Autoimmune encephalitis (AIE) is a very frequently diagnosed type of encephalitis in middle-to-high-income countries. One of the most common forms of AIE is anti-N-Methyl-D-Aspartate receptor encephalitis (NMDARE). In a study conducted in California, the incidence of NMDARE was higher than any individual viral encephalitis. It predominantly affects young females, with many of those cases associated with teratomas.² 

In the last decade, there has been a significant increase in diagnostic recognition and awareness of treatment modalities for this disorder. Approximately 25% of cases are refractory to first- and second-line therapies, which have been delineated as such by expert consensus primarily based on data from retrospective studies, as there have not been any clinical trials to date. First-line therapies include high dose steroids, intravenous immunoglobulin (IVIG) and plasmapheresis. Second-line therapies typically include rituximab and cyclophosphamide. Newer therapies utilized as third-line treatments include agents such as tocilizumab and bortezomib. One possible pathophysiological mechanism that could explain the failure of intravenous therapies is that plasma cells can potentially migrate through the blood-brain barrier, seed the meninges, and lead to the formation of intrathecal antibodies. In support of this potential mechanism, Martinez-Hernandez et al. found significant infiltration of lymphocytes and plasma cells in perivascular, interstitial, and Virchow-Robins spaces.⁴ In the longest follow-up study to date, Hansen et al. found intrathecal NMDA antibody synthesis in a patient 15 years after her initial presentation.⁵ Although the persistence of intrathecal antibodies and immune-mediating cells is of no clinical significance in most cases, it can lead to refractory or relapsing symptoms in a subset of patients. This pathophysiology has raised the possibility of intrathecal immunomodulation as an attractive form of treatment. Some potential intrathecal therapies can include methotrexate, steroids, and rituximab. We present the case of a patient with severe refractory NMDARE in whom intrathecal therapies were utilized.

 A 13-year-old female with seizures and behavioral changes was diagnosed with refractory NMDARE and an associated unilateral ovarian teratoma. She is status post tracheostomy and remains mechanical ventilator dependent 6 months after her initial diagnosis. She failed to respond to treatments including plasma exchange (PLEX), IVIG, steroids, IV rituximab, cyclophosphamide, and left oophorectomy. Intra-op visualization of the right ovary was reported to be normal. Although she had temporary improvement, after a few months she again had worsening of her symptoms with a marked rise in serum NMDA antibody titers. Immunotherapy was restarted with IV rituximab and cyclophosphamide, but she went into super-refractory status epilepticus requiring a pentobarbital coma. Given her clinical worsening, the decision was made to remove her remaining right ovary, however no teratoma was ultimately identified on pathological examination. Less than 2 weeks later, she was also started on intrathecal rituximab therapy at 25 mg weekly for 4 weeks. Within a week of IT rituximab she was able to wean off pentobarbital and transition to maintenance phenobarbital. After 4 weeks of therapy, she experienced significant neurological improvement and was transitioned to rehabilitation. Subsequent visits confirmed a steady neuro-cognitive improvement. No more doses of inthrathecal rituximab were given.

This patient case highlights the potential benefit of intrathecal therapies for patients with refractory AIE, particularly NMDARE. The most frequently utilized intrathecal drug has been methotrexate, with multiple recent case series and one pilot study demonstrating potential benefit.^6-9 Although none of these studies mentioned severe side effects, methotrexate has a well-known risk of neurotoxicity; presenting as encephalopathy, seizures, and even malignant cerebral edema in some cases.¹⁰ Rituximab has also been utilized with increasing frequency in patients with AIE, especially NMDARE, as its mechanism of action—working directly on CD20 presenting cells (B cells)—seems intuitive as a treatment option for these conditions. However, rituximab has poor blood-brain barrier penetration (only about 0.1%).¹¹ Nevertheless, trials of intrathecal administration of rituximab have been described in a few case reports and small series. In all these cases, including our own experience in two children’s hospitals in Florida, the patients had neurological improvement ranging from mild to significant after the administration of intrathecal rituximab. At one of these hospitals, the protocol used in the presented case was utilized, with 4 once-weekly doses administered over 4 weeks. In a 2019 case report, Casares et al. reported recovery in a patient refractory to first- and second-line therapies after utilizing the same dosing protocol.¹² In their 2022 case series, Krishnan and Thomas reported complete neurological recovery after utilizing this dosing protocol in two teenage females whose cases had been refractory to cyclophosphamide, neither of which were associated with teratomas.¹³ More recently, in a 2024 case series from Lebanon, Reda et al. reported significant improvement in two females, again without teratomas, who had been refractory to both IV rituximab and cyclophosphamide. Of note, none of these cases, including ours, reported significant adverse effects from the intrathecally administered rituximab.

With recent advances in the care of patients with AIE and NMDARE, a significant area of focus has been on the treatment of those cases that remain refractory, and the use of immunomodulation with intrathecal and other unconventional routes of administration is a growing area of interest. Further research including clinical trials is essential to better understand the use of intrathecally administered immunomodulatory treatments.

Author Affiliations:

Nicolas Chiriboga, MD

Assistant Professor of Pediatrics, Division of Pediatric Critical Care Medicine

University of Tennessee Health Science Center/LeBonheur Children’s Hospital

Jose Irazuzta, MD

Professor of Pediatrics, Division of Pediatric Critical Care Medicine

University of Florida College of Medicine-Jacksonville/Wolfson Children’s Hospital