John Lindsey

Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis : results from the 15-year analysis of the US prospective open-label study of glatiramer acetate

The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of continuous immunomodulatory therapy in relapsing—remitting multiple sclerosis (RRMS). The objective of this study was to evaluate up to 15 years of GA as a sole disease-modifying therapy. Two hundred and thirty-two patients received at least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%, Ongoing cohort) continued as of February 2008. Patients were evaluated every 6 months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were 8.6 ± 5.2, 4.81 ± 3.69, and 13.6 ± 1.3 years and mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12 ± 0.82 at baseline to 0.25 ± 0.34 per year; 57% had stable/improved EDSS scores (change ≤ 0.5 points); 65% had not transitioned to secondary progressive multiple sclerosis (SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA therapy (the mITT cohort), ARRs declined from 1.18 ± 0.82 to 0.43 ± 0.58 per year; 54% had stable/improved EDSS scores; 75% had not transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion, multiple sclerosis patients with mean disease duration of 22 years administering GA for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS. There were no long-term safety issues.

Sudden unexpected death on fingolimod

Dear Sir, Fingolimod is well known to cause bradycardia following the first dose, but has not been associated with more severe cardiac arrhythmias. One of our patients unexpectedly expired in the fifth month of fingolimod treatment. An autopsy found extensive contraction band necrosis in the heart, suggesting pre-mortem hypoperfusion due to ventricular arrhythmia. The patient developed the first symptoms of MS at age 41, and had multiple relapses over the next seven years, reaching the Expanded Disability Status Scale (EDSS) 5.5. She started fingolimod at age 48, and had transient, asymptomatic bradycardia to 48 beats per minute with the first dose. Her MS symptoms remained stable, but after almost five months on fingolimod, she was unexpectedly found deceased. She had no new complaints, acute illness, or emotional stress preceding her sudden demise. In addition to MS, she had persistent moderate hypertension, with a typical blood pressure around 160/95. She had a 3/6 systolic murmur which was intermittently present. An electrocardiogram carried out before the initiation of fingolimod had minimal inferior ST elevation suggestive of possible early repolarization, but no conduction delays or arrhythmias. An echocardiogram carried out two months before her death had trivial mitral and tricuspid regurgitation, with no obvious source of murmur. Her medications at the time of death were losartan and fingolimod. Several findings on post-mortem examination strongly suggested that the immediate cause of death was a ventricular arrhythmia leading to a sustained period of hypoperfusion followed by asystolic cardiac arrest. Most importantly, there were multiple foci of cardiomyocytes in the ventricular myocardium exhibiting changes of contraction band necrosis as well as cardiomyocytes in the subendocardium exhibiting the vacuolar change of myocytolysis. These lesions are characteristic of acute ischemic injury which can result from global coronary hypoperfusion.1-3 In human pathology, contraction band lesions have been correlated with conditions of adrenergic stress linked with malignant arrhythmia, particularly ventricular fibrillation.1-3 The interventricular septal endocardium just below the aortic valve had a focus of patchy hemorrhage, a typical lesion seen in various forms of shock and hypoperfusion of the myocardium. The lungs exhibited vascular congestion and focal alveolar edema consistent with acute left ventricular failure. The brain and spinal cord had the expected lesions for MS, including plaques in the left rostral medulla, the right pons, and encircling the cerebral aqueduct. The cause of the arrhythmia is uncertain, but hypertension, autonomic dysfunction due to MS, and fingolimod should all be considered. Her hypertension and the hypertensive changes seen on autopsy were mild. She did have brainstem lesions, which have been associated with arrhythmia.4 Fingolimod has well known effects on cardiac conduction, primarily at initiation of treatment. There is a reported case of a patient with asystole 21 hours after the first dose,5 and a case of unexpected death in the first 24 hours of treatment, but no reports of arrhythmia after longer periods. There were no cases of asystole, cardiac arrhythmia, or sudden unexpected death in the clinical trials. Surveillance for similar events in patients on fingolimod should continue.

Chronic Cerebrospinal Venous Insufficiency: Case–Control Neurosonography Results

Chronic cerebrospinal venous insufficiency (CCSVI) has been implicated in the pathophysiology of multiple sclerosis (MS). We sought to determine whether neurosonography (NS) provides reliable information on cerebral venous outflow patterns specific to MS.

Variable results after rituximab in neuromyelitis optica

Our objective was to assess the efficacy of rituximab (RTX) in neuromyelitis optica (NMO). We conducted a retrospective review of cases personally treated by the authors. We identified nine subjects meeting criteria for either NMO or recurrent longitudinally extensive transverse myelitis (LETM) who were treated with RTX and documented their clinical course. Six of the nine subjects continued to have relapses after RTX treatment. RTX was the first immunosuppressive treatment used after diagnosis in five subjects, and four of these continued to have relapses. We conclude that outcomes after RTX treatment of NMO are inconsistent. The observed variability may reflect differences in disease activity between individuals, differences in disease activity over time, or differences in the underlying immunopathogenesis of NMO. More effective treatments are needed.

The CombiRx trial of combined therapy with interferon and glatiramer acetate in relapsing remitting MS: Design and baseline characteristics

BACKGROUND Interferon-β1a (IFNB) and glatiramer acetate (GA) are distinct therapies which are both partially effective for relapsing MS. It is not known if combining the two treatments would be more effective. OBJECTIVE To review the rationale, design, and baseline characteristics of the CombiRx study of combined treatment with IFNB and GA. METHODS The key inclusion criteria included a diagnosis of relapsing MS, at least 2 episodes of MS activity in the previous 3 years, expanded disability status scale of 0-5.5, and no prior treatment with either IFNB or GA. Subjects were randomized to IFNB+GA, IFNB monotherapy, or GA monotherapy in a 2:1:1 ratio. RESULTS From 2005 to 2009, we enrolled 1008 subjects. The participants were 72.4% female and 87.6% Caucasian with a mean age of 37.7 years. The median duration of symptoms was 2 years at entry into the study, and the mean EDSS was 2.1. On the baseline MRI, the mean total lesion load was 12.2ml, and 40% of the participants had enhancing lesions. CONCLUSION We have recruited a population of patients with clinical and MRI characteristics typical for early MS. The study results will aid in deciding on the optimum early treatment. This trial should serve as a model for future studies of combination therapy.

Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials

Background: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). Objectives: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). Methods: Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. Results: We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. Conclusions: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders.

PCR for bacterial 16S ribosomal DNA in multiple sclerosis cerebrospinal fluid.

The cause of multiple sclerosis (MS) is currently unknown. The hypothesis of this study is that MS is caused by a chronic bacterial infection of the central nervous system (CNS) and the ensuing immune response. We developed a sensitive two-stage polymerase chain reaction method using nested or semi-nested primers specific for the bacterial 16S ribosomal DNA to test for the presence of bacterial DNA in cerebrospinal fluid. We designed seven sets of primers to amplify DNA from spirochetes , Campylobacter, Mycoplasma, Chlamydia, Bartonella , Mycobacteria and Streptococcus and tested cerebrospinal fluid from patients with relapsing—remitting MS, primary progressive MS, transverse myelitis and controls. We did not detect DNA from any of the groups of bacteria in patients or controls. We conclude that we were unable to find evidence for CNS infection with any of these seven groups of bacteria in MS. Multiple Sclerosis 2008; 14: 147—152. http://msj.sagepub.com

Chronic cerebrospinal venous insufficiency: masked multimodal imaging assessment

Background: Chronic cerebrospinal venous insufficiency (CCSVI) was implicated in the pathophysiology of multiple sclerosis (MS). Objective: We evaluated neurosonography (NS), magnetic resonance venography (MRV), and transluminal venography (TLV) in subsets of MS patients drawn from a single-center, prospective, case-control study of 206 MS and 70 non-MS volunteers. Methods: As previously reported, findings on high-resolution B-mode NS imaging with color and spectral Doppler of the extracranial and intracranial venous drainage consistent with CCSVI were similar among MS and non-MS volunteers (3.88% vs 7.14%; p = 0.266). Ninety-nine MS participants consented to intravascular contrast-enhanced 3D MRV to assess their major systemic and intracranial venous circulation, and 40 advanced to TLV that included pressure measurements of the superior vena cava, internal jugular, brachiocephalic, and azygous veins. Results: NS findings and MRV patterns were discrepant for 26/98 evaluable subjects, including four with abnormal findings on NS that had normal venous anatomy by MRV. In no instance were TLV pressure gradients indicative of clinically significant functional stenosis encountered. The three imaging approaches provided generally consistent data with discrepancies referable to inherent technique properties. Conclusions: Our findings lend no support for altered venous outflow dynamics as common among MS patients, nor do they likely contribute to the disease process.

Effect of in-painting on cortical thickness measurements in multiple sclerosis: A large cohort study.

A comprehensive analysis of the effect of lesion in‐painting on the estimation of cortical thickness using magnetic resonance imaging was performed on a large cohort of 918 relapsing‐remitting multiple sclerosis patients who participated in a phase III multicenter clinical trial. An automatic lesion in‐painting algorithm was developed and implemented. Cortical thickness was measured using the FreeSurfer pipeline with and without in‐painting. The effect of in‐painting was evaluated using FreeSurfers paired analysis pipeline. Multivariate regression analysis was also performed with field strength and lesion load as additional factors. Overall, the estimated cortical thickness was different with in‐painting than without. The effect of in‐painting was observed to be region dependent, more significant in the left hemisphere compared to the right, was more prominent at 1.5 T relative to 3 T, and was greater at higher lesion volumes. Our results show that even for data acquired at 1.5 T in patients with high lesion load, the mean cortical thickness difference with and without in‐painting is ∼2%. Based on these results, it appears that in‐painting has only a small effect on the estimated regional and global cortical thickness. Hum Brain Mapp 36:3749–3760, 2015.