23 White Matter Pathology in
Systemic Immune- Mediated Diseases
Marco Rovaris and Massimo Filippi
M. Rovaris, MD; M. Filippi, MD
Neuroimaging Research Unit, Department of Neurology, Scientifi c Institute and University Ospedale San Raffaele, Milan, Italy
23.1
Introduction
Systemic immune-mediated diseases (SID) can affect the central nervous system (CNS), either as the onset clinical manifestation or as a late complication in the context of a multiple organ involvement (Calabrese et al. 1997; Fieschi et al. 1998). Among SID, systemic lupus erythematosus (SLE), Behçet disease (BD), small-vessel vasculitides (SVV) and primary an- tiphospholipid antibody syndrome (APS) may often have a fl are-like clinical course which closely resem- bles that of multiple sclerosis (MS) and, therefore, be considered in the differential diagnosis of this latter condition.
Numerous studies reported that conventional, T2- weighted brain magnetic resonance imaging (MRI) is sensitive for detecting CNS lesions in patients with SID (Miller et al. 1987; Coban et al. 1996; Liem et al. 1996; Provenzale and Allen 1996; Gumà et al.
1998; Hachulla et al. 1998). A wide spectrum of non-specifi c MRI abnormalities has been described in these patients, including cerebral infarctions, brain atrophy, dural sinus thrombosis and, more rarely, hemorrhages or meningeal involvement. In a signifi cant proportion of patients with SID, however, multiple brain white matter lesions mimicking those due to MS can be the only MRI-visible abnormali-
ties (Miller et al. 1987; Nadeau 1997; Triulzi and Scotti 1998) (Fig. 23.1). Unfortunately, the limited pathological specifi city of the latter fi ndings hampers their diagnostic accuracy, as well as their prognostic value and relevance in the work-up of SID patients.
Quantitative MR-based techniques, such as mag- netization transfer (MT) MRI, diffusion-weighted (DW) MRI and magnetic resonance spectroscopy (MRS), make it possible to obtain information about white matter damage with increased pathological specifi city over T2-weighted sequences (Miller et al. 2003). In addition, all these techniques have the ability to assess and quantify the extent of white matter pathology beyond the resolution of conven- tional MRI, e.g. in the so-called normal-appearing white matter (NAWM). NAWM pathology seems to be a relevant contributor to the neurological impair- ment in patients with MS (Miller et al. 2003) and its accurate assessment might also be useful for the differential diagnosis between SID and other CNS diseases, as well as for a better understanding of the mechanisms leading to CNS dysfunction in the for- mer conditions.
This chapter reviews the contributions of conven- tional and modern MRI techniques to the in vivo in- vestigation of white matter pathology in SID.
23.2
Conventional MRI
Between 30% and 70% of patients with SLE develop neuropsychiatric complications (NSLE) during the course of the disease. In NSLE patients, brain MRI is abnormal in 40%–60% of cases (Csépàny et al. 2003;
Jennings et al. 2004), but the observed fi ndings are not disease-specifi c, the commonest being cerebral infarcts, brain atrophy and multiple, MS-like white matter lesions. The prevalence of brain MRI abnor- malities in patients with BD and CNS involvement (NBD) varies between 30% and 86% (Akman-Demir et al. 1999; Coban et al. 1996; Gerber et al. 1996; Lee
CONTENTS
23.1 Introduction 343 23.2 Conventional MRI 343
23.3 Magnetization Transfer MRI 346 23.4 Diffusion-Weighted MRI 348
23.5 Magnetic Resonance Spectroscopy 349 23.6 Conclusions 350
References 350
et al. 2001). Most frequently, these abnormalities con- sist of brainstem and basal ganglia lesions that may shrink or disappear at follow-up (Lee et al. 2001). In 20%–40% of NBD cerebral white matter is diffusely involved (Akman-Demir et al. 1999; Lee et al. 2001).
Among patients with SVV, only a minority of those with Wegener granulomatosis (WG) may show some degree of brain MRI abnormalities (Provenzale and Allen 1996), although the prevalence of clinical CNS involvement ranges between 22% and 54% of cases (Fieschi et al. 1998). Focal infarcts are the common- est MRI abnormalities described in APS, but brain atrophy and diffuse, T2-hyperintense white matter lesions can also be found in a high percentage of cases (Hachulla et al. 1998; Ijdo et al. 1999; Weingarten
et al. 1997). Moreover, recent reports found that up to 20% of MS patients with brain MRI fi ndings highly suggestive for this disease (Ijdo et al. 1999; Karussis et al. 1998) can be consistently positive for antiphos- pholipid antibodies, thus suggesting the possibility of a concomitant diagnosis of MS and APS.
It is worthy noting that, in SID patients, the use of fast fl uid-attenuated inversion recovery (fFLAIR) sequences, which are known to be more sensitive than conventional T2-weighted MRI for detecting lesions in the brain of patients with infl ammatory or demyelinating diseases of the CNS (Maubon et al. 1998), does not seem to increase the sensitivity of brain scanning for the detection of white matter abnormalities (Rovaris et al. 2000a). Among the po-
g h
a c
e b
d f
i
Fig. 23.1a–i. Axial pro- ton density-weighted spin echo (a, d, g), T2- weighted spin echo (b, e, h) and post-contrast T1-weighted spin echo (c, f, i) images of the brain obtained from patients with NSLE (a–c), WG (d–f) and relaps- ing-remitting MS (g–i) just above the roof of the lateral ventricles.
The pattern of T2-visible abnormalities is similar for the three patients, al- though fewer lesions can be seen on the images from the patient with WG (d, e) than on those from the patients with MS and NSLE. [Reproduced with permission from Rovaris et al. (2000b)]
tential explanations for this fi nding, the pathological heterogeneity of white matter damage in SID also has to be considered. Brain pathology in SID may range from infl ammation to acute and chronic ischaemia, which can be secondary to vessel thrombosis or vas- culitis. Small chronic infarcts can appear isointense to normal tissue on fFLAIR scans, and, therefore, go undetected when using this sequence.
White matter abnormalities detected on T2- weighted and post-contrast T1-weighted MRI of the brain have a limited diagnostic specifi city for SID. Several studies (Boumpas et al. 1990; Deodhar et al. 1999; Mascalchi et al. 1998; Mok et al. 1998;
Morrissey et al. 1993; Provenzale et al. 1994;
Salmaggi et al. 1994; Yoshioka et al. 1996) have sug- gested that MRI abnormalities in the cord of patients with SID are well correlated with ongoing symptoms of myelopathy and that they can completely disap- pear after steroid or immunosuppressive treatment (Boumpas et al. 1990; Lee et al. 2001; Mascalchi et al. 1998; Rovaris et al. 2000c; Salmaggi et al. 1994;
Yoshioka et al. 1996). On the other hand, spinal cord MRI abnormalities can be detected in up to 90%
of MS patients (Lycklama à Nijeholt et al. 1998;
Miller et al. 1998; Rocca et al. 1999), often without a concomitant clinical involvement, and the presence of such lesions may increase the confi dence when di- agnosing MS at its clinical onset (Fazekas et al. 1999).
Against this background, the detection of MRI-visi- ble white matter pathology in the cord might provide useful information for the work-up of patients with CNS disturbances, especially when a differential diag- nosis between SID and MS has to be made. In a cross- sectional study of 44 patients with SID (Rovaris et al. 2002), of whom 48% had had clinical manifesta- tions of CNS involvement, cervical cord MRI scans were always found to be normal, whereas brain MRI revealed white matter lesions in 52% of the cases. The application of standardized criteria for brain MR im- age interpretation (Barkhof et al. 1997), which were originally developed for predicting the evolution to established MS in patients at presentation with clini- cally isolated neurological syndromes suggestive of MS, yielded an accuracy of about 85% in differentiat- ing SID from age-matched MS patients and, by using the presence or absence of cervical cord MRI lesions as a dichotomized criterion, a correct re-classifi ca- tion of 77% of MS patients and two SLE patients who were misclassifi ed based upon their patterns of brain abnormalities was possible (Rovaris et al. 2002). The additional value of cord MRI in the differentiation of MS from SID and other neurological diseases of ischaemic etiology has been emphasized by another
study (Bot et al. 2002), where asymptomatic cord le- sions were found in 92% of MS and 6% of non-MS pa- tients and the concomitant evaluation of both brain and cord MRI fi ndings achieved a 95% diagnostic ac- curacy (Fig. 23.2). Both these studies (Bot et al. 2002;
Rovaris et al. 2002) confi rm that conventional MRI patterns of brain white matter damage related to SID do not have a clear-cut diagnostic value and they also underpin the importance of a careful interpretation
a
b Fig. 23.2a,b. Brain and spinal cord MR images in a patient with MS (a) and in a patient with Sjögren disease associated with clinical CNS dysfunction (b). Brain images fulfi ll diagnostic criteria for MS in both cases. However, sagittal cord images reveal the presence of diffuse abnormalities in the cervical tract and one focal lesion in the thoracic tract of the patient with MS, whereas no abnormalities can be seen in the patient with Sjögren disease. [Reproduced with permission from Bot et al. (2002)]
of MRI fi ndings based on a comprehensive image evaluation, which should consider, on the one hand, the radiologist’s opinion and, on the other, the appli- cation of standardized criteria.
Several studies have investigated whether the con- ventional MRI patterns of white matter pathology in SID patients may correlate with their clinical or immunological status and, therefore, have a value as paraclinical outcomes to monitor the disease evolu- tion.
The severity of neuropsychological dysfunction in SLE patients seems to be associated with the presence of cerebral infarcts (Waterloo et al. 2001) rather than with the overall burden of white matter lesions (Kozora et al. 1998; Sailer et al. 1997). The limited functional relevance of T2-visible white matter ab- normalities is also consistent with their weak cor- relation with neuroimaging correlates of brain me- tabolisms (Sailer et al. 1997; Waterloo et al. 2001).
On the other hand, however, it has been found (Bell et al. 1991; West et al. 1995) that NSLE patients with non-focal psychiatric symptoms more frequently show an MRI pattern of multiple white matter abnor- malities and have higher titers of antineurofi lament antibodies than those with focal CNS disturbances.
Two recent studies of NSLE patients also reported a signifi cant relationship of MRI fi ndings with the pres- ence of antiphospholipid antibodies (Csèpàny et al.
2003) and the levels of biochemical markers of axonal damage in the cerebrospinal fl uid (Trysberg et al.
2003). These fi ndings suggest that, in NSLE, different pathogenic mechanisms may be responsible for brain tissue damage, including both vasculopathic and im- mune-mediated neuronal injury, and underpin the need of MRI-derived measures with higher patholog- ical specifi city to monitor the disease course and its response to treatment. In patients with NBD, conven- tional MRI patterns of CNS involvement do not seem to have a clear-cut prognostic value (Akman-Demir et al. 1999; Lee et al. 2001), even though the presence of brainstem lesions, together with other clinical and laboratory characteristics, make it possible to iden- tify those patients with a poorer clinical outcome (Akman-Demir et al. 1999). In a study of patients with SVV (Mattioli et al. 2002), the presence of multiple white matter MRI abnormalities was fre- quently associated with subclinical cognitive impair- ment. Admittedly, caution must be exercised when in- terpreting MRI data from the latter study (Mattioli et al. 2002), which were obtained from a small sample of patients. However, the observation that less than 15% of cognitively impaired SVV patients in this se- ries had a normal brain MRI (Mattioli et al. 2002)
may indicate that the presence of MRI-visible white matter lesions signifi cantly increases the possibility for an SVV patient to have neuropsychological im- pairment.
23.3
Magnetization Transfer MRI
MT MRI has several advantages over conventional T2- and T1-weighted MRI for the in vivo structural investigation of CNS disorders. First, it provides in- formation with a high pathological specifi city. Low magnetization transfer ratio (MTR) indicates a re- duced capacity of the molecules in the brain tissue matrix to exchange magnetization with the sur- rounding (MRI-visible) water molecules and is as- sociated with severe demyelination and axonal loss (Brochet and Dousset 1999). Secondly, MT MRI enables us to assess the “invisible” disease burden in the normal-appearing brain tissue (NABT). Thirdly, MT MRI can provide, from a single procedure, mul- tiple parameters infl uenced by both the MRI-visible and MRI-undetectable disease burden. They are ob- tained after the automated creation of MTR maps, where the signal intensity of each pixel represents its MTR value. The analysis can then be done on a region-of-interest (ROI) basis or more globally using MTR histograms (van Buchem et al. 1996).
An ROI-based study comparing MT MRI fi ndings from 21 patients with MS and nine with SLE showed that the average MTR values of T2-visible white mat- ter lesions and NAWM in the brain were signifi cantly lower for the former group (Campi et al. 1996). In the same study, MTR values from the NAWM of SLE pa- tients were found not to differ from those of healthy controls. Using histogram-based analysis, an MT MRI study of 44 patients with SID, of whom 15 with SLE, nine with NSLE, fi ve with BD, nine with WG and six with APS, was also conducted (Rovaris et al. 2000b).
Ten patients with MS served as a control group. T2-
weighted brain MRI abnormalities were found in all
MS cases and in 52% of patients with SID, for whom
a white matter lesion pattern indistinguishable from
that of MS was observed in 40% of cases. MS pa-
tients had signifi cantly lower lesion MTR than SLE
and WG patients; NSLE had signifi cantly lower le-
sion MTR than SLE patients. MS patients had signifi -
cantly lower average MTR values in the NABT than
all SID but NSLE patients, who, in turn, had signifi -
cantly lower average NABT MTR than SLE patients
(Fig. 23.3). Both T2-weighted lesion volume and av-
erage lesion MTR fi tted a multiparametric model signifi cantly separating MS from SID patients, with a signifi cantly higher risk of having MS with increas- ing lesion volume and decreasing lesion MTR values.
No conventional or MT MRI-derived variables signif- icantly separated MS patients as a group from NSLE patients. Similar results were obtained by Bosma et al. (2000a,b), who found that NSLE patients had sig- nifi cantly lower brain MTR histogram peak height than age-matched healthy controls and SLE patients without overt CNS involvement, independent of the presence of T2-visible white matter lesions. In pa- tients during the acute stage of NSLE (Bosma et al.
2000b), the average MTR histogram peak height was found to be lower than that of patients with chronic inactive NSLE, SLE and MS. More recently, Bosma et al. (2002) also investigated the relationship between brain MTR histogram-derived quantities and clini- cal status in 24 patients with NSLE. Signifi cant cor- relations were found between MTR histogram peak height and measures of neurologic, cognitive and
psychiatric functioning, whereas no signifi cant rela- tionship was observed between MT MRI fi ndings and NSLE patients’ disease duration.
Available data show that the presence of CNS dysfunction in SLE is associated with a diffuse, MT MRI-detectable damage of the brain parenchyma, whereas this does not seem to be the case for other SID (Rovaris et al. 2000b). Such damage is probably primarily present in the NABT and does not greatly depend upon the burden of T2-visible white matter abnormalities. Indeed, the latter abnormalities can also be found in 30%–40% (Rovaris et al. 2000b;
Bosma et al. 2000a,b) of SLE patients without overt CNS disturbances, but MTR histogram-derived quan- tities of these patients do not signifi cantly differ from those of healthy controls. Moreover, when brain MTR histograms are obtained after the exclusion of pixels belonging to T2-visible lesions, the observed differ- ences between NSLE patients and normal controls or patients with other SID do not change (Rovaris et al. 2000b). It remains to be established which is the
a
b
Fig. 23.3a,b. NABT MTR histograms from healthy controls, patients with relapsing-remitting MS, patients with SLE without clinical signs of CNS in- volvement (a) or patients with NSLE (b). For SLE patients, the shape of the histogram resembles that of healthy controls and average NABT MTR values are signifi cantly higher than those of MS patients, whilst there are no signifi - cant differences between MS and NSLE patients in terms of NABT MTR his- togram-derived metrics. [Reproduced with permission from Rovaris and Filippi (2003)]
causal relationship between the extent and nature of NSLE-related diffuse brain tissue damage and MT MRI-detectable abnormalities. The contribution of NAWM pathology appears to be relevant for a num- ber of reasons. First, despite the concomitant fi nding of brain atrophy in NSLE (Bosma et al. 2000a,b), the magnitude of the decrease of brain MTR histogram peak height in comparison with SLE and healthy con- trols did not change when this metric was normalized for brain volume, thus suggesting that atrophy per se cannot explain the observed MT MRI abnormalities.
Second, a preliminary, ROI-based study (Campi et al.
1996) did not fi nd any difference in NAWM MTR val- ues between SLE patients and age-matched healthy subjects. Third, on the one hand, macromolecules that contribute to the MT effect in the brain tissue are mainly cerebrosides and phospholipids, which are the major components of myelinated white matter tracts (Brochet and Dousset 1999), and, on the other, NAWM constitutes a great portion of the NABT. Thus, it is conceivable that changes in the MTR histogram characteristics of the latter compartment mainly depend upon diffuse, MRI-undetectable white mat- ter abnormalities leading to demyelination and loss of axons. Admittedly, these speculations need to be confi rmed by further studies with a separate analysis of white and gray matter MTR histograms in NSLE and other SID. Preliminary MT MRI data (personal observations, unpublished results) seem to suggest that normal-appearing gray matter damage, if any, is minimal in SID, independently of the presence of overt CNS involvement or T2-visible white matter abnormalities. This is in contrast with what has been found in MS patients, for whom gray matter damage seems to play a central role in the pathobiology of CNS dysfunction (Miller et al. 2003).
The potential usefulness of MT MRI as a paraclini- cal tool to monitor SID evolution is suggested by the ability of the technique to differentiate the active from the chronic stage of NSLE (Bosma et al. 2000b), as well as by the observed, signifi cant association between volumetric MT MRI data and NSLE patients’ clinical status (Bosma et al. 2002). As regards the application of MT MRI to the diagnostic work-up of SID patients with CNS disturbances, Bosma et al. (2000a) found nearly no overlap between the individual MTR histo- gram peak height values of NSLE patients and those of either SLE patients or healthy controls, yielding a 95% specifi city in the diagnostic classifi cation of sub- jects with a cut-off value of 96.8. When the multipa- rametric model proposed by Rovaris et al. (2000b) was used to classify patients with MRI-visible white matter abnormalities as MS or SID other than NSLE,
60% of patients with MS and 91% of those with SID were correctly classifi ed. More recently (Rovaris et al. 2002), the value of brain MTR histogram-derived fi ndings for the differential diagnosis between MS and SID other than NSLE in individual cases has been investigated. Only one SLE of 44 SID patients had an average brain MTR one standard deviation below the control group mean value, whereas this was the case for 33 of 64 MS patients (52%); the combined evalua- tion of cervical cord MRI and brain MT MRI fi ndings made it possible to correctly classify as MS or SID all but one patient, supporting a more extensive use of these two techniques to differentiate between MS and SID when non-specifi c MRI abnormalities of brain white matter are detected. That MT MRI might serve as a diagnostic tool in the work-up of SLE patients has also been indicated by the preliminary results ob- tained by Dehmeshki et al. (2002), using a multivari- ate discriminant analysis approach.
23.4
Diff usion-Weighted MRI
Diffusion is the microscopic random translational motion of molecules in a fl uid system. In the CNS, diffusion is infl uenced by the microstructural com- ponents of tissue, including cell membranes and organelles. The diffusion coeffi cient of biological tissues (which can be measured in vivo by MRI) is, therefore, lower than the diffusion coeffi cient in free water and, for this reason, is named apparent diffusion coeffi cient (ADC) (Le Bihan et al. 1986).
Pathological processes which modify tissue integrity, thus resulting in a loss or increased permeability of
“restricting” barriers, can determine an increase of the ADC. Since some cellular structures are aligned on the scale of an image pixel, the measurement of diffusion is also dependent on the direction in which diffusion is measured. As a consequence, diffusion measurements can give information about the size, shape, integrity and orientation of tissues (Le Bihan et al. 1991). A measure of diffusion which is inde- pendent of the orientation of structures is provided by the mean diffusivity (MD), the average of the ADCs measured in three orthogonal directions. A full characterization of diffusion can be obtained in terms of a tensor (Basser et al. 1994), a 3×3 matrix which accounts for the correlation existing between molecular displacement along orthogonal directions.
From the tensor, it is possible to derive MD, equal to
one third of its trace, and some other dimensionless
indexes of anisotropy, such as fractional anisotropy (FA) (Basser and Pierpaoli 1996). Infl ammation and demyelination have the potential to alter the per- meability or geometry of structural barriers to water molecular diffusion in the brain white matter, thus leading to DW MRI-detectable changes. Recently, a preliminary, post mortem high fi eld MRI study of the spinal cord of patients with MS (Mottershead et al.
2003) reported that myelin content and axonal den- sity of the specimens correlated strongly with diffu- sion anisotropy, but only weakly with ADC values.
Available DW MRI studies of SLE patients (Moritani et al. 2001; Bosma et al. 2003; Jennings et al. 2003) reveal that areas with decreased ADC val- ues, corresponding to T2-visible white matter lesions, can be seen in 10%–20% of patients (Moritani et al. 2001; Jennings et al. 2003), suggesting the pres- ence of acute or subacute ischemic damage. Less frequently, ADC values can be increased within T2-isointense or slightly T2-hyperintense lesions (Moritani et al. 2001), indicating the presence of va- sogenic edema or demyelination. Bosma et al. (2003), using a histogram analysis technique, found that the average ADC values in the brain of 11 NSLE patients were signifi cantly higher than those of age-matched healthy controls, even though the visual inspection of DW images did not reveal other abnormalities than those visible on the corresponding T2-weighted MRI scans, i.e. subtle white matter hyperintensities, in about 50% of these patients. These data are con- sistent with those obtained using MT MRI (Rovaris et al. 2000b; Bosma et al. 2000a, b), indicating the presence of diffuse, structural brain damage. On the contrary, DW MRI studies of NBD (Hiwatashi et al.
2003; Kunimatsu et al. 2003) show that both acute and chronic white matter lesions have higher ADC values than the NABT areas, confi rming the primarily infl ammatory pathogenesis of white matter damage in this condition.
23.5
Magnetic Resonance Spectroscopy
MRS can complement conventional MRI in the as- sessment of patients with CNS disorders, by defi n- ing several chemical correlates of the pathological changes occurring within and outside T2-visible lesions (De Stefano and Federico 2001). Proton MRS of the brain at long echo times reveals major resonances from tetramethylamines [mainly from choline-containing phospholipids (Cho)], from cre-
atine and phosphocreatine (Cr) and from N-acetyl groups [mainly N-acetyl-aspartate (NAA)]. Reduced N-acetyl aspartate (NAA) levels are associated with axonal dysfunction, while increased Cho, inositol and lactate concentrations are correlated with membrane turnover, possibly secondary to infl ammation and demyelination (De Stefano and Federico 2001).
Partially confl icting results have been achieved by MRS studies of patients with SLE and CNS involve- ment (Davie et al. 1995; Chinn et al. 1997; Sibbitt et al. 1997; Sabet et al. 1998; Friedman et al. 1998; Lim et al. 2000; Handa et al. 2003). Sibbitt et al. (1997) found that lower NAA/Cr and higher lipid levels in the NAWM of patients with major symptoms of NSLE than in patients without or with minor CNS distur- bances. Increased lipid levels were not associated with the presence of T2-visible white matter lesions.
These fi ndings have been confi rmed by more recent studies (Lim et al. 2000; Handa et al. 2003). Other au- thors (Davie et al. 1995), however, failed to demon- strate signifi cant correlations between MRS-derived measures and presence or severity of neuropsychiat- ric symptoms. In the latter study (Davie et al. 1995), the pattern of MSR abnormalities did not allow dif- ferentiation of SLE lesions from MS plaques. Sabet et al. (1998) investigated the MRS patterns of SLE patients with or without secondary APS. They found that the burden of T2-weighted MRI abnormalities and the severity of brain atrophy were signifi cantly higher in SLE patients with APS than in those with- out. In addition, in SLE patients with APS, NAA/Cr levels were signifi cantly decreased and Cho/Cr levels increased when compared to normal controls and pa- tients without APS. These changes were present both within MRI-visible white matter lesions and in the NAWM. Interestingly, the results of a linear regres- sion analysis showed that reduced NAA/Cr was more closely related to increased levels of IgG antiphos- pholipid antibodies (aPL) than the presence of APS.
These data suggest that the presence of aPL indicates an increased risk for brain injury in SLE patients, in- dependently of the development of concomitant APS.
The presence of brain abnormalities at a microscopic
level might be a consequence of direct, immune-me-
diated tissue damage secondary to SLE more than the
result of diffuse ischemic injury due to APS. However,
these fi ndings may also be consistent with a direct in-
teraction between IgG aPL and brain cells, leading to
progressive tissue damage in SLE patients with aPL
positivity, even when the clinical features of APS are
absent. On the other hand, Friedman et al. (1998), in
an MRI/MRS study of 42 patients with SLE, reported
a signifi cant association between small, focal white
matter lesions and decreased NAA/Cr ratios, as well as between increased Cho/Cr ratios and cerebral infarctions, concluding that cerebrovascular abnor- malities may be the basis of diffuse cerebral damage in NSLE, with small vessel injury as the major fac- tor responsible for white matter axonal loss. Recently, an MRS study (Cellerini et al. 2003) of 17 BD pa- tients has found that NAA/Cr and Cho/Cr levels in the NAWM do not differ between patients and age- matched healthy controls, nor between patients with and those without CNS disturbances. MR spectra from contrast-enhancing white matter lesions were also obtained in two cases, both in the acute phase and at follow-up, showing a normalization of NAA/
Cr and Cho/Cr values after steroid therapy.
23.6 Conclusions
Conventional MRI can demonstrate the presence of white matter focal damage in the brain of patients with SID, but the observed patterns of T2-visible le- sions have a limited diagnostic specifi city, as well as a modest correlation with the clinical manifesta- tions of CNS dysfunction related to these disorders.
Available data underpin the need for developing stan- dardized criteria for diagnostic image interpretation in the work-up of patients with SID, similar to what has been done for MS, with particular emphasis on cases at the onset of the neurological disturbances.
The integration of brain scanning with imaging of the spinal cord might reasonably improve the diagnostic value of conventional MRI fi ndings when a differen- tial diagnosis between MS and SID has to be made.
Quantitative MR-based techniques seem to be able to contribute both to the in vivo investigation of white matter pathology in SID and to the diagnostic work- up of individual patients. The results of MT MRI, DW MRI and MRS studies of NSLE were all consistent with the presence of clinically relevant NAWM dam- age in this condition, whereas this does not seem to be the case for other SID. The pathogenesis of NAWM damage in NSLE might be secondary to both small- vessel ischemic injury and immune-mediated brain tissue disruption. The few available data obtained in patients with BD seem to indicate that the pathobiol- ogy of white matter damage in this condition is pri- marily infl ammatory-based and limited to T2-visible abnormalities. Further multiparametric and longi- tudinal studies will probably allow us to better de- fi ne the role of quantitative MR-based techniques for
helping in the diagnostic work-up of SID, investigat- ing the natural course of these diseases and, ideally, providing surrogate markers of disease evolution to monitor treatment effi cacy in experimental trials.
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