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.

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 (β = 1.32, P < 0.01) and spinal cord lesions (β = 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 (β = − 0.79, P < 0.01) and Symbol Digit Modalities Test (β = −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.

Objective To estimate the relation between alcohol consumption and risk of death, the level of alcohol consumption at which risk is least, and how these vary with age and sex. Design Analysis using published systematic reviews and population data. Setting England and Wales in 1997. Main outcome measures Death from any of the following causes: cancer of lip, oral cavity, pharynx, oesophagus, colon, rectum, liver, larynx, and breast, essential hypertension, coronary heart disease, stroke, cirrhosis, non-cirrhotic chronic liver disease, chronic pancreatitis, and injuries. Results A direct dose-response relation exists between alcohol consumption and risk of death in women aged 16-54 and in men aged 16-34. At older ages the relation is U shaped. The level at which the risk is lowest increases with age, reaching 3 units a week in women aged over 65 and 8 units a week in men aged over 65. The level at which the risk is increased by 5% above this minimum is 8 units a week in women aged 16-24 and 5 units a week in men aged 16-24, increasing to 20 and 34 units a week in women and men aged over 65, respectively. Conclusions Substantially increased risks of all cause mortality can occur even in people drinking lower than recommended limits, and especially among younger people.

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The findings confirm that brain atrophy occurs during the earliest phases of MS and suggest that 1 year longitudinal measures of MRI change, if considered together with baseline MRI variables, might help to predict clinical status 6 years after the first demyelinating event in CIS patients, better than measurements such as lesion or brain volumes on baseline MRI alone.

Thinning of the retinal nerve fiber layer (RNFL) of clinically unaffected eyes is seen in patients with multiple sclerosis (MS). It is uncertain when this thinning occurs, and whether ongoing RNFL loss can be measured over time with optical coherence tomography (OCT). Using time-domain OCT, we studied 34 patients with progressive MS (16 primary progressive MS, 18 secondary progressive; 14 male; 20 female; mean age at study entry 51 years; median EDSS 6; mean disease duration at study entry 12 years) on two occasions with a median interval of 575 (range 411-895) days apart. Eighteen healthy controls (10 male; eight female; mean age at study entry 46 years) were also studied twice, with a median interval of 656 days (range 398-890). Compared to controls, the patients had significant decreases in the RNFL thickness and macular volume of their clinically unaffected eyes at study entry. No significant decrease in RNFL thickness was observed between baseline and follow-up in either patients or controls. Macular volume declined significantly in patients and controls, but there was no difference in this change between the two groups. The study findings suggest that time domain OCT detects little disease-related ongoing loss of retinal axons in progressive forms of MS and has limited use for monitoring potential neuroprotective therapies at this stage of disease. Further studies are needed using higher-resolution OCT systems and in larger groups of patients, to elucidate the timing and mechanism of RNFL loss that is observed in clinically unaffected nerves in MS.

Improvements in symptom control and psychosocial support for patients who die from stroke are needed, as is better communication between health professionals and patients and their families. Education of doctors and nurses working with stroke patients in the principles of palliative care may help ensure that all dying stroke patients receive high-quality care.

Spinal cord, infratentorial, and gadolinium lesions within 3 months of optic neuritis onset and new T2 lesions after 3 months predicted disability after 6 years; only spinal cord lesions were predictive of disability in those developing clinically definite multiple sclerosis.