The enthusiasm for natalizumab, a highly efficacious agent in the treatment of multiple sclerosis (MS), has been tempered by the risks of progressive multifocal leukoencephalopathy associated with its use, and strategies to minimize those risks are of great interest. Extended interval dosing (EID) has been proposed as a way to maintain the efficacy of natalizumab while reducing exposure to it. We reviewed a cohort of patients who received natalizumab at 6-8-week intervals instead of the typical infusions every 4 weeks with the goal to assess if patients on EID had an increase in clinical relapses.
There has been a growing interest in using next-generation sequencing (NGS) to profile extracellular small RNAs from the blood and cerebrospinal fluid (CSF) of patients with neurological diseases, CNS tumors, or traumatic brain injury for biomarker discovery. Small sample volumes and samples with low RNA abundance create challenges for downstream small RNA sequencing assays. Plasma, serum, and CSF contain low amounts of total RNA, of which small RNAs make up a fraction. The purpose of this study was to maximize RNA isolation from RNA-limited samples and apply these methods to profile the miRNA in human CSF by small RNA deep sequencing. We systematically tested RNA isolation efficiency using ten commercially available kits and compared their performance on human plasma samples. We used RiboGreen to quantify total RNA yield and custom TaqMan assays to determine the efficiency of small RNA isolation for each of the kits. We significantly increased the recovery of small RNA by repeating the aqueous extraction during the phenol-chloroform purification in the top performing kits. We subsequently used the methods with the highest small RNA yield to purify RNA from CSF and serum samples from the same individual. We then prepared small RNA sequencing libraries using Illuminas TruSeq sample preparation kit and sequenced the samples on the HiSeq 2000. Not surprisingly, we found that the miRNA expression profile of CSF is substantially different from that of serum. To our knowledge, this is the first time that the small RNA fraction from CSF has been profiled using next-generation sequencing.
We describe the case of a 33-year-old woman who presented with a 2-month history of worsening head tremor. The medical evaluation led to the new diagnosis of MS and the MRI of brain demonstrated prominently active disease. Intravenous rituximab was started according to the HERMES trial, and significant improvement was noted. She has received additional rituximab dosing approximately every 6 months, and at the 2-year follow-up the tremor has not recurred. The resolution of head tremor likely resulted from the complete suppression of MS disease activity, which must have allowed restoration of normal neural circuitry. In agreement with a growing body of evidence that supports early control of MS disease activity to prevent accumulation of fixed disability, this case advocates for aggressive immunological therapy at the onset of tremor in MS patients.
Under the therapeutic point of view, neuromyelitis optica (NMO) poses major challenges. Patients with NMO manifest severe disability from recurrent demyelinating lesions and the therapies are only partially effective. We performed a retrospective analysis of the records of patients followed at our institution and provide suggestions for management of acute relapses and preventive therapy.
Natalizumab inhibits the influx of leukocytes into the central nervous system (CNS) via blockade of alpha-4 subunit of very late activation antigen (VLA)-4. The association of natalizumab therapy with progressive multifocal leukoencephalopathy (PML) suggests a disturbance of CNS immune surveillance in a small percentage of Multiple Sclerosis (MS) patients exposed to the medication. Natural killer (NK) cells are known to play an important role in modulating the evolution of different phases of this lymphocyte mediated disease, and we investigated the effects of natalizumab on the NK cell phenotype and infiltration in the CNS in experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Our data show that both resting (from naïve mice) and activated (from EAE mice) NK cells express high levels of VLA-4, and anti-VLA-4 antibody treatment significantly decreases NK cells frequency in the CNS of EAE mice. Moreover, we find that anti-VLA-4 possibly impairs NK cells migratory potential, since unblocked VLA-4 expression levels were downregulated on those NK cells that penetrate the CNS. These data suggest that treatment with antibody to VLA-4 may alter immune surveillance of the CNS by impacting NK cell functions and might contribute to the understanding of the mechanisms leading to the development of PML in some MS patients.
Discoveries of the mechanisms that underlie the pathogenesis of multiple sclerosis have been acquired at an impressive rate over the last few decades and, as a consequence, a growing number of treatments are becoming available for this disease. This review first analyzes the experience from the early stages of the disease-modifying therapies, then, expanding on the concept of early treatment for improved outcomes, it focuses on natalizumab and its major complication, progressive multifocal leukoencephalopathy. We offer views on the risks associated with the use of natalizumab by underscoring the importance of the JC virus serology and by providing preliminary data on our experience with the extended interval dosing of natalizumab. This approach, which advocates individualized treatment plans, raises the question of the minimum effective natalizumab dose. Extended interval dosing suggests efficacy can be maintained while providing advantages of costs and convenience over regular monthly dosing. More data examining this strategy are necessary.
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