The management of multiple sclerosis is becoming increasingly complex with the emergence of new and more effective disease-modifying therapies (DMT). We propose a new treatment paradigm that individualises treatment based on a choice between two interchangeable therapeutic strategies of maintenance-escalation or induction therapy. We propose treating- to-target of no evident disease activity (NEDA) as defined using clinical and MRI criteria. This algorithm requires active monitoring with a rebaselining MRI, at a point in time after the specific DMT concerned has had sufficient time to work, and at least annual MRI studies to monitor for subclinical relapses. Disease activity on the maintenance-escalation therapy arm of the algorithm indicates a sub-optimal treatment response and should trigger a discussion about switching, or escalating, therapy or the consideration of switching to the induction therapy arm of the algorithm. In comparison, disease activity on an induction therapy arm would be an indication for retreatment or a switch to the maintenance-escalation therapy arm. We envisage the definition of NEDA evolving with time as new technological innovations are adopted into clinical practice, for example the normalisation of whole, or regional, brain atrophy rates and cerebrospinal fluid neurofilament levels.

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 β-1a (IFNβ, 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 INFβ (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 IFNβ 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.

BackgroundWhilst the dangers of ‘legal highs’ have been widely publicised in the media, very few cases of the neurological syndrome associated with the inhalation of nitrous oxide (N2O) have been reported. Here we set out to raise awareness of subacute degeneration of the spinal cord arising from recreational N2O use so that formal surveillance programs and public health interventions can be designed.MethodsCase series documenting the clinical and investigational features of ten consecutive cases of subacute degeneration of the spinal cord presenting to a hospital with a tertiary neurosciences service in East London.ResultsSensory disturbance in the lower (± upper) limbs was the commonest presenting feature, along with gait abnormalities and sensory ataxia. MRI imaging of the spine showed the characteristic features of dorsal column hyperintensity on T2 weighted sequences. Serum B12 levels may be normal because subacute degeneration of the spinal cord in this situation is triggered by functional rather than absolute B12 deficiency.DiscussionA high index of suspicion is required to prompt appropriate investigation, make the diagnosis and commence treatment early. This is the largest reported series of patients with subacute degeneration of the spinal cord induced by recreational use of N2O. However, the number of patients admitted to hospital likely represents the ‘tip of the iceberg’, with many less severe presentations remaining undetected. After raising awareness, attention should focus on measuring the extent of the problem, the groups affected, and devising ways to prevent potentially long-term neurological damage.

Vaccines are key to preventing contagious, or serious, infections. However, their use in people with multiple sclerosis (pwMS) has often been problematic because of misguided concerns that vaccinations may exacerbate the disease and also because some disease-modifying therapies (DMTs) may influence the immune response to immunisations and/or their safety. PwMS may have higher morbidity and mortality from vaccine-preventable infections. It is, therefore, important to address any patient’s reluctance to accept vaccination and to provide clear guidance for clinicians on which vaccinations to consider proactively. We have reviewed the current literature and provide recommendations regarding vaccines in adults with MS, including specific advice regarding vaccination safety in patients receiving—or going to receive—DMTs, vaccination during pregnancy, pretravel counselling and patient education. Our aim is to endorse vaccination as one of the most efficient methods for protecting pwMS from infections and to provide a framework to ensure vaccinations are safe and effective.

Objective To explore the potential of a post-processing technique combining FLAIR and T 2 * (FLAIR*) to distinguish between lesions caused by multiple sclerosis (MS) from cerebral small vessel disease (SVD) in a clinical setting. Methods FLAIR and T 2 * head datasets acquired at 3T of 25 people with relapsing MS (pwRMS) and ten with pwSVD were used. After post-processing, FLAIR* maps were used to determine the proportion of white matter lesions (WML) showing the 'vein in lesion' sign (VIL), a characteristic histopathological feature of MS plaques. Sensitivity and specificity of MS diagnosis were examined on the basis of >45% VIL + and >60% VIL + WML, and compared with current dissemination in space (DIS) MRI criteria. Results All pwRMS had >45% VIL + WML (range 58-100%) whilst in pwSVD the proportion of VIL + WML was significantly lower (0-64%; mean 32±20%). Sensitivity based on >45% VIL + was 100% and specificity 80% whilst with >60% VIL + as the criterion, sensitivity was 96% and specificity 90%. DIS criteria had 96% sensitivity and 40% specificity.

Objective:To compare the cancer risk of cladribine and other disease-modifying drugs (DMDs) in trials of people with relapsing multiple sclerosis (pwRMS).Methods:Meta-analysis of phase III trials of licensed DMDs for pwRMS and a phase III trial of cladribine (CLARITY). Cancer rates were compared using Fisher exact test.Results:Eleven trials were included. Investigated treatments included cladribine, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, alemtuzumab, and glatiramer acetate. The cancer rate in the CLARITY treatment group (0.34%) was not increased compared to all other treatment groups, whether including placebo-controlled trials only (0.6%, p = 0.4631) or all trials, i.e., including those with an active comparator arm (0.67%, p = 0.3669). No cancer was reported in the CLARITY placebo group, whereas the combined cancer rate of all other placebo groups was 1.19% (p = 0.0159). The cancer rate of zero in the CLARITY placebo group was also lower than that in the phase III trial of cladribine in people with clinically isolated syndrome (ORACLE MS, 2.91%, p = 0.0012). In fact, no difference was detected between cancer rates in the treatment groups of CLARITY (0.34%) and ORACLE MS (0.49%) (p = 0.6546).Conclusions:Our study does not support an increased cancer risk from cladribine in the doses used in CLARITY and ORACLE MS, which previously contributed to refusal of market authorization of cladribine in Europe. Longer-term follow-up is required to assess the safety profile of cladribine, as well as currently licensed DMDs, to definitively assess cancer risk.

Pathology and magnetic resonance imaging (MRI) studies have provided evidence of widespread axonal loss and reductions of cerebral and spinal cord volume in multiple sclerosis (MS). Atrophy measures on MRI may be a useful surrogate marker of worsening disability in MS, but the published studies are of relatively short duration. Change in brain volume (atrophy) was measured over a four-year period in 20 patients with relapsing-remitting (RR) and 18 with secondary progressive (SP) MS using three-dimensional (3D) MRI acquired during treatment trials of interferon-beta-1a (Rebif). Brain parenchymal and lateral ventricle volume changes were determined and correlated with clinical measures. Over four years, brain parenchymal volume (BPV) decreased in RRMS and SPMS patients by 0.9% (P = 0.006) and 0.3% (P = 0.118), respectively, and the lateral ventricle volumes increased by 15% (P < 0.0001) and 13% (P < 0.0001), respectively. In RRMS patients both lateral ventricle volume (r = 0.63, P = 0.004) and BPV change (r = -0.47, P = 0.037) were related to disability change, as measured by the Expanded Disability Status Scale. Even though a small study and despite the possible confounding effects of interferon treatment, this study demonstrated an association between measures of cerebral atrophy and worsening disability. The data also provides evidence that brain atrophy can be detected early in the disease course and central white matter atrophy as reflected by ventricle enlargement appears to be a continuous process.

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.