The central nervous system in systemic lupus erythematosus. Part 1. Clinical syndromes: a literature investigation

F. G. I. Jennekens and L. Kater,1

Department of Neurology and
1 Department of Rheumatology and Clinical Immunology, University Medical Centre, Utrecht, The Netherlands


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Associated diseases
 Discussion
 References
 
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.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Associated diseases
 Discussion
 References
 
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 1Go illustrates the divergence in the percentages of patients with SLE-induced CNS syndromes in five large studies [15]: 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.


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TABLE 1.  Incidence of CNS manifestations attributable in part or wholly to SLE in five studies

 
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 [6]. The other is a nomenclature system comprising 12 items [7]. 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 [8].


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    Methods
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 Abstract
 Introduction
 Methods
 Results
 Associated diseases
 Discussion
 References
 
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 has/had 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 [9, 10]. For studies published before 1983, the preliminary criteria published in 1971 are/were considered valid [11].

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 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.


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.

 


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Associated diseases
 Discussion
 References
 
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 2Go). The wide range in frequency of the diagnoses in these studies is striking. In case series published in 1995 or earlier, organic brain 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 [1, 3] and are diagnosed frequently in two others [2, 4]. The term ‘psychosis’ is probably also used for delirium in some studies. ‘Cognitive disorder’ is mentioned only in the most recently published case series [5]. Thirteen diagnoses are not used at all, some of them presumably because of their rarity (parkinsonian syndrome, lymphocytic hypophysitis, etc.).


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TABLE 2.  CNS syndromes and associated CNS autoimmune diseases as described in the literature and diagnoses of CNS manifestations in five index studies [15]

 
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) [1214], 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 syndromes are similar to those of various other chronic diseases [1518]. 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 [19]. In a study of 80 patients, mood disorder was found to be related to psychological and social factors [20].

(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 [13].

(d) Positron emission tomography (PET) of 12 SLE patients revealed hypometabolism in anterior parts of the brain in those with psychiatric symptoms [21]. PET of non-SLE patients with depression showed also hypometabolism in the anterior brain regions [22].

(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 [23].

Conclusions
Anxiety and depression are frequent in SLE [argument (a) above] and likely to be predominantly psychoreactive in many patients [argument (b) supported by argument (a)]. There may be, in some cases, a role for biological factors [argument (c)]. On an individual basis, it is not possible to identify depression definitely as biological in origin [argument (e)]. 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 [24]. An investigation in the USA showed that approximately 18% of females and 6% of males had at least one migraine attack per year [25]. 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 [2628]. 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 [26]. 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 [27]. 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 [28]. 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 [29]. 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 [25, 30].

(c) Migraine in SLE was not associated with Raynaud’s phenomenon [26, 29], the presence of anticardiolipin antibodies [27, 31], or the presence of lupus anticoagulant [27]. 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 [26, 27].

Conclusions
There is serious doubt about the previously suggested relationship between migraine and SLE [arguments (a) and (b) above]. 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 [argument (a)]. No method is available that can establish that migraine in a given individual was induced by SLE [argument (c)].

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 [3235] (Table 3Go). 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 [6].


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TABLE 3.  Headache of recent onset in SLE

 
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.

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 [23]. 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 1/106 per year [23]. Moreover, SLE psychosis and schizophrenia differ with regard to their clinical features [23].

A case of SLE psychosis may present with paranoia and visual and auditory hallucinations [2, 36]. Recovery is complete but relapses are not uncommon [2, 36]. 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 [4]. 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 [2]. The available data indicate that psychosis in childhood is no less frequent than in adulthood [3638].

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 [23]. 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) [3942] and from 43 (n=58) to 67% (n=62) in two other studies [43, 44]. 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) [45, 46], but this is disputed by others (51 patients) [42]. Two possible causes of cognitive disorder have been suggested—small vessel vasculopathy and an antibody-mediated effect on neuronal functioning [39, 47].

Dementia in SLE is reported in occasional adults with multiple infarcts and in patients with (rare) leucoencephalopathy [for description of imaging features, see reference 8] and is unlikely to occur in controls of similar age without such changes [2, 12, 48, 49; case 1 of reference 50].

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 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 4Go) (MeSH terms: SLE plus the following: delirium; seizures; antidiuretic hormone, inappropriate secretion) [7, 23, 5153]
Organic brain syndrome [51] has been one of the most frequently diagnosed CNS syndromes in patients with SLE (Table 2Go). 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’ [7, 53]. Acute confusional state is, however, not a DSM-IV term either. According to the ACR it is the equivalent of delirium [53], so we prefer the latter term. Delirium is the neurobehavioural abnormality associated with encephalopathy. For some authors, the terms ‘encephalopathy’ and ‘delirium’ are interchangeable [23, 54]. 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 [5564] (Table 5Go). Hypertension may well be the most frequent cause of delirium/encephalopathy in SLE but hypertensive encephalopathy is considered here as a secondary manifestation [see also reference 8].


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TABLE 4.  Meaning of terms used to denote conditions with decreased consciousness

 

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TABLE 5.  Causes of SLE-induced delirium/encephalopathy

 
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 (Table 2Go). Generalized tonic–clonic seizures, simple and complex partial seizures, reflex seizures and status epilepticus all occur [2, 36, 65, 66]. 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’ [2]. It has been suggested that SLE may induce temporal limbic dysfunction, thus causing partial seizures, possibly in some cases with secondary generalization [6668]. However, autoimmune epilepsy is at present a hypothesis and has not been established definitely in any disease [69].

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 lupus-like disease. It often refers to relapsing myelopathy or optic neuropathy in patients whose laboratory abnormalities support the diagnosis of lupus-like disease or SLE [7074]. 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 [15, 30, 7577]. The mean age at the time of stroke in SLE patients is approximately 42 yr [75, 76]. Figures on the frequency of stroke in different case series vary from 3% to at least 15% [for additional references, see reference 75]. 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 [75].

(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 [78]. 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 [79], 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 [75, 76]. 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 [for review, see reference 8]. 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 [for review, see references 8, 76].

Subarachnoid haemorrhage in SLE is well documented in the literature [76, 8084]; 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 [85]. 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 [15].

Figures on transient ischaemic attacks (TIAs) in SLE indicate that the incidence is raised [30, 75, 77]. Interviews with 175 unselected SLE patients revealed seven with previous TIAs and 10 with previous ‘transient monocular blindness’ [30]. In a partly retrospective and partly prospective study, seven of 91 patients had TIAs [75] and in a prospective study 35 of 500 patients had TIAs [77]. 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 [argument (a) supported by argument (b)]. 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 [35, 86, 87], 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 [8890]. Spontaneous subdural or epidural haematomas in the general population are rare. They are very rare in the spinal column [89, 90]. 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 [35]. 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 [91].

Until 1994, 18 patients with SLE had been reported as suffering from PTC [for review, see reference 92]. 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 [92]. 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%) [93]. 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 [92, 94], 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 non-invasive imaging techniques. It was unexceptional for patients with SLE and CVT to present with a PTC syndrome without any other neurological abnormality [60, 61, 95], confirming observations on CVT patients not associated with SLE [34].

The chance of venous thrombosis is increased in SLE patients with APL [for review, see reference 8]. These antibodies are suggested to occur also with increased frequency in SLE patients with CVT [96].

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 [36, 97, 98]. Evidence of a preceding infection, as in Sydenham's chorea, is lacking. The imaging features and histopathological studies point to 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 [99, 100].

Hemiballism due to ischaemic infarcts has been reported in one adult with well-defined SLE [101] and in one other case with undefined SLE [102].

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 [103, 104], and in one other case with undefined SLE [105].

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 [62, 106110]. 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 [111]. 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 [112]. 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 SLE-induced 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 [for case reports and review, see reference 113; see also 114, 115]. A definite cause (or causes) has (have) not been identified. Onset is often associated with vertigo and other signs of labyrinthine dysfunction [113, 116] and in general not with signs of CNS involvement [but see case 2 in reference 113]. It has been suggested that the syndrome may result from occlusion of either the internal auditory artery or the labyrinthine artery [115, 116]. Non-functioning of the posterior communicating artery was established in a majority of patients with sudden sensorineural hearing loss investigated by ultrasonography [117]. 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: Brainstem/cerebellar 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 [2, 3]. They comprise eye movement disorders, cranial nerve palsies, pyramidal changes, sensory disturbances and ataxia, and in some patients they were due to autopsy-proven ischaemic infarcts or vasculitis. In some other patients, magnetic resonance imaging (MRI) showed abnormalities compatible with ischaemic infarcts [118122]. 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 [123, 124]. Anti-Purkinje cell antibody was discovered in another patient with SLE that was not fully defined [125].

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 [for review, see reference 126] but higher percentages are mentioned by some tertiary referral centres [5]. At least 25% of patients with myelopathy develop optic neuropathy, usually bilaterally (Devic's syndrome) [126]. Optic neuropathy is estimated to occur in 1% of patients with SLE, in some cases associated with myelopathy but often without such an association [127]. Though a vascular origin (small vessel disease, vasculitis) has been suggested for these syndromes, other causes are conceivable [for review, see reference 8]. 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 [33, 53]. 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 [15]. Case reports indicate that SLE-induced aseptic meningitis may be associated with either of two neurological disorders: myelopathy [128; for aseptic meningitis followed by transverse myelitis in incompletely defined SLE, see also reference 129] and brain or brainstem vasculitis [56, 130]. Aseptic meningitis has been reported in two patients with stroke or ‘ischaemic brain lesions’; vasculitis was not demonstrated but was not ruled out [131, 132]. In contrast to some other inflammatory connective tissue diseases, lymphocytic inflammation of the leptomeninx is not a feature of SLE [for review, see reference 33].

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
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 Abstract
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 Methods
 Results
 Associated diseases
 Discussion
 References
 

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 [133]. It has been reported in at least two non-pregnant patients with SLE [134, 135], which may well be not explainable by chance. There is another case report in the Japanese literature [136].

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 [137]. Autoantibodies, including antinuclear antibodies, APL and others, are variously reported to be present in less than 5 to 50% of patients with MS [138140]. 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 [141142]. Demyelination is the histopathological hallmark of MS. Small and larger ischaemic infarcts are the most prominent CNS lesions in SLE [74]. Analysis of 27 patients with the differential diagnosis SLE or MS in a tertiary referral centre led to the conclusion that sharing of clinical features was more likely than association of the two diseases [74].

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
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 Abstract
 Introduction
 Methods
 Results
 Associated diseases
 Discussion
 References
 
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 SLE-induced 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 6Go). 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 [143].


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TABLE 6.  CNS syndromes induced by SLE and CNS autoimmune disease associated with SLE

 
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) [6]. The second meeting was organized in order to construct a system of nomenclature (Appendix 1, part B) [7]. The primary aim of this latter system was to facilitate research. Experience shows that the use of a nomenclature system may have a profound effect on diagnoses made by clinicians [144, 145].


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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 7Go. This modification reflects the findings in the literature that are presented above. The modified system includes the 16 SLE-induced CNS syndromes, but not 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 [74; for more discussion, see reference 8].‘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 [146]. ‘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.


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TABLE 7.  Clinical syndromes of the CNS induced by SLE: a modification of the ACR nomenclature system

 
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.


APPENDIX 1.  CNS manifestations of SLE

 


    Acknowledgments
 
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.


    Notes
 
Correspondence to: L. Kater, Bevelandselaan 11, 1181 JL Amstelveen, The Netherlands. Back


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Submitted 20 April 2001; Accepted 28 December 2001