HLA-DRB1*1501 influences long-term disability progression and tissue damage on MRI in relapse-onset multiple sclerosis.

BACKGROUND: Whether genetic factors influence the long-term course of multiple sclerosis (MS) is unresolved. OBJECTIVE: To determine the influence of HLA-DRB1*1501 on long-term disease course in a homogeneous cohort of clinically isolated syndrome (CIS) patients. METHODS: One hundred seven patients underwent clinical and MRI assessment at the time of CIS and after 1, 3, 5 and 15 years. HLA-DRB1*1501 status was determined using Sanger sequencing and tagging of the rs3135388 polymorphism. Linear/Poisson mixed-effects models were used to investigate rates of change in EDSS and MRI measures based on HLA-DRB1*1501 status. RESULTS: HLA-DRB1*1501 -positive (n = 52) patients showed a faster rate of disability worsening compared with the HLA-DRB1*1501 -negative (n = 55) patients (annualised change in EDSS 0.14/year vs. 0.08/year, p < 0.025), and a greater annualised change in T2 lesion volume (adjusted difference 0.45 mL/year, p < 0.025), a higher number of gadolinium-enhancing lesions, and a faster rate of brain (adjusted difference -0.12%/year, p < 0.05) and spinal cord atrophy (adjusted difference -0.22 mm2/year, p < 0.05). INTERPRETATION: These findings provide evidence that the HLA-DRB1*1501 allele plays a role in MS severity, as measured by long-term disability worsening and a greater extent of inflammatory disease activity and tissue loss. HLA-DRB1*1501 may provide useful information when considering prognosis and treatment decisions in early relapse-onset MS.

The prognostic significance of early blood neurofilament light chain concentration and magnetic resonance imaging variables in relapse-onset multiple sclerosis.

BACKGROUND: Improved prognostication remains vital in multiple sclerosis to inform personalized treatment approaches. Blood neurofilament light (bNfL) is a promising prognostic biomarker, but to what extent it provides additional information, independent of established MRI metrics, is yet to be established. METHODS: We obtained all available bNfL data for 133 patients from a longitudinal observational cohort study. Patients were dichotomized into good or poor outcome groups based upon clinical and cognitive assessments performed 15 years after a clinically isolated syndrome. We performed longitudinal modeling of early NfL and MRI variables to examine differences between outcome groups. RESULTS: The bNfL dataset was incomplete, with one to three (mean 1.5) samples available per participant. Within 3 months of onset, bNfL was similar between groups. The bNfL concentration subsequently decreased in those with a good outcome, and remained persistently elevated in those with a poor outcome. By year 5, NfL in the poor outcome group was approximately double that of those with a good outcome (14.58 [10.40-18.77] vs. 7.71 [6.39-9.04] pg/ml, respectively). Differences were reduced after adjustment for longitudinal changes in T2LV, but trends persisted for a greater rate of increase in NfL in those with a poor outcome, independent of T2LV. CONCLUSIONS: This analysis requires replication in cohorts with more complete bNfL datasets, but suggests that persistently elevated blood NfL may be more common in patients with a poor long-term outcome. Persistent elevation of blood NfL may provide additional prognostic information not wholly accounted for by standard monitoring techniques.

Early imaging predictors of long-term outcomes in relapse-onset multiple sclerosis.

The clinical course of relapse-onset multiple sclerosis is highly variable. Demographic factors, clinical features and global brain T2 lesion load have limited value in counselling individual patients. We investigated early MRI predictors of key long-term outcomes including secondary progressive multiple sclerosis, physical disability and cognitive performance, 15 years after a clinically isolated syndrome. A cohort of patients with clinically isolated syndrome (n = 178) was prospectively recruited within 3 months of clinical disease onset and studied with MRI scans of the brain and spinal cord at study entry (baseline) and after 1 and 3 years. MRI measures at each time point included: supratentorial, infratentorial, spinal cord and gadolinium-enhancing lesion number, brain and spinal cord volumetric measures. The patients were followed-up clinically after ∼15 years to determine disease course, and disability was assessed using the Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test. Multivariable logistic regression and multivariable linear regression models identified independent MRI predictors of secondary progressive multiple sclerosis and Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test, respectively. After 15 years, 166 (93%) patients were assessed clinically: 119 (72%) had multiple sclerosis [94 (57%) relapsing-remitting, 25 (15%) secondary progressive], 45 (27%) remained clinically isolated syndrome and two (1%) developed other disorders. Physical disability was overall low in the multiple sclerosis patients (median Expanded Disability Status Scale 2, range 0-10); 71% were untreated. Baseline gadolinium-enhancing (odds ratio 3.16, P < 0.01) and spinal cord lesions (odds ratio 4.71, P < 0.01) were independently associated with secondary progressive multiple sclerosis at 15 years. When considering 1- and 3-year MRI variables, baseline gadolinium-enhancing lesions remained significant and new spinal cord lesions over time were associated with secondary progressive multiple sclerosis. Baseline gadolinium-enhancing (ß = 1.32, P < 0.01) and spinal cord lesions (ß = 1.53, P < 0.01) showed a consistent association with Expanded Disability Status Scale at 15 years. Baseline gadolinium-enhancing lesions was also associated with performance on the Paced Auditory Serial Addition Test (ß = - 0.79, P < 0.01) and Symbol Digit Modalities Test (ß = -0.70, P = 0.02) at 15 years. Our findings suggest that early focal inflammatory disease activity and spinal cord lesions are predictors of very long-term disease outcomes in relapse-onset multiple sclerosis. Established MRI measures, available in routine clinical practice, may be useful in counselling patients with early multiple sclerosis about long-term prognosis, and personalizing treatment plans.

Inclusion of optic nerve involvement in dissemination in space criteria for multiple sclerosis.

OBJECTIVE: To investigate the effect of including optic nerve involvement in dissemination in space (DIS) criteria for diagnosis of multiple sclerosis (MS) in patients with clinically isolated syndrome (CIS). METHODS: We studied 160 patients with CIS: 129 with optic neuritis (ON) and 31 with non-ON CIS. MRI brain/spinal cord was done at the time of presentation and a follow-up MRI brain after 3-12 months. We evaluated optic nerve involvement clinically or with visual evoked potentials (VEPs, n = 42). We investigated the performance of the McDonald 2017 DIS criteria and modified DIS criteria including optic nerve involvement for development of clinically definite MS after ∼15 years. RESULTS: In the ON group, including symptomatic optic nerve involvement identified an additional 15 patients with DIS. The modified DIS criteria that included optic nerve involvement were more sensitive (95% vs 83%) and more accurate (81% vs 78%) than the McDonald 2017 DIS criteria, but less specific (57% vs 68%). In combination with dissemination in time criteria, the modified DIS criteria remained more sensitive (83% vs 74%) and accurate (81% vs 75%), and the specificity was the same (77%). Including asymptomatic optic nerve involvement in DIS the non-ON group did not identify any additional patients and the performance of the McDonald 2017 criteria and the modified criteria was the same. CONCLUSION: The inclusion of symptomatic optic nerve involvement in DIS in patients with ON improved the overall performance of MS diagnostic criteria. Including asymptomatic optic nerve involvement in DIS in patients with a non-ON CIS may be of limited value. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with suspected MS, inclusion of symptomatic optic nerve involvement in DIS criteria improves the overall performance of diagnostic criteria for MS.

Imaging Investigation of Thyroid Eye Disease.

INTRODUCTION: Thyroid eye disease (TED), is a term referring to the extrathyroidal manifestation of Grave's disease, a disorder which is currently the most common cause of hyperthyroidism and is characterised by underlying autoimmunity.The pathogenic course of the disease can be broadly classified into two stages, an early inflammatory and a late fibrotic stage. These stages are reflected in clinical severity and activity classifications, such as Clinical Activity Score and Class 0: No signs or symptoms, 1: Only signs, no symptoms (e. g. lid retraction), 2: Soft tissue involvement, 3: Proptosis, 4: Extraocular muscle involvement, 5: Corneal involvement, 6: Sight loss (NOSPECS). Classifications based on the latter, have important implications in treatment decisions since patients in the early active stage of the disease are more likely to respond to anti-inflammatory and immunosuppressive therapies, whereas patients in the late fibrotic stage require different therapeutic approaches, including rehabilitative surgery. METHODS: We reviewed cases of TED investigated with CT and Magnetic Resonance Imaging (MRI) in our department. We assessed the findings of imaging studies and their role in the clinical investigation of patients with TED as well as in the differential diagnosis from other disorders. RESULTS: Imaging has a significant role in the investigation of TED, however a consensus on the use of different imaging modalities in the course of disease has yet to be reached. Nevertheless, imaging and specifically CT and MRI can have a vital role in the initial diagnosis of clinically atypical presentation of TED, in surgical planning, as well as in the differential diagnosis from other orbital disorders. CONCLUSION: In this review, we attempt to present current trends in imaging investigation of TED. Rather than focusing on the findings of each imaging modality separately, we present the two main imaging modalities focusing on CT and MRI, in the context of pathogenic stages of the disease.

Periventricular lesions and MS diagnostic criteria in young adults with typical clinically isolated syndromes.

In patients who present with a clinically isolated syndrome (CIS), whose features are suggestive of multiple sclerosis (MS), fulfilling McDonald 2010 magnetic resonance imaging (MRI) criteria for dissemination in space (DIS) and dissemination in time (DIT) enables a diagnosis of MS. While ⩾1 periventricular lesion is included in the 2010 DIS criteria, earlier McDonald criteria required ⩾3 periventricular lesions to confirm DIS and recent Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS)-recommended DIS criteria also require ⩾3 lesions. We investigated the effect of varying the required number of periventricular lesions and found that the best combination of specificity and sensitivity for clinically definite MS was seen for ⩾1 periventricular lesion using both the McDonald 2010 and MAGNIMS 2016 criteria.

Should the symptomatic region be included in dissemination in space in MRI criteria for MS?

OBJECTIVES: To investigate whether inclusion of lesions in the symptomatic region influences the performance of dissemination in space (DIS) criteria for a diagnosis of clinically definite multiple sclerosis (CDMS) in patients with a clinically isolated syndrome (CIS). METHODS: We studied 30 patients with CIS with brainstem/cerebellar and spinal cord syndromes who had MRI scans at the time of CIS and were followed up for the development of CDMS. We retrospectively applied the McDonald 2010 DIS criteria (excluding all lesions in the symptomatic region) to baseline MRI scans and 2 modified DIS criteria: (1) the inclusion of asymptomatic lesions in the symptomatic region in DIS, and (2) the inclusion of any lesion in the symptomatic region in DIS. The performance of the McDonald 2010 DIS criteria and the 2 modified criteria for the development of CDMS was compared. RESULTS: The sensitivity, specificity, and accuracy of the DIS criteria was, respectively, 73%, 73%, and 73% for the McDonald 2010 criteria, 80%, 73%, and 77% when asymptomatic lesions in the symptomatic region were included, and 87%, 73%, and 80% when any lesion in the symptomatic region was included in DIS. CONCLUSIONS: Including lesions in the symptomatic region in DIS increases the sensitivity of MRI criteria for diagnosing multiple sclerosis without compromising specificity. These findings may help inform future revisions of the diagnostic criteria for multiple sclerosis. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with CIS, including lesions in the symptomatic region as part of the criteria for DIS does not significantly increase the accuracy for predicting the development of CDMS. The study lacks the precision to detect an important change in accuracy.

Grey matter involvement by focal cervical spinal cord lesions is associated with progressive multiple sclerosis.

BACKGROUND: The in vivo relationship of spinal cord lesion features with clinical course and function in multiple sclerosis (MS) is poorly defined. OBJECTIVE: The objective of this paper is to investigate the associations of spinal cord lesion features on MRI with MS subgroup and disability. METHODS: We recruited 120 people: 25 clinically isolated syndrome, 35 relapsing-remitting (RR), 30 secondary progressive (SP), and 30 primary progressive (PP) MS. Disability was measured using the Expanded Disability Status Scale. We performed 3T axial cervical cord MRI, using 3D-fast-field-echo and phase-sensitive-inversion-recovery sequences. Both focal lesions and diffuse abnormalities were recorded. Focal lesions were classified according to the number of white matter (WM) columns involved and whether they extended to grey matter (GM). RESULTS: The proportion of patients with focal lesions involving at least two WM columns and extending to GM was higher in SPMS than in RRMS (p = 0.03) and PPMS (p = 0.015). Diffuse abnormalities were more common in both PPMS and SPMS, compared with RRMS (OR 6.1 (p = 0.002) and 5.7 (p = 0.003), respectively). The number of lesions per patient involving both the lateral column and extending to GM was independently associated with disability (p < 0.001). CONCLUSIONS: More extensive focal cord lesions, extension of lesions to GM, and diffuse abnormalities are associated with progressive MS and disability.

Early factors associated with axonal loss after optic neuritis.

OBJECTIVE: Acute optic neuritis due to an inflammatory demyelinating lesion of the optic nerve is often seen in association with multiple sclerosis. Although functional recovery usually follows the acute episode of visual loss, persistent visual deficits are common and are probably due to axonal loss. The mechanisms of axonal loss and early features that predict it are not well defined. We investigated clinical, electrophysiological, and imaging measures at presentation and after 3 months as potential markers of axonal loss following optic neuritis. METHODS: We followed 21 patients after their first attack of acute unilateral optic neuritis for up to 18 months. Axonal loss was inferred from optical coherence tomography measures of retinal nerve fiber layer (RNFL) thickness at least 6 months following the episode. Visual function, visual evoked potential, and optic nerve magnetic resonance imaging measures obtained during the acute episode and 3 months later were investigated for their association with later axonal loss. RESULTS: After multivariate analysis, prolonged visual evoked potential latency and impaired color vision, at baseline and after 3 months, were significantly and independently associated with RNFL thinning. Low-contrast acuity measures exhibited significant univariate associations with RNFL thinning. INTERPRETATION: The association of RNFL loss with a prolonged visual evoked potential (VEP) latency suggests that acute and persistent demyelination is associated with increased vulnerability of axons. VEP latency and visual function tests that capture optic nerve function, such as color and contrast, may help identify subjects with a higher risk for axonal loss who are thus more suitable for experimental neuroprotection trials.

Neuroplasticity predicts outcome of optic neuritis independent of tissue damage.

OBJECTIVES: To determine whether lateral occipital complex (LOC) activation with functional magnetic resonance imaging (fMRI) predicts visual outcome after clinically isolated optic neuritis (ON). To investigate the reasons behind good recovery following ON, despite residual optic nerve demyelination and neuroaxonal damage. METHODS: Patients with acute ON and healthy volunteers were studied longitudinally over 12 months. Structural MRI, visual evoked potentials (VEPs), and optical coherence tomography (OCT) were used to quantify acute inflammation, demyelination, conduction block, and later to estimate remyelination and neuroaxonal loss over the entire visual pathway. The role of neuroplasticity was investigated using fMRI. Multivariable linear regression analysis was used to study associations between vision, structure, and function. RESULTS: Greater baseline fMRI responses in the LOCs were associated with better visual outcome at 12 months. This was evident on stimulation of either eye (p = 0.007 affected; p = 0.020 fellow eye), and was independent of measures of demyelination and neuroaxonal loss. A negative fMRI response in the LOCs at baseline was associated with a relatively worse visual outcome. No acute electrophysiological or structural measures, in the anterior or posterior visual pathways, were associated with visual outcome. INTERPRETATION: Early neuroplasticity in higher visual areas appears to be an important determinant of recovery from ON, independent of tissue damage in the anterior or posterior visual pathway, including neuroaxonal loss (as measured by MRI, VEP, and OCT) and demyelination (as measured by VEP).

Gray matter atrophy is related to long-term disability in multiple sclerosis.

OBJECTIVE: To determine the relation of gray matter (GM) and white matter (WM) brain volumes, and WM lesion load, with clinical outcomes 20 years after first presentation with clinically isolated syndrome suggestive of multiple sclerosis (MS). METHODS: Seventy-three patients were studied a mean of 20 years from first presentation with a clinically isolated syndrome (33 of whom developed relapsing-remitting MS and 11 secondary-progressive MS, with the rest experiencing no further definite neurological events), together with 25 healthy control subjects. GM and WM volumetric measures were obtained from three-dimensional T1-weighted brain magnetic resonance images using Statistical Parametric Mapping 2. RESULTS: Significant GM (p < 0.001) and WM atrophy (p = 0.001) was seen in MS patients compared with control subjects. There was significantly more GM, but not WM atrophy, in secondary-progressive MS versus relapsing-remitting MS (p = 0.003), and relapsing-remitting MS versus clinically isolated syndrome (p < 0.001). GM, but not WM, fraction correlated with expanded disability status scale (r(s) = -0.48; p < 0.001) and MS Functional Composite scores (r(s) = 0.59; p < 0.001). WM lesion load correlated with GM (r(s) = -0.63; p < 0.001), but not with WM fraction. Regression modeling indicated that the GM fraction explained more of the variability in clinical measures than did WM lesion load. INTERPRETATION: In MS patients with a relatively long and homogeneous disease duration, GM atrophy is more marked than WM atrophy, and reflects disease subtype and disability to a greater extent than WM atrophy or lesions.

MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicentre retrospective study.

BACKGROUND: The 2001 and 2005 McDonald criteria allow MRI evidence for dissemination in space (DIS) and dissemination in time (DIT) to be used to diagnose multiple sclerosis in patients who present with clinically isolated syndromes (CIS). In 2006, new criteria were proposed in which DIS requires at least one T2 lesion in at least two of four locations (juxtacortical, periventricular, infratentorial, and spinal-cord) and DIT requires a new T2 lesion on a follow-up scan. We applied all three criteria in a large cohort of CIS patients to assess their performance by use of conversion to clinically definite multiple sclerosis (CDMS) as the outcome. METHODS: Patients who had two MRI scans within 12 months of CIS onset were identified in four centres in the Magnims European research network. The specificity and sensitivity of MRI criteria for CDMS after 3 years was assessed in 208 patients. A Cox proportional hazards model was applied in a larger cohort of 282 patients that included all patients irrespective of length of follow-up. FINDINGS: The specificity of all criteria for CDMS was high (2001 McDonald, 91%; 2005 McDonald, 88%; new, 87%). Sensitivity of the new (72%) and 2005 McDonald (60%) criteria were higher than the 2001 McDonald criteria (47%). The Cox proportional hazards model showed a higher conversion risk for all three criteria in those with both DIS and DIT than those with either DIS or DIT alone. When all three criteria were included in the model, only the new criteria had an independent significant effect on conversion risk. INTERPRETATION: The new criteria are simpler than the McDonald criteria without compromising specificity and accuracy. The presence of both DIS and DIT from two MRI scans has a higher specificity and risk for CDMS than either DIS or DIT alone.

Imaging of the lacrimal gland.

The lacrimal gland is situated superolateral to the eye and produces tears that moisten, lubricate, and protect the delicate corneal and conjunctival epithelium. Anatomically related to the orbit but embryologically and functionally more closely related to the salivary glands, radiological imaging has proven invaluable in delineation and differentiation of the unique range of pathological processes affecting the lacrimal gland. This article details traditional and new imaging techniques used in investigating such pathology and discusses the imaging findings and patterns of spread characteristic of various neoplastic, inflammatory, and structural processes ranging from benign adenomas, adenocarcinomas, and lymphomas to sarcoidosis, Mickulicz's syndrome, histiocytosis, and benign dacrocysts.

Optic nerve diffusion measurement from diffusion-weighted imaging in optic neuritis.

BACKGROUND AND PURPOSE: Increases in apparent diffusion coefficient (ADC) from diffusion-weighted (DW) imaging are thought to be due to axonal disruption, and changes have been well documented in multiple sclerosis lesions. DW imaging of the optic nerves, however, presents many challenges. The goal of this study was to measure ADC in patients with optic neuritis by using zonal oblique multisection echoplanar imaging. METHODS: The optic nerves of eighteen patients who had experienced an attack of optic neuritis 1 year previously and 11 control subjects were imaged with the diffusion sequence (usable data were available from 16 patients and 10 control subjects). The orbital optic nerves were segmented by a blinded observer by using a computer-assisted threshold-based contouring technique, and the mean ADC was determined. RESULTS: The mean ADC from diseased optic nerves was 1324 x 10(-6) mm2/s, compared with 990 x 10(-6) mm2/s from healthy contralateral optic nerves (P = .005 versus diseased optic nerves) and 928 x 10(-6) mm2/s from control optic nerves (P = .006 versus diseased optic nerves and P = .40 versus healthy contralateral optic nerves). The diseased optic nerve ADC correlated with both visual (e.g., r(S) = 0.73; P = .001 for logMAR visual acuity) and electrophysiological parameters (e.g., r(S) = -0.57, P = .021 for visual evoked potential central field amplitude [VEP]). CONCLUSION: It has been possible to apply DW imaging in a patient population, and, in the chronic phase following optic neuritis, the correlation of mean ADC with the clinical and electrophysiological parameters suggests that the ADC is giving a surrogate measure of axonal disruption in the chronic, postinflammatory optic nerve lesion.

Adaptive cortical plasticity in higher visual areas after acute optic neuritis.

The ability to distinguish adaptive cortical reorganization may help to target future therapeutic strategies after neurological insult. We investigated cortical plasticity by prospectively applying visual functional magnetic resonance imaging (fMRI) and optic nerve MRI to 20 patients with acute optic neuritis at baseline, 1, 3, 6, and 12 months. We performed three types of correlation analyses to investigate the relationships between fMRI activity, clinical function, and optic nerve structure. The first analysis directly correlated the fMRI response to clinical function or optic nerve structure and found dynamic relations especially within the first 3 months. The second analysis used a novel technique that modeled the fMRI response and optic nerve structure together with clinical function, to determine the contribution fMRI made to clinical function after accounting for structural factors. Significant effects were found at baseline only, within the right peristriate cortex, and bilaterally in the lateral occipital complexes, which are normally involved in higher order visual processing. The third analysis investigated the relation between the modeled visual recovery rate and fMRI response but found no significant effects. The key findings of this study are from the second analysis and suggest a genuine adaptive role for cortical reorganization within extrastriate visual areas early after optic neuritis.

Visual recovery following acute optic neuritis--a clinical, electrophysiological and magnetic resonance imaging study.

This study reports the prospective follow-up of a cohort of patients with acute optic neuritis examined with serial visual tests, visual evoked potentials (VEPs), conventional and triple-dose gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) to examine which factors are important in visual recovery. Thirty-three patients were recruited with acute unilateral optic neuritis. A clinical and VEP assessment was performed on each. Optic nerve MRI was performed using fast spin echo (FSE) (on all) and triple-dose Gd-enhanced T1-weighted sequences (n = 28). Optic nerve lesion lengths were measured. Serial assessments were performed on 22 of the patients up to one-year. Serial Gd-enhanced optic nerve imaging was performed on 15 of the patients until enhancement ceased. The final 30-2 Humphrey visual field mean deviation (MD) was 2.55 dB higher in patients in the lowest quartile of initial Gd-enhanced lesion length compared with the other quartiles (p < 0.01) but recovery was not related to the duration of enhancement. The initial recovery of Humphrey MD was 4.60 dB units per day in patients with good eventual recoveries (MD > -6.0 dB) and 0.99 dB per day in poor-recovery patients (p = 0.02).Good-recovery patients had mean central field VEP amplitudes 2.29 microV higher during recovery than poor-recovery patients (p = 0.047). The results suggest that factors which are associated with a better prognosis are: having a short acute lesion on triple-dose gadolinium enhanced imaging, higher VEP amplitudes during recovery and a steep gradient of the initial improvement in vision.

Effect of natalizumab on conversion of gadolinium enhancing lesions to T1 hypointense lesions in relapsing multiple sclerosis.

BACKGROUND: Natalizumab, a humanized monoclonal anti-adhesion molecule antibody, reduces the frequency of new gadolinium (Gd) enhancing lesions and relapses in multiple sclerosis (MS). Its effect on evolution of new Gd enhancing lesions to T1 hypointense lesions is unknown. METHODS: 213 patients were randomized to receive 3 mg/kg or 6 mg/kg natalizumab or placebo monthly for 6 months and then followed for a further 6 months. A subset of patients who had one or more new gadolinium enhancing lesions from Month 0 to Month 6 and available electronic data were analysed. Each new Gd enhancing lesion that developed during treatment (months 1-6) was investigated for conversion to a new T1 hypointense lesion at month 12. Lesions were classified as large or small if their cross-sectional area was greater or less than 20 mm2. Because of the similarity of both doses of natalizumab on the frequency of new Gd enhancing lesions, the two natalizumab arms were combined in all analyses. RESULTS: Compared with the placebo group, the natalizumab group exhibited significant decreases in: (i) the proportion of patients with new Gd enhancing lesions that evolved to T1-hypointense lesions (10/38 [26 %] versus 27/40 [68 %]; p<0.01); (ii) the proportion of patients who developed large T1 hypointense lesions (2/38 [5 %] versus 16/40 [40 %]; p<0.01); (iii) the proportion of new Gd enhancing lesions that became T1 hypointense (11/75 [15 %] versus 118/466 [25 %]; p=0.045); (iv) the mean proportion per patient of new Gd enhancing lesions that converted to T1-hypointense lesions (0.15 versus 0.28; p=0.005), and (v) the odds ratio (OR) of converting from Gd enhancing to T1-hypointense lesions (OR=0.48; 95% CI=0.24, 0.94, p=0.031). CONCLUSION: Natalizumab significantly suppresses the evolution of new Gd enhancing to T1-hypointense lesions. This may reflect several mechanisms including reduced cell migration across the blood brain barrier, reduced T cell activation within lesions, an inhibitory effect on subsequent axonal damage within the new central nervous system lesion, and a reduced likelihood of recurrent lesion inflammation.

Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes.

While brain atrophy occurs early in the clinical course of multiple sclerosis, exactly how early, which tissues are affected and the rate at which early atrophy occurs are unclear. Regional brain atrophy was investigated in 58 patients recruited within 3 months of onset of a clinically isolated syndrome (CIS) suggestive of multiple sclerosis, who were followed-up for 3 years. At 3 years, 31 subjects had developed multiple sclerosis as defined by the McDonald criteria, while 27 had not (13 had MRI-visible brain lesions and 14 did not). In those who developed multiple sclerosis, the mean decrease in grey matter fractional volume (GMF, as a fraction of total intracranial volume) was -0.017 (-3.3%) and was significantly larger than in the combined lesion-positive and lesion-negative CIS subjects [-0.005 (-1.1%), P = 0.001]. No decrease in white matter fractional volumes (WMF) was seen. Change in GMF correlated only modestly with the change in T2 lesion volume from baseline to year 3 (r = -0.428, P = 0.004). These results suggest that progressive grey matter, but not white matter, atrophy is seen in the earliest clinically observable stages of relapse onset multiple sclerosis, and this is only moderately related to lesion accumulation. Longer-term follow-up is required to determine whether early grey matter atrophy is associated with subsequent disability or cognitive impairment.

New T2 lesions enable an earlier diagnosis of multiple sclerosis in clinically isolated syndromes.

In clinically isolated syndromes, the new McDonald criteria for multiple sclerosis diagnosis require new gadolinium-enhancing lesions for dissemination in time at a 3-month follow-up magnetic resonance imaging scan. In a cohort of 56 patients, these criteria were specific (95%) but less sensitive (58%) for clinically definite multiple sclerosis at 3 years. If new T2 lesions were allowed as an alternative for dissemination in time, sensitivity increased (74%) with maintained specificity (92%), enabling an accurate diagnosis of multiple sclerosis in more patients.

A controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.