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Systemic Lupus Erythematosus is a chronic autoimmune disorder which currently affects approximately 50,000 people within the UK, a large proportion of which are female (1). This illness presents with fluctuating periods of flares and remissions, where a patient can feel well on one day, but awfully fatigued on another. Those most commonly affected are women in their early 20s and 30s (2). With a diverse range of clinical symptoms, SLE has the potential to affect almost every organ in the human body.
The symptoms are largely debilitating, ranging from fatigue, which is commonly found in 80 - 100% of patients, to weight gain, myalgia and individual organ pathologies (2). Patients often present with skin lesions, the most prevalent being a butterfly rash over the nose and cheeks, which often materialises after exposure to the sun. Alongside this common indicator of SLE, numerous non-specific symptoms have also been identified to be signs of lupus. One of these is Raynauds Phenomenon, which is indicated by a colour change of the skin and nails of digits in response to cold temperatures or changes in emotional state (2). Arthritis is also common, with over 90% of patients experiencing joint symptoms (2).
The exact scientific reasoning behind the occurrence of SLE remains questionable, but it is known to occur as a result of hormonal, environmental and genetic factors, alongside abnormalities of the immune system. SLE therefore has a multifactorial aetiology (3). Precipitating factors associated with the occurrence of SLE include:
Exposure to sunlight
Stress is also thought to contribute to the onset of flares.
Curing the illness completely is a challenge to the scientific community; as a result treatment often involves control of symptoms, and is dependent upon the extent of clinical manifestation that is expressed.
More recently, three genes have been identified to play a role in the occurrence of SLE. One of these genes, the KIAA1542 gene, has no definite known function (4). The role of the PXK gene also remains ambiguous. Lupus has also been found to be associated with variations of the ITGAM gene, which codes for the complement pathway, an integral part of the body's immune system. This supports the finding that people with Lupus are often found to have decreased amounts of complement in their blood. Two other genes - LYN and BLK, influence the activity of B cells, which in turn affect the production of antibodies. Autoantibodies hinder the activity of the body's proteins, and are known to have a profound effect in the pathogenesis of Lupus. Lupus sufferers have been found to have raised levels of antibodies to certain antigens found on the cell surface. These include anti-nuclear antibodies and antiphospholipid antibodies, which can cause cell injury and even death (3). A study published in The New England Journal of Medicine concluded that 'autoantibodies are typically present many years before the diagnosis of SLE' (5). As well as this, it was also found that autoantibodies can accumulate within the body of sufferers for prolonged periods of time, with no distinguishing symptoms of SLE until much later.
Introduction to Neuropsychiatric Systemic Lupus Erythematosus
Neurological and Psychiatric involvement is much more common in SLE than in other autoimmune disorders (6), occurring in up to 80% of SLE sufferers (7). Symptoms associated with both the central and peripheral nervous system are encompassed by the term 'Neuropsychiatric Systemic Lupus Erythematosus' (NPSLE). It has previously been difficult to define exactly the diagnostic criteria for NPSLE, hence the prevalence has appeared rather sporadic in the past. Earlier, one out of the 11 categories for defining SLE was entitled 'neurologic'. The two broad groupings of 'seizures' and 'psychosis' fell under this title (8). In 1999, the American College of Rheumatology's published their comprehensive nomenclature, which describes nineteen distinct syndromes identified in NPSLE (9), allowing inclusion of certain syndromes which may have been overseen earlier. Variation is still found within results of studies, for generic reasons such as individual differences between patients. Patients have different psychological reactions to being told that they are suffering from SLE; it is therefore important to distinguish between organic and functional psychiatric illness. This is discussed further in the section titled 'diagnosis'. An association of NPSLE with anti-phospholipid antibodies has arisen (10), providing further insight into the pathogenesis of this illness.
Table showing ACR classification of NPSLE syndromes (10)
Central nervous System
Headache (including migraine and benign intracranial hypertension)
Movement Disorders (chorea)
Acute confusional state
Peripheral Nervous System
Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre´ syndrome)
Mononeuropathy, single multiplex
A defined set of criteria widely broaden the scope for research by allowing comparability between different studies. However, these criteria may be misleading, as they could indicate that these syndromes are specific to SLE, which is incorrect. Borchers et al stated that, in a study of NPSLE from Finland, '91% of SLE patients as well as 56% of control subjects fulfilled at least one of the ACR criteria' (10). To improve the reliability and specificity of the results, syndromes which did not appear to cause neuronal damage were excluded. This resulted in a considerable decrease in prevalence of NPSLE, from '91% to 46%' in patients suffering from SLE. The specificity also increased from '0.46 to 0.93' (10).
Antinuclear antibodies are found in during serologic testing of most SLE sufferers (1`). They are therefore not particularly specific to NPSLE. As mentioned earlier, it has been found that NPSLE is often coupled with the presence of certain antibodies in the patient's blood.
Autoantibodies are proteins produced by the body which act against ones self. Antiphospholipid autoantibodies are a group of antibodies, namely 'lupus anticoagulant' and 'anticardiolipin antibody'. There are also antibodies against specific molecules, for example 'anti-beta 2 glycoprotein 1' and 'anti-prothrombin' (12). They act on phospholipids with a negative charge. The presence of antiphospholipid antibodies in the blood can indicate either primary or secondary Antiphospholipid Syndrome (APS), which is thought to contribute to NPSLE (See section titled 'Pathogenesis')
Antiphospholipid antibodies are known to cause vasculopathy and thrombosis (12). This can then result in 'cerebrovascular accidents, vascular dementia' and 'seizures' but to name a few.
There comes an issue in determining the aetiology of NPSLE, as it is often challenging to establish whether the displayed symptoms are due to organic causes or if they have a functional backing (10). Neuropsychiatric manifestations that occur due to underlying organic abnormalities fall under the descriptive term of 'lupus cerebritis' (13). To help distinguish between this and illness due to psychological processes, cognitive function tests are implemented to indicate functional illness, often alongside psychometric testing and interviews.
Cerebrospinal fluid analysis has shown that levels of anti-DNA antibodies, IgG and markers of B-cell activation are elevated in patients presenting with neuropsychiatric symptoms. Alongside this, levels of neurofilament triplet protein (NFL) and glial fibrillary acidic protein (GFAP) were considerably higher in SLE sufferers than those in a control group (11).
Although conventional neuroimaging techniques are considered essential to investigate NPSLE, there is, as of yet, no single technique that can be used to definitively diagnose NPSLE (14).
Computed tomography (CT) scanning is useful in emergency situations for detecting significant infarcts and oedema, although it remains insensitive to numerous pathologies such as demyelination (14).
Conventional Magnetic Resonance Imaging (MRI) scanning is of indispensable use in the diagnosis of NPSLE. A study by BuÄ‡a et al (15) found that eight out of ten SLE patients experiencing neuropsychiatric symptoms presented with cortical atrophy. MRI also shows diffuse 'nonfocal presentations of sle' (14) as well as focal lesions. As stated by Govoni et al (14), 'small punctuate focal lesions in subcortical white matter are the most common finding', presenting in 15-60% of patients. Appenzeller et al (16) found that a reduction in the volume of both the corpus callosum and the cerebrum occurred in SLE patients when compared to healthy non-sufferers.
This MRI scan of a forty-eight year old woman shows numerous small 'subocortical lesions' (17). She had suffered from SLE for fifteen years at the time this image was produced, and the presence of lupus anticoagulant was also detected.
Reference for image: (17)
Electroencephalogram (EEG) mapping has also been found to be abnormal in SLE patients, with 'diffuse slow wave activity' as the most common abnormality observed in those suffering from organic neurologic illness (11). However, this diagnostic tool is often considered to not be specific enough. Although it is very sensitive and detects focal changes, it has shown abnormal results for patients who do suffer from neurological syndromes without central nervous system lupus (CNS lupus) as well as those who do. Quantitative EEG is considered to be more specific, and therefore a more valued method of investigation.
It is thought that there are numerous factors contributing to the pathogenesis of NPSLE, and the exact aetiology remains unknown. Different symptoms are displayed according to the severity of the illness - it therefore affects the nervous system at different levels.
There are thought to be three major ways in which the nervous system is affected by SLE (18). These are 'vasculopathy, autoantibodies and inflammatory mediators' (18).
Tatsukawa et al (19) aimed to evaluate the cerebral blood flow in patients suffering from NPSLE. They did this using the 'brain perfusion index', which provides an estimate of the blood flow to a patient's brain. As BPI values are known to be affected by age, the BPI ratio was used throughout the study. This is the 'ratio of age predicted BPI to measured BPI value' (19). It was found that the BPI ratio in those diagnosed with NPSLE was considerably lower than in patients without NPSLE, indicating that a decreased cerebral blood flow is associated with the neuropsychiatric manifestations of SLE. This is further emphasised by considering a study by Bresnihan et al (20), which found a clear aberration in cerebral blood flow in patients who displayed neuropsychiatric abnormalities. Vasculopathy can result in damage to the blood-brain barrier (7), allowing an increased proportion of antibodies to enter the cerebral blood flow and elicit an immune response. A reduction in the proliferation of astrocytes, which play a role in maintaining the blood-brain barrier, is also thought to contribute further to the pathogenesis of NPSLE (21). Patients with SLE were found to have lower levels of complement and immunoglobulin deposits in the choroids plexus - a group of blood vessels located in the ventricles of the brain, responsible for the secretion of cerebrospinal fluid. These patients also had lowered levels of cerebrospinal fluid (20).
As mentioned earlier, autoantibodies contribute largely to the damage mechanisms of NPSLE. Zandman-Goddard et al identified twenty antibodies that contribute to the pathophysiology of NPSLE (22). These include both systemic antibodies and those that are specific to the brain.
There are numerous proposed mechanisms for the pathogenesis of NPSLE with regards to antiphospholipid antibodies. Essentially, these antibodies are known to inhibit the clotting cascade by using co-factors such as Beta-2 Glycoprotein 1 to bind to phospholipids. The function of Beta-2 Glycoprotein 1 is to inhibit the clotting cascade by binding to certain molecules found expressed on endothelial cells, therefore exerting an antithrombotic effect. If this co-factor is targeted by an antiphospholipid antibody, the glycoprotein can no longer inhibit the coagulation pathway, inducing thrombus formation. Platelets produce a greater amount of thromboxane as a result of the antibody binding to phospholipids, and the activation of Protein C is reduced (23). Both these events result in vasoconstriction, and encourage coagulation. It has been suggested that low levels of complement in patients suffering from SLE is due to 'complement activation rather than complement deficiency' (24). Levels of serum complement have been shown to be lower in patients suffering from primary antiphospholipid syndrome. Antiphospholipid syndrome can result in pregnancy complications alongside thrombosis (24).
It has been suggested that antiribosomal P antibodies contribute to the pathogenesis of the psychiatric symptoms of NPSLE. Little association has been found as of yet with 'cognitive dysfunction or psychological distress' (8). The current evidence is conflicting, with some studies establishing links between antiribosomal P antibodies and lupus cerebritis, and others finding no connection (25). Findings indicate that these antibodies attack three types of phosphoproteins which can be found on the 60s subunit of ribosomes (25), therefore inhibiting the synthesis of proteins. Further research has found an increased level of antiribosomal P antibodies in patients with 'diffuse NPSLE' compared to those with 'focal NPSLE' (26). In particular, it has been suggested that the multiple complex symptoms of NPSLE could be explained by the presence of 'IgG anti-ribosomal P antibodies' (27) in the cerebrospinal fluid of patients displaying these symptoms. Anti-ribosomal P antibodies also inhibit protein synthesis by binding to the cell and localising in the nucleus and cytoplasm (27).
It has been found that antineuronal antibodies, i.e. antibodies that 'react to neuronal components' (22) are more prevalent in patients suffering from NPSLE than those who suffer from SLE without the presence of any neuropsychiatric syndromes. Research has found that serum levels of anti-neuronal antibodies range from 43% - 95%, with levels in cerebrospinal fluid at 74% (22). In patients who did not display neuropsychiatric features of SLE, the prevalence of these antibodies was only 5% (6), indicating that they do play a role in the pathogenesis of NPSLE.
Zandman-Goddard et al compiled a table of other antibodies which have been found to contribute to the pathogenesis of NPSLE:
Diffuse NP manifestations
Glial fibrillary acidic protein
Organic/major type NP manifestations
Endothelial cell (AECA)
Psychosis; mood disorders
Table adapted from reference (22)
As can be seen, there is an extensive list of antibodies, each of which has been linked to specific symptoms of NPSLE. However, the current research surrounding a large proportion of these is conflicting, and cannot confirm definite associations.
Certain inflammatory mediators have been implemented in the pathogenesis of NPSLE.
Trysberg et al concluded that patients with CNS lupus have higher levels of intrathecal matrix metalloproteinases (28). These are a group of enzymes which are essential for normal function of the body. They play a key role in the mechanisms of processes such as remodeling of the extracellular matrix, as well as certain 'pathological processes' (18). Specific cytokines also contribute to the pathogenesis. In the same study as mentioned above, intrathecal levels of certain interleukins - IL-6 and IL-8 - were found to be elevated. These are known to 'upregulate MMP-9', suggesting that this particular matrix metalloproteinase may be involved. Another study by Trysberg et al found that the levels of the interleukins named above were, again, elevated in a group of patients diagnosed with CNS lupus compared to those without neuropsychiatric symptoms (29). The value of the CSF: serum IL-6 ratio was also raised. They conducted a follow up of five patients in which they found that, after treatment, the levels of IL-6 in the cerebrospinal fluid of patients had, in fact, decreased considerably.
Clinical presentations of NPSLE
The symptoms of NPSLE can be divided into two broad groups: neurological and psychiatric.
As mentioned earlier, the pathogenesis of NPSLE encompasses vasculopathy, which can result in impaired cerebral blood flow. It has been noted that SLE sufferers have an increased risk of stroke, with 14 out of 91 patients suffering from strokes in a study by Futrell et al (30). Out of these fourteen, nine had 'multiple cerebral infarcts'. Bernatsky et al reported that SLE patients had an increased risk of death from cerebrovascular incidents than those who did not suffer from SLE (31). It has also been found that young people who have been diagnosed with SLE are at an increased risk of suffering from 'ischemic stroke and intracerebral haemorrhage' (32).
10-20% of SLE patients are known to suffer from seizures through the course of their illness (6). Appenzeller et al found that 60 out of 519 patients (which equates to 11.6% of patients) with SLE suffered from epileptic seizures (33). Epileptic seizures are those that occur more than once i.e. are not isolated events. Of these, the most common time of occurrence was after the onset of SLE rather than directly at the onset. Of those experiencing seizures, 53 out of 60 (88.3%) were found to have 'acute symptomatic epileptic seizures' while the remaining 7 (11.7%) had 'recurrent epileptic seizures'. The causes of seizures are known to differ greatly between patients (6). The study mentioned above suggested an association of the acute seizures with both antiphospholipid antibodies and stroke. A longitudinal study conducted at the University of Maryland observed patients attending Lupus clinics from 1992 to 2004. Patients with any of the following were found to have an increased risk of seizures:
Increased 'disease activity' at onset
History of neuropsychiatric disease
Anti-cardolipin and anti-smith antibodies.
This is an extremely common symptom in patients with SLE. There is a continuous debate about the relationship of headache with SLE, as it is a common complaint that many otherwise healthy people may suffer from. The presentation of a headache must therefore be treated with caution, and NPSLE should only be established as a cause if other neuropsychiatric symptoms are present. If every headache in an SLE patient was attributed to NPSLE, it is highly likely that there would be an overestimation of the prevalence of CNS lupus (35). A study published in 'Lupus' concluded that 'headache is no more prevalent in patients with SLE than in the general population'. An association with antiphospholipid antibodies was considered, but most studies have found no concrete evidence to support this. The pathogenesis of headaches in SLE therefore remains unknown.
10-15% of SLE patients are known to develop neuropathies (6). This is therefore considered one of the less common clinical presentations. Peripheral neuropathy is generally the most common form of neuropathy observed, resulting in paresthesia and a lack of sensation for many patients. Goransson et al conducted a study which supported that neuropathy of 'small diameter' nerve fibres may occur in SLE (36). This could occur alongside a 'large diameter' nerve fibre neuropathy.
Patients suffering from this organic syndrome may present with any of the following symptoms, quoted from UpToDate (13):
'difficulty in short or long-term memory
impaired judgment and abstract thinking
This syndrome has been described as 'evanescent'(13), showing no significant correlation with disease progression. Certain studies have reported an association with antiphospholipid antibodies - in particular IgG and IgA anticardolipin antibodies (37). Others, however, report no similar association (38, 13). There is therefore a continuous debate about the exact pathogenesis of cognitive dysfunction, and whether it can be attributed to the main factors thought to be implemented in the pathogenesis of NPSLE.
Encompassing both organic and functional syndromes, this can occur as a direct result of SLE, or due to the use of drugs such as corticosteroids (39). Symptoms can include 'delusions and hallucinations' (13), as well as agitation and decreased attention. Appenzeller et al observed acute psychosis in 11.3% of the 520 SLE patients in their cohort (39). The presence of antiphospholipid antibodies was identified as a risk factor, alongside the manifestation of other neuropsychiatric symptoms. Psychosis of an organic aetiology may perhaps appear to be more common than functional psychosis, with Purandare et al reporting 4 out of the 30 patients in their study as suffering from organic psychosis ('visual and transient auditory hallucinations'), but none with functional psychosis (40). It has been suggested that auditory hallucinations more commonly occur as a result of corticosteroid use, whereas 'visual and tactile disturbances' manifest as a result of CNS lupus (13).
Treatment and prognosis
The fact that there are so many different ways in which NPSLE can manifest, and numerous different pathogenic mechanisms behind each syndrome, makes this an especially difficult condition to manage. Borchers et al (10) noted that neuropsychiatric symptoms in fact account for the majority of 'organ system damage' in SLE.
A study conducted in Hong Kong uncovered that patients with NPSLE incur higher costs of healthcare than those without neuropsychiatric manifestations. They found costs of 'USD 13 307 per patient', with 52% of this being attributed to the cost of inpatient healthcare (41).
As this is such a varied illness, there must be an individual approach to treatment for each patient to maximise the efficacy. Suggested divisions for treatment regimes include 'symptomatic, immunosuppressive and anticoagulant or antiaggregant therapies.' Anticoagulant therapies can be implicated in cognitive dysfunction that is due to antiphospholipid antibodies (13), as well as for treatment of stroke syndromes (7). Hanly suggested analysis of CSF after diagnosis to establish the presence of autoantibodies and inflammatory mediators (42), allowing further insight into the pathogenic mechanisms for the patient in question. Steroid treatment is known to be effective for organic psychosis and seizures, alongside antipsychotic drugs if required (13). Glucocorticoid therapy is used for the treatment of neuropathies, whilst the treatment of headache remains the same as for the general population (7).
The table below shows common manifestations of NPSLE and their respective treatments:
(Reference for table: 43)
The prognosis of NPSLE varies widely between patients. The introduction of various treatment therapies means that there are survival rates as high as 93% after 5 years of diagnosis of SLE (43). This may be due to improved treatment options as well as advances in diagnostic imaging. However, a poorer prognosis has been reported for patients with a history of neuropsychiatric symptoms, with 21-47% of patients needing treatment for recurrent symptoms. It has been reported that, in certain cohorts, mortality occurred in 5% of patients as a result of CNS involvement. As many as 72% of NPSLE patients still require corticosteroid treatment to manage symptoms ten years after diagnosis. Seizures in particular have been identified as a predictor of mortality in NPSLE (10). Transverse myelitis is another presentation of NPSLE, and has the potential to leave a patient in a greatly debilitated state (8).
As NPSLE remains an ambiguous illness, with little information about the exact pathogenesis, clinicians remain challenged and should aim for an early diagnosis so that treatment and management can commence as soon as possible. A team approach is required, involving healthcare professionals from many different backgrounds ranging from rheumatology to neurology (44).
There is constant research into how to improve the quality of life of SLE patients, with the recent development of a new tool named 'L-QoL' to measure the quality of life in SLE (45). This is a questionnaire consisting of 55 items, used to obtain measures of outcome, which can be used in further research. It has proven to have high reliability, and researchers concluded that L-QoL appears to be of great use in establishing outcome in SLE patients.
I believe that the lack of knowledge about the exact pathogenesis of this illness remains a hindrance to treatment. However, the introduction of the ACR criteria has greatly aided diagnosis and research, allowing the comparison and collaboration of several different studies. Advances in imaging and technology allow the identification of specific cortical changes in NPSLE, and association of these with certain syndromes to help establish an accurate course of treatment.
NPSLE remains a condition that constantly challenges healthcare experts, and further research is most certainly required in this area in order to strive for the best possible outcome for sufferers. NPSLE patients remain at a higher risk of morbidity due to the active illness, as well as due to the effects of drug therapy (46). The importance of early diagnosis must be stressed, as this could be vital for reducing the impact of devastating syndromes and achieving a comfortable quality of life for the patient.