The case is a 42-year-old female patient, diagnosed with SLE (ACR criteria 1997) 5 years ago, with joint and hematological involvement, immunological changes and low C3. Her disease was inactive for the past 3 years (SLEDAI 0) and she was being treated with hydroxychloroquine 200mg/day.

She had no family history of neurological or rheumatic disorders. She denied toxic habits, illicit drug use or a history of drug allergy. No history of surgery or trauma was present, with 3 daughters born at terms pregnancies without obstetric complications.

She came spontaneously to the clinic on April 8, 2010 for involuntary movements of the foot and the left hand that had begun the day before, which determined her hospitalization.

On physical examination there were no clinical signs of SLE activity or infectious diseases. Neurological examination revealed the presence of increased tendon reflexes on the left leg and a positive Babinski sign. Magnetic resonance imaging (MRI) showed T2 hyperintense lesions in the cortico-subcortical right frontal and parietal regions that stood out with gadolinium (Fig. 1). The patient began treatment with oral prednisone 50mg/day and was discharged from the hospital after 48h.

Fig. 1.

Central nervous system MR showing hyperintense lesions in T2 on the frontal, temporal and parietal right regions.

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A week later (April 17), the patient reported a fall after loss of consciousness, for which she was readmitted to the hospital with the conclusion that she had a generalized seizure. On neurological examination she was found to have rhythmic movements, persistent hemiparesis of her left lower limb (foot) and positive Babinsky.

During an electroencephalogram (EEG) she developed a tonic-clonic generalized seizure with loss of consciousness and postictal coma with ad integrum restitution. The EEG showed mild impairment of cortical bioelectrical activity, excess beta rhythms and parieto-temporal isolated sharp waves. On April 24, the patient developed a third generalized seizure.

CT scans of the brain and chest were normal. The blood count, erythrocyte sedimentation rate, renal function, anticardiolipin antibodies, lupus anticoagulant, C3, C4, AAN, and anti-dsDNA antibodies were normal. The blood and urine cultures were negative. A lumbar puncture was performed, resulting in a cerebrospinal fluid (CSF) with a normal cytochemical analysis, with negative cultures (including fungi, bacteria, mycobacteria tuberculosis, Cryptococcus, Nocardia, and Listeria). We also performed polymerase chain reaction (PCR) for varicella zoster, herpes simplex, and Epstein-Barr virus, which was negative in all cases.

Seizures located on the left foot continued despite treatment with immunosuppressive intravenous methylprednisolone (3 pulses of 1g/day for 3 on consecutive days) and azathioprine 50mg/day, and the additive treatment of antiepileptic drugs such as pregabalin, carbamazepine, phenytoin, and valproic acid. There was a hypersensitivity syndrome with skin reactions, fever, and elevated transaminase levels. Suspecting a skin drug reaction, these were suspended and a skin biopsy was performed. It reported erythema multiforme with negative cultures and therefore it was assumed as an adverse drug reaction. By suspending anticonvulsant drugs, clonazepam was employed at a dose of 2g/day orally as well as IV immunoglobulin (2g/kg for 5 consecutive days and then 4 monthly doses of 0.5g/kg). The seizures stopped after a month of starting treatment.

SLE remained inactive and the prednisone dose was gradually lowered. In March 2011 (after 10 months of being neurologically asymptomatic) she showed cognitive deterioration. A brain MRI revealed hyperintense lesions on T2 with the same features as above. We indicated a new pulse of 30mg IV gamma globulin without improving the clinical response and with partial epilepsy still present, this time of the right leg. We performed a new brain MRI that showed lesions which had now become bilateral. We decided to perform a biopsy of the right frontal lobe brain which reported: cortical nervous parenchyma with increased cellularity at the expense of a reactive astrogliosis. No vasculitis or neoplastic proliferation was seen. Immunostaining: GFAP+CD68+NOGO A (−), P53 (−), IDH1 (−) (Fig. 2).

Fig. 2.

Diffuse astrogliosis of the cerebral cortex and GFAP+, CD68+ reactive astrocytes (Luxol Fast blue–hematoxylin–eosin).

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Treatment was initiated with 1g of IV cyclophosphamide, which resulted in restitution ad integrum of the lesions (Fig. 3) with clinical improvement after the first pulse.

Fig. 3.

Central nervous system MR after treatment with intravenous cyclophosphamide without evident lesions.

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At present, the patient has inactive SLE and is free of seizures while being treated with prednisone, hydroxychloroquine 200mg/day, clonazepam 1mg/day, and monthly pulse IV cyclophosphamide.

When faced with a patient with SLE presenting seizures, the first step in diagnostic reasoning should be to ask whether there is a secondary underlying pathology and concomitant conditions the treatment thereof.

Our patient had clinical features of a continuous RE with intractable partial epilepsy and hemiparesis. Radiologically we found cortical–subcortical hyperintense lesions on T2, not highlighted with gadolinium, and histological evidence of brain swelling. Therefore, having ruled out other causes of CLD, I assume that the patient has an autoimmune disease associated to RE as the primary disease.

A brain biopsy is not necessary in all cases of RE, because other criteria may be sufficient to diagnose the disease, and this is reserved for cases of doubtful clinical diagnosis or atypical presentations of RE. It should be taken from an area where the T2/FLAIR signal is increased in the MR.18 In cases in which MRI lesions are not clear, other studies such as PET or SPECT may be useful in determining the site of the biopsy.19

A German group described inflammatory cells and reactive astrocytes in brain samples obtained from regions with abnormalities on MRI. In areas where hyperintensity was observed, increased numbers of T cells, nodules of microglia and GFAP+ astrocytes are regarded as the chronically most affected areas.18

Another relevant diagnostic observation is that less than 5% of CD68+ cells had macrophage morphology; the vast majority had microglial20 morphology.

These histopathological changes are similar to those observed in our patient, so the final diagnosis was that of RE in a patient with SLE.

Although RE has long been considered a childhood disease (it has a more rapid and severe onset), adolescent and adult patients (with a more protracted and milder course, with a long and relatively nonspecific prodromal phase) have been described by several groups on the basis of the study of Hart et al., estimated at about 10% of cases of RE.21–24

Clinically, RE is characterized by intractable focal seizures, called EPC, and cognitive impairment secondary to hemispheric involvement.22

There have been three special features of epilepsy in patients with RE: (a) the polymorphism of seizures in a given patient, (b) refractory to medical treatment of seizures, especially EPC, and (c) simple partial motor seizures involving one side of the body (77% of cases).

One can also see secondarily generalized tonic-clonic seizures (42%), complex partial seizures (19% with generalized and 31% with subsequent unilateral motor), postural seizures probably originating in the supplementary motor area (24%) and somatosensory seizures (21%).22,24

RE is an example of an autoimmune disease of the CNS. Serum samples from patients with this disease contain antibodies against glutamate receptors GluR3 and GluR (against the epsilon subunit 2). These patients may also have stimulated GluR epsilon 2T cells in peripheral blood, and it has also been shown that both cellular and humoral autoimmunity against GluR epsilon 2 may contribute to pathophysiological processes in RE. Their presence in other autoimmune disorders suggests similar pathological mechanisms, but not RE markers. The serum of some patients with RE also contain high levels of ‘classic’ autoimmune antibodies (glutamic acid decarboxylase, anti-cardiolipin, B2-glycoprotein I and SS-A, and RNP nuclear antigens).25

The diagnosis of Rasmussen's report is based on clinical studies, electrophysiological (EEG) and morphological (MRI and, in some cases, histopathology) .26

Our patient had two unusual features of RE, she was 42 years of age and had bilateral involvement.

Bilateral RE is very rare. Some of the clinical and electrophysiological characteristics in typical unihemispheric cases or bilateral cerebral involvement have been suggested to be, for example, as a secondary spread of focal seizures in the contralateral side, intercritical epileptiform abnormalities on the contralateral side or contralateral mild atrophy.27 Therefore, the term ‘bilateral RE’ should be reserved for cases with inflammatory lesions in both hemispheres. Until 2005, about 200 cases were reported in the literature, with only 924 having bihemispheric involvement.

There is now a wide range of available therapeutic strategies, such as bolus intravenous methylprednisolone, immunosuppressants, intravenous immunoglobulin (IVIG), plasmapheresis, cyclophosphamide, and rituximab. Surgical treatment is reserved for seizure control in refractory children and adults.24,28

Protection of human and animal subjects. The authors declare that no experiments were performed on humans or animals for this investigation.

Confidentiality of Data. The authors declare that no patient data appears in this article.

Right to privacy and informed consent. The authors have obtained the informed consent of the patients and /or subjects mentioned in the article. The author for correspondence is in possession of this document.

The authors have no disclosures to make.