Jack H. Simon

International consensus diagnostic criteria for neuromyelitis optica spectrum disorders

Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.

Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial†

Rituximab, a monoclonal antibody selectively depleting CD20+ B cells, has demonstrated efficacy in reducing disease activity in relapsing‐remitting multiple sclerosis (MS). We evaluated rituximab in adults with primary progressive MS (PPMS) through 96 weeks and safety through 122 weeks.

Revised Recommendations of the Consortium of MS Centers Task Force for a Standardized MRI Protocol and Clinical Guidelines for the Diagnosis and Follow-Up of Multiple Sclerosis

This is a comprehensive group of guidelines for imaging patients with demyelinating disease, from an international group of neurologists and radiologists. Suggestions for MR imaging protocols are given for the brain, for surveillance imaging for progressive multifocal leukoencephalopathy, for spinal cord imaging, and for the orbit. Recommendations are also given for what type of material should be included in the report. SUMMARY: An international group of neurologists and radiologists developed revised guidelines for standardized brain and spinal cord MR imaging for the diagnosis and follow-up of MS. A brain MR imaging with gadolinium is recommended for the diagnosis of MS. A spinal cord MR imaging is recommended if the brain MR imaging is nondiagnostic or if the presenting symptoms are at the level of the spinal cord. A follow-up brain MR imaging with gadolinium is recommended to demonstrate dissemination in time and ongoing clinically silent disease activity while on treatment, to evaluate unexpected clinical worsening, to re-assess the original diagnosis, and as a new baseline before starting or modifying therapy. A routine brain MR imaging should be considered every 6 months to 2 years for all patients with relapsing MS. The brain MR imaging protocol includes 3D T1-weighted, 3D T2-FLAIR, 3D T2-weighted, post-single-dose gadolinium-enhanced T1-weighted sequences, and a DWI sequence. The progressive multifocal leukoencephalopathy surveillance protocol includes FLAIR and DWI sequences only. The spinal cord MR imaging protocol includes sagittal T1-weighted and proton attenuation, STIR or phase-sensitive inversion recovery, axial T2- or T2*-weighted imaging through suspicious lesions, and, in some cases, postcontrast gadolinium-enhanced T1-weighted imaging. The clinical question being addressed should be provided in the requisition for the MR imaging. The radiology report should be descriptive, with results referenced to previous studies. MR imaging studies should be permanently retained and available. The current revision incorporates new clinical information and imaging techniques that have become more available.

MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials

Over the past 15 years, MRI lesion activity has become the accepted surrogate primary outcome measure in proof-of-concept placebo-controlled clinical trials of new immunomodulating therapies in relapse-onset multiple sclerosis (MS). In parallel, the number of patients that are available for the placebo arm of trials has declined, and more-aggressive drugs are being developed. A critical review is warranted to ensure efficient MRI—and patient—resource utilization. Recently, an international panel reviewed the methodology for efficient use of MRI-monitored trials in relapse-onset MS. In this article, we provide up-to-date recommendations for scan acquisition, image analysis, outcome-measure definition and standards of reporting. Factors to consider for optimizing trial design, such as outcome measure selection and the unique requirements of phase II and phase III trials, including active-comparator studies, are outlined. Finally, we address safety considerations in the use of MRI in MS trials, and the safety-related responsibilities of the various parties involved in conducting such trials.

Prevalence of brain magnetic resonance imaging meeting Barkhof and McDonald criteria for dissemination in space among headache patients

Background: Incidental T2 white matter hyperintensities (WMHs) in headache patients on brain magnetic resonance imaging (MRI) may prompt concern for demyelinating disease. Objective: We reviewed brain MRI studies in patients with headaches without known demyelinating disease to determine the prevalence meeting imaging criteria for multiple sclerosis (MS) using two different definitions of “juxtacortical” and “periventricular”. Methods: Consecutive patients undergoing pre- and post-contrast MRI for headaches over a 25-month period were retrospectively identified. Exclusions included patients under age 10 and over 55 years or with known demyelinating disorder. Patients were classified as meeting: 1) Barkhof and 2) 2010 McDonald dissemination in space criteria for MS based on: FLAIR/T2 scans for WMH and enhanced T1-weighted images for enhancement. Both groups were further differentiated by defining “periventricular” and “juxtacortical” as WMH contacting ventricle and cortex (Barkhof “touching”, McDonald “touching”) versus WMH within 3 mm (Barkhof – 3 mm, McDonald – 3 mm). Results: 326/564 (58%) studies met inclusion criteria. WMH prevalence was 168/326 (51.53%). Barkhof “touching” criteria were met in 4/168 (2.4%) and in 12/168 (7.1%) of the 3 mm group. McDonald criteria were met in 41/168 (24.4%) for “touching” and 58/168 (34.5%) for 3 mm, respectively. Conclusion: Barkhof and McDonald criteria were met in 2.4–7.1% and 24.4–34.5%, respectively.

The radiologically isolated syndrome: Is it very early multiple sclerosis?

Neurologists frequently consult on patients who have had asymptomatic white matter T2 hyperintensities discovered incidentally on brain MRI. The consult often comes with the question “Does this person have multiple sclerosis (MS)?” Usually the patient has nothing clinically to indicate MS, the pattern of white matter changes is not suggestive of MS, and the T2 hyperintensities can be attributed to another cause.1 However, occasionally the patient has no signs or symptoms of MS but the appearance of the white matter abnormalities on MRI are highly suggestive of MS. What is our diagnosis for such patients and do we treat them for MS? In this issue of Neurology ®, Okuda et al.2 describe a cohort of subjects who had an initial brain MRI highly suggestive of MS but no signs or symptoms of the illness. They propose calling this condition the radiologically isolated syndrome (RIS). The cohort consisted of 44 individuals. All had a baseline brain MRI with ovoid foci of white matter T2 hyperintensities and met at least three of four of the Barkhof criteria …

Variants of Multiple Sclerosis

The classic multiple sclerosis variants including Devics neuromyelitis optica (NMO), Balos concentric Sclerosis, Schilders disease, and Marburg MS are both interesting and instructive from a disease pathophysiology perspective. Although rare, the variants are important as they often arise in the differential diagnosis for severe, acute demyelinating disease, including MS and acute disseminated encephalomyelitis. In the case of NMO, an originally unsuspected and entirely new pathophysiology based on water channels has been described, only after the recent original description of the more specific diagnostic test for NMO based on serum immunoglobulin.

Multiple Sclerosis and Chronic Cerebrospinal Venous Insufficiency: The Neuroimaging Perspective

In patients with multiple sclerosis (MS), Zamboni et al[1][1] described anomalies of venous outflow at color Doppler high-resolution examination and multiple severe extracranial stenosis at venography, affecting the internal jugular, the vertebral, and the azygous veins. The authors focused their

MRI outcomes in the diagnosis and disease course of multiple sclerosis.

Despite major advances in MRI, including practical implementations of multiple quantitative MRI methods, the conventional measures of focal, macroscopic disease remain the core MRI outcome measures in clinical trials. MRI enhancing lesion counts are used to assess inflammation, and new T2-lesions provide an index of (interval) activity between scans. These simple MRI measures also have immediate significance for early diagnosis as components of the 2010 revised dissemination in space and time criteria, and they provide a mechanism to monitor the subclinical disease in patients, including after treatment is initiated. The focal macroscopic injury, which includes demyelination and axonal damage, is at least partially linked to the diffuse injury through pathophysiologic mechanisms, such as secondary degeneration, but the diffuse diseases is largely independent. Quantitative measures of the more widespread pathology of the normal appearing white and gray matter currently remain applicable to populations of patients rather than individuals. Gray matter pathology, including focal lesions of the cortical gray matter and diffuse changes in the deep and cortical gray has emerged as both early and clinically relevant, as has atrophy. Major technical improvements in MRI hardware and pulse sequence design allow more specific and potentially more sensitive treatment metrics required for targeting outcomes most relevant to neuronal degeneration, remyelination and repair.

Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course

It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5 to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS.