Superficial white matter damage in anti-NMDA receptor encephalitis

Abstract

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.

Figure 1. Whole brain superficial white matter mean diffusivity in patients with anti-NMDAR encephalitis and healthy controls

* Indicates significant difference between groups. There was a significant difference between controls and non-recovered patients (p < 0.001) but no significant difference between controls and recovered patients (p>0.05). Box plots show the average superficial white matter mean diffusivity value for each group. Mean diffusivity units: 10⁻³mm²/s.

Figure 2. Superficial white matter damage in non-recovered patients with anti-NMDAR encephalitis

Probability maps show effects of NMDAR encephalitis on the superficial white matter (group difference between non-recovered patients and controls): Mean diffusivity controlling for age and gender was mapped at high-spatial resolution at thousands of homologous locations within the superficial white matter. Vertex-based mapping was carried out only in lobar regions where there was a significant difference between non-recovered patients and controls. The direction of effects is indicated by the color bar: purple/red/yellow colors indicate increased diffusivity and cyan/green/blue indicates reduced diffusivity in in non-recovered patients relative to healthy controls.

Figure 3. Mean diffusivity percentage difference between non-recovered patients with anti-NMDAR encephalitis and healthy controls

Vertex based percentage difference maps show the difference between non-recovered patients and controls. Heat map color bar indicates percentage difference between the two groups at each vertex point.

Figure 4. Correlation between superficial white matter damage and cognitive deficits in patients with anti-NMDAR encephalitis

All scatter plots reflect significant correlations between the cognitive domain and whole brain superficial white matter mean diffusivity. Vertex-based mapping was carried out only in lobar regions where there was a significant correlation between the cognitive domains in question (see Table 3). For verbal memory, visuospatial memory and working memory, higher scores indicate better performance; for attention, higher scores indicate worse performance; for mRS, higher scores indicate higher disease severity. In the vertex-based correlation maps, the direction of effects is indicated by the color bar: purple/red/yellow colors indicate higher diffusivity with worse performance and cyan/green/blue indicates higher diffusivity with a better performance. Correlations included all patients (Recovered and Non-recovered).