Seizures, Epilepsy, and NORSE Secondary to Autoimmune Encephalitis: A Practical Guide for Clinicians

Abstract

The most recent International League Against Epilepsy (ILAE) classification has included "immune etiology" along with other well-known causes of epilepsy. This was possible thanks to the progress in detection of pathogenic neural antibodies (Abs) in a subset of patients, and resulted in an increased interest in identifying potentially treatable causes of otherwise refractory seizures. Most autoimmune encephalitides (AE) present with seizures, but only a minority of cases evolve to long-term epilepsy. The risk of epilepsy is higher for patients harboring Abs targeting intracellular antigens (T cell-mediated and mostly paraneoplastic, such as Hu, CV2/CRMP5, Ma2, GAD65 Abs), compared with patients with neuronal surface Abs (antibody-mediated and less frequently paraneoplastic, such as NMDAR, GABAbR, LGI1, CASPR2 Abs). To consider these aspects, conceptual definitions for two entities were provided: acute symptomatic seizures secondary to AE, and autoimmune-associated epilepsy, which reflect the different pathophysiology and prognoses. Through this manuscript, we provide an up-to-date review on the current state of knowledge concerning diagnosis and management of patients with Ab-mediated encephalitis and associated epilepsy. Special emphasis is placed on clinical aspects, such as brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) specificities, electroencephalographic (EEG) findings, cancer screening and suggestions for a rational therapeutic approach.

Keywords: EEG; FIRES; ketogenic diet; limbic encephalitis; paraneoplastic neurological syndromes.

Figure 1

Pathophysiology of autoimmune encephalitis and its relationship with the risk of autoimmune-associated epilepsy. The diagram focuses on forms of autoimmune encephalitis commonly presenting with acute symptomatic seizures. In encephalitis associated with antibodies targeting cell surface antigens, the antibodies have access to their targets and can alter the structure and function of the antigen (A). This alteration is usually treatment responsive, especially at early stages. Therefore, few patients develop autoimmune-associated epilepsy. Conversely, in encephalitis associated with antibodies against intracellular epitopes, the antibodies cannot reach the intracellular antigens, and cytotoxic T-cell mechanisms are mainly involved (B). This process can lead to neuronal loss, and it is therefore less treatment responsive: many patients develop autoimmune-associated epilepsy.

Figure 2

Electroencephalographic findings in patients with antibody-positive autoimmune encephalitides. (A) Electrical seizure triggered by hyperventilation in a male patient with anti-LGI1 encephalitis. Its onset is best appreciated with left temporal theta–delta sharp abnormalities that evolve in terms of frequency and location, showing contralateral diffusion. (B) The same patient of (A): during sleep (N2-NREM phase) shows the presence of lateralized fronto-temporal delta slowing (red arrow). (C) Female patient with anti-LGI1 encephalitis: EEG demonstrates a focal slow wave on frontal electrodes (red arrow) preceding faciobrachial dystonic seizure (see muscle artifacts on electrocardiogram channel *). (D) Awake EEG in a male patient with anti-GABAbR encephalitis shows intermittent lateralized left temporal delta slowing (red arrows) with anterior and contralateral diffusion (blue arrow). Parameters of EEG recordings: figures A, B, D bipolar 10/20 standard international montage; high frequency filter: 1.0 Hz; low frequency filter: 70 Hz; notch filter ON; sensitivity 100 microV/mm; 15 mm/s; figure C average reference montage; high frequency filter: 0.5 Hz; low frequency filter: 70 Hz; notch filter ON; sensitivity 100 microV/mm; 15 mm/s).

Figure 3

Proposed therapeutic algorithm in patients with suspected immune-mediated seizures and epilepsy. Abbreviations: AE, autoimmune encephalitis; ASMs, antiseizure medications; CBZ, carbamazepine; FIRES, febrile infection-related epilepsy syndrome; IV, intravenous; IVIG, intravenous immunoglobulin; LEV, levetiracetam; LCM, lacosamide; LTG, lamotrigine; OXC, oxcarbazepine; PLEX, plasma exchange; PER, perampanel.