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Keywords:

  • Systemic lupus erythematosus;
  • Neuropsychiatric syndrome of systemic lupus erythematosus;
  • Mesial temporal lobe epilepsy;
  • Electroencephalography

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Additional Contributors
  7. Disclosures
  8. References

In this study, we aimed to investigate the types of seizures and epilepsy associated with systemic lupus erythematosus (SLE). We searched the medical records at a tertiary referral center to identify a cohort of epilepsy patients with SLE who were treated between January 2000 and August 2011. We analyzed the clinical and immunologic profiles of these patients, their seizure and epilepsy classifications, electroencephalography (EEG) and magnetic resonance imaging (MRI) assessments, and the treatment administered for epilepsy and SLE. As the result, 17 patients with SLE and epilepsy were identified. Seven patients had mesial temporal lobe epilepsy (MTLE), eight had epilepsy secondary to stroke, and two had generalized epilepsy. Of the seven patients with MTLE, anteriotemporal spikes were noted in all patients with EEG, and MRI findings suggesting hippocampal sclerosis were noted in four patients. Clobazam and levetiracetam were effective in treating three patients, and one patient underwent amygdalohippocampectomy. In conclusion, MTLE may be a characteristic manifestation of neuropsychiatric syndrome of systemic lupus erythematosus.

The American College of Rheumatology (ACR) has developed a standard nomenclature and case definitions for neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE), 19 of which include seizure disorders. However, different types of seizures are grouped together without distinction from epilepsy. Sibbitt et al. (2002) was among the first to distinguish epilepsy from isolated seizures among patients with pediatric SLE. Moreover, previous reports of epilepsy with SLE that provided a detailed description of epilepsy diagnosis are unavailable. We classified patients according to the International League Against Epilepsy (ILAE) classification of epilepsies and epileptic syndromes.

Seizures (unprovoked and acute symptomatic seizures) are common in patients with SLE (6.8–51%) (Sibley et al., 1992; Brey et al., 2002; Sibbitt et al., 2002; Appenzeller et al., 2004; Shoenfeld et al., 2004; Mikdashi et al., 2005) but “epilepsy” is less common (1.4–15%) (Mackworth-Young & Hughes, 1985; Toubi et al., 1995; Liou et al., 1996; Sibbitt et al., 2002; Appenzeller et al., 2004; Mikdashi et al., 2005; Adelöw et al., 2012). And few reports of epileptiform activities on electroencephalography (EEG) in epilepsy patients with NPSLE exist (Liou et al., 1996; Appenzeller et al., 2004).

Many previous studies reported the relationship between seizures or epilepsy and antiphospholipid antibodies (aPLs) (Toubi et al., 1995; Liou et al., 1996; Appenzeller et al., 2004; Shoenfeld et al., 2004). Stroke also increases seizure risk in SLE (Appenzeller et al., 2004; Mikdashi et al., 2005). Epileptic seizures in patients with aPLs may be related to ischemic events due to hypercoagulability (Asherson et al., 1989).

In this study, we report on chronic epilepsy in NPSLE, excluding acute symptomatic seizures, and elaborate on seizures not secondary to stroke. In addition, we report EEG, magnetic resonance imaging (MRI) findings, and antiepileptic treatment for all included patients.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Additional Contributors
  7. Disclosures
  8. References

Patient selection

We reviewed medical records of patients with epilepsy and SLE using the search system of the electronic medical records in the University of Occupational and Environmental Health School of Medicine (UOEH), Japan. These patients were treated between January 2000 and August 2011. All patients were Japanese and had been diagnosed with SLE according to the ACR criteria, by the board-certified rheumatologists (K.S. and Y.T.). Disease onset was defined as the time at which the patient met four ACR criteria for SLE. Neuropsychiatric manifestations were clinically ascertained and classified into distinct syndromes using the ACR nomenclature. Activity of SLE was measured using the SLE Disease Activity Index (SLEDAI) score. This study was approved by the ethical standards committee of UOEH.

Immunologic testing

Serologic profiling of patients was performed using standard immunoassays. Anti-dsDNA (double-stranded DNA) antibodies were examined by the Crithidia luciliae assay, and anti-Smith (Sm) antibodies were detected by the Ouchterlony double-immunodiffusion method. Antinuclear antibodies were detected by indirect immunofluorescence on Hep-2 cell slides. Quantitation of aPLs was determined by anti-cardiolipin (aCL) immunoglobulin G (IgG) and anti-β2-GPI (β2GPI), using enzyme linked immunosorbent assay (ELISA) kit. The presence of the lupus anticoagulant (LAC) was scored using guidelines established by the 1991 Scientific and Standardization Committee for LAC. According to Wilson’s criteria, a diagnosis of antiphospholipid syndrome (APS) is made when aCL or LAC-positive scores (in two samples at least 6 weeks apart) are associated with at least one clinical criterion (i.e., thrombosis or pregnancy morbidity).

Neurologic evaluation

Epilepsy was defined by standard clinical criteria as at least two separate episodes of unprovoked seizures with an interval >24 h. Epileptic seizures were classified according to criteria suggested by ILAE. Acute symptomatic seizures were excluded.

EEG recordings of more than 30 min were made in the interictal period using a 21-channel analog EEG recorder (Neurofax PV-101A; Nihon Kohden, Tokyo, Japan) before 2005 and 21-channel digital EEG recorder (EEG 1100 Nihon Kohden) thereafter, according to the international 10–20 system of electrode placement. All records were reported by the board-certified electroencephalographer who was unaware of the clinical diagnosis.

MRI

Brain MRI was performed using a 3.0-T MR system (Signa EXCITE; GE Healthcare, Milwaukee, WI, U.S.A.) by using a dedicated eight-channel phased-array coil (USA Instruments, Aurora, OH, U.S.A.). T1-, T2-, and diffusion-weighted, and fluid-attenuated inversion recovery (FLAIR) protocols. Special protocols for evaluating hippocampal sclerosis were used and all images were interpreted by the board-certified neuroradiologists.

Epilepsy classification

Epilepsy classification was based on ILAE criteria published in 1989. The diagnostic criteria for mesial temporal lobe epilepsy (MTLE) consist of a history of typical aura or complex partial seizures and the presence of interictal anterior temporal spikes.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Additional Contributors
  7. Disclosures
  8. References

Seventeen patients were identified with both epilepsy and SLE. Among these, seven patients were diagnosed with MTLE (Table 1), eight with epilepsy secondary to cerebral infarction or bleeding, and two with generalized epilepsy. On August 2011, 175 SLE patients were identified, and five patients had active MTLE, so that prevalence of MTLE in SLE was 2.9%.

Table 1.   Clinical, EEG, and MRI findings of SLE patients with mesial temporal lobe epilepsy
Case no./gender (M/F)Age at seizure onset (years)Age at diagnosis of SLE (years)Type of seizuresEEG findings (interictal)Abnormality on MRITreatment (per day)Prognosis
  1. SPS, simple partial seizure; CPS, complex partial seizure; sGTC, secondarily generalized tonic–clonic seizure; seizure free, no seizures for more than 1 year; persistent seizure, more than two seizures per month; rare seizure, <1 seizure per month; VPA, valproate; CZP, clonazepam; CLB, clobazam; LEV, levetiracetam; CS, continuous slow.

1/F2940Epigastric aura, CPSRight anterior-temporal spikeCerebral atrophy, right mesial temporal lobe atrophyVPA 1,200 mg, CZP 2 mgNot followed
2/F1818Visual aura, sGTCLeft anterior-temporal spikeNormalVPA 400 mg, CLB 10 mgSeizure free
3/F2517Psychic aura, CPS, sGTCRight anterior-temporal spikeRight mesial temporal lobe high signal intensityVPA 800 mg CLB 5 mg Right amygdalo-hippocampectomyRare seizures
4/F4545Abdominal aura, sGTCLeft anterior-temporal spikeNormalCLB 10 mgSeizure free
5/F3120Psychic aura, CPS, sGTCBilaterarl anterior-temporal spikeCerebral atrophyVPA 1,800 mgPersistent seizures
6/M1918CPS, sGTCRight anterior-temporal sharp wave α-decreased, right CS, right posterior quadrantRight cerebral atrophy, right mesial temporal lobe atrophyVPA 1,000 mg, LEV 1,000 mgSeizure free
7/M6154Epigastric aura sGTC status epilepticusLeft anterior-temporal spikeLeft mesial temporal lobe high signal intensity, multiple cerebral infarctionsVPA 1,000 mgNot followed (transfered)

EEG and MRI findings

Interictal EEG and MRI of the brain were performed on all SLE patients with MTLE (Table 1). All patients had anteriotemporal sharp waves or spikes. One patient had normal EEG findings in the routine records and had interictal temporal spikes only when she underwent video-EEG monitoring. She had a rhythmic theta wave in the right temporal on ictal EEG.

Epilepsy treatment and prognosis

Treatment was initiated with valproate (VPA) by attending physicians. Often seizures were not controlled by VPA alone. Three patients became seizure free after clobazam or levetiracetam was added later. One patient underwent amygdalohippocampectomy because of poor seizure control with medications, and became well controlled. One patient had persistent seizures with VPA monotherapy. Two were lost to follow-up (Table 1).

Serum autoimmune antibodies, SLE manifestations and complications

SLE manifestations and complications are presented in Table 2.

Table 2.   Clinical findings and laboratory results of SLE patients with mesial temporal lobe epilepsy
Case no./gender (M/F)SLE manifestationsSLEDAIComplicationsAntibodiesaTreatment
ANdsDNASmaPL (IgG)β2-GPILA
  1. SLEDAI, SLE Disease Activity Index; AN, antinuclear; DM, diabetes mellitus; dsDNA, double-stranded DNA; Sm, anti-Smith; aPL, anti-phospholipid antibody; β2-GPI, β2-glycoprotein; LA, Lupus anticoagulant; AIHA, autoimmune hemolytic anemia; IP, interstitial pneumonia; APS, antiphospholipid syndrome; RA, rheumatoid arthritis; =, not tested.

  2. aReference ranges for blood tests: dsDNA, 0.4–5.7 IU/ml; Sm, 0–14 IU/ml; aPL (IgG), <10 U/ml; β2-GPI, <3.5 U/ml; LA, <1.3.

1/FArthritis, oral ulcers, proteinuria18APS, AIHA1,2804003=2.92.0Corticosteroids, aspirin
2/FMalar rash, nephritis13=1,280=111.8==Corticosteroids, immunosuppressants
3/FMalar rash, photosensitivity, arthritis, nephritis,12APS1,280>40017.94.0=+Corticosteroids, aspirin
4/FNephritis15DM, Type I5,120>40015=2.12.9Corticosteroids, immunosuppressants, immunoabsorption
5/FMalar rash, arthritis, nephritis18=32036.240.519=Corticosteroids, immunosuppressants, immunoabsorption
6/FMalar rash, arthritis12=5,1208.03=1.2=Corticosterioids, immunosuppressants
7/MNephritis arthritis19Sjögren’s syndrome, RA, IP2,56016564===Corticosteroids, immunosuppressants, aspirin

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Additional Contributors
  7. Disclosures
  8. References

This is the first study to report that MTLE is prevalent in SLE. Our main study finding is that MTLE is common in NPSLE except in cases when epilepsy is secondary to stroke. In this study, 7 (41%) of 17 epilepsy patients with SLE had MTLE. This indicates that the proportion of MTLE in our SLE cohort is greater than in epilepsy-center–based adult population with epilepsy. As the proportion of temporal lobe epilepsy (TLE) including MTLE is reported 20–35% of all the epilepsy patients (Currie et al., 1971).

In this study, six of seven patients with SLE and MTLE had epileptic seizures after disease onset, and one (Case no. 1) had seizure years prior to SLE diagnosis. The patient may have had SLE by chance. Another one (Case no. 7) had rheumatoid arthritis and Sjögren’s syndrome complications, and it is therefore possible that immune-mediated diseases other than SLE may also be associated with epilepsy.

We confirmed that high disease activity including increased DNA binding and nephritis at baseline correlate with MTLE in SLE as described before (Appenzeller et al., 2004; Mikdashi et al., 2005), but not with severity of epilepsy. All seven SLE patients with MTLE had high disease activity at baseline but not at seizure onset; SLEDAI score was decreased to almost 0 at seizure onset. This tendency is interesting and may be related to the key process of maturing MTLE in SLE. Further cases are necessary to ensure this correlation.

MRI abnormalities of the mesial temporal lobe were noted in four patients, supporting the diagnosis of MTLE. Previous reports focused on small, multifocal white matter lesions that may present cerebral microinfarcts and cerebral atrophy. Temporal lobe atrophy was not focused on except for Appenzeller et al. (2004).

Carbamazepine and lamotrigine cannot be used to treat epilepsy in SLE patients because side-effects include inducing an SLE like–syndrome. Therefore, attending physicians usually treated epilepsy patients with SLE using high-dose VPA. For cases that were difficult to control with VPA alone, combined treatment was initiated by neurologists, which led to improved seizure control (Table 1). We consider that clobazam and levetiracetam are useful alternatives for treating MTLE with SLE. They are also better for treatment of childbearing age women with epilepsy in SLE because of a low incidence of congenital malformation.

Furthermore, amygdalohippocampectomy is a treatment option in patients with MTLE with hippocampal sclerosis. We propose that surgical treatment should be aggressively considered in SLE patients with hippocampal sclerosis because it can decrease the need for antiepileptic drugs.

Unfortunately, our research has limitations. The total number of the MTLE with SLE patients studied was seven, which is too small a sample to make a firm conclusion. The prevalence of MTLE in SLE was estimated as 2.9% in our study, which may suffer significant sampling error. Further study is necessary to elucidate the prevalence of MTLE in SLE. This is a retrospective case study. Further studies using a prospective method should be carried out to reveal the characteristics of the MTLE in SLE.

Additional Contributors

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Additional Contributors
  7. Disclosures
  8. References

Dr. Toyota: diagnosis, therapy, analysis of records, data collection, design of the study, drafting/revising the manuscript. Dr. Akamatsu: diagnosis, therapy, analysis of records, data collection, revising the manuscript, design of the study. Dr. A Tanaka: diagnosis, therapy. Dr. Shouzaki: diagnosis, therapy. Dr. Tsuji: diagnosis, therapy, design of the study, study supervision. Dr. Saito: diagnosis, therapy, analysis of records. Dr. Y Tanaka: diagnosis, therapy.

Disclosures

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Additional Contributors
  7. Disclosures
  8. References

Authors report no disclosures. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Additional Contributors
  7. Disclosures
  8. References
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