Rheumatology 2002;41:605–618
Review
The central nervous system in systemic lupus
erythematosus. Part 1. Clinical syndromes:
a literature investigation
F. G. I. Jennekens and L. Kater1
Department of Neurology and 1Department of Rheumatology and Clinical
Immunology, University Medical Centre, Utrecht, The Netherlands
Abstract
Objectives. To establish the central nervous system (CNS) manifestations of systemic lupus
erythematosus (SLE) as described in the literature and to compare the results with two previously
published classifications.
Methods. Using PUBMED, a systematic search was performed for publications from 1980
onwards on CNS syndromes of patients with SLE. A distinction was made between CNS
syndromes induced by SLE and the CNS autoimmune diseases associated with SLE. Criteria
were defined for inclusion of CNS syndromes or diseases as SLE-induced or SLE-associated.
Results. The literature search yielded names of 30 syndromes and two diseases, but only
16 syndromes and one disease fulfilled the set of predefined criteria. Two syndromes—depression
and anxiety—were predominantly psychological in origin in most patients; other syndromes were
biological.
Discussion. Strengths and weaknesses of two classifications of CNS syndromes are evaluated.
The older of the two is long and has not been accepted fully. Brevity is an advantage of the
American College of Rheumatology (ACR) nomenclature system. A disadvantage of this system
is the concealment of differences in health risks by the pooling of items. Furthermore, the items
of the system do not all belong to the same dimension: one is pathological and the others are
clinical. To remedy these drawbacks, we suggest the rephrasing and subdivision of items and that
the predominantly psychopathological syndromes should be dealt with separately in
epidemiological studies.
Conclusions. SLE may induce 16 different clinical syndromes of the CNS and is occasionally
associated with one other CNS autoimmune disease. A modification of the ACR nomenclature
system is proposed.
KEY WORDS: Systemic lupus erythematosus, Central nervous system-syndromes, Nomenclature.
Central nervous system (CNS) manifestations of
systemic lupus erythematosus (SLE) are highly diverse
and often have major prognostic consequences. The
incidence of CNS manifestations attributable to SLE is
not entirely clear. Table 1 illustrates the divergence
in the percentages of patients with SLE-induced CNS
syndromes in five large studies w1–5x: two prospective
studies, two often-quoted retrospective case series and
a recent retrospective case series. This divergence has
several reasons, one being differences of opinion concerning the syndromes that constitute the neurology and
psychiatry of SLE. Whether or not a syndrome is due
directly to SLE may have consequences for therapeutic
strategies.
Two classifications of the neurological and psychiatric
disorders of SLE have been published in the past decade
(Appendix 1). One consists of a list of 26 so-called CNS
descriptors, ranked according to diagnostic weight w6x.
The other is a nomenclature system comprising 12 items
w7x. Both were constructed on the basis of consensus
among experts. The purpose of the present investigation
was to establish the CNS manifestations of SLE on
the basis of a systematic search of the literature. The
results are considered in relation to these two classification schemes and a modification of the nomenclature
system will be proposed. The pathogenetic mechanisms
underlying CNS syndromes induced by SLE will be
reviewed in a companion paper w8x.
Submitted 20 April 2001; accepted 28 December 2001.
Correspondence to: L. Kater, Bevelandselaan 11, 1181 JL
Amstelveen, The Netherlands.
605
ß 2002 British Society for Rheumatology
F. G. I. Jennekens and L. Kater
606
TABLE 1. Incidence of CNS manifestations attributable in part or wholly to SLE in five studies
Design
Patients (no.)
Patients (no.) with
CNS syndromes
Percentage
Kaell et al.,
1986 w1x
Sibley et al.,
1992 w2x
Futrell et al.,
1992 w3x
West et al.,
1995 w4x
Rood et al.,
1999 w5x
Prospective
Retrospective
Prospective
Retrospective
180
56
266
48
Retrospectiveu
prospective
91
63
196
52
191
38
31
18
69
21
20
Methods
Patients and their disorders
The investigation concerned CNS manifestations in
children and adults of either sex with SLE. Disorders
of fetuses and neonates from mothers with SLE were
not included. CNS syndromes or diseases in the selected
articles had been diagnosed by physicians on the basis
of adequate medical investigations.
Definitions
SLE. SLE is considered present if a patient hasuhad
any four or more of the 11 criteria defined by the
American College of Rheumatology (ACR) in 1982
or the ACR criteria as modified in 1997 w9, 10x. For
studies published before 1983, the preliminary criteria
published in 1971 areuwere considered valid w11x.
Induced CNS syndromes and associated CNS
autoimmune diseases. A CNS syndrome was considered
as ‘induced’ when it was causally related to SLE or
when it was assumed, on good grounds, to be causally
related to SLE or occurred more frequently in patients
with SLE than could be explained by chance. A disease was considered as ‘associated’ when it was an
autoimmune disease originating in the CNS; when it
occurred in patients with SLE more frequently than
could be explained by chance; when a causal relation
was unlikely or had not been detected; and when the
disease was known to occur not only simultaneously
with SLE but also as an independent entity.
Secondary CNS syndromes. A CNS syndrome was
considered to be of a ‘secondary’ nature when it was
a side-effect of drugs used for treatment of SLE
(e.g. intracranial haemorrhage in a patient using anticoagulants), when it was due to the immunocompromised status of a patient (intracranial infection), or
when it was obviously due to hypofunction or dysfunction of other internal organs. A CNS syndrome was
also considered secondary when it was secondary to
another CNS syndrome (e.g. headache of recent onset
due to aseptic meningitis, or coma in a stroke patient).
The effects of hypertension were defined as secondary
(e.g. hypertensive encephalopathy); however, they were
not always sufficiently identifiable (e.g. hypertension
contributing to premature atherosclerosis of the CNS
vascular system).
The search for literature
A PUBMED search was performed for studies in English,
French or German addressing CNS manifestations of
SLE from 1980 onwards. Reviews and original publications (articles and letters), including those about
single cases, were accepted. We asked first for articles
covering the combinations ‘SLE and CNS’ and ‘SLE
and CNS diseases’. Subsequently, we asked for combinations of SLE and specific CNS syndromes. In this
search, we used 40 medical subject headings (MeSH
terms); they will be specified in the subheadings in the
Results section.
Abstracts of titles that seemed promising were
studied. Articles of interest were selected and analysed.
The references in these articles were screened for other
studies of interest. An article was of interest when it
provided information on the incidence or prevalence
of specific neurological or psychiatric syndromes in
SLE, on the causal relationship of these syndromes
with SLE; on the incidence or prevalence of specific
CNS autoimmune diseases in SLE; and on the presence
or absence of a causal relationship of specific CNS
autoimmune diseases with SLE.
Eligibility of publications
We considered original publications and reviews eligible
when they dealt with distinct CNS syndromes that
possibly resulted from well-defined SLE or an autoimmune disease originating in the CNS in patients with
SLE. These studies were used as the basis for our
conclusions. Results of other studies will be mentioned
to confirm or weaken the conclusions. References to
mixed case series composed of patients with definite SLE
and lupus-like disease were avoided. A secondary origin
of a CNS syndrome was considered to be ruled out or
unlikely when it had been excluded by the authors on
sufficient grounds or when a secondary origin was not
explicitly ruled out but was unlikely.
Data extraction
Data were extracted that were relevant for the identification of a distinct CNS syndrome as being induced
by SLE or of a CNS autoimmune disease as being
associated with SLE. The nature of the extracted data
depended on the type of study (cohort study, case report,
etc). The data concerned clinical features of syndromes
Central nervous system manifestations of SLE
or diseases, data on imaging or other laboratory findings related to specific syndromes or diseases, and the
incidences or prevalences of syndromes or diseases.
Criteria for inclusion of syndromes and
associated disease
The criteria are presented in Box 1. A syndrome
was included as ‘induced’ if all criteria were positive except Criterion 6, or when all criteria were
positive except Criteria 3 and 6. A disease was accepted
as ‘associated’ if all criteria were positive except
Criterion 3. CNS syndromes or CNS autoimmune
diseases described in only one patient with SLE were
disregarded.
Results
CNS manifestations of SLE as mentioned in the
literature (MeSH terms: SLE plus the following: CNS;
CNS diseases)
We traced 30 CNS syndromes and two CNS autoimmune diseases, possibly induced by or associated with
SLE. Nineteen of the CNS syndromes and none of the
CNS diseases were diagnosed in the five case series
mentioned in the Introduction (Table 2). The wide range
in frequency of the diagnoses in these studies is striking.
In case series published in 1995 or earlier, organic brain
607
syndrome (including ‘confusion’) is the most frequent
diagnosis. Seizures and stroke are frequent in all case
series. Brainstem and cerebellar disorders are not diagnosed as such in two case series w1, 3x and are diagnosed
frequently in two others w2, 4x. The term ‘psychosis’ is
probably also used for delirium in some studies.
‘Cognitive disorder’ is mentioned only in the most
recently published case series w5x. Thirteen diagnoses
are not used at all, some of them presumably because
of their rarity (parkinsonian syndrome, lymphocytic
hypophysitis, etc.).
For each syndrome or disease, numbered 1–32 in the
subheadings below, we shall evaluate the available data
and decide whether it should indeed be included in the
list of CNS syndromes of SLE or diseases associated
with SLE.
1, 2: Depression and anxiety disorders (MeSH terms:
SLE plus the following: mood disorders; depression;
anxiety disorders; emission-computed tomography).
(a) Anxiety and depression were diagnosed frequently
in SLE (e.g. in 103 of 414 out-patients from two
studies and 19 of 43 hospitalized patients from one
other study) w12–14x, though not in similar proportions
in different studies. It has not been shown that they
occur more frequently in patients with SLE than in
those with rheumatoid arthritis or other chronic diseases. In fact, four studies on 132 outpatients with
undefined SLE indicate that the incidences of these
BOX 1. Criteria for inclusion of CNS syndromes or CNS autoimmune diseases as SLE-induced or SLE-associated
1. A syndrome or disease of the CNS including the hypophyseal gland and the leptomeninx.
2. A syndrome or disease with distinct clinical neurological or psychiatric features, differing in essential aspects from the clinical
features of other CNS syndromes or diseases.
3. A syndrome shown to be or likely to be causally related to SLE.
4. A syndrome or disease occurring in patients with SLE more frequently than in controls, or more frequently than can be explained by
chance.
5. A syndrome not exclusively or predominantly secondary in nature, e.g. secondary to other manifestations of the CNS, side-effects of
drugs, intracranial infection, or hypofunction or hyperfunction of internal organs.
6. An autoimmune disease predominantly of the CNS.
TABLE 2. CNS syndromes and associated CNS autoimmune diseases as described in the literature and diagnoses of CNS manifestations in five
index studies w1–5x
No.
Description
1
2
3, 4
Depression
Anxiety
Headache,
migraine
Headache of
recent date,
intractable
Psychosis
Cognitive
Dementia
Delirium
5
6
7
8
9
Range
(%)
n.c.
n.c.
0–14
–
0–23
0–16
0–2
–
No.
Description
10
Organic brain
syndrome
(Sub)coma
Seizures
Lupoid
sclerosis
Cerebritis
Stroke
TIA or TP
Subdural
haematoma
11
12
13
14
15
16
17
Range
(%)
No.
Description
2–40
18
4–25
17–37
–
19
20
21
22
23
24
25
26
27
Epidural
haematoma
PTC
Chorea
Ballism
Parkinsonism
SIADH
Hyperprolactinaemia
Sudden deafness
Brainstemucerebellar
Cerebellar
–
8–22
0–10
–
Range
(%)
–
0–2
0–2
–
–
–
–
–
0–25
0–3
No.
Description
Range
(%)
28
29
30
31
32
Optic neuropathy
Myelopathy
Aseptic meningitis
Lymphocytic hypophysitis
Multiple sclerosis
0–2?
0–8
0–5
–
–
The percentages were calculated by the authors and were based on data extracted by them from the index studies. The sequence of syndromes
is arbitrary. Psychiatric and hemispheric syndromes are listed first, followed by disorders of the brainstem and cerebellum, spinal disorders and
a meningeal disorder. The list is completed with two supposedly associated diseases.
n.c., calculation of percentages not possible; TP, transient paresis; PTC, pseudotumour cerebri; SIADH, syndrome of inappropriate antidiuretic
hormone secretion.
–, not diagnosed in w1–5x.
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F. G. I. Jennekens and L. Kater
syndromes are similar to those of various other
chronic diseases w15–18x. Similar frequencies in various
diseases favours a psychological reaction to stress as
the main cause.
(b) When SLE causes health problems, patients
develop mild psychosocial disorders, including anxiety
and depression. These tend to disappear when the health
problems are overcome, as observed in a longitudinal
study of 20 patients w19x. In a study of 80 patients, mood
disorder was found to be related to psychological and
social factors w20x.
(c) In a large retrospective study (n = 349), patients
with depression had CNS disease more often than
patients without depression. According to the authors,
this supports the view that depression is not purely a
response to stress w13x.
(d) Positron emission tomography (PET) of 12 SLE
patients revealed hypometabolism in anterior parts of
the brain in those with psychiatric symptoms w21x. PET
of non-SLE patients with depression showed also
hypometabolism in the anterior brain regions w22x.
(e) The diagnostic criteria for depression and anxiety
disorder, as specified by the Diagnostic and Statistical
Manual of Mental Disorders, 4th edition (DSM-IV),
do not allow absolute distinction between psychological
and biological origins w23x.
Conclusions. Anxiety and depression are frequent
in SLE wargument (a) abovex and likely to be predominantly psychoreactive in many patients wargument
(b) supported by argument (a)x. There may be, in
some cases, a role for biological factors wargument
(c)x. On an individual basis, it is not possible to identify depression definitely as biological in origin wargument (e)x. The syndromes comply with inclusion
Criteria 1, 2, 4, 5 and probably 3, which is sufficient
for inclusion.
3, 4: Headache and migraine (MeSH terms: SLE plus
the following: headache; headache disorders; migraine).
(a) The prevalence of headache in the general population is high. Up to 40% of individuals experience severe
disabling headache at least once per year w24x. An investigation in the USA showed that approximately 18% of
females and 6% of males had at least one migraine
attack per year w25x. Every statement about chronic or
episodic headache in SLE should therefore account for
base rates in the general population.
(b) There are three controlled studies in the literature
on chronic or episodic headache that cannot be tracked
back to other SLE syndromes w26–28x. The results are
conflicting and do not allow a definite conclusion. In
a small questionnaire study of 30 patients with mostly
pregnant women as controls, classical migraine was significantly more frequent in patients with SLE. Common
migraine and common and classical migraine together
were not significantly more frequent w26x. In a second,
larger study (n = 90), oral interviews showed migraine
(common and classical together) to be more frequent in
SLE patients than in controls. A standard protocol was
not used and no attempt was made to prevent bias w27x.
In a more recent investigation, a standard protocol was
used in oral interviews (n = 71) and the results were
assessed independently by two authors. Headache
including migraine was not found to be more frequent
in patients with SLE than in controls w28x. A similar
conclusion was drawn in a Greek study (n = 78) in
which the authors compared their findings with the
results of an investigation of healthy men w29x. Also of
interest is the fact that, in a series of Dutch patients
(n = 175), standardized questionnaires, administered
orally, showed the percentage of patients suffering
from migraine to be 11%, well within the range for the
general population in the USA w25, 30x.
(c) Migraine in SLE was not associated with
Raynaud’s phenomenon w26, 29x, the presence of anticardiolipin antibodies w27, 31x, or the presence of lupus
anticoagulant w27x. There was no evidence that SLE
was more likely to be associated with severe migraine
than with mild migraine. A link between migraine and
SLE activity or flare-ups was not definitely established
w26, 27x.
Conclusions. There is serious doubt about the previously suggested relationship between migraine and
SLE warguments (a) and (b) abovex. If future research
confirms that migraine is indeed induced by SLE, the
neurological burden of SLE would still be overestimated by including migraine without restriction in
the list of SLE manifestations wargument (a)x. No
method is available that can establish that migraine in
a given individual was induced by SLE wargument (c)x.
Non-migrainous chronic headache does not comply
with Criterion 4. There is at present insufficient evidence
that migraine complies with Criterion 4. Neither is
admitted for inclusion.
5: Intractable headache or headache of recent onset.
Acute, subacute or persistent headache is a symptom
of several CNS syndromes induced by SLE w32–35x
(Table 3). The severity of headache and the response
to treatment are not decisive for a relationship with
SLE. The ACR therefore considers intractable headache as non-specific w6x.
We conclude that intractable headache does not
comply with Criterion 2 and headache of recent onset
does not comply with Criterion 5. These forms of
headache are not acceptable for inclusion.
TABLE 3. Headache of recent onset in SLE
Syndrome
Stroke
Encephalopathy
Tumour-like
syndrome
Aseptic
meningitis
Cause
Intracerebral haemorrhage
Subarachnoid haemorrhage
Arterial dissection w32x
Vasculitis w33x
Idiopathic intracranial
hypertension
Cerebral sinus
thrombosis w34x
Subdural
haematoma w35x
Non-infectious
meningitis
Persistent
headache
+
+
+
+
+
Acute
headache
+
+
+
+
Central nervous system manifestations of SLE
6: Psychosis (MeSH terms: SLE plus psychotic disorders). Psychosis is defined here as a psychotic
disorder due to a general medical condition according
to the criteria of DSM-IV w23x. A causal relationship
with SLE has not been demonstrated but is likely in
view of the association of the two disorders. The main
primary psychosis in the population is schizophrenia.
The risk of schizophrenia occurring by chance in a
patient with SLE is low in view of its incidence rate—
approximately 1u106 per year w23x. Moreover, SLE psychosis and schizophrenia differ with regard to their
clinical features w23x.
A case of SLE psychosis may present with paranoia
and visual and auditory hallucinations w2, 36x. Recovery
is complete but relapses are not uncommon w2, 36x. The
incidence of psychosis in SLE is not easy to estimate
reliably because the literature often fails to distinguish
psychosis as defined here from delirium and other
conditions and because the distinction from corticosteroid psychosis is difficult. In a prospective study,
three of 196 SLE patients evaluated consecutively had a
psychosis w4x. In a large and often-quoted retrospective
study, 11 of 266 patients developed psychosis during a
mean follow-up period of at least 90 months w2x. The
available data indicate that psychosis in childhood is
no less frequent than in adulthood w36–38x.
Conclusion. SLE psychosis complies with Criteria 1,
2, 5 and probably 3 and 4, and is accepted for inclusion. There is a need for careful descriptions of
psychosis in SLE.
7, 8: Cognitive disorder and dementia (MeSH terms:
SLE plus the following: cognition disorder; dementia).
According to DSM-IV, ‘cognitive disorder’ can be
compensated for at least partially; the diagnosis therefore requires neuropsychological assessment w23x. The
percentage of patients with SLE suffering from cognitive disorder varies among studies (365 SLE patients
examined) from 21 to 35% in four studies (245
patients) w39– 42x and from 43 (n = 58) to 67% (n = 62)
in two other studies w43, 44x. This variation is due in
part to the different cut-offs chosen for normality
by different authors. The available data indicate
that cognitive disorder in SLE is not obviously progressive and not usually the first step towards dementia. Some authors contend that the degree of cognitive
disorder fluctuates over time (108 patients examined)
w45, 46x, but this is disputed by others (51 patients)
w42x. Two possible causes of cognitive disorder have
been suggested—small vessel vasculopathy and an antibody-mediated effect on neuronal functioning w39, 47x.
Dementia in SLE is reported in occasional adults with
multiple infarcts and in patients with (rare) leucoencephalopathy wfor description of imaging features,
see reference 8x and is unlikely to occur in controls of
similar age without such changes w2, 12, 48, 49; case
1 of reference 50x.
Conclusions. In patients with SLE, cognitive disorder
differs from dementia in degree and presumably aetiology. Distinction of the two syndromes is justifiable
for clinical reasons and research purposes. Cognitive
609
TABLE 4. Meaning of terms used to denote conditions with decreased
consciousness
Term
Organic brain syndrome w51x
Delirium w23, 52x
Acute confusional state w7, 53x
Encephalopathy
Meaning
(1) Cognitive dysfunction
including dementia
(2) Delirium
(3) Decreased consciousness, coma
Acute mental change with
abnormal attention and
fluctuating course
Delirium
Widespread brain disorder
TABLE 5. Causes of SLE-induced deliriumuencephalopathy
Small vessel vasculopathy or vasculitis w55, 56x
Leucoencephalopathy w57, 58; see also reference 8x
Perivenous spongiform encephalopathy (acute disseminated
encephalomyelitis?) w59x
Brain oedema due to cerebral venous thrombosis w60, reference 61 case 3x
SIADH w62x
Other causes, not clearly defined w63, 64x
disorder complies with Criteria 1, 2, 4, 5 and possibly
3, and dementia with Criteria 1, 2, 3, probably 4 and
5. Both are accepted for inclusion.
9, 10, 11: Delirium, organic brain syndrome and coma
(Table 4) (MeSH terms: SLE plus the following:
delirium; seizures; antidiuretic hormone, inappropriate
secretion) w7, 23, 51–53x. Organic brain syndrome w51x
has been one of the most frequently diagnosed CNS
syndromes in patients with SLE (Table 2). However,
in order to be consistent with DSM-IV, the ACR
advises that one should no longer use this term and
suggests instead ‘acute confusional state’ for the ‘whole
spectrum from delirium to coma’ w7, 53x. Acute confusional state is, however, not a DSM-IV term either.
According to the ACR it is the equivalent of delirium
w53x, so we prefer the latter term. Delirium is the neurobehavioural abnormality associated with encephalopathy. For some authors, the terms ‘encephalopathy’
and ‘delirium’ are interchangeable w23, 54x. In some
SLE patients, delirium (encephalopathy) is preceded
by depression and seizures and may be reversible, or
it may progress towards coma. It has many causes
w55–64x (Table 5). Hypertension may well be the most
frequent cause of deliriumuencephalopathy in SLE but
hypertensive encephalopathy is considered here as a
secondary manifestation wsee also reference 8x.
The main causes of coma in patients with SLE
are stroke and encephalopathy; there is no need to
distinguish coma as a separate syndrome.
Conclusions. Delirium (encephalopathy) has many
causes and complies with all criteria except 6. It is
accepted for inclusion. Organic brain syndrome is a
category rather than a syndrome and does not comply
with Criterion 2 and coma does not comply with
Criterion 5.
12: Epileptic seizures (MeSH terms: SLE plus the
following: seizures; epilepsy). Epileptic seizures are
among the most common CNS manifestations in SLE
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F. G. I. Jennekens and L. Kater
(Table 2). Generalized tonic–clonic seizures, simple
and complex partial seizures, reflex seizures and status
epilepticus all occur w2, 36, 65, 66x. One would presume
that most seizures in patients with SLE would be
elicited by vascular abnormalities in the brain, or
would be either due to CNS infections or secondary to
other manifestations, but this cannot always be
demonstrated. In a large retrospective study of 266
cases, in 18 patients seizures were not attributable to
any cause other than ‘SLE’ w2x. It has been suggested
that SLE may induce temporal limbic dysfunction,
thus causing partial seizures, possibly in some cases
with secondary generalization w66–68x. However, autoimmune epilepsy is at present a hypothesis and has not
been established definitely in any disease w69x.
Conclusions. Epileptic seizures comply with Criteria
1, 2 and 4. In some cases, a secondary origin is not
demonstrable (Criterion 5) and no cause other than
SLE is present (Criterion 3). Epileptic seizures are
accepted for inclusion.
13, 14: Lupoid sclerosis and cerebritis. Lupoid sclerosis was suggested as a label for multiple sclerosis
(MS)-like syndromes of patients with SLE or lupuslike disease. It often refers to relapsing myelopathy or
optic neuropathy in patients whose laboratory abnormalities support the diagnosis of lupus-like disease
or SLE w70–74x. The name illustrates the difficulty of
the differential diagnosis of SLE and MS in occasional
patients presenting with neurological abnormalities
(see also below, under Syndrome 32: Multiple sclerosis).
The diagnosis of cerebritis is now little used because
modern imaging methods allow structures and blood
flow in the skull to be visualized. It has been suggested
as a tentative diagnosis in patients who could not be
diagnosed more definitely.
Conclusions. ‘Lupoid sclerosis’ and cerebritis do not
refer to distinct CNS syndromes. As they do not
comply with Criterion 2, they are not included.
15, 16: Stroke and transient ischaemic attacks
(MeSH terms: SLE plus the following: stroke; ischaemic attack, transient; infarction, cerebral; cerebral haemorrhage; subarachnoid haemorrhage). (a) Stroke is
among the CNS diagnoses in all large series of patients
with SLE w1–5, 30, 75–77x. The mean age at the time
of stroke in SLE patients is approximately 42 yr
w75, 76x. Figures on the frequency of stroke in different
case series vary from 3% to at least 15% wfor additional references, see reference 75x. Yearly strokes rates
were calculated, using data from 91 patients with SLE
observed for 599 patient-yr. The stroke rate dropped
from 6.6% in year 1 to 0.6% during years 6–10 w75x.
(b) The increased incidence of stroke observed in case
series corresponds to the results of an epidemiological
investigation. The International Classification of
Diseases (ICD-9) code for SLE was used to trace
patients admitted to hospitals in California. Using
figures from these patients, it was estimated that
‘cerebrovascular accidents’ were 10 times more frequent
in 18- to 44-yr-old women with SLE than in those of
similar age without SLE w78x. In middle age (45–64 yr)
‘cerebrovascular accidents’ were approximately twice
as frequent and in old age the frequency was slightly
below normal.
Causes of stroke in SLE include large artery occlusion, as demonstrated in 30 patients reported in the
literature w79x, intracerebral haemorrhage and subarachnoid haemorrhage. In two large studies of stroke
in SLE (one study from Japan; see below for subarachnoid haemorrhages), six of 27 patients had
haemorrhages, three of them intracerebral and three
subarachnoidal w75, 76x. It is not known how often
stroke in SLE is due to cerebral venous thrombosis
(CVT). Stroke due to vasculitis is probably rare.
Ischaemic stroke in SLE is attributed at least in part
to circulating antiphospholipid antibodies (APL),
(premature) atherosclerosis and other causes wfor
review, see reference 8x. It is not known exactly why
the risk of intracranial haemorrhages is increased by
changes in vessel walls induced by hypertension,
corticosteroids or SLE, and thrombopenia is likely to
play a role wfor review, see references 8, 76x.
Subarachnoid haemorrhage in SLE is well documented in the literature w76, 80–84x; however, by far the
most reports are from one country, Japan. A study of
the medical records of patients with SLE in one
Japanese centre covering a 20-yr period revealed that
10 of 258 patients with SLE had at some time experienced a (clinically defined) subarachnoid haemorrhage
w85x. There was no other cause than ‘SLE’ in at least
five of these patients (1.9%). The diagnosis ‘subarachnoid haemorrhage’ was not mentioned in any of
five large American and European studies comprising
257 patients with SLE-induced CNS syndromes w1–5x.
Figures on transient ischaemic attacks (TIAs) in SLE
indicate that the incidence is raised w30, 75, 77x. Interviews with 175 unselected SLE patients revealed seven
with previous TIAs and 10 with previous ‘transient
monocular blindness’ w30x. In a partly retrospective
and partly prospective study, seven of 91 patients had
TIAs w75x and in a prospective study 35 of 500 patients
had TIAs w77x. An embolic source of TIAs in SLE is
possible but is at present an assumption. The role of
haemodynamic causes remains to be evaluated.
Conclusions. Patients with SLE are at increased risk
of stroke at a relatively young age wargument (a) supported by argument (b)x. Stroke and TIAs comply
with all inclusion criteria except Criterion 6. They are
accepted for inclusion.
17, 18: Subdural and epidural haematomas (MeSH
terms: SLE plus the following: subdural haematoma;
epidural haematoma). There are case reports and
autopsy reports on intracranial and spinal subdural
and epidural haematomas in four patients with SLE
w35, 86, 87x, suggesting a relationship between these
disorders. This is supported by several case series
in which reference is made to four patients with
(undefined) SLE who were found to have intraspinal
epidural or subdural haematomas w88–90x. Spontaneous subdural or epidural haematomas in the general
population are rare. They are very rare in the spinal
Central nervous system manifestations of SLE
column w89, 90x. It is therefore unlikely that they occur
in SLE by chance. Intracranial subdural haematoma
presents clinically with headache and other features of
a tumour cerebri syndrome w35x. The spinal subdural
and epidural haematomas cause myelopathy.
Conclusions. Subdural and epidural haematoma
cannot be accepted as such, as they are the causes of
clinical syndromes, not the syndromes themselves.
The latteris required by Criterion 2. They give rise
to a tumour cerebri syndrome (see below, Syndrome
19: Pseudotumour cerebri) or to myelopathy (see
below, Syndromes 28 and 29: Optic neuropathy and
myelopathy).
19: Pseudotumour cerebri (MeSH terms: SLE plus
pseudotumour cerebri). The main clinical characteristics
of pseudotumour cerebri are headache and nausea
with visual obscurations and papilloedema. Obese
women of reproductive age are most at risk of pseudotumour cerebri (PTC). The incidence rate of PTC in
women in the age category of 15–44 yr in Rochester,
MN, USA, is approximately 3.3 per 105 per yr w91x.
Until 1994, 18 patients with SLE had been reported
as suffering from PTC wfor review, see reference 92x. In
some patients PTC was idiopathic but in several others
a cerebral venous or sinus thrombosis had been diagnosed. A hypercoagulable state was demonstrated in
eight of 18 cases w92x. In a retrospective analysis of the
medical records of 127 patients with lupus nephritis,
PTC appeared to have been diagnosed in six patients
(4.7%) w93x. These subjects had all gone through
episodes of symptomatic arterial or venous thrombosis
and they had laboratory evidence of procoagulant
activity. Though other cases of idiopathic PTC have
been reported since 1994 w92, 94x, there was more
interest in raised intracranial hypertension caused by
cerebral venous or sinus thrombosis. This diagnosis has
become easier since the introduction of improved noninvasive imaging techniques. It was unexceptional for
patients with SLE and CVT to present with a PTC
syndrome without any other neurological abnormality
w60, 61, 95x, confirming observations on CVT patients
not associated with SLE w34x.
The chance of venous thrombosis is increased in SLE
patients with APL wfor review, see reference 8x. These
antibodies are suggested to occur also with increased
frequency in SLE patients with CVT w96x.
Conclusions. PTC shares its clinical features with the
tumour cerebri syndrome and cannot be included as a
separate item in view of Criterion 2. However, tumour
cerebri syndrome (see also Syndromes 17 and 18) is
acceptable as it complies with Criteria 1, 2 and 5 and
is estimated to comply with Criterion 4.
20, 21, 22: Chorea, hemiballism, parkinsonism
(MeSH terms: SLE plus the following: chorea; dyskinesias; parkinsonian disorders). Chorea occurs in approximately 1% of patients with SLE and is one of the
most characteristic neurological manifestations of the
disease w36, 97, 98x. Evidence of a preceding infection,
as in Sydenham’s chorea, is lacking. The imaging
features and histopathological studies point to
611
abnormalities of the basal ganglia, but it is not yet
clear whether chorea is due to a vascular insult or to
antibody-induced neuronal dysfunction w99, 100x.
Hemiballism due to ischaemic infarcts has been
reported in one adult with well-defined SLE w101x and
in one other case with undefined SLE w102x.
Parkinsonism is rare in young adults and adolescence
and is not usually due to idiopathic Parkinson’s
disease. It has been observed in at least two women
with well-defined SLE, varying in age from 16 to 42 yr
w103, 104x, and in one other case with undefined
SLE w105x.
Conclusions. Chorea complies with Criteria 1, 2, 4, 5
and probably 3. Parkinsonian syndrome complies with
Criteria 1, 2 and 5 and is estimated to comply with
Criterion 4. Both are accepted for inclusion. Hemiballism does not comply with Criterion 4, as only one case
has been reported in definite SLE, and is not included.
23: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (MeSH terms: SLE plus
antidiuretic hormone, inappropriate secretion). The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been described in at least six
patients with well-defined SLE w62, 106–110x. It
may provoke encephalopathy with cerebral oedema,
delirium and seizures. An investigation of 36 patients
with SLE, all in a stable condition, disclosed an
increase in the plasma concentration of antidiuretic
hormone irrespective of SLE activity and the responsiveness of the kidneys to antidiuretic hormone w111x.
It was suggested that antibody-mediated damage to
neurones in the hypothalamus might be the cause.
It is concluded that the neurological features of
SIADH are similar to those of delirium (encephalopathy) (see above, Syndromes 9–11). This means that
SIADH in SLE does not comply with Criterion 2. It
will therefore not be included as a separate clinical
syndrome.
24: Hyperprolactinaemia (MeSH terms: SLE plus
hyperprolactinaemia). Hyperprolactinaemia has many
causes, including hypothalamic disorders and lymphocytic hypophysitis (see below, Syndrome 31:
Lymphocytic hypophysitis). It has been estimated that
up to 20% of SLE patients are hyperprolactinaemic
w112x. The clinical picture of hyperprolactinaemia is
characterized by endocrinological abnormalities.
Conclusions. Even though the cause of hyperprolactinaemia in patients with SLE may well be in
the CNS, it cannot be included in the list of SLEinduced CNS syndromes as it lacks neurological
features. It therefore does not comply with Criterion 2.
25: Sudden sensorineural hearing loss (MeSH terms:
SLE plus hearing loss sensorineural). Sudden sensorineural hearing loss has been reported in at least six
SLE patients wfor case reports and review, see reference
113; see also 114, 115x. A definite cause (or causes) has
(have) not been identified. Onset is often associated
with vertigo and other signs of labyrinthine dysfunction w113, 116x and in general not with signs
of CNS involvement wbut see case 2 in reference 113x.
612
F. G. I. Jennekens and L. Kater
It has been suggested that the syndrome may result
from occlusion of either the internal auditory artery or
the labyrinthine artery w115, 116x. Non-functioning of
the posterior communicating artery was established in a
majority of patients with sudden sensorineural hearing
loss investigated by ultrasonography w117x. APL were
detected in the serum of most patients with SLE and
sudden sensorineural hearing loss.
Conclusions. In most cases, sudden sensorineural
hearing loss probably does not comply with
Criterion 1. It is therefore not included.
26, 27: Brainstemucerebellar syndrome and cerebellar syndrome (MeSH terms: SLE plus the following:
brainstem; cerebellar diseases; cranial nerve diseases).
Among the CNS syndromes of SLE, acute and subacute brainstem and cerebellar syndromes are probably
not rare, as suggested in two large case series w2, 3x.
They comprise eye movement disorders, cranial nerve
palsies, pyramidal changes, sensory disturbances and
ataxia, and in some patients they were due to autopsyproven ischaemic infarcts or vasculitis. In some other
patients, magnetic resonance imaging (MRI) showed
abnormalities compatible with ischaemic infarcts
w118–122x. These syndromes are in fact strokes at the
level of the brainstem and the cerebellum. Most of these
patients were adults or adolescents, in whom such
syndromes are highly unusual for non-SLE patients.
Chronic or subacute cerebellar ataxia with MRI
evidence of cerebellar atrophy has been reported in a
few cases w123, 124x. Anti-Purkinje cell antibody was
discovered in another patient with SLE that was not
fully defined w125x.
Conclusions. Brainstem and acute or subacute cerebellar syndromes in SLE are strokes at the brainstem
and cerebellar level and therefore do not comply with
Criterion 2. They form part of syndrome 15 (see above).
Chronic cerebellar ataxia complies with Criteria 1, 2
and 5, and is estimated to comply with Criteria 4 and
possibly 3. It is therefore included.
28, 29: Optic neuropathy and myelopathy (MeSH
terms: SLE plus the following: optic neuritis; myelitis;
neuromyelitis optica). Myelopathy is estimated to
develop in 1–2% of patients with SLE wfor review, see
reference 126x but higher percentages are mentioned
by some tertiary referral centres w5x. At least 25% of
patients with myelopathy develop optic neuropathy,
usually bilaterally (Devic’s syndrome) w126x. Optic
neuropathy is estimated to occur in 1% of patients
with SLE, in some cases associated with myelopathy
but often without such an association w127x. Though a
vascular origin (small vessel disease, vasculitis) has
been suggested for these syndromes, other causes are
conceivable wfor review, see reference 8x. In a few
cases, myelopathy is due to spinal subdural or epidural
haematoma of non-traumatic origin, as mentioned
above (see above, Syndromes 17, 18: Subdural and
epidural haematomas).
Conclusions. Myelopathy and optic neuropathy
comply with Criteria 1, 2, 4 and 5 and are accepted
for inclusion.
30: Aseptic meningitis (MeSH terms: SLE plus the
following: aseptic meningitis; cerebrospinal fluid).
Currently, the term ‘aseptic meningitis’ is often used
for a meningeal syndrome of non-infectious origin
with some degree of nuchal rigidity and pleocytosis in
the cerebrospinal fluid w33, 53x. In the index studies
mentioned in the Introduction, aseptic meningitis was
diagnosed in four out of 257 patients with CNS manifestations and was probably related to an anti-inflammatory drug and not directly to SLE in one of these
patients w1–5x. Case reports indicate that SLE-induced
aseptic meningitis may be associated with either of two
neurological disorders: myelopathy w128; for aseptic
meningitis followed by transverse myelitis in incompletely defined SLE, see also reference 129x and brain
or brainstem vasculitis w56, 130x. Aseptic meningitis has
been reported in two patients with stroke or ‘ischaemic
brain lesions’; vasculitis was not demonstrated but
was not ruled out w131, 132x. In contrast to some other
inflammatory connective tissue diseases, lymphocytic
inflammation of the leptomeninx is not a feature of
SLE wfor review, see reference 33x.
Conclusions. Aseptic meningitis in SLE may be heterogeneous in origin and is due to vasculitis in some
cases. It is accepted for inclusion as it complies with
Criteria 1, 2, 3, 5 —and probably 4.
Associated diseases
31: Lymphocytic hypophysitis (MeSH terms: SLE
plus hypophysis). This rare autoimmune disorder may
cause enlargement of the pituitary gland, headache,
hypopituitarism and visual field defects. Lymphocytic
hypophysitis affects preferentially young women late
in pregnancy or thereafter w133x. It has been reported
in at least two non-pregnant patients with SLE
w134, 135x, which may well be not explainable by
chance. There is another case report in the Japanese
literature w136x.
Conclusions. Lymphocytic hypophysitis complies
with Criteria 1, 2, 5 and 6 and is estimated to comply
with Criterion 4. It is acceptable for inclusion as an
associated disease.
32: Multiple sclerosis (MeSH terms: SLE plus
multiple sclerosis). Multiple sclerosis (MS) is an autoimmune disease, or a disorder with prominent autoimmune reactions, which occurs with increased frequency
in association with other autoimmune diseases w137x.
Autoantibodies, including antinuclear antibodies, APL
and others, are variously reported to be present in less
than 5 to 50% of patients with MS w138–140x. At
onset, MS and SLE presenting with CNS manifestations may share several clinical features and many
MRI features, and are therefore not always easily distinguishable w141–142x. Demyelination is the histopathological hallmark of MS. Small and larger
ischaemic infarcts are the most prominent CNS lesions
in SLE w74x. Analysis of 27 patients with the differential diagnosis SLE or MS in a tertiary referral
Central nervous system manifestations of SLE
centre led to the conclusion that sharing of clinical
features was more likely than association of the two
diseases w74x.
Conclusions. There are insufficient grounds for
including MS in the group of associated autoimmune
diseases. MS is not accepted as it does not comply
with Criterion 2.
Discussion
The foregoing shows that 14 out of 30 CNS syndromes
traced in the literature (numbers 3–5, 10, 11, 13, 14, 17,
18, 21 and 23–26) are not admissible as distinct SLEinduced syndromes, and that one out of two CNS
autoimmune diseases is not admissible as being associated with SLE. This implies that SLE may induce
16 different CNS syndromes and is associated with
one CNS autoimmune disease (Table 6). The clinical
picture of SLE, as far as the CNS is concerned, may be
further complicated by secondary CNS syndromes and
by associated autoimmune diseases that do not involve
the CNS predominantly, e.g. idiopathic thrombotic
thrombocytopenic purpura w143x.
The striking variability of SLE-induced CNS manifestations may easily create difficulty in diagnosis and
research. To prevent such problems, a classification of
CNS syndromes and a well-defined terminology is
helpful. As mentioned in the Introduction, the results
of two consensus meetings on CNS manifestations of
SLE have been published in the last decade. The first
meeting aimed to provide a full list of CNS syndromes
and to rank them according to their importance in the
diagnosis SLE (Appendix 1, part A) w6x. The second
meeting was organized in order to construct a system
of nomenclature (Appendix 1, part B) w7x. The primary
aim of this latter system was to facilitate research.
Experience shows that the use of a nomenclature system
TABLE 6. CNS syndromes induced by SLE and CNS autoimmune
disease associated with SLE
Syndrome
(1)
(2)
(6)
(7)
(8)
(9)
(12)
(15)
(16)
(17)
(20)
(22)
(27)
(28)
(29)
(30)
Depression
Anxiety
Psychosis
Cognitive disorder
Dementia
Deliriumuencephalopathy
Epileptic seizures
Stroke
TIA
Tumour cerebri syndrome
Chorea
Parkinsonian syndrome
Cerebellar syndrome
Optic neuropathy
Myelopathy
Aseptic meningitis
Disease
(31) Lymphocytic hypophysitis
Figures in parentheses refer to the syndrome and disease numbers
in Table 2 and in the subheadings in the Results section.
613
may have a profound effect on diagnoses made by
clinicians w144, 145x.
A classification of disease manifestations should meet
several demands. It should not be unduly long, the
manifestations should, if possible, be classified according to one dimension (e.g. aetiological, pathological or
clinical), overlap between items should be avoided and
the system should be transparent. The classification
proposed by the first consensus meeting (Appendix 1,
part A) is long, the items are defined by clinical or
laboratory characteristics and belong therefore to more
than one dimension, and several psychiatric diagnoses
appear not to be used in the literature. The nomenclature system (Appendix 1, part B) is more recent and
has brevity as an important advantage. However, to
achieve brevity a price had to be paid. Items had to
be pooled and some rare items were omitted. Pooling
decreases transparency. Examples of pooling are
‘cerebrovascular disease’ as an umbrella diagnosis for
stroke and TIAs, and ‘headache’ as an umbrella
diagnosis for migraine and idiopathic intracranial
hypertension. For some research purposes, ‘cerebrovascular disease’ may be a sufficient label, but for
clinical research pooling of TIAs and strokes will often
be detrimental as this conceals important differences in
health risks. Another point is that the nomenclature
system is not confined to one dimension, as one of the
items is defined by histopathological features whilst
the others are clinical.
A modified nomenclature system
The difficulties described may be solved by rephrasing
some items and by subdivision of items, as shown in
Table 7. This modification reflects the findings in the
literature that are presented above. The modified system
includes the 16 SLE-induced CNS syndromes, but not
TABLE 7. Clinical syndromes of the CNS induced by SLE: a
modification of the ACR nomenclature system
1
2
2.1
2.2
3
3.1
3.2
3.3
4
5
5.1
5.2
5.3
6
7
8
8.1
8.2
9
10
11
Meningitis, aseptic
Cerebrovascular disease
Stroke in hemispheric, brainstem and cerebellar regions
TIA
Myelopathy, optic neuropathy
Myelopathy and optic neuropathy (Devic’s syndrome)
Myelopathy only
Optic neuropathy
Tumour cerebri syndrome (subdural haematoma or
pseudotumour cerebri)
Movement disorders
Chorea
Parkinsonism
Cerebellar disorder
Epileptic seizures
Delirium (or encephalopathy)
Cognitive dysfunction
Cognitive disorder
Dementia
Psychosis
Anxiety disorders
Mood disorder
614
F. G. I. Jennekens and L. Kater
the only associated CNS disease. ‘Demyelination syndrome’, number 3 in the original nomenclature system,
is replaced by ‘myelopathy and optic neuropathy’ for
two reasons. ‘Myelopathy and optic neuropathy (Devic’s
syndrome)’ refers to clinical syndromes in contrast to
‘demyelination syndrome’, which has no clear clinical
annotation. A demyelinating syndrome of the brain or
brainstem induced by SLE is at present a hypothesis for
which little evidence is available w74; for more discussion, see reference 8x.‘Tumour cerebri syndrome’ is not
defined in the ACR nomenclature. However, it refers
to the symptoms of pseudotumour cerebri, which has
been defined by the ACR, and it allows mention
of subdural haematoma. ‘Seizure disorders’ are now
named ‘epileptic seizures’ because not all seizures are
epileptic w146x. ‘Acute confusional state’ is replaced
by ‘delirium’, as this is a term used by DSM-IV. Coma
is not mentioned separately. It is considered here as
a clinical state seen in some patients with stroke and
may develop in patients with delirium. There are four
items with subdivisions. Migraine has been left out
because it is does not comply at present with the
criteria for a SLE-induced CNS syndrome.
It is advocated that, in epidemiological investigations of CNS manifestations, numbers 10 and 11 of the
modified nomenclature system are kept separate from
the others as they are not predominantly due to
biological processes and differ in this respect from
numbers 1–9.
Acknowledgements
The authors are grateful to Dr G. J. E. Rinkel for
advice and to Dr A. Jennekens-Schinkel and Professor
Dr T. W. Huizinga for reading a previous version of
this manuscript.
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APPENDIX 1. CNS manifestations of SLE
(A) Descriptors ranked according to decreasing importance w5x
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Seizures, primary generalized
Psychosis (brief reactive or atypical)
Transverse myelitis
Global cognitive dysfunction (dementia)
Seizures focal (motor or sensory)
Seizures, complex partial
Stroke syndrome
Limited cognitive dysfunction (objective)
Status epilepticus
Optic neuropathy
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Meningitis, aseptic
Movement disorders
Attentional cognitive dysfunction
EEG abnormality
CSF abnormality
Schizophreniform disorder
Cerebral angiographic abnormality
Brain scan abnormality
Major affective disorder
Absence attacks
21.
22.
23.
24.
25.
26.
27.
28.
29.
Transient ischaemic attacks
Headache, vascular
Headache, intractable
Schizophrenia
Benign intracranial hypertension
Limited cognitive dysfunction (subjective)
Other psychiatric syndromeusymptoms
Generalized anxietyupanic disorder
Headache tension
9.
10.
11.
12.
Anxiety disorder
Cognitive dysfunction
Mood disorder
Psychosis
(B) Nomenclature system w6x
1.
2.
3.
4.
Aseptic meningitis
Cerebrovascular disease
Demyelinating syndrome
Headache (including migraine and
benign intracranial hypertension)
5.
6.
7.
8.
Movement disorder (chorea)
Myelopathy
Seizure disorders
Acute confusional state