neuropsychiatric lupus erythematosus and the elderly

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, VOL. 9: 97-106 (1994)

REVIEW NEUROPSYCHIATRIC LUPUS

ERYTHEMATOSUS AND THE ELDERLY MICHAEL DENNIS

Senior Lecturer in Psychiatry for the Elderly, Leicester General Hospital, Gwendolen Rd, Leicester LE5 4 P W, UK

SUMMARY

Recent research suggests systemic lupus erythematosus (SLE) is more common in the elderly than previously thought. Neuropsychiatric disorder occurs in the majority of patients at some time during the course of the illness. Frequently neuropsychiatric features occur early, and may precede other typical features of multisystem disease by some years. An organic brain syndrome is the most frequently encountered neuropsychiatric manifestation of SLE. It is important that cases presenting to elderly services are recognized, as organic brain disorders resulting from SLE are potentially treatable.

KEY woms-Systemic lupus erythematosus, organic brain syndromes, elderly, geriatric psychiatry.

Systemic lupus erythematosus is a multisystem inflammatory disorder characterized by the presence of autoantibodies and a variety of immunological abnormalities which are responsible for tissue damage. The aetiology remains unknown but it is likely to be multifactorial, with genetics, hormonal and environmental influences all being important (Hopkinson, 1991). The clinical presentation may be diverse, reflecting the wide range of systems involved (Dubois and Tuffanelli, 1964).

This article examines systemic lupus erythematosus in the elderly, with detailed reference to neuropsychiatric manifestations and psychiatric practice. Also included are general reviews of the epidemiology of SLE, and of neuropsychiatric systemic lupus erythematosus (NP-SLE). These areas are particularly relevant to the understanding and research of NP-SLE in the elderly.

EPIDEMIOLOGY

Early American studies showed that the peak incidence of SLE was among young women. There were marked racial variations, with a particularly high incidence and prevalence in the young Afro- Caribbean female community (Siege1 and Lee, 1973). A recent hospital-based study in Baltimore (1 970-77) confirmed the marked female preponder-

ance with a sex ratio of 6: 1. Age-specific incidence rates were again highest among Afro-Caribbean females (peak 25-34 age group) (Hochberg, 1985).

Nived et al. (1985) conducted a detailed study of both inpatients and outpatients in southern Swe- den for the years 1981 and 1982. They found an annual incidence of 4.8 cases, a mortality of 1.3, and a prevalence of 39 cases per 100 000. Leonhardt (1964) had studied SLE in the same area during the early 1960s, and this represented a tenfold increase in prevalence. An increased knowledge of the disorder with the diagnosis of milder cases and more sensitive diagnostic tests may have been responsible for this increase. A good prognosis was indicated by incidence in excess of mortality, high median age of sample and deaths occurring after 60 years of age.

Three of the most recent studies, all from Scandi- navia, have questioned the traditionally held belief that SLE principally afflicts young females. First a Finnish study examining hospital discharge records for the period 1972-78 showed highest prevalence rates for the 70-79 age group for both sexes (Helve, 1985). This could be a reflection of improved management and prognosis. However, a case register study of the population of Iceland for the period 1975-84 showed a peak incidence for females in the 50-74 age group (Gudmunsson and Steinsson, 1990). The female to male ratio was

ccc 08854230/94/020097-10 0 1994 by John Wiley & Sons, Ltd.

98 M. DENNIS

approximately 6: 1, the median age of diagnosis 50 years, with a mean diagnostic delay of 8.8 years and a 10-year survival rate of 78%. Interestingly, 25% of patients were managed solely outside hospital. A community survey of a southern Swedish population used multiple sources of retrieval (Jons- son et al., 1990). Case identification was from four sources: a computerized diagnosis register, referrals from primary care and from private practitioners, and records of ANA-positive individuals from the single laboratory serving the area. Highest incidence was for those aged 55-74.

SYSTEMIC LUPUS ERYTHEMATOSUS IN THE ELDERLY

The presentation of SLE in the elderly tends to be frequently insidious, often with a delay of some years between original symptoms and diagnosis. Font et al. (1991) found that the mean interval between the time of onset of symptoms and diagnosis was 5 years in the elderly group (over 50 years of age) compared to 3 years in younger adults. Simi- lar findings are reported by Cattogio et a1 (1984): 4 years for the elderly versus 2 years for younger adults. Many elderly patients are frequently diagnosed as suffering from other autoimmune disorders such as rheumatoid arthritis and polymyalgia rheumatica (Foad et al., 1972; Baer and Pincus, 1983). Baker et al. (1979) reported over 50% of their 31 patients over the age of 50 had been misdiagnosed, usually as suffering from rheumatoid arthritis.

There is also a general agreement that SLE in the elderly is a milder disease than in younger age groups (Hashimoto et al., 1987; Ballou et al., 1982; Hochberg et al., 1985), with longer periods of remission (Wilson et al., 1981).

Certain clinical features appear to be more pro- minent in the elderly than in younger age groups. Most studies have found serositis (pleuritis and pericarditis), arthritis, and muscle pain and weakness to be more typical of SLE in this age group than in younger patients (Catoggio et al., 1984; Baker et al., 1979; Hashimoto et al., 1987; Ballou et al., 1982; Wilson et al., 1981; Jonsson et al., 1988). Renal disease and cutaneous manifestations have frequently been found to occur less often in elderly patients (Font et al., 1991; Catoggio et al., 1984; Hashimoto et al., 1987; Wilson et al., 1981; Jonsson et af., 1988). There is a higher frequency of secondary Sjogren’s syndrome, and lower of Raynauld’s

phenomena in patients suffering from late onset SLE (Catoggio et al., 1984; Hochberg et al., 1985; Jonsson et al., 1988).

Studies have frequently shown little difference in the frequency of neuropsychiatric symptomatology between SLE presenting in young and in elderly patients (Ballou et al., 1982; Wilson et al., 1981; Jonsson et al., 1988). Baker et al. (1979) describe the clinical features of 31 patients with late onset SLE, only eight of whom had either psychosis or an organic brain syndrome. Gossat and Walls (1982), however, describe a case series of 14 patients who developed SLE after the age of 45. At some time during the course of their disease 13 of the patients had some neurological and/or psychiatric disturbance. In the comprehensive study conducted by Hochberg et al. (1985) at John Hopkins, Baltimore, a high incidence of neuropsychiatric abnormalities was detected in over half (55%) of the sample with no overall age differences apart from peripheral neuropathy, which was found to occur significantly more often in the elderly patients. In Font and colleagues’ study (1991), there was a low incidence of neuropsychiatric features at original presentation both in young and in elderly patients, rates increased during the follow-up period particularly in the younger group, but differences between the two age groups failed to reach significance. Catoggio et al. (1984) found that although the incidence of neuropsychiatric features was no different between the young and the elderly, they were an important presenting feature.

Besides clinical features, the more recent com- parisons of young and elderly onset SLE patients have examined the differences in immunological findings between the two groups. Antibodies to double-stranded DNA (dsDNA) are highly specific to SLE, but are found in decreased frequency in the elderly onset patient (Font et al., 1991; Catog- gio et al., 1984; Wilson et al., 1981; Jonsson et al., 1988). Hypocomplementaemia (C3 and C4 frac- tion) occurs during active disease, and is inversely correlated with age (Ballou et al., 1982; Wilson et al., 1981; Jonsson et al., 1988). Antibodies to cytoplasmic antigen anti-Ro (SSA) and anti-La (SSB) are found in increasing frequency in elderly patients presenting with SLE (Catoggio et al., 1984; Hashi- mot0 et al., 1987; Hochberg et al., 1985; Jonsson et al., 1988). These antibodies are found almost exclusively in connective tissue disease and only rarely in the normal population. Hochberg et al. (1985) found anti-Ro present in 47%, and Cattogio et al. (1984) in 92% of their elderly patients with

LUPUS ERYTHEMATOSUS 99

SLE. Anti-La was found in 31% and 61% of elderly patients respectively. In both these studies this was a significant difference from younger patients. As antibody to dsDNA is often absent in the elderly, the detection of antibodies to Ro (SSA) and La (SSB) represents a useful diagnostic aid in the laboratory diagnosis of SLE in the elderly. The incidence of rheumatoid factor also increases with age in patients with SLE, and this combined with the presence of chronic arthritis may make the distinc- tion between rheumatoid arthritis and SLE in some elderly patients particularly difficult (Catoggio et al., 1984; Wilson et al., 1981). Interestingly, Font et al. (1991) in Barcelona found an increased incidence of antiphospholipid antibodies in elderly onset patients (anticardiolipin antibodies, lupus anticoagulant or both). This may have particular relevance for the presence of NP-SLE in the elderly. Immunological investigations in elderly patients with SLE are summarized in Table 1.

Table 1 . Antibodies found in elderly patients with SLE

Antibody Comment

Nuclear antibodies Antinuclear antibody (A" Low specificity High titre

Double-stranded DNA Highly specific (dsDNA) Lower frequency in elderly

Extractable nuclear antigen (ENA) psychosis)

Present in 95% of cases of SLE

important

( < 50%) Includes Sm, RNP (linked with

Lower titres in SLE compared to MCTD

Cytoplasmic antibodies Anti-Ro (SSA) Common in elderly patients with

SLE, but not as specific as dsDNA Seen in ANA-ve SLE Frequently found in elderly, not as specific as dsDNA

Anti-La (SSB)

Antiphospholipids Anticardiolipin Responsible for +ve VDRL Lupus anticoagulant Linked to cerebral embolism and

thrombosis

There are two possibilities to explain the different clinical and serological patterns in older and younger patients. First, it may be a result of the ageing process in the immune system (Ford, 1986) and mucocutaneous tissues (Whaley et al., 1972).

Secondly, there may be different genetic determi- nants of disease and SLE may be triggered by different mechanisms. Evidence for the latter has come from the work of Hochberg et al(l985). Their data suggest the existence of two serologic-genetic subsets of SLE with different ages at diagnosis. HLA- DR2 was associated with the presence of anti-Ro (SSA) antibody, while HLA-DR3 was associated with the presence of both anti-Ro (SSA) and anti- La (SSB) antibody. In whites, the frequency of both anti-Ro (SSA) and anti-La (SSB) increased with increasing age as did that of HLA-DR3. HLA-DR2 was more frequent in those with early onset disease. Interestingly, other studies have shown that the presence of anti-Ro (SSA) antibody and anti-La (SSB) antibody together in the serum of SLE patients is rarely associated with significant renal disease (Maddison et al., 1981; Wasicek and Reich- lin, 1982). We have seen earlier that most studies of the elderly have shown a decreased incidence of renal disease.

NEUROPSYCHIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS (NPSLE)

The recognition and treatment of the neuropsychiatric manifestations of SLE remains one of the most difficult challenges in the management of the disorder. Early recognition and intervention is essen- tial to forestall other, potentially more severe neurological problems (McCune and Golbus, 1988). The severity and duration of individual neuropsychiatric episodes ranges from the mild and transient to the severe and progressive (Bresnihan, 1982). Neuropsychiatric problems in SLE frequently occur early in the course of the illness, and may precede other typical features of SLE by several years (Feinglass et al., 1976; Ward and Studenski, 1991; Bennet et al., 1972).

Between 50 and 66% of patients suffering from SLE experience neuropsychiatric problems at some time during their illness (McCune and Golbus, 1988; Bluestein, 1987). The clinical manifestations of CNS SLE are very diverse, and can be either primary as a direct result of immunopathological mechanisms on the CNS or secondary to disease of other organs or complications of therapy. Secondary events are often as a result of uraemia, hypertension or electrolyte imbalance in nephritis or as a result of superimposed infection. There is a third group, namely functional psychiatric dis-

I00 M. DENNIS

order caused by the psychological and social stress of disease (Hay et al., 1992).

Neuropsychiatric manifestations of SLE are often divided into groups explainable in terms of focal or non-focal pathology (Table 2). Seizures are often classed separately (McCune and Golbus, 1988). By far the commonest neuropsychiatric com- plication of SLE is an organic brain syndrome, usually a transient acute or subacute confusional state and occasionally dementia (Bresnihan, 1982; Feinglass et al., 1976; Bennet et al., 1972; Bluestein, 1987). Recent studies which have concentrated specifically on the presence of cognitive impairment in patients suffering from SLE have shown prevalence rates of 55-66% (Hay et al., 1992; Carbotte et al., 1986; Long et al., 1990). These high rates of cognitive impairment are significant obser- vations. They could not be explained by treatment with steroids or psychological stress, and a high proportion of patients had no current or previous neuropsychiatric symptomatology . Cognitive function in these studies was assessed psychometrically, and included the Wechsler Adult Intelligence Scale (WAIS), Benton Visual Retention Test and Wechsler Memory Scale. The studies based at McMaster University, Ontario (Carbotte et al., 1986; Long et al., 1990) defined cognitive impairment as a score of more than two standard deviations below a derived estimate of the individual’s premorbid level. Hay et a1 (1992) classified a WAIS score as abnormal if the difference between the ver- bal and performance scores, adjusted for age, was more than two standard deviations from the mean value for normal subjects. These studies indicate a high prevalence of subclinical involvement of the central nervous system.

Psychosis, commonly schizophreniform, and depression are also common in SLE (Bresnihan, 1982; Feinglass et al., 1976; Bennet et al., 1972; Buchbinder et al., 1988). In Hay’s study (Hay et al., 1992), functional psychiatric disorder was identified in 15 patients from a sample of 73 (20.5%). Eight patients were suffering from depression, six anxiety and one paranoid psychosis. There was no association with CNS disease, general activity or steroid treatment, but a significant association with measures of stress and social support.

Seizures have been reported in 15-35% of patients with SLE (McCune and Golbus, 1988). Virtually any type of seizure may occur. Genera- lized convulsions are the most common, reflecting diffuse involvement of the central nervous system. Complex partial, focal and petit ma1 seizures are

Table 2. Neuropsychiatric features of SLE

Diffuse Acute and subacute confusional states Dementia Depression Psychosis

Seizures Generalized Partial

Focal Stroke TIAs Cranial and peripheral neuropathy Transverse myelitis Chorea Parkinsonism

also seen. Seizures may appear in isolation preced- ing other manifestations of illness (Feinglass et al., 1976) or accompany another neurological event such as stroke, haemorrhage or psychosis (Carbotte et al., 1992).

Other manifestations of neurological disorder reflect focal disease. Cranial and peripheral neuropathy, and stroke are all common. Movement disorders such as chorea, cerebellar ataxia and Parkinsonian features, although rare, have all been reported in patients with SLE.

There is no diagnostic test for neuropsychiatric SLE. Non-specific pathological changes occur in the cerebrospinal fluid (CSF), on electroencephalo- graphy (EEG) and neuroimaging. There may also be particular immunological associations with certain focal and non-focal manifestations of the disorder.

The abnormalities that are detected within the CSF in patients with neuropsychiatric SLE are elevated cell counts and protein and decreased levels of complement C4 (Bresnihan, 1982; Feinglass et al., 1976; Bennet et al., 1972). The most common EEG finding is a generalized non-specific diffuse slowing (70-800/0 of patients). EEG changes have failed to differentiate patients with active CNS disease from other patients without clinically detec- table CNS involvement (Bresnihan, 1982; Feinglass et al., 1976).

The detection of brain atrophy and focal lesions is best achieved by computerized tomography (CT) scanning or magnetic resonance imaging (MRI). There is a general agreement that CT scanning is insensitive in NP-SLE in comparison to MRI (Car-


botte et al., 1992; McCune and Golbus, 1988). The commonest finding on CT scanning is a mild cerebral atrophy. Focal changes of infarct and haemorrhage are less common, and frequently CT scans fail to detect changes in patients who clinically have evidence of localized brain pathology (Bilanuik et al., 1977; Carette et al., 1982; Kaell et al., 1986). Not only does MRI accurately identify focal lesions, but Bell et al. (1991) found that in patients with non-focal disease there appear to be areas of increased signal intensity which are subcor- tical and larger and more numerous than in patients with focal CNS lupus. These changes did not correspond to the territory of any major vessel, were associated with elevated levels of antineurofilament antibodies, and resolved after treatment with high- dose steroids. Functional imaging techniques may also have a role in the identification and understanding of central nervous system involvement in SLE. Single-photon emission computed tomography (SPECT) is highly sensitive in detecting regional cerebral blood flow (rCBF). Nossent et al. (1991) found SPECT scanning had good sensiti- vity in patients suspected of NP-SLE, but there was no correlation between SPECT findings and overall disease activity or immunological findings. Studies of glucose metabolism using positron emission tomography (PET) have identified areas of altered cerebral metabolism even when there are no structural lesions on MRI (Hiraiwa et al., 1983; Stoppe et al., 1990). In a small case series, Carbotte et al. (1992) found that not only did I8F-deoxyglu- cose (FDG) uptake abnormalities correspond with localizable cognitive deficits, but changes in cognitive function were simultaneously mirrored by PET changes.

The clinical manifestations of SLE suggest two different pathological processes; diffuse and potentially reversible as in the case of confusional states and psychosis, and multifocal in cranial and peripheral neuropathies, stroke, epilepsy and movement disorders. The underlying causes of these clinical presentations are not fully established, but it is believed that the classical immune mediated vasculitis accounts for focal changes. Immune complex deposition leads to tissue destruction and vascular disruption which subsequently leads to haemorrhagic and ischaemic zones (Moskowitz, 1989). Focal and generalized seizures have a high correlation with areas of cortical infarction, or intracerebral or subarachnoid haemorrhage secondary to small vessel pathology (Johnson and Richardson, 1968). Increased risk of cerebral

thrombosis has also been linked to the presence of antiphospholipid antibodies-anticardiolipin antibody and lupus anticoagulant (McCune and Golbus, 1988; Hughes, 1983). Bell et al. (1991) found that patients with MRI evidence of focal CNS lupus had elevated anticardiolipin antibody and lupus anticoagulant compared to patients with diffuse CNS lupus.

In recent years, research has concentrated on establishing the pathological mechanisms involved in the more common and potentially reversible diffuse process. Autoantibodies are thought to act on neuronal membrane antigens. The evidence for IgG antineuronal antibody is still inconclusive (Blues- tein, 1987; Bell et al., 1991; Bresnihan et al., 1979). However, there is good evidence linking other antibodies with specific manifestations of diffuse NP- SLE. IgM lymphocytotoxic antibody has been implicated in cognitive impairment (Long et al., 1990), and antiribosomal protein antibody in psychosis (Bonfa et al., 1987).

NEUROPSYCHIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS AND PSYCHIATRY

OF THE ELDERLY

There have been very few descriptions of patients presenting to either general or elderly psychiatric services. It is only over recent years that clinicians have become more confident in making the diagnosis as the diversity of presentation and severity becomes more publicised. In 1969, Chynoweth and Foley reported a series of three patients with dementia who responded to steroid therapy. Diag- nosis was uncertain, though they did suggest colla- gen-vascular disorder was a possibility. It is more likely that retrospectively these were cases of NP- SLE. Poulson (1983) also described a series of four patients who had a steroid-sensitive dementia, at least one of whom had SLE. More recently, Green described two cases of NP-SLE, both originally labelled as ‘hysterical’ and diagnosed as affective disorder, who subsequently developed movement disorder and cognitive impairment (Green, 1989, 1991). In a project specifically designed to screen for undiagnosed SLE in acute psychiatric admissions of all ages, Hopkinson et a1 (1992) detected three cases-two aged 78 and one 54. This represented 1% of admissions. Dennis et al. (1992) reported five elderly patients presenting with NP- SLE who were referred to a sectorized elderly psychiatric service. They represented 2% of patients

102 M. DENNIS

admitted over a period of 2 years. Two patients presented with a subacute confusional state, two with dementia and one with depression. Three patients responded well to treatment. All but one of the patients had antibodies to double-stranded DNA, a test which is highly specific for SLE. In the other case, a drug-induced syndrome was con- sidered, but this was felt unlikely in view of the response to steroids and that organic mental syndromes are rare in drug-induced SLE. Interestingly, however, all cases only satisfied three of the Ameri- can Rheumatism Association’s criteria.

The paucity of literature specific to neuropsychiatric SLE in the elderly is not surprising when we consider some of the factors outlined earlier. There may be difficulty in making the diagnosis for a variety of reasons. CNS symptoms frequently occur in isolation and early in the course of the illness, therefore dementia and acute or subacute confusional states may be attributed to other pathological processes. In the case series described by Dennis et al. (19921, three patients had either focal CT changes suggestive of infarct or history of a discrete neurological event such as stroke or transient ischaemic attack which to the unwary might have led to a diagnosis of vascular dementia. The features of chronic arthritis, muscle pain and weakness are common in the elderly, and may be associated with rheumatoid factor. Therefore, despite the presence of cognitive impairment or other neuropsychiatric features, a diagnosis of rheumatoid arthritis or polymyalgia rheumatica may be made without consideration of the possibility of SLE.

There may also be difficulty in interpreting immunological indicators of disease. Lymphopae- nia is non-specific and often accompanies common medical conditions seen in the elderly such as acute infection, malnutrition, depression and even Alz- heimer’s disease (Moran, 1981; Tollefson et al., 1989; Schleifer et al., 1985). The total peripheral lymphocyte count falls with ageing as a result of reduction in circulating T-cells (De Paoli et al., 1988; Alexopoulos and Babitis, 1976; Augener et al., 1976). The presence of an abnormal titre of antinuclear antibody (ANA) could also be mislead- ing, as the titre has a tendency to be more positive in elderly patients (Hooper et al., 1972). Antibodies to double-stranded DNA (dsDNA) are highly specific to SLE, but are seen less frequently in the elderly (Font et al., 1991; Catoggio et al., 1984; Wilson et al., 1981; Jonsson et al., 1988).

Another reason for the shortage of literature on NP-SLE in the elderly is the inadequacies of the

American Rheumatism Association’s criteria (ARA criteria) when dealing with this population (Table 3). These are comprised of both clinical and laboratory characteristics of SLE, and at least four of 11 are required to be present serially or simultaneously for a definite diagnosis to be made (Tan et al., 1982). The criteria have been used extensively in all areas of clinical and epidemiological research in SLE. Others have already suggested that the ARA criteria are too strict for making the diagnosis in patients presenting with neuropsychiatric illness and that more weight should be placed on lupus serology (Markusse and Vecht, 1986). The ARA criteria also have a very narrow definition of neurological disorder which consists of only seizures or psychosis. Therefore, organic brain syndromes and the presence of cognitive impairment, as well as depression, are excluded from the criteria. Cuta- neous manifestations are less common with increasing age, yet they account for four of the 11 criteria.

Table 3. The 1982 revised criteria for the classification of systemic lupus erythematosus

Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis (non-erosive) Serositis (pleuritis or pericarditis) Renal disease (persistent proteinuria or cellular casts in the urine) Neurological disorder (seizures or psychosis) Haematological disorder (haemolytic anaemia or leucopenia or lymphopenia or thrombocytopenia) Immunological disorder (LE cells or anti-DNA or anti-Sm or false positive serologic test for syphilis) Antinuclear antibody

In view of the recent epidemiological findings of a peak incidence of SLE in the 55-75 age group and reports of elderly patients presenting with neuropsychiatric SLE to mental health services, it appears that SLE in this population is more common than originally thought. Research in this area needs to be encouraged. In order to study the mechanisms involved and to improve upon clinical management of the disease there need to be better criteria for diagnosing neuropsychiatric systemic lupus erythematosus (Kassan and Lockshin, 1979). At a recent consensus conference it was suggested that global cognitive dysfunction and possibly


transverse myelitis should be added to the ARA criteria for neurological/psychiatric involvement (Singer and Denburg, 1990). Besides clinical features, classification could include psychometric testing, magnetic resonance imaging (MRI) or the presence of certain autoantibodies. In the wider study of SLE in the elderly, broader diagnostic criteria such as those suggested by Fries and Holman might be more appropriate (Fries and Holman, 1978). These require evidence of a typical multisystem disorder in combination with immunological abnormalities in the absence of any alternative diagnosis.

For the purposes of clinical practice there are a number of laboratory features that should alert the psychiatrist to the possibility of SLE in elderly patients. Although lymphopaenia is a common finding among an elderly inpatient population (Nicolson et al., 1993), its presence is an indicator for further investigation, especially if accompanied by a raised erythrocyte sedimentation rate (ESR) (Hopkinson et al., 1992; Dennis et al., 1992). Screening for SLE would include an autoantibody screen and assay for antibody to double-stranded DNA (dsDNA). Antinuclear antibody (ANA) is present in 95% of cases, of SLE, but has low specificity. Hopkinson et al. detected the presence of antinuclear antibody in 8% of acute psychiatric admission, but this was generally of low titre (Hop- kinson et al., 1992). Although antibody to dsDNA is highly specific for SLE, it is frequently absent in the elderly. Under these circumstances it may be worthwhile testing for the presence of other antibodies such as antibody to extractable nuclear antigen (ENA) and to the cytoplasmic antigens anti-Ro (SSA) and anti-La (SSB). The latter are found in increasing frequency in the elderly, and CNS disease is rarely found in other connective tissues disorders (Hochberg et al., 1985). A positive VDRL should also raise the possibility of SLE, as anticardiolipin antibody can give a false result (Hughes, 1983).

Once a diagnosis of NP-SLE has been confirmed, other tests may be important. In the case of focal CNS involvement, where embolism or cerebral thrombosis is suspected tests for the antiphospholipid antibodies (anticardiolipin and lupus anticoagulant) should be performed (Hughes, 1983; Devinsky et al., 1988).

Besides longitudinal evaluation of clinical neuropsychiatric features such as the presence and degree of cognitive impairment, certain immunological markers may be useful for monitoring disease

activity. ESR, in conjunction with C-reactive protein (CRP) levels, can help to distinguish between exacerbation of disease and infection. A raised ESR could indicate either, but CRP in the absence of serositis is less elevated in disease exacerbation than infection (Borg et al., 1990). Low plasma complement levels (C3, C4) can be used as an approximate indicator of increasing disease activity, and C3 degradation products (C3d) are a sensitive measure of complement activation and are useful in the diagnosis and monitoring of patients with SLE (Mor- row et al., 1983). If available, anti-ribosomal P protein (anti-RNP) antibody levels may be useful specifically in psychosis (Bonfa et al., 1987).

In view of the fact that some drugs encountered in psychogeriatric practice such as L-dopa, chlor- promazine and phenytoin have been linked to lupus-like syndromes, differentiation between drug-induced and idiopathic SLE is important. CNS involvement in drug-induced SLE is, however, rare, and symptoms respond not to steroids but to stopping the causative agent. In a drug- induced syndrome complement C3 and C4 levels are usually normal, antibody to dsDNS is absent, and antihistone antibody is present (Byron and Hughes, 1987).

TREATMENT

The treatment of NP-SLE in the elderly can be divided into symptomatic directed management and treatment of the underlying disorder. Psychotic patients should receive neuroleptic medication, and similarly prompt treatment of seizures should be initiated with anticonvulsants.

Despite the lack of controlled trials, case reports suggest that corticosteroids are indicated and help- ful in NP-SLE (Adelman et al., 1986). The elderly rarely need more than 0.5 mg per kg weight per day of oral prednisolone. The dose regime used by Dennis et al. (1992) was 20-30 mg of prednisolone daily. However, steroid treatment is not without difficulties. In a large review of adult patients of all ages, receiving steroids for various medical conditions, psychiatric syndromes were reported in 5%; female sex, SLE and high-dose steroid (more than 25 mg prednisolone a day) were all factors associated with increased risk (Lewis and Smith, 1983). One of the problems in this area is differen- tiating complications of steroid therapy from a primary manifestation of NP-SLE. Hay et al. (1992) found no association between corticosteroid ther-

104 M. DENNIS

apy and the presence of cognitive impairment and psychiatric disorder, and Buchbinder et al. (1988) concluded that psychiatric symptoms in their case series were more commonly due to cerebral involvement than steroid therapy. Steroids, however, may be associated with an increased risk of infection, and possible myocardial infarction (Adelman et al., 1986).

There has been no real evaluation of the use of other immunosuppressive agents in the management of NP-SLE. Azathioprine and cyclophosphamide have been used to allow replacement of or a reduction in corticosteroid dose (Dennis et al., 1992; Adelman et al., 1986). Azathioprine is less toxic than cyclophosphamide, and therefore may be preferable for use in the elderly, though monitoring of full blood count is still required.

PROGNOSIS

Due to the paucity of knowledge specifically relat- ing to NP-SLE in the elderly, comments concerning prognosis refer to NP-SLE generally. Feinglass et al. (1 976) reported that 84% of episodes of NP-SLE resolved completely or partially, and that corticosteroids were of benefit. However, recent evidence suggests that the presence of NP-SLE is associated with a poorer prognosis. In a 6-year follow-up study of a Caucasian cohort, Jonsson et al. (1989) reported that patients with repeated exacerbations in illness had a high frequency of neuropsychiatric disease. Serological features often associated with severe disease such as antibodies to dsDNA, anticardiolipin antibodies and hypocomplementaemia were commonly seen in patients with neuropsychiatric manifestations. Seven out of nine patients that died during the study period had neuropsychiatric disease, and they concluded that the need for long- term treatment can be underestimated. In a study of 35 patients with NP-SLE, Buchbinder et al. (1988) found that most also had evidence of severe systemic disease and a high proportion of renal and haematological abnormalities. The high mortality in this group (30% in l year) was related to systemic disease rather than specific neuropsychiatric features.

Patients with focal disease also appear to be non- responsive to steroids and have a less favourable outcome compared to those with evidence of a diffuse disorder (Kaell et al., 1986 Bell et al., 1991). In the series of five elderly patients presenting with NP-SLE described by Dennis et al. (1992), three

patients had a good response to steroids, two of whom had evidence of focal disease. However, these two patients were also suffering from an organic brain syndrome and presumably steroids were acting on a concurrent diffuse pathology.

CONCLUSIONS

Recent reports concerning the epidemiology of SLE suggest that the disorder is more common in the elderly than originally thought. There is a high incidence of organic brain syndromes and functional psychiatric disorder in patients with SLE, and neuropsychiatric symptoms may appear in isolation before other manifestations of the disease. Most importantly, SLE is a potentially treatable cause of organic brain disorders. Psychiatrists working with the elderly need to be alert to the possibility of seeing patients with undiagnosed SLE. In patients with lymphopaenia, raised ESR and/or antinuclear antibody, it is advisable to per- form more specific serological investigations for SLE.

There is a need for further general research on NP-SLE in old age, and more specifically into organic brain disorders. Studies will require the development of more appropriate criteria for this population. Areas of particular interest are immunological associations, the application of the newer neuroimaging techniques, and the evaluation of treatment and outcome.

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