Seizures in anti‐Hu–associated extra‐limbic encephalitis: Characterization of a unique disease manifestation

Abstract

Anti‐Hu–associated neurologic autoimmunity most often occurs in the context of small cell lung cancer and typically presents with peripheral neuropathy, cerebellar ataxia, and/or limbic encephalitis. Extra‐limbic encephalitis causing seizures is a rare disease manifestation, with only sparse reports in the literature. Herein we present a patient with seizures in anti‐Hu–associated extra‐limbic encephalitis, and review the literature for other cases to more fully characterize this entity. Among 27 patients we identified, the median age was 46 years (range: 2–69 years) and 18 of 27 (67%) were female. Focal motor seizures were most common, followed by ictal expressive speech difficulty. Seizure semiologies along with neuroimaging findings most frequently suggested the involvement of the peri‐Rolandic cortex, more anterior frontal operculum, and insula, although other cortical regions were rarely affected as well. In contrast to other classical paraneoplastic neurologic syndromes, good response to treatment with attainment of seizure‐free survival was often reported, although over one‐third still died. A propensity for chronic seizures among children indicated the potential to develop autoimmune‐associated epilepsy. The predilection for certain extra‐limbic regions, as well as the possibility of good response to treatment, may reflect unique disease mechanisms that would benefit from further study.

Seizure characteristics and outcomes in patients with neurological conditions related to high‐risk paraneoplastic antibodies

“…36 However, extralimbic seizures with involvement of the perirolandic region have also been reported in patients with ANNA1-IgG, and perisylvian involvement has been found in patients undergoing stereo-EEG for postencephalitis epilepsy. 21,37 Consistent with these prior findings, the localization of seizures for the majority of our patients was temporal, although extratemporal onset seizures were present in 22%. There was a high burden in this cohort of subclinical seizures, which were present in almost half of the patients.…”

“…Localization of seizures is typically temporal with underlying autoimmune causes 36 . However, extralimbic seizures with involvement of the perirolandic region have also been reported in patients with ANNA1‐IgG, and perisylvian involvement has been found in patients undergoing stereo‐EEG for postencephalitis epilepsy 21,37 . Consistent with these prior findings, the localization of seizures for the majority of our patients was temporal, although extratemporal onset seizures were present in 22%.…”

“…Drug‐resistant epilepsy, frequently with temporal onset, has been reported among patients with Ma2‐IgG encephalitis 11,12 . Epilepsia partialis continua (EPC) and extra‐LE have been described in cases with ANNA1‐IgG 13–21 . Although many of these disorders are associated with acute symptomatic seizures in the setting of active encephalitis, the exact risk of autoimmune‐associated epilepsy in these patients is unknown 6,22 .…”

“…11,12 Epilepsia partialis continua (EPC) and extra-LE have been described in cases with ANNA1-IgG. [13][14][15][16][17][18][19][20][21] Although many of these disorders are associated with acute symptomatic seizures in the setting of active encephalitis, the exact risk of autoimmuneassociated epilepsy in these patients is unknown. 6,22 The objective of this study was to describe the outcome of seizures in the setting of neurological disorders with high-risk PN antibodies.…”

Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults

“…Cortical-subcortical T2/FLAIRhyperintense lesions are characteristic of GABA(A)R antibody encephalitis, and have also been reported with several other neural antibodies including those targeting Hu. [88][89][90][91][92][93] Unilateral cortical T2/FLAIR-hyperintense lesions with hypointensity of the adjacent subcortical white matter have been described in patients with encephalitic presentations of MOG antibody-associated Cell-based assays (CBA) Anti-NMDAR, LGI1, CASPR2, GABA(B)R, AMPAR, DPPX, GAD65, IGLON5, MOG, GLYR CBA reported to have higher sensitivity than TIIF/IHC for certain neural antibodies (e.g., LGI1, CASPR2); however, higher sensitivity may come at cost to specificity (46,21) Specificity of isolated positivity by CBA varies across analytes and is lower in the absence of corresponding positivity by second assay (e.g., TIIF/IHC); for weak/low isolated serum positivity by CBA, discuss further evaluation with testing laboratory (e.g., testing at higher dilution for anti-CASPR2) (63,(65)(66)(67) Note that CBAs for anti-MOG and anti-GlyR are not routinely incorporated in neural antibody panels for autoimmune encephalitis, but should be ordered in patients with compatible disease phenotypes (e.g., ADEM and unilateral cerebral cortical encephalitis/FLAMES for anti-MOG, PERM for anti-GlyR); restricting testing of these antibodies to patients with compatible disease phenotypes reduces proportion of false-positives, which usually occur as low levels of positivity in serum( 68 disease. 73,74,94,95 T2/FLAIR hyperintensities restricted to the claustrum have been reported to be useful markers of seizures related to autoimmune encephalitis.…”