WSO - April 2023 - 384

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International Journal of Stroke 18(4)
antiphospholipid antibodies (aPL), detected on two or more
consecutive occasions, at least 12 weeks apart.2 There is
clinical overlap with systemic lupus erythematosus (SLE),
with estimates that 7-15% of SLE patients also have APS.3,4
While SLE-associated APS exhibits female preponderance,
primary thrombotic APS is evenly distributed between
sexes.1 APS is typically diagnosed in younger patients, with
population-based studies suggesting a mean age at diagnosis
of around 50 years.1 Notably, late-onset APS may be
associated with a higher frequency of arterial thrombosis.5
Beyond thrombosis and obstetric morbidity, APS can be
also associated with a variety of other manifestations, including
neurological conditions, such as neuropsychiatric symptoms,
headache, seizures, movement disorders, multiple
sclerosis-like disease, transverse myelitis, peripheral neuropathy,
and autonomic symptoms. These, and their possible
pathogenetic mechanisms, have been discussed elsewhere.6
We focus here on APS-associated stroke and other cerebrovascular
disorders.
APS-associated cerebrovascular
disorders
Acute ischemic stroke and transient
ischemic attacks
Acute ischemic stroke (AIS) and transient ischemic attack
(TIA) are the most common manifestations of arterial
pathology in APS,7 with approximately 20% of patients
with APS suffering a stroke more than 10 years.8 In individuals
aged below 50 years, 17% of strokes and 12% of
TIA are associated with aPL,9 suggesting APS is an important
cause of strokes in younger patients.
Thrombosis is thought to be the most common mechanism,
with intracranial large arteries, particularly the
middle cerebral artery (MCA), being the most common site
of occlusion.10 Embolism from valvular heart disease
(Libman-Sacks endocarditis), extracranial carotid artery
lesions,11 vasculitis-like manifestations,12 chronic occlusive
vasculopathy affecting small- and medium-sized
intracerebral arteries,13 and carotid or vertebral artery dissection14
are also described.
The clinical picture depends on the arterial territory
involved. Moreover, in cases with retinal artery involvement,
eye events, such as branched or central retinal artery
occlusion, can also occur.15
Cerebral vein thrombosis
Cerebral vein thrombosis (CVT) is an uncommon manifestation
of APS (7 CVT in 1000 APS cases in the EuroPhospholipid
cohort)16. It has been estimated that about
80% of APS-associated CVT cases represent the first APS
clinical manifestation.17 CVT in APS patients seems clinically
similar to CVT by other causes, with the most affected
International Journal of Stroke, 18(4)
individuals being women.17,18 This highlights the importance
of aPL testing in CVT, even in cases with possible
alternative etiologies, as the literature reports coexistence of
multiple risk factors in CVT with APS,17 and increased
thrombotic risk in APS patients with additional risk factors.19,20
The presence of APS may also affect management.
Much like the general CVT patient population,21 in
APS-related CVT, the recurrence rate seems low; however,
patients can experience subsequent thrombosis in other
locations.17 Retinal veins can be involved, and branched or
central retinal vein occlusions have been described.15
Catastrophic antiphospholipid syndrome
Catastrophic antiphospholipid syndrome (CAPS) is a lifethreatening
variant seen in approximately 1% of APS
patients, characterized by rapid onset of multifocal, predominantly
microvascular, thrombosis (affecting three or
more organ systems within 1 week).22 Central nervous system
(CNS) involvement is frequent, along with renal, lung,
and cardiac involvement, with each found in more than
50% of cases in the international " CAPS Registry " .22 CNS
manifestations include ischemic and hypertensive encephalopathy,
ischemic stroke, and CVT.22
Cognitive impairment
Cognitive impairment, particularly involving memory,
attention, and executive functions, appears common, affecting
11-60% of APS patients, whether primary or SLEassociated,
although evidence is limited by the use of
heterogeneous neuropsychological tests and confounders,
such as age, gender, and education levels.23 Interestingly,
deficits in global cognition were found to be associated
specifically with anticardiolipin (aCL) positivity.23
Cognitive dysfunction might be explained by hypercoagulability
and occlusive thrombosis, due to aPL, causing
not only small vessel ischemic damage but also brain volume
loss. Indeed, the cognitive profile is similar to that
observed in vascular cognitive impairment, and cognitive
dysfunction seems to be associated with white matter
hyperintensities (WMH), ischemic lesions, and cortical
atrophy on structural magnetic resonance imaging (MRI).23
However, animal models of cognitive deficits following
exposure to aPL also suggest a possible direct pathogenic
effect of aPL.24,25
Other aPL-associated neurological manifestations
Reversible cerebral vasoconstriction syndrome, a neurovascular
disorder with headache and radiologically reversible
vasoconstriction, has been described in APS.26 The
hypothesis is that aPL may activate endothelial cells, causing
vasoconstrictor release.27 Sneddon's syndrome, a
rare non-inflammatory thrombotic vasculopathy affecting
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