Cortical Encephalitis with Overlapping Anti-N-Methyl-D-Aspartate Receptor and Anti-Myelin Oligodendrocyte Glycoprotein Antibodies: Report of Two Cases

Cortical Encephalitis with Overlapping Anti-N-Methyl-D-Aspartate Receptor and Anti-Myelin Oligodendrocyte Glycoprotein Antibodies: Report of Two Cases

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (NMDARE) is a potentially lethal autoimmune disease characterized by a spectrum of neurological symptoms, including psychosis, memory deficits, dyskinesia, involuntary movements, decreased level of consciousness, and central hypoventilation. The clinical presentation of NMDARE can be heterogeneous, ranging from complete to mild or partial forms, with some cases being asymptomatic. Anti-myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) is recognized as a diagnostic biomarker for a distinct spectrum of central nervous system (CNS) inflammatory demyelinating diseases (IDDs). This report describes two cases of cortical encephalitis with overlapping NMDAR-Ab and MOG-Ab, highlighting the complexity of diagnosing and managing such conditions.

The first case involved a 32-year-old Chinese man who presented with acute headache, fever, and seizure. He had no prior medical history or hereditary diseases. Brain magnetic resonance imaging (MRI) at admission revealed high-intensity lesions in the right temporal, parietal, and occipital cortex without enhancement. Cerebrospinal fluid (CSF) analysis showed elevated pressure (250 mmH2O), leukocytosis (142 cells/mm3), and increased protein levels (66.9 mg/dL). Oligonucleotide bands were negative, and CSF was positive for immunoglobulin (Ig)G but not IgM to rubella virus, herpes simplex types I and II, cytomegalovirus, and Epstein-Barr virus. Electroencephalograms (EEG) demonstrated slow and sharp wave activity in the right hemisphere. Initial treatment with intravenous acyclovir and dexamethasone improved CSF pressure, leukocyte count, and protein levels. However, symptoms recurred three weeks later. Further testing for autoimmune encephalitis (AIE), demyelinating diseases, and paraneoplastic neurologic syndrome was negative. Treatment with methylprednisolone (80 mg/d for 5 days) normalized CSF parameters and MRI findings.

Six months later, the patient returned with right hemianesthesia and left upper limb numbness. MRI revealed new lesions in the left medulla oblongata and right temporal lobe. Follow-up MRI showed lesion enlargement and new enhanced lesions. Despite negative serum/CSF Abs, the patient was treated with intravenous immunoglobulin G (IVIG) (0.4 g/kg daily for 5 days) for three consecutive months combined with azathioprine. After a stable phase of six months, he developed orbital pain and decreased visual acuity in the left eye. New enhanced lesions in the brainstem and left optic nerve were detected. Re-testing revealed positive serum/CSF MOG-Ab (1:320/1:32) and NMDAR-Ab (negative/1:1). Treatment with IVIG and methylprednisolone via retrobulbar injection resulted in incomplete visual recovery over one year.

The second case involved a 50-year-old Chinese man with a history of headache, fever, and seizures. He had been diagnosed with viral encephalitis 15 years prior, but clinical data were unavailable. His seizures were well-controlled until February 2011, when he experienced a recurrence. Fluid attenuation inversion recovery (FLAIR) imaging revealed high-intensity lesions in the left insula and parietal cortex. EEG showed multiple sharp and slow waves in the left central and parietal regions. Neurosurgical consultation considered gray matter heterotopia, and he underwent a parietal lobotomy. During hospitalization, he experienced paroxysmal visual and auditory hallucinations, which resolved with carbamazepine and levetiracetam.

In October 2017, the patient was admitted to the CNS demyelinating disease registry due to progressive cognitive decline, somnolence, visual hallucinations, and abnormal behavior. MRI revealed multiple lesions with mild enhancement. Serum/CSF testing was positive for NMDAR-Ab (1:100/1:32) and MOG-Ab (1:32/1:10). CSF was also positive for IgG to cytomegalovirus and Epstein-Barr virus. Initial treatment with pulse intravenous methylprednisolone (1000 mg/d for 5 days) and IVIG (0.4 g/kg daily for 5 days) improved symptoms. Maintenance therapy included oral prednisone, azathioprine, olanzapine, oxcarbazepine, and levetiracetam, with no adverse events.

The clinical courses of the two patients were notably different. Patient 1 experienced two demyelinating attacks without typical NMDARE symptoms, while Patient 2 had a 15-year history of seizures before presenting with NMDARE-like symptoms in 2017. The earlier attacks in Patient 2, including seizures, paroxysmal visual and auditory hallucinations, and cortical lesions, suggested a possible AIE rather than gray matter heterotopia. However, the ability to detect AIE-associated Abs via cell-based assays was not available until 2014 in Shanghai.

The most prominent symptoms in both patients appeared to correlate with the titers of NMDAR-Abs and MOG-Abs. Patient 1, who had a higher CSF MOG-Ab titer than NMDAR-Ab, experienced demyelinating events. The low NMDAR-Ab titer may have led to atypical symptoms, or immune responses against myelin may have simultaneously involved NMDAR. In contrast, Patient 2 had higher NMDAR-Ab titers, with no typical demyelination events, and the demyelinating lesion in the basal ganglia was only detected on MRI.

The association between NMDARE and viral infections has been reported, with NMDAR-Abs detected in approximately 30% of polymerase chain reaction-positive herpes simplex encephalitis patients without tumors. This suggests that viral infections may trigger CNS injury or autoimmunity by inducing NMDAR-Ab production. Further studies are needed to better understand the pathogenesis of this disorder.

NMDARE has been reported to precede or follow demyelinating episodes, while MOG-IDDs can be associated with AIE Ab-negative cortical encephalitis. The co-occurrence of MOG-IDDs and NMDARE adds complexity to the diagnosis and management of these conditions. Differentiating the contributions of NMDAR-Ab and MOG-Ab is challenging, although oligodendrocytes express NMDAR.

The cases described here underscore the importance of accurate recognition and prompt testing for NMDAR-Ab and MOG-Ab in patients with overlapping symptoms of cortical encephalitis and demyelination. Clear description of atypical cases is crucial for improving diagnostic accuracy and guiding appropriate treatment strategies.

doi.org/10.1097/CM9.0000000000000894

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