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Background Non-arteritic anterior ischaemic optic neuropathy (NA-AION) can cause disabling visual loss and traditionally, visual prognosis has been considered poor, although recent studies have demonstrated improvements in visual acuity in about 30% of patients over time. The aim of the study was to determine whether there was significant cortical reorganisation with functional MRI (fMRI) after acute NA-AION by comparing affected individuals with healthy controls. Methods 9 patients with NA-AION were studied acutely and then after 1, 2, 3 and 6 months. 23 healthy volunteers underwent scanning at least twice. At each time point, patients were assessed clinically and with fMRI. For the fMRI experiments, subjects underwent monocular visual stimulation (wearing goggles with flashing LED displays). Results When stimulating the affected eye, occipital activation was reduced in patients compared with controls. Also, within the NA-AION group, activation in the right Brodmann areas (BA) 44 and 45 was seen during the early phase of the condition. The same areas were activated within the NA-AION group several months later for fellow eye stimulation. When the NA-AION and healthy control groups were formally compared however, these areas (BA 44/45) were not significantly different. NA-AION subjects did show greater activation in visual related areas compared with controls when stimulating the fellow eye. Visual acuity was correlated with more occipital cortex activation when stimulating the affected eye. Conclusions There is cortical re-organisation of the fMRI response in extra-visual areas, seen when both affected and fellow eyes are stimulated after NA-AION.

Objective To investigate whether T2 lesion load and magnetisation transfer ratio (MTR) in the normal-appearing white matter (NAWM) and grey matter (GM) at study entry are independent predictors of progression and whether their changes correlate with the accrual of disability, over 5 years in early primary progressive multiple sclerosis (PPMS). Methods Forty-seven patients with early PPMS and 18 healthy controls were recruited at baseline and invited to attend clinical 6-monthly assessments for 3 years, and after 5 years. Patients were scored on the Expanded Disability Status Scale and multiple sclerosis functional composite subtests (25-foot timed walk test (TWT), nine-hole peg test and paced auditory serial addition test). At each time point, all subjects underwent brain MRI including T2-weighted, magnetisation transfer and volumetric sequences. T2 lesion load (T2LL), MTR histogram parameters and volumes for NAWM and GM were calculated. Statistical analyses identified predictors of progression and correlations between MRI changes and clinical changes over time. Results Baseline T2LL and GM peak location and peak height MTR were independent predictors of progression, as measured by TWT; a model including these three predictors explained 91% of the variance of the progression on TWT, a significantly higher percentage than that obtained when the predictors were modelled individually (80%, 74% and 68%, respectively). A greater progression rate correlated with a steeper increase in T2LL and a faster decline in GM mean and peak location MTR. Conclusions The combined assessment of both visible white matter damage and GM involvement is useful in predicting progression in PPMS.

Conventional MRI lesion measures modestly predict long term disability in some clinically isolated syndrome (CIS) studies. Brain atrophy suggests neuroaxonal loss in multiple sclerosis (MS) with the potential to reflect disease progression to a greater extent than lesion measures.To investigate whether brain atrophy and lesion load, during the first year in patients presenting with CIS, independently predict clinical outcome (development of MS and disability at 6 years).99 patients presenting with CIS were included in the study. T1 gadolinium enhanced and T2 weighted brain MRI was acquired at baseline and approximately 1 year later. Percentage brain atrophy rate between baseline and follow-up scans was analysed using SIENA.Mean annual brain atrophy rates were -0.38% for all patients, -0.50% in patients who had developed MS at 6 years and -0.26% in those who had not. Brain atrophy rate (p = 0.005) and baseline T2 lesion load (p0.001) were independent predictors of clinically definite MS. While brain atrophy rate was a predictor of Expanded Disability Status Scale (EDSS) score in a univariate analysis, only 1 year T2 lesion load change (p = 0.007) and baseline gadolinium enhancing lesion number (p = 0.03) were independent predictors of EDSS score at the 6 year follow-up. T1 lesion load was the only MRI parameter which predicted Multiple Sclerosis Functional Composite score at the 6 year follow-up.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.

To determine the long-term outcome of a cohort of 436 patients with multiple sclerosis (MS) seen in 1985 and long-term predictors of benign MS.The initial 1985 group of 436 patients with possible MS, including 53 benign patients, were followed for 21 years. Disability was recorded using the Expanded Disability Status Scale (EDSS). Survival from disease onset was calculated. The indicators of benign MS in the initial 1985 cohort and in the survivors in 2006 were determined.Of the original 436 patients, the 21-year follow-up outcome in 397 (91%) was established. The diagnosis of MS was incorrect in 41/397 (10%) of the whole cohort and in 2/53 (4%) of the benign group. Median survival of 356 patients with MS was 43.6 years from disease onset. Of 47/51 (92%) patients with benign MS followed in 2006, 7 (15%) remained benign, 18 had died and 22 were disabled. Median survival advantage for the 47 benign patients in 1985 compared to the 88 non-benign patients, when corrected for age, was 6 years (p0.08). In 2006, 40/356 (11%) patients had a benign outcome at a mean follow-up of 26.1 years. A benign course was significantly associated with female sex, younger age of onset and absence of motor symptoms at presentation.Although designating patients as having a benign course after 10 years has a poor predictive value, three factors at presentation indicate a better prognosis.

Background: The use of self-report measurements in clinical settings has increased. The underlying assumption for self-report measurements is that the patient understands the questions fully and is able to give a reliable assessment of his or her own health status. This might be problematic in patients with limitations that interfere with reliable self-assessment such as cognitive impairment or serious mood disturbances, as may be the case in multiple sclerosis. In these situations proxies may provide valuable information, provided we can be certain that proxies and patients give consistent ratings. Objective: To examine whether patients with multiple sclerosis and their partners agree on the impact of multiple sclerosis on the daily life of the patient by using the Multiple Sclerosis Impact Scale (MSIS-29). Methods: 59 patients with multiple sclerosis and their partners completed the MSIS-29. Agreement was examined, comprehensively at scale score levels and item functioning, using both traditional and less conventional psychometric methods (Rasch analysis). Results: Agreement between patients and partners was good for the physical scale, and slightly less but still adequate for the psychological scale. Mean directional differences did not show considerable systematic bias between patients and proxies. Intraclass correlation coefficients (ICCs) satisfied the requirements for agreement, but were higher for the physical scale (0.81) than for the psychological scale (0.72). These findings were supported by Rasch analyses. Conclusion: In this sample, albeit small, partners provided accurate estimates of the impact of multiple sclerosis. This supports the value of self-rating scales and indicates that partners might be useful sources of information when assessing the impact of multiple sclerosis on the daily life of patients.

Background and objective: The onset of multiple sclerosis is relapsing remitting or primary progressive. An improved understanding of the causes of early progressive disability in primary progressive multiple sclerosis (PPMS) could provide mechanistic targets for therapeutic intervention. Methods: Five magnetic resonance imaging (MRI) parameters that could potentially cause progressive disability were investigated in 43 patients with early PPMS and in 37 patients with early relapsing remitting multiple sclerosis (RRMS): atrophy in brain, both grey matter and white matter; intrinsic abnormality in brain, both grey matter and white matter (measured by the magnetisation transfer ratio (MTR)); and atrophy of the upper cervical spinal cord. Both groups were also compared with controls. Results: Patients with PPMS were older and more likely to be men. Both patient groups had atrophy of brain grey matter and white matter, and intrinsic abnormality in MTR of normal-appearing grey matter and white matter. Cord atrophy was present only in the PPMS (mean cord area: PPMS, 67.8 mm 2 ; RRMS, 72.7 mm 2 ; controls, 73.4 mm 2 ; p = 0.007). This was confirmed by multivariate analysis of all five MRI parameters, age and sex. Conclusion: Grey matter and white matter of the brain are abnormal in both early RRMS and PPMS, but cord atrophy is present only in PPMS. This is concordant with myelopathy being the usual clinical presentation of PPMS. Measurement of cord atrophy seems to be clinically relevant in PPMS treatment trials.

Background: The McDonald criteria include MRI evidence for dissemination in space and dissemination in time for the diagnosis of multiple sclerosis in young adult patients who present with clinically isolated syndromes (CIS) typical of the disease. Although a major advance, the criteria have limited sensitivity for making an early diagnosis. Objective: To compare the performance of McDonald criteria and modified McDonald criteria for dissemination in space and time for assessing the development of clinically definite multiple sclerosis. Methods: McDonald criteria were modified using the combination of a less stringent definition for dissemination in space and allowing a new T2 lesion per se after three months as evidence for dissemination in time. Modified and McDonald criteria were applied in 90 CIS patients at baseline and at three month follow up scans. Results: Both criteria were highly specific (>90%) but the modified criteria were more sensitive (77% v 46%) and more accurate (86% v 73%). Conclusions: These modified criteria should be evaluated in other CIS cohorts.

Objective: To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study. Methods: In total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral Δ 9 -tetrahydrocannabinol (Δ 9 -THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to12 months in the follow up study reported here. Results: Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (Δ 9 -THC mean reduction 1·82 (n = 154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n = 172, 95% CI −0.99 to 1.19), placebo −0.23 (n = 176, 95% CI −1.41 to 0.94); p = 0.04 unadjusted for ambulatory status and centre, p = 0.01 adjusted). There was suggestive evidence for treatment effects of Δ 9 -THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease. Conclusions: These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

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One hundred and fifteen patients with clinically isolated optic neuritis underwent magnetic resonance imaging (MRI) of the brain and spinal cord within 3 months of the onset of symptoms.Eighty one (70%) patients had brain lesions and 31 (27%) had cord lesions. Cord lesions were seen in 12% with a normal brain MRI, 21% with between one and eight brain lesions, and 45% with nine or more brain lesions. When the new diagnostic criteria for MS were applied, MRI cord imaging used for evidence of dissemination in time and space allowed a diagnosis of MS in only one additional asymptomatic patient at 1 year, two additional asymptomatic patients at 3 years.Using existing criteria, spinal cord imaging rarely contributes to the diagnosis in patients with clinically isolated optic neuritis.

The efficacy of interferon beta (IFN beta) is well established in relapsing-remitting multiple sclerosis (MS). However, the use of this drug in clinical practice is complex, especially because it is only partially effective, its long term efficacy and side effects are unknown, its efficacy may be abrogated by the development of neutralising antibodies, compliance is variable, and its cost effectiveness is controversial.Analysis of a prospectively followed up series of 101 MS patients treated with IFN beta was undertaken to: (1) monitor the outcome of IFN beta treatment in clinical practice; (2) compare the immunogenicity of the three commercial IFN beta preparations available; (3) assess the proportion of patients fulfilling the current guidelines of the Association of British Neurologists for stopping IFN beta therapy.During a median treatment period of 26 months (range 2-85), the relapse rate decreased by 41%. Although the reduction in the relapse rate was similar for all three commercial products, none of the Avonex treated patients were relapse free, compared with 19% of the Betaferon treated and 27% of the Rebif treated patients (p=0.02). Neutralising antibodies were not detected in Avonex treated patients (0 of 18), compared with 12 of 32 (38%) Betaferon treated and 10 of 23 (44%) Rebif treated patients (p=0.02). Forty of 101 (40%) patients satisfied the current (2001) Association of British Neurologists criteria for stopping IFN beta treatment at some stage during their treatment.IFN beta is effective in reducing the relapse rate in patients with relapsing-remitting MS in routine clinical practice. However, after a median treatment duration of 26 months, 40% of initially relapsing-remitting MS patients seem to have ongoing disease activity, presenting as disabling relapses or insidious progression.

OBJECTIVES—Routine data collection is now considered mandatory. Therefore, staff rated clinical scales that consist of multiple items should have the minimum number of items necessary for rigorous measurement. This study explores the possibility of developing a short form Barthel index, suitable for use in clinical trials, epidemiological studies, and audit, that satisfies criteria for rigorous measurement and is psychometrically equivalent to the 10 item instrument. METHODS—Data were analysed from 844 consecutive admissions to a neurological rehabilitation unit in London. Random half samples were generated. Short forms were developed in one sample (n=419), by selecting items with the best measurement properties, and tested in the other (n=418). For each of the 10 items of the BI, item total correlations and effect sizes were computed and rank ordered. The best items were defined as those with the lowest cross product of these rank orderings. The acceptability, reliability, validity, and responsiveness of three short form BIs (five, four, and three item) were determined and compared with the 10 item BI. Agreement between scores generated by short forms and 10 item BI was determined using intraclass correlation coefficients and the method of Bland and Altman. RESULTS—The five best items in this sample were transfers, bathing, toilet use, stairs, and mobility. Of the three short forms examined, the five item BI had the best measurement properties and was psychometrically equivalent to the 10 item BI. Agreement between scores generated by the two measures for individual patients was excellent (ICC=0.90) but not identical (limits of agreement=1.84±3.84). CONCLUSIONS—The five item short form BI may be a suitable outcome measure for group comparison studies in comparable samples. Further evaluations are needed. Results demonstrate a fundamental difference between assessment and measurement and the importance of incorporating psychometric methods in the development and evaluation of health measures.

Atrophy of the spinal cord is known to occur in multiple sclerosis but the cause and the timing of its onset are not clear. Recent evidence suggests that atrophy may start to occur early in the disease. The aim was to determine whether atrophy of the spinal cord could be detected in vivo using MRI techniques, in patients presenting with a clinically isolated syndrome, which in many cases is the earliest clinical stage of multiple sclerosis. The cross sectional area of the spinal cord was measured in 43 patients presenting with a clinically isolated syndrome and 15 matched controls. T2 weighted imaging of the brain was also performed to determine the number and volume of high signal lesions consistent with disseminated demyelination. Both patients and controls were restudied after 1 year. The spinal cord area was significantly smaller in the 74% of patients with an abnormal brain MRI at presentation than in controls (mean areas 73.9 mm 2 and 78.1 mm 2 respectively, p=0.03). No significant difference was found in the spinal cord area between controls and patients with normal baseline brain imaging. The annual rate of change in patients did not differ significantly from controls. In conclusion , the finding of a smaller cord area in the subgroup of patients with clinically isolated syndrome with the highest risk of developing multiple sclerosis—that is, with an abnormal brain MRI, suggests that atrophy has developed in some patients with multiple sclerosis even before their first clinical symptoms. However, the lack of a detectable change in cord area over 1 year of follow up contrasts strikingly with the results of an earlier study of patients with relapsing-remitting multiple sclerosis, suggesting that the rate of atrophy increases as the disease becomes more established.

OBJECTIVES—People with multiple sclerosis often have multiple complex needs that require input from a wide range of services. Many complain that services are inadequate and poorly coordinated. Few studies have been undertaken to support this contention and objective data are scarce. The level of services and home modifications received by people with multiple sclerosis across a broad range of disease severity has been investigated. METHODS—As part of a quality of life study, 150 adults with clinically definite multiple sclerosis were interviewed, using a structured questionnaire, to determine their current use of outpatient and community services and the home modifications in place. Disability, handicap, and emotional status were also measured. RESULTS—Forty five per cent of people did not receive any community services other than contact with their general practitioner. Thirty nine per cent of people with moderate and 12% with severe disability failed to receive community services. For the services received: 17% had contact with a community nurse; 33% with a care attendant or home help; 23% with a physiotherapist, 21% with an occupational therapist, and 10% with a social worker. Fifty eight per cent of people had modifications to their home as a direct result of multiple sclerosis. The relation between level of disability and number of services and adaptations received was moderate (r=0.58 and 0.54 respectively) and the relation between level of services and age (r=0.12), living alone (r=0.16), and emotional status (r=0.10) was negligible. CONCLUSIONS—Despite a shift of emphasis from hospital to community care, and the establishment of standards of care for multiple sclerosis, many people with moderate or severe disability fail to receive assistance. These results provide evidence to support the dissatisfaction felt by people with multiple sclerosis in relation to the services they receive. It raises questions about equitable allocation of resources and highlights the urgent need for a review of community services.

Objectives—To investigate the eVects of EMG guided botulinum toxin (BTX-A) on impairment and focal disability in adults presenting with focal hypertonia. Methods—A prospective, randomised, double blind, placebo controlled, parallel group trial was carried out with standardised assessment before and at 3 week intervals until 12 weeks after injection, in patients with focal hypertonia aVecting upper or lower limbs. Botulinum toxin or placebo was injected with EMG guidance after multidisciplinary assessment. The modified Ashworth scale of spasticity, percentage passive range of joint motion, subjective rating of problem severity, the Rivermead motor assessment scale, a timed 10 metre walk (lower limb patients), nine hole peg test (upper limb patients), and a modified goal attainment scale were used as outcome measures. The patients were 52 adults; 34 male, 18 female; mean age 40.31, range 16‐79 years; mean duration of symptoms 35 months (range 3 months to 22 years). Diagnoses included cerebrovascular accidents (23), head injury (12), incomplete spinal cord injury (six), tumour (five), cerebral palsy (three), and anoxic episodes (three). Results—For each variable an overall score for the treatment period was computed by summing the scores from the 3, 6, 9, and 12 week assessments. These overall scores were significantly better in the treated group for the Ashworth scale, percentage passive range of movement, Rivermead lower limb, and subjective rating of problem severity. The significant treatment eVect on the Ashworth scale was seen on analysis of variance (ANOVA) at 3 weeks and the subjective rating of problem severity at 3 and 6 weeks. The goal attainment scale score in both groups was similar at 12 weeks. Conclusion—Selective use of botulinum toxin to weaken muscles can lead to a reduction in resistance to passive movement about a distal limb joint. This allows for improvements in passive range of movement and focal disability, particularly in patients presenting with focal spasticity of the lower limb. (J Neurol Neurosurg Psychiatry 2000;69:499‐506)

Diffusion tensor imaging (DTI) fully characterises water molecule mobility in vivo, allowing an exploration of fibre tract integrity and orientation in the human brain. Using DTI this study demonstrates reduced fibre coherence (anisotropy) associated with cerebral infarction and in the corticospinal tract remote from the lesion, in five patients 2 to 6 months after ischaemic stroke. The study highlights the potential of DTI to detect and monitor the structural degeneration of fibre pathways, which may provide a better understanding of the pattern of clinical evolution after stroke.

OBJECTIVES—Multiple sclerosis lesions appear as areas of high signal on T2 weighted MRI. A proportion of these lesions, when viewed on T1 weighted MRI, appear hypointense compared with surrounding white matter. These hypointense T1 lesions are thought to represent areas of greater tissue damage compared with the more non-specific, total T2 lesion load. This study aimed to better characterise the properties of high signal T2 lesions with differing appearances on T1 weighted MRI using quantitative MR techniques. METHODS—Eleven patients with secondary progressive multiple sclerosis were studied. Two high signal T2 lesions were selected from each patient—one of which appeared hypointense and one isointense on a T1 weighted image. A voxel was positioned around each lesion and for this volume of brain the metabolite concentrations were estimated using proton MR spectroscopy (1H-MRS) and the T1 relaxation time within each voxel calculated from a T1 map generated using a multislice technique. RESULTS—Compared with isointense T1 lesions, hypointense T1 lesions exhibited a significantly lower absolute concentration of N-acetyl derived metabolites (tNAA) and a significantly higher absolute concentration of myo-inositol (Ins). T1 relaxation time correlated significantly with both tNAA (r=−0.8, p < 0.001) and Ins (r=0.5, p=0.012). There was no correlation between T1 relaxation times and creatine/phosphocreatine or choline containing compounds. CONCLUSIONS—Prolonged T1 relaxation times seem to reflect the severity of axonal damage or dysfunction (inferred by a low tNAA) and possibly also gliosis (inferred by a high Ins) in chronic multiple sclerosis lesions.

Objectives—Recovery to normal or near normal visual acuity is usual after acute demyelinating optic neuritis, despite the frequent persistence of conduction abnormalities as evidenced by the visual evoked potential (VEP). This raises the possibility that cortical adaptation to a persistently abnormal input contributes to the recovery process. The objective of this study was to investigate the pattern of cerebral response to a simple visual stimulus in recovered patients in comparison to normal subjects. Methods—Functional magnetic resonance imaging (fMRI) was used to study the brain activation pattern induced by a periodic monocular 8Hz photic stimulus in seven patients who had recovered from a single episode of acute unilateral optic neuritis, and in seven normal controls. VEPs and structural optic nerve MRI were performed on patients. Results—Stimulation of either eye in controls activated only the occipital visual cortex. However, in patients, stimulation of the recovered eye also induced extensive activation in other areas including the insula-claustrum, lateral temporal and posterior parietal cortices, and thalamus; stimulation of the clinically unaVected eye activated visual cortex and right insulaclaustrum only. The volume of extraoccipital activation in patients was strongly correlated with VEP latency (r=0.71, p=0.005). Conclusions—The extraoccipital areas that were activated in patients all have extensive visual connections, and some have been proposed as sites of multimodal sensory integration. The results indicate a functional reorganisation of the cerebral response to simple visual stimuli after optic neuritis that may represent an adaptive response to a persistently abnormal input. Whether this is a necessary part of the recovery process remains to be determined. (J Neurol Neurosurg Psychiatry 2000;68:441‐449)

OBJECTIVES To examine cognitive and neurological changes and their relation to brain pathology in patients with multiple sclerosis during acute relapse. METHODS Thirteen patients with multiple sclerosis were examined with a battery of neuropsychological tests during acute relapse and six weeks later. Their performance was compared with the performance of 10 controls matched for age and premorbid IQ. Gadolinium (Gd) enhanced MRI was also performed in patients on both occasions. RESULTS The patients with multiple sclerosis performed significantly worse than controls on most tests of attention and memory during acute relapse and in remission. At follow up there was a significant or trend of improvement in performance on some tests of attention for patients in whom the Gd enhanced lesion load had decreased. In this subgroup of patients, their improvement also correlated significantly with the reduction in acute lesion load. CONCLUSIONS The findings suggest that certain neuropsychological deficits detected during an acute relapse may be reversible, particularly in patients who initially have mild cognitive impairment.

OBJECTIVES Conventional T2 weighted MRI studies have highlighted the fact that the presence of clinically silent brain lesions increases the risk of developing clinically definite multiple sclerosis after an isolated syndrome of the optic nerve, brain stem, or spinal cord. The objectives of the present study are: (1) to show whether or not these patients also have asymptomatic abnormalities of the spinal cord, and (2) to recruit a new cohort of such patients using high resolution MRI of both brain and spinal cord. METHODS The brain was imaged in the axial plane with 3 mm thick contiguous slices using a proton density and T2 weighted fast spin echo (FSE) sequence; a T1 weighted sequence after the injection of gadolinium-DTPA; and a fast fluid attenuated inversion recovery (fFLAIR) sequence. The spinal cord was imaged in the sagittal plane with 3 mm thick slices using a T2 weighted FSE and a T1 weighted gadolinium enhanced sequence. RESULTS Thirty three patients, mean age 31 (16–46) were recruited. There were 14 men and 19 women. Brain MRI was abnormal in 22 (67%); no patient was seen with abnormalities on only one or other sequence. Six patients (18%) displayed one or more gadolinium enhancing lesions on brain MRI. In the spinal cord, nine (27%) patients displayed one or more clinically silent lesions on FSE. Two patients showed one and two gadolinium enhancing lesions in the spinal cord respectively. CONCLUSION This high incidence of spinal cord lesions emphasises that asymptomatic demyelinating lesions may also involve clinically eloquent pathways. Follow up studies are required to determine their prognostic importance.

OBJECTIVES—Quantitative measurement of lesion load on proton density or T2 weighted brain MRI in multiple sclerosis is a widely used marker of disease progression in treatment trials and natural history studies. However, it has proved difficult to obtain highly reproducible measurements. Several factors account for this, one of which is uncertainties in lesion identification, particularly very small white matter abnormalities. This paper aims to ascertain the significance of very small white matter abnormalities in the measurement of lesion load in multiple sclerosis. METHODS—All visible lesion areas identified by an experienced observer on proton density weighted spin echo brain MRI with 5 mm thick slices were measured by using a contouring technique in 15 patients with secondary progressive multiple sclerosis (SPMS) and 13 with relapsing remitting multiple sclerosis (RRMS). The size distribution of these lesions was analysed. RESULTS—80% of the number of the lesions were smaller than 80 mm2. Lesions that were smaller than 10 mm2 (equivalent diameter

OBJECTIVES: Since Devic's original description of neuromyelitis optica in 1894 there has been much debate regarding its aetiology. A specific cause has been identified in a minority of cases but in most the question has arisen whether or not Devic's neuromyelitis optica is a variant of multiple sclerosis. This study was undertaken to help clarify this issue. METHODS: Neuromyelitis optica was defined as (1) a severe transverse myelitis; (2) an acute unilateral or bilateral optic neuropathy; (3) no clinical involvement beyond the spinal cord or optic nerves, and (4) a monophasic or multiphasic illness. The clinical and autoantibody status was documented. Patients underwent CSF examination and MRI of brain and spinal cord. RESULTS: Twelve patients, with a mean age of presentation of 35.1 years, were seen. Eleven were women; vision was reduced to counting fingers or worse in 10 patients and seven became confined to a wheelchair. Examination of CSF showed local synthesis of oligoclonal bands in only two patients and a neutrophil pleocytosis in two. A possible aetiology was identified in five: a specific connective tissue disorder (two), pulmonary tuberculosis (one), and possible acute disseminated encephalomyelitis (two). Six had non-specific increases in various autoantibodies. Eleven patients underwent MRI of the brain and spinal cord. In 10 there were diffuse abnormalities involving cervical and thoracic cords with extensive swelling in the acute phase. Brain MRI was normal in five; in five there were multiple deep white matter lesions, and one patient had minor age related changes. CONCLUSION: It is proposed that Devic's neuromyelitis optica is a distinctive disorder with some clinical, CSF, and MRI features different from those found in classic multiple sclerosis. In most cases a specific aetiology is not identified, but an immunological mechanism of tissue damage seems likely.

OBJECTIVE--To assess the usefulness of serial cord MRI in patients with progressive multiple sclerosis. METHODS--Monthly MRI of the brain and spinal cord with and without gadolinium enhancement was carried out in 19 patients with progressive multiple sclerosis (10 primary progressive, nine secondary progressive) over the course of one year. RESULTS--During this period there were 132 active lesions in the brain and only six in the cord. One hundred and twelve (85%) active brain lesions occurred in the secondary progressive group; three new cord lesions occurred in each group. In the secondary progressive group MRI activity was high in patients who had superimposed relapses, whereas in those who progressed without relapse and in the primary progressive group it was low. Cross sectional areas of the cord decreased at the C5 level in both groups, implying progressive atrophy of fibre tracts. There was no relation between either brain or cord MRI activity and change in disability over the study period. CONCLUSIONS--Although the detection of new lesions by frequent cord imaging using current technology has little role in the monitoring of disease activity in progressive multiple sclerosis, the serial measurement of cord cross sectional area may be important. There is also evidence to suggest that the mechanism underlying irreversible disability in patients with progressive multiple sclerosis may be different in patients who continue to relapse than in those who do not.

At separate institutions, pattern reversal visual evoked potentials (VEPs) were recorded in children and older patients with phenylketonuria and compared with MRI of the brain. In nine patients aged less than 14 years, who were still on a diet low in phenylalanine, VEPs were clearly abnormal in only one and the abnormalities seen on MRI were mild. In 27 patients aged 14-31 years VEPs were abnormal in more than 80%, with significant reduction of amplitude and prolongation of latency despite the general absence of visual symptoms and abnormalities on routine neuro-ophthalmological examination. Among the older patients there was no significant correlation between VEP measures and plasma phenylalanine or tyrosine concentrations; neither was the incidence of VEP abnormalities dependent on whether or not the patients were still on a low phenylalanine diet. Some VEP amplitude measures were inversely correlated with the MRI lesion score, perhaps reflecting the severity of white matter abnormalities in the parieto-occipital region. In the older patients the amplitude of VEPs to stimulation of the central 8 degrees of the visual field was significantly correlated with IQ. The study confirms the high incidence of subclinical visual pathway involvement in older children and adults with phenylketonuria, and suggests the possibility of a link between the abnormal appearance of subcortical white matter on MRI and a physiological index of function of the CNS. As there was no evidence of general intellectual decline, it is suggested that the correlation between central field VEP amplitude and IQ may reflect abnormal development during infancy. Abnormalities on MRI, on the other hand, seem to be more closely related to current dietary state and phenylalanine concentration.

Seventy-six homosexual or bisexual men underwent two cranial MRI studies at a mean interval of 13 months; 23 were HIV seronegative, 41 seropositive but asymptomatic (Center for Disease Control (CDC) groups II/III), and 12 had AIDS related complex (ARC)/AIDS (CDC group IV). Agreement between two neuroradiologists was rated as very good for assessment of enlargement of ventricles and good for widening of cerebral sulci and the presence of focal lesions. For assessment of serial studies, the agreement was moderate. The prevalence of cerebral atrophy and focal white matter lesions was no higher in the asymptomatic patients (CDC group II/III) than in appropriate seronegative controls. Some patients with ARC/AIDS showed evidence of developing cerebral atrophy during the study period when serial scans were compared. The imaging evidence supports the other data obtained from this cohort, which suggest that no significant CNS involvement occurs in HIV infection before the development of ARC/AIDS.

The MRI data of seven patients with clinically definite multiple sclerosis who developed epileptic seizures are presented. Six of these cases demonstrated new or enhancing lesions. Cerebral biopsy in one of these lesions confirmed inflammation with myelin breakdown products. Lesions implicated in the causation of seizures involved the cortex or subcortical area. In one patient, a new lesion was associated with EEG abnormalities which resolved as the lesion reduced in size. In three patients epileptic activity was the only clinical manifestation of disease. Large, unresolving lesions tended to be associated with continuing seizures.

Serial gadolinium enhanced MRI of the brain detects much clinically silent disease activity in early relapsing-remitting and secondary progressive multiple sclerosis (MS), and thus has an important role in monitoring the effects of therapy. Based on the proceedings of a recent Commission of the European Communities (CEC) workshop and a review of the literature, guidelines are presented for using MRI to monitor treatment trials in MS. The guidelines consider: A) MRI system and techniques; B) patient selection; C) trial design; D) analysis of results. Priorities for future research are also indicated.

Background 1.5Tesla 1H-magnetic resonance spectroscopy (MRS) demonstrates reduced spinal cord (SC) N-acetyl-aspartate (NAA) following SC relapses in MS but it remains unknown whether glutamate-glutamine (Glx) metabolism is also affected, as in the brain. Using 3Tesla MRS, we quantified Glx following SC relapse and assessed the clinical relevance of metabolite changes. Methods SC metabolites were quantified in 20 RRMS patients (14F; mean age 41 yrs.) within 4 weeks of cervical SC relapse and 22 controls (17F; mean age 44 yrs.) using a cardiac-gated PRESS sequence; TE=30 ms; MOIST water suppression on a 3T Philips scanner. MSFC and EDSS scores were obtained for patients. Results SC NAA was reduced (p=0.023) and Glx was elevated (p=0.036) compared to controls. In patients, higher EDSS scores were independently predicted by higher creatine (p=0.032) and choline (p=0.041) and longer timed walk was independently predicted by higher creatine (p=0.002), myoinositol (p=0.025) and choline (p=0.044). Conclusions Higher choline, creatine and myoinositol are associated with disability and may reflect important pathological processes. Elevated Glx wasn9t predictive of disability but may cause excitotoxicity and hinder recovery; longitudinal study is therefore needed.

It has been suggested that spasticity may be increased in primary progressive multiple sclerosis (PPMS) following treatment with interferon beta.1 In an open study using the Ashworth Scale and a reflex scale, Bramanti et al measured change in spasticity in 19 subjects treated with interferon beta-1b and in 19 untreated subjects. An increase in spasticity during treatment was seen in 68% of the treated participants compared with 11% of the untreated participants. To investigate this phenomenon further, we conducted a retrospective analysis of the spasticity studied in the recently published randomised controlled trial of interferon beta-1a in PPMS.2 We …

Background Plasma and B cells have been implicated in multiple sclerosis (MS). The presence of intrathecal oligoclonal IgG and free light chains (FLCs) is a feature of MS and rituximab has been shown to be effective in MS. Plasma and B cells produce excess FLC that are excreted in the urine. Urinary FLC excretion is therefore a putative marker of MS activity. Objectives To confirm that subjects with demyelinating diseases have increased urinary excretion of FLCs. Methods in a cross-sectional study, urine FLCs were measured by ELISA and presented as a ratio to albumin to control for urine concentration. 40 patients with MS and 10 patients with clinically isolated syndromes (CIS) were compared to 20 subjects with posterior uveitis (PU), 19 with AIDS, 34 with rheumatoid arthritis (RA) and 19 normal controls (NC). Results Subjects with DD, PU, RA and AIDS have significantly higher free kappa, lambda and total urinary light chain excretion than NC (p Conclusions Increased urinary FLC are a biomarker of plasma cell and B cell activity and raised in subjects with MS and CIS. Further studies are required to see if raised urine FLC excretion correlates with MS disease activity and whether it is predictive of the development of MS in subjects with CIS.

PRION-1, the largest clinical trial in prion disease to date, showed no effect of the experimental therapeutic quinacrine on survival. Here we report analyses showing that quinacrine had no demonstrable benefit (p>0.4) when assessed by a range of rating scales. These included neurocognitive (Mini-Mental State Examination, ADAScog), psychiatric (Brief Psychiatric Rating Scale), global (Rankin and Global Impression of Change), clinician-rated (Clinician9s Dementia Rating (CDR)) and functional (Barthel) scales. These rating scales have several potential benefits over survival as an outcome measure: here we assess their validity and performance over 77 person-years follow-up in 101 symptomatic patients in PRION-1. Overall, across a range of models applied, we found that the Barthel and CDR scales were most robust to the difficulties posed by a prion disease clinical trial. A combination of selected subcomponents from these two scales gave increased power to detect clinically relevant effects in a future clinical trial of feasible size, compared to use of survival alone. We also discuss our work refining the use of these scales in the National Prion Monitoring Cohort, an ongoing prospective observational study of all types of human prion disease in the UK, and how this will inform the planning of future therapeutic trials.

Giovannoni and colleagues are to be commended for their detailed analysis of the impact of neutralising antibodies (NAB) to interferon β (IFNβ) during the treatment of multiple sclerosis.1 We are in general agreement with many of their statements and conclusions, but a few points should be discussed in a wider context. With respect to the clinical significance of neutralising antibodies to IFNβ, the authors state that “IFNβ has little if any clinical and MRI efficacy in the presence of neutralising antibodies.” We think it is appropriate to be more circumspect, as most published studies suggest that in NAB positive patients, clinical (and MRI) efficacy of interferon treatment is present when compared to placebo, and that there is some evidence that more immunogenic higher dose treatment can …

Three cases are reported of meningioma involving the orbital apex presenting with either progressive or episodic retroocular pain. In two cases pain was steroid responsive and in one of these patients this led to an initial diagnosis of orbital pseudotumour. Pain preceded visual loss and other symptoms by many months and these cases illustrate the importance of full investigation and where necessary surgical exploration in cases of apparent orbital inflammatory disease with an atypical or progressive course.

A serial study of peripheral blood T lymphocytes in 27 patients with clinically definite multiple sclerosis and 11 healthy controls was carried out over a 12 month period. This showed that contrary to many previous reports, relapses were not consistently associated with reduced numbers of peripheral blood suppressor T lymphocytes or any other T cells. Persistently low T cells numbers, including both the helper and suppressor T cell subsets, were, however, associated with disease activity as measured by the development of increased disability during the course of the study. This was true both for the patients with relapsing/remitting disease and those with progressive disease. The importance of carrying out a serial study was emphasised by the consistent and significant differences that were detected between individuals in both the control and the patient groups. A serial study is the most reliable means by which clinical events can clearly be correlated with laboratory estimations. The association in this study between the development of increased disability and persistently low levels of peripheral blood T lymphocytes suggest that both may be related to the underlying disease process in multiple sclerosis.

CSF immunoglobulins were examined in 103 patients with clinically definite multiple sclerosis, 106 patients with either suspected or progressive possible multiple sclerosis and 72 patients with other neurological diseases. Raised CSF IgG index and oligoclonal banding were found in 71% and 75% of clinically definite multiple sclerosis patients respectively and both tests were abnormal in 11% of patients with other neurological diseases. The CSF IgG index and the presence of oligoclonal IgG did not relate to the severity or duration of established disease in these patients. In patients with suspected and progressive possible multiple sclerosis, both a raised IgG index and the presence of oligoclonal banding were found significantly more frequently than in the OND group. Abnormalities of these parameters were significantly correlated with the presence of an abnormal evoked response in these patients (chi 2 = 10.16 p less than 0.01). When 47 patients with suspected multiple sclerosis were studied prospectively the presence of oligoclonal banding at presentation was associated with development of further disease activity.

This study demonstrates a significant reduction in the number of both total T cells and suppressor T cells identified by monoclonal antibodies in multiple sclerosis patients in acute relapse but not in those in remission. The reduction in the number of suppressor T cells was shown by all three monoclonal antibodies used but was most clearly demonstrated using Leu 2a rather than either OKT 8 or OKT 5. These findings suggest that the choice of monoclonal antibody used in a study of suppressor T cell numbers will influence the results and may help explain the lack of agreement in previous studies.