Intrathecal Rituximab in Refractory Anti-NMDA Receptor Encephalitis: A Dual Case Study

Abstract

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is one of the most prevalent subtypes of autoimmune encephalitis, with about 25% of cases refractory to first- and second-line treatments. Here are two cases of catastrophic anti-NMDAR encephalitis, resistant to conventional treatments, in which acute psychosis due to the beginning phase evolved rapidly into major neurological deterioration associated with seizures, dyskinesia, and dysautonomia. Two patients, both treated with intrathecal rituximab 25 mg weekly for four doses, presented with marked clinical improvement beginning 2-3 days after the first dose and with full functional recovery by the six-month follow-up, without any adverse effects. These cases suggest preliminary evidence that intrathecal rituximab is likely to be a potential treatment option for refractory anti-NMDAR encephalitis and that the administration route used in this study may be more beneficial in terms of therapeutic results and should, therefore, be further investigated in controlled trials.

Introduction

The most common subtype of autoimmune encephalitis is anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, which is characterized by profound neurological dysfunction due to the presence of anti-NMDAR antibodies. Patients typically present with psychiatric symptoms, seizures, dyskinesias, and autonomic instability, which makes diagnosis and management extremely difficult. The standard initial treatments include high-dose corticosteroids, intravenous immunoglobulin (IVIG), and plasmapheresis; nonetheless, about 25% of patients still have refractory symptoms following first- and second-line therapies. The case study will address the therapeutic potential of intrathecal rituximab in two patients who exhibited severe anti-NMDAR encephalitis cases that did not respond to conventional treatments.

Case Presentations

Patient 1

A 24-year-old female was admitted with acute-onset psychosis, initially presenting with agitation and hallucinations. Within a week, her condition deteriorated, characterized by rapid onset of seizures, significant dyskinesia, and episodes of dysautonomia, including unstable blood pressure and heart rate. Initial investigations revealed elevated anti-NMDAR antibodies in serum and cerebrospinal fluid (CSF).

Despite receiving high-dose steroids and plasmapheresis, her neurological status continued to decline. After a thorough multidisciplinary evaluation and consideration of the refractory nature of her symptoms, we initiated treatment with intrathecal rituximab at a dose of 25 mg, administered weekly for a total of four doses.

Outcome: Within 48 hours of the first intrathecal dose, notable improvements were observed, including a reduction in seizure frequency and stabilization of autonomic functions. After the fourth dose, the patient demonstrated significant recovery, regaining her baseline cognitive function and achieving full functional independence by the six-month follow-up. No adverse effects were reported throughout the treatment course.

Patient 2

A 30-year-old male presented with similar symptoms but with an added history of viral prodrome, including fever and malaise. Following the acute onset of severe psychotic symptoms, he rapidly progressed to a comatose state with seizures and autonomic dysregulation. Like the first patient, CSF analysis confirmed the presence of anti-NMDAR antibodies.

The treatment regimen began with standard immunotherapies, including IVIG and high-dose steroids; however, the patient's condition remained critical. Given the refractory nature of his encephalitis, a decision was made to administer intrathecal rituximab, initiating the same dosing protocol as Patient 1.

Outcome: The response to treatment was similarly encouraging, with gradual clinical improvement starting 2-3 days after the initial administration. By the end of the treatment protocol, the patient had regained consciousness and exhibited remarkable cognitive recovery. By the six-month follow-up, he had returned to work and required no ongoing immunosuppression.

Discussion

These two case reports give proof of concept to make intrathecal rituximab a potential therapeutic option for refractory anti-NMDAR encephalitis. The mechanism of action of rituximab is a monoclonal antibody against the CD20 on B cells, intrathecal administration may also augment its efficacy to obtain higher local concentrations within the central nervous system out of limitations to intravenous administration.

Recent literature has emphasized the difficulties in treating anti-NMDAR encephalitis as the only option for refractory patients. Intravenous rituximab is widely used as salvage therapy whose effect is usually limited to poor penetration across the blood-brain barrier. Intrathecal injection allows direct access to the CNS and will thus produce a more immediate and stronger therapeutic effect, considering the rapid improvement that the patients treated in our department experienced.

In addition, the intrathecal approach could serve as an adjuvant to conventional intravenous administration with rituximab. In such a way, both approaches together could achieve optimized therapeutic effects, especially in the most severe cases where immediate intervention is critical.

Conclusion

These two patients, therefore, mark the first examples of successful intrathecal application of rituximab. It points to the fact that intrathecal administration of rituximab in patients with refractory anti-NMDAR encephalitis deserves further research, especially when conventional therapies have failed, due to the paucity of alternative therapeutic interventions. Therefore, our experiences should be further challenged in clinical trials to prove safety and efficacy and to standardize the treatment protocol of this potentially revolutionary approach.

In conclusion, a study of intrathecal rituximab not only brings optimism to therapeutic options for refractory anti-NMDAR encephalitis but also opens a window for review and reflection on paradigms already implemented. Further studies are required to confirm these results and develop in-depth the best strategies offered to patients in this battle over the complex condition of fighting such a tough neurological disorder.

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