INTRODUCTION

              

Systemic lupus erythematosus (SLE) is a multisystem disease that is caused by autoantibodies to a variety of autoantigens. It is characterized by a wide variety of clinical, serological manifestations and relapsing remitting course¹. Neuropsychiatric manifestations are commonly found in patients with SLE and are an important cause of morbidity and mortality in these patients². In 1999, the American College of Rheumatology developed case definitions for 19 neuropsychiatric syndromes in SLE (NPSLE) to standardize definitions, diagnostic criteria, exclusions, associations and diagnostic testing³. 

Central nervous system (CNS) symptoms occur much more frequently than peripheral nervous system symptoms in NPSLE. Moreover, diffuse CNS manifestations, such as cognitive dysfunction, psychosis, acute confusional state, anxiety and mood disorders occur more commonly than focal CNS symptoms in most studies. The focal CNS symptoms including; stroke, demyelinating syndromes, chorea and transverse myelitis are most frequently secondary to vascular events caused by antiphospholipid antibodies^4-7.

Neuroimaging can be a useful part of the initial assessment when NP manifestations are suspected following clinical evaluation in patients with SLE⁷. Magnetic resonance imaging (MRI) is currently considered the standard technique for evaluating morphological brain abnormalities in NP­SLE. Most research studies have identified diffuse cerebral atrophy, small cortical infarcts and non-specific foci of increased signal in gray and white matter on T₂-weighted images, but the clinical significance of these findings is often unclear^8-11. However, substantial populations of patients with SLE do not have abnormal brain MRI and have only NP symptoms^10-11.

Magnetic resonance spectroscopy (MRS), a non invasive technique that measures biochemical metabolites in the brain, is a promising imaging modality⁷. In SLE, MRS has been performed in an attempt to detect early CNS involvement or to demonstrate abnormalities in some patients with NPSLE in whom structural MRI failed to showed any focal changes^12-15. Many authors, found a decrease in N-acetyl aspartate (NAA) /creatine (Cr) ratio and an increase in choline (Cho) /Cr ratio in white matter of NPSLE patients^10,12-15.

The aim of this study was to assess the role of 1H-MRS in detection of spectral changes in NPSLE patients especially when MR imaging failed to show any abnormalities, and, to correlate their clinical data with MRI and 1H-MRS abnormalities.

 

PATIENTS AND METHODS

              

This study was carried out on  patients who fulfilled the 1997 updated American College of Rheumatology criteria for SLE¹⁶. They were recruited from inpatient and outpatient clinics of Neurology and Rheumatology & Rehabilitation Departments of Zagazig University Hospitals.  

Inclusion criteria: All patients had NP manifestations which were defined according to American College of Rheumatology (ACR) nomenclature for NPSLE³.

Exclusion criteria: We excluded patients with (1) SLE without NP manifestations, (2) who were unable to undergo MRI technique such as patients with claustrophobia, pacemaker and prosthetic valves, and (3) NP manifestations secondary to infection, drug side effects and malignancy.

Disease duration was defined as the time between initial manifestations clearly attributed to SLE and the day of magnetic resonance spectroscopy acquisition.

Twenty-three patients with NPSLE and 8 healthy volunteers with similar age and gender distribution (control group) were included in this study. The study was approved by the Ethical Committee of our Faculty and informed written consent was obtained from patients and controls. 

 

All patients and controls were subjected to:

1-      Full history taking.

2-      Thorough general and neurological examinations

3-      Assessment of disease activity, using SLE Disease Activity Index (SLE DAI)¹⁷.

4-      Neuropsychological assessment:

-        Assessment of depression was based on clinical interview and the Beck Depression Inventory (BDI)¹⁸.

-        Cognitive function was assessed by using a comprehensive test battery included: (1) Digit span: forward and backward, to assess verbal memory / attention domains¹⁹; (2) Digit symbol: to test sustained attention and concentration¹⁹; (3) Similarities: to test abstract reasoning; (4) Controlled Oral Word Association Test (COWA): to test language domain²⁰; (5) Trial making test(B): to detect executive function²¹; (6) Benton visual retention test: it measure immediate visual recall memory and visuospatial ability²². The individual test results were compared with the available data of the controls. Patients with a score of two or more standard deviation below the normative value in any of the six domains (attention, memory, language, visuospatial ability, reasoning and executive function) were considered impaired.    

5-      Neuroradiologial studies: Brain MRI and 1H-MRS were done for patients and controls.

 

MRI and MRS Techniques:

MR imaging and single-voxel 1H brain spectroscopic examinations were performed with a 1.5-T whole-body MR imaging and spectroscopic system (MR Achieva Philips Medical Systems) equipped with actively shielded gradients and a quadrature head coil. The MRI examination included axial and sagittal  Tı-weighted images, axial T₂ – weighted images and axial FLAIR (Fluid attention inversion recovery). The MRI was evaluated for cortical atrophy, ventricular enlargement, T₂/FLAIR high signal intensity lesions in periventricular white matter and large infarcts.

Three dimensional proton spectroscopic imaging was performed with a repetition time (TR) of 1500 ms and an echotime (TE) of 135 ms using single voxel MRS. Water suppression was achieved using three Gaussin shaped chemical shift selective pulses (CHESS) technique.

The voxel was placed over the parieto-occipital periventricular white matter in all examined patients and healthy volunteers. In patients with abnormal MRI lesions, a second voxel was placed over the lesions (white matter hyperintensities, focal hyperintensities or large infarctions). The size of the voxel was approximately 8 cm³ (2 x 2 x 2 cm).

The number of peaks fitted included the chemical shift ranges restricted to 3.1–3.3 ppm. for choline (Cho), 2.9–3.1 ppm. for creatine (Cr) and 1.9–2.1 ppm. for N-acetyl aspartate (NAA). The lipid-macromolecule-lactate peaks at 1.25–1.35 ppm were integrated. The relative ratios of NAA/Cr and of Cho/Cr were evaluated in the parieto-occipital white matter in all patients and volunteers and in areas of MRI abnormal lesions.

 

Statistical Analysis

               The collected data were statistically analyzed using SPSS version 11, comparison between group means was done using student's t-test and (ANOVA) F- test, while chi-squared test and Kappa agreement were used for qualitative data. The significance level was considered at P value <0.05.    

 

RESULTS

              

This study included 23 patients with NPSLE, 21 females and 2 males, their age ranged from 18 to 36 years (mean±SD= 26.4±5.3 years). The mean duration of the disease was 32.5±5.3 months, While, the mean SLE DAI was 17.3±6.1. The NPSLE diagnosis that was present at study entry is shown  in table (1). The most common NP manifestations were headache in 9 patients (39.1%), cognitive deficits in 9 patients (39.1%), while, cerebrovascular events occur only in 2 patients (8.7%), as shown in Table (1) .

Nine of the 23 patients (39.1%) had abnormal findings on MRI. These findings were cerebral atrophy, scattered single or multiple foci or patchy areas of increased signal intensity on T₂-weighted or FLAIR images in the periventricular white matter and infarction. NPSLE patients were divided into two groups according to the presence or absence of MRI abnormalities. Group I included 14 patients with normal MRI, while group II included the remaining 9 patients with abnormal MRI. Table 2, showed that there was no significant difference between the 2 groups regarding clinical data.    

The mean NAA/ Cr and Cho/Cr ratios and their ranges for the 23 NPSLE patients and for the eight controls were measured. We found a significant decrease in NAA/Cr  ratio and a significant increase in Cho/Cr ratio in the parieto-occipital WM in 20 patients (86.9%) compared with those in the controls. Eleven of these patients in group I  and 9 patients were in group II.   

Using Kappa agreement, we found that spectral changes in 1H-MRS was in agreement and statistically significant (0.46±0.17, P=0.001**) with NP manifestations, compared with MRI changes (0.08±0.07, P=0.8 NS). Table (3).

When comparing neurometabolities ratio of MRS with both groups and the reference control, we found that, in patients with abnormal MRI, NAA/Cr ratio was significantly lower than those with normal MRI and control groups (1.35±0.16* Vs 1.6±0.1 and 1.75±0.13 respectively), and Cho/Cr ratio was significantly higher than those with normal MRI and control groups (0.9±0.05* versus 0.85±0.06 and 0.77±0.065 respectively). The mean NAA/Cr ratios in parieto-occipital white matter were reduced in patients groups while mean Cho/Cr ratios were higher than in the control.( Table 4).

 

Table 1. General characteristics, neuropsychological features of our NP SLE patients.

 

Criteria	NPLSE patients (n = 23)
Age         (years±SD)	26.4±5.65
Sex          (F/M)	21/2
Disease duration (months±SD)	32.5±5.3
SLE DAI ±SD	17.3±6.1
	No	%
Acute confusional state	1	4.3
Cognitive dysfunction	9	39.1
Mylopathy	2	8.7
Headache	9	39.1
Mood disorder (Depression)	6	26.1
Peripheral neuropathy	1	4.3
Stroke	2	8.7
Movement Disorders( Chorea)	2	8.7
Seizures	5	21.7
MRI abnormalities	9	39.1
1H-MRS changes	20	86.9

SD standard deviation, SLE DAI Systemic lupus erythematosus disease activity index

 

Table 2. Demographic characteristics and neuropsychological features between studied groups.

 

Variables	Group I (n = 14)		Group II (n = 9)		P-value
Age (Mean±SD) years	24.67±6.0		27.5±5.3		0.24
Sex (F/M)	13/1		8/1		0.66
Disease duration(mean±SD) months	30.3±5.5		34.6±5.1		0.07
SLEADI (mean±SD)	16.4±7		18.2±6		0.5
Neuropsychological features	No	%	No	%
Acute confusional state	0	0.0	1	11.1	0.39
Cognitive impairment	4	28.4	5	55.5	0.38
Mylopathy	2	14.2	0	0.0	0.5
Headache	6	42.8	3	33.3	0.98
Mood disorder (Depression)	4	28.4	2	22.2	0.16
Peripheral neuropathy	1	7.14	0	0.0	0.25
Stroke	0	0.0	2	22.2	0.14
Movement Disorders( Chorea)	1	7.14	1	11.1	1.0
Seizures	2	14.2	3	33.3	1.0

Table 3. Agreement between 1H-MRS changes, MRI abnormalities and clinical features.

 

Neuropsychological features	Clinical features		MRI abnormality		MRS changes
	No	%	No	%	No	%
Acute confusional state	1	4.3	1	100.0	1	100.0
Cognitive impairment	9	39.1	5	55.5	8	88.9
Mylopathy	2	8.7	0	0.0	1	50.0
Headache	9	39.1	3	33.3	8	88.9
Mood Disorder (Depression)	6	26.0	2	33.3	5	83.3
Peripheral neuropathy	1	4.3	0	0.0	0	0,0
Stroke	2	8.7	2	100.0	2	100.0
Movement disorder (Chorea)	2	8.7	1	50.0	2	100.0
Seizures	5	21.7	3	60.0	5	100.0
Kappa agreement Kappa Coefficient			0.08±0.07 0.8		0.46±0.17 0.001*

* Significant at p<0.01

 

Table 4. Metabolic ratio of ¹H-MRS of patients and control groups.

 

POWM MRS ratios	Group I  (n = 14)	Group II  (n = 9)	Control (n=8)	P-value
NAA-Cr	1.6±0.1	1.35±0.16*	1.7±0.13	<0.001*
Cho-Cr	0.85±0.06	0.9±0.05*	0.77±0.065	<0.01*

POWM Parieto-occipital white matter

* Significant at p<0.01

 

			(B)
	(A)

 

 

Figure 1. (A) MRS voxel placement upon the LT parieto-occipital white matter

of healthy volunteer. (B) NAA/Cr ratio= 1.78 and Cho/Cr ratio=0.77

 

 

 

Figure 3.               MRS curve of 25 years old female  with headache and depression, MRI showed no abnormalities, while MRS curve showed decrease in N-acetyle aspartate  level with NAA/Cr = 1.62 and increase in Choline level with Cho/Cr = 0.91.

					(C)
			(B)
	(A)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 4. (A) T₂WI of 28 years old female with seizures showed multiple periventricular white matter areas of high signal mostly represent ischemia with vasculitis. (B) MRS curve of the LT POWM shows increase in choline and reduction of NAA, with NAA/CR=1.11 and Cho/Cr=0.89. (C) MRS curve of the detected lesions shows further increase in choline with reversed Cho/Cr ratio = 1.17.

 

			(A)		(B)
	(A)

 

 

Figure 5. (A) T₂WI of 30 years old female with headache and seizures showed LT temporal lobe (LT hippocampus region) high signal intensity suggest vasculitis with tissue inflammation. (B) MRS curve shows increase in choline with reversed Cho/Cr ratio = 1.2, with decrease NAA/Cr ratio = 1.31.

 

 

DISCUSSION

 

               System   ic lupus erythematosus is a multisystem autoimmune disease, in which NP manifestations are a common cause of significant morbidity¹.  The ACR has identified 19 distinct NP syndromes associated with SLE³. NPSLE manifestations may be caused by hypercoagulability and endothelial damage in cerebral vessels (vasculopathy), proinflammatory cytokines, autoantibody effects on neuronal structures or receptors, BBB disruption and metabolic derangements^2,5,6.

           In the present study, the most frequent NP syndromes among our 23 patients were headache (39.1%), cognitive dysfunction (39.1%), depression (26%) and seizures (21.7%). A literature search from April 1999 to May 2008 was performed by Unterman et al.⁴, to identify studies investigating NP syndromes in patients with definite SLE. They reported that, when all 17 studies were pooled together, the most frequent NP syndromes among 5051 patients were headache, mood disorders, seizures, cognitive dysfunction and cerebrovascular diseases.

Cognitive impairment is one of the most common and clinically challenging manifestations of SLE, but its pathophysiology remains poorly understood^2,7,23. Cognitive dysfunction was defined by the ACR as significant deficits in any or all of the following cognitive functions: attention, reasoning, executive skills, memory, visuospatial processing, language and psychomotor speed^3,7,23. Using neuropsychological tests, cognitive dysfunction was detected in 9 patients (39.1%) out of 23 NPSLE patients. This figure is in agreement with those reported by Abdel-Naser et al.²⁴ and Brey et al.²⁵  where cognitive impairment was detected in 37.5% and 41.4% respectively. However, the prevalence of cognitive dysfunction is higher than our results^4,23. 

Conventional MRI sequencing of the brain is a technique that is widely used for evaluating NPSLE and has proven to be more sensitive than CT⁸. The most common findings seen with MRI include areas of increased signal in various locations of the white matter on T₂-weighted imaging, infarction, and brain atrophy^8-11. In the present study such morphological brain abnormalities were present in 9 of the 23 SLE patients (39.1%) entering the study with NP manifestations. This is markedly lower than the 60-70-86% seen in  previous studies^9,13,14, but it is in agreement with Oku et al.²⁶, who found MRI abnormalities in 35% of NPSLE.

Although MRI appears sensitive for detecting abnormalities in patients with focal neurological defects, its sensitivity is very low in patients with diffuse neuropsychiatric disturbances such as headache, cognitive dysfunction and depression. Furthermore, many patients with NPSLE have no abnormal findings on MRI^{9-11,13,27,28}. These findings may explains the lower percentage of MRI abnormalities as the most frequent NP manifestations in our study were headache, cognitive dysfunction and depression. In addition, we found 14 (60.9%) NPSLE patients with normal MRI.

MRS is the only non invasive technique that routinely used in clinical practice and research that allows assessment of in vivo metabolism at the molecular level^6,12,14,28. This technique shows four major spectra corresponding to different metabolites. NAA which can be considered a marker of neuronal integrity, Cho that are released during active myelin breakdown; Cr which has a constant concentration throughout the brain and tends to be resistant to change and lactate^12,15,29.

Several previous studies of MRS in patients with NPSLE have demonstrated a decrease in NAA/Cr ratio in the basal ganglia, frontal white matter, peritrigonal white matter and parieto-occipital WM^{10,12-15,28-30}. The reduction in NAA is believed to be a result of neuronal injury caused by microinfarcts from extensive small vessels damage. Raised Cho has been ascribed to inflammatory process rather than to demyelinating or cell membrane degradation^10,15,31,32.

In accordance with these studies, our results demonstrated a significant decrease in NAA/Cr ratio and a significant increase in Cho/Cr ratio in the parieto-occipital WM in 20 patients (86.9%) compared with those in the controls. These patients include 11 in group I (normal MRI) and all patients in group II with abnormal MRI. These results support the idea that MRS abnormalities could precede the appearance of hyperintense lesions in T₂ or FLAIR sequences due to CNS involvement of SLE. These metabolic abnormalities suggested that they could represent an early sign of neuronal injury in NPSLE patients, even in the presence of normal brain MRI. Thus is useful in making a diagnosis at the subclinical stage of the disease^13-15,28-30.

A follow up study of the patients who had a further MRI some years later was performed by Castellino et al.²⁹, three of them showed new MRI lesions in areas previously positive to MRS and negative on MRI examination. These data, if confirmed, may be predictive of future parenchymal damage, as suggested by Axford et al.¹⁵. However in the Appenzellar et al.³⁰ study, after 19 months of follow up, they did not observe that the low NAA/Cr ratio predispose to the appearance of structural lesions detected by MRI. Perhaps longer periods of observation are necessary to detect the appearance of these lesions as suggested by Castellino et al.²⁹.

In our study, we found significant differences in the metabolic ratios between patients with abnormal MRI and those with normal MRI and controls. Similarly. These significant differences were detected in previous studies^{10,13,28,31,32}. In contrast, the study of Sundgen et al.¹⁴ was not able to demonstrate any differences in spectroscopic parameters between patients with and without MRI abnormalities. Appenzellar et al.³⁰ reported that NAA/Cr ratio were lower in SLE patients with MRI abnormalities but no difference in Cho/Cr values.

In the current study, we found non significant relation between cognitive dysfunction and MRI abnormalities. In one small study of patients with NPSLE  individuals with cognitive impairment had more cerebral atrophy and large T₂-weighted lesions than NPSLE patients with normal cognitive abilities¹¹. Other studies, however, have not found significant associations between specific MRI findings and cognitive function in SLE^7,8,9,33. On the contrary, we detected significant relation between cognitive dysfunction and MRS abnormalities. Preliminary studies of MRS in patients with NPSLE suggested that decreased level of NAA and increased Cho/Cr ratio in gray and WM correlate with cognitive abnormalities in adult SLE^31,33,34. Lapteva et al.³⁴ reported that MRS in patients with SLE with moderate or severe cognitive dysfunction had significantly higher Cho/Cr ratio compared with patients with mild cognitive dysfunction or normal cognition.

Conclusion

          In our NPSLE patients, MRS findings seem to reflect the cerebral metabolic disturbances even in absence of morphological lesions detectable by MRI. MRS may be a useful technique in the early detection and evaluation of CNS abnormalities in NPSLE. The combination of MRI and MRS may be useful to improve the diagnostic value and gain a better understanding of the pathophysiological mechanisms responsible for brain damage in SLE.

 

[Disclosure: Authors report no conflict of interest]

 

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