Journal of the Neurological Sciences 304 (2011) 87–92

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Journal of the Neurological Sciences

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s

Hematological disorders related cerebral infarctions are mostly multifocal

Ombeline Fagniez a,d, Gérard Tertian b, Marie Dreyfus b, Denis Ducreux c,d,e,
David Adams a,d,e, Christian Denier a,e,⁎
a
Departments of Neurology, Centre Hospitalo — Universitaire de Bicêtre, Assistance Publique — Hôpitaux de Paris, France
b
Department of Hematology, Centre Hospitalo — Universitaire de Bicêtre, Assistance Publique — Hôpitaux de Paris, France
c
Department of Neuroradiology, Centre Hospitalo — Universitaire de Bicêtre, Assistance Publique — Hôpitaux de Paris, France
d
Université Paris-11, France
e
INSERM U788, le Kremlin-Bicêtre, F-94275, France

a r t i c l e i n f o a b s t r a c t

Article history: Hematological disorders (HD) have been estimated to implicate approximately 1% of patients with arterial
Received 13 January 2011 ischemic stroke. However, previously published studies are mostly retrospective or based on case reports or
Received in revised form 28 January 2011 small series in selected young patients.
Accepted 4 February 2011
We herein prospectively included consecutive patients with MRI-confirmed cerebral arterial infarctions
among individuals admitted in our stroke unit during a 32 month period to determine the clinical and
Keywords:
neuroradiological features of ischemic stroke due to HD. Patients with both HD and other identified sources of
Hematological disorders
Multifocal stroke were excluded.
Anticoagulation Among patients who were admitted for suspected stroke, 590 had diffusion-weighted MRI confirmed acute
Cancer arterial infarcts. Cause of the cerebral infarction was HD in 13 patients (2.2%): myeloproliferative disorders
(n= 4), multiple myeloma (1), lymphoma (1), chronic lymphocytic leukemia (1), disseminated intravascular
coagulation (2), thrombotic thrombocytopenic purpura (1), antiphospholipid antibody syndrome (2) and
homozygous Q506 factor V mutation associated with lupus anticoagulant (1). The HD were previously known in 6
patients. The only significant difference between the groups of patients with or without HD was the prevalence of
multiple acute infarcts in different vascular territories, detected in 53.8% of patients with HD versus 7.8% of
patients without HD (mostly due to atherosclerosis, small vessel disease or cardioembolism) (pb 0.0001; Fisher
exact test). Initial treatment in stroke unit included anticoagulation, steroids, chemotherapy, phlebotomy or
plasmatic exchanges, according to etiology. Rankin score at six months was ≤2 in 8 patients.
A large spectrum of hematological diseases can be associated with cerebral infarction. In the etiologic work up, HD
should be particularly looked for in patients with multifocal acute infarcts to adapt specific therapeutic
management.
© 2011 Elsevier B.V. All rights reserved.

1. Introduction hematological or coagulation abnormalities play an important role in

In approximately 1% of all patients and 4% of young adults with
cerebral infarctions, the major trigger of brain ischemia is a
hematological or coagulation disorder that predisposes to thrombosis
[1–3]. However, previous studies have been largely retrospective,
based only on CT scan or on case reports or small series in selected
young patients.
The aim of this study was to determine the clinical and radiological
features of arterial ischemic stroke associated with hematological
disorders in a prospective hospital based cohort and to assess which
⁎ Corresponding author at: Department of Neurology, Centre Hospitalier de Bicêtre,
78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre Cedex, France. Tel.: +33
145213149; fax: +33 145212853.
E-mail address: christian.denier@bct.aphp.fr (C. Denier).
ischemic stroke and change stroke management.
2. Materials and method
Our cohort includes 1220 consecutive patients, admitted for stroke
or transient ischemic attack suspicion in our stroke unit, between June
2007 and February 2010. All patients had magnetic resonance imaging
(MRI) including diffusion-weighted sequences within 48 h of admis-
sion, which showed acute cerebral arterial infarctions in 590 patients;
other patients presented other various acute cerebro-vascular diseases
(mostly transient ischemic attacks, intracerebral hemorrhages or
cerebral vein thrombosis) or stroke mimics (mostly seizures/postictal
paresis, hypoglycemias, complicated migraines, conversion disorders,
and various myelopathies or brain tumors (not shown)). Patients with
arterial ischemic events underwent etiologic investigations including
systematically an electrocardiogram, cervical and trans-cranial Doppler,

0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2011.02.004
88 O. Fagniez et al. / Journal of the Neurological Sciences 304 (2011) 87–92
Fig. 1. Diffusion MRI of patients with HD related cerebral infarctions. Patients are numbered according to Table 2.
echocardiography and ECG monitoring for at least 48 h as well as
routine laboratory workout including blood cell count, prothrombin
time, thrombin time and activated partial thromboplastin time,
fibrinogen level, erythrocyte sedimentation rate, glycemia, creatinine-
mia, albuminemia and cholesterolemia. In patients without any
identified etiology after these first explorations (such as atherosclerosis,
dissection or cardioembolic disease), transoesophageal echocardiogra-
phy, and more complete laboratory screening including lumbar
puncture were systematically performed. Complementary biological
tests included a search for anticardiolipin (aCL), antinuclear and anti-
beta2-glycoprotein I antibodies and lupus anticoagulant (LA) as well as
serological tests for human immunodeficiency virus (HIV1 and 2),
Treponema pallidum hemagglutination and Venereal Disease Research
Laboratory tests (TPHA/VDRL). In addition, screening was also done for
coagulation inhibitor deficiency (antithrombin, protein C, and protein
S), prothrombin mutation (G20210A), Q506 factor V mutation and
hyperhomocysteinemia. Finally, conventional cerebral angiography was
occasionally performed. Based on the results of these studies, causes
were classified according to the TOAST classification [4].
Patients' characteristics including age, gender, history of hyper-
tension, diabetes mellitus, current tobacco use, stroke severity based
on NIHSS score, involved vascular territories based on initial diffusion-
weighted MRI and categories of aetiologies were prospectively
entered in our database. Among 590 patients with cerebral infarction,
we identified those due to hematological disorders (HD). HD included
coagulation and fibrinolysis anomalies, erythrocyte abnormalities,
myeloproliferative disorders, other hematologic malignancies and the
antiphospholipid syndrome [3]. Antiphospholipid syndrome (APS)
was only considered if aCL or anti-beta2-glycoprotein I antibodies or
LA was positive on two laboratory examinations with an interval of
twelve weeks and if aCL or anti-beta2-glycoprotein I antibodies of Ig G
and/or IgM isotype was present in titer N99th percentile [5]. The
present study is based on patients with HD as the only identified
etiology for cerebral infarction excluding those with both HD and
other identified sources of stroke (such as atherosclerosis, cardioem-
bolism or dissection).
HD patients were compared with all the others (mostly due to
atherosclerosis, small vessel disease or cardioembolism) using Chi2 or
 O. Fagniez et al. / Journal of the Neurological Sciences 304 (2011) 87–92 89

Fisher's exact tests for categorical variables, and Kruskal–Wallis test
for quantitative variables.
3. Results
Of the 590 consecutive patients with an acute MRI-confirmed
arterial infarcts, 13 (2.2%) had a stroke attributed to one of the following
hematological pathologies : polycythemia vera (n = 1), essential
thrombocytemia (n= 1), primary myelofibrosis (n = 1), chronic mye-
lomonocytic leukemia (n = 1), multiple myeloma (n = 1), lymphoma
(n = 1), chronic lymphocytic leukemia (n = 1), antiphospholipid
antibody syndrome (n= 2), disseminated intravascular coagulation in
cancer patient (n= 2), thrombotic thrombocytopenic purpura (n = 1)
and homozygous Leiden factor V mutation associated with lupus
anticoagulant (n= 1). This group of patients comprised 10 men and 3
women with a mean age of 56 years (range of 27–83). Table 1
summarizes the clinical features (age, gender, diabetes, hypertension,
smoking, and NIHSS) and vascular territories involved in these 13
patients compared with the remaining stroke cohort (n= 577).
Cerebral infarction revealed the hematologic abnormality in 7
patients, namely thrombotic thrombocytopenic purpura (n = 1),
myeloproliferative disorder (n = 1), homozygous Leiden factor V
mutation (n = 1), antiphospholipid antibody syndrome (n = 2) and
disseminated intravascular coagulation (n = 2; both associated with
lung cancers, of which one was previously known and treated). HD
were previously known in the 6 remaining patients, and already
treated in 5 (Table 2).
The comparison of patients with HD related cerebral infarction
with the 577 others showed no significant differences concerning
mean age, prevalence of hypertension, hypercholesterolemia, diabe-
tes or current tobacco and initial NIHSS score. The only significant
difference was the prevalence of multiple infarcts, i.e. multiple acute
lesions in different vascular territories on initial diffusion-weighted
imaging, detected in 53.8% of patients with HD versus 7.8% of patients
without HD (mostly due to atherosclerosis, small vessel disease or
cardioembolism) (p b 0.0001) (Table 1 and Fig. 1).
Acute antithrombotic treatment included antiplatelet therapy in 9
patients and anticoagulation by low molecular weight heparin in the 4
others (one with antiphospholipid antibody syndrome, one with
homozygous Leiden factor V mutations associated with lupus antico-
agulant, one with disseminated intravascular coagulation and one with
chronic myelomonocytic leukemia who also had an associated
splanchnic venous thrombosis (Table 2). One patient with disseminated
intravascular coagulation and a large cerebral infarct was treated by
aspirin alone instead of heparin, for fear of bleeding. In addition,
associated acute specific treatment for HD included phlebotomy for the
patient with essential thrombocytemia, plasmatic exchanges and
steroid therapy for the patient with thrombotic thrombocytopenic
purpura and intravenous steroid therapy for the patient with antipho-
spholipid antibody syndrome secondary to systemic lupus erythema-
tous. Cytoreduction was prescribed few days after stroke in two
previously untreated patients: one with essential thrombocythemia
and one with chronic myelomonocytic leukemia. Chemotherapy was
started in the patient with disseminated intravascular coagulation and
previously unknown lung cancer. Finally, cytoreduction or chemother-
apy was increased in the 5 other patients with previously known HD
(Table 2).
During the follow up, one patient with disseminated intravascular
coagulation and multiple infarcts associated with lung cancer died
during the first month. At sixth month following stroke, Rankin score
was 0–1 in 7 patients and ≥4 in two. Long term antithrombotic
treatment was oral anticoagulants in 3 patients (two with antipho-
spholipid antibody syndrome and one with homozygous Leiden factor V
mutations associated with lupus anticoagulant) and antiplatelet therapy
in the others. Long term HD treatment included steroids in 2 patients
and cytoreduction or chemotherapy in 9 (of which one with scheduled
autologous hematopoietic progenitor cell transplantation) (Table 2).
4. Discussion
HD related cerebral infarctions were identified in 2.2% of our
cohort. This percentage appears higher than previously reported
(from 0.47% to 1.32%) [6,7]. HD, particularly coagulation abnormal-
ities such as APS [8,9], are reported to be more common in young
stroke patients (from 5.8 to 15%)[10–14], but by contrast to previous
studies, we found no difference regarding age between patients with
or without HD, possibly because our study was underpowered to
reach statistic threshold or because we have included patients with
myeloproliferative syndromes and other malignant diseases. In older
patients, these prothrombotic states may play probably a role as
synergistic contributors but associated atherosclerosis makes it
difficult to assess their role [2]. However in the present study we
have excluded from the HD related group of cerebral infarction those
with other potential cause such as atrial fibrillation or atheromatous
lesions.
The only significant difference observed in this study between HD
related cerebral infarctions and the others (which included cardioem-
bolic strokes) was the higher prevalence of simultaneous multiple
acute infarcts in patients with HD related cerebral infarctions, as
already specifically reported in APS where multiple cerebral infarctions

Table 1
Comparative data of patients with or without hematological disorders.

Infarctions due to hematological Others causes⁎ of stroke Total (n = 590) Statistical analysis
disorders (n = 13) (n = 577)

Clinical data
Age (mean) +/− SD (range) 55.8 +/−17.7 (27–83) 64.7 +/− 15.4 (17–99) 64.5 +/− 15.5 (17–99) NS
Sex (males/females) 10/3 (77%/23%) 345/232 (60%/40%) 355/235 (60%/40%) NS
Hypertension 5 (38%) 357 (62%) 362 (61%) NS
Diabetes mellitus 0 126 (22%) 126 (21%) NS
Hypercholesterolemia 2 (15%) 182 (32%) 184 (31%) NS
Smoking 8 (62%) 243 (42%) 251 (43%) NS
Initial NIHS score (mean) +/− SD (range) 5.8 +/− 5.2 (1–18) 5.2 +/− 6.0 (0–28) 5.2 +/− 5.9 (0–28) NS

Involved arterial territories on MRI (based on initial diffusion MRI)

MCA 3 (23.1%) 305 (52.8%) 308 (52.0%) NS
PCA 0 41 (7.1%) 41 (6.9%) NS
ACA 1 (7.7%) 10 (1.7%) 11 (1.9%) NS
AChA 1 (7.7%) 28 (4.8%) 29 (4.9%) NS
Brainstem/cerebellum 1 (7.7%) 109 (18.9%) 110 (18.6%) NS
Multifocal infarcts 7 (53.8%) 45 (7.8%) 52 (8.8%) b0.0001
Watershed infarcts 0 39 (6.8%) 39 (6.6%) NS
⁎ Mostly due to atherosclerosis, small vessel disease or cardioembolism.
90 O. Fagniez et al. / Journal of the Neurological Sciences 304 (2011) 87–92

Table 2
Clinical, biological, radiological characteristics and treatment of patients with hematological disorders related cerebral infarctions.

Patient/ Initial NIHS score Risk factors Hematologic Previously known/ Biological abnormalities Initial treatment Rankin score
sex/age and stroke location disorders unknown HD following stroke at 6th month
(treated/untreated) following stroke

Pt 1 NIHSS = 3 Hypertension Multiple myeloma Known (treated) Monoclonal gamma Aspirin, chemotherapy RS = 1
M/83 multiple infarcts smoking globulin = 18.8 g/l
ESR = 74 mm

Pt 2 NIHSS = 1 Smoking Polycythemia vera Known (treated) Hemoglobin = 18,7 g/dl Aspirin, phlebotomy, RS = 0
M/66 MCA infarction hematocrit = 54.8% hydroxyurea
platelet = 109 giga/l
mutation JAK2 V617F+

Pt 3 NIHS = 8 Hypertension Lymphoma Known (treated) Leukocyte 51 giga/l Aspirin, chemotherapy RS = 4

M/83 brainstem infarction dyslipidemia lymphocyte 41 giga/l
platelet 103 giga/l

Pt 4 NIHS = 14 None Chronic lymphocytic Known (treated) Fibrinogen = 6.5 g/l Aspirin, chemotherapy RS = 1
M/62 multiple infarcts leukemia ESR = 60 mm
Leukemic cells in blood
and cerebrospinal fluid

Pt 5 NIHS = 4 Smoking Disseminated Unknown (but known Prothrombin time = 52% Heparin, chemotherapy RS = 6
M/57 multiple infarcts intravascular and treated lung cancer) platelet 81 giga/l
coagulation fibrin degradation
products N 40

Pt 6 NIHS = 7 Smoking Chronic Unknown Leukocyte 36 giga/l Heparin, hydroxyurea RS = 3

F/63 AChA myelomonocytic neutrophilia 32 giga/l
leukemia platelet 500 giga/l
mutation JAK2 V617F+

Pt 7 NIHS = 6 Smoking, Disseminated Unknown (as unknown Fibrinogen 1.4 g/l Aspirin, chemotherapy RS = 3
M/57 multiple infarcts dyslipidemia intravascular lung cancer) prothrombin time 64%
coagulation Fibrin degradation
products N 40

Pt 8 NIHS = 2 Hypertension Antiphospholipid Unknown (but known Partial thromboplastin Heparin, corticosteroid RS = 0
M/27 MCA infarction antibody syndrome systemic lupus) time 74/35
aCL 64 GPL-U
platelet 57 giga/l

Pt 9 NIHS = 1 Hypertension Essential Known (untreated) Hemoglobin 18.5 g/dl Aspirin, phlebotomy, RS = 0
M/47 ACA infarction thrombocytemia platelet 506 giga/l hydroxyurea
hematocrit 0.53
mutation JAK2 V617F+

Pt 10 NIHS = 7 None Primary myelofibrosis Known (treated) Leukocyte 22 giga/l Clopidogrel, RS = 2

M/56 multiple infarcts platelet 883 giga/l hydroxyurea,
hemoglobin 9.4 g/dl anagrelide
mutation JAK2 V617F+

Pt 11 NIHS = 18 Smoking Homozygous Leiden Unknown Homozygous Q506 factor Heparin RS = 3

M/32 MCA infarction factor V mutations V mutations
and lupus anticoagulant lupus anticoagulant+

Pt 12 NIHS = 4 Smoking Thrombotic Unknown Hemoglobin 8.7 g/dl Aspirin, RS = 0

F/31 multiple infarcts thrombocytopenic platelet 43 giga/l plasmapheresis,
purpura schistocyte 4.5% corticosteroid
LDH 1356 U/l
creatinine 114 μmol/l

Pt 13 NIHSS = 1 Smoking, Antiphospholipid Unknown Partial thromboplastin Aspirin, then heparin RS = 1

F/61 multiple infarcts hypertension antibody syndrome time 97/35 at 3rd month
lupus anticoagulant+

All 13 patients underwent etiologic investigations including all the comprehensive complementary biological tests (including screening for specific coagulation deficiencies; see
Materials and method section) and transoesophageal echocardiography (except 3 individuals who refused, and underwent only transthoracic imaging (patients 1, 3 and 5).”
Abbreviations: M/F : males/females; ESR: erythrocyte sedimentation rate; MCA, ACA, AChA and PCA: respectively middle, anterior, anterior choroidal and posterior cerebral artery;
RS: Rankin score.

are associated with high aCL titers [15] and in patients with cancer
particularly when associated with disseminated intravascular coagula-
tion [16,17]. Our result is strengthened by a previously reported study
which included 383 consecutive patients with acute supratentorial
infarcts and which described that bilateral simultaneous multiple
infarctions were preferentially associated with unusual causes of stroke
such as hematological disorders in addition to cardioembolic disease
[18].
To date, several HD are undoubtedly considered as causes of cerebral
infarctions such as polycythemia vera, essential thrombocythemia,
 O. Fagniez et al. / Journal of the Neurological Sciences 304 (2011) 87–92
disseminated intravascular coagulation, malignancies and thrombotic
thrombocytopenic purpura [2,19]. Myeloproliferative disorders were
the main cause of stroke in this study (4 out of our 13 patients; all 4
carrying an acquired JAK2 V617F mutation). In these conditions, the
individual thrombotic risk seems to be related to high hematocrit in
polycythemia vera, to age and previous thrombotic episode for both
essential thrombocythemia and polycythemia vera [20,21]. By contrast
the presence of acquired mutation of JAK2 V617F, which is found in a
vast majority of polycythemia vera patients (90–95%) and in almost half
of those with essential thrombocytemia and primary myelofibrosis,[22]
is not presently identified as an independent risk factor for arterial
thrombosis [20]. Concerning treatment, low dose aspirin (75–100 mg
daily) is recommended in patients with polycythemia vera or essential
thrombocytemia [23,24]. On the other hand, while myelosuppressive
drugs such as hydroxyurea can reduce the rate of thrombosis, there is
concern that their use is associated with an increased risk of
transformation into acute leukemia [25]. In polycythemia vera, patients
at low risk for vascular complications are treated with phlebotomy to
maintain hematocrit under 0.45 while hydroxyurea is the drug of choice
in high risk patients or in patients with progressive myeloproliferation
[25]. Anagrelide is commonly used as first line therapy for high risk
patients with essential thrombocytemia but hydroxyurea seems to be
superior to anagrelide for prevention of arterial thrombosis [25].
In a large autopsy study of patients with cancers, 14.6% had
pathologic evidence of cerebro-vascular disease which was symp-
tomatic in 7.4% [26]. Association between cancer and cerebral
infarctions has been reported via various mechanisms, such as
disseminated intravascular coagulation (DIC) or nonbacterial throm-
botic endocarditis [26,27]. Indeed, DIC, responsible for stroke in 0.3%
of our cohort, has previously been implicated in one fourth of patients
with cancer and symptomatic cerebral infarctions [26,27]. Other
“paraneoplasic” coagulopathies are probably also associated knowing
that hypercoagulable state is a common condition in patients with
cancer [17,28]. Recently, a high prevalence of embolic signal
suggestive of embolic-origin was observed by trans-cranial Doppler
in cancer patients with ischemic strokes, especially in those without
identified conventional stroke mechanisms (atherosclerosis, atrial
fibrillation, small vessel disease, endocarditis or APS syndrome) [28].
Moreover, higher D-dimer levels were associated with the presence of
this embolic signal, suggesting combined hypercoagulopathy [28].
Finally, in these cancer patients with ischemic strokes without
conventional stroke mechanisms, diffusion-weighted imaging pat-
terns of multiple lesions involving multiple arterial territories have
been more frequently reported than in cancer patients with identified
conventional stroke mechanisms [28].
Thrombotic thrombocytopenic purpura (TTP) is a rare disease with
frequent focal cerebral deficits associated in the majority of patients
with changes in the level of consciousness and seizures [29–31].
While TTP was fatal in 90% of patients prior to the availability of
effective plasmatic exchanges, urgent diagnosis and treatment now
allow 90% of patients to survive [29].
Among other hematological diseases considered as risk factors for
stroke, paraproteinemias can lead to cerebral infarctions via hyper-
coagulable state, though the relationships with stroke are not always
clearly demonstrable [32,33]. Indeed, while neurologic deficits occur
frequently in patients with myeloma and hyperviscosity syndrome,
cerebral infarcts remain rare and their mechanisms debated [32,33].
Finally, while stroke has been clearly associated with chronic
myelomonocytic and acute leukemias or lymphomas [2,3,33], chronic
lymphocytic leukemia is not classically associated with cerebral
arterial thrombosis. However, the patient in our study had an
unusually aggressive chronic lymphocytic leukemia with leptomenin-
geal infiltration, a well established mechanism for neurological
manifestations in hematologic malignancies [32,34,35]. Furthermore,
etiologic investigations for other sources of multifocal cerebral
infarctions were normal.
91
Other HD are considered as moderate risk factors for arterial cerebral
infarcts such as lupus anticoagulant, anticardiolipin antibodies and
heparin associated thrombocytopenia [19]. Antiphospholipid antibodies
have been demonstrated to be independent risk factors for stroke in
large cohort studies [5,36,37]. Antiphospholipid antibody syndrome
(APS), defined by the persistent presence of antiphospholipid anti-
bodies in patients with recurrent venous or arterial thromboembolism
or pregnancy morbidity, was present in two of our patients. It was
primary in one and associated with systemic lupus erythematous in the
other. Suspected on the presence of thrombocytopenia or prolonged
activated partial thromboplastin time, APS requires long term oral
anticoagulation, with INR 2–3 [38].
Lastly, other HD which are major causes of cerebral venous
thrombosis remain debated risk factors for arterial ischemic stroke:
antithrombin, protein C and protein S deficiencies, APC resistance and
fibrinolytic disorders [19]. While several reports have implicated them
in the etiology of arterial ischemic stroke [9], it is now admitted that
their role, if any, is negligible or irrelevant [39,40]. Concerning patients
carrying homozygous Leiden FV mutations, as in our case, additional
associated trigger mechanisms are necessary to explain cerebral
infarction [41]. This thrombophilic work up may still be warranted in
a sub-group of young patients with a cryptogenic stroke where the
prevalence is slightly increased. The significance of this finding remains
largely unclear, leading most often to no particular therapeutic
intervention [39,40], as regards to secondary prevention which remains
essentially based on antiplatelet drugs. The presence of congenital
thrombophilia leads by contrast to the implementation of simple
measures to prevent venous thromboembolic episodes.
5. Conclusion
In conclusion, in the etiologic work up of cerebral infarction, HD
should be particularly looked for in patients with multiple acute infarcts
in different vascular territories. Indeed, it appeared to be of first
importance to detect such HD as it leads to a different management of
arterial ischemic stroke. Many of these patients may benefit from urgent
anticoagulation, steroids, chemotherapy, phlebotomy or plasmatic
exchanges. A complete blood count and standard hemostasis workout
provide sufficient initial screening for the majority of patients. The
inherited thrombophilia work up probably needs to be performed only
in young patients with “cryptogenic” arterial infarcts [39,40]. In older
populations, additional coagulation studies need to be performed only
in the absence of cause and if there is a high degree of suspicion because
of biological abnormalities or a suggestive family history.
Acknowledgement
We thank Pr M-G. Bousser for helpful discussions and critical
reading of this manuscript.
References
[1] Bogousslavsky J, Van Melle G, Regli F. The Lausanne stroke registry: analysis of 1 000
consecutive patients with first stroke. Stroke 1988;19:1083–92.
[2] Hart RG, Kanter MC. Hematologic disorders and ischemic stroke. A selective
review. Stroke 1990;21:1111–21.
[3] Weksler BB. Hematologic disorders and ischemic stroke. Curr Opin Neurol 1995;8:
38–44.
[4] Adams Jr HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al.
Classification of subtype of acute ischemic stroke. Definitions for use in a
multicenter clinical trial. Toast. Trial of org 10172 in acute stroke treatment. Stroke
1993;24:35–41.
[5] Turiel M, Sarzi-Puttini P, Peretti R, Rossi E, Atzeni F, Parsons W, et al. Thrombotic
risk factors in primary antiphospholipid syndrome: a 5-year prospective study.
Stroke 2005;36:1490–4.
[6] Gonthier A, Bogousslavsky J. Cerebral infarction of arterial origin and haemato-
logical causation: the Lausanne experience and a review of the literature. Rev
Neurol (Paris) 2004;160:1029–39.
[7] Arboix A, Besses C. Cerebrovascular disease as the initial clinical presentation of
haematological disorders. Eur Neurol 1997;37:207–11.
92 O. Fagniez et al. / Journal of the Neurological Sciences 304 (2011) 87–92
[8] Terashi H, Uchiyama S, Hashimoto S, Miyazaki K, Tsutsumi Y, Yamazaki M, et al.
Clinical characteristics of stroke patients with antiphospholipid antibodies.
Cerebrovasc Dis 2005;19:384–90.
[9] Martinez HR, Rangel-Guerra RA, Marfil LJ. Ischemic stroke due to deficiency of
coagulation inhibitors. Report of 10 young adults. Stroke 1993;24:19–25.
[10] Hart RG, Miller VT. Cerebral infarction in young adults. Stroke 1982;4:110–4.
[11] Adams Jr HP, Butler MJ, Biller J, Toffol GJ. Nonhemorraghic cerebral infarction in
young adults. Arch Neurol 1986;43:793–6.
[12] Lisovoski F, Rousseaux P. Cerebral infarction in young people. A study of 148
patients with early cerebral angiography. J Neurol Neurosurg Psychiatry 1991;54:
576–9.
[13] Adams Jr HP, Kappelle LJ, Biller J, Gordon DL, Love BB, Gomez F, et al. Ischemic
stroke in young adults. Experience in 329 patients enrolled in the iowa registry of
stroke in young adults. Arch Neurol 1995;52:491–5.
[14] Kristensen B, Malm J, Carlberg B, Stegmayr B, Backman C, Fagerlund M, et al.
Epidemiology and etiology of ischemic stroke in young adults aged 18 to 44 years
in northern Sweden. Stroke 1997;28:1702–9.
[15] Briley DP, Coull BM, Goodnight Jr SH. Neurological disease associated with
antiphospholipid antibodies. Ann Neurol 1989;25:221–7.
[16] Collins RC, Al-Mondhiry H, Chernik NL, Posner JB. Neurologic manifestations of
intravascular coagulation in patients with cancer. A clinicopathologic analysis of
12 cases. Neurology 1975;25:795–806.
[17] Kim SG, Hong JM, Kim HY, Lee J, Chung PW, Park KY, et al. Ischemic stroke in
cancer patients with and without conventional mechanisms: a multicenter study
in Korea. Stroke 2010;41:798–801.
[18] Arquizan C, Lamy C, Mas JL. Simultaneous supratentorial multiple cerebral
infarctions. Rev Neurol (Paris) 1997;153:748–53.
[19] Tatlisumak T, Fisher M. Hematologic disorders associated with ischemic stroke.
J Neurol Sci 1996;140:1–11.
[20] Carobbio A, Finazzi G, Guerini V, Spinelli O, Delaini F, Marchioli R, et al.
Leukocytosis is a risk factor for thrombosis in essential thrombocythemia:
interaction with treatment, standard risk factors, and JAK2 mutation status.
Blood 2007;109:2310–3.
[21] De Stefano V, Za T, Rossi E, Vannucchi AM, Ruggeri M, Elli E, et al. Recurrent
thrombosis in patients with polycythemia vera and essential thrombocythemia:
incidence, risk factors, and effect of treatments. Haematologica 2008;93:372–80.
[22] Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, et al. Widespread occurrence
of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood
2005;106:2162–8.
[23] Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, et al. Efficacy and
safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350:114–24.
[24] Squizzato A, Romualdi E, Middeldorp S. Antiplatelet drugs for polycythaemia vera
and essential thrombocythaemia. Cochrane Database Syst Rev 2008;2:CD006503.
[25] Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, et al.
Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia.
N Engl J Med 2005;353:33–45.
[26] Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with
cancer. Medicine (Baltimore) 1985;64:16–35.
[27] Cestari DM, Weine DM, Panageas KS, Segal AZ, DeAngelis LM. Stroke in patients
with cancer: incidence and etiology. Neurology 2004;62:2025–30.
[28] Seok JM, Kim SG, Kim JW, Chung CS, Kim GM, Lee KH, et al. Coagulopathy and
embolic signal in cancer patients with ischemic stroke. Ann Neurol 2010;68:
213–9.
[29] Vesely SK, George JN, Lämmle B, Studt JD, Alberio L, El-Harake MA, et al.
ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic
syndrome: relation to presenting features and clinical outcomes in a prospective
cohort of 142 patients. Blood 2003;102:60–8.
[30] Rinkel GJ, Wijdicks EF, Hene RJ. Stroke in relapsing thrombotic thrombocytopenic
purpura. Stroke 1991;22:1087–9.
[31] Gruber O, Wittig L, Wiggins CJ, von Cramon DY. Thrombotic thrombocytopenic
purpura: MRI demonstration of persistent small cerebral infarcts after clinical
recovery. Neuroradiology 2000;42:616–8.
[32] Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Semin
Thromb Hemost 2003;29:467–71.
[33] Recht L, Mrugala M. Neurologic complications of hematologic neoplasms. Neurol
Clin 2003;21:87–105.
[34] 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.
[35] Kastenbauer S, Wiesmann M, Pfister HW. Cerebral vasculopathy and multiple
infarctions in a woman with carcinomatous meningitis while on treatment with
intrathecal methotrexate. J Neurooncol 2000;48:41–5.
[36] Brey RL. Antiphospholipid antibodies in young adults with stroke. J Thromb
Thrombolysis 2005;20:105–12.
[37] Janardhan V, Wolf PA, Kase CS, Massaro JM, D'Agostino RB, Franzblau C, et al.
Anticardiolipin antibodies and risk of ischemic stroke and transient ischemic
attack: the Framingham cohort and offspring study. Stroke 2004;35:736–41.
[38] Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, Julian JA, et al. A
comparison of two intensities of warfarin for the prevention of recurrent
thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J
Med 2003;349:1133–8.
[39] Hankey GJ, Eikelboom JW, van Bockxmeer FM, Lofthouse E, Staples N, Baker RI.
Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke
2001;32:1793–9.
[40] Hankey GJ, Eikelboom JW. Editorial comment — routine thrombophilia testing in
stroke patients is unjustified. Stroke 2003;34:1826–7.
[41] Allroggen A, Dittrich R, Ritter M, Dziewas R, Junker R, Nabavi DG. Homozygosity
for factor V Leiden mutation and ischemic stroke: two case-reports and review of
the literature. J Neurol 2004;251:1406–7.