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Research paper
Superficial white matter damage in anti-NMDA receptor encephalitis
  1. Owen Robert Phillips1,
  2. Shantanu H Joshi2,
  3. Katherine L Narr2,
  4. David W Shattuck2,
  5. Manpreet Singh1,
  6. Margherita Di Paola3,4,
  7. Christoph J Ploner5,
  8. Harald Prüss5,6,
  9. Friedemann Paul5,7,8,9,
  10. Carsten Finke5,10
  1. 1 Department of Psychiatry, Division of Child and Adolescent Psychiatry, Stanford University School of Medicine, Stanford, California, USA
  2. 2 Department of Neurology, Ahmanson Lovelace Brain Mapping Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  3. 3 Department of Mental Health, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
  4. 4 Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy
  5. 5 Department of Neurology, Charité University Medicine Berlin, Berlin, Germany
  6. 6 German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
  7. 7 NeuroCure Clinical Research Center, Berlin, Germany
  8. 8 Experimental and Clinical Research Center, Charité Universitätsmedizin, Berlin, Germany
  9. 9 Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
  10. 10 Berlin School of Mind and Brain, Humboldt-Universität zu Berlin, Berlin, Germany
  1. Correspondence to Professor Carsten Finke, Department of Neurology, Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; carsten.finke{at} and Professor Friedemann Paul, Department of Neurology Charité University Medicine Berlin, Berlin, Germany; friedemann.paul{at}


Background Clinical brain MRI is normal in the majority of patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, extensive deep white matter damage wasrecently identifiedin these patients using diffusion weighted imaging. Here, our aim was to study a particularly vulnerable brain compartment, the late myelinating superficial white matter.

Methods Forty-six patients with anti-NMDAR encephalitis were included. Ten out of these were considered neurologically recovered (modified Rankin scale of zero), while 36 patients were non-recovered. In addition, 30 healthy controls were studied. MRI data were collected from all subjects and superficial white matter mean diffusivity derived from diffusion tensor imaging was compared between groups in whole brain, lobar and vertex-based analyses. Patients underwent comprehensive cognitive testing, and correlation analyses were performed between cognitive performance and superficial white matter integrity.

Results Non-recovered patients showed widespread superficial white matter damage in comparison to recovered patients and healthy controls. Vertex-based analyses revealed that damage predominated in frontal and temporal lobes. In contrast, the superficial white matter was intact in recovered patients. Importantly, persistent cognitive impairments in working memory, verbal memory, visuospatial memory and attention significantly correlated with damage of the superficial white matter in patients.

Conclusions Anti-NMDAR encephalitis is associated with extensive superficial white matter damage in patients with incomplete recovery. The strong association with impairment in several cognitive domains highlights the clinical relevance of white matter damage in this disorder and warrants investigations of the underlying pathophysiological mechanisms.

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  • Contributors ORP and CF: wrote the manuscript and designed the analysis. SHJ, DWS and ORP: contributed to analysis methods development. CF, CJP, HP and FP: contributed to the acquisition, analysis and interpretation of data. All authors: contributed to the writing and editing of the manuscript and provided important intellectual content.

  • Funding This work was supported in part by the NIH National Institute of Neurological Disorders and Stroke award R01 NS074980 (DWS). FP is supported by Deutsche Forschungsgemeinschaft (DFG Exc 257).

  • Disclaimer The content is solely the responsibility of the authors and not an official position of the institution or funder and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the Ethics Committee of the Charité - Universitätsmedizin Berlin.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice Since this paper was first published online, the author name Paul Friedmann has been updated to read Friedmann Paul.