Multiple Sclerosis and Related Disorders (2014) 3, 284–293
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The role of imaging in diagnosing neuromyelitis optica spectrum disorder Lucy A. Matthewsa,b,n, Jacqueline A. Palacea,b a
Oxford University Hospitals NHS Trust, United Kingdom Nufﬁeld Department of Clinical Neurosciences, University of Oxford, United Kingdom
Received 13 May 2013; received in revised form 31 October 2013; accepted 14 November 2013
Neuromyelitis optica; Multiple sclerosis; MRI; Imaging
Early identiﬁcation of neuromyelitis optica allows aggressive acute and prophylactic relapse management aimed at preventing disability. Since the discovery of pathogenic aquaporin-4 antibodies the neuromyelitis optica spectrum has widened signiﬁcantly: brain lesions no longer preclude the diagnosis and there are reports of symptoms of cerebral origin presenting as the ﬁrst manifestation of the condition, prior to optic nerve or spinal cord disease. Deﬁning antibody negative neuromyelitis optica, and distinguishing it from other inﬂammatory disorders such as multiple sclerosis can therefore be a challenge. In this review we discuss the role of conventional imaging in the diagnosis of neuromyelitis optica, and the scope of quantitative MRI modalities to identify more speciﬁc pathophysiological features to aid in the differentiation from other conditions and assess treatment response. & 2013 Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 Conventional MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 2.1. Spinal cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 2.2. Optic nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 2.3. Brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 Non-conventional MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 3.1. Diffusion tensor and Magnetisation Transfer Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 3.1.1. Spinal cord DTI and MTR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 3.2. Magnetic resonance spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 3.3. Volumetric imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 3.4. Functional MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
Correspondence to: Department of Neurology, Level 3 West Wing, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom. Tel.: +44 1865 222799. E-mail address: [email protected]
(L.A. Matthews). 2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.11.003
Role of imaging in diagnosis of neuromyelitis optica 4. Future challenges . . . . . . . . . . . . . . . . . . . . . . . . . 5. Summary: useful imaging discriminators that favour NMO Conﬂicts of interest and funding statements. . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Neuromyelitis optica (NMO) is an autoimmune demyelinating condition with a speciﬁc biomarker—serum antibodies against the aquaporin-4 water channel, which are present in up to 77% with the diagnosis (Lennon et al., 2004, 2005; Waters et al., 2012). There is an overlap in the early clinical features of NMO and MS (optic neuritis, myelitis, cerebral symptoms) but follow-up of patients with NMO has revealed a high morbidity and mortality linked to its relapse related disability and progressive deterioration between relapses is exceedingly rare (Wingerchuk et al., 2007, 2006; Merle et al., 2007). Therefore unlike MS rapid treatment of relapses is vital (Sellner et al., 2010), and aggressive immunosuppression to prevent relapses should be initiated at the time of diagnosis (Wingerchuk, 2007). Additionally β-interferon, a disease modifying therapy commonly used in MS, can worsen NMO (Palace et al., 2010). Early and accurate diagnosis is therefore very important. There are recent reports of patients with AQP4 antibodies who present atypically with brain symptoms prior to any optic nerve or spinal cord involvement (Kim et al., 2011; Apiwattanakul et al., 2010; McKeon et al., 2008), and limited forms of the disease such as recurrent severe optic neuritis and transverse myelitis (Matthews et al., 2009; Waters et al., 2008). We therefore commonly use the term NMO spectrum disorder (NMOSD) to encompass all of these phenotypes. Clearly it can be difﬁcult to deﬁne the boundaries of antibody negative NMOSD and in particular to differentiate it from MS. There is clinical need for other differentiating biomarkers, not only to identify seronegative NMOSD but also to assess the sensitivity of aquaporin-4 antibody assays and to enable us to monitor the effectiveness of treatments in clinical practice and trials. The following review discusses the role of conventional MRI and the potential of quantitative measures in the diagnosis of NMOSD.
The conventional imaging features of NMOSD are summarised in Table 1, and Figs. 1 and 2.
The conventional MRI appearances for a patient presenting with an MS-like illness provide a strong clue that they may have NMOSD. Longitudinally extensive (i.e., greater than three vertebral segments in length) spinal cord lesions, which can be visualised as high signal on T2 weighted spinecho MRI, form part of the 2006 revised diagnostic criteria for NMO (Fig. 1a) (Wingerchuk et al., 2006). They have high sensitivity and speciﬁcity, and are currently the most important MRI marker of NMOSD and should prompt testing for aquaporin-4 antibodies. In the acute stage these lesions
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may be associated with gadolinium contrast enhancement and probable cord swelling (Wingerchuk et al., 1999; de Seze et al., 2002). Shorter lesions can be seen either early in a relapse (in the ﬁrst days) or in patients who have had other attacks with longitudinally extensive lesions (Krampla et al., 2009). Consequently imaging during the established relapse phase is important. MS is characterised by short and often multiple spinal cord lesions or diffuse changes particularly in the later stages (Bot et al., 2004). In large cross-sectional Dutch and Australian studies of multiple sclerosis spinal cord imaging the prevalence of longitudinally extensive T2 signal change is estimated at 2.9% and 2.3% respectively (Bot et al., 2004; Qiu et al., 2010), and is very exceptionally a presenting feature (4/574 patients in the Qiu et al., 2010 study). T1 hypointensity has been reported during the acute phase of NMO transverse myelitis but is not usually seen in MS (Miller et al., 2008; Downer et al., 2012). Asymptomatic spinal lesions are a feature of MS but not recognised in NMO (O'Riordan et al., 1998). NMOSD spinal lesions, like those found in MS, are most often located in the cervical cord (Wingerchuk et al., 2006, 1999; de Seze et al., 2002). Extension of these lesions superiorly into the medulla is a feature of NMOSD (Wingerchuk et al., 2006; de Seze et al., 2002), and has been found to be highly predictive (Lu et al., 2010). Axial T2 weighted MRI commonly, but not invariably, reveals NMOSD lesions to be centrally located (Fig. 1b) (Krampla et al., 2009; Nakamura et al., 2008). This is in contrast to MS where lesions are more often found in the lateral white matter (Nakamura et al., 2008). The central location of NMOSD lesions corresponds to sites of high aquaporin-4 water channel concentration i.e., in the spinal grey matter (as shown in immunopathological studies) (Roemer et al., 2007). Nakamura et al. (2008) demonstrated that over 60% of NMO spinal lesions occupied the central grey matter in the acute stage, compared to less than 20% of MS lesions on conventional cervical and thoracic spinal imaging. The important message is that the length of the spinal cord lesion on clinical MRI can be a very useful diagnostic aid. It helps distinguish between MS and NMOSD but it is not absolute, because in addition to the rare appearance of long lesions in MS, short lesions have been described in seropositive NMO (Krampla et al., 2009). LETM has also been reported in systemic lupus erythematous (SLE), Sjogren's syndrome and related to infectious myelitis and parainfectious idiopathic transverse myelitis (Kitley et al., 2012) However the observed coexistence of other autoantibodies and antibody mediated conditions in patients with NMO may explain LETM in Sjogrens syndrome and SLE (Pittock et al., 2008)) Hence all patients with LETM should be tested for serum AQP-4 antibodies; where negative the differential becomes wider, and without biopsy and pathological examination differentiating an MS phenotype with LETM from AQP4ab negative NMOSD presents a dilemma because there are no other speciﬁc diagnostic tools.
L.A. Matthews, J.A. Palace
Conventional MRI Findings in NMO. Imaging sequence
Spinal Sagittal T2 spin echo cord
Longitudinally extensive (greater than three
Sagittal T1 spin echo
Post gadolinium T1
Orbits Fat suppressed T2 spin echo
Post gadolinium T1
T2 weighted spin echo/proton density/ﬂuid attenuated T2
vertebral segments) increased signal indicative of lesion (majority located in cervical or thoracic cord; Fig. 1a) (Wingerchuk et al., 2006, 1999) Cervical spinal lesions extending into medulla (Wingerchuk et al., 1999; Lu et al., 2010) Cord swelling ( 50%; Fig. 1a) (Wingerchuk Lesions that extend over less than et al., 1999; de Seze et al., 2002) 3 vertebral segments (Krampla et al., Spinal lesions are symptomatic 2009) T1 hypointensity within acute lesions (Miller et al., 2008) T1 hypointensity and atrophy at site of chronic lesions (Fig. 1c) (Wingerchuk et al., 1999; de Seze et al., 2002; Krampla et al., 2009) Lesions centred on grey matter ( 60%, Fig. 1b) (Krampla et al., 2009; Nakamura et al., 2008) White matter lesions (Nakamura et al., 2008) Contrast enhancing lesions during/shortly after relapse (up to 64%) (Wingerchuk et al., 1999; de Seze et al., 2002)
Hyperintensity within optic nerve, which can extend to chiasm, during optic neuritis (Wingerchuk et al., 1999; Li et al., 2008) Chronic optic nerve atrophy Chronic optic nerve sheath thickening (Li et al., 2008) Gadolinium enhancement of optic nerves and chiasm during and shortly following optic neuritis ( 83%) (Wingerchuk et al., 1999; Li et al., 2008)
Non-speciﬁc deep white matter/subcortical
hyperintensities (prevalence 55–82%; Fig. 2d) (Pittock et al., 2006a; CabreraGomez et al., 2008; Matthews et al., 2013) Typical for NMO i.e., distributed in areas of high AQP4 expression e.g., periventricular grey matter ( 7%; Fig. 2a–c) (Pittock et al., 2006a, 2006b; Kim et al., 2011) Medullary lesions contiguous with spinal cord lesions (Wingerchuk et al., 1999; de Seze et al., 2002) Conﬂuent/hemispheric (Pittock et al., 2006a; Kim et al., 2011) Odematous/tumefactive (particularly in children) (McKeon et al., 2008; Ikeda et al., 2011) Lesions which satisfy MS diagnostic criteria Linear or round periventricular/corpus callosum signal abnormality, but not ovoid, at onset ( 5%) (Pittock et al., 2006a) Cortical lesions (Pittock et al., 2006a; and not in Dawson ﬁnger conﬁguration Isose et al., 2011) (Miller et al., 2008; Matthews et al., 2013)
Role of imaging in diagnosis of neuromyelitis optica
Table 1 (continued ) Imaging sequence
Post gadolinium T1
T1 hypointensity and atrophy in chronic lesions (Kim et al., 2011) Symptomatic contrast enhancing lesions (Pittock et al., 2006a) Contrast enhancement can be “cloud like” in appearance (Ito et al., 2009)
Case reports of asymptomatic contrast enhancing lesions at the time of an optic nerve/spinal cord relapse (Kim et al., 2011; Cabrera-Gomez et al., 2008)
Fig. 1 (a) Acute longitudinally extensive transverse myelitis in an AQP-4 antibody positive patient visualised on a sagittal T2 MRI. Note the cord swelling. (b) Axial gradient echo showing a centrally located NMO lesion at C3 vertebral level involving both grey and white matter. MS lesions can also be found to involve the grey matter, an example is shown (C5 vertebral level). (c) T1 hypointensities (black holes) in a seropositive NMO patient, at the site of a residual myelitic lesion seen on T2.
Optic neuritis is a common feature of NMO and compared to that seen in MS has a poorer prognosis in terms of functional recovery (Merle et al., 2007; Wingerchuk et al., 1999; Pirko et al., 2004). It is also more commonly bilateral (Wingerchuk et al., 1999). The literature on optic nerve MRI features speciﬁc to NMOSD is lacking: during an inﬂammatory optic neuritis of any cause there can be high signal within the optic nerve on a fat-suppressed T2 weighted scan, gadolinium contrast enhancement and in the longterm atrophy of the affected optic nerve occurs (Kidd et al., 2003; Rizzo III et al., 2002; Wang et al., 2011). Contrast enhancement post optic neuritis can last for at least 30 days (Hickman et al., 2004)). Bilateral optic nerve enhancement with extension to the optic chiasm should alert the clinician to the possibility of NMOSD (Li et al., 2008). Li et al. (2008) reported optic nerve sheath thickening in NMOSD patients with previous recurrent optic neuritis. There is a growing body of evidence that NMOSD is restricted to lesions and does not feature the widespread neurodegeneration associated with MS. Interestingly MR signal abnormalities have been found in the optic nerve of patients with MS who have not been affected by optic neuritis (Miller et al., 1988); this has not been reported in NMOSD.
NMOSD is deﬁned by the presence of serum AQP4 antibodies, and the discovery of this biomarker has revealed the true frequency and nature of brain lesions associated with the condition. It has now been widely published that over time the prevalence of NMO patients (who fulﬁl the Mayo clinic 2006 criteria) with lesions on brain MRI is greater than 50% (McKeon et al., 2008; Downer et al., 2012; Li et al., 2008; Pittock et al., 2006a; Kim et al., 2011). A normal brain MRI at onset is unusual for MS (Miller et al., 2008; Polman et al., 2011). In NMO, brain MRI is more likely to be normal the closer it is performed to the initial symptoms (Wingerchuk et al., 1999; Pittock et al., 2006a). Pittock et al. (2006a) documented that 52% of 27 patients with NMO who were imaged within 6 months of their ﬁrst symptoms had an abnormal brain MRI. NMO typical lesions have been described in approximately 7% of patients (Pittock et al., 2006b). These include signal change in areas of high aquaporin-4 expression, namely the brainstem, hypothalamus and in the periependymal tissue bordering the lateral, third and fourth ventricles, and the Sylvian aqueduct (Fig. 2a–c) (Downer et al., 2012; Pittock et al., 2006a, 2006b; O’Riordan et al., 1996; Poppe et al., 2005). Lesions in the area postrema are indicative of NMO (Downer et al., 2012; Popescu et al., 2011). T2 hyperintensities within the corpus callosum are also frequent (Pittock et al.,
L.A. Matthews, J.A. Palace
Fig. 2 (a) “Typical” NMO brain lesions, shown as hyperintensities on T2 FLAIR, bordering the Sylvian aqueduct, 4th ventricle and lateral ventricles. There are also lesions within the medulla oblongata and corpus callosum, and a large hemispheric white matter lesion that has been biopsied. The patient is AQP-4 antibody positive. (b) Lesion adjacent to the 4th ventricle visualised on axial FLAIR in an AQP4-ab positive patient. (c) Large periventricular lesion extending into the white matter in a seropositive NMO patient. There is a corresponding area of T1 hypointensity. Note also the non-speciﬁc deep white matter lesions. (d) Atypical deep white matter/subcortical brain lesions in two seropositive NMO patients. (e) MS-like brain lesions in a seropositive NMO patient who fulﬁls Barkhof's MRI criteria for MS.
2006a; Nakamura et al., 2009). The commonest brain abnormality however is non-speciﬁc deep or subcortical white matter lesions, which are found in approximately 55–82% of patients on long-term follow-up (Fig. 2d) (Pittock et al., 2006a; CabreraGomez et al., 2008; Matthews et al., 2013). MS-like lesions have been reported in 5–6% on initial imaging (Downer et al., 2012; Pittock et al., 2006a), and 10–16% on the last available scan (Pittock et al., 2006a; Matthews et al., 2013). Several studies have investigated whether brain lesion distribution can distinguish NMO from MS (Downer et al., 2012; Li et al., 2008; Pittock et al., 2006a; Matthews et al., 2013; Matsushita et al., 2010). Pittock found that 66% of NMO patients (4 of 6 patients) with MS-like brain lesions fulﬁlled Barkhof's MRI criteria for MS (an example is shown in Fig. 2e) (Pittock et al., 2006a; Barkhof et al., 1997).
However Dawson's ﬁngers (ovoid lesions perpendicular to the lateral ventricles) and s-shaped U-ﬁbre lesions have been found to be very unusual in seropositive NMO (Downer et al., 2012; Matthews et al., 2013). Particular caution should be observed with antibody negative patients, as the current NMO diagnostic criteria would favour against the diagnosis if they fulﬁl MS MRI criteria at onset (Downer et al., 2012). As in MS, NMO lesions can show gadolinium contrast enhancement especially during relapse (Kim et al., 2011; Cabrera-Gomez et al., 2008; Ito et al., 2009). A particular “cloud-like” pattern of enhancement has been described as well as accompanying oedema (Ito et al., 2009). Tumefactive, enhancing and symptomatic brain lesions are particularly prevalent in the paediatric population (McKeon et al., 2008).
Role of imaging in diagnosis of neuromyelitis optica
Clinical or conventional MRI sequences (i.e., T1 weighted imaging, spin echo T2 and gadolinium enhanced T1) are sensitive means of screening for inﬂammatory demyelinating central nervous system disease. However signal change abnormalities on T2 imaging are non-speciﬁc and give little information about the underlying pathophysiology. For example T2 signal reﬂects water content, which may be altered with oedema, demyelination or axonal damage. In the challenge of ﬁnding a consistent diagnostic imaging marker for NMOSD and a method of measuring disease activity to monitor therapies, conventional MRI falls short. Non-conventional approaches to MRI, where the signal is harnessed quantitatively, are able to give information more speciﬁc to pathological processes and to assess change over time. Such techniques have been extensively applied to MS and have demonstrated that even in areas of the MS brain that appear normal on conventional imaging there are diffuse abnormalities (Tortorella et al., 2006; Larsson et al., 1992; Grifﬁn et al., 2001). In contrast to MS, NMO tends to cause severe symptomatic inﬂammatory damage (usually of the optic nerve or spinal cord) and is not associated clinically with a progressive phase Wingerchuk et al., 2007. It is hence anticipated that NMO should not be associated with either diffuse normal appearing white matter damage (away from tracts affected by lesions) or progressive changes outside of relapses. Therefore characterising the normal appearing brain tissue and assessing change over time could provide a useful method of diagnostic distinction. The next section of this review discusses a selection of studies that have applied these techniques to NMO.
3.1. Diffusion tensor and Magnetisation Transfer Imaging Diffusion MRI and Magnetisation Transfer Imaging (MTI) provide in-vivo quantitative measurements of tissue structure not detected on standard imaging. The underlying principles of DTI and MTI are discussed elsewhere. Two indices used to describe the diffusion properties of tissue are fractional anisotropy (FA), where a reduction in FA represents a reduction in the directionality of white matter tracts often interpreted as a reduction in tissue integrity, and mean diffusivity (MD), where an increase in MD represents less restriction to the diffusion of water molecules and therefore is also interpreted as a reduction in tissue integrity. Magnetisation transfer ratio (MTR) is the commonly used measure in MTI. MRI research investigating whether there are occult abnormalities in the normal appearing brain tissue of NMO patients, using DTI and MTI, has shown variable results. The ﬁrst quantitative imaging study by Filippi et al. (1999) demonstrated no group differences in the normal appearing brain tissue MTR between eight NMO patients compared to healthy controls, whereas they did ﬁnd a difference when comparing MS patients to controls. Later the same research group were able to identify reduced MTR and increased MD within the grey matter when compared to controls, but no signiﬁcant difference in the white matter (Rocca et al., 2004a). Yu et al. (2006) also found abnormalities within the normal appearing brain tissue, but in
289 contrast reported changes in the white matter with low FA, and elevated MD within the region of the optic and corticospinal tracts. Conversely in the region of the corpus callosum they showed no signiﬁcant difference between NMO and control DTI indices, and in a subsequent publication suggested that NMO and relapsing remitting MS (RRMS) could be differentiated using these corpus callosum values, as they were signiﬁcantly lower in the RRMS group (Yu et al., 2007). Further work showed correlation between disability scores measuring visual and pyramidal function, and the optic and corticospinal tract diffusion measures respectively (Yu et al., 2008). The authors postulated this was due to Wallerian degeneration secondary to a lack of sensory input. Consistent with these ﬁndings are those of a more recent study by Pichiecchio et al. (2012) that utilised a method known as Tract-Based Spatial Statistics (TBSS) (Smith et al., 2006), aimed at improving the sensitivity and reliability of multi-subject DTI studies, and found localised reductions in FA in the optic radiations. In this study 4 of 7 patients were aquaporin-4 antibody seropositive. Using the same method of DTI analysis (TBSS) Liu et al. published a study in the same year (2012) that reported a widespread signiﬁcant increase in the diffusion indices MD, λ1 and λ23 in the white matter of patients with clinically deﬁned NMO when compared to controls (Liu et al., 2012). Although a relatively large group of NMO patients was recruited (n=27), neither aquaporin-4 antibody nor NMO-Ig testing was available to the authors. It is not clear whether lesioned tissue was excluded from this latter study. Although more comparative data between NMO and MS is required, the results of the majority of these studies may indicate that a lack of diffuse white matter DTI abnormalities suggests a diagnosis of NMO rather than MS. 3.1.1. Spinal cord DTI and MTR The spinal cord has to date been relatively poorly studied with quantitative imaging techniques due to the challenges presented by its size and acute sensitivity to motion such as cardiac pulsation and respiration. In one of the few existing studies fractional anisotropy was reduced in the dorsal and lateral white matter of the NMO cervical spinal cord in 10 antibody positive patients, which correlated with disability (Qian et al., 2011). Filippi et al. (1999) also studied the MTR of the upper cervical cord in their 1999 study, and found reduction within lesioned spinal cord that was indistinguishable from the changes found in lesioned MS spinal cord.
Magnetic resonance spectroscopy
Proton or magnetic resonance spectroscopy (MRS) measures the MR signal from hydrogen-bound neural metabolites and quantiﬁes the biochemical constitution of tissues. In support of the hypothesis that NMOSD is lesion focused and spares the normal appearing brain tissue, the metabolite n-acetyl aspartate (NAA; a surrogate marker of neural integrity) as a ratio to creatine was at normal levels when measured over multiple voxels positioned in the deep white matter in a group of 8 seropositive NMOSD patients (Aboul-Enein et al., 2010). The research also demonstrated normal choline: creatine ratios. This result was reproduced in a larger study of 24 patient showing, as well, normal myoinositol:creatine ratio (de Seze et al., 2010). Conversely NAA has been found
L.A. Matthews, J.A. Palace
to be consistently low in the normal appearing brain tissue of MS patients (Chard et al., 2002; Davie et al., 1997)). Thus normal NAA levels in the normal appearing white matter may be in favour of NMO versus MS. Ciccarelli et al. (2013) have recently reported that in ﬁve NMO patients with LETM lower myo-inositol/creatine values were found within NMO spinal cord lesions, when compared to healthy control spinal cord tissue and MS spinal cord lesions. Myo-inositol is thought to be a surrogate marker of astrocyte density, therefore a relatively lower concentration in NMO lesions may be expected due to the autoimmune attack of aquaporin-4 water channels, which are situated on astrocytic foot processes.
Structural MRI, particularly if acquired with a three dimensional sequence, can be analysed in such a way to quantify and compare the volumes of whole brains, sub-cortical structures and tissue types. Filippi et al. (1999) reported in his MTI paper that there was no signiﬁcant difference between the whole brain volumes of NMO patients when compared to the healthy control group. In contrast to this signiﬁcant atrophy of MS brains and subcortical structures has been widely reported, even at the earliest stage (e.g., Dalton et al., 2004). A voxel-based morphometry study looking at differences in grey matter volume between NMO patients, RRMS patients and controls showed no signiﬁcant differences between NMO patients when compared to the healthy volunteers, when corrected for multiple comparisons (Duan et al., 2012), but widespread signiﬁcant reductions in grey matter volume in RRMS compared with both controls and NMO patients. An analysis of cortical thickness in NMO using the Freesurfer tool found mild thinning in some cortical areas (the postcentral, precentral and calcarine gyri) and the thalamus when compared to controls Calabrese et al., 2012).
Two studies from the same research group in Beijing have found disruption in the amplitude and homogeneity in the resting state functional networks of NMO patients with normal brain MRIs, when compared to controls (Liang et al., 2011; Liu et al., 2011). The abnormalities were localised to areas of the frontal, cingulate and temporal cortex as well as the thalamus and caudate. The serological status of these patients is not known. Disruption to the resting state networks of MS patients has also been demonstrated (e.g., Bonavita et al., 2011). Rocca et al. (2004b) measured the hand movement related activation of the cortex in NMO patients with spinal cord lesions, ﬁnding increased recruitment of sensorimotor, temporal and occipital cortical areas when compared to controls. The increased activation in these regions correlated with MTR measures of spinal cord damage. Functional cortical reorganisation in MS patients with spinal cord disease has also been reported (Filippi et al., 2002).
With our newly found appreciation for the expanded features of AQP4 antibody disease, the future potential for imaging is threefold: (1) To clarify the features that differentiate AQP4 antibody disease from the more prevalent mimic relapsing remitting MS in order to apply this to AQP4 antibody negative NMOSD.
Longitudinally extensive spinal lesions and T2 hyperintensities in the area postrema and periaqueductal regions of the brainstem are indicative of NMO and atypical for MS. Panel 2 summarises useful differentiating features on conventional imaging and some potential discriminators from preliminary studies of quantitative measures. (2) To provide a means of measuring disease activity and treatment response (in the clinic and in treatment trials). (3) To study in-vivo the pathophysiological mechanisms of this recently characterised inﬂammatory demyelinating condition.
Quantitative measures of the integrity of normal appearing tissue in NMO suggest that neurodegeneration is limited to lesions and the white matter tracts affected by those lesions, in contrast to the diffuse and global changes found in MS. This ﬁnding could provide the basis of the development of more speciﬁc biomarkers of NMO.
5. Summary: useful imaging discriminators that favour NMO over MS
Longitudinally extensive (greater than three vertebral
segments) spinal cord lesions, which may be contiguous with lesions of the brainstem. Spinal lesions centred on the grey matter. The absence of asymptomatic spinal lesions. Increase of T2 signal and/or contrast enhancement within the optic nerve that extends to the chiasm. Brain lesions in the area postrema of the brainstem. Periventricular brain lesions can be found in both conditions, but the absence of perpendicular ovoid morphology and Dawson's ﬁngers is in favour of NMO. Absence of cortical lesions. Absence of s-shaped U-ﬁbre juxtacortical lesions. Initial quantitative studies suggest a lack of normal appearing white matter abnormalities is in favour of NMO over MS.
Conﬂicts of interest and funding statements Dr. Lucy Matthews has no conﬂicts of interest relevant to this submission. She has previously received funding from the Medical Research Council, UK (G0901996) and currently
Role of imaging in diagnosis of neuromyelitis optica receives funding from the Guthy–Jackson Charitable Foundation. Dr. Jacqueline Palace is on the advisory boards of Biogen Idec, Merck Serono, Teva Aventis, Bayer Schering and Novartis. She has received funding from the MS Society UK, Medical Research Council, UK and currently the Guthy– Jackson Charitable Foundation. She has a patent pending with ISIS Innovation (Oxford University). She has received conference support from Merck Serono and Novartis.
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