The Latest Evidence-Based Medicine to Diagnose and Treat MS
Optic Neuritis and Multiple Sclerosis: The Latest Evidence-Based Medicine to Diagnose and Treat MS
Steven L. Galetta, MD, Director, Neuro-Ophthalmology, Van Meter Professor of Neurology, University of Pennsylvania School of Medicine, Philadelphia
Over the past decade, our understanding of the natural history of optic neuritis and multiple sclerosis (MS) has been greatly enhanced by advances in neuro-imaging and the never-ending flow of new clinical trial information. In the early 1990s, the Optic Neuritis Treatment Trial (ONTT) found no difference in final visual outcome at 6 months for those receiving corticosteroids versus placebo. However, that trial was able to identify a cohort of optic neuritis patients at high risk for the development of MS. Patients with three or more white-matter lesions on a baseline T2-weighted magnetic resonance imaging (MRI) scan had a 51% chance of developing MS in 5 years, compared with a 16% risk for those with a normal baseline MRI. Furthermore, those patients with high-risk scans who received intravenous steroids at baseline had a short-term delay in the onset of MS compared with those who received placebo. This information provided the impetus for the formation of the Controlled High Risk Multiple Sclerosis Prevention Study (CHAMPS).
CHAMPS set out to answer the question, Could interferon beta-1a (Avonex, Biogen) reduce the occurrence of MS in high-risk monosymptomatic patients? The results of this study were quite robust, demonstrating a 44% reduction in the risk of developing clinically definite MS in those patients receiving Avonex compared with patients receiving placebo (p = .002; Kaplan-Meier analysis). Even more compelling were the MR data, which showed beneficial effect on new T2 lesions, gadolinium enhancement, and T2 lesion volume.
There is growing consensus that multiple sclerosis is a silent disorder in its early stages until a threshold of disease burden is reached and disability ensues. For instance, MRI studies show 5 to 10 times more gadolinium-enhancing lesions than clinical relapses. In CHAMPS, 82% of the patients in the placebo arm had a new subclinical MR lesion at 18 months. This finding suggests that most of the CHAMPS patients will have silent MS in a short period of time. Furthermore, magnetic resonance spectroscopy studies of MS patients show abnormalities in normal-appearing white matter and may even predict those at greatest risk for disease progression. Even in relapsing-remitting disease, brain atrophy may become silently apparent on serial neuro-imaging studies without onset of clinical signs. This explosion of MR information in multiple sclerosis patients corresponds very well with the pathology studies that have found axonal degeneration occurring in acute lesions. Sure, we knew axonal degeneration occurred in MS; however, we did not know its extent or timing. Furthermore, cognitive dysfunction in multiple sclerosis has largely been ignored, but recent data show that it may occur in 50% of patients with relapsing-remitting disease. Importantly, treatment with interferon beta-1a may curtail its progression.
Taken together, this information speaks strongly for early intervention. We are now moving forward with the concept of neuroprotection in established MS and in those high-risk monosymptomatic patients. Our definition of multiple sclerosis will need to change to incorporate those patients with clinically isolated attacks (CIAs) and positive MRI scans.
The abstracts below fortify our understanding of the pathogenesis of optic neuritis and multiple sclerosis while emphasizing the need for new measures of disease progression. We are clearly at the threshold of a paradigm shift in multiple sclerosis in terms of our definitions and therapeutics.
The History of the Diagnosis and Management of Optic Neuritis
Nicholas J. Volpe, MD, Associate Professor of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia
Much of what was known about optic neuritis was well established over 100 years ago. "Patients could be counseled in 1985 much the same way they could be counseled in 1885,"said Nicholas J. Volpe, MD, who took session attendees through a brief history of the disorder. "But information available in the last 15 years has revolutionized our thinking and approach to patients with optic neuritis," he said.
The invention of the ophthalmoscope in 1845 moved the knowledge base forward substantially, allowing physicians to localize vision loss to the optic nerve. But it was not until 140 years later, with the application of randomized clinical trials, magnetic resonance imaging (MRI), and the science of immunomodulation, that dramatic strides were made in managing this disease.
By 1860, all of the salient features of idiopathic optic neuritis had been described, and several individuals had accumulated a large series of patients by the turn of the century. The literature was sprinkled with discussions of possible etiologies, mostly infectious or toxic, and some proposals of rather barbaric treatments that often claimed success because of the under-appreciated rate of spontaneous recovery, Dr. Volpe said.
Before the invention of the ophthalmoscope, diseases of the fundus were impossible to recognize, and optic neuritis was not well distinguished from other forms of blindness. References are made in antiquity, however, to the optic nerve and its importance to vision, including references to optic nerve dysfunction as a mechanism for vision loss in early Arabic texts from the 9th century.
Little seemed to change from the 10th to the 19th centuries. Most writings about the disorder presented a confused picture of optic nerve and retinal disease. With the widespread use of the ophthalmoscope, the various diseases affecting the optic nerve and retina became distinguishable. Von Graefe in 1860 described the first series of optic neuritis patients with some uniformity. And Nettleship in 1884 identified the salient features of the disease, but did not relate them to other relapsing and remitting neurologic symptoms.
In addition to von Graefe and Nettleship, other authors figured prominently in the early description of the largest series of patients with optic neuritis-including Parinaud, Uhthoff, Buzzard, and Gunn. Each emphasized different features of the complex disease and helped to define the syndrome. Charcot was the first to recognize visual failure in the absence of ophthalmoscopic signs as an early symptom of multiple sclerosis (MS).
Thereafter, the relationship of optic neuritis to MS became better appreciated. In various early series, the rate at which MS developed after optic neuritis was quoted as between 12% and 85%. Modern prospective studies have yielded more valid-but not necessarily less confusing-information, finding this proportion to be 6%-71%.
Later, throughout the 20th century, observations became centered on four major features of the disease: 1) the distinction of optic neuritis from other optic neuropathies, 2) the prognostic significance of various aspects of the clinical presentation (such as pain), 3) the relationship of optic neuritis to multiple sclerosis, and finally 4) the role of corticosteroids in its treatment.
All of the early describers of optic neuritis recognized the common feature of pain and described vision loss and its characteristics, especially the progression of a vision deficit followed by recovery. The significance of the fundus appearance has been recognized since the earliest descriptions, and the prevalence of disc swelling and disc hemorrhage has been variably reported. Although the importance of cerebrospinal fluid (CSF) analysis in MS was appreciated early in the clinical description of the disorder, the literature is less compelling-and continues to be so.
The early terminology related to optic neuritis is also confusing, since "neuritis" often referred to other cases of disc swelling or optic nerve dysfunction. Because of this confusion, early reported cases probably contained a variety of other diagnoses. True cases of optic neuritis were considered to have many possible causes, including infections, hereditary disorders, sinus disease, compression, toxins, gout, rheumatic disease, and tobacco use. Many authors were aware of the high rate of spontaneous resolution, but others mistakenly attributed recovery to "successful treatments."
Treatment of Optic Neuritis
In the Bible, Mark (8:23) wrote, "and he took the blind man by the hand and led him out of town, and when he had spit on his eye and put his hand upon him, he asked if he saw aught, and he saw things clearly." It is unlikely that Mark was describing a patient with optic neuritis, but this quote highlights the basis of all ophthalmic therapeutics between ancient times and the latter part of the 19th century, when various compounds were rubbed in the eye. When the specific syndrome of optic neuritis was recognized more than 100 years ago, treatment centered on emetics, identification of toxic substances, sinus surgery, and optic canal decompression.
By the mid-20th century, clinicians were advocating salicylates, sweats and open bowels, intravenous sodium nitrite, intramuscular acetylcholine, and inhalations of amyl nitrite. By the 1930s, interest shifted from intoxications and infections to primary inflammation of the optic nerve. Beginning in the 1950s, corticosteroid treatment was advocated. Significant advances in managing acute optic neuritis did not occur during the 20th century until the emergence of the modern clinical trial and MRI. The major strides made before the last decade were in distinguishing optic neuritis from other disorders. Still today, the exogenous influence causing the disorder remains unidentified.
Using the Latest Evidence-Based Medical and Clinical Data From the Optic Neuritis Treatment Trial and the Longitudinal Optic Neuritis Study to Enhance Patient Outcomes
Craig H. Smith, MD, Director, Swedish Medical Center MS Center, Seattle The initial findings of the Optic Neuritis Treatment Trial (ONTT) dramatically changed the management of optic neuritis, with neuro-ophthalmologists almost universally discontinuing the use of oral prednisone for optic neuritis, as the effect was equal to placebo. The ONTT continues in the form of the Longitudinal Optic Neuritis Study (LONS), further demonstrating that clinical trials in neuro-ophthalmology can generate key information regarding the natural history of this demyelinating event, said Craig Smith, MD, at the symposium.
"The emergence of further information from the LONS has continued to enhance our knowledge of optic neuritis and its characteristics, as well as long-term prognosis," Dr. Smith said. "Pivotal trials also change the behavior of clinicians."
The ONTT found that patients with three or more white-matter lesions had a 51% chance of developing clinically definite MS (CDMS) within 5 years, while those with normal MRI scans had only a 16% risk.
"This 16% is the population we are particularly interested in at the 10-year follow-up," he said. "We want to determine what distinguishes patients with negative MRIs at baseline who remain negative, to see what predictors may be present."
Visual Field Deficits
Within the last two years, the ONTT/LONS trial has yielded valuable new information for the management of optic neuritis. One area is the analysis of visual field defects. Keltner et al. (Am J Ophthalmol 1999;128:543) compared the results of peripheral kinetic visual field testing and central static perimetry for 448 patients enrolled in the ONTT. They found that for both affected and fellow eyes at all visits, central static perimetry yielded abnormal results more frequently than did peripheral kinetic visual field testing. Recovery of the far periphery of the visual field was also more rapid and complete. Automated central static perimetry appeared to provide effective visual field monitoring for patients with acute optic neuritis, the study concluded.
Fang et al. (Am J Ophthalmol 1999;128:554) studied whether particular areas of the visual field are preferentially affected in patients with acute optic neuritis. In a baseline evaluation of 440 ONTT patients, among those with diffuse visual field loss, a relative equal diminution of visual threshold was present throughout the entire 30-2 field. Depressions of visual threshold were greatest centrally among patients with localized central and cecocentral scotomas. However, depression of the entire tested visual field was also present in these patients, even among those whose central defects were mild. The degree of peripheral depression was greatest for those with the most severe central defects.
These ONTT findings provided evidence that optic neuritis may affect the entire central visual field, even in patients with apparently localized defects, Dr. Smith reported.
"The message to glean from this is that the return of visual function based upon central static perimetry is extensive-over 80%-and does not appear to differ based on the type of field deficit that is seen," he said.
Also emanating from the ONTT is information suggesting that certain genetic markers may help predict the development of MS. Hauser et al. (Neurology 2000;54:1859) assessed 178 patients in the ONTT for an association between the human leukocyte antigen (HLA)-DR2 allele and brain MRI signal abnormalities. The study found the HLA-DR2 haplotype to be associated with an increased odds ratio (OR 1.92) of developing probable or definite MS at 5 years (p = 0.04), with the strongest association among patients with signal abnormalities on baseline MRI.
"What we are beginning to see, based on the work of Hauser and others, is that after an initial event it may be possible to predict which patients will go on to develop clinical disease and to select patients for treatment with immunomodulating agents," Dr. Smith said. "The MRI combined with genetic testing may be the thing of the future, in terms of predictability and the importance of early treatment."
Changes in Treatment Patterns
The ONTT/LONS results significantly altered the treatment of acute optic neuritis, the mainstay of which had been oral prednisone.
In a random sample of 987 ophthalmologists and 900 neurologists (865 responding), Trobe et al. (Am Acad Ophthalmol Focal Points. March 1994;12) found that three quarters of physicians had encountered at least one optic neuritis case during the previous year; they analyzed the 465 responses.
"The most dramatic, and I believe gratifying, finding of this survey was the percentages of both ophthalmologists (90%) and neurologists (95%) reporting changes in their use of oral prednisone," he said. "That was a huge change in practice style."
Ophthalmologists were less inclined than neurologists to treat acute optic neuritis, while neurologists were more likely to use intravenous methylprednisolone. Among these intravenous steroid users, significantly more neurologists than ophthalmologists reported being swayed by an "improvement in one-year visual outcome." Actually, the study found no difference in visual outcome between treatment groups. "They misinterpreted the ONTT results," he said.
The reasons for ordering MRI scans also differed according to specialty. Significantly more ophthalmologists (36%) than neurologists (7%) reported using MRI to decide whether to treat patients with acute optic neuritis, and a significantly greater proportion of neurologists (65%) versus ophthalmologists (45%) ordered MRI to determine the risk of a future neurologic event indicative of MS (p = 0.0001 for both).
"The neurologist is thinking 'MS,' while the ophthalmologist is thinking 'optic neuritis,'" he noted. "This study points out that practitioners change practice styles as a result of collaborative clinical trials, but their reasons for doing so are often based upon faulty conclusions. It is also clear that the interspecialty differences may reflect differing perspectives on the implications of acute optic neuritis and its role as a potential first manifestation of MS, even in the setting of a normal MRI," said Dr. Smith.
"It's clear from the prodigious and clinically relevant output of this trial that neuro-ophthalmology is more than a phenomenology-related discipline. We are not just doing 'look and tell.' We are also doing good clinical research," Dr. Smith remarked.
Update on the CHAMPS Data
Steven L. Galetta, MD, Director, Neuro-Ophthalmology, Van Meter Professor of Neurology, University of Pennsylvania School of Medicine, Philadelphia
The CHAMPS trial (Controlled High Risk Avonex Multiple Sclerosis Trial) clearly established the benefit of Avonex treatment in patients considered to be at high risk for developing clinically definite MS (CDMS). Additional analyses from this trial have solidified this mandate. The updated findings were presented at this meeting by Steven L. Galetta, MD, a CHAMPS investigator.
The ONTT demonstrated that patients with isolated acute demyelinating syndromes and brain lesions on MRI scans were at high risk for developing MS. These findings provided the rationale to study interferon beta-1a (Avonex, Biogen, Inc.) versus placebo in a group of high-risk patients. Earlier trials had already established a beneficial effect in reducing disability and relapses in relapsing-remitting MS (RRMS) patients treated with Avonex.
The CHAMPS study was initiated at 50 centers across the United States and Canada. Patients had an acute isolated demyelinating event involving the optic nerve, spinal cord, or brainstem/cerebellum. In addition, each patient had two or more clinically silent brain MR lesions that were at least 3 mm in size and at least one of which was periventricular or ovoid. All patients received intravenous methylprednisolone within 14 days of symptom onset, followed by an oral prednisone taper. Patients were randomized to receive weekly intramuscular injections of Avonex or placebo.
The primary outcome measure was the development of CDMS, defined by the appearance of new neurologic or ophthalmologic events or progressive neurologic deterioration. Serial brain MRI studies provided secondary outcome measures.
CHAMPS was terminated early in February 2000 after showing that Avonex may reduce the conversion to CDMS in high-risk patients by about half. Even more compelling was the MR data, which found that 82% of the placebo group developed new but silent MR lesions by 18 months. "This finding emphasizes that many demyelinating lesions may go undetected clinically. In addition, it shows that a large number of high-risk patients have ongoing demyelination," Dr. Galetta pointed out.
Data from a subgroup analysis were also presented. The benefit of interferon beta-1a was seen regardless of whether the patient presented with optic neuritis, a spinal cord syndrome, or brainstem/cerebellar dysfunction. Furthermore, treatment benefit was observed irrespective of baseline MRI T2 lesion number or volume.
Ten Reasons to Treat High-Risk Optic Neuritis Patients Early
By Steven Galetta, MD
Natural history studies suggest that MS is not benign: 50% of patients convert to a progressive course within 10 years, and approximately 90% do so within 25 years.
Fatigue and cognitive dysfunction may occur without evidence of new T2 lesions on MR imaging.
MR scans show early brain atrophy, black holes on T1-weighted images, and decreased N-acetylaspartate (NAA), a neuronal marker. Black holes and NAA are suggestive of axonal dropout or dysfunction.
In the Controlled High Risk Avonex Multiple Sclerosis (CHAMPS) trial, 82% of untreated patients developed a new subclinical MR lesion within 18 months of study onset.
Pathologic studies show that axonal degeneration occurs early in the disease and in acute plaques.
The cost-effectiveness of early treatment is debatable, but some studies show substantial cost savings, particularly when viewed over the long term.
Various studies with Avonex (interferon beta-1a ) across the spectrum of disease suggest that therapy is more effective early in the disease course. CHAMPS showed a reduction in new attacks in high-risk patients by about half. The initial Avonex study in relapsing-remitting patients found a 32% reduction in new attacks and a 37% reduction in disability progression.
The Early Treatment of MS (ETOMS) study, using 22 µg (low dose) Rebif (interferon beta-1a, Ares-Serono) once a week subcutaneously, showed clinical benefit in monosymptomatic patients but not in relapsing-remitting patients, substantiating the importance of early treatment. (Rebif has not been approved by the FDA for use in the United States.)
ETOMS patients experienced a 24% reduction in progression to CDMS, while similar patients in the CHAMPS study demonstrated a 44% reduction. Patients in the ETOMS study appeared to have more advanced disease, by both clinical and MR data.
In long-term follow-up, placebo-treated patients in the original Rebif and glatiramer acetate (Copaxone, Teva Marion) trials are not doing as well as patients initially randomized to active treatment.
New Immunomodulatory Therapy and Imaging Techniques for the Diagnosis and Treatment of Multiple Sclerosis
Evolving Concepts in the Pathogenesis of MS and Their Therapeutic Implications
Richard A. Rudick, MD, Director, The Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Cleveland
In recent years, concepts of MS pathogenesis have evolved rapidly. While still considered an immune-initiated inflammatory disease, there is increasing awareness of several features of the disease that have therapeutic implications, said Richard A. Rudick, MD, one of the foremost researchers in the field. Dr. Rudick cited the following:
1. There is an increasing recognition that MS is largely subclinical in its early stages. In many patients, the pathologic process is continuously active despite few symptoms.
2. Axonal and neuronal pathology is common, is present early during the disease course, and may have a complex pathogenesis.
3. Patients enter a secondary progressive (SP) stage relatively late in the pathologic process, probably because the extent of axonal pathology exceeds a threshold.
Traditionally, patients with RRMS have been viewed as having a relatively benign form of the disease, probably because of minimal disability between relapses, and have often been reassured rather than treated. But multiple lines of evidence have converged to demonstrate that silent-but active-disease is irreversibly destroying brain tissue, and disability eventually strikes the vast majority of patients.
After 11-15 years' disease duration, 58% of RRMS patients have evolved to the SPMS stage; after 25 years, this figure rises to 89% (Weinshenker et al., Brain 1989;112:133). "Benign" courses, in fact, do not exclude the possibility of subclinical disease, as demonstrated by multiple MRI studies showing gadolinium-enhancing brain lesions in patients without clinical symptoms, probably reflecting inflammation. The number of gadolinium-enhancing lesions on semiannual MRI scans has been found to predict the relapse rate during a 12-month period, though the relationship to progressive disability remains unclear, he said.
Other MR studies have demonstrated reduced levels of NAA in brain lesions and in normal-appearing white matter from RRMS patients, suggesting that axonal pathology is a consistent and early feature of the disease process. In the later stages, there is profound axonal loss, according to recent studies that have found axonal loss to be as high as 80% in some patients.
Loss of brain tissue early in the course of MS has also been documented. In the Avonex (interferon beta-1a, Biogen, Inc.) clinical trial, serial MRI scans in the placebo group showed significant increases in ventricular diameter and corresponding decreases in corpus callosum area and brain width. Gadolinium-enhancing lesions at baseline were the strongest predictor of progressive enlargement of the third ventricle.
A normalized measure of whole brain atrophy-termed the brain parenchymal fraction (BPF)-has also been applied to patients in the Avonex clinical trial. More than 70% of placebo recipients had significant decreases in BPF during the 2-year observation. Furthermore, these patients had BPF more than 5 standard deviations below the mean of a healthy control group.
In addition, patients with the most brain atrophy at baseline were significantly more likely to become severely disabled. A Kurtzke Expanded Disability Status Scale (EDSS) score of і6.0 (a high degree of disability) was noted at follow-up for 11.8% of patients with no atrophy and 51.5% of patients in the highest quartile of baseline atrophy, Dr. Rudick reported (Neurology 1999;53:1698).
"Importantly, decreasing BPF occurred in many patients without clinical relapses, and in many patients without worsening EDSS scores, implying the presence of a subclinical pathologic process resulting in brain tissue loss," he noted.
These findings support the hypothesis that MS is active in many patients from early in the disease, but that clinical symptoms only loosely reflect its severity. Patients may appear stable between relapses because compensatory mechanisms are adequate to maintain neurologic function. Once patients move into the SPMS stage, they rapidly decline because the extent of irreversible tissue injury has progressed beyond a critical threshold. Neurologic disability becomes irreversible, and restorative therapy may be unrealistic at this stage, Dr. Rudick proposed.
"The clinical implications are that you really need to think about diagnosing MS early," he said. "Don't send patients away, because they may be in a wheelchair the next time you see them. You have to treat the patient early and continuously with disease-modifying agents, because they are demonstrably effective. And patients should be proactively monitored for disease progression, whether they are on therapy or not, because this is largely a subclinical disease."Contemporary and New Immunomodulatory Therapy
Because of the mounting evidence that MS is continuously active from the early stages of the disease, and that the pathologic process includes irreversible tissue injury and diffuse axonal pathology, there is growing consensus that disease-modifying therapy should be initiated early.
Clinical trials involving more than 1,100 MS patients have led to the approval of four immunomodulating agents for RRMS, which demonstrated efficacy in preventing relapses and/or slowing time to disability progression.
The main findings from the randomized, placebo-controlled, double-blind trials in RRMS are as follows:
Interferon beta-1b (Betaseron, Berlex), the first immunomodulatory agent to be approved, was tested in 372 patients who received subcutaneous injections of 250 µg or 50 µg of agent or placebo every other day for up to 5 years. Treatment with the higher dose reduced the relapse rate by 33%, increased the proportion of relapse-free patients from 16 to 31%, and reduced by two-fold the number of patients having moderate or severe relapses. (The IFN-beta Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology 1995;45:1277)
Interferon beta-1a (Avonex) was tested in 301 patients given weekly intramuscular injections of agent or placebo for up to 2 years. Treatment significantly lowered the probability of sustained disability progression by 37%, and significantly fewer treated patients became severely disabled (defined as a 6-month sustained worsening at least to the EDSS 4.0 or EDSS 6.0 levels). Treatment with Avonex also reduced the relapse rate by 32% in patients treated for 2 years. (Jacobs et al. Ann Neurol 1996;39:285)
Interferon beta-1a (Rebif, approved in Europe and Canada) was tested in 560 patients given 44 µg, 22 µg, or placebo by subcutaneous injection three times per week for 2 years. At 2 years, relapses were reduced by 29% with the lower dose and by 32% with the higher dose. Treatment reduced the number of severe relapses, number of steroid courses, and number of hospital admissions for MS, and produced significant benefits on EDSS changes. (PRISMS Study Group. Lancet 1998;352:1498)
Glatiramer acetate (Copaxone, Teva Marion) was tested in 251 patients given daily subcutaneous injections or placebo for 2 years. Copaxone reduced the relapse rate by 29%. No benefit was observed on sustained changes on EDSS. (Johnson et al. Neurology 1995;45:1268)
Both interferon beta-1a and interferon beta-1b appear to inhibit new brain lesion formation. In clinical trials, Betaseron resulted in significantly fewer new or enlarging T2 lesions and significantly less annual accumulation of T2 lesions and gadolinium-enhancing lesions. Avonex significantly reduced gadolinium-positive brain lesions and decreased the number of new and enlarging T2 lesions. Glatiramer acetate reduced gadolinium-enhancing lesions, but the effect was delayed (4-6 months) and less significant compared with the interferons.
Mechanisms of Action
The mechanism of action of the available therapies is not completely understood. Interferon beta induces the expression of many genes, so the mechanisms of action in MS are likely to be complex, including inhibition of autoreactive T cells, inhibition of major histocompatibility complex (MHC) class II antigen expression, inhibition of metalloproteases or altered expression of cell-associated adhesion molecules (reducing cellular migration into the CNS), induction of immunosuppressive cytokines, and inhibition of pro-inflammatory cytokines (leading to resolution of the inflammatory process).
Glatiramer acetate is a polypeptide consisting of a random arrangement of four basic amino acids. This drug is thought to mimic myelin basic protein and is postulated to induce myelin-specific suppressor T cells and inhibit myelin-specific effector T cells.
Pulsed Steroids: A Promising Approach?
A new, as yet unpublished Italian study of pulsed methylprednisolone in early RRMS patients has shown encouraging results, Dr. Rudick reported. The randomized, controlled, 5-year, phase II trial by Zivadimov and colleagues included 88 patients with early disease who received methylprednisolone only at the time of relapse (controls) or pulsed doses of the drug every 4 months for 3 years, then every 6 months for 2 years. The principal outcome was change in lesions on MRI.
At study completion, the final EDSS scores were significantly higher in the relapse-treatment (control) group, indicating that the pulsed treatment may have delayed disability. MRI scans also showed changes in T2-weighted lesions and significantly more T1 black holes, as well as a significant loss of brain parenchyma in the controls. "There was virtually no loss of tissue in the pulsed group and a significant loss in the relapse-treated group," he said.
The patients receiving pulsed steroids also had a 32% reduction in sustained EDSS worsening, lower EDSS scores at follow-up, and fewer patients moving into the secondary progressive stage. "The bottom line is that this is a single, but interesting, study that could be important," Dr. Rudick observed.
Interferon in Secondary Progressive MS
The results of interferon beta trials in 2,931 patients with SPMS have thus far been mixed; therefore, these agents are not approved for this stage of the disease. This is particularly striking with the two Betaseron studies, which were similar in design but yielded conflicting results. The European study showed a highly significant, though modest, benefit on disability progression, while the North American Study showed no effect on this end point.
Since the North American population was significantly older at entry and had a longer disease duration, fewer relapses in the prior 2 years, greater change in EDSS in the 2 years before study entry, and fewer gadolinium-enhancing lesions at study entry, they appear to have had less inflammatory disease at the time of treatment. While speculative, this analysis would conclude that interferon beta therapy is most effective in the earlier, inflammatory stage of MS and increasingly less effective in later stages characterized by progressive disability, Dr. Rudick suggested.
A similar study with Rebif produced a treatment effect that was "intermediate" between the two Betaseron studies, with a slight increase in time to progression and a significant effect on relapses and lesion criteria.
The Avonex SPMS study, using the Multiple Sclerosis Functional Composite (MSFC) index as a primary end point, showed that the treated group had a delayed MSFC index deterioration compared to the placebo-treated patients.A different type of drug, mitoxantrone (Novantrone, Immunex) shows some promise in SPMS, according to results of the MIMS trial (Mitoxantrone in Multiple Sclerosis), a double-blind, placebo-controlled study of 107 secondary progressive or remitting-progressive patients. Subjects received high or low doses of mitoxantrone or placebo every 3 months for 2 years. By stringent multivariate analysis, a statistically significant treatment effect was shown on five outcome measures, and a number of secondary outcomes were also positive and even robust, Dr. Rudick reported.
"All the high-dose patients got better. But patients taking this drug develop alopecia, amenorrhea, and potentially cardiac toxicity. Nevertheless, mitoxantrone looked very promising," he said. Mitoxantrone has been approved by the FDA for the treatment of secondary progressive and worsening relapsing forms of MS.Investigational Agents
Dr. Rudick said that the current immunomodulatory agents are not the final answer to MS management. While early treatment with these drugs is important, the search for new types of agents is vital, including 1) altered peptide ligands, a form of antigen-specific immunotherapy that has protected animal models from disease development, 2) the inhibition of leukocyte trafficking (movement of cells across endothelial barriers and into tissues); inhibition of a particular leukocyte integrin has been studied using a humanized monoclonal antibody (Antegren, Elan Pharmaceuticals) in MS patients, providing proof of principle, and 3) co-stimulatory molecules, specifically anti-CD40 ligands, which are in early clinical trials.
Outcome Measures in Clinical Trials
Laura J. Balcer, MD, Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia
The need for new and more sensitive clinical outcome measures in MS has been fueled not only by the characteristics of the disease process, but also by advances in the field, particularly the development of effective therapies. Several aspects of neurologic function-such as vision-have been under-measured by traditional scales. Efforts are currently under way to fill this gap, said Laura J. Balcer, MD, MSCE.
In MS, there has been a trend for the use of performance measures, standardized procedures used to quantitate neurologic function that are sensitive to changes over time. Clinical outcome scales in MS measure impairment, disability, or a combination of both. The most commonly used clinical outcome measure in MS has been the Kurtzke Expanded Disability Status Scale (EDSS). The EDSS is scored in 0.5 increments up to 10.0, the lowest scores representing the least disability. While it is useful for categorizing patients clinically, its use as a clinical trial outcome measure has been criticized because of its subjectivity, its focus on ambulation, and its lack of cognitive and visual measures, as well as other factors.
In response to perceived difficulties with the EDSS, the National MS Society Clinical Outcomes Assessment Task Force recently developed the MS Functional Composite (MSFC). This new scale has three components that yield objective and quantitative results: 1) a timed 25-foot walk, 2) the 9-hole peg test, and 3) the paced auditory serial addition test (PASAT-3). A composite score is obtained, which represents the number of standard deviation units above or below the average score from a standardized MS population. The MSFC has recently been used as the primary outcome measure for neurologic impairment in the IMPACT study of Avonex in SPMS.
Visual Function Outcome Measures
The quantitative assessment of visual function in MS clinical trials has been generally limited to measures of Snellen visual acuity. The MSFC, despite its potential advantages, does not yet include an assessment of visual function.
Several investigations suggest that measures of contrast sensitivity and contrast letter acuity are the most sensitive measures of visual dysfunction in MS, even among patients with Snellen acuities of 20/20 or better. A new set of contrast letter acuity charts, the Low-Contrast Sloan Letter Charts (LCSLC) (Precision Vision, LaSalle, IL), has a standardized format based on that of the Early Treatment for Diabetic Retinopathy Study visual acuity charts. Each LCSLC has several contrast levels, ranging from high contrast to 0.6%.
Dr. Balcer described a series of studies that demonstrated feasibility and excellent inter-rater agreement for both MS and volunteer groups tested with the LCSLC, including a substudy of the IMPACT trial (International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial). In the reliability study, levels of inter-rater agreement were comparable to those reported for other low-contrast vision testing methods, including the Pelli-Robson chart. LCSLC testing thus demonstrates excellent potential as a visual outcome measure for MS trials.
Eighty-eight of the 100 MS patients in the inter-rater reliability substudy had binocular visual acuities of 20/20 or better. In fact, 73 had acuities of 20/16, the upper limit of the 100% contrast chart at 2 meters. However, among patients with 20/20 or better binocular visual acuities, there was a high degree of variability in LCSLC letter scores, especially at the 0.6% contrast level, Dr. Balcer reported.
"These results suggest that the lowest-contrast chart [1.25% and 0.6%] may capture information on visual function that is most distinct from that provided by high-contrast visual acuity. Our data also provide strong evidence that LCSLC testing is likely to be capturing an aspect of vision that traditional measures of Snellen acuity as used in the EDSS are not capturing," Dr. Balcer said.
"In addition, when assessing ambulation status-whether patients needed no assistance, a cane, or a walker-we again saw variability in the lowest-contrast chart scores, indicating more compelling evidence that these charts have a complementary role in assessing patients with MS."
"But we all know that eye charts, MS Functional Composite, and EDSS only provide part of the picture when we evaluate a patient with MS, and this is where health-related quality-of-life (HRQOL) measures come in. These measures are gaining increasing importance in clinical trials and are often used to complement measures of impairment. They are unique in that they capture the patient's, rather than the physician's, perspective of how MS or its treatment has affected the patient," she said.
The most widely used measure is the MS Quality of Life Inventory, which consists of a core generic scale, the SF-36, and nine other scales that capture various symptoms and aspects of HRQOL, including a 5-item Impact of Visual Impairment Scale. Another scale, the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25), has been validated as a measure of vision-specific HRQOL. There is a modest, yet significant, correlation between scores on the VFQ-25 and visual acuity; therefore, it seems to be capturing some aspect of visual acuity not captured by Snellen measures, according to Dr. Balcer.
In the ONTT cohort, the VFQ-25-and the larger 51-item version-found that self-perceived visual dysfunction was more common among patients who went on to develop CDMS. This relation was observed even though neurologic impairment in these patients was generally mild. A study from the University of Pennsylvania MS Center found that VFQ-25 scores were significantly lower (worse) in MS patients versus a reference group on 10 of 12 subscales. The study also showed that ambulation status did not predict VFQ-25 composite scores, and that variability in VFQ-25 scores was present even among the 83% of patients who had binocular acuities of 20/20 or better.
"These results provide even stronger evidence that patients with MS have a high degree of self-reported visual dysfunction, and that the VFQ-25 is likely effective in demonstrating such vision-specific, health-related quality of life deficits in MS populations," she said.
New Imaging Techniques in Multiple Sclerosis
Robert I. Grossman, MD, Department of Radiology, University of Pennsylvania Medical Center, Philadelphia
Magnetic resonance imaging has had a profound impact on the diagnosis and treatment of MS. New techniques offer the opportunity for much better understanding of the underlying pathology of MS and should someday provide the most accurate methods of assessing treatment effects. New and forthcoming imaging techniques were described by Robert I. Grossman, MD, at the symposium.
Simple MRI quantitative measures-T2 lesion number and volume and T1 enhanced lesions-are easy to obtain and quantitate, and simple to understand. But these measures do not offer enough information, Dr. Grossman said. "Do they really tell us about disease burden? Probably not. They don't measure the normal brain, they don't really tell us about activity, and there is a spectrum of pathology we are not able to discern. The challenge for neuroradiologists is to be able to detect all lesions, including the normal-appearing abnormal brain, to subcategorize lesions, and to be able to improve our diagnostic acumen and our ability to detect therapeutic effects."
Take, for example, hypointense T1 "black hole" lesions thought to be so harmful, he said. "You have to ask how black is a black hole, and to realize there is variation of signal intensity within the black hole. Black holes are not really black holes, and on more sophisticated imaging you see that they actually extend beyond the boundaries of what you traditionally think of as a lesion," he pointed out.
Dr. Grossman added that some of the newer techniques that can produce more accurate measures include the following:
FLAIR (fluid-attenuated inversion recovery) imaging is a pulse sequence that increases the conspicuity of lesions at the interface between brain and CSF. "Fast FLAIR" combines this technique with a fast spin echo pulse sequence to produce even better lesion detectability, lesion conspicuity, and lesion-to-CSF contrast, with the advantage of speed.
Magnetization transfer imaging provides information on the structure of CNS tissue-specifically monitoring myelin loss-by reflecting the concentration of proton molecules associated with myelin. This method demonstrates abnormalities not only in lesions but also in normal-appearing white matter.
Diffusion weighted imaging is a noninvasive technique for measuring the movement of water molecules, used mostly in stroke imaging but also providing an indication of myelin injury and perhaps axonal integrity. Diffusion imaging may be capable someday of stratifying both the clinical and imaging subtypes of MS patients, and should become useful in the assessment of treatment outcomes.
MR spectroscopy provides a means of identifying particular biochemical abnormalities that may be the initial step in categorizing the disease process. Most studies today use single voxel methods and chemical shift imaging, but 3-dimensional multivoxel technology is expected to be much more appropriate in the evaluation of MS patients.
Whole brain N-acetylaspartate (NAA) quantification overcomes some of the limitations of MR spectroscopy by acquiring the NAA signal from the whole brain. Whole brain NAA can provide a relative measure of neuronal and axonal losses in the entire brain. It is described in more detail below.
Whole Brain NAA Quantification
This 20-minute procedure examines the whole brain for loss of NAA, a very sensitive marker of irreversible neuronal loss. NAA reflects neuronal viability, and its signal decreases with any brain injury. NAA loss is not limited to lesions but appears to be widespread in the brains of MS patients.
NAA remains "outstandingly constant" over time in healthy persons, said Dr. Grossman. However, RRMS patients demonstrate a loss of NAA that is ten times faster than the loss seen in normal subjects of the same age (almost 1% per year), and the loss precedes brain atrophy.
Loss of NAA could be rapid, moderate, or fairly negligible, according to a study in 45 RRMS patients. "From this data, I would hypothesize that in the future, NAA whole brain measurements can help predict the course of MS and may help guide treatment decisions," Dr. Grossman said. "NAA may provide important prognostic information, may help stage patients, provide stratification for clinical trials, and be an arbiter of drug efficacy."
Diagnosis and Treatment of Devic's Neuromyelitis Optica
Eric R. Eggenberger, DO, Michigan State University, East Lansing
Distinguishing multiple sclerosis from Devic's neuromyelitis optica (DNO) can be difficult for the clinician. DNO involves optic neuritis (unilateral or bilateral) and myelitis without any clinical features of demyelination elsewhere. The visual loss in DNO is usually painless.
DNO, which is primarily a disease of younger adults, affects both sexes equally and does not appear to have a genetic component. It has two clinical forms, monophasic and relapsing. Monophasic DNO is characterized by onset of optic neuritis and myelitis in close proximity (often simultaneous) and more severe symptoms. Patients with relapsing DNO present with milder symptoms and a longer time between index events (optic neuritis and myelitis, not necessarily in that order); their long-term outlook is worse, with higher rates of respiratory failure and death.
Most useful in determining a diagnosis is the MRI. In DNO patients, the spinal cord MRI shows single cord lesions extending over two vertebral segments (most of the lesions are hypointense on T1 imaging), and the brain MRI is usually normal. Only rarely will a patient with DNO have abnormal protein in the cerebrospinal fluid. In one study (Wingerchuk et al., Neurology 1999;53:1107), 44 of 50 patients with DNO had longitudinal, confluent spinal cord lesions extending 3 or more segments (often 6 to 10 segments). Of those patients, only half had cord edema and only 64% had abnormal enhancement (factors that depend, in part, on the timing of imaging).
Treatment for acute DNO includes the administration of high-dose steroids; alternate immunosuppressive agents, such as serial steroids, azathioprine, intravenous immunoglobulin, and interferons, may be added upon relapse. Most patients will improve with treatment, but complete recovery is rare. DNO often leads to severe disability, and continued study of its pathogenesis (which, like that of MS, is enigmatic) and treatment is required.
Panel Question-and-Answer Session
Panelists: Nicholas J. Volpe, MD; Craig H. Smith, MD; Steven L. Galetta, MD; Eric R. Eggenberger, DO; Richard A. Rudick, MD; Laura J. Balcer, MD; Robert I. Grossman, MD
The panelists unanimously agreed that data from CHAMPS serve as a mandate for the early treatment of patients with optic neuritis and MRI lesions. Dr. Volpe said that ophthalmologists who diagnose optic neuritis should have, as their primary concern, the possibility that optic neuritis might herald MS and should order an MRI scan.
Neil Miller, MD, president of NANOS, noted the value of this informative symposium and commented, "After the CHAMPS trial was reported, a couple of things occurred to me: that overnight, the standard of care for optic neuritis changed. These patients must have an MRI scan with gadolinium, and at the minimum you must provide the patients with information. It's obvious that early treatment is the way to go, and patients have to think about this and make that decision. This is the message we should be getting out to our colleagues."
Dr. Volpe said all patients with more than three white-matter lesions on MRI scan should be treated with intravenous solumedrol, and with assistance from a neurologist MS expert, they should be considered for long-term Avonex.
Dr. Smith added, "What CHAMPS showed us was that the first event means we should start treatment soon with an immunomodulating agent." While Dr. Smith thought any of the immunomodulating agents could be prescribed for the high-risk monosymptomatic optic neuritis patient, Dr. Galetta maintained that Avonex would be his first choice, since this is the only agent supported by data in the high-risk population.
There are situations, however, that are not straightforward, and attendees asked for guidance in managing such patients. For patients with optic neuritis but no other suggestive symptoms, the panelists would take more of a wait-and-see approach.
"For patients with isolated optic neuritis and normal MRI scans, who would be considered at low risk, I would not automatically treat with immunomodulating agents. I would consider doing serial MR scans on a yearly basis to see if anything happens silently that might change my mind," stated Dr. Galetta.
Regarding the role of combination therapy, Dr. Rudick was hesitant to make recommendations because of the lack of data. He commented, "As in diabetes, we want to achieve tight control, but unlike diabetes we don't have a test to tell us how to do this, though we are trying to go in that direction. What is being added to immunomodulating agents is all over the map. What seems most common is methylprednisolone, methotrexate, azothiaprine, and mitoxantrone. What I am most interested in are period pulses of methylprednisolone along with an immunomodulating agent, but we do not have a method of identifying partial responders or a standardized methodology for treating with a combination."
Dr. Smith added, "We are seeing combinations being used, but it would be wise to wait until we have data from structured clinical trials. Currently, I know of trials evaluating mitoxantrone in combination with interferon or glatiramer acetate, so these studies are in progress."