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Improving clinical practice with an old friend from the neuroimmunology toolkit: acute corticosteroids in LGI1 antibody encephalitis

Autoantibodies against leucine glioma inactivated 1 (LGI1) are well recognised in elderly men without tumours who present with frequent, focal seizures and a hippocampalcentric pattern of cognitive impairment. These patients often progress over more than 3 months and show little evidence of inflammation on routine CSF testing, defying diagnostic criteria for autoimmune encephalitis. Furthermore, as the LGI1antibodies are of the ‘noninflammatory’ IgG4 subclass, several first principles collectively question a rationale for immunotherapy administration in this cohort. Yet, this form of autoantibodymediated central nervous system disease is clearly, and often exquisitely, sensitive to immunotherapies. We have witnessed patients whose seizure frequency plummets from 100/day to nil after just three doses of corticosteroids. Larger studies have confirmed timedependent immunotherapy sensitivity. For example, cessation of faciobrachial dystonic seizures (the most characteristic semiology in these patients) was observed in 75/85 (88%) patients 90 days after immunotherapy administration: an effect most marked in those who received early immunotherapies. However, the question of which immunotherapies to administer remains unanswered. The only randomised controlled trial in LGI1antibody encephalitis reported modest seizure and cognitive outcome improvements in those administered IVIG versus the placebo arm. Yet, ~75% of these LGI1antibody encephalitis patients progressed to receive corticosteroids, hinting that neuroimmunology’s most faithful agent may be centre stage in optimising patient outcomes. Now, Rodriguez et al summarise data from 118 patients with LGI1antibody encephalitis (seen over 11 years), which strongly advocates for acute corticosteroid therapy. Their main finding at followup after a median of 1.4 months (range, 0–20) revealed that, by comparison to a group administered IVIG (n=21), the 49 patients treated with corticosteroids alone showed lower median absolute scores on the modified Rankin Scale (mRS; 1 vs 3; p=0.004), greater overall improvement in mRS (2 vs 0; p=0.008), more frequent seizure resolution (74% vs 21%; p≤0.001, including faciobrachial dystonic seizures (61% vs 7%; p=0.002)) and greater improvement in the Kokmen bedside cognitive assessment (5 vs 0 points; p=0.01). However, these striking group differences were not sustained at >24month followup. At this epoch, available in a subset of 54/118, seizures had almost universally resolved, Kokmen scores were no different between the two groups, and an mRS of 0–2 (often termed ‘favourable’) was reached in 87%. This apparently negative result may be explained by an insensitivity of the mRS to capture more subtle longer term differences, as previously well demonstrated in both this disease and in Nmethyl Daspartate receptorantibody encephalitis. And, despite its wider dynamic range, the Kokmen assessment may have shown no difference as only seven patients remained in the IVIGtreated cohort for this assessment. The authors appropriately acknowledge largely inevitable limitations of collecting data in uncommon conditions over many years: underpowered subset analyses, reduced potential to account for differing regimes of corticosteroid and IVIG administration and inconsistent followup durations. Nevertheless, in light of these collective findings, it now appears unethical to exclude the current standard of care— namely corticosteroids—from future clinical trials in LGI1antibody encephalitis. Such trials are likely to benefit from incorporating longitudinal seizure and cognitive outcomes, as these core clinical observations may offer different insights across the disease course. Yet, both may fail to capture sensitive features of key interest to patients, including fatigue, mood and employment status, and may not be easily extrapolated to other LGI1antibodyassociated syndromes, such as patients with relatively pure seizure disorders, neuropathic pain and peripheral nerve hyperexcitability. 7 In the absence of costly, highly coordinated, sequential, multicentre randomised controlled trials, carefully gathered clinical observations remain the mainstay of an evidence base in autoimmune encephalitis. To date, such studies have effectively informed our routine clinical practice in neuroimmunology, typically concur closely with expert clinical observations and continue to enhance our understanding of how to best manage our patients.