Cerebral Multiple Sclerosis Lesions

Although previous studies have shown that the lesions of Multiple Sclerosis may involve the Cerebral Cortex, there is little published research on the prevalence and distribution of such lesions.

Using NeuroPathological techniques and MRI, a series of studies has been undertaken in order to assess this, in particular to identify their relationship to Cortical Veins.

A serial MRI study showed that the use of Gadolinium proffered an increase in Cortical lesion detection of 140% and showed that 26% of active Lesions arose within or adjacent to the Cortex.

In a post-mortem study, MRI under-reported lesions subsequently analyzed NeuroPathologically, particularly those arising within the Cortex.

In a further 12 cases examined, 478 Cortical lesions were identified, of which 372 also involved the SubCortical White Matter.

Seven different lesion types were identified; the majority arose within the territory of the principal Cortical Veins, whilst the remaining quarter arose within the territory of the small branch or superficial veins.

Small Cortical lesions are common in Multiple Sclerosis and are under-reported by MRI.

Investigation of the Cortical Venous Supply shows how such Lesions may arise, and why the majority also involve the underlying White Matter.

Purpose
We evaluated the appearance of enhancing Multiple Sclerosis (MS) lesions on unenhanced T₁-weighted MR images and the natural course of enhancing MS lesions on serial unenhanced T₁-weighted and Magnetization Transfer (MT) MR images.

Methods
One hundred twenty-six enhancing lesions were followed up monthly for 6 to 12 months to determine their signal intensity on unenhanced T₁-weighted and MT MR images.

At the time of initial enhancement, the size of the lesion and the contrast ratio of enhancement were calculated for each enhancing lesion.

During follow-up, the contrast ratio on the corresponding unenhanced T₁-weighted image was measured, and an MT Ratio (MTR) was calculated.

Results
Twenty-five enhancing lesions (20%) appeared IsoIntense and 101 lesions (80%) appeared HypoIntense relative to Normal-Appearing White Matter on unenhanced T₁-weighted images.

During 6 months of follow-up, four MR patterns of active lesions were detected initially:

1. IsoIntense lesions remained IsoIntense (15%)
2. IsoIntense lesions became HypoIntense (5%)
   - most of which re-enhanced
3. HypoIntense lesions became IsoIntense (44%)
4. HypoIntense lesions remained HypoIntense (36%)

MTR was significantly lower for HypoIntense lesions as compared with IsoIntense lesions at the time of initial enhancement.

For lesions that changed from HypoIntense to IsoIntense, MTR increased significantly during 6 months of follow-up.

Multiple regression analysis showed that strongly decreased MTR at the time of initial enhancement and enhancement duration of more than one scan were predictive of a HypoIntense appearance on unenhanced T₁-weighted images at 6 months' follow-up.

Ring enhancement was found to be the only (weak) predictor of persistently HypoIntense signal intensity.

Conclusion
Most enhancing lesions appear slightly to significantly HypoIntense on unenhanced T₁-weighted images.

Although most HypoIntensities are reversible, only those lesions that fail to recover on unenhanced T₁-weighted and MT images may have considerable irreversible structural changes.

We report the findings in 60 patients with Secondary/Progressive Multiple Sclerosis who had monthly Brain MRI studies for 4 months (one baseline and three follow-up scans).

The purpose was to define the short-term MRI natural history in a large cohort with Secondary/Progressive disease and to ascertain its relationship with other clinical and MRI features.

The patients were participating in either a natural history study or the placebo arm or non-treatment phase of a therapeutic trial.

The cohort had clinical features typical of Secondary/Progressive disease: thus, all had moderate or severe LocoMotor Disabilities [Expanded Disability Status Scale(EDSS), score 3.5-8], with a median disease duration of 12 years. There was equal representation of males and females.

During the 3 months of follow-up there was a total of 362 new enhancing lesions seen in 42 patients, and there were 24 relapses in 20 patients.

There was no correlation between new enhancing lesions and age at study entry, age of disease onset, gender disease duration or EDSS.

But there was a strong correlation with the number of enhancing lesions on the baseline scan (r = 0.65, P < 0.0001) and subsequent activity.

There was a non-significant trend for higher numbers of new enhancing lesions in those having relapses during the 3 months of scanning (P = 0.14) or in the preceding 6 months (P = 0.06).

The 34 patients who did not relapse in either period had significantly fewer new active lesions (P = 0.02) than those who relapsed at some stage during the 9 months.

Nevertheless, considerable activity was seen in the Non/Relapsing cohorts: there was a mean of 3.5 (median 2) new enhancing lesions in those not Relapsing during the 3 month study, and 5.5 (median 2) in those not Relapsing in the previous 6 months.

We conclude that short-term MRI activity is generally high in Secondary/Progressive disease, confirming a useful role for the technique in exploratory trials.

Further work should concentrate on elucidating the mechanisms of Secondary/Progression by longer term follow-up studies of larger cohorts using multiple MRI and clinical measurements.

We compared MRI criteria used to predict conversion of suspected Multiple Sclerosis to Clinically Definite Multiple Sclerosis. Seventy-four patients with Clinically Isolated Neurological symptoms suggestive of Multiple Sclerosis were studied with MRI.

Logistic regression analysis was used to remove redundant information, and a diagnostic model was built after each MRI parameter was dichotomized according to maximum accuracy using receiver operating characteristic analysis.

Clinically Definite Multiple Sclerosis developed in 33 patients (prevalence 45%). The optimum cut-off point (number of lesions) was:

1. One for most MRI criteria (including Gadolinium-enhancement & JuxtaCortical lesions)
2. Three for PeriVentricular lesions
3. Nine for the total number of T₂-lesions

Only Gadolinium-enhancement and JuxtaCortical lesions provided independent information.

A final model which, in addition, included InfraTentorial and PeriVentricular lesions, had an accuracy of 80%, and having more abnormal criteria, predicted conversion to Clinically Definite Multiple Sclerosis strongly.

The model performed better than the criteria of: Paty et al. (Neurology 1988; 38: 180-5) and of Fazekas et al. (Neurology 1988; 38: 1822-5).

We concluded that a four-parameter dichotomized MRI model including Gadolinium-enhancement, JuxtaCortical, InfraTentorial and PeriVentricular lesions best predicts conversion to Clinically Definite Multiple Sclerosis.

In order to evaluate whether Cortical Motor Reorganization occurs in the earliest phase of Multiple Sclerosis, we studied patients after a first clinical attack of HemiParesis.

From a consecutive series of 70 patients enrolled in a study of patients with Clinically Isolated Syndrome and serial MRI findings indicative of Multiple Sclerosis, we retrospectively selected 10 patients.

With HemiParesiss as the onset symptom and no further clinical episode [mean age 32 +/- 9 years, disease duration 24 +/- 14 months, median Expanded Disability Status Score (EDSS) 1.25]. Ten age-matched, healthy subjects served as controls.

Each subject was submitted to two functional MRI trials (one per hand) using a 1.5 T magnet during a sequential finger-to-thumb opposition task. Image analysis was performed using SPM99 software.

Movements of both the 'affected' and the 'unaffected' hand activated significantly larger areas in patients than in controls in both the ContraLateral and IpsiLateral Cortical Motor Areas.

Patients activated a greater number of foci than controls during both the right-hand and the left-hand movement.

Most of these foci were located in Cortical areas which were less or not at all activated in controls, such as the Lateral Premotor Cortex [Brodmann area (BA) 6], the Insula and the Inferior Parietal Lobule (BA 40).

Between-group analysis of patients versus controls showed significant (P < 0.001) foci in these areas, principally located in the IpsiLateral Hemisphere during right-hand movement and in both the Cerebral Hemispheres during left-hand movement.

Time since clinical onset showed a significant positive correlation with the extent of activation in the IpsiLateral Motor Areas (P = 0.006) during the right-hand movement and with the extent of activation in both the IpsiLateral (P = 0.02) and ContraLateral (P = 0.006) Motor Areas during the left-hand movement.

The T₁ lesion load along the Motor Pathway showed a significant positive correlation (P = 0.007) with the extent of activation in the ContraLateral Motor Areas during right-hand movement.

Our study shows functional adaptive changes that involve both the symptomatic and asymptomatic Hemisphere during a simple motor task in patients who had suffered a single clinical attack of HemiParesis.

The extent of these changes increased with the time elapsed since disease onset and the severity of Brain damage.

The extent and pattern of DeMyelination in the Cerebral Cortex was determined in 78 tissue blocks from the Brains of 20 Multiple Sclerosis (MS) patients and 28 tissue blocks from 7 patients without Neurological Disease.

Tissue blocks from 4 predetermined areas (Cingulate Gyrus, Frontal, Parietal, and Temporal Lobe) were studied, irrespective of macroscopically evident MS plaques.

All tissue blocks contained Cerebral Cortex and PeriVentricular and/or SubCortical White Matter.

One hundred and nine DeMyelinating lesions were detected in the Cerebral Cortex, of which 92 (84.4%) were purely IntraCortical and 17 (15.6%) were lesions extending through both White and Gray Matter areas.

In 5 of the 20 MS Brains, SubPial DeMyelination was extensive in the 4 widely spaced Cortical areas studied, thus considered to represent a general Cortical SubPial DeMyelination.

The percentage of DeMyelinated area was significantly higher in the Cerebral Cortex (mean 26.5%, median 14.1%) than in White Matter (mean 6.5%, median 0%) (p = 0.001).

Both Gray and WhiteWhite Matter DeMyelination was more prominent in the Cingulate Gyrus than in the other areas examined (p < 0.05).

These results indicate that the Cerebral Cortex is likely to be a predilection site for MS lesions and identify general Cortical SubPial DeMyelination as a distinct pattern occurring in a significant subpopulation of MS patients.

Background And Purpose
Cortical lesions constitute a substantial part of the total lesion load in Multiple Sclerosis (MS) Brain.

They have been related to NeuroPsychological deficits, Epilepsy, and Depression. However, the proportion of purely Cortical lesions visible on MR images is unknown.

The aim of this study was to determine the proportion of IntraCortical and mixed Gray Matter (GM)-White Matter (WM) lesions that can be visualized with postmortem MR imaging.

Methods
We studied 49 Brain samples from nine cases of chronic MS. Tissue sections were matched to dual-echo T₂-weighted Spin-Echo (T₂SE) MR images.

MS lesions were identified by means of Myelin Basic Protein ImmunoStaining, and lesions were classified as IntraCortical, mixed GM-WM, deep GM, or WM.

Investigators blinded to the HistoPathologic results scored postmortem T₂SE and 3D Fluid-Attenuated Inversion Recovery (FLAIR) images.

Results
ImmunoHistoChemistry confirmed 70 WM, eight deep GM, 27 mixed GM-WM, and 63 purely Cortical lesions.

T₂SE images depicted only 3% of the IntraCortical lesions, and 3D FLAIR imaging showed 5%.

Mixed GM-WM lesions were most frequently detectable on T₂SE and 3D FLAIR images (22% and 41%, respectively).

T₂SE imaging showed 13% of deep GM lesions versus 38% on 3D FLAIR. T₂SE images depicted 63% of the WM lesions, whereas 3D FLAIR images depicted 71%.

Even after side-by-side review of the MR imaging and HistoPathologic results, many of the IntraCortical lesions could not be identified retrospectively.

Conclusion
In contrast to WM lesions and mixed GM-WM lesions, IntraCortical lesions remain largely undetected with current MR imaging resolution.

Purpose
To prospectively compare the depiction of IntraCortical lesions by using multislab Three-Dimensional (3D) Double Inversion-Recovery (DIR), multislab 3D Fluid-Attenuated Inversion-Recovery (FLAIR), and T₂-weighted Spin-Echo (SE) Magnetic Resonance (MR) imaging in patients with Multiple Sclerosis.

Materials And Methods
Local ethics review board approval and informed consent were obtained.

Conventional T₂-weighted SE and multislab 3D FLAIR and DIR images were acquired in 10 patients with Multiple Sclerosis (five women, five men) and 11 age-matched healthy control subjects (seven women, four men).

Mean age was 40 years (range, 25-54 years) in patients and 34 years (range, 24-55 years) in control subjects.

Lesions were classified according to seven anatomic regions: IntraCortical, mixed White Matter-Gray Matter, JuxtaCortical, deep Gray Matter, PeriVentricular White Matter, deep White Matter, and InfraTentorial lesions.

The numbers of lesions per category were compared between techniques (Dunnett-corrected analysis of variance).

Gain or loss (with 95% Confidence Intervals [CIs]) of numbers of lesions detected at 3D DIR imaging was calculated in comparison with those detected at T₂-weighted SE and 3D FLAIR imaging.

Results
Total number of lesions did not differ between 3D DIR and 3D FLAIR sequences, but the 3D DIR sequence showed a gain of 21% (95% CI: 4%, 41%) in comparison with the T₂-weighted SE sequence.

Because of high Gray Matter-White Matter contrast, DIR images depicted more IntraCortical lesions (80 lesions in 10 patients) than both SE (10 lesions) and FLAIR (31 lesions) images.

Gains with DIR were 538% (95% CI: 191%, 1297%) and 152% (95% CI: 15%, 453%) compared with SE and FLAIR, respectively.

Only four IntraCortical lesions were detected in control subjects. Also, DIR imaging enabled a better definition of mixed White Matter-Gray Matter lesions because of greater contrast between the lesion and its surroundings.

Conclusion
MR imaging with 3D DIR enables increased IntraCortical lesion detection in the Multiple Sclerosis Brain, as well as improved distinction between JuxtaCortical and White Matter-Gray Matter lesions.

Copyright RSNA, 2005

Background And Purpose
Corpus Callosum lesions are of specific interest in the evaluation of suspected Multiple Sclerosis in Brain MR imaging.

Using thin-section sagittal Fluid-Attenuated Inversion Recovery images, researchers have shown that the finding of "SubCallosal striations" correlates significantly with the diagnosis of Multiple Sclerosis.

Using the same MR imaging technique, we describe a finding of Ependymal irregularity that we call the "Dot-Dash" sign, which we believe to be associated with early Multiple Sclerosis.

Methods
Sagittal 2-mm fast Fluid-Attenuated Inversion Recovery images were obtained in 70 patients. Thirty-five patients had Multiple Sclerosis according to the Poser criteria, and 35 were age-matched controls.

The images were reviewed in a blinded fashion by an experienced NeuroRadiologist for the presence or absence of the Dot-Dash sign.

Results
The correlation between the Dot-Dash sign and definite clinical Multiple Sclerosis is highly significant (P < .001), with a sensitivity of 91.4% and a specificity of 65.7%.

In the age group of < or =50 years, the sensitivity was 95.7% and the specificity, 71.9%.

Conclusion
The Dot-Dash sign of Ependymal irregularity on thin-section sagittal Fluid-Attenuated Inversion Recovery images is an early marker for Multiple Sclerosis, which is particularly useful in the younger patient.

This finding appears to be more sensitive for early lesion detection than any other Multiple Sclerosis imaging finding yet described in the literature.

Objective
To identify determinants visible on Magnetic Resonance Imaging of the Brain that explain the subsequent rate of Cerebral Atrophy in patients with recently diagnosed Multiple Sclerosis.

Design
Magnetic Resonance Imaging of the Brain was performed at baseline and after 2 years.

T₂ HyperIntense lesion load, black hole lesion load, presence of contrast-enhancing lesions, and normalized Brain Volume were derived from the baseline Magnetic Resonance Imaging.

And considered as possible explanatory variables for the subsequent annualized Percentage of Brain Volume Change (PBVC/y) using forward stepwise multiple linear regression analysis.

Setting
MS Center Amsterdam, Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.

Patients & Main Outcome Measure
Eighty-nine patients recently diagnosed as having Multiple Sclerosis were included at the time of diagnosis from our outpatient clinic. Annualized percentage of Brain Volume change.

Results
The mean (SD) annualized rate of Cerebral Atrophy was -0.9 (0.8) PBVC/y.

Baseline normalized Brain Volume (standardized coefficient, 0.426; P = .001) and baseline T₂ lesion load (standardized coefficient, -0.244; P = .02) were identified as explanatory variables for subsequent PBVC/y and yielded a regression model that explained 31.2% of the variance in PBVC/y.

Conclusions
In patients with recently diagnosed Multiple Sclerosis, the extent of accumulated Brain Tissue loss and overall lesion load partly explain the subsequent rate of Cerebral Atrophy.

Background
Although NeuroPsychiatric complications are well recognized, the presentation of Multiple Sclerosis with Cognitive or NeuroPsychiatric symptoms has generally been considered a rare occurrence and to reflect SubCortical pathology.

Objectives
To document the clinical, NeuroPsychological, and Radiological features of six cases of Cognitive presentation of Multiple Sclerosis, to review the relevant literature, and to propose a possible Cortical basis for this clinical presentation.

Subjects
Six patients (five women; age range 38 to 60 years) presented to the Memory and Cognitive Disorders clinic in Cambridge with an initially undiagnosed Cognitive/NeuroPsychiatric Syndrome.

All underwent NeuroPsychological evaluation, Brain imaging, and ancillary investigations to establish a diagnosis of Multiple Sclerosis.

Results
The six cases all had a progressive Dementia Syndrome with prominent Amnesia (partial or total Memory loss), often accompanied by classic Cortical features including Dysphasia, Dysgraphia, or Dyslexia.

Mood disturbance was ubiquitous and in three patients there was a long history of preceding severe Depression. All six developed characteristic physical signs on follow up, with marked disabilities.

A review of 17 previously reported cases highlighted the prominence of Memory impairment and Depression in the early stages.

Conclusions
On clinical, pathological, and radiological grounds, the NeuroPsychiatric presentation of Multiple Sclerosis may represent a ClinicoPathological entity of "Cortical Multiple Sclerosis."

Failure to recognize this will delay diagnosis and may expose patients to potentially dangerous and invasive investigation.

Because the NeuroPsychiatric features of Cortical Multiple Sclerosis are a major cause of handicap, their early recognition may be particularly important in view of emerging treatments.

Purpose Of Review
Multiple Sclerosis is the most common chronic, disabling Central Nervous System disease in young adults, characterized by Inflammatory DeMyelinating White Matter lesions with Glial Scar formation and Axonal Loss.

Lately, evidence has accumulated that large areas of Gray Matter are affected in Multiple Sclerosis patients.

Recent Findings
Findings in post-mortem Brain Tissue support the notion that Cortical DeMyelination is frequent and extensive, especially in patients with Chronic Multiple Sclerosis.

Cortical Lesions differ from White Matter lesions with respect to inflammatory cell infiltration, Gliosis, and ReMyelination.

Thus, differences in Cortical and White Matter lesion pathogenesis have been proposed. Experimental models suggest a decisive role for AntiMyelin AntiBodies in Cortical DeMyelination.

Topical studies focus on damage to Neurons, Dendrites, and Synapses in Cortical Multiple Sclerosis lesions.

Improved imaging techniques for the detection of Cortical Lesions are currently developed and will provide the basis for future ClinicoPathological correlative studies.

Summary
In summary, recent years have opened our eyes to the extensive Gray Matter involvement in Multiple Sclerosis.

Studies on the pathogenesis of Cortical DeMyelination, Cortical damage, and repair will elucidate basic principles of Multiple Sclerosis lesion formation.

However, more sensitive imaging tools are required to study the impact of Cortical Lesions on clinical symptoms, disability, and disease progression.