Introduction

The advent of immunomodulatory therapy has produced dramatic advancements in the treatment of many diseases including hepatitis, renal cell carcinoma and rheumatoid arthritis. Nowhere is the emergence of immunomodulatory therapy more evident than in the treatment of multiple sclerosis (MS), a disease considered untreatable until a short time ago. Interferon therapy offers reduction in relapses, improvement in cognitive dysfunction and most importantly, the ability to slow disability progression. However, as questions concerning dose, route and frequency of administration of interferon continue to be explored, clinical issues remain to be fully resolved. For example, the clinical relevance and therapeutic impact of neutralizing antibodies on interferon therapy continues to be investigated. This report touches upon many of these issues as they were presented at a Multiple Sclerosis Key Opinion Leaders Meeting May 4-5, 2002 in Las Vegas, Nevada.

MS is an immune-mediated, chronic, inflammatory disease of the central nervous system (CNS). Patients can experience sustained physical disability, cognitive dysfunction, and relapses. According to Edward Fox, MD, PhD, Director of the Multiple Sclerosis Clinic of Central Texas, Round Rock, Texas, the disease has 3 components-inflammation, demyelination, and axonal loss.¹ Dr. Fox noted that no treatments exist for demyelination or axonal loss. "The only modality we have is to affect the immune system."

Dr. Fox explained that there are two major types of immunity, innate (e.g., polymorphonuclear leukocytes) and adaptive (T cells, macrophages, and B cells). "Our current model of immune mechanisms in MS suggests that in the very first step something triggers the nonself antigens that macrophages attack. They present this information to Type 1 (Th1) helper T cells, forming the trimolecular complex (nonself antigens complexed with Class II major-histocompatibility-complex (MHC) molecules on macrophages, and the antigen receptor on Th1 cells). The Th1 cells, which are proinflammatory, cross the endothelial cells of the blood brain barrier (BBB) and enter the CNS." Potential nonself antigens that could trigger MS include viruses such as Herpes, Adenovirus, Rubella, or Retrovirus, and bacteria/toxins, such as Borrelia, Chlamydia, or Superantigens. Potential self-antigens include myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein, and myelin associated glycoprotein. Dr. Fox stated, "I don't believe that there is any one pathogen that causes MS in a large population of people. I think that in any one individual who has a susceptibility to MS there is one or more antigens that can trigger the MS."

Inflammation

Dr. Fox pointed out that animal models of demyelination, such as the mouse and chicken, are imperfect homologues for human MS, which makes understanding the pathophysiology of the disease and devising new treatments more challenging. However, it appears that, "A 'misguided' and over-active pro-inflammatory Th1 profile appears to underlie inflammation in MS." Th1 cells produce pro-inflammatory cytokines, such as interleukin-2 (IL-2), tumor necrosis factor (TNF)-α, and interferon-gamma. Th1 cytokines activate antigen-presenting cells (APCs), promote Th1 differentiation, and inhibit Type 2 (Th2) helper T cell differentiation. Th2 cells produce anti-inflammatory cytokines, such as interleukin (IL)-4, IL-5, IL-6, IL-10, and IL-13. Th2 cytokines regulate humoral immunity and down-regulate local inflammation, promote Th2 differentiation, and inhibit Th1 differentiation. Th2 cytokines appear to inhibit the MS disease process.

Cell-Mediated Immunity

"Cell-mediated immunity is the cause of most of the pathology that we generally see. And in all of the medications that are used for MS, you will see a swing from Th1 to Th2." Macrophages also produce a great deal of damage, but they are very hard to down-regulate. More evidence that Th1 cells are to blame is the observation that interferon-gamma up-regulates the immune system and makes MS worse.

Epitope Spreading

One theoretical concept that argues for early MS treatment is "epitope spreading." Demyelination and axonal loss resulting from the original nonself antigen releases other antigens that are attacked by other macrophages, which cause more damage, release more antigens, and activate more T-cell populations. Dr. Fox advised, "If you limit the immune [response] early on, you will not get the [resulting] damage that is occurring, and get more successful treatment."

Mechanism of Action - Interferons

Interferon beta-1a (Avonex, Biogen, Inc.), interferon beta-1a (Rebif, Serono, Inc.) and interferon beta-1b (Betaseron, Berlex Laboratories, Inc.) are cytokines, secreted proteins that act as messenger molecules of the immune system. There are two major structural differences between interferon beta-1a and beta-1b. Interferon beta-1a is glycosylated^2,3, whereas interferon beta-1b is not.⁴ Glycosylation prevents the formation of molecular aggregates. Clumping of interferon beta-1b results in the need for a higher dose. Interferon beta-1a has a similar amino acid sequence to human interferon beta, but interferon beta-1b substitutes serine for the cysteine residue found at position 17.

Unlike many pharmacologic agents, which are antagonists, many cytokines are agonists; only a fraction of receptors need to be activated to elicit cell change. After interferons bind to a cell, there is a secondary effect that can last long after the drug is gone. Potential sites of action of interferon-beta include T cells, B cells, natural killer (NK) cells and monocytes. Interferons may also affect antigen presentation in systemic and CNS compartments, cytokine production, and entry of leukocytes into the CNS.

When a Type I interferon-beta receptor complex forms at the cell membrane, signal transduction occurs to the cell nucleus, with resultant production of neopterin, β₂-microglobulin, MxA protein and IL-10. Altered cell populations of dendritic cells, NK cells, B cells, and Th2 cells could also have therapeutic effects. For example, treatment with Avonex increases levels of IL-10, which correlates with favorable clinical response (p < 0.0001).⁵

In MS, interferon-beta has immunomodulatory effects that can decrease the inflammatory process, decrease antigen presentation and T-cell migration into the CNS. Antiproliferative effects of interferon-beta include down-regulation of interferon-gamma⁶ and TNF-α⁷, expression of IL-2 cell surface receptor and its affinity for the T-cell surface,⁶ and inhibition of pre-activated and autoreactive T cells.⁸ Antiviral effects include inhibition of possible viral infection that may trigger MS.

Mechanism of Action - Glatiramer Acetate

Glatiramer acetate (Copaxone, Teva Neuroscience, Inc.) acts on immune cells in the periphery. It has high affinity for the major histocompatibility complex (MHC) groove and can compete and displace antigens in the trimolecular complex. Acting as an altered peptide ligand, glatiramer acetate interferes with T-cell activation by competing with myelin basic protein for MHC molecules that bind to the antigen-specific T-cell receptor. This binding can cause a Th2 response. However, patients treated with glatiramer acetate have a transient elevated interferon-gamma response and an increase in IgG, both of which are pro-inflammatory. Treatment with glatiramer acetate may not show significant effects for several months.

Mechanism of Action - Mitoxantrone

Mitoxantrone (Novantrone, Immunex Corp.) is an anthracenedione antineoplastic agent that has a cytocidal effect on both proliferating and nonproliferating cells.⁹ In laboratory studies, mitoxantrone reduces the number of B cells, inhibits helper T cells, and impairs antigen presentation and blocks peritoneal macrophages from degrading myelin. Mitoxantrone has been shown to significantly decrease the number of relapses in relapsing-remitting MS in a randomized, placebo-controlled, multicenter trial.¹⁰ The role of macrophages appears more important in secondary progressive MS, and this is where mitoxantrone may be particularly helpful. The use of mitoxantrone has been associated with cardiotoxicity; this risk increases with cumulative dose.⁹

Differences in Pharmaceutical Formulation Among Interferons

Patients take Avonex 30 mcg intramuscularly once a week², Rebif 44 mcg subcutaneously three times a week³, and Betaseron 250 mcg subcutaneously every other day.⁴ Avonex and Betaseron have sodium phosphate buffers, but Rebif uses sodium acetate. Both Betaseron and Rebif contain mannitol. The pH of Avonex and Betaseron are physiologic, 7.3 and 7.2, respectively, while Rebif is more acidic at pH 3.8. Dr. Fox pointed out, "The more often you give interferon, the more often you are likely to get neutralizing antibodies." Compared to the other two drugs, Avonex has the advantage of once weekly intramuscular injection, a route and schedule of administration that results in greater potency and lower neutralizing antibody production. Avonex has an incidence of neutralizing antibodies of only 2-5%¹¹, while Betaseron has 26-38%¹², and Rebif 14-25%.¹³

Efficacy of interferon beta does not appear to improve with increasing dose or frequency of exposure. Tachyphylaxis may also occur with frequent administration. Dr. Fox concluded, "Optimal dosing of interferon-beta leads to the induction of relevant genes and cell populations but may require an off-period to prevent desensitization to the drug."

Natural History of Untreated MS

According to John Richert, MD, Professor and Chair of the Department of Microbiology and Immunology and Professor of Neurology, Georgetown University Medical School, Washington, DC¹⁴, "Thirty to 50% of patients worsen by 1.0 EDSS [Extended Disability Status Scale] unit within 2 to 3 years. Up to 44% of patients need an assistive device for walking within 5 years. Relapsing MS leads to progressive MS after 10 years in 50% of cases. Forty-five to 65% of patients with MS experience cognitive impairment, affecting employment, social life, and daily functioning." Consequently, relapse rate is only one way of looking at disease progression. "The most important issue in terms of treatment is slowing disability progression."

PRISMS-4

The PRISMS-4 study assessed long-term efficacy of interferon beta-1a (Rebif) in relapsing MS.¹⁵ It followed on the heels of the original PRISMS study¹⁶, which demonstrated significant clinical and magnetic resonance imaging (MRI) benefit¹⁷ at 2 years for interferon beta-1a, 22 mcg or 44 mcg three times a week, compared to placebo; at 2 years, the proportion of progression-free patients on placebo was 61.7%, compared to 70.3% on the 22 mcg dose and 73.2% on the 44 mcg dose. There were no significant differences between the low and high doses. In the PRISMS-4 study, patients who crossed over from placebo experienced a relapse rate of 1.02, those who continued the 22 mcg dose had a relapse rate of 0.80 (p < 0.001), and patients on 44 mcg had a relapse rate of 0.72 (p < 0.001). However, at the end of 4 years, the percentage of patients remaining free from progression was similar in the crossover groups (placebo to 22 mcg) (46%), the 22 mcg-treated group (51%), and the 44 mcg-treated group (56%), suggesting that the group that had been on active drug for 4 years progressed at a more rapid rate than the placebo group that had crossed over to Rebif. The authors of PRISMS-4 stated, "efficacy decreased with neutralizing antibody formation."

Glatiramer Acetate Phase III

A Phase III disability trial of glatiramer acetate measured time to neurologic worsening as determined by sustained ≥ 1.0 EDSS for a period of 90 days.¹⁸ The percent of patients who worsened was slightly lower on glatiramer acetate than placebo, 22% vs. 25%, respectively, however, this was not statistically significant (p = 0.48). An extension of the original study demonstrated similar nonsignificant results, only 23.2% of patients on glatiramer acetate worsened, compared to 29.4% of patients on placebo (p = 0.199).¹⁹ Glatiramer acetate did not have a significant impact on sustained disability, and the reduction in relapses due to glatiramer acetate was similar to that found with interferons. However, according to the study's authors, patients who selected to enroll in the open label phase had "fared better during the blinded phase in terms of relapse rate and neurologic disability than those who declined to enter," suggesting that these favorable long-term results reflect the success of a particular subgroup.

Interferons Reduce Sustained Disability

In the 2-year Avonex sustained disability trial²⁰, Avonex patients demonstrated a 37% reduction in sustained disability of ≥ 1 point on the EDSS for six months compared to the placebo group, which was statistically significant (p = 0.024). According to Rudick et al²¹, using a more rigorous definition of disability showed that Avonex produced even better results. Avonex patients had a 61% chance of reducing sustained disability of 1 point for 12 months at 2 years (p = 0.002). In addition, Avonex patients had a 67% chance of reducing sustained disability of 2 points sustained for six months at 2 years (p = 0.028). Herndon et al²² reported that only 2% of Avonex patients discontinued therapy because of adverse events in the long-term safety-extension study. Injection site reactions were rare, occurring in only 3% of patients. None of the patients experienced or reported skin necrosis. The incidence of neutralizing antibodies was approximately 5%.

A comparison of Phase III data across different studies reveals that a reduction in disability progression (≥ 1 point sustained for 6 months in Avonex trial and 3 months in Betaseron, Rebif and glatiramer acetate Phase III trials) was 37% for Avonex, 23% for Betaseron, 22% for Rebif 22 mcg dose, 30% for Rebif 44 mcg dose and 12% for glatiramer acetate. Avonex once weekly has the highest reduction in disability progression of the beta interferons, while all the beta interferons appear superior to glatiramer acetate. However, only Avonex and Rebif are indicated to slow disability progression in MS.

Relapse Rate Improves on Avonex at 2 Years

Another outcome measure evaluated during the clinical studies was relapse rate. For patients completing therapy at 2 years, Avonex had a 32% reduction, Rebif 22 mcg a 29% reduction, Rebif 44 mcg a 32% reduction, Betaseron a 31% reduction, and glatiramer acetate a 29% reduction. All interferon reduction rates were statistically significant, but glatiramer acetate's effect was borderline (p = 0.055). The median time to first relapse was longest for Avonex (402 days) compared to Rebif (22 mcg-228 days; 44 mcg-288 days) and Betaseron (250 mcg-295 days). The relapse reduction rate for Avonex increased in the second year from 29% to 35%, while it decreased for all the other interferons (Rebif 22 mcg-33 to 23%; Rebif 44 mcg 37-28%; Betaseron 33 to 28%).

Role of Neutralizing Antibodies

One explanation for the loss of efficacy of Rebif and Betaseron over time is the development of neutralizing antibodies. According to Dr. Richert, "If you get neutralizing antibodies, your drug is not going to take you very far." Dr. Richert observed that the development of neutralizing antibodies is associated with route and frequency of administration as well as the molecule itself. Subcutaneous injections may induce neutralizing antibodies more frequently due to the rich population of immune cells in subcutaneous tissue. Compared to intramuscular injections, subcutaneous injections also produce more pain, local reactions, inflammation and necrosis. Necrosis has not been reported with intramuscular injections.

No Increased Benefit with Higher Interferon Doses

Although physicians may be tempted to treat refractory patients with higher interferon doses, Dr. Richert noted that this approach might be counterproductive because there appears to be a clinical dose ceiling effect. He noted, "Binding [interferon receptor levels] decreased by approximately 50% when interferon-beta was administered repetitively at shorter [less than one week] intervals and that interferon receptors were down-regulated." The implication being that, in the long term, there is no increase in efficacy for higher or more frequent doses of interferon beta.

Phase III Trials Provide Class I Evidence

Phase III studies, used to obtain drug approval from the Food and Drug Administration (FDA), are large, double blind, placebo-controlled, long duration studies, which constitute Class I evidence and are often the best-blinded sources of data (gold standard). Open-label studies (Phase IV), often performed after drug licensing, are not placebo-controlled and often designed to support marketing initiatives. Joseph Lacy, MD, Head of the Department of Neurology at the Palo Medical Foundation and a Clinical Associate Professor at Stanford University, Palo Alto, California observed, "Short-term, open label trials may not be valid for therapeutic efficacy evaluation...MS is a long-term disease." Treatments with only a short-term effect on relapses may not necessarily affect the long-term progression of MS.

Measuring sustained disability is more reliable and relevant than relapse rate in determining drug efficacy. Assessing relapse rate can be difficult, because symptoms can fluctuate from day to day. Patients may also recover spontaneously from relapses, to a variable degree, independent of treatment. Relapses aren't sensitive to ongoing disease. There are 5-10 times more MRI lesions for each relapse. Although relapse rate and percent of relapse free patients are important, the clinical standard for measurement of therapeutic efficacy in MS trials remains disability progression, advised Dr. Lacy.

Two recent studies, INCOMIN²³ and EVIDENCE¹³, are both randomized, but neither is double blind. [The INCOMIN trial did have a blinded MRI portion, but the treating physicians and patients were not blinded The EVIDENCE trial had blinded clinical and MRI evaluation]. This lack of blinding may have introduced bias when patients had unscheduled visits for complications. In addition, the consent form in certain study centers may have introduced study expectation bias by stating that the trial was being done to determine the benefits of Betaseron or Rebif versus Avonex. Blinded trials have revealed remarkable consistency regarding the proportion of relapse-free patients treated with interferons. Neither the INCOMIN nor EVIDENCE studies were placebo-controlled.

According to Dr. Lacy, study durations for MS trials "should be a minimum of 2 years. Short-term studies that measure relapses, not sustained disability, should be interpreted with caution. Short-term studies do not take into account the effects of neutralizing antibodies. Side effects which can affect patient compliance may not be reflected in short term studies." [EVIDENCE with Rebif had a 12-month design].

Dr. Lacy added that age stratification is also an important issue in study design. "Older age of onset and male sex portend a worse prognosis." This factor was not taken into account in the INCOMIN study, where comparatively speaking, the Betaseron group had 5% less males than the Avonex group, and the age at entry was almost 2 years younger than the Avonex group. Betaseron patients also had a younger age of onset, shorter disease duration, and lower median number of T2 lesions, all factors suggesting better short-term prognosis. These factors may have contributed to the result favoring Betaseron over Avonex. In addition, the high percentage of relapse-free patients (51%) seen with Betaseron at 2 years was not consistent with the Betaseron Phase III data, which revealed a relapse-free rate of only 31%. According to Dr. Lacy, results of open-label trials that are inconsistent with more rigorously conducted Phase III trials need to be interpreted with caution.

The EVIDENCE trial, which compared Avonex 30 mcg once weekly to Rebif 44 mcg 3 times weekly, also had significant design limitations. Its primary outcome was the proportion of relapse-free patients, not sustained disability, determined at 6 months. Secondary outcome was the number of active lesions on MRI. At 48 weeks, the percent of relapse free patients on Rebif was 62%, compared to 52% on Avonex. Despite this 10% difference, there was no significant difference in relapse rate and disability progression between Avonex- and Rebif-treated patients.²⁴ This result is inconsistent with Phase III data that demonstrates no significant differences in effect on relapses between Avonex (48%) and Rebif (48%) at 1 year, or Avonex (35%), Rebif (32%), and Betaseron (31%) at 2 years. As for the MRI changes, at 24 weeks, Rebif had a mean of 0.8 MRI lesions, while Avonex had a mean of 1.2 MRI lesions, a 33% relative difference. The baseline number of lesions was higher in the Avonex group by 17% (2.9 vs. 2.4), which potentially could have biased the data in favor of Rebif. However, there was no difference when comparing changes in MRI lesions from baseline between the Avonex-treated (1.7) and Rebif-treated (1.6) patients.

During the second 24-week period of the EVIDENCE trial, Avonex was essentially equivalent to Rebif in the proportion of remaining relapse-free patients. Eighty-three percent of Avonex patients were relapse free vs. 82% of Rebif patients resulting in an absolute difference of 1%. The effect of Avonex and Rebif were similar on the moderate to severe relapses.

Dr. Lacy concluded that physicians must closely examine clinical trial results in light of trial design. "Patients rely on physicians to provide accurate and clear data, helping them make an informed decision on medication choice."

Added Value of MRI

In addition to symptoms and findings on clinical examination, MRI allows serial observation of pathological changes in the brain. It has value in diagnosis, monitoring of disease activity, prognosis, and evaluation of treatment efficacy. According to Nancy Richert, MD, PhD, Staff Clinician at the National Institute of Health and Assistant Clinical Professor at the Children's National Medical Center and George Washington University Hospital, Washington, DC²⁵, "MRI is the strongest data that we have that these drugs are working."

Dr. Richert noted that MRI provides additional information not available in the clinical exam. "If we look serially every month at contrast enhancing lesions, some go away, but new ones appear. There is continuous activity of contrast enhancing lesions over time, even if the patient is clinically stable. It turns out that contrast enhancing lesions are about 10 times more sensitive than the clinical exam with respect to disease activity." T2 weighted and Flair images are the best for detecting MS plaques.

"Black Holes" are Poor Prognostic Sign

The majority of patients have one new enhancing lesion a month, but some patients can have as many as 50-60 per month. The evolution of MRI lesions proceeds in the following pattern; blood brain barrier disruption, inflammation, increased inflammation, demyelination, reactivated lesions, gliosis, and axonal loss. The last step in the evolution of an MS lesion is the "black hole" on T1, which reflects a significant reduction in axonal density. T1 holes at diagnosis are a bad prognostic feature, indicating severe disease. There is a better correlation between T1 holes and disability than between gadolinium enhancing lesions and disability, because T1 holes reflect what is going on in the axon, while gadolinium-enhancing lesions reflect a disruption in the blood brain barrier. "The substrate of disability is axonal loss and matrix destruction," observed Dr. Richert. T1 black holes demonstrate a "robust correlation with clinical disability in secondary progressive MS."

Magnetization Transfer Ratio

A new technique, magnetization transfer imaging, allows clinicians to follow evolving lesions and provides prognostic information. Magnetization transfer imaging measures the free water and bound water pool. Two sets of images are obtained; one is T1, the second has a saturation pulse. Subtracting one image from the other gives a magnetization transfer ratio for every voxel in the brain. If there's damage to the myelin or to the axon, one observes a decrease in the magnetization transfer ratio. If the ratio falls dramatically and doesn't recover, this will be a T1 black hole.

This technique has potential to improve care in MS because the magnetization transfer ratio starts to fall 12-24 months before a gadolinium-enhancing lesion appears. In addition, the magnetization transfer ratio may be abnormal in MS patients even in normal appearing white matter, suggesting diffuse subclinical disease.

Magnetic Resonance Spectroscopy Imaging

Another MRI technique that may improve the treatment of patients with MS is magnetic resonance spectroscopy imaging (MRS). MRS provides three major peaks: choline, creatine, and N-acetylaspartate (NAA). Abnormalities of NAA, a metabolite localized in the axon and neuron, may reflect the development of Wallerian degeneration or axonal metabolic dysfunction. A significant drop occurs in NAA in MS white matter lesions. A loss of NAA ultimately results in neurologic damage and disability. In addition, normal appearing white matter in MS patients may also demonstrate a decrease in NAA. Similar to the finding of an abnormal transfer ratio in normal appearing white matter, a low NAA provides insight into the pathology of MS. Dr. Richert noted, "This is a global process, which is spreading throughout the white matter. It's not just the inflammatory lesions."

Importance of Cerebral Atrophy

Cerebral atrophy is a measure of global irreversible tissue damage, both microscopic and macroscopic, including demyelination and axonal loss. Regional measures of atrophy include third ventricle diameter, biventricular diameter, and measures of the corpus callosum. Accurate measurement can be difficult. One approach is the central slab method, which evaluates a 20 mm transverse tissue slice. Another method is the registration and subtraction technique. A reliable and accurate measure is the normalized measure of whole brain atrophy, the brain parenchymal fraction (BPF). BPF represents the ratio of brain parenchymal volume (BPV) to total brain volume (BV); BPF = BPV/BV. According to Dr. Richert, BPF is an "automated, very robust measurement for atrophy."

Brain atrophy may be more prevalent in MS patients than previously appreciated. Dr. Richert related one study where whole brain, grey matter and white matter fractions were reduced compared to normal controls for all fractions (p < 0.001) in 26 patients with early relapsing-remitting MS (median EDSS 1.0; mean delay from first symptom to scan 1.8 years).²⁶

Treatment Effects on MRI Lesions

Beta interferon drugs work at the blood brain barrier and are very strong inhibitors of contrast enhancing lesions. Dr. Richert explained that beta interferons work immediately and produce an 80-90% reduction in contrast enhancing lesions. Ultimately, the beta interferons may have a protective effect against the development of brain atrophy. "If you reduce gadolinium enhancing lesions, you will reduce new T2 lesions, which will decrease T1 [black hole] lesions as well." She noted that Avonex reduced the rate of cerebral atrophy by 55% compared to placebo in a 2-year observation study.²⁷ Similar effects have not been seen with Rebif. In fact, one trial noted a higher rate of brain atrophy in patients receiving Rebif 44 mcg 3 times weekly.²⁸

Glatiramer acetate doesn't work at the blood brain barrier, but rather converts Th1 (proinflammatory) to Th2 (anti-inflammatory) cells. It takes several months longer than interferons to produce results. Glatiramer acetate reduced relapse rate, gadolinium enhancing lesions and new T2 lesions all by 33, 30, and 30%, respectively, but it is unclear whether it reduces cerebral atrophy. In a 9-month study that compared glatiramer acetate to placebo, there was no statistically significant effect of glatiramer acetate in the reduction of T1 hypointense lesion load.²⁹ Further, in a 9-month extension phase of that same study, patients treated with glatiramer acetate showed nonsignificant reductions in the mean total number of enhancing lesions (20%) and mean volume of enhancing lesions (27%).³⁰

Cognitive Dysfunction Affects More than 50% of MS Patients

In 1877, Charcot observed, "...most of the patients affected by multi-locular sclerosis whom I have had occasion to observe...there is marked enfeeblement of the memory; conceptions are formed slowly; the intellectual and emotional faculties are blunted in their totality." Stephen Rao, PhD, Professor of Neuropsychology at the Medical College of Wisconsin, Milwaukee, WI³¹ noted that prevalence studies of cognitive dysfunction in MS patients consistently reveal a rate of cognitive dysfunction between 54 and 65%.

Neuropsychological functions affected in MS patients include problem solving, attention, learning and memory, language, perception, and psychopathology/personality problems. In general, Intelligence Quotient (IQ) is not significantly dropped. However, conceptional or abstract reasoning tests are difficult for MS patients, such as the Wisconsin Card Sorting Test. Dr. Rao explained, "The importance of this test is, many patients with MS make an inordinate number of perseverative errors. They have difficulty making the transition to the next principle." Dr. Rao noted that this lack of cognitive flexibility could have profound implications in the workplace. "This test has been very predictive, especially with relatively high performing individuals, of whether they can actually function in their job."

Language problems are rarely seen in MS, affecting only 8-9% of the population. They may be caused by the development of a plaque and are usually transient. Visuo-spatial perception problems are more common, occurring in 12-19% of patients.

Cerebral Atrophy Correlates with Cognitive Decline

Dr. Rao has previously demonstrated that patients with moderate to severe cerebral atrophy on CAT scan have worse verbal and spatial performance scores than those with mildly reduced or normal ventricular size.³² In 1986, Dr. Rao began a longitudinal study³³ of 100 MS patients and 100 age-matched controls to examined the relationship between MRI lesion burden and neuropsychological test scores. He found that the number of tests where MS patients performed at < 5th percentile had a direct correlation with the total T2 lesion area (square centimeters). "There's a threshold effect that goes on. The more lesions you have, the higher the probability that you will experience cognitive dysfunction." However, MRI T2 burden did not correlate well with EDSS. Dr. Rao explained that cognitive test scores and MRI T2 burden track different things than EDSS, as EDSS primarily reflects ambulation skills. After three years, 25% of the patients who had cognitive deterioration had more T2 lesions.

Treatment for Cognitive Dysfunction

According to Dr. Rao, treatment modalities for cognitive dysfunction in MS patients include pharmacological, cognitive rehabilitation, and immunomodulatory. Although not FDA-approved specifically for MS, pharmacological treatments employed by some clinicians include psychostimulants (e.g., methylphenidate, pemoline), acetylcholinesterase inhibitors (e.g., physostigmine, donepezil), potassium channel blockers (4-aminopyridine, 3,4 diaminopyridine), and antidepressant medications.

Cognitive rehabilitation methods include the use of memory aids such as diaries, notebooks, palm pilots, tape recorders and systematic treatments for attention, memory, and reasoning. This approach is similar to the treatment of traumatic head injury patients.

Immunomodulatory treatments may prevent the formation of new or enlarging cerebral lesions. In one study, significant improvement was seen in 30 patients with relapsing-remitting patients in neuropsychological tests at 24 and 48 months on one of thirteen neuropsychological tests (delayed visual memory) after treatment with Betaseron.³⁴ However, a trial of glatiramer acetate in 248 patients with relapsing-remitting MS failed to reveal a difference in cognitive test performance between the treated and placebo groups.³⁵ Fischer's Phase III of study Avonex in relapsing multiple sclerosis began with 64% of the patients with cognitive impairment at baseline.³⁶ At two years, the Avonex group had statistically higher Z-score changes for information processing and memory compared to controls reflecting a 46.7% reduction in the risk of cognitive deterioration. Furthermore, the Avonex group had a 47% improvement on the Paced Auditory Serial Addition Test (PASAT).

Dr. Rao emphasized that cognitive impairment is important to treat; cognitively impaired MS patients are much less likely to work and be in greater need of social assistance.³⁷ Factors suggestive of cognitive impairment include the need for assistance in activities of daily living out of proportion to physical disability, unemployment or underemployment, mood disorders, withdrawal from usual activities, changes in personality, MRI showing age inappropriate atrophy, and MRI with a high total lesion load.

Treatment Options for the Patient with Multiple Sclerosis
An Interview with Frederick E. Munschauer III, MD, Professor of Clinical Neurology and Internal Medicine at the State University of New York (SUNY) at Buffalo, Buffalo, New York and the Jacobs Neurological Institute.

Millennium: Do you change therapy when a patient on interferon therapy experiences new symptoms?

Munschauer: The real issue is that we've evolved a philosophy of minimal or zero tolerance for clinical disease activity. Any new symptoms require a thorough reevaluation of therapy. This represents a major shift in best practice standards over the last 3 years.

When you're faced with a patient with new symptoms, first of all you want to make sure that the symptoms really represent disease activity that the patient doesn't have a medical condition that makes certain symptoms emerge, such as a UTI or depression, or other comorbid conditions that may make the disease appear worse. One needs to treat these causes directly in order to alleviate the patient's symptoms, which we call a pseudoexacerbation.

The algorithm is really fairly straightforward. If you feel that the symptoms are evidence of disease activity, then you really need to assess compliance with the medication. Since we don't do interferon levels, you assess compliance by taking a history. If it is breakthrough disease, then theoretically you could [as an option] consider combination therapies.

Millennium: What about switching from one interferon beta-1a to another?

Munschauer: Should you switch from Avonex 30 mcg IM weekly to Rebif 44 mcg SC three times a week? For one thing, that's not only a change in brands, but also a change in route of administration, frequency of administration, and a significant increase in dose. When you look at the Phase III trials, there is no evidence that one preparation of interferon has clinically significant greater impact in treatment of multiple sclerosis over a multiyear period of time. In addition, there is no evidence from any of the Phase III trials that increasing the dose will be more effective. Increasing the frequency of administration may theoretically increase the chances of neutralizing antibody formation as well. Long-term therapy with a drug that is less likely to develop antibodies is what I prefer.

Millennium: Are there any other factors that influence your choice of treatment?

Munschauer: For patients who are on beta interferons, we do believe that you should determine whether they have neutralizing antibodies. If they have neutralizing antibodies in high titer, say greater than 1:20, these neutralizing antibodies from one interferon preparation might cross-react with other beta interferons. In that case, it is important to seek alternate therapeutic options.

Millennium: Are there any other treatment alternatives?

Munschauer: Mitoxantrone, which is the remaining FDA-approved drug for multiple sclerosis, is reserved for people with aggressive disease and rapid deterioration because it is a major immunosuppressive drug. However, it has a limited lifelong dose that you can give to somebody (120-140 mg/m2)-if you exceed that dose they are at higher risk for cardiomyopathy.

Millennium: So, in your clinic, when it appears that a patient has breakthrough disease on interferon therapy, what do you do?

Munschauer: We feel that when somebody has breakthrough disease and they are antibody negative, if they are on interferons, our recommendation is to begin using pulse steroids. The evidence for this is not Class I clinical trial data, and we don't have large randomized clinical trials of any combination therapy yet. The standard of care in clinical disease is to first try steroids. If the patients are rapidly progressive, you may try mitoxantrone. If there's evidence of disease progression on interferon and steroids, but the patient is not sick enough for mitoxantrone, many investigators add in such drugs as azathioprine, methotrexate, or intravenous immunoglobulin. There may be a role for interferon plus glatiramer acetate, and we hope to study this in the near future in a NIH study.

References

1. How and Why Immunomodulatory Therapies Work in MS. Edward Fox, MD, PhD. Multiple Sclerosis Leaders Meeting Conference Highlights and Commentary, May 4-5, 2002, Las Vegas, Nevada. Presented May 4, 2002.
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