Acute psychosis in systemic lupus erythematosus

To evaluate the frequency and risk factors of acute psychosis in a large cohort of patients with systemic lupus erythematosous (SLE). To identify clinical and laboratory variables useful in differentiating acute psychosis as a primary manifestation of central nervous system (CNS) from corticosteroid induced psychosis. Five hundred and thirty seven consecutive patients with SLE were studied, with follow-up ranging from 4 to 8.8 years. A standardized medical history, neurological, rheumatologic, and psychiatric examinations and serologic testing were performed in all patients. The type and frequency of risk factors associated with acute psychosis as a primary manifestation of CNS system and corticosteroid induced psychosis was determined using multivariate regression with automatic backward stepwise selection. We identified acute psychosis in 89 of 520 (17.1%) SLE patients. Psychosis primary to CNS involvement was diagnosed in 59 of these patients, corticosteroid induced psychosis in 28 and primary psychotic disorder not related to SLE or medication in two patients. Psychosis secondary to SLE at disease onset occurred in 19 patients and was associated with disease activity (p = 0.001; OR = 2.4; CI = 1.5-6.2). Psychosis during follow-up of SLE was observed in 40 patients and associated with positive antiphospholipid antibodies (p = 0.004; OR = 3.2; CI = 1.9-4.5) and less frequently with renal (p = 0.002; OR = 1.9; CI = 0.0-0.6) and cutaneous (p = 0.04; OR = 1.1; CI = 0.0-0.8) involvement. We identified 28 patients with 38 episodes of psychosis associated with corticosteroid therapy. All the patients had severe active disease and ten of these patients had hypoalbuminemia when psychosis developed. At the time of psychotic event, all the patients were taking prednisone in doses varying from 0.75 to 1 mg/kg day(-1). Psychosis resolved after tapering prednisone down in all patients. Acute psychosis related to SLE was observed in 11.3% of our cohort. Recurrence of primary psychosis was associated with other CNS manifestations related to SLE.     

Psychopathology in systemic lupus erythematosus. II. Relation to clinical observations, corticosteroid administration, and cerebrospinal fluid C4

A consecutive series of 17 patients with SLE were studied psychiatrically in a prospective manner with semistructured interview techniques and mental status observation. Patients with and without psychiatric syndromes complicating their SLE were compared as to neurological observations, laboratory test findings, and corticosteroid administration.There was no correlation between psychopathology and either the severity of SLE (as judged by laboratory tests), the degree of renal impairment, or the associated nonpsychiatric central nervous system manifestations. Analysis of CSF C4 in four patients with psychiatric syndromes did not support the hypothesis that immunological mechanisms underlie the psychiatric manifestations of SLE.Eleven discrete episodes of significant psychopathology were noted in seven patients. This group did not differ significantly from those patients without psychiatric illness as regards the interval since corticosteroid therapy was initiated, the minimum and maximum dosages, whether it had ever been possible to terminate corticosteroid therapy, and the dosage of corticosteroids at the time of index admission.Detailed consideration of the events in corticosteroid therapy surrounding the episodes supports the contention that systemic lupus erythematosus itself is the cause of the large majority of the psychiatric manifestations. Therefore, in most individual patients, the dosage of corticosteroids should not be reduced because of the development of psychiatric symptomatology, especially in those patients who either develop psychiatric syndromes at a time other than immediately following an increase in steroid administration.     

Ocular complications in renal transplant recipients

The ocular complications in renal transplant recipients were evaluated in 44 patients and in 22 control patients with renal failure. Of the 44 patients 33 showed some ocular abnormality, but only posterior subcapsular cataracts which occurred in 34 per cent of post-transplant patients could be related to post-transplant corticosteroid therapy. There was no correlation between posterior subcapsular cataracts and either the duration of daily doses or total doses of corticosteroids in patients under 25 years of age in whom the incidence of posterior subcapsular cataracts tended to be higher than in older patients. There appeared to be a significant correlation between the duration of therapy and the total corticosteroid dose and the incidence of posterior subcapsular cataracts in the older age group.     

Circulating DNA in systemic lupus erythematosus. Association with central nervous system involvement and systemic vasculitis.

Circulating double-stranded DNA (dsDNA) in the form of immune complexes has long been thought to play an important pathogenetic role in systemic lupus erythematosus (SLE) glomerulonephritis. However, attempts to demonstrate circulating DNA in patients with SLE have led to conflicting conclusions, largely for technical reasons. Using methods designed to avoid these limitations it was previously shown that circulating DNA occurs infrequently if at all in normal subjects. Surprisingly, the same was reported to be true of unselected patients with SLE although sensitivity of the assay used was relatively low. Preliminary experiments in this laboratory, using an assay with improved sensitivity, suggested an association between circulating dsDNA and the relatively uncommon SLE manifestations of vasculitis and/or central nervous system (CNS) involvement. In the present study the possibility on this association was explored by prospectively classifying patients with active SLE into those with systemic vasculitis, CNS involvement or neither. Patients with other clinical states which themselves are known or believed to be associated with circulating DNA were excluded. Multiple plasma specimens from each patient were examined by a modified counterimmunoelectrophoresis (CIE) assay capable of detecting 20 to 50 ng/ml of dsDNA. Patients were considered to have circulating dsDNA only when the latter was demonstrated on multiple separate occasions. Of 20 patients with CNS involvement and/or systemic vasculitis, 16 had persistently circulating DNA. In contrast, one of 18 patients with active SLE but without these manifestations demonstrated circulating DNA, a highly significant difference. This association was also seen in longitudinal studies of four individual patients with SLE who had multiple episodes of activity, some of which included CNS involvement or vasculitis. Circulating dsDNA was not found in patients with active systemic inflammation alone or in those receiving corticosteroids or cytostatic agents. Similarly, differences in the prevalence of anti-dsDNA antibodies between the patient groups could not account for the results. Hence, it is concluded that persistently circulating dsDNA occurs specifically in patients with SLE who have vasculitis and CNS involvement. Furthermore, the prevalence of circulating dsDNA in patients with active SLE who lack these manifestations appears to be negligible within the limits of the assay used. Possible pathogenetic implications of these results are discussed.     

Elevated levels of cerebrospinal fluid guanosine 3',5'-cyclic monophosphate (C-GMP) in systemic lupus erythematosus.

Cerebrospinal fluid samples from patients with systemic lupus erythematosus (SLE) and neurologic involvement were evaluated for guanosine 3',5'-cyclic monophosphate (C-GMP) and cyclic adenosine monophosphate (C-GMP) content by radioimmunoassay and radioassay, respectively. Twenty-five samples from 15 patients with SLE had an average C-GMP level of 2.4 nM +/- 0.44 (average +/- SE) compared with 0.68 nM +/- 0.14 in a control group with lumbosacral pain (p less than 0.0002). No significant difference was noted in C-AMP content between patients with SLE and control subjects. C-GMP levels in cerebrospinal fluid samples from patients with SLE who had changing neurologic disease were higher than in those with stable neurologic disease. Elevated C-GMP levels in cerebrospinal fluid correlated with the leukocyte number in cerebrospinal fluid (r = 0.53 p less than 0.01), but not with the initial pressure, protein concentration or daily prednisone dosage. Experimental results suggested that leukocytes in the cerebrospinal fluid were not the source of elevated C-GMP levels. Thus, elevated C-GMP levels in cerebrospinal fluid of patients with SLE appeared to reflect neurologic involvement. C-GMP levels were alos found to be elevated in five patients with other active neurologic diseases; thus, measurement of C-GMP in cerebrospinal fluid may have more general diagnostic value.     

Intrathecal IgG synthesis and blood-brain barrier impairment in patients with systemic lupus erythematosus and central nervous system dysfunction

Paired serum and cerebrospinal fluid specimens from 19 patients with SLE and central nervous system dysfunction were studied with respect to cerebrospinal fluid IgG index (a measure of intrathecal IgG synthesis), isoetectric focusing using immunoperoxidase staining techniques to detect ollgoclonal IgG, and determination of the cerebrospinal fluid/serum albumin quotient (Q albumin) as a measure of blood-brain barrier integrity. Twenty-five patients without neurologic disease and 70 patients with a variety of non-SLE neurologic disorders were also studied for comparison. Of most interest was the observation that 42 percent of the patients with SLE had cerebrospinal fluid ollgoclonal IgG, usually in association with elevation of the cerebrospinal fluid IgG index. In addition, two of the cerebrospinal fluid specimens that exhibited oligoclonal IgG also had increased titers of alpha-lnterferon. Q albumin was normal (under 9.0) in 12 of 13 patients with SLE, who had seizure, psychosis, or cranial neuropathy as principal central nervous system manifestations (mean ± SD = 5.3 ± 2.4), but was significantly elevated (mean ± SD = 27.4 ± 18.8, p < 0.001) in five of six patients with diffuse, major central nervous system injury, for example, encephalopathy with coma, transverse myetopathy, paraparesis. Blood-brain barrier impairment was not correlated either with presence of circulating immune complexes or with other clinical or serologic evidence for extra-central nervous system disease activity. Taken together, the data suggest that, within the limitations of the techniques used, impairment of the blood-brain barrier in SLE may be secondary to the central nervous system lesion, rather than a result of systemic immune complex injury. In addition, substantial evidence is provided for an ongoing humoral immune response within the central nervous system in this disorder, which, in certain patients, may be associated with the production of intrathecal alpha-interferon.     

Constrictive pericarditis in procainamide-induced lupus erythematosus syndrome

A rare case of constrictive pericarditis in procainamide-induced lupus erythematosus syndrome is reported. After 6 months of procainamide therapy fever, pleuritic chest pain, arthralgia and muscle soreness developed in a 47 year old man. These symptoms were soon followed by the onset of acute pericarditis and rapidly accumulating massive pericardial effusion. After withdrawal of procainamide therapy and administration of corticosteroids in large doses, there was marked subjective improvement and rapid reduction in pericardial effusion. However, constrictive pericarditis with massive leg edema and ascites developed 6 weeks after admission as corticosteroid therapy was gradually discontinued. These manifestations subsided after pericardiectomy was performed.     

Neurologic manifestations of systemic vasculitis: A retrospective and prospective study of the clinicopathologic features and responses to therapy in 25 patients

A combined retrospective and prospective study of a patient population with either or both biopsy and angiographic evidence of systemic necrotizing vasculitis was undertaken in order to delineate the neurologic manifestations of this syndrome. The type, extent and natural history of the lesions in the peripheral and central nervous system were evaluated, together with the response of the nervous system disease to corticosteroids or cytotoxic agents or both. In 60 percent of the patients, there was involvement of the peripheral nervous system. Four patterns of neuropathy were seen: mononeuritis multiplex, extensive mononeuritis, cutaneous neuropathy and polyneuropathy. The central nervous system was involved in 40 percent of the patients, manifested predominantly by diffuse and focal disturbances of cerebral, cerebellar and brain stem function. This study demonstrates the complexity and heterogeneity of the neurologic complications of the systemic necrotizing vasculitides. With treatment of the vasculitic process and prevention of further insult, both the peripheral and central nervous system make significant, and at times, dramatic, recovery.     

Lupus pregnancy. Case-control prospective study demonstrating absence of lupus exacerbation during or after pregnancy

To assess whether pregnancy is associated with exacerbation of systemic lupus erythematosus (SLE), a variety of clinical markers of disease activity in 28 pregnant patients with SLE (33 pregnancies) were compared with the same markers in age-, race-, organ system-, and disease severity-matched nonpregnant women with SLE. Both groups were followed up for periods of up to one year after delivery. Eight patients elected abortion for nonmedical reasons. In all patient groups, there were no differences between pregnant and nonpregnant patient groups in frequency of any disease activity marker studied including therapy. However, new proteinuria occurred in four pregnant patients compared with one nonpregnant patient, and thrombocytopenia attributable to SLE occurred in five pregnant patients and one nonpregnant patient. Renal disease, when it occurred, more closely resembled pregnancy-induced hypertension than lupus nephritis. It is concluded that pregnancy complications are frequent, but the assertion that pregnancy causes exacerbation of SLE remains unproved.     

Psychiatric disorder and cognitive impairment in systemic lupus erythematosus.

OBJECTIVES. To determine the point prevalence of psychiatric disorder in patients with systemic lupus erythematosus (SLE). To investigate associations between psychiatric disorder and social stress, cognitive impairment, systemic disease activity, and corticosteroid therapy. METHODS. A cross-sectional study of 73 consecutive patients with SLE assessed using standardized psychiatric and clinical research methods. RESULTS. Current psychiatric disorder was present in 15 patients (20.5%) and was significantly associated with social stress, lack of social support, and impairment on 2 tests of cognitive function (Verbal Fluency Test and Benton Visual Retention Test, Part A, number of errors). There was no association with systemic disease activity or corticosteroid therapy. Cognitive impairment on 2 or more tests was found in 26% and was associated with clinical evidence of central nervous system (CNS) disease, but not systemic disease activity or corticosteroid therapy. CONCLUSIONS. The point prevalence of psychiatric disorder in this cohort of patients with SLE was found to be similar to that observed in patients with rheumatoid arthritis. It was independently associated with social stress and 2 indicators of cognitive impairment, but not with systemic disease activity or corticosteroid therapy. Marked cognitive impairment was present in a significant percentage of patients even when there was no overt evidence of CNS involvement.     

Organic brain syndrome in rheumatoid arthritis following corticosteroid withdrawal

Six patients with seropositive nodule-forming rheumatoid arthritis developed severe central nervous system manifestations consistent with a diagnosis of organic brain syndrome. Organic brain syndrome occurred while 5 of these patients were undergoing corticosteroid withdrawal after prolonged administration. Neuropsychiatric symptoms rapidly cleared, responding to reinstitution of oral or parenteral corticosteroids in large doses in 4 patients, to increase in dosage in 1 patient, and to no drug therapy in the remaining 1. Marked reduction in rheumatoid factor in sera and demonstration of IgM deposits in the choroid plexus in 1 of the patients raised the possibility of immune complex-mediated central nervous system vasculitis.     

Association of IgG Anti-Brain Antibodies with Central Nervous System Dysfunction in Systemic Lupus Erythematosus

Sera from 20 patients with systemic lupus erythematosus (SLE) and active central nervous system (CNS) dysfunction were examined by indirect immunofluorescence for antibodies to neuronal membrane determinants. Warm-reactive IgG antibodies were demonstrable in 82% (9/11) of patients with clinical evidence for seizures or diffuse CNS disease, but these antibodies generally were absent in non-CNS SLE sera or when focal neurologic deficit or psychosis was the primary CNS manifestation. Cold-reactive antibodies of the IgM class were equally prevalent in patients with or without CNS disease and appeared to be more directly correlated with extra-CNS systemic illness. Absorption experiments with lymphocytes, brain homogenate, and various other tissues suggested a predominant brainspecificity for IgG antibodies and partial lymphocyte cross-reactivity for IgM antibodies. Interpretations of this special association between IgG anti-brain antibodies and diffuse CNS dysfunction in SLE are discussed.     

Association of IgG anti-brain antibodies with central nervous system dysfunction in systemic lupus erythematosus.

Sera from 20 patients with systemic lupus erythematosus (SLE) and active central nervous system (CNS) dysfunction were examined by indirect immunofluorescence for antibodies to neuronal membrane determinants. Warm-reactive IgG antibodies were demonstrable in 82% (9/11) of patients with clinical evidence for seizures or diffuse CNS disease, but these antibodies generally were absent in non-CNS SLE sera or when focal neurologic deficit or psychosis was the primary CNS manifestation. Cold-reactive antibodies of the IgM class were equally prevalent in patients with or without CNS disease and appeared to be more directly correlated with extra-CNS systemic illness. Absorption experiments with lymphocytes, brain homogenate, and various other tissues suggested a predominant brain-specificity for IgG antibodies and partial lymphocyte cross-reactivity for IgM antibodies. Interpretations of this special association between IgG anti-brain antibodies and diffuse CNS dysfunction in SLE are discussed.     

Ribosomal P antibodies and CNS lupus

Within two years of the recognition of autoantibodies to ribosomal P proteins in patients with systemic lupus erythematosus (SLE) an association with anti-P autoantibodies with psychosis was noted. While there has been some controversy about this association, ample evidence suggests a meaningful relationship between anti-P antibodies and central nervous system (CNS) disease. This evidence consists of 1) seven independent studies showing a strong relationship between anti-P antibodies and CNS disease; 2) longitudinal studies showing fluctuations of anti-P antibodies with episodes of psychosis; 3) correlation of anti-P antibodies with general disease activity; and 4) acid eluates form lupus renal tissue were found to contain anti-P antibodies enriched 30-fold with respect to their specific activity in serum heralding a direct role of anti-P antibodies in disease expression. Finally, there is evidence that the P protein resides on normal cells in an immunologically accessible way and evidence exists that anti-P antibodies are able to bind and penerate cells in culture, and once inside cells can affect a profound inhibition of protein synthesis in living cells. Taken together, these observations provide evidence linking anti-P antibodies to various forms of CNS disease. While this is true, there are other autoantibodies in SLE patients such as anti-dsDNA and antiglial fibrillary protein which may also play a role in the CNS disease of SLE patients. Continued study will inform us of the relative contribution of these autoantibodies to CNS disease in SLE patients.     

Acute central nervous system complications after pulse steroid therapy in patients with systemic lupus erythematosus

We describe 2 patients with systemic lupus erythematosus (SLE) who developed an acute psychosis and a cerebrovascular accident after pulse methylprednisolone therapy. A literature review revealed 8 additional patients with SLE with acute central nervous system complications after pulse therapy.     

Psychiatric disorder and cognitive impairment in systemic lupus erythematosus

Objectives. To determine the point prevalence of psychiatric disorder in patients with systemic lupus erythematosus (SLE). To investigate associations between psychiatric disorder and social stress, cognitive impairment, systemic disease activity, and corticosteroid therapy. Methods. A cross-sectional study of 73 consecutive patients with SLE assessed using standardized psychiatric and clinical research methods. Results. Current psychiatric disorder was present in 15 patients (20.5%) and was significantly associated with social stress, lack of social support, and impairment on 2 tests of cognitive function (Verbal Fluency Test and Benton Visual Retention Test, Part A, number of errors). There was no association with systemic disease activity or corticosteroid therapy. Cognitive impairment on 2 or more tests was found in 26% and was associated with clinical evidence of central nervous system (CNS) disease, but not systemic disease activity or corticosteroid therapy. Conclusions. The point prevalence of psychiatric disorder in this cohort of patients with SLE was found to be similar to that observed in patients with rheumatoid arthritis. It was independently associated with social stress and 2 indicators of cognitive impairment, but not with systemic disease activity or corticosteroid therapy. Marked cognitive impairment was present in a significant percentage of patients even when there was no overt evidence of CNS involvement.     

Neurological complications of connective tissue and other "collagen-vascular" diseases

A variety of neurological complications may occur in the various connective tissue and "collagen-vascular" diseases. Most of these complications are due to vasculitis affecting various sites in the central or peripheral nervous system. While the evidence for definitive vasculitis in SLE is not strong, small vessel damage usually is present in anatomic sites which correlate well with clinical features. Although patients with rheumatoid arthritis also may have vasculitis, neurological complications are usually related to nerve compression by rheumatoid nodules or the arthritic process itself. Considerable controversy exists regarding the accuracy of various diagnostic tests. While corticosteroids are the mainstay of therapy for these conditions, there are no definitive studies proving their efficacy.     

Systemic lupus erythematosus in patients with chronic renal failure

The clinical courses of 36 patients with systemic lupus erythematosus (SLE) in whom chronic renal failure developed and who required dialysis for more than three months were studied. At the time dialysis was initiated, 14 of 36 patients (38.9 percent) had clinically active SLE, but only three of 24 (12.5 percent) had activity in subsequent years while receiving dialysis therapy. In the majority of patients, however, renal disease progressed to end-stage despite clinical quiescence of SLE. During the follow-up period (mean +/- SD, 36 +/- 39.8 months), eight patients died--six from infections and two from cardiac disease. Actuarial survival rates at one, two, and five years after dialysis treatment were 91.1, 78.8, and 68.9 percent, respectively. This study suggests that the progression of renal disease to end-stage in patients with SLE may be mediated by nonimmunologic mechanisms as well as SLE-related immunologic insults. In most of these patients undergoing long-term dialysis, SLE remains clinically inactive despite persistent serologic abnormalities. Survival of the patients undergoing dialysis is comparable with that of the general dialysis population.     

Isolated angiitis of the central nervous system: Prospective diagnostic and therapeutic experience

Isolated angiitis of the central nervous system is an uncommon clinicopathotogic entity characterized by vasculitis restricted to the vessels of the central nervous system without other apparent systemic vasculitis. Experience with the diagnosis, treatment, and follow-up evaluation in four patients with this disease is presented. Early manifestations of disease include severe headaches, altered mental function, and focal neurologic deficits. The pattern of progression from headaches and altered mental status to multifocal neurologic deficits is particularly suggestive of the diagnosis of vasculitis of the central nervous system. Systemic symptoms such as fever, myalgia, arthralgia, and arthritis, which occur frequently in other vasculitic syndromes, are generally not present in patients with isolated angiitis of the central nervous system. Mo single laboratory study can firmly establish or completely exclude the diagnosis; consequently, tissue diagnosis with biopsy of the brain parenchyma and leptomeninges may be required. In two patients, recurrent disease developed despite treatment with corticosteroids alone. Sustained clinical remission was induced in all four patients with a regimen of dally cyclophosphamide and alternate-day prednisone therapy. Cyclophosphamide and alternate-day prednisone therapy are considered the treatment of choice in severe, progressive, or corticosteroid-resistant isolated angiitis of the central nervous system.     

The incidence and prognosis of central nervous system disease in systemic lupus erythematosus.

In a review of our experience with systemic lupus erythematosus (SLE) since 1975, we found 48 of 266 patients with major central nervous system (CNS) manifestations for which a non-SLE explanation could not be identified. Eleven patients developed more than one type of CNS event. The commonest symptom was seizure (18 patients), followed by brainstem dysfunction (12 patients), psychosis (11 patients), organic brain syndrome (11 patients) and stroke (7 patients). In 19% of cases, CNS manifestations were accompanied by a flare of multisystem SLE disease activity. Anticonvulsants were able to be discontinued safely in the majority of patients with seizures. Most CNS events were self-limited, reversible and not associated with poor outcome unless accompanied by multisystem disease activity. Therapy with corticosteroids did not appear to offer substantial benefit.