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October2013 Vol.50 Issue:      4 Table of Contents
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Neuropsychiatric Manifestations in Clinically Silent Patients with Systemic Lupus Erythematosus

Enas Mahmoud Hasen1, Hana Ahmed Sadek2, Salwa Mohamed Rabee3, Lamia Hamdy4

Departments of Neurology1, Rheumatology2, Psychiatry3, Clinical Pathology4, Minia University; Egypt


Background: The diagnosis of neuropsychiatric syndromes concurrent with systemic lupus erythematosus (SLE) is one of the most difficult challenges in medicine. Objective: The study aimed to determine the neuropsychiatric (NP) manifestations in clinically silent SLE patients and to study the effectiveness of cognitive evoked potential studies in assessment. Methods: Twenty-five SLE patients were evaluated for NP manifestations and compared with 15 healthy controls. The patients were subjected to neuropsychiatric examinations: laboratory, Mini-Mental State Examination (MMSE), Hamilton Depression Scale, and Hamilton Anxiety Scale as well as disease activity markers and neurophysiology; nerve conduction study (NCS) and P300 evoked potential. Results: The most prevalent NP manifestations were headache and depression 17 patients (68%), epileptic symptoms in 15 cases (60%), peripheral neuropathy signs in 12 patients (48%) and anxiety in 10 patients (40%). Abnormal EEG findings were observed in 11 cases (44%). The MMSE showed cognitive impairment in 9 patients (36%). There was sensorimotor neuropathy in SLE patients and positively correlated with markers of disease activity. Prolonged P300 latency was found in one SLE patient with negative correlation with disease activity markers. Conclusion: The presence of subclinical neuropsychiatric affection even in asymptomatic patients should be investigated. Its early management may affect quality of life or even the disease process itself. P300 wave reflects the cognitive level of SLE, which is more objective than MMSE score and may be a valuable and noninvasive new index for evaluating the level of cognitive function in SLE patients. [Egypt J Neurol Psychiat Neurosurg.  2013; 50(4): 403-409]

 Key Words: SLE, SLEDAI, SLAM, cognitive function, depression, anxiety, neurological disorders.

 Correspondence to Enas Mahmoud Hasen.Department of Neurology, Minia University, Egypt. Tel.: +201224477931    e-mail: enas_mahmoud1 @yahoo .com. 



Systemic lupus erythematosus (SLE) is a relapsing-remitting autoimmune disease with wide ranging organ involvement and clinical symptoms varying from mild and transient symptoms to death.1The neurological and psychiatric manifestations of SLE reflect either transient or chronic injury to the CNS, and one may assume that similar processes contribute to neuropsychological testing abnormality in this disease. The reported percentage of patients with neuropsychiatric involvement has varied in the literature due to a lack of uniform clinical criteria.2 In 1999, an American College of Rheumatology (ACR) committee defined 19 neuropsychiatric (NP) SLE features or syndromes, categorized as either central or peripheral nervous system, and focal or diffuse. The diagnosis of neuropsychiatric syndromes concurrent with SLE is one of the most difficult challenges in medicine.3


Cognitive impairment could be viewed as a distinct subset of neuropsychiatric manifestations of SLE, which might be affected by a variety of disease factors including hypertension or SLE therapy (for example, immunosuppressive drugs), in addition to concurrent medical and psychosocial issues. Given the complexity of this issue, the importance of accurately defining cognitive impairment in patients with SLE using standardized, objective testing, with appropriate controls in place, cannot be over emphasized.4

Studies of cognitive evoked potentials (also known as the P300 or P3 cognitive evoked potentials) have been used in research settings to correlate changes in cognitive evoked potentials with clinical changes in cognitive function in patients with dementia (as Alzheimer's disease and Parkinson's disease). However, there is insufficient evidence regarding the effectiveness of cognitive evoked potential studies in diagnosing or rendering treatment decisions that would affect health outcomes.  Furthermore, there is a lack of studies comparing cognitive evoked potential studies with standard neuropsychiatric and psychometric tests used in diagnosing cognitive dysfunction.5

Aim of the work

In the present study, we aimed to determine some of the neuropsychiatric manifestations (NP) of systemic lupus erythematosus (SLE) in patients apparently not complaining from NP manifestation and to study the effectiveness of cognitive evoked potential studies in assessing SLE and comparing it with standard neuropsychiatric and psychometric tests used in diagnosing cognitive dysfunction.




Twenty-five SLE patients (24 females and 1 male) were selected at the Rhumatology outpatient clinic of Minia University Hospital.

All patients met the diagnostic criteria of SLaccording to American College of Rheumatology (ACR).6 Patients aged above 18 years old and apparently not suffered from neurological or psychiatric symptoms were included in the study. They were subjected to; full medical, neurological, and rheumatological evaluation. Rheumatologic evaluation was completed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)7, and systemic lupus activity measurement index (SLAM).8  SLEDAI is a reliable and valid instrument for measuring the clinical state of SLE patients.7,9

Patients were subjected to neurophysiological assessment including;  scalp EEG recordings were obtained and coded as normal (within the range of frequency and amplitude distribution for age and conscious state, as defined in standard clinical EEG literature10), epileptiform (spikes, sharp waves, spike-slow wave or sharp-slow wave complexes of focal or generalized distribution) or abnormal non-epileptiform (deviations from normal in terms of background frequency patterns, usually in the form of excessive slow activity). Secondly, motor nerve conduction velocity (MCS) studies were performed on the ulnar, median and common peroneal nerves. Sensory Conduction Studies (SCS) of median, ulnar and sural nerves were also done. Finally, P300 evoked potential in Nihon Coden-Neuropack manger v08.01 apparatus. Two types of auditory stimulation were presented at the rate of 0.5Hz. High frequency sounds appear at random with an occurrence rate of 20% and low frequency sounds appear at regular train with an occurrence rate of 80%. During the test, the patient was asked to count the occasionally high frequency sounds (target stimulation) in the regular train of low frequency sounds (non-target stimulation). This is commonly called an oddball task.

Patients were also subjected to psychometric assessment including; mini-mental state examination (MMSE) which is a widely used scale for screening for cognitive affection.11  As some of our subjects in the present study were illiterate, the two points testing reading and writing were excluded, and the full score was calculated as 28 instead of 30 points. The cutoff point of affection was 22 instead of 24 points.12 In the present study, dementia was diagnosed if the clinical presentation fulfilled criteria of dementia as well as when the subject scored ≤21 on the MMSE.13 Secondly, Hamilton Depression Scale (HDS), a widely used and reliable scale14, where the cutoff point of depression in this scale is ≥17, according to Michele and Bolino.15 Finally, the Hamilton Anxiety Scale (HAS) which lists 14 types of symptom. The total score ranges from zero to 56. A total score of 18 or more means anxiety.16

All patients had laboratory investigations done including; (a) complete blood count, ESR, kidney & liver functions, urine protein in 24 hours, (b) antinuclear (ANA) and anti-double-stranded DNA (anti-dsDNA) were measured using enzyme-linked immunosorbent assay method.

We excluded: (1) severe or comatose patients, (2) patients with pre-existing clinical cardiovascular or cerebrovascular events as angina, myocardial infarction, transient ischemic attack, or stroke, (3) other systemic diseases (such as renal, liver, or endocrinal diseases) or taking drugs known to have central nervous system effects, and (4) other rheumatological diseases.

Fifteen healthy individuals matched for age and sex, were selected as a control group. These control groups were examined for nerve conduction study (NCS) and p300 evoked potential.


Statistical Analysis

Data entry and analyses were done using software SPSS version 16.Quantitative data were presented by mean and standard deviation, while qualitative data were presented by frequency distribution. Independent sample t test was used for comparison. The probability of less than or equal to 0.05 was used as a cut off point for significance.




We studied 25 (24 females and 1 male) patients with age ranged from 18-48 (mean 25±5.3) years old. The duration of illness ranged from 5 months to 8 years (3±2.3).

Frequencies of neuropsychiatric manifestations were illustrated in (Table 1). The neuropsychiatric manifestations arranged by their order of frequency were headache as well as depression (n: 17, 68%), followed by epileptic symptoms (n: 15, 60%) then peripheral neuropathy signs (n: 12, 48%) and anxiety (n: 10, 40%).

In the MMSE, 16 patients (64%) had within average normal scores. The other 9 patients (36%) were divided into 6 patients with probable cognitive impairment and 3 patients with definite cognitive impairment.

Abnormal EEG findings were observed in 11 cases (44%) of SLE [six (24%) showed high-voltage slow waves and spike slow waves and sharp waves; four (16%) focal and one (4%) bifrontal sharp activity] (Figure 1).

The frequency of the peripheral neuropathy signs (as glove &stock hypothesia) in SLE patients were 12 (48%) while in NCS were 19 (76%) [12 sensory and 7 sensori-motor], which means subclinical neuropathic affection.

In table (2),  there was a highly significant difference of all parameters of NCS of the median, ulnar, common peroneal and sural nerves between SLE patients and the control group, except some parameters [median and ulnar sensory amplitude] which reflects sensorimotor neuropathy [mixed axonal and demyelinating] in SLE patients. There was no significant difference between SLE patients and control groups in p300 evoked potential latency except for prolonged latency of P300 evoked potential in one SLE patient.

A series of Pearson correlation coefficients between SLEDAI; SLAM; ANA; ESR; 24hour urine protein as anti DNA ab [markers of disease activity] and duration of illness; neuropsychiatric manifestation, MMSE [especially attention and memory recall] was calculated. There were significant negative correlations between HDS and 24h protein [r: -0.5, p≥0.01] which may indicates that the depression was masked by the activity (severity) of the SLE itself. The HAS was positively and highly significantly correlated with the duration of the illness (r: 0.78 & p≥0.0001).

There was significant negative correlation between some of SCV of ulnar (r:-0.39, P ≥0.05) and sural (r: -0.46, P≥ 0.02) nerves with markers of the disease activity (SLAM). This means that increasing in the disease activity was associated with decreasing in the sensory conduction velocity indicating the underlying systemic pathology of neuropathy due to SLE disease.

The P300 evoked potential showed no significant statistical difference between SLE patients and control groups. The P300 evoked potential latency showed negative significant correlation with disease activity markers (r: -0.58, P≥0.002). However, MMSE was not significantly correlated with disease activity markers. This indicates that the increase in disease activity leads to delay in the P300 latency but this is not the case in the MMSE reflecting the sensitivity of P300 evoked potential over MMSE.



Table 1. Frequency of Neuropsychiatric manifestations in patients with systemic lupus eryethmatosus.


Neuropsychiatric manifestations

Number 25



vascular without aura

vascular with aura











Vertginous attacks

Tonic-clonic seizures







Neurological examination

pyramidal tract affection

















Neuropathic signs



















not affected








HDS Hamilton Depression Scale, HAS Hamilton Anxiety Scale, TIAS Transient Ischemic Attacks



Figure 1. The frequency of electroencephalography changes in patients withsystemic lupus erythematosus


Table 2. Comparison of different nerve study parameters between SLE patients and control groups.


Nerve parameter

Control: 15


Cases: 25





Median          M



3.5 ± 0.5

3.4 ± 1.5


3.6 ± 0.7

2.8± 0.4







Ulnar             M


3.1 ± 0.5

2.6 ± 0.5

3.6 ± 0.8

3.1 ± 1





Common peroneal

3.6 ± 0.5

5.9 ± 1.6



Amplitude CMUP

Median          M



9 ± 2.7

20.6 ± 9.5


4.09 ± 0.5

16.1 ± 4







Ulnar            M


10.7 ± 1.9

16.8 ± 3.5

5.7 ± 1.8

17.6 ± 3.4





Common peroneal

4.7 ± 2.1

2.8 ± 1.5




Median         M



55.6 ± 2.6

57.8 ± 8


49.5 ± 4.6

42.7± 7.4







Ulnar            M


57 ± 2.5

57.2 ± 2.8

53.4 ± 5

38.1 ± 11.4





Common peroneal

51.7 ± 3.5

47.6 ± 8



Sural           DL



3.2 ± 0.3

13.2 ± 0.5

44 ± 2.8

3.9 ± 0.6

9.5 ± 3.6

36 ± 5.3







CV Conduction Velocity, CMUP Compound Motor Unit Potential, DL Distal Latency, M Motor, S Sensory, SCV Sensory Conduction Velocity **Significant at p<0.01




The most prevalent neuropsychiatric manifestation was headache 17 (68%) as well as depression 17 (68%), followed by epileptic symptoms 15(60%) then peripheral neuropathy signs 12 (48%) and anxiety in 10 cases (40%).This was in agreement with Nery and colleagues17, who found thirty-five cases out of 71 (49.2%) presented with major depression, and 37 cases (52.1%) presented with anxiety disorders. Shehata and colleagues18 also reported anxiety in 65%, depression in 58% and headache in 38% of their SLE patients. Several factors might explain these high prevalence rates including the stress of having a chronic disease and the high doses of corticosteroids commonly used in its treatment.

On the other hand, there were significant negative correlations between HDS and 24h protein, which may indicates that the depression was masked by the activity of the SLE itself.  In contrast to Nery and colleagues19, who found that the antiribosomal P antibody is highly associated with both lupus psychosis and severe depression  and explained by the intriguing evidence suggesting that some patients with SLE may have organic forms of depression caused by autoimmune lesions in the CNS.

HAS was positively and highly significantly correlated with the duration of the illness (r: 0.78& p≥ 0.0001). This result in agreement with Nery and colleagues17, who hypothesized that the high prevalence of some anxiety disorders could be linked to feelings of embarrassment experienced in public by some SLE patients due to the skin and facial disfigurements that can result from the disease or treatment.

There is no specific or unique pattern of cognitive impairment in SLE, and many individual patients have subclinical deficits. In our study, the MMSE showed that 9 patients (36%) had cognitive affection [6 patients with probable cognitive impairment and 3 patients with definite cognitive impairment]. This was in accordance with Hanly20, who revealed subclinical cognitive impairment in 11%-54% of patients. Fisk and colleagues21 reported that impaired immediate memory and concentration implies increased disease activity that may represent transient and diffuse CNS effects, however in the present study, there was no significant correlation between MMSE and markers of disease activity.

In the present study, the three cases with definite cognitive impairment in MMSE score presented with fronto-temporal sharp activity in the EEG record, this in accordance with Monastero and colleagues22, who proposed that a fronto- temporo-parietal dysfunction might account for the cognitive deficits found in SLE patients.

Abnormal EEG findings were observed in 11 cases (44%) of SLE [6 cases (24%) showed high-voltage slow waves and spike and sharp waves; 4 cases (16%) showed focal activity, and 1case showed (4%) bifrontal sharp activity] indicating diffuse slow activity, which is generally considered a sign of organic brain disease and is the most common EEG abnormality recorded for SLE as reported by Khedr and colleagues23, and Shehata et al.18

In our study, there was a highly significant difference between all parameters of NCS [median, ulnar, common peroneal and sural nerves] in patients with SLE and the control group, indicating sensori-motor peripheral neuropathy among SLE patients. Significant negative correlation of the SCV of ulnar and sural nerves with SLAM indicates the underlying systemic pathology of neuropathy due to SLE disease process. The NCS showed frequency (n: 19, 76%) higher than the frequency of clinical signs of peripheral neuropathy (n: 12, 48%) and this finding means subclinical affection. These results in partial accordance with Hanly20, who reported that sensorimotor neuropathy had been found in up to 28% of SLE patients and frequently occur independently of other disease characteristics, and Khedr and colleagues23, who observed significant reduction in amplitude of motor NCS of ulnar, median, and common peroneal nerves among SLE patients compared with the control group.

There was no significant difference between SLE patients and control groups in p300 evoked potential latency except of prolonged latency of P300 evoked potential in one SLE patient. This might be explained by small sample size. This is in accordance with Khedr and colleagues23, who found abnormal prolongation of the P300 component of event-related potentials was recorded in 2 patients (12.5%) of the asymptomatic group.  However, in the present study, there was negative significant correlation between P300 and MMSE meaning that prolonged latency was associated with decrease in the MMSE score. As P300 wave reflects the cognitive level, therefore it might be more objective than MMSE score in detecting cognitive affection in SLE patients. Consequently P300 evoked potential might be a valuable and noninvasive new index for evaluating the level of cognitive function in SLE patients.



The presence of subclinical neuropsychiatric affection even in asymptomatic patients and should be investigated and treated to prevent their complications, so this may lead to improvement in quality of life or even in disease process (activity) itself. P300 wave reflects the cognitive level of SLE, which is more objective than MMMSE score and may be a valuable and noninvasive new index for evaluating the level of cognitive function in SLE patients.


[Disclosure: Authors report no conflict of interest]




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الملخص العربي


الأعراض النفسية والعصبية في مرضى الذئبة الحمراء الذين لا يعانوا من أعراض اكلينكيا


تمثل الأمراض النفسية والعصبية فى مرضى الذئبة الحمراء نسبه كبيرة حتى لو لم تكن محل شكوى وتشخيصها من أكثر الأمور صعوبة. تهدف هذه الدراسة إلي تقييم وتحديد الأعراض النفسية والعصبية فى مرضى الذئبة الحمراء الذين لا يعانون من أعراض ظاهره ودراسة فاعليه الجهد المستثار المعرفى لتحديد تأثر القدرات المعرفية فى هؤلاء المرضى. فقد شملت هذه الدراسة خمسه وعشرون من مرضى الذئبة الحمراء وقورنوا بخمسه عشر كعينه ضابطه. وقد خضع مرضى الذئبة الحمراء  للأتي:

-        أخذ التاريخ المرضي  وفحص روماتزمى وفحص للجهاز العصبى شامل.

-        فحص عصبى مصغر للقدرات المعرفية، مقياس هاملتن للأكتئاب والقلق.

-        فحص معملى شامل وخاصة دلالات نشاط المرض.

-        كما تمت دراسة توصيل الأعصاب الطرفية والجهد المستثار المعرفى فى المرضى والعينة الضابطة P300 evoked potential.


ونستخلص من نتائج هذه الدراسة الأتى: أن أكثر الأعراض وجودا هى الصداع والأكتئاب (68%) تليها أعراض التهاب الأعصاب الطرفية (48%) ثم القلق (40%). وقد لوحظ أنه يوجد تغيرات برسم المخ الكهربائى بنسبه (44%) من المرضى. ولقد وجد تأثر بالأعصاب الطرفية ذات دلالة إحصائية بين المرضى والأصحاء وهذه التغيرات تتناسب طرديا مع دلالات نشاط المرض. وقد وجدنا تأثر الجهد المستثار المعرفى فى مريض واحد فقط. كما وجدنا أن الجهد المستثار المعرفى p300 يتناسب عكسيا مع دلالات نشاط المرض فى حين أن الفحص  العصبى مصغر للقدرات المعرفية لم يظهر هذا الفرق وهذا يعنى أن الجهد المستثار المعرفى يستطيع أن يقيم تأثر القدرات المعرفية.

ونستنتج من هذه الدراسة أن الأعراض النفسية والعصبية توجد برغم من عدم وجود شكوى فى مرضى الذئبة الحمراء والقيام بتشخيصها وعلاجها يمكن أن يؤثر فى تحسن نوعيه الحياة أو تدهور المرض نفسه. كما نستنج ان الجهد المستثار المعرفى يعكس المستوى الإدراكى بشكل أفضل من الفحص العصبى المصغر للقدرات المعرفية مما يجعله أكثر وأسهل انتشارا فى تقييم الوظائف المعرفية فى مرضى الذئبة الحمراء.


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