ACHAIKI IATRIKI | 2021; 40(3):160–174
Review
Athanasia Dara, Christina Adamichou, Eleni Pagkopoulou, Theodoros Dimitroulas
4th Department of Internal Medicine, Hippokration Hospital, School of Medicine, Aristotle University Thessaloniki, Thessaloniki, Greece
Received: 27 Apr 2021; Accepted: 09 Jun 2021
Corresponding author: 4th Department of Internal Medicine, Hippokration Hospital, School of Medicine, Aristotle University Thessaloniki, Thessaloniki, Greece, E-mail: dimitroul@hotmail.com
Key words: Systemic lupus erythematosus, neuropsychiatric systemic lupus erythematosus, cerebral small vessel disease, cerebral blood flow, non-invasive imaging techniques.
Abstract
Neuropsychiatric symptoms are expressed in approximately 40% of SLE patients. The underlying alterations in the microstructure of the brain in systemic lupus erythematosus (SLE) patients are caused by the activation of pathogenic pathways, such as antibody-mediated and cytokine-induced neurotoxicity or vasculopathy caused by anti-phospholipid antibodies. Neuropsychiatric involvement in SLE manifests through a diverse range of symptoms, none of which are pathognomonic signs of SLE. The wide variety of neurologic symptoms and confounding disorders, in addition to the uncertainty surrounding their aetiopathogenesis, makes it difficult to establish their connection to the underlying disease and to clinically diagnose neuropsychiatric lupus eythematosus (NPSLE). Conventional magnetic resonance imaging (MRI) is considered the gold standard for diagnosing CNS involvement, by detecting small and large vessel disease and inflammatory-type lesions, whereas computer tomography (CT) is used to establish acute complications, such as hemorrhage or large infarcts and to assess differential diagnoses. However, since one in two NPSLE patients will have normal MRI findings upon examination, especially when they are presented with diffuse disorders, such as headache, mood alterations and psychiatric disease, it is becoming increasingly evident that more advanced MRI techniques should be integrated in a multimodal diagnostic strategy aiming to detect microstructural brain damage in early disease stages. Magnetization transfer imaging (MTI), diffusion tensor imaging (DTI), positron emission tomography with fluorine-18 fluorodeoxyglucose [(18) F-FDG-PET], single-photon emission computed tomography (SPECT), arterial spin labeling magnetic resonance imaging (ASL-MRI), as well as dynamic susceptibility contrast-enhanced perfusion magnetic resonance imaging (DSC-MRI) for the evaluation of cerebral blood flow, are all complementary non-invasive methods discussed in the present article that could contribute to the functional and morphological assessment of brain’s circulation and microstructure in SLE and NPSLE patients.
Introduction
Systemic Lupus Erythematosus is an inflammatory autoimmune disease with several phenotypes and diverse clinical presentation, ranging from mild manifestations to multi-organ and severe central nervous system involvement [1]. Vascular disease is a common occurrence in SLE patients, either as an acute/subacute manifestation of the disease in the context of antiphospholipid syndrome or lupus vasculitis, or as an accompanying co-morbidity due to steroid-related atherosclerosis or accelerated atherosclerosis cause by a pro-inflammatory environment [2]. Cerebral small vessel disease (CVD) is an intrinsic disorder of the brain’s perforating arterioles and it is one of the most common and severe manifestations of the aforementioned vascular pathology [3]. An important mechanism that could be held responsible for CVD is an increase in pro-inflammatory cytokine production that might disintegrate the blood-brain barrier, which in turn facilitates the entrance of neurotoxic antibodies into the CNS [4, 5]. Neuroinflammation, microangiopathy, chronic diffuse ischemia, thromboembolism and atherosclerosis also take place [6, 7].
Moreover, activation of the microglia by circulating auto-antibodies, IFN-α and other immune reactants, augments the inflammatory response worsening neuronal damage. Inflammation, cell infiltration in the perforating arteriolar walls, microglial activation in the perivascular tissue, alterations in brain perfusion and metabolism, vasculopathy and neuronal impairment all take place in neuropsychiatric systemic lupus erythematosus (NPSLE) [8, 9]. NPSLE manifestations vary from mild disturbances such as headaches, mood disorders and cognitive dysfunction to more severe events such as myelitis, seizures and stroke [10]. As a matter of fact, stroke is a primary cause of morbidity, mortality and disability in SLE patients, who appear to have a greater risk of stroke compared to healthy subjects. Especially, young SLE patients appear to have a ten-fold increase in the risk of stroke compared to age-matched controls [11]. Interestingly enough, while the overall prognosis of SLE has improved, mortality rates due to cerebrovascular events remain unchanged, accounting for 15% of deaths in SLE [12,13]. Strokes that are ascribed to systemic inflammation, endothelial activation or an affiliation for thrombosis due to aPL usually occur close to the time of diagnosis, while those attributed to atherosclerosis take place later on [14, 15].
NPSLE poses a formidable diagnostic challenge due to the multifarious neurological and psychiatric manifestations that characterize it, which are usually not pathognomonic of the disease. These symptoms are often overlooked despite their connection with increased mortality and morbidity [16]. Suspicion of disease arises primarily from clinical observation and experience due to the heterogeneity of NPSLE and the absence of etiological insight [17]. A noteworthy progress in the diagnosis of NPSLE was made in 1999, when the ACR Research Committee presented a uniform classification and a standardized methodology for recognizing NPSLE patients [18]. This classification includes 19 neuropsychiatric syndromes in SLE, which can be divided into CNS and PNS manifestations. These criteria enable a better case definition, through a detailed exclusion method. Even though no clear physiological and pathological mechanisms are explained under this categorization, it provides rheumatologists with a useful tool for the identification of neurological involvement in SLE. Inspired by this classification, Hanly et al. developed a model for determining the correlation between NP events and SLE, that assessed three parameters; firstly, the temporal relationship between NP symptoms and SLE diagnosis, secondly, the type of NP event that occurred, and lastly, a comprehensive list of exclusions and associations consistent with ACR nomenclature [19, 20, 21]. Bortoluzzi et al. proposed two additions to this algorithm; a careful evaluation of several risk factors that could aid the attribution process, as well as, the assignment of a numerical score to each selected item and the establishment of a global score; the greater the score, the higher the probability that the NP symptoms can be credited to SLE [22]. Ultimately however, the attribution of an NP event to this specific underlying disease remains to this day a challenge based on clinical judgment and expert opinion.
Early diagnosis of NPSLE, as well as close monitoring of disease progression, are of paramount importance to better patient management and the prevention of more severe CNS manifestations. Non-invasive imaging techniques that could contribute to a multimodal diagnostic algorithm are discussed below.
Research strategy
A MedLine and Embase search was carried out according to published guidance on narrative reviews using the following terms: systemic lupus erythematosus, neuropsychiatric systemic lupus erythematosus, cerebral small vessel disease, cerebral blood flow, non-invasive imaging techniques [23]. Original research papers and review articles registered until the end of December 2020 were selected to be included in this review. Publications not in English and data from ongoing research were excluded (Table I).
Non-invasive imaging techniques
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is the standard radiologic imaging modality for NPSLE diagnosis, with the most frequent findings being hyper intensive lesions in the white matter (WMHI lesions) on T2 and FLAIR weighted sequences. However, these alterations were also observed in non NPSLE patients [24, 25]. On the other hand, 45% of NPSLE patients had no visible MRI abnormalities [26]. A study of 83 SLE patients with brain MRIs, obtained from the National University of Malaysia Medical Centre, indicated that the presence of these WMHI lesions was associated with high SLE activity, cerebral infarcts and aPL positivity. Inflammation and ischaemia were suggested as the underlying pathologies [27].
A different study by Nystedt et al. examined alterations in white matter microstructure in SLE patients with and without neuropsychiatric symptoms [28]. For this purpose, structural MRI and DTI were performed in 64 female SLE patients and 21 healthy controls. Results suggested that the alteration of white matter microstructure was not limited to the NPSLE subgroup and that it appeared to be related to disease duration and fatigue. Ainiala et al. performed a study on 43 SLE patients, who were found to have increased volumes of both T1- and T2- weighted lesions and increased cerebral atrophy, findings that were also related to specific NP manifestations [29].
Takahashi et al., reported the case of a 28-year-old woman, diagnosed with SLE, who suddenly developed dyplopia, unconsciousness and general convulsions [30]. Asymmetrical, multifocal, high signal intensity lesions on T2-weighted images and low signal intensity lesions on T1-weighted images were observed especially in subcortical white matter and the overlying cerebral cortex. The significance of this case report was that lesions were described using MRI but also when using both apparent diffusion coefficient imaging (ADCI) and diffusion weighted images (DWI) in a SLE patient with symptoms from the CNS.
The above-mentioned data suggests that conventional MRI may detect T1- and T2- weighted lesions, signs of cerebral atrophy and other findings indicative of inflammatory microangiopathy and ischemic changes. However, its inability to detect alterations in a significant number of NPSLE patients suggests that a multimodal diagnostic algorithm would significantly increase sensitivity and specificity for CNS involvement in SLE.
Functional Magnetic Resonance Imaging
Functional magnetic resonance imaging (fMRI) is used for measuring specific neuronal activity in regional brain structures during cognitive tasks by detecting the differences in the ferromagnetic properties of oxygenated and deoxygenated blood [31]. A systematic review of fMRI studies leads to the conclusion that disturbances in working memory and executive function brain regions are the most common findings in SLE patients [32]. Furthermore, increased functional connectivity strength in the fronto-parietal cortex, in resting state, correlates to disease activity. A study, conducted by Shuang Liu et al., assessed fMRI data acquired from 118 non-NPSLE patients and 81 healthy controls [33]. Resting stated fMRI data was used to calculate regional homogeneity (ReHo) in all subjects. The results indicated decreased ReHo values in the fusiform gyrus and thalamus and increased ReHo values in the parahippocampal gyrus and uncus. Disease activity correlated positively with ReHo values of the cerebellum and negatively with values in the frontal gyrus. Therefore, the aforementioned study suggests that abnormal brain activities might occur before NPSLE and that they might be the underlying cause of depressive and anxiety conditions.
McKay et al. used fMRI to determine whether disease duration was associated with brain injury [34]. For this purpose, 13 SLE patients were stratified by disease duration of ≤2 years (short-term [ST]) or ≥10 years (long-term [LT]). Findings from this process include increased amygdale and superior parietal activation, as well as significantly increased cortical activation in the ST group in areas linked with cognition. These differences were attributable to SLE effects on the CNS and were related to disease activity.
The assessment of 9 NPSLE patients compared to 9 RA patients and 9 healthy controls demonstrated that NPSLE patients showed greater frontoparietal activation than other groups during the memory task [35]. This is possibly credited to the need for extra cortical pathways recruitment during such tasks, in order to supplement the impaired standard pathways. Another study of 14 subjects, using fMRI, dual-echo and DTMR images, aimed to investigate the degree of cortical reorganization in NPSLE patients and its association with the extent of brain pathology [36]. T2 sequences showed abnormalities in 11 NPSLE patients, while NPSLE subjects also demonstrated significant activation of the contralateral primary sensorimotor cortex, putamen and dentate nucleus. More specifically, sensorimotor activation was closely linked to the extent and severity of brain damage. Lastly, as demonstrated by DiFrancesco et al., fMRI irregularities can also be identified in childhood-onset SLE, as an imbalance between active and inhibitory responses to stimuli [37]. These altered activation patterns are likely the result of abnormalities in white matter connectivity and neuronal network dysfunction.
All in all, fMRI detects neuronal dysfunction in regional brain structures during cognitive tasks. The recruitment of extra cortical pathways during such tasks leads to alterations in activation patterns, proportional to the extent and severity of brain degeneration.
Magnetization Transfer Imaging
Magnetization transfer imaging (MTI) is based on the principle that protons in macromolecules (e.g. myelin) which are not visible with conventional MRI, can be studied by measuring their effect on visible mobile protons. As a result, normal white matter that has a dense structure, has a high MT ratio. In general, MT provides valuable indications of demyelination and axonal loss in many chronic systemic diseases [38].
A study by Bosma et al., attempted to determine whether MTI histogram analysis can identify irregularities in patients with active NPSLE, and whether these findings can be compared with similar irregularities in MS patients [39]. Those results were encouraging, as it was observed that volumetric MTI analysis can indeed detect cerebral changes during the active phase of NPSLE. Furthermore, abnormalities in brain parenchyma of chronic NPSLE patients demonstrated similar MTI values to those of patients with inactive MS. On the contrary, MTI values in the active phase of NPSLE differed from those presented in the chronic state, most likely due to underlying inflammation.
A multimodal MRI study conducted on 9 active NPSLE patients, 9 SLE patients without NP symptoms and14 healthy controls showed that the co-analysis of MTI and DTI data contributes to the understanding of the microstructural damage in NPSLE and can improve diagnosis [40].
Steens et al. collected MTI data from 24 female SLE patients and 24 age- and sex-matched healthy controls. MTR maps were calculated for both grey matter and white matter separately and MTR histograms were produced [41]. The results indicated that SLE patients with a history of NP manifestations, with or without accompanying focal MRI abnormalities, had a significantly lower GM PH. This neuronal damage shows a susceptibility of the GM to small-vessel disease and the antineuronal action of auto-antibodies that managed to penetrate the compromised blood brain barrier. MTI was also recruited in a study aimed to assess its correspondence with clinical changes in NPSLE patients [42]. Twenty-four (24) pairs of scans corresponding to 19 patients were examined for significant differences. The peak height of whole-brain MTR histograms was found to match changes in the clinical status of NPSLE patients, suggesting that MTI could prove to be a useful tool for an effective clinical evaluation.
In conclusion, MTI detects cerebral changes, attributable to demyelization and axonal loss in patients with, either active NPSLE, or a history of NP symptoms. It is noteworthy that these changes may be undetectable using exclusively conventional MRI.
Diffusion Tensor Imaging
Diffusion tensor imaging (DTI) is an MRI technique that assesses the diffusion of water molecules. It is directly dependent on orientation, spacing and structural barriers in brain tissue, such as myelin and cellular membranes [43]. White matter (WM) restricts free water movement in the direction of diffusion that is perpendicular to the WM tracts with a mechanism called anisotropy. DTI employs anisotropic diffusion in order to estimate the axonal organization of the brain [44]. It holds great promise as a method of recognizing microstructural alterations and their progression with neuropathology and treatment. Thus, it can be used for the identification of white matter pathologies, such as ischemia, myelination, axonal damage, inflammation and edema [45].
Fifteen female SLE patients, with no history of major NP manifestations, underwent MRI with DTI at baseline and 1.5 years later. [46] The DTI abnormalities found included decreased fractional anisotropy and increased mean diffusivity in bilateral cerebral WM and GM. These abnormalities were not associated with emergent NP activity, medical decline or medication changes, nor were they developed on the grounds of an MRI visible macrostructural change. They are more likely to be considered the result of the ongoing inflammation.
The topological properties of brain WM structural networks in SLE patients were examined by Ling Zhao et al. [47]. Results from DTI datasets, acquired from 29 non-NPSLE patients and 24 healthy controls, were used to recreate their brain WM structural networks by using a deterministic fiber tracking approach. Abnormal diffusion parameters in the bilateral corticospinal tract and the right superior longitudinal fasciculus-temporal terminations were found in the non-NPSLE patients. These results suggest that brain WM connectivity appears to be damaged even in SLE patients who do not exhibit any NP symptoms.
A similar study applied DTI and tract based spatial statistics to examine 19 NPSLE patients, 19 non-NPSLE patients and 18 healthy controls [48]. All groups were age- and sex-matched. Data analysis of both SLE groups indicated several regions of compromised prefrontal WM integrity. The alterations found in non-NPSLE patients were similar to those in the NPSLE group but less pronounced.
A systematic review of 37 articles with a total of 195 NPSLE patients, 299 no-NPSLE patients and 423 healthy controls, indicated that both SLE and NPSLE patients had reduced FA values, suggesting subclinical CNS involvement, and elevated MD values in most WM areas [49]. Nonetheless, follow-up studies are required in order to determine whether these microstructural alterations are transient or permanent.
All in all, DTI can be used to detect white matter pathologies indicative of ischemia, axonal damage or inflammation. Moreover, it may prove to be useful for monitoring disease progression and the differential diagnosis of transient and permanent microstructural damage.
Positron Emission Tomography
Positron emission tomography with fluorine-18 fluorodeoxyglucose [(18) F] FDG PET/CT assesses the increase in glucose uptake of infiltrating granulocytes and tissue macrophages. Moreover, due to the increased glucose metabolism of activated lymphocytes it can also be used to visualize large concentrations of these cells. One of the most common and remarkable PET/CT findings in NPSLE patients is parieto-occipital hypometabolism [50].
PET using F-18 –labelled fluorodeoxyglucose was performed in 28 SLE patients who were classified according to their clinical state, as having severe neuropsychiatric manifestations (n=12) or mild neuropsychiatric symptoms (n=11) or without any signs of CNS involvement (n=5). Subjects were also compared to 10 healthy controls [51]. PET scan results indicated hypometabolism in at least one brain region in all patients with severe or mild CNS symptoms, compared to non-symptomatic patients. Again, parieto-occipital regions were most commonly afflicted, followed by parietal regions. Comparatively, MRI images showed abnormalities in only 50% of NPSLE subjects and only in 25% of non-NPSLE patients.
Another study aimed to investigate the efficacy of (18) F-FDG-PET for the detection of CNS involvement in SLE patients with no MRI findings [52]. For this purpose, 20 NPSLE patients with headaches, seizures or mood disorders and a normal MRI underwent brain (18) F-FDG-PET. Significant abnormalities in glucose metabolism were observed in 15 out of 20 patients, mainly in the temporal, the occipital and the frontal lobe. Nonetheless, neuropsychiatric manifestations did not correlate geographically with specific imaging findings.
In summary, data indicates that (18) F-FDG-PET could be used as a diagnostic tool complementary to MRI, when the latter fails to provide confirmation of brain involvement in SLE patients.
Single-photon Emission Computed Tomography
Single-photon emission computed tomography is another method used to determine the connection between cerebral hypoperfusion, cumulative tissue damage and disease clinical activity. Two groups of patients underwent (99mTc-ECD) SPECT, while SLE disease activity index, SLICC/ACR damage index and native anti-DNA antibodies were also measured [53]. Group A was compiled of 10 women with SLE, but no history of major neuropsychiatric manifestations and no minor neuropsychiatric symptoms in the last six months, while group B included 57 unselected women with SLE. In group A, cerebral SPECT yielded abnormal findings (moderate or severe hypoperfusion) in five non-NPSLE patients. Moreover, patients with significant cerebral hypoperfusion had greater clinical disease activity and ESR. In group B, cerebral SPECT was normal in 30 patients and indicated moderate or severe hypoperfusion in 27. Thus, it may be assumed that cerebral hypoperfusion, identified using SPECT, is related to both clinical activity and cumulative tissue damage.
SPECT scans were also performed on 20 young patients with acute CNS manifestations, in order to determine whether this method can be used for monitoring CNS disease activity during childhood [54]. SPECT scan pattern was abnormal in 86% of patients, showing widespread small areas of decreased uptake, indicative of generalized hypoperfusion. However, it should be noted, that SPECT scans did not clearly indicate clinically visible CNS involvement in children.
A systematic review by Sahebari et al. assessed the diagnostic value of SPECT scan and fMRI as imaging tools for the detection of subtle brain abnormalities in SLE patients with cognitive impairment [55]. The analysis of 14 articles demonstrated that both SPECT and fMRI could be considerably beneficial for the diagnosis, as well as the initial management of SLE patients with CNS manifestations.
Overall, SPECT scans indicate areas of hypoperfusion caused by cumulative tissue damage that correlate positively to disease clinical activity. As a result, especially when combined with fMRI, SPECT may prove valuable for monitoring disease progression in non paediatric SLE patients with cognitive dysfunction.
Arterial Spin Labeling Magnetic Resonance Imaging
Arterial spin labeling (ASL) is a non-invasive MRI technique that measures cerebral blood flow, while also eliminating the risk of nephrogenic systemic fibrosis in patients with renal dysfunction, as is often the case with SLE patients [56]. Moreover, the absence of contrast agents and radiation exposure encourages the employment of this method for the assessment of paediatric patients [57]. ASL measures tissue perfusion rate and not macrovascular blood flow. Tissue perfusion, water and nutrient tissue exchange happens along the entire length of the capillaries and thus ASL uses blood water molecules as a free diffusible tracer from the arterial body to the tissue capillary bed [58].
A study by Zhuo et al. used 3D ASL-MRI to quantify cerebral perfusion of 31 NPSLE and 24 non-NPSLE patients compared to 32 healthy controls [59]. Results indicated that compared to the control group, NPSLE patients had increased blood flow (CBF) within WM, but decreased CBF within GM. On the other hand, non-NPSLE patients demonstrated increased CBF in both GM and WM. Additionally, compared to the non-NPSLE group, the NPSLE group showed considerably reduced CBF in the frontal gyrus, cerebellum and corpus callosum.
Jia et al. also used 3D ASL-MRI to estimate CBF in 16 NPSLE, 19 non-NPSLE and 30 healthy controls [60]. Perfusion was unevenly reduced in the frontal, temporal, parietal and occipital lobes of all SLE patients compared to controls. Whereas all patients with impaired frontal lobe perfusion had acute CNS symptoms, approximately 40% of the hypoperfusion in other regions was observed in non-NPSLE patients suggesting that a subclinical pathological process was underway. Consequently, CBF measured by non-invasive 3D ASL could potentially serve as a practical biomarker for the diagnosis and monitoring of disease progression in both NPSLE and non-NPSLE patients.
Dynamic Susceptibility Contrast-enhanced Perfusion Magnetic Resonance Imaging
Dynamic susceptibility contrast-enhanced perfusion MRI (DSC-MRI) is another non-invasive technique that measures cerebral perfusion and could contribute to distinguishing lupus from non-lupus neuropsychiatric events. Much like the aforementioned ASL-MRI, this method also limits patients’ exposure to radiation, while at the same time providing higher spatial resolution and the ability to measure simultaneously cerebral blood volume and cerebral blood flow [61].
Papadaki et al. assessed a total of 76 patients (37 primary NPSLE, 16 secondary NPSLE, 23 non-NPSLE) and 31 healthy controls using conventional MRI and DSC-MRI [62]. Patients with primary NPSLE had a lower CBF and volume in otherwise normal-appearing WM areas compared to controls. Furthermore, they had a lower CBF in the semioval centre bilaterally, compared to both non-NPSLE and secondary NPSLE patients. In greater detail, this decrease in CBF was used to differentiate between primary NPSLE, secondary NPSLE and non-NPSLE, with an 80% sensitivity and 67-69% specificity. The combination of conventional MRI and DSC-MRI seems to grant 94-100% specificity for discerning primary from secondary NPSLE. Another study by the same team performed DSC-MRI on 31 NPSLE, 19 non-NPLSE and 23 healthy controls focusing on brain regions linked with emotional response [63]. Hypoperfusion in frontostriatal and limbic structures proved to correlate positively with more severe anxiety symptoms due to the heamodynamic disturbances in NPSLE.
According to the above data, alterations in cerebral tissue perfusion, detected by ASL-MRI and DSC-MRI, could aid to determine which NP signs may be attributed to SLE. Furthermore, it may be used to evaluate disease severity, as well as to differentiate between primary NPSLE, secondary NPSLE and non-NPSLE.
Magnetic Resonance Spectroscopy
As explained above, MRI may draw attention to focal ischemic lesions, white matter hyperintensity, ventricular dilation and cortical atrophy in SLE patients [64]. However, lack of MRI findings does not exclude neuronal dysfunction, as is the case with metabolic alterations [65, 66]. Unlike MRI, MRS utilizes the signal from hydrogen protons to determine the concentration of brain metabolites, such as N-acetyl aspartate (NAA), choline (Cho), creatine (Cr) and tissue lactate [67].
Tinelli et al. reported the case of a 39-year-old female patient who underwent MRI and H-MRS scans when she presented with recurring catamenial migraines without aura on the grounds of pre-diagnosed arthritis, autoimmune, SLE and Sjogren’s syndrome [68]. Multivoxel H-MRS was performed to assess posterior periventricular white matter, thalamus and basal ganglia that appeared normal in the cMRI. Results were compared to a control group of 6 other SLE patients without aura. Results from the H-MRS indicated a considerable increase in Cho/Cr peaks during headaches, compared to results during remission and to data acquired from the control group. This metabolic change may be attributed to brain injury, due to microinfarction, cell infiltration, membrane activation or neuronal degradation [69, 70, 71]. Moreover, while a decrease in NAA has been reported in SLE patients, possibly reflecting neuronal loss and dysfunctions, in the case of the aforementioned patient NAA values were normal [72]. The absence of fluctuation in NAA value can be attributed to the reversibility of symptoms and the absence of neuronal death.
Another study of 90 SLE patients and 23 healthy volunteers examined the axonal alterations in SLE using single voxel proton MRS [73]. Signals from NAA, Cho and Cr compounds were used to determine NAA/Cr ratios. Patients were then categorized into the following subgroups, according to disease activity; 29 patients with active NPSLE, 28 with active non-NPSLE, 14 patients with inactive NPSLE and 19 with inactive non-NPSLE. NAA/Cr ratios were considerably lower in patients with active SLE, regardless of whether they presented symptoms from the CNS, compared to the subgroup with inactive SLE and controls. There was a significant increase in NAA/Cr ratio in 15 of the patients who had active SLE during the initial MRS and inactive SLE at the follow-up. On the other hand, a noteworthy decrease in the NAA/Cr ratio was observed in 10 patients with active SLE in both the initial MRS and the follow-up, while an even greater reduction was noticed in 15 patients with inactive SLE at the initial MRS, but active SLE at the follow-up. These findings confirm an axonal dysfunction in patients with active SLE regardless of CNS involvement. This dysfunction seems to be at least partly reversible during periods of disease regression.
Axford et al. used quantitative MRS to determine neurometabolite changes that herald permanent neuronal loss in 9 female NPSLE patients and 8 healthy sex- and age- matched volunteers [74]. Patients with mild SLE showed a considerable increase in tCho and a smaller reversible increase in myo-inositol levels (mI). Conversely, patients with severe SLE demonstrated a significantly and permanently reduced NAA and a greatly raised mI. In this group tCho levels were normal. The above findings were once again confirmed in a systemic review that examined 26 articles [75]. It concluded that NAA/Cr ratios were considerably lower and Cho/Cr ratios relatively more increased in several brain areas in patients with SLE, SS, RA and SSc.
Lastly, a multimodal imaging study was carried out in order to evaluate metabolic and microstructural changes in the brain of SLE subjects with cognitive impairment [76]. For this purpose, 22 NPSLE patients, 21 non-NPSLE patients and 20 healthy volunteers underwent multivoxel MRS, T1-weighted volumetric images for voxel-based morphometry (VBM) and diffusional kurtosis imaging (DKI) scans. The most prominent findings were located, but not limited to, the posterior cingulated gyrus (PCG), and they were also observed in other basal ganglia regions. Even though metabolite concentrations were reduced in both patient groups, they were more severely depleted in NPSLE patients. Moreover, both groups exhibited lower diffusional kurtosis values in the PCG bilaterally compared to healthy controls. VBM scans showed GM reduction in the PCG of the NPSLE group.
To recapitulate, MRS measures alterations in neurometabolite concentrations as a determinant of neuronal degeneration and dysfunction. More research is essential for asserting whether the aforementioned method can be used to differentiate between NPSLE and non-NPSLE patients.
Conclusion
SLE is an autoimmune disease that often targets the CNS, leading to the manifestation of neuropsychiatric symptoms of mild to severe intensity. Degeneration of the brain’s perforating arterioles is the underlying vascular pathology that leads to cerebral small vessel disease. Disruption of the blood-brain barrier, increased cytokine production, as well as the neurotoxicity of circulating auto-antibodies are the key mechanisms leading to neuroinflammation, microangiopathy, chronic diffuse ischemia, thromboembolism and premature atherosclerosis. Timely diagnosis and careful monitoring of disease progression are vital for lowering mortality rates due to cerebrovascular events. Conventional MRI is considered the gold standard in diagnosing NPSLE as it is widely effective in identifying hyper intensive lesions in white matter on T2 and FLAIR weighted sequences, alterations attributable to inflammation and ischemia. On the other hand, fMRI uses differences in the ferromagnetic properties of oxygenated and deoxygenated blood to detect altered activation patterns in white matter connectivity and neuronal network dysfunction. MTI is suitable for locating signs of demyelination and axonal loss due to small-vessel disease in grey matter areas and the antineuronal action of auto-antibodies. DTI has proven to be of great assistance for identifying white matter pathologies, such as ischemia, myelination, axonal damage, inflammation, edema and impaired white matter connectivity. Additionally, FDG PET/CT demonstrates abnormalities in glucose metabolism, even in patients without any MRI findings indicative of CNS involvement. Especially when combined with fMRI, SPECT can recognize areas of cerebral hypoperfusion, due to cumulative tissue damage. Cerebral blood flow assessed using both ASL-MRI and DSC-MRI, indicates perfusion impairment located in the frontal, temporal, parietal and occipital lobes as well as the limbic structures. Lastly, MRS can detect neurometabolite changes in the posterior cingulated gyrus and other basal ganglia, which seem to signify neuronal damage or permanent neuronal loss. Future research will show whether the aforementioned non-invasive imaging techniques could be incorporated in a multimodal algorithm that would have a high sensitivity and specificity for effectively diagnosing and monitoring CNS involvement in SLE. Unfortunately, early diagnosis of NPSLE remains, to this day, a challenge for clinicians who are expected to rely mainly on observation and past patient experience.
Conflict of interest disclosure
None to declare.
Declaration of funding sources
None to declare.
Author contributions
AD, EP: writing the manuscript, original draft preparation; CA: review and editing of the manuscript; TD: supervision of the manuscript.
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