Abstract
Objective: To evaluate the frequency and risk factors of epileptic seizures in a large cohort of patients with systemic lupus erythematosus (SLE).
Methods: Five hundred nineteen consecutive patients with SLE were studied, with follow-up ranging from 4 to 7.8 years. The type and frequency of risk factors associated with acute and recurrent epileptic seizures in SLE were determined.
Results: Sixty (11.6%) patients with epileptic seizures were identified. Epileptic seizures occurred at the onset of SLE symptoms in 19 (31.6%) and after the onset of SLE in 41 of 60 (68.3%) patients. Fifty-three of 60 (88.3%) patients had acute symptomatic epileptic seizures, and 7 of 60 (11.7%) had recurrent epileptic seizures. Variables associated with acute epileptic seizures at SLE onset were stroke (p = 0.0004) and antiphospholipid antibodies (p = 0.0013). Epileptic seizures during follow-up were related to nephritis (p = 0.001), antiphospholipid antibodies (p = 0.005), and epileptic seizures at disease onset (p = 0.00001). All seven patients who presented recurrent epileptic seizures had antiphospholipid syndrome and interictal epileptic abnormalities on EEG.
Conclusions: Epileptic seizures were observed in 11.2% of systemic lupus erythematosus (SLE) patients. Antiphospholipid antibodies and stroke were related to epileptic seizures at SLE disease onset. Patients with renal flares, epileptic seizures at SLE disease onset, and antiphospholipid antibodies were at greater risk for acute symptomatic seizures during follow-up. Recurrence of epileptic seizures occurred in 1.3% of patients and was associated with antiphospholipid syndrome.
Neuropsychiatric involvement in systemic lupus erythematosus (SLE) is considered as one of the major manifestations of the disease.1-3⇓⇓ Single epileptic seizure episodes have been documented in about 10 to 20% of patients with SLE.1-6⇓⇓⇓⇓⇓ Most studies analyzed risk factors associated with the occurrence of epileptic seizures,1-12⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ whereas specific risk factors associated with recurrence of epileptic seizures have been rarely reported.
Epileptic seizures can be a primary event resulting from the direct effect of active SLE manifestation in the CNS or occur independently of lupus activity itself, being associated with CNS infections, uremia, hypertension, or electrolytic disturbance.
Generalized tonic-clonic seizures are by far the most common, but simple partial and complex partial seizures have also been described.3,6⇓ The pathogenesis of epileptic seizures in SLE remains unknown, but ischemic vascular disease or antibodies that bind to cerebral tissues have been considered as probable causes.2,13-15⇓⇓⇓
We sought to determine the frequency and risk factors for epileptic seizures in a large cohort of patients with SLE. We also analyzed clinical and laboratory features associated with the occurrence of single episodes and recurrence of epileptic seizures.
Patients and methods.
The records of 519 consecutive patients with four or more criteria for SLE diagnosis16 from January 1974 to December 2002 had their medical histories and clinical and serologic characteristics documented in computer database programs. All patients were followed and examined by one of the authors at the Rheumatology and Neurology Unit of the State University of Campinas. Therefore, medical records and protocols for investigations were homogeneous among patients. All patients had their clinical and laboratory evaluation performed at diagnosis and quarterly during the follow-up period. Patients with incomplete clinical and laboratory evaluations or who were lost to follow-up were not included in this series. The mean duration of follow-up of these patients was 5.7 years (SD 1.2 years), ranging from 4.0 to 7.8 years.
Only patients with epileptic seizures indicating CNS involvement by SLE17 were included in this study. Patients who had epilepsy and associated structural MRI abnormalities diagnosed prior to SLE and patients with seizures secondary to acute metabolic causes such as uremia, hypertension, diabetes mellitus, and electrolytic abnormalities were not included in the frequency determination and in analysis of epileptic seizures, although they were followed to observe if they would have recurrent seizures attributable to SLE.
Neurologic evaluation.
Epileptic seizures were classified according to the criteria suggested by the International League Against Epilepy.18 EEGs were recorded in the interictal period in a 16-channel analog or 32-channel digital EEG recorder with the International 10–20 System of electrode placement for 20 to 30 minutes in 38 (63.3%) patients. We tabulated the presence and localization of interictal epileptiform abnormality and slow wave abnormality.
Clinical features.
The age at onset of epileptic seizures was determined in relation to the age at which the first well-described sign or symptom indicating SLE occurred. Patients with a diagnosis of seizures before the onset of SLE had their clinical history carefully evaluated to determine if SLE was drug induced or occurred concomitantly to seizures. In seizures occurring at disease onset or during follow-up, SLE disease flares and other triggering events were searched for. To determine the risk factors for occurrence of epileptic seizures, we analyzed clinical manifestations and serologic features at disease onset and during follow-up according to the American College of Rheumatology criteria.16,17⇓
Laboratory features.
Anticardiolipin antibodies of the IgG and IgM isotypes were measured by the ELISA method as described.19 They were recorded as negative titers (<5 IgG antiphospholipid antibodies [GPL] units or <3 IgM antiphospholipid antibodies [MPL] units), low positive titers (5 to 15 GPL units or 3 to 6 MPL units), moderate positive titers (15 to 80 GPL units or 6 to 50 MPL units), or high positive titers (>80 GPL units or >50 MPL units). The lupus anticoagulant activity was detected by coagulation assays in platelet-free plasma obtained by double centrifugation, following the recommendation of the Subcommittee on Lupus Anticoagulant of the Scientific and Standardization Committee of the International Society of Thrombosis and Homeostasis.20 Patients with SLE diagnosis prior to 1991 had their anticardiolipin antibodies and lupus anticoagulant assays done during the follow-up period.
Statistical analysis.
We used multivariate logistic regression with stepwise selection, including all variables, to determine the association between clinical and laboratory features and the presence of epileptic seizures. This model included corrections for multiple comparisons. A p value of <0.05 was considered as indicative of significance.
Results.
Epileptic seizures were observed in 88 (17%) SLE patients. In 23 of these patients, acute metabolic causes such as uremia (6), hypertension (10), diabetes mellitus (2), and electrolytic abnormalities (5) were identified as underlying the epileptic seizures. These patients were followed for a minimum of 25 months (mean 28 months, SD 3.2 months). As none of these patients had recurrence of seizures after correction of the underlying acute metabolic disorder, these events were not attributed to primary CNS manifestations of SLE. Therefore, these patients were excluded from further analysis.
Five patients had epilepsy diagnosis before the onset of SLE (table 1). Structural MRI abnormalities that were considered epileptogenic were observed in four of them (60%). Three had MRI signs of mesial temporal sclerosis (figure 1), and one patient had a giant cerebral aneurysm of the posterior communicating artery. All these patients were excluded from the analysis after careful follow-up because of the lack of evidence of primary CNS involvement by SLE. One patient (Patient 5; see table 1) was followed at the Neurology Unit with clinical and EEG diagnosis of juvenile myoclonic epilepsy for 10 years when she developed clinical evidence of SLE. As she was lost to follow-up before completing SLE investigation, she was also excluded for further analyses.
Table 1 SLE patients with seizures before diagnosis of SLE
Figure 1. Coronal T1 inversion recovery images showing right hippocampal atrophy in a patient with temporal lobe epilepsy prior to onset of systemic lupus erythematosus.
Sixty patients (11.6%) had epileptic seizures that were considered as a primary manifestation of CNS involvement of SLE. Nineteen (31.6%) of these 60 patients had epileptic seizures at disease onset. Epileptic seizures occurred after the onset of the SLE in 41 of 60 (68.3%) patients. Fifty-three (88.3%) patients had a single seizure episode, and 7 (11.7%) had recurrent epileptic seizures. There was no statistical difference in the follow-up period of patients with single and recurrent epileptic seizures.
Twenty-five of 60 patients with epileptic seizures were referred from primary care centers or emergency units where general physicians prescribed 100 mg of phenobarbital once a day. Because all patients tolerated phenobarbital well and a high rate of seizure relapse was observed during early tapering down, phenobarbital was maintained in most patients. If seizures relapsed while phenobarbital was being used, we introduced carbamazepine or phenytoin and discontinued phenobarbital. For patients with single epileptic seizures who were already taking antiepileptic drugs (AEDs), the medications were maintained for the period of 1 year. We did not introduce AEDs for patients with single epileptic seizures who were not on AED treatment. We introduced carbamazepine for patients with recurrent epileptic seizures.
Seizures at onset of SLE.
Epileptic seizures at onset of SLE occurred in 19 (31.6%) of 60 patients with epileptic seizures: all women with mean age of 22.9 years. Twelve patients presented with generalized tonic-clonic seizures and seven with complex partial seizures. None of these patients had a family history of epilepsy. Variables associated with acute epileptic seizures at SLE onset were the occurrence of stroke (p = 0.0004; odds ratio [OR] = 10.36; 95% CI = 2.8, 38.2) and the presence of IgG antiphospho- lipid antibodies in moderate to high titers (p = 0.0013; OR = 6.69; 95% CI = 2.1, 21.4).
Seizures during SLE disease course.
Forty-one of the 60 (68.3%) patients with epileptic seizures had their first seizure during the course of SLE. All these patients had generalized tonic-clonic seizures, without partial onset identified or recorded. None of them had a family history of seizures. There were 39 (95%) women and 2 (5%) men. Mean age at SLE diagnosis was 23.8 years, similar to the age of patients with acute epileptic seizures at disease onset. The occurrence of nephritis, in the absence of uremia and arterial hypertension (p = 0.001; OR = 3.2; 95% CI = 1.6, 6.5), the presence of IgG antiphospholipid antibodies in moderate to high titers (p = 0.005; OR = 3.9; 95% CI = 1.5, 9.9), and epileptic seizures at disease onset (p = 0.00001; OR = 8.27; 95% CI = 2.9, 23.3) were variables associated with epileptic seizures during disease course in this study.
Recurrent seizures.
Recurrent, unprovoked epileptic seizures were observed in 7 of 60 (11.7%) SLE patients. All seven patients had clinical and laboratory evidences of antiphospholipid syndrome.
Mortality.
Death was observed in 58 patients in this cohort of 519 patients during the follow-up period of 2 to 27 years. Status epilepticus was the primary cause of death in two patients with recurrent, unprovoked epileptic seizures since SLE onset. No clinical evidence of other major organ system involvement could be identified at the time of death in these two patients who died secondary to status epilepticus.
EEG findings.
Interictal EEG was performed in 38 of 60 (63.3%) patients with epileptic seizures (table 2). Twenty-eight of 31 patients with single epileptic seizure had normal interictal EEG findings. All patients with recurrent epileptic seizures had abnormal EEG findings, with predominant interictal epileptiform abnormalities in temporal lobe regions.
Table 2 SLE: interictal EEG findings in patients with single and recurrent seizures
MRI findings.
MRI was performed in all patients with recurrent epileptic seizures and in 25 of 53 patients with single seizure episodes. Global cerebral atrophy was identified in all patients with recurrent seizures and in 11 of 25 patients with single epileptic seizures (figure 2). Multiple small periventricular and cortical–subcortical lesions (figure 3) suggestive of small-vessel occlusive disease were more frequently observed in patients with recurrent epileptic seizures than in patients with single seizures (p = 0.06). The small number of patients with recurrent epileptic seizures may account for these results. Ischemic lesions were identified in 2 of 7 patients with recurrent seizures and in 6 of 25 patients with single epileptic seizures (table 3).
Figure 2. Axial T1-weighted and T2-weighted images showing diffuse cerebral atrophy and multiple small periventricular lesions in a patient with systemic lupus erythematosus and recurrent epileptic seizures.
Figure 3. Axial fluid-attenuated inversion recovery (FLAIR) images showing small cortical–subcortical hyperintense lesions in two patients (A and B) with systemic lupus erythematosus who had single epileptic seizures.
Table 3 SLE: Clinical and MR findings of SLE patients with recurrent seizures
Discussion.
In this cohort of 519 patients, 60 (11.6%) had epileptic seizures associated with SLE disease activity. The frequency of epileptic seizures in previous studies ranged between 8.3 and 28%.1,5-10,21⇓⇓⇓⇓⇓⇓⇓ Epileptic seizures at disease onset were identified in 19 (31.7%) of these 60 patients. Epileptic seizures occurred after the onset of the disease in 41 (68.3%) patients. Fifty-three (88.3%) patients had a single epileptic seizure episode, and 7 (11.7%) had recurrent epileptic seizures. Generalized tonic-clonic and complex partial seizures were the most common epileptic seizures observed in this study. At disease onset, epileptic seizures were associated with stroke and the presence of moderate to higher titers of IgG antiphospholipid antibodies. The association between higher titers of antiphospholipid antibodies and seizures has been demonstrated previously.2,4,9,22-26⇓⇓⇓⇓⇓⇓⇓
Epileptic seizures may occur in isolation or accompany other neurologic manifestations,4,5,10,27-29⇓⇓⇓⇓⇓ especially stroke, as demonstrated in this study. Previous studies suggested that antiphospholipid antibodies may have a direct effect in seizure genesis by increasing neuronal excitability through inhibition of γ-aminobutyric acid receptor–ion channel complex30 or as consequence of antibody binding to neurons.31 Other studies concluded that epileptic seizures in patients with antiphospholipid antibodies may be the expression of ischemic events secondary to hypercoagulability.11,32-34⇓⇓⇓ We believe that stroke and antiphospholipid antibodies are confounding factors: Antiphospholipid antibodies cause ischemic strokes that may be directly responsible for the occurrence of seizures. However, the design of our study does not allow definite conclusions about the underlying mechanisms of seizures in SLE.
During follow-up of SLE, epileptic seizures were related to nephritis, the presence of antiphospholipid antibodies, and seizures at disease onset. Our study also supports the idea that disease flares are not solely responsible for epileptic seizures in SLE. Except for the relation between the presence of nephritis and seizures during disease course, other clinical manifestations were not related to the development of epileptic seizures in SLE patients.
Although most seizure episodes were usually self-limited in this study and the study design did not allow us to determine mortality, we observed two deaths secondary to status epilepticus. These two patients had epileptic seizures since SLE onset, and no other cause of death could be determined.
MRI was not performed in all our SLE patients, because several patients were investigated before the MRI era. MRI was available in 32 of 60 patients with SLE who had epileptic seizures. Although the MRI of patients with recurrent epileptic seizures showed more frequently multiple hyperintense lesions, suggestive of small-vessel disease, these findings did not reach significance, probably because of the small sample size. These findings underscore the need of MRI investigations in SLE patients with CNS manifestations.
EEG findings, although not performed in all patients, showed interictal epileptic activity in all patients with recurrent epileptic seizures. On the other hand, the majority of patients with single epileptic seizures had normal interictal EEG. These findings are important, as interictal EEG abnormalities may help to predict recurrence of seizures. We suggest that SLE patients with single seizure episode should be investigated with interictal EEG and MRI. Patients with antiphospholipid antibodies and single epileptic seizures should be followed carefully, because the risk of recurrent seizures is greater than in patients without antiphospholipid syndrome. However, most SLE patients who present with first epileptic seizure will not need to be treated with AEDs as only 1.3% had recurrent, unprovoked epileptic seizures.
Acknowledgments
Supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) grant no. 03/015270.
The authors thank the statisticians Andrea Ferreira Semolini and Helymar da Costa Machado for reviewing the statistical analysis.
- Received February 16, 2004.
- Accepted July 21, 2004.
References
Letters: Rapid online correspondence
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Hemiplegic Migraine Associated With PRRT2 Variations A Clinical and Genetic Study
Dr. Robert Shapiro and Dr. Amynah Pradhan