REVIEWS

Diagnosis and management of

neuropsychiatric SLE
John G. Hanly
Abstract | Nervous system involvement in systemic lupus erythematosus (SLE) can manifest as a range
of neurological and psychiatric features, which are classified using the ACR case definitions for 19
neuropsychiatric syndromes. Approximately one-third of all neuropsychiatric syndromes in patients with SLE
are primary manifestations of SLE-related autoimmunity, with seizure disorders, cerebrovascular disease,
acute confusional state and neuropathy being the most common. Such primary neuropsychiatric SLE (NPSLE)
events are a consequence either of microvasculopathy and thrombosis, or of autoantibodies and inflammatory
mediators. Diagnosis of NPSLE requires the exclusion of other causes, and clinical assessment directs the
selection of appropriate investigations. These investigations include measurement of autoantibodies, analysis
of cerebrospinal fluid, electrophysiological studies, neuropsychological assessment and neuroimaging to
evaluate brain structure and function. Treatment involves the management of comorbidities contributing
to the neuropsychiatric event, use of symptomatic therapies, and more specific interventions with either
anticoagulation or immunosuppressive agents, depending upon the primary immunopathogenetic mechanism.
Although the prognosis is variable, studies suggest a more favourable outcome for primary NPSLE
manifestations compared with neuropsychiatric events attributable to non-SLE causes.
Hanly, J. G. Nat. Rev. Rheumatol. advance online publication 11 February 2014; doi:10.1038/nrrheum.2014.15

Introduction
Systemic lupus erythematosus (SLE) is a chronic, sys­ research methodology, bias in the selection of patients
temic, autoimmune inflammatory disease of unknown for study, or changes over time in global disease sever­
aetiology,1 and is characterized by autoantibody pro­ ity. Many early studies of NPSLE prognosis were limited
duction and protean clinical manifestations. The dis­ by several factors: lack of standardized definitions or
ease incidence has a striking 9:1 female predominance cri­teria for neuro­psychiatric events, including the attri­
and peaks during childbearing years.1 The overall pre­ bution of neuropsychiatric events to SLE and non-SLE
valence of SLE is 1:2,000, and it is more common in causes; failure to use validated instruments to measure
particular ethnic or racial groups, such as Asian and important outcomes such as organ damage and quality
Afro-Caribbean people.1 Although arthritis and skin of life; and retrospective, single-centre study design.
disease are the most frequent manifestations of SLE, vis­ This article reviews advances in this important aspect
ceral involvement is more serious. In particular, involve­ of SLE. Current thinking on the classification and attri­
ment of the lungs, kidneys and central nervous system bution of neuropsychiatric events in patients with SLE
accounts for most of the morbidity and mortality attrib­ is discussed. Pertinent aspects of immunopathogenetic
uted to SLE.2–4 Of these visceral manifestations, nervous path­w ays are reviewed, and provide the basis for a
system involvement poses the greatest clinical challenge. propos­ed diagnostic and therapeutic approach to NPSLE.
Nervous system involvement in SLE encompasses
a variety of neurological and psychiatric features. Clinical manifestations of NPSLE
Neuro­psychiatric events attributed to SLE (NPSLE) are Classification
primary manifestations of the disease, rather than com­ Many classifications of NPSLE lack definitions of indivi­
plications of the disease (for example, hyper­tension) dual manifestations and standardization for investi­
or its therapy (for example, infection), or concurrent, gation and diagnosis. In 1999, the ACR produced a
non-SLE neuropsychiatric disease (Figure 1). The preva­ standard nomenclature and set of case definitions for
Division of lence of NPSLE, which ranges from 21% to 95%,5–12 and 19 neuro­psychiatric syndromes known to occur in SLE
Rheumatology,
Department of
the prognosis following a neuropsychiatric event are (as listed in Box 1).20 These syndromes can be segregated
Medicine and both highly variable. Several studies of NPSLE have into central and peripheral,20 diffuse and focal neuro­
Department of reported an increase in mortality,13–16 whereas others psychiatric events.21 The ACR classification is compre­
Pathology, Capital
Health and Dalhousie have not.17–19 This variance could reflect differences in hensive in the scope of neuropsychiatric manifestations
University, Halifax, it describes, and provides guidance on investigations
NS B3H 4K4, Canada.
john.hanly@ Competing interests and diagnostic criteria for each. However, the classifica­
cdha.nshealth.ca The author declares no competing interests. tion is not, and in fact was never intended to be, specific

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REVIEWS

Key points dis­orders are the most frequent neuropsychiatric com­

plaints overall in patients with SLE, seizure disorders,
■■ Neuropsychiatric events are common in patients with systemic lupus
erythematosus (SLE) but only one-third of such events are attributed directly
cerebrovascular disease, acute confusional states and
to SLE neuropathies are the most common neuropsychiatric
■■ Autoimmune-mediated inflammatory injury and vascular injury are separate syndromes attributed to SLE. The cumulative occurrence
pathogenetic mechanisms responsible for neuropsychiatric SLE (NPSLE) of neuropsychiatric events increases over time, although
■■ The diagnosis of NPSLE is determined primarily by clinical assessment the proportion of events attributed to SLE and non-SLE
■■ Investigations in support of the clinical diagnosis include measurement of causes remains the same.24,25
autoantibodies, analysis of cerebrospinal fluid, electrophysiological studies, Regardless of attribution, neuropsychiatric events
neuropsychological assessment and neuroimaging
in patients with SLE are associated with a substantial
■■ Treatment options for NPSLE include addressing comorbidities, symptomatic
therapies, immunosuppression and anticoagulation
negative effect on health-related quality of life (HRQoL)
(Figure 2), even when factors such as global SLE disease
activity, cumulative organ damage and medications are
taken into account.22,23 Correctly attributing neuro­
Primary NPSLE
psychiatric events to SLE and non-SLE causes is critical
to determining the most appropriate treatment plan.
Vasculopathy (+++) Inflammatory mediators (+++)
aPL (+++) Antineuronal antibodies (++)
Inflammatory mediators (+) Antiribosomal antibodies (++) Cognitive dysfunction in SLE
aPL (+) Cognition is the sum of intellectual functions that result
Vasculopathy (+) in thought, and includes reception of external stimuli,
information processing, learning, storage and expression.
Focal neuropsychiatric disease Diffuse neuropsychiatric disease
Disturbance of even one of these functions can result in
disruption of normal thought production and present as
Complications
of SLE
cognitive dysfunction. Cognitive complaints and objec­
Complications tively confirmed cognitive impairment are frequently
of SLE therapy encountered in patients with SLE. Although cognitive
Concurrent non-SLE impairment can be viewed as a distinct syndrome, it can
Secondary NPSLE neuropsychiatric disease
also serve as an indicator of overall brain health, which
can be affected by a number of factors including other
Figure 1 | Factors contributing to neuropsychiatric events in patients with SLE. Focal
and diffuse nervous system events can result from autoimmune or inflammatory neuropsychiatric syndromes. Owing to the poor correla­
mechanisms directly related to SLE (primary NPSLE), as a consequence of tion between cognitive symptoms and objective findings
complications of the disease (for example, uraemia or hypertension) or its therapy on formal neuropsychological assessment,26 the presence,
(for example, infection) (secondary NPSLE), or as a concurrent neuropsychiatric characteristics and severity of cognitive impairment
event unrelated to SLE. Abbreviations: +, minor contribution to NPSLE; ++, should first be confirmed by formal neuropsycho­
moderate contribution to NPSLE; +++, substantial contribution to NPSLE; aPL, logical assessment. Cognitive dysfunction identified
antiphospholipid antibodies; NPSLE, neuropsychiatric SLE; SLE, systemic lupus in this way has been reported in up to 80% of patients
erythematosus. Adapted with permission from Springer © Hanly, J. G. Curr.
with SLE,27 although most studies report a preva­lence
Rheumatol. Rep. 3, 205–212 (2001).
in the range 17–66%.28,29 Many individual patients have
subclinical cognitive deficits. For example, a review of
for neuropsychiatric events caused exclusively by SLE. 14 cross-sectional studies of cognitive function in SLE
Thus, whether using the ACR classification in clinical revealed subclinical cognitive impairment in 11–54% of
practice or as part of a research study, it is important to patients.28 A single pattern of SLE-associated cognitive
attribute events to SLE and non-SLE causes to optimize dysfunction has not been found, but commonly iden­
the care of individual patients presenting with neuro­ tified cognitive abnormalities include overall cognitive
psychiatric events or to ensure the validity of clinical slowing, decreased attention, impaired working memory
research studies of NPSLE. To this end, the ACR classi­ and executive dysfunction (for example, difficulty with
fication lists causes other than SLE that could be respon­ multitasking, organization or planning).
sible, in part or entirely, for each of the neuropsychiatric
syndromes. This component of the ACR classification, Aetiology and pathogenesis of NPSLE
in combination with other variables such as the relation­ Neuropsychiatric events attributable to SLE—that is, as
ship between time of onset of neuropsychiatric events to pri­mary manifestations of the disease—are thought to
diagnosis of SLE and the high frequency of some neuro­ arise from vascular abnormalities, autoantibodies and
psychiatric events in the general population, have been inflammatory mediators. As discussed below, these factors
used to develop attribution models for neuropsychiatr­ic interact in various pathogenic mechanisms of NPSLE.
events in SLE.22,23
Depending upon the stringency of the attribu­ Contributing factors
tion models, neuropsychiatric events occur in 6–12% Vascular abnormalities
of patients with newly diagnosed SLE over the first A bland, noninflammatory microangiopathy in associ­
year of the illness, and the proportion attributed to SLE ation with brain microinfarction is the predominant
varies from 19% to 38%.22 Although headache and mood neuropathological finding of NPSLE.30,31 By contrast,

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inflammatory disease of small or large blood vessels Box 1 | Neuropsychiatric syndromes in SLE*
(vasculitis) is rare.
Central nervous system
■■ Aseptic meningitis
Autoantibodies ■■ Cerebrovascular disease
Antineuronal antibodies in NPSLE have been demon­ ■■ Demyelinating syndrome
strated to have a temporal relationship with neuro­ ■■ Headache
psychiatric events,32 to be present in cerebrospinal fluid ■■ Movement disorder
(CSF)33 and to occur in postmortem neuronal tissues ■■ Myelopathy
from patients with NPSLE.34 The occurrence of auto­ ■■ Seizure disorders
■■ Acute confusional state
antibodies in the CSF is due to passive transfer from the
■■ Anxiety disorder
circulation through increased permeability of the blood– ■■ Cognitive dysfunction
brain barrier 35 and, independently, to intra­thecal pro­ ■■ Mood disorder
duction.33,35 A subset of anti-DNA anti­bodies in human ■■ Psychosis
SLE and in a mouse model of the disease crossreact Peripheral nervous system
with neuronal NR2 glutamate receptors.36 In contrast ■■ Acute inflammatory demyelinating
to earlier studies of antineuronal antibodies, anti-NR2 polyradiculoneuropathy (Guillain–Barré syndrome)
antibodies induce apoptotic cell death in vitro 36 and ■■ Autonomic neuropathy
in vivo.37 In animal models, enhanced permeability of ■■ Mononeuropathy
■■ Myasthenia gravis
the blood–brain barrier is critical for the access of anti-
■■ Cranial neuropathy
NR2 antibodies to neuronal cells.38 The blood–brain ■■ Plexopathy
barrier can be permeabilized by both SLE factors (for ■■ Polyneuropathy
example, immune complex deposition or cytokines) and *Defined by ACR nomenclature and case definitions for
non-SLE factors (for example, smoking or hypertension). neuropsychiatric SLE syndromes. Abbreviation: SLE, systemic
lupus erythematosus. Adapted with permission from John Wiley &
In human SLE, the association between circulating anti- Sons, Inc. © Arthritis Rheum. 42, 599–608 (1999).20
NR2 antibodies and NPSLE is inconsistent, 39 but the
strongest association has been found with auto­antibodies
in the CSF.40,41 Anti-ribosomal P antibodies have been cells,55 probably in response to autoantibodies within the
associated with NPSLE, particularly psychosis, in some intrathecal space.61,62 In vitro studies suggest that cyto­
but not all studies. 42–47 Discrepancies between these kine production occurs as a consequence of binding of
studies might be attributable to differences in diagnostic immune complexes (formed of autoantibodies and RNA-
criteria for psychiatric disease, variance in the tempo­ protein antigens) to FcγRII on plasmacytoid dendritic
ral relationship between clinical events and serologi­ cells, followed by endocytosis and activation of Toll-like
cal testing, and differences in assay technique (perhaps receptor 7 (TLR7). Further support for this mecha­nism
related to antigen preparation and purity). includes evidence of neuronal and glial degrada­t ion
Autoimmune antiphospholipid antibodies (aPL), products (a potential source of antigen) in the CSF of
directed against phospholipid-binding proteins such patients with SLE,63 and findings of elevated CSF levels
as β2-glycoprotein I and prothrombin, induce a proco­ of matrix metalloproteinase 9,63 which increases the
agulant state48,49 and are associated predominately with permeability of the blood–brain barrier, thus providing
focal manifestations of NPSLE. Most of these are vascular in­trathecal access to circulating autoantibodies.
events, such as stroke,50 and seizure disorders.8 Additional
studies have reported an association of aPL with cogni­ Pathogenic mechanisms
tive impairment, even in the absence of stroke.50,51 The Taken together, the evidence presented earlier sug­gests
favoured pathogenetic mechanism for this family of two separate and potentially complementary auto­immune
autoantibodies in NPSLE is thrombosis within vessels pathogenic mechanisms for NPSLE (Figure 3). The first
of different calibres and consequent cerebral ischa­emia. mechanism implicates injury to large and small blood
How­ever, a possible direct pathogenic effect of aPL on vessels, mediated by aPL, immune complexes and leuko­
neuronal cells is suggested by their intrathecal produc­ agglutination. Clinical sequelae to this vascular-injury
tion in patients with NPSLE,35 their association with mechanism include focal neuro­psychiatric events such
diffuse cognitive impairment,51,52 and their modulation as stroke and diffuse neuro­psychiatric events such as
of neuron­al cell function in vitro.53 cognitive dysfunction. The second mechanism involves
auto­immune inflammation injury, with increased perme­
Inflammatory mediators ability of the blood–brain barrier, intrathecal formation of
Proinflammatory cytokines might have a role in NPSLE. immune complexes, and production of IFN‑α and other
Initial studies reported associations between increased inflammatory mediators. Clinical sequelae of this mecha­
intracranial production of IL‑6 with seizures,54 and the nism include diffuse neuropsychiatric manifestations
production of IFN‑α with lupus psychosis.55 Subsequent such as psychosis and acute confusional state.
studies provided further evidence of intrathecal produc­
tion of IL‑656–58 and other cytokines including IL‑10,59 Diagnostic approach and investigation
IL‑260 and IL‑858 in patients with NPSLE. Cytokines asso­ In the assessment of a patient with SLE and a neuro­
ciated with NPSLE are produced by neuronal55,57 and glial psychiatric event, it is important to first determine if

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80 the identification of metabolic abnormalities, infection

70 and use of psychoactive drugs, and a search for diabetes
mellitus and vitamin B12 deficiency should be undertaken
SF-36 subscale score

60
in those who present with peripheral sensory neuropathy.
50

40 SLE disease activity

30 The evaluation of SLE disease activity in organ systems
20
other than the nervous system is important to ensure
appropriate management of neuropsychiatric events
10 in patients with SLE. Such assessment might also help
0 attribute these events to SLE and non-SLE causes.
Physical Role Bodily General Vitality Social Role Mental
function physical pain health function emotional health Some studies,67–69 but not all,70,71 have found an associa­
tion between increased global SLE disease activity and
50 neuro­psychiatric events attributed to SLE. This associa­
NP event present tion is probably more robust for diffuse rather than focal
40 NP event absent neuropsychiatr­ic events.
SF-36 composite score

30 Autoantibodies in the circulation and CSF

Of the circulating autoantibodies, aPL are likely to pro­vide
20 the greatest diagnostic yield, especially in patients with
focal neuropsychiatric events or cognitive decline.50–52
10 The association between circulating anti-NR2 antibodies
and NPSLE is less clear. Omdal et al.72 found an associa­
0 tion between levels of these antibodies and depression,
Physical Mental
decreased short-term memory and learning. Apart from
Figure 2 | Negative effect of NP events on HRQoL in patients with SLE.22 The another report of an association of anti-NR2 anti­bodies
difference in HRQoL of patients newly diagnosed with SLE with and without NP events with depression,73 three cross-­sectional studies74–76 (one
is indicated by SF‑36 subscale scores (upper panel) and physical and mental of which had a 5-year follow-up period74) did not con­
composite scores (lower panel), expressed as means ±SEM. Those patients with
firm these findings. Yoshio et al.40 studied both serum
NP events, regardless of attribution to SLE or non-SLE causes, had consistently lower
scores, indicating poorer HRQoL. Abbreviations: HRQoL, health-related quality of life;
and CSF samples from 80 patients with SLE (53 of whom
NP, neuropsychiatric; SF‑36, short form 36; SLE, systemic lupus erythematosus. had NPSLE) and found the strongest association between
Reproduced with permission from John Wiley & Sons, Inc. © Hanly, J. G. et al. Arthritis neuropsychiatric events and CSF auto­a ntibodies.
Rheum. 56, 265–273 (2007).22 Another study of CSF samples from 56 patients with
SLE found anti-NR2 antibodies in 44% and 82% of
the neuropsychiatric event is a primary manifestation patients with focal and diffuse NPSLE, respectively. 41
of the disease, a complication of the disease or its therapy, Thus, although in practice the examination of CSF is
a coincidental disease process, or a combination thereof done primarily to exclude infection, its availability pro­
(Figure 1). Given the absence of a diagnostic gold standard vides an opportunity to measure levels of this interesting
for most neuropsychiatric events, the correct attribution is autoantibody, which might contribute to the diagnosis
made largely by a process of exclusion. Information from of NPSLE in indivi­dual patients. The measurement of
a variety of sources might be utilized to a varying extent, CSF cytokines and biomarkers of neurological damage
depending upon the clinical circumstances (Box 2). holds considerable academic interest for the study of
pathogenetic mechanisms, but at this time is neither
Generic investigations recommend­ed nor even feasible in practice.
As emphasized by the EULAR task force recommen­ Neuromyelitis optica (NMO), also known as Devic
dations for the management of NPSLE,64 in patients syndrome, is a severe demyelinating disorder of the
with new or unexplained symptoms or signs suggestive central nervous system that causes longitudinal trans­
of neuro­psychiatric disease, the diagnostic work-up verse myelitis of at least three vertebral segments and
should consider any investigations that would be done recurrent optic neuritis. NMO has been reported in
in non-SLE patients presenting with the same manifesta­ patients with SLE77 and is associated with NMO-specific
tions. For example, a patient with SLE who presents with auto­antibodies whose antigenic target is aquaporin 4,78
a transient ischaemic attack or stroke should undergo a the most abundant water channel in the central nervous
screening echocardiogram and Doppler ultrasono­graphy system.79 Although NMO is a rare clinical presentation,
of the carotid arteries, in addition to testing for SLE- suspicion of this syndrome in a patient with SLE warrants
specific causes such as aPL. In addition, given the higher- the measurement of autoantibodies to aquaporin 4.
than-expected frequency of premature cardio­vascular
disease in SLE patients,65,66 cardiac risk factors such as Electrophysiological studies
poorly controlled hypertension and hype­rlipidaemia Electroencephalography is primarily used to investigate
should also be considered.67 Similarly, investigations in seizure disorders, and detects abnormalities includ­
patients who present with acute confusion should include ing asymmetry of the electric cerebral activity, diffuse

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Vascular Inflammatory facilitates efficient screening of patients with SLE by non-

Mediators experts,83 but formal testing remains the only definitive
aPL Autoantibodies way to diagnose cognitive impairment; thus, patients with
Immune complexes MMPs, cytokines
suspected impaired cognitive ability should be referred
for full neuropsychological assessment. The battery of
Mechanism
neuropsychological tests proposed by the ACR for the
Thrombosis BBB permeability assessment of cognitive function in SLE20 is comprehen­
Microangiopathy Immune complexes
pDC activation sive, but its widespread use remains limited, as such test
series are time-consuming, require specialized training
Outcome
and are subject to practice effects with repeated use. If
abnormalities are detected by use of these tests, repeat
Focal neuropsychiatric disease
Diffuse neuropsychiatric disease Diffuse neuropsychiatric disease testing using the same battery should be done after a
reasonable interval, usually several months, to measure
Figure 3 | Autoimmune pathogenesis of NPSLE. Vascular injury involving both large change in cognition following observation or treatment.
and small-calibre vessels is mediated by aPL, immune complexes and
leukoagglutination, and can result in focal neuropsychiatric events (for example, Neuroimaging
stroke) or diffuse neuropsychiatric events (for example, cognitive dysfunction). Standard and advanced neuroimaging of brain structure
Inflammatory injury, involving increased permeability of the BBB, formation of and function help to localize intracranial abnormali­
immune complexes and production of IFN‑α and other inflammatory mediators, can ties, determine whether the lesions involve white or grey
lead to diffuse neuropsychiatric manifestations (for example, psychosis, acute
matter, and assess their chronicity and change over time.
confusional states). Abbreviations: aPL, antiphospholipid antibodies; BBB, blood–
brain barrier; MMP, matrix metalloproteinase; NPSLE, neuropsychiatric systemic The assessment of brain structure by CT has largely been
lupus erythematosus; pDC, plasmacytoid dendritic cell. replaced by MRI, which is more sensitive (especially
T2-weighted images). Abnormalities in patients with SLE
include changes in white and grey matter, in addition to
Box 2 | Investigations in NPSLE global and regional cerebral atrophy.84 However, with the
■■ Measurement of autoantibodies (antineuronal, exception of large cerebral infarcts, the correlation between
antiribosomal P and antiphospholipid antibodies) structural changes and clinical neuropsychiatric manifes­
■■ Analysis of cerebrospinal fluid to exclude infection, tations of SLE is low, thus making MRI-determined struc­
assess the blood–brain barrier, and measure ture a poor marker of disease progression or treatment
autoantibodies, inflammatory mediators and
outcomes.85 More advanced MRI methodology for the
degradation proteins
■■ Electrophysiological assessment
detection of structural abnormalities include magnetiza­
■■ Neuropsychological assessment tion transfer imaging (MTI), diffusion-weighted imaging
■■ Neuroimaging to evaluate brain structure (CT, MRI, (DWI) and diffusion-tensor imaging (DTI).86
MTI, DWI, DTI) and brain function (PET, SPECT, MRA, MTI measures magnetization transfer between bound
MRS, fMRI) and unbound hydrogen molecules (for example, between
Abbreviations: DTI, diffusion-tensor imaging; DWI, diffusion- white matter and CSF). Magnetization transfer is dimin­
weighted imaging; fMRI, functional MRI; MRA, magnetic
resonance angiography; MRS, magnetic resonance spectroscopy;
ished by either a decrease in bound molecules (as occurs in
MTI, magnetization transfer imaging; NPSLE, neuropsychiatric demyelination) or an increase in unbound molecules (as in
systemic lupus erythematosus; SPECT, single-photon emission oedema). Decreased whole-brain magnetization transfer
computed tomography.
has been reported in patients with SLE, even in the absence
of other MRI-detected structural changes,87 and tends to
disorganized background activity and focal epileptiform be greater in longstanding NPSLE compared with active
discharges.80 Electrophysiological abnormalities in a or acute disease.86 Diffusion MRI enables the study of dif­
study of 1,533 patients with SLE and various peripheral fusion of water in the brain, which is dependent upon the
neuropathies in 207 (14%) patients, 60% of which were interaction of water with macromolecules and membranes,
attributed to SLE, found evidence of axonal neuropathy thereby enabling the assessment of tissue architecture.
in 70% and signs of demyelination in 20%.68 DWI is particularly effective in identifying hyperacute
brain injury, such as the acute ischaemia that follows a
Neuropsychological assessment stroke, when the acute shift of fluid into the intracellular
Formal neuropsychological testing is carried out when compartment and cytotoxic oedema restrict the diffusion
there is a clinical suspicion of impaired cognitive ability. of water.85,88 DTI uses a similar technology to assess the
This formal testing does not need to be performed rou­ integrity of neural white matter tracts in the brain.86
tinely in all patients, as the detection of isolated subtle PET is the most objective method of imaging brain
subclinical cognitive deficits is not clinically impor­ function; however, its clinical utility is limited as is not
tant. At present, no simple screening test for cognitive widely available.89 Single-photon emission CT (SPECT)89
dysfunction is available for use in patients with SLE, as is used to analyse regional cerebral blood flow and
most such tests lack sensitivity for mild but clinically metabolism, and is exquisitely sensitive in the detection
relevant dysfunction. Self-report instruments used to of neuro­imaging abnormalities. In patients with SLE,90–94
screen for cognitive difficulties have been validated by SPECT has identified both diffuse and focal deficits,
some studies81,82 but not others.26 Computerized testing which can be fixed or reversible. However, these findings

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Box 3 | Management of neuropsychiatric events in patients with SLE DTI, MRS and fMRI suffer from variability in results
between scanners and a lack of normative or standard­
Establish diagnosis of neuropsychiatric SLE
Investigations might include CSF examination (primarily to exclude infection),
ized guidelines for interpretation. In the future, however,
autoantibody profiling, neuroimaging to assess brain structure and function, and multimodal imaging is likely to become the standard of
neuropsychological assessment. practice in the diagnosis and monitoring of neurological
Identify confounding factors disorders, including NPSLE.
Comorbidities contributing to the neuropsychiatric event can include hypertension,
infection and metabolic abnormalities. Treatment of neuropsychiatric events
Symptomatic therapy Given the variety of clinical manifestations and the chal­
The symptoms of some neuropsychiatric events might be eased by treatment with lenges associated with diagnosis, attribution and treat­
anticonvulsant, psychotropic and anxiolytic agents. ment, the management of patients with SLE presenting
Immunosuppression with neuropsychiatric events is optimized by a multi­
Immunosuppressive agents such as corticosteroids, azathioprine, disciplinary approach, ideally led by a rheumatologist
cyclophosphamide, mycophenolate mofetil and B‑lymphocyte depletion can be (Box 3). As mentioned earlier, a thorough clinical assess­
used to treat neuropsychiatric events arising primarily from inflammatory injury. ment and appropriate investigations should be used to
Anticoagulation determine the attribution of the neuro­psychiatric event.
Neuropsychiatric manifestations arising primarily from a prothrombotic vascular The identification and treatment of non-SLE-related
injury should be treated with anticoagulants such as acetylsalicylic acid, heparin factors is important in all cases, even in those patients in
and warfarin.
whom SLE is the main contributing factor. For example,
Abbreviations: CSF, cerebrospinal fluid; SLE, systemic lupus erythematosus. Adapted with
permission from Springer © Hanly, J. G. Curr. Rheumatol. Rep. 3, 205–212 (2001). any serious infections or metabolic abnormalities should
be addressed in patients presenting with acute neuro­
psychiatric events such as acute confusion and seizures,
are not specific for SLE90 and do not always corre­late with and patients with vascular neuro­psychiatric events should
clinical neuropsychiatric manifestations.95 In fact, find­ be screened for cardiovascular risk factors. Likewise, the
ings of SPECT imaging can be abnormal in up to half use of pharmacological therapies for relieving anxiety
of patients with SLE and no clinical manifestations of and depression, improving poor sleep hygiene and main­
neuropsychiatric disease.84 Thus, the clinical relevance taining normal blood pressure could relieve cognitive
of these imaging abnormalities is not always clear. complaints. More specific therapies to address primary
Magnetic resonance angiography (MRA) enables the manifestations of SLE are selected on the basis of which
noninvasive visualization of cerebral blood flow. One immunopathogenic mechanism of NPSLE, namely
potential drawback of this method is that it is not ideal inflammation-mediated injury or vascular-mediated
for the visualization of blood flow in small-calibre vessels, injury, is predominant. Only one randomized controlled
which are the vessel type primarily involved in NPSLE. trial of immunosuppressive therapy in NPSLE has been
Magnetic resonance spectroscopy (MRS) measures undertaken,98 as highlighted by a 2013 Cochrane review
biochemical compounds including N‑acetylaspartate, of this therapy.99
choline and creatine within pre-determined regions of
interest. Decreased levels of N‑acetylaspartate, believed Autoimmune-mediated inflammatory injury
to reflect neuronal or axonal loss or dysfunction, have The standard of care for patients with SLE and serious
been reported in patients with SLE, even in the absence of visceral involvement, in particular lupus nephritis,
visible damage on structural MRI scans.84,86 Whereas MRS includes treatment with high-dose corticosteroids,
examines biochemical changes in brain tissues, functional azathioprine, cyclophosphamide and mycophenolate
MRI (fMRI) measures changes in local brain deoxy­ mofetil. A similar approach is inferred to be appropriate
haemoglobin levels, which probably reflect neuronal for those neuro­psychiatric manifestations arising from
activity and thereby provide an indirect measure of brain ­autoimmune-induced inflammation, despite a relative lack
function. In a study of blood-oxygen-level-­dependent of clinical evidence. In an open-label study of 13 patients
fMRI (BOLD-fMRI),96 frontoparietal activation while with lupus psychosis, treatment with oral cyclophospha­
performing a task that engaged working memory was mide for 6 months followed by maintenance therapy with
greater in the nine patients with NPSLE than in the same azathio­prine produced clinical improvement.100 A 2‑year
number of patients with RA and healthy controls. These randomized, controlled trial by Barile-Fabris et al.98 in 32
findings were thought to show an adaptation of neuronal patients with acute, severe NPSLE reported a significantly
function, through the recruitment of extra-cortical path­ better response to therapy with intermittent intra­venous
ways, to compensate for the impaired function of stand­ cyclophosphamide than with intravenous methyl­
ard pathways. Another study revealed differences in brain prednisone (95% versus 54%, P <0.03). More targeted
activation patterns between 10 patients with childhood- immuno­suppressive therapies, such as B‑lymphocyte
onset SLE and healthy controls.97 Thus, fMRI could be depletion with anti-CD20 antibody used alone or in com­
informative regarding dysfunction or redistribution of bination with cyclophosphamide,101 are promising but
functions as a result of SLE.86 require further study. In most studies in NPSLE, immuno­
Despite its limitations, at this time, structural MRI suppressive therapy has been used in combination with
remains the neuroimaging method routinely used in cortico­steroids, and alongside symptomatic therapies such
clinical practice. More advanced methods such as MTI, as psychoactive medications.

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60 Much worse prednisone reportedly improved cognition in five of

50
Worse eight patients who completed the trial.107 In a single-
No change centre, placebo-controlled study in 51 patients with SLE,
Improved
40 memantine, an NMDA-receptor antagonist used to treat
NP events (%)

Much improved
30 Resolved
Alzheimer disease, did not improve cognitive perfor­
mance compared with placebo over 12 weeks.108 Given
20 the observed association between cognitive impairment
10
and aPL, 51,52 the use of antiplatelet or anticoagulant
therapy in aPL-positive patients is logical; however, evi­
0 dence for the efficacy of this approach is lacking. The use
NPSLE (model A) NPSLE (model B) NP-non-SLE
of immuno­suppressive therapy in patients with presumed
Figure 4 | Physician-generated outcome scores for NP events at enrolment into an in­flammation-mediated brain injury is also logical, but
international inception cohort of patients with SLE.23 NP events were attributed to again lacks evidence of efficacy from controlled trials,
SLE or non-SLE causes using one of two different attribution models. Using especially in patients with cognitive im­pairment as the
attribution model A, the NP event was attributed to SLE unless onset of NP events sole manifestation of NPSLE.
occurred before the study enrolment window, non-SLE factors that contributed to or Cognitive rehabilitation therapy aims to help indivi­
were responsible for the NP event were identified, or NP events with a high frequency
duals functionally adapt to cognitive deficits, typically
in the general population (as defined by Ainiala et al.5) occurred. Using attribution
model B, the NP event was attributed to SLE unless onset of NP events occurred
through intensive retraining of cognitive skills. This
>10 years before the diagnosis of SLE, non-SLE factors responsible for the NP event approach has been applied in numerous conditions,
were identified, or NP events with a high frequency in the general population (as including stroke, dementia, traumatic brain injury and
defined by Ainiala et al.5) occurred. Those NP events that were attributed to SLE multiple sclerosis. One study of cognitive rehabilita­
using either model A or model B had a significantly better outcome than NP events tion enrolled 17 women with SLE aged 25–60 years who
not attributed to SLE (P <0.001). Abbreviations: NP, neuropsychiatric; SLE, systemic reported cognitive difficulties that either interfered with
lupus erythematosus. Reproduced with permission from John Wiley & Sons, Inc. © adaptive functioning or caused emotional distress.109
Hanly, J. G. et al. Arthritis Care Res. 59, 721–729 (2008).23
All participants completed the MINDFULL (Mastering
the Intellectual Navigation of Daily Functioning and
Vascular injury Undoing the Limitations of Lupus) programme, which
Treatment of focal neuropsychiatric disease attributed involved eight weekly 2 h “psychoeducational group
to aPL requires anticoagulation, and such therapy will intervention” sessions focused on cognitive-strategy
usually be lifelong.27 In the absence of controlled clinical training applied across multiple real-life situations.
trials to guide the type and intensity of anticoagulation In addition, the MINDFULL programme included a
therapy required to treat NPSLE due to thrombosis, one psycho­social support component. The feasibility of this
must rely on studies of prevention of recurrent throm­ approach for the SLE population was demonstrated by
bosis (at any anatomical location) in patients with the study’s 100% retention rate. Patients reported better
antiphospholipid syndrome. Two controlled studies affect and overall quality of life, as well as memory self-
in antiphospholipid syndrome found no significant efficacy (which has been linked to cognitive performance
difference between low-intensity treatment (target in daily life). Although these results are encouraging,
inter­national normalised ratio [INR] 2.0–3.0) and high- controlled and long-term studies are required to confirm
intensity treatment (target INR >3.0) with warfarin in these prelimi­nary findings and determine their durabili­ty
the prevention of recurrent thrombosis.102,103 However, a over time.
minority of patients in these studies had arterial throm­
bosis, and controversy remains on the optimal target INR Prognosis
for the manage­ment of such cases.104 Potential adjunctive The outcome of neuropsychiatric events in patients
thera­pies to consider, especially in patients with recurrent with SLE, whether attributed to SLE or non-SLE causes,
thrombosis whilst on warfarin, are antiplatelet agents, has been examined in only a small number of studies.
antimalarial agents105 and statins.106 Clinical trials of therapy for these disorders have been
uncontrolled, of short duration or focused upon a
Cognitive impairment single neuropsychiatric manifestation.98,100,101,107,110,111
Non-SLE causes of cognitive dysfunction, including Longitudinal studies of cognitive function have gener­
sleep deprivation, mood disorders, fatigue and medica­ ally reported stable performance on cognitive tests over
tions, should be sought and addressed. Several medi­ time, with persistent or progressive cognitive dysfunc­
cations commonly used for the treatment of SLE, such tion seen in only a minority of patients.112,113 Outcomes
as anti­depressant, anticonvulsant and antihypertensive of observational cohorts have been inconsistent. For
agents, can induce reversible cognitive impairment; these example, some studies have reported increased mortal­
effects might be improved by changes in the choice or ity in patients with neuropsychiatric events,13–16 whereas
dose of drug. Pharmacological treatment and cognitive others have not.17–19 In a follow-up study of 32 patients
re­habilitation can also be considered. hospitalized for NPSLE, neurological deficits had either
In a placebo-controlled trial of pharmacologic substantially improved (69%) or stabilized (19%) after
therapy for SLE-associated cognitive dysfunction in 10 2 years.117 In a prospective study of patients with SLE fol­
patients with mild SLE, daily treatment with 0.5 mg/kg lowed for up to 7 years (mean 3.6 years),24 approximately

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© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS

15% of neuropsychiatric events were resolved at each assessment of the patient and the selection of appropriate
annual assessment; however, most events persisted. investigations. Recent studies have provided insight into
Notably, whether or not an event resolved could not be the immunopathogenetic mechanisms of NPSLE, the
predicted by its attribution to SLE or non-SLE causes. contribution of non-SLE factors and the short-term and
In contrast to this finding, two reports from a cohort long-term prognosis of patients presenting with NPSLE.
study of patients recently diagnosed with SLE demon­ Current therapeutic strategies are largely empiric, based
strate a more favourable short-term outcome over a on known immunopathogenetic mechanisms and what
mean follow-up of 3.7 months 23 and 1.9 years 25 for has been observed from the treatment of other serious
neuro­psychiatric events attributed to SLE compared organ disease in SLE. Further insight into the immuno­
with non-SLE events (Figure 4). The possibility exists pathogenetic mechanisms and clinical outcomes of
that early treatment of NPSLE leads to better outcomes, NPSLE are required to inform the design and execution
akin to the therapeutic ‘window of opportunity’ seen in of therapeutic clinical trials.
other rheumatic diseases.118,119

Conclusion Review criteria

The occurrence of neuropsychiatric events in patients The articles cited in this Review were selected from the
with SLE poses a diagnostic and therapeutic challenge. author’s personal library of articles on neuropsychiatric
The precise characterization and correct attribution SLE. Selections were made on the basis of the expert
opinion of the author. The reference list was last updated
of these events to SLE and non-SLE causes is critical.
in October 2013.
The correct diagnosis relies heavily on careful clinical

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