Maturitas 122 (2019) 44–50

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Maturitas
journal homepage: www.elsevier.com/locate/maturitas

Cryptogenic stroke – How to make sense of a non-diagnostic entity T

⁎
Ursula G. Schulz
Centre for the Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK

A R T I C LE I N FO A B S T R A C T

Keywords: Secondary preventive strategies in ischaemic stroke depend on the underlying aetiology. However, approxi-
Ischaemic stroke mately one-third of ischaemic strokes remain unexplained, or ‘cryptogenic’. There is a wide range of possible
Risk factors underlying causes in cryptogenic stroke, and the best approach to secondary prevention of these may differ. To
Aetiology date, though, the widely accepted and uniform secondary preventive strategy in this group consists of mod-
ification of vascular risk factors, and of treatment with a combination of antiplatelet therapy and anti-
hypertensive and lipid-lowering medication.
Among the potential causes for cryptogenic stroke are occult atrial fibrillation, patent foramen ovale, atrial
cardiopathy, aortic arch atheroma and hypercoagulable states. While it is possible to diagnose these conditions,
in individual patients there is often uncertainty over whether they have a directly causative role, are markers of
disease, or are innocent bystanders. Similarly, even if the cause is found, the best secondary preventive strategies
remain uncertain, which questions the benefit of extensive investigations in a clinical setting. More recently, the
concept of “embolic stroke of unknown source (ESUS)” has been introduced, in the hope that anticoagulation
may offer better secondary prevention than antiplatelet therapy, but trials so far have been negative.
At present, there is little justification for introducing extensive new investigative strategies into the man-
agement of patients with cryptogenic stroke. Investigations should be targeted at identifying those high-risk
conditions which lead to a change in management. Further investigations need to be tailored individually,
according to clinical circumstances. This should include identifying patients for participation in clinical trials, as
the significance and best management of many of the potential causes for cryptogenic stroke require further
research.

1. Background on the classification system that is used. The TOAST classification

Ischaemic stroke is common, and the risk of recurrent stroke is high
[1,2]. Secondary prevention strategies depend on the underlying ae-
tiology. Approximately one third of ischaemic strokes remain un-
explained or cryptogenic [3,4]. In this group, the widely accepted
secondary preventive strategy consists of modification of vascular risk
factors, and of treating patients with a combination of antiplatelet
therapy, antihypertensive and lipid-lowering medication [1]. However,
there is a wide range of possible underlying causes in cryptogenic
stroke, and the best approach to secondary prevention of these may
differ. This paper reviews the diagnosis of cryptogenic stroke, explores
the range of potential aetiologies, and how this may impact on in-
vestigation and treatment strategies in the future.
2. Definition and prevalence of cryptogenic stroke
The definition of stroke subtype and of cryptogenic stroke depends
system is widely used, and easy to apply in a clinical setting [5]. It
classifies strokes as being due to large vessel disease, small vessel dis-
ease, cardiac embolism, other defined causes, or as being of un-
determined aetiology. A stroke can be of undetermined aetiology if it
has more than one possible cause, if aetiological investigations have
been incomplete, or if despite extensive investigations no cause has
been found. Since its inception in 1993, the TOAST classification has
been updated, and other classification systems have been introduced
[6]. These can broadly be divided into “causative” (attempt to identify
the one most likely aetiology) and “phaenotypic” (assign a degree of
probability to each possible stroke aetiology). The definitions and re-
quired investigations for each of the aetiological categories can differ
between classification systems. For example, the TOAST classification
requires the presence of ≥50% atheromatous stenosis of a major brain
artery to classify a stroke as due to large vessel disease, whereas the CCS
classification also accepts < 50% stenosis if there is concomitant plaque
ulceration [6]. Clearly, the criteria and the extent of investigations

⁎
Corresponding author.
E-mail address: ursula.schulz@ndcn.ox.ac.uk.

https://doi.org/10.1016/j.maturitas.2019.01.004
Received 2 January 2019; Accepted 10 January 2019
0378-5122/ © 2019 Elsevier B.V. All rights reserved.
U.G. Schulz
required to assign a stroke to a defined aetiological category will de-
termine the proportion of strokes that remain undefined. So far, there is
no wide consensus which classification to use, which explains the dif-
ferent proportions of unexplained stroke between aetiological studies of
stroke. Nevertheless, the proportion of strokes that remain “crypto-
genic” or unexplained despite sufficient investigation is frequently
around 30% [3,4,7].
3. Demographic factors and risk factor profiles in cryptogenic
stroke
Several studies have reviewed demographic and risk factor profiles
for cryptogenic stroke patients. The Northern Manhattan Stroke Project
found a higher proportion of cryptogenic stroke in patients younger
than 45 years compared to those of age 45 years or older [8]. This
finding was not confirmed in other studies, which found a higher pro-
portion of cryptogenic stroke in older patients [9,10]. A recent popu-
lation based study of 2555 patients with TIA or ischaemic stroke in
Oxford found that patients with cryptogenic events (mean age 70.4
years) were younger than patients with either large vessel (73.3 years)
or cardioembolic aetiology (77.9 years), and of a similar age as patients
with small vessel aetiology (69.7 years). They were older than patients
who had strokes of other defined aetiology (56.7 years). The pattern
that patients with “other” defined aetiology are younger than the re-
maining aetiological subgroups is also seen in other studies, with age
differences between patients with cryptogenic stroke and patients with
large vessel, small vessel or cardioembolic stroke less consistent and
less marked [4,11]. The age distribution among patients with crypto-
genic stroke does not allow any conclusions to be drawn with regards to
a potential predominant underlying aetiology in this subgroup.
In the Oxford study, the proportion of cryptogenic events was the
same between men and women, and other studies also did not find any
sex differences in the prevalence of cryptogenic stroke [4,7]. This is
despite other aetiological subgroups showing sex differences in their
prevalence: cardioembolic stroke occurs more frequently in women,
whereas strokes due to large vessel and to small vessel disease tend to
be more common in men [12]. The higher incidence of cardioembolic
stroke is generally thought to be due to a higher prevalence of atrial
fibrillation in older age, and a higher age specific stroke incidence in
women [13]. Furthermore, there are several factors unique to women,
which influence stroke risk. These include exposure to endogenous and
exogenous hormones, late effects of pregnancy related complications
such as gestational diabetes or pre-eclampsia, and the menopause [14].
The potential mechanisms by which these factors confer changes in
stroke risk are multiple. They include vascular protective effects of
oestrogen pre-menopause, a higher risk of developing hypertension
post-menopause, and a higher sensitivity to vascular risk factors such as
hyperlipidaemia. All of these may differentially increase the risk of
certain stroke subtypes between men and women, and could also result
in sex differences in the distribution of potential aetiologies for cryp-
togenic stroke patients [14,15].
In the Oxford study, the prevalence of vascular risk factors, such as
hypertension, diabetes mellitus, hypercholesterolaemia and smoking,
was lower in the cryptogenic group compared to those with established
stroke aetiology [7]. The low prevalence of traditional vascular risk
factors in cryptogenic stroke was also found in other studies [3]. In
addition, the Oxford study found that, compared to patients with events
due large or small vessel disease, patients with cryptogenic events had
fewer markers of cardiac embolism, such as minor echocardiographic
abnormalities, new atrial fibrillation or presumed cardioembolic events
during follow-up [7].
The Oxford study found an 8.8% risk of recurrent ischaemic stroke
following cryptogenic stroke at 1 year. This increased to 23.2% at 5
years, and 28.6% at 10 years. These risks did not differ significantly
from the risk of recurrence in stroke of defined aetiology, and they were
similar to the risks reported in other studies [7].
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Maturitas 122 (2019) 44–50
4. Potential causes of cryptogenic stroke
There are multiple potential causes of cryptogenic stroke, and at-
tempts have been made to identify common themes, that may help to
determine the most effective secondary prevention strategies for a large
group of people. While it has been suggested that a large number of
cryptogenic strokes are caused by atherothrombotic disease, this is
made less likely by the low prevalence of vascular risk factors among
cryptogenic stroke patients compared to other aetiological groups.
Similarly, the idea that cardiac embolism accounts for many crypto-
genic strokes is made less likely by the low prevalence of minor echo-
cardiographic abnormalities in this group, and the low rate of presumed
cardioembolic events during follow-up [7]. Risk factor profiling hence
does not point towards a predominant type of pathological process
among cryptogenic stroke patients, and emphasizes the importance of
further research in this patient group.
Several studies have suggested that a large proportion of crypto-
genic strokes is due to embolic events, either from cardiac or athero-
thrombotic sources. On this basis, the concept of ESUS (Embolic Stroke
of Unknown Source) was formed [16]. This is defined as a nonlacunar
stroke not associated with significant stenosis in a feeding artery in the
absence of a high-risk cardioembolic source or other known cause
[16,17]. It takes into account that several low-risk embolic sources will
often co-exist in individual patients, and that it will not be possible to
determine the causative embolic source in individuals with certainty.
As embolism is the common mechanism, however, ESUS may be suf-
ficiently uniform for a common secondary preventive strategy. Trials
are currently under way and will be referred to later in this paper in
Section 6.
The mechanisms implicated in cryptogenic stroke often carry a re-
latively low risk of causing a stroke on a population basis, but may well
be causative in individuals. Among the potential mechanisms, occult
atrial fibrillation, paradoxical embolism through a patent foramen
ovale (PFO), and non-stenotic atheromatous disease have recently re-
ceived particular attention.
4.1. Occult atrial fibrillation
The risk of recurrent cardioembolic events can be significantly re-
duced with anticoagulation [1,2]. As antiplatelet therapy is the main-
stay in secondary stroke prevention, it is important to identify strokes of
probable cardioembolic aetiology, as this would result in a change in
management.
Cardiac monitoring for at least 24 h to identify atrial fibrillation
(AF) is now a routine recommendation in various national stroke
management guidelines [1,2]. However, the optimum duration of car-
diac monitoring remains uncertain, as does the duration at which a run
of AF becomes clinically significant. Several studies have shown that
the frequency with which paroxysmal AF is found increases with the
time of monitoring: in the CRYSTAL-AF study, 441 patients with a
cryptogenic stroke or TIA in the preceding 90 days were randomised to
conventional follow-up or cardiac monitoring with an implantable loop
recorder. Time to detection of first atrial fibrillation with a duration of
at least 30 s was recorded. The detection rates at 6 and 12 months were
8.9% and 12.4% with an implantable loop recorder vs 1.4% and 2.0%
with conventional follow-up (hazard ratio, 7.3; 95% CI, 2.6–20.8;
P < 0.001) [18]. In the EMBRACE study, 572 patients with crypto-
genic stroke or TIA in the preceding 6 months were randomised to 24 h
Holter monitoring vs 30 day event triggered recording. The detection
rate for ≥30 s of AF was significantly higher with 30 day monitoring
compared to 24-h Holter monitoring (16.1% versus 3.2%; P < 0.001)
[19]. The significance of these short episodes, which may occur a long
time after the index event, is uncertain, as is the best preventive
strategy for stroke in these patients, as many patients with atrial fi-
brillation will also have evidence of atheromatous disease. The ongoing
ARTESIA study randomises patients at high risk of stroke, and with at
U.G. Schulz
least 6 min of AF on continuous monitoring, to treatment with antic-
oagulation (Apixaban) vs aspirin to determine whether oral antic-
oagulation therapy with apixaban reduces the risk of stroke or systemic
embolism in patients with subclinical AF and additional risk factors
[20].
4.2. Atrial cardiopathy
While there is a clear association between the presence of atrial fi-
brillation and risk of ischaemic stroke, the temporal relationship be-
tween the occurrence of AF and stroke onset is often only circum-
stantial. In the ASSERT study, while there was an association between
risk of stroke and presence of occult AF, only 25% of patients were in
AF in the 30 days prior to their embolic event [21]. This has led to the
suggestion that rather than being the direct cause of thromboembolism,
atrial fibrillation is a marker of atrial dysfunction [22]. This could lead
to thrombus formation in the left atrium even in the absence of AF.
Several biomarkers for atrial cardiopathy are currently under review.
These include imaging markers, such as left atrial enlargement, spon-
taneous echo contrast in the left atrium, and changes in the left atrial
appendage. Furthermore, ECG markers, such as paroxysmal supraven-
tricular tachycardia and increased P-wave terminal force in V1 have
been proposed. Finally, N-Terminal pro-Brain Natriuretic Peptide
(NTpro-BNP) is a serum marker of cardiac disease and has also been
found to be independently associated with atrial fibrillation. All of these
markers are still relatively novel, and their predictive value and po-
tential impact on secondary preventive strategies remain to be estab-
lished [22].
4.3. Patent foramen ovale
Paradoxical embolism through a patent foramen ovale (PFO) is a
potential mechanism for otherwise unexplained stroke. However, given
that a PFO is present in about 25% of the general population, the causal
relationship in individual patients with cryptogenic stroke and a coin-
cidental PFO is uncertain. According to the RoPE-score (Risk of
Paradoxical Embolism), the likelihood that a stroke occurred because of
paradoxical embolism is higher in younger patients, and also higher,
the fewer vascular risk factors (smoking, diabetes, hypertension, prior
TIA or stroke) the patient has [23]. The two year risk of recurrent stroke
or TIA was lowest in those with the highest probability of their index
event being related to their PFO, compared to those who were unlikely
to have had a PFO-related event, and who had a higher risk of recur-
rence (2% vs 20%, respectively).While the RoPE score suggests that a
PFO is mainly a risk factor for stroke in young people, a recent popu-
lation based study found that PFO associated risk may persist into older
age. The study reported a higher prevalence of a right-to-left shunt in
patients with cryptogenic stroke and TIA, compared to those in whom
the cause was known (37% vs 23%, Odds ratio 1.3 [95% CI 1.32–2.82],
p = 0·001) [24].
There are several PFO-related characteristics that may indicate a
higher risk of being related to a current stroke, or a higher risk of future
events. The presence of an interatrial septal aneurysm has been most
commonly reported. Bigger shunt size, the presence of a Chiari net-
work, and prominent Eustachian valves have also been proposed as
increasing stroke risk, but studies have been inconsistent [3].
Transoesophageal echocardiography is generally seen as the method
of choice to diagnose a PFO, but is invasive and has risks. Transthoracic
echocardiography with bubble contrast is commonly used, but may at
times only offer limited views. Transcranial Doppler with bubble con-
trast is less invasive and can identify right-to-left shunts, although
cannot visualise the PFO. Given that up to 95% of right-to-left shunts
are related to a PFO, a positive transcranial Doppler study is a strong
indicator of the presence of a PFO, and may prompt more detailed
cardiac imaging if PFO closure is considered. In recent years, cardiac
MRI has become more readily available to diagnose potential cardiac
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Maturitas 122 (2019) 44–50
causes of ischaemic stroke, including the presence of a PFO [25,26].
Previous studies of the benefit of PFO closure were equivocal, but a
recent meta-analysis of five randomised controlled trial showed that
PFO-closure and antiplatelet therapy reduced the risk of recurrent
stroke compared to antiplatelet therapy alone. Over a mean-follow up
of 4.1 years, the risk of recurrent stroke was reduced by 58% (RR 0.42,
95% CI 0.20 to 0.91, p = 0.03), with a number needed to treat (NNT) of
38 [27]. However, there was also an increase in device related com-
plications, and in newly diagnosed atrial fibrillation. Furthermore, it
remains uncertain if the higher use of dual antiplatelet therapy in the
device closure group might have contributed to the lower risk of early
recurrent events. The relatively high NNT, together with the high pre-
valence of PFO in the general population highlights the need for further
studies to identify those in whom the stroke is causally related to the
PFO, and who are therefore most likely to benefit from PFO closure.
4.4. Aortic arch atheroma
There is an association between the presence of aortic arch
atheroma and ischaemic stroke, and circumstantial evidence that aortic
arch atheroma is a risk factor or potential cause of ischaemic stroke.
Parts of the atheromatous deposits may embolise, or the irregular sur-
face of complex plaque may give rise to thrombus formation and sub-
sequent embolisation.
A large post-mortem study showed a higher prevalence of aortic
arch atheroma in patients dying from cerebrovascular disease com-
pared to other neurological causes (28% vs 5%), and a higher pre-
valence of aortic arch atheroma in patients dying from stroke of un-
known cause vs having an identified cause (61% vs 22%) Similar
associations were reported in a case-control study of transoesophageal
echocardiography. Stroke patients had a higher prevalence of aortic
arch atheroma than matched controls without stroke (14% vs 2%), and
the prevalence of aortic arch atheroma was particularly high in those
with unexplained stroke (28% vs 8%) [28]. Several studies have shown
an association between plaque size and morphology and stroke risk.
Plaque of > 4 mm thickness or ulcerated, protruding plaque is asso-
ciated with a 3–4 fold higher stroke risk than mild or moderate plaque
of < 4 mm thickness (12–15% vs 3–5%) [28,29].
The best imaging technique for aortic arch atheroma remains con-
troversial. Transoesophageal echocardiography is widely seen as the
gold standard, but has risks. This also applies to catheter angiography,
which may directly dislodge plaque and cause embolization. CT or MR-
angiography provide good resolution, make it possible to image larger
parts of the vasculature than transoesophageal echocardiography, and,
depending on the protocol, can provide detail about plaque composi-
tion and surface. However, it remains to be determined if any addi-
tional imaging specifically aimed at further defining the presence and
severity of aortic arch atheroma adds diagnostic and therapeutic value
to the management of stroke patients.
Currently, only few data on the management of aortic arch
atheroma exist. Surgical techniques, such as stenting or en-
darterectomy, have a high risk, and have not shown any benefit [1].
Observational studies suggest that statins may reduce the risk of re-
current events. The Aortic Arch Related Cerebral Hazard (ARCH) trial
compared dual antiplatelet therapy (aspirin and clopidogrel, each
75 mg daily) with anticoagulation (warfarin, INR 2–3) in patients with
aortic arch atheroma > 4 mm or with a mobile component. The trial
had to be stopped early, due to slow recruitment and lower than ex-
pected event rates. There was a non-significant trend for vascular
events being less frequent in the antiplatelet arm, but this was seen as
hypothesis generating rather than conclusive [30].
At present, there is still uncertainty whether aortic arch atheroma
should be seen as a marker of atheromatous disease, contributing to the
large vessel aetiology of ischaemic stroke, or whether it is a unique
entity, which requires separate treatment. Until further data become
available, the recommended secondary preventive strategy mirrors that
U.G. Schulz
for atheromatous disease in general, and includes antiplatelet drugs,
statins, antihypertensives and risk factor modification [1].
4.5. Non-stenotic arteriosclerotic disease
In the currently used classifications of stroke aetiology, stroke is
classified as being due to large vessel atheroma if there is vascular
stenosis of at least 50% [5,6]. However, atheromatous plaque
causing < 50% stenosis can also give rise to artery-to-artery embolism.
Several studies have suggested that complex plaque, with intra-plaque
haemorrhage identified on MR-angiography, is a risk factor for stroke.
They found complex plaque more commonly ipsilateral than con-
tralateral to an acute stroke, although this was not confirmed by others
[31]. A CT-angiogram study found a higher prevalence of thick, non-
stenosing plaque in the ipsilateral compared to the contralateral,
asymptomatic carotid artery [32]. Finally, a combined MRI and FDG-
PET study showed increased FDG uptake in plaques identified as vul-
nerable on MRI, and reported that vulnerable plaque was more
common ipsilateral than contralateral to an acute stroke [33].
These studies provide some evidence that unstable, non-stenotic
plaque may cause atheroembolic stroke. However, the best imaging
technique to identify unstable plaque still needs to be determined.
Furthermore, the clinical relevance of using advanced techniques for
plaque imaging is currently uncertain, as the recommended secondary
preventive strategy in atheromatous disease (antiplatelet drugs and
statins) mirrors that for cryptogenic stroke.
4.6. Pro-thrombotic and hypercoagulable states
Hypercoagulable states can be due to inherited and due to acquired
factors. While the role of inherited thrombophilias in venous throm-
botic disease is well established, their association with arterial occlusive
disease is less understood. This shows the difficulty of establishing a
clear link between a single genotype and the risk of cardiovascular
disease, which is due to multiple factors. As an example, hyperhomo-
cysteinaemia is frequently associated with a point mutation in the
MTHFR-gene, and it is also associated with an increased risk of vascular
events, but so far a clear association between the point mutation and
vascular risk has not been confirmed [34]. A large meta-analysis
showed that, in addition to their role in venous events, factor V Leiden
and prothrombin G20210 A gene mutations are also associated with a
moderate risk increase for coronary arterial events [35]. As an acquired
pro-thrombotic state, anti-phospholipid syndrome increases the risk for
venous and arterial thrombotic events. Further acquired pro-thrombotic
states are related to medication, such as the oral contraceptive pill,
inflammation, dehydration, or a smoking history. Given the multiplicity
of contributing factors, specific testing for pro-thrombotic conditions
should be restricted to patients with a high pre-test probability, and
tends to be advised for those of younger age, with recurrent un-
explained events, and in the absence of usual vascular risk factors [34].
When conducting thrombophilia testing, it is important to bear in
mind that some tests (Protein C, Protein S) can be falsely abnormal in
the acute phase and testing should be delayed for several weeks, and for
when a patient is off anticoagulation. Similarly, an initially positive
antiphospholipid antibody result needs to be confirmed three months
later.
The best management of stroke patients in whom a pro-thrombotic
condition is diagnosed is uncertain. The evidence for using antic-
oagulation over antiplatelet therapy is limited for inherited thrombo-
philias, whereas limited trial data suggest that anticoagulation does not
confer any benefit over aspirin in patients with antiphospholipid syn-
drome and cryptogenic stroke. Nevertheless, current guidelines re-
commend anticoagulation for stroke patients with a thrombophilia [1].
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Maturitas 122 (2019) 44–50
4.7. Malignancy and stroke
Patients with a malignancy have a higher risk of stroke [3,4]. Pos-
sible mechanisms include hypercoagulability, or, more rarely, embo-
lism from marantic endocarditis, tumour embolism or disseminated
intravascular coagulation. More recent studies also suggest a role of
atherosclerosis, potentially as a result of stroke treatment and post-ra-
diation vascular changes.
Strokes related to malignancy often affect multiple vascular terri-
tories. Occult malignancy should be considered in patients with re-
current unexplained strokes, especially in older age groups and if there
are other factors suggesting malignancy, such as weight loss.
Investigations should be led by the clinical findings, and include CT-
scanning of chest, abdomen and pelvis.
Treatment of the underlying malignancy may reduce the risk of
recurrent stroke. There is less certainty about the best medication for
secondary prevention. On the assumption of an underlying hypercoa-
gulable state, some authors recommend that anticoagulation is used,
and on the basis of small case series, low molecular weight heparin is
favoured over vitamin K antagonists. More recent studies, which sug-
gest a role of atheroma in malignancy related stroke, favour antiplatelet
therapy. Trial evidence is lacking [4].
4.8. Migraine and stroke
A two-fold increased risk of ischaemic stroke has been described in
people with migraine [36,37]. This is only present in migraine with
aura, and more marked in women compared to men. In the Nurses’
Health Study II, a higher prevalence of conventional vascular risk fac-
tors was found in women with migraine [38]. As this and other studies
corrected for such risk factors, it is unlikely that they would entirely
explain the higher risk for stroke. Nevertheless, the risk for stroke seems
to be particularly high in women who have migraine with aura, who
smoke, and who are on the oral contraceptive pill. Smoking cessation
should be strongly recommended in this setting, and the use of alter-
native contraceptive methods should be considered, alongside general
control of vascular risk factors [36,37].
Some studies have reported an association of migraine with aura
with a patent foramen ovale (PFO). As PFOs have also been implicated
as a potential cause for cryptogenic stroke, one hypothesis is that the
presence of a PFO may explain the higher stroke risk in migraine pa-
tients, but this remains unproven [37,39].
Overall, the reasons for the association between migraine and stroke
risk remain elusive. Mechanisms that have been considered include
common genetic factors, hypercoagulability, inflammatory processes,
and anatomical vascular variants. Similarly, there is no specific primary
prevention strategy for stroke in patients with migraine, other than
control of vascular risk factors, particularly smoking in women with
migraine with aura [36,37].
4.9. Genetic factors
About 1% of strokes are thought to have an underlying genetic
cause. Genetic conditions should be considered in the appropriate set-
ting, for example in younger patients with otherwise unexplained
stroke and a relevant family history. Fabry’s disease is an x-linked ly-
sosomal storage disorder due to alpha-galactosidase A deficiency. It is
associated with multiple problems, including a vasculopathy, leading to
cerebral small vessel disease and strokes, which typically affect the
posterior circulation. As outcome may be improved by enzyme re-
placement therapy, testing needs to be considered in the appropriate
setting [40]. Other monogenetic causes of stroke exist, specifically as-
sociated with cerebral small vessel disease. Treatment and preventive
options are limited, but recognition is important for ongoing support
and to enable genetic counselling [41]. In most cases, an individual’s
risk of stroke will be influenced by multiple genetic factors, each
U.G. Schulz
conferring a small modification in risk, and interacting with multiple
environmental factors.
4.10. Autoimmune and rheumatological causes
Similar to genetic conditions, autoimmune conditions are rare, but
need to be considered in patients with otherwise unexplained stroke
and suggestive clinical factors or investigation results. The causative
link can be very clear, for example, in conditions directly affecting the
cerebral blood vessels, such as large or small vessel vasculitis. In other
autoimmune conditions, an increased risk of stroke is conferred by
multiple mechanisms. For example, 20% of patients with systemic lupus
erythematosus (SLE) suffer a stroke. This increased risk of stroke can
partly be explained by directly disease related factors, such as an as-
sociation with antiphospholipid antibodies, endothelial changes, or
endocarditis related cardiac embolism, but also by the disease leading
to an increase in more generic risk factors, such as hypertension, hy-
percoagulability, and accelerated atherosclerosis [42]. While more
difficult to define, such factors may well play a role in patients who
have been classified as having a cryptogenic stroke.
5. Investigation strategies in cryptogenic stroke
The aim of investigations following a stroke is to identify high-risk
conditions that have a clear association with stroke, and whose iden-
tification will influence management. For example, carotid imaging
aims to identify carotid stenosis and may prompt endarterectomy, and
cardiac monitoring may identify atrial fibrillation and prompt antic-
oagulation rather than antiplatelet therapy [1]. There is, however, little
agreement in what constitutes the best approach to investigate patients
with stroke, and investigations strategies vary widely, even in high
income countries [43,44]. Particular areas of variability include CT- vs
MRI-based imaging protocols, the extent of vascular imaging, especially
if intracranial vascular imaging should be done routinely, the duration
of cardiac monitoring, the use and modality of cardiac imaging, and the
extent of blood tests that are used, such as thrombophilia screening.
For the conditions that have been proposed to have a role in patients
with cryptogenic stroke, the causative relationship with stroke, and risk
of subsequent stroke is not clear cut. For example, the significance of
short runs of atrial fibrillation on prolonged cardiac monitoring remains
uncertain. In addition, even if such conditions are found, then it is not
clear how this would influence management. For example, there is no
established benefit of anticoagulation over antiplatelet therapy in aortic
arch atheroma, and treatment reflects the standard secondary pre-
ventive therapy for stroke [1,30].
At present, the minimum investigation of stroke patients should be
geared towards identifying high-risk causes of stroke for which there is
an established treatment. This will include brain and vascular imaging,
as well as ECG-monitoring and, in most places, also echocardiography
[1]. Further investigations should be done as suggested by clinical
circumstance, for example, specific MRI techniques if an arterial dis-
section is suspected. Currently, there is little place for the routine use of
further potentially expensive and invasive investigation techniques,
such as prolonged cardiac monitoring, transoesophageal echocardio-
graphy, or cardiac MRI. Similarly, extensive genetic and autoimmune
screening should not be done routinely. Their use should be limited to
selected cases in the appropriate setting, and also needs to form part of
further research to inform the relevance and best treatment of different
investigation findings in patients with cryptogenic stroke [44].
6. Secondary preventive treatment
The standard secondary preventive treatment for patients with a
cryptogenic ischaemic stroke consists of antiplatelet therapy, statins,
and antihypertensive medication, as well as risk factor modification
[1,2]. The aim of any investigative and treatment studies is to identify
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subgroups of patients who may benefit from a different treatment re-
gimen. This will usually consist of anticoagulation instead of anti-
platelet therapy, or potentially of an invasive treatment, such as device
closure of a PFO, which has already been discussed above (Section
4.3.).
Anticoagulation reduces the risk of recurrent stroke in atrial fi-
brillation, although its benefit in “occult AF” found on prolonged car-
diac monitoring remains to be established. In non-valvular AF, direct
oral anticoagulants (DOACs) have over the past years become the
treatment of choice, but for other sources of cardiac embolism, Vitamin
K antagonists remain the first-line treatment.
From the limited trial data available up to now, anticoagulation
does not confer any added benefit in patients with non-stenosing
atheroma or aortic arch atheroma [30,45]. Any small risk reduction in
ischaemic events is made up for by an increase in haemorrhagic events.
These trials were conducted with Vitamin K antagonists. Whether
DOACs, with their lower risk of haemorrhage, may provide an ad-
vantage over antiplatelet agents in this setting, remains to be estab-
lished.
Several trials are investigating if anticoagulation with DOACs for
patient with embolic stroke of unknown source (ESUS) reduces the risk
of recurrent stroke compared to antiplatelet therapy. The NAVIG-
ATE-ESUS trial, which compared Rivaroxaban with aspirin, was
stopped early due to an excess rate of bleeding in the Rivaroxaban
group (annualised rate 1.8% vs 0.7%, p < 0.001). This was not set off
by a reduction in recurrent ischaemic stroke, which had an annualised
rate of 4.7% in both treatment groups [46]. The preliminary results for
the RE-SPECT ESUS trial, which compared Dabigatran with aspirin
were recently presented, but have not yet been published. In this study,
Dabigatran was not superior to aspirin for the prevention of recurrent
stroke. There was no statistically significant excess in major haemor-
rhage in the Dabigatran group ([47], initial results presented at World
Stroke Congress, Montreal, October 2018) A further trial, ATTICUS, is
ongoing, and will compare the occurrence of new ischaemic lesions on
MRI in patients with ESUS, who will be randomised to either aspirin or
Apixaban [48].
These negative trial results suggest that cardiac embolism including
occult AF only forms a relatively minor part of patients with crypto-
genic stroke, or that anticoagulation in these patients does not confer
any additional benefit over antiplatelet therapy. More detailed analyses
of these recent trials, and future research will be needed.
7. Conclusion
Cryptogenic stroke is not a diagnostic entity. It is a heterogeneous
group, with strokes due to multiple different potential aetiologies, for
which the causal relationship with stroke is less clear than for the
widely accepted aetiological groups, for example the presence
of > 50% vascular stenosis for large vessel stroke.
While some advocate to investigate each patient as fully as possible
to identify the underlying aetiology of a stroke, such wide ranging in-
vestigations in a third of all stroke patients would be costly, not ne-
cessarily widely available, and they would only have a limited impact
on treatment, as the best management for many of these conditions is
still uncertain. Another approach is therefore to find a common de-
nominator, such as “embolic mechanism” in ESUS, and to try and im-
prove secondary prevention for a larger subgroup of cryptogenic stroke
patients. Trials in ESUS so far have failed to find a better approach to
secondary prevention than the well-established combination of anti-
platelet therapy, and cholesterol lowering and antihypertensive treat-
ment.
At present, there is no clear justification to introduce new in-
vestigative strategies, for example long term cardiac monitoring or
routine use of transoesphageal echocardiography, into the management
for patients with cryptogenic stroke. Investigations should be targeted
at identifying those high risk conditions which lead to a change in
U.G. Schulz
management. Further investigations need to be tailored individually,
and this will be determined by the clinical circumstances, local avail-
ability, and potential impact on treatment. This should also include
identifying patients for participation in clinical trials, as the sig-
nificance and best management of many of the potential causes of
cryptogenic stroke still require further research.
Contributors
This is an invited narrative review of the topic by a single author,
who conducted the literature review, and who drafted and reviewed the
manuscript.
Conflict of interest
The author declares that she has no conflict of interest.
Funding
The author of this work was supported by the National Institute for
Health Research (NIHR)Oxford Biomedical Research Centre (BRC). The
views expressed are those of the author(s) and not necessarily those of
the NHS, the NIHR or the Department of Health.
Provenance and peer review
This article has undergone peer review.
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