Anti-NMDAR Encephalitis: A Case Series

By: Dr. Stephanie Karvosky and Dr. Dawn MacElroy

ABSTRACT

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune illness caused by the production of antibodies against the N-methyl-D-aspartate (NMDA) receptor 1 (NR1) subunit of the NMDA receptor. It presents most commonly in younger females, with a median age of 21 years, and is frequently associated with ovarian teratomas. Symptoms and clinical manifestations include viral-like prodromal syndrome, psychiatric manifestations, motor dysfunction, and autonomic instability. Treatment consists of immunotherapy and resection of the underlying tumor if present. Psychiatric sequelae, such as agitation, mania, and catatonia, often require additional treatment.

PROBLEM/BACKGROUND

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neurological disease characterized by a complex range of symptoms, including prodromal syndrome, psychiatric manifestations, motor dysfunction, and autonomic instability.1-3 First described by Dalmau and colleagues in 2007, the condition is predominantly present in younger adults and children.4 In particular, those diagnosed are frequently females with an associated tumor.1 In up to 50% of females, the underlying tumor identified is an ovarian teratoma.5 Detection of anti-NMDAR immunoglobulin G (IgG) antibodies within the cerebrospinal fluid (CSF) is diagnostic for the disease.5-6 In the following case series, we describe anti-NMDAR encephalitis treatment management in two patients with related catatonic symptoms requiring electroconvulsive therapy (ECT) at a community hospital.

ANALYSIS AND RESOLUTION

CASE ONE

A 25-year-old Hispanic female (weight 68.1 kg) with no significant past medical history presented from an outside facility for disorganized thinking, pressured speech, catatonic-like behavior, and agitation. Treatment initiated at the facility included lithium, quetiapine, haloperidol, and clonazepam. She continued to decline, with subsequent worsening of manic behavior, posturing, and catatonic-like behavior. Lorazepam was initiated with poor response. Per outside records, pertinent findings included a lithium level of 0.77 mEq/L, prolactin 51.52 ng/mL, TSH 4.19 mIU/mL, negative rapid plasma reagin, negative heavy metal screening, and MRI brain showed

no acute abnormalities. She was transferred for evaluation for ECT management.

At the time of transfer, medications included valproic acid 1000 mg daily orally, lorazepam 2 mg every 4 hours orally, and zolpidem 10 mg nightly orally. On admission, she was admitted to the intensive care unit for close monitoring and neurological workup. A repeat brain MRI and abdominal and chest CT did not reveal any abnormalities. Electroencephalography results revealed diffuse slowing without seizures. Due to the rapidity of symptoms, a neurological workup for infectious and autoimmune etiologies ensued. HIV, HSV, and syphilis assays were unrevealing. A lumbar puncture was collected, and CSF autoimmune antibody panels were sent. Empiric treatment was then initiated with intravenous immune globulin (IVIG) 0.4 mg/kg/day and methylprednisolone 1000 mg/day intravenously for five days.

Ultrasound imaging of the pelvis revealed an ovarian mass consistent with a 1.6 cm dermoid cyst. The patient underwent a successful oophorectomy with pathology consistent with a mature cystic teratoma. Plasmapheresis was considered post-IVIG but is unavailable at this institution and would have necessitated transfer to another facility. Thus, a rituximab 1000 mg infusion was initiated following the completion of IVIG and steroids, with a second dose two weeks after the initial and a third dose one month later. Premedication consisted of acetaminophen, diphenhydramine, and steroids. Following treatment, anti-NMDA receptor antibodies were detected on the CSF paraneoplastic panel, and anti-NMDAR encephalitis was confirmed as the primary diagnosis.

Amid the patient’s anti-NMDAR encephalitis confirmation, her course was complicated by concomitant catatonia. Lorazepam was titrated to effect with dosing as high as 9 mg every three hours intravenously. However, her symptoms progressed to malignant catatonia, with worsening dysautonomia and fever. Medication trials included lorazepam, amantadine, memantine, bromocriptine, dantrolene, benztropine, and zolpidem. A zolpidem challenge was initiated for augmentation to lorazepam without clinical response. ECT was initiated throughout the hospital stay. The ECT schedule consisted of a range of frequencies, including twice daily, daily, and three times weekly, with the only complication being a bradycardic episode. Two sessions per ECT treatment day were administered for a period of one week of three times weekly treatments due to the severity of the patient’s dysautonomia. These sessions appeared not to cause significant complications; however, the patient began to demonstrate more autonomic instability and was then transitioned to daily ECT. Once medically stable during this stay, the patient was transferred to the rehabilitation unit to continue lorazepam, zolpidem, and ECT. At discharge, she had completed 34 ECT treatments and was transitioned to an outpatient regimen of every two-week treatment. The patient’s hospital course was also complicated by an Escherichia coli urinary tract infection and probable aspiration pneumonia, both of which were appropriately treated with antimicrobial agents. At the time of discharge, she was prescribed lorazepam 4 mg three times daily orally with a weekly taper and zolpidem 10 mg nightly orally. Upon follow-up, the patient’s every two-week ECT treatments were discontinued after 36 treatments. Per the documentation, she is continuing occupational and speech therapy with improving short-term memory and intact long-term memory. Lorazepam and zolpidem have successfully been discontinued without recurrence of symptoms.

CASE TWO

A 37-year-old African American female (weight 75.8 kg) with no significant past medical history presented to an institution within our health system from an outside facility for seizure-like activity, agitation, and mania. The outside facility provided pertinent information, including MRI brain and CT brain with no acute abnormalities and detection of anti-NMDAR positive antibodies. She had completed IVIG 0.4 mg/ kg/day intravenously and highdose methylprednisolone 1000 mg daily intravenously for five days.

Before admission to our facility, she was transferred to an intensive care unit within our health system. Electroencephalography results initially revealed diffuse slowing without seizures, and repeated results throughout her

stay revealed continuing diffuse slowing with delta slowing and delta brush. In the setting of confirmed anti-NMDA encephalitis and lack of improvement after treatment, plasmapheresis and cyclophosphamide 750 mg/ m2 intravenously were initiated. She received a total of five plasmapheresis treatments. An ultrasound of the pelvis revealed an adnexal cystic lesion that was then resected with pathology, confirming a mature cystic teratoma. With no further response, she received a second course of IVIG 0.4 mg/kg/day intravenously for five days post-plasmapheresis and rituximab 1000 mg intravenously for two total doses. Due to a continued lack of improvement, a repeat anti-NMDAR assay was sent and confirmed positive after treatment. Prolonged steroid therapy continued throughout her hospitalization and transfer to this facility.

The patient’s hospital course before admission to our facility also included concomitant dyskinesias, dysautonomia, and intermittent fevers related to her anti-NMDAR encephalitis diagnosis. In total, she was trialed on clonazepam, lorazepam, phenobarbital, trihexyphenidyl, diphenhydramine, benztropine, baclofen, gabapentin, and a botulinum injection. Lorazepam, with a maximum dose administered of 9 mg every three hours intravenously, was initiated. The patient showed slight improvement, and ECT three times weekly was begun for underlying catatonia.

The patient was then transferred to our facility on lorazepam 10 mg every 6 hours intravenously, memantine 10 mg twice daily orally, and zolpidem 20 mg nightly orally to continue ECT treatment. Treatments with ECT were scheduled three times weekly, and once stable, she was transferred to our inpatient rehabilitation unit to continue ECT treatments. By admission to the rehabilitation unit, the patient was receiving prednisolone 21 mg daily orally along with Pneumocystis jirovecii pneumonia prophylaxis, lorazepam 2 mg every six hours orally, memantine 1 mg twice daily orally, and zolpidem 10 mg nightly orally. At discharge, she was prescribed a weekly taper of prednisolone and lorazepam orally, memantine, and zolpidem. She had received a total of 24 ECT treatments by hospital discharge.

Her hospital courses across institutions were complicated by bilateral upper extremity deep vein thrombosis, MRSA pneumonia, and thyroid hypertrophy requiring partial thyroidectomy for tracheostomy placement. She markedly improved throughout her multiple hospital admissions and has a third dose of rituximab scheduled. She initially continued ECT treatments in the outpatient setting and has since established neurology care outside of this health system.

DISCUSSION

Anti-NMDAR encephalitis is one of the most common types of autoimmune encephalitis, often detected in females with a median age of 21 years.1,5 It is caused by IgG antibodies targeting the NRI subunit of the NMDAR. Laboratory testing is often nonspecific, apart from the detection of IgG antibodies within the CSF, and imaging of the brain frequently does not show an acute abnormality.5 Nonspecific findings on electroencephalography (EEG) are most often seen with anti-NMDAR encephalitis. However, the finding of delta brushes, which are identified by delta waves with overlaying bursts of beta activity, have been reported to result in a higher likelihood of poor outcomes.6,7,9 This finding is often found on neonatal EEGs and is present in approximately one-third of patients diagnosed with anti-NMDAR encephalitis.8 Due to the high rate of correlation between anti-NMDAR encephalitis and ovarian teratomas in females, imaging of the pelvic region should be completed in younger females presenting with symptoms indicative of encephalitis.Resection of the underlying tumor, if present, can rapidly improve symptoms.1

As the disease is caused by the targeting of NMDAR by IgG antibodies, immunotherapy is the first-line treatment. These therapies include high-dose corticosteroids, IVIG, and plasmapheresis.1,6 The peak effect of IVIG often takes weeks, whereas plasmapheresis effects are seen more rapidly. Available literature suggests that plasmapheresis may be more effective at improving clinical outcomes in those with refractory anti-NMDAR encephalitis, and it may be suggested as first-line over IVIG for these reasons.10 A limitation of this facility is that it does not perform plasmapheresis, and as such, IVIG is considered the available first-line treatment option for our patients.

Common first-line, second-line, and maintenance therapies, along with the most common dosing, are listed in Table 1.1,3,57 After second-line therapies, guidelines suggest utilizing more experimental therapies such as interleukin-6 inhibitors or bortezomib.3,6 Prompt treatment should be initiated empirically after a lumbar puncture, and CSF studies are obtained in suspected anti-NMDAR encephalitis.6

Early identification and the removal of an underlying tumor generally provide better outcomes, and treatment is more effective.1,6 Upwards of 50% of patients will recover, with approximately 46% having lasting deficits such as impaired memory or cognition. Relapse rates have been reported to be between 12% and 24%, with an estimated mortality rate of approximately 20%. In those without underlying tumors, the prognosis for recovery is often worse.3,6

Psychiatric manifestations of anti-NMDAR encephalitis often evolve into a catatonic state. Evidence suggests that approximately 20% of catatonia has a non-psychiatric cause, with almost a third of this cohort caused by CNS inflammation and immunological conditions. Benzodiazepines and ECT treatment are generally considered the cornerstone of treatment. The severity of catatonia may warrant intensive care due to symptoms such as dyskinesia and dysautonomia. ECT has been shown to be activating in single sessions and down-regulate the immune system in multiple sessions.11 ECT has been found to be safe as a treatment for catatonia in anti-NMDAR encephalitis.12 Interestingly, anti-NMDAR encephalitis is strongly associated with catatonia, particularly malignant catatonia. It is theorized that the cause of co-occurring catatonia may be due to adaptive immunity, which would coincide with anti-NMDAR encephalitis as an adaptive immune system disorder.11 To the authors’ knowledge, no other published literature describes the use of ECT twice-daily treatments for patients in general, let alone in anti-NMDAR encephalitis. It can be reported from the above case that this regimen was relatively safe, and no long-term deleterious effects were seen.

CONCLUSION

Anti-NMDAR encephalitis is a potentially fatal condition with a range of symptoms, including psychiatric manifestations. Empiric treatment should be initiated promptly, and immunotherapy should be recognized as the first line. Additional treatment for psychiatric manifestations, such as catatonia, is often warranted. This case series provides validation of the growing literature surrounding treatment in anti-NMDAR encephalitis. To the authors’ knowledge, no published literature has reported twice-daily ECT regimens. As such, this case series adds to the literature surrounding the condition and various treatments, including treatment for concomitant catatonia.

Authors: Stephanie Karvosky, PharmD, BCPS, at the time this article was submitted, was a PGY2 resident in internal medicine at Duke Regional Hospital. She is now a Heart Failure Clinical Pharmacy Specialist at Cape Fear Valley Hospital in Fayetteville, NC; skarvosky@capefearvalley. com. Dawn MacElroy PharmD, BCPS, is a Critical Care Clinical Pharmacist at Duke Regional Hospital in Durham, NC.

References

1. Ford B, McDonald A, Srinivasan S. Anti-NMDA receptor encephalitis: a case study and illness overview. Drugs Context. 2019;8:212589. Published 2019

Aug 30. doi:10.7573/dic.212589. 2. Bhat P, Ahmed A, Jolepalem P,

Sittambalam C. A case report: anti-NMDA receptor encephalitis.

J Community Hosp Intern Med

Perspect. 2018;8(3):158-160.

Published 2018 Jun 12. doi:10.10 80/20009666.2018.1481326. 3. Barry H, Byrne S, Barrett E,

Murphy KC, Cotter DR. Anti-N-methyl-d-aspartate receptor encephalitis: review of clinical presentation, diagnosis and treatment. BJPsych Bull. 2015;39(1):19-23. doi:10.1192/ pb.bp.113.045518. 4. Dalmau J, Gleichman AJ, Hughes

EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.

Lancet Neurol. 2008;7(12):10911098. doi:10.1016/S14744422(08)70224-2. 5. Huang Q, Xie Y, Hu Z, Tang X.

Anti-N-methyl-D-aspartate receptor encephalitis: A review of pathogenic mechanisms, treatment, prognosis.

Brain Res. 2020;1727:146549. doi:10.1016/j.brainres.2019.146549. 6. Samanta D, Lui F. Anti-NMDA

Receptor Encephalitis. StatPearls [Internet]. Treasure Island (FL):

StatPearls Publishing; 2022. 7. Shin YW, Lee ST, Park KI, et al. Treatment strategies for autoimmune encephalitis. Ther Adv Neurol Disord. 2017;11:1756285617722347.

Published 2017 Aug 16.