Imaging in CNS lupus

Best Practice & Research Clinical Rheumatology Vol. 19, No. 5, pp. 727–739, 2005 doi:10.1016/j.berh.2005.04.001 available online at http://www.sciencedirect.com

3 Imaging in CNS lupus Pamela L. Peterson*

BSc (Hons), MB ChB, MRCP (UK)

John S. Axford St George’s Hospital Medical School, Sir Joseph Hotung Centre for Musculoskeletal Disorders, Blackshaw Road, SW17 0QT, Tooting, London, UK

David Isenberg University College, London, UK

The diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) is complex not only on account of the heterogeneous nature of neurological presentation but also because of the difficulty of differentiating lupus-related pathology from other neuropsychiatric diseases. Magnetic resonance imaging (MRI) remains the gold standard for the non-invasive assessment of NPSLE but there are problems, both with sensitivity and specificity. Both T2 quantitation and the use of gadolinium have shown promise in differentiating acute from chronic lesions. Nonetheless, the lack of sensitivity of conventional MRI has led to the exploration of other MR-based techniques. Magnetic resonance spectrosocopy (MRS) allows the measurement of brain metabolites, whereas diffusion weighted imaging and diffusion tensor imaging allow assessment of white matter structure and integrity. MRS studies in NPSLE have consistently shown a reduction in N-acetyl aspartate (a neuronal marker). Diffusion weighted imaging has had only limited application in lupus and the results to date have shown abnormal diffusivity in lupus patients consistent with inflammation and loss of white matter structure. These techniques remain research tools at this early stage. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) have also been explored as functional imaging tools in lupus and both appear to be more sensitive in detecting subtle brain changes in NPSLE but there are issues with specificity which deter their use in the clinical setting Key words: diffusion weighted imaging (DWI); magnetic resonance imaging (MRI); magnetic resonance spectroscopy (MRS); magnetization transfer imaging (MTI); neuropsychiatriv systemic lupus erythematosus (NPSLE); positron emission tomography (PET); single photon emission tomography (SPECT).

* Corresponding author. Tel.: C44 208 266 6811; Fax: C44 208 266 6814. E-mail address: [email protected] (P.L. Peterson).

1521-6942/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.

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A hundred years ago syphilis was widely regarded as the great masquerader—the disease that can mimic virtually all others. Its modern equivalent is systemic lupus erythematosus (SLE), a condition that can present to virtually any subspecialty and be a cause of significant diagnostic confusion. Nowhere are its manifestations more diverse than in the central nervous system, where anything from ‘migraine to madness’ can be found. For practical reasons, determining the precise immunopathology in CNS lupus is greatly restricted by the general reluctance to biopsy the brain (and, to a lesser extent, the peripheral nervous system) compared to the relative ease with which the skin, kidneys, lymph node and bone marrow can be biopsied. As discussed later in this chapter, significant problems are also evident in the interpretation of the more sophisticated forms of scanning of the CNS that are now much more widely available. Equally challenging have been attempts to link particular neurological clinical features to individual autoantibodies. With few exceptions, correlations between individual antibodies and CNS lupus have not been very compelling and the history of these associations has frequently been of claims made and not confirmed, or of significant disagreements in the literature as to the presence or absence of particular autoantibodies. This chapter reviews the features ascribed to CNS lupus and discusses their aetiopathogenesis, but focuses on the modalities of imaging that should, in due course, ‘shed light’ on the aetiopathogenesis of individual CNS features and provide a more rational basis for the classification criteria.

CONUNDRUM CRITERIA It is a rather odd paradox that the standard revised classification criteria for SLE provided by the American College of Rheumatologists lists just two neuropsychiatric features—psychosis and seizures1—whereas an ad hoc committee of the American College of Rheumatology (ACR) has proposed 12 features associated with SLE in the CNS and seven in the peripheral nervous system:2 † Central nervous system: aseptic meningitis cerebrovascular disease demyelinating syndrome headache (including migraine and benign intracranial hypertension) movement disorder (chorea) myelopathy seizure disorders acute confusion state anxiety disorder cognitive dysfunction mood disorder psychosis † Peripheral nervous system: acute inflammatory demyelinating polyradiculopathy (Guillain-Barre´ syndrome) autonomic disorder mononeuropathy, single/multiplex

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myasthenia gravis neuropathy, cranial plexopathy polyneuropathy. Neurological involvement in patients with SLE was first mentioned by Kaposi in 1872.3 In 1904, Baum related active delirium, aphasia and hemiparesis to ‘probable discoid lupus erythematosus’4 and in 1945, Daley correlated clinical symptoms with abnormal cerebrospinal fluid findings and with the presence of vasculitis.5 However, it was Dubois who, in 1953, first described clinical neurological subsets in 62 patients.6 Lewis was the first to focus on the importance of electro-encephalogram (EEG) findings and psychometric testing in 1954.7 Undoubtedly the most common neurological manifestation of lupus is headache, the cause of which can range from simple migraine to the so-called lupus-specific headache, which is severe and does not respond to simple analgesia. Of much greater concern are grand mal seizures and psychosis however. Seizures can be an initial manifestation in lupus patients in around 5% of cases but are present in around 20% eventually. They might represent primary cerebral disease or be secondary to other linked problems, including uraemia and hypertension. Similarly, hemiplegia can be due to primary neurological involvement, secondary to hypertension or associated with the presence of antiphospholipid antibodies. Cerebellar disease and aseptic meningitis are much less common but a variety of organic brain syndromes and impaired temporo-spatial orientation, pulmonary and intellectual deficit are well recognised and difficult to treat. Sanna and colleagues8, in the largest published review of the features of CNS lupus using the recent ACR definitions11, noted the following in descending order of prevalence in 323 patients followed up for a mean of 10.9C7.9 years: headache (24%) cerebrovascular disease (17.6%) mood disorders (16.7%) cognitive dysfunction (10.8%) seizures (8.3%) psychosis (7.7%) anxiety disorder (7.4%) acute confusional state (3.7%). These figures are broadly similar to some other series, although variations are observed in the prevalence of cognitive dysfunction and headache in particular. Table 1 reviews our own and some recently published data. Around 10% of patients with lupus in the course of their disease develop a peripheral neuropathy. These are usually sensory, occasionally sensorimotor. Cranial nerve involvement is less common and is usually associated with more active systemic disease. Feinglass et al11 reported that the most commonly affected cranial nerves in their study were VII, III, VI, V and IX in order of decreasing frequency. Optic neuritis was uncommon although it might, on rare occasions, be a presenting feature. A more detailed description and analysis of the features of CNS lupus can be found in Chapter 7.

730 P. L. Peterson et al

Table 1. The most common neuropsychiatric lupus manifestations.

Lupus patients studied (nZ) Disease duration (nZ) Cognitive dysfunction Headache Mood disorder Cerebrovascular Seizures Psychosis

Sanna et al (Ref. 8)

Isenberg et al (unpublished observations)

323 10.9 grG8 11 24 w60% 18 8 8

268 10G8 15 24 17 8 4 3

Brey et al (Ref. 9) 120 8 69 52 40 – – –

Ainiala et al (Ref. 10) 46 11G8 80 54 – 15 – –

NEUROIMAGING IN LUPUS The diagnosis of NPSLE is complex not only because of the variety of syndromes already discussed but also because of the difficulty in differentiating active NPSLE from drug side effects and other unrelated pathology, such as cerebrovascular disease, depression and simple headache. These challenges have resulted in the search for laboratory markers and imaging techniques to try to aid diagnosis. In many ways, the wealth of imaging techniques that has been applied to NPSLE is evidence that no satisfactory diagnostic tool has yet been found. In the clinical setting, computerised tomography (CT) scanning has largely been superseded by the more sensitive technique of magnetic resonance imaging (MRI), although CT is still in use for the emergency exclusion of cerebral haemorrhage. The development of non-invasive MRI techniques and functional imaging such as positron emission tomography (PET) has added to our understanding of the pathophysiology of NPSLE and at least some of the techniques discussed in this chapter are likely in the future to be used clinically as surrogate markers of NPSLE. Magnetic resonance imaging (MRI) MRI is the current gold standard in the imaging assessment of NPSLE both for cerebrovascular and spinal pathologies. Transverse myelitis is reported to occur in 1–2% of SLE patients.12 T2-weighted images, in which oedema is best visualized, show high signal lesions that can be extensive or more focal13, in keeping with the clinical pattern of disease. It is not possible to comment on the underlying pathophysiology from the scan and this is an area of some controversy. Cerebral pathology in NPSLE is more common than peripheral or cord disease but, as shown above, can take many forms. MRI using T2-weighted imaging and the fluid attenuated inversion recovery technique (FLAIR) allow visualization of high signal lesions most clearly.14–16 Fluid appears white and therefore inflammatory lesions and oedema are clearly seen; T1-weighted images are usually normal. MRI is more likely to show abnormalities in focal neurological presentations than diffuse. In one study, only 19% of patients with diffuse presentations including psychosis and seizures had an abnormal MRI scan.17 In this regard, early scanning within 24 hour of presentation is advised because the lesions can resolve rapidly. For the same reasons, all patients with

Imaging in CNS lupus 731

active disease should be scanned before administration of corticosteroids or other immunosuppressive therapy.18,19 Lesions seen on MRI are diverse but small white matter hyperintensities in the frontoparietal regions remain most common.19 Periventricular lesions have been particularly associated with the antiphospholipid syndrome (APS) and can be impossible to differentiate on MRI from multiple sclerosis.20 White matter hyperintensities increase with age in the general population and are also associated with hypertension and it is not possible to differentiate between NPSLE from other vasculopathies using conventional MRI. The differentiation of acute active disease from old chronic lesions is also difficult. It has been noted that the presence of indiscrete lesion borders, intermediate intensity of T2 lesions and grey matter lesions are all indicative of active disease.19 The use of gadolinium has also been shown to be helpful in delineating active inflammatory lesions.21 It is thus clear that the involvement of an experienced neuroradiologist in MRI interpretation is invaluable. Quantitation of T2 values has also been shown to be helpful in distinguishing active from chronic lesions.22,23 T2 values appear to be increased in the normal appearing frontal grey matter of patients with active diffuse neurological syndromes. Interestingly, the T2 values from white-matter lesions in patients with NPSLE-APS differ significantly from those without antiphospholipid antibodies, which is suggestive of a different underlying aetiology. However, the authors themselves note that there was a large standard deviation within this last group and so diagnostically, this is unlikely to be helpful. Unfortunately, the finding of a normal MRI scan is common in NPSLE and this has prompted the research of other MR-based techniques to increase sensitivity in the assessment of NPSLE. Magnetic resonance spectroscopy (MRS) MRS is a non-invasive MRI technique that allows the biochemical metabolites in brain tissue to be quantified. The majority of human studies have used 1H (proton) MRS, because hydrogen is abundant in human tissue. The signal from an individual proton is dependent on the chemical structure in which it is contained. Different biomolecules can be separated by their frequency and can be quantified by the signal obtained at their specific frequencies. The information is generally displayed as a spectrum (Figure 1). The biomolecules measured in the human brain are N-acetyl aspartate (NAA), a neuronal marker; creatine/phosphocreatine (Cr), which is present in glial tissue and neurones and is involved in phosphate transport systems; and total choline (tCho), which comprises phosphocholine, glycerophosphocholine and choline and is thought to be a marker of cell membrane metabolism. At short echo times (TEZ30 ms) other visible metabolites include myoinositol (mI), which is found in glial tissue and thought to be involved as a second or third messenger for neurotransmitters. All of these have been reported in the SLE literature.24–34 Other metabolites including lactate, glutamate and lipids/macromolecules have not been shown to be relevant in SLE. The results of the major brain MRS studies are shown in Table 2. Most of the studies report ratios of metabolite peaks (e.g. NAA/tCho). Using this technique, quantification of individual metabolites is not possible. Both for this reason and to allow for examination of additional metabolites such as myoinositol, more recent studies employ

732 P. L. Peterson et al tCho + 18%

NAA - 26%

mI + 41%

5

4

3

2

1

ppm 0

Figure 1. T2 weighted magnetic resonance imaging (MRI) and 1H magnetic resonance spectroscopy (MRS) in chronic neuropsychiatric systemic lupus erythematosus.

shorter echo times and use brain tissue water (which is relatively constant) as a reference.34 In NPSLE (minor and major), NAA is reduced in normal-appearing white matter, grey matter and in high signal lesions. The most marked reduction in NAA is seen in patients with major NPSLE. In a study comparing NPSLE with NPSLE-APS, it was noted that the greatest reduction of NAA was seen in those with antiphospholipid antibodies with a significant correlation with the actual level of IgG APL rather than the presence of stroke.29 A reduced NAA has also been correlated with cerebral atrophy30 and neurocognitive dysfunction.26 Although permanent loss of neurones is implied by the current data, this might not be the case. In other diseases, most notably temporal lobe epilepsy, a resolution of NAA has been noted after successful treatment, suggesting that there is neuronal dysfunction rather than neuronal loss.35 Longitudinal studies in NPSLE are required to examine metabolite changes with treatment. Cho/Cre ratios have been shown to be elevated in NPSLE particularly in active disease and more recent data has concurred that the absolute concentration of Cho is

Table 2. Results from the major brain MRS studies. Acute NPSLE Lesions NAA/Cre NAA/Cho Cho/Cre NAA Cho MI

Y27 Y27

NAWM

Chronic NPSLE BG

Lesions

NAWM

Y32

Y25

[32

[27,29,31

Y24,30,31 YY [30,27,29,31 Y30a YY34 [34 [34

YY28

Y34 [[34

BG, basal ganglia; Cho, choline; Cre, creatine/phosphocreatine; mI, myoinositol; NAA, N-acetyl aspartate; NAWM, normal appearing white matter; NPSLE, neuropsychiatric lupus. a Cho reduced in major NPSLE thought to be secondary to severe cortical atrophy.

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elevated in active NPSLE.34 Early data also suggest that mI is raised early in the course of an active flare of NPSLE prior to changes on MRI. Again, further longitudinal studies are required. It is interesting to note that lactate peaks (indicator of anaerobic metabolism) are not observed in NPSLE, despite the suggestion that ischaemia is one of the main underlying pathophysiological mechanism of NPSLE. At this time, MRS remains a research tool. The changes observed are not specific to NPSLE. In particular, a reduction in NAA is seen in degenerative brain pathologies including multiple sclerosis36 and Alzheimer’s disease37, and intriguingly in sleep apnoea.38 However, the technique might be used to diagnose brain pathology in lupus and, if lupus related, has the potential of doing so before it becomes irreversible. In addition, MRS might be helpful in monitoring the progression of pathology over time and/or the response to treatment; as has been demonstrated in viral infections.38 Automated pattern recognition techniques for categorizing brain tumour type and histological grade are currently being developed for clinical use and perhaps in the future we will see similar pattern recognition techniques to aid differentiation of acute from chronic disease in NPSLE39, as well as other brain pathologies such as Bec¸het’s disease40, epilepsy41 and schizophrenia.42 Diffusion-weighted imaging (DWI) DWI, a non-invasive MR technique, measures the diffusion of water in the brain. The degree of diffusion depends on temperature, viscosity and barriers to movement. In brain tissue, water preferentially flows along white-matter tracts. If there is an acute ischaemic event, there is initially reduction in water diffusion, which can be measured by a reduction in a parameter known as the apparent coefficient of diffusion (ADC).43 By contrast, inflammatory lesions causing damage to white-matter tracts will result in an increase in ADC, as occurs in multiple sclerosis.44 Diffusion tensor imaging, a more sophisticated form of diffusion imaging, measures directionality as well as the integrity of the tissue allowing quantification of the degree of damage in white-matter diseases.45 The application of diffusion imaging to NPSLE is in its infancy, with only three publications using DWI. Two of these used a whole brain ADC histogram analysis46,47, and showed an overall increase in diffusion in NPSLE compared with age-matched healthy controls, suggesting inflammation with loss of white-matter integrity. Interpretation of the results from the third study is less clear.48 DWI is already in clinical use as an early diagnostic tool in acute cerebrovascular stroke, with changes noted as early as 40 minutes after the ischaemic event.43 Examining NPSLE patients during an acute flare of their disease might help us elucidate whether ischaemia is the initial underlying mechanism of damage in NPSLE. Magnetization transfer imaging (MTI) Unlike DWI, MTI quantifies the exchange of protons between those bound in macromolecules, such as cholesterol in myelin, and free water. Either an increase in fluid due to oedema, or a decrease in myelin, will alter the transfer of protons, decreasing the signal as expressed quantitatively as the magnetization transfer ratio (MTR). Four main studies have examined MTR.49–52 All have used a histogram analysis.

734 P. L. Peterson et al

Normally, a sharp well-defined peak is obtained, showing that the MTR across the normal brain is uniform. In diseases in which the integrity of the white matter is compromised, this peak diminishes in height and becomes broader on account of the variation in white-matter structure secondary to patchy loss of myelin or inflammatory lesions. To summarise the results, patients with chronic NPSLE show significantly lower peak height than those without NPSLE and than healthy controls. This reduction in peak height has been shown to be similar but slightly less severe than in multiple sclerosis. When the MTI analysis was combined with T1-weighted image analysis, multiple sclerosis could be further differentiated from NPSLE, emphasising the need for a multimodal diagnostic approach. In another attempt to differentiate similar patient groups, Dehmeshki et al53 performed a histogram analysis of MTR followed by a multivariate discriminant analysis (MDA) on the data. Looking at pairs of groups (e.g. acute versus chronic NPSLE), it was noted that individual patients could be assigned to the correct diagnostic group, with only four errors in 76 tests. This is perhaps the first analysis of its kind to address specificity issues at the individual level. The authors noted that the patient groups chosen were well defined and that numbers in each group were small but nevertheless, this technique looks promising as a potential diagnostic tool in NPSLE. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) Metabolic activity including glucose uptake and oxygen utilisation can be measured by PET. Glucose uptake is most frequently measured using 2-18F-fluoro-2-deoxyglucose (FDG). In NPSLE, grey-matter lesions are seen more frequently than white matter lesions and although various areas of the brain are affected in different studies, the most frequent observations of hypometabolism occur in the parieto-occipital and parietal regions.54,55 Most studies report a greater sensitivity than MRI in detecting subtle brain changes in lupus patients.54–56 In addition, PET appears to be useful in differentiating SLE patients with and without NPSLE but does not appear to be superior to MRI in this regard.54,56 Interestingly, in three studies in which longitudinal follow-up was carried out, areas of abnormal hypometabolism resolved with successful treatment of the NPSLE.55,57,58 In at least two studies, patients had normal MRI scans at onset, suggesting that there are functional abnormalities that can be noted before structural change is evident by MRI. There are limitations, however, both in the literature reported and in clinical practice. Many studies do not report correction for cerebral atrophy, which can result in larger areas of apparent hypometabolism. With a few exceptions, the majority of studies have not compared data from SLE patients with healthy controls (probably for the ethical issues of an invasive procedure in a healthy population). With particular reference to the minor NPSLE syndromes such as headache, depression and mild cognitive dysfunction, there are no studies comparing groups of NPSLE patients with patients with simple headache or primary depression, despite the knowledge that similar PET abnormalities have been reported in these conditions. These specificity issues have obvious implications for clinical practice. PET is also both time consuming and very expensive. In each case, an MRI scan is required as well as the PET scan to localise any focal pathology before analysis. For these reasons, it is highly unlikely that PET will find a place in routine clinical practice.

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A far cheaper and more accessible functional imaging tool is single photon emission computed tomography (SPECT), which measures cerebral perfusion using commercially available radiolabelled tracers injected into the blood stream. The most common of these is Tc-99m HMPAO. There have been at least two recent reports of comparison of PET and SPECT in NPSLE (25 and 37 patients, respectively).56,59 In both studies, PET and SPECT were sensitive in detecting abnormalities in major NPSLE but SPECT was less specific; detecting brain abnormalities in SLE patients without neuropsychiatric involvement. In the NPSLE groups, the areas of hypometabolism on PET did not correlate with the areas of abnormal perfusion on SPECT, which is perhaps surprising. There has been one study to date comparing the newer MR technique of perfusion weighted imaging and SPECT.60 Here again, there appeared to be more frequent false positives in SPECT than in PWI. Further larger studies comparing these two modalities in NPSLE are warranted. The most common SPECT abnormality in NPSLE is patchy diffuse hypoperfusion. This has been associated more frequently with acute major NPSLE events, whereas focal lesions appear to be more common in patients with longer duration of disease.61 When focal lesions are demonstrated, they are most commonly seen in the frontal and parietal lobes62,63 with some reports of temporal lobe involvement64 and a few with basal ganglia involvement.65,66 In all studies examined, there has been no reported association with active serology other than PR3 cANCA.67 For the majority of SPECT studies, the abnormalities are most notable in patients with major NPSLE67 and in general the suggestion is that SPECT is not helpful in either diagnosing or monitoring mild syndromes of NPSLE either in adults or children.62,68,69 The use of SPECT for long-term follow-up is again variable. A study in children suggested no association of SPECT with clinical improvement.70 However, a recent study in 15 patients with normal MRI and abnormal SPECT scans showed resolution of SPECT abnormalities following treatment with corticosteroids.71 Although SPECT is less invasive and more readily available than PET, there are still limitations to its use in the clinical setting in view of the lack of specificity in SLE. However, further research may help us understand the relationship between hypoperfusion and brain metabolism and there is certainly scope for coupling SPECT and MR-based techniques such as MRS.

SUMMARY At this stage, MRI remains the imaging tool of choice in the evaluation of patients with NPSLE. The use of MRI early in the acute phase of the disease is important if fleeting changes are to be seen. The aid of an experienced neuroradiologist is invaluable in assessing the scans and it is also helpful to use gadolinium injection or T2 quantitation techniques when differentiation of acute from chronic lesions is important. MTI might prove to be a more specific diagnostic tool in the future but further research is required. MRS looks promising as an early diagnostic tool and one with which to monitor disease progression at a metabolic level and DTI might help us to quantify the degree of damage relating to NPSLE over time. These non-invasive techniques benefit from the fact that they can be combined in one clinical scanning session. A multimodal approach might, in the future, allow us to understand more about the metabolic and structural changes that occur in all of the various neurological syndromes associated with SLE.

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Practice points † MRI is the current gold standard for imaging in NPSLE † small, white-matter hyperintensities in frontoparietal regions are most common † scanning early in the course of disease flare is recommended † gadolinium enhancement might be helpful in delineating active lesions † T2 quantitation might be helpful in differentiating acute from chronic lesions † MRI scan can be normal † metabolite changes are noted in NPSLE † the changes in NAA, a neuronal marker are more marked in major than in minor NPSLE † abnormal brain diffusivity has been noted in NPSLE † differentiation of other brain degenerative disorders such as MS from NPSLE might be possible using MTI combined with T1 weighted image analysis

Research agenda † DWI analysis during acute neuropsychiatric events are needed † longitudinal studies of the response of metabolites to treatment might be helpful † further studies involving absolute quantitation of metabolites are needed † DTI analysis might help to quantify white matter damage † further studies are necessary to develop the potential diagnostic role of this technique † SPECT has shown resolution of hypometabolic changes with corticosteroid treatment; this area warrants further research ACKNOWLEDGEMENTS Thanks to F.A. Howe, Honorary Senior Lecturer, CRC Biomedical Research Group. St George’s Hospital Medical School, London, and C.A. Clark, Senior Lecturer. Department of Clinical Neurosciences, St George’s Hospital Medical School, London, UK.

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