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Structural and functional neuroimaging features of pediatric multiple sclerosis

PART OF MS Alumni FEATURE
Structural and functional neuroimaging features of pediatric multiple sclerosis
  • Neurology

Maria A.Rocca, MD.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Introduction

Magnetic resonance imaging (MRI) is one of the most important paraclinical tools for the diagnosis of MS and for monitoring disease progression and treatment response. The goals of MRI in MS include: confirmation of an MS diagnosis before a second clinical attack in individuals with an acute demyelinating syndromes (ADS), exclusion of alternative diagnoses, and prediction of outcome. In addition, clinicians caring for patients with MS rely on comparison of serial scans to qualitatively evaluate the rate of new lesion accrual for diagnosis, to inform on treatment decisions, and to monitor disease evolution apparent by formation of confluent lesions and atrophy.

Lesion appearance on conventional MRI sequences

The MRI appearance of childhood MS is typically with multiple WM lesions. In adult patients, brain MS lesions are frequently located asymmetrically in the periventricular and juxtacortical WM regions, the CC and infratentorial areas (with the pons and cerebellum more frequently affected than the medulla and midbrain), and are sometimes characterized by oval or elliptical shapes. In many respects, lesions visualized on MRI in children with MS are similar to those of adults. However, there are also distinctive neuroimaging features in pediatric MS in comparison to adult cases. Conceptually, there are many possible reasons why the MRI appearance of lesions in children with MS may differ from that of adults: 1) the subclinical phase of the disease process is inherently brief in young patients by virtue of their young age, and thus there may be fewer pre-existing lesions notable on MR scans obtained at the time of the first demyelinating event; 2) although the majority of developmental modifications in myelin biochemistry take place during the first 24 months of life, full myelin maturation proceeds in a caudal-rostral pattern until early adulthood, and thus myelin maturity may influence the regional proclivity for MS lesions, particularly in the very young MS patients; 3) the capacity for transmigration of immune cells through the blood-brain barrier and secretion of cytokines may differ between children and adults, leading to differences in the inflammatory nature of lesions in children compared to adults; and 4) children may differ from adults in their innate capacity for myelin repair, leading to fundamental differences in the MRI appearance of lesion evolution.

Lesion distribution and burden

Direct comparison of lesion distribution and volume between pediatric and adult-onset MS cohorts are rare. Ghassemi et al. (1)evaluated lesion characteristics of children with a first attack of demyelination to the lesion distribution and volumes of an adult MS cohort. They obtained quantitative lesion probability maps (LPMs) of pediatric CIS and reported the following findings for those children with brain lesions: (1) total T2 lesion volumes are remarkably similar to those of adults with established MS, suggesting that the capacity for widespread brain involvement exists even at the first clinical presentation in children; (2) supratentorial T2 lesion distribution is similar to that of adult MS, implying that lesion accrual may not require a prolonged period of subclinical disease; and (3) lesion distribution in the infratentorial regions is distinctly different in children than adults, with pontine lesions being particularly prominent in male pediatric patients. The preferential distribution of infratentorial lesions in children with CIS relative to adult MS was confirmed in another study that recruited 41 children.(2) Differences in lesion prevalence and location could reflect immunological differences between children and adults or differences in the state of myelination in the pons relative to supratentorial WM, since, as previously mentioned, myelination proceeds along in a caudorostral gradient.(3) The fact that the pons myelinates faster in male than female individuals(4) was consistent with the observation of preferential involvement of this structure in boys.

            Another work(5) evaluated lesion count, distribution and volume in pediatric and adult MS patients matched for disease duration (time since first attack) in order to explore whether the low risk of early disability in children relates to a lower lesion burden, and to evaluate whether lesion distribution in children is influenced by the potential for greater lesion repair in the context of active, primary, age-expected myelination. In this study there were used advanced image processing techniques to segment tissues in brain images, compute regional lesion load, and generate lesion frequency maps for children and adults with RRMS. Despite their young age, children with MS accrued greater overall volumes of T2 and T1-w lesions than adult RRMS patients. Regional analyses revealed that the infratentorial region was more affected in children than in adults with MS. These findings are in agreement with those of Yeh et al.(6) who reported comparable overall T2w lesion volume between children and adults and a trend towards higher T1w lesion volume in children with RRMS.(6) It was also confirmed that pediatric RRMS patients were more likely than adult-onset MS patients to have infratentorial lesions, potentially implicating a preferential targeting of more mature WM in children. A tendency for large T2 lesions has been reported in pediatric MS,(7) but this might reflect larger lesions, rather than a greater number of discrete lesions.

A higher total T2w lesion count in pediatric compared to adult-onset MS patients was reported by Waubant et al.(2) However, the fact that their two populations were not matched for disease duration limits the validity of their study. In addition to higher total lesion volume in pediatric-onset MS, the accrual of tissue injury differed by brain regions. In the supratentorial region, a smaller fraction of T2–hyperintense lesion was T1-hypointense in the children with MS than in the adults, whereas in the infratentorial region, the T1/T2 lesion volume ratio was similar. This finding raises the intriguing possibility that active primary myelination, as would be expected in the supratentorial regions during childhood and adolescence, might serve to more effectively remyelinate lesions in this region, limiting T1w lesion formation.(5)

A recent study(8)with the aim to characterize the nature and topographical distribution of T2 lesions in patients with pediatric MS (CIS and RRMS)  in comparison with adult patients at similar disease stages demonstrated that the T2 lesion burdens of the whole brain and the supra- and infratentorial compartments, separately, were not significantly different between the two cohorts of pediatric MS patients (CIS and RRMS) as well as between them and the corresponding adult groups. However, the analysis of the regional patterns of lesion frequency revealed a higher occurrence of lesions in the posterior periventricular regions in adult patients with RRMS in comparison with adult CIS and pediatric RRMS patients.

Normal appearing white matter damage

In adult patients with MS, a series of MRI studies has evaluated the contribution of NAWM damage to motor disability and cognitive impairment, using advanced quantitative MRI techniques. However, in pediatric MS patients only a few investigations have addressed this issue.

H-MRS

1H-MRS is similar in technique to MR imaging, but instead of using the signal from water protons to provide structural information, it acquires information from hydrogen nuclei of molecules or metabolites present in tissues, and this metabolic information has pathologic specificity not obtainable from water proton signals.(9) Four major metabolite resonances are revealed in the brain at long echo times (e.g., TE= 144 milliseconds): (1) the methyl resonance of tetramethylamines, especially the choline-containing phospholipids (choline, phosphocholine, glycerophosphocholine, and betaine); (2) methyl resonance of creatine and phosphocreatine; (3) methyl resonance of N-acetyl (NA)-containing compounds, especially N-acetylaspartate (NAA) (4) methyl resonance of lactate as a doublet.(10) At shorter echo times, signals from molecules with short T2 relaxation times can be obtained. These metabolite resonances include amino acids such as γ-aminobutyric acid and glutamate, and sugars such as myoinositol.

The application of 1H-MRS to children with MS has been limited to 3 studies. The first study(11) included 8 individuals with pediatric-onset MS and the findings mimic that seen in patients with adult-onset disease, showing decreased NAA and Cr resonances and increased resonances of choline and myoinositol within lesions relative to healthy age-matched controls. In contrast to observations in adults, 2 studies(11), (12)have shown that the 1H-MR spectra of the NAWM of pediatric patients are not different from WM of healthy controls. Moreover, the second study evaluated the resonance of citrulline in the brains of 27 children with MS compared with 23 control individuals. (13)Citrullination is a posttranslational modification of MBP, the only essential structural proteolipid protein for myelin formation, and increased citrullination of MBP diminishes its ability to organize lipid bilayers, resulting in myelin instability.(14), (15)Increased levels of citrullinated MBP have been shown in brain specimens from MS patients,(16) suggesting that citrullination may predispose the WM to demyelination. The analysis of citrulline resonance in the previous study(13) showed that 44% of children with MS had a citrulline peak compared with only 13% of control individuals who were imaged for headache or syncope, both in the NAWM and T2 hyperintense lesions. This finding conforms with histopathologic evidence of increased citrullinated MBP in the WM of MS patients.(17) The NAA/Cr and choline/Cr ratios were not different between pediatric-onset patients and controls, raising the possibility of better metabolic neuroaxonal recovery in children. However, mean myoinositol/Cr ratio was significantly higher within lesions than NAWM of patients and the WM of controls, suggesting significant glial proliferation, as suggested by other studies. (18)The third study(19)included 7 children with ADEM with the goal of identifying a signature of monophasic ADEM that is distinct from that reported in MS.  The investigators reported a substantial reduction in the myoinositol/Cr ratio in children with ADEM,(19) which contrasts with the increased intralesional myoinositol/Cr ratio reported in patients with MS.

Magnetization transfer MRI

Using gradient-echo or spin-echo sequences with and without an off-resonance saturation pulse, MT MRI allows calculation of an index, the MTR, a reduction in which indicates a diminished capacity of the protons bound to the brain tissue matrix to exchange magnetization with the surrounding free water. As a consequence, this index provides an estimate of the extent of tissue structure disruption.     

Only 3 studies(6), (20), (21)have evaluated microstructural tissue abnormalities in children with MS using MT MRI. A preliminary study evaluated the average MTR and histogram peak height (i.e., the most frequently occurring MTR value) in both the normal-appearing brain tissue and cervical cord of 13 children with MS compared with age- and sex-matched healthy controls. However, no significant differences were found.In a subsequent study of 23 children with MS and 16 age- and sex-matched healthy controls, average MTR and histogram peak height in both the NAWM and GM were similar between patients and controls.(21) In a study comparing 33 adults with pediatric-onset MS with 381 adults with adult-onset disease, MTR values tended to be lower within T2 lesions, NAWM, and GM,(6) suggesting a greater degree of microstructural abnormality in pediatric-onset adult patients than adult-onset patients, perhaps explained by a longer disease duration.

Diffusion tensor MRI

Diffusion imaging is a powerful and sensitive technique used to noninvasively measure restriction of water diffusion in vivo within an image voxel, thereby providing information on the structural organization of the brain and spinal cord, as well as pathologic changes not visualized on conventional MR imaging scans. The principal eigenvector (λ1) represents the diffusion direction of greatest magnitude within the voxel and is parallel to the WM fibers. The secondary (λ2) and tertiary (λ3) eigenvectors are perpendicular to λ1 and transverse to WM fiber tracts. Four diffusion parameters derived from the DT are typically reported in DT imaging studies: (1) mean diffusivity (MD) is the arithmetic average of the 3 diffusivities; (2) fractional anisotropy (FA) is a measure of the eccentricity of the ellipsoidal confidence region(22); (3) parallel (axial) diffusivity (λ|| or AD) is the same as λ1; and (4) transverse (radial) diffusivity (λ⊥or RD) is the average of λ2 and λ3.

One study combined DT MRI and MT MRI in 13 children with RRMS and 14 age-matched controls(23), and showed no abnormalities in the brain normal-appearing brain tissue of these patients using these techniques. A DT MRI study analyzed separately damage to the NAWM and GM and found that, contrary to what happens in adult-onset MS, pediatric RRMS patients do not have GM abnormalities, showing only mild structural abnormalities in the NAWM.(24) In another study, the extent of microscopic damage in the NAWM of pediatric CIS and RRMS patients in comparison to the adult phenotypes of disease was quantified by means of DT MRI and histogram analysis.(25) No DT MRI abnormalities were detected in the CIS cohorts (independently of the age at onset) and a similar extent of DT MRI abnormalities [reduced FA and increased MD] were found in pediatric and adult patients with the RR form of the disease. The finding of a relatively mild NAWM involvement in CIS patients agrees with the results of previous studies in adult patients, which have demonstrated absent or only subtle NAWM abnormalities. NAWM DT MRI abnormalities were correlated with the extent of T2 lesions, suggesting that Wallerian degeneration of axons passing through focal lesions is likely to be one of the factors contributing to NAWM damage in this disease. A regions of interest (ROI) DT MRI study, analyzed the major WM tracts in 18 pediatric MS patients, 15 pediatric patients with ADEM(26) and age-matched healthy controls. Both groups of patients showed a decreased FA and an increased RD in the analyzed WM tracts; however, a significant decrease of AD was found in the MS group only.(26)

Recently, using a DT MRI tractography, Rocca et al.(27) assessed the extent of structural damage of the CC and the corticospinal tracts (CSTs) in 17 pediatric RRMS in comparison to adult CIS and RRMS patients. Significant between-group differences were found for NAWM FA values of the CC and the right (R) CST, as well as for NAWM MD and FA values of the left (L) CST. Adult RRMS patients had lower NAWM average FA of these structures and increased NAWM average MD of the L CST in comparison with the values in pediatric RRMS and adult CIS patients. Another study used a tract-based approach to characterize diffusion abnormalities of the callosal, projection and association pathways in children with MS.(28) In lesional WM, mean apparent diffusion coefficient (ADC) values within CC, posterior limb of the internal capsule and long association fiber regions of interest were higher in children with MS compared with healthy individuals, whereas FA values were lower. When considering only NAWM, tract-based measures of fibers showed higher ADC and lower FA values in children with MS compared with healthy controls.(28)

Globally these studies suggest that damage to the NAWM occurs early in the disease, and that WM integrity disruption is widespread. A tract-based spatial Statistic Analysis (TBSS) study of adults with pediatric-onset MS and adult-onset MS(29) showed that NAWM damage was more severe in pediatric-onset compared with adult-onset MS patients, suggesting that WM microstructural changes are more attributable to age of onset than a simple function of disease duration and age. Another study investigated whether DT MRI abnormalities were present at the time of a first attack in children and whether early DT MRI features could predict the development of MS.(30) The authors assessed tract-based mean ADC and FA values for 3 major WM tracts (interhemispheric, projection and intrahemispheric) and NAWM in 20 children with established MS, 27 children with forms of CIS (including ADEM) and controls. Significant DT MRI abnormalities were found in the NAWM of children with established MS; in contrast there were no abnormalities in pediatric patients with CIS compared with controls. DT MRI measures did not predict conversion to MS.

Gray matter lesions

By suppressing the signal from both WM and CSF, double inversion recovery (DIR) sequences result in an increased lesion contrast, thus improving the detection of cortical lesions (CLs) in vivo.(31) Compared to pathologic assessment, DIR sequences detect only 10%–20% of CLs.(32) Nevertheless, their use has allowed to demonstrate focal CLs in the majority of adult patients with MS. Although such lesions are more frequent in patients with the progressive phenotypes of the disease, they have been identified in about 40% of CIS patients.(33) At present, only one study has assessed the presence, frequency, and type of CLs in 24 pediatric patients with RRMS in comparison to 10 adult RRMS patients.(25) The main result is the demonstration that CLs are rare in patients with pediatric MS, since less than 10% of pediatric population had such lesions, in comparison to a figure of 66% in adult patients with MS.25 This suggests that CL formation is not an early event in the course of the disease. This agrees with pathologic studies showing that CLs are much more frequent in the SP phase of MS.(33) Two other factors might contribute to explain the paucity of CLs in pediatric MS, i.e., their immunologic profile, which differs from that of adult patients with MS,(34) and the degree of GM maturation, which might yield to a different susceptibility to MS-related damage. Brain GM volume show a prepuberal increase, which is followed by a postpuberal loss, consistent with postmortem observations of an increased synaptic pruning and increasing intracortical myelination during adolescence and early adulthood. Furthermore, postmortem studies have demonstrated a late myelination in several cortical regions, including the frontal and parietal cortices.(35)

Gray matter damage

Although MS is classically considered a WM disease, the involvement of GM has been confirmed by pathology studies.(36) Several MRI studies have shown the involvement of GM in adult MS patients and the association between such a GM damage and physical disability, and cognitive impairment.(37) In pediatric MS, only a few studies have investigated the extent and role of GM involvement with conflicting results. An early 1H-MRS study in 8 pediatric MS patients detected a reduced NAA in the cortical GM neighboring MS lesions.(38)

A seminal DT MRI study found no abnormalities in the cortical GM of pediatric patients with RRMS in comparison with matched healthy volunteers.24 These results were confirmed by a subsequent investigation, in a larger group of patients(39) which provided compelling evidence for a sparing of cortical GM in pediatric-onset MS.

An appealing method for quantifying the extent and severity of GM damage is the assessment of GM T2 hypointensity, which is thought to reflect pathological iron deposition in the presence of disease.(40) In patients with adult MS, T2 hypointensity has been shown mainly in the deep GM nuclei, including the basal ganglia, thalamus, red nucleus and dentate nucleus.(40) In patients with progressive MS, an involvement of the rolandic cortex has also been demonstrated.(41) Such abnormal iron deposition has been correlated with disease duration,(41) neurological impairment and cognitive dysfunction. T2 hypointensity is present in the head of the L caudate in patients with pediatric MS compared with age-matched controls,(42) suggesting that iron deposition is not an early phenomenon in the course of pediatric MS.

Atrophy and thalamic involvement

Atrophy of both GM and WM has been detected in the brains of adults with MS, with a faster development of GM atrophy compared with that of WM.(43)GM atrophy involves both cortical and deep GM and correlates with cognitive impairment and physical disability.(44), (45)Among deep GM structures, the thalamus and the basal ganglia seem to be more susceptible to atrophy.(43) To quantify GM and WM volumes on conventional MRI, methods based on structure segmentation and voxel-based analysis have been employed. One voxel-based method, voxel-based morphometry (VBM), spatially normalizes individual GM tissue maps to allow group analysis of specific tissue densities at the voxel level. Another voxel-based method, tensor-based morphometry (TBM), calculates the Jacobian determinant for each voxel of the deformation field warping an individual brain to a common template space, thus providing a measure of tissue growth or shrinkage for each voxel of the brain.

Thalamic involvement in MS has been reported by both pathologic and imaging studies. Such an involvement consisted not only of macroscopic T2-visible lesions,(46) but also of microscopic damage, revealed by 1H-MRS,(47) DT MRI,(48) and T1 relaxation(49) measurements. In patients with adult-onset MS and a RR or SP disease course, the demonstration of significant volume loss associated with a decrease of NAA in the thalamus, even in the absence of focal inflammatory-demyelination, supported the notion of a neurodegenerative component of the pathologic process in this structure.(50) VBM studies demonstrated GM loss in the thalamus not only in patients with PPMS,(50) but also in those with early RRMS.(51) In both these disease phenotypes, thalamic GM loss tends to worsen over time and is significantly correlated with the extent of T2-visible lesions of the entire brain. Using voxel-based analysis of MT maps, thalamic damage has also been demonstrated in patients with CIS(52) with DIS.

Thalamic damage might be the consequence of local inflammatory activity or, alternatively, but not mutually exclusive, it might result from changes secondary to axonal transection of fibers passing through areas of diseased brain WM. A few studies investigated thalamic involvement in pediatric MS patient. A study reported lesions in the basal ganglia and thalami(53)on the initial MRI in 46% of children with MS, while another study described thalamic lesions in 25% of patients with MS.(54)

Using VBM, selective atrophy of the thalamus has been found in a group of 28 pediatric MS patients, with sparing of the cortical GM and of the remaining deep GM nuclei. The correlation found in this study between thalamic atrophy and T2 lesion burden suggested that Wallerian degeneration is one of the key factors driving tissue loss in this structure.(55) These results have been confirmed by a recent TBM study(56), which showed that compared to healthy controls, pediatric MS patients exhibited significantly reduced volumes of the thalamus and splenium of the CC and significant enlargement of the ventricles.(56) Significant volume reductions was seen in the pulvinar and anterior nuclei of the left and right thalami as well as in the splenium of the CC, supporting the notion of Wallerian degeneration of the crossing nerve fiber tracts caused by axonal transection within hemispheric WM focal lesions.

An alternative approach for the quantification of atrophy is based on the use of a ROI analysis. Kerbrat et al.(57) analyzed more comprehensively the relationship between global and regional brain volumes (intracranial volume, normalized brain volume, normalized WM and GM volume, and volumes of the thalamus, globus pallidus, putamen, and caudate) in the cohort of the previous study.(56) They found a significant whole-brain volume reduction, after normalization for skull size, in pediatric MS patients vs controls. After correction for global brain volume, thalamic volumes in pediatric MS patients was lower than those of healthy controls, indicating an even greater loss of thalamic tissue relative to more global brain measures. Moderate correlations were found between: a) T2 lesion load vs normalized thalamic volumes and normalized brain volume; and b) disease duration vs normalized thalamic volume and normalized brain volume. Long-term atrophy was investigated by Yeh et al.(58)Adult MS patients, with mean disease duration of 20 years, were classified into two groups according to their age at the disease onset, obtaining a group of 33 patients with pediatric-onset and a second group of 300 patients with an adult-onset. The Authors found similar degrees of brain atrophy in the two groups of patients after 20 years of disease duration. Considering the younger age of the pediatric-onset group (mean age 36.5 years) compared to the adult onset group (50.5 years) and the fact that aging normally leads to significant yearly increases in atrophy, this result suggests a higher level of damage and a lower level of remyelination in the pediatric-onset MS group.(58) In a recent study(59) no differences of regional GM atrophy were found between adults patients with pediatric-onset MS vs adult-onset MS matched for age or disease duration.

Spinal cord involvement

A recent study(60) has investigated the features of cord lesions in 36 pediatric RRMS patients showing that these lesions preferentially involved the cervical region, were predominantly focal, and involved only part of the transverse cord diameter. Children with the highest clinical relapse rate also tended to have more spinal cord lesions and were more likely to develop new lesions on serial scans.(60) These data suggest that MS lesions of the spinal cord in children are radiologically similar to that of adult-onset MS, supporting a common biology of pediatric- and adult-onset disease. However, ten of 36 patients demonstrated longitudinally extensive lesions, suggesting that such lesions may be less specific for diseases such as NMO in pediatric patients. All patients recovered well from spinal cord attacks, and the presence of spinal cord lesions in the first few years of disease did not correlate with physical disability. When compared spinal cord MRI features in children with MS with those with monophasic TM, both groups had a median lesion count of 1, but 88% of patients with TM had lesions extending 3 vertebral body segments or more compared with only 17% of children with MS. Focal lesions (<3 vertebral segments) were rare (9%) in patients with monophasic TM compared with those with MS (75%).(61) The frequency of clinically silent spinal cord involvement in children with MS is not known, and will be important in determining the added value of spinal cord MRI in MS diagnosis in children.

Moreover, the presence of extensive spinal cord lesions may be useful for diagnosing ADEM vs MS in pediatric patients with an ADS.(62) In this study a pediatric cohort of MS and CIS patients underwent a spinal cord MRI within 3 months after disease onset and showed T2-hyperintense cord lesions that were less extensive compared with ADEM patients.

The development of sophisticated MR receiver coils and fast imaging techniques has led to a more reliable imaging of the cord, which also includes the use of quantitative techniques. Only one study has applied MT MRI to quantify the extent of cervical cord damage in 13 children with MS and 14 age-matched controls(23) and found that MTR did not differ between patients and healthy controls.

Correlation with physical disability

Correlative and predictive studies in patients with pediatric MS are extremely rare and provided inconclusive results. In the French pediatric demyelination cohort, WM lesion number did not correlate with early development of physical disability (mean duration of clinical observation=4.9±3 years).(53) No significant correlations were also found between disability and DT and MT MRI measures of WM and GM damage(24), (39)and thalamic atrophy(55) in other more recent studies.

Correlation with cognitive impairment

The finding that cognitive impairment can also affect subjects with pediatric MS is relatively recent. As a clear correlation between disease duration and cognitive impairment was not found in earlier studies,(63), (64)the evaluation of neuropsychological outcomes with respect to MRI quantitative biomarkers may provide important insights into factors affecting functional outcomes in these patients. Till et al. evaluated the correlation between normalized brain volume and volumes of key brain areas important for efficient information processing, including the thalamus and CC, and cognitive impairment in 35 patients with pediatric MS. Cognitive impairment (defined as three or more individual test scores below 1.5 SD on the test battery) was identified in 29% of this MS cohort. Cognitive deficits predominantly involved attention and processing speed, expressive language, and visuo-motor integration. Relative to controls, MS patients showed significantly lower thalamic volume, total brain volume, and GM volume. CC area and thalamic volume differentiated patients with cognitive impairment from those without. Regression models controlling for disease duration and age indicated that thalamic volume accounted for significant incremental variance in predicting global IQ, processing speed, and expressive vocabulary and was the most robust MRI predictor of cognitive impairment relative to other MRI metrics.

Another study(65) explored the relationship between academic function and WM integrity among children with MS compared with age and sex-matched healthy controls. These authors specifically analyzed math performances since they are strictly related to efficient processing speed, working memory (e.g., carrying and borrowing digits), and visual-spatial processing (e.g., alignment of columns), all of which are commonly affected in MS. In this cohort, difficulties with written arithmetic ability were observed in 26% of patients. FA was used as a measure of the functional integrity of WM in regions of the CC and for lateralized cerebral hemisphere lobes. The main finding was that arithmetic ability correlated with FA values across all segments of the CC and in R frontal and parietal regions.

Till et al.(66) explored also executive dysfunction association with structural MRI abnormalities in pediatric MS patients. Executive dysfunction was moderately correlated with atrophy of the whole brain, frontal lobe and thalamus; while no correlation was found with T2 lesion volume.

Long-term memory is one of the most consistently impaired cognitive functions in MS and it is affected in 40-65% of adult patients.(67) Recently, Fuentes et al.(68) applied quantitative brain volumetric measures to better understand the neural correlates of learning and memory functioning in children and adolescents with MS. Reduced volume was found in the whole brain, amygdalae and thalami. Notably, differently from what is usually observed in adult MS patients, the hippocampi were not atrophied. Globally, this investigation showed that whole brain volume is a good predictor of memory outcome in young patients with MS, and it is more robust than measures of inflammatory activity (i.e., T2-lesion volume), which were not correlated with any outcome.(68)

A recent study(69) using voxel-wise methods, determined the relationship between the regional distribution of damage to the WM and GM and cognitive impairment in these patients. This analysis showed that the presence and severity of cognitive impairment was associated with structural damage to a set of brain regions (precuneus and angular gyrus) which form the posterior node of the default mode network. These regions had a high probability of harbouring focal T2 lesions, loss of WM and GM as well as FA and RD abnormalities. The pattern of structural abnormalities associated to cognitive impairment in pediatric RRMS patients differs significantly from that described in adult RRMS patients, in whom GM loss from the frontal, parietal and temporal lobes, only marginally linked to the presence of focal lesions, has been consistently described.(70), (71)A distributed pattern of WM FA abnormalities has also been detected in adult MS patients with cognitive impairment.(72) The co-localization of T2 lesions, GM and WM atrophy and DT MRI abnormalities in brain posterior regions of pediatric MS patients suggests that degeneration of axons passing through focal lesions and areas of demyelination (as indicated by decreased FA and increased RD),(73) may lead to de-afferentation and atrophy, pointing to a pivotal role of WM damage (lesions and microstructural abnormalities) in the pathogenesis of cognitive impairment in these patients. In agreement with previous studies,(55), (56)the analysis of regional GM atrophy confirmed that thalamic atrophy is typically seen in pediatric MS and that it is strongly correlated with the extent of WM lesions, but not with disease duration.(55), (56), (69)Cognitive impairment in these patients was associated with more pronounced atrophy of the right precuneus and left middle temporal gyrus. including visuo-spatial imagery, episodic memory and self-processing operations.(74)

Surprisingly, patients’ global cognitive performance as well as their performance in executive tests were not associated with atrophy of frontal lobe regions.(69) Different features of cognitive impairment in adult and pediatric patients (with prominent effects on linguistic abilities in children)(75), (76)as well as a different regional vulnerability to damage due to the variability of maturation and myelination of CNS structures might account for the discrepancies between pediatric and adult MS patients. Indeed, age-related structural changes in GM and WM volumes and diffusivity characteristics, with a caudo-rostral pattern of myelination, have been demonstrated consistently through childhood and adolescence by several studies.(3), (77)Maturation of the frontal lobe WM during the second decade of life has been suggested as a possible mechanism which confers a sort of protection from MS-related damage.(78)

Functional reorganization in pediatric multiple sclerosis patients

Two studies have evaluated cortical activation patterns and functional connectivity using active fMRI of the motor system in children with MS.(27), (79)Natural history studies have shown that time to reach physical disability in children with MS is on average 10 years longer than that seen in adults. One plausible explanation for this finding is the enhanced capacity for brain network reorganization in pediatric-onset versus adult-onset patients. To test this hypothesis, the first study evaluated the movement-associated pattern of cortical activations and motor network connectivity in 17 children with MS compared with 9 age- and sex-matched healthy controls.(79) Increased activation was observed in the contralateral sensorimotor cortex compared with controls, which was correlated with T2 lesion volume. The investigators suggested that the increased contralateral activation represents an adaptation to the presence of tissue disruption. In a functional connectivity analysis, the investigators found reduced connectivity between the left primary sensorimotor cortex and left thalamus, left insula and left secondary sensorimotor cortex, supplementary motor area and the left secondary sensorimotor cortex, left thalamus and left insula, and the left thalamus and left secondary somatosensory cortex, when compared with controls. The investigators speculated that this connectivity downregulation could be compensatory, representing a functional reservoir that may be upregulated when irreversible structural damage accumulates.

The investigators expanded on these findings in a second study by evaluating effective connectivity changes within the motor network in children with MS compared with adult-onset patients, and considered the influence of structural damage to the CC and corticospinal tracts on connectivity.(27) No changes in effective connectivity were detected between pediatric MS patients and age- and sex-matched healthy controls, suggesting that the adaptive properties or plasticity of the cortex may be preserved in children. The effective intrahemispheric and interhemispheric motor network connectivity was increased in adults with a first attack of CNS demyelination, and such an increase was more pronounced in adults with RRMS compared with children with RRMS. These connectivity changes were associated with microstructural changes within the CC and corticospinal tracts as measured by MD and FA. Taken together, the incremental recruitment of networks in adult-onset compared with pediatric-onset MS and the association between this recruitment and structural damage suggests that the propensity for brain plasticity or the functional reservoir may deplete over time, and manifest as accrual of physical disability.

            A recent study(69) combined structural and functional MRI to better understand the mechanisms responsible for cognitive impairment in pediatric MS patients. The analysis of RS FC of the DMN disclosed that functional abnormalities of the posterior regions of the network (in particular the precuneus) paralleled abnormalities detected by structural MRI in pediatric patients with cognitive impairment. On the other hand, cognitively preserved patients experienced an increased RS FC of the ACC. Also, for the analysis of RS FC, the pattern of abnormalities found in pediatric patients with MS with cognitive impairment differs from that described in adult patients, in whom a consistent reduced RS FC of the anterior regions of the DMN(39), (80)and an enhanced RS FC of the posterior ones have been described.(80), (81)As previously argued for the regional distribution of structural abnormalities, maturation effects might influence a different functional reorganization in adult vs pediatric patients with MS. Indeed, the long-range connections between the posterior cingulate cortex and the anterior prefrontal cortex have been shown to mature with age (being immature in 7-year-old children),(82), (83)and to be associated with the development of cognitive abilities.(3) Importantly, the multimodal prediction model that integrated structural and functional MRI measures showed that cognitive impairment was highly associated with the extent of structural damage and reduced RS FC of the posterior node of the DMN.

References

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Preceptorship
Milan, Italy
Oct 30 - 31, 2014
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Clinicians and scientists currently involved in MS and/or NMO management., Radiologists
EACCME®
by Excemed
Neurology

MS Alumni

The MS Alumni programme is an educational initiative of EXCEMED that is intended to provide ongoing support for young physicians and specialists in neurology.