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N‐methyl‐d‐aspartate receptor antibody encephalitis: how much treatment is enough?

N-methyl-D-aspartate receptor antibody (NMDAR-Ab) encephalitis was first described in a small cohort of females with ovarian teratoma, although historical cases of sudden catastrophic encephalopathy with relatively good outcomes (as reported by Sebire and others) probably represent this condition as well. NMDAR-Ab encephalitis is now recognized to be a major cause of adult and childhood-onset autoimmune encephalitides. As we start to diagnose this condition with greater ease, major challenges still face clinicians managing these patients. Current immune therapeutic strategies seek to (1) remove circulating NMDAR-Abs (intravenous immunoglobulins and plasmapheresis) and (2) attenuate the autoimmune production of pathogenic NMDAR-Abs (steroids and other immunosuppressive agents) to ameliorate this severe polysymptomatic syndrome and induce disease remission. To date, no controlled trial has been conducted to provide highquality evidence on the optimal therapeutic strategy for NMDAR-Ab encephalitis. The recommendation for treatment of NMDAR encephalitis in both adults and children is based on authoritative reviews, supported by a large cohort analysis, that suggests that the concomitant and early use of intravenous steroids and intravenous immunoglobulins and/or plasmapheresis (deemed first-line therapy) are often very effective in achieving control of symptoms and remission. These treatments have the additional benefits of second-line therapy such as rituximab and cyclophosphamide, when first-line therapy fails or is partially effective. Importantly, patients often remain symptomatic despite first-and second-line treatment, prompting physicians to repeat therapeutic cycles. This decision to escalate immune treatment is primarily reliant on the clinical syndrome as there are no radiological or immunological biomarkers that can reliably inform this decision-making. Tatencloux et al. report three children with NMDARAb treated with intrathecal methotrexate and methylprednisolone after an unsatisfactory response to initial therapeutic options. Infiltrates of antibody-secreting lymphocytes have been identified in the cerebral spinal fluid (CSF) of patients with NMDAR-Ab encephalitis, although it remains unclear if these cells are primed and activated systemically or centrally. Direct administration of immune therapeutic agents into the CSF aims to target the central population of activated lymphocytes to decrease the production of intrathecal antibodies and attenuate other potential cellular effector mechanisms, a strategy that has been used in B-cell acute lymphoblastic leukaemia and lymphohistiocytosis with neurological involvement, as discussed by Tatencloux et al. The modest outcome of the children as being attributable to this intrathecal strategy has to be cautiously interpreted. First, not all the children within this cohort were managed systematically, as currently proposed. One child (case 1) was given rituximab as a first immunomodulatory therapy, and subsequently given intrathecal methotrexate and steroids 5 months after initial presentation; and in another child (case 3), plasmapheresis was initiated followed by one dose of rituximab 3 weeks later and subsequently intrathecal methotrexate and steroids at week 15 when symptoms were unabating. Second, improvement following NMDAR-Ab encephalitis may continue over a protracted period of up to 2 years in patients, even if less aggressively managed. Nevertheless, a small proportion of children have an intractable form of NMDAR-Ab encephalitis and may respond to intrathecal therapy. Reassuringly, the neuroradiological sequelae that can follow intrathecal methotrexate were not reported by the authors in the three patients with refractory NMDAR-Ab encephalitis undergoing intrathecal therapy. Importantly, when balancing the risks and benefits of such strategies, evidence from oncological studies where this strategy is more widely used suggests longer-term cognitive impairment that may at least in part be attributable to intrathecal methotrexate therapy. Crucially, such cognitive deficits may yet not be apparent in the patients treated in this cohort, nor be easily distinguishable from the sequelae of NMDAR-Ab encephalitis. Efficacy of this therapy requires further evaluation and questions surrounding longer-term effects remain. It is therefore imperative that intrathecal methotrexate (and steroid) therapy is only considered in highly aggressive NMDAR disease, and only after currently recommended therapies have been exhausted. When considering if therapy is adequate for NMDAR-Ab encephalitis, the multitude of pathomechanisms contributing to central nervous system dysfunction require consideration, such as receptor internalization, recycling and secondary effects on synaptic remodelling. Ultimately, the strategy producing optimal outcome may not solely rely on escalating immunotherapy but include targeting these biological perturbations.