Types of MS
For multiple sclerosis patients who have transitioned to secondary progressive disease despite use of disease-modifying treatments (DMTs), their management must still rely on physicians' instincts and the patients' wishes, clinicians here agreed.
Evidence-based medicine has almost nothing to say about whether DMTs continue to offer a benefit to patients who have moved from relapsing-remitting to secondary progressive MS (SPMS) because the existing trials were badly flawed, said Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center here.
Taking the "stop DMTs" side in a point-counterpoint debate at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, Stüve argued that the lack of demonstrable benefit and the adverse effects of DMTs militates against continuing them.
But his opposite number on the debate platform -- Michael Carrithers, MD, PhD, of the University of Wisconsin in Madison -- as well as audience members countered that there are some biological reasons to believe that DMTs could be beneficial, even if the hard trial evidence is lacking.
And, Stüve admitted (to the audience's murmured approval), stopping DMTs "is a difficult decision because patients feel like you're abandoning them."
Several clinicians in the packed meeting room agreed that, purely from a patient engagement perspective, it's necessary to give them some kind of treatment. For example, one said he routinely adds methotrexate.
"You have to do something," another said. If the clinician has nothing to offer, added a third, patients "think you're giving up." But nobody advocated mitoxantrone -- the only FDA-approved treatment for SPMS -- the evidence for which has been criticized.
In the end, Stüve lost an electronically recorded vote by a landslide -- only about 10 of the nearly 100 attendees indicated they would stop DMTs in a hypothetical patient with progressing disability, no relapses in 20 years, and no significant adverse effects from his long-standing DMT.
The only current evidence backing DMTs such as interferon-beta for SPMS comes from three trials conducted in the 1990s and early 2000s with interferon-beta.
For all three of them -- one conducted in Europe and two in the U.S. -- the topline results indicated a benefit. But Stüve called attention to these trials' inclusion criteria and the resulting sample characteristics. Patients experiencing relapses within the past year were accepted, mean disease durations were under 10 years, and time since SPMS diagnosis was just 2 years.
All of which, he suggested, indicates that many of the patients in these trials probably did not have true SPMS. One of the trials actually reported a reduction in relapse rates as one of the favorable outcomes -- even though SPMS patients aren't supposed to be having relapses.
As a result, the overall benefits seen in the trial probably were concentrated in those who still had substantial inflammatory activity not consistent with SPMS, Stüve suggested.
But Carrithers and some audience members responded that inflammation does not always die down completely when a patient transitions to SPMS.
Carrithers pointed to a small study published in 2005 in which SPMS patients who had interferon-beta withdrawn showed accelerated disability progression and, importantly, new MRI lesions.
On the other hand, he noted that many of the patients in the earlier "successful" trials of interferon-beta in SPMS had not received the drug previously. Hence, the results can't be generalized to those currently on such medications, for whom the question is whether to withdraw them.
One audience member insisted that inflammation remains a feature in SPMS but is "locked behind the blood-brain barrier" where it is less apparent in standard tests. She argued that it is vital to keep treating patients with DMTs in order to keep these smoldering inflammatory processes in check.
During the electronic vote, most of the audience indicated that they would like to switch a hypothetical patient who had been on interferon-beta to another type of DMT. About two-thirds of those voters wanted specifically to try natalizumab (Tysabri), a very potent drug for relapsing-remitting MS but with unclear benefits in progressive forms.
Debate moderator Dennis Bourdette, MD, of Oregon Health and Science University in Portland, tried to canvas the audience for an explanation of that choice. He never got one, but some in the room complained that health system and insurer policies would prevent it anyway. Natalizumab is relatively expensive and since it is not approved for SPMS, most payers won't cover it.
A phase III trial of natalizumab in SPMS is now underway -- with enrollment criteria more to Stüve's liking -- and both he and Carrithers indicated that its results would go at least part way toward settling the now-unanswered question of DMTs for the condition.
Carrithers said that a trial specifically aimed at withdrawal of DMTs in SPMS patients is needed as well. Bourdette pointed out that just such a trial was reported last month at the American Academy of Neurology's annual meeting -- it found that 90% of those stopping DMTs remained stable after a median of 3 years off treatment, but a few showed renewed MRI lesion activity.
Until the evidence is clearer, though, panelists and audience members seemed to agree that physicians will have to base their clinical decision-making on their own experience and individual patients' characteristics and wishes.
Stüve and Carrithers both said MRI scans are vital. Patients should continue to be treated as long as they still show lesion activity, they agreed.
The debate was organized with support from the Department of Veterans Affairs, with which Bourdette, Carrithers, and Stüve are affiliated.
Carrithers reported research funding from Biogen Idec. Bourdette and Stüve declared they had no relevant financial interests.
Source: MedPage Today © 2014 MedPage Today, LLC (04/06/14)
Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment for clinical trials, and treatment decision-making. Researchers at Icahn School of Medicine at Mount Sinai, part of the International Committee on Clinical Trials of MS, collaborated to re-examine the standardized MS clinical course descriptions originally published in 1996 and recommend refined phenotype descriptions that include improved clinical descriptive terminology, MRI and other imaging techniques, analysis of fluid biomarkers and neurophysiology. The proposed 2013 revisions will appear in the May 28, 2014, online issue of Neurology, the medical journal of the American Academy of Neurology.
"Our goal for modifying the 1996 definitions is to better characterize patients with MS and provide a framework for both clinical research and ongoing clinical care," says Fred D. Lublin, MD, Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at The Icahn School of Medicine at Mount Sinai, and the article's lead author. "These revisions should make communication with patients and among physicians clearer and should also enhance the design, recruitment and conduct of clinical trials, which will further help us understand the disease."
Multiple sclerosis is a potentially debilitating disease in which the body's immune system eats away at the protective sheath (myelin) that covers the nerves. Damage to myelin causes interference in the communication between the brain, spinal cord and other areas of the body and may result in deterioration of the nerves themselves. MS can be difficult to diagnose because symptoms often come and go, symptoms vary widely and there is no cure. However, treatments may help reduce MS attacks, manage symptoms and lessen disease progression.
The 1996 clinical course descriptions provided standardized definitions for four MS clinical courses, which included: relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP), and progressive relapsing (PR). While these descriptions were believed to represent the spectrum of clinical subtypes of MS, it was recognized that the descriptions might change over time as a result of advanced imaging techniques and biological markers.
In reconsidering the prior MS disease course descriptors, the advisory group recommends that the core MS phenotype descriptions of relapsing and progressive disease be retained, with some modifications. The consensus is that disease activity detected by clinical relapses or imaging (gadolinium-enhancing lesions or new or unequivocally enlarging T2 lesions) as well as progression of disability can be meaningful additional descriptors of either relapsing or progressing disease. Evidence of disease activity and clinical progression, which by current understanding reflects ongoing inflammatory or neurodegenerative disease, may impact prognosis, therapeutic decisions and clinical trial designs and outcomes.
To assess disease activity, the group recommends at least annual clinical assessment and brain imaging for relapsing MS. For progressive MS, annual clinical assessment is recommended, but there was no consensus on the optimal frequency of imaging. They suggest that progression be determined annually by history or objective measure of change. Thus, the existing course descriptions should be sub-categorized based on activity or progression. For example a patient with relapsing-remitting (RR) MS who had a new gadolinium-enhancing lesion on a current MRI would be considered to be RR-active. Conversely, "non-active" could be used the same way to indicate a patient with a relapsing course but no relapses or new MRI lesions during the assessment period. Inclusion of activity as a modifier of basic clinical course phenotype allows elimination of the progressive relapsing (PR) category because a PPMS patient who has an acute attack (thus fulfilling the prior criteria for PRMS) would be considered PP-active.
Another recommendation is that clinically isolated syndrome (CIS), which was not included in the initial MS clinical descriptors, but is now recognized as the first clinical presentation of a disease that shows characteristics of inflammatory demyelination that could be MS, be included in the spectrum of MS phenotypes. Prospective follow-up of most such patients should determine their subsequent disease phenotype. Radiologically isolated syndrome (RIS), where incidental imaging findings suggest inflammatory demyelination in the absence of signs or symptoms should not be considered a separate MS phenotype.
"Our understanding of multiple sclerosis has come a long way since the original phenotype classifications were standardized 18 years ago," says Dr. Lublin. "Future long-term longitudinal and cohort studies, imaging studies, prospective follow up and research is needed to better understand and define MS phenotypes, allowing us to continue to refine the framework for clinical research and care for the patients who turn to us for help."
Source: Medical Xpress © Medical Xpress 2011-2014 (29/05/14)
A recently completed study at University College London Hospital suggests that administration of certain drugs can block the entry of sodium ions in nerve cells that in turn can prevent aggressive nerve cell damage. The research team proposed that delaying nerve cell destruction can limit the rate of disability in secondary progressive MS patients. The supporting study, which was completed after two years of testing, was aimed at employing nerve cell blockers like lamotrigine to monitor the rate of worsening disability in secondary progressive MS patients.
The Primary Outcome of this double-blind interventional study was to monitor changes in the volume of the whole brain with the help of the Loseff method using MRI technology (to monitor cerebral atrophy due to loss of axons). Secondary Outcomes for the study included monitoring the changes in the volume of whole brain with the help of Brain Boundary Shift Integral; the rate of atrophic changes in the spinal cord; appearance of new high intensity lesions on an MRI scan; ratio calculation of new T1 and T2 lesions; and the overall rate of changes in the MS Functional Composite and Impact Scale.
The cerebral and spinal volumes and cross-sectional area of the cervical spinal cord were tested at baseline, at 12 months into the study, and towards the end of the study period (24th month). Brain volume was measured more periodically at the 6th and 18 month marks, as well as at the 12 and 24 month marks. The clinical visits were planned for every 3 months.
Details of the Study:
The research team enrolled 120 patients with a positive history of MS and a progressive course of illness as seen in secondary progressive MS patients (patients with frequent episodes of clinical relapses resulting in disability were excluded). The study sample was divided into a test group and control groups, and the patients were randomly selected to receive either placebo or lamotrigine.
The research team explained that degenerative spinal or cerebral diseases can respond fairly well to neuroprotective treatments. The cause of disease progression in multiple sclerosis is degeneration of nerve axons. Previous research projects conducted by investigators at the University College London Hospitals have concluded that inflammatory mediators like nitric oxide can contribute to axonal degeneration. Various in-vitro studies confirm that blocking the activity of sodium channels can reduce the degeneration of axonal processes. Several pharmacological agents are currently available that are used to block sodium channels in the brain tissue (like phenytoin and flecainide in addition to lamotrigine).
Positive results from the Phase 2 clinical trial will pave the way for Phase 3 clinical trials and also confirm the neuroprotective role of sodium channel blockers in the nerve cell disorders, like secondary progressive MS, to limit the rate of complications and long-term disability.
Lamotrigine is a sodium channel blocker that is widely prescribed for the management of epilepsy and seizure disorders under the brand name of Lamictal XR. Other indications for lamotrigine use are bipolar disorders, mood disorders, attention deficit hyperactivity disorder, and sleep disorders. Like all anti-conculsants, it is also associated with dose-dependent side-effects and is therefore sold as a prescription drug in most parts of the world.
Source: BioNews Texas (03/02/14)
Mice injected with CSF from PMS patients develop MS-like lesions.
A new mouse model of progressive multiple sclerosis (PMS) promises to help researchers illuminate its pathophysiology. Massimiliano Cristofanilli, Ph.D., presented evidence at this year’s meeting of the Society for Neuroscience in San Diego of a new rodent model of progressive MS.
Unlike relapsing-remitting MS (RRMS), PMS affords its victims no breaks, no cooling-off periods in which to recover from the disease’s ravages. Treatments seldom work against PMS, and research has been stymied by the lack of animal models.
Cristofanilli and his colleagues at the Tisch MS Research Center in New York collected cerebrospinal fluid (CSF) from human patients with untreated primary or secondary PMS, RRMS, or from control subjects with neurodegenerative diseases other than MS. After removing cells and debris from the CSF samples, they injected wild-type mice twice per week for up to 4 weeks with the CSF supernatant via a cannula implanted directly into the third ventricle. Later, the researchers perfused the mice and examined their tissues for signs of gross pathology using immunohistochemistry.
After 4 weeks, none of the mice displayed a disease phenotype as measured by rotarod motor tests, in which mice attempt to stay on a rotating rod suspended a short distance above the cage floor. The investigators did not find this surprising considering the resilience of wild-type mice. But what did surprise the team, Cristofanilli said, were the lesions they found in the brains of about 70% of the mice injected with PMS CSF. In contrast, only 14% of the mice injected with RRMS-CSF and none injected with control CSF developed lesions. The team plans to continue looking for signs of disease phenotype at later time points.
Demyelinated lesions appeared after 2 weeks of injections, when T cells were also detectable. After 4 weeks, axons were lost at the lesion sites, B cells and plasma cells had infiltrated, and astrogliosis was rampant. Based on the timing of the immune cells’ appearances during lesion development, the researchers believe that demyelination begins before the massive infiltration of peripheral immune cells. “We think T cells are more involved in demyelination, and then B- and plasma cells may contribute more to neurodegeneration,” Cristofanilli told MSDF.
In a subset of the mice, the investigators examined changes in gene expression using ELISA and microarrays. “Genes related to immune cells were the most interesting—they had the highest variation,” Cristofanilli told MSDF. Focusing on genes related to the Th17 pathway, known to play a role in MS pathophysiology, “we found a strong upregulation of Th17-cell activity in the central nervous system of PMS-CSF-injected mice compared to controls,” Cristofanilli said in his presentation of the findings.
In order to see whether a disease-modifying treatment would alter the pathogenicity of PMS CSF, the researchers next took CSF from four rare patients who became clinically stable following therapy with intrathecal methotrexate or natalizumab. Compared to mice injected with PMS CSF from the same patients before they received the drugs, “patient treatment drastically reduced the number of mice that developed lesions” following injection, Cristofanilli said, suggesting that the therapy had reduced the pathogenic agent in patients’ CSF.
“We think we are now in a position to study PMS in mice, and we are focusing on elucidating the nature of the agents responsible for the lesion pathology,” Cristofanilli said in his presentation. When asked what the pathological agent in the patients’ CSF might be, he answered, “That’s the million-dollar question.”
No members of the research team made any disclosures. The research was supported by the Tisch Center’s private funds as well as a grant from the Emerald Foundation.
Key open questions
How closely does the new mouse model recapitulate progressive MS seen in humans, and how will it contribute to a better understanding of the disease?
What elements present in CSF from progressive MS patients caused the pathology seen in injected mice?
What are the relationships between PMS and RRMS? Are they separate diseases or variants of the same pathological processes?
Source: Multiple Sclerosis Discovery Forum Copyright © 2013 MGH and ACP (17/12/13)
With the recent approvals of several oral drugs to reduce disease flares in relapsing-remitting multiple sclerosis, the top researchers agree that the next major frontier is the disease's progressive forms.
But, on the basis of presentations and discussions at last week's annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), progressive MS now stands at about the same place that relapsing-remitting MS stood 3 decades ago -- that is, still many years away from an effective therapy or even a solid understanding of its pathophysiology.
At an ECTRIMS session devoted to progressive MS, opening speaker Robert Fox, MD, of the Cleveland Clinic in Ohio, said an international collaboration has been formed to take on the condition's challenges. Initial meetings have produced a list of five major research needs.
That list highlights how far the field needs to advance before it can even test a potential therapy properly. Currently lacking, but necessary for development of treatments, are the following:
An experimental model for preclinical research
High-throughput screening tools for drug discovery
Appropriate outcome measures for phase II trials
Appropriate outcome measures for phase III trials
Outcomes to target for symptomatic treatments
Fox was followed to the platform by Finn Sellebjerg, MD, of the University of Copenhagen (the meeting's host city), who delved into the heterogeneity of progressive MS. This goes beyond the familiar distinction between primary and secondary progressive forms, to include what is sometimes called progressive-relapsing MS, in which periodic disease flares are superimposed on a background of steadily worsening symptom severity and disability.
Sellebjerg also argued that progressive MS may, in some cases, be a misnomer -- in many patients, their disease course may better be characterized as "incomplete remission after relapse" rather than true progression.
Other speakers in the session discussed different aspects of progressive versus relapsing-remitting forms, such as measures of axonal damage, cerebrospinal fluid protein levels, and variant genes for NMDA (N-methyl-D-aspartate) neurotransmitter receptors.
But none of these appeared to be foolproof approaches to distinguishing the different forms of MS clinically, let alone offering therapeutic targets for drug development.
On the other hand, Fox and Sellebjerg noted that a host of drugs are now or soon will be in clinical trials for progressive MS, because preclinical tests or findings in other neurodegenerative diseases suggested a potential for benefit.
These include simvastatin (Zocor), natalizumab (Tysabri), and alemtuzumab (Lemtrada), as well as a combination of ibudilast, amiloride, and riluzole. This last drug failed in a monotherapy trial in relapsing MS reported at the meeting. On the other hand, drugs for relapsing MS have mostly failed to show benefit in progressive forms, and it would not be surprising if the reverse were true, since the conditions are believed to be fundamentally different.
Sellebjerg said results from a pilot study of natalizumab, in which he had been an investigator, would be reported soon. The topline finding was that the drug showed positive effects in some measures, but brain atrophy continued. Also, although the drug appeared to improve disability scores, Sellebjerg called the magnitude "clinically questionable."
Source: MedPage Today © 2013 MedPage Today, LLC (11/10/13)
Global N-acetylaspartate concentration in benign and non-benign MS patients of long disease duration(23/09/13)
BACKGROUND AND OBJECTIVE: To examine whether clinically benign multiple sclerosis patients (BMS) show similar losses of their global N-acetylaspartate (NAA) neuronal marker relative to more clinically disabled patients of similar disease duration.
METHODS: The whole-brain NAA concentration (WBNAA) was acquired with whole-head non-localizing proton MR spectroscopy. Fractional brain parenchymal volume (fBPV), T2 and T1 lesion loads, were obtained from the MRI in: (i) 24 BMS patients: 23.1±7.2 years disease duration, median Expanded Disability Status Scale (EDSS) score of 2.0 (range: 0-3); (ii) 26 non-benign MS patients (non-BMS), 24.5±7.4 years disease duration, median EDSS of 4.0 (range: 3.5-6.5); (iii) 15 healthy controls.
RESULTS: Controls' 12.4±2.3mM WBNAA was significantly higher than the BMS's and non-BMS's 10.5±2.4 and 9.9±2.1mM (both p<0.02), but the difference between the patients' groups was not (p>0.4). Likewise, the controls' 81.2±4.5% fBPV exceeded the BMS and non-BMS's 77.0±5.8% and 76.3±8.6% (p<0.03), which were also not different from one another (p>0.7). BMS patients' T1-hypointense lesion load, 2.1±2.2cm3, was not significantly different than the non-BMS's 4.1±5.4cm3 (p>0.08) and T2-hyperintense loads: 6.0±5.7cm3 and 8.7±7.8cm3, were also not different (p>0.1).
CONCLUSIONS: WBNAA differentiates normal controls from MS patients but does not distinguish BMS from more disabled MS patients of similar disease duration. Nevertheless, all MS patients who remain RR for 15+ years suffered WBNAA loss similar to the average RR MS population at fourfold shorter disease duration suggesting relative global neuronal sparing or leveling-off of the neurodegeneration rate.
Achtnichts L, Gonen O, Rigotti DJ, Babb JS, Naegelin Y, Penner IK, Bendtfeld K, Hirsch J, Amann M, Kappos L, Gass A.
Departments of Neurology and Neuroradiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
Source: Eur J Radiol. 2013 Sep 4. pii: S0720-048X(13)00450-6. doi: 10.1016/j.ejrad.2013.08.037. [Epub ahead of print] © 2013 Elsevier Ireland Ltd & Pubmed PMID: 24041438 (23/09/13)