Studies on Neuropsychiatric SLE
Steup-Beekman, G.M.
Citation
Steup-Beekman, G. M. (2011, June 17). Studies on Neuropsychiatric SLE.
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CHAPTER 1
General Introduction
Systemic Lupus Erythematosus
Epidemiology and Symptomatology
Systemic lupus erythematosus (SLE) is a chronic multisystem inflammatory autoimmune disor- der, characterized by flares and remissions. There is a broad spectrum of clinical presentations ranging from rash and arthritis through anemia and thrombocytopenia to serositis, nephritis and neuropsychiatric manifestations. Therefore, it may easily be confused with other diseases.
Diagnosis is based on clinical assessment supported by investigations, including the finding of autoantibodies. SLE is potentially fatal when major organs are affected. The original 1971 criteria established by the American College of Rheumatology (ACR) for the classification of SLE
Table 1. The ACR 1982 revised classification criteria for SLE.* 1
Criterion Definition
1. Malar rash Fixed malar erythema, flat or raised
2. Discoid rash Erythematosus raised patches with keratotic scaling and follicular plugging;
atrophic scarring may occur in older lesions
3. Photosensitivity Skin rash as an unusual reaction to sunlight, by patient history or physician observation
4. Oral ulcers Oral or nasopharyngeal ulcers, usually painless, observed by physician 5. Arthritis Non erosive arthritis involving two or more peripheral joints, characterized by
tenderness, swelling or effusion
6. Serositis a. Pleuritis (convincing history of pleuritic pain or rub heard by physician or evidence of pleural effusion) or
b. Pericarditis (documented by ECG or rub or evidence of pericardial effusion) 7. Renal disorder a. Persistent proteïnuria >0.5 g/day or >3+ or
b. Cellular casts of any type
8. Neurologic disorder a. Seizures (in the absence of other causes) or b. Psychosis (in the absence of other causes) 9. Hematologic disorder a. Hemolytic anemia or
b. Leucopenia (<4.0*109/l on two or more occasions) or c. Lymphopenia (<1.5*109/l on two or more occasions) or
d. Thrombocytopenia (<100*109/l in the absence of offending drugs) 10. Immunologic disorder a. Anti-dsDNA: antibody to native DNA in abnormal titer or
b. Anti-Sm: presence of antibody to Sm nuclear antigen or c. Positive finding of antiphospholipid antibodies based on
1) an abnormal serum level of IgG or IgM anticardiolipin antibodies or 2) a positive test for lupus anticoagulant using a standard method or 3) a false positive serologic test for syphilis known to be positive for at least six months and confirmed by Treponema Pallidum immobilization or fluorescent treponemal antibody absorption test
11. Antinuclear antibody An abnormal titer of ANA by immunofluorescence or an equivalent assay at any time and in the absence of drugs known to be associated with ‘drug-induced lupus syndrome’
* ACR, American College of Rheumatology; SLE, systemic lupus erythematosus; ECG, electrocardiogram;
anti-dsDNA, antibodies against double stranded DNA ; anti-Sm, antibodies against Smith antigen; ANA, antinuclear antibody.
have been revised in 1982 and updated in 1997, resulting in a list of eleven items.1,2 The diag- nosis SLE is based on these ACR criteria and requires at least four of the eleven listed features at some time in the course of the disease (Table 1).
Up to 90% of patients with SLE are female. There is a peak age of onset of the disease between the late teens and early forties. SLE occurs more frequently in ethnic groups of African or Asian ancestry. The estimated prevalence ranges from 40 cases per 100.000 persons among Northern Europeans to more than 200 per 100.000 persons among blacks, in whom the disease can be more severe than in white patients.
In SLE patients, life expectancy has improved from an approximate 4-year survival rate of 50% in the 1950s to a 15-year survival rate of 80% today.3 Most important causes of death are manifestations of the lupus itself, infections and cardiovascular disease.
During the course of the disease 20-35% of SLE patients will develop the antiphospholipid syndrome.4 This syndrome is defined as the association of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin and anti-β2glycoprotein I antibodies) with arterial and venous thrombosis or recurrent fetal loss.5,6 It was first described in patients with SLE (secondary antiphospholipid syndrome) but it may also occur in the absence of any other disorder (primary antiphospholipid syndrome).7 Antiphospholipid syndrome complicating SLE substantially increases the risk of organ damage and death.8
Several drugs may cause a variant of SLE called drug-induced lupus. The best known of these drugs are procainamide, hydralazine, and quinidine. Patients with drug-induced lupus usually present with skin and joint manifestations; renal and neurological manifestations are rare.
The use of anti-tumor necrosis factor alpha (anti-TNFα) therapies is associated with the induc- tion of autoantibodies. However, anti-TNFα-induced lupus is rare, though renal and cerebral involvement as well as the presence of anti-double stranded DNA (anti-dsDNA) antibodies is more common compared to classical drug-induced lupus, suggesting different pathogenetic mechanisms.9
Pathogenesis
Autoantibodies play a major role in the pathogenesis of SLE, but the exact pathogenetic mechanism remains largely unclear. An important hypothesis is that clinical disease in SLE is the end stage of a process where normal immunity progresses from benign autoimmunity to pathological autoimmunity and finally clinical disease under the influence of genetic and environmental factors.10 Defects in the clearance of apoptotic cells have been described which could lead to aberrant uptake by antigen-presenting cells. These cells subsequently present the previously intracellular antigens to T and B cells, thus driving the immune process.11
Autoantibodies
The hallmark of SLE is the production of a variety of autoantibodies binding a normal component or peptide of the patient’s cells and tissues, for example antinuclear, anti-dsDNA, anti-histone,
anti-SSA, anti-SSB, anti-Sm, anti-RNP, anti-C1q, antiphospholipid and anti-ribosomal P protein antibodies. The development of autoantibodies long before the onset of clinical symptoms of lupus was demonstrated, showing the presence of antibodies to dsDNA, which are highly spe- cific for SLE, on average 2.7 years and up to 9.3 years before diagnosis.10 Anti-Sm and anti-RNP antibodies appeared shortly before diagnosis, suggesting a peak of auto-immunity resulting in clinical illness. The data also suggest that autoantibodies alone do not necessarily result in clinical disease and additional factors play a role.
Genetics
The concordance rate for lupus is 25% among monozygotic twins and 2% among dizygotic twins, indicating that genetic contribution is important, but not sufficient to cause lupus.12,13 Genes of the major histocompatibility complex, particularly HLA-A1, -B8 and -DR3 have been linked to lupus.14 Genetic susceptibility to lupus is inherited as a complex trait and eight sus- ceptibility loci with confirmed linkage to SLE have been identified. In particular, an interval on the long arm of chromosome 1, 1q23-24, is linked with SLE. Clinically active SLE is character- ized by high erythrocyte sedimentation rates but normal C-reactive protein (CRP) levels. CRP, complement and serum amyloid P protein are important in clearing apoptotic cell debris and the genes for CRP have been mapped to chromosome 1, 1q23-24.
Aberrant cytokine patterns play a possible role in the pathogenesis. Analyzing the expres- sion of mRNA of white blood cells from SLE patients compared to controls has revealed that a gene signature attributed to overexpression of the interferon alpha pathway is present in patients. Abnormal signal transduction is also observed in cells from SLE patients compared to cells from healthy controls.15
Environmental factors
Ultraviolet radiation is the most obvious and well known environmental factor that can exac- erbate disease manifestations in SLE. Silica exposure is also postulated as a risk factor for the development of lupus, as is occupational exposure to mercury. Unlike scleroderma, there is no association with solvent use.
Bacterial and viral infections can be responsible for an aberrant immune response leading to a loss of tolerance towards native proteins. A temporal association between the onset of lupus and the occurrence of Epstein-Barr virus (EBV) infection has been reported.16-18 Furthermore, investigators showed increased frequencies of infected B cells, increased EBV viral loads and viral gene expression in lupus patients. However, the immune dysregulation of the disorder itself could also result in aberrant EBV expression.15
Hormonal factors
SLE is a disease predominantly affecting women of child bearing age and a role for female hormones seems likely. It is not clear though, how sex hormones could promote lupus, and the impression that exogenous estrogens may negatively influence lupus disease activity is
not derived from reproducible direct evidence. In the SELENA trial, adding a short course of hormonal replacement therapy was associated with a small risk for increasing the natural flare rate in lupus, most of them mild to moderate.19 A prospective randomized trial evaluating the effect of oral contraceptives on lupus disease activity demonstrated no increase in severe or mild-moderate flares in lupus patients.20 This was also concluded in a recent review on the safety of contraceptive method use among women with SLE.21 However, combined hormonal contraception is not warranted in women with positive antiphospholipid antibodies given their baseline elevated risk of thrombosis.
Therapy and prognosis
A number of medications are commonly used in the treatment of SLE, including nonsteroidal anti-inflammatory drugs, antimalarials (primarily hydroxycholoquine), glucocorticoïds and immunosuppressive agents (including cyclophosphamide, methotrexate, azathioprine and mycophenolate mofetil). High dose systemic glucocorticoïds (e.g. 1 to 2 mg/kg/day of predni- sone or equivalent, or as intermittent intravenous ‘pulses’ of methylprednisolone) used alone or in combination with immunosuppressive agents are generally reserved for patients with significant organ involvement, particularly renal and central nervous system disease.22 Trials of hormonal treatments for lupus, such as dehydroepiandrosterone, have been disappointing.23 In patients with APS complicating SLE, antithrombotic therapy is the mainstay of treatment to reduce the risk of recurrent thrombo-embolism.24
Despite advances in the treatment of SLE, SLE-associated infections and renal failure, increased mortality rate in SLE patients (standardized mortality ratio 2.4) compared with the general population remains a major concern. Mortality rates in a large SLE cohort suggested particular risk associated with female sex, younger age, shorter SLE duration, and black/African American race. The risk for death primarily related to lupus activity (such as renal disease), has decreased over time, while the risk for deaths due to circulatory disease does not appear to have diminished.25
Neuropsychiatric Systemic Lupus Erythematosus
Definition and clinical symptoms
Neuropsychiatric symptoms in SLE (NPSLE) are frequently observed. Prevalence ranges from 15 to 91%, depending on definitions, diagnostic criteria and patient selection and is estimated to be 56% in selected prospective studies.26-29 Around the time of diagnosis of SLE, 28% of SLE patients experience at least one neuropsychiatric symptom.30 Clinical symptoms arise from central and peripheral nervous system dysfunction and vary from mild cognitive dysfunction to severe neurological and psychiatric manifestations such as stroke and psychosis. The spectrum
of nervous system abnormalities in SLE includes diffuse and focal manifestations. Focal neuro- logical symptoms, such as paralysis or sensory deficits, have been associated with the occur- rence of thrombo-embolic events. Neuropsychiatric manifestations in SLE patients may occur in the absence of either serological activity or other systemic disease manifestations.31
A major difficulty in studying NPSLE has been the lack of consensus in defining the disease.
The heterogeneity of clinical NPSLE manifestations and the often unspecific nature of these syndromes have contributed to the difficulty rheumatologists have in defining NPSLE. Up to now, there is no specific test to diagnose NPSLE and attribution of neuropsychiatric events to SLE activity primarily requires exclusion of secondary causes of neuropsychiatric symptoms by appropriate assessment of clinical presentation, laboratory results, and imaging data. NPSLE is still a diagnosis made ‘per exclusionem’ by expert opinion. In literature, NPSLE is defined as
‘neurological syndromes of the central, peripheral and autonomic nervous system and psychi-
atric syndromes observed in patients with SLE in which other causes have been excluded’.32 In 1999 ‘The ACR Nomenclature and Case Definitions for Neuropsychiatric Lupus Syndromes’, a consensus document with in,- and exclusion criteria, was published to serve as a guide for researchers and clinicians to identify individual NPSLE disorders and facilitate research (Table 2).33 Examination of this classification system, describing case definitions for 19 central and peripheral nervous system syndromes, shows that NPSLE is not a uniform entity, nor is it likely to be the consequence of a single pathogenetic mechanism. The ACR nomenclature defines several associated conditions that must be excluded for each syndrome before a definitive diagnosis is made that a neuropsychiatric manifestation is the result of the disease itself (pri- mary NPSLE). Possibly 40% of all neuropsychiatric events in SLE patients are the consequence of secondary conditions related to SLE, such as metabolic derangement based on lupus nephritis, hypertension and side effects of medication (secondary NPSLE).34
Table 2. Neuropsychiatric syndromes in SLE defined by the ACR.* 33 Central Nervous System Peripheral Nervous System 1. Aseptic meningitis
2. Cerebrovascular disease
13. Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome)
3. Demyelinating syndrome 14. Autonomic disorder
4. Headache 15. Mononeuropathy single / multiplex
5. Movement disorder (chorea) 16. Myastenia Gravis
6. Myelopathy 17. Cranial neuropathy
7. Seizure disorders 18. Plexopathy 8. Acute confusional state 19. Polyneuropathy 9. Anxiety disorder
10. Cognitive dysfunction 11. Mood disorder 12. Psychosis
*ACR, American College of Rheumatology.
Central Nervous System (CNS) manifestations
The most frequent neuropsychiatric syndromes in SLE are headache, mood disorders, cognitive dysfunction, seizures and cerebrovascular disease, though there is significant heterogeneity of prevalence estimates between studies.29
Headaches are often reported by patients with SLE and the incidence of migraine has been suggested to be higher than in general population.27,28 However, a meta-analysis has refuted this.35
Psychiatric manifestations are also common in patients with SLE. Their rate of occurrence varies widely, from 17% to 75% of patients, as a result of the lack of standardized definitions for SLE-related psychiatric syndromes.36,37 Though mood disorders can be direct manifestations of SLE activity, they may also be a secondary response to a life-altering chronic disease. Depres- sion seems to be the predominant psychiatric manifestation, with rates ranging from 2% to 54% reflecting the large variation in diagnostic criteria. Psychosis is rare and develops in up to 8% of SLE patients. Psychosis has also been reported in 1.3–5% of SLE patients taking high-dose corticosteroids.36
The prevalence of cognitive dysfunction is within the 17–66% range in most studies, but when neuropsychological evaluation tools are used, cognitive dysfunction is found in nearly 80% of SLE patients. The majority of patients have mild to moderate cognitive dysfunction with a favorable prognosis, while severe cognitive impairment develops in 3-5% of SLE patients.
Cognitive dysfunction has been linked to antiphospholipid antibodies in adults.38-40
Cerebrovascular disease (transient ischemic attack (TIA) and stroke) occurs in 5-20% of SLE patients. Ischemic stroke is the most common manifestation. The mechanisms underlying cerebrovascular disease in SLE include thrombosis (related to antiphospholipid antibodies), hypertension, and thrombocytopenia (bleeding). Lupus anticoagulant is strongly associated with stroke, both in SLE and the general population. This effect is even stronger in young age groups (<45 years).41
Seizures are a well recognized complication and have been reported in 14-25% of SLE patients compared to 0.5-1% in the general population.40,42 Seizures in SLE patients are often general- ized, but also focal seizures may occur. Seizures may be related to active SLE, post ischemic scar tissue, or acute inflammation. The risk of epilepsy in SLE is increased in those patients with higher disease activity at baseline, prior NPSLE, and with anti-cardiolipin and anti-Sm antibodies.43
Abnormal movements occur in only 1-3% of patients, the most common pattern being chorea.40,42 Both chorea and transverse myelitis are associated with the presence of antiphos- pholipid antibodies.44,45 Transverse myelitis manifests as paraplegia, usually of abrupt onset.
Demyelinating syndrome is a rare syndrome of unknown cause described as a combination of multiple sclerosis symptoms and imaging findings and SLE antibodies. Lupus meningitis may be inaugural and usually runs a self-limiting course, although with multiple episodes. Lympho- cytes or, occasionally, polymorphonuclear leukocytes predominate in the cerebrospinal fluid, which is clear and free of organisms.
Peripheral Nervous System (PNS) manifestations
Peripheral neuropathy is far less common in SLE than in necrotizing vasculitis. Cranial or periph- eral nerve involvement occurs in 10–15% of SLE patients, usually concomitantly with lupus flares. The three main patterns of peripheral neuropathy are predominant sensory neuropathy in a stocking-glove distribution, single or multiplex mononeuropathy with asymmetric hand or foot drop, and ascending polyradiculoneuropathy (Guillain-Barré syndrome).
Pathogenesis and pathology
The pathogenesis of primary NPSLE manifestations is not fully understood, but is likely to be multifactorial. Three potential mechanisms of nervous system injury in SLE are frequently described and investigated: vascular damage (microangiopathy, vasculitis and thrombosis), autoantibody mediated cytotoxicity (antineuronal, antiribosomal-P and antiphospholipid antibodies) and inflammatory mediators (intrathecal production of proinflammatory cytokines, Il-2, Il-6, Il-8 and Il-10, TNFα, interferon alpha and matrix metalloproteinase-9).
Twenty autoantibodies associated with NPSLE, detected in the serum or CSF, are reported in the literature: eleven autoantibodies related to brain components and nine systemic auto- antibodies which are also found in general SLE populations. However, no specificity was found among these 20 autoantibodies for any single NPSLE manifestation.46 A wide spectrum of focal as well as diffuse neuropsychiatric manifestations has been associated with the presence of antiphospholipid antibodies (anti-cardiolipin IgM and IgG antibodies, anti- β2glycoprotein I IgM and IgG antibodies and lupus anticoagulant) including cerebral ischemia, migraine, cogni- tive dysfunction, seizures, chorea, transverse myelitis, psychosis, depression and Guillain-Barré syndrome. Cerebral involvement is common in antiphospholipid syndrome and was already highlighted in the original description of the syndrome in 1983.7 Recently, evidence from animal studies showed the importance of the integrity of the blood-brain barrier in SLE-related neuropathology and it plays a crucial role in facilitating autoantibody-mediated CNS effects.
Antibodies against the N-methyl-D-aspartate (NMDA) receptor may be important in NPSLE. The NMDA receptor, a glutamate receptor distributed in the whole brain, is important in processes that influence learning and memory. NMDA is an excitatory amino acid released by neurons.
In 2001 a subset of anti-dsDNA antibodies cross-reacting with the NR2 subunit of the NMDA receptor was described by DeGiorgio and colleagues.47 They showed that anti-NMDA receptor autoantibodies from the cerebrospinal fluid of a patient with NPSLE caused neuronal death when it was injected into a mouse brain. In a subsequent study in which these antibodies were induced in mice, neuronal damage occurred only when a breach in the integrity of the blood- brain barrier was present.48
Brain pathology studies in SLE patients reveal a wide range of brain abnormalities caused by multifocal microinfarctions, gross infarctions, cortical atrophy, hemorrhage, ischemic demyelin- ation and patchy multiple sclerosis-like demyelination. Microvasculopathy appears to be the most common microscopic brain finding in SLE and non-inflammatory proliferative changes
seem to be responsible for areas of microinfarction. True vasculitis (inflammatory infiltrate and destructive change within the blood vessel wall) is a rare finding in pathology studies of NPSLE.49-52
In the last years, many publications assess the prevalence and risk factors for the develop- ment of accelerated atherosclerosis in patients with SLE. This increased risk of premature ath- erosclerosis persists after accounting for traditional cardiac risk factors. Recent studies strongly suggest that the mechanism is due in part to a combination of inflammatory and immune mechanisms.53
Diagnostic evaluation
There are several clinical, laboratory, neuropsychological and imaging tests which have been used to assess SLE patients presenting with neuropsychiatric manifestations. Altogether, studies suggest that no single clinical, laboratory, neuropsychological and imaging test can be used to differentiate NPSLE from non-NPSLE patients with similar neuropsychiatric manifes- tations. A combination of these tests provides optimal information in assessment of selected SLE patients presenting with neuropsychiatric symptoms. In clinical practice, the diagnostic evaluation should be similar to the evaluation in patients without SLE who exhibit the same neuropsychiatric manifestations.
Autoantibodies
Antinuclear antibodies (ANA) and antibodies against extractable nuclear antigens (ENA) are commonly tested in all SLE patients. Although many groups have tried to identify specific autoantibodies that associate with specific neuropsychiatric manifestations in SLE, until now no such specific antibodies have been described. However, we know from the literature on antibody mediated neurological dysfunction such as the antibodies associated with the stiff man’s syndrome, that these antibodies do exist.54,55 Moreover, studies on the anti NMDA recep- tor autoantibodies and the blood-brain barrier have illustrated the possibility of such a putative mechanism.47,48
As antiphospholipid antibodies are commonly encountered in SLE patients and are associ- ated with focal as well as diffuse neuropsychiatric manifestations, testing for antiphospholipid antibodies is recommended in the initial evaluation of patients with SLE and should be re- evaluated if new risk factors for thromboembolic events are present.56
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is regarded as the diagnostic imaging technique of choice in the evaluation of neuropsychiatric manifestations in SLE patients.57-59 It has the capacity to identify brain infarctions as well as confounding disorders such as space-occupying lesions, infectious meningitis or brain abcesses. There is however no one MRI finding or pattern that is diagnostic or specific for NPSLE. MRI often shows no abnormalities or non-specific abnormalities
such as small white matter hyperintensities or atrophy.57,58 In a clinical study of 81 SLE patients with neuropsychiatric symptoms, MRI was normal or nearly normal in 34%. In 60% white mat- ter hyperintensities were observed in the frontal and parietal subcortical white matter. Other abnormalities included infarct-like lesions involving gray and white matter, areas of restricted diffusion, loss of brain volume, hemorrhage, meningeal enhancement, and bilateral high signal in occipital white-matter. The MRI findings alone cannot distinguish between thromboembolic and inflammatory events in many patients.60
Quantitative MRI techniques
Advanced MRI techniques can detect CNS damage in the absence of abnormalities on con- ventional MRI. Some of these techniques are promising in the evaluation of SLE patients with neuropsychiatric symptoms. Magnetization transfer imaging (MTI), diffusion weighted imaging (DWI) and magnetic resonance spectroscopy (MRS) are MRI techniques with higher sensitivity to structural disturbances of the brain than conventional MRI. Furthermore, with these imag- ing techniques, cerebral damage can be quantified.57,61,62 The functional relevance of these changes was suggested by the observation of associations between neurologic, psychiatric and neuropsychological measures and chronic disease burden as detected by MTI.63
MTI is based on the exchange of protons between a pool of protons that is bound to mac- romolecules such as cholesterol (found in myelin in the CNS) and a pool of free water protons that exists in biologic tissues (cellular water). The exchange of protons can be assessed with MRI by diminishing the magnetization of the bound proton pool using a saturation pulse prior to application of a conventional MR sequence. Because a conventional MR sequence derives its signal from the protons in free water and, because following a saturation pulse their mag- netization is diminished due to an influx of saturated protons from the bound pool, there is a lowering of the signal intensity of the tissue. This lowering can be quantified by assessing the magnetization transfer ratio (MTR). MTR histograms represent the integrity of brain tissue.
Both loss of myelin or accumulation of fluid (due to edema) alters the amount of transfer. In multiple sclerosis, but also in NPSLE, lower MTR peak heights are reported, indicating loss of macromolecular structure of brain tissue. MTR values can be calculated in regions of interest to assess tissue composition locally.
DWI is based on the random motion of protons. Acute ischemic lesions result in reduced diffusion of water. The apparent diffusion coefficient (ADC) indicates the amount of diffusion and is a quantitative measure for tissue integrity. DWI helps in discriminating ischemic from inflammatory disease, in which reduction of diffusion is not seen.
1H-MRS allows noninvasive biochemical assessment of brain tissue, using a similar technique as MRI. Reduction of N-acetylaspartate (NAA), a metabolite which is abundant in neurons, or reduction in the NAA/creatine ratio, indicates neuronal damage or dysfunction.64
Therapy and prognosis
Due to the lack of controlled randomized trials, current therapeutic approach is still empiri- cal and based on retrospective series, clinical experience and expert opinion.65 Therapy for neuropsychiatric syndromes must be tailored to the individual SLE patient and may include symptomatic treatment, immunosuppressive and anticoagulant therapies. The therapeutic choice depends on accurate diagnosis, the most probable underlying pathogenetic mecha- nism, the severity of the presenting neuropsychiatric symptoms, and contributing secondary causes of neuropsychiatric symptoms. It is important to distinguish between thrombotic and non-thrombotic etiology as different treatment is warranted. Anticoagulation is the mainstay of treatment in patients with thrombotic disease (stroke, TIA), particularly in those SLE patients with the antiphospholipid syndrome.
Because more than one neuropsychiatric manifestation as well as a combination of different pathogenetic mechanisms may occur in the individual patient, optimal treatment of NPSLE is a true challenge. The EULAR (European League Against Rheumatism) recommendations for treatment of NPSLE are based on both a systematic review of the literature as well as expert opinion.66 In mild non-thrombotic neuropsychiatric manifestations (e.g. headache, depres- sion), symptomatic treatment may be sufficient. More severe NPSLE manifestations generally require (high-dose) corticosteroids in the first instance, adding pulse intravenous cyclophos- phamide therapy in selected cases. One randomized controlled trial showed benefit of adding cyclophosphamide to methylprednisolone in the treatment of transverse myelitis.67 Beneficial effects of cyclophosphamide in treatment of severe NPSLE (eg. refractory seizures, peripheral and cranial neuropathy and optic neuritis) have also been suggested in nonrandomized con- trolled studies.68. Plasmapheresis may be added in severe cases of NPSLE refractory to conven- tional treatment. Intravenous immunoglobulins, mycophenolate mofetil, rituximab, intrathecal methotrexate and dexametasone, and autologeous hematopoietic stem cell transplantation deserve further studies to confirm their usefulness in the treatment of NPSLE.69,70
The occurrence of neuropsychiatric events in SLE patients is associated with reduced quality of life, worse prognosis, more cumulative damage and an increase in mortality.30,71-73
Outline and Aims of the thesis
From the preceding paragraphs it can be concluded that several aspects of NPSLE are not fully understood and need further research. In this thesis we describe our studies that were aimed at etiology and clinical, pathogenetic and imaging aspects of NPSLE. In the first part, we describe clinical-pathogenetic studies focused on the possible autoimmune mediated mechanisms of NPSLE. In the second part of the thesis, studies using conventional and quantitative MRI techniques in NPSLE patients are described.
Part I. Clinical-pathogenetic studies
In animal models an immune-mediated pathway has been demonstrated in the pathogen- esis of NPSLE. In Chapter 2 patient characteristics and time of occurrence of neuropsychiatric manifestations in a large cohort of SLE patients was described in order to assess whether these features fit an immune-mediated pathogenetic mechanism in human SLE patients.
In SLE mouse models, the presence of a subset of anti-dsDNA autoantibodies resulted in neuronal damage when the integrity of the blood-brain barrier was affected by bacterial lipo-polysaccharide. In Chapter 3 an analysis was performed to investigate whether seasonal variation in first occurrence or flares of NPSLE could be established to support the concept that infections are a contributing factor for neuropsychiatric symptoms in SLE.
In SLE mouse models, anti-NMDA receptor autoantibodies can cause neuronal damage. These autoantibodies may be associated with various neuropsychiatric manifestations. To determine wether anti-NMDA receptor antibodies could be involved in SLE or NPSLE, anti-NMDA receptor autoantibodies were measured in SLE patients with or without neuropsychiatric manifesta- tions, their first-degree relatives and unrelated controls in the study described in Chapter 4.
Autoantibodies specifically affect the hippocampus and amygdala in a mouse model of SLE. In Chapter 5 we used a quantitative MRI technique to investigate if selective damage in the hip- pocampus or amygdala could be demonstrated in NPSLE patients, and whether the presence of anti-NMDA receptor autoantibodies in serum correlated with the observed damage.
Cerebral involvement is common in the antiphospholipid syndrome and 20-35% of patients with SLE will develop secondary antiphospholipid syndrome during the course of the disease.
Chapter 6 gives an overview of current diagnostic and management strategies of the different manifestations of the antiphospholipid syndrome.
Although anticardiolipin antibodies are associated with thromboembolic events and macro- scopic brain infarctions in NPSLE patients, their role in the development of brain changes that are not apparent on conventional MRI is less clear. In Chapter 7 we investigated whether quan- titative MTI parameters correlated with the presence of anticardiolipin antibodies in the serum of NPSLE patients in order to evaluate whether microscopic brain damage, as can be detected by MTI, could be a possible explanation for neuropsychiatric symptoms in these patients.
Mutations in the TREX1 gene, encoding the major mammalian 3’-5’ DNA exonuclease, were recently found in patients with SLE. In addition, TREX1 gene has been associated with disorders that are associated with cerebral white matter hyperintensities, migraine and other manifes- tations of brain disease. Consequently, we considered TREX1 a candidate gene for NPSLE. In
the study described in Chapter 8 the genomic DNA of NPSLE patients was scanned for exonic TREX1 mutations.
Part II. Imaging studies
MRI is regarded as the diagnostic imaging technique of choice in the evaluation of neuro- psychiatric manifestations in SLE patients. In Chapter 9 the conventional MRI manifestations observed in active primary NPSLE patients were evaluated. The findings were interpreted in relation to possible underlying pathogenetic mechanisms.
Previous studies have shown that MTI detects abnormalities in the brain of NPSLE patients with diffuse neuropsychiatric manifestations. However, for MTI to provide a useful surrogate marker of disease activity, it must not only be able to detect abnormalities, but parameters must also change in concordance with changes in disease activity. In Chapter 10 we investigated whether clinical changes in disease activity in NPSLE patients correlated with MTI parameters.
Treatment with corticosteroids is known to have an effect on the nervous system. It is con- ceivable that brain abnormalities detected by quantitative MRI methods in NPSLE patients are partially induced by corticosteroid treatment, since many of these patients are on cortico- steroid medication. In Chapter 11 we investigated the effect of chronic use of low dose oral corticosteroids on MTI, DWI and MRS measurements of the brain in patients with rheumatoid arthritis, a disease that has no known cerebral involvement.
MTI can be used to detect cerebral changes in normal appearing brain tissue of NPSLE patients.
However, the underlying pathology of these MTI abnormalities is unclear. Furthermore, it is unknown if a correlation with specific neuropsychiatric syndromes or SLE criteria exists. In Chapter 12 we investigated in SLE patients with and without neuropsychiatrc symptoms and healthy controls, whether the MTI parameters correlated with neurochemical findings obtained with 1H-MRS, a technique that is sensitive in establishing and quantifying neuronal damage.
Subsequently it was investigated whether MTI parameters were linked to specific SLE and NPSLE characteristics.
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