18 Demyelinating Diseases of the Spinal Cord Roland Bammer, Franz Fazekas,

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18 Demyelinating Diseases of the Spinal Cord

Roland Bammer, Franz Fazekas, and Siegrid Strasser-Fuchs

R. Bammer, PhD

Lucas MRS/I Center, Department of Radiology, Stanford, California, USA

F. Fazekas, MD

Department of Neuroradiology, Medical University Graz, Auenbruggerplatz 22, 8036 Graz, Austria

S. Strasser-Fuchs, MD

Department of Neurology, Medical University Graz, Auenbruggerplatz 22, 8036 Graz, Austria

CONTENTS

18.1 Introduction 269 18.2 Multiple Sclerosis 269

18.2.1 Acute Disseminated Encephalomyelitis 272 18.2.2 Neuromyelitis Optica 273

18.3 Transverse Myelitis 274

18.3.1 MRI Evaluation of Spinal Cord Damage in Relation to Function 275

18.4 Conclusion 276 References 277

18.1 Introduction

Magnetic resonance imaging (MRI) has opened a new window on the visualization of abnormalities associated with white matter diseases in the brain.

The contribution of MRI with regard to delineat- ing such disorders in the spinal cord is even more impressive considering the fact that MRI has been the fi rst technique to allow for a direct and detailed in vivo evaluation of morphological abnormalities of the spinal cord at all. Of course, MRI of the spinal cord still poses technical diffi culties and may thus be more variable in quality than MRI of the brain. Not all pulse sequences which contribute to our understanding of cerebral disorders can easily and equally be applied to this region of the body. The small size of the cord, its position within the dural sac surrounded by pul- sating cerebrospinal fl uid (CSF), and the motion of the body and its organs during the examination are all factors that may degrade image quality and have to be considered in the examination protocol. Also

signal intensities and resulting contrasts between tis- sue classes generated by conventional sequences are somewhat different from the brain due to the speciﬁ c texture of the cord. This is also relevant for the detec- tion of lesions within the cord and necessitates the choice of appropriate sequences. A recent review ad- dressed these technical aspects of spinal cord imag- ing especially with regard to multiple sclerosis (MS) as the most frequent demyelinating disease of the spinal cord (Lycklama et al. 2003).

Applying these techniques, characteristic MRI fi ndings can be elicited for a distinction between the various demyelinating disorders of the cord and their separation from other diseases which may also affect the spinal cord (Fazekas and Kapeller 1999; Bot et al. 2002). Herein we concentrate especially on the patterns which are typically seen with the different so-called idiopathic infl ammatory demyelinating disorders (Weinshenker and Miller 1998). Despite obvious specifi cs, it needs to be emphasized that the interpretation of MRI abnormalities must always take place in the context of clinical fi ndings and, where necessary, together with other biological (e.g. CSF) and electrophysiologic investigations (Transverse Myelitis Consortium Working Group 1999). In addition to primarily diagnosis-related issues, we also review current possibilities for a quantitation of spinal cord damage from demyelinating diseases es- pecially in relation to function, and we speculate on future prospects for the evaluation of this important part of the central nervous system by MRI.

18.2 Multiple Sclerosis

Multiple sclerosis most commonly causes distinct le- sions within the spinal cord (Fazekas et al. 1999; Bot et al. 2004). These lesions typically occupy less than half of the cross-sectional area of the cord and affect both white and grey matter (Tartaglino et al.1995;

Thielen and Miller 1996).

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With advancing disease focal MS lesions may merge to larger areas of high signal intensity (Fig. 18.4). A small proportion of MS patients also show only dif- fuse abnormalities of the spinal cord (Lycklama et al. 1997; Bot et al. 2004). These abnormalities consist mostly of a subtle increase of signal intensity on pro- ton-density-weighted images and have been observed especially in patients with high disability and a pri- mary progressive course of the disease (Lycklama et al. 1998). MRI–histopathological correlations have shown that both diffuse and focal signal hyperin- tensities in the spinal cord correspond primarily to demyelination (Nijeholt et al. 2001). Axonal dam- age, however, appears to occur largely independent of intramedullary T2-hyperintensities (Bergers et al.

2002a). This may also explain why a large proportion of spinal cord lesions obviously remain asymptom- atic and can at least partly account for reportedly dis- appointing correlations between clinical symptoms and imaging ﬁ ndings on conventional MRI of the spinal cord (Kidd et al. 1993; Lycklama et al. 1998;

O’Riordan et al. 1998; Brex et al. 1999).

Some investigators have found a prevalence of up to 30-40% of spinal cord lesions in patients with a

clinically isolated syndrome suggestive of MS, i.e. at the ﬁ rst clinical presentation of the disease, and even in those presenting with optic neuritis (O’Riordan et al. 1998; Brex et al. 1999). In patients with es- tablished MS, the prevalence of intramedullary le- sions increases to 80% and higher (Bot et al. 2004).

Including diffuse cord changes, probably more than 90% of MS patients have some form of spinal involve- ment at some point in their disease (Lycklama et al.

1998).

In later stages of MS and with advanced disabil- ity spinal cord atrophy becomes readily apparent as well. Volume changes of the spinal cord, although occurring much earlier, can otherwise be reliably established only by the use of exact measurement techniques as described below. Distinct focal areas of cord atrophy are rarely seen except following re- covery from very large MS lesions. Different from the brain, spinal cord lesions also do not evolve into so- called black holes, i.e. cystic lesions within the cord are not seen in typical MS. It is also common for the signal hyperintensity of spinal cord MS lesions to decrease over time, and together with the shrinkage of the lesion, causes them to disappear, or at least to

Fig. 18.1a–e. Patient with a second episode of spinal cord symptoms. A sensory level and gait ataxia correspond to an acute lesion at T10 which shows minimal swelling on T2 (b) and faint contrast enhancement (c). The lesion affects primarily the centre of the cord and the posterior tracts in a wedge-shaped manner (d,e). An old lesion at C3/C4 is barely seen (a)

a b c

d

e

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Fig. 18.2a–c. Patient with relapsing–remitting multiple sclerosis (MS). Multiple hyperintense intramedullary lesions without mass effect on T2-weighted fast-spin-echo images (a,b). One of the le- sions shows contrast enhance- ment (c)

Fig. 18.3a–d. Unusually large intramedullary lesion with marked oedema (a) and con- trast enhancement (c,d) in a patient who subsequently developed clinically deﬁ nite MS

a b c

a b

c d

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become very difﬁ cult to detect on routine follow-up scanning (Fig. 18.2).

Formal integration of spinal cord MRI ﬁ ndings in MS into current diagnostic criteria may still be viewed as suboptimal (McDonald et al. 2001; Bot et al. 2004;

Miller et al. 2004). Earlier limitations regarding MRI examinations of the spinal cord at a high resolu- tion with reproducibly good quality and a paucity of data regarding the diagnostic and prognostic value of the demonstration of MS lesions in the cord made the International Panel simply state that “one spinal cord lesion can be substituted for one brain lesion”

(McDonald et al. 2001). Whether this substitution simply is additive to the number of total brain lesions or could also serve to fulﬁ l the requirement of an in- fratentorial lesion, as deﬁ ned by Barkhof ’s criteria, remains unclear. Similarly, the proposed diagnostic criteria for primary progressive MS have remained somewhat vague (Thompson et al. 2000; McDonald

et al. 2001) but recognise the higher speciﬁ city of spi- nal cord lesions compared with brain lesions, as they do not occur with ageing per se (Thorpe et al. 1993).

In addition to previous recommendations on the role of spinal cord MRI in the algorithm for MS diagno- sis, which focussed primarily on the need to rule out other disorders (Fazekas et al. 1999), recent data also conﬁ rm a higher probability to prove disease dis- semination in space by such examination. In a cohort of 104 patients with newly diagnosed MS, Bot et al.

(2004) found that substitution of one spinal cord le- sion for one brain lesion increased the sensitivity of the McDonald’s dissemination in space criteria from 66 to 85%, and it reached 94% when allowing for an unlimited substitution of brain lesions by spinal cord lesions. In a more selective manner such contribution has already been reported previously for patients with suspected MS, but no or only very few cerebral lesions (Thorpe et al. 1996b). Whether evidence for spinal cord lesions also conveys some prognostic in- formation is still a matter of debate (Lycklama et al. 2003).

18.2.1 Acute Disseminated Encephalomyelitis

By deﬁ nition, acute disseminated encephalomyelitis (ADEM) is a monophasic demyelinating disorder which usually follows a viral infection (Wingerchuk 2003) or vaccination. Children are more frequently affected than adults. The MRI ﬁ ndings in the brain consist of multiple, frequently large lesions with perifocal oedema and contrast enhancement as evi- dence of their acute nature. Lesions can involve the cerebral white matter as well as the basal ganglia, the brain-stem and cerebellum and, according to their appearance and distribution, have been categorized into different patterns including a haemorrhagic variant (acute haemorrhagic encephalomyelitis;

Tenenbaum et al. 2002). As part of the central ner- vous system, the spinal cord can also be involved.

In comparison with MS, ADEM lesions of the spi- nal cord are typically larger and more oedematous (Fig. 18.5).The clinical presentation following a po- tentially triggering event and the absence of oligo- clonal bands should point towards such a diagnosis.

A corresponding MRI of the brain with multiple, exclusively acute-appearing lesions is also very sug- gestive of ADEM (Fig. 18.5).The notion that normal- appearing brain white matter of ADEM patients is truly unaffected (Inglese et al. 2002), while in con- trast more severe damage is found in the basal gan-

Fig. 18.4 Conﬂ uence of intramedullary lesions in a patient with secondary progressive MS

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glia (Holtmannspötter et al. 2003), may also help to differentiate ADEM from MS. In individual cases, however, this may still be difﬁ cult, at least in the early stages (Dale et al. 2000; Tenenbaum et al. 2002).

Contrast enhancement needs not to occur absolutely simultaneously in all lesions caused by ADEM. At the same time, contrast enhancement of both lesions in the brain and spinal cord is not uncommon for MS, as mentioned previously (Thorpe et al. 1996a).

With more advanced MS, however, there is almost always a larger proportion of non-enhancing lesions, with some appearing as T1 hypointensities or so- called black holes, that strongly argue against ADEM.

Nevertheless, in many instances clinical and imaging follow-up is necessary to make a ﬁ nal diagnosis from the absence of further disease activity, although it is known that a second bout of ADEM may also occur (Tenenbaum et al. 2002).

18.2.2 Neuromyelitis Optica

Neuromyelitis optica (NMO), or Devic’s syndrome, is a severe form of idiopathic infl ammatory demy- elinating disease and is increasingly considered as a separate entity (Weinshenker 2003). The specifi c features include its topographic restriction to the op- tic nerve and spinal cord, and a greater attack sever- ity than MS (Wingerchuk et al. 1999). This is also refl ected by much more extensive spinal cord lesions on MRI than those seen in MS (Fig. 18.6). These le- sions usually involve large segments of the cord with diffuse swelling and extensive contrast enhancement.

The necrotising character of this type of demyelin- ation is also evidenced in the post-acute phase by the frequent occurrence of cystic areas within the cord together with severe focal or diffuse atrophy as

Fig. 18.5a–f. Patient presenting with rapidly progressing multifocal neurological symptoms shortly after an upper respiratory tract infection. Multiple hyperintense intramedullary lesions were seen on T2-weighted scans of the spinal cord (a) and tended to markedly enhance following the application of Gd-DTPA (b). A similar but more diverse lesion pattern was also seen on MRI of the brain (c,d T2-weighted scans; e,f corresponding contrast-enhanced scans). The patient fully recovered and for the next years experienced no further bouts of disease, supporting the diagnosis of acute disseminated encephalomyelitis

a b e

c d

f

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indicators of extensive tissue destruction (Figs. 18.6, 18.7).

In terms of disease evolution, it is important to note that NMO can have both a monophasic and a relapsing course. In a review of 70 patients with NMO at the Mayo Clinic, patients with a monopha- sic course usually presented with rapidly sequential index events with moderate recovery. Two thirds of patients, however, presented with an extended inter- val between index events followed within 3 years by clusters of severe relapses isolated to the optic nerves and spinal cord. In these patients severe disability developed in a stepwise manner; thus, a prolonged interval between damage to the spinal cord and op- tic nerves does not rule against a diagnosis of NMO (Wingerchuk et al. 1999).

Absence of brain MRI changes is a hallmark ﬁ nd- ing of NMO and part of the diagnostic criteria for this disorder [30]. Unaffected brain white matter has also been shown in one study using magnetisation

transfer (Filippi et al. 1999). Non-speciﬁ c abnormali- ties, however, do not preclude a diagnosis of NMO.

18.3 Transverse Myelitis

Acute transverse myelitis can be caused by a number of bacterial, viral, fungal or parasitic infections, by connective tissue diseases, such as sarcoidosis, Behçet’s disease, Sjögren’s syndrome, systemic lu- pus erythematosus, antiphospholipid syndrome, and mixed connective tissue disease, and can be the presenting feature of NMO and less likely also of MS (Transverse Myelitis Consortium Working Group 2002). In rare cases no aetiology can be de- ﬁ ned, and it may therefore be suggested to group such disorders under the umbrella of the idiopathic inﬂ ammatory demyelinating disorders as well. Some

Fig. 18.6a–d. A 25-year-old patient with recurrent spastic paraparesis and complete visual loss of the left eye. The mid-thoracic spinal cord is diffusely swollen and hyperintense (a). Slight enhancement after application of contrast material surrounding and above intramedullary areas with signal isointense to cerebrospinal ﬂ uid consistent with necrotising inﬂ ammation (b–d). Magnetic resonance imaging of the brain was normal and there was no evidence of oligoclonal bands

a b d

c

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reports and our own experience suggest a similarity of spinal cord abnormalities with those observed in NMO. This has been especially true for patients with relapsing acute transverse myelitis (Fig. 7; T. Seifert et al., submitted). Support for this hypothesis comes from the fact that some of the patients with relapsing transverse myelitis subsequently also developed optic neuritis but otherwise showed a normal or at least non-speciﬁ c MRI of the brain (Katz and Ropper 2000). Marked inﬂ ammatory CSF changes and the ab- sence of oligoclonal bands are also more commonly found in this type of spinal cord disorder than with MS (Transverse Myelitis Consortium Working Group 2002).

18.3.1 MRI Evaluation of Spinal Cord Damage in Relation to Function

Spinal cord lesions do correlate with spinal cord symptoms as shown in cross-sectional and follow- up studies (Thorpe et al. 1996a; Lycklama et al.

1998); however, the relationship between a patient’s symptoms and spinal cord ﬁ ndings frequently re- mains limited. The reasons for this are manifold. As in the brain, conventional MRI cannot serve to grade the severity of axonal destruction within lesions or

Fig. 18.7 Patient with recurrent transverse my- elitis. Note the swelling and enhancement of the cervical portion of the spinal cord as evidence of acute inﬂ ammation in comparison with the atrophic thoracic portion with diffuse signal ab- normality from previous inﬂ ammation

display other factors which may impact on function- ing also at non-morphological levels (Caramia et al.

2004). In addition, it is even more difﬁ cult to quantify the total extent of damage in the spinal cord than in the brain. This has also been seen in histopathologi- cal comparisons where the actual spinal cord damage was frequently much more pronounced than would have been expected from imaging alone (Bergers et al. 2002b). Finally, quantiﬁ cation of tissue loss, i.e. of spinal cord atrophy, is also not satisfactory by visual analysis. For this reason it has been attempted to use various MRI metrics for the global description of spinal cord damage from demyelinating diseases, especially in MS.

Much work has been done on the measurement

and longitudinal follow-up of spinal cord atrophy

(Zivadinov and Bakshi 2004). Measuring the cross-

sectional size of the spinal cord, however, always has

to be performed at the exactly same cervical level,

and various technical problems may cause signiﬁ cant

variance in the measurements. With the appropriate

techniques, however, longitudinal follow-up can show

small but statistically signiﬁ cant decreases in spinal

cord area (Stevenson et al. 1998) and a relatively

strong relationship between degree of spinal cord at-

rophy and EDSS values has been reported (Losseff

et al. 1996). Especially in primary progressive MS,

atrophy measurements may be more important in

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relation to function than those of lesion volumes (Ukkonenen et al. 2003).

In the brain, magnetisation transfer imaging (MTI) has shown the capability of detecting white matter abnormalities not accessible with conventional MRI (Filippi 2003). It was therefore speculated that this technique should also allow delineation of diffuse changes of the spinal cord from and independent of focal abnormalities. First studies in relatively small cohorts of patients conﬁ rmed that the cervical cord of MS patients had lower MTR values than those of controls (Inglese et al. 2002). Histogram analyses, however, showed that compared with control sub- jects patients with relapsing, -remitting MS had simi- lar cervical cord MTR histogram-derived measures, whereas those with primary progressive and second- ary progressive MS had abnormal MTR histograms (Filippi et al. 2000). More importantly, the cervical cord MTR histogram parameters were independent predictors of loco-motor disability. A further study conﬁ rmed that MTR metrics do not differ between primary and secondary progressive MS, and they also appear to be independent of the cerebral lesion load (Rovaris et al. 2000, 2001).

With technical advances it has also become pos- sible to apply diffusion-weighted MRI (DWI) to the spinal cord (Bammer et al. 2002; Clark and Werring 2002). A preliminary study assessed water diffusion in seven cord lesions of three MS patients with loco-motor disability and found in- creased diffusivity compared with healthy volun- teers (Weeler-Kingshott et al. 2002); however, for the individual patient no useful contribution can yet be expected from DWI, and especially in the early phase of MS only very subtle changes appear detectable (Mezzapesa et al. 2004). The develop- ment of techniques which allow to incorporate trac- tography into spinal cord MRI may be an important next step. Currently, DWI of the spinal cord still faces signiﬁ cant technical challenges that can limit the reproducibility of quantitative measurements.

Speciﬁ cally, motion of the patient and the cord it- self, and the inhomogeneous magnetic environment within and around the spinal column, can cause del- eterious artefacts.

Magnetization transfer imaging and DWI promise to provide complementary biophysical information about microstructural changes of the spinal cord.

While MT is more targeted to the chemical–struc- tural environment of the myelin sheath, DWI probes for potential changes in the micro-environment that may impair or facilitate the mobility of protons. In combination or individually these two biophysical

mechanisms can help to provide insight and improve contrast beyond conventional MRI methods.

Recent technological developments in MR hard- ware, especially improved radio-frequency (RF) coils and higher fi eld strengths, have furthered MRI’s ca- pability to image the spinal cord at highest spatial resolution. At numerous centres, neuroimaging is currently migrating from 1.5 to 3 T or even higher, trying to capitalize on the increased signal strength afforded by the stronger magnetic fi eld. Here, es- pecially for the spinal cord, the excessive signal-to- noise ratio can be invested in greatly improved spa- tial resolution. In combination with dedicated spine arrays, this strategy allows imaging of the entire spi- nal cord at once and at a higher spatial resolution, which should defi nitely impact diagnostic sensitivity and also specifi city.

One issue associated with higher fi eld strength that has to be kept in mind is the increased energy deposi- tion in the patient’s body, especially when transmitting with the large-body-volume coil. This can have major implications for pulse sequences with relatively high RF duty cycles, such as MT sequences. Fortunately, if only the spine needs to be imaged, its unique location in the body allows for the use of transmit/receive coils which demonstrate much fewer problems with energy deposition. Thus far, only little has been reported on the overall benefi ts of using higher magnetic fi elds in demyelinating diseases, especially when focused on the spinal cord. One should also be aware that the T1 relaxation times of semi-solid tissues changes with fi eld strength, while CSF remains almost unchanged;

therefore, certain adaptations in pulse sequence are mandatory to maintain contrast properties, and the altered relaxation properties should be kept in mind when interpreting/comparing studies performed at different ﬁ eld strengths.

18.4 Conclusion

Magnetic resonance imaging of the spinal cord pro-

vides characteristic patterns of abnormalities in dif-

ferent demyelinating diseases. It has to be recognised,

however, that other aetiologies may mimic these ab-

normalities and have to be considered in the dif-

ferential diagnosis as described elsewhere (Fazekas

and Kapeller 1999; Bot et al. 2002). On the other

hand, the recognition of spinal cord abnormalities as

a consequence of demyelinating diseases makes an

important contribution to their diagnosis. Future de-

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velopments also promise to generate insights beyond these diagnostic contributions in terms of informa- tion relevant for function and repair.

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