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

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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

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

* Corresponding authors.
E-mail addresses: [email protected] (A. Rodriguez-Hernandez), [email protected] (J. Ortiz-Orendain), [email protected]
(L.E. Alvarez-Palazuelos), [email protected] (L. Gonzalez-Lopez), [email protected] (J.I. Gamez-Nava), [email protected]
(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. Seizure: European Journal of Epilepsy 86 (2021) 161–167

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

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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

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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

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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 immunosuppression for seizures associated to lupus flares, including
hemisphere [40]. glucocorticoids as first line treatment, and consider the addition of
Cerebrospinal fluid (CSF) analysis in SLE patients, is useful to another immunosuppressive, such as intravenous pulses of cyclophos­
exclude CNS infection or inflammatory NPSLE [41]. Even more, a phamide or hydroxychloroquine, if the remission is not achieved with
case-control study found an association of NPSLE and high levels of IL-6, glucocorticoids [38].
IL-8, IL- 17 in CSF [42]. Gonzalez-Duarte and colleagues found mild Since, hydroxychloroquine exhibits an anti-thrombotic effect, its use
pleocytosis or elevated proteins only in 12.5 % of patients [11]. Blue­ together with aspirin anticoagulation is considered the mainstay therapy
stein and colleagues also conducted a case-control study where NPSLE for seizures related to thrombosis or aPL antibodies [47].
manifestations were in association to IgG anti-neuronal antibodies in the
CSF [43].
4.5. Prognosis of SLE patients with seizures

4.4. Seizure treatment in SLE Prognosis of SLE patients with central nervous system involvement
should be reserved. Neuropsychiatric manifestations have positively
There is no consensus in the antiepileptic treatment for SLE patients, correlated with poor quality of life as assessed with the HQOL with
individual decisions are made depending on clinical presentation (par­ higher disability to work and with and increased rate of organ damage
tial seizure, generalized tonic-clonic crisis or status epilepticus). Addi­ [48]. Prompt treatment, based on the accurate diagnosis and identifi­
tionally, disease activity and seizure recurrence should be considered for cation of risk for seizures recurrence, might change comorbidities in SLE
adequate treatment [44] (Fig. 1). patients with seizures, shifting the balance of autoimmunity towards
The European League Against Rheumatism (EULAR) recommends seizure reduction.
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 5. Limitations
recurrences, such as > 2 unprovoked seizures occurring in a 24 -h in­
terval or either evidence of symptomatic or imaging recorded brain le­ Our scoping review was focused to seizures in SLE, we aimed at
sions or epileptiform discharge on EEG [45]. Patients with SLE mainly mapping evidence on a very complicated topic and summarized findings
present focal onset seizures, and if one of the previous risk factors for from a body of knowledge that is heterogeneous in methods and disci­
recurrence is corroborated then, patients can be treated with sodium plines. The diversity of our results was attributable to diverse study
valproate or lamotrigine as a second line therapy. The use of AED in designs, methodologies for the reported outcomes (seizure), distinct
patients with recurrent SLE seizures is likely to reduce the risk of seizure populations, and interventions in analyzed studies addressing treatment
recurrence, primarily within the first 2 years of onset [46]. for seizures, made complicated the comparison of results.
Furthermore, in 2010 EULAR recommended in favor of the use of Another limitation of our study is that we only searched for

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