Barry A. Singer, MD
Introduction
Cerebrospinal fluid analysis and brain imaging were 2 topics discussed during the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), September 27-30, 2006, in Madrid, Spain. The highlights of new findings are reviewed, and implications for clinical practice are described.
Cerebrospinal Fluid Analysis
Newer techniques of analyzing cerebrospinal fluid may result in improved diagnosis and prognosis of multiple sclerosis (MS). With an alkaline phosphatase technique to study immunoglobulin (Ig)M oligoclonal bands, the sensitivity for diagnosing MS was shown to be as high as 96.2% in a study of 132 MS patients and 385 patients with other inflammatory central nervous system disorders.[1] The specificity of the testing was even higher at 99.5%. The presence of the IgM subtype of oligoclonal bands is prognostic for the conversion of a clinically isolated syndrome to clinically definite MS. In addition, the finding of IgM oligoclonal bands confers a higher risk for secondary progressive disease (P = .0009), a second relapse within a year, and disability progression to expanded disability system scores of greater than 6. The patients with IgM oligoclonal bands directed at myelin lipids appeared to have a particularly aggressive form of disease.
A larger study confirmed the predictive value of the presence of oligoclonal bands in patients with a clinically isolated syndrome.[2] Of 572 patients with a clinically isolated syndrome, 415 had oligoclonal band testing. The presence of oligoclonal bands almost doubled the risk of developing clinically definite MS at 5 years (hazard ratio, 1.7). Of the total cohort, 61% of patients were oligoclonal band-positive. Only 30% of patients had oligoclonal bands in the cerebrospinal fluid in the group with 0 Barkhof MRI criteria. Sixty-nine percent of patients with 1-2 Barkhof MRI criteria and 85% of patients with 3-4 Barkhof MRI criteria had oligoclonal bands (P < .0001).
Brain Imaging Updates
Interferon beta-1a Studies
The MRI T2 burden of interferon beta-1a given 30 micrograms (mcg) intramuscularly weekly vs 44 mcg subcutaneously thrice weekly was studied in a post hoc analysis of the 48-week data from the Evidence for Interferon Dose Response: European-North American Comparative Efficacy (EVIDENCE) study.[3] The median absolute change in burden of disease was -189.5 mm3 for patients who received the 44-mcg dose and -19 mm3 for patients who received the 30-mcg dose. The adjusted mean treatment difference in percentage change of burden of disease from baseline to week 48 was -4.6% in favor of the 44-mcg thrice-weekly dose (P = .002).
Traboulsee and colleagues[4] presented data on the clinical benefits of subcutaneous interferon beta-1a from the Prevention of Relapses and Disability by Interferon-beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) trial long-term follow-up study. Those patients randomized originally to 44 mcg thrice weekly had a 5.0% increase in T2 burden of disease compared with a 24.5% increase in the late treatment group (P = .002). The 22-mcg thrice-weekly group had a more modest 17.4% increase in disease burden, but this increase was not statistically significant compared with the late treatment group (P = .114).
The effect of interferon beta-1a 30 mcg weekly on black hole volume was studied in a post hoc analysis of 160 patients from the Multiple Sclerosis Collaborative Research Group study.[5] In this study, the median increase in T1-hypointense lesion volume over 2 years was 40 mm3 for treated patients and 124 mm3 for placebo patients. This 68% reduction was statistically significant (P = .045) when adjusted for the number of baseline enhancing lesions. Baseline T2 lesion volume and T1-enhancing lesion volume significantly correlated with T1 hypodensity volume evolution.
Prospective Magnetic Resonance Spectroscopy
Khan and colleagues[6] studied prospective magnetic resonance spectroscopy in 18 relapsing-remitting MS patients on glatiramer acetate and 4 untreated patients over 4 years. N-acetylaspartate to creatine ratio determination was performed as a method of assessing axonal injury. The mean ratio for an area centered around the corpus callosum was 1.97 ± 0.24 at baseline for all 18 patients and 2.21 ± 0.16 at 4 years for the 15 patients still on glatiramer acetate. The mean ratio for normal-appearing white matter was 2.075 ± 0.30 at baseline and 2.27 ± 0.2 at 4 years. The mean ratio conversely dropped from baseline in the untreated patients. The rise in the N-acetylaspartate to creatine ratio in patients taking glatiramer acetate might reflect axonal metabolic recovery.
The BECOME Study
The Betaseron vs. Copaxone in MS with triple-dose gadolinium and 3-T MRI Endpoints (BECOME) study prospectively analyzed T1 hypodensity evolution in relapsing MS patients randomized to receive interferon beta-1b or glatiramer acetate treatment.[7] Enhancing lesions were monitored to assess the development of black holes. Lesions were considered to be permanent black holes when the T1 hypodensities persisted for 12 or more months. With interferon beta-1b, 6 of 45 black holes (13.3%) became permanent at 12 months, and at 9 months, 8 of 37 black holes became permanent. With glatiramer acetate, the permanent black holes developed from 7 of 16 T1 hypodensities (43.7%) at 6 months and from 4 of 7 (57.1%) T1 hypodensities at 9 months. Therefore, fewer lesions evolved to permanent black holes with interferon beta-1b than with glatiramer acetate at 6 months (P = .01) and 9 months (P = .05). Over 12 months of treatment, the T1 hypointense volume decreased 354.1 ± 859.7 mm on interferon beta-1b and 320.5 mm ± 935 mm on glatiramer acetate; this difference was not significant (P = .9). The percentage of the original enhancing lesion area that became a permanent black hole area was smaller with interferon beta-1a than glatiramer acetate (P = .01).
Mitoxantrone Study
Mitoxantrone is approved for the treatment of worsening relapsing-remitting and secondary progressive MS. Walczak and colleagues[8] investigated the development and evolution of T1-weighted lesions, proton density (PD)-weighted lesions, and brain atrophy in MS patients treated with mitoxantrone for 18 months. In total, 23 patients treated with a cumulative dose of 120-140 mg of mitoxantrone over 18 months were compared with 15-untreated MS patients. Although the mean number of new T2 lesions was shown to decrease by 85% with mitoxantrone in the Mitoxantrone in Multiple Sclerosis (MIMS) trial,[9]this trial examined T1 changes. The T1-weighted lesion volume increased by 66.6% in the control group and increased by 43.5% in the mitoxantrone-treated group. Brain parenchymal fraction decreased by 0.581% in the control group and by 0.538% in the mitoxantrone-treated group. Therefore, mitoxantrone favorably reduced the rate of new T1-hypodense lesion volume and reduced the rate of brain atrophy compared with control patients who did not receive treatment.
Magnetization Transfer MRI
Agosta and colleagues[10] examined the value of magnetization transfer MRI in predicting the accumulation of disability. Seventy-three patients with relapsing-remitting, secondary progressive, or clinically isolated syndrome demyelinating disease were studied with magnetization transfer at baseline and 12 months later. Forty-four patients (60%) had significant disability worsening. Independent predictors of worsening disability over a median period of 8 years were the baseline gray matter magnetization transfer ratio histogram peak height (P = .029) and the average lesion magnetization transfer ratio percentage change after 12 months (P = .016). Of interest, the gray matter change was a significant predictor in a primarily white matter disease.
Impact of Higher Magnetic Field Strength
Will higher magnetic field strength aid in the diagnosis and monitoring of MS patients? Stosic-Opincal and colleagues[11] estimated the advantage of 3.0-T over 1.0-T field strength MRI systems in the evaluation and follow-up of patients with MS. Twenty-three patients underwent 1.0-T and 3.0-T MRI imaging on the same day. At 1.0 T, 41 gadolinium-enhancing lesions were detected in 10 of 23 patients. With the 3.0-T MRI system, 51 enhancing lesions, representing a 24.4% increase in the number of lesions, were detected in 13 of 23 patients. The number of lesions on fluid-attenuated inversion recovery images also increased by 14.6% with the 3.0-T MRI system. These data indicate that increased sensitivity in lesion detection can be obtained with high magnetic field imaging.
Pathologic tissue blocks can also demonstrate more lesions in a higher magnet. Schmierer and colleagues[12] explored whether a 9.4-T MRI system is more sensitive at assessing MS pathology than a 1.5-T MRI system. One block demonstrated only a single white matter lesion on a 1.5-T MRI system and 5 lesions on a 9.4-T MRI system. The study authors concluded that a 9.4-T MRI system is a powerful tool to detect white matter lesions in pathologic tissue.
Predicting Disability
The ability to predict a patient's degree of disability, 20 years after a clinically isolated syndrome, would be a powerful tool to assist in treatment decision making. Fisniku and colleagues[13] reported on the correlation of baseline MRI activity with disability status 20 years later. Forty-nine of 57 patients (86%) with T2 MRI lesions at baseline went on to develop clinically definite MS after a mean of 19.5 years. In contrast, only 6 of 30 patients (20%) without T2 MRI lesions at baseline developed clinically definite MS. After 20 years of follow-up for 87 patients, 33 had relapsing-remitting disease, including 22 patients with an expanded disability system score of ≤ 3. Twenty-two patients had developed secondary progressive disease with a median expanded disability system score of 7.5, including 3 patients who had died from severe disease. T2 lesion volume moderately correlated with 20-year disability scores (P < .001).
Dirty-appearing White Matter
Dirty-appearing white matter is a description of diffuse areas of slightly increased signal intensity in the white matter on T2 images, which are distinct from the typically focal high-signal-intensity lesions that are usually well demarcated. Miropolsky and colleagues[14] determined the relationship between dirty-appearing white matter and changes in T2 lesion volume and brain volume in a group of MS patients followed for up to 8 years. Of the 348 patients who returned for 8-year follow-up in the PRISMS study, dirty-appearing white matter was seen in 88 (25.3%) at baseline. Only 3 additional patients developed this white matter change at the 8-year follow-up. For patients with dirty-appearing white matter at baseline, the volume increased in 2.2%, decreased in 28.4%, and remained the same in 69.3% of patients. Patients with dirty-appearing white matter at baseline also had lower T2 burden of disease at baseline (P = .0014). The whole-brain ratio was studied as a marker of brain volume. Patients with dirty-appearing white matter had a larger whole-brain ratio at baseline (P < .001) and a greater reduction in the whole-brain ratio at long-term follow-up (P = .038).
COGIMUS Study
The COGIMUS study evaluated cognitive impairment in 430 early relapsing-remitting MS patients with relationship to MRI parameters.[15] One third of patients exhibited impairment on 2 tests or more in Rao's Neuropsychological Screening Battery. Impairment of spatial recall, symbol-digit modalities, and paced auditory 3-second tests were significantly associated with brain MRI T2 and T1 lesion loads. A significant correlation with brain atrophy was seen with symbol-digit modalities and selective reminding-consistent long-term retrieval tests. Multivariate logistic regression showed that age, disease duration, and T2 lesion load were significant predictors of cognitive impairment. The results from this study confirmed that cognitive impairment can occur early in the disease course and is associated with MRI T2 lesion load, T1 lesion load, and brain atrophy.
Conclusion
The finding of oligoclonal bands in the cerebrospinal fluid almost doubles the risk of developing clinically definite MS. Subtyping oligoclonal bands can increase diagnostic sensitivity and specificity as well as help predict disease progression. MRI studies have demonstrated the benefit of interferon and mitoxantrone on the development of T1 hypodensities. Cognitive dysfunction seen early in MS is associated with increased MRI T2 and T1 lesion load as well as brain atrophy. Magnetization transfer ratio, magnetic resonance spectroscopy, and higher field magnets may all improve disease prognosis and the ability to assess therapeutic response.
References
Alvarez-Cermeno JC. Diagnostic utility of CSF testing and beyond. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 73.
Tintoré M, Pelayo R, Rovira Á, et al. Do oligoclonal bands add information to baseline MRI in first attacks of multiple sclerosis? Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 74.
Traboulsee A, AL-Sabbagh A, Bennett R, et al; on behalf of the EVIDENCE Study Group and UBC MS/MRI Research Group. Greater reduction of MRI T2 burden of disease with interferon beta-1a 44 mcg administered subcutaneously three times weekly then 30 mcg administered intramuscularly once weekly: analysis of 48-week data from the EVIDENCE study. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Poster 678.
Traboulsee A, Li D, Kappos L; on behalf of the PRISMS LTFU Study Group and the UBC MS/MRI Research Group. Long-term clinical benefits from subcutaneous interferon beta-1a: a phased analysis of the PRISMS long-term follow-up study. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Poster 677.
Radue EW, Saharain M, Pace A, et al. The evaluation of black hole volume evolution as it relates to lesion load, extent of enhancement, and treatment with intramuscular interferon-beta-1a in two relapsing-remitting multiple sclerosis studies. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Poster 608.
Khan O, Shen Y, Mackenzie M, et al. Prospective long-term study of proton brain magnetic resonance spectroscopy in relapsing-remitting multiple sclerosis: effect of glatiramer acetate on axonal injury. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Poster 171.
Cadavid D, Gómez-Choco M, Alemany M, et al. Outcome of T1 hypodensities in patients with early forms of multiple sclerosis randomised to Betaseron or Copaxone and followed prospectively by monthly 3T MRI for up to 2 years: preliminary analysis of the BECOME study. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Poster 365.
Walczak A, Berkowicz T, Wartolowska K, et al. Effect of mitoxantrone therapy on T1 lesion load and atrophy in multiple sclerosis patients. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Poster 609.
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Agosta F, Rovaris M, Pagani E, et al. Magnetisation transfer MRI metrics predict the accumulation of disability eight years later in patients with multiple sclerosis. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Poster 198.
Stosic-Opincal T, Gavrilov M, Lavrnic S, et al. Comparison of 1.0T and 3.0T MRI findings in follow-up of patients with multiple sclerosis. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Poster 190.
Schmierer K, Parkes HG, So PW, et al. High field-high yield: detecting multiple sclerosis white matter lesions at 9.4 tesla. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Poster 191.
Fisniku L, Brex P, Altmann DR, et al. Disability status and the relationship between the T2-MRI abnormalities in CIS patients and the long-term outcome in a 20-year follow-up. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 6.
Miropolsky V, Vertinsky T, Zhao GJ, et al. Dirty-appearing white matter in multiple sclerosis: relationship to T2 disease burden increase and brain volume decrease with 8-year long-term follow-up. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Poster 621.
Patti F, Amato MP, Tola MR, et al. Cognitive impairment and MRI features in early relapsing-remitting multiple sclerosis patients: results of an Italian multicentre study (COGIMUS). Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 82.
