Kathleen Hawker

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.

The utility of MRI in suspected MS Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies for MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both time and space. Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation. Prospective studies have shown that the presence of such lesions predicts future conversion to clinically definite (CD) MS. Indeed, in a young to middle-aged adult with a clinically isolated syndrome (CIS), once alternative diagnoses are excluded at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS within the next 7 to 10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T2 lesions or new Gd enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term. By contrast, normal results on MRI at the time of clinical presentation makes the future development of CDMS considerably less likely.

MRI characteristics of the MLF in MS patients with chronic internuclear ophthalmoparesis

Objective: The authors imaged the medial longitudinal fasciculus (MLF) in 58 patients with MS and chronic internuclear ophthalmoparesis (INO) to determine which MRI technique best shows the characteristic lesion associated with this ocular motor syndrome. Methods: Using quantitative infrared oculography, the authors determined the ratios of abduction to adduction for velocity and acceleration, to confirm the presence of INO and to determine the severity of MLF dysfunction in 58 patients with MS and INO. Conventional MRI techniques, including proton density imaging (PDI), T2-weighted imaging, and fluid-attenuated inversion recovery (FLAIR) imaging, were used to ascertain which technique best shows MLF lesions within the brainstem tegmentum. T1-weighted imaging was performed to determine the frequency of brainstem tegmentum hypointensities. Results: All patients studied had evidence of an MLF lesion hyperintensity on PDI, whereas T2-weighted imaging and FLAIR imaging showed these lesions in 88% and 48% of patients, respectively. With PDI, dorsomedial tegmentum lesions were seen in the pons in 93% of patients and in the midbrain of 66% of patients. Lesions were observed at both locations in 59% of patients. One patient had an MLF lesion with a corresponding T1 hypointensity. Conclusions: PDI best shows the MLF lesion in patients with MS and INO.

Quantitative oculographic characterisation of internuclear ophthalmoparesis in multiple sclerosis: the versional dysconjugacy index Z score

Background: There is a poor correlation between multiple sclerosis disease activity, as measured by magnetic resonance imaging, and clinical disability. Objective: To establish oculographic criteria for the diagnosis and severity of internuclear ophthalmoparesis (INO), so that future studies can link the severity of ocular dysconjugacy with neuroradiological abnormalities within the dorsomedial brain stem tegmentum. Methods: The study involved 58 patients with multiple sclerosis and chronic INO and 40 normal subjects. Two dimensional infrared oculography was used to derive the versional dysconjugacy index (VDI)—the ratio of abducting to adducting eye movements for peak velocity and acceleration. Diagnostic criteria for the diagnosis and severity of INO were derived using a Z score and histogram analysis, which allowed comparisons of the VDI from multiple sclerosis patients and from a control population. Results: For a given saccade, the VDI was typically higher for acceleration v velocity, whereas the Z scores for velocity measures were always higher than values derived from comparable acceleration VDI measures; this was related to the greater variability of acceleration measures. Thus velocity was a more reliable measure from which to determine Z scores and thereby the criteria for INO and its level of severity. The mean (SD) value of the VDI velocity derived from 40 control subjects was 0.922 (0.072). The highest VDI for velocity from a normal control subject was 1.09, which was 2.33 SD above the normal control mean VDI. We therefore chose 2 SD beyond this value (that is, a Z score of 4.33) as the minimum criterion for the oculographic confirmation of INO. Of patients thought to have unilateral INO on clinical grounds, 70% (16/23) were found to have bilateral INO on oculographic assessment. Conclusions: INO can be confirmed and characterised by level of severity using Z score analysis of quantitative oculography. Such assessments may be useful for linking the level of severity of a specific clinical disability with neuroradiological measures of brain tissue pathology in multiple sclerosis.

Vertigo in MS: Utility of positional and particle repositioning maneuvers

Article abstract A 4-year experience with new-onset vertigo in a university-based MS population was retrospectively reviewed. Of 1,153 patients with MS, 25 could be clinically evaluated during the vertiginous episode. Of these, 13 (52%) were diagnosed with benign paroxysmal positioning vertigo and eight (32%) had acute MS exacerbations with corresponding lesions within the brainstem. All patients diagnosed with benign paroxysmal positioning vertigo were treated successfully with particle repositioning maneuvers.–1568

Disease modifying agent related skin reactions in multiple sclerosis: prevention, assessment, and management:

Background: The objective for this article is to highlight some of the adverse skin manifestations associated with injectable disease modifying therapy for multiple sclerosis (MS). Early identification and intervention can often lead to minimal consequences and prolonged patient tolerance and compliance with these agents. A t the University of Texas Southwestern Medical C enter at Dallas and Texas Neurology in Dallas we actively follow appro ximately 5000 MS patients. The majority of our patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) are treated with one of the currently available disease modifying agents (DMA s). O ur experience with these patients, and the challenges they face in continuing long-term treatment, constitutes the basis of our proposed treatment strategies. Conclusion: Skin reactio ns in response to injectable DMA therapy in MS are generally mild. However, some reactio ns can evolve into potentially serious lesions culminating in infection, necro sis, and in some circumstances requiring surgical repair.

A one-year prospective, randomized, placebo-controlled, quadruple-blinded, phase II safety pilot trial of combination therapy with interferon beta-1a and mycophenolate mofetil in early relapsing–remitting multiple sclerosis (TIME MS)

Background: Mycophenolate mofetil (MMF) is an oral DNA base synthesis inhibitor with immunomodulatory effects on B cells, T cells, and macrophages. Objective: To conduct a safety and tolerability pilot study of interferon beta-1a (IFN-b1a) in combination with either placebo or oral MMF in multiple sclerosis (MS). Methods: Twenty-four treatment-naïve R—RMS patients participated in a one-year prospective, placebo-controlled, blinded, safety pilot clinical trial. Every patient injected weekly intramuscular interferon beta-1a. The cohort was then randomized (1 : 1) to either active oral MMF or identical-appearing placebo tablets. Clinical evaluations were assessed every 3 months, along with brain MRI scans performed at baseline and repeated every 60 days for one year. Comprehensive laboratory assessments were monitored for safety, along with adverse events. Results: In this small pilot investigation, no differences were identified between the two treatment groups with respect to patient-reported adverse events, MRI metrics, or laboratory abnormalities. Notwithstanding these observations, and the limited number of patients treated, trends appeared to favor the combination therapy regimen. Conclusions: The combination treatment regimen of interferon beta-1a and MMF appeared to be well tolerated in this pilot study. Despite the small sample size, therapeutic trends were observed in favor of combination therapy. An adequately powered controlled trial of MMF in MS appears warranted.

Ocular contrapulsion in multiple sclerosis: clinical features and pathophysiological mechanisms

The objective was to describe in multiple sclerosis, a cerebellar eye movement syndrome that resulted from an acute episode of inflammatory demyelination. Contrapulsion is an ocular motor disturbance characterised by a triad of (1) hypermetric saccadic eye movements in a direction opposite from a precisely localised lesion within a specific white matter pathway, the uncinate fasciculus, at the level of the superior cerebellar peduncle (SCP); (2) hypometric saccades towards the side of the lesion; (3) oblique saccades directed away from the side of the lesion on attempted vertical saccades.  Infrared oculography was used to demonstrate the characteristic features of contrapulsion in two patients with multiple sclerosis.  Brain MRI showed lesions within the region of the uncinate fasciculus and superior cerebellar peduncle in both patients. Eye movement recordings showed saccadic hypermetria away from the side of the lesion and saccadic hypometria towards the side of the lesion. The hypometria decomposed into a series of stepwise movements as the eye approached the target. Oblique saccades directed away from the side of the lesion were seen on attempted vertical saccades. In conclusion, ocular contrapulsion can be seen in patients with multiple sclerosis and results from a lesion in the region of the SCP, involving the uncinate fasciculus.

MRI characteristics of the MLF in MS patients with chronic internuclear ophthalmoparesis.1

ObjectiveThe authors imaged the medial longitudinal fasciculus (MLF) in 58 patients with MS and chronic internuclear ophthalmoparesis (INO) to determine which MRI technique best shows the characteristic lesion associated with this ocular motor syndrome. MethodsUsing quantitative infrared oculography, the authors determined the ratios of abduction to adduction for velocity and acceleration, to confirm the presence of INO and to determine the severity of MLF dysfunction in 58 patients with MS and INO. Conventional MRI techniques, including proton density imaging (PDI), T2-weighted imaging, and fluid-attenuated inversion recovery (FLAIR) imaging, were used to ascertain which technique best shows MLF lesions within the brainstem tegmentum. T1-weighted imaging was performed to determine the frequency of brainstem tegmentum hypointensities. ResultsAll patients studied had evidence of an MLF lesion hyperintensity on PDI, whereas T2-weighted imaging and FLAIR imaging showed these lesions in 88% and 48% of patients, respectively. With PDI, dorsomedial tegmentum lesions were seen in the pons in 93% of patients and in the midbrain of 66% of patients. Lesions were observed at both locations in 59% of patients. One patient had an MLF lesion with a corresponding T1 hypointensity. ConclusionsPDI best shows the MLF lesion in patients with MS and INO.

B cells as a target of immune modulation

B cells have recently been identified as an integral component of the immune system; they play a part in autoimmunity through antigen presentation, antibody secretion, and complement activation. Animal models of multiple sclerosis (MS) suggest that myelin destruction is partly mediated through B cell activation (and plasmablasts). MS patients with evidence of B cell involvement, as compared to those without, tend to have a worse prognosis. Finally, the significant decrease in new gadolinium-enhancing lesions, new T2 lesions, and relapses in MS patients treated with rituximab (a monoclonal antibody against CD20 on B cells) leads us to the conclusion that B cells play an important role in MS and that immune modulation of these cells may ameliorate the disease. This article will explore the role of B cells in MS and the rationale for the development of B cell–targeted therapeutics. MS is an immune-mediated disease that affects over 2 million people worldwide and is the number one cause of disability in young patients. Most therapeutic targets have focused on T cells; however, recently, the focus has shifted to the role of B cells in the pathogenesis of MS and the potential of B cells as a therapeutic target.