Role of susceptibility weighted imaging and evoked potential studies in early detection of neuropsychiatric manifestations in the patients with systemic lupus erythematosus

Peer review under responsibility of Alexandria University Faculty of Medicine.

Available online 13 January 2014

Abstract

Background

Central nervous system involvement in SLE as a part of neuropsychiatric lupus is a complex diagnostic entity due to its multiple clinical presentations.

Objective

This study aimed to assess the value of susceptibility weighted imaging (SWI) and neurophysiological assessment on 30 patients with SLE in order to determine the value in the early diagnosis and management of neurological manifestation of lupus.

Materials and methods

Thirty patients with ACR criteria for SLE are involved in this study. Antiphospholipid antibodies, SWI, and evoked response studies were used to assess neurological involvement in SLE.

Results

Eighteen patients presented with clinical neurological manifestations attributed to neurological lupus. Abnormal SWI findings were found in 16 patients. 11 SLE patients were positive for antiphospholipid. 17 patients presented with abnormal neurophysiological parameters. No correlation between individual neurophysiological disorders (NPD) and specific neuropsychiatric symptoms was observed. There was no significant correlation between the electro physiologic findings and SLE related auto antibodies.

Conclusions

SWI and neurophysiological studies may provide a useful test in the evaluation and management of early neurological lupus.

Abbreviations:

• SLE
• systemic lupus erythematosus
• CNS
• central nervous system
• SWI
• susceptibility weighted imaging
• PA
• antiphospholipid antibodies
• aCL
• anticardiolipin antibodies
• LA
• lupus anticoagulant

KEYWORDS:

• Systemic lupus erythematosus
• Neurological lupus
• Susceptibility weighted imaging
• Neurophysiological tests

Introduction

Systemic lupus erythematosus (SLE) is a chronic, autoimmune, multiorgan disease with a broad spectrum of clinical manifestations. SLE with involvement of the central nervous system (CNS), which is often called neuropsychiatric SLE (NP-SLE), is one of the most important manifestations of SLE.¹ The condition may be both neurological and psychological,^2,3 and the reported prevalence of CNS involvement varies in different studies.^4–8 This probably reflects differences in patient selection, different criteria for NP-SLE, differences in the neuropsychological tests used and the lack of standard diagnostic instruments for CNS manifestations.

The pathogenesis of CNS dysfunction in SLE is not well understood. The observation of both diffuse and focal CNS involvement in SLE has led to the hypothesis that there are several pathogenic mechanisms in NP-SLE, such as micro vascular damage, small-vessel vasculopathy and autoantibody-mediated neuronal cell injury.^9–12

Many biochemical and immunological studies have been undertaken in an attempt to identify specific abnormalities which might be helpful to the clinician.¹³ In addition, the value of imaging techniques has been investigated.¹⁴ However, despite considerable research, the management of neurological lupus has not been facilitated by the emergence of sufficiently reliable or practical investigative techniques. Neurophysiological techniques have been of value in the assessment of neurological symptoms occurring in other diseases such as multiple sclerosis.^15,16

The aim of the present study was to assess the value of susceptibility weighted imaging (SWI) and neurophysiological studies on thirty randomly selected patients with SLE in order to determine whether this form of assessment might be of value in the diagnosis and management of neuropsychiatric manifestations of SLE and to correlate the radiological and electrophysiological abnormalities with SLE related auto antibodies.

Methods and patients

Thirty SLE patients were randomly selected from a population attending the Department of Rheumatology. All patients fulfilled the American Rheumatism Association, 1982 revised criteria for SLE. A detailed history and clinical examination of all patients were performed. The study also included 15 age and sex matched healthy control subjects. The entire protocol was approved by Human Ethics Committee of the Faculty of Medicine, Alexandria University, Egypt and informed consent was obtained from each human subject prior to participation.

Several investigations like autoantibody batteries [antiphospholipid antibodies (PA), anticardiolipin antibodies (aCL) and lupus anticoagulant (LA)], susceptibility weighted imaging (SWI), and electro diagnostic studies [somatosensory evoked potential (SSEP), visual evoked potential (VEP) and brain stem auditory evoked response (BAEP)] were all used to study neuropsychiatric involvement in SLE.

Patients were evaluated with routine MRI sequences; namely axial and sagittal T1-weighted images, axial and coronal T2-weighted images and coronal T2-weighted images as well as FLAIR sequences, in addition to susceptibility weighted imaging. Studies were performed on a 1.5 T MRI scanner (General Electric Medical Systems). T1-weighted images were acquired utilizing 500/20/2 TR, TE, excitations, 256 × 256 matrixes, FOV of 20 cm, 6 mm slice thickness, and 0.6 mm inter-slice gap. The T2-weighted images were acquired utilizing 4000/100/2 TR, TE, excitations, 256 × 256 matrixes, FOV of 22 cm, 5 mm slice thickness and 0.5 mm inter-slice gap. The SWI sequence parameters were TR/TE 500/30, number of excitations 2, flip angle 20°, 5 mm contiguous slices.¹⁷

Statistical analysis

The data were collected and entered into the personal computer. Statistical analysis was done using Statistical Package for Social Sciences (SPSS/version 20) software.

Arithmetic mean, standard deviation, for more than two groups ANOVA test was used. The level of significance was 0.05.

Results

The study included thirty SLE patients, the patient characteristics are summarized in Table 1. The mean age of the patients was 31.3 ± 9.9 years (range: 9–49).

Table 1 Patient characteristics and neuropsychiatric manifestations in SLE.

Patient characteristics	Number	Percent
Age (years)
Range	9–49
Mean ± SD	31.3 ± 9.9
Sex
Male/female	2/28	6.7/93.3
Disease duration (years)
Range	1–20
Mean ± SD	6.7 ± 4.9
Positive clinical findings:
Hypertension	11	36.7
Nephritis	6	20.0
Neuropsychiatric complaints
Absent	12	40.0
Psychotic manifestation	3	10.0
Headache (migraine)	6	20.0
Mood disorder (depression)	2	6.7
Seizure disorders	3	10.0
Polymyositis	3	10.0
Cerebrovascular diseases	7	23.3
Total	30	100.0

Twenty-eight patients were females (93.3%), while two patients were males (6.7%). The duration of SLE ranged between 1 and 20 years with a mean of 6.7 ± 4.9.

Hypertension was found in 11 patients (36.7%) and nephritis was found in 6 patients (20%).

There were 18 (60%) patients who presented with definite neuropsychiatric events and twelve (40%) patients were neurologically free. Stroke was the most frequent neurological manifestation (7 patients), another 6 patients presented with headache mostly migraines, 3 patients with psychosis, 3 patients with epilepsy, two patients with mood disorder like depression, and 3 patients with polyneuropathy. Six SLE patients had more than one neuropsychiatric symptom. Seizures can occur at any time during the course of the disease. Psychosis was found in the younger age group (ranged between 12 and 29 years) while patients with polyneuropathy were about 45 years of age. Neuropsychiatric signs were significantly present in patients with hypertension (p = 0.02) and nephritis (p = 0.03).

The routine MR imaging sequences were relatively insensitive for small micro hemorrhages resulting from underlying vasculopathy and only detecting the residual area of encephalomalacia; however the SWI was sensitive for detection of areas of old micro hemorrhages and abnormal vasculopathy resulting in the formation of hemosiderin that causes local magnetic field in homogeneity.

Abnormal SWI findings were found in 16 patients. Patients with abnormal SWI were divided into 14 patients with focal parenchyma lesions, 2 patients with brain atrophy. Patients with focal parenchyma lesions were subdivided into 9 patients with multiple lesions <1 cm located in the sub cortical white matter (SSCL) and 5 cases with lesion >1 cm (infarcts). One of these patients had mixed small sub cortical lesions and infarct. There was no statistical significant difference between the age of the patients and the abnormal SWI findings (p = 0.36). Moreover, the duration of the disease did not differ significantly among those with normal or abnormal SWI (p = 0.51).

The presence of abnormal radiological findings and the distribution of the different SWI categories were significantly more frequent in the hypertensive patients (p = 0.004, p = 0.00, respectively). There were twelve (40%) patients without neuropsychiatric manifestations but the SWI was abnormal in 5 of them, 3 of them had small sub cortical lesions and 2 had cortical cerebral atrophy (Figs. 1 and 2).

Figure 1 Female patient 42 years old suffering from SLE presented with neurologic deficit. (A) Axial T2-weighted image, (B) axial FLAIR images, (C) axial SWI revealed old sizable ischemic insult targeting the left temporo-parietal region with hemosiderin deposition due to underlying vasculopathy.

Figure 2 Male patient 41 years old suffering from SLE presented with neurological deficit. (A) Axial T1-weighted image, (B) axial FALIR image, (C) axial T2-weighted image, (D) SWI image revealed sizable ischemic insult targeting the right temporo-parietal region with hemosiderin deposition elicited on SWI.

Assessment of SLE related auto antibodies revealed, eleven SLE patients (37%) were PA positive. Of the patients with PA positive, 5 (17%) had positive aCL and 3 (10%) had positive LA and another 3 (10%) had both aCL and LA. The mean age of patients with or without positive PA was not significantly different. The frequency of positive auto antibodies in patients with vascular insults was higher than those without but with no statistical significant difference. The distribution of immunoserological findings was different among the different SWI categories (Table 2).

Table 2 Radiological changes associated with phospholipid antibodies.

SWI		PA-	aCL Ig G+	aCL Ig M+	LA+
		N = 19	N = 8	N = 4	N = 6
Normal	NO	10	2	2	2
	%	52.6	25.0	50.0	33.3
Atrophy	NO	2	0	0	0
	%	10.5	0	0	0
Infarct	NO	2	2	1	2
	%	10.5	25.0	25.0	33.3
SSCL	NO	4	3	0	2
	%	21.1	37.5	0	33.3
SSCL and infarct	NO	0	1	1	0
	%	0	12.5	25.0	0
SSCL and atrophy	NO	1	0	0	0
	%	5.3	0	0	0

SSCL: small subcortical lesions, infarcts larger than 10 mm lesions.

PA: antiphospholipid.

aCL IgG/IgM: anticardiolipin immunoglobulin G, M.

LA: lupus anticoagulant.

As shown in Table 3, the mean evoked potential study parameters were significantly altered in SLE patients compared to controls. Evoked potential abnormalities were detected in seventeen patients (57%). In SLE patients with neuropsychiatric symptoms, 12 patients out of 18 had neurophysiological abnormalities as shown in the prolonged latencies and diminished amplitudes in SSEP and VEP. Also, altered BAEP as manifested by prolonged wave L1 absolute latency and prolonged interpeak interval 111-V.

Table 3 Comparison between SLE patients and controls regarding evoked potential parameters.

	Patient group	Control group	P
SSEP
Latency (ms)	20.21 ± 3.65	19.84 ± 0.98	0.658
Amplitude (uv)	3.04 ± 0.89	5.78 ± 1.64	0.048^*
VEP
Latency (ms)	130.03 ± 166.37	98.98 ± 2.7	0.022^*
Amplitude (uv)	9.36 ± 2.69	12.61 ± 4.73	0.043^*
BS auditory EP (wave latency/ms)
L1	2.01 ± 1.15	1.64 ± 0.25	0.048^*
L2	2.94 ± 0.22	2.74 ± 0.22	0.522
L3	4.69 ± 1.30	3.89 ± 0.21	0.107
L4	5.47 ± 0.41	5.06 ± 0.27	0.336
L5	6.33 ± 0.36	5.75 ± 0.30	0.277
BAEP (interpeak latency/ms)
I–III	2.95 ± 0.40	2.17 ± 0.37	0.582
I–V	4.79 ± 0.35	4.11 ± 0.38	0.692
III–V	2.57 ± 0.42	1.86 ± 0.27	0.042^*

SSEP: somatosensory evoked potential.

VEP: visual evoked potential.

BAEP: brain stem auditory evoked potential.

* P value <0.05 was considered statistically significant.

Abnormalities in the peripheral nerve conduction were found in two patients. In patients with no neuropsychiatric symptoms, five (42%) had abnormalities in SSEP, VEP and BAEP.

Abnormal BAEP was significantly more frequent in the older age group as shown in prolonged wave L2 latency (p = 0.4) and prolonged interpeak intervals 1-V and 111-V (p = 0.00, p = 0.01, respectively). Moreover, BAEP wave L4 latency was significantly more prolonged in patients with longer disease duration (p = 0.015).

There was no statistical significant correlation between individual neurophysiological disorders and specific neuropsychiatric symptoms. Moreover, there was no significant correlation between abnormal electrophysiologic findings and SLE related auto antibodies.

Discussion

In the present study, there was no statistical significant correlation between abnormal radiological findings in SWI and the age of the patients and the duration of the disease. Csepany et al.¹⁸ reported that no correlation was found between the MRI findings and age of the patient at the time of the diagnosis and the duration of SLE which means that involvement of the CNS may occur any time during the course of SLE. In contrast, Gonzales¹⁹ reported that CNS lesions in patients with SLE were associated with patient age and with disease duration, but the patients in their study were younger, the duration of SLE was shorter. With the progress of the disease, the effect of risk factors as age and hypertension might have more significant influence on the MRI findings.

SWI is a three dimensional velocity-compensated gradient echo sequence that combines both magnitude information (used in conventional MR images, including T2^∗ GE with phase information to accentuate the visibility of susceptible foci such small veins and hemorrhage. Micro-hemorrhages contain hemosiderin, which is paramagnetic relative to normal tissue and leads to large variations in local magnetic fields and a local reduction in T2^∗. The signal intensity loss is proportional to the amount of hemosiderin present. SWI, with its unique sensitivity to blood products and hemorrhage, is well-suited to detect imaging changes consistent with cerebral angiopathy.^14–17

In the current study, abnormal radiological findings detected by SWI in SLE are more common in patients with neurological deficits than those without and these abnormalities are significantly more frequent in the hypertensive patients. Moreover, the distribution of the different SWI findings especially infarcts differed significantly between hypertensive and normotensive patients. The American College of Rheumatology for NP-SLE provided case definitions for 19 neuropsychiatric syndromes seen in SLE.¹ Some authors consider that stroke is one of the most important complications of SLE.^20,21

Various auto antibodies have been implicated in pathogenesis of NP-SLE including aCL and LA. In this study, 37% of patients with SLE were PA positive. Abnormal aCL and LA were more frequent in patients of cerebrovascular insult. However, there was no statistically significant difference in the percentage of the patients with or without positive PA subtypes and neuropsychiatric involvement.

In the present study, small sub cortical lesions <1 cm detected in SWI were more frequent (10 out of 30) than larger lesions (5 out of 30), and the presence of these lesions did not significantly correlate with the immunological status of the patients. In this context, several studies found that the frequency of increased serum level of aCL was higher in patients with active NP-SLE compared to those without CNS affection.^22,23

Case studies of patients with antiphospholipid syndrome and lupus have demonstrated microscopic infarcts of the cortical gray matter and fresh and recanalized thrombi with fibro muscular webs of the leptomeningeal arteries.²⁴ This type of CNS involvement might remain unrecognized by MRI because of limited resolution of the examination. The small sub cortical lesions might be related to vessel wall changes caused by either SLE itself or hypertension whereas the larger infarcts associated with PA of thrombotic origin result in unique vascuolopathy.^25,26 Many studies suggest that this unique vasculopathy seen in SLE is highly associated with PA antibodies.^27,28

In the present study, 19 patients (63%) had within normal serum PA although the majority of them had abnormal evoked potential parameters implying that these SLE related auto antibodies may not be involved in the pathogenesis of abnormal electrophysiological findings in the subclinical NP-SLE. Mowaffak et al.²⁹ studied 20 patients with SLE and they reported that almost all patients with SLE (except two) had within normal serum aCL level although all except one had abnormal motor evoked potential parameters. Also, they concluded that the normal levels of the assessed antibodies in the study pointed out to their negligible pathogenic contribution to the motor evoked potential changes in neurologically asymptomatic patients.

Similarly, Ainiala et al.³⁰ stated that the motor evoked potential abnormalities are most probably related to brain ischemia due to small vessel vasculopathy not mediated by SLE related auto antibodies.

From the current study, it can be concluded that electrophysiological studies can be a useful tool to detect subtle CNS involvement in neurologically asymptomatic patients. However, to confirm its efficiency and reliability as a screening tool, it should be compared with one of the MRI techniques that detects CNS involvement at the microscopic level. Detecting electrophysiological abnormalities in neurologically asymptomatic SLE patients should improve treatment decisions and management.

Therefore, we suggest performing the SWI and electrophysiological studies in SLE patients, even in the asymptomatic ones, early in the course of the disease in order to detect the CNS involvement.

In our study, the presence of neurophysiological and radiological abnormalities in neurologically asymptomatic patients may have a value in early detection of the neuropsychiatric manifestations. If these observations are extended and confirmed, SWI and neurophysiological studies may provide a useful test to the clinician in the evaluation and management of neurological lupus.

Conflict of interest

None declared.

Notes

Peer review under responsibility of Alexandria University Faculty of Medicine.

Available online 13 January 2014