Predicting intrathecal immunoglobulin synthesis in the ICU: a comparative study of IgG-based indexes

Central nervous system autoimmune diseases (CNS-AD) such as autoimmune encephalitis and myelitis are severe conditions, often requiring ICU admission. Early diagnosis is crucial but difficult, as initial steps facing sub-acute neurological disorders try to exclude non-immune causes such as stroke or infections through MRI and multiplex PCR assays. Current acute-phase autoimmune identifiers are lacking, with definitive diagnosis hinging on delayed tests like antibody detection or intrathecal immunoglobulin synthesis (ISI) identification via iso-electric focalization (IEF). This study evaluates surrogate markers, such as the IgG quotient (QIgG), IgG index, and Reiber's formula, which are rapidly obtainable, to quickly predict ISI in the ICU setting, aiming to expedite treatment initiation.

We screened all neuro-ICU admissions from 2008 to 2022 in our center, including patients who underwent a lumbar puncture (LP) and were tested for ISI via IEF. We excluded those lacking concomitant CSF/serum albumin and IgG data. Patients were categorized by final diagnosis as "CNS-AD" or "other", and whether ISI was present. We calculated QIgG, IgG index, and Reiber's formula, comparing their performance to IEF for sensitivity (Se) and specificity (Sp).

ISI was detected in 35% of patients (93/266). In the "CNS-AD" group, 54% were ISI-positive, while 21% of patients in the "Other" group also showed ISI. Among the three indexes, only the IgG index showed strong specificity (95%) but moderate sensitivity (56%). QIgG and Reiber's formula had similar sensitivity (67% and 66%) but lower specificity (41% for both). Multivariable analysis identified age < 50 years (OR 2.5 [95% CI 1.3-4.7]) and an IgG index > 0.7 (OR 14.2 [95% CI 6.6-32.0]) as factors independently associated with ISI positivity. Using the Youden index and likelihood ratio, we recalibrated thresholds to improve performance. A "grey zone" was defined for the IgG index (0.67-0.80), below which ISI was unlikely and above which it was considered probable.

While the IgG index's low sensitivity limits its standalone diagnostic use, its high specificity makes this index a good one when positive, to weigh in the decision-making process to treat or not a patient with suspected CNS-AD, while awaiting IEF results, which can take days or even weeks in some centers.