The relationship of brain and cervical cord volume to disability in clinical subtypes of multiple sclerosis: a three-dimensional MRI study.

OBJECTIVES: Brain and cervical cord volume is a potentially valuable index marker of irreversible pathological processes in multiple sclerosis (MS). Volume in both brain and cervical cord regions in the same patients has only been investigated in a small number of subjects. We aimed at measuring volume in different parts of the central nervous system, and its relationship with clinical measures, in relapsing-remitting (RR) and secondary progressive (SP) MS patients. MATERIAL AND METHODS: Conventional dual echo and three-dimensional (3-D) magnetization prepared rapid acquisition gradient echo imaging was performed on 97 (49 RR and 48 SP) MS patients, and on 31 age- and gender-matched healthy controls. The volumes of the supratentorial brain, lateral ventricles, brainstem, cerebellum and upper cervical cord (UCC) were determined on 3-D magnetic resonance imaging. RESULTS: RR MS patients had significantly smaller supratentorial brain (P=0.002) and larger lateral ventricles (P=0.047) compared with controls, but no differences were found for cerebellum, brainstem and UCC volumes. Significantly smaller supratentorial brain (P<0.0001), cerebellum (P=0.007), brainstem (P=0.0004) and UCC (P<0.0001) volumes, and larger lateral ventricles (P<0.0001) were observed in SP MS patients than in controls. In RR MS, T2-lesion volume correlated with supratentorial (r=-0.46, P=0.0009), lateral ventricular (r=0.65, P<0.0001), cerebellar (r=-0.42, P=0.003) and brainstem (r=-0.35, P=0.01) volumes, but not with UCC volume (r=-0.18, P=0.22). In SP MS, apart from lateral ventricular volume (r=0.52, P=0.0002), none of the estimated structural volumes correlated with T2-lesion volume. The UCC volume correlated with brainstem volume in both RR MS (r=0.35, P=0.016) and SP MS (r=0.38, P=0.007). Multiple regression analysis showed that supratentorial brain volume in RR group, and UCC volume in SP group, were single significant contributors (P=0.01 and 0.04, respectively) to the Expanded Disability Status Scale of all factors entered into the regression model. CONCLUSION: Atrophy is confined to the supratentorial compartment early in the disease course corresponding to the RR stage, but becomes more pronounced in the brain and cervical spinal cord in the SP phase. The estimate of cervical cord volume for SP MS is relevant to functional disability and may be helpful in monitoring MS evolution in the progressive form of disease.

Spinal cord atrophy and disability in multiple sclerosis over four years: application of a reproducible automated technique in monitoring disease progression in a cohort of the interferon beta-1a (Rebif) treatment trial.

BACKGROUND: Pathology in the cervical spinal cord is considered an important cause of disability in multiple sclerosis. However, the majority of serial studies have failed to find a correlation between spinal cord atrophy and disability. OBJECTIVES: To use a highly reproducible and accurate method to quantify spinal cord area change on three dimensional magnetic resonance imaging and relate this to disability change in patients with multiple sclerosis. METHODS: 38 patients with multiple sclerosis (20 with the relapsing-remitting (RRMS) form and 18 with the secondary progressive (SPMS) form) were imaged at baseline and at months 6, 12, 18, and 48 during two treatment trials of the high dose subcutaneous thrice weekly interferon beta-1a (IFNbeta, Rebif). Thirty one healthy subjects were also imaged at baseline. Upper cervical cord area (UCCA) was measured using Sobel edge detection. RESULTS: The intraobserver coefficient of variation of the method was 0.42%. A significant reduction in UCCA was detected at month 6 in the placebo group (p = 0.04) and at month 12 for INFbeta (p = 0.03). The mean reduction of UCCA at month 48 was 5.7% for patients initially on placebo who received treatment at 24 months (RRMS) or at 36 months (SPMS), and 4.5% for those on IFNbeta throughout the study (p = 0.35). The change in UCCA was significantly correlated with change in the expanded disability status scale at month 12 (r = 0.4, p = 0.016), month 18 (r = 0.32, p = 0.05), and month 48 (r = 0.4, p = 0.016) in the total cohort. CONCLUSIONS: Despite the small number of patients studied and the possible confounding effects of interferon treatment, this study showed that edge detection is reproducible and sensitive to changes in spinal cord area, and that this change is related to changes in clinical disability. This suggests a role for measurement of spinal cord atrophy in monitoring disease progression and possible treatment effects in clinical trails.

Pyramidal tract mapping by diffusion tensor magnetic resonance imaging in multiple sclerosis: improving correlations with disability.

BACKGROUND: Current magnetic resonance imaging (MRI) outcome measures such as T2 lesion load correlate poorly with disability in multiple sclerosis. Diffusion tensor imaging (DTI) of the brain can provide unique information regarding the orientation and integrity of white matter tracts in vivo. OBJECTIVE: To use this information to map the pyramidal tracts of patients with multiple sclerosis, investigate the relation between burden of disease in the tracts and disability, and compare this with more global magnetic resonance estimates of disease burden. METHODS: 25 patients with relapsing-remitting multiple sclerosis and 17 healthy volunteers were studied with DTI. An algorithm was used that automatically produced anatomically plausible maps of white matter tracts. The integrity of the pyramidal tracts was assessed using relative anisotropy and a novel measure (L(t)) derived from the compounded relative anisotropy along the tracts. The methods were compared with both traditional and more recent techniques for measuring disease burden in multiple sclerosis (T2 lesion load and "whole brain" diffusion histograms). RESULTS: Relative anisotropy and L(t) were significantly lower in patients than controls (p < 0.05). Pyramidal tract L(t) in the patients correlated significantly with both expanded disability status scale (r = -0.48, p < 0.05), and to a greater degree, the pyramidal Kurtzke functional system score (KFS-p) (r = -0.75, p < 0.0001). T2 lesion load and diffusion histogram parameters did not correlate with disability. CONCLUSIONS: Tract mapping using DTI is feasible and may increase the specificity of MRI in multiple sclerosis by matching appropriate tracts with specific clinical scoring systems. These techniques may be applicable to a wide range of neurological conditions.

Improved white matter fiber tracking using stochastic labeling.

Diffusion tensor imaging (DTI) promises a robust means of visualizing in vivo white matter fibers in individual subjects, and of inferring direct connectivity between distant points in the brain. By following the primary eigenvector of the diffusion tensor, trajectories may be defined that trace the path of the underlying fiber tract. However, fiber tracking is prone to cumulative error from acquisition noise and partial volume, which limits the repeatability of such techniques. An image-processing method based on stochastic labeling, by which the noisy primary eigenvectors may be reconfigured according to anatomically reasonable assumptions, is described. The method's potential to improve fiber tracking is first demonstrated on numerical test data. It is then applied to real data acquired from healthy volunteers. Trajectories defined within the corpus callosum and the pyramidal tracts are rendered using 3D graphic imaging software, and the results are compared before and after processing. Fiber tracking was shown to produce anatomically plausible results, and typical errors were largely resolved by the method. Further, the sensitivity of trajectories to their start point was greatly reduced after processing. The use of stochastic labeling may therefore improve the reliability of experiments using white matter fiber tracking.

Quantitative diffusion characteristics of the human brain depend on MRI sequence parameters.

Quantitative diffusion-weighted MRI has been applied to the study of neurological diseases, including multiple sclerosis, where the molecular self-diffusion coefficient D has been measured in both lesions and normal-appearing white matter. Histograms of D have been used as a novel measure of the "lesion load", with potential applications that include the monitoring of efficacy in new treatment trials. However different ways of measuring D may affect its value, making comparison between different centres and research groups impossible. We aimed to assess the effect, if any, of using two different MRI sequences on the value of D. We studied 13 healthy volunteers, using two different quantitative diffusion sequences (including different b(max) values and gradient applications). Maps of D were analysed using both regions of interest (ROI) in white matter and "whole brain" histograms, and compared between the two sequences. In addition, we studied three standardised test liquids (with known values of D) using both sequences. Histograms from the two sequences had different distributions, with a greater spread and higher peak position from the sequence with lower b(max). This greater spread of D was also evident in the white matter and test liquid ROI. "Limits of agreement" analysis demonstrated that the differences could be clinically relevant, despite significant correlations between the sequences obtained using simple rank methods. We conclude that different quantitative diffusion sequences are unlikely to produce directly comparable values of D, particularly if different b(max) values are used. In addition, the use of inappropriate statistical tests may give false impressions of close agreement. Standardisation of methods for the measurement of D are required if these techniques are to become useful tools, for example in monitoring changes in the disease burden of multiple sclerosis.

Combined monitoring of motor and somatosensory evoked potentials in orthopaedic spinal surgery.

OBJECTIVES: To demonstrate possible advantages of combined (motor and sensory) versus single modality (either motor or sensory) intra-operative spinal cord monitoring and to investigate risk factors for post-operative neurological sequelae. METHODS: Recordings of lower limb motor evoked potentials (MEPs) to multi-pulse transcranial electrical stimulation (TES), and tibial nerve somatosensory evoked potentials (SEPs), were attempted during 126 operations in 97 patients (79 with spinal deformity and 18 with miscellaneous spinal disorders). RESULTS: Combined motor and sensory monitoring was successfully achieved in 104 of 126 (82%) operations. No response to either modality could be recorded in two patients with Friedreich' s ataxia. In 18 patients monitoring was possible in only one modality: SEPs could not be recorded in two patients and MEPs in 16. Significant intra-operative EP changes occurred in one or both modalities in 16 patients; in association with instrumentation in 10 cases, and with systemic changes in 6. After appropriate remedial measures, SEPs recovered either fully or partially in 8/8 patients and MEPs in only 67% (10/15 patients). New deficits were present post-operatively in 6 of the 16 patients with abnormal intra-operative EPs. Normal MEPs at the end of the operation correctly predicted the absence of new motor deficits in all cases. SEPs either remained unchanged or recovered fully after remedial measures in 3 patients with new post-operative motor deficits. Neurological complications were more frequent in patients with miscellaneous spinal disorders and/or pre-existing neurological deficits. No complications occurred in patients with idiopathic scoliosis. CONCLUSIONS: Combined SEPs and multi-pulse TES-MEPs provide a safe, reliable and sensitive method of monitoring spinal cord function in orthopaedic surgery. This method is superior to single modality techniques, both for increasing the number of patients in whom satisfactory monitoring of spinal cord function can be achieved and, for improving the sensitivity and predictivity of monitoring. Combined SEP/MEP methods may enhance the impact of neuromonitoring on the intra-operative management of the patient and favourably influence neurological outcome.

Randomized, double-blind, placebo-controlled study of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis: a categorical disability trend analysis.

The treatment effects of recent immunomodulatory therapies on disease progression in relapsing-remitting multiple sclerosis (MS) have been mostly established from 'confirmed progression' endpoints. However, the reliability of this outcome measure is poor and a significant proportion of patients may be erroneously classified. We previously proposed the area under disability/time curves to quantify in-trial disability changes, but although these have advantages, they lack information on the direction of change. We have therefore performed disease trend analyses and categorical classifications using serial Expanded Disability Status Scale (EDSS) scores from the 533 complete datasets in a double-blind, randomized, placebo-controlled, phase III trial of subcutaneous interferon beta-1a (IFNbeta-1a) (PRISMS study). We found significant treatment benefits for IFNbeta-1a on in-trial disability course (P=0.002). Therapeutic advantages remained when relapse-related assessments were excluded (P=0.018). Post hoc analyses demonstrated that IFNbeta-1a was mainly effective in both increasing the proportion of patients with a 'stable' course and reducing those with prolonged, disabling deteriorations. Baseline disease duration and EDSS levels, but not MRI lesion load, predicted the subsequent disability trends. Mean 'numbers needed to treat' (NNTs) to obtain preferred disability courses were reduced in patients with shorter disease duration. These results have important implications for the targeting of immunomodulatory therapies in MS.

International consensus statement on the use of disease-modifying agents in multiple sclerosis.

OBJECTIVE: To provide recommendations on the use of disease-modifying agents in the management of multiple sclerosis (MS) and to ensure that treatment will be available to those patients who may benefit. METHODS: An initial draft of the consensus statement was prepared by the Steering Committee and amended in the light of written comments from a group of MS specialists. At a subsequent workshop, the wording of the consensus statement was discussed, modified if necessary, and the participants indicated their level of support using an electronic voting system. A new draft of the statement was then sent to a much larger group of international opinion leaders in MS for further comment. RESULTS: A number of statements were agreed, which outline the criteria for consideration of disease-modifying therapy for MS and recommendations for treatment. Each statement was accepted completely, or with only minor reservations by 95% or more of those present at the workshop. CONCLUSIONS: Periodic reviews and modifications to the statement will be required, as new approaches to the treatment of MS and other therapeutic agents become available.

White matter mapping using diffusion tensor MRI.

Diffusion tensor MRI is used to define trajectories that reflect the long-range order of in vivo white matter (WM) fiber tracts. Fiber tracking is particularly prone to cumulative error from noise and partial volume along the length of the trajectory paths, but the overall shape of each path is anatomically meaningful. By considering only the long-range similarity of path shapes, a method of constructing 3D maps of specific WM structures has been developed. A trajectory is first computed from an operator-selected seed voxel, located within the anatomical structure of interest (SOI). Voxels from the same structure are then automatically identified based on the similarity of trajectory path shapes, assessed using Pearson's correlation coefficient. The corpus callosum and pyramidal tracts in 14 patients with multiple sclerosis, and in 10 healthy controls were mapped by this method, and the apparent diffusion coefficient (ADC) was measured. The ADC was significantly higher in patients than in controls, and higher in the corpus callosum than in the pyramidal tracts for both groups. Using this method the different functional structures in the WM may be identified and mapped. Within these maps, MRI parameters can be measured for subsequent comparison with relevant clinical data.

Evaluation of cognitive assessment and cognitive intervention for people with multiple sclerosis.

OBJECTIVES: Cognitive problems in multiple sclerosis are common but any possible benefits of treatment remain uncertain. The aim of the study was to evaluate the benefits of providing a psychology service, including cognitive assessment and intervention, to patients with multiple sclerosis. METHOD: The study was a single blind randomised controlled trial. A total of 240 patients with clinically definite, laboratory supported, or clinically probable multiple sclerosis were recruited from an multiple sclerosis management clinic and assessed on a brief screening battery. They were randomised into three groups. The control group received no further intervention. The assessment group received a detailed cognitive assessment, the result of which was fed back to staff involved in the patients' care. The treatment group received the same detailed cognitive assessment and a treatment programme designed to help reduce the impact of their cognitive problems. Patients were followed up 4 and 8 months later on the general health questionnaire (GHQ-28), extended activities of daily living scale, SF-36, everyday memory questionnaire, dysexecutive syndrome questionnaire, and memory aids questionnaire. RESULTS: The three groups were compared on the outcome measures at 4 and 8 months after recruitment. There were few significant differences between the groups and those that occurred favoured the control group. Overall, the results showed no effect of the interventions on mood, quality of life, subjective cognitive impairment or independence. CONCLUSIONS: The study failed to detect any significant effects of cognitive assessment or cognitive intervention in this cohort of people with multiple sclerosis.

Once weekly interferon beta for multiple sclerosis is superseded by higher and more frequent dosing.

Therapy with interferon (IFN) beta can significantly alter the disease course in relapsing-remitting multiple sclerosis. Evidence indicates that the efficacy of this agent is related to treatment regimen (dose, route and dose frequency). A higher total weekly dose administered several times a week provides greater clinical benefit than a lower dose given once weekly (q.w.). This dose- and dose frequency-dependency of the efficacy of IFN beta has been clearly demonstrated in three recent head-to-head studies, as well as in other major clinical trials, and pharmacodynamic, pharmacokinetic and pre-clinical studies. The use of a q.w. dose regimen of IFN beta is likely to have a negative impact on patients in both the short and long-term because it allows additional accumulation of irreversible tissue damage in the central nervous system. Patients should receive the optimal, more rapid benefits from higher and more frequent doses of IFN beta, administered as early as possible after diagnosis.

Cognitive correlates of supratentorial atrophy on MRI in multiple sclerosis.

OBJECTIVES: We aimed to investigate associations between neuropsychological indices and normalized volumes of supratentorial structures, and the area of the corpus callosum. MATERIALS AND METHODS: We studied 40 patients with clinically definite MS, using 3D-acquired MRI (MPRAGE, Magnetization Prepared Rapid Acquisition Gradient Echo) and stereology. Subjects underwent a neuropsychological battery interrogating multiple cognitive domains, from which a global Cognitive Index Score (CIS) was derived. RESULTS: White matter volumes were significantly correlated with CIS (rho= -0.59, P<0.0001) and with many of the individual cognitive tests. CIS was also significantly correlated with the corpus callosal area (rho= -0.49, P<0.002). Grey matter volumes did not significantly correlate with any cognitive test. CONCLUSIONS: These volume/function relationships presumably reflect the effects of subcortical axonal and myelin loss on the neural networks that subserve cognition. If serial MRI volume estimations can index accumulating cognitive deficits, this simple technique may be useful in therapeutic trials.

Inflammation and atrophy in multiple sclerosis: MRI associations with disease course.

Brain atrophy may be a useful surrogate marker of axonal loss and disease progression in multiple sclerosis (MS). Several studies have suggested that inflammatory disease activity is a risk factor for atrophy in the early stages of the disease, but may become less important later in the disease course. We aimed to investigate the relationships between atrophy and active inflammation at different stages of the disease course using brain volume measurements from magnetic resonance imaging (MRI) in patients with both relapsing-remitting (RR) (n=95) and secondary progressive (SP) (n=76) MS. Conventional dual echo and three-dimensional magnetization-prepared rapid-acquisition gradient echo imaging were performed in all patients and in 31 healthy controls. Supratentorial and infratentorial brain, and lateral ventricular volumes were determined using modern design stereology. Patients with SP MS had smaller supratentorial (p=0.003) and infratentorial brain volumes (p=0.0003), and larger lateral ventricles (p=0.02) than patients with RR MS. RR MS patients with T(1)-enhancing lesions had smaller supratentorial (p=0.02) and infratentorial (p=0.002) brain volumes and larger ventricles (p=0.002) than those without enhancing lesions. SP MS patients with enhancing lesions also had significantly larger lateral ventricles (p=0.03). Categorical analysis showed that more RR MS patients with enhancing lesions had smaller supratentorial brain (p=0.005), or larger lateral ventricular (p=0.028) volumes, and more SP MS patients with enhancing lesions had increased lateral ventricle volumes (p=0.013), than patients without enhancements. The number of enhancing lesions was significantly correlated with lateral ventricular volumes in both RR MS (r=0.39, p=0.0001) and SP MS (r=0.46, p<0.0001). Our data shows that the presence of active inflammation on a single MRI in the course of RR and SP MS, is associated with a higher risk and higher level of brain atrophy. These findings emphasise the important long-term relationship between inflammation and atrophy in MS and provide additional support for the strategy of early anti-inflammatory treatment to protect tissue integrity.

Ventricular enlargement in multiple sclerosis: a comparison of three-dimensional and linear MRI estimates.

Atrophy of central white matter is related to irreversible clinical disability in multiple sclerosis (MS) and ventricular enlargement may be a sensitive marker of this tissue loss. Therapeutic trials in MS have provided MRI data for investigation of cerebral atrophy in MS. These studies use almost exclusively two-dimensional (2-D) images, which may be limited in the assessment of three-dimensional (3-D) structures. We used 3-D MRI data to estimate ventricular volumes in 40 patients with MS and 10 healthy controls, to look at associations with clinical disability and the stage of the disease. We then compared simple linear measures of ventricular size from conventional 2-D images, with 3-D volume estimates to establish the best available linear indices of ventricular volume. Mean ventricular volumes were increased in the patients and significantly larger in the more disabled patients. The estimated volume of the third ventricle obtained from 3-D MRI showed the strongest association with the clinical stage of the disease, duration of symptoms and levels of disability. Finally, we confirmed that in patients with MS accurate data on ventricular size can be obtained from 2-D images by two simple and convenient linear measures, the width of the third ventricle and of the anterior horn of the lateral ventricle.

The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies.

The clinical and laboratory phenotype of a paraproteinaemic neuropathy syndrome termed chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies is described in a series of 18 cases. Previous single case reports have outlined some features of this syndrome. All 18 cases were defined by the presence of serum IgM antibodies which react principally with NeuAc (alpha2-8)NeuAc(alpha2-3)Gal-configured disialosyl epitopes common to many gangliosides including GDlb, GD3, GTlb and GQlb. In 17 out of 18 cases, the serum contained benign IgM paraproteins, and in four of these cases at least two IgM paraproteins were present. The IgM antibodies were also cold agglutinins in 50% of cases. The clinical picture comprised a chronic neuropathy with marked sensory ataxia and areflexia, and with relatively preserved motor function in the limbs. In addition, 16 out of 18 cases had motor weakness affecting oculomotor and bulbar muscles as fixed or as relapsing-remitting features. When present in their entirety, these clinical features have been described previously under the acronym CANOMAD: chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies. This distribution of clinical features is reminiscent of Miller Fisher syndrome, in which acute-phase anti-disialylated ganglioside IgG antibodies are found. Clinical electrophysiology and nerve biopsy show both demyelinating and axonal features. A partial response to intravenous immunoglobulin and other treatments is reported in some cases.

Quantitative diffusion weighted magnetic resonance imaging, cerebral atrophy, and disability in multiple sclerosis.

OBJECTIVES: To investigate the relations between quantitative diffusion coefficient MRI histograms, clinical variables, and cerebral atrophy. METHODS: Twenty two patients with clinically definite multiple sclerosis and 11 healthy volunteers were studied. Histograms of apparent diffusion coefficient (ADC) from a volume of interest that included multiple slices encompassing the lateral ventricles were processed from diffusion weighted MRI. In addition, total lesion load was measured on T2 weighted dual echo images, and cerebral volume from 3D magnetisation prepared rapid acquisition gradient echo scans. All patients underwent neurological assessment, including disability on the expanded disability status scale (EDSS). RESULTS: Histograms from the patient group showed a reduced peak height and a "right shift" compared with healthy controls. Peak height of the diffusion histogram correlated with both EDSS (r=-0.54, p=0.0101) and disease duration (r=-0.52, p=0.0140), but not with age. Brain volume correlated with peak height of the ADC histogram (r=0.55, p=0.0129), but not with disability. Total lesion load also correlated moderately with EDSS (r=0.46, p=0.03). CONCLUSIONS: This study shows for the first time that quantitative MRI measures of diffusion correlate with clinical variables (disability, disease duration) and cerebral atrophy in multiple sclerosis. Cerebral atrophy and fixed neurological deficit may be attributed to axonal loss, which would be expected to have a significant effect on ADC. Extension of this method to more patients and longitudinal studies will further elucidate its sensitivity, reproducibility, and potential role in clinical practice and treatment trials.

Benefits of glatiramer acetate on disability in relapsing-remitting multiple sclerosis. An analysis by area under disability/time curves. The Copolymer 1 Multiple Sclerosis Study Group.

New immunomodulatory therapies for relapsing-remitting multiple sclerosis (RRMS) have well-documented effects in reducing relapses, but it has been difficult to demonstrate their benefits on disability in relatively short treatment trials. Commonly utilised disability outcome measures are problematic both in usefulness and clinical interpretation when applied to MS subjects with fluctuating and variable disease courses. An alternative technique is to use the summary measure 'area under the disability/time curve' (AUC) to index the total in-trial morbidity experienced by patients. In this study, we applied AUC analyses to the serial Expanded Disability Status Scale (EDSS) scores from the U.S. multicentre, Phase III, two-year core study of glatiramer acetate in 251 RRMS patients. When all available EDSS evaluations were analysed with AUC(CHANGE) ('combined data', including relapse-related assessments), active treatment was significantly superior to placebo (P=0.018). The benefits of glatiramer acetate persisted when transient relapse effects were reduced by using 'scheduled visit data' only (P=0.021). With the more conservative AUC(SUM) measure, significant active treatment effects remained (P=0.029 and 0.046, for both 'combined' and 'scheduled visit' data, respectively). Subgroup calculations performed with baseline disability stratified at EDSS 3.5 also showed benefits of treatment over placebo, but statistical significance was not reached. This analysis of data from a Phase III treatment trial illustrates the AUC summary measure technique and provides further evidence of the efficacy of glatiramer acetate in RRMS.

Long term azathioprine fails to prevent onset of multiple sclerosis: report of two cases.

Azathioprine is an immunosuppressive drug widely used in the treatment of chronic inflammatory diseases, including Multiple Sclerosis (MS). We report two patients who developed the first manifestations of clinically definite multiple sclerosis while on long term (3.5 and 10 years, respectively) treatment with azathioprine for Crohn's disease. Both patients developed the first MS symptoms during a quiescent phase of their inflammatory bowel disease. These cases show that long term azathioprine, while possibly maintaining inflammatory bowel disease under control, could not prevent the onset of MS. Multiple Sclerosis (2000) 6 362 - 363

A quality network model for the daily care of multiple sclerosis.

The urgent need to optimise treatment strategies for patients with Multiple Sclerosis (MS) was recognised by the participants at the 1998 European Charcot Foundation (ECF) symposium in Nice. The 'Nice Declaration' led to the formation of a Task Force Essentials Group charged with developing measures of the quality of MS care in Europe. Algorithms for nine critical domains (disability, spasticity, ataxia, pain, cognition, mood, fatigue, bladder function and sexual activity) and 'educated guesses' have been developed to measure interventions and outcomes which reflect the quality of clinical decision-making processes. A generic model called a 'quality network', consisting of a group of clinics connected to a central server, has been successfully applied to the care of diabetes across Europe. This model will now be developed and applied to MS management, to provide clinicians with longitudinal epidemiological data and, to evolve treatment algorithms and further quality measures. The ECF will next validate the system in a 1-year pilot study using a net of 10 clinics. Finally, an extended European network working in a learning environment will continuously assess, update and improve the quality of care of MS patients. Multiple Sclerosis (2000) 6 231 - 236

Working memory dysfunction in major depression: an event-related potential study.

OBJECTIVES: To study working memory function in untreated major depression using a digit probe identification and matching task. METHODS: We compared behavioural performance and event-related potentials during processing of the Sternberg working memory task in 14 depressed patients and 14 healthy matched control subjects. RESULTS: Patients made more mistakes than controls as the memory load was increased from one to 5 digits and had significantly slower reaction times at all levels of memory load. The patients' event-related potentials (ERPs) differed significantly from controls. Pathological changes were similar for auditory and visual presentation. Surface negative activity in the 157-210 ms section of the waveform was reduced for all levels of memory load, suggesting abnormal sensory/perceptual processing in the modality-specific association cortices, possibly due to a failure of selective attention mechanisms. In the 375-840 ms epoch, the patients' responses showed large amplitude sustained negative activity, maximal at Cz and a reduced late positive wave. The large prolonged negativity in the patients' ERPs suggests activation of additional neuronal assemblies than those normally participating in the task. This could reflect either compensatory mechanism or dysfunction of inhibitory systems. These changes were sensitive to memory load, suggesting that they reflect alterations of memory-related processes. CONCLUSIONS: This study provides objective evidence that major depression significantly affects working memory. The ERP changes in depression could be accounted for by dysfunction of the central executive control of working memory.