Lupus (2018) 27, 1404–1414

journals.sagepub.com/home/lup

REVIEW

Neurologic manifestations of antiphospholipid syndrome

IF Ricarte1, LA Dutra1,2, FF Abrantes1, FF Toso1, OGP Barsottini1, GS Silva1,2, AWS de Souza3 and D Andrade3
1
Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, Brazil; 2Hospital Israelita Albert Einstein, São Paulo, Brazil;
3
Rheumatology Division, Department of Internal Medicine, Universidade Federal de São Paulo, São Paulo, Brazil; and 4Rheumatology Division,
Department of Internal Medicine, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

Neurological involvement in antiphospholipid antibody syndrome (APS) is common, and its

occurrence increases morbidity and mortality. Patients may present variable neurological
involvement, such as cerebrovascular disease, cognitive dysfunction, headache, seizures, move-
ment disorders, multiple sclerosis-like syndrome, transverse myelitis and ocular symptoms.
Most neurological manifestations are associated with thrombosis of the microcirculation or of
large vessels; nonetheless, there is compelling evidence suggesting that, in some cases, symp-
toms are secondary to an immune-mediated pathogenesis, with direct binding of aPL on
neurons and glia. Herein we describe clinical characteristics and management of neurological
APS manifestations. Lupus (2018) 27, 1404–1414.

Key words: Antiphospholipid syndrome; antiphospholipid antibodies; APS; central nervous

system; neurological manifestations; stroke

Introduction recently APS neurological manifestations were clas-

sified as thrombotic and non-thrombotic.6 Central
Antiphospholipid syndrome (APS) is a systemic nervous system (CNS) thrombotic manifestations
autoimmune disorder defined by venous and/or include stroke, transient ischemic attack (TIA),
arterial thrombosis, and pregnancy morbidity in and cerebral venous thrombosis (CVT). CNS
the presence of antiphospholipid antibodies (aPL). non-thrombotic manifestations include cognitive
Anticardiolipin antibodies (aCL) are found in 70% dysfunction (CD), migraine, seizure, multiple scler-
of the cases, lupus anticoagulant (LA) in 20% and osis (MS)-like syndrome, transverse myelitis (TM),
anti-b2 glycoprotein antibodies (anti-b2GPI) in movement disorders, and psychiatric symp-
10%, either isolated or in combination.1–4 For toms.6–10 We aim to review neurological manifest-
APS diagnosis, patients should meet the clinical ations in APS, discussing diagnosis and
and laboratory criteria of Sidney classification management.
(Table 1).1
Neurological involvement in APS is common,
and its occurrence increases morbidity and mortal- Pathophysiology
ity.2 Solely aPL positivity in association with
neurological manifestations should be interpreted Although the mechanisms of cerebral involvement
carefully for the following reasons: lack of control in APS are not completely understood,9,11 data
at 12 weeks apart, discrepancies in methods for aPL suggest that aPLs induce a prothrombotic state
detection and low titers. through: (a) interference with endogenous anti-
The original description from Hughes included coagulant mechanisms (disruption of the annexin
cerebrovascular disease and myelitis as APS neuro- A5 anticoagulant shield, inhibition of protein C
logical manifestations.5 Thereafter, a wide spec- pathway, inhibition of antithrombin); (b) binding
trum of manifestations were described and more and activation of platelets; (c) inducing expression
of adhesion molecules and tissue factor in endo-
thelial cells; and (d) activation of the complement
Correspondence to: Lı́via Almeida Dutra, Universidade Federal de
São Paulo, Rua Pedro de Toledo 650, São Paulo, SP 04039-002, Brazil.
cascade.12,13 However, many of the CNS manifest-
Email: liviaadutra@hotmail.com ations cannot be explained solely by thrombotic
Received 19 December 2017; accepted 17 April 2018 events.9,11 Direct binding of aPL to CNS antigens
! The Author(s), 2018. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203318776110

a 23
Table 1 Revised classification criteria for APS.
Clinical criteria (at least one of the following):
1. Vascular thrombosis
 One or more clinical episodes of arterial, venous, or small vessel
thrombosis, in any tissue or organ.
2. Pregnancy morbidity
 One or more unexplained deaths of a morphologically normal fetus
at or beyond the 10th week of gestation.
 One or more premature births of a morphologically normal neonate
before the 34th week of gestation because of eclampsia or severe
preeclampsia (placental insufficiency).
 Three or more unexplained consecutive spontaneous abortions
before the 10th week of gestation.
Laboratory criteria (at least one):
1. Anticardiolipin antibody immunoglobulin (Ig)G and/or IgM isotype
in medium or high titer (>40 GPL or MPL, or >the 99th percentile),
on two or more occasions, at least 12 weeks apart.
2. Anti-beta-2-glycoprotein-I antibody IgG and/or IgM in titer >the
99th percentile or >40 IU, present on two or more occasions, at
least 12 weeks apart.
3. Lupus anticoagulant in plasma, on two or more occasions at least
12 weeks apart, detected according to the guidelines of the
International Society on Thrombosis and Haemostasis.
APS: Antiphospholipid syndrome; IU: international units.
a
Adapted from Miyakis.1
has also been postulated.14,15 Data from in vitro
experiments and animal models support the idea
of an immune-mediated pathogenesis in which
aPL directly binds neurons and glial cells.9,11
Moreover, anti-B2GPI also binds to endothelial
cells,9 disrupting blood–brain barrier permeability,
causing inflammation and neurodegeneration.9,11
Neurological manifestations in APS
Cerebrovascular disease
Ischemic stroke and TIA
Ischemic stroke (IS) is the most common and severe
arterial complication of APS.6,16 In the Euro-
Phospholipid Project Group Study, the cumulative
prevalence of stroke was 19.8% and TIA, 11.1%.17
It has been suggested that more than 20% of
strokes in patients younger than 45 years are asso-
ciated with APS;18 however, this estimate may be
inaccurate due to potential referral bias.13 Patients
with stroke and aPL positivity are younger and are
more likely to be female than aPL-negative stroke
patients.8 The data on the association between
aPLs and stroke recurrence in older patients is
conflicting.19
Stroke mechanism in APS may be either throm-
botic or cardioembolic.8,13 Clinical manifestation
of APS-associated IS depends on the location and
size of the occluded vessel.20–22 Cerebrovascular
disease frequently involves small arteries leading
Neurologic manifestations of APS
IF Ricarte et al.
1405
to lacunar and subcortical IS. Nonetheless, intra-
cranianal stem or branch arterial occlusions and
stenosis were reported in 50% of APS patients
with stroke.24 In the absence of cardiogenic
source of emboli, in situ thrombosis appears to be
the most likely mechanism for arterial occlusion.25
Narrowing of multiple intracranial arteries (vascu-
litis-like pattern) may occur in APS and indicates
vasculopathy rather than inflammation of the
vessel wall.25
Occasionally, the extracranial carotid artery may
be involved. In one of only a few reports of angio-
graphic findings in APS patients with stroke, 7 of
17 patients (32%) had extracranial arterial abnorm-
alities. This latter study classified the abnormalities
into three types: common carotid or internal caro-
tid artery (ICA) stenosis or occlusion, stenosis or
occlusion of the origin of two or more great vessels
(Takayasu-like pattern) and narrowing of the ICA
in a pattern typical of atherosclerotic disease.25
Rarely, APS may overlap with Takayasu arter-
itis.26–28 Two small studies using digital angiog-
raphy reported that approximately 30% of APS
patients with stroke presented extracranial abnorm-
alities.25 However, other studies reported a preva-
lence of 15% of asymptomatic carotid stenosis,
using vascular ultrasound.29 A recent meta-analysis
showed that patients with APS have higher fre-
quency of carotid plaques when compared to
patients without the syndrome. However, these
results were not confirmed in patients with primary
APS (pAPS).30 The natural progression of carotid
extracranial stenosis in APS in unknown.31
Cerebral embolism in APS is associated with left
cardiac valvular abnormalities and, rarely, intracar-
diac thrombus.13 The valvular pathologies include
irregular thickening of the valve leaflets due to
deposition of immune complexes, vegetations
(Libman–Sacks endocarditis), and valve dysfunc-
tion.13,32 The mitral valve is the most commonly
affected and mitral insufficiency the most common
lesion.33,34 Cardiac involvement was found between
10% to 60% of APS patients using transthoracic
echocardiography.32 Transesophageal echocardio-
gram (TEE) detects cardiac involvement in 75.9%
to 82% of patients.32
APS patients with stroke should be evaluated
preferably with brain magnetic resonance imaging
(MRI), intracranial and extracranial vascular ima-
ging (MRI or computerized tomography (CT)
angiogram). Given the frequently found cardiac
abnormalities, some authors recommend TEE in
all APS patient with stroke13 The risk of stroke
for LA-positive patients was multiplied twofold in
Lupus
 Neurologic manifestations of APS
IF Ricarte et al.
1406

smokers and was multiplied sixfold in smokers hyperreflexia, and asymmetrical quadriparesis.51
receiving oral contraceptives.35 The most frequent finding on MRI is cerebral
Whether atherosclerosis is associated with circu- atrophy.51
lating aPLs or occurs secondary to co-occurring Sneddon’s syndrome is characterized by non-
risk factors is a matter of debate.36–40 inflammatory thrombotic vasculopathy, cerebro-
Hypertension, diabetes, hypercholesterolemia, vascular disease (stroke and TIA) and livedo
obesity, and tobacco use should be managed to reticularis (LR).52 Other neurological symptoms
minimize additional thrombotic risks.13 are headache, cerebral hemorrhage, seizures, cogni-
tive and psychiatric disturbances. Skin biopsy may
Less common types of cerebrovascular disease reveal thrombosis of subcutaneous arterioles and
CVT usually presents with refractory headache and compensatory capillary dilation with blood stagna-
nausea, occasionally associated with seizures, focal tion causing livedo reticularis.52–54 Approximately
deficits, or intracranial hypertension. MRI or CT 40–50% of patients with Sneddon’s syndrome pre-
venous angiogram should be performed when CVT sent aPL antibodies, suggesting that some patients
is suspected as sensibility of noncontrast CT ima- should be classified as APS.52
ging is around 30% for CVT diagnosis.41 In
patients with CVT, reported frequency of aCL Cognitive dysfunction
positivity ranged from 7% to 22%.42,43 APS is
CD is a decline in prior cognitive performance and
responsible for approximately 6–17% of cases,
is present in several rheumatic diseases. In aPL-
being one of the prothrombotic conditions most
positive patients, the frequency of CD ranges
frequently associated with CVT.44 The presence of
between 19% and 40%.7 In pAPS, 42–80% of
aCL predisposes to CVT at a relatively younger age
patients develop CD (usually a subcortical pattern,
and to a more extensive cerebral venous
characterized by impairment in attention, concen-
involvement.44
tration, information processing speed and executive
Reversible cerebral vasoconstriction syndrome
functioning.7,55 CD may occur in a spectrum and
(RCVS), which is characterized by thunderclap
some patients may present mild cognitive impair-
headaches, and neurological deficits associated
ment and others dementia.14,56,57 APS patients with
with transitory constriction of cerebral arteries,
dementia were older, and more commonly pre-
was described in APS.45 RCVS manifestations are
sented abnormal brain CT and electroencephalo-
attributed to a transient disturbance of the arterial
gram (EEG) when compared to non-demented
tone regulation. Thunderclap headache, which is a
patients.57
severe pain peaking in seconds, is usually the first
There is an association between neuropsycho-
symptom and typically recurs within the first
logical deficits, livedo reticularis and white matter
2 weeks, IS or hemorrhagic stroke being the
lesions (WMLs) on brain MRI in patients with
major complications.46–48
APS.56 Nonetheless, CD occurs independently of
There are a few reports regarding the association
previous neurological involvement and cannot be
between aPL and Moyamoya disease,49 a vasculo-
explained solely by vascular pathology.56 Animal
pathy of unknown aetiology characterized by pro-
models showed that cognitive dysfunction was not
gressive narrowing of the anterior vasculature of
associated with the vascular ischemic lesions.58
the brain with the formation of a collateral vessels.
Moreover, intraventricular injection of neuronal-
Moyamoya vasculopathy is found in other variable
binding IgG from APS patients in mice impairs
conditions such as neurofibromatosis type 1, Sickle-
cognitive performance in the swimming maze, sug-
cell disease or Down’s syndrome,50 Of the 16 cases
gesting a direct effect of aPL in cognitive impair-
reported in a small series of Moyamoya and aPL,
ment, learning and memory.14 This supports the
21% fulfilled APS criteria. Nonetheless, 65% of the
concept that CD is multifactorial and that ischemic
described cases presented various comorbidities
events, genetic predisposition, antibody specificity,
and some of them were found to be associated
exposure time to antibodies and blood-brain bar-
with Moyamoya, such as autoimmune thyroid dis-
rier disruption leading to direct binding of aPL to
ease, SLE, and type 1 diabetes mellitus.49
the brain may play a role.58
Acute ischemic encephalopathy is a rare feature
of SLE patients, with aPLs found in only 1.1% of
Migraine
patients from the EuroPhospholipid Project Group
study.17 This neurologic manifestation was first Headache is the most prevalent neurological mani-
described in association with APS in 1989, and is festation in APS, with migraine being the most
characterized by confusion, disorientation, common type. Estimated migraine prevalence in
Lupus

59
APS is around 20% of patients. Antiphospholipid
antibodies are more prevalent among migraineurs
(12% vs 3%) when compared to controls, suggest-
ing that migraine might be an early APS symptom
or a comorbid condition.60 Migraine associated
with APS may be difficult to control with typical
analgesic regimens and occurs years before the
diagnosis.6,61
One possible mechanism for migraine and APS
association is the platelet activation and alterations
in serotonin metabolism driven by APS,61 leading
to a central neurochemical imbalance of this neuro-
transmitter implicated in migraine pathophysi-
ology. Nonetheless, due to methodological
limitations of previous studies that evaluated
migraine in APS, there is not enough evidence to
support a clear association between migraine
and APS.62
Seizures and epilepsy
Estimated seizure prevalence among APS patients
is 3.2–10%.63–65 Almost half of the patients develop
epilepsy after APS diagnosis.64 Seizures occurs in
patients with abnormal or normal brain MRIs, sug-
gesting a direct effect of autoantibodies,63 altering
the depolarization and membrane permeability,
reducing GABA response and binding to neuro-
transmitters.66–68 Apart from stroke, other risk fac-
tors for seizures are tobacco use, livedo reticularis
and valvular heart disease.63,65
The association between seizures with aPL anti-
bodies is still a matter of debate due conflicting
results.62,69–71 In non-SLE patients, a positive asso-
ciation was described, with prevalence of aPL
reported between 19%– 43%.66,72–74 Studies are
difficult to compare due to lack of large case-
control studies, heterogeneity in aPL testing, exclu-
sion of APS patients with history of stroke, and
inclusion of secondary APS (sAPS).7
MS-like syndrome
MS-like syndrome, also called lupoid sclerosis, was
described as a rare neurologic manifestation of pri-
mary APS.75 Patients may present unbalance,
visual or sensory complaints and other neurological
deficits with relapsing–remitting course, similar to
MS.76 Furthermore, APS patients may present
brain MRI with T2 hyperintense brain lesions,
which may not be easily differentiated from MS.77
In these particular cases, a careful interview may be
helpful in distinguishing between MS and APS: the
acute onset and resolution of symptoms, especially
regarding visual symptoms (i.e. amaurosis fugax),
presence of headache or epilepsy, prior history of
Neurologic manifestations of APS
IF Ricarte et al.
1407
thrombotic events and pregnancy morbidity
strongly suggest APS rather than MS.16
Several studies evaluated aPL in definite MS
patients and in MS-like patients; however, their rele-
vance are still unknown due high variability findings
and methodological limitations. Prevalence of aCL
of 6% for the IgG isotype and between 2% and 69%
for the IgM isotype in MS patients have been
described.7,78,79
Transverse myelitis
TM is a rare neurologic complication of APS with a
prevalence estimated of 0.4–4% of APS
patients.17,80 TM is characterized by acute inflam-
mation that may affect the white and gray matter of
the spinal cord.81,82 Clinical presentation is charac-
terized by motor neurologic dysfunction, associated
with sensory abnormalities and sphincter disturb-
ances.81 Pathophysiology involved is uncertain,
although vasculitis and arterial thrombosis result-
ing in ischemic cord necrosis have been suggested.16
Neuromyelitis optica spectrum disorder
(NMOSD) is an autoimmune disorder character-
ized by recurrent episodes of optic neuritis (ON)
and longitudinally extensive transverse myelitis
(LETM) defined as a lesion involving three
or more contiguous vertebral segments.83
Approximately 70% of the patients harbor aqua-
porin-4-IgG (AQP4-IgG).83 Because NMO and
APS may occur in overlap, patients with APS pre-
senting with myelitis or ON should be screened for
AQP4-IgG.84
Neuro-ophthalmologic involvement
Amaurosis fugax refers to a transient loss of vision
in one or both eyes. It is one of the most common
ocular manifestations of APS and indicates cerebral
ischemia,6 being reported in 5.4% of patients in a
large cohort.17
Optic neuropathy (ON) is a rare manifestation of
APS, occurring in 1% of the patients.17 It may pre-
sent either anterior non-arteritic ischemic optic
neuropathy (NAION) or retrobulbar ON.85
NAION develops as a result of ciliary blood vessels
thrombosis, whereas retrobulbar optic neuropathy
probably involves thrombotic and inflammatory
mechanisms.86 Both are characterized by sudden
visual decline and unilateral color vision impair-
ment; nonetheless, papillary edema with linear
hemorrhages are considered as a typical NAION
feature.85 Retrobulbar ON is most frequently
found in secondary APS, but it has also been
reported in primary APS.85
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 Neurologic manifestations of APS
IF Ricarte et al.
1408
Rarely, an orbital ischemic syndrome, character-
ized by bilateral ophthalmoparesis, proptosis,
increase of intraocular pressure and necrosis of
orbital tissue, may be found in patients with cata-
strophic APS (CAPS).87
Psychiatric manifestations
APS patients may present several psychiatric syn-
dromes including psychosis, mania, acute depres-
sion, bipolar disorders, obsessive–compulsive
disorders and schizophrenia.7 Risk factors asso-
ciated with psychiatric disorders in APS are older
age, cerebral ischemia and triple positivity.7,88 In a
retrospective cohort analysis of 100 Iranian
patients APS, more than 10% of patients with
APS presented with depression.89 Another study
suggested that risk for depression and anxiety
among APS patients ranged from 1.57 to 1.64.88
Increased levels of aCL and LA have been
detected in patients with schizophrenia. The fre-
quency of aCL in psychotic patients varied from
4 to 24% among studies.7
Movement disorders
Chorea, although rare, is the movement disorder
most frequently described in patients with primary
APS, and is found in 1.3–4.5% of patients.17,90 Data
is limited mostly to case reports. It occurs most often
in women and severity is mild to moderate.90,91
Movement disorders rarely found in APS are dys-
tonia, ballismus, paroxismal dyscinesias, myoclonus,
Figure 1 MRI in APS. Axial fluid attenuated inversion recovery (FLAIR) images showing multiple white-matter hyperintensities.
MRI: Magnetic resonance imaging; APS: antiphospholipid syndrome.
Lupus
tremor, tics, corticobasal degeneration-like syn-
drome parkinsonism and progressive supranuclear
palsy phenotype; both syndromes with poor
response to levodopa.91–93 Movement disorders in
APS are more commonly associated with a
thrombo-occlusive vasculopathy, often associated
with cerebral infarctions and white-matter changes
on brain MRI. Nonetheless, an immune-mediated
neuronal attack against the basal ganglia was also
reported.7,93,94
Neuroimaging
Neuroimaging abnormalities have been reported in
35% to 90% of APS patients.95 Most common
findings were infarcts, reported in 22% to 45.7%,
and white-matter hyperintensities (WMH) found in
17% to 45% of pAPS patients (Figure 1).23,96–98
Ischemic lesions can be small or large and involve
both superficial and deeper areas of the brain
(Figure 2).22,23 The WMH lesions are non-specific
and similar to those seen in demyelinating, inflam-
matory, or vascular diseases.22,95 Recent studies
using diffusion tensor imaging (DTI), detected ear-
lier microstructural white matter abnormalities in
APS, compatible with alterations in axonal struc-
ture and in the myelin sheath.99
Another frequent finding in patients with APS is
brain atrophy (Figure 3). It has been reported in
12–36% of patients, isolated or associated with par-
enchymal lesions.23,95,96,100 A significant correl-
ation was found between brain atrophy and LA.100
 Neurologic manifestations of APS
IF Ricarte et al.
1409

Figure 2 Brain MRI showing different stroke patterns in APS. (a) FLAIR sequence: small lacunar infarct (arrow). (b) Diffusion-
weighted sequence: right middle cerebral artery infarction, illustrating a large-vessel ischemic stroke (arrow). (c) FLAIR sequence:
cortical infarction (arrow).

Figure 3 Cortical atrophy in APS. A 57-year-old female with primary APS and cognitive impairment. She was triple positive for
aPL antibodies. (a)–(c) Brain MRI T1 sequence with global cortical atrophy. (a) Observe the cortical atrophy (arrow), (b) Sylvian
fissure atrophy (arrow), (c) temporal lobe atrophy (arrow).

Management and treatment Antiphospholipid Antibodies reinforced that INR

Management of neurologic thrombotic manifestations
Long-term anticoagulation with oral warfarin is the
cornerstone treatment in APS.101 Patients with def-
inite APS and first venous thrombosis event should
receive oral anticoagulation with heparin
bridging.101
There remains a lack of consensus regarding
optimal antithrombotic management of patients
with ischemic stroke/TIA and APS.101–103 Data
of the XV International Congress on
>3.0 or INR 2.0–3.0 and an antiplatelet agent
should be used for secondary thromboprophylaxis
in patients with APS with arterial thrombotic
events;103 however, this recommendation did not
reach panel consensus,101,103 due to lack of clinical
trials and alternative explanations for stroke rather
than thrombosis in APS,102
The recurrence of thrombotic events is mostly
associated with inadequate anticoagulation.104
When recurrence occurs in patients within INR
therapeutic of 2.0–3.0, target should be increased
Lupus
 Neurologic manifestations of APS
IF Ricarte et al.
1410
to 3.0–4.0 or aspirin should be added.104,105 For
patients who are inadequately anticoagulated with
warfarin, an alternative is low molecular weight
heparin (LMWH).104 Rituximab, intravenous
immunoglobulin and plasma exchange have been
used in refractory cases despite adequate
anticoagulation.105,106
Direct oral anticoagulants
The role of direct oral anticoagulants (DOAC),
such as direct thrombin inhibitors (dabigatran)
and anti-factor Xa (rivaroxaban, apixaban and
edoxaban) remains unclear. Recently, a systematic
literature review identified 122 published APS
patients treated with DOACs; among them 19
experienced recurrent thrombosis while on
DOACs. Triple positivity (positivity of all three
laboratory criteria for APS) was associated with a
3.5-fold increased risk of recurrent thrombosis.107
The RAPS trial, a randomized controlled, open
label non-inferiority trial that compared rivaroxa-
ban with warfarin in APS patients showed that
endogenous thrombin potential (ETP) for rivarox-
aban did not reach the non-inferiority threshold,
but there was no increase in thrombotic risk com-
pared with standard-intensity warfarin. It did not
include patients with previous arterial manifest-
ations or with recurrent venous thrombosis while
on therapeutic warfarin dose. Moreover, a low per-
centage of patients with triple positivity was
included (25 %).108
Current guidelines recommend the use of
DOACs for patients with known warfarin allergy,
warfarin intolerance, or poor anticoagulation con-
trol.109 Several trials in thrombotic APS (TRAPS
and ASTRO-APS) are ongoing and will help to
establish the role of DOACs in the management
of APS.110,111
Hydroxychloroquine
Hydroxychloroquine (HCQ) should be used as an
adjunctive treatment in APS refractory
cases.109,112,113 However, randomized clinical trials
should confirm the efficacy and safety of HCQ in
APS patients for both primary and secondary
thrombosis prevention.109,113
Statins
Statins presents anti-inflammatory effects and
potential to reduce b2-GPI-endothelium bind-
ing.104,105 A prospective open-label pilot study of
fluvastatin 40 mg daily for 3 months showed signifi-
cantly reduction of proinflammatory and pro-
thrombotic biomarkers (IL1b, VEGF, TNFa,
Lupus
IP10, sCD40L, and sTF) by 50% in aPL-positive
patients.114
Based on the available data, statins cannot be
recommended in APS patients in the absence of
hyperlipidemia. However, a subgroup of aPL-positive
patients with recurrent thrombosis despite adequate
anticoagulation might benefit from statins.109
Management of non-thrombotic neurological
manifestations
There are limited data on the treatment of non-
thrombotic neurological APS and most therapeutic
options are based on case reports or retrospective
non-randomized studies.91,92,115–118 Considering
the potential autoimmune mechanism of these
manifestations, one would suggest that antiplatelet
or anticoagulant agents would play a minor role in
the treatment.4 Conversely, evidence of improve-
ment has been reported in patients with refractory
migraine,115,116 psychiatric disorders (obsessive–
compulsive behavior) and movement disorders.117
There are reports of cognitive improvement of
patients on anticoagulation due to other clinical
manifestations,18 although some authors recom-
mend low-dose antiplatelet therapy combined
with hydroxichloroquine,77,104
Prednisone and neuroleptics appear to be effect-
ive in most of the patients with chorea and APS,91
Benefit of early steroid has also been reported in
treatment of psychotic symptoms.118 Intravenous
immunoglobulin therapy has shown a beneficial
effect against chorea in pediatric cases.119
In patients with atypical demyelinating syn-
dromes or transverse myelitis there are reports of
antiplatelet or anticoagulation therapy in addition
to steroids and immunosuppressive agents.4
The RITAPS study, an open-label phase II pilot
study, observed the effectiveness and safety of
rituximab for the treatment of non-criteria aPL
manifestations (thrombocytopenia, cardiac valve
disease, skin ulcer, aPL nephropathy, and/or cog-
nitive dysfunction) in patients with primary APS,
including six patients with cognitive dysfunction.
Although the sample size was small, the authors
observed an improvement in attention, visuomotor
speed, and flexibility.120
Conclusion
Neurological manifestations are variable and fre-
quently found among APS patients.
Pathophysiology involves both thrombotic and
non-thrombotic mechanisms. Most manifestation

are managed with long-term oral anticoagulation,
although non-thrombotic neurological manifest-
ations may benefit from immunomodulation (ster-
oids, IVIG, hydroxichloroquine and rituximab).
Despite a growing body of evidence that patho-
genic mechanisms are involved in APS, additional
studies regarding clinical course of neurological
manifestations and therapeutic options are needed.
Declaration of conflicting interests
The authors declared no potential conflicts of inter-
est with respect to the research, authorship, and/or
publication of this article.
Funding
The authors received no financial support for the
research, authorship, and/or publication of this
article.
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