This report was reviewed for medical and scientific accuracy by Andrew R. Pachner, MD, Professor, Department of Neurology and Neurosciences, University of Medicine & Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey.

Expert Commentary

Robert Zivadinov, MD, PhD, Director, Buffalo Neuroimaging Analysis Center; Associate Professor of Neurology, Department of Neurology, School of Medicine and Biomedical Sciences, The Jacobs Neurological Institute, Buffalo, New York

Throughout the last decade, significant advances have been made in the clinical management of multiple sclerosis (MS). The introduction of immunomodulatory agents has offered patients with MS safe and efficacious treatment options for the long-term maintenance of their disease. However, the course of MS remains variable and inflicts a significant emotional toll on its patients, as well as family and caregivers. As investigational trials continue to explore new and promising treatment options, as well as combinations of therapies, many challenges remain. Data presented at the 18^th Annual Meeting of the Consortium of Multiple Sclerosis Centers exemplify the efforts made to address those challenges.

Data presented at this meeting included issues surrounding the practical management of MS, and the importance of the neuropsychological evaluation and its impact on early diagnosis and disease management, as well as the recognition of the significance of psychosocial intervention. Information was presented on the importance of, and clinical implications of, brain atrophy in patients with MS. Advances in diagnostic technology, such as imaging techniques, and preliminary data from several trials illustrating new trends in add-on therapy for MS were also presented. Collectively, these data hold great promise for patients with MS.

This Multiple Sclerosis Forum Report^TM reviews data presented on the practical management of MS, the development of brain atrophy, new treatments for secondary-progressive MS, advances in magnetic resonance imaging (MRI), neuroprotection in MS, and the newest trends in add-on therapy.

Practical Management of Multiple Sclerosis

Treatment Strategies to Reduce Anxiety Associated with Self-Injection

Anxiety concerning self-injection of interferon beta formulations creates a potential obstacle to patient compliance and to optimal treatment among patients with MS. Up to 50% of patients initiating treatment with weekly intramuscular interferon beta-1a (Avonex) choose to have someone else administer their injection.¹ Initiatives to train patients to self-inject are designed to promote adherence to therapy, minimize lifestyle disruption, and preserve an acceptable quality of life.^2,3 Studies have shown higher discontinuation rates among patients who are unable to self-inject due to anxiety, compared with patients who are able to self-inject.¹

A study by Cox and colleagues examined a brief, manualized, individual, nurse-administered, cognitive-behavioral treatment for patients with self-injection phobia.⁴ Thirty patients with relapsing-remitting MS with self-injection phobia were randomly assigned to either cognitive-behavioral treatment or a telephone-based support program. The results demonstrate that patients who received cognitive-behavioral treatment were significantly more likely to be able to self-inject at the end of the treatment period, compared with those who received telephone support (P = 0.02). Thus, these findings suggest that nurse-administered cognitive-behavioral treatment may enhance treatment adherence to MS therapies. The investigators suggest that strategies for applying these techniques in MS clinics and neurology practices should be widely used.

Management of Flu-like Symptoms at Initiation of Interferon Beta Therapy

According to the interim results of a study by Brandes et al,⁵ flu-like symptoms associated with the initiation of treatment with Avonex can be managed by gradually titrating the dose of Avonex and administering acetaminophen or ibuprofen. Twenty-seven patients with relapsing MS were randomized to 1 of 3 treatment groups: standard doseof Avonex (30 mcg, no titration) plus acetaminophen (Group 1); one-quarter dose titration of Avonex every 2 weeks plus acetaminophen (Group 2); and one-quarter dose titration of Avonex every 2 weeks plus ibuprofen (Group 3), for a total of 12 weeks. One-quarter dose titration was defined as 7.5 mcg for weeks 1 and 2, 15 mcg for weeks 3 and 4, 22.5 mcg for weeks 5 and 6, and 30 mcg for weeks 7 to 12. Presence and intensity of fever, muscle aches, chills, and weakness were assessed and scored on a scale from 0 (absent) to 3 (severe, bed rest required).

Both the intensity and frequency of flu-like symptoms were reduced in Groups 2 and 3 compared with Group 1. There was a significant reduction in intensity of flu-like symptoms during the first 2 weeks (P = 0.018, 4 hours post-injection) in the patients receiving titrated dosing of Avonex compared with the standard dosing. No differences were observed in the intensity or frequency of flu-like symptoms between Groups 2 and 3, indicating no difference in efficacy between acetaminophen and ibuprofen in relieving flu-like symptoms. Moreover, the mean weekly dose of analgesic required by patients was substantially reduced as the dose of Avonex was titrated. As might be expected, acetaminophen and ibuprofen were taken more often by patients who received the standard weekly 30 mcg dose of Avonex. All study discontinuations occurred in the full-dose group (Group 1) during the first 2 weeks of therapy and were due to flu-like symptoms. These interim results suggest that the first 2 weeks of therapy are critical in determining if patients will remain on treatment and that there is a significant effect of dose titration on the intensity of flu-like symptoms in patients initiating Avonex therapy.

Pain Medications for the Management of Interferon-Related Side Effects

Initiation of interferon beta therapy has been associated with headache, fever, chills, and injection-site pain. Over-the-counter analgesics such as naproxen, ibuprofen, and acetaminophen can often attenuate such interferon-related adverse events. However, fatigue, muscle or joint pain may continue to be a significant problem. Leuschen et al conducted a 5-week open-label feasibility study in 60 patients with relapsing-remitting MS to evaluate the efficacy of naproxen, ibuprofen, and acetaminophen for the management of adverse events associated with Avonex therapy (30 patients initiating an escalating Avonex therapy and 30 patients who had been receiving Avonex for at least 6 months with continued adverse effects associated with the weekly injections).⁶ Adverse events were assessed using a modified fatigue impact scale (mFIS). In patients randomized to acetaminophen, mean mFIS was higher at study initiation than at study end (P = 0.04); however, neither physical nor psychosocial subsets changed. Patients who initiated escalating therapy with Avonex had significant improvement in mFIS with naproxen or ibuprofen over the 5 weeks with the greatest change in physical subset (P = 0.002 for naproxen and P<0.01 for ibuprofen). In addition, in those patients with continued adverse effects associated with Avonex, physical function was improved for those on naproxen (P<0.05) and ibuprofen (P<0.03). Investigators concluded that naproxen and ibuprofen were more effective than acetaminophen in reducing side effects known to be associated with Avonex therapy.

The Clinical Implications of Brain Atrophy in Multiple Sclerosis

Central Nervous System Atrophy in Multiple Sclerosis

According to a presentation conducted by Nancy Richert, MD, PhD, Laboratory of Diagnostic Radiology Research, National Institutes of Health, symptoms associated with MS depend on the site of lesions and the type of disease.⁷ As central nervous system (CNS) damage accumulates, enduring symptoms are indicative of progressive disability. In addition to physical and cognitive dysfunction, MS characteristic symptomatology includes weakness, fatigue, ataxia, bladder complaints, bowel problems, sensory effects, and visual impairment. Until recently, the most supported measure of grading functional effects of MS was the Expanded Disability Status Scale (EDSS). However, this scale is biased toward ambulation and is not able to precisely detect deterioration of cognitive domain. Evidence is emerging that MS is not likely to remit following the development of cognitive dysfunction.⁸ It has been suggested that physical and cognitive impairment are correlated, although modestly, with T2 lesion burden on brain MRI. However, more robust correlations are observed with non-conventional MRI measures, such as magnetization transfer imaging and brain atrophy. The relationship between MRI findings and clinical disability at various stages of MS is depicted in Figure 1.

T2 lesions are pathologically non-specific and the lifetime of the lesions is a gradual process; initiating as a disruption in the blood brain barrier followed by intensifying inflammation resulting in demyelination. Reactivated lesions are frequently preceded by gliosis and axonal loss with concomitant matrix destruction. During this process, it is possible that a subset of T2 lesions transforms into T1 "black holes". Evidence is mounting that MS is a global disease characterized by axonal damage, which can be monitored by use of global quantitative MRI measures (i.e., whole brain N-acetylaspartate [NAA], magnetization transfer ratios [MTR] histograms, and cerebral atrophy [a measure of irreversible tissue damage]).

Several factors contribute to cerebral atrophy development including loss of axons within lesions, Wallerian degeneration in related fiber pathways, astrocyte proliferation and microglial activation, and vasogenic edema, which could increase brain mass. The pathological processes responsible for the development of brain atrophy in MS are not yet well understood. But, in the long term, it may mostly depend on the loss of CNS tissue, especially axons, which are the likely substrate of irreversible and progressive functional deterioration. In the short term, other factors, mainly changes in hydrational state, steroid treatment, and edema caused by acute inflammation may alter the measurement of true tissue loss.

Patients exhibit significant brain and spinal cord atrophy from the earliest stages of MS. Whether the rate of brain atrophy varies within the same individual or among subjects in different stages of the disease is still an open question. We do not yet know with certainty when this process begins, whether brain atrophy develops to the same degree in all disease subtypes, or whether the rate of brain atrophy is fairly constant in an individual over time.

Dr. Richert summarized that CNS atrophy is a robust measure of axonal loss that progresses from the onset of the disease, occurring both in gray and white matter, with a modest correlation to the lesional component of the disease process. In clinical trials evaluating treatment options for prevention of disability, Dr. Richert recommended CNS atrophy measurements to be used as secondary outcome.

Detection and Quantitative Assessment of Brain Atrophy

Rohit Bakshi, MD, Center for Neurological Imaging, Partners MS Center, Brigham & Women's Hospital, Harvard Medical School, Boston, reviewed the detection and quantitative assessment of brain atrophy in MS.⁹ Dr. Bakshi discussed various approaches to measure brain atrophy in MS, on the premise that existing anti-inflammatory immunomodulatory agents and immunosuppressive treatments, although effective at preventing clinical deterioration, have been only partially effective in preventing CNS atrophy. Therefore, it is critical that brain atrophy serve as a measurable outcome to assist in the implementation of protective treatment strategies against the destructive aspects of MS. This approach would enhance long-term neurological functioning with resulting improvement in the quality of life for patients with MS.

Dr. Bakshi reviewed many methodologies for measuring different types of atrophy and outlined the pros and cons of various techniques. Atrophy measurement may be qualitative (visual) or quantitative (computer-assisted). Qualitative MRI scan analysis invovles measuring size of parenchyma, enlarged ventricles, and shrinkage of subarachnoid spaces (cisterns/fissures). The beneficial aspects of qualitative MRI scan analysis include low cost, wide availability, and ease of implementation. In contrast, their sensitivity and reproducibility are highly limiting, and thorough operator training is required.

Quantitative MRI measurement of brain atrophy involves both 2-D and 3-D methods capable of measuring whole brain and, regional atrophy. Bicaudate ratio (the minimum intercaudate distance divided by brain width along same line) serves as a marker of brain atrophy in MS. A higher bicaudate ratio is associated with atrophy and is statistically significantly higher in MS patients, compared with normal individuals (P<0.001)¹⁰ (Figure 2). In the same study, bicaudate ratio was shown to predict the Symbol Digit Modalities Test (SDMT), an assessment of cognitive function, whereas T1, T2 lesions volume did not.

Using a 3-D MRI parcellation technique, Bermel et al have shown damage to deep gray matter to be an integral component of the MS disease process.¹¹ In that study, the caudate volume did not correlate with disease duration, physical disability score, whole-brain atrophy, total T2 hyperintense, or T1 hypointense lesion load (all P>0.05). Further, normalized bicaudate volume was 19% lower in MS controls (P<0.001), an effect that persisted after adjusting for whole-brain atrophy (P<0.008).

The role of 3-D MRI analysis of regional atrophy has not been universally accepted. Although it is quantitative, its increased sensitivity and higher clinical relevance are questionable; its practical utility is hampered by high cost, training requirements, and challenging implementation.

Confounding factors related to brain atrophy measurement may skew assessment results. Such factors include automated versus semi-automated algorithms, different software packages, pulse sequences (2-D/3-D, T1/T2), field strength (0.5T, 1.5T, 3.0T), scanning platform (vendor), and brain volume fluctuations. Furthermore, there are no established standards to evaluate the in vivo accuracy of various atrophy and volumetric measurement techniques. Accuracy is completely subjective and observer-dependent.

Dr. Bakshi summarized that although an assortment of methods is available, from simple to complex, in measuring the loss of brain bulk due to MS disease process, the measurements are confounded by a variety of non-disease related factors causing errors in assessments. Nonetheless, anticipated technological advances should enhance the quality of currently available methods of atrophy measurement.

Clinical Significance of Brain Atrophy in Multiple Sclerosis

Although MRI has been employed extensively to visualize the CNS effects of MS, its utility as a surrogate marker for disease progression is limited because of non-dependable measurement techniques, non-specific image characteristics, and the dynamic characteristics of MS, according to a presentation by Richard A. Rudick, MD, Director, Mellen Center for Multiple Sclerosis; Director, Center for Clinical Research, Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio.¹² In contrast, brain atrophy is an important marker for assessing progression of MS and other neurodegenerative diseases, since it measures the net effect of tissue destruction. A highly reproducible measurement is vital for accurate calculation of atrophy, as brain volume changes over time are exponential.

Brain atrophy occurs early in the course of MS and continues throughout the disease course, resulting in substantial brain parenchymal tissue loss in later stages. During the early stages of MS, much of the disease activity and progression is subclinical. Thus, lesion development and brain atrophy have been suggested as surrogate markers of prognosis. Atrophy begins early in MS and progresses at a rate of about 0.5%-1% a year. It is one of the best MRI predictors of disability development in the long term. The most acceptable measure of brain atrophy relies on calculation from segmented images of brain parenchymal fraction (BPF), defined as the ratio of brain parenchymal volume to the total volume within the brain surface contour.

Brex et al measured atrophy by detecting ventricular enlargement in patients at the earliest clinical stage of MS¹³ (Figure 3). Patients who developed clinically definite MS had higher rates of atrophy than control patients with a mean rate of change of approximately 20% per year. Significant ventricular enlargement occurred in the group that developed MS; however, this was not observed in the control group.

Evidence also suggests that normal-appearing white matter and cortical gray matter are involved in the disease process. Significant decline in BPF, white matter fraction, and gray matter fraction in early relapsing-remitting MS (mean rate of change 0.61% per year), and secondary-progressive MS (mean rate of change 1.3% per year) has been demonstrated in patients with MS compared with controls.¹⁴

Dr. Rudick mentioned a previous study in which he found no significant differences in rate of change of atrophy between relapsing-remitting MS and secondary-progressive MS categories.¹⁵ In early relapsing-remitting MS patients (mean duration of disease, 5 years; mean age, 36 years; mean EDSS, 2.5), the BPF was 83% and narrowly distributed. Patients with early, mild MS displayed significant atrophy (P<0.001 compared with healthy age-matched controls). During 2 years of follow-up, the same patients lost a mean of 0.5% of BPF per year; a rate much higher than that observed in serial studies of healthy individuals. Atrophy rates (as measured by BPF) in patients with MS, compared with healthy controls, have shown escalations of 1.4-, 5.1-, and 6.3-fold for clinically isolated syndrome (CIS), relapsing-remitting MS, and secondary-progressive MS, respectively. Strategies that reduce the progression of brain atrophy early in the course of MS would be most beneficial.

Immunomodulatory agents are effective in reducing measures of disease related to brain inflammation (e.g., relapses and gadolinium-enhanced lesions). Dr. Rudick described evidence indicating that early immunomodulatory therapy attenuates the destructive pathology of MS. Anti-inflammatory therapies (e.g., interferon beta and corticosteroids) are known to slow atrophy progression in relapsing-remitting MS. Because brain inflammation has been linked to irreversible brain tissue injury, immunomodulatory agents should be effective in decreasing the rate of brain atrophy progression.

In pivotal phase III trials, interferon beta and glatiramer acetate were comparably effective in reducing the relapse rate in patients with MS by approximately 30%, although differences exist in other outcome measures.^16-20

However, current evidence suggests that interferon beta effects on brain atrophy may be dose- or frequency-dependent. Weekly administrations of interferon beta have proven effective in slowing brain atrophy compared with placebo, while more frequent or higher doses of interferon beta did not show differences between placebo and treated patients.²¹ In fact, during the second year of treatment with weekly Avonex, there was a 55% reduction in the rate of brain atrophy progression as measured by change in BPF.¹⁵

Dr. Rudick stated that intravenous methylprednisolone is often used for the treatment of relapse. The effects of intravenous methylprednisolone on brain parenchymal volume were investigated in a randomized, single-blind trial of 88 patients with relapsing-remitting MS (EDSS scores of ≤5.5).²² At 5 years, the absolute change from baseline in brain parenchymal volume was +2.6 mL in the methylprednisolone treatment group compared with -74.5 mL in the relapse-only treatment group (P = 0.003). In this study, pulsed intravenous methylprednisolone slowed progression of brain atrophy; however, further large randomized, double-blind, placebo-controlled trials should provide more definitive conclusions.

Because atrophy relates to disability in MS, Dr. Rudick presented a hypothetical graphic illustrating the extent of CNS injury as a function of atrophy progression over 30 years in patients ranging between 30 and 60 years of age (Figure 4).

According to Dr. Rudick, brain atrophy progresses at different rates in patients with MS. During the early stages of the disease, brain atrophy is clinically silent because the brain has the ability to compensate and maintain neurological function. Once the amount of tissue damage progresses beyond a threshold; however, the patient begins to deteriorate and is classified as having "secondary-progressive MS". When the rate of atrophy is rapid, secondary-progressive MS occurs earlier; when it is slower, secondary-progressive MS occurs later. In some patients, the rate of brain atrophy is so slow that the patient never enters the secondary-progressive stage of disease. The sharpest rise in the rate of atrophy was observed for "severe MS" (secondary-progressive MS in 30- to 40-year old patients) crossing the progressive disability threshold within 7 years after onset of disease. "Typical MS" (secondary-progressive MS) progresses 10 to 20 years after onset, but at an intermediate rate. "Benign MS" never progresses but is rare. While there is some relationship between the rate of brain atrophy progression and the number of relapses, the relationship is very weak. Therefore, Dr. Rudick recommended that methods be developed to routinely measure brain atrophy during clinical practice. Measuring the rate of atrophy progression over periods of 2-3 years would provide important information for treating neurologists on the overall severity of the disease. Furthermore, a relationship exists between brain atrophy and the number of relapses in patients with relapsing-remitting MS; but the correlation is weak because the brain compensates for tissue loss in order to maintain function. In relapsing-remitting MS, atrophy progression is largely subclinical with the rate of atrophy predictive of future disability.

Concluding his presentation, Dr. Rudick indicated that brain atrophy should be utilized in MS patients as a metric of the severity of the underlying disease process, and suggested that therapies designed to slow the rate of atrophy progression are probably more than likely to be neuroprotective.

Inflammation and Secondary-Progressive Multiple Sclerosis

Recent evidence has shown the occurrence of extensive axonal pathology, principally irreversible and independent of MRI-visible inflammation, in patients at the earliest clinical stages of MS, according to a presentation by Ruth Whitham, MD, and James Bowen, MD, of the Veterans Affairs MS Center of Excellence-West, Portland, Oregon.²³ Using data from the interferon beta trials in secondary-progressive MS as an example, Dr. Whitham asked that clinicians investigate supplementary anti-inflammatory therapies to complement the efficacy of existing immunomodulatory agents.

Axonal loss is a major pathologic process responsible for irreversible neurological disability in patients with MS.²⁴ The current concept that inflammation is detrimental in the pathophysiology of MS, and may eventually lead to the end-stage axonal pathology of MS, has been challenged by emerging data.²⁵ New genetic and MRI data, as well as immunopathological evidence, suggest that inflammation has two functional properties: destructive and protective. The evidence suggests that inflammation is a tightly regulated process, and may have some beneficial effects in certain circumstances. In order to target therapies, it is critical to delineate the inflammatory pathways that occur during different phases of MS. Moreover, the timing of appropriate intervention in an individual is also important, because intervention may not be appropriate in all cases. According to Dr. Whitham, these findings have important clinical implications.

Dr. Bowen reviewed the use of mitoxantrone, glatiramer acetate, cyclophosphamide, and methylprednisolone in secondary-progressive MS; summarizing the difficulties inherent in studies of secondary-progressive MS. Dr. Bowen indicated that it is uncertain whether secondary-progressive MS is a single- or non-inflammatory disease, stating that studies conducted to date lack sufficient power for analysis.

Dr. Bowen noted the efficacy of natalizumab in a study of 213 patients with relapsing-remitting or relapsing secondary- progressive MS. In that study, patients were randomized to receive placebo (n = 71), natalizumab 3 mg/kg (n = 68) or natalizumab 6 mg/kg (n = 74). MRI scans were conducted monthly for 6 months; follow-up scans were obtained at months 9 and 12. A statistically significant dose-dependent decline in new enhancing lesions was observed in those patients with secondary-progressive MS who received natalizumab compared with placebo (mean 1.0 for natalizumab 3 mg/kg [P = 0.005], mean 2.0 for natalizumab 6 mg/kg [P = 0.08], versus mean 5.4 for placebo).²⁶ Other novel treatments mentioned for secondary-progressive MS included azathioprine, cladribine, plasma exchange, intravenous immunoglobulin, total lymphoid irradiation, and stem-cell transplants.

Investigation of Neuroprotection

Neuroprotection: The Future for the Treatment of Progressive Multiple Sclerosis?

Dennis Bourdette, MD, of the Veterans Affairs MS Center of Excellence-West, Department of Neurology, Oregon Health & Science University, Portland, Oregon, reviewed evidence showing that axonal damage is directly related to permanent neurological disability;²⁷ thus necessitating the need for neuroprotective therapies to arrest progressive disease. Dr. Bourdette recommended development of strategies for efficacious anti-inflammatory therapy to prevent injury to oligodendrocytes and axons, and therapies designed to promote remyelination.

Dr. Bourdette also discussed evidence related to the neuroprotective effects of glutamate receptor blockade. Glutamate is released in large quantities by activated immune cells, and excitotoxicity appears to be an important mechanism in autoimmune demyelination. In an experimental autoimmune encephalomyelitis mouse model, glutamate receptor blockade resulted in substantial amelioration of disease, increased oligodendrocyte survival, and reduced dephosphorylation of neurofilament H (an indicator of axonal damage).²⁸ Dr. Bourdette reviewed additional data on the neuroprotective effect on axons by phenytoin (sodium channel blockade) and suppression of spinal cord white matter damage by tacrolimus, an immunosuppressant drug used in solid organ transplantation that also appears to have profound neuroprotective/neuro-regenerative properties. Agents such as tacrolimus may be valuable treatment options in MS due to their immunosuppressive and neuroprotective effects. Potential therapies for remyelination included mesen-chymal cell transplantation, which has been used successfully in heart transplant patients.

Trends in Add-on Therapy for the Treatment of Multiple Sclerosis

Potential Neuroprotection from Combination Therapy with Avonex and Topiramate

Although immunomodulatory therapy has had a significant impact on the disease course of MS, disease progression occurs in most patients. Such progression is thought to be primarily due to axonal degeneration. Topiramate, indicated for treatment of seizures, has several properties that may be useful in MS, including blockade of voltage-gated and constitutive sodium channels and receptor signal transduction, actions thought to have a neuroprotective effect. Greenstein et al described a study evaluating the safety and potential neuroprotective effects of the combination of Avonex and topiramate in patients with early relapsing-remitting MS for a period of 24 months.²⁹ In addition, treatment effects on BPF, gadolinium-enhancing lesions, and T1- and T2-weighted lesions will be examined. Safety is the primary outcome. Relapse rate, EDSS, and MS Functional Composite (MSFC) will be assessed as secondary efficacy outcomes.

According to study protocol, all patients (N = 30) will initiate Avonex 30 mcg therapy once weekly. After one month, 15 patients will be randomized to a target dose of topiramate 50 mg twice a day and 15 patients to placebo. The study design will allow the investigators to evaluate the safety of this combination as a strategy to add potential neuroprotective therapies to immunomodulatory therapy in treating MS. Furthermore, the outcome parameters selected will allow evaluation of both clinical and MRI correlates of disease progression, delineating the underlying neurodegenerative processes in MS.

Concomitant Dexamethasone at Initiation of Interferon Beta Therapy

Despite the efficacy of immunomodulatory therapy, such therapy only partially abolishes MS disease activity. Adjunctive therapy, such as short-course intravenous corticosteroids are often needed. During the first year of interferon beta therapy, breakthrough relapses and disability progression may be difficult to control. The addition of intravenous corticosteroid pulses may significantly reduce functional and structural CNS disease progression during the first few years of interferon beta therapy.

A randomized, clinical and MRI evaluator-blinded pilot study by Stanley L. Cohan, MD, PhD, Providence Pacific NW MS Center, Portland, Oregon, has been designed to enroll 46 untreated patients with relapsing-remitting MS or CIS to compare treatments over 2 years of once weekly Avonex 30 mcg or once weekly Avonex 30 mcg plus intravenous dexamethasone 160 mg every 4 weeks for the first 12 months.³⁰

The primary objectives of the study are to determine the safety and efficacy of intravenous pulses of dexamethasone administered every 4 weeks for one year, determine differences in the progression of sustained disability by measuring the MSFC score, and examine differences in the rate of brain atrophy at 12 and 24 months between the 2 treatment arms. Secondary objectives include differences in relapse rate per subject year, time to first relapse, and proportion of relapse-free patients. Additional outcomes include evaluation of MRI differences in the number of new or enlarging T2 lesions and gadolinium-enhancing lesions at 12 and 24 months. The study also will assess the development of neutralizing antibodies.

Fludarabine Adjunct Therapy in Relapsing-Remitting Multiple Sclerosis

Fludarabine is a cytolytic, pro-apoptotic, purine analogue that is effective against indolent lymphoproliferative disorders and may be effective as adjunct therapy in Avonex-treated MS patients. Greenberg and colleagues conducted an open-label, phase II clinical trial of 20 patients with relapsing-remitting MS experiencing 2 or more exacerbations annually while on Avonex therapy (> 1 year) to evaluate combination therapy of fludarabine and Avonex.³¹ All patients received once-weekly Avonex 30 mcg, but were randomized to receive either 3 consecutive monthly cycles of intravenous fludarabine 25 mg/m² daily for 5 days or 3 monthly infusions of intravenous methylprednisolone 1 gm daily for 1 day after a standard induction of intravenous methylprednisolone 1 gm daily for 3 days. Primary outcomes were safety and tolerability, which were assessed by physical and neurological exams and adverse events. Efficacy was assessed by exacerbation frequency, EDSS, MSFC, MRI, and methylprednisolone interventions.

Data were presented for 18 patients. No significant differences were observed between the fludarabine and methylprednisolone treatment arms with respect to adverse events, although a trend was seen toward more total adverse events in the fludarabine treatment arm. Trends toward greater improvements in fludarabine-treated patients were observed in components of the MSFC during the titration period (0 to 3 months) compared with the methylprednisolone treatment arm including the 25-feet timed ambulation (P = 0.054) and Paced Auditory Serial Addition Test (PASAT) (P = 0.053). Similarly, between 0 and 6 months, a trend toward improvement was observed in the fludarabine-treated patients in PASAT (P = 0.054) and 9-hole peg test (9-HPT) (P = 0.056). Statistically significant improvements were seen in the fludarabine treatment arm from 0 to 12 months in PASAT (P = 0.038) and 9-HPT (P = 0.017).

Significant deterioration in EDSS scores was observed in methylprednisolone-treated patients (P = 0.038), but did not reach statistical significance in fludarabine-treated patients during the first 6 months of the study. Further, the median time to first relapse was significantly longer in fludarabine-treated patients compared with methylprednisolone-treated patients (10 vs 8 months, respectively; P<0.01) (Figure 5).

Mean (median) contrast-enhancing lesions were 1.8 (2) and 1.7 (2) for fludarabine- treated and methylprednisolone-treated patients, respectively.³¹ The investigators concluded that fludarabine adjunctive therapy may be useful in controlling breakthrough disease, while maintaining patients on single-agent immunomodulatory therapy.

Modafinil Adjunct Therapy for Breakthrough Cognitive Symptoms

Recent data indicate that Avonex slows the progression of MS-associated cognitive dysfunction.³² However, limited data exist with regard to the treatment of breakthrough cognitive symptoms (e.g., attention, processing speed, and memory problems). Modafinil is a novel wakefulness-promoting agent that has demonstrated benefits as adjunctive therapy in the treatment of MS-related fatigue.³³ Based on these findings, Wilken and colleagues conducted a multi-center, randomized, parallel-group pilot study to determine whether combination therapy of modafinil plus Avonex was safe and effective in treating breakthrough cognitive symptoms in MS patients.³⁴ A total of 22 patients with relapsing-remitting MS have been enrolled to date.

Patients on once weekly Avonex 30 mcg were screened for attention problems. Patients demonstrating attention problems were randomized to receive adjunct therapy of modafinil 100 mg daily for the first 3 days then increased to 200 mg daily, or to receive no additional treatment (Avonex monotherapy).

Results thus far revealed add-on modafinil therapy was associated with significant improvement from baseline in multiple neurocognitive measures, compared with Avonex monotherapy (P<0.05), including measures of complex attention, speed of visuo-motor construction, incidental recall, recognition memory, information processing speed, and working memory. Moreover, significant improvements were observed in emotional well-being and mental health in the combination therapy group (P<0.05).

Importantly, significant improvement in patient-reported quality of life (as assessed by the Multiple Sclerosis Quality of Life Emotional Well Being and Short Form Health Survey-36 Mental Health Scales) was observed for the adjunctive modafinil group (P<0.05), and not noted in a previous interim analysis with fewer subjects.³⁵ Both treatment regimens were well tolerated. The authors anticipate that the increased statistical power (i.e., greater number of subjects) at the time of final analysis will reveal these trends to be statistically significant.

Although results from this small trial are encouraging, large randomized trials are needed to confirm these findings.

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Disclosure

Robert Zivadinov, MD, PhD:
Grant/Research Support-Biogen Idec^TM, Teva; Consultant-Biogen Idec^TM; Speakers Bureau-Biogen Idec^TM

Andrew R. Pachner, MD:
Grant/Research Support-Berlex Laboratories, Inc., Biogen Idec^TM; Consultant-Biogen Idec^TM, Berlex Laboratories, Inc.; Speakers Bureau-Biogen Idec^TM, Serono

This report contains information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Multiple Sclerosis Forum Report^TM was made possible through an educational grant from Biogen Idec^TM.

© 2004 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education

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