New MRI Technology Provides Insights into Multiple Sclerosis
abstracts & commentary
Sources: Van Walderveen MAA, et al. Development of hypointense lesions on T1-weighted spin-echo magnetic resonance images in multiple sclerosis. Arch Neurol 1999;56:345-351; Filippi M, et al. Comparison of MS clinical phenotypes using conventional and magnetization transfer MRI. Neurol 1999;52:588-594; Filippi M, et al. Magnetization transfer imaging of patients with definite MS and negative conventional MRI. Neurol 1999;52:845-848; Sailer M, et al. Quantitative MRI in patients with clinically isolated syndromes suggestive of demyelination. Neurol 1999;52:599-606; Edwards SGM, et al. Infratentorial atrophy on magnetic resonance imaging and disability in multiple sclerosis. Brain 1999;122:291-301; Stevenson VL, et al. Primary and transitional progressive MS: A clinical and MRI cross-sectional study. Neurol 1999;52:839-845.
Conventional mri of the brain is sensitive in detection of MS lesions and is the most important paraclinical measure of disease activity. Surprisingly, several previous studies have shown limited correlation between clinical disability in MS and MRI findings. Recently, several new MRI techniques with potential for higher pathologic specificity have been used to monitor MS, including magnetization transfer (MT) MRI, diffusion-weighted (DW) MRI, and magnetic resonance spectroscopy. In standard MRI, increased signal on T2-weighted images reflects increased water content that occurs in a range of pathology, from early inflammation and edema to severe demyelination with axonal loss. This may be one reason hyperintense signal on T2 MRI does not correspond closely to clinical disability.
Van Walderveen and colleagues, in their study of 38 MS patients over an average of 40 months, focused on the accumulation of hypointense lesions on T1-weighted MRI ("black holes," which indicate areas of axonal loss and tissue matrix destruction) and the development of disability in MS. Such black hole formation on T1 MRI appeared to correlate with a new enhancing lesion rate and initial T1 lesion load, suggesting that certain patterns of MS are prone to develop destructive lesions. The hypointense T1 lesion load at the end of the study period correlated with clinical disability better than the T2 lesion volume.
In addition to gross MS pathology with cystic degeneration, microscopic damage has been shown histologically to occur in normal appearing white matter (NAWM), and is not detected by conventional MRI. The process, nevertheless, also may contribute to brain atrophy and MS disability. In MT MRI, a low MT ratio indicates a reduced capacity of macromolecules to exchange magnetization with surrounding water molecules, reflecting damage to the myelin or axonal membranes. Filippi and colleagues performed conventional MT MRI on 11 patients with clinically definite MS or laboratory supported MS with positive CSF findings and negative brain images. Six of the 11 patients, however, expressed MRI lesions in the cervical or thoracic spinal cord. Compared with control subjects, the MS patients had significantly lower MT ratios in the pons, cerebellum, and periventricular regions (P < 0.0001). In a second study, Filippi et al used MT MRI in a variety of MS clinical phenotypes. Patients with secondary progressive (SP) MS had significantly lower MT ratios that corresponded more accurately to clinical disability than did T2 lesion load. Patients with primary progressive MS had a lower MT peak height consistent with diffuse white matter pathology not revealed on T2-weighted imaging.
Dousset and colleagues performed serial MT-MRI studies in four MS patients for 9-12 months (Dousset V, et al. Neurol 1998;51:1150-1155). Monitoring 15 new lesions, 13 had a marked decrease in the MT ratio for two months after the onset of the lesion, followed by a variable increase. Two other lesions showed a progressive decline in the MT ratios suggesting continuing demyelination and tissue destruction.
Goodkin and colleagues performed a more comprehensive analysis of 22 relapsing remitting (RR) MS patients and 11 normal controls over 12 months (Goodkin DE, et al. Neurol 1998;51:1689-1697). In 129 new lesions identified in 11 patients, there were differences in the MT ratios that preceded by months the new gadolinium-enhanced lesion formation in NAWM. Residual abnormalities beyond two months were more evident on MT and proton density MRI, consistent with irreversible tissue damage.
Most patients present with an RR course and subsequently enter a secondary progressive (SP) phase with or without relapses. However, 10% of patients have a primary progressive (PP) course from onset. A multi-center European MRI study (Stevenson et al) was performed on 158 PP MS patients, 33 with transitional progressive MS (TP MS, a progressive course with a significant relapse at some point in the disease). The SP and TP MS patients had significantly more lesions in the spinal cord than PP patients. There was a correlation of Expanded Disability Status Scale Scores (EDSS) in the PP and TP MS patients with brain and spinal cord atrophy, but not lesion load.
A longitudinal, quantitative MRI study was performed by Sailer and colleagues at Queen Square, London, in 58 patients with their first attack of MS, with a follow-up five and 10 years later. The total initial lesion volume on T2-weighted MRI correlated significantly (P = 0.0001) with the 10-year lesion volume and EDSS. Sailer et al concluded that the initial brain MRI strongly predicted the subsequent development of clinically definite MS and future level of disability. Thus, a high lesion load on an initial MRI would imply a poor prognosis and would support early immunodulatory treatment intervention to slow new lesion formation and minimize long-term disability.
Recognizing that brain atrophy may provide an important index of fixed neurological dysfunction, Edwards and colleagues determined the infratentorial volumes on MRIs from 21 RR and 20 SP MS patients. The volume of the C1-C3 cervical spinal cord correlated with a composite spinal cord disability score derived from the EDSS as well as disease duration (P < 0.01). There was also a weak correlation with the Scripps Neurological Disability Rating score with the cerebellar (P < 0.01) and brain stem (P < 0.05) volumes.
Commentary
The imprecise correlation of burden of disease on brain MRI with neurological disability may be related to the pathological heterogeneity of T2-weighted lesions. The series of MRI studies reviewed above document the lack of specificity of T2-weighted MRI for reversible demyelination vs. permanent axonal loss. The greater sensitivity of MT MRI will aid in assessing demyelination, axonal loss, and early pathology in "normal" white matter. New measures of brain atrophy may correspond more accurately to neurologic disability. Investigators at the Cleveland Clinic have developed an index of brain atrophy, brain parenchymal fraction (BPF), which may serve as a sensitive, early marker of MS-related disease activity. Treatment with interferon beta-1a after one year was shown to stabilize the reduction in the BPF (RA Ruddick, personal communication). It is expected that such MRI technology will improve our ability to test drug efficacy in slowing progression of the disease.
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