Magnetic resonance imaging spectrum of succinate dehydrogenase-related infantile leukoencephalopathy

Abstract

Objective: Succinate dehydrogenase-deficient leukoencephalopathy is a complex II-related mitochondrial disorder for which the clinical phenotype, neuroimaging pattern, and genetic findings have not been comprehensively reviewed.

Methods: Nineteen individuals with succinate dehydrogenase deficiency-related leukoencephalopathy were reviewed for neuroradiological, clinical, and genetic findings as part of institutional review board-approved studies at Children's National Health System (Washington, DC) and VU University Medical Center (Amsterdam, the Netherlands).

Results: All individuals had signal abnormalities in the central corticospinal tracts and spinal cord where imaging was available. Other typical findings were involvement of the cerebral hemispheric white matter with sparing of the U fibers, the corpus callosum with sparing of the outer blades, the basis pontis, middle cerebellar peduncles, and cerebellar white matter, and elevated succinate on magnetic resonance spectroscopy (MRS). The thalamus was involved in most studies, with a predilection for the anterior nucleus, pulvinar, and geniculate bodies. Clinically, infantile onset neurological regression with partial recovery and subsequent stabilization was typical. All individuals had mutations in SDHA, SDHB, or SDHAF1, or proven biochemical defect.

Interpretation: Succinate dehydrogenase deficiency is a rare leukoencephalopathy, for which improved recognition by magnetic resonance imaging (MRI) in combination with advanced sequencing technologies allows noninvasive diagnostic confirmation. The MRI pattern is characterized by cerebral hemispheric white matter abnormalities with sparing of the U fibers, corpus callosum involvement with sparing of the outer blades, and involvement of corticospinal tracts, thalami, and spinal cord. In individuals with infantile regression and this pattern of MRI abnormalities, the differential diagnosis should include succinate dehydrogenase deficiency, in particular if MRS shows elevated succinate.

Figure 1. Special Features of SDH-related Leukoencephalopathy

(1A) Signal abnormalities are seen in the pyramidal tracts in the pons (Image from Individual 1). (1B) The transverse pontine fibers are often affected and in a few cases, the central tegmental tracts (white arrow) (Image from Individual 13). (1C and 1D) Signal abnormalities are seen lateral portions of the middle cerebellar peduncles (Arrows, Images from Individuals 7 and 4, respectively). (1E and 1F) In some cases, a transverse band across the pons is observed with extension into the middle cerebellar peduncles (Images from Individuals 2 and 8, respectively). (1G and 1H) The dorsal portion of the cervical and sometimes also thoracic spinal cord is often affected (Images from Individual 1). The inner and outer blades are spared (white arrow). (1I and 1J) Extensive cerebral hemispheric white matter abnormalities are seen predominantly involving the frontal, parieto-occipital, and posterior temporal regions, sparing the juxtacortical fibers in all lobes (Images from Individuals 8 and 10, respectively). (1K) Diffuse abnormalities involving the juxtacortical, central and periventricular white matter may also occur (Individual 15). (1I) The inner and outer blades are spared (White Arrow), while the rest of the corpus callosum is affected (Individual 8). (1J and 1K) The thalamic nuclei anterior and medial portions of the thalamic nuclei are involved (White Arrow), as well as the medial pulvinar (Arrow Head), or medial and lateral geniculate bodies bilaterally (Black Arrow, Individual 10 (1J) and Individual 15 (1K)). (1L). Single voxel MRS (TE 35 msec) with voxel of interest placed over the mid pontine signal abnormalities. Large metabolic peak at 2.4 ppm represents marked succinate elevation. Macromolecular peak centered at 1.3 ppm is consistent with abnormal lactate.

Figure 2. Evolution of lesions in SDH-related leukoencephalopathy

(A-D) Top Row – Early stage MRI. The abnormal white matter looks swollen, especially the corpus callosum. Myelin micro-vacuolization is suspected in areas of restricted diffusion seen on ADC maps. There is no enhancement. (E-H) Middle Row – Intermediate stage MRI. Tissue necrosis is suspected based on MRI findings with white matter rarefaction seen on FLAIR imaging and small foci of contrast enhancement. Areas of low ADC values continue to be present. (I-L) Bottom Row – Late stage MRI. Atrophy and collapse of the affected white matter is seen, with cysts. ADC values are low and no further contrast enhancement is present. (A,E,I) T₂-weighted imaging from select patients. (B,F,J) FLAIR imaging from select patients. (C,G,K) Diffusion weighted imaging from select patients. (D,H,L) Contrast enhanced images from select patients.