ARTHRITIS & RHEUMATISM
Vol. 42, No. 4, April 1999, pp 599–608
© 1999, American College of Rheumatology
SPECIAL ARTICLE
THE AMERICAN COLLEGE OF RHEUMATOLOGY NOMENCLATURE
AND CASE DEFINITIONS FOR
NEUROPSYCHIATRIC LUPUS SYNDROMES
ACR AD HOC COMMITTEE ON NEUROPSYCHIATRIC LUPUS NOMENCLATURE
Objective. To develop a standardized nomencla-
ture system for the neuropsychiatric syndromes of sys-
temic lupus erythematosus (NPSLE).
Methods. An international, multidisciplinary
committee representing rheumatology, neurology, psy-
chiatry, neuropsychology, and hematology developed
Supported in part by NIH grant no. AR-36308 and meeting
grants from the American College of Rheumatology and the Lupus
Foundation of America (New York Chapter).
Members of the American College of Rheumatology Ad
Hoc Committee on Neuropsychiatric Lupus Syndromes are as
follows. Steering committee: Matthew H. Liang, MD, MPH, Chair,
Michael Corzillius, MD, MPH, Co-Chair, Sang-Cheol Bae, MD,
MPH, Co-Chair, Robert A. Lew, PhD: Brigham and Women’s
Hospital, Harvard Medical School, Boston, Massachusetts; Paul R.
Fortin, MD, MPH: Montreal General Hospital, McGill University,
Montreal, Quebec, Canada; Caroline Gordon, MD, MRCP: Uni-
versity of Birmingham, Birmingham, UK; David Isenberg, MD,
FRCP: University College London, London, UK. Committee mem-
bers: Graciela S. Alarcón, MD, MPH, Karin V. Straaton, MD:
University of Alabama at Birmingham; Judah Denburg, MD, Susan
Denburg, PhD: McMaster University, Hamilton, Ontario, Canada;
John M. Esdaile, MD, MPH: Mary Pack Arthritis Center, Vancou-
ver, British Columbia, Canada; Bonnie I. Glanz, PhD, Elizabeth W.
Karlson, MD, Shahram Khoshbin, MD, Malcolm P. Rogers, MD,
Peter H. Schur, MD: Brigham and Women’s Hospital, Harvard
Medical School, Boston, Massachusetts; John G. Hanly, MD:
Dalhousie University, Halifax, Nova Scotia, Canada; Elizabeth
Kozora, PhD, Sterling West, MD: University of Colorado Health
Sciences Center, Denver; Robert G. Lahita, MD, PhD: Saint Luke’s
Roosevelt Medical Center, New York, New York; Michael D.
Lockshin, MD, MPH: Hospital for Special Surgery, New York, New
York; Joseph McCune, MD: University of Michigan Medical
Center, Ann Arbor; Patricia M. Moore, MD: University Health
Center, Detroit, Michigan; Michelle Petri, MD, MPH: Johns Hop-
kins University, Baltimore, Maryland; W. Neal Roberts, MD:
Medical College of Virginia, Richmond; Jorge Sanchez-Guerrero,
MD, MPH: Instituto Nacional de la Nutricion, Mexico City,
Mexico; Martin Veilleux, MD: McGill University, Montreal Gen-
eral Hospital, Montreal, Quebec, Canada. Consultants: Robin Brey,
MD: University of Texas, San Antonio; Wayne D. Cornblath, MD:
University of Michigan, Ann Arbor; Christopher M. Filley, MD:
University of Colorado Health Sciences Center, Denver; John D.
Fisk, PhD: Dalhousie University, Halifax, Nova Scotia, Canada;
Pontus Harten, MD: Christian-Albrechts University, Kiel, Ger-
many; Elaine M. Hay, MD: North Staffordshire Hospital, Stafford-
shire, UK; Grant Iverson, PhD: University of British Columbia,
Port Coquitlam, British Columbia, Canada; Steven R. Levine, MD:
599
case definitions, reporting standards, and diagnostic
testing recommendations. Before and after the meeting,
clinician committee members assigned diagnoses to sets
of vignettes randomly generated from a pool of 108
NPSLE patients. To assess whether the nomenclature
system improved diagnostic agreement, a consensus
index was developed and pre- and postmeeting scores
were compared by t-tests.
Results. Case definitions including diagnostic cri-
teria, important exclusions, and methods of ascertain-
ment were developed for 19 NPSLE syndromes. Recom-
mendations for standard reporting requirements,
minimum laboratory evaluation, and imaging tech-
niques were formulated. A short neuropsychological test
battery for the diagnosis of cognitive deficits was pro-
posed. In the postmeeting exercise, a statistically signif-
icant improvement in diagnostic agreement was ob-
served.
Conclusion. The American College of Rheumatol-
ogy (ACR) Nomenclature for NPSLE provides case
definitions for 19 neuropsychiatric syndromes seen in
SLE, with reporting standards and recommendations
for laboratory and imaging tests. It is intended to
facilitate and enhance clinical research, particularly
multicenter studies, and reporting. In clinical settings,
consultation with other specialists may be required. It
should be useful for didactic purposes but should not be
used uncritically or as a substitute for a clinical diag-
nosis. The complete case definitions are available on the
ACR World Wide Web site: http://www.rheumatology
.org/ar/ar.html.
Henry Ford Health Sciences Center, Detroit, Michigan; Elizabeth
Waterhouse, MD: Medical College of Virginia, Richmond; Daniel
J. Wallace, MD: University of California, Los Angeles; John B.
Winer, MD: University of Birmingham, Birmingham, UK.
Address reprint requests to Matthew H. Liang, MD, MPH,
Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115.
Submitted for publication June 15, 1998; accepted in revised
form October 9, 1998.
600 ACR NEUROPSYCHIATRIC LUPUS NOMENCLATURE COMMITTEE
Neuropsychiatric systemic lupus erythematosus
(NPSLE) includes the neurologic syndromes of the
central, peripheral, and autonomic nervous system and
the psychiatric syndromes observed in patients with SLE
in which other causes have been excluded. Since the first
report of stupor and coma in SLE by Hebra and Kaposi
in 1875 (1), a multitude of neuropsychiatric syndromes
have been reported in SLE patients (2–10). These
manifestations can precede the onset of lupus or occur
at any time during its course (11,12); they can occur in
the setting of active SLE or during quiescent periods,
and may present as single or multiple neurologic events
in the same individual.
In the English-language literature, neurologic
and psychiatric manifestations of SLE have been termed
central nervous system (CNS) vasculitis, CNS lupus,
neurolupus, neuropsychiatric lupus, or lupus cerebritis.
The term “CNS lupus” is inappropriate because the
peripheral nervous system may also be involved; the
term “neuro-” does not include psychiatric manifesta-
tions; and the terms “cerebritis” and “vasculitis” imply
inflammatory processes that may not always be present
(13–15). The term “neuropsychiatric lupus,” on the
other hand, encompasses the range of manifestations
and is therefore used in this discussion.
Reports on the prevalence of NPSLE in general
and of distinct syndromes vary widely. The definition
and nomenclature of neuropsychiatric lupus are not
standardized, which probably explains some of this vari-
ation, reduces the comparability of published studies,
and limits the design and conduct of research. On this
latter point, SLE is a relatively uncommon disease and
NPSLE even more uncommon: no one center or inves-
tigator can assemble enough cases of the many forms of
NPSLE to perform meaningful research, and multi-
center studies are needed. The lack of standard termi-
nology arises from a lack of explicit case definitions and
definitions of terms, a lack of understanding of their
pathogenesis, the absence of pathognomonic test find-
ings or pathology, and the fact that such patients may be
seen by clinicians from different medical specialties
using different terminology.
Kassan and Lockshin first proposed a classifica-
tion system in 1979 (16) and specified key dimensions
such as chronology and isolated occurrence versus oc-
currence during systemic flare, etc., at a time when the
use of magnetic resonance imaging and other radioim-
aging techniques in SLE was limited. Eleven years later,
Singer et al published a consensus list of “descriptors” or
elements important to the diagnosis of NPSLE (17).
Although a glossary is available for these descriptors,
details on diagnostic criteria and exclusions are not
provided. Neither of these systems has been utilized
widely.
For these reasons, the American College of
Rheumatology (ACR) Committee on Research con-
vened an ad hoc multidisciplinary committee, which in
turn requested input from consultants, to develop stan-
dard nomenclature for NPSLE. The committee included
27 clinician investigators who represented rheumatology
(19 members), neurology (3 members), hematology (1
member), psychiatry (1 member), and clinical psychol-
ogy (3 members). The consultants included 7 neurolo-
gists, 2 psychologists, and 2 rheumatologists. This report
presents the case definitions, reporting standards, rec-
ommendations for diagnostic testing, and an experiment
to test the usefulness of the nomenclature system in
improving reproducibility of diagnostic labeling.
METHODS
Conceptualization of proposed nomenclature. To es-
tablish standard terminology, two approaches are often taken.
One method assumes that current usage is correct and defines
current usage. Since conventional usage is so variable, this
method cannot be used exclusively. The other technique
requires a conceptual definition and its rationale, puts forth a
system of terms (nomenclature), and specifies how each term
is operationalized (definitions or glossary) (18). For research it
is important that homogeneous groups of diseases be studied.
This is particularly true in etiologic research. Without a
complete understanding of pathogenesis, nomenclature should
not imply causation. A critical test of any proposed nomencla-
ture is its reproducibility.
An ideal nomenclature system would place all lupus
patients with a neuropsychiatric syndrome in mutually ex-
clusive, collectively exhaustive categories, but the committee
believed this was inappropriate because multiple neuropsy-
chiatric syndromes can occur in the same individual, be-
cause syndromes may overlap, and because their pathogen-
esis is often not fully understood. Furthermore, other
potential causes may not be excluded absolutely, and
concurrent illness or current or past treatment may them-
selves cause neuropsychiatric manifestations. Therefore,
this nomenclature provides case definitions for classifica-
tion and reporting purposes and a recommendation for a
basic multidimensional description of patients who are
reported or studied. As with other nomenclature and classi-
fication systems, it should not be used for making diag-
noses in individual patients. One will note that the case
definitions deal indirectly with the attribution of any given
neuropsychiatric syndrome to lupus, its treatment, concom-
itant illness, or a combination. Instead, exclusions are given,
or when it is impossible to exclude a concomitant illness as
a cause, its presence is indicated by reporting it as an
“association.”
Development of the nomenclature. Building on the
work of Kassan and Lockshin (16) and of Singer et al (17), the
ACR NOMENCLATURE FOR NPSLE
steering committee compiled a comprehensive list of neuro-
psychiatric syndromes in SLE. Draft case definitions for each
syndrome were prepared based on published neurologic and
psychiatric classification systems (19–22), published diagnostic
guidelines (23–29), standard textbooks (30,31), and standard-
ized clinical instruments (31–37). In April 1997, the committee
assembled in Woods Hole, Massachusetts. The draft case
definitions were discussed and revised, and basic reporting
requirements, as well as recommendations for laboratory tests
and imaging procedures, and a brief neuropsychological test
battery for cognitive deficits were developed. Committee
members suggested experts in neurology, psychology, and
rheumatology who were sent the nomenclature for comments.
Where there were alternatives or disagreement, committee
members voted, and the nomenclature was revised until con-
sensus was achieved.
Experiment on reproducibility of case definitions.
Before the meeting, SLE patients with neuropsychiatric signs
and symptoms from Boston, Massachusetts, Richmond, Vir-
ginia, Montreal, Canada, Birmingham, UK, and London, UK,
were identified. The steering committee abstracted the data on
these patients into a standardized format providing the clinical
data available to the clinician at presentation. For rare syn-
dromes, vignettes were derived from published case reports or
case series. A total of 108 vignettes were developed.
Fourteen clinician committee members specializing in
the treatment of SLE but not involved with the preparation of
the vignettes or with the care of these patients participated in
the experiment. Each rater was given a randomly generated set
of 30 vignettes to evaluate before the meeting. For each
abstracted case the rater was asked to make a diagnosis, to rate
his or her confidence in the diagnosis (1 5 “not certain”; 5 5
“very certain”), to rate how likely it was that signs and
symptoms were attributable to SLE (1 5 “definitely not due to
SLE”; 5 5 “definitely due to SLE”), and to rate the severity of
SLE (1 5 “mild”; 3 5 “severe”). The results from this exercise
were used to focus the committee on the syndromes with the
most variation and to guide the construction of case definitions
that would improve agreement.
A second exercise was done after the meeting to test
whether the case definitions improved diagnostic consensus.
Each clinician received a new set of randomly selected vi-
gnettes different from the first round and was asked to assign
a diagnosis based on the newly developed case definitions.
Statistical methods. Measures of agreement were 1)
the number of different diagnoses assigned to the same
vignette by different raters, 2) the proportion of responses in
the most frequently chosen diagnostic category (modal diag-
nostic category), and 3) a consensus index as a summary
measure that reflects both 1 and 2 above. For any given
vignette, the consensus index (E) was defined as E 5 2S pi 3
log(pi), where i is a diagnosis and pi the proportion of raters
who chose this diagnosis (38). For discrete distributions, the
consensus index is an analog of the standard deviation for
continuous distributions (39) and is equivalent to entropy as
used in physics. Low scores indicate a high degree of agree-
ment. In case of perfect agreement (all raters making the same
diagnosis), the score equals zero.
Other frequently used measures of agreement did not
fit in this setting, in which a varying number of raters had to
assign one out of a multitude of nominal diagnostic categories
601
Table 1. Reporting requirements: basic descriptors*
Demographic
Age
Sex
Ethnicity
Highest schooling completed
SLE descriptors
Duration of SLE (time from clinical diagnosis of SLE)
Number of and which ACR criteria met
Basic laboratory data (see Appendix B)†
Current medications
NP descriptors
Associations
Duration
Chronology (episodic, remittent, sustained, progressive)
Isolated or with evidence of systemic SLE activity
Initial NP diagnosis or diagnoses (before management initiated)
Final NP diagnosis or diagnoses
Severity (mild, moderate, severe)
* SLE 5 systemic lupus erythematosus; ACR 5 American College of
Rheumatology; NP 5 neuropsychiatric.
† Located on the ACR World Wide Web site: http://www.rheumatology
.org/ar/ar/html.
to a varying number of cases. Each clinician also rated a
different, randomly generated subset of cases, and no rater
received the same case in both rounds. The intraclass correla-
tion coefficient (40) applies to continuous variables. Cohen’s
kappa (41) applies best to a fixed set of raters and cases where
every rater assesses every case.
RESULTS
The nomenclature system provides case defini-
tions of the neuropsychiatric syndromes in lupus, report-
ing standards, and recommendations for diagnostic eval-
uation including laboratory tests, imaging techniques,
and neuropsychological testing. The features of the
system are described below.
Reporting standards: basic descriptors (Table 1).
The committee recommends that all reports include
minimum descriptive information on critical dimensions
that are essential for interpreting data and ensuring
homogeneity of patient groups. These include demo-
graphic variables, information on duration, manifesta-
tions, disease activity, and treatment of SLE, and basic
descriptors of the neuropsychiatric syndrome(s), includ-
ing severity and chronology (16).
Case definitions for NPSLE syndromes. Case
definitions were developed for all 19 syndromes listed in
Table 2. The complete case definitions (Appendix A)
are available on the American College of Rheumatology
World Wide Web site at http://www.rheumatology.org/
ar/ar.html. Each case definition includes a definition,
diagnostic criteria, and methods for ascertainment. Co-
morbid conditions and concomitant factors (e.g., drugs)
602 ACR NEUROPSYCHIATRIC LUPUS NOMENCLATURE COMMITTEE
Table 2. Neuropsychiatric syndromes observed in systemic lupus
erythematosus
Central nervous system
Aseptic meningitis
Cerebrovascular disease
Demyelinating syndrome
Headache (including migraine and benign intracranial
hypertension)
Movement disorder (chorea)
Myelopathy
Seizure disorders
Acute confusional state
Anxiety disorder
Cognitive dysfunction
Mood disorder
Psychosis
Peripheral nervous system
Acute inflammatory demyelinating polyradiculoneuropathy
(Guillain-Barré syndrome)
Autonomic disorder
Mononeuropathy, single/multiplex
Myasthenia gravis
Neuropathy, cranial
Plexopathy
Polyneuropathy
that may cause identical symptoms and which should be
excluded before attributing the syndrome to SLE were
listed (“exclusions”). In some instances it may not be
possible to judge whether neuropsychiatric findings are
due to lupus or to other causes, such as irreversible,
existing conditions (e.g., diabetes) that cannot be cured
or corrected, or drugs that cannot be withheld, replaced,
or withdrawn for the purpose of exclusion (e.g., cortico-
steroids). These are termed “associations” (as opposed
to “exclusions”). Associations should always be re-
ported. Finally, a patient may have more than one
NPSLE manifestation at the same time or accumulated
over time, and all syndromes that satisfy NPSLE case
definitions should be noted. Recognizing the diagnostic
importance of careful observation over time and re-
sponse to trials of therapy (including stopping a poten-
tially offending medication), the committee believed
that the usefulness and comparability of reported cases
would be improved by reporting both the initial diagno-
sis at presentation and the final diagnosis.
Laboratory and radiologic evaluation. The com-
mittee’s recommendations regarding the laboratory and
diagnostic imaging tests that should be performed to
assess SLE disease activity and to exclude other diag-
noses that could cause neurologic symptoms are shown
in Appendix B, which can be found on the American
College of Rheumatology World Wide Web site at
http://www.rheumatology.org/ar/ar.html. Basic labora-
tory tests for the assessment of lupus disease activity and
the evaluation of other organ systems were suggested,
but most of the immunochemical tests studied in NPSLE
were judged investigational at this time except testing for
antiphospholipid antibodies and, in limited circum-
stances, antiribosomal P. Recommendations for the use
of computed tomography (CT), standard magnetic res-
onance imaging (MRI), angiography, electroencepha-
lography (EEG), echocardiography, and duplex ultra-
sound were included. Others were judged investigational
until more data become available.
Diagnostic agreement. In the premeeting exer-
cise there was complete agreement in assigning a diag-
nosis in 24 cases and maximum disagreement (all raters
assigned different diagnoses) in 12 cases. (The mean
number of diagnoses assigned to the same case was 2.1.)
On average, 71% of the raters chose the most frequently
selected diagnostic category in a given case, and the
mean consensus score was 0.564. Using the ACR case
definitions in the postmeeting exercise, the number of
cases with complete agreement increased to 29. Com-
plete disagreement occurred in only 6 cases. The mean
proportion of raters who agreed on the most frequently
selected diagnosis increased to 77%. The mean consen-
sus score decreased to 0.449, which was a statistically
significant difference from the premeeting score (P ,
0.04) (Table 3). The increase in the proportion of raters
choosing the modal diagnostic category also was statis-
tically significant (P , 0.04) (Table 3). Changes in
diagnostic certainty and severity grading were not sig-
nificant.
The cases with diffuse CNS disease (including
psychosis, mood disorder, cognitive dysfunction, acute
confusional states) had higher degrees of disagreement
observed in the premeeting exercise, compared with
focal CNS disease and peripheral neurologic syndromes
(Table 4). Diffuse CNS syndromes also showed the
largest improvements in the postmeeting exercise, with a
mean increase of agreement of 26% compared with the
premeeting results.
Raters expressed how much confidence they had
in their diagnoses on a 5-point Likert scale ranging from
1 (not certain) to 5 (very certain). These ratings were
Table 3. General diagnostic agreement
Premeeting Postmeeting P
Mean no. of diagnoses 2.1 1.8 0.06
per case
Proportion (%) of modal 71 77 ,0.04
diagnostic category
Consensus index 0.564 0.449 ,0.04
ACR NOMENCLATURE FOR NPSLE
Table 4. Diagnostic agreement by clinical category
Consensus
index
Clinical category (premeeting)
Diffuse psychiatric/ 0.672
neuropsychological syndromes*
Neurologic syndromes of the central 0.513
nervous system†
Neurologic syndromes of the peri- 0.507
pheral nervous system‡
* Includes anxiety disorder, acute confusional state, cognitive disorder,
mood disorder, psychosis.
† Includes cerebrovascular disease, demyelinating syndrome, head-
ache, aseptic meningitis, chorea, seizures, myelopathy.
‡ Includes acute inflammatory demyelinating polyradiculoneuropathy,
mononeuropathy, autonomic disorder, plexopathy, polyneuropathy.
already high in the premeeting exercise (mean 4.0, SD
1.15) and increased slightly and nonsignificantly in the
postmeeting exercise (mean 4.2, SD 1.07). Severity
gradings remained essentially unchanged (premeeting
mean 2.23, SD 0.73; postmeeting mean 2.15, SD 0.71).
Attribution of neuropsychiatric syndromes to SLE did
not change significantly (premeeting mean 3.57, SD
1.22; postmeeting mean 3.84, SD 1.09).
DISCUSSION
The ACR Ad Hoc Committee on Neuropsychi-
atric Lupus Nomenclature has developed reporting stan-
dards, recommendations for laboratory and imaging
evaluation, and case definitions for 19 neuropsychiatric
syndromes observed in SLE, and these have been ap-
proved by the Board of Directors of the ACR. The case
definitions give a basic clinical description, along with a
delineation of the rules and methods of ascertainment,
exclusions, and associations. Structural definition of the
brain (e.g., by CT, MRI, or other radioimaging tech-
niques) and neurophysiologic studies (EEG, electro-
myography) serve as criteria for specific syndromes and
are recommended in others to exclude conditions that
can have the same clinical presentation in practice.
The new ACR nomenclature system is intended
to expand the neuropsychiatric criteria of the ACR
classification criteria for SLE (42,43), and, with more
study, could be done with confidence for some syn-
dromes. Thus, subjects might be said to have a given
neuropsychiatric lupus syndrome if they meet the case
definition for neuropsychiatric lupus and in addition
meet 3 or more of the ACR (non-NPSLE) criteria for
603
SLE. If a patient meets the definition for a neuropsychi-
Increase in atric syndrome but meets an insufficient number of
agreement ACR criteria for SLE, he or she is classified as having
(%) from possible NPSLE. Like the ACR classification criteria for
premeeting to
postmeeting
SLE, the classification criteria for NPSLE are intended
for purposes of classification and reporting, and it
0.176 (26.2)
should be emphasized that they are not meant to replace
0.069 (13.5) clinical judgment or intended for use in making a clinical
diagnosis in a given patient.
0.091 (18.2)
Laboratory and radiologic evaluation. Identifica-
tion of antibodies to neuronal cell constituents, cyto-
kines, and other immunochemical phenomena in neuro-
psychiatric lupus has provided insights into potential
mechanisms of disease (44–49). However, the data are
not widely available, standardized, or strongly correlated
with specific neuropsychiatric syndromes, the only ex-
ceptions being antiphospholipid antibodies (50–53) and
possibly antiribosomal P (54–56). Other than testing for
antiphospholipid antibodies, the committee decided that
these antibody tests should be viewed as investigational
at this time.
The cerebrovascular diseases observed in SLE
illustrate how neuropsychiatric syndromes might be ra-
tionally classified once pathogenic mechanisms are elu-
cidated. The process marked by the presence of
antiphospholipid antibodies suggests that not all SLE
manifestations must be inflammatory and that such
disparate syndromes as Sneddon’s syndrome, transverse
myelopathy, stroke, and chorea may have a common
etiology (52). If nothing else, it is imperative to report
antiphospholipid antibody status in every SLE patient
with focal neurologic manifestations.
The evolving technologies for imaging brain
structure and function have the potential to rewrite the
literature of neuropsychiatric lupus and may become
gold standards for classification. Indeed, they have be-
come the modern “tissue diagnosis.” However, their
increased sensitivity (57–61) is also their weakness in
that the prognosis and clinical significance of subtle or
unexpected findings such as unidentified bright objects
and abnormalities on single-photon–emission computed
tomography are unknown at this time (62–65). Indeed,
one of the major applications of the case definitions
would be to define homogeneous patient groups to study
the importance of such abnormalities. Current imaging
technologies are continually improving, and the commit-
tee considered them to be an essential component of
some case definitions.
For the most part, focal neurologic syndromes
appeared to be diagnosed with little disagreement. We
604 ACR NEUROPSYCHIATRIC LUPUS NOMENCLATURE COMMITTEE
found most disagreement with diffuse neuropsychiatric
syndromes.
Psychiatric disorders, cognitive deficits, and
acute confusional states. In SLE a variety of psychiatric
disorders are reported, including depression (66,67),
psychosis (3,68,69), and anxiety (70). These were the
most problematic for the committee since it is often
difficult to determine whether these are neuropsychiat-
ric manifestations caused by SLE or psychological reac-
tions to the stress of having a major chronic systemic
illness. Despite these difficulties, we believed that the
syndromes should be defined to facilitate study of the
question. The case definitions for anxiety, mood disor-
der, and psychosis require a clinical evaluation to ex-
clude merely reactive psychological disturbances, and
psychiatric consultation may be required. If the syn-
drome is judged to be a neuropsychiatric manifestation
of SLE, the presence of marked psychosocial stress
should be reported as an association. The committee
adopted the terminology of the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition (DSM-IV)
(22) wherever possible since use of the DSM has been
widespread since 1952 and reflects an iterative process
whose reliability has been studied extensively. Detailed,
explicit criteria, methods of ascertainment, rationale,
and a manual for its use are available. Its codes are
consistent with the International Classification of Dis-
eases, Ninth Revision, which provides additional advan-
tages for research. The committee believed it would be
inadvisable to develop new psychiatric nomenclature.
For all major psychiatric disorders, the DSM-IV
distinguishes primary entities from secondary disease
due to underlying medical conditions or substance
abuse. Among the psychoses, for instance, the term
“schizophrenia” is defined as primary disease; a causal
relationship to any other medical disorders must be
excluded to make the diagnosis. Therefore, the term
“schizophrenia” should not be used to classify psychosis
due to SLE. The DSM-IV category “brief reactive
psychosis” was not considered appropriate because it
describes a purely psychological reaction to an external
stressor such as coping with a serious chronic disease,
and a psychotic disturbance must be excluded in order to
make the diagnosis. The case definition for lupus psy-
chosis is, therefore, based on the DSM-IV entity “psy-
chosis due to a general medical condition” (DSM-IV
293.81/82) (22). To be consistent with the DSM-IV, the
committee recommended that terms used in previous
reports of neuropsychiatric lupus be dropped. These
include separate “organic” versus “nonorganic” disor-
ders, e.g., in “organic brain syndrome,” and the term
major affective disorder (which is not a defined entity in
the DSM-IV).
SLE patients may demonstrate significant cogni-
tive defects (71–76) such as difficulties in attention,
concentration, memory, and word-finding, which may
fluctuate or worsen over time. The use of standardized
mental status examinations such as the Mini–Mental
State (32) and the Neurobehavioral Cognitive Status
Examination (34) may provide a means of tracking a
patient’s cognitive status over time, focus the neuropsy-
chological consultation, and help identify patients about
whom there is the most concern and ambiguity for
further evaluation. However, these screening tests to
identify cognitively impaired patients have substantial
rates of false-negative findings (77,78). The limited data
within and across specific cognitive domains inherent in
short screening tools limits their usefulness in manage-
ment. Screening tests cannot substitute for detailed
neuropsychological assessment when milder (but poten-
tially clinically important) deficits are suspected.
The diagnostic criteria for cognitive dysfunction
require documentation by neuropsychological testing
and a decline from a higher former level of functioning.
Many neuropsychological test batteries are available
(79,80), and they are often time consuming. To make
them more practical, the committee recommends a short
battery, which takes approximately 1 hour. It is shown in
Appendix C, which can be found on the ACR World
Wide Web site at http://www.rheumatology.org/ar/
ar.html. Its components have been part of batteries used
in lupus patients and other medical populations. The
interpretation of test results and the identification of
impairment for clinical decision-making must be based
on normative data appropriate for age, education, sex,
and ethnic group, wherever possible, and consultation is
strongly recommended. Further study of the brief bat-
tery compared with a comprehensive battery, to assess
its sensitivity in identifying deficits in SLE patients
compared with normal and appropriate controls, was
recommended.
Formal neuropsychological testing and functional
assessment are two ways to assess the impact of brain
disease on the individual and, because they are nonin-
vasive, they could be used serially to monitor changes or
to assess the effects of interventions. Repeat testing can
introduce artifacts from learning or practice effects.
These are dealt with by 1) allowing sufficient time lapse
between tests, 2) using alternative forms of the same
test, and 3) using a statistical approach, such as the
Reliable Change Index, but none is perfect; we recom-
mend that strategies 1 and 3 be applied.
ACR NOMENCLATURE FOR NPSLE
Another syndrome of diffuse neurologic dysfunc-
tion, termed “acute confusional state,” is defined as
disturbance of consciousness or level of arousal with
reduced ability to focus, maintain, or shift attention,
accompanied by cognitive disturbance and/or changes in
mood, behavior, or affect. This term is equivalent to the
term “delirium” as used in the DSM-IV and should be
used instead of “organic brain syndrome.” The syn-
drome usually develops over a short period of time,
tends to fluctuate during the course of the day, and
encompasses a spectrum from mild disturbances of
consciousness to coma, including hypoaroused (e.g.,
somnolence, stupor) and hyperaroused (e.g., delirium
tremens) states.
Neurologic syndromes of the central nervous
system. Seizures are part of the revised ACR classifica-
tion criteria for SLE (42,43). The different types of
seizures and their distinction from epilepsy were
grouped together in a single case definition. Diagnostic
criteria are based on international terminology (21).
Headache is a common symptom in SLE patients
(81–83), but whether there is a unique syndrome attrib-
utable to SLE is not clear. For pragmatic reasons the
different types of headache that occur in SLE (84–89)
are incorporated in one case definition and include
migraine and benign intracranial hypertension. The In-
ternational Classification System for defining types of
headaches (20) has been used extensively in clinical
trials of therapeutic agents (a revision is planned in
2001), and the committee recommended its use in SLE.
The entity “lupus headache” has been defined as a
severe, disabling, persistent headache that is not respon-
sive to narcotic analgesics (87,88), but was judged non-
specific since severe migraine with or without lupus may
have these characteristics as well (89). Such headaches
can be denoted under “nonspecific intractable head-
aches.”
The term “lupoid sclerosis” has been used to
describe SLE patients with complex neurologic deficits
similar to those seen in multiple sclerosis (90–97).
Whether this entity actually exists is not clear. The term
implies knowledge of causation and pathology that goes
beyond the data available, particularly as new insights
into the role of inflammation and axonal transection
may also change the views on the pathology of multiple
sclerosis (98). The committee recommends instead a
case definition for demyelinating syndrome with the ap-
propriate basic and specific descriptors to facilitate
further research on this rare condition.
For the movement disorders, the committee
chose to define chorea only. Chorea is the most common
605
movement disorder observed in SLE, particularly in
children (99–101), whereas reports on Parkinson’s dis-
ease and hemiballismus are rare.
Case definitions were also developed for myelop-
athy (102–105) and aseptic meningitis (104,106).
Neurologic syndromes of the peripheral nervous
system. Disturbances of the cranial (107–110) and peri-
pheral nerves—single and multiplex (111), plexus
(112,113), sensorimotor (84,114,115), and autonomic
lesions (114,116–118), myasthenia gravis (119,120), and
acute inflammatory demyelinating polyradiculoneuropa-
thy (Guillain-Barré syndrome) (121–123)—have been
described in SLE, but their epidemiology and pathology
have had limited study.
In summary, the identification of antibodies to
neuronal cell constituents and of antiphospholipid anti-
bodies, and powerful radioimaging of both brain struc-
ture and function open new possibilities for improved
understanding and management of NPSLE disorders.
Many neuropsychiatric SLE syndromes are rare. There-
fore, it is mainly by multicenter studies or pooling of
high-quality data collected and reported in a comparable
manner that knowledge will be advanced. The case
definitions improved diagnostic agreement in a study of
individuals involved with their development. Whether
they improve agreement in new users should be investi-
gated. Nevertheless, they should be useful clinically and
for didactic purposes. As with the ACR classification
criteria, they are not a substitute for clinical diagnosis or
for consultation when there is uncertainty. The commit-
tee recognizes that the work is far from perfect and that
it will provoke comment, but it is a start. We recommend
that the nomenclature be used and then revised as new
knowledge is discovered. Nomenclature without a true
understanding of pathogenesis, in the final analysis, is
arbitrary, but development of a system whereby all
investigators call the same thing by the same name is a
necessary step to advance knowledge and to study
mechanisms of disease.
ACKNOWLEDGMENTS
We are grateful to Ms Rita DeLuca and Ms Mary
Scamman who coordinated the meeting and provided invalu-
able secretarial and administrative support without which the
project would not have been possible, to 3 anonymous review-
ers for their provocative and insightful comments, and to Dr.
Tony Lorenzo for his review of the cerebrospinal fluid chem-
istry recommendation.
606 ACR NEUROPSYCHIATRIC LUPUS NOMENCLATURE COMMITTEE
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