Книги по МРТ КТ на английском языке / MR Imaging in White Matter Diseases of the Brain and Spinal Cord - K Sartor Massimo Filippi Nicola De Stefano Vincent Dou

Davie et al. 1994; De Stefano et al. 1995a). Recovery of NAA may be related to resolution of edema, increases in the diameter of previously shrunk axons secondary to remyelination and clearance of inflammatory factors and reversible metabolic changes in neurons.

2.Chronic MS lesions are characterized by markedly reduced NAA/Cr peaks. These changes are more pronounced in severely hypointense MS lesions than in isoor mildly hypointense lesions (van Walderveen et al. 1999) and in chronic lesions from patients with SPMS than in those from patients with benign MS (Falini et al. 1998).

3.Cho increase, probably reflecting an altered myelin chemistry or the presence of inflammation, and a decrease in NAA have been also shown in prelesional NAWM (Narayana et al.1998;Sarchielli et al. 1999; Tartaglia et al. 2002).

of the fact that T2-visible lesions represent just a small component of overall brain damage and calls for an accurate assessment of NABT pathology for a better understanding of MS pathophysiology.

3.Metabolite abnormalities, including decrease of NAA and Cho and increase of mI, have also been shown in the cortical GM of MS patients (Kapeller et al. 2001; Sarchielli et al. 2002; Sharma et al. 2001; Chard et al. 2002), since the early phases of the disease (Chard et al. 2002), but not in CIS patients (Kapeller et al. 2002). These changes are more pronounced in patients with SPMS than in those with RRMS (Adalsteinsson et al. 2003). More recently, NAA reduction has also been demonstrated in the thalamus of SPMS (Cifelli et al. 2002) and RRMS patients (Wylezinska et al. 2003).

1H-MRS also has the potential to provide information on MS pathological changes outside T2-visible lesions. The following are the main findings obtained from the study of the NABT in MS patients using 1H-MRS:

1.Studies of limited and/or selected portions of the brain (Fu et al. 1998; Sarchielli et al. 1999; De Stefano et al. 2002) have shown that NAA reduction is not restricted to MS lesions, but also occurs in the NAWM. These changes are more severe in SPMS and PPMS patients than in those with RRMS (Fu et al. 1998; Suhy et al. 2000); however, they can be detected even in patients with no overt clinical disability (De Stefano et al. 2002) and in those in the early phase of the disease (De Stefano et al. 2001). Diffusely elevated Cho and Cr concentrations have also been described in the NAWM of RRMS (Inglese et al. 2003b) and PPMS (Suhy et al. 2000) patients.

2.The recent development of an unlocalized 1H-MRS sequence for measuring NAA levels in the whole brain (WBNAA) (Gonen et al. 1998) has shown the presence of marked axonal pathology in clinically definite MS (Gonen et al. 2000; Bonneville et al. 2002) and in patients at the earliest clinical phases of MS (Filippi et al. 2003). Interestingly, no correlation has been found between WBNAA concentrations and T2-weighted lesion volumes in patients with RRMS (Bonneville et al. 2002) and in those at presentation with CIS (Filippi et al. 2003a). The lack of such a correlation is likely to be the result

As already mentioned, axonal loss and/or dysfunction is likely to have a major role in the development of fixed clinical disability in MS. In agreement with this notion, a post-mortem study (Bjartmar et al. 2000) has shown a strong correlation between neurological impairment and both axonal density and NAA reduction in the spinal cord of patients with MS. The following are the main in vivo findings obtained from the application of 1H-MRS to the understanding of MS-related disability:

1.Following an acute MS relapse,reversible decreases in NAA have been observed not only in macroscopic lesions responsible for the clinical symptomatology (De Stefano et al. 1995b; Reddy et al. 2000a), but also in the NAWM of the hemisphere contralateral to acute lesions (De Stefano et al. 1999) (Fig. 15.5) and have been correlated with reversal of functional impairment.

2.In patients with RRMS, a longitudinal decrease over time of NAA/Cr in the NAWM correlates strongly with EDSS worsening (De Stefano et al. 1998; Fu et al. 1998), suggesting that progressive axonal damage or loss may be responsible for functional impairment in MS. More recently, it has been demonstrated that brain axonal damage begins in the early stages of MS, develops more rapidly in the earlier clinical stages of the disease and correlates more strongly with disability in patients with mild than in those with more severe disease (De Stefano et al. 2001).

3.NAA levels have also been quantified in specific brain regions, whose damage has been related to the impairment of the corresponding functional systems. Davie et al. (1995) showed a significant reduction of NAA concentration in the cerebellar WM of patients with MS and severe ataxia compared with those having little or no cerebellar deficits. Lee et al. (2000a) demonstrated an association between reduction of NAA in the internal capsule and selective motor impairment. Pan et al. (2001) found a relation between cognitive function and NAA levels in the periventricular WM. More recently, Gadea et al. (2004) found a relationship between attentional dysfunction in early RRMS patients and NAA/Cr values in the locus coeruleus nuclei of the pontine ascending reticular activation system.

15.4.4

1H-MRS to Monitor Treatment E cacy

Only four studies have been conducted to evaluate the effect of disease-modifying MS treatments on 1H-MRS-derived parameters (Sarchielli et al. 1998; Narayanan et al. 2001; Schubert et al. 2002; Khan et al. 2003). Using monthly 1H-MRS scans, Sarchielli et al. (1998) found that treatment with interferon beta-1a is associated with increased Cho peaks in spectra of lesions from RRMS patients, suggesting an increase in lesion membrane turnover during the first period of treatment. Narayanan et al. (2001) found an increase of NAA/Cr in a small group of RRMS patients after 1 year of treatment with interferon beta-1b, suggesting a potential effect of treatment in preventing chronic, sublethal axonal

injury. More recently, Schubert et al. (2002) showed a stability of metabolite concentration over time in patients with RRMS treated with interferon beta1b. Finally, Khan et al. (2003) showed an increase of NAA/Cr levels in lesions and NAWM of RRMS patients after 2 years of treatment with glatiramer acetate.

15.5 Functional MRI

Although the resolution of acute inflammation, remyelination, redistribution of voltage-gated sodiumchannels in persistently demyelinated axons, and recovery from sublethal axonal injury are all factors likely to limit the clinical impact of damaging MS pathology (Waxman and Ritchie 1993; De Stefano et al. 1995b), other mechanisms have been recently recognized as potential contributors to the recovery or to the maintenance of function in the presence of irreversible MS-related axonal damage. Brain plasticity is a well known feature of the human brain which is likely to have several pathologic substrates, including an increased axonal expression of sodium channels (Waxman 1998), synaptic changes, increased recruitment of parallel existing pathways or “latent” connections, and reorganization of distant sites. All these changes might have a major adaptive role in limiting the functional consequences of axonal loss. The application of fMRI to the study of the motor, visual and cognitive systems in patients with MS has provided new insights into the mechanisms contributing to the progressive clinical worsening of these patients.

Functional cortical changes have been demonstrated in all MS phenotypes, using different fMRI paradigms. A study of the visual system (Werring et al. 2000b), in patients who had recovered from a single episode of acute optic neuritis (ON), demonstrated that such patients had an extensive activation of the visual network compared to healthy volunteers. An altered brain pattern of movement-associated cortical activations, characterized by an increased recruitment of the contralateral primary sensorimotor cortex (SMC) during the performance of simple tasks (Rocca et al. 2003b; Filippi et al. 2004a) (Fig. 15.6) and by the recruitment of additional “classical” and “higher-order” sensorimotor areas during the performance of more complex tasks (Filippi et al.2004a) has been demonstrated in patients with CIS. An increased recruitment of several sensorimotor areas, mainly located in the cerebral hemisphere ipsilateral to the limb

a

b

Fig. 15.6a,b. Relative contralateral primary sensory-motor cortex (SMC) activation in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis during the performance of a simple motor task with the right hand in comparison to healthy volunteers (a). The scatterplot of the correlation between the relative activation of the contralateral primary SMC and whole brain N-acetyl aspartate concentrations is shown in (b)

which performed the task has also been demonstrated in patients with early MS and a previous episode of hemiparesis (Pantano et al. 2002a). Interestingly, in patients with similar characteristics, but who presented with an ON, this increased recruitment involved sensorimotor areas which were mainly located in the contralateral cerebral hemisphere (Pantano et al. 2002b). In patients with established MS and a RR course, functional cortical changes have been shown during the performance of visual (Rombouts et al. 1998), motor (Lee et al. 2000b; Reddy et al. 2000a, 2000b; Filippi et al. 2002b; Rocca et al. 2002a), and

cognitive (Staffen et al. 2002; Hillary et al. 2003; Parry et al. 2003) tasks. Movement-associated cortical changes, characterized by the activation of highly specialized cortical areas, have also been described in patients with SPMS (Rocca et al. 2003c) during the performance of a simple motor task. Two fMRI studies of the motor system (Filippi et al. 2002c; Rocca et al. 2002b)of patients with PPMS suggested a lack of “classical” adaptive mechanisms as a potential additional factor contributing to the accumulation of disability.

The results of all these studies suggest that there might be a “natural history” of the functional reorganization of the cerebral cortex in MS patients, which might be characterized,at the beginning of the disease, by an increased recruitment of those areas “normally” devoted to the performance of a given task, such as the primary SMC and the supplementary motor area (SMA) in case of a motor task.At a later stage, bilateral activation of these regions is first seen, followed by a widespread recruitment of additional areas, which are usually recruited in normal people to perform novel/ complex tasks. This notion has been supported by the results of a recent study (Filippi et al. 2004b), which has provided a direct demonstration that MS patients, during the performance of a simple motor task,activate some regions, that are part of a fronto-parietal circuit, whose activation occurs typically in healthy subjects during object manipulation (Filippi et al. 2004b).

factor modulating movement-associated cortical reorganization, as shown by studies of patients with various disease phenotypes and different levels of disability (Reddy et al. 2000b), patients at presentation with CIS suggestive of MS (Rocca et al. 2003b) (Fig. 15.6), patients with RRMS and no clinical disability (Rocca et al. 2002a), and PPMS and SPMS patients with different degrees of clinical involvement (Filippi et al. 2002c; Rocca et al. 2003c).

d)Subtle GM damage may play a role in modulating cortical excitability, as demonstrated in patients with SPMS (Rocca et al. 2003c) and in patients with clinically definite MS and non-specific (less than three lesions) cMRI findings (Rocca et al. 2003d).

e)Finally, the demonstration of strong correlations between cortical activations and cervical cord damage, quantified using MT MRI, in patients with PPMS (Filippi et al. 2002c), patients with a previous episode of acute myelitis of probable demyelinating origin (Rocca et al. 2003e), and patients with Devic’s neuromyelitis optica (Rocca et al. 2004) suggests that not only brain, but also spinal cord pathology can induce cortical changes with the potential to limit the functional impact of the disease.

The following are the main findings supporting the adaptive role of functional cortical changes in MS:

a)An increased cortical recruitment with increasing T2 lesion load has been shown in patients with relapsing (Lee et al. 2000a; Pantano et al. 2002a; Rocca et al. 2002a), SP (Rocca et al. 2003c) and PP (Rocca et al. 2002b) MS.

b)The severity of intrinsic T2-visible lesion damage has been found to modulate the activity of some cortical areas. A strongly increased recruitment of the primary SMC has been shown to be correlated with the severity of lesion damage of the corticospinal tracts, measured using T1-weighted images (Pantano et al. 2002b) and with the whole brain average lesion MT ratio and mean diffusivity (Rocca et al. 2002a).

c)The severity of NABT damage,measured using 1H- MRS (Reddy et al. 2000b; Rocca et al. 2003b), MT MRI or DW MRI (Filippi et al. 2002c; Rocca et al. 2002a; Rocca et al. 2003c) is another important

Although the actual role of cortical reorganization on the clinical manifestations of MS remains unclear, the demonstration that MS patients may have a normal level of performance despite the presence of diffuse tissue damage suggests that cortical adaptive changes are likely to contribute in limiting the clinical consequences of MS-related structural damage (Filippi and Rocca 2003). The most compelling evidence that cortical reorganization may have a role in recovery from axonal damage derives from the study by Reddy et al. (2000a), who followed a patient after the onset of an acute hemiparesis and a new, large demyelinating lesion located in the corticospinal tract with serial 1HMRS and fMRI exams.In this patient,clinical recovery preceded complete normalization of NAA and was accompanied by increased recruitment of ipsilateral primary SMC and SMA. In line with these findings, in a group of patients who complained of fatigue when compared to matched non-fatigued MS patients,there was a reduced activation of a complex movement-as-

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sociated cortical/subcortical network, including the cerebellum,the rolandic operculum,the thalamus and the middle frontal gyrus (Filippi et al.2002b).In these patients, a strong correlation between the reduction of thalamic activity and the clinical severity of fatigue was found, indicating that a less marked cortical recruitment might be associated to the appearance of clinical symptomatology in MS. Preliminary work has shown that the pattern of movement-associated cortical activations in MS is determined by both the extent of brain injury and disability and that these changes are distinct (Reddy et al. 2002).

15.6 Conclusions

The application of modern MRI techniques to the assessment of MS patients has considerably improved our understanding of MS pathophysiology and has provided new objective metrics that might be useful to monitor disease evolution, either in natural history studies or in treatment trials. However, none of the quantitative MR-based techniques considered, taken in isolation, is able to provide a complete picture of the complexity of the MS process and this should call for the definition of aggregates of MR quantities, thought to reflect different aspects of MS pathology, to improve our ability to monitor the disease. At present, longitudinal natural history data collected in large samples of MS patients using structural, metabolic and functional MR techniques are needed to gain additional insight into MS pathobiology and on the actual value of modern MR technologies in the management of MS.

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CONTENTS

16.1Introduction 241

16.2.1General Features 242

16.2.2Neuropathology 244

16.2.3Imaging 244

16.2.4Differential Diagnosis 246

16.3.1General Features 246

16.3.2Neuropathology 246

16.3.3Imaging 247

16.3.4Differential Diagnosis 247

16.4.1General Features 247

16.4.2Neuropathology 248

16.4.3Imaging 248

16.4.4Differential Diagnosis 250

16.5Schilder’s Disease 250

16.5.1General Features 250

16.5.2Neuropathology 251

16.5.3Imaging 251

16.5.4Differential Diagnosis 251 References 252

16.1 Introduction

Around the turn of the last century, several unusual demyelinating conditions were described, including Devic’s disease (1894, neuromyelitis optica), Marburg disease (1906, acute multiple sclerosis, “encephalitis periaxialis diffusa”), Schilder disease (1912, recognized as a childhood variant of Marburg encephalitis periaxialis diffusa by Schilder) and

J. H. Simon, MD, PhD

Departments of Radiology, Neurology, Neurosurgery, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262, USA

B. K. Kleinschmidt-DeMasters, MD

Departments of Pathology, Neurology, Neurosurgery, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262, USA

Balo disease (1928, “encephalitis periaxialis concentrica,” concentric sclerosis, recognized by Balo to be similar to Marburg and Schilder diseases). All except Devic’s disease were considered by the original authors to represent rare, acute, and/or severe variants of multiple sclerosis (MS).

Debate raged almost immediately as to whether these represented unique demyelinating disorders or MS variants as the original author had often contended. Since several of these original reports were only single cases it took some time before sufficient numbers of patients were accrued by other workers, with tissues reviewed by neuropathologists at autopsy, to put these cases in proper perspective. Adding to the confusion was the fact that Schilder himself subsequently reported two more children with acute demyelinating disorders which he thought represented acute childhood MS, but which subsequently proved to be adrenoleukodystrophy and subacute sclerosing panencephalitis (Prineas et al. 2002).

There are valid differences of opinion as to how rigidly these terms, especially “Devic” and “Balo”, should be applied. Some workers use these eponymic designations when specific distribution patterns are predominantly, but not exclusively, present. An example of this would be the use of the term “Devic’s disease” for MS patients in whom the initial presentation was severe optic nerve and/or spinal cord disease, but who later in the course of the disease develop pathologically proven demyelinative plaques in other central nervous system (CNS) sites. A second instance is the use of these terms when the key variant feature is only minimally or focally present. An example of this would be the use of “Balo disease” for cases of large acute demyelinating lesions that may contain one or more “rings” by neuroimaging studies only in a single lesion, as opposed to the original use of the term which required widespread multiple concentric ring formation throughout cerebral hemispheres, as documented pathologically at autopsy. A final difference is those experts who favor use of