Neuropsychiatric Illness in Systemic Lupus Erythematosus: Insights From a Patient With Erotomania and Geschwind's Syndrome

Ms. A, a 28-year-old African American woman, developed migratory myalgias, symmetric arthritis, and hematuria at age 20. When laboratory evaluation revealed proteinuria, a strongly positive antinuclear antibody screen, and a double-stranded DNA antibody titer elevated at greater than 1:2,560, she was diagnosed with SLE.

A few months later, Ms. A developed a severe illness characterized by pericardial and pleural effusions, ascites, hemolytic anemia, pancreatitis, and increased proteinuria. Her anticardiolipin immunoglobin G (IgG) and IgM titers were found to be elevated, her C-reactive protein level was significantly elevated at 8.7 mg/dl, and her partial thromboplastin time was elevated at 41.9 seconds. The patient improved with a brief course of corticosteroids, but 1 month later she had a generalized tonic-clonic seizure. Laboratory studies done at that time showed a C-reactive protein level significantly elevated at 6.3 mg/dl, elevated but normalizing anticardiolipin antibody titers, and low complement (C3, C4) levels. The partial thromboplastin time was again elevated at 43.5 seconds. CSF studies were unremarkable, and an EEG showed generalized slowing. A cranial MRI showed changes consistent with edema throughout the brain. The patient improved with high-dosage corticosteroids, intravenous cyclophosphamide, and phenytoin. She received anticoagulation therapy and was continued on cyclophosphamide for 6 months after hospital discharge. She then received intravenous cyclophosphamide every 3 months for 2 years, after which she was maintained on 5 mg/day of prednisone and 200 mg/day of hydroxychloroquine. After a seizure-free year on phenytoin, a subsequent seizure-free year on carbamazepine, and a normal repeat EEG and cranial MRI (with the exception of a few subcentimeter white matter hyperintensities in the right inferior frontal lobe), the patient was weaned from anticonvulsants.

At age 24, Ms. A was referred for psychiatric evaluation due to religious preoccupation. She was living with her mother and younger brother at that time. Her mother said that Ms. A had developed an interest in Christian spirituality and religion at age 20 and that it intensified at age 23 (e.g., the patient insisted that she had been "called to preach"; she had to be forcibly removed from a church once when she felt she was going to be "delivered"). A few months before the psychiatric evaluation, Ms. A insisted that it was God's intention that she marry her pastor. She later insisted that a church elder loved her and was destined to become her husband. At the time of the psychiatric evaluation, Ms. A insisted that a church bishop was in love with her and planned to marry her; she said she knew this because the bishop had looked at her and smiled. While discussing this, she produced a framed picture of the bishop from her purse. She denied having any sexual interest in these men. Ms. A's religious preoccupation had led to poor performance in her technical college coursework. Her mother said that Ms. A's religious and romantic preoccupations did not change when her hydroxychloroquine was stopped for a time. In discussing other signs and symptoms, the patient's mother said that Ms. A had a 5-year history of minor recent memory impairment and a 10-year history of interest in writing. She said there was no history of clear mania or hypomania. On examination, the patient was noted to have oddly halting speech and to be socially awkward. Examination of thought form revealed circumstantiality and a rigid, viscous style. Suspiciousness was noted. Insight was poor. An EEG done at this time was normal. Quetiapine was prescribed, but the patient refused to take it.

Ms. A was not seen again until 2 years later, at age 26, when she returned with ongoing religious preoccupation and poor academic performance. She insisted then that her church choir director was romantically interested in her. She also expressed a desire to become a civil rights attorney. She was taking low-dosage prednisone but was no longer taking hydroxychloroquine. On examination, circumstantiality and perseveration were noted. On cognitive testing, the patient remembered only three of four words after a 5-minute delay, and signs suggestive of executive dysfunction were noted (segmentation was noted when the patient copied a cube; the patient made impulsive errors with right/left orientation testing, and she struggled in copying the Luria alternating sequence and performing the serial hand sequence). No problems were noted with brief attention, language, finger identification, or praxis. Around this time, the patient's anticardiolipin IgM antibody titer was elevated, but her complement levels and other anticardiolipin antibody titers were normal, lupus anticoagulant testing was negative, and antiribosomal P and antineuronal nuclear antibody (ANNA-1 and ANNA-2) tests were negative. After this visit, Ms. A dropped out of school, did not comply with a referral for neuropsychological testing, and again did not return for follow-up.

About 9 months later, Ms. A returned with a recent history of hyperreligiosity, hypersexuality, and agitation. She believed she was about to marry her pastor and had been planning their wedding and talking about having his child. She became agitated when her brother removed religious items and pictures of the pastor from her room. Two weeks before the onset of these problems, the patient developed a rash and was restarted on hydroxychloroquine. When she deteriorated mentally, the hydroxychloroquine was stopped. Over the month after she returned to the clinic, Ms. A required several involuntary admissions to our county psychiatric hospital because of insomnia, thought disorganization, delusions (she believed she was married to a church elder; she was afraid of "demons" and "monsters"), hypersexuality, and agitation. The author is not on staff at this facility and could only be peripherally involved in the patient's inpatient care. Laboratory studies done during the hospitalizations revealed normal complement levels, a C-reactive protein level <0.5 mg/dl, normal anticardiolipin and beta-2 glycoprotein antibody titers, and absent double-stranded DNA, ANNA-1 and -2, ribosomal P protein antibodies, and lupus anticoagulant. Serum cryptococcal antigen testing was negative, as were spinal fluid analysis and EEG. MRI showed only the small white matter hyperintensities in the right inferior frontal lobe that had been present 4 years earlier, and an MR angiogram was normal. The patient's hyperreligiosity and agitation finally remitted with court-ordered treatment with ziprasidone at 80 mg orally twice a day. Around this time, the patient's rheumatologists began to express the opinion that she had a primary psychotic disorder, such as schizophrenia, and "happens to have SLE."

Over the next 5 months, Ms. A developed mild apathy (decreased "ambition" and "drive") but remained stable otherwise while being treated with ziprasidone, 60 mg orally in the morning and 80 mg at night. Her apathy was addressed with a trial decrease in the ziprasidone dosage to 40 mg in the morning and 80 mg at night. About 6 weeks after this decrease, Ms. A began talking, eating, and drinking less and again developed hyperreligiosity and suspiciousness. A rash developed on her arms at this time as well. When she was readmitted to the county psychiatric hospital, her WBC count was mildly elevated at 16,000/μl, her sedimentation rates mildly elevated at 35–41 mm/hour, and her C-reactive protein levels mildly elevated at 1.5–2 mg/dl. A cranial CT scan was normal. Given the patient's withdrawal, the possibility of catatonia was raised, and she was started on lorazepam. On hospital discharge, Ms. A was taking lorazepam, 2 mg orally three times a day, and ziprasidone, 40 mg in the morning and 100 mg at night. Her decreased speech and poor oral intake persisted, however, necessitating rehospitalization at the county facility 11 days later. During this admission, because Ms. A had been so ill and had been admitted several times recently, she was treated with multiple medications, including oral risperidone, haloperidol, and lorazepam. Her symptoms improved, and she was discharged on extended-release risperidone (50 mg intramuscularly every 2 weeks), haloperidol (5 mg orally twice daily), and lorazepam (1 mg orally three times a day), with a plan to slowly taper the haloperidol and lorazepam later. When seen after hospital discharge, Ms. A was still mildly hyperreligious. When seen 2 months later, she complained of depression, anhedonia, and early morning awakening, and sertraline, at 50 mg/day, was added to her medication regimen. When seen 1 month later, Ms. A said that her depressive symptoms had improved. After this visit, she again failed to follow up.

Our patient initially presented for psychiatric evaluation with chronic, intensifying hyperreligiosity that correlated with clinical SLE and a more recent history of erotomania. Hypergraphia that preceded the onset of clinical SLE by several years was also reported. In addition to hyperreligiosity and erotomanic delusions, the initial mental status examination revealed suspiciousness and a formal thought disorder. Later, the patient was found to have signs suggestive of cognitive impairment (memory and executive dysfunction) and, at times, signs and symptoms suggestive of mania, depression, apathy, and catatonia.

As the case progressed, the patient's rheumatologists became convinced that she suffered from schizophrenia and were skeptical about her mental illness being caused by SLE brain disease. This conclusion was affirmed when the patient's case was reviewed in a rheumatology case conference. The rheumatologists' argument against SLE-related brain disease was predicated on the fact that the patient's chronically elevated anti-double-stranded DNA antibody titer did not vary appreciably during changes in her mental illness and that her complement levels remained normal. This notion that neuropsychiatric illness in SLE patients is probably secondary to SLE if it correlates with other clinical, laboratory, or imaging indicators of active disease is widely held (30) and has been codified in the ACR diagnostic criteria for SLE with neuropsychiatric manifestations (16). To receive a diagnosis of SLE with neuropsychiatric manifestations using ACR criteria, a patient must have a neuropsychiatric syndrome and meet three or more non-neuropsychiatric criteria for SLE (e.g., arthritis, a renal disorder, a hematologic disorder, and the like). These criteria also require the exclusion of a primary mental illness, a drug- or substance-induced mental illness, and a "psychologically mediated reaction to SLE" before a diagnosis of SLE with neuropsychiatric manifestations can be given. In keeping with this concept, mental illness is often deemed not to be due to SLE in modern SLE research if it occurs prior to the diagnosis of SLE (31).

Nevertheless, even in the rheumatology literature there is an acknowledgment that patients with early SLE may fail to meet these strict diagnostic criteria (30). There is likewise a long-standing awareness that neuropsychiatric manifestations of SLE can present before the disease is recognized (32). Several lines of evidence suggest that our patient's neuropsychiatric illness was related to SLE brain disease. Her hyperreligiosity began around the time she developed myalgias, arthralgias, and hematuria and was diagnosed with SLE. She had a clear episode of diffuse brain involvement with seizure activity a few months later. This episode led to treatment with cyclophosphamide for 2 years, and around the time the cyclophosphamide was stopped, the patient's religiosity intensified. Some subsequent flares of the patient's neuropsychiatric illness correlated with the appearance of a skin rash. The patient was also found at times during her illness to have evidence of elevated antiphospholipid antibody levels, antibodies that have been implicated in the pathogenesis of SLE with neuropsychiatric manifestations (19, 20, 33). It should again be emphasized, however, that such correlations between neuropsychiatric symptoms, SLE disease activity, and medication use should probably not be required to make a presumptive diagnosis of psychosis due to SLE. Neuropsychiatric illness due to SLE can precede the appearance of other manifestations of the disease, and it can appear when an established illness is otherwise quiescent (16, 34). One study (33) of SLE patients followed for several years showed no correlation between the development of cognitive impairment and anti-double-stranded DNA antibody titers, just as our patient's illness did not correlate with changes in her titers. There is also inconsistency in the relationship between clinical SLE with neuropsychiatric manifestations and evidence of CNS damage when routine methods of detection are used (35). Studies of SLE patients using brain MR spectroscopy, an MRI technique that examines the biochemical composition of the brain, have revealed evidence of injury not detectable with routine MRI scans. Specifically, reduced N-acetylaspartic acid signals suggestive of neuronal injury or death have been found in SLE patients with psychosis, and it has been postulated that cytotoxic autoantibodies or inflammatory mediators may have caused this injury (36).

If our patient's mental illness was due to SLE brain disease, its localization is suggested by certain aspects of her history and examination. Her hyperreligiosity and interest in moral issues, exaggerated sense of destiny, hypergraphia, circumstantiality and viscosity, suspiciousness, occasional agitation, and changes in sexual behavior are reminiscent of Geschwind's syndrome and may point to an abnormality in the temporal lobes. While Geschwind's syndrome has traditionally been associated with temporal lobe epilepsy, a report of these traits (including hyperreligiosity and hypergraphia) occurring in a patient with frontotemporal dementia who did not have epilepsy (37) suggests that they can be caused by disease processes other than epilepsy. Our patient's erotomania may also point to temporal lobe dysfunction given the reports of erotomania occurring in diseases involving the temporal lobes, as discussed above. The patient also had signs and symptoms suggestive of dysfunction in the frontal/subcortical circuits, including hypergraphia, executive dysfunction, and apathy (38, 39). Findings suggestive of frontal/subcortical and temporal lobe dysfunction have been reported in patients with primary erotomania as well as in patients with erotomania resulting from diverse neurological conditions, including subarachnoid hemorrhage and epilepsy (40).

Possible etiologies of the patient's frontal/subcortical and temporal lobe dysfunction would include the multiple pathological processes related to SLE. In SLE, focal brain disease (e.g., infarction) is usually related to antiphospholipid antibodies and cerebrovascular disease (usually small vessel noninflammatory vasculopathy). SLE increases the risk of seizures, probably via antiphospholipid antibodies and cerebrovascular disease (28) as well. Diffuse SLE brain disease is usually related to autoantibodies and inflammatory mediators (e.g., interleukins, interferon-α, and tumor necrosis factor-α [28]). Focal brain disease, seizure activity, and diffuse brain disease could all cause cognitive, emotional, and behavioral problems. Our patient had a focus of white matter disease in her right inferior frontal lobe that may have played a role in some of her signs and symptoms; she had no other imaging evidence of focal disease, however. The patient had a generalized tonic-clonic seizure within months of her diagnosis of SLE. While she subsequently had no clear seizures and had multiple normal routine EEGs, the possibility of temporal lobe dysfunction due to subclinical seizure activity should be considered given the elements of Geschwind's syndrome present and the fact that the patient's mental illness worsened around the time that her carbamazepine was tapered off. In the absence of marked cerebrovascular disease and epilepsy, the most likely cause of the patient's frontal/subcortical and temporal lobe dysfunction would be autoantibodies and inflammatory mediators. Interestingly, research in SLE patients has shown a correlation between chronic, persistent anticardiolipin antibody positivity and the development of signs of frontal/subcortical dysfunction, including psychomotor slowing, impairment in conceptual reasoning, and executive dysfunction (34). How anticardiolipin antibodies may have caused this cognitive dysfunction was not clear. Our patient had elevated anticardiolipin antibodies at multiple points in her illness. The episode of diffuse brain involvement our patient developed early in the course of her SLE may have been the culmination of a chronic autoimmune process that left her with lasting frontal/subcortical and temporal lobe damage such as that seen in cases of degenerative frontotemporal dementia; the appearance on her MRI of a persisting right frontal lobe white matter abnormality after this episode may be supportive of this idea. Alternatively, her symptoms may have been related to chronic, continuous engagement of the brain by autoantibodies and inflammatory mediators. A reversible frontotemporal dementia-like illness due to an autoimmune process has been described in the literature (41). A report of erotomania occurring in a patient with frontotemporal dementia with motor neuron disease may also support the idea that our patient had a frontotemporal dementia-like illness (12).

Psychosis and other forms of psychopathology are common in patients with SLE. The etiology of this psychopathology is often unclear and can become a bone of contention between psychiatrists, rheumatologists, and other caregivers. Nonpsychiatric physicians may be unreceptive to the idea that psychopathology in a patient with SLE is secondary to SLE brain disease unless there is a correlation between the mental symptoms and objective indicators of disease activity (e.g., the presence of autoantibodies suspected to cause psychopathology, brain imaging evidence of new disease, and so on). The literature suggests, however, that relationships between neuropsychiatric manifestations of SLE, general medical manifestations of the disease, and objective measures of disease activity are imprecise. If psychopathology in SLE patients can be caused by both active SLE brain disease and its long-term consequences (i.e., static brain damage), this may explain some of this imprecision. Standard laboratory testing and imaging studies may not always detect active brain disease or static damage.

In a world where treatment of mentally ill SLE patients may be dispersed among multiple psychiatrists, rheumatologists, and other caregivers, as it was in this case, it is important to differentiate between primary psychiatric illness and psychopathology secondary to SLE for a number of reasons. Diagnosing a primary psychiatric illness such as schizophrenia in a patient with SLE may stigmatize a person already struggling to live with a major illness. Since SLE can cause neuropsychiatric illness via multiple mechanisms (e.g., infarcts, seizure activity, and autoantibody injury), proper attribution of neuropsychiatric symptoms will obviously have implications for disease management. For example, an inappropriate diagnosis of primary mental illness could lead a rheumatologist to a decreased sense of "ownership" of neuropsychiatric symptoms, and this could lead to less attention being paid to medical factors that can aggravate the neuropsychiatric manifestations of SLE, such as hypertension (28). Until the etiology of SLE with neuropsychiatric manifestations is better understood, patients with these syndromes will have to be treated symptomatically with traditional psychiatric medications. Enhanced awareness of SLE brain disease could lead to improved psychotropic medication management (e.g., increased consideration of the seizure risk associated with some psychotropic medications). Further research aimed at properly diagnosing and effectively treating psychopathology in patients with SLE is needed.