New Insights Into Antibody Overlap Syndromes


If an anti-NMDAR patient has evidence of demyelination on MRI, look for other antibodies that may complicate the picture.

Patients with anti–N-methyl-D-aspartate receptor (anti-NMDAR) associated encephalitis have a now clearly recognized typical clinical phenotype: seizures, psychiatric manifestations, and memory disturbances associated with CNS inflammation on CSF analysis in association with anti-NMDAR antibodies in the CSF. Typically, the MRIs of these patients show some FLAIR abnormalities in limbic gray matter structures or are only subtly abnormal. However, among these patients there are sometimes those with far more prominent white matter abnormalities on MRI. Conversely, sometimes patients with white matter disease who come to the attention of multiple sclerosis specialists have seizures and psychiatric manifestations and a more waxing and waning course.

A recent study by Titulaer and colleagues1 has some interesting insights into this clinical situation. The authors studied their very large cohort of anti-NMDAR syndrome patients (691 patients) and found 23 with prominent white matter features consistent with demyelination; 12 of these 23 patients had discreet and separate episodes of demyelination that were associated either with anti-AQP4 (Aquaporin 4) antibodies or anti-MOG (Myelin Oligodendrocyte Glycoprotein) antibodies. The other 11 patients had simultaneous anti-NMDAR syndrome and demyelination attacks and were also divided between patients with anti-AQP4 and those with anti-MOG antibodies in most cases.

The clinical characteristics of the patients with anti-NMDAR plus demyelination syndromes were distinct from those with solely anti-NMDAR. Patients with the combined syndromes required more intensive immunotherapy than the anti-NMDAR alone patients. This is similar to the situation with anti-AQP4 patients, who also usually require intensive therapy. The combined patients were also far less likely to have ovarian teratomas than the anti-NMDAR alone patients.

The take home here is that clinicians need to be on the lookout for discordance in these populations. If an anti-NMDAR patient has evidence of demyelination on MRI, look for other antibodies that may complicate the picture and be aware that the patient may need higher intensity therapy. Likewise, if a patient with demyelination on MRI has psychosis, dyskinesias, or seizures, consider checking their anti-NMDAR status.

These patients also raise further questions about the potential risk factors for patients to develop multiple autoantibody syndromes simultaneously. It seems likely that there are other common immunologic or genetic features of these patients that remain to be explored.


1. Titulaer MJ, Höftberger R, Iizuka T, et al, Overlapping demyelinating syndromes and anti–N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2014;75:411-428.

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