Ischemia and Multiple Sclerosis: Perfusion MR Imaging Provides Insight into an Underexplored Pathophysiology

The past two decades have been an exciting period in the field of MR imaging of multiple sclerosis (MS), because it has provided the tools required to answer new questions and to generate and address new hypotheses. In the late 1980s, MR imaging was shown to be the best technology for providing sensitive and objective measures of the mostly subclinical disease of MS. MR imaging became fundamental in evaluating the disease in clinical trials, including its utilization as primary outcome measure in phase II trials. MR studies of MS at the time of a clinically isolated syndrome (CIS) provided objective criteria and a new basis for determining dissemination in space and time that have been recently incorporated into the “McDonald” criteria for diagnosis and that can be used to expedite the diagnosis after a CIS (1). Multiple quantitative MR methodologies (e.g., magnetization transfer and diffusion-based imaging) were instrumental in establishing the prevalence and importance of the “invisible” disease in the normal-appearing white matter (NAWM), and more recently the normal-appearing gray matter (2). In the late 1990s, the MS community was reoriented to the importance of early axonal injury in MS. Axonal injury and transection are now thought to be in part the previously missing links in understanding disability and progression that could not be accounted for by demyelination alone (3). MR spectroscopy confirmed axonal injury in vivo based on reduced n-acetylaspartate, and MR-based atrophy measures now provide a relatively simple, practical measure of the destructive, mostly irreversible injury that can be detected even in early MS.

We did not have to wait long for another stimulating development in MS that already has important implications for imaging. On the basis of neuropathologic studies from biopsy material, Lucchinetti et al (4) suggested that MS is best characterized as a heterogeneous disease that is relatively homogeneous within individuals. A new classification was proposed such that MS would fit neatly into four categories. The underlying pathology in MS in all four types remained chronic T lymphocyte–mediated inflammation, accompanied by activated macrophages and microglia and their toxic products (pattern I). But additional amplification factors generate patterns II–IV (5). Pattern II could be characterized by deposition of immunoglobulins and components of activated complement (resembling an antibody-mediated process); pattern III by distal dying back oligodendrogliopathy (DDBO) with oligodendrocyte apoptosis; and pattern IV, relatively rare, by degeneration and oligodendrocyte death in the periplaque white matter (5). One obvious implication of this classification is that, if the underlying pathology is heterogeneous, the one treatment fits all approach is not likely to be optimal. In addition, there has been an interesting attempt (but not as neat) to relate MS variants and possibly MS phenotype to this classification scheme, for example Devic’s neuromyelitis optica with pattern II and Balo concentric sclerosis and lesions with ill-defined contours to pattern III. It should be noted that this classification scheme is not free from healthy controversy and may be best described as a working and stimulating model.

From an imager’s perspective, this is all very pleasing, because there may finally be a path to understanding the striking MR imaging heterogeneity we see in the clinic when evaluating “MS.” For example, some individuals show numerous tiny focal lesions, others multiple large “punched-out” lesions, still others have lesions with ill-defined borders. We do not know whether these varied appearances reflect a differential host response to a common insult or the heterogeneity is primary, related to etiology, pathogenesis, or comorbid factors. Attempts to relate MR imaging features to pathology have to date been stimulating, but direct histopathology-MR imaging material is limited.

Although all the patterns are interesting, pattern III may now have special attraction for imagers, because this pattern has been associated with hypoxia (5). The characteristic DDBO of pattern III was described in demyelination and specific toxic demyelinations from agents that interfere with cellular energy metabolism such as cuprizone, and this pathology is also found in acute white matter stroke (5). In stroke and a subset of MS lesions with DDBO, there is profound expression of an hypoxia-inducible factor called HIF 12 α, an antigen recognized as a marker of hypoxic tissue damage (5). Mechanisms responsible for this metabolic state resembling hypoxia could be secondary to microcirculation disturbances, and/or toxic metabolites, such as those interfering with mitochondrial energy metabolism. In acute inflammation, edema and locally constrained tissue may be the basis for circulatory disturbances. Possibly more important, inflammatory changes in the vessel wall with activation of a clotting cascade, or direct endothelial damage, may contribute to this injury. Toxic disturbances from liberated excitotoxins, reactive oxygen species, and nitric oxide intermediates may also contribute to DDBO, metabolic injury, and ischemic states in MS.

This brings us back to MR imaging. MR imaging is an important technique for the evaluation of vascular abnormalities and assessment of the microcirculation based on perfusion imaging, but, apart from attempts to understand the blood-brain-barrier, the microcirculation has received only little attention in MS. The report by Ge et al in this issue of the AJNR has special significance in view of the background pathophysiology highlighted by Luchinetti et al, Lassman, and others, not just because of the possible relationship of ischemia to MS, but also related to the potential for helping us understand normal and disturbed regulatory events at the capillary and postcapillary level in MS. In Ge et al’s study, dynamic susceptibility contrast MR imaging was used to evaluate focal MS lesions in patients with relapsing MS. An important methodologic detail is that perfusion measures were referenced to control white matter, by using the arterial input function, rather than contralateral NAWM. This is important because the latter has been shown by the same group (6) and others (7) to be abnormal in MS and therefore a suboptimal reference tissue. Perfusion measures of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were analyzed in 75 lesions from 17 patients with the NAWM of 17 MR imaging negative control subjects as reference.

MTT values were found to be significantly prolonged for the enhancing and nonenhancing MS lesions and importantly for the NAWM in MS patients compared with normal control white matter. With an eye toward determining whether perfusion measures would segregate focal lesions into perfusion types, a cluster analysis was performed, which resulted in three clusters, with two nonenhancing lesion subtypes (called class 1 and class 2), and a cluster of enhancing lesions. Compared with the enhancing lesions, the nonenhancing lesion cluster—called class 1—had relatively low CBV and calculated CBF compared with nonenhancing class 2 lesions characterized by relatively high CBV and CBF.

This perfusion-based differentiation would not be apparent by conventional T2-weighted imaging. The magnitude of the prolonged MTT and reduced CBF indicating perfusion deficits for all these focal lesion clusters and the NAWM is provocative in itself and especially so in view of the new pathology literature and the direction it is leading us in determining factors in MS relevant to the microcirculation and ischemia. The authors interpret their findings as a primary vascular pathology rather than reflecting decreased metabolic demand. They also speculate regarding increased CBF in enhancing lesions compared with contralateral tissue (increased perfusion beyond a baseline ischemic background accompanying inflammation). This finding is more difficult to interpret but is not entirely unexpected, in view of the known vasoactive factors associated with inflammation and supported by recent studies showing increased perfusion weeks before gadolinium enhancement (7). Whether class 2 lesions represent a pre-enhancing stage of early inflammatory activity as suggested will require longitudinal confirmation.

The results of Ge et al suggest that microcirculatory disturbances can be detected with surprisingly high frequency in MS. There are many unanswered and new questions. We do not know to what extent if any the perfusion patterns demonstrated by Ge et al correlate with those of DDBO or type III patterns. One recent study suggests that type III lesions may not be exclusively limited to a subset of MS patients but may in fact represent an early stage in formation of most MS lesions associated with acute exacerbation (8). This study did not relate perfusion findings to lesion size, lesion duration, treatment status, or presence or absence of T1 black holes, which are a well-defined, more severely injured subset of T2-hyperintense lesions. There is literature suggesting hypometabolism in MS, a factor which needs to be accounted for in interpretating these results and relevant to discussion of perfusion abnormalities as representing a primary rather than secondary pathology. Most intriguing, as suggested by the authors, are possibilities for in vivo microperfusion measures in understanding the vasoactive components of inflammation, and the effect of more targeted therapy on these, because the endothelium of the microvasculature and the release of vasoactive molecules are certainly central components of the early inflammatory cascade in MS. We need to know when these perfusion deficits first occur, how they progress, and specifically whether they present in the earliest stages of disease, for example at the time of a CIS.

Future studies will determine how perfusion measures will be used in demyelinating disease in the reading room. For now there is the opportunity with high-resolution perfusion MR imaging, diffusion MR imaging, and cellular and molecular imaging to look specifically at the normal and abnormal processes occurring at the endothelial level in MS. This will bring us closer to understanding the effects of intervention, including treatments targeting cellular migration and CNS surveillance, vasoreactivity, and the specific “good” and “bad” components of the inflammatory events in MS. This work by Ge et al provokes us to look at the microscopic pathology of MS by MR imaging in new ways. Whether perfusion abnormalities are cause or effect, we are delivered to a fork in the road of considerable interest.

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