Rohit Bakshi, MD
In recent years, the neurologic community has seen numerous important advances in the diagnosis and treatment of multiple sclerosis (MS). These developments have created new hope for patients and their caregivers that the devastating effects of MS can be prevented or ameliorated. Continuing research pertaining to the immunomodulatory treatment, pathophysiology, and cognitive effects of MS was presented at this year's Annual Meeting of the American Academy of Neurology.
New Treatments Strategies in MS
Do We Need Better Therapies for MS?
Three immunotherapies, interferon beta-1a, interferon beta-1b, and glatiramer acetate, are FDA-approved for the treatment of relapsing-remitting MS (RRMS) in adults. A fourth, mitoxantrone, is approved for reducing neurologic disability and the frequency of clinical relapses in patients with progressive, or worsening RRMS. These medications are clearly beneficial in limiting the natural history of the disease but are not curative. Some patients with MS continue to experience relapses or disease progression despite the best available therapies. These include patients with RRMS who continue to experience relapses or accumulation of disability, those with progressive MS who accumulate worsening physical disability, and patients with conditions related to MS for which proven therapies do not exist. Thus, there is a continuing search for additional treatments to supplement those that are already available.
Hormonal Therapy for MS
The rationale for using estriol therapy for women is derived from several observations. Pregnancy decreases cell-mediated immunity and increases humoral immunity to promote fetal survival. Estriol levels rise in the third trimester of pregnancy, at time when pregnant patients with MS are protected from disease effects. Estriol leads to beneficial clinical and immunologic changes in experimental animal models of MS, even in the absence of pregnancy. Sicotte and colleagues from Los Angeles, California, presented data from a pilot study on the use of estriol in women with MS. Of 12 patients given estriol 8 mg per day orally for 6 months, 6 patients with RRMS showed reduced gadolinium magnetic resonance imaging (MRI) activity. Oral estriol was well tolerated (only minor menstrual abnormalities). This pilot study is not conclusive but indicates that further study is warranted in a larger controlled trial of patients with MS.
Combination Therapy for MS
Several studies presented at the meeting showed that various combinations of immunotherapies were safe and well tolerated in phase 1 and phase 2 trials in patients with MS,[6-11] providing the impetus to pursue these strategies in larger clinical trials. For example, Havrdova and colleagues from the Czech Republic reported interim results of a blinded study of 105 patients with RRMS who received interferon beta 1-a (30 mcg weekly) plus either placebo, azathioprine (50 mg/day), or azathioprine and oral prednisone (10 mg every other day). Both combination strategies showed beneficial effects on physical disability and relapse rates. The therapies were safe and well tolerated. The study is encouraging, but firm conclusions should not be drawn until final results are available in 2003. It is clear that combination therapies will continue to capture the attention of the MS community and it is likely that such approaches will enter the clinical realm in the near future.
Treatment of children with MS
In 3% to 5% of cases, MS begins before adulthood and presents in children.[12,13] The most widely accepted diagnostic criteria for MS in adults can be used to diagnose MS in children and adolescents.[12, 13] Despite the clear benefit of FDA-approved immunomodulatory agents in adult patients with MS,[1-4] there are no guidelines on the use of these therapies in children with MS. Tenembaum and associates from Buenos Aires, Argentina, presented important data on the tolerability and efficacy of disease-modifying therapies -- beta interferons and glatiramer acetate -- in 19 pediatric patients with MS, including childhood and juvenile cases.
Seventeen patients with relapsing and 2 with progressive MS had been under treatment since 1997 (mean duration of immunotherapy was 24 months, range 6-42 months). Fifteen patients received interferon beta-1a, 2 received interferon beta-1b, and 4 were given glatiramer acetate. For those patients under 16 years of age, doses were escalated gradually starting at one fourth or one half of the full dose to enhance tolerability. Elevations of liver function tests were seen in 42% of patients, but these were transient and asymptomatic. The authors showed that full doses were most effective and that the side-effect profile was similar to that in adults. These data will bolster the confidence of clinicians in using the self-injected disease-modifying therapies in children with MS. It will be important to obtain follow-up information on the long-term safety and efficacy of these agents over several years and even decades, since MS is a chronic disease.
Treatment of Secondary Progressive MS
As recently reviewed,[16,17] one of the goals of early treatment of patients with MS in the relapsing-remitting stage is to prevent the development of a secondary progressive (SP) disease course. A National Multiple Sclerosis Society Advisory Committee has defined SP-MS as sustained progression of physical disability occurring separate from relapses that develops in patients who previously had RRMS. Secondary progressive MS is an advanced stage of disease that commonly leads to sustained loss of neurologic function. To date, marginal but statistically significant results have been reported on the use of disease modifying immunotherapies in SP-MS. Three large, randomized, multicenter, double-blind, placebo-controlled treatment trials of interferons in SP-MS have been completed.[19-21] A European trial found a significant clinical and MRI effect of interferon beta-1b. However, the SPECTRIMS study found that interferon beta-1a reduced the relapse rate and MRI progression but did not ameliorate sustained physical disability in 618 patients with SP-MS. A North American trial found that interferon beta-1b reduced relapses and MRI parameters but not the accumulation of disability in 939 SP patients. Mitoxantrone may also have partial benefit in SP-MS, although it has been studied in smaller numbers of SP-MS patients to date.
Cohen and colleagues presented data from a recently completed randomized, double-blind, placebo-controlled, 2-year multicenter phase 3 trial of interferon beta-1a (60 mcg intramuscular weekly) in 436 patients with SP-MS. The study, known as the International MS Secondary Progressive Avonex Controlled Trial (IMPACT), was conducted at 42 sites in the United States, Canada, and Europe. Dr. Cohen reported at the meeting that interferon beta-1a was associated with a 40% reduction in the accumulation of disability as measured by the MS Functional Composite (MSFC) (P = 0.033), meaning that the medication achieved benefit according to the primary end point. Interferon beta-1a also showed a significant benefit on relapses, MRI, and quality of life, but not on ambulation or expanded disability status scale scores. This study underlines the importance of early treatment of MS to limit the development of secondary progressive disease, which is more difficult to treat. It also suggests that patients with SP-MS will partially but significantly benefit from disease-modifying treatments.
MS is More Than a White Matter Disease
As reviewed by Dr. M. Filippi, although MS is traditionally thought of as a white matter disease, a growing body of evidence shows that the gray matter in the brain is commonly involved in patients with MS, with abnormalities including hypometabolism, hypointensity on T2-weighted images (probable iron deposition),[25,26] magnetization transfer and spectroscopic MRI changes, and direct plaque formation.[27,28] For example, a previous pathologic study, showed that 18 of 20 brains (averaging 6 lesions per patient) had demyelinating plaques in the cortical gray matter. Findings presented at the meeting extend and confirm these previous observations.
Peterson and colleagues from Cleveland, Ohio, studied autopsied brains of 50 patients with MS using immunocytochemical analysis. In total, 112 cortical lesions were identified in these patients. Axonal and dendritic transection was detected in active and chronic active cortical lesions. Neurons undergoing apoptosis were most prominently seen in demyelinated chronic active and inactive lesions. The cortical lesions had less inflammation than noncortical (white matter) lesions. These data show that greater attention should be paid to direct gray matter involvement as potentially related to the pathophysiology of clinical impairment in patients with MS. By coincidence, data published in the current issue of Archives of Neurology also highlights the importance of gray matter involvement in MS and the ability of advanced MRI methods to aid in their noninvasive in-vivo detection.
Bickerstaff's benign brainstem encephalitis (BBBE) was first described in 1951 as an inflammatory demyelinating disorder presenting most commonly with acute ophthalmoplegia and other cranial nerve involvement, ataxia, and usually a benign course. Siccoli and colleagues from Bern, Switzerland, described the frequency and clinical spectrum of 10 patients with BBBE. They defined the disease as the subacute onset of brainstem dysfunction with no recognizable etiology and a monophasic course. Mean age of the patients was 33 years (range, 15-64 years). Clinical findings included:
Cognitive Dysfunction in MS
At least half of patients with MS suffer from cognitive impairment that may significantly affect their daily functioning and quality of life. The pattern of cognitive impairment usually includes difficulties with information processing speed, learning capacity, and problem-solving behaviors. There is keen interest in identifying cognitive dysfunction as early as possible in patients with MS to minimize the deleterious effects. Neuroimaging has a central role in understanding the causes of cognitive dysfunction and recognizing patients who may be at highest risk for developing this complication of MS.
Christodoulou and associates from Stony Brook, NY, studied 14 patients with MS using quantitative volumetric MRI, multi-voxel MR spectroscopy (MRS) and neuropsychological testing. A range of cognitive tasks correlated with measures of both atrophy and axonal integrity. Central atrophy was associated with impairments in semantic fluency, sustained attention, and information processing speed. MRS showed that neuronal/axonal dysfunction/injury in the right posterior periventricular region showed similar associations with cognitive dysfunction. These data indicate that central atrophy and neuronal function are related to commonly seen, clinically relevant cognitive impairments in patients with MS. MRI measurements of atrophy and neurochemistry may provide sensitive noninvasive tools to predict neuropsychological deficits in patients with MS and provide longitudinal surrogate markers of cognitive ability.