PMC7782967_01
Illustration of treatment escalation in refractory course of anti-NMDA receptor encephalitis with special focus on antibody titer in CSF and serum as well as the clinical development over 27 months. mRS: modified Rankin scale (0, No symptoms; 1, No significant disability; 2, Slight disability, able to look after own affairs without assistance, but unable to carry out all previous activities; 3, Moderate disability. Requires some help, but able to walk unassisted; 4, Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted; 5, Severe disability. Requires constant nursing care and attention, bedridden, incontinent, 6 - Dead).
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F1
Positive oligoclonal bands and anti-NMDA-receptor antibodies were found in cerebrospinal fluid (CSF) and serum (Figure 1), as well as anti-AMPAR- and anti-mGLUR5-antibodies, both in serum and CSF, which allowed the diagnosis of autoimmune limbic encephalitis. The patient could be transferred to intermediate care 9 months after disease onset and 220 ICU days, followed by a rehabilitation program (Figure 1). Even so, the correlation of anti-NMDA-antibody titer and the patient's symptoms is poor as described by Gresa-Arribas et al. and reflected by this case (Figures 1, 2).
Phenotyping lymphocytes before and after daratumumab treatment. Peripheral blood lymphocytes were analyzed by flow cytometry 2 days before (A,B) and 12 days after daratumumab (C) has been administered. Due to prior rituximab application CD20/CD19high B cells were lacking. Cells were first gated on singlet lymphocytes according to their FSC vs. SSC properties and then analyzed in the gates indicated on the top of each dot plot. Dots stained positive in the CD19+CD38+ gate are shown emphasized for better visibility. (D) Depict data obtained during cytometric rituximab monitoring showing the absence of any CD19+ cells at the indicated time points after first daratumumab application.
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F2
The clinical state remained unimproved; anti-NMDA receptor antibody titers showed a stable high level (1:1,600) (Figure 2), while a peripheral fluorescence-activated cell sorting (FACS) analysis rendered CD20 cell depletion after rituximab. Approximately, 0.81% of all lymphocytes were CD19low and CD38 positive cells, 36.4% of which co-expressed CD27, fulfilling the marker criteria of plasma cells/plasmablasts in peripheral blood (Figures 2A,B), yielding 0.029% of all lymphocytes or 41/ml (normal range: 1-635/ml). The lack of detecting CD38+ cells, including all antibody-secreting cells such as plasma cells/plasmablasts, therefore indicates either the depletion or the saturated covering of the targeted cells unavoidably subjecting them soon to death (Figure 2C). In addition, the nearly comlette absence of CD19+ cells confirms at least a complete plasmablast depletion for nearly 1 year after starting daratumumab therapy (Figure 2D). Even so, the correlation of anti-NMDA-antibody titer and the patient's symptoms is poor as described by Gresa-Arribas et al. and reflected by this case (Figures 1, 2).
Level of immunoglobulin classes and influence of daratumumab. (A) Immunoglobulins in serum. (B) Immunoglobulins in CSF.
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F3
Furthermore, the persisting anti-NMDAR titer, despite falling IgG levels, indicates a specific non-depleted plasma cell population possibly in the CNS in this case (Figure 3).