Bartolomé Bejarano

Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS

Objectives: To assess the association between the thickness of the retinal nerve fiber layer (RNFL), assessed by optical coherence tomography (OCT), retinal periphlebitis (RP), and multiple sclerosis (MS) disease activity. Methods: We studied a prospective cohort of 61 patients and 29 matched controls for 2 years, performing a neurologic assessment every 3 months and an ophthalmologic evaluation, including OCT scans, every 6 months. Baseline MRI studies were also carried out from which brain volume and lesion load were assessed. Results: We found that the RNFL thickness in patients with MS was thinner than in controls, particularly in the temporal quadrant (p = 0.004). Although RNFL atrophy was greater in patients who also had optic neuritis (p = 0.002), it also augmented in MS patients who did not have optic neuritis compared with controls (p = 0.014). RNFL atrophy was correlated with greater disability (r = −0.348, p = 0.001) and longer disease duration (r = −0.301, p = 0.003). Furthermore, baseline temporal quadrant RNFL atrophy was associated with the presence of new relapses and changes in the Expanded Disability Status Scale by the end of the study (p < 0.05 in all cases). Indeed, RNFL thickness was correlated with white matter volume (r = 0.291, p = 0.005) and gray matter volume (r = 0.239, p = 0.021). The presence of RP was a risk factor for having new relapses in the next 2 years (odds ratio = 1.52, p = 0.02), and patients with RP had larger gadolinium-enhancing lesions volume (p = 0.003). Conclusion: Retinal nerve fiber layer atrophy and the presence of retinal periphlebitis are associated with disease activity, suggesting that retinal evaluation can be used as biomarkers of multiple sclerosis activity.

Fatigue in multiple sclerosis is associated with the disruption of frontal and parietal pathways

Background Fatigue is one of the most frequent and disturbing symptoms in multiple sclerosis (MS), directly affecting the patient’s quality of life. However, many questions remain unclear regarding the anatomic brain correlate of MS-related fatigue. Objective To assess the relationship between fatigue and white matter lesion location and gray matter atrophy. Methods In this study, 60 patients with MS were evaluated with the Modified Fatigue Impact Scale and magnetic resonance imaging. Location of white matter lesion was analyzed using a voxel-by-voxel lesion probability mapping approach and gray matter atrophy degree and location using an optimized voxel-based morphometry method. Results We found a correlation between lesion load and fatigue score (T2 lesion load: r = 0.415, P = 0.001; T1 lesion load r = 0.328, P = 0.011). Moreover, fatigue correlated with lesions in the right parietotemporal (periatrial area, juxtaventricular white matter deep in the parietal lobe and callosal forceps) and left frontal (middle-anterior corpus callosum, anterior cingulum and centrum semiovale of the superior and middle frontal gyri) white matter regions (P < 0.001 in all cases). Finally, fatigue score significantly correlated with gray matter atrophy in frontal regions, specifically, the left superior frontal gyrus and bilateral middle frontal gyri (P < 0.001 in all cases). Conclusion Our results suggest that the symptom of fatigue is associated with a disruption of brain networks involved in cognitive/attentional processes.

Retinal nerve fiber layer atrophy is associated with physical and cognitive disability in multiple sclerosis

Background Studying axonal loss in the retina is a promising biomarker for multiple sclerosis (MS). Our aim was to compare optical coherence tomography (OCT) and Heidelberg retinal tomography (HRT) techniques to measure the thickness of the retinal nerve fiber layer (RNFL) in patients with MS, and to explore the relationship between changes in the RNFL thickness with physical and cognitive disability. We studied 52 patients with MS and 18 proportionally matched controls by performing neurological examination, neuropsychological evaluation using the Brief Repetitive Battery-Neuropsychology and RNFL thickness measurement using OCT and HRT. Results We found that both OCT and HRT could define a reduction in the thickness of the RNFL in patients with MS compared with controls, although both measurements were weakly correlated, suggesting that they might measure different aspects of the tissue changes in MS. The degree of RNFL atrophy was correlated with cognitive disability, mainly with the symbol digit modality test (r = 0.754, P < 0.001). Moreover, temporal quadrant RNFL atrophy measured with OCT was associated with physical disability. Conclusion In summary, both OCT and HRT are able to detect thinning of the RNFL, but OCT seems to be the most sensitive technique to identify changes associated with MS evolution.

Prognostic value of residual fluorescent tissue in glioblastoma patients after gross total resection in 5-aminolevulinic Acid-guided surgery.

BACKGROUND There is evidence in the literature supporting that fluorescent tissue signal in fluorescence-guided surgery extends farther than tissue highlighted in gadolinium in T1 sequence magnetic resonance imaging (MRI), which is the standard to quantify the extent of resection. OBJECTIVE To study whether the presence of residual fluorescent tissue after surgery carries a different prognosis for glioblastoma (GBM) cases with complete resection confirmed by MRI. METHODS A retrospective review in our center found 118 consecutive patients with high-grade gliomas operated on with the use of fluorescence-guided surgery with 5-aminolevulinic acid. Within that series, the 52 patients with newly diagnosed GBM and complete resection of enhancing tumor (CRET) in early MRI were selected for analysis. We studied the influence of residual fluorescence in the surgical field on overall survival and neurological complication rate. Multivariate analysis included potential relevant factors: age, Karnofsky Performance Scale, O-methylguanine methyltransferase methylation promoter status, tumor eloquent location, preoperative tumor volume, and adjuvant therapy. RESULTS The median overall survival was 27.0 months (confidence interval = 22.4-31.6) in patients with nonresidual fluorescence (n = 25) and 17.5 months (confidence interval = 12.5-22.5) for the group with residual fluorescence (n = 27) (P = .015). The influence of residual fluorescence was maintained in the multivariate analysis with all covariables, hazard ratio = 2.5 (P = .041). The neurological complication rate was 18.5% in patients with nonresidual fluorescence and 8% for the group with residual fluorescence (P = .267). CONCLUSION GBM patients with CRET in early MRI and no fluorescent residual tissue had longer overall survival than patients with CRET and residual fluorescent tissue.

Contribution of white matter lesions to gray matter atrophy in multiple sclerosis: evidence from voxel-based analysis of T1 lesions in the visual pathway.

BACKGROUND The biological basis of gray matter (GM) atrophy in multiple sclerosis is not well understood, but GM damage seems to be the most critical factor leading to permanent disability. OBJECTIVE To assess to what extent white matter (WM) lesions contribute to regional GM atrophy in multiple sclerosis. DESIGN Because optic pathway GM atrophy and optic radiation lesions, rather than being related to each other, could be independent results of the disease, we applied a nonaprioristic WM method to analyze the interrelationships of both phenomena. On a voxel-by-voxel basis, we correlated T1 magnetic resonance imaging-derived lesion probability maps of the entire brain with atrophy of the lateral geniculate nuclei and calcarine/pericalcarine cortices. SETTING Multiple sclerosis center, University of Navarra, Pamplona, Spain. PATIENTS Sixty-one patients with multiple sclerosis. MAIN OUTCOME MEASURE Mapping of WM regions contributing to GM atrophy in the optic pathway. RESULTS Patients with multiple sclerosis had lateral geniculate nucleus atrophy, which correlated with the presence of lesions specifically in the optic radiations but not in the rest of the brain. Optic pathway lesions explained up to 28% of the change of variance in lateral geniculate nucleus atrophy. Patients also had occipital cortex atrophy, which did not correlate with lesions in the optic radiations or any other WM region. CONCLUSIONS Focal WM damage is associated with upstream GM atrophy, suggesting that retrograde damage of the perikarya from axonal injury in multiple sclerosis plaques is one of the significant factors in the genesis of GM atrophy, although other neurodegenerative processes are probably at work as well.

Fractal dimension and white matter changes in multiple sclerosis

The brain white matter (WM) in multiple sclerosis (MS) suffers visible and non-visible (normal-appearing WM (NAWM)) changes in conventional magnetic resonance (MR) images. The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of a complex object. Our aim was to assess the usefulness of FD analysis in the measurement of WM abnormalities in conventional MR images in patients with MS, particularly to detect NAWM changes. First, we took on a voxel-based morphometry approach optimized for MS to obtain the segmented brain. Then, the FD of the whole grey-white matter interface (WM border) and skeletonized WM was calculated in patients with MS and healthy controls. To assess the FD of the NAWM, we focused our analysis on single sections without lesions at the centrum semiovale level. We found that patients with MS had a significant decrease in the FD of the entire brain WM compared with healthy controls. Such a decrease of the FD was detected not only on MR image sections with MS lesions but also on single sections with NAWM. Taken together, the results showed that FD identifies changes in the brain of patients with MS, including in NAWM, even at an early phase of the disease. Thus, FD might become a useful marker of diffuse damage of the central nervous system in MS.

Mapping the brain pathways of declarative verbal memory: Evidence from white matter lesions in the living human brain.

Understanding the contribution of the brain white matter pathways to declarative verbal memory processes has been hindered by the lack of an adequate model in humans. An attractive and underexplored approach to study white matter region functionality in the living human brain is through the use of non-aprioristic models which specifically search disrupted white matter pathways. For this purpose, we employed voxel-based lesion-function mapping to correlate white matter lesions on the magnetic resonance images of 46 multiple sclerosis patients with their performance on declarative verbal memory storage and retrieval. White matter correlating with storage was in the temporal lobe-particularly lateral to the hippocampus and in the anterior temporal stem-, in the thalamic region and in the anterior limb of the internal capsule, all on the left hemisphere, and also in the right anterior temporal stem. The same volumes were relevant for retrieval, but to them were added temporo-parieto-frontal paramedian bundles, particularly the cingulum and the fronto-occipital fasciculus. These 3D maps indicate the white matter regions most critically involved in declarative verbal memory in humans.

Fractal dimension analysis of grey matter in multiple sclerosis

The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of a complex object. Among other applications, FD has been used to identify abnormalities of the human brain in conventional magnetic resonance imaging (MRI), including white matter abnormalities in patients with Multiple Sclerosis (MS). Extensive grey matter (GM) pathology has been recently identified in MS and it appears to be a key factor in long-term disability. The aim of the present work was to assess whether FD measurement of GM in T1 MRI sequences can identify GM abnormalities in patients with MS in the early phase of the disease. A voxel-based morphometry approach optimized for MS was used to obtain the segmented brain, where we later calculated the three-dimensional FD of the GM in MS patients and healthy controls. We found that patients with MS had a significant increase in the FD of the GM compared to controls. Such differences were present even in patients with short disease durations, including patients with first attacks of MS. In addition, the FD of the GM correlated with T1 and T2 lesion load, but not with GM atrophy or disability. The FD abnormalities of the GM here detected differed from the previously published FD of the white matter in MS, suggesting that different pathological processes were taking place in each structure. These results indicate that GM morphology is abnormal in patients with MS and that this alteration appears early in the course of the disease.

The semantic organization of the animal category: evidence from semantic verbal fluency and network theory

Semantic memory is the subsystem of human memory that stores knowledge of concepts or meanings, as opposed to life-specific experiences. How humans organize semantic information remains poorly understood. In an effort to better understand this issue, we conducted a verbal fluency experiment on 200 participants with the aim of inferring and representing the conceptual storage structure of the natural category of animals as a network. This was done by formulating a statistical framework for co-occurring concepts that aims to infer significant concept–concept associations and represent them as a graph. The resulting network was analyzed and enriched by means of a missing links recovery criterion based on modularity. Both network models were compared to a thresholded co-occurrence approach. They were evaluated using a random subset of verbal fluency tests and comparing the network outcomes (linked pairs are clustering transitions and disconnected pairs are switching transitions) to the outcomes of two expert human raters. Results show that the network models proposed in this study overcome a thresholded co-occurrence approach, and their outcomes are in high agreement with human evaluations. Finally, the interplay between conceptual structure and retrieval mechanisms is discussed.

Memory decline evolves independently of disease activity in MS

Background The natural history of cognitive impairment in multiple sclerosis (MS) and its relationship with disease activity is not well known. In this study, we evaluate a prospective cohort of 44 MS patients who were followed every 3 months for 2 years. Cognitive evaluation was done at baseline and by the end of the study using the Brief Repeatable Battery-Neuropsychology. Clinical evaluation included assessment of new relapses and changes in disability (Extended Disability Status Scale (EDSS)) confirmed at 6 months. Results We found that verbal memory performance deteriorates after 2 years in patients with MS. These changes were observed in stable and active patients both in terms of relapses and disability progression, even at the beginning of the disease, and in patients with or without cognitive impairment at study entry. Attention and executive functions measured with the symbol digit modality test (SDMT) declined after 2 years in patients with confirmed disability progression. Furthermore, SDMT performance correlated with the EDSS change. Conclusions Our findings indicate that verbal memory steadily declines in patients with MS from the beginning of the disease and independently of other parameters of disease activity.