JLE

Epileptic Disorders

MENU

Effectiveness of multimodality treatment for autoimmune limbic epilepsy Volume 16, numéro 4, December 2014

Illustrations


  • Figure 1

  • Figure 2

Tableaux

Limbic encephalitis (LE) is characterized by confusion, cognitive difficulty, memory impairment, and seizures caused by inflammation in the limbic structures. LE is generally felt to be a paraneoplastic condition attributed to an underlying malignancy, with antibodies directed against the intracellular antigens, such as Hu, Ma2, CRMP51, and amphiphysin. However, antibodies directed against the cell membrane or synaptic receptors (e.g. VGKC, NMDAR, LGI1, Caspr, GABAB, GAD2) have also been associated with LE, with or without an underlying malignancy (Davis and Dalmau, 2013). Although LE can present with various neuropsychiatric manifestations, seizures are common in this disorder, often leading to refractory autoimmune limbic epilepsy (ALE). Besides optimizing antiepileptic drugs (AEDs) and treating the underlying tumour (if identified), no clear guidelines exist for managing ALE (Ozkara and Vivegano, 2011). When seizures are intractable, immunomodulators (e.g. intravenous methylprednisolone [IVMP], intravenous immunoglobulin [IVIG], and plasmapheresis) have been used as first-line therapy with variable success. Immunosuppressants (e.g. cyclophosphamide) have been tried as second-line agents, but are not favoured because of serious adverse effects. In this article, we present a series of three consecutive patients (table 1) with refractory ALE who achieved successful outcome after receiving multimodality treatment with conventional AEDs, various immunomodulators, and an immunosuppressant (rituximab). Our aim is to add to the expanding literature on ALE, and to provide practical guidelines on prompt diagnosis and management of this potentially reversible illness.

Case studies

Patient 1 was a 53-year-old Caucasian male with a history of hypertension, hyperlipidaemia, and coronary artery disease, who presented with new-onset seizures of eight weeks duration. His seizures were characterized by staring, left head deviation, left facial twitching, and generalized tonic-clonic activity. Seizures remained intractable to multiple AEDs, and he developed anterograde memory loss, agitation, visual and auditory hallucinations, and worsening confusion leading to persistently altered mental status. Upon transfer to our facility, the patient was severely disoriented and confused without focal neurological deficits. Video-EEG monitoring (VEM) showed focal non-convulsive status epilepticus (FNCSE) with clinical and electrographic seizures originating from the right temporo-parietal region (figure 1A). Interictal EEG showed periodic lateralized epileptiform discharges (PLEDs) in the right temporo-parieto-occipital region. Brain MRI showed FLAIR hyperintensity in the medial right temporal lobe (figure 2A). CSF studies showed normal glucose, mildly elevated protein (55 mg/dL), normal nucleated cell count, negative HSV PCR, and negative West Nile virus (WNV) antibodies. Although FNCSE eventually resolved on a combination of levetiracetam, lacosamide, and phenobarbital, he remained amnestic and confused, with subsequent VEM showing electrographic seizures of left temporal onset. He was treated empirically with 5 g IVMP over 5 days. Because of only minimal improvement in mental status, he received five cycles of plasmapheresis. Paraneoplastic panel showed anti-VGCC3 (P/Q and N type) and anti-GABAB antibodies. CT of chest and abdomen was negative for tumour. Cervical lymph node biopsy showed no evidence of malignancy. Despite improvement in the mental state, he continued to have short-term memory impairment and developed visual hallucinations. This prompted a course of 2 g/kg IVIG over 5 days, followed by 1 g IV rituximab to achieve long-term immunosuppression. At the time of discharge from the acute care setting to a rehabilitation facility, the seizures were controlled but mild disorientation and short-term memory impairment persisted. At the last follow-up visit, 91 days after inpatient discharge, the patient had one witnessed complex partial seizure; he had residual memory impairment and behavioural problems, despite significant improvement.

Patient 2 was a 33-year-old African-American female with a history of glutamic acid decarboxylase 65 (GAD65) antibody-positive stiff person syndrome and seizures, who presented with progressively worsening memory impairment and intractable seizures. She also reported a one-year history of fatigue, gait ataxia, rigidity, and myoclonus triggered by loud noise (hyperekplexia). Upon admission, she was noted to have dysconjugate gaze, increased tone, bilateral dysmetria, and wide-based ataxic gait. VEM showed brief but frequent electrographic seizures of independent right and left temporal onset (figure 1B). Interictal EEG showed frequent right temporal sharp waves. Brain MRI showed bilateral FLAIR hyperintensities involving the parahippocampal gyri (figure 2B), raising the possibility of ALE as a new diagnosis despite prior history of epilepsy. CSF studies were unremarkable. Seizures improved with IV fosphenytoin, lacosamide, and lamotrigine. Given the history of GAD65-positive syndrome, she was empirically treated with IVIG, at 2 g/kg over five days. Serum paraneoplastic panel showed anti-GAD65 (4,531 nmol/L) and anti-VGKC (0.04 nmol/L) antibodies. CT chest and abdomen did not show underlying malignancy. Because of persistent left posterior temporal electrographic seizures, she was treated with 500 mg IV rituximab without complications. Subsequent monitoring showed resolution of electrographic seizures. Two months later, she was readmitted with increased frequency of clinical and electrographic seizures of bitemporal independent onset (left greater than right), prompting an increase in baseline AEDs and a second dose of 500 mg IV rituximab. At the time of discharge, CD19 count was 0.1%, and the electrographic seizures had resolved, but she continued to have spasms that were non-epileptic, felt to be related to the underlying stiff-person syndrome. At the last follow-up visit, 63 days after inpatient discharge, she had remained seizure-free, however, she continued to have intermittent muscle spasm and back pain.

Patient 3 was a healthy 55-year-old Caucasian male who presented to the outside facility with worsening memory impairment, behavioural problems, agitation, and FNCSE with clinical seizures of right temporal onset. Brain MRI showed T2 hyperintensity involving the right medial temporal lobe (figure 2C). CSF studies showed elevated protein (77 mg/dL), normal glucose, and normal cell count. Studies for infectious aetiology were unremarkable. Biopsy of the right temporal lobe was non-diagnostic, consistent with non-specific inflammation. Upon transfer to our facility, the seizures were controlled by a combination of levetiracetam, valproate, lamotrigine, and phenobarbital, but he remained confused and agitated without focal neurological deficits. VEM showed no clinical or electrographic seizure activity, but showed frequent right posterior temporal-occipital interictal epileptiform discharges (figure 1C). He received 5 g IVMP over 5 days. Levetiracetam was discontinued due to concern of behavioural problems, but the other AEDs were continued. Quetiapine was started for agitation and visual hallucinations. Lack of improvement in mental status prompted five cycles of plasmapheresis followed by IVIG, at 2 g/kg over 5 days. Quetiapine was stopped and haloperidol was started. Paraneoplastic panel was positive for anti-VGKC antibodies (0.13 nmol/L). CT chest and abdomen did not show underlying malignancy. Because of persistently altered mental status, he was treated with rituximab 500 mg IV. At the time of discharge to an inpatient rehabilitation facility, CD19 count was 0.2%, and the seizures were completely controlled and the agitation was markedly improved. At last follow-up visit, 68 days after inpatient discharge, the patient had remained seizure-free, and had no more behavioural outbursts or agitation, however, he continued to have residual memory impairment.

Discussion

For patients with new-onset seizures in the setting of acute or subacute neurocognitive manifestations, a diagnosis of autoimmune limbic epilepsy (ALE) should be entertained. However, no definitive guidelines exist for treating ALE (Ozkara and Vivegano, 2011). Our study demonstrates that if seizures remain refractory to conventional AEDs, immunomodulation can be beneficial while the diagnostic workup is pursued. If an underlying malignancy is discovered, the treatment of the tumour seems to be most effective. However, when the malignancy workup is negative, rituximab appears to be an effective and safe option as our study demonstrates. Our series is along the lines of a recent study which reported success with various combinations of IVMP, IVIG, plasmapheresis, and cyclophosphamide in 12 patients with autoimmune epilepsy (Quek et al., 2012). Our series expands the literature and highlights the effectiveness of rituximab in a heterogeneous group of ALE patients with different types of antibodies.

The rationale for immunotherapy in ALE is based on multiple lines of evidence. It has been shown that the antibodies from patients bind to the GABAB receptors in rat neurons, and disruptions of the rodent GABAB receptors result in clinical phenotypes similar to limbic encephalitis and epilepsy (Lancaster et al., 2010). Immunoglobulins from patients with anti-NMDAR antibodies have been shown to cause neuronal dysfunction in cultured hippocampal neurons, while infusion of CSF from these patients resulted in a reduction of hippocampal NMDAR immunostaining in rats (Hughes et al., 2010). Brain biopsies of patients with LE have revealed inflammatory changes, such as extensive neuronal loss, gliosis, microglial nodules, perivascular lymphocytic cuffing, and leptomeningeal mononuclear cell infiltrates (Graus et al., 2008). Thus, these findings point towards immune-mediated neuronal damage which can be curbed by immunosuppressants.

Besides the conventional AEDs to control the seizures, we hypothesize that multimodality immunotherapy is effective in ALE because of different mechanisms of action on the immune system. First, glucocorticoids reduce inflammation by modulating chemokine and cytokine production, adhesion molecule expression, and white blood cell production (Rhen and Cidlowski, 2005). Second, plasmapheresis, an extracorporeal blood purification technique, removes large molecular-weight molecules, such as immunoglobulins, and filters out plasma membrane proteins such as VGKC complexes from the blood (Winters, 2012). Third, IVIG, a sterile, purified IgG product from pooled human plasma, helps modulate complement activation, suppress idiotypic antibodies, saturate Fc receptors on macrophages, and suppress cytokines, chemokines, and metalloproteinases (Boros et al., 2005). Finally, rituximab, a humanized monoclonal IgG, targets CD20, the surface antigen of B lymphocytes, thereby eliminating the latter prior to their differentiation into plasma cells (Dropcho, 2013).

None of our patients underwent PET, thus there remained a small possibility that an underlying malignancy could still exist. We could also not determine which therapy may have provided the greatest impact on outcome, since all of the therapies were administered over a short period of time. Nevertheless, our series demonstrates successful treatment of intractable non-paraneoplastic ALE using conventional AEDs, empiric immunomodulation, and rituximab, the latter being a potentially less toxic alternative to cyclophosphamide. Further studies are needed to support our findings and determine the optimum duration of immunotherapy to prevent relapse.

Disclosures

None of the authors have any conflict of interest to disclose.


1 CRMP: collapsin response mediator protein.

2 Caspr: contactin-associated proteinlike; GABAB: gamma aminobutyric acid type B; GAD: glutamic acid decarboxylase; LGI: leucine-rich glioma inactivated; NMDAR: N-methyl D-aspartate receptor; VGKC: voltage-gated potassium channel.

3 VGCC: voltage-gated calcium channel.