Adult-onset temporal lobe epilepsy suspicious for autoimmune pathogenesis: Autoantibody prevalence and clinical correlates

Abstract

Temporal lobe adult-onset seizures (TAOS) related to autoimmunity represent an increasingly recognized disease syndrome within the spectrum of epilepsies. In this context, certain autoantibodies (autoABs) were often associated with limbic encephalitis (LE). Here, we aimed to gain insights into (a) the distribution of ‘neurological’ autoABs (neuroABs, defined as autoABs targeting neuronal surface structures or ‘onconeuronal’ ABs or anti-glutamate acid decarboxylase 65 (GAD65) autoABs) in a large consecutive TAOS patient cohort, to characterize (b) clinical profiles of seropositive versus seronegative individuals and to find (c) potential evidence for other autoABs. Blood sera/cerebrospinal fluid (CSF) of TAOS patients (n = 800) and healthy donors (n = 27) were analyzed for neuroABs and screened for other autoABs by indirect immunofluorescence on hippocampal/cerebellar sections and immunoblots of whole brain and synaptosome lysates. Serological results were correlated with clinico-neuropsychological features. 13% of TAOS patients (n = 105) were neuroAB + , with anti-GAD65 and anti-N-methyl-D-aspartate receptors (NMDAR) as most frequent autoABs in this group. In our screening tests 25% of neuroAB - patients (n = 199) were positive (screening + ), whereas all control samples were negative (n = 27). Intriguingly, key clinico-neuropsychological characteristics including magnetic resonance imaging (MRI) findings, epileptiform electroencephalographic (EEG) activity, and inflammatory cellular infiltrates in CSF were shared to a greater extent by neuroAB + with neuroAB - /screening + patients than with neuroAB - /screening - patients. Serological testing in a large consecutive TAOS patient series revealed seropositivity for anti-GAD65 autoABs as the most frequent neuroAB. Intriguingly, neuroAB + individuals were virtually indistinguishable from neuroAB - /screening + patients in several major clinical features. In contrast, neuroAB - /screening - TAOS patients differed in many parameters. These data support the potential presence of so far unrecognized autoABs in patients with TAOS.

Prevalence of Neural Autoantibodies in Epilepsy of Unknown Etiology: Systematic Review and Meta-Analysis

“…In order to avoid pitfalls in the interpretation of neural antibodies results, it is advisable to perform panel testing of multiple autoantibodies rather than single antibody testing, screen both CSF and serum, and discuss cases with reference centers if antibodies directed to surface antigens are found at low titers in serum only, or if results do not match with the clinical presentation [ 30 ]. In recent studies in patients with epilepsy of suspected autoimmune etiology [ 31 , 32 ] where CSF analysis was systematically performed, only one patient had a positive result in CSF and was negative in serum [ 31 ]. Instead, eight patients had a positive result in serum but were not positive in CSF.…”

Neuropathological Insights into Unexpected Cognitive Decline in Epilepsy

“…The lack of corresponding "LE‐like" findings in the control group may indicate that the neuropsychological course of patients has a strong potential impact to identify "LE‐like" HS patients. These data may emphasize the necessity of intensified presurgical analyses for biomarkers including potentially new autoantibodies in serum and cerebrospinal fluid to determine LE(‐like) status features presurgically and, depending on the results, a reconsideration of patient management 71 …”

“…That the majority of patients in this subgroup lack proof of seropositivity for specific autoantibodies is compatible with recently published data on the presence of seropositivity for specific autoantibodies in only a subfraction of patients strongly suspicious for LE. 71 Of note, a history of a definitely expired LE is not perceived as a contraindication for epilepsy surgery. An emerging, static lesion generally given by HS secondary to a previous (and now inactive) inflammatory process may be a surgical target for the treatment of epilepsy after the careful clinicoserological confirmation of the expired LE status of the patient.…”

The study of neural antibodies in neurology: A practical summary

“…Patients should be studied for neural antibodies if they present a neurological syndrome typically associated with these antibodies (8)(9)(10)(11):…”