Autoimmune encephalitis-associated epilepsy

Abstract

Autoimmune encephalitis (AE), defined by clinical criteria and its frequent association with neural autoantibodies, often manifests with seizures, which usually stop with immunotherapy. However, a subset of encephalitic conditions present with recurrent seizures that are resistant to immunotherapy. Three primary neurological constellations that fall within this subset are discussed in this Perspective: temporal lobe epilepsy with antibodies against glutamic acid decarboxylase, epilepsy in the context of high-risk paraneoplastic antibodies, and epilepsy following adequately treated surface antibody-mediated AE. These entities all share a common mechanism of structural injury and potentially epileptogenic focal neural loss, often induced by cytotoxic T cells. Recently, we have proposed conceptualizing these conditions under the term autoimmune encephalitis-associated epilepsy (AEAE). Here, we discuss the new concept of AEAE as an emerging field of study. We consider the clinical characteristics of patients who should be investigated for AEAE and highlight the need for judicious use of traditional epilepsy therapeutics alongside immunotherapeutic considerations that are of uncertain and incomplete efficacy for this group of disorders. Last, we discuss future efforts needed to diagnose individuals before structural epileptogenesis has superseded inflammation and to develop improved therapeutics that target the specific immunological or functional disturbances in this entity.

Fig. 1 ∣. Mechanisms of seizures in AEAE.

a, Mediotemporal density of CD3⁺ T lymphocytes in brain parenchyma of individuals with anti-Ma2 antibodies or temporal lobe epilepsy with glutamic acid decarboxylase antibodies (GAD-TLE). In both conditions, T cell density decreases over time, but at different rates. The data are from refs. , and from a patient (a case with unpublished neuropathological data) with Ma2 antibody-positive disease with a duration of 9 years. The dashed line indicates the 75th percentile of T cell density of a mixed sample of hippocampal specimens obtained during epilepsy surgery (n = 50) as an estimate of ‘normal’ hippocampal T cell infiltration in pharmacoresistant epilepsy. b, The ‘hippocampal sclerosis score’ in people with a paraneoplastic syndrome and Ma2 antibodies or GAD-TLE. Neuronal loss in the CA1–4 and dentate gyrus (DG) was semiquantitatively estimated by dividing the sum of the CA and DG scores ranging from 0 to 2 (0, no obvious neuronal loss;1, moderate loss; 2, severe loss) by the number of scored CA and DG regions. Of note, hippocampal neuronal loss, if present, is found even in patients with a disease duration of only 0.5 years. The GAD-TLE data are from ref. , and the anti-Ma2 data were newly determined from ref. and from a patient (an unpublished case) with a disease duration of 9 years. c, Summary of data from parts a (red) and b (blue). Autoimmune encephalitis-associated epilepsy (AEAE) results form a transition from a primarily inflammatory process to a progressively more structural epilepsy. The slope of inflammation and structural injury vary between conditions and individuals.

Fig. 2 ∣. Example of GAD-TLE disease course.

Disease course in a female patient with temporal lobe epilepsy with glutamic acid decarboxylase antibodies (TLE-GAD), onset at age 15 years over one decade (patient 3 in Tröscher et al.). An early, subacute stage (‘limbic encephalitis’) occurs in the first half of 2009. Coronal fluid attenuated inversion recovery MRI (bottom) shows signal and volume increases in the left hippocampus. Seizure frequency rises sharply, and the GAD antibody concentration is high. The patient receives several immunotherapies and increasing doses of lamotrigine (LTG). The antibody concentration and seizure frequency fall transiently but rise again. The left hippocampus becomes sclerotic and is surgically removed (OP) ~2 years after onset. Mycophenolate mofetil (MMF) is continued to avoid involvement of the right temporal lobe. The patient becomes seizure-free for a short time but develops recurrent seizures thereafter, albeit at a much lower frequency. The discontinuation of MMF because of a planned pregnancy does not lead to deterioration. The LTG concentration in blood decreases as expected during pregnancy. Of note, the LTG blood levels remain stable despite a reduction in dosing, implying previously poor adherence. This correlation between seizure control and antiseizure medication (ASM) levels highlights the need to monitor all aspects of treatment that one would consider in the clinical care of epilepsy, and not to focus mainly on immunotherapy. Abs, antibodies; Cyc, intravenous cyclophosphamide; GAD, glutamic acid decarboxylase; IA, immunoadsorption; IVMP, intravenous methylprednisolone; RIA, radioimmunoprecipitation assay; TLE, temporal lobe epilepsy.

Fig. 3 ∣. Pathology of early and late stages of GAD-TLE.

a–g, Images from an individual with shortduration (7 months) temporal lobe epilepsy with glutamic acid decarboxylase antibodies (GAD-TLE) who underwent epilepsy surgery (patient 2 in Tröscher et al.), outcome Engel IV, 16 years after surgery. MRI shows swelling and signal increase in the left hippocampus (part a). Early neuronal loss is observed especially in regions CA1, CA3 and CA4 (arrows, part b). B cells are present in perivascular cuffs (part c), whereas CD138⁺ plasma cells have infiltrated the hippocampal parenchyma (part d). A large number of T cells are present in both perivascular cuffs and the parenchyma (part e), most of which are CD8⁺ (part f). Multiple cytotoxic (CD8⁺ and granzyme B⁺ (GrB)) T cells are in close contact with neurons; a stronger CD8 signal at the site of contact between T cells and the neuronal membrane suggests the formation of an immunological synapse (arrows, part g). h–n, Images from an individual with late, inactive GAD-TLE with a duration of 36 years, outcome Engel III, 2 years after surgery (patient 14 in Tröscher et al.). Hyperintensity in the left hippocampus is observed on MRI (part h). Regions CA1, CA3 and CA4 are intact (parts i and j) with minor neuronal loss in the CA2 region (arrows, part j), demonstrating that even long-standing GAD-TLE does not necessarily imply hippocampal cell loss. Assessment of inflammation shows that, in contrast to early, active GAD encephalitis, very few CD3⁺ and CD8⁺ T cells are present in a perivascular position (parts k and l). CD20⁺ B cells (part m) and CD138⁺ plasma cells (part n) are very rare and found only in blood vessels. Stain-positive cells are indicated by arrows.

Fig. 4 ∣. Pathology of Ma2 antibody-positive paraneoplastic encephalitis.

a–e, Autopsy samples from an individual with subacute (disease duration 7 months) Ma2 antibody-positive paraneoplastic encephalitis (patient from Barnett et al.). As in acute–early GAD-TLE, the parenchyma of the hippocampus is infiltrated with large numbers of CD3⁺ T cells (part a). Most T cells are CD8⁺ cytotoxic T cells that are often in close contact with neurons (arrows in inset, part b). Cytotoxic granules are present at the neuron surface (arrowhead, part c). In addition, a moderate number of CD20⁺ B cells can be seen in a perivascular position (part d). Activated microglia and multiple microglia nodules are also present (part e); the arrow in the inset indicates a nodule surrounding a neuron. f–j, Autopsy samples from an individual with chronic anti-Ma2 with seizure onset at age 23 years, epilepsy diagnosis at age 29 years after the first tonic–clonic seizures, and epilepsy surgery at age 32 years (2-year outcome Engel IIB; case 3 in Steriade et al.). Three MRI scans in consecutive years show obvious right amygdalar hyperintensity and swelling at age 29 years that largely diminishes until surgery, but no clear hippocampal atrophy evolves (part f). Neuronal loss is apparent in the CA4 region (part g), indicating that hippocampal neuron loss is not always visible on routine MRI. GFAP staining shows fibrillary gliosis typical of hippocampal sclerosis (part h). Inflammation by CD3⁺ T cells and CD8⁺ T cells (parts i and j) is much lower than in the subacute stage of the disease (parts a and b). GrB, granzyme B.

Fig. 5 ∣. Pathological features of anti-LGI1 encephalitis.

a, Clinical and radiographic evolution of anti-leucine rich, glioma inactivated protein 1 (LGI1) encephalitis in a 42-year-old woman. Left hippocampal hyperintensity (arrow) corresponds to an area of hypermetabolism 10 months after disease onset, after which a diagnosis was made and immunotherapy initiated. After another 10 months, seizures had reduced but persisted, and MRI signs of hippocampal sclerosis were present with corresponding PET hypometabolism, indicating structural injury that was unlikely to respond to further immunotherapy. b–g, Pathology of a 72-year-old man with acute anti-LGI1 (1 m disease duration) who presented with confusion, aggressive behaviour and cognitive deficits. In the hippocampus, no neural loss is observed (part b) and CD3⁺ T lymphocytes are present only in the perivascular space of blood vessels (part c). Staining in consecutive sections shows that the T cells are CD8-positive (part d) and a single CD20⁺ B cell (arrow) is also present (part e). Astrocytes located between neurons (arrows) in the CA4 region are not activated (part f); however, microglial cells have upregulation of major histocompatibility (MHC) class II (part g). h–l, MRI and pathology in a 56-year-old man with anti-LGI1 and 8-month disease duration (patient ‘VGKC/1’ from Bien et al.), still fulfilling the criteria for autoimmune encephalitis. Fluid-attenuated inversion recovery MRI (part h) shows enhanced signal in the left amygdala (arrow) and hippocampus. Despite increased signal on MRI, staining of needle biopsy tissue from the amygdala shows no clear neuronal loss (part i). However, due to the biopsy technique, no larger areas can be evaluated, so a potential sampling error might have hidden neuronal loss. Inflammatory infiltration of CD3⁺ T cells is moderate with most cells present in the perivascular space of blood vessels and only very few cells (arrow) infiltrated in the parenchyma (part j). The presence of astrogliosis (part k) indicates a long-standing pathological condition, and minor activation of microglial cells (part l) suggests the absence of a severe neurodegenerative process. IVIg, intravenous immunoglobulin; MMF, mycophenolate mofetil.