NMDA-Receptor Encephalitis Presenting as New-Onset Refractory Status Epilepticus: A Case Series with Review of Literature

Abstract

New-onset refractory status epilepticus (NORSE) is defined as a condition, not a specific diagnosis, with NORSE without a clear acute or active structural, toxic, or metabolic cause in a patient without active epilepsy. We herein report four cases of NORSE, of which three patients had preceding history of behavioral changes and psychiatric manifestations and one had history of preceding fever. All patients had abnormal electroencephalogram finding. Cerebrospinal fluid and serum examination was positive for anti-N-methyl D-aspartate receptor antibody. All cases received Intravenous pulse methylprednisolone, followed by plasmapheresis in two cases. In these two-patient seizure stopped, and they improved clinically. Two patients died due to ventilator associated pneumonia and sepsis. Our cases highlight that in patient presenting NORSE, preceding history of behavioral or psychiatric abnormality or confusion points toward autoimmune etiology. Early diagnosis and treatment prevent morbidity and mortality in these patients.

Keywords

NORSE - anti-NMDA receptor encephalitis - psychiatric manifestation

Introduction

New-onset refractory status epilepticus (NORSE) is a rare and serious condition where a person experiences prolonged seizures that don't respond to standard treatments. It occurs in individuals with no prior history of epilepsy, and, often, no clear cause can be identified, such as brain damage, toxins, or metabolic disturbances.[1] If no cause is found after initial evaluation, it's termed cryptogenic NORSE. However, if an underlying cause is later identified, the diagnosis is updated to reflect that. While several potential causes have been found in different cases, autoimmune encephalitis is one of the leading contributors, accounting for approximately 40% of NORSE cases. In many others, the cause remains elusive. There are few cases reported in literature where NORSE is the presenting complaint of N-methyl D-aspartate (NMDA) encephalitis. We hereby present four cases of anti-N-methyl D-aspartate receptor encephalitis (NMDARE) who presented to us as NORSE. This study adds clinical value by providing real-world data from a low-resource setting, highlighting the heterogeneity in presentation, and emphasizing red-flag features that can guide early suspicion for autoimmune causes in NORSE.

Methods

We prospectively included four patients of NORSE fulfilling the diagnostic criteria of NMDA encephalitis. Demographic, clinical, biochemical, neuroimaging findings, and their in-hospital treatment outcome were noted. Refractory status epilepticus (SE) was diagnosed based on recurrent clinical seizures with refractoriness to two antiepileptic drugs (AEDs).[1] All patients underwent screening for underlying malignancy. Female patients (Case 1 and 4) underwent pelvic ultrasonography. Clinical examination and computed tomography (CT) imaging of the chest, abdomen, and pelvis were performed for all patients where feasible. Positron emission tomography (PET)-CT was not performed due to resource constraints. In line with international guidelines, both serum and cerebrospinal fluid (CSF) samples were sent for anti-NMDAR antibody testing using a cell-based assay for confirmatory diagnosis, recognizing that CSF testing has higher specificity.[2] [3] The meningoencephalitis panel tested for the following pathogens: HSV-1/2, VZV, CMV, EBV, enterovirus, adenovirus, JE virus, TB-PCR, and standard bacterial culture. In all cases, intravenous (IV) midazolam infusion was initiated at 0.1 to 0.2 mg/kg/h and titrated upward to achieve both clinical seizure cessation and electrographic suppression (burst–suppression pattern) on intermittent electroencephalogram (EEG) monitoring. Weaning was attempted after 24 to 48 hours of seizure control. Midazolam was tapered gradually over 2 to 3 days under clinical observation and EEG monitoring.

Results

Case 1

A 16-year-old girl presented to the emergency department with sudden-onset generalized tonic–clonic seizures (GTCS). Over the preceding 24 hours, she had developed confusion and memory loss. Family members reported behavioral changes, including aggression, paranoia, and hallucinations. The patient continued to experience frequent clinical seizures refractory to benzodiazepines, phenytoin, and valproic acid, leading to a diagnosis of SE based on ongoing clinical seizures ([Table 1]). Patient was intubated and started on midazolam infusion as per protocol. Perioral dyskinesia was observed during intensive care unit stay. Complete blood count, renal function test, serum electrolytes, liver function test, random blood sugar, and serum ammonia were normal. EEG showed generalized background slowing. Magnetic resonance imaging (MRI) showed subtle T2/FLAIR hyperintensity in bilateral medial temporal lobes ([Fig. 1]). Lumbar puncture revealed an elevated white blood cell count (10/µL) with mildly raised protein and normal sugar levels (72 mg/dL). Meningoencephalitis panel was negative. CSF was positive for antibodies against the NMDAR (cell-based assay). Ultrasonography of the pelvis was normal. The patient was treated with intravenous (IV) methylprednisolone. She had clinical and electrographic seizure control. Midazolam infusion was tapered after 48 hours. IV methylprednisolone was continued for 5 days. Plan for IV immunoglobulin was made. However, on day 7 of admission, she developed ventilator-associated pneumonia (VAP) and succumbed to VAP by day 15.

Table 1 Clinical timeline of cases

Hospital day	Case 1 (16F)	Case 2 (22M)	Case 3 (36M)	Case 4 (66F)
	Prodrome: Confusion, memory loss, psychiatric symptoms (24 h)	Prodrome: Abnormal behavior, personality changes (2 mo)	Prodrome: Confusion, hallucinations, lethargy (2 d)	Prodrome: Fever (2 d)
Day 0 (Admission)	Presentation: GTCS → RSE Management: Intubated, IV BDZ/PHT/VPA EEG: Generalized slowing	Presentation: GTCS → persistent coma Management: IV BDZ/LEV EEG: Generalized slowing (NCSE suspected) Autonomic dysfunction noted	Presentation: Multiple GTCS → RSE Management: IV BDZ/PHT EEG: GPDs → Electrographic SE	Presentation: GTCS → RSE Management: Intubated, IV BDZ/PHT/LEV EEG: Generalized slowing
Day 1	Management: Midazolam infusion started MRI: Temporal lobe hyperintensity Diagnostics: LP performed Clinical: Perioral dyskinesia noted	Management: Midazolam infusion started MRI: Normal Diagnostics: LP performed	Management: Intubated, Midazolam infusion started MRI: Normal Diagnostics: LP performed	Management: Midazolam infusion continued MRI: Normal Diagnostics: LP performed
Day 2	Diagnostics: CSF NMDAR Ab-positive Management: IVMP started	Diagnostics: CSF/Serum NMDAR Ab-positive Management: IVMP started	Diagnostics: CSF/Serum NMDAR Ab-positive Management: IVMP started, Midazolam tapered	Management: Midazolam tapered → Seizure recurrence → Midazolam restarted Diagnostics: CSF/Serum NMDAR Ab-positive
Day 3	Management: Seizure control achieved, Midazolam taper begun	Management: PLEX initiated (Session ⅕)	Management: PLEX initiated (Session ⅕)	Management: IVMP started Diagnostics: Malignancy screen-negative
Day 4	Management: IVMP continued	Management: PLEX Session 2	Management: PLEX Session 2 Clinical: Seizure-free, improving cognition	Management: Midazolam infusion continued
Day 5	Management: IVMP continued, midazolam taper completed	Management: PLEX Session 3 Clinical: Seizure control achieved, Midazolam taper begun	Management: PLEX Session 3	Management: Seizure control achieved, Midazolam taper begun
Day 6	Plan: IVIG planned	Management: PLEX Session 4 Clinical: Marked improvement	Management: PLEX Session 4	Complication: Sepsis with AKI developed
Day 7	Complication: VAP developed	Management: PLEX Session 5	Management: PLEX Session 5, Extubated	Management: Supportive care for sepsis
Day 8–9	Management: VAP management	Clinical: Continued improvement	Clinical: Near-complete cognitive recovery	Clinical: Remains comatose
Day 10	Clinical: Condition deteriorating	–	–	Outcome: Succumbed to sepsis/AKI
Day 15	Outcome: Succumbed to VAP	–	–	–
Follow-up	–	Outcome: Discharged (Day ∼21) FU (3 mo): Seizure-free on LEV, mRS 1	Outcome: Discharged FU (2 mo): Seizure-free on VPA, mRS 0–1	–

Abbreviations: AKI, acute kidney injury; BDZ, benzodiazepine; CSF, cerebrospinal fluid; EEG, electroencephalogram; GDP, generalized periodic discharges; IVIG, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; LEV, levetiracetam; LP, lumbar puncture; mRS, modified Rankin score; NCSC, nonconvulsive status epilepticus; NMDAR, N-methyl-D aspartate receptor; PHT, phenytoin; PLEX, plasma exchange; VAP, ventilator-associated pneumonia; VPA, valproate.

Fig. 1 T2-FLAIR, DWI, and gadolinium-enhanced magnetic resonance images of brain in axial sections demonstrates hyperintense signal in the bilateral medial temporal lobes (A), bilateral insular cortex and cingulate cortex (B), without restricted diffusion, (C) no postcontrast enhancement (D). DWI, diffusion-weighted imaging.

Case 2

A 22-year-old male presented with a sudden onset of GTCS lasting for approximately 30 minutes, even after giving IV lorazepam and phenytoin followed by persistent altered sensorium ([Table 1]). The altered sensorium persisted despite initial treatment with benzodiazepines and levetiracetam. Although convulsions ceased after initial therapy, the patient remained comatose. EEG showed continuous generalized epileptiform discharges ([Supplementary Fig. S1], available in the online version only). He had autonomic dysfunction in the form of tachycardia and fluctuating blood pressure. On retrograde history, it was found that he had a prodromal phase of abnormal behavior, abusive language, and changed personality for the last 2 months; however, his emergency presentation was for SE. MRI brain was unremarkable. CSF analysis showed mildly elevated protein (52 mg/dL) and pleocytosis (18/µL). Meningoencephalitis viral panel was negative. Serum and CSF testing revealed positive antibodies against the NMDAR. The patient was treated with a combination of IV lorazepam, phenytoin, and continuous midazolam infusion. After failing to control seizures, IV methylprednisolone followed by plasmapheresis were initiated. A rapid improvement in seizure control was seen after 48 hours of treatment. Midazolam infusion was tapered over 48 hours. After 3 weeks, the patient was discharged with full recovery from seizures but had mild residual cognitive impairment. At 3-month follow-up, he remained seizure-free on levetiracetam 1,500 mg/d, with a modified Rankin Scale (mRS) score of 1 due to minor short-term memory issues.

Case 3

A 36-year-old male was brought to the hospital after experiencing multiple GTCS, which were preceded by a 2-day history of confusion, visual hallucinations, and progressive lethargy ([Table 1]). The seizures did not respond to initial benzodiazepine therapy and phenytoin infusion. MRI brain studies were normal. EEG revealed frequent generalized periodic discharges (GPDs) of 1 Hz frequency at interval of 2 seconds ([Supplementary Fig. S2], available in the online version only). He was started on IV midazolam infusion with tapering after 48 hours as per protocol. CSF analysis showed a mildly elevated white blood cell count (12/µL) and protein (60 mg/dL). Meningoencephalitis viral panel was negative. NMDAR antibodies were detected in both serum and CSF. The patient was treated with 5 days of IV methylprednisolone followed by 5 sessions of plasmapheresis. After 3 sessions of plasmapheresis, the patient became seizure-free with significant improvement in cognition. He recovered almost fully with only minor deficits in short-term memory. At 2-month follow-up, he was seizure-free on valproate 1,000 mg/day, with an mRS of 0 to 1.

Case 4

A 66-year-old lady presented with 2 days of fever followed by GTCS ([Table 1]). The seizures were refractory to benzodiazepines, phenytoin, and levetiracetam. MRI brain was normal. EEG revealed generalized background slowing. CSF analysis showed elevated white blood cell count (110/µL) protein (47 mg/dL), and sugar (83 mg/dL). Meningoencephalitis viral panel was negative. NMDAR antibodies were detected in both serum and CSF. Patient was put on midazolam infusion with mechanical ventilation. Midazolam infusion was tapered on day 2 with recurrence of clinical seizures. Midazolam infusion was again continued for 48 hours. Five days of methylprednisolone was given. Seizures were controlled on day 5 with tapering of midazolam infusion. Malignancy screening with CT chest–abdomen–pelvis was negative. Patient developed sepsis with acute kidney injury and in spite of adequate sepsis management died on day 10 of admission.

Discussion

N-methyl D-aspartate receptor encephalitis (NMDARE) is increasingly recognized as a cause of refractory SE. In autoimmune encephalitis, the body's immune system produces antibodies that attack the brain. Antibodies targeting neuron cell surface proteins, such as the NMDAR (anti-NMDAR), are more common in autoimmune encephalitis and are linked to significant neurological dysfunction.[4]

While NORSE is a recognized presentation of NMDARE, our study provides valuable insights from a low-resource setting. We demonstrate that early immunotherapy decisions can be made based on clinical suspicion, even in the absence of definitive MRI findings. Furthermore, we highlight the heterogeneity in presentation, from a prolonged behavioral prodrome (Case 2) to an acute febrile illness (Case 4), underscoring the need for a high index of suspicion.

All our cases presented with NORSE (GTCS) with history of neuropsychiatric symptoms such as confusion, memory loss, hallucinations, and behavioral changes. These findings are consistent with the hallmark features of anti-NMDARE. In our study, three cases reported prodromal symptoms, which are commonly seen in anti-NMDARE and were also reported by Mahadeen et al and Monti et al.[5] [6] Case 2 exhibited autonomic dysfunction, a feature frequently associated with anti-NMDARE, as highlighted by Kaplan and Probasco[7] ([Table 2]). Notably, no patient exhibited classic movement disorders, indicating the variable phenotype of the disease.

Table 2 Summary of cases reported in literature of NMDA encephalitis presenting as new-onset refractory status epilepticus

Serial number	Age	Prodrome	CSF	MRI	EEG	Outcome
19	31 F	Fever, dyskinesia, restlessness, and psychiatric manifestation. History of operation for ovarian teratoma 10 y ago	Cell: 10/µL Protein: 29 mg/dL	Normal	Generalized slow background activity with low voltage	Recovered fully
25	12 M	2-wk history of recurrent headache with blurred vision	Cell: 136/µL Protein: 115 mg/dL	Normal	Multiple bilateral independent parietal–occipital epileptic discharges	Recovered fully
36	50 M	Acute onset of psychiatric symptoms (confabulations and delirious ideas)	Cell: 16/µL Protein: 105 mg/dL	Normal	Generalized epileptiform discharges	Partially Recovered
48	13y M	None		Normal	Normal	Recovered fully
57	29y M	Behavioral changes, hallucinations, memory deficits	Cell: 12/µL Protein: 25 mg/dL Sugar: 58 mg/dL	Low voltage α and theta activity	Normal	Recovered fully
612	13 F	None	10 lymphocytes, mildly elevated protein (69 mg/dL), normal sugar	Asymmetric hyperintense signal changes in bilateral temporal, basi-frontal, and opercular area	Focal epileptiform discharges	Recovered with subaverage IQ
713	Of 83 patients with anti-NMDAR encephalitis, 24 required intensive care. Out of 24,13 had status epilepticus. In the SE group, 38.5% (5 of 13) of patients developed refractory SE (RSE), and 21.3% (3 of 13) of patients developed super RSE. Outcome: All the patients with SE became seizure-free after the acute phase of disease.
814	29 patients with seizures during acute NMDARE. Twelve (41.4%) patients had SE. No data on refractory status epilepticus. Outcome: One patient developed chronic epilepsy. The remaining patients were seizure-free at the last follow-up (median: 23 mo, range: 2–163 mo).

Abbreviations: CSF, cerebrospinal fluid; EEG, electroencephalogram; MRI, magnetic resonance imaging.

On MRI brain imaging, only one case showed abnormalities, underscoring the variability in imaging findings, as noted by Monti et al and Khan et al.[6] [8] The diagnosis was ultimately confirmed via antibody testing in CSF and serum, with CSF offering higher specificity as per guidelines. All of our cases demonstrated mild pleocytosis with elevated protein in the CSF, similar to findings reported by Mahadeen et al and Alemdar et al.[5] [9]

The rapid improvement in seizure control and cognition after immunotherapy in Cases 2 and 3 aligns with the findings of Monti et al and Alemdar et al, who reported favorable outcomes with early immunotherapy.[6] [9] [10] The use of plasmapheresis in Cases 2 and 3 resulted in significant clinical improvement, consistent with the literature.[10] The mortality in Cases 1 and 4 due to VAP and sepsis, respectively, underscores the critical importance of aggressive supportive care, as emphasized by Khan et al.[8] The favorable functional outcomes (mRS 0–1) in the survivors at follow-up reinforce the goal of aggressive treatment.

The association between NMDARE and NORSE can make diagnosis challenging. In these four cases, the patients presented with seizures as the dominant feature. As routine diagnostic tools are often nonspecific, the definitive diagnosis relies on identifying specific autoantibodies in suspected patients.[11] Our experience, along with other series like Panda et al,[12] confirms that a high clinical suspicion is paramount for early recognition and treatment.

Conclusion

These cases highlight the importance of considering NMDARE as a differential diagnosis of NORSE, especially when seizures are refractory to standard treatment and accompanied by unexplained neuropsychiatric symptoms. A high clinical suspicion helps in early recognition and aggressive treatment, which is crucial for a better outcome in these patients. The heterogeneity in presentation and the potential for good outcomes with immunotherapy, even in resource-limited settings, are key takeaways.

Limitations

The small sample size is a limitation. PET-CT for comprehensive malignancy screening could not be performed due to logistical constraints. Extended long-term follow-up data would be valuable. Studies including a larger number of cases are needed to further support these findings.

Conflict of Interest

None declared.

Ethics Approval and Consent to Participate

Consent taken by the patients.

Authors' Contributions

Abhay Ranjan: Concept, Literature overview and discussion; Amitabh Kumar: Data collection, Literature overview; Neetu Sinha: Data collection, interpretation of radiological data, and discussion; Ashok Kumar: Literature overview and discussion.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Publication History

Article published online:
19 February 2026