo SP et al. Spontaneous intracerebral
haemorrhage caused by extra-adrenal phaeochromocy-
toma. J Clin Neurosci 2006;13:388–90.
122. Ogawa R, Tanaka K, Satoh H, Sekizawa K. Intra-tumor
hemorrhage associated with brainstem metastasis from
lung cancer. Intern Med 2006;45:487–8.
123. Minette SE, Kimmel DW. Subdural hematoma in patients
with systemic cancer. Mayo Clin Proc 1989;64:637–42.
124. Jourdan E, Dombret H, Glaisner S, Miclea JM, Castaigne
S, Degos L. Unexpected high incidence of intracranial
subdural haematoma during intensive chemotherapy for
acute myeloid leukaemia with a monoblastic component.
Br J Haematol 1995;89:527–30.
125. Porcu P, Cripe LD, Ng EW et al. Hyperleukocytic leu-
kemias and leukostasis: a review of pathophysiology,
clinical presentation and management. Leuk Lymphoma
2000;39:1–18.
126. Subramaniam S, Puetz V, Dzialowski I, Barber PA. Cere-
bral microhemorrhages in a patient with mycotic aneu-
rysm: relevance of T2-GRE imaging in SBE. Neurology
2006;67:1697.
127. Izawa M, Chernov M, Hayashi M, Kubota Y, Kasuya
H, Hori T. Fatal intratumoral hemorrhage immediately
after gamma knife radiosurgery for brain metastases:
case report. Minim Invasive Neurosurg 2006;49:251–
4.
128. Cheng KM, Chan CM, Fu YT, Ho LC, Cheung FC, Law
CK. Acute hemorrhage in late radiation necrosis of the
temporal lobe: report of five cases and review of the
literature. J Neurooncol 2001;51:143–50.
129. Lee JK, Chelvarajah R, King A et al. Rare presentations
of delayed radiation injury: a lobar hematoma and a
cystic space-occupying lesion appearing more than
15 years after cranial radiotherapy: report of two cases.
Neurosurgery 2004;54:1010–3.
130. Raizer JJ, DeAngelis LM. Cerebral sinus thrombosis
diagnosed by MRI and MR venography in cancer
patients. Neurology 2000;54:1222–6.
131. Matsumoto K, Ohta M, Takeshita I. Reversible non-
thrombotic occlusion of the superior sagittal sinus caused
by metastatic malignant lymphoma – case report. Neurol
Med Chir (Tokyo) 2003;43:349–51.
15
Grisold et al.
132. Kim AW, Trobe JD. Syndrome simulating pseudotumor
cerebri caused by partial transverse venous sinus
obstruction in metastatic prostate cancer. Am J Oph-
thalmol 2000;129:254–6.
133. Meininger V, James JM, Rio B, Zittoun R. Dural venous
sinus occlusions in hemopathies. Rev Neurol (Paris)
1985;141:228–33.
134. Masjuan J, Pardo J, Callejo JM, Andres MT, Alvarez-
Cermeno JC. Tamoxifen: a new risk factor for cerebral
sinus thrombosis. Neurology 2004;62:334–5.
135. Lenz RA, Saver J. Venous sinus thrombosis in a patient
taking thalidomide. Cerebrovasc Dis 2004;18:175–7.
136. Bienfait HP, Gijtenbeek JM, van den Bent MJ, de Bruin
HG, Voogt PJ, Pillay M. Cerebral venous and sinus
16
thrombosis with cerebrospinal fluid circulation block after
the first methotrexate administration by lumbar puncture.
Neuroradiology 2002;44:929–32.
137. Feeman WE Jr. Thrombotic stroke in an otherwise healthy
middle-aged female related to the use of continuous-
combined conjugated equine estrogens and medroxypro-
gesterone acetate. J Gend Specif Med 2000;3:62–4.
138. Ellie E, Becouarn Y, Brunet R, Gonday G, Julien J.
Paraneoplastic cerebral venous thrombosis. Rev Neurol
(Paris) 1993;149:297–9.
139. Ferro JM, Morgado C, Sousa R, Canhao P. Interobserver
agreement in the magnetic resonance location of cerebral
vein and dural sinus thrombosis. Eur J Neurol 2007;
14:353–6.