Seizure: European Journal of Epilepsy 86 (2021) 161–167

Contents lists available at ScienceDirect

Seizure: European Journal of Epilepsy

journal homepage: www.elsevier.com/locate/seizure

Review

Seizures in systemic lupus erythematosus: A scoping review

Adrian Rodriguez-Hernandez a, Javier Ortiz-Orendain b, Lucia E. Alvarez-Palazuelos a, c,
Laura Gonzalez-Lopez d, Jorge Ivan Gamez-Nava d, *, Maria G. Zavala-Cerna e, *
a
Facultad de Medicina, Universidad Autónoma de Guadalajara, Guadalajara, Jalisco, Mexico
b
Department of Psychiatry, Mayo Clinic- Rochester, Rochester, MN, United States
c
Doctorado en Ciencias Biomédicas Neurociencias, Universidad de Guadalajara, Mexico
d
Programa de Doctorado en Salud Publica y Doctorado en Farmacologia, Centro Universitario de Ciencias de la Salud universidad de Guadalajara, 44340 Guadalajara,
JAL, Mexico
e
Immunology Research Laboratory, International Program of Medicine, Universidad Autonoma de Guadalajara, Zapopan, JAL, Mexico

A R T I C L E I N F O A B S T R A C T

Keywords: Systemic lupus erythematosus is a systemic autoimmune disease that affects the central nervous system, either by
Systemic lupus erythematosus direct neuronal damage, injury to brain vessels, or by pathogenic mechanisms indirectly induced by immune
Neuropsychiatric lupus mechanisms related to the production and deposition of immune complexes. The prevalence of explicit episodes
Seizures
of seizures among SLE patients, varies from 2 to 8%. In some cases, patients with positivity for antiphospholipid
Epilepsy
or anti-β2 glycoprotein antibodies are found to be more prone to exhibit seizures compared to seronegative
Immunosuppressive treatment
Anti-epileptic drugs patients, other subjects at risk are carries of gene abnormalities codifying for ion channels. The exclusion of
vasculitis or thrombosis is required for accurate treatment, imaging studies and alternative sequences are
mandatory in patients with known SLE who present with a seizure. Several statements regarding SLE-related
seizure remain to be decoded. In this scoping review we analyzed published information about prevalence,
pathogenesis, clinical characteristics, diagnostic and therapeutic SLE patients that manifest a seizure, our
objective is to provide with useful information for prompt diagnosis and individualized treatment.

1. Introduction the general population [4]. Nervous system involvement encompasses a

Systemic lupus erythematosus (SLE) is a chronic systemic autoim­
mune disease, characterized by a fluctuating course [1]. Worldwide,
incidence and prevalence vary substantially in attribution to ethnicity
and geographic exposure to diverse environmental factors. Updated
estimates reported an annual incidence of 0.3–31.5 and prevalence of
3.2–517.5 cases per 100,000 individuals, with the highest numbers
observed in childbearing years women, predominantly those of
African-American, Asian, Hispanic and Aboriginal ancestry [2].
Currently SLE diagnosis is based on two classification criteria,
created originally for research standardization: the 1997 American
College of Rheumatology criteria (ACR 1997), and the 2012 Systemic
Lupus International Collaborating Clinics (SLICC), the later with greater
sensitivity (94 % versus 86 %) and similar specificity (92 % versus 93 %)
when compared to the ACR diagnostic criteria [3].
SLE increases the risk of mortality by more than 3-fold compared to
wide spectrum of neurologic and psychiatric syndromes divided into
central and peripheral damage [5]. According to a recent meta-analysis,
prevalence of neuropsychiatric SLE (NPSLE) was estimated in 56.3 %
(95 % CI 42.5–74.7 %) [6]. Manifestations may vary from subtle signs,
frequently undiagnosed during clinical evaluations, to severe conditions
associated with hospitalizations and increase risk of death up to 10-fold
[7]. A prospective cohort of 370 SLE patients followed over 3 years,
reported CNS involvement in 4.3 % of the studied population, amongst
neurological manifestations they found seizures (1.6 %), strokes (1.4 %),
myelopathy (1.1 %), optic neuritis (0.3 %), aseptic meningitis (0.3 %)
and acute psychosis (0.3 %) [8]. Seizure is defined as a transient
occurrence of signs and/or symptoms (sensory, motor and autonomic)
caused by abnormal excessive or synchronous neuronal activity in the
brain, and epilepsy is defined as 2 or more unprovoked seizure events
[9]. Seizure development is considered as a severe manifestation, and
probably the most ominous and relevant clinical expression in SLE,

* Corresponding authors.
E-mail addresses: adrian_rodriguezh@hotmail.com (A. Rodriguez-Hernandez), jaortzor@gmail.com (J. Ortiz-Orendain), lucia.palazuelos@edu.uag.mx
(L.E. Alvarez-Palazuelos), dralauragonzalez@prodigy.net.mx (L. Gonzalez-Lopez), drivangamez@prodigy.net.mx (J.I. Gamez-Nava), maria.cerna@edu.uag.mx
(M.G. Zavala-Cerna).

https://doi.org/10.1016/j.seizure.2021.02.021
Received 20 October 2020; Received in revised form 11 February 2021; Accepted 12 February 2021
Available online 17 February 2021
1059-1311/© 2021 British Epilepsy Association. Published by Elsevier Ltd. This article is made available under the Elsevier license
(http://www.elsevier.com/open-access/userlicense/1.0/).
A. Rodriguez-Hernandez et al.
which often occurs around disease onset [10–13]. Given the clinical
relevance of seizures in SLE, it is mandatory to increase awareness of
relevant aspects associated to their onset, risk factors, and implications
for diagnosis and treatment. Here we provide a scoping review, to
determine what is known about seizure attributable risk factors, path­
ogenesis, diagnosis, and treatment within the context of SLE, our
objective was to provide an analytic insight for the generation of rec­
ommendations that could aim in a prompt diagnosis and individualized
treatment.
2. Methods
The articles for this review were selected as follows: we first iden­
tified all the neuropsychiatric manifestations in SLE and/or types of
seizures in SLE and validated by further analytical techniques. Publi­
cations relating to seizures and SLE were gathered from PubMed and
Google Scholar using the strategy ("Lupus Erythematosus, Systemic"
AND "Seizures") OR "Epilepsy") AND “lupus”, “SLE”, “seizures”, “epi­
lepsy” “NPSLE” and “neurolupus”. The search was confined to articles
published in English, and included all years of publication, duplicated
papers were eliminated by creating and EndNote library. Articles
retrieved where analyzed by all authors for pertinence and a series of
discussions were made before final decision on the included publica­
tions. Further articles were identified from the reference lists of these
publications and they were added on the basis of their relevance for the
present review.
3. Results
Based on our search criteria and analysis of retrieved articles, we
included 48 references of which 14 were review articles, and 34 original
articles with different study designs; 16 were cohort studies, 4 had a
cross-sectional design, 6 were case-control studies, 3 were case series, 3
were results from experimental studies with animals and 2 were
metanalysis.
To address the differences in ethnicity as a risk factor for seizure
development in SLE, two multi-ethnic cohort studies were conducted
since 2008, the Genetic Profile Predicting the Phenotype study (PRO­
FILE) [14] and the Lupus in Minorities: Nature vs. Nur-ture (LUMINA)
[10] (Table 2). According to the PROFILE study Hispanic-Texan and
African American ethnicity represented the group with the higher risk to
develop seizures, while in the LUMINA study African American popu­
lation had the shorter time prior to seizure occurrence; Table 1 sum­
marizes information about seizures in SLE cohort studies.
4. Discussion
4.1. Clinical characteristics and risk factors for seizures in SLE
Seizure prevalence among SLE patients has a wide range from 2 to 8
% [5,8,11]. Their incidence is higher in young females (22.9–36.5 years
old) [10,11,14–16]. Up to two thirds of these patients will manifest a
seizure within the first year, with a median time of 51 days from diag­
nosis to first seizure [16]. The most common presentation is tonic-clonic
(60–88 %), including secondary generalized, followed by seizure with
impaired consciousness, and seizure with retained consciousness [11,12,
15]. Status epilepticus (SE), defined as a single epileptic seizure of
>30 min or a series of epileptic seizures, without function regain, be­
tween ictal events in a 30-minute period [9], is rarely found in SLE
patients (0.1 %), and whenever present correlates with brain structural
abnormalities [17].
High scores of disease activity evaluated by the SLE Disease Activity
Index (SLEDAI) and SLICC/ACR Damage Index (SDI) are considered risk
factors previously associated with a shorter time for the presentation of
the first seizure [14,16].
Peripheral organ involvement such as diffuse proliferative
162
Seizure: European Journal of Epilepsy 86 (2021) 161–167
glomerulonephritis class IV (>50 % of glomeruli affected with necro­
tizing and sclerosing lesions), serositis, vasculitis, psychosis, and stroke;
were all associated with a shorter time onset or recurrence of seizures
[14].
Several autoantibodies have been described in association to the
presence of seizures in SLE, including antiphospholipid antibodies (aPL)
which was also associated to epilepsy; although this finding was not
restricted to SLE [10,18,19].
Regarding to aPL antibodies, Malik et al. found that patients with
seropositivity to Lupus anticoagulant (La) demonstrated a reduction in
the incidence of seizures compared to patients with Ro ribonucleopro­
tein positiveness [20]. Additionally, Hawro et al. found that patients
with anti-β2 glycoprotein antibodies (anti-β2 GPI) IgG were 11 times
more likely to exhibit seizures and 9 times more likely to have
tonic-clonic seizures when compared to seronegative patients [21].
Association genetic studies, pointed towards a potential suscepti­
bility locus for seizures in SLE patients, localized in chromosome 15q22
that includes codifying genes for a cluster of alpha and beta subunits of
the neuronal nicotinic acetylcholine receptor, the first ligand-gated ion
channel strongly associated with the onset of seizures [22].
Finally, treatment has also been implied as an indirect factor asso­
ciated to the presence of seizures, the LUMINA study reported that pa­
tients treated with cyclophosphamide or glucocorticoids presented
seizures more frequently [10]. Nevertheless, this association might be
due to disease activity motivating the use of these drugs rather than a
casual effect, Table 2 summarizes information with respect to risk fac­
tors attributable to the development of seizures in SLE patients.
4.2. Pathogenesis of seizures in SLE
In the presence of SLE, a widely accepted explanation for NPSLE
development includes the role of autoantibodies in the CNS. Two ex­
planations account for autoantibodies induction of focal or diffuse CNS
damage, mostly attributable to aPL antibodies, although could be
extrapolated to others. The first implies induction of ischemic strokes,
secondary to blood vessel deposition and occlusion [12,23]. The second
relates to non-ischemic mechanisms by increasing the neuronal excit­
ability through inhibition of gamma-aminobutyric acid receptor-ion
channel complex [24], or by permeabilizing and depolarizing brain
synaptoneurosomes after binding to phospholipids of the cellular
membrane [25]. Non-ischemic mechanisms are recognized after the
finding that up to 50 % of seropositive patients with seizures, lack ab­
normalities in conventional magnetic resonance imaging (MRI),
demonstrating that thrombosis is not always the mechanism responsible
for seizure development in SLE [26].
Penetrance of autoantibodies within the CSF implies a loss of
blood–brain barrier (BBB), some previous causes of this loss in SLE
include the presence of aseptic meningitis, bacterial meningitis as a
consequence of immunosuppression, or the use of NSAIDs [27]. Much of
what we know in reference to the loss of the BBB is based on an empirical
inference by the presence of serum albumin within the CSF, although it
does not necessarily indicates vascular leakage per se, other mechanisms
could be responsible such as diffusion, active, or vesicular transport;
although still speculative, they represent alternative mechanisms for the
presence of autoantibodies without BBB disruption, even more, anti­
bodies could be directly synthesized by plasma cells intrathecally. As
alternative mechanisms two fluid transport mechanisms have been
identified in the CNS: the glymphatic pathway and the intradural
lymphatic network, representing potential side roads for immune cells
and molecules transport in and out of the CNS [28].
Another potential site for immunological entrance into the CNS is the
choroid plexus, an epithelial structure situated within the ventricles of
the CNS, bathed in CSF, and highly vascularized. It is due to this prop­
erties, that the choroid plexus has been implied as the source of
inflammation in multiple sclerosis [29] and age-related inflammatory
changes during cognitive decline [30], even in SLE there is evidence of
A. Rodriguez-Hernandez et al. Seizure: European Journal of Epilepsy 86 (2021) 161–167

Table 1
Study cohorts of patients with SLE and seizures.
Characteristics Andrade Huang 2016 Mikdashi 2005 Ramsey- Hanly 2012 Gonzalez- Apenzeller Kampylafka
(LUMINA) 2008 Goldman Duarte 2008 2004 2016
(PROFILE) 2008

Country USA USA USA USA Eleven Mexico Brazil Greece

countries*
Prospective Prospective Prospective Retrospective Prospective Retrospective Retrospective Retrospective
Type of study
Multicenter Single center Single Center Multicenter Multicenter Single Center Single center Single center
Number of
600 2,203 195 1,260 1,631 1,200 491 459
participants
46% with
Mean Follow
NA more than 5 7 ± NA NA 3.5 ± 2.9 5± NA 5.7 ± 1.2 2.6 ± 1.2
Up (years)
years
Hispanic
(Mexican, Hispanic
Central (Mexican or
American or Predominantly Puerto Rican
White, African Predominantly Hispanic
Ethnicity Puerto Rican African Americans ancestry), NA NA
and Asian Caucasian (Mexican)
ancestry), (65%) African
African American and
American and Caucasian
Caucasian
Female Gender 89.8% 92.5% 90% NA 89.4% NA NA NA
Mean Age at
time of first
NA NA NA 31.4 ± 11.8 NA 27 ± NA NA 32 ± 15
seizure
(years)
40 (6.7%) At diagnosis 28 (14.3%) 80 (6.1%) 78 (4.8%) 75 (6.2%) At diagnosis 39 (8.4%)
Baseline and Baseline and Baseline and Base line and
37 (1.7%) 19 (3.8%)
Seizures Follow Up Follow Up Follow Up Follow Up
secondary to Baseline and According to the Baseline and
SLE follow Up After diagnosis ACR After diagnosis follow up
nomenclature
120 (5.4%) NA 41(8.3%)
Evaluated by
According to
Patient self- According to Clinical features Description medical
Definition of International
report or the ACR and associated from a reliable personnel at the NA
seizure League Against
medical record nomenclature EEG. witness emergency
Epilepsy
department
NA NA TCS 21 (75%) NA n = 78 n = 75 n = 60 n = NA
SPMS 2 (3.5%) TCS 47 (60.2%) TCS 58 (77%) TCS 53 (88%) TCS 70%
Status
SPSS 2(3.5%) Atonic 1 (1.2%) CPS 9 (12%) CPS 7 (12%) Epilepticus
Seizure Types 30%
Absence 2
CPS 5 (18%) SPMS 5(7%)
(2.5%)
SPS 15(19%) SGTCS 3 (4%)
CPS 13(16%)
NA NA Described: NA NA NA Described 66: Described 38: Described 5:
Normal 16 Normal 28 Normal 2
Mostly diffuse (24%) (74%) (40%)
EEG findings in slowing with theta Epileptiform Epileptiform
patients with and delta discharges 33 discharges 2
seizures background, (50%) (5%) Abnormal 3
infrequent focal Diffuse Slow Slow waves 1 (60%)
abnormalities Activity 17 (3%)
(28.3%) Mix** 7 (18%)
NA Described 120: Described NA Described 36: Described 32: Described 10:
Normal 104 Ischemic Stroke
Global cerebral PRESS 3 (30%),
(87%) in 33 patients
Mostly white
MRI in patients atrophy, Microinfarcts
matter lesions, NA NA
with seizures Ischemic and white
Abnormal 16 cortical atrophy, (Lacunar 30 %,
lesions, cortical matter lesions 4
(13%) areas of infarction. Cortical 70%)
and subcortical (40%),
lesions. normal 3 (30%)
Described 24: NA Described 7:
21 (88%)
normal,
CSF in patients
NA NA NA NA NA 1 (4%) Normal 7
with seizures
pleocytosis, (100%)
2 (8%) elevated
proteins

163
A. Rodriguez-Hernandez et al. Seizure: European Journal of Epilepsy 86 (2021) 161–167

Table 2 TCS: Tonic clonic seizures; CPS: Complex partial seizures; SPMS: Secondary
Previous identified risk factors for seizures in SLE (p < 0.05). Progressive Multiple Sclerosis; SPS: Simple Partial Seizure; SGTCS: Secondary
generalized tonic-clonic seizures.
Risk factor Risk Confidence Country Reference
Interval

Risk for shorter time to seizure occurrence

immune complex deposition at this anatomical region. Irrespective of
Younger Age HR 1.00-1.08 United (10) the form of entry, there is no question that the presence of CSF auto­
1.04 States antibodies are important triggers of NPSLE manifestations, including
Ethnicity seizures.
HR
1.40-3.70 (14) Apart from aPL antibodies, others related to the development of
2.30 United
African- American
HR States seizures include a subset of anti-double-stranded DNA antibodies with
1.26- 22.87 (10)
5.37 cross-reactivity to subunits of the N-methyl-D-aspartate receptor
Hispanic
HR
1.30-5.10
United
(14)
(NMDARs) on neuronal cells trigger neuronal death by excito-toxicity
2.60 States and apoptosis [31]; and anti-ribosomal P protein antibodies which
Disease Activity
Higher Number ACR HR United
target specific brain parenchymal structures and have been previously
1.10-1.50 (14) identified in association with seizures in SLE [32]. Upon binding, au­
criteria 1.30 States
SLAM- R score at diagnosis HR United toantibodies could trigger activation of microglial cells, T cells, and
1.07-1.15 (10)
and baseline 1.11 States activation of the complement system by the classical pathway.
HR United
SDI score at diagnosis 1.23-1.76 (10) With respect to immune cells as mediators of pathological changes in
1.47 States
CNS Involvement NPSLE, microglial cells are the predominant CNS immune cells potent
HR cytokine producers driving inflammatory changes [33], however there
2.20-6.90 (14)
Cerebrovascular disease
3.90 United is limited information about the role of microglial driven inflammatory
HR States changes on the human brain and this needs to be further explored.
1.11- 5.29 (17)
2.42
HR
Experimental studies in mouse models have also pointed towards the
1.50-6.90 (14) role of cytokines for NPSLE including INF-a, TNF, and IL-6; with some
3.30 United
Psychosis
HR States findings being corroborated in humans [34], however their role in the
1.20-6.80 (10)
3.85 development of seizures has not been described.
Other Organs
Brain structural changes could be associated to the development of
Diffuse Proliferative HR United
Glomerulonephritis (IV) 4.18
2.16-8.09
States
(10) seizures, such as the local scarring associated to a chronic inflammatory
HR condition or secondary to damage from a thrombotic event [28].
1.12-4.38 (10)
Renal Damage
2.22 United Finally, after the conduction of genome wide association studies in
HR States SLE patients, three variants of a single nucleotide polymorphism (SNP)
1.40- 3.30 (14)
2.10
in the TREX1 gene, which encodes a repair exonuclease, namely
HR United
Serositis 1.20- 2.90 (14) rs922075, rs6776700, rs6442123, rs2242150 and rs11797 were found
1.80 States
HR United to be significantly associated with the development of seizures [35].
Antiphospholipid 1.26- 6.52 (10)
2.87 States
Risk for first Occurrence of seizure
HR Eleven
4.3. Diagnostic procedures to evaluate seizure in SLE
< High School 1.34-3.44 (16)
2.15 Countries
Disease Activity MRI is the gold standard technique for the evaluation of NPSLE,
HR United including seizures [36]. In general MRI performs better than CT in the
SLEDAI> 16 1.34-3.44 (17)
2.15 States
detection of reversible focal lesions, infarct, atrophy, intracranial hem­
HR Eleven
High Damage Index
1.40
1.03-1.89
Countries
(16) orrhage, and other CNS lesions that occur commonly SLE [37]. Fig. 1
CNS Involvement represents diagnostic procedures and treatment in patients with SLE and
Organic Brain Syndrome
RR
1.59- 5.50
United
(13) seizures. It is recommended that MRI protocol includes conventional
2.96 States T1/T2- weighted fluid attenuated inversion recovery (FLAIR), diffusion
RR United
Neuropathy
2.01
1.11- 3.65
States
(13) weighted imaging (DwI), and gadolinium - enhanced T1- weighted se­
RR United quences for any patient with seizures. MRI evaluation could discard
Cognitive impairment 1.14- 4.17 (13)
2.18 States differentials for seizures (i.e., brain mass or abscess, progressive multi­
RR United focal encephalomyelitis, and CNS infections) [38]. Brain imaging ab­
Psychosis 1.98- 6.96 (13)
3.68 States
normalities are present in 25 % of patients with newly diagnosed SLE
Other organs
RR United [39], including cerebral atrophy, ischemic lesions and white matter le­
Proteinuria 1.12- 2.31 (13)
1.61 States sions. Mikdashi and colleagues, studied 195 patients with SLE, of which
Antibodies and Complement 28 had seizures and 12 of them had recurrent epilepsy. MRI of these
HR United patients showed focal lesions in the white matter, cortical atrophy and
Anti- Cardiolipin 1.30-9.50 (17)
3.70 States
RR United
areas of large infarctions [17]. Additionally, electroencephalography
Anti- Smith 1.19-2.71 (13) (EEG) is a fundamental tool in the study of seizures in NPSLE [38]. SLE
1.80 States
RR United patients with recurrent seizures usually have abnormal findings on EEG,
Low C3 1.30-2.93 (13)
1.95 States consistent with focal aware events, epilepsy with impaired awareness
RR United
Abnormal CT 1.15- 3.99 (13) and focal to bilateral tonic-clonic epilepsy, as demonstrated by
2.15 States
Protective Risk Factors Appenzeller and colleagues who found that 9.7 % of patients with single
HR epileptic seizure had abnormal EEG findings, compared to 100 %
Musculoskeletal 0.01-0.34 (14)
0.18 United abnormal EEG findings, commonly on temporal lobe, in patients with
HR States recurrent seizures [12]. Another study found that up to 42 % of SLE
Involvement 0.04-0.21 (10)
0.09
Mucocutaneus HR United
patients had an interictal EEG anomaly (seizure pattern with sharp
0.01-0.34 (10) spikes and/or multiple spikes) in association with the presence of
Manifestations 0.18 States
HR United recurrent seizures [11]. With respect to hemispheres affection, a previ­
Hydroxychloroquine 0.10-0.34 (10)
0.18 States ous study showed that about 80 % of patients presented EEG

164
A. Rodriguez-Hernandez et al.
Fig. 1. Flow chart for accurate diagnosis and personalized treatment of seizure in SLE patients.
abnormalities on the left hemisphere in contrast to 7.4 % in the right
hemisphere [40].
Cerebrospinal fluid (CSF) analysis in SLE patients, is useful to
exclude CNS infection or inflammatory NPSLE [41]. Even more, a
case-control study found an association of NPSLE and high levels of IL-6,
IL-8, IL- 17 in CSF [42]. Gonzalez-Duarte and colleagues found mild
pleocytosis or elevated proteins only in 12.5 % of patients [11]. Blue­
stein and colleagues also conducted a case-control study where NPSLE
manifestations were in association to IgG anti-neuronal antibodies in the
CSF [43].
4.4. Seizure treatment in SLE
There is no consensus in the antiepileptic treatment for SLE patients,
individual decisions are made depending on clinical presentation (par­
tial seizure, generalized tonic-clonic crisis or status epilepticus). Addi­
tionally, disease activity and seizure recurrence should be considered for
adequate treatment [44] (Fig. 1).
The European League Against Rheumatism (EULAR) recommends
that Anti-Epileptic Drugs (AED) therapy should not be started in patients
with single or infrequent events, unless there is a high-risk for seizure
recurrences, such as > 2 unprovoked seizures occurring in a 24 -h in­
terval or either evidence of symptomatic or imaging recorded brain le­
sions or epileptiform discharge on EEG [45]. Patients with SLE mainly
present focal onset seizures, and if one of the previous risk factors for
recurrence is corroborated then, patients can be treated with sodium
valproate or lamotrigine as a second line therapy. The use of AED in
patients with recurrent SLE seizures is likely to reduce the risk of seizure
recurrence, primarily within the first 2 years of onset [46].
Furthermore, in 2010 EULAR recommended in favor of the use of
165
Seizure: European Journal of Epilepsy 86 (2021) 161–167
immunosuppression for seizures associated to lupus flares, including
glucocorticoids as first line treatment, and consider the addition of
another immunosuppressive, such as intravenous pulses of cyclophos­
phamide or hydroxychloroquine, if the remission is not achieved with
glucocorticoids [38].
Since, hydroxychloroquine exhibits an anti-thrombotic effect, its use
together with aspirin anticoagulation is considered the mainstay therapy
for seizures related to thrombosis or aPL antibodies [47].
4.5. Prognosis of SLE patients with seizures
Prognosis of SLE patients with central nervous system involvement
should be reserved. Neuropsychiatric manifestations have positively
correlated with poor quality of life as assessed with the HQOL with
higher disability to work and with and increased rate of organ damage
[48]. Prompt treatment, based on the accurate diagnosis and identifi­
cation of risk for seizures recurrence, might change comorbidities in SLE
patients with seizures, shifting the balance of autoimmunity towards
seizure reduction.
5. Limitations
Our scoping review was focused to seizures in SLE, we aimed at
mapping evidence on a very complicated topic and summarized findings
from a body of knowledge that is heterogeneous in methods and disci­
plines. The diversity of our results was attributable to diverse study
designs, methodologies for the reported outcomes (seizure), distinct
populations, and interventions in analyzed studies addressing treatment
for seizures, made complicated the comparison of results.
Another limitation of our study is that we only searched for
A. Rodriguez-Hernandez et al.
information about seizures in SLE, our information could only be
generalizable to that clinical manifestation and not to NPSLE.
6. Conclusions
Seizures might be an early manifestation of SLE, frequently man­
ifested as focal-onset seizures. Neuroimaging with MRI, EEG recording,
and CSF analysis can help in the diagnosis. Treatment should be pro­
vided in an individualized form, taking into consideration disease ac­
tivity and recurrence of seizures.
Even though there is no consensus regarding therapeutic approach to
seizures in SLE, many authors emphasize on the use of immunosup­
pressive medication. The addition of AEDs is recommended only for
patients with recurrent seizures (2 events in a period of 24 h) and for
those with MRI structural abnormalities, focal neurological signs, focal
impaired awareness seizures and evidence of epileptiform waves on the
EEG.
As we go further in the understanding of the pathogenic role of in­
flammatory cells and autoantibodies in the generation of seizures, new
targets for treatment might be discovered. While we wait for new
therapies, prompt recognition and personalized treatment might have
an impact in reduction of comorbidities associated to chronic AED
administration in line with the accomplishment of long-term better
outcomes related to functionality and quality of life.
Ethical approval
The study did not involve human or animal subjects.
Funding
None.
CRediT authorship contribution statement
Adrian Rodriguez-Hernandez: Conceptualization, Methodology,
Formal analysis, Investigation, Data curation, Writing - original draft,
Writing - review & editing. Javier Ortiz-Orendain: Methodology,
Formal analysis, Investigation, Data curation, Writing - original draft,
Writing - review & editing. Lucia E. Alvarez-Palazuelos: Formal
analysis, Investigation, Data curation, Writing - original draft, Writing -
review & editing. Laura Gonzalez-Lopez: Methodology, Formal anal­
ysis, Investigation, Data curation, Writing - review & editing. Jorge Ivan
Gamez-Nava: Conceptualization, Methodology, Formal analysis,
Investigation, Data curation, Writing - review & editing. Maria G.
Zavala-Cerna: Conceptualization, Formal analysis, Investigation, Data
curation, Writing - original draft, Writing - review & editing.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
None.
References
[1] Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008;358(9):
929–39.
[2] Carter EE, Barr SG, Clarke AE. The global burden of SLE: prevalence, health
disparities and socioeconomic impact. Nat Rev Rheumatol 2016;12(10):605–20.
[3] Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation
and validation of the Systemic Lupus International Collaborating Clinics
classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64
(8):2677–86.
166
Seizure: European Journal of Epilepsy 86 (2021) 161–167
[4] Yurkovich M, Vostretsova K, Chen W, Avina-Zubieta JA. Overall and cause-specific
mortality in patients with systemic lupus erythematosus: a meta-analysis of
observational studies. Arthritis Care Res (Hoboken) 2014;66(4):608–16.
[5] Hanly JG, Urowitz MB, Sanchez-Guerrero J, Bae SC, Gordon C, Wallace DJ, et al.
Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus:
an international inception cohort study. Arthritis Rheum 2007;56(1):265–73.
[6] Unterman A, Nolte JE, Boaz M, Abady M, Shoenfeld Y, Zandman-Goddard G.
Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis.
Semin Arthritis Rheum 2011;41(1):1–11.
[7] Zirkzee EJ, Huizinga TW, Bollen EL, van Buchem MA, Middelkoop HA, van der
Wee NJ, et al. Mortality in neuropsychiatric systemic lupus erythematosus
(NPSLE). Lupus 2014;23(1):31–8.
[8] Kampylafka EI, Alexopoulos H, Kosmidis ML, Panagiotakos DB,
Vlachoyiannopoulos PG, Dalakas MC, et al. Incidence and prevalence of major
central nervous system involvement in systemic lupus erythematosus: a 3-year
prospective study of 370 patients. PLoS One 2013;8(2):e55843.
[9] Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, et al. Epileptic
seizures and epilepsy: definitions proposed by the International League Against
Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46
(4):470–2.
[10] Andrade RM, Alarcon GS, Gonzalez LA, Fernandez M, Apte M, Vila LM, et al.
Seizures in patients with systemic lupus erythematosus: data from LUMINA, a
multiethnic cohort (LUMINA LIV). Ann Rheum Dis 2008;67(6):829–34.
[11] Gonzalez-Duarte A, Cantu-Brito CG, Ruano-Calderon L, Garcia-Ramos G. Clinical
description of seizures in patients with systemic lupus erythematosus. Eur Neurol
2008;59(6):320–3.
[12] Appenzeller S, Cendes F, Costallat LT. Epileptic seizures in systemic lupus
erythematosus. Neurology 2004;63(10):1808–12.
[13] Huang X, Magder LS, Petri M. Predictors of incident seizure in systemic lupus
erythematosus. J Rheumatol 2016;43(3):565–75.
[14] Ramsey-Goldman R, Alarcon GS, McGwin G, Petri M, Vila LM, Edberg JC, et al.
Time to seizure occurrence and damage in PROFILE, a multi-ethnic systemic lupus
erythematosus cohort. Lupus 2008;17(3):177–84.
[15] Kampylafka EI, Alexopoulos H, Fouka P, Moutsopoulos HM, Dalakas MC,
Tzioufas AG. Epileptic syndrome in systemic lupus erythematosus and neuronal
autoantibody associations. Lupus 2016;25(11):1260–5.
[16] Hanly JG, Urowitz MB, Su L, Gordon C, Bae SC, Sanchez-Guerrero J, et al. Seizure
disorders in systemic lupus erythematosus results from an international,
prospective, inception cohort study. Ann Rheum Dis 2012;71(9):1502–9.
[17] Mikdashi J, Krumholz A, Handwerger B. Factors at diagnosis predict subsequent
occurrence of seizures in systemic lupus erythematosus. Neurology 2005;64(12):
2102–7.
[18] Gibbs 3rd JW, Husain AM. Epilepsy associated with lupus anticoagulant. Seizure
2002;11(3):207–9.
[19] Ranua J, Luoma K, Peltola J, Haapala AM, Raitanen J, Auvinen A, et al.
Anticardiolipin and antinuclear antibodies in epilepsy–a population-based cross-
sectional study. Epilepsy Res 2004;58(1):13–8.
[20] Malik S, Bruner GR, Williams-Weese C, Feo L, Scofield RH, Reichlin M, et al.
Presence of anti-La autoantibody is associated with a lower risk of nephritis and
seizures in lupus patients. Lupus 2007;16(11):863–6.
[21] Hawro T, Bogucki A, Krupinska-Kun M, Maurer M, Wozniacka A. Intractable
headaches, ischemic stroke, and seizures are linked to the presence of anti-
beta2GPI antibodies in patients with systemic lupus erythematosus. PLoS One
2015;10(3):e0119911.
[22] Bautista JF, Kelly JA, Harley JB, Gray-McGuire C. Addressing genetic
heterogeneity in complex disease: finding seizure genes in systemic lupus
erythematosus. Epilepsia 2008;49(3):527–30.
[23] Kumral E, Evyapan D, Keser G, Kabasakal Y, Oksel F, Aksu K, et al. Detection of
microembolic signals in patients with neuropsychiatric lupus erythematosus. Eur
Neurol 2002;47(3):131–5.
[24] Liou HH, Wang CR, Chou HC, Arvanov VL, Chen RC, Chang YC, et al.
Anticardiolipin antisera from lupus patients with seizures reduce a GABA receptor-
mediated chloride current in snail neurons. Life Sci 1994;54(15):1119–25.
[25] Chapman J, Cohen-Armon M, Shoenfeld Y, Korczyn AD. Antiphospholipid
antibodies permeabilize and depolarize brain synaptoneurosomes. Lupus 1999;8
(2):127–33.
[26] Steup-Beekman GM, Zirkzee EJ, Cohen D, Gahrmann BM, Emmer BJ, Steens SC,
et al. Neuropsychiatric manifestations in patients with systemic lupus
erythematosus: epidemiology and radiology pointing to an immune-mediated
cause. Ann Rheum Dis 2013;72(Suppl. 2):ii76–9.
[27] Yelehe-Okouma M, Czmil-Garon J, Pape E, Petitpain N, Gillet P. Drug-induced
aseptic meningitis: a mini-review. Fundam Clin Pharmacol 2018;32(3):252–60.
[28] Schwartz N, Stock AD, Putterman C. Neuropsychiatric lupus: new mechanistic
insights and future treatment directions. Nat Rev Rheumatol 2019;15(3):137–52.
[29] Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, et al. C-C
chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the
choroid plexus is required for the initiation of EAE. Nat Immunol 2009;10(5):
514–23.
[30] Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, et al. Aging-
induced type I interferon response at the choroid plexus negatively affects brain
function. Science 2014;346(6205):89–93.
[31] DeGiorgio LA, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B. A subset
of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in
systemic lupus erythematosus. Nat Med 2001;7(11):1189–93.
[32] Moscavitch SD, Szyper-Kravitz M, Shoenfeld Y. Autoimmune pathology accounts
for common manifestations in a wide range of neuro-psychiatric disorders: the
A. Rodriguez-Hernandez et al.
olfactory and immune system interrelationship. Clin Immunol 2009;130(3):
235–43.
[33] Duprez T, Nzeusseu A, Peeters A, Houssiau FA. Selective involvement of the
choroid plexus on cerebral magnetic resonance images: a new radiological sign in
patients with systemic lupus erythematosus with neurological symptoms.
J Rheumatol 2001;28(2):387–91.
[34] Fragoso-Loyo H, Atisha-Fregoso Y, Llorente L, Sanchez-Guerrero J. Inflammatory
profile in cerebrospinal fluid of patients with headache as a manifestation of
neuropsychiatric systemic lupus erythematosus. Rheumatology (Oxford) 2013;52
(12):2218–22.
[35] Ceccarelli F, Perricone C, Borgiani P, Ciccacci C, Rufini S, Cipriano E, et al. Genetic
factors in systemic lupus erythematosus: contribution to disease phenotype.
J Immunol Res 2015;2015:745647.
[36] Toledano P, Sarbu N, Espinosa G, Bargallo N, Cervera R. Neuropsychiatric systemic
lupus erythematosus: magnetic resonance imaging findings and correlation with
clinical and immunological features. Autoimmun Rev 2013;12(12):1166–70.
[37] Sibbitt Jr WL, Sibbitt RR, Griffey RH, Eckel C, Bankhurst AD. Magnetic resonance
and computed tomographic imaging in the evaluation of acute neuropsychiatric
disease in systemic lupus erythematosus. Ann Rheum Dis 1989;48(12):1014–22.
[38] Bertsias GK, Boumpas DT. Pathogenesis, diagnosis and management of
neuropsychiatric SLE manifestations. Nat Rev Rheumatol 2010;6(6):358–67.
[39] Petri M, Naqibuddin M, Carson KA, Wallace DJ, Weisman MH, Holliday SL, et al.
Brain magnetic resonance imaging in newly diagnosed systemic lupus
erythematosus. J Rheumatol 2008;35(12):2348–54.
167
Seizure: European Journal of Epilepsy 86 (2021) 161–167
[40] Glanz BI, Schur PH, Khoshbin S. EEG abnormalities in systemic lupus
erythematosus. Clin Electroencephalogr 1998;29(3):128–31.
[41] Govoni M, Bortoluzzi A, Padovan M, Silvagni E, Borrelli M, Donelli F, et al. The
diagnosis and clinical management of the neuropsychiatric manifestations of lupus.
J Autoimmun 2016;74:41–72.
[42] Yao Y, Wang JB, Xin MM, Li H, Liu B, Wang LL, et al. Balance between
inflammatory and regulatory cytokines in systemic lupus erythematosus. Genet
Mol Res 2016;15(2).
[43] Bluestein HG, Williams GW, Steinberg AD. Cerebrospinal fluid antibodies to
neuronal cells: association with neuropsychiatric manifestations of systemic lupus
erythematosus. Am J Med 1981;70(2):240–6.
[44] Hanaya R, Arita K. The new antiepileptic drugs: their neuropharmacology and
clinical indications. Neurol Med Chir (Tokyo) 2016;56(5):205–20.
[45] Bertsias GK, Ioannidis JP, Aringer M, Bollen E, Bombardieri S, Bruce IN, et al.
EULAR recommendations for the management of systemic lupus erythematosus
with neuropsychiatric manifestations: report of a task force of the EULAR standing
committee for clinical affairs. Ann Rheum Dis 2010;69(12):2074–82.
[46] England MJ, Liverman CT, Schultz AM, Strawbridge LM. Epilepsy across the
spectrum: promoting health and understanding. A summary of the Institute of
Medicine report. Epilepsy Behav 2012;25(2):266–76.
[47] Popescu A, Kao AH. Neuropsychiatric systemic lupus erythematosus. Curr
Neuropharmacol 2011;9(3):449–57.
[48] Hanly JG, Urowitz MB, Su L, Bae SC, Gordon C, Wallace DJ, et al. Prospective
analysis of neuropsychiatric events in an international disease inception cohort of
patients with systemic lupus erythematosus. Ann Rheum Dis 2010;69(3):529–35.