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Centralnervoussysteminvolvementinsystemiclupuserythematosus:Overviewonclassificationcriteria

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Autoimmunity Reviews 12 (2013) 426–429

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Review

Central nervous system involvement in systemic lupus erythematosus: Overview onclassification criteria

Savino Sciascia a,b,⁎, Maria Laura Bertolaccini a, Simone Baldovino b, Dario Roccatello b,Munther A. Khamashta a,c, Giovanni Sanna a,c

a Lupus Research Unit, The Rayne Institute, Division of Women's Health, King's College London, UKb Centro di Ricerche di Immunologia Clinica ed Immunopatologia e Documentazione su Malattie Rare (CMID), Università di Torino, Ospedale G. Bosco, Turin, Italyc Louise Coote Lupus Unit, Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, UK

⁎ Corresponding author at: Lupus Research Unit, TLambeth Wing, St Thomas' Hospital, London SE1 7EHfax: +44 2076202658.

E-mail address: savino.sciascia@unito.it (S. Sciascia)

1568-9972/$ – see front matter © 2012 Elsevier B.V. Allhttp://dx.doi.org/10.1016/j.autrev.2012.08.014

a b s t r a c t

a r t i c l e i n f o

Article history:Accepted 15 August 2012Available online 25 August 2012

Central nervous system (CNS) involvement is one of the major causes of morbidity and mortality in systemiclupus erythematosus (SLE) patients. Clinical manifestations can involve both the central and peripheral ner-vous systems, and they must be differentiated from infections, metabolic complications, and drug-inducedtoxicity. Recognition and treatment of CNS involvement continues to represent a major diagnostic challenge.In this Review, we sought to summarise the current insights on the various aspects of neuropsychiatric SLEwith special emphasis on the terminology and classification criteria needed to correctly attribute the partic-ular event to SLE.

© 2012 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4262. Search strategy and selection criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4263. American College of Rheumatology (ACR) classification criteria for SLE and neuropsychiatric involvement . . . . . . . . . . . . . . . . . . 4274. ACR case definitions for neuropsychiatric SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4275. Current ACR classification criteria: grey areas and potential solutions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429

1. Introduction

Nervous system involvement has been recognised in systemiclupus erythematosus (SLE) patients for over 100 years and severalclassification criteria have been proposed in an attempt to capturethe diverse clinical expressions. Since the first description in the19th century by Kaposi and Osler of an SLE patient with pleurisy,pneumonia, disturbed neurologic function, and rapid progression todeath [1,2], it soon became obvious that neuropsychiatric manifesta-tions in SLE are frequent and broad and that management is not aneasy task. Neuropsychiatric SLE includes a variety of focal, diffuse,central, peripheral, psychiatric, isolated, complex, simultaneous and

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sequential symptoms and signs, representing both active and inactivedisease states. Central nervous system disease predominates and maytake the form of either diffuse disease (e.g. psychosis or depression)or focal disease (e.g. stroke or transverse myelitis) [3–7].

In this Review, we sought to summarise the current insights onthe various aspects of neuropsychiatric SLE with special emphasison the terminology and classification criteria needed to correctly at-tribute the particular event to SLE.

2. Search strategy and selection criteria

References were selected by a PubMed search of English languagepublications and covered the period from 1946 to April 2012. Searchterms included “systemic lupus erythematosus”, “lupus”, “neuropsy-chiatric”, “neuropsychiatric lupus classification”, “neuropsychiatriclupus criteria”, “neuro-lupus”, and “cerebrovascular lupus”. Further

427S. Sciascia et al. / Autoimmunity Reviews 12 (2013) 426–429

articles were identified through the references cited in those articles.Abstracts were reviewed, and when relevant findings were reported,the full article was retrieved and reviewed. We also identified articlesfrom our personal knowledge on the subject and from our own files.

3. American College of Rheumatology (ACR) classification criteriafor SLE and neuropsychiatric involvement

The first preliminary classification criteria for SLE dates backto 1971 when seizures, psychosis and focal neurologic disorderswere the only neuropsychiatric manifestations encompassed [8].The succeeding 1982 revised criteria considered dementia andcoma among the NP clinical settings to be evaluated. Neverthe-less, only seizures and psychosis were formally included in thisrevised classification criteria [9], which is far from enough tocover the whole spectrum of neuropsychiatric involvement inSLE.

Kassan and Lockshin were probably among the first researchers todraw attention to the complexity of nervous systemmanifestations inSLE, and they highlighted the need for a more ‘organised and easilytranslatable’ classification [10]. It was clear that because of the diver-sity of neurologic manifestations in this disorder and their complexpathogenesis, no single test was sufficient to confirm the diagnosisrapidly and accurately in all cases.

In 1985, How et al. developed the first classification model ofneuropsychiatric SLE which also took into account the presence ofautoantibodies (i.e. antineuronal antibodies) [11]. Major and minorneurologic and psychiatric manifestations were established tosupport the diagnosis of neuropsychiatric SLE. The presence of onemajor criterion alone or one minor criterion plus an abnormalityon electroencephalography, nuclear brain scanning, cerebrospinalfluid (CSF) examination or cerebral angiography was necessary forthe diagnosis. This approach was also an attempt to rule out otherpotential aetiologies, such as infection, drugs, uremia or hyperten-sion, prior to attributing the neuropsychiatric event to SLE. Howev-er, this classification scheme did not prove to be engaging and,despite the number of years that have gone by, it has not yet beenproperly validated.

In their 1990 paper [12], Singer and Denburg reported the con-clusions of a consensus conference held in 1987 which aimed toascertain the level of agreement on neuropsychiatric SLE manifesta-tions amongst a group of international experts in autoimmunediseases. Although the majority of participants (70%) felt that theACR criteria for neuropsychiatric SLE were ‘insufficient for clinicalusage’, the level of agreement on grading the different elements topotentially evaluate for the diagnosis of neuropsychiatric SLE waspoor. Starting from a list of more than 50 possible clinical, laborato-ry and imaging manifestations of neuropsychiatric SLE, only fouritems were selected, namely atypical psychosis, several categoriesof seizures, transverse myelitis and global cognitive dysfunction.This approach would have represented the basis for further studiesand could have possibly expanded the ACR classification criteria forSLE.

Although this was a valuable exercise subsequent validation stud-ies were never performed.

4. ACR case definitions for neuropsychiatric SLE

An ad hocmultidisciplinary committee of 35 members representingthe areas of rheumatology, neurology, psychiatry, neuro-psychiatry andhaematology was convened by the American College of RheumatologyResearch Committee in April of 1997 for the purpose of developingstandard nomenclature for neuropsychiatric SLE [13]. The committeedeveloped neuropsychiatric SLE case definitions with diagnostic cri-teria, exclusions, associations and ascertainment. Standards and recom-mendations were also included for essential laboratory evaluations

and imaging techniques. This inclusion was probably one of themain advances that were made and it addressed many of the previ-ous flaws that had hampered attempts to classify neuropsychiatricSLE [14].

The committee aimed to use the existing nomenclature anddefinitions whenever possible rather than to create an ex novoclassification.

Case definitions for 19 neuropsychiatric syndromes were devel-oped and their diagnostic agreement by the committee memberswas empirically evaluated by comparing diagnoses of randomly gen-erated vignettes from a pool of 108 neuropsychiatric SLE patients be-fore and after the nomenclature evolved.

Aetiologies other than SLE were identified by exclusion, or whenthey were recognised as an ‘association’ for each NP syndrome.

The ACR case definitions were firstly validated in a cross-sectional population-based study by Ainiala et al. [15] involving ageographical area with 440,000 subjects. A total of 46 patients,aged 16 to 65 years, fulfilled the criteria for a definite diagnosis ofSLE. One control for each patient, matched by age, sex, educationand place of residence was randomly chosen from the populationregister. Although all the syndromes included in the proposed ACRcriteria for neuropsychiatric SLE were more frequent among SLEpatients, most of them were also found among controls. These find-ings resulted in low specificity for the proposed ACR case definitioncriteria. In addition, at least one neuropsychiatric manifestation wasidentified in 91% of the SLE patients and in 54% of the controls, witha 9.5 fold increase in risk, a specificity of 0.46 and a detection rate of91% among SLE patients.

Headache, anxiety, mild depression, mild cognitive impairmentand polyneuropathy are common in otherwise healthy subjectsand even more so among patients with a chronic disease [16,17],making the attribution of such symptoms to SLE itself a challengein those settings. Taking into account the high prevalence of someNP manifestations in both SLE and control groups, they set up a dif-ferent model excluding headache, anxiety, mild depression, mildcognitive impairment and polyneuropathy without electrophysio-logical confirmation. With this approach, the prevalence of neuro-psychiatric disease fell to 46% in their SLE patients and to 7% incontrols. This provided an odds ratio of 7.0 (95% CI 2.09–23.47)and specificity of 93% [15].

Several other groups have used the ACR nomenclature to classifyneuropsychiatric SLE [18–21]. The overall prevalence of neuropsy-chiatric disease in these study populations varies widely, rangingfrom 37% up to as much as 95%. Surprisingly, this range in preva-lence is as wide as what had been reported prior to the introductionof the ACR nomenclature [14].

Thus, although the ACR classification represented a big step for-ward in the field in its efforts to standardise the classification for neu-ropsychiatric SLE, it was in no way fully inclusive of all the possibleneuropsychiatric manifestations that may occur in SLE.

5. Current ACR classification criteria: grey areas andpotential solutions

Several studies have criticised the ACR nomenclature [22] andsome of them have proposed revised versions for the classification,claiming that the proposed 19 ACR criteria did not differentiate SLEpatients from controls, nor neuropsychiatric SLE patients from otherSLE patients [15,22–26]. Some authors have reported an inadequateperformance of the proposed ACR criteria, criticising the lack ofcriteria based on neuro-pathogenic features [15].

As a matter of fact, some milder and more subjective signs and/orsymptoms, such as migraine, cognitive dysfunction and minor psychi-atric disorders are still the most challenging to identify [15] as thereare no gold standards, they have a high prevalence in otherwise

428 S. Sciascia et al. / Autoimmunity Reviews 12 (2013) 426–429

healthy subjects and, most importantly, because the possible patho-genic attribution to SLE is still under debate.

Migraine has been reported as being the most prevalent manifes-tation in SLE patients, associated with depression as it occurs in thegeneral population, but with no disease activity or abnormalitiesdetected on cerebral MRI or CSF, with the exception of photosensi-tivity [27] . More recently, a study [28] analysing seventy-two SLE/control pairs and 48 multiple sclerosis patients for a 12‐monthfollow-up period showed that migraine should no longer be consid-ered a neurologic manifestation of systemic or organ-specific auto-immunity, since the higher prevalence of migraine in SLE patientscould be due to methodological weaknesses [28]. At the moment,the inclusion of migraine among the SLE disease activity features re-mains questionable.

Cognitive defects are relatively common in patients with SLE,with an incidence ranging from 21% to 80% when applying testssuch as the Stanford–Binet Intelligence Test, the Wechsler Adult In-telligence Scale, the Complex Attention Task and the PatternComparison Task [29–31]. There is great disagreement on the asso-ciation of cognitive dysfunction, and antibodies, cytokines, matrixmetalloproteinases, vascular abnormalities, and neuropeptides pos-sibly implicated in this setting [32]. Although the underlying patho-genic mechanism is still unclear, some evidence [33] shows thatantiphospholipid antibodies, disease activity, and chronic damageare associated with cognitive dysfunction in SLE. These results alsosuggest that neuropsychological testing should be used for the as-sessment of SLE patients when cognitive defects are suspected. Nev-ertheless, although desirable for research purposes, their routineuse in a clinical setting is complex.

Psychiatric disorders, especially when they appear as mild mani-festations, represent another controversial topic and grey area ofthe ACR case definition [34]. Estimated prevalence of psychiatricsyndromes alone is even more heterogeneous among centres whencompared to other neuropsychiatric SLE manifestations [35]. Mooddisorders have been reported in 6–44% of SLE patients, mainly includ-ing depressive disorders. Maniac or mixed disorders have beenreported in 0–4.4% [18,36] and anxiety in 13–27% [18,37] .

Distinguishing between depressive–anxious psychopathologicsyndromes resulting from the underlying organic disease and those

Table 1Neuropsychiatric manifestations in SLE as defined by the different classifications.

1971 [8] 1982 [9] 1999 [13] 2001 [15]

Seizures Seizures Aseptic meningitis Aseptic meningiPsychosis Psychosis Cerebrovascular disease CerebrovascularFocal neurologic disorders Demyelinating syndrome Demyelinating s

Headache Movement disorMovement disorder MyelopathyMyelopathy Seizure disorderSeizure disorders Acute confusionAcute confusional state Cognitive dysfunAnxiety disorder (moderate or seCognitive dysfunctionMood disorder Severe depressioPsychosis PsychosisGuillain Barre syndrome Acute inflammaAutonomic neuropathyMononeuropathyMyasthenia gravis Autonomic disorCranial neuropathy MononeuropathPlexopathyPolyneuropathy Myasthenia grav

Neuropathy, craPlexopathyPolyneuropathy

that are the consequence of the negative influence of the debilitatingand chronic illness is very difficult and sometimes, not possible [38].Most authors have failed to find a relationship between psychiatricsymptoms and SLE activity [39]. In addition, Shortall et al. [40], didnot observe any relationship between anxiety and mood disordersand psychosocial factors, but highlighted the importance of themeaning and perceived consequences of the illness for the patient.Patients' interpretations of their illness and its impact on daily lifewere found to have a greater influence on mood and mood disordersthan any clinical or biological factors. Interestingly, Ishikura et al.[41] proved that the prevalence and intensity of anxious and de-pressive symptoms in the course of SLE positively correlated withinsufficient knowledge on the disease and its therapy as perceivedby the patient at the beginning of disease, and did not correlatewith SLE activity. These findings were in agreement with those byHawro et al. [35], who reported shorter SLE duration in patientswith anxiety disorder, speculating that anxiety was the conse-quence of inadequate knowledge about the course of the diseaseand treatment methods.

In summary, in these complex settings, accurate differential di-agnosis and the attribution of the neuropsychiatric event as beingprimary to SLE or secondary to another concomitant conditionwhich may concur in SLE are mandatory before any therapeutic ap-proach can be decided [42].

Although the ACR case definition represents a step forward in thediagnosis and management of SLE patients [29], some manifesta-tions such as headache, some forms of anxiety and mood disorders,as well as cognitive dysfunction are still being misdiagnosed andconsequently mistreated. Thus, from a clinical point of view, dis-tinguishing between severe and mild manifestations and betweenthrombotic and non-thrombotic neuropsychiatric SLE disease maybe helpful [43]. Since making a clear-cut differentiation can some-times be challenging, this practical approach could represent avalid tool in the daily clinical-decision making practice. Focusingon the severity of the disease and on the thrombotic or non-thrombotic nature of the neuropsychiatric manifestation could rep-resent the first practical approach, reserving the attempt of a furtherdefinition according to the ACR criteria to a second step in the diag-nostic process (Table 1).

2008 [43]

tis Severe/mild manifestationsdisease Thrombotic/non-thrombotic diseaseyndromeder (chorea)

sal statectionvere)

n

tory demyelinating polyradiculo‐neuropathy

dery, single/multiplex

isnial

(with ENMG confirmation)

429S. Sciascia et al. / Autoimmunity Reviews 12 (2013) 426–429

Take-home messages

• Central nervous system involvement is one of the major causes ofmorbidity and mortality in systemic lupus erythematosus (SLE) pa-tients.

• Neuropsychiatric SLE includes a variety of focal, diffuse, central, pe-ripheral, psychiatric, isolated, complex, simultaneous and sequen-tial symptoms and signs, representing both active and inactivedisease states.

• The American College of Rheumatology case definition represents astep forward in the diagnosis and management of SLE patients; inspite of this, some manifestations such as headache, some formsof anxiety and mood disorders, as well as cognitive dysfunctionare still being misdiagnosed and consequently mistreated.

• From a clinical point of view, distinguishing between severe andmild manifestations and between thrombotic and non-thromboticneuropsychiatric SLE disease may be helpful and could represent avalid tool in the daily clinical-decision making practice.

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