NPSLE

Before 1999, characterization of CNS events in lupus was hampered by confusing terminology and differences among studies in attribution and methods of ascertainment. A consensus conference convened by the American College of Rheumatology (ACR) in 1999 to facilitate clinical and basic research of NPSLE resulted in the elucidation of 19 different neuropsychiatric syndromes attributable to SLE ( Box 1 ). Case definitions, reporting standards, and diagnostic criteria were provided by the group. Identification of these 19 syndromes has allowed the rheumatology community to classify more precisely and universally individual clinical presentations, thereby paving the way for translational research investigating mechanisms of disease.

Effective use of the NPSLE classification scheme relies on correct attribution of the NP event. Approximately two-thirds of NP events occurring in patients with SLE are attributable to other causes; it is critically important that all other possible entities have been investigated and excluded for each syndrome. Three conditions, in particular, must be excluded as they may mimic CNS disease resulting from active SLE. First, infections are a major confounding condition. Immunosuppressive therapies and inherent immune abnormalities in patients with SLE contribute to the increased infectious risk in SLE. In North America and Western Europe, most infections are bacterial, whereas in other parts of the world, fungal and mycobacterial infections are common. If unrecognized and untreated, these conditions can be fatal. Reports of progressive multifocal leukoencephalopathy (PML) in patients with SLE treated with rituximab or other immunosuppressive therapies highlight the need for increased vigilance in detecting infection in immunosuppressed patients with altered NP status. Another condition, thrombotic thrombocytopenic purpura (TTP), presents with mental status changes and thrombocytopenia, microanigopathic hemolytic anemia, renal disease, and fever. Appropriate treatment is mandatory; untreated, TTP is always fatal. The pathologic lesion is platelet microthrombi, often a result of failure to cleave von Willebrand factor and ensuing platelet activation. Treatment of hypertension in patients with SLE is crucial. Posterior reversible encephalopathy syndrome (PRES) occurs in patients with hypertensive lupus, frequently in the setting of acute renal failure, recent cyclophosphamide treatment, TTP, or preeclampsia, and leads to increased cerebral vascular permeability and brain edema. Thus, 3 potentially fatal conditions (infection, TTP, and PRES) may be confused with SLE disease activity as they can all mimic an acute diffuse presentation of CNS NPSLE.

The 1999 classification scheme has been useful to the clinician considering diagnostic and therapeutic options in an individual patient, but is perhaps less useful in probing disease pathogenesis. Of the multiple symptoms encompassed by NPSLE, CNS symptoms occur much more frequently than peripheral nervous system symptoms. Moreover, diffuse CNS symptoms, such as cognitive dysfunction, psychosis, acute confusional state, anxiety, and mood disorders, occur more commonly than focal CNS symptoms in most studies. The focal CNS symptoms, including stroke, demyelinating syndromes, movement disorders, and transverse myelitis, are most frequently secondary to vascular events caused by antiphospholipid antibodies. The diffuse CNS symptoms have a less certain pathogenic mechanism. Cognitive impairment and mood disturbance are among the most frequently reported diffuse CNS syndromes. The cognitive impairment derives most often from memory impairment involving verbal memory and executive function and attention. These symptoms are insidious and usually develop slowly over time, independent of disease activity. Their presence is also independent of current or previous medication use and cannot be explained solely on the basis of coexisting antiphospholipid antibodies that are known to cause chronic cerebrovascular disease that may result in cognitive difficulty.

Multiple studies conducted in lupus cohorts worldwide have consistently reported that cognitive impairment occurs with a high frequency. However, comparisons among studies are difficult. Variability in reported results is attributable to the different instruments used for cognitive assessment, differences in definition of impairment, and potential inherent differences in selected populations. Traditionally, cognitive ability has been assessed in a one-on-one setting by a neuropsychologist who administers a battery of tests. Assessment of cognitive ability recommended by the ACR consensus panel includes 10 tests administered over 1 hour that evaluate 8 cognitive domains (intelligence, reasoning, attention, learning, recall, fluency, language, perception). However, despite these recommendations, there has been little uniformity in the selection of tests used. More recently, a computer-based neuropsychiatric assessment (ANAM) has been used to assess cognitive function. This is, in general, less time consuming, less dependent on strong language skills, and less dependent on the establishment of a rapport between the tester and the subject. The ANAM has the additional advantage that the practice effect, improvement over time from repeated performances of the test, is less pronounced in longitudinal studies of cognitive function. However, the individual tests chosen by investigative groups remain variable. More significantly, the performance criteria to identify impairment vary among investigators. The lower frequency of cognitive impairment in some cohorts reflects a more stringent definition of impairment. Patients with memory deficits only are not identified as cognitively impaired in those cohorts, although they would be considered impaired by investigators reporting on other lupus cohorts.

Mechanistic studies of NPSLE

The etiopathogenesis of cognitive impairment and mood disorder remain a mystery. Studies of serum antibodies and cytokines have failed to show a reproducible signal that predicts the development of diffuse NPSLE symptoms in the CNS or that correlates with the presence of these symptoms. For example, serum antiphospholipid antibodies have been shown to correlate with cognitive decline in some studies but not in others. Numerous studies of serum antineuronal and antiribosomal p antibodies report inconclusive results. Further complexity is introduced because these symptoms can wax and wane, or can be irreversible. Thus, it is not clear whether one mechanism or multiple mechanisms are responsible for these symptom complexes. Many, if not most, neuroimaging studies of NPSLE have sought to associate active NPSLE with reproducible neuroimaging abnormalities. Given that active NPSLE comprises a fairly large group of disparate syndromes, it is not surprising that this has proven to be extremely difficult, despite the use of numerous imaging modalities including computerized tomography (CT), magnetic resonance imaging (MRI), functional MRI (fMRI), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and positron emission tomography (PET) scans. Differences in patient populations, instrumentation, technique, and metrics for interpretation all prevent comparisons among studies. Nonetheless, MRS identified regional increased choline/creatine ratios in gray and white matter in patients with cognitive dysfunction. Functional MRI also distinguished differences in global and regional brain activation patterns between patients with SLE, healthy controls, and disease controls (rheumatoid arthritis [RA]) in response to specific memory tasks.

Studies of cerebrospinal fluid (CSF) in patients with active NPSLE have proven to be more revealing and are furthering our understanding of the pathophysiology of NPSLE. Significantly elevated interleukin (IL)-6 levels are a consistent finding in patients with active CNS disease, particularly psychosis, and the concentration of this cytokine correlates with symptom severity. Additionally, patients with active NP disease (defined as ≥2 of the following: psychosis, aseptic meningitis, transverse myelitis, seizures, pathologic brain MRI, severely abnormal NP tests, oligoclonal bands in CSF) have 20- and 200-fold increases in intrathecal levels of a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF), respectively, compared with patients without NPSLE. Immune complexes formed by autoantibodies in CSF from patients with active diffuse CNS symptoms (psychosis, acute confusional state, seizure disorders, mood and anxiety disorders) and added apoptotic debris has been shown to significantly induce production of IFNα by IFN-producing cells, although CSF alone does not do so. Other inflammatory mediators identified in CSF of patients with active NPSLE include chemokines (MCP-1, RANTES, MIG, IP-10), IL-8, and MMP-9. There are no studies of CSF abnormalities specific for insidious manifestations of NPSLE, such as cognitive impairment, as CSF is not routinely obtained from these individuals. Markers for cognitive impairment and mood disorder that can be reliably measured in an easy-to-use assay are clearly needed. The inability to identify such a marker for these manifestations of NP disease has hampered our understanding of its pathogenesis and has also made design of clinical trials in NPSLE extremely problematic. Clinical investigation of the course of NPSLE is also made difficult as there is no reliable assessment for measurement of improvement in symptoms or to determine whether progression of symptoms has been retarded.

Mechanistic studies of NPSLE

The etiopathogenesis of cognitive impairment and mood disorder remain a mystery. Studies of serum antibodies and cytokines have failed to show a reproducible signal that predicts the development of diffuse NPSLE symptoms in the CNS or that correlates with the presence of these symptoms. For example, serum antiphospholipid antibodies have been shown to correlate with cognitive decline in some studies but not in others. Numerous studies of serum antineuronal and antiribosomal p antibodies report inconclusive results. Further complexity is introduced because these symptoms can wax and wane, or can be irreversible. Thus, it is not clear whether one mechanism or multiple mechanisms are responsible for these symptom complexes. Many, if not most, neuroimaging studies of NPSLE have sought to associate active NPSLE with reproducible neuroimaging abnormalities. Given that active NPSLE comprises a fairly large group of disparate syndromes, it is not surprising that this has proven to be extremely difficult, despite the use of numerous imaging modalities including computerized tomography (CT), magnetic resonance imaging (MRI), functional MRI (fMRI), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and positron emission tomography (PET) scans. Differences in patient populations, instrumentation, technique, and metrics for interpretation all prevent comparisons among studies. Nonetheless, MRS identified regional increased choline/creatine ratios in gray and white matter in patients with cognitive dysfunction. Functional MRI also distinguished differences in global and regional brain activation patterns between patients with SLE, healthy controls, and disease controls (rheumatoid arthritis [RA]) in response to specific memory tasks.

Studies of cerebrospinal fluid (CSF) in patients with active NPSLE have proven to be more revealing and are furthering our understanding of the pathophysiology of NPSLE. Significantly elevated interleukin (IL)-6 levels are a consistent finding in patients with active CNS disease, particularly psychosis, and the concentration of this cytokine correlates with symptom severity. Additionally, patients with active NP disease (defined as ≥2 of the following: psychosis, aseptic meningitis, transverse myelitis, seizures, pathologic brain MRI, severely abnormal NP tests, oligoclonal bands in CSF) have 20- and 200-fold increases in intrathecal levels of a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF), respectively, compared with patients without NPSLE. Immune complexes formed by autoantibodies in CSF from patients with active diffuse CNS symptoms (psychosis, acute confusional state, seizure disorders, mood and anxiety disorders) and added apoptotic debris has been shown to significantly induce production of IFNα by IFN-producing cells, although CSF alone does not do so. Other inflammatory mediators identified in CSF of patients with active NPSLE include chemokines (MCP-1, RANTES, MIG, IP-10), IL-8, and MMP-9. There are no studies of CSF abnormalities specific for insidious manifestations of NPSLE, such as cognitive impairment, as CSF is not routinely obtained from these individuals. Markers for cognitive impairment and mood disorder that can be reliably measured in an easy-to-use assay are clearly needed. The inability to identify such a marker for these manifestations of NP disease has hampered our understanding of its pathogenesis and has also made design of clinical trials in NPSLE extremely problematic. Clinical investigation of the course of NPSLE is also made difficult as there is no reliable assessment for measurement of improvement in symptoms or to determine whether progression of symptoms has been retarded.

Antibodies and the brain

In SLE, tissue injury is initiated by antibodies. This observation is true in the kidneys, skin, blood vessels, and in all organs for which there is an appreciation of pathogenesis and inflammatory pathways. For decades it has been known that the serum of many patients with SLE contains brain-reactive antibodies. The specific antigens that are recognized by these antibodies were not identified, nor was their functionality known. Additionally, no correlations were found between the presence of these antibodies in serum and aspects of NPSLE. Antiribosomal p antibody has been extensively studied with respect to NPSLE. Several clinical studies examining whether serum antiribosomal p correlates with psychosis have yielded conflicting results, and a recent meta-analysis of 14 published studies concluded that serum antiribosomal p measurements were not sensitive in diagnosing NPSLE and did not distinguish between NPSLE subsets. Interest in the antibody diminished because it was also not clear how an antibody directed against an intracellular protein could mediate brain dysfunction. Recently, a team of investigators from Chile has showed that the antiribosomal p antibody cross-reacts with a membrane protein on neurons and that binding of the antibody to neurons can initiate an apoptotic cascade. Thus, there is now a plausible mechanism for brain pathology resulting from antiribosomal p antibodies.

Antibodies to the N-Methyl-D-Aspartate Receptor and function of the NMDAR

Our own interest is in a subset of anti-DNA antibodies that cross-reacts with a consensus pentapeptide present in the NR2A and NR2B subunits of the NMDAR.

Many anti-DNA antibodies derived from patients with lupus and from some spontaneous mouse models of SLE are of the IgG isotype and display extensive somatic mutation in variable region sequences. These are characteristics of the molecular signature of a T-cell–dependent, germinal center matured B-cell response. Generally, protein antigens induce a germinal center B-cell response; we therefore asked whether an anti-DNA antibody can bind to a peptide sequence. The anti-DNA antibody that we used in these studies, R4A, deposits in glomeruli, causes proteinuria, and therefore has features of a pathogenic lupus anti-DNA antibody. R4A binds a consensus pentapeptide sequence (D/E W D/E Y S/G) comprising l or d amino acids. This sequence is contained within the NR2A and NR2B subunits of rodent and human NMDARs. The antibody binds each subunit on ELISA and Western blot, and can immunoprecipitate the subunits from a mouse brain lysate.

NMDARs are receptors for the neurotransmitter glutamate, the major excitatory neurotransmitter in the brain and critically important for many brain functions. Most neurons in the brain contain high levels of glutamate stored inside synaptic vesicles that is released, in a carefully controlled fashion, to convey sensory information, respond to motor commands, and to form thoughts and memories that translate to cognitive and emotional abilities. Excessive exposure to glutamate results in increased excitotoxic cell death, and disturbances of glutamate or NMDAR activity have been implicated in several neurologic syndromes including traumatic brain and cord injuries, stroke, Alzheimer disease, Huntington disease, Parkinson disease, seizures, multiple sclerosis, HIV-associated dementia, schizophrenia, and amyotrophic lateral sclerosis.

NMDARs are present throughout the brain and subunits are differentially expressed regionally in the brain and temporally during development. They are composed of 2 NR1 subunits that have a binding site for glycine, a coagonist, and 2 of any 4 NR2 subunits (A–D). Receptors containing NR2A and NR2B are most dense on neurons in the CA1 region of the hippocampus, and in the amygdala. Pertinent to our concerns in SLE, hippocampal NMDARs subserve learning and memory and, in the amygdala, NMDARs are critical in the fear-conditioning response. These receptors function as voltage-gated calcium channels; following electrical stimulation to the nerve, glutamate and glycine bind an NR2 or NR1 subunit respectively and allow calcium to flux into the cell. Activation of the receptor requires that magnesium exits from the pore of the receptor, at which time calcium is free to enter. The magnitude of the calcium influx is proportional to the time the pore remains in the open position. The change in intracellular calcium is crucial for cellular function. An excessive flux of calcium into neurons causes mitochondrial stress and activates caspase cascades, leading to neuronal death. Proper regulation of NMDAR activation is, therefore, essential for cognitive performance and appropriate emotional responses. Consequences of alterations in NMDAR function can be severe; MK-801 is an NMDAR antagonist that effectively blocks excitotoxicity but can produce seizures and coma. Memantine is another NMDAR antagonist that successfully blocks the open channel with few of the sedating side effects. Other NMDAR antagonists with different kinetics produce hallucinations (phencyclidine/PCP/angel dust) or excessive drowsiness (ketamine). The observation that PCP produces hallucinations suggests the possibility that NMDAR abnormalities may contribute to schizophrenia.

The murine monoclonal antibody R4A, which binds DNA and NMDAR, functions to enhance NMDAR activation. Studies of hippocampal slices from mice show that binding of cross-reactive, anti-DNA antibodies to NMDARs on neurons results in apoptotic neuronal death. Further study has shown that the antibody modulates NMDAR activation, synergizing with the natural agonist glutamate to increase excitatory postsynaptic potentials. At higher concentrations, it synergizes with glutamate to cause mitochondrial stress and caspase activation. The death-inducing function is mediated through NMDAR binding as NMDAR antagonists block caspase activation. The antibody’s effects are dependent only on antibody binding and do not require complement activation or antibody-dependent cell-mediated cytotoxicity as Fab′ ₂ fragments of antibody provoke cell death.

Mechanistic studies of the interaction of R4A with NMDARs show that R4A preferentially binds the NMDAR when the pore is open; thus, the antibody can be presumed to augment the time of opening of the pore and enhances the calcium influx. R4A decreases the concentration of glutamate needed to trigger excitatory postsynaptic potentials and to induce apoptosis.

Regional brain effects of anti-NMDAR antibodies: murine models of cognitive and behavioral effects

To study the potential effects of anti-NMDAR antibody on cognition we immunized mice with a multimeric form of the DWEYS peptide. These mice develop anti-DNA/anti-NMDAR cross-reactive antibodies. Although these antibodies are present in the circulation, there is no evidence of brain pathology and no alteration of learning or memory, presumably because the endothelial cells in the brain microvasculature form a blood-brain barrier (BBB) that is impenetrable to antibody. There are, however, conditions known to compromise the integrity of the BBB. Infection has long been recognized as a threat to barrier integrity. Bacterial lipolysaccharide (LPS) induces production of IL-1 and tumor necrosis factor, both of which alter permeability of the BBB. When mice immunized with the multimeric peptide are subsequently given LPS, antibody penetrates the BBB and preferentially targets the hippocampus. Anti-NMDAR antibodies bind hippocampal neurons with an ensuing death of hippocampal neurons that is immediate. As the BBB integrity is reconstituted quickly following LPS administration, there is no accumulation of damage following the initial event. Most notably, there is no inflammation in regions of neuronal loss, nor activation of resident inflammatory cells in the brain, and no influx of blood borne inflammatory cells. Mice with antibody-mediated neuronal loss perform poorly on several tests of memory function, but are unimpaired in tasks that measure other cognitive domains.

Similar findings are observed when normal mice are given human lupus serum or CSF containing anti-DNA/anti-NMDAR antibody followed by administration of LPS. Human lupus anti-NMDAR antibody binds to hippocampal neurons in the mouse, causing apoptotic neuronal loss. These mice also perform poorly in tests of memory function.

Another agent recognized to compromise the integrity of the BBB is epinephrine. When mice immunized with multimeric peptide and harboring high titers of anti-DNA/anti-NMDAR antibodies are given epinephrine systemically, the antibodies transit from the vasculature into the amygdala. The hippocampi of these mice are histologically normal and there are no cognitive deficits detected in testing of memory and learning functions. However, these mice do have impaired performance in a fear-conditioning paradigm. In this paradigm, normal mice exposed to a neutral stimulus followed by a noxious stimulus learn to associate the noxious stimulus with the neutral one. Therefore, conditioned mice will freeze as soon as the neutral stimulus is delivered in anticipation of the noxious stimulus. Mice with antibody-mediated amygdala damage fail to freeze appropriately. Because there is no impairment of memory, the failure to freeze is a behavioral impairment. This study was highly informative for several reasons. It showed that anti-NMDAR antibodies could cause behavioral changes. It also showed that the same anti-NMDAR antibodies could result in two distinct manifestations of NPSLE. Finally, it showed that agents that breach the BBB do so with regional specificity. Thus antibody-related brain symptoms will depend on the nature of the agent that permits antibody penetration into brain, and the specific antibody.

These models show permanent loss of function in the hippocampus or the amygdala. However, it is clear that some cognitive or behavioral changes in patients are transient. We postulate that this reflects the observation that lower concentrations of antibodies are needed to affect synaptic plasticity than to cause apoptosis. Thus, low titers of antibody may lead to transient dysfunction and high titers lead to permanent impairment ( Fig. 1 ).

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