Current Neurology and Neuroscience Reports (2021) 21:41

https://doi.org/10.1007/s11910-021-01124-z

NEUROLOGY OF SYSTEMIC DISEASES (J. BILLER, SECTION EDITOR)

Neurologic Manifestations of the Antiphospholipid

Syndrome — an Update
Miguel Leal Rato 1,2 & Matilde Bandeira 3,4 & Vasco C. Romão 3,4 & Diana Aguiar de Sousa 1,2,5

Accepted: 25 May 2021

# The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Abstract
Purpose of Review In recent years, the spectrum of neurological manifestations of antiphospholipid syndrome (APS) has been
growing. We provide a critical review of the literature with special emphasis on presentation, proposed mechanisms of disease,
and treatment of neurological involvement in APS.
Recent Findings Although stroke is the most common cause of neurological manifestations in patients with APS, other neurological
disorders have been increasingly associated with the disease, including cognitive dysfunction, headache, and epilepsy. Direct oral
anticoagulants have failed to show non-inferiority compared to vitamin K antagonists for the prevention of major thrombotic events.
Antiphospholipid antibodies are often found in patients with acute COVID-19 but clear evidence supporting an association between
these antibodies and the risk of thrombotic events, including stroke and cerebral venous thrombosis, is still lacking.
Summary APS patients may present with several distinct neurological manifestations. New criteria will facilitate the classifica-
tion of patients presenting with increasingly recognized non-criteria neurological manifestations.

Keywords Antiphospholipid . Thrombosis . Stroke . Headache . Anticoagulation

Introduction anticoagulant (LA), anticardiolipin (aCL), and anti-β2-

glycoprotein I antibodies (aB2GPI), among several others, all
Antiphospholipid syndrome (APS) is an immune-mediated of which directed against phospholipid-binding proteins [2].
disorder characterized by pregnancy morbidity and arterial or Overall, aPL are present in 1–5% of the general population,
venous thrombotic events associated with persistent with a higher prevalence in older subjects [3]. However, only
antiphospholipid antibodies (aPL) [1]. These include lupus a subset of patients actually develops APS [3]. The estimated
prevalence of APS is 40–50/100,000 subjects, with an inci-
Miguel Leal Rato and Matilde Bandeira contributed equally to this work. dence of 5 cases per 100,000 subjects per year [4]. APS is a
major cause of thrombosis, with a classically cited “20% rule,”
This article is part of the Topical Collection on Neurology of Systemic
Diseases
as it was said to account for up to 20% of unprovoked deep
vein thrombosis (DVT), 20% of strokes in young adults (<50
* Diana Aguiar de Sousa years), and up to 20% of women with recurrent fetal loss.
[email protected] These figures have been more recently updated to 20% of
DVT, 20–30% of strokes in young adults (<50 years), and
1
Neurology, Department of Neurosciences and Mental Health, 10–15% of women with recurrent fetal loss [5, 6].
Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa APS is usually divided into two groups: primary APS, also
Norte, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal
named Hughes syndrome, and secondary APS, associated
2
Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal with another systemic inflammatory rheumatic disease. In
3
Rheumatology Department, Hospital de Santa Maria, Centro fact, approximately 50% of patients with APS have a second-
Hospitalar Universitário Lisboa Norte, Lisbon, Portugal ary form in association with an inflammatory disease, most
4
Rheumatology Research Unit, Instituto de Medicina Molecular João commonly systemic lupus erythematosus (SLE) [7]. It has
Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, been shown that up to 10% of patients with primary APS
Lisbon, Portugal
are diagnosed with SLE within 10 years and redefined as
5
Instituto de Medicina Molecular João Lobo Antunes, secondary APS [8]. In turn, around a third of SLE patients
Lisbon, Portugal
 41 Page 2 of 13 Curr Neurol Neurosci Rep (2021) 21:41

have identifiable antiphospholipid antibodies, with roughly especially in the venous territory [20]. These are part of the
10% developing APS [9]. Infections and drugs, such as phe- so-called non-criteria aPL, some of which are displayed in
nothiazines, procainamide, quinine, and anti-TNF agents, are Table 2. Non-criteria aPL are generally not assessed in clinical
apparently able to induce aPL, usually transiently and without practice. However, they are currently an intense area of inves-
associated hypercoagulability [10–12]. Current classification tigation, with special attention on their relevance for the diag-
criteria require the presence of both clinical and laboratory nosis, pathogenesis, and phenotype of APS. Some have been
findings and are represented in Table 1 [1]. They may assist described to a greater extent, such as the phosphatidylserine-
but are not intended for diagnosis, which should always be dependent antiprothrombin antibody (aPS/PT). Studies have
established clinically by the attending physician [13]. shown an association between aPS/PT and thrombosis besides
In rare cases, catastrophic APS, also named Asherson syn- higher diagnostic sensitivity and specificity for APS when
drome, occurs as a rapidly progressive thromboembolic dis- compared to aCL [31]. It also seems to be relevant in throm-
ease characterized by the involvement of three or more organ bosis [32–35] and obstetric [36] risk stratification in APS [28,
systems, simultaneously or within 1 week, with histological 37].
evidence of predominant small vessel occlusion [14]. The most common location of arterial thrombosis is the
In addition to the clinical features considered in the classi- cerebral circulation, with ischemic stroke or transient ischemic
fication criteria, APS can present with other common non- attack (TIA) being the initial presentation in almost 30% of
criteria manifestations, including thrombocytopenia, livedo adults with APS [38•]. However, more recent evidence sup-
reticularis, arthralgia, or heart valve disease (mitral valve more ports the concept that APS-associated neurologic dysfunction
frequently involved) [15]. New criteria are being developed, extends beyond the classical thromboembolic events and is
including some of the aforementioned non-criteria manifesta- also related with immune-mediated vascular, inflammatory,
tions [16]. and direct neuronal effects [39]. Increased permeability of
Vascular thrombosis, the main clinical feature, can occur in the blood–brain barrier can be due both to small/microvessel
any tissue or organ, with a wide range of events and symptoms thrombosis, with subsequent ischemia, but also to the direct
that may include many neurological manifestations. effects of antiphospholipid antibodies [40]. These have been
This article summarizes the central and peripheral nervous shown to trigger leukoadhesion and complement activation,
system involvement in APS. further breaching this barrier and resulting in neurotoxicity
from cytokines and antibodies [40].
Risk factors for each clinical phenotype of neurological
Pathophysiology involvement have been suggested but are not yet fully under-
stood. In a recent study by Volkov et al. [21••], assessing the
Currently, over 30 different types of aPL are known [17, 18]. presence of 20 different aPLs and its correlation to different
B2GPI is recognized as one of the most relevant antigens in manifestations in APS, central nervous system (CNS) mani-
the pathophysiology of APS [19]. Autoantibodies targeting festations were shown to be correlated to a specific aPL pro-
this antigen are diverse, but the presence of anti-domain I file, with simultaneous positivity for IgG antibodies against
antibodies has been strongly correlated to thrombosis, prothrombin, phosphatidylglycerol, phosphatidylinositol, and

Table 1 Revised classification criteria for APS [1]

Clinical criteria (≥1 of the following)

Vascular thrombosis ≥1 clinical episodes of venous, arterial, or small vessel thrombosis in any tissue or organ

Pregnancy morbidity ≥1 unexplained deaths of a morphologically normal fetus at or beyond the

10th week of gestation
≥1 premature births of a normal neonate before the 37th week of gestation
caused by placental insufficiency (eclampsia or severe preeclampsia)
≥3 unexplained consecutive abortions before the 10th week of gestation
Laboratory criteria (≥1 of the following)
Lupus anticoagulant in plasma, on ≥2 occasions at least 12 weeks apart (detected according to the
International Society of Thrombosis and Haemostasis)
Anticardiolipin antibody (IgG or IgM) in serum or plasma and in medium or high titer on ≥2
occasions at least 12 weeks apart (measured by standardized ELISA)
Anti-β2-glycoprotein-I antibody (IgG or IgM) in serum or plasma and in high titer on ≥2
occasions at least 12 weeks apart (measured by standardized ELISA)
Curr Neurol Neurosci Rep (2021) 21:41 Page 3 of 13 41

Table 2 Non-criteria aPL and their association to APS manifestations

Non-criteria aPL Associated APS manifestation

Antibodies against prothrombin (aPT) Arterial thrombosis [21, 22] and disease severity [23]
CNS manifestations (copresence of aPT, aPG, aAN, and aPI) [21]
Considerably more prevalent in males [21]
aB2GPI (including IgA) Chorea in young female patients [24, 25]
Thrombosis [26]
Phosphatidylserine/prothrombin complex Strongly correlates with the presence of LA [27]
Arterial and venous thrombosis [28]
Thrombotic microangiopathy (considered a milestone for catastrophic APS) [28]
Anti-phosphatidylserine (aPS) Pregnancy morbidity (copresence with aCL) [21]
Anti-phosphatidylglycerol (aPG) CNS manifestations (copresence of aPT, aPG, aAN, and aPI) [21]
Anti-vimentin Disease severity [23]
Anti-annexin 5 (aAN) Pregnancy morbidity [21, 29]
CNS manifestations (copresence of aPT, aPG, aAN, and aPI) [21]
Anti-phosphatidic acid IgM inversely associated to venous thrombosis [21]
Fetal loss but not thrombosis [26]
Anti-phosphatidylinositol (aPI) CNS manifestations (copresence of aPT, aPG, aAN, and aPI) [21]
Significantly associated with thrombosis in patients with APS and SLE [30]
Anti-phosphatidylethanolamine (aPE) Disease severity [23]

annexin-5. Previous studies have also suggested a correlation Ischemic Stroke and TIA Stroke and TIA are the most common
between cognitive deficit and higher titers of aPLs [41]. forms of clinical manifestation related with arterial circulation
Female patients had a higher prevalence of migraine, while in APS [4, 38]. In the Euro-Phospholipid cohort, which in-
epilepsy was more common in men [42]. In turn, chorea was cluded 1000 patients, stroke had a reported prevalence of
more frequent in young female patients with APS carrying 20%; and TIA occurred in 11% of all patients [38•]. On the
aB2GPI [24, 25]. More studies, however, are needed to better other hand, the frequency of positive aPLs in stroke patients
understand which pathological pathways are involved in APS- ranges between 7% and 15% [43], with an apparent age-
associated neurological disease, as well as additional clinical dependent relationship between aPL positivity and stroke:
and biological predictors, including the value of non-criteria the mean age of aPL-positive stroke patients is younger than
aPLs [23]. the general population [44–46]; APS has been suggested to
account for a significant proportion of acute ischemic stroke in
young patients [47]; and the presence of aPL determines an
Neurological Manifestations of APS over 5-fold increase in cerebrovascular thrombotic events
(odds ratio [OR] of 5.48, 95% confidence interval [CI]: 4.42
The main neurological manifestations of APS are summarized to 6.79) in stroke patients under 50 years (median age of 37
in Fig. 1. years) [48]. In older patients, aPL positivity may be a less
significant risk factor due to the competing cardiovascular risk
Central Nervous System Manifestations factors, a differential effect between different aPLs, and bias
derived from study design, as studies often exclude pa-
Cerebrovascular Disease tients with cardioembolic stroke [49, 50]. The stroke
mechanism in APS is thought to be mostly either
Cerebrovascular disease is the most common cause of neuro- thrombotic or cardioembolic. Still, intracranial occlu-
logical manifestations in patients with APS and, as a throm- sions and stenosis are present in 50% of patients with
boembolic event, can be considered part of the clinical criteria APS and stroke [45], and a vasculitis-like pattern has
for classifying APS. It includes acute ischemic stroke and been observed, suggesting a concurrent vasculopathic
TIA, for which APS is a known risk factor; cerebral venous process in some cases [51–53]. Cardioembolic mecha-
thrombosis (CVT); and other less frequent disorders such as nisms include left-sided cardiac valve abnormalities (ir-
Sneddon’s syndrome and reversible cerebral vasoconstriction regular thickening due to immune complex deposition,
syndrome. vegetations, valve dysfunction) and, rarely, intracardiac
 41 Page 4 of 13 Curr Neurol Neurosci Rep (2021) 21:41

Seizures and Epilepsy

Epilepsy has a prevalence of around 6 to 9% in people with

APS [38, 68, 69]. Seizure risk differs between primary and
secondary APS, with a prevalence of epilepsy higher in the
latter (6% and 14%, respectively) [68]. In a group of 240
primary APS patients, seizures were part of the neurological
findings in 8% of the patients [70]. The exact pathogenesis of
seizures related to APS is unknown, in part due to the com-
bined inclusion of primary and secondary APS in most co-
horts. Nevertheless, there are several proposed mechanisms
including microthrombosis-induced ischemia leading to vas-
cular epilepsy, aPL neuronal binding and injury, aPL-
mediated inhibition of GABA receptors, and immune-
mediated neuronal damage [69, 71, 72]. Although there have
been several studies assessing the association of aPL with
seizures or epilepsy in primary and secondary APS patients,
results have been contradictory (see Noureldine et al. [72•] for
a review). Clinical manifestations are protean, and all types of
seizures may be reported, including electroencephalographic
abnormalities without clinically evident seizures [46, 72].
Testing for aPL is only recommended in young patients with
atypical seizures or in individuals with multiple MRI abnor-
malities for which no other plausible cause is found [72•].
There are no specific anti-epileptic drug regimens recom-
Fig. 1 The main neurological manifestations of APS mended for seizures in APS patients, and anticoagulation in
the absence of ischemic lesions or a clear diagnosis of APS —
that is, with isolated aPL and no other typical APS manifesta-
thrombi [54–56]. Small vessel cerebrovascular disease is tions — is controversial.
also often reported, leading to lacunar and subcortical
strokes [57]. Cognitive and Neuropsychiatric Manifestations

Cerebral Venous Thrombosis CVT is a rare complication of The frequent comorbidity of APS and aPL positivity with
APS, with a reported prevalence of 0.7% [38•]. On the other other autoimmune disorders, in particular with SLE, has ham-
hand, APS contributes to a significant proportion of CVT pered the establishment of a clear-cut cognitive profile and
cases (6–17% in cohort studies) [58], and aCL positivity risk of neuropsychiatric abnormalities in patients with APS
may be found in 7–22% of patients [59, 60]. CVT may be [73]. Proposed pathophysiologic mechanisms include a
the presenting symptom of APS [61]. Treatment should fol- prothrombotic state, an inflammatory response, and a neuro-
low the general guidelines for CVT [62] and usually includes nal immune-/aPL-mediated response [73]. Cognitive impair-
long-term anticoagulation [58]. ment is present in 19–40% of aPL-positive patients and 42–
80% of primary APS patients [39, 73–76]. A study enrolling
Other Cerebrovascular Disorders Sneddon’s syndrome is a 143 APS patients with moderate and high aPL titers found a
slowly progressive noninflammatory thrombotic vasculopa- linear relationship between aPL titers and cognitive dysfunc-
thy characterized by livedo racemosa and recurrent cerebro- tion [76]. The prototypical manifestation in primary APS is a
vascular (ischemic or hemorrhagic) events [63]. It is classical- subcortical pattern of mild cognitive impairment [46, 74].
ly classified as aPL negative or aPL positive (41% of patients Dementia (classified as multi-infarct dementia) was shown
in one case series) [63, 64]. aPL-positive patients may have a to affect 2.5% of APS patients included in the Euro-APS co-
clinical course similar to primary APS patients [63, 65]. hort that includes both primary and secondary APS [38•]. APS
Knowledge about the specific role of aPL in this syndrome, should therefore be ruled out in young subjects with otherwise
its clinical course, and ideal treatment is severely limited by unexplained dementia [77]. Chronic ischemic cerebrovascular
the scarcity of reports. Less consistent associations of cerebro- disease associated with aCL antibodies may be responsible for
vascular disorders with APS include reversible cerebral vaso- a vascular/multi-infarct dementia that may partially improve
constriction syndrome [66] and Moyamoya disease [67]. with the institution of APS therapy [47, 77, 78]. Reports on
Curr Neurol Neurosci Rep (2021) 21:41 Page 5 of 13 41

favorable cognitive outcomes with immunosuppression Demyelinating and Inflammatory Disorders

(rituximab) also exist [79], but lack of evidence precludes
therapeutic guidelines for cognitive dysfunction in APS. Neuroimmune and neuroinflammatory disorders related to
Other neuropsychiatric symptoms including psychotic, APS are particularly remarkable as they are proof of the con-
mood, and anxiety disorders have been reported in APS [73, tribution of non-thrombotic mechanisms to APS pathophysi-
80, 81]. It has been postulated that the high prevalence of aPL ology. Inflammatory CNS involvement in APS may be due to
in patients with psychosis may be due to aPL induction of a local immunologic dysregulation, blood–brain barrier dys-
some antipsychotic drugs [82–84]. Nevertheless, older age, function yielding access to the CNS immune compartment,
cerebral lesions, and triple aPL positivity are considered direct neurotoxic effect of aPL antibodies, or molecular mim-
risk factors for psychiatric manifestations in APS [46, icry and cross-reactivity between myelin/myelin-related pro-
84]. Acute encephalopathy characterized by confusion, teins and cerebral phospholipids [94••].
disorientation, and hyperreflexia was reported in 1.1%
of APS patients [38, 85]. Multiple Sclerosis-Like Disease The differential diagnosis be-
tween multiple sclerosis (MS), MS-like disease, and MS-
SLE overlap syndrome, although supported by clinical and
Headache imaging features, remains challenging [46, 70, 95, 96]. MS
predominantly affects women of childbearing age, similarly
Although migraineurs more frequently have aPL antibodies, to APS, and the prevalence of aPL antibodies in MS patients
migraine is most likely a comorbid condition with aPL posi- has been reported in a wide range of 2 to 88% [94, 97, 98].
tivity than a consequence of APS [86–88]. With an estimated aPL positivity may be more frequent during MS relapses/
prevalence of 20% in people with APS [38•], migraine may be exacerbations and in secondary progressive MS compared to
a result of the high prevalence of headache in the general relapsing–remitting MS [99–101]. Nevertheless, autoim-
population and an age overlap between migraineurs and mune disorders, such as MS, are more frequently associated
APS patients. On the other hand, data from some cohorts with autoreactive antibodies, and the significance of aPL
suggested migraine as a possible risk factor for stroke in antibodies and MS is still to be determined [102–104].
aPL-positive patients [89], and both migraine with aura and MRI is useful to distinguish between MS and APS mimick-
aPL were found to be independent predictors of thrombotic ing MS. Lesions in APS tend to maintain shape and size on
event recurrence in young patients in an Italian multicenter repeat scanning, have lower total lesion volumes, are pre-
cohort study [90]. dominantly subcortical instead of periventricular, do not
To further the matter, Cavestro et al. [91•] recently con- show the typical ovoid shape nor predilection for the corpus
ducted a study assessing the association among migraine, callosum, may affect the putamen, and are less associated to
thrombophilic conditions, and vascular events. Among the a reduction in brain parenchymal fraction [96, 97, 105, 106].
329 included migraine patients, 32% had at least one Cerebrospinal fluid (CSF) analysis with a normal cell count
thrombophilic marker, and aPL positivity was more common and absence of oligoclonal bands is in favor of APS [107].
than in controls (12.5% vs. 5.2%, OR 2.6, 95% CI 1.5–4.7). As such, previous thrombotic events, acute onset of atypical
There was an association between thrombophilic changes and symptoms, abnormal MRI lesion location, and response to
history of arterial — but not venous — vascular events in anticoagulation can help affirm the diagnosis of APS [70,
migraine patients but not in controls. The authors concluded 97]. As a rule, screening of aPL in MS patients should be
that aPLs are associated with both migraine and thrombotic reserved for patients with atypical characteristics [108].
events and that migraine is probably secondary to the Early initiation of disease-modifying treatments in MS is
thrombophilic changes [88, 92]. As aPL is a common precur- associated with improved outcomes [109], so all laboratory,
sor to both conditions and an association was expected, cau- imaging, and clinical data must be carefully reviewed before
sality cannot be assumed. Another recent retrospective study diagnosing an MS-like APS syndrome, MS with aPL posi-
of 75 patients with refractory migraine and aPL described that tivity, or the coexistence of both MS and APS.
most patients had an improvement in the frequency and/or
severity of migraine after a 2–4-week trial of anti-thrombotic Neuromyelitis Optica Spectrum Disorders Neuromyelitis
therapy (aspirin, clopidogrel, and/or anticoagulants) [93•]. optica (NMO) and its spectrum disorders (NMOSD) are a
Notably, treatment was associated with low bleeding risk, group of autoimmune astrocytopathies/channelopathies
and the response was overall sustained during a mean with secondary demyelination [110] associated with a
follow-up period of 29.9 months (5 to 100 months) [93•]. highly specific and pathogenic biomarker, the anti-
Randomized controlled trials (RCTs) are needed to effectively aquaporin-4-IgG (AQP4-IgG) [110]. The hallmark of
assess this therapeutic option in this subset of migraine these disorders is a longitudinally extensive transverse
patients. myelitis (LETM) and a severe, often recurrent, optic
 41 Page 6 of 13 Curr Neurol Neurosci Rep (2021) 21:41

neuritis [111]. NMOSD is frequently associated with resolution of symptoms after a trial of anticoagulant ther-
other autoimmune rheumatic disorders such as apy with warfarin [123]. Treatment of APS-related chorea
Sjögren’s syndrome, rheumatoid arthritis, and SLE may include symptomatic relief with dopaminergic
[112, 113]. In particular, aPL antibodies are found in agents, anticoagulation, and immunossupression [83].
19–46% of NMOSD patients [114, 115]. Due to this Other movement disorders have been reported in pri-
overlap, APS patients with optic neuritis or LETM mary or secondary APS and in the presence of aPL
should be screened for AQP4, as instead (or in addition antibodies, although less frequently, including ballismus
to) anticoagulation, long-term immunosuppression may (0.3% prevalence), dyskinesia, parkinsonism, and cere-
be warranted [112, 116, 117]. bellar ataxia [38, 124–127].

Transverse Myelopathy and Myelitis Transverse myelitis is

infrequent in APS (0.4–4%) and may be a result of vascular Peripheral Nervous System Manifestations
or thrombotic mechanisms (i.e., vasculitis, ischemic cord ne- of APS
crosis) [38, 118]. The onset of motor or sensorial symptoms is
most often sudden but may be subacute (up to 14 days); CSF Peripheral nerve involvement in primary APS may be a con-
analysis shows elevated protein and pleocytosis in a minority sequence of ischemic thrombosis of the vasa nervorum, vas-
of patients, and early diagnosis and treatment are vital to pre- culitis (with the prototypical mononeuritis multiplex presen-
vent morbidity [119]. As TM may be the initial presentation of tation), or direct nerve damage by pathogenic antibodies
NMOSD or MS, adequate investigation, especially in the [128]. Although reports on the relationship between aPLs
presence of an LETM or recurrent myelitis, should always and immune-mediated peripheral nerve syndromes exist
be pursued. (e.g., Guillain–Barré syndrome), they are scarce and con-
founded by concomitant intravenous immunoglobulin
Movement Disorders (IVIG) administration [129, 130]. An electrophysiological
study in a sample of 26 primary APS patients (8 of whom
Movement disorders, although rare, are classically considered with clinical signs of neuropathy) found abnormalities in
non-thrombotic neurological manifestations of APS. The his- nerve conduction studies (NCS) in 35% (n = 9) of the patients,
torical hypothesis is that lenticulo-striate artery occlusion pro- independently of previous thrombotic events [131•]. The most
duces ischemia of basal ganglia and explains the occurrence of frequent findings were carpal tunnel syndrome (23%),
these disorders [120]. Against this thrombotic hypothesis, polyneuropathy (19%), and distal axonal sensorimotor
there are several reports of patients with normal MRI and good neuropathy (15%). Most patients with abnormal NCS
response to immunomodulation and an increasingly studied findings had no clinical signs of neuropathy (subclinical
direct effect of aPL on neuronal tissue, as explained previous- neuropathy) [131•].
ly [120]. Whether APS-related movement disorders are due to Autonomic disorders (such as complex regional pain syn-
aPL-induced white matter and basal ganglia damage or to drome, labile hypertension, or postural tachycardia syndrome)
cerebrovascular disease is still to be ascertained [52, 78]. have been described as presenting manifestations of APS and
Chorea occurs in around 1% of patients with primary or are postulated to be due to thrombotic or immune-mediated
secondary APS [38•]. It is more common in females, with a small-fiber dysfunction [132].
mean age of onset between 20 and 44 years. In a minority of
patients (5.5 to 16.1%), there are ischemic signs on the basal
ganglia [24, 25, 120, 121]. Clinically, aPL-related chorea can General Management of APS
involve all body parts, is usually mild to moderate in severity,
and is often associated with other neurologic and movement The current standard of care for APS is based on
disorders such as ataxia and dystonia at the onset [24]. anticoagulation and, in some cases, antiplatelet drugs.
Moreover, chorea may appear in patients with high titers Besides clinical manifestations, the aPL type, number, persis-
of aPLs without overt APS syndrome or other manifesta- tence, and titers are important factors on the prognosis of APS
tions of immune-mediated conditions [120, 122]. Short as, for instance, a triple-positive profile is associated with a
follow-up times, fluctuating positive aPL titers, and het- higher thrombotic risk. This so-called aPL profile should dic-
erogeneous investigation and treatment response cast tate the intensity of the treatment, particularly for primary
doubt on the relationship between these entities. prophylaxis in patients with aPL but non-criteria manifesta-
Interestingly, a fairly recent report described a 74-year tions, such as neurological involvement [133]. Treatment of
old woman with a 6-month history of isolated patients with APS and neurological manifestations is mostly
oromandibular chorea, thrombocytopenia, and persistently based on indirect evidence from similar syndromes in non-
positive LA and aCL antibodies who showed a complete APS patients. There are some case reports, small case series,
Curr Neurol Neurosci Rep (2021) 21:41 Page 7 of 13 41

and retrospective studies suggesting a possible benefit of COVID-19 and Antiphospholipid Antibodies
anticoagulation and/or immunomodulation even in the ab-
sence of an overt thrombotic event (e.g., in patients with my- Coronavirus disease 2019 (COVID-19) patients have a
elitis or headache), but the decision still relies mostly on a hypercoagulable state with a high prevalence of venous
case-by-case analysis, without strong evidence to support it. and arterial thrombosis [145], including ischemic stroke
Primary thromboprophylaxis in aPL-positive individuals is and CVT [146–148]. It is currently unclear, though, if
usually low-dose aspirin, which was shown to reduce by half these strokes have unique characteristics [146–148].
the risk of the first thrombosis [134]. For patients with venous Some studies have proposed a connection between the
thrombotic APS, the standard treatment is warfarin (or another increased thrombotic risk in COVID-19 patients and the
vitamin K antagonist [VKA]) for a target international normal- presence of antiphospholipid antibodies. In fact, there is
ized ratio [INR] of 2–3 [133]. In patients with arterial throm- a high prevalence of LA in severe COVID-19 patients,
bosis or recurrent venous thrombosis, an INR of 3.0–4.0 or the up to 88% in several studies [145, 149, 150], which is
association of a VKA with low-dose aspirin is indicated [133]. significantly higher compared to other infections [151].
The use of direct oral anticoagulants (DOACs) has been an The association of this finding with thrombosis is how-
area of great interest, as this would facilitate treatment adher- ever not fully established [145, 150]. Concomitant use
ence. However, there is no current definite use for DOACs in of anticoagulation, hydroxychloroquine, and high levels
APS after several major trials failed to reach primary efficacy of C-reactive protein may have influenced the LA test
and safety endpoints [135–137]. The European League [152, 153].
Against Rheumatism (EULAR) guidelines issued in 2019 aCL and aB2GPI have also been found in around 10
warrant a single exception for rivaroxaban, which could be to 12% of critically ill COVID-19 patients [154]. In a
considered in patients with contraindications for VKA or un- multicenter study with 122 COVID-19 patients, preva-
able to reach the target INR despite proper adherence [133]. lence and titers of aPL were neither consistently in-
Still, DOACs should not be used in patients with high titer creased nor associated with thrombosis [155]. In a sys-
aPL as evidenced in a recent RCT that was prematurely ter- tematic review of patients with CVT associated to
minated because of an excess of arterial events in the COVID-19, thrombophilia screening results were avail-
rivaroxaban arm [138]. DOACs should also be avoided in able for 12 out of 28 cases, of which three had positive
patients with a history of arterial thrombosis due to a particu- lupus anticoagulant and two anticardiolipin antibodies
larly high risk of recurrent thrombosis. This is a recommen- [148]. As mentioned before, infection-induced, usually
dation of major importance when focusing on neurological transient, aPLs are not associated with a higher throm-
manifestations of APS, as stroke is one of the most common botic risk. Studies with larger cohorts, including less
events. Efforts are being made towards assessing whether oth- severe patients and evaluating the persistence of aPLs,
er DOACs are useful in APS, with no positive results so far are needed to assess this relationship.
[139–141].
For obstetric APS, the association of low-dose aspirin
with prophylactic dose low molecular weight heparin Conclusions
(LMWH) is warranted [133]. The addition of
hydroxychloroquine in obstetric APS refractory to Cerebrovascular disease is the most common cause of neu-
anticoagulation and antiplatelet therapy may be considered rological manifestations in APS. However, these patients
[133, 142]. aPL-positive women without previous pregnan- may present with other distinct neurological manifestations,
cy complications or thrombotic manifestations should be most of which still have unclear pathophysiology. There is a
started on low-dose aspirin alone [133, 142]. In turn, pa- growing interest in better assessing the role of inflammatory
tients with thrombotic APS should switch VKA to full- and direct neuronal effects in the pathogenesis of non-
dose LMWH, as the former is teratogenic [133, 142]. The criteria manifestations and in establishing optimal therapy.
recent 2020 American College of Rheumatology (ACR) There are a few recent reports suggesting a possible benefit
guidelines strongly recommend against the addition of of anticoagulation for selected non-criteria manifestations
prednisone or IVIG in refractory obstetric APS, whereas that are not classically considered to be thrombotic, al-
EULAR guidelines suggest that this treatment may be con- though evidence is generally of poor quality. VKAs contin-
sidered in selected cases [133, 143]. Catastrophic APS may ue to be the mainstay of therapy for patients with thrombotic
be treated with a combination of glucocorticoids, heparin, manifestations despite several trials evaluating the safety
and plasma exchange or IVIG as the first-line treatments and efficacy of DOACs. The new classification criteria that
[133, 142]. Rituximab or eculizumab are selected for refrac- are being developed are expected to facilitate the diagnosis
tory catastrophic APS based on successful data from case in patients with non-criteria manifestations, such as neuro-
reports [133, 144]. logical involvement, improve patient selection in clinical
 41 Page 8 of 13 Curr Neurol Neurosci Rep (2021) 21:41

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Conflict of Interest Miguel Leal Rato and Matilde Bandeira each de- Rheumatol. 1994;21(1):94–9.
clare no potential conflicts of interest. Vasco C. Romão reports grants 12. Dlott JS, Roubey RAS. Drug-induced lupus anticoagulants and
from MSD, personal fees from Janssen, and nonfinancial support from antiphospholipid antibodies. Curr Rheumatol Rep. 2012;14(1):
Novartis, Pfizer, and Medac. Diana Aguiar de Sousa reports nonfinancial 71–8. https://doi.org/10.1007/s11926-011-0227-1.
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Human and Animal Rights and Informed Consent This article does not
1002/acr.
contain any studies with human or animal subjects performed by any of
the authors. 14. Cervera R, Rodríguez-Pintó I, Colafrancesco S, Conti F, Valesini
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