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Secondary post-geniculate involvement in Leber's hereditary optic neuropathy.
Leber's hereditary optic neuropathy (LHON) is characterized by retinal ganglion cell (RGC) degeneration with the preferential involvement of those forming the papillomacular bundle. The optic nerve is considered the main pathological target for LHON. Our aim was to investigate the possible involvement of the post-geniculate visual pathway in LHON patients. We used diffusion-weighted imaging for in vivo evaluation. Mean diffusivity maps from 22 LHON visually impaired, 11 unaffected LHON mutation carriers and 22 healthy subjects were generated and compared at level of optic radiation (OR). Prefrontal and cerebellar white matter were also analyzed as internal controls. Furthermore, we studied the optic nerve and the lateral geniculate nucleus (LGN) in post-mortem specimens obtained from a severe case of LHON compared to an age-matched control. Mean diffusivity values of affected patients were higher than unaffected mutation carriers (P<0.05) and healthy subjects (P<0.01) in OR and not in the other brain regions. Increased OR diffusivity was associated with both disease duration (B = 0.002; P<0.05) and lack of recovery of visual acuity (B = 0.060; P<0.01). Post-mortem investigation detected atrophy (41.9% decrease of neuron soma size in the magnocellular layers and 44.7% decrease in the parvocellular layers) and, to a lesser extent, degeneration (28.5% decrease of neuron density in the magnocellular layers and 28.7% decrease in the parvocellular layers) in the LHON LGN associated with extremely severe axonal loss (99%) in the optic nerve. The post-geniculate involvement in LHON patients is a downstream post-synaptic secondary phenomenon, reflecting de-afferentation rather than a primary neurodegeneration due to mitochondrial dysfunction of LGN neurons
Top: neuron soma size by layer type for LHON and control LGN.
<p>The ratio of the magnocellular to parvocellular layers for the two LGN is similar suggesting that the atrophy seen in the LHON case was consistent across all layers. Middle: average cell density of the magnocellular and parvocellular layers for both the LHON and control LGNs. LHON LGN exhibits a decrease in neuron density consistent across both cell layer types. Bottom: axonal counts for LHON and control left optic nerve.</p
MD values of optic radiation, prefrontal white matter and cerebellar white matter in LHON patients, LHON healthy carriers and controls with group comparison results (first two sections).
<p>The bottom of the table shows the results of GLM analysis used to evaluate the effect of genetic, clinical and demographic data on optic radiation MD values in LHON patients.</p>*<p> = mean of left and right MD values.</p>#<p> = corrected for multiple comparisons.</p><p>Values are reported as mean and standard deviation.</p><p>MD: mean diffusivity; WM: white matter; n.s.: not significant; GLM: general linear model.</p
Segmentation of ROIs including prefrontal white matter (A), cerebellar white matter (B) and optic radiation (C) on axial T2 images.
<p>D: 3D reconstruction of optic radiation ROIs on a registered T1 volumetric image. E: Box-plot of MD values of optic radiations in controls, LHON healthy carriers and LHON patients. (Each box shows the median, quartiles, extreme values; * = P<0.01).</p
Top panel: optic nerves in cross-section and stained by p-Phenylenediamine for control and LHON patient (25x magnification).
<p>In the LHON patient only a small patch of fibers remains (arrow) in the super-nasal quadrant. Bottom panel: lateral geniculate nuclei (LGN) of control and LHON patients with all magnocellular (1 and 2) and parvocellular (3–6) layers identified (25x magnification). Insets represent samples of each zone at 200x magnification.</p