Magnetic Resonance Imaging studies on
neuropsychiatric systemic lupus erythematosus
Steens, S.C.A.
Citation
Steens, S. C. A. (2006, May 31). Magnetic Resonance Imaging studies
on neuropsychiatric systemic lupus erythematosus. Retrieved from
https://hdl.handle.net/1887/4416
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Introduction and aims
MRI studies on NPSLE
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er
1
Introduction
Systemic lupus erythematosus (SLE) is an infl ammatory disorder that involves many organ systems. The disease primarily affects young women, and the prevalence has been reported to be as high as 1 in 20001;2. Many patients with SLE experience neurologic, psychiatric and/
or psychologic manifestations during the course of their disease, a condition which is called “neuropsychiatric systemic lupus erythematosus” (NPSLE). In 1999, the American College of Rheumatology established a nomenclature and case defi nition system for neuropsychiatric lupus syndromes3, intended to facilitate research studies in NPSLE. Despite the improvement in clinical
classifi cation using this system, recent studies still show considerable variations in the reported prevalence of neuropsychiatric manifestations in SLE populations (37-95%)4. From a clinical
perspective, the major problem of classifying these patients is the aspecifi c nature of signs and symptoms of NPSLE patients, combined with a limited knowledge of the pathogenesis of the disease and a lack of a diagnostic gold standard. The present lack of therapeutic strategies with a proven effi cacy for NPSLE patients is partly due to this diagnostic dilemma2;4;5.
Neuropsychiatric manifestations in SLE patients may result from secondary causes such as drug side effects (eg., corticosteroids, CS), concurrent illnesses (eg., infections) or metabolic derangements (eg., metabolic encephalopathy based on lupus nephritis with renal insuffi ciency)4.
Such cases are referred to as secondary NPSLE. After exclusion of these secondary factors, neuropsychiatric manifestations are attributed to direct involvement of the nervous system by the SLE disease process, which is referred to as primary NPSLE. Considering the diversity in neuropsychiatric manifestations in SLE patients, it is unlikely that all manifestations are based on a single pathogenetic mechanism. The fi ndings of clinical, laboratory, pathological and radiologic and nuclear imaging studies suggest key roles for autoantibodies against phospholipid-associated proteins, neuronal antigens and ribosomes, and infl ammatory mediators such as cytokines2;4. How
these autoantibodies give rise to the observed neuropsychiatric symptoms is presently unknown. However, it is believed that antiphospholipid antibodies contribute to the development of the frequently observed brain infarcts in NPSLE patients with focal neuropsychiatric manifestations through interference with the blood coagulation cascade4. The role of these, and certainly that of
the other autoantibodies in the pathogenesis of NPSLE in patients with diffuse neuropsychiatric manifestations remains to be elucidated.
Magnetic resonance imaging (MRI) is regarded as the diagnostic imaging technique of choice in the evaluation of neuropsychiatric manifestations in SLE patients5-7. It has the capacity
to identify brain infarcts as well as confounding disorders such as space-occupying lesions, infectious meningitis or brain abcesses7. However, apart from excluding other causes for the
neuropsychiatric symptoms, MRI often shows no or only non-specifi c abnormalities such as small white matter hyperintensities or atrophy5-7. In an effort to reduce this clinicoradiological
paradox, studies were initiated applying quantitative MRI techniques, such as magnetization transfer imaging (MTI) and diffusion-weighted imaging (DWI), in NPSLE patients with diffuse neuropsychiatric manifestations. These quantitative MRI techniques have two advantages over conventional MRI: I) they are more sensitive to structural brain damage, and II) they permit easy and robust quantifi cation of such structural damage8;9. The results of previous MTI and
DWI studies were published in 2004 in the thesis of dr. G.P.Th. Bosma10 and are summarized in
Chapter 2. In summary, MTI and DWI detected brain changes in patients with NPSLE who lacked explanatory abnormalities on conventional MR images11;12. The functional relevance of these
changes was suggested by the observation of associations between neurologic, psychiatric and neuropsychologic measures and global disease burden as detected by MTI13. Furthermore, MTI
could differentiate between patients with neuropsychiatric symptoms caused by active NPSLE and patients with the same symptoms caused by residual disease14.
Aims
1
Data from MTI and DWI are not unconditionally reproducible with different MRI systems and different acquisition parameters. For diagnostic purposes such measures should be reproducible on different MRI systems, so that quantitative parameters in a given patient can be compared to reference data that are applicable to MRI systems of all major vendors. The fi rst aim of this thesis is to investigate the sources of variation in MTI and DWI parameters and to investigate if sequences can be developed to generate reproducible MTI and DWI data on different MRI systems.2
Treatment with CS is known to have an effect on the nervous system15. It is conceivablethat brain abnormalities previously detected by quantitative MRI methods are (partially) induced by CS treatment, since many NPSLE patients are on CS medication. The second aim of this thesis is to investigate if CS treatment has an effect on the measures of cerebral lesion load acquired with the quantitative MRI techniques MTI, DWI and magnetic resonance spectroscopy (MRS).
3
Previous studies have shown that MTI detects abnormalities in the brain of NPSLE patients with diffuse neuropsychiatric manifestations. However, for MTI to provide useful surrogate markers of disease it must not only be able to detect lesions and to assess lesion load, but it must also be able to detect changes in lesion load. The third aim of this thesis is to investigate whether MTI parameters refl ect changes in lesion load in NPSLE patients.4
Since in previous MTI studies in NPSLE patients without visible changes on MRI that could explain the signs and symptoms only whole-brain analysis was used, the spatial distribution of abnormalities in such patients is unknown. The fourth aim of this thesis is to investigate whether brain MTI abnormalities in NPSLE patients occur in white matter, gray matter, or both.5
Different quantitative MRI methods, such as MTI, DWI, MRS and spin-spin relaxometry, have been applied to NPSLE patients in different studies. To date it is not known whether abnormalities found using these different techniques refl ect different pathophysiologic processes in a heterogeneous group of patients, or whether they refl ect different aspects of the same pathophysiologic process. The fi fth aim of this thesis is to investigate the relationships between MTI, DWI, MRS, and spin-spin relaxometry fi ndings in a clinically diverse group of NPSLE patients with diffuse neuropsychiatric manifestations.MRI studies on NPSLE
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11
6
Although anticardiolipin antibodies (aCL) are associated with thromboembolic events and macroscopic brain infarcts in NPSLE patients, their role in the development of brain changes that are not apparent on conventional MRI is less clear. The sixth aim of this thesis is to investigate if the abnormalities detected with MTI are related to the presence of aCL.MRI studies on NPSLE Chapt er
1
12References
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2. Scolding NJ, Joseph FG. The neuropathology and pathogenesis of systemic lupus erythematosus. Neuropathol Appl Neurobiol 2002;28:173-189.
3. ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature. The American College of Rheumatology nomenclature and case defi nitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599-608.
4. Hanly JG, Harrison MJ. Management of neuropsychiatric lupus. Best Pract Res Clin Rheumatol 2005;19:799-821.
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8. Tofts PS, Steens SC, van Buchem MA. MT: Magnetization Transfer. In: Tofts PS, ed. Quantitative MRI of the Brain: Measuring Changes Caused by Disease. 1st ed Chichester, Wiley 2003;257-298.
9. Wheeler-Kingshott CA, Barker GJ, Steens SC, van Buchem MA. D: the Diffusion of Water. In: Tofts PS, ed. Quantitative MRI of the Brain: Measuring Changes Caused by Disease. 1st ed Chichester, Wiley
2003;203-256.
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12. Bosma GP, Huizinga TW, Mooijaart SP, van Buchem MA. Abnormal brain diffusivity in patients with neuropsychiatric systemic lupus erythematosus. AJNR Am J Neuroradiol 2003;24:850-854. 13. Bosma GP, Middelkoop HA, Rood MJ, Bollen EL, Huizinga TW, van Buchem MA. Association of global
brain damage and clinical functioning in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 2002;46:2665-2672.
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