Simon J. Hickman

Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis.

Traditionally, multiple sclerosis (MS) has been diagnosed on the basis of clinical evidence of dissemination in time and space. Previously, it could not be diagnosed in patients with single clinical episodes of demyelination known as clinically isolated syndromes. New diagnostic criteria from the International Panel of McDonald and colleagues incorporate MRI evidence of dissemination in time and space to allow a diagnosis of MS in patients with clinically isolated syndromes. From clinical and MRI examinations performed prospectively at baseline, 3 months, 1 year, and 3 years of follow‐up, the frequency of developing MS was ascertained by the application of both the new McDonald criteria and the Poser criteria for clinically definite MS. The specificity, sensitivity, positive and negative predictive value, and accuracy of the new criteria for the development of clinically definite MS were assessed. At 3 months, 20 of 95 (21%) patients had MS with the McDonald criteria, whereas only 7 of 95 (7%) had developed clinically definite MS. After 1 year, the corresponding figures were 38 of 79 (48%) and 16 of 79 (20%), and after 3 years, they were 29 of 50 (58%) and 19 of 50 (38%). The development of MS with the new MRI criteria after 1 year had a high sensitivity (83%), specificity (83%), positive predicative value (75%), negative predictive value (89%), and accuracy (83%) for clinically definite MS at 3 years. Use of the new McDonald criteria more than doubled the rate of diagnosis of MS within a year of presentation with a clinically isolated syndrome. The high specificity, positive predictive value, and accuracy of the new criteria for clinically definite MS support their clinical relevance.

Diffusion MRI in multiple sclerosis

Diffusion imaging is a quantitative, MR-based technique potentially useful for the study of multiple sclerosis (MS), due to its increased pathologic specificity over conventional MRI and its ability to assess in vivo the presence of tissue damage occurring outside T2-visible lesions, i.e., in the so-called normal-appearing white and gray matter. The present review aims at critically summarizing the state-of-the-art and providing a background for the planning of future diffusion studies of MS. Several pieces of evidence suggest that diffusion-weighted and diffusion tensor MRI are sensitive to MS damage and able to detect its evolution over relatively short periods of time. Although a significant relationship between diffusion-weighted MRI findings and MS clinical disability was not found in the earliest studies, with improved diffusion imaging technology correlations between diffusion abnormalities and MS clinical aspects are now emerging. However, the best acquisition and postprocessing strategies for MS studies remain a matter of debate and the contribution of newer and more sophisticated techniques to diffusion tensor MRI investigations in MS needs to be further evaluated. Although changes in diffusion MRI indices reflect a net loss of structural organization, at present we can only speculate on their possible pathologic substrates in the MS brain. Postmortem studies correlating diffusion findings with histopathology of patients with MS are, therefore, also warranted.

Investigating cervical spinal cord structure using axial diffusion tensor imaging.

This study describes a new technique for Diffusion Tensor Imaging (DTI) that acquires axial (transverse) images of the cervical spinal cord. The DTI images depict axonal fiber orientation, enable quantification of diffusion characteristics along the spinal cord, and have the potential to demonstrate the connectivity of cord white matter tracts. Because of the high sensitivity to motion of diffusion-weighted magnetic resonance imaging and the small size of the spinal cord, a fast imaging method with high in-plane resolution was developed. Images were acquired with a single-shot EPI technique, named ZOOM-EPI (zonally magnified oblique multislice echo planar imaging), which selects localized areas and reduces artefacts caused by susceptibility changes between soft tissue and the adjacent vertebrae. Cardiac gating was used to reduce pulsatile flow artefacts from the surrounding cerebrospinal fluid. Voxel resolution was 1.25 x 1.25 mm(2) in-plane with 5-mm slice thickness. Both the mean diffusivity (MD) and the fractional anisotropy (FA) indices of the cervical spinal cord were measured. The FA index demonstrated high anisotropy of the spinal cord with an average value of 0.61 +/- 0.05 (highest value of 0.66 +/- 0.03 at C3), comparable to white matter tracts in the brain. The diffusivity components parallel and orthogonal to the longitudinal axes of the cord were lambda( parallel) = (1648 +/- 123) x 10(-6) mm(2)s(-1) and lambda( perpendicular) = (570 +/- 47) x 10(-6) mm(2) s(-1), respectively. The high axial resolution allowed preliminary evaluation of fiber connectivity using the fast-marching tractography algorithm, which generated traces of fiber paths consistent with the well-known cord anatomy.

Management of acute optic neuritis

Optic neuritis is a common condition that causes reversible loss of vision. It can be clinically isolated or can arise as one of the manifestations of multiple sclerosis. Occasional cases are due to other causes, and in these instances management can differ radically. The treatment of optic neuritis has been investigated in several trials, the results of which have shown that corticosteroids speed up the recovery of vision without affecting the final visual outcome. Other aspects of management, however, are controversial, and there is uncertainty about when to investigate and when to treat the condition. Here we review the diagnostic features of optic neuritis, its differential diagnosis, and give practical guidance about management of patients. The conditions association with multiple sclerosis will be considered in the light of studies that define the risk for development of multiple sclerosis and with respect to results of trials of disease-modifying drugs in these individuals.

Optic radiation changes after optic neuritis detected by tractography-based group mapping

Postmortem data suggest that trans‐synaptic degeneration occurs in the lateral geniculate nucleus after optic nerve injury. This study investigated in vivo the optic radiations in patients affected by optic neuritis using fast marching tractography (FMT), a diffusion magnetic resonance imaging (MRI) fiber tracking method, and group mapping techniques, which allow statistical comparisons between subjects. Seven patients, 1 year after isolated unilateral optic neuritis, and ten age and gender‐matched controls underwent whole‐brain diffusion tensor MR imaging. The FMT algorithm was used to generate voxel‐scale connectivity (VSC) maps in the optic radiations in each subject in native space. Group maps of the left and right optic radiations were created in the patient and control group in a standardized reference frame using statistical parametric mapping (SPM99). The reconstructed optic radiations in the patient group were localized more laterally in the posterior part of the tracts and more inferiorly than in the control group. Patients showed reduced VSC values in both tracts compared with controls. These findings suggest that the group mapping techniques might be used to assess changes in the optic radiations in patients after an episode of optic neuritis. The changes we have observed may be secondary to the optic nerve damage. Hum Brain Mapp, 2005.

ADC mapping of the human optic nerve: increased resolution, coverage, and reliability with CSF-suppressed ZOOM-EPI.

The mean apparent diffusion coefficient (ADC) of the human optic nerve (ON) has been quantified in vivo, and mean ADC maps are shown along the complete length of the nerve from the globe to the optic chiasm. The mean ADC, over the whole nerve, is shown to be 1058 × 10–6 mm2 s–1 (standard deviation (SD), over nine 3‐mm slices, 101×10–6 mm2 s–1; range (833–1178)×10–6 mm2 s–1). The robustness of the method relies on acquisition of high‐resolution coronal images of the ON using the ZOOM‐EPI technique, which makes use of a shortened echo train length for increased resolution with decreased susceptibility‐induced distortions. Suppression of the cerebrospinal fluid (CSF) and fat signals from tissues that surround the ON also helps successful identification and delineation of the nerve. Averaging of magnitude images is used to compensate for the inherently low signal‐to‐noise ratio (SNR) of the acquired images; the effects of the Rayleigh distributed noise in such images are allowed for during ADC calculations. Magn Reson Med 47:24–31, 2002.

Adaptive cortical plasticity in higher visual areas after acute optic neuritis

The ability to distinguish adaptive cortical reorganization may help to target future therapeutic strategies after neurological insult. We investigated cortical plasticity by prospectively applying visual functional magnetic resonance imaging (fMRI) and optic nerve MRI to 20 patients with acute optic neuritis at baseline, 1, 3, 6, and 12 months. We performed three types of correlation analyses to investigate the relationships between fMRI activity, clinical function, and optic nerve structure. The first analysis directly correlated the fMRI response to clinical function or optic nerve structure and found dynamic relations especially within the first 3 months. The second analysis used a novel technique that modeled the fMRI response and optic nerve structure together with clinical function, to determine the contribution fMRI made to clinical function after accounting for structural factors. Significant effects were found at baseline only, within the right peristriate cortex, and bilaterally in the lateral occipital complexes, which are normally involved in higher order visual processing. The third analysis investigated the relation between the modeled visual recovery rate and fMRI response but found no significant effects. The key findings of this study are from the second analysis and suggest a genuine adaptive role for cortical reorganization within extrastriate visual areas early after optic neuritis. Ann Neurol 2005;57:622–633

Visual recovery following acute optic neuritis--a clinical, electrophysiological and magnetic resonance imaging study.

Abstract.This study reports the prospective follow–up of a cohort of patients with acute optic neuritis examined with serial visual tests, visual evoked potentials (VEPs), conventional and triple–dose gadolinium (Gd)–enhanced magnetic resonance imaging (MRI) to examine which factors are important in visual recovery. Thirty–three patients were recruited with acute unilateral optic neuritis. A clinical and VEP assessment was performed on each. Optic nerve MRI was performed using fast spin echo (FSE) (on all) and triple-dose Gdenhanced T1–weighted sequences (n = 28). Optic nerve lesion lengths were measured. Serial assessments were performed on 22 of the patients up to one–year. Serial Gd–enhanced optic nerve imaging was performed on 15 of the patients until enhancement ceased. The final 30–2 Humphrey visual field mean deviation (MD) was 2.55 dB higher in patients in the lowest quartile of initial Gd–enhanced lesion length compared with the other quartiles (p < 0.01) but recovery was not related to the duration of enhancement. The initial recovery of Humphrey MD was 4.60 dB units per day in patients with good eventual recoveries (MD > –6.0 dB) and 0.99 dB per day in poor-recovery patients (p = 0.02).Good–recovery patients had mean central field VEP amplitudes 2.29 µV higher during recovery than poor-recovery patients (p = 0.047). The results suggest that factors which are associated with a better prognosis are: having a short acute lesion on triple–dose gadolinium enhanced imaging, higher VEP amplitudes during recovery and a steep gradient of the initial improvement in vision.

Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial

BACKGROUND Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision through neurodegeneration in the optic nerve and in its fibres in the retina. Inhibition of voltage-gated sodium channels is neuroprotective in preclinical models. In this study we aimed to establish whether sodium-channel inhibition with phenytoin is neuroprotective in patient with acute optic neuritis. METHODS We did a randomised, placebo-controlled, double-blind phase 2 trial at two UK academic hospitals in London and Sheffield. Patients with acute optic neuritis aged 18-60 years, presenting within 2 weeks of onset, with visual acuity of 6/9 or worse, were randomly assigned (1:1) by minimisation via a web-based service to oral phenytoin (maintenance dose 4 mg/kg per day if randomised before or on July 16, 2013, and 6 mg/kg per day if randomised on or after July 17, 2013) or placebo for 3 months, stratified by time from onset, centre, previous multiple sclerosis diagnosis, use of disease-modifying treatment, and use of corticosteroids for acute optic neuritis. Participants and treating and assessing physicians were masked to group assignment. The primary outcome was retinal nerve fibre layer (RNFL) thickness in the affected eye at 6 months, adjusted for fellow-eye RNFL thickness at baseline, analysed in a modified intention-to-treat population of all randomised participants who were followed up at 6 months. Safety was analysed in the entire population, including those who were lost to follow-up. The trial is registered with ClinicalTrials.gov, number NCT 01451593. FINDINGS We recruited 86 participants between Feb 3, 2012, and May 22, 2014 (42 assigned to phenytoin and 44 to placebo). 29 were assigned to phenytoin 4 mg/kg and 13 to phenytoin 6 mg/kg. Five participants were lost to follow-up, so the primary analysis included 81 participants (39 assigned to phenytoin and 42 to placebo). Mean 6-month RNFL thickness in the affected eye at 6 months was 81.46 μm (SD 16.27) in the phenytoin group (a mean decrease of 16.69 μm [SD 13.73] from baseline) versus 74.29 μm (15.14) in the placebo group (a mean decrease of 23.79 μm [13.97] since baseline; adjusted 6-month difference of 7.15 μm [95% CI 1.08-13.22]; p=0.021), corresponding to a 30% reduction in the extent of RNFL loss with phenytoin compared with placebo. Treatment was well tolerated, with five (12%) of 42 patients having a serious adverse event in the phenytoin group (only one, severe rash, was attributable to phenytoin) compared with two (5%) of 44 in the placebo group. INTERPRETATION These findings support the concept of neuroprotection with phenytoin in patients with acute optic neuritis at concentrations at which it blocks voltage-gated sodium channels selectively. Further investigation in larger clinical trials in optic neuritis and in relapsing multiple sclerosis is warranted. FUNDING US National Multiple Sclerosis Society, Multiple Sclerosis Society of Great Britain and Northern Ireland, Novartis, UK National Institute for Health Research (NIHR), and NIHR UCLH/UCL Biomedical Research Centre.

The incidence and prevalence of idiopathic intracranial hypertension in Sheffield, UK.

Background and purpose:  The purpose of this study was to identify the incidence and prevalence of idiopathic intracranial hypertension (IIH) in Sheffield, UK.