Abstract Objective Grey matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS. Methods We analysed 3,604 brain high-resolution T1-weighted MRI scans from 1,417 participants: 1,214 MS patients (253 clinically-isolated syndrome[CIS], 708 relapsingremitting[RRMS], 128 secondary-progressive[SPMS], 125 primary-progressive[PPMS]), over an average follow-up of 2.41 years (standard deviation[SD]=1.97), and 203 healthy controls (HCs) [average follow-up=1.83 year, SD=1.77], attending 7 European centres. Disability was assessed with the Expanded-Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem and cerebral white matter. Hierarchical mixed-models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression. Results SPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio=0.73, 95% CIs 0.65, 0.82; p <0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (-1.45%), PPMS (-1.66%), and RRMS (-1.34%) than CIS (-0.88%) and HCs (-0.94%)[ p <0.01]. The rate of temporal GM atrophy in SPMS (-1.21%) was significantly faster than RRMS (-0.76%), CIS (-0.75%), and HCs (-0.51%). Similarly, the rate of parietal GM atrophy in SPMS (-1.24-%) was faster than CIS (-0.63%) and HCs (-0.23%) (all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta=0.04, p <0.001). Interpretation This large multi-centre and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions.
The effectiveness of avoidance of house-dust-mite allergen (Dermatophagoides pteronyssinus 1 [Der p1]) in the management of asthma is uncertain.We conducted a double-blind, randomized, placebo-controlled study of allergen-impermeable bed covers involving 1122 adults with asthma. The primary outcomes were the mean morning peak expiratory flow rate over a four-week period during the run-in phase and at six months and the proportion of patients who discontinued inhaled corticosteroid therapy as part of a phased-reduction program during months 7 through 12. Der p1 was measured in mattress dust in a 10 percent random subsample of homes at entry and at 6 and 12 months.The prevalence of sensitivity to dust-mite allergen was 65.4 percent in the group supplied with allergen-impermeable bed covers (active-intervention group) and 65.1 percent in the control group supplied with non-impermeable bed covers. The concentration of Der p1 in mattress dust was significantly lower in the active-intervention group at 6 months (geometric mean, 0.58 microg per gram vs. 1.71 microg per gram in the control group; P=0.01) but not at 12 months (1.05 microg per gram vs. 1.64 microg per gram; P=0.74). The mean morning peak expiratory flow rate improved significantly in both groups (from 410.7 to 419.1 liters per minute in the active-intervention group, P<0.001 for the change; and from 417.8 to 427.4 liters per minute in the control group, P<0.001 for the change). After adjustment for base-line differences (by analysis of covariance), there was no significant difference between the groups in the peak expiratory flow rate at six months (difference in means, active-intervention group vs. control group, -1.6 liters per minute [95 percent confidence interval, -5.9 to 2.7] among all patients [P=0.46] and -1.5 liters per minute [95 percent confidence interval, -6.9 to 3.9] among mite-sensitive patients [P=0.59]). There was no significant difference between the groups in the proportion in whom complete cessation of inhaled corticosteroid therapy was achieved (17.4 percent in the active-intervention group and 17.1 percent in the control group) or in the mean reduction in steroid dose, either among all patients or among mite-sensitive patients.Allergen-impermeable covers, as a single intervention for the avoidance of exposure to dust-mite allergen, seem clinically ineffective in adults with asthma.
Objective: To investigate baseline MRI predictors of long-term disability in patients with clinically isolated syndromes (CIS).
Background: Baseline T2-hyperintense lesion number is only a modest predictor of long term disability in patients with CIS. Measures of brain lesion location/activity and atrophy have been associated with disability in the short-to-medium term (5-7 years) but how they relate to long-term outcomes is unknown.
Methods: 178 patients (mean age 32.3 years, 114 female) had MRI within 3 months of CIS and were followed up 15 years later. Baseline MRI variables included measures of lesion load (brain T2-hyperintense and T1-hypointense lesion number and volume), lesion location (periventricular, juxtacortical, infratentorial, spinal cord), lesion activity (gadolinium-enhancing lesion number) and atrophy (normalised whole brain, grey matter and white matter volume plus upper cervical cord cross-sectional area). The CIS symptomatic lesion was excluded. At follow-up, MS was diagnosed using the McDonald 2010 criteria and disability measured using the Expanded Disability Status Scale (EDSS). Significant disability after 15 years was defined as EDSS ≥3. Univariable and multivariable binary logistic regression was used to identify MRI predictors of long-term disability.
Results: 164 patients (92[percnt]) were followed up after a mean of 15.1 years; 119 (73[percnt]) developed multiple sclerosis (MS) and 45 (27[percnt]) remained CIS. 42 (26[percnt]) patients had an EDSS ≥3. In the multivariable model, baseline brain T2 lesion number (odds ratio [OR] 1.81, p=0.003) and baseline spinal cord lesions (OR 3.77, p=0.001) were independently associated with disability. Only spinal cord lesions were associated with disability in patients who developed MS (OR 2.73, p=0.013).
Conclusions: In this cohort with uniquely long follow-up, asymptomatic spinal cord lesions at the time of CIS were most strongly associated with disability after 15 years. These findings suggest that spinal cord lesions may be an important factor underpinning long-term disability in relapse-onset MS. Disclosure: Dr. Brownlee has nothing to disclose. Dr. Altmann has nothing to disclose. Dr. Wheeler-Kingshott has received personal compensation for activities with Biogen Idec as a consultant. Dr. Wheeler-Kingshott has received research support from the UK MS Society, UCL/UCLH, NIHR, BRC, EPSRC, ISRT, Wings for Life, and New Zealand Brain R Dr. Miszkiel has nothing to disclose. Dr. Ciccarelli has received personal compensation for activities with Novartis, Biogen and GE as a consultant. Dr. Miller has nothing to disclose.
The McDonald criteria allow multiple sclerosis (MS) to be diagnosed in patients with a clinically isolated syndrome (CIS) who have MRI evidence of dissemination in time and space.1–3 There have been successive versions of the criteria in 2001,1 20052 and 20103 with different requirements for dissemination in time and space. Although each version has been shown to have a high sensitivity and specificity for the development of clinically-definite MS (CDMS), few studies have investigated how much sooner4 and how more often5 MS can be diagnosed in patients with CIS using the McDonald criteria.
We recruited 178 patients with CIS presenting to Moorfields Eye Hospital and the National Hospital for Neurology and Neurosurgery between 1995 and 2004. The study was approved by ethics committees at both hospitals. Patients were seen at baseline, then for follow-up after 3 months, 1 year, 3 years and 6 years. At each study visit informed consent was obtained. Patients were assessed with a detailed review of neurological symptoms and neurological examination. Relapses were recorded at study visits, but patients were also encouraged to contact the research team at the time of new neurological symptoms. MRI of the brain and whole spine was obtained at each visit on the same 1.5 T Signa scanner, as described elsewhere.6 Each scan was reviewed by a neuroradiologist blinded to the patient's clinical status. The number, location and activity (ie, gadolinium enhancement) of T2 lesions was recorded.
During follow-up CDMS was defined according …
We have noticed an error in the “Methods” section. The error, which has no impact on the results or conclusions reached in the article, is detailed as follows:
The reported gender composition in the article was 8 males and 10 females for the patient group and 6 males and 15 females for the control group. It should have been reported as 10 males and 8 females for the patient group and 9 males and 12 females for the control group. The reported results for the gender comparison in the “Results” section on page 461, first paragraph, line 4 [“There were no significant differences in gender distribution (χ2 = 0.62, df = 1, P = 0.43) ”] still remains true, as this analysis was based on the true gender composition of 10 males and 8 females for the patient group and 9 males and 12 females for the control group. All other analyses incorporating gender also incorporate the true gender values.
Finally, in the section “Diffusing processing and analysis” on page 460, paragraph 2, line 20, “180°” should read “80°”.
We apologize for any inconvenience these errors may have caused.
In patients with chronic spinal cord injury, imaging of the spinal cord and brain above the level of the lesion provides evidence of neural degeneration; however, the spatial and temporal patterns of progression and their relation to clinical outcomes are uncertain. New interventions targeting acute spinal cord injury have entered clinical trials but neuroimaging outcomes as responsive markers of treatment have yet to be established. We aimed to use MRI to assess neuronal degeneration above the level of the lesion after acute spinal cord injury.In our prospective longitudinal study, we enrolled patients with acute traumatic spinal cord injury and healthy controls. We assessed patients clinically and by MRI at baseline, 2 months, 6 months, and 12 months, and controls by MRI at the same timepoints. We assessed atrophy in white matter in the cranial corticospinal tracts and grey matter in sensorimotor cortices by tensor-based analyses of T1-weighted MRI data. We used cross-sectional spinal cord area measurements to assess atrophy at cervical level C2/C3. We used myelin-sensitive magnetisation transfer (MT) and longitudinal relaxation rate (R1) maps to assess microstructural changes associated with myelin. We also assessed associations between MRI parameters and clinical improvement. All analyses of brain scans done with statistical parametric mapping were corrected for family-wise error.Between Sept 17, 2010, and Dec 31, 2012, we recruited 13 patients and 18 controls. In the 12 months from baseline, patients recovered by a mean of 5·27 points per log month (95% CI 1·91-8·63) on the international standards for the neurological classification of spinal cord injury (ISNCSCI) motor score (p=0·002) and by 10·93 points per log month (6·20-15·66) on the spinal cord independence measure (SCIM) score (p<0·0001). Compared with controls, patients showed a rapid decline in cross-sectional spinal cord area (patients declined by 0·46 mm per month compared with a stable cord area in controls; p<0·0001). Patients had faster rates than controls of volume decline of white matter in the cranial corticospinal tracts at the level of the internal capsule (right Z score 5·21, p=0·0081; left Z score 4·12, p=0·0004) and right cerebral peduncle (Z score 3·89, p=0·0302) and of grey matter in the left primary motor cortex (Z score 4·23, p=0·041). Volume changes were paralleled by significant reductions of MT and R1 in the same areas and beyond. Improvements in SCIM scores at 12 months were associated with a reduced loss in cross-sectional spinal cord area over 12 months (Pearson's correlation 0·77, p=0·004) and reduced white matter volume of the corticospinal tracts at the level of the right internal capsule (Z score 4·30, p=0·0021), the left internal capsule (Z score 4·27, p=0·0278), and left cerebral peduncle (Z score 4·05, p=0·0316). Improvements in ISNCSCI motor scores were associated with less white matter volume change encompassing the corticospinal tract at the level of the right internal capsule (Z score 4·01, p<0·0001).Extensive upstream atrophic and microstructural changes of corticospinal axons and sensorimotor cortical areas occur in the first months after spinal cord injury, with faster degenerative changes relating to poorer recovery. Structural volumetric and microstructural MRI protocols remote from the site of spinal cord injury could serve as neuroimaging biomarkers in acute spinal cord injury.SRH Holding, Swiss National Science Foundation, Clinical Research Priority Program "NeuroRehab" University of Zurich, Wellcome Trust.
Following an episode of optic neuritis, thinning of the retinal nerve fibre layer, which indicates axonal loss, is observed using optical coherence tomography. The longitudinal course of the retinal changes has not been well characterized. We performed a serial optical coherence tomography study in patients presenting with optic neuritis in order to define the temporal evolution of retinal nerve fibre layer changes and to estimate sample sizes for proof-of-concept trials of neuroprotection using retinal nerve fibre layer loss as the outcome measure. Twenty-three patients (7 male, 16 female, mean age 31 years) with acute clinically isolated unilateral optic neuritis were recruited to undergo optical coherence tomography, visual assessments and visual evoked potentials at presentation (median 16 days from onset of visual loss) and after 3, 6, 12 and 18 months. Compared with the clinically unaffected fellow eye, the retinal nerve fibre layer thickness of the affected eye was significantly increased at presentation and significantly reduced at all later time points. The evolution of retinal nerve fibre layer changes in the affected eye fitted well with an exponential model, with thinning appearing a mean of 1.6 months from symptom onset and the rate of ongoing retinal nerve fibre layer loss decreasing thereafter. At presentation, increased retinal nerve fibre layer thickness was associated with impaired visual acuity and prolonged visual evoked potential latency. Visual function after 12 months was not related to the extent of acute retinal nerve fibre layer swelling but was significantly associated with the extent of concurrent retinal nerve fibre layer loss. Sample size calculations for placebo-controlled trials of acute neuroprotection indicated that the numbers needed after 6 months of follow up are smaller than those after 3 months and similar to those after 12 months of follow-up. Study power was greater when investigating differences between clinically unaffected and affected eyes rather than retinal nerve fibre layer thickness of the affected eye alone. Inflammation in the optic nerve and impaired axonal transport (implied by retinal nerve fibre layer swelling) are associated with visual dysfunction and demyelination (long visual evoked potential latency) during acute optic neuritis. Retinal nerve fibre layer thinning is usually evident within 3 months. Optical coherence tomography-measured retinal nerve fibre layer loss after 6 months is a suitable outcome measure for proof-of-concept trials of acute neuroprotection in optic neuritis.
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