Review

published: 06 June 2018

doi: 10.3389/fimmu.2018.01146

Neurological Disease in Lupus:

Toward a Personalized Medicine
Approach
Sarah McGlasson 1,2,3, Stewart Wiseman 2, Joanna Wardlaw 2, Neeraj Dhaun4
and David P. J. Hunt1,2,3*
1
 MRC Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom, 2 The UK Dementia Research Institute,
University of Edinburgh, Edinburgh, United Kingdom, 3 The Anne Rowling Clinic, University of Edinburgh, Edinburgh, United
Kingdom, 4 Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh,
United Kingdom

The brain and nervous system are important targets for immune-mediated damage in
systemic lupus erythematosus (SLE), resulting in a complex spectrum of neurological
syndromes. Defining nervous system disease in lupus poses significant challenges.
Among the difficulties to be addressed are a diversity of clinical manifestations and a
Edited by:
lack of understanding of their mechanistic basis. However, despite these challenges,
George C. Tsokos, progress has been made in the identification of pathways which contribute to neurolog-
Harvard Medical School, ical disease in SLE. Understanding the molecular pathogenesis of neurological disease
United States
in lupus will inform both classification and approaches to clinical trials.
Reviewed by:
Vasileios Kyttaris, Keywords: neurolupus, personalized medicine, lupus erythematosus, systemic, targeted therapy, interferon type I
Beth Israel Deaconess
Medical Center, Harvard
Medical School, United States INTRODUCTION
Tamar Rubinstein,
Albert Einstein College of Medicine, Systemic lupus erythematosus (SLE, lupus) is a multiorgan autoimmune disease, initially described
United States on the basis of its cutaneous manifestations (1). During the nineteenth century, the true multisystem
*Correspondence: nature of the disease was recognized with the initial descriptions of severe brain involvement (2, 3).
David P. J. Hunt The first dedicated clinical studies of neurological dysfunction in lupus were reported in 1945 by
david.hunt@igmm.ed.ac.uk David Daly (4). His observations were astute, noting a high degree of heterogeneity in the neuro­
logical manifestations, and a prominent contribution of neurovascular disease. Over the following
Specialty section: decades, the effects of lupus on all levels of the nervous system have been recognized.
This article was submitted to The diversity of neurological disease in lupus stimulated calls for a classification system to facilitate
Inflammation, a section of the its clinical and scientific study (5). In 1999, the American College of Rheumatology (ACR) developed
journal Frontiers in Immunology
criteria for case definitions for neurolupus (6). These broadly distinguish between complications
Received: 09 March 2018 which affect the central nervous system and peripheral nervous system (Table 1 and Figure 1). While
Accepted: 07 May 2018 minor modifications have been proposed to these criteria, they have remained largely unchanged for
Published: 06 June 2018
almost two decades (7, 8). Neurological events have also been incorporated into diagnostic criteria
Citation: for lupus, as well as outcome metrics such as the SLICC/ACR Damage index (9, 10).
McGlasson S, Wiseman S, The development of the ACR neurolupus definitions helped stimulate the epidemiological study
Wardlaw J, Dhaun N and Hunt DPJ
of neurological disease in lupus, and has demonstrated that nervous system involvement is a major
(2018) Neurological Disease in
Lupus: Toward a Personalized
negative determinant of quality of life (11–13). However, such studies have highlighted one of the
Medicine Approach. major problems in the field—the issue of establishing a causal association between a neurological
Front. Immunol. 9:1146. syndrome and lupus (14). For example, the ACR criteria include terms such as headache and mood
doi: 10.3389/fimmu.2018.01146 disorder which are highly prevalent in the general population and observed at similar frequency in

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McGlasson et al. Neurological Disease in Lupus

healthy, matched controls, as well as patients with other chronic events develop in about 5% of patients with SLE, followed over
inflammatory diseases (15). As such they are less likely to be 3  years (17). Magnetic resonance imaging evidence (MRI) of
caused directly by lupus. When “minor events” such as headache brain changes indicating microvascular disease can develop early
and anxiety disorders are included in population studies, then in disease course and in young patients (18, 19).
40% of patients had at least one neuropsychiatric event (12). Much of the difficulty in classification stems from a compara­
Exclusion of minor symptomatology leads to much improved tive lack of understanding as to how neurological disease develops
specificity of the criteria (15). Neurological manifestations can in people with lupus. It is notable that the ACR definitions focus
occur at any stage of disease. Longitudinal studies of newly diag­ largely on neurological syndromes, rather than pathophysio­
nosed patients show that neurological events attributable to lupus logical mechanisms. This is in major contrast to renal lupus,
can occur around the time of diagnosis in approximately 5–10% where pathophysiological classification influences treatment and
of cases (16). Prospective studies show that major neurological prognosis (Figure 2) (20). With the development of increasingly
targeted treatments, an understanding of the molecular patho­
genesis of brain disease is ever more important if it is to inform
Table 1 | Clinical syndromes seen in people with systemic lupus clinical trial design and, ultimately an individualized therapeutic
erythematosus. approach.
Syndrome Implicated mechanisms
and potential therapeutic targets PATHOPHYSIOLOGY OF NEUROLOGICAL
CNS Large and small vessel • Large vessel atheromatous DISEASE IN LUPUS
disease disease (57)
• Accelerated cerebral small vessel Genetics
disease (18)
Genome-wide association studies of large cohorts of lupus
• Antiphospholipid antibodies (49)
Seizures • Unknown (69) patients have identified an increasing number of associations
Myelopathy • Antibody-mediated [aquaporin-4, with pathways involved in both the innate and adaptive immune
myelin oligodendrocyte glycoprotein systems (24). However, to date there has been little dedicated
(MOG)] (21, 147, 148) genetic study of neurolupus. An evaluation of TREX1, a 3′–5′
• Vascular
Meningitis • Unknown (78)
exonuclease associated with SLE (25, 26), revealed a common
Movement disorder • Unknown (84) risk haplotype in lupus patients with brain manifestations, par­
Demyelinating syndrome • Not clearly associated with SLE (89) ticularly seizures (27, 28). While these mechanistic insights are of
Headache • Not clearly associated with SLE (90) interest, testing of TREX1 is unlikely to be of clinical utility (27,
Psychiatric disease • Cytokine dysregulation (107) 29) given the relatively high frequency of variants in the general
• Antibody-mediated (NMDA-R,
Ribosomal-P) (97)
population (30).
Cognitive dysfunction • Cytokine dysregulation (38)
• Small vessel disease (18, 61) Cytokines
PNS Peripheral neuropathy • Vasculitis (124) There is dysregulation of multiple cytokine pathways in patients
• Antibody-mediated (ganglioside) (149)
with SLE (31), and recent work has focused on the extent to which
Cranial neuropathy • Vasculitis
• Antibody-mediated (aquaporin-4/MOG)
these pathways might contribute to brain damage. Approximately
(132, 150) 80% of individuals with lupus have aberrant activation of their
Myasthenia Gravis • Antibody-mediated (anti-AChR) (151) type I interferon pathway, identified by either a transcriptomic

Figure 1 | The spectrum of neurological disease in lupus. Lupus can affect all levels of the nervous system, including the brain and spinal cord, as well as the
peripheral nervous system. See text for detailed descriptions of individual syndromes.

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McGlasson et al. Neurological Disease in Lupus

Figure 2 | Classifying neurological disease in lupus. Both the brain and kidney can be severely affected in up to 10% of patients with lupus. (A) While lupus
nephritis can present with different clinical syndromes, it is largely defined by a pathological classification of the renal biopsy. Image created with Biorender.
(B) In contrast, neurological forms of lupus are usually classified according to neurological syndrome, and pathological material is rarely obtained. (C) We have an
increasingly precise understanding of the syndrome previously described as “lupus myelopathy,” T2-weighted magnetic resonance imaging of long inflammatory
lesion in person with lupus shown, with high signal from within the thoracic spinal cord. A proportion of such spinal cord presentations are driven by antibodies
directed against aquaporin-4, a glial water channel (21). Other cases are caused by spinal cord inflammation without these antibodies, while some cases are
associated with spinal cord ischemia (22, 23). Each of these causes may require consideration of differing therapeutic approaches. As such, what was previously
considered a single disease entity can be caused by differing pathogenic mechanisms, with implications for treatment and clinical trial design.

signature, or ultrasensitive detection of the interferon-alpha cognitive dysfunction in these patients and causes brain disease
proteins (32, 33). Detailed longitudinal studies have shown that in brain-targeted overexpression experiments (38, 39). Type II
activation of this pathway influences lupus disease phenotype (33). interferons, interleukins (IL-2, IL-12, IL-18, IL-23), and TNF
The ability of type I interferon proteins to cause brain damage cytokine families are all dysregulated in lupus and their roles in
and affect mood is well documented in clinical trials of recombi­ brain disease are being evaluated (40).
nant type I interferon proteins (34–36). Activation of the type I
interferon response in the post-mortem brains of lupus patients Inflammatory Cells
has been shown (37), and multiple cell types within the brain, Although B cells and T cells undoubtedly play an important role in
including endothelial cells, microglia, and neurons, respond to the pathogenesis of SLE, neuropathological analyses in individu­
type I interferon activation. als with lupus show little in the way of immune cell infiltration
Many other cytokines are dysregulated in SLE, with potential within the brain (41). This contrasts with other neuroinflamma­
neurotoxic effects. For example, IL-6 has been associated with tory diseases such as multiple sclerosis (MS) where abundant B

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McGlasson et al. Neurological Disease in Lupus

and T  cells are found within inflammatory brain lesions (42). (Figure 3A) (18). Sophisticated MRI imaging techniques such
There has been an increasing focus on how brain-resident as diffusion imaging and quantitative tractography can map
immune cells, such as microglia, might mediate brain disease. the brain’s white matter tracts and have identified evidence of
Recent elegant studies have shown that microglia are sensitive to microstructural damage in SLE (Figure  3C), although robust
elevated circulating cytokines such as type I interferon, and the association between such changes and neurological dysfunction
resulting activation can lead to activation of a number of effec­ remains unclear (38).
tor pathways within these cells, including the ability to engulf
and “prune” synaptic connections (37, 43). These studies show CLINICAL APPROACH IN NEUROLUPUS
how dysregulated cytokines can cause structural brain damage
by manipulating the normal physiological processes of brain- The European League against Rheumatism recommendations
resident immune cells. for management of neurolupus emphasizes the importance of
careful evaluation of new neurological events in individuals
Antibodies with SLE (55). It is important to remember that neurological
Antibodies are a major mediator of organ damage in SLE, symptoms may not be caused by lupus, and may simply represent
and antibodies directed against multiple brain antigens are highly prevalent neurological disease such as migraine or tension
frequently produced (44). The extent to which such antibod­ headache. Furthermore neurological symptoms may be caused
ies cause neurological disease remains to be fully determined. directly or indirectly by drug therapies (14, 56). As such investiga­
In some cases, for example, antibodies directed against the tion of these symptoms should involve a detailed history, careful
astrocytic water channel aquaporin-4 (AQP4), there is evidence examination and further investigation where indicated, including
to support a causal relationship with spinal cord and optic MRI scan, cerebrospinal fluid analysis, and neurophysiology (56).
nerve inflammation (21, 45). Antibodies against neuronal cell Multidisciplinary discussion with a neurologist with an interest
surface proteins such as the NMDA-receptor (NMDA-R) have in neuroinflammatory disease and SLE can help.
also been described in lupus, but a causal association with
neurological symptomatology is less clear, despite their ability to Recognized Clinical Syndromes
mediate brain disease in animal models. Although anti-NMDA- The recognized clinical neurological syndromes associated with
R antibodies can cause a very distinct clinical phenotype of lupus are based loosely on the framework of the ACR criteria.
autoimmune encephalitis (46), this syndrome is rarely seen in
SLE, and the degree to which lower titers of such antibodies Stroke
can cause neuropsychiatric dysfunction outside this clinical The earliest descriptions of lupus brain disease emphasized a
picture is unclear (47). Interestingly, more classic lupus- prominent role for neurovascular disease (4). Subsequent studies
associated antibodies directed against nucleic acids, can also have shown that stroke occurs more frequently in people with
cross-react with NMDA-R epitopes and cause neurological SLE than in the general population, with ischemic stroke deve­
dysfunction in rodent models (48). In patients with SLE who loping in up to 20% of lupus patients (57–61). This observation of
have co-existing antiphospholipid syndrome there is a role for an increased stroke risk has been confirmed in large prospective
antiphospholipid antibodies in the mediation of thrombotic registry based studies (59) and meta-analyses (61). Recognized
events including intracranial thromboembolism (49). Therefore, risk factors, such as hypertension, smoking, and hypercholes­
a broad spectrum of antibodies is implicated in the pathogenesis terolemia may play an important role in this increased risk (60),
of neurolupus, though neurological expertise may be needed in but do not fully account for the excess of cases, implicating an
their interpretation. additional inflammatory etiology (62). As such, addressing the
modifiable stroke risk factors of smoking, diet, and blood pres­
Pathology and Imaging sure, is an important priority for lupus patients. Patients with
Brain biopsies are performed rarely in people with lupus. lupus who present with stroke should be carefully evaluated for
Consequently, much of our understanding of the pathological the antiphospholipid syndrome, given that this may direct a dif­
basis of neurolupus comes from post-mortem studies, which ferent strategy based on anti-coagulation rather than anti-platelet
introduce a bias toward severe disease. The first dedicated therapies. Intracranial vasculitis causing stroke—either ischemic
studies identified prominent cerebral small vessel disease as a or subarachnoid hemorrhage—is rare in SLE, but can sometimes
major neuropathological feature in most cases (50). Importantly, occur and may be identified by abnormal angiographic appear­
this is not a small vessel vasculitis, but rather a noninflamma­ ances or biopsy (63–65), highlighting the heterogeneity of
tory microangiopathy associated with microinfarction (50). underlying mechanisms which drive neurovascular disease in
Pathological changes of small blood vessels include necrosis of lupus.
the vessel wall, endothelial cell proliferation, and hypertrophy
(41, 50, 51). Subsequent studies have confirmed these findings Small Vessel Disease (SVD)
(52, 53). Paired pathology-imaging studies show that these cer­ Cerebral SVD is a disorder of the brain’s perforating arterioles
ebral small vessel lesions seen on brain pathology correspond with typical MRI brain imaging features which include white
to “white matter hyperintensities” identifiable on MRI of the matter hyperintensities (WMH, Figure  3A). Such appearances
brain (54). These MRI abnormalities are seen in the majority of can occasionally cause diagnostic confusion with MS, although
people with lupus, even with mild neurological symptomatology improved imaging should aid the distinction. Accelerated

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McGlasson et al. Neurological Disease in Lupus

Figure 3 | Magnetic resonance imaging (MRI) imaging in lupus brain disease. (A,B) Fluid-attenuated inversion recovery MRI scan of a representative
individual with lupus, showing accelerated cerebral small vessel disease, highlighted red arrows. (C,D) Advanced MRI techniques such as diffusion tensor
imaging and tractography can allow identification of individual white matter tracts and parameters such as mean diffusivity can identify microstructural disease.
Tractography images of lupus patient shown, each line represents individual white matter tract. Credit: Mark Bastin, Joanna Wardlaw, and Stewart Wiseman.

cerebral SVD is a major cause of dementia in the general popu­ recurrence rate of seizures appears to relatively low (69), large-
lation, although the neurological significance of these findings scale epidemiological analyses of large databases confirm higher
in lupus remains to be determined (18). Quantified MRI brain rates of epilepsy in people with lupus (72). Seizures should be
studies of individuals with lupus show significantly accelerated carefully evaluated with a neurologist for underlying cause and
cerebral SVD, suggesting that this is the most frequently observed use of anticonvulsant agents discussed in those at high risk of sei­
radiological–pathological brain abnormality in lupus (41, 54, 66), zure recurrence. If anticonvulsant medication is used, particular
seen even in patients with mild and inactive disease (18). It is attention may need to be paid to issues such as drug interactions
likely that inflammatory mediators such as cytokines play a direct and teratogenicity.
role (67), though the precise factors—and whether they might be
more accurately targeted—remain to be determined. Myelopathy
Spinal cord disease is an uncommon but serious neurological
Seizures complication in people with lupus. Over the past decade, the
Seizures can occur in approximately 5% of individuals with lupus. identification of pathogenic antibodies against glial antigens
These are often generalized, though can also be of focal onset such as the AQP4 water channel has demonstrated that “lupus
(68, 69). It remains unclear as to whether such events represent myelitis” can, in part, be explained by concomitant neuromyelitis
a form of autoimmune epilepsy, or a lowered seizure threshold. optica spectrum disorder (NMOSD) (73). These autoantibodies,
Seizures can also occur in the context of underlying disorders, together with anti-myelin oligodendrocyte glycoprotein (MOG)
such as infection, macrophage activation syndrome (MAS) (70), antibodies, should be tested in spinal cord presentations, espe­
or posterior reversible encephalopathy syndrome (PRES) (71), cially in the context of “longitudinally extensive transverse
highlighting the need for appropriate investigation of seizures myelitis” where inflammation extends over at least three vertebral
depending on the clinical context. There is no clear association segments (74). The presence of AQP4 antibodies is associated
between seizures and autoantibody formation, including the with a risk of relapse and immunosuppression is typically used to
potentially epileptogenic anti-NMDA-R antibody (68). While prevent further events. The B-cell depleting monoclonal antibody

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McGlasson et al. Neurological Disease in Lupus

rituximab is increasingly used as a first- or second-line agent demyelination seen in MS lesions (42, 86). Active MS lesions
(21, 74, 75). Antibodies against AQP4 can be generated in people often display incomplete ring enhancement, and typically occur
with lupus without an opticospinal inflammatory event. These in a more periventricular distribution. True co-existence of
antibodies can be associated with other neurological syndromes lupus and MS is uncommon (19, 87), and there is no convinc­
such as intractable hiccups and vomiting due to lesions in the ing evidence that lupus can cause an MS-like syndrome (87). In
area postrema, highlighting the broadening spectrum of AQP4- patients with both lupus and convincing clinical and paraclinical
associated neurological disease, both with and without lupus evidence of MS (88), a more plausible explanation is that, as is
(45, 76). Spinal cord disease in SLE is heterogeneous and short sometimes seen autoimmunity, the two diseases co-exist in a
transverse myelitis and ischemic transverse myelitis can also single individual (89). This presents a specific management chal­
occur (22, 77). Our increased understanding of the pathogenesis lenge of identifying immunotherapies that might offer efficacy
of spinal cord disease in lupus highlights that a myelopathic against both diseases.
presentation can be caused by multiple different etiologies (77),
with diverse treatment options (23), requiring careful evaluation Headache
(Figure 2C). Headache is a highly prevalent disorder in people with SLE (90),
but there is no convincing evidence that this incidence is higher
Meningitis than that seen in the general population (91). Thus the entity of
Meningitis, as described in the ACR case definitions, specifically “lupus headache” is controversial (92). Headache in individu­
refers to an autoimmune aseptic meningitis. This can occur in als with lupus should be approached in the same way as in the
lupus patients in isolation, but can also accompany other events general population, noting the broader differential diagnosis of
such transverse myelitis (78). It is rare. Given that many indi­ any new acute headache to include a higher risk of infectious and
viduals with lupus are immunosuppressed, a critical differential neurovascular etiologies (64).
diagnosis is one of infectious meningitis caused by typical or
opportunistic pathogens. A broad spectrum of pathogens includ­ Psychiatric Disease
ing Cryptococcus neoformans and Listeria monocytogenes can The term “lupus psychosis” has been used to describe single or
cause meningitis in lupus patients and microbiological advice repeated episodes of thought disorders such as hallucinations
should be sought (78). The clinical presentation of opportunistic and delusions occurring in people with SLE (93, 94). Like many
organisms may vary, for example, fungal meningitis or listeriosis neuropsychiatric symptoms, the biology of psychosis remains
may present with raised intracranial pressure and cranial neu­ poorly understood, although the possibility of an autoimmune
ropathies rather than meningism and fever (78). Aseptic menin­ contribution is the subject of intense current research interest (47,
gitis has also been described as a consequence of drugs used to 95). Individuals with lupus are exposed to a number of biological
treat lupus, including NSAIDs (79). substances which can cause psychosis, in particular corticosteroids
and circulating antibodies directed against the NMDA-R (47). An
Movement Disorders association has also been identified between psychosis in lupus
Chorea, a hyperkinetic movement disorder, has been reported and anti-ribosomal-P antibodies (96), which can react against
in lupus patients (80), although reversible forms of parkinson­ neuronal cell surface antigens (97). However, while antibodies
ism, a hypokinetic movement disorder, has also been described, directed against dsDNA, NMDA-R, and ribosomal-P may exhibit
particularly in young-onset disease (81, 82). Myoclonus has also some neurotoxic effects in adoptive transfer experiments, their role
been described (83). The etiology of these movement disorders in mediating psychiatric symptomatology and other brain symp­
is poorly understood and neuroimaging studies do not usually toms in humans is not clear (98). A proportion of psychotic events
identify evidence of a localizing lesion (84). Both ischemic and in lupus are temporally related to corticosteroid use, although
antibody-mediated causes have been postulated, though not such observations are likely to be confounded by increases in
convincingly demonstrated. systemic disease activity which might precede increased steroid
dose (99–101). Differentiation of steroid-induced psychosis from
Demyelinating Syndrome lupus-associated psychosis is particularly challenging (100).
An association between lupus and MS-like brain changes have Depression and anxiety are common in the general popula­
been suggested, and sometimes termed “lupoid sclerosis” (85). tion and observed more frequently in chronic disease states. It
However, many such studies pre-date high quality MRI brain is, therefore, not surprising that about 15% of patients diagnosed
imaging which has greatly facilitated accurate diagnosis of MS. with lupus develop mood disorders and 5% an anxiety disorder
Much of this confusion stems from the superficial similarities (12, 102). However, the use of both interviews and validated
between the presence of small white matter lesions on the MRI scales to quantify affective disorders suggest that the prevalence of
brain scans of patients with both MS and lupus. Advances in our mood and anxiety disorders may be significantly higher, around
understanding of the pathogenesis of MS in the past decades 20–40% (103–106). It has been established in clinical trials of
highlight that these lesions are distinct from those observed in therapeutic cytokines that inflammatory factors, such as type I
lupus (86). Lesions in MS can usually be distinguished from those interferon proteins, can induce depressive illness in humans (36,
of lupus with MRI brain imaging. For example, lesions in lupus 107). Therefore, the degree to which lupus-related inflammatory
rarely enhance and correlate at a pathological level with small factors contribute to the high burden of psychiatric disorders in
vessel injury (54), rather than the lymphocytic infiltration and this condition remains unresolved.

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McGlasson et al. Neurological Disease in Lupus

Cognitive Dysfunction suggest that the commonest electrophysiological pattern is

Longitudinal cognitive assessment in people with SLE show that that of a sensorimotor axonal neuropathy (122). Among lupus-
cognition can vary over time (108, 109), though true dementia associated neuropathies, the identification of demyelinating
is not common (110). There is no clear association with lupus inflammatory neuropathies is of particular importance, given
activity (111). Screening tools are of use to identify cognitive dys­ the demonstrated response of such neuropathies to intrave­
function in the clinic and should prompt more detailed neuropsy­ nous immunoglobulin (125). Identification of inflammatory
chological testing if abnormal (112). However, cognitive changes demyelination on nerve conduction studies should provoke
can be transient and their substrate poorly defined. While some examination of the CSF and a search for paraproteinemic
correlation with MRI abnormalities has been identified, this is not comorbidities (126). Very rarely, Guillain–Barré Syndrome—
a robust association (113). Associations with elevated cytokines an acute inflammatory neuropathy—has been observed (127)
such as IL-6 have also been identified, but again a causal relation­ as has myasthenia gravis.
ship is unclear (38). Evaluation of cognitive symptoms in people
with lupus requires careful clinical evaluation, paying attention to Cranial Neuropathy
additional factors such as depression and medication which can Optic neuropathies, manifesting as either optic neuritis or
contribute to cognitive dysfunction. Neither corticosteroids (114) ischemic optic neuropathy, have been observed in SLE (128–132).
nor NMDA-R antagonists (115) have been shown to improve Given the association of NMOSD with lupus, evaluation of anti-
cognitive functioning in SLE, though cognitive rehabilitation AQP4/MOG antibodies is important and may potentially guide
approaches have shown some promise (116). treatment (74, 133). Cranial neuropathies affecting all cranial
nerves have been reported in lupus (134–137), either as single
Rare Entities events or as a cranial mononeuritis multiplex (137, 138).
Posterior reversible encephalopathy syndrome is a clinical–
radiological syndrome of headache, seizures, and encephalopathy Functional Disorders
associated with white matter changes which occur mainly toward Functional symptoms are real but are not caused by underlying
the posterior regions of the brain (117). Despite its name, the neurological disease. Functional neurological disorder is a com­
neurological damage caused by PRES is not necessarily reversible mon cause of neurological symptoms, in both general medicine
and can occur throughout the brain. A number of cases of PRES and neurology clinics, and can, therefore, frequently co-exist
in people with SLE have been reported (71), but this syndrome with inflammatory diseases such as lupus (139). Incorrectly
can be confounded by associations with immunosuppressive attributing functional symptoms to an inflammatory cause
medications and uncontrolled hypertension, and, therefore, the can lead to an inappropriate escalation in immunotherapy or
precise etiological factors are not fully understood (71). PRES- unnecessary investigation. A specialist neurological opinion
like appearances on neuroimaging can be mimicked by venous can help to identify positive findings of functional neurological
sinus thrombosis, which is an important differential diagnosis. disease. The incidence of functional symptomatology in lupus
Another rare manifestation of lupus is the macrophage activa­ and other inflammatory diseases is unknown and merits further
tion syndrome which can occur with prominent neurological study (139).
involvement including seizures and encephalopathy (70). This is
an important differential diagnosis of the acutely unwell lupus Treatment of Neurolupus
patient with multisystem involvement and requires prompt While efforts have been made to guide best practice in the
identification and treatment. diagnosis and management of neurolupus, there is only a weak
Inflammatory Neuromuscular Disease evidence base on which to develop such recommendations (55).
Neuromuscular disease is an important cause of morbidity in There have been a handful of clinical studies for the treatment
SLE. The ACR neurolupus case definitions consider cranial of lupus-associated neurological disease, none which provide
nerve, peripheral nerve, and neuromuscular junction disease high quality evidence. A small randomized trial of cyclophos­
together, stopping at the motor end-plate and excluding muscle phamide suggested potential benefit, but interpretation of these
disease, which is classified separately. Muscle disease is, therefore, data are limited by small sample size and methodological issues
not reviewed in depth here, although it should be noted that a (140, 141). There have also been observational studies of azathio­
spectrum of inflammatory muscle disease can occur in about 10% prine (142) and rituximab (143), but the high degree of variability
of patients with SLE, including myositis and vasculitis, sometimes of clinical symptomatology and a lack of standardized neurologi­
requiring biopsy confirmation (118–120). cal outcome measures makes these results difficult to interpret.
Furthermore, meaningful metrics of neurological disease are
Peripheral Neuropathy rarely captured in large lupus clinical trials, and patients with
Peripheral neuropathy can occur in approximately 8% of neurological disease are often excluded from such studies (144).
patients with lupus, presenting mainly as a symmetrical
polyneuropathy (121, 122). Mononeuritis multiplex can also FUTURE DIRECTIONS
occur occasionally in lupus and is associated with small vessel
vasculitic change on nerve biopsy, often developing during Systemic lupus erythematosus is a strong candidate for a
periods of high lupus activity (123, 124). Prospective studies, “personalized immunotherapy” approach, since individual
based on electrophysiological studies rather than symptoms, patients may have different molecular pathways driving their

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McGlasson et al. Neurological Disease in Lupus

Figure 4 | A stratified medicine approach for neurolupus. Brain disease in lupus is clinically heterogeneous (left), but may be driven by certain molecular pathways
(e.g., type I interferon pathway, pathogenic autoantibodies), allowing stratification of populations. Improvements in biomarkers will allow identification of aberrant
pathways in patients, such that they can be directed to clinical trials targeted at the specific pathway. Central to the success of such a strategy is the development
of brain biomarkers (e.g., magnetic resonance imaging scans, markers of brain damage) to supplement clinical assessment.

disease. Longitudinal studies of lupus patients, together with There is a particular need to develop validated imaging and
their peripheral transcriptomic responses, support this approach laboratory biomarkers of neurological disease in lupus which
to developing targeted therapies. These analyses show that can supplement complex clinical assessment. MRI brain scans
targetable pathways—or combinations of pathways—can drive are invariably abnormal in lupus, and change over time. As such,
different aspects of lupus (33). For example, activation of the imaging biomarkers may play a role as our ability to quantify
type I interferon response is an important determinant of organ- macrostructural and microstructural damage (Figure 3). Serum
specific disease and is implicated in aspects of brain disease. and CSF biomarkers of “brain damage,” such as ultrasensitive
Similarly, B-cell pathways play an important role in neurological detection of neurofilament protein, have been developed as a
syndromes caused by pathogenic autoantibodies. Thus, with the surrogate marker for clinical trials in neuroinflammatory and
advent of more accurate biomarkers to identify aberrant immu­ neurodegenerative diseases (146). Thus the rapid progress in
nological pathways, heterogeneous populations could be divided our understanding of both pathophysiology and biomarkers of
into those who are predicted to respond to targeted therapies, neurolupus is providing a much-needed roadmap to advance the
acting as a basis for rational trial design (Figure 4) (32, 37, 145). field.
If this approach is to provide a logical framework for developing
therapies, then we need to incorporate such a molecular under­
standing into clinical classification.
SUMMARY
At present, the classification system for neurological disease Neurological disease is an area of major unmet need for people
in lupus is largely based on neurological syndromes and does with lupus, providing a complex conceptual and practical chal­
not incorporate a pathophysiological understanding of the dis­ lenge. An improved molecular understanding of how lupus can
ease (Figure 2). The need to move from a syndromic toward a damage the brain and nervous system is providing opportunities
mechanistic classification is perhaps best exemplified by spinal to pursue stratified medicine approaches. Advancing the field
cord disease in lupus (Figure  2C). The 1999 ACR case defini­ will require our tools for classifying and measuring neurological
tions refer to a broad syndrome of “lupus myelopathy.” However, disease in lupus to be reevaluated.
as we describe above, our understanding of the pathogenesis
of spinal cord disease in lupus has advanced, together with the
discovery of strong biomarkers and improved imaging. It is clear AUTHOR CONTRIBUTIONS
that “lupus myelopathy” can be caused by at least three different
pathophysiological processes. These include antibodies against DH and SM drafted the original manuscript. Further revisions
AQP4, antibody-independent inflammation, and spinal vascular were made by SW, ND, and JW. SW and JW provided additional
disease. It is likely that each of these different mechanisms may images.
require a different therapeutic approach. Furthermore, some
syndromes, such as “lupus headache,” may not exist at all. As such FUNDING
the classification system used in neurolupus requires substantial
revision, reflecting the transition to a molecular understanding DH is supported by the Medical Research Foundation Emerging
of disease. Leaders Prize. DH and SM are supported by the Wellcome Trust
A critical step in the future success of neurolupus clinical trials WT101153MA. Research by SW has been supported by Lupus
will be improving the quantification of neurological outcomes. UK. SM is supported by the Anne Rowling Clinic.

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McGlasson et al. Neurological Disease in Lupus

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03302lu205oa construed as a potential conflict of interest.
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Isolated hypoglossal nerve palsy: an unusual rare presentation in systemic Copyright © 2018 McGlasson, Wiseman, Wardlaw, Dhaun and Hunt. This is an
lupus erythematosus. Arq Neuropsiquiatr (2011) 69(5):843–4. doi:10.1590/ open-access article distributed under the terms of the Creative Commons Attribution
S0004-282X2011000600025 License (CC BY). The use, distribution or reproduction in other forums is permitted,
137. Gaber W, Ezzat Y, El Fayoumy NM, Helmy H, Mohey AM. Detection of asymp­ provided the original author(s) and the copyright owner are credited and that the
tomatic cranial neuropathies in patients with systemic lupus erythematosus original publication in this journal is cited, in accordance with accepted academic
and their relation to antiribosomal P antibody levels and disease activity. Clin practice. No use, distribution or reproduction is permitted which does not comply
Rheumatol (2014) 33(10):1459–66. doi:10.1007/s10067-014-2679-y with these terms.

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