Review Article Perspectives on Multiple Sclerosis Robert I. Grossman and Joseph C. McGowan There is no question that MR imaging is presently the sensitivity of MR imaging, as the study does not best method for imaging multiple sclerosis (MS); yet, include state-of-the art spinal cord imaging. Com- even today, MS remains a clinical diagnosis, with the bined brain and spinal cord imaging can increase the relationship between clinical course and MR findings sensitivity to almost 100% (19). still problematic (1, 2). MR imaging appears to be the MS is a disease characterized by a variety of clinical most important test performed in the diagnostic courses. Terminology regarding clinical classification workup of MS; it has much greater impact than CSF can be confusing and even contradictory (20). Relaps- analysis and evoked potential testing (3). It is far ing-remitting MS is the most common course of the more sensitive than a clinical examination in revealing disease, initially occurring in up to 85% of patients. disease activity, as MR abnormalities are found five Exacerbations are, at the beginning, followed by re- to 10 times more often than clinical abnormalities missions, but over a period of years, additional exac- detected by standard neurologic examination (4–8). erbations result in incomplete recovery. Within 10 In this review, we briefly summarize the clinical and years, 50% (and within 25 years, 90%) of these pa- pathologic hallmarks of MS and discuss the MR find- tients enter a progressive phase, termed secondary- ings in this disease, examining the strengths and progressive (or relapsing-progressive) MS, in which weakness of conventional imaging protocols in rela- deficits are progressive without much remission in the tion to their clinical utility. Additionally, we consider disease process (21). Less commonly, MS is progres- how newer imaging techniques may add to our un- sive from the start. This classification was first distin- derstanding of this most interesting and challenging guished in 1952 and has been termed primary-pro- disorder. gressive (or chronic-progressive) MS (22). These patients (5% to 10% of the MS population) may present at a later age, with progressive neurologic Clinical Diagnosis findings, including paraparesis, hemiparesis, brain MS is primarily a disease of young adults, with peak stem syndromes, or visual loss. Patients in this group age of onset at about 30 years; however, it does occur typically have a more severe disability; they may have in children and adolescents (3% to 5%) and in per- occasional plateaus and temporary improvements, sons over the age of 50 years (9%) (9–15). As noted, but they do not have distinct relapses. Patients with the diagnosis of MS is presently based on clinical and primary-progressive disease tend to have less lesion paraclinical criteria alone. These parameters were load, fewer new lesions on monthly T2-weighted MR initially proposed to select patients for treatment tri- images, and fewer enhancing lesions as compared als (16, 17). The criteria designed by Poser et al (17) with patients with secondary-progressive disease, de- in 1983 establish two major groups: definite MS and spite progressively declining neurologic status (23, probable MS, each with two subgroups, clinical and 24). Progressive-relapsing MS, a rare clinical course, laboratory supported. Clinically definite MS is de- is defined as progressive disease with clear acute fined by the occurrence of two attacks and clinical relapses, with or without full recovery, and with the evidence of two separate lesions, or by two attacks periods between relapses characterized by continuing with clinical evidence of one lesion and paraclinical disease progression (2). Some investigators lump all evidence of another, separate lesion. Clinically prob- these groups together into a category called chronic- able MS is defined by the occurrence of two attacks progressive MS; however, Lublin et al (2) believe the and clinical evidence of one lesion, one attack and term should be abandoned because of its vague na- clinical evidence of two separate lesions, or one attack ture and the variable clinical courses and correspond- and clinical evidence of one lesion and paraclinical ing MR patterns (2, 25). Benign MS describes cases in evidence of another, separate lesion. Paraclinical ev- which, after initial clinical symptomatology, no clini- idence includes CSF, CT, or MR imaging data. MR cal progression is seen for a period of approximately imaging is by far the best paraclinical test, depicting 10 to 15 years. Conversely, a rapidly progressive abnormalities in 95% of patients with clinically defi- course leading to significant disability or death shortly nite MS (18). This number probably understates the after disease onset has been termed malignant MS (2). Funded in part by the National Institutes of Neurological Disorders and Stroke, National Institutes of Health grants NS29029, NS34353, and 5MO1-RR00040–34. From the Department of Radiology, University of Pennsylvania Medical Center, 3400 Spruce St, Philadelphia, PA 19104. Address reprint requests to Robert I. Grossman, MD. © American Society of Neuroradiology 1251 1252 REVIEW ARTICLE AJNR: 19, August 1998 In addition to these well-described clinical pat- myelin loss. Histopathologic hallmarks of the disease terns, there is the dilemma of the monosymptomatic include multifocal lesions showing inflammation, lym- patient. This presentation consists of a single episode phocytes and macrophages, demyelination, gliosis, at- of neurologic deficit, such as optic neuritis, transverse tempts at remyelination, and relative sparing of axons myelitis, or brain stem syndrome. Seventy-seven per- (44). However, the sparing of axons has recently been cent of patients presenting with an isolated brain stem challenged in a provocative article by Trapp et al (45), syndrome have been reported to have asymptomatic who found transsected axons to be common and hy- brain lesions (26). Miller et al (27) reported that pothesized that these could be responsible for neuro- progression to MS occurs in about 57% of patients logic impairment. Active histologic lesions show loss with isolated brain stem syndrome and in 42% of of myelin, infiltration with lipid-laden macrophages patients with spinal cord syndrome. Jacobs et al (28) (Gitter cells), perivascular inflammatory cuffing with found that 50% of patients with optic neuritis had T- and B-cell lymphocytes, and plasma cells associ- lesions in their brain 3 weeks to 7 years after their ated with perivascular demyelination. Reactive astro- attack. The risk of MS developing after optic neuritis cytes, containing nuclear atypia, are observed within has been estimated to be between a few percent to and on the border of plaques. Depletion of oligoden- 75% or more. The presence and the number of droglia has been seen in some patients early in their asymptomatic lesions on MR images markedly in- disease course, whereas in other cases there appears crease the risk of progression to MS, not only in to be preservation of the oligodendroglia, suggesting patients with optic neuritis but also in those with that the pathogenesis of demyelination in MS may isolated brain stem or spinal cord lesions (29–34). vary among different patients and may change over Patients with isolated acute syndromes and no asymp- time within the same patient (46). Attempts by the tomatic brain lesions are at lower risk of progressing oligodendroglia at remyelination have been observed to MS (27). MR imaging thus possesses good predic- in both acute and chronic plaques (47–49). The ex- tive power in patients who have clinically isolated tent of this process can vary from a narrow rim syndromes suggestive of MS (32, 35). around silent lesions to a zone of macroscopic satel- Clinical evaluation of MS most commonly relies on lites contiguous with demyelinated lesions, the latter the Expanded Disability Status Scale (EDSS) devised being known as shadow plaques (50). What is not by Kurtzke in 1955 (and improved in 1983) to evalu- understood is the relationship, if any, between at- ate isoniazid (36, 37). It is an ordinal system from 0 to tempts at remyelination and clinical recovery. Inac- 10, with incremental 0.5-unit steps (except at 1.0), tive plaques are hypocellular without perivascular in- designed to categorize deterioration in the pyramidal, flammation. The borders of these lesions are discrete, cerebellar, brain stem, sensory, bowel and bladder, gliosis is present, and there may be axonal loss (45). visual, and cerebral (mental) functions, as well as to The histopathologic correlates of the various clini- characterize any other neurologic finding attributed cal courses are still not fully understood. Excellent to MS. The test has been criticized for being insensi- correspondence has been reported between contrast tive, for being heavily weighted to motor disability, enhancement and macrophage infiltration, but the and for having substantial intra- and interrater vari- association is weaker with perivascular lymphocyte ability (38–40). Controversy regarding clinical out- infiltration (51). Blood-brain barrier (BBB) disrup- comes measures also pertains to the evaluation of tion and demyelination appear to be linked, but how neuropsychological dysfunction, which until recently strongly remains open to debate. In general, the was not appreciated as an important cause of disabil- longer the course of the disease, the greater the ac- ity and usually not examined in a sensitive