Abstract
Epilepsy Surgery in Drug Resistant Temporal Lobe Epilepsy Associated with Neuronal Antibodies
Carreño M, Bien CG, Asadi-Pooya AA, Sperling M, Marusic P, Elisak M, Pimentel J, Wehner T, Mohanraj R, Uranga J, Gómez-Ibáñez A, Villanueva V, Gil F, Donaire A, Bargalló N, Rumià J, Roldán P, Setoain X, Pintor L, Boget T, Bailles E, Falip M, Aparicio J, Dalmau J, Graus F. Epilepsy Res 2017;129:101–105.
We assessed the outcome of patients with drug resistant epilepsy and neuronal antibodies who underwent epilepsy surgery. Retrospective study, information collected with a questionnaire sent to epilepsy surgery centers. Thirteen patients identified, with antibodies to GAD (8), Ma2 (2), Hu (1), LGI1 (1) or CASPR2 (1). Mean age at seizure onset: 23 years. Five patients had an encephalitic phase. Three had testicular tumors and five had autoimmune diseases. All had drug resistant temporal lobe epilepsy (median: 20 seizures/month). MRI showed unilateral temporal lobe abnormalities (mainly hippocampal sclerosis) in 9 patients, bilateral abnormalities in 3, and was normal in 1. Surgical procedures included anteromesial temporal lobectomy (10 patients), selective amygdalohippocampectomy (1), temporal pole resection (1) and radiofrequency ablation of mesial structures (1). Perivascular lymphocytic infiltrates were seen in 7/12 patients. One year outcome available in all patients, at 3 years in 9. At last visit 5/13 patients (38.5%) (with Ma2, Hu, LGI1, and 2 GAD antibodies) were in Engel's classes I or II. Epilepsy surgery may be an option for patients with drug resistant seizures associated with neuronal antibodies. Outcome seems to be worse than that expected in other etiologies, even in the presence of unilateral HS. Intracranial EEG may be required in some patients.
Commentary
Our understanding of the etiologic factors contributing to the development of focal epilepsy is still quite limited. It is easy to see how epilepsy follows a structural lesion of the brain, such as a tumor, intracerebral hemorrhage, traumatic injury, or acute infection, and yet, we follow a significant group of patients who develop focal epilepsy in their adult life, sometimes with aggressive presentation, and we still cannot find the cause for such occurrence. We treat the symptoms in these patients with medications, surgery, neurostimulator devices and diet, with the treatment arsenal that is available to us and without much thought on etiology or specific treatment for an underlying condition once structural etiologies have been ruled out.
The discovery of paraneoplastic onconeural antibodies (Ab) first (1), followed by the identification of neuronal antigen-specific Ab and their expression resulting in neurologic presentations varying from acute encephalitis to neurobehavioral changes and insidious chronic epilepsy, has expanded our understanding into the mechanisms by which specific antibody reactions, or the inflammation they cause, can result in the development of focal epilepsy. This new knowledge arrives with a dose of hope as immunotherapies seem to offer promising results for the treatment of these conditions but also an immense responsibility as we recognize that many of the patients we treated in the past or those we still treat in the clinic who have chronic epilepsies of unknown etiology (with or without hippocampal sclerosis) may indeed have an autoimmune cause or component; thus, it is up to us to stop scratching the surface and start digging deeper into the possible etiology and cause-driven therapy for the patients under our care.
Many questions come to mind when considering this scenario from the inpatient neurology and epilepsy service as well as from the outpatient epilepsy clinic. This interesting study by Carreño et al. (2), as well as studies by others who have looked into the clinical presentation, diagnostic yield, treatment options, and outcome; allow us to start developing a better understanding of what autoimmune epilepsy (AE) entails and how to integrate this new and growing knowledge into our everyday practice.
In Which Patients Should I Consider the Diagnosis of AE?
The classic clinical presentation associated with paraneoplastic epilepsy—behavioral changes, cognitive decline, and refractory seizures (1, 3)—is still a good starting point to consider when the presentation is acute. Carreño et al. included patients who had acute encephalitis presentation and went on to develop chronic epilepsy as well as patients with chronic epilepsy refractory to medical management in whom the surgical pathology (presence of perivascular lymphocytic infiltration) led to the search for autoimmune etiology. They identified a high seizure burden (mean of 20 seizures per month), temporal lobe or autonomic semiology, and the presence of an abnormal MRI (unilateral or bilateral swelling or atrophy of mesial temporal structures) as reliable clinical characteristics for this group of patients. A recently published prospective study (4) looked into the prevalence of AE among patients with epilepsy of unknown etiology and found strong suggestion of AE in at least 20.5% of them. Furthermore, they were able to identify clinical features that predicted the presence of neuronal antibodies. These clinical features include new onset and rapidly progressive seizures or mental status changes, behavioral or psychiatric changes, autonomic dysfunction, a viral prodrome preceding the onset of seizures or behavioral changes, faciobrachial dystonia or dyskinesias, refractory epilepsy, CSF findings suggestive of inflammation, abnormal brain MRI with unilateral or bilateral swelling or atrophy of mesial temporal structures, and the presence of underlying malignancy. The authors composed an antibody prevalence in epilepsy score (APE score) with these clinical findings and were able to reliably predict the presence of AE-related antibodies. We should also consider that epilepsy is more prevalent in patients with other autoimmune disorders like systemic lupus erythematous and antiphospholipid syndrome (5).
Which Diagnostic Tests Should be Conducted?
Antineuronal Abs most frequently reported to be associated with autoimmune epilepsy include (6, 7) N-methyl-D-aspartate receptor Ab, leucine-rich glioma-inactivated Ab, voltage gated potassium channel complex Ab, glutamic acid decarboxylase Ab (8), contactin-associated protein-like 2, GABA-A receptor and GABA-B receptor Abs (9), AMPAR Ab, and antineuronal nuclear Ab Type 1 ANNA-1 Ab. Others related to autoimmune epilepsy include Purkinje cell cytoplasmic Ab type 2 Ab, amphiphysin Ab, collapsin-response mediator protein 5 Ab, and thyroperoxidase Ab. Detection and titers for these Abs in serum and CSF are already available in specialized institutions as autoimmune epilepsy panels.
What Therapeutic Options Are Available for Patients with AE?
Intravenous immunoglobulin, plasma exchange, and intravenous methylprednisolone have been used in patients with refractory epilepsy and suspected autoimmune etiology with satisfactory response when Abs are detected (7, 9, 10). Second-line treatment includes rituximab or cyclophosphamide (11). In the case of paraneoplastic epilepsy, a cornerstone of the treatment is primary tumor identification and removal when appropriate.
Is Epilepsy Surgery Still an Option for these Patients?
This study by Carreño et al. shows that surgery is an option for patients with focal AE refractory to immunotherapy and antiepileptic medication treatment. These patients had a worse outcome than expected for their epilepsy profile; however, their seizure burden was high, and they had long-standing history of epilepsy before surgery was considered. Early suspicion, diagnosis, and treatment of AE; invasive EEG evaluation; or the combination of surgery and immunotherapy can potentially improve the outcome of this population by more accurately targeting the affected areas while actively treating the underlying inflammatory process.
The true prevalence of AE is still unknown, but we already have enough information to suspect that about 14% to 20%4,8 of our patients with refractory epilepsy of unknown etiology (with or without mesial temporal sclerosis) may have positive neuronal antigen-specific Abs. We are also able to offer these patients diagnostic and immunotherapy treatment options that may lead to better outcomes for them and in the long run may deepen and broaden our understanding of this condition.