Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study

Abstract

Summary Background We aimed to assess the sensitivity/specificity of serum and CSF antibody-testing in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, and the correlation between titers, relapses, outcome, and epitope repertoire. Methods In this observational study, brain immunohistochemistry and cell-based assays (CBA) with fixed and live NMDAR-expressing cells were used to determine the sensitivity/specificity of antibody-testing in paired serum/CSF obtained at diagnosis of 250 patients with anti-NMDAR encephalitis and 100 control subjects. A patient was considered antibody-positive if either serum or CSF tested positive with both immunohistochemistry and CBA; titers were determined with serial sample dilution using brain immunohistochemistry. Samples from 45 patients (25 good-outcome: modified Rankin Scale [mRS] 0–2; 10 poor-outcome: mRS 3–6; 10 relapses) were examined at ≥3 disease time points. Epitope repertoire was determined with CBA expressing GluN1-NMDAR mutants Findings All 250 patients had NMDAR-antibodies in CSF but only 214/250 had antibodies in serum (sensitivity 100% [98.5–100%] versus 85.6% [80.7–89.4%], p<0.0001). Serum immunohistochemistry-testing was more often in agreement with CBA with fixed than live cells (77/108 versus 63/108, p=0.0056). In multivariable analysis, CSF and serum titers were higher in patients with poor-outcome than in those with good-outcome (CSF dilution 340 versus 129, difference 211, [95%-CI 1.1–421], p=0.049; serum 7370 versus 1243, difference 6127 [2369–9885], p=0.0025), and in patients with teratoma than in those without (CSF 395 versus 110, difference 285 [134–437], p=0.0079; serum 5515 versus 1644, difference 3870 [548–7193], p=0.024). Over time there was a decrease of antibody-titers regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288–788]; serum 5460 to 1564, difference 3896 [2428–5362], both p<0.0001). Relapses correlated better with the titer-change in CSF than that in serum (14/19 versus 7/16, p=0.037). After recovery, 24/28 CSF and 17/23 serum from patients remained antibody-positive. Patients’ antibodies targeted a main epitope region at GluN1 aa369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. Interpretation NMDAR antibody-testing is more sensitive in CSF than serum. Antibody-titers in CSF and serum are higher in patients with poor-outcome or teratoma. The titer-change in CSF correlates better with relapses than that of serum. Funding The Dutch Cancer Society, the National Institute of Health, the McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, Erasmus MC fellowship and Fundació la Marató de TV3.

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody

“…By reconstructing functional autoantibodies from CSF cePc in the form of rhuMab, we demonstrate the presence of a CNS‐specific antigen‐driven humoral immune response in the CSF compartment of patients with anti‐NMDAR encephalitis, consistent with studies showing that the sensitivity of NMDA receptor antibody testing is higher in CSF than in serum and CSF antibody levels correlate with the course of the disease 5. Whether autoreactive B‐cell affinity maturation indeed occurs inside the CNS compartment and some of the clonally related B cells migrate to the peripheral system to produce self‐reactive antibodies, or CNS‐specific B‐cell clones transmigrate the BBB and proliferate in the “B‐cell friendly” environment of the CNS, remains to be elucidated in further studies.…”

“…Irrespective of the trigger of anti‐NMDAR encephalitis, data from previous studies suggested an enhancement of the immune response within the CNS, with potential antigen‐driven affinity maturation and clonal expansion of plasma cells 16. This hypothesis was suggested by three findings, (1) a frequent intrathecal synthesis of NMDAR antibodies even early in the disease course,1 (2) biopsy and autopsy material from patients showing brain inflammatory infiltrates containing plasma cells,6, 7 and (3) the better correlation of the course of the disease with CSF antibody titers than with serum antibody titers 5. All four treatment‐naive patients with recent onset anti‐NMDAR encephalitis in the current study showed intrathecal B‐cell and plasma cell accumulation and intrathecal production of NMDAR‐specific IgG.…”

“…The pathogenic relevance of these antibodies is supported by the response of clinical symptoms to immunotherapy and the correlation between antibody titers and neurological outcome 5. The intrathecal source of pathogenic antibodies in anti‐NMDAR encephalitis has been suggested to originate from CD138 + plasma cells identified in perivascular and interstitial spaces in biopsy and autopsy studies 6, 7…”

Elevated LGI1‐IgG CSF index predicts worse neurological outcome

“…Aquaporin‐4‐IgG, the effector of neuromyelitis optica spectrum disorders, is detected in serum more readily than in cerebrospinal fluid,7 but some intrathecal production of aquaporin‐4‐IgG occurs 8. In contrast, NMDAR‐IgG is detected more readily in the CSF,9 despite at least some NMDAR‐IgG production in peripheral immune responses 10. Preliminary data by Irani et al.…”

Bortezomib treatment for severe refractory anti‐NMDA receptor encephalitis

“…Escalation to a CyBorD regimen was also not effective in improving mRS scores. Decrease in the serum and CSF antibody titers of more than twofold, considered as a substantial change,21 were not achieved after 2 cycles of bortezomib in any of the patients.…”