The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease

Myotonic dystrophy types 1 and 2 are progressive multisystemic disorders with potential brain involvement. We compared 22 myotonic dystrophy type 1 and 22 myotonic dystrophy type 2 clinically and neuropsychologically well-characterized patients and a corresponding healthy control group using structural brain magnetic resonance imaging at 3 T (T1/T2/diffusion-weighted). Voxel-based morphometry and diffusion tensor imaging with tract-based spatial statistics were applied for voxel-wise analysis of cerebral grey and white matter affection (Pcorrected < 0.05). We further examined the association of structural brain changes with clinical and neuropsychological data. White matter lesions rated visually were more prevalent and severe in myotonic dystrophy type 1 compared with controls, with frontal white matter most prominently affected in both disorders, and temporal lesions restricted to myotonic dystrophy type 1. Voxel-based morphometry analyses demonstrated extensive white matter involvement in all cerebral lobes, brainstem and corpus callosum in myotonic dystrophy types 1 and 2, while grey matter decrease (cortical areas, thalamus, putamen) was restricted to myotonic dystrophy type 1. Accordingly, we found more prominent white matter affection in myotonic dystrophy type 1 than myotonic dystrophy type 2 by diffusion tensor imaging. Association fibres throughout the whole brain, limbic system fibre tracts, the callosal body and projection fibres (e.g. internal/external capsules) were affected in myotonic dystrophy types 1 and 2. Central motor pathways were exclusively impaired in myotonic dystrophy type 1. We found mild executive and attentional deficits in our patients when neuropsychological tests were corrected for manual motor dysfunctioning. Regression analyses revealed associations of white matter affection with several clinical parameters in both disease entities, but not with neuropsychological performance. We showed that depressed mood and fatigue were more prominent in patients with myotonic dystrophy type 1 with less white matter affection (early disease stages), contrary to patients with myotonic dystrophy type 2. Thus, depression in myotonic dystrophies might be a reactive adjustment disorder rather than a direct consequence of structural brain damage. Associations of white matter affection with age/disease duration as well as patterns of cerebral water diffusion parameters pointed towards an ongoing process of myelin destruction and/or axonal loss in our cross-sectional study design. Our data suggest that both myotonic dystrophy types 1 and 2 are serious white matter diseases with prominent callosal body and limbic system affection. White matter changes dominated the extent of grey matter changes, which might argue against Wallerian degeneration as the major cause of white matter affection in myotonic dystrophies

Concomitant Fractional Anisotropy and Volumetric Abnormalities in Temporal Lobe Epilepsy: Cross-Sectional Evidence for Progressive Neurologic Injury

BACKGROUND: In patients with temporal lobe epilepsy and associated hippocampal sclerosis (TLEhs) there are brain abnormalities extending beyond the presumed epileptogenic zone as revealed separately in conventional magnetic resonance imaging (MRI) and MR diffusion tensor imaging (DTI) studies. However, little is known about the relation between macroscopic atrophy (revealed by volumetric MRI) and microstructural degeneration (inferred by DTI). METHODOLOGY/PRINCIPAL FINDINGS: For 62 patients with unilateral TLEhs and 68 healthy controls, we determined volumes and mean fractional anisotropy (FA) of ipsilateral and contralateral brain structures from T1-weighted and DTI data, respectively. We report significant volume atrophy and FA alterations of temporal lobe, subcortical and callosal regions, which were more diffuse and bilateral in patients with left TLEhs relative to right TLEhs. We observed significant relationships between volume loss and mean FA, particularly of the thalamus and putamen bilaterally. When corrected for age, duration of epilepsy was significantly correlated with FA loss of an anatomically plausible route - including ipsilateral parahippocampal gyrus and temporal lobe white matter, the thalamus bilaterally, and posterior regions of the corpus callosum that contain temporal lobe fibres - that may be suggestive of progressive brain degeneration in response to recurrent seizures. CONCLUSIONS/SIGNIFICANCE: Chronic TLEhs is associated with interrelated DTI-derived and volume-derived brain degenerative abnormalities that are influenced by the duration of the disorder and the side of seizure onset. This work confirms previously contradictory findings by employing multi-modal imaging techniques in parallel in a large sample of patients

Significant correlation between volume (mm³) expansion of the ipsilateral temporal horn of the lateral ventricle and duration of epilepsy in patients with unilateral TLEhs, corrected for age.

<p>Significant correlation between volume (mm³) expansion of the ipsilateral temporal horn of the lateral ventricle and duration of epilepsy in patients with unilateral TLEhs, corrected for age.</p

Selected significant correlations between regional mean FA (×1000) and duration of epilepsy (years), corrected for age.

<p>Unilateral structures are illustrated ipsilateral or contralateral to the medial temporal epileptogenic focus (yellow/white star). A. Ipsilateral temporal lobe white matter. B. Ipsilateral thalamus. C. Brainstem. D. Whole corpus callosum.</p

Summary of demographic and clinical information of participants.

<p>Abbreviations: n, no; SD, standard deviation; uk, unknown; y, yes.</p

FA and volume alterations of the hippocampus and thalamus in patients with unilateral TLEhs relative to controls.

<p>The top row indicates mean (with 95% CI) FA (left) and volume (right) of the left and right hippocampus across controls (C), patients with left TLEhs (L) and patients with right TLEhs (R). The bottom row is the same for the thalamus. Structures are colour-coded: light blue for FA, yellow for hippocampal volume (as per standard FreeSurfer colour classification) and dark green for thalamic volume (as per standard FreeSurfer colour classification). FA values are the mean for each structure ×1000. Volumes are mm³. LH, left hemisphere. RH, right hemisphere. * = significant at p<0.05 (corrected). ** = significant at p<0.01 (corrected). *** = significant at p>0.001 (corrected).</p

FA differences between controls (n = 68), patients with left MTS (n = 41) and patients with right MTS (n = 21).

<p>Note the more bilateral distribution of FA alterations in patients with left MTS. When the sample of patients with left MTS was randomly reduced to n = 21, all differences observed in the full sample remained highly significant with the exception of the right parahippocampal gyrus (F = 3.15, p = 0.07).</p><p>Significant at *p<0.05, **p<0.01, ***p<0.001, corrected for multiple comparisons.</p><p>Abbreviations: BFL, Bilateral Frontal Lobe White Matter; BIC, Bilateral Internal Capsule; CC, Corpus Callosum; G, Genu; Hipp, hippocampus; L, Left; PHG, parahippocampal gyrus; R, Right; S, Splenium; SD, Standard Deviation; TLWM, Temporal Lobe White Matter; W, Whole.</p

Direct significant correlations between FA and volume in patients with unilateral TLEhs.

<p>(A) Ipsilateral thalamus. (B) Contralateral thalamus. (C) Ipsilateral putamen. (D) Contralateral putamen. Structures are illustrated ipsilateral or contralateral to the medial temporal epileptogenic focus (yellow/white star). FA values are the mean for each structure ×1000.</p

DTI and volumetric ROI approaches.

<p>A. Masks used for calculation of ROI mean FA. Examples shown are hippocampus (i), parahippocampal gyrus (ii), temporal lobe white matter (iii), and thalamus (iv). B. Automated labelling and volume estimation using FreeSurfer in a patient with right TLEhs. A supratentorial axial view (with infratentorial brain removed) is used to emphasize right hippocampal atrophy (red arrow) in this case. Yellow = hippocampus, blue = amygdala, purple = lateral ventricle, green/white = right/left cerebral white matter, pink = cortex. R, right. L, left.</p