Reader Benefit: Systemic lupus erythematosus can present with neuropsychiatric symptoms; clinicians should consider the diagnosis even when routine neuroimaging and cerebrospinal fluid analysis are normal.
3D=three-dimensional; CNS=central nervous system; CSF=cerebrospinal fluid; FDG=F-18 fluorodeoxyglucose; MRI=magnetic resonance imaging; NPSLE=neuropsychiatric SLE; PET=positron emission tomography; SLE=systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a chronic immune-mediated multisystem disorder that affects women much more than men. The highest incidence is in non-white persons aged 15 to 44 years (Danchenko et al, 2006). Population-based studies in the United States have estimated an overall incidence of 1.8 to 7.2 per 100,000 persons and a prevalence of 40 to 78.5 per 100,000 (Danchenko et al, 2006).
Many patients with SLE have nervous system involvement, which can cause a range of clinical manifestations. The American College of Rheumatology (“The American College of Rheumatology nomenclature,” 1999) has developed standardized case definitions for 19 specific neuropsychiatric syndromes associated with SLE (NPSLE). The central nervous system (CNS) disorders include cognitive dysfunction, seizure, movement disorder, cerebrovascular disease, demyelinating syndrome, meningitis, headache, myelopathy, acute confusional state, psychosis, and affective syndrome. The peripheral nervous system disorders include cranial and peripheral neuropathies, myasthenia gravis, dysautonomia, and plexopathy. Because of the lack of standardized diagnostic criteria for these syndromes, as well as the lack of specific diagnostic tests that can distinguish NPSLE from coexisting pathologies causing similar symptoms, the estimated prevalence of NPSLE in adult patients has ranged from 38% to 90% (Ainiala et al, 2001; Brey et al, 2002; Jönsen et al, 2002; Mikdashi and Handwerger, 2004).
Magnetic resonance imaging (MRI) findings have been shown to be normal in up to 40% to 50% of patients with NPSLE; in the others, MRI has shown single or multifocal hyperintensities in the white matter and the deep or cortical gray matter (Luyendijk et al, 2011; Stimmler et al, 1993). MRI may also show cortical laminar necrosis, restricted diffusion, pathologic contrast enhancement, or focal atrophy (Luyendijk et al, 2011). Patients with focal neurologic deficits are more likely to have an abnormal MRI (Baum et al, 1993; Stimmler et al, 1993).
F-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET), which measures metabolic activity, can reveal cerebral hypometabolism in patients with any degree of NPSLE, even if they have a normal MRI; FDG-PET is normal in most patients with SLE who do not have any neuropsychiatric symptoms (Kao et al, 1999a, 1999b; Stoppe et al, 1990; Volkow et al, 1988; Weiner et al, 2000). Some FDG-PET studies have shown that the parieto-occipital regions are most commonly affected in NPSLE (Otte et al, 1997; Weiner et al, 2000).
An estimated 38% to 80% of patients with NPSLE have cerebrospinal fluid (CSF) abnormalities (Joseph et al, 2007; Winfield et al, 1983), including elevated intrathecal immunoglobulin IgG or IgM synthesis, elevated oligoclonal bands, elevated antineuronal antibodies, elevated protein, pleocytosis, and/or evidence of blood-brain barrier impairment. These abnormalities are more likely to be seen in patients with diffuse rather than focal CNS dysfunction (West et al, 1995).
We present a patient with SLE who had prominent cognitive difficulties and an abnormal FDG-PET scan of the brain despite normal MRI and CSF findings. Immunosuppressive treatment brought her both clinical improvement and normalization of neuropsychological and FDG-PET scan findings. We propose that functional imaging with an FDG-PET scan can be a useful tool both in the diagnosis of CNS involvement in SLE and as a relatively objective marker of improvement.
Our patient underwent neuropsychological assessment twice, at the time of her NPSLE diagnosis and again after 3 months of treatment. Because the battery of neuropsychometric tests differed between the 2 assessments, we list the tests, grouped by cognitive domains, in Table 1. As shown, we converted index scores to Mayo Older American Normative Studies age-adjusted scaled scores (Ivnik et al, 1992; Ivnik et al, 1996; Lucas et al, 1998; Machulda et al, 2007) or Oklahoma normative studies age- and education-corrected scaled scores (Duff et al, 2003). We converted all normative test scores to Z scores (mean=0 and standard deviation=1) to aid in the comparison of test performance. We averaged Z scores for all domains except attention/concentration, for which there was only 1 test.
We performed MRI at 1.5 T (GE Healthcare, Waukesha, WI). For high-resolution T1-weighted images, we used 3-dimensional (3D) high-resolution spoiled gradient recalled acquisition in the steady state. We also performed a fluid-attenuated inversion recovery sequence.
We performed PET using a PET/computed tomography system (Discovery RX, GE Healthcare) operating in 3D mode. We tested the patient twice, using the same instrument and the same methods. For each test, the patient was injected with FDG (average, 564 MBq; range, 449 to 691 MBq); after a 30-minute uptake period, we obtained an 8-minute scan. We also took a computed tomography image for attenuation correction.
We reconstructed the PET images using a fully 3D iterative reconstruction algorithm that incorporated corrections for attenuation, scatter, random coincidences, decay, and dead time. We processed the FDG-PET scans using CortexID software (GE Healthcare). The metabolic activity in each FDG-PET data set was normalized to the pons (Minoshima et al, 1995) and compared with an age-segmented normative database, yielding Z score 3D-Static Strength Prediction metabolic maps.
A 64-year-old right-handed woman experienced the acute onset of dizziness, unsteadiness, and episodic confusion. She did not have vertigo or an illusion of movement. Two weeks after her symptoms began, she also developed profound fatigue; asthenia; myalgias; migratory arthralgias, primarily involving both shoulders, elbows, wrists, hips, and knees; and early morning stiffness.
After a month of progressive symptoms, her doctor found that her erythrocyte sedimentation rate and C-reactive protein were normal, but she had an elevated antinuclear antibody titer. A left temporal artery biopsy did not show giant cell arteritis. She was started on prednisone 40 mg/day for possible polymyalgia rheumatica.
Over the next month, as the prednisone was gradually tapered, her symptoms worsened. Her family noted that she had ever greater word-finding difficulties, episodes of forgetfulness, and trouble recalling how to perform daily activities such as preparing a meal. She agreed that she was having difficulties with attention and concentration, as well as navigational problems when driving. She felt mildly depressed. She complained of having headaches as often as several times a day; she described bifrontal throbbing pain lasting seconds to minutes, without visual symptoms, nausea, photophobia, or phonophobia. During that month she also had dry eyes and a dry mouth.
During the week before admission, she developed a nonpruritic erythematous macular rash on her upper chest and back. She did not have weight loss or fevers, but she did report chills and cold intolerance.
She was evaluated in our hospital’s emergency department for her progressive decline, and was admitted.
The patient was a college graduate who worked as a high-level administrator. She lived alone, but had a grown child nearby. She had undergone a total thyroidectomy for thyroid cancer, and was maintained on thyroxine. She had a remote history of migraine headaches.
Her family history was pertinent for rheumatoid arthritis in her father, Hashimoto thyroiditis in 1 sister, and autoimmune hepatitis and non-Hodgkin lymphoma in another sister. Her mother had died at 86 from “old age,” but she had a history of multiple strokes and had developed dementia in her 80s. There was no other family history of dementia, cognitive disorders, epilepsy, neuropathy, headaches, Parkinson disease or other movement disorders, psychiatric disease, or other neurologic disorders.
The patient’s physical examination revealed only a blanching macular rash involving her neck, upper chest, and back. There was no evidence of active synovitis. She was given a Kokmen Short Test of Mental Status (Kokmen et al, 1987), and scored a normal 37 of 38, missing only 1 point on delayed recall. Cranial nerve, strength, sensory, reflexes, and cerebellar examinations were normal.
Her diagnostic workup showed a normal erythrocyte sedimentation rate of 13 mm/L and an elevated C-reactive protein of 9.1 mg/L (normal=≤8 mg/L). The antinuclear antibody titer was strongly positive at >12 (normal=≤1), anti-double-stranded DNA IgG elevated at 131 IU/mL (normal=<30 IU/mL), C3 low at 37 mg/dL (normal=75 to 175 mg/dL), and C4 low at 7 mg/dL (normal=14 to 40 mg/dL). SSA IgG, SSB IgG, RNP IgG, Smith IgG, Jo1 IgG, SCl 70 IgG, and rheumatoid factor were all negative. Antiphospholipid IgG was borderline-positive at 13.3 GPL (normal=10 to 14.9 GPL). There was no evidence of lupus anticoagulant. A paraneoplastic panel was negative.
Routine laboratory studies showed hyponatremia, with a serum sodium of 126 mmol/L (normal=135 to 145 mmol/L). The aspartate aminotransferase was elevated at 234 U/L (normal=8 to 43 U/L), and the alanine transaminase at 145 U/L (normal=7 to 45 U/L). The aldolase was elevated at 11.2 U/L (normal=<7.7 U/L). The total creatine kinase was normal at 66 U/L. She had leukopenia at 2.9×109/L (normal=3.5 to 10.5×109/L), with slight lymphocytopenia. The creatinine was normal. Urinalysis showed mild proteinuria. Thyroid hormone levels and thyroid-stimulating hormone were within normal limits.
The patient underwent neuropsychological testing, perseverating mildly throughout. The tests showed (Figure 1) particular deficits in processing speed, executive function, complex and sustained attention, and lexical fluency. She had mildly impaired visuospatial abilities. Verbal learning was low-average. Verbal and visual delayed recalls were mildly impaired. Confrontation naming and semantic fluency were average.
Brain MRI (Figure 2) showed a chronic infarct in the left inferior cerebellar hemisphere, as well as mild generalized cerebral atrophy and a small venous angioma within the left occipital lobe. There was no pathologic contrast enhancement or restricted diffusion. Magnetic resonance angiography of the head was normal.
CSF analysis revealed 1 total nucleated cell per mcL, glucose 52 mg/dL, protein 52 mg/dL, no oligoclonal bands, and neuron-specific enolase in the indeterminate range at 16 ng/mL (<15 ng/mL normal, >30 ng/mL elevated). The CSF was negative for bacteria, herpes simplex virus, and varicella zoster virus polymerase chain reactions.
FDG-PET of the brain showed bilateral frontal, temporal, parietal, and occipital lobe hypometabolism. Supplemental Digital Content 1 (http://links.lww.com/CBN/A34) is a composite of 3D-Static Strength Prediction images from this scan (top panels) and from a follow-up FDG-PET scan done after the patient had been treated for 3 months (bottom panels). From left to right in each row, the images represent Z score projection maps for the right lateral, left lateral, right medial, and left medial views. As the upper row of maps illustrates, warmer colors correspond to higher Z scores, which indicate more significant hypometabolism.
We gave the patient a diagnosis of SLE based on the revised American Rheumatism Association criteria (Tan et al, 1982). We raised her prednisone dose back to 40 mg/day and discharged her from the hospital.
When she returned home, she had problems with attention and concentration. Her children had to manage her finances and administer her medications because she made so many errors. She experienced an occasional formed visual hallucination and she had auditory hallucinations of someone working in another room. She complained of waves of extreme fatigue and daytime sleepiness. She continued to have asthenia, diffuse pain in her muscles and joints, and early morning stiffness. She also continued having problems with balance, and suffered a few falls.
Several weeks after the patient went home, her rheumatologist added mycophenolate mofetil 1 g twice a day to her regimen, and began slowly tapering her prednisone dose from 40 mg/day.
At a follow-up visit 3 months later, the patient reported enough improvement in her cognition that she had been able to return to work part-time. She no longer experienced any hallucinations. She was still taking mycophenolate mofetil 1 g twice a day. By this time her prednisone dose had been tapered to 10 mg/day. Her neurologic examination remained normal.
Repeat neuropsychological testing (Figure 1) showed significant improvement in her complex and sustained attention, executive function, lexical fluency, verbal learning and memory, and visuospatial abilities. She still had mildly impaired processing speed, although it was much better than at her prior testing.
Also at 3 months, a repeat FDG-PET scan of the brain showed that the earlier hypometabolism had resolved. In Supplemental Digital Content 1 (http://links.lww.com/CBN/A34), the bottom row has Z score projection maps for images from the repeat scan. Again, from left to right, the maps show the right lateral, left lateral, right medial, and left medial views. Compared to the pretreatment images in the top row, the later images in the bottom row show only cool colors, corresponding to lower Z scores and indicating correction of the hypometabolism.
At her most recent evaluation, 11 months after discharge, the patient remained on mycophenolate mofetil 1 g twice a day. By this time her prednisone dose had been reduced to 4 mg/day. Her cognitive status remained stable and her neurologic examination was normal.
Our patient had late-onset SLE, with cognitive difficulties starting early in her course. She and her family reported a significant decline in her cognition over the few months before her diagnosis, although routine bedside mental status testing was not sensitive enough to detect her impairment. Her case demonstrates the importance of detailed neuropsychological assessment in a patient with SLE who reports a functional decline and whose bedside mental status testing is within normal limits.
MRI and a magnetic resonance angiogram of the brain did not show any acute abnormality. The CSF was normal.
The patient’s FDG-PET scan was much more sensitive than any other study in detecting her CNS involvement. FDG-PET showed significant hypometabolism in the precuneus region. The scan also showed more global hypometabolism, but with relative sparing of the primary sensorimotor and primary visual cortices.
This pattern of hypometabolism is the same one observed in Alzheimer disease (Whitwell and Jack, 2007). Had our patient not been started on immunosuppressive therapy and had the FDG-PET scan not been repeated, then Alzheimer disease would have been high among the differential considerations for the cause of her cognitive decline. With a diagnosis of Alzheimer disease and without immunosuppressive therapy, the patient’s prognosis and outcome would have been very different.
Despite extensive research, the pathophysiology of NPSLE is not entirely known. A combination of factors is likely involved. Vasculopathy and various autoantibodies, cytokines, and chemokines have each been implicated in the pathogenesis of NPSLE (Efthimiou and Blanco, 2009). We attribute our patient’s treatment response to both prednisone and mycophenolate mofetil. Her cognitive symptoms stabilized at first with prednisone, but worsened as the dose was being tapered before her hospitalization. It was not until she started taking mycophenolate mofetil that her cognition began to improve. The fact that she was taking immunosuppressive treatment when she improved clinically and when her FDG-PET scan abnormalities resolved suggests an immune-mediated pathogenesis for her cognitive dysfunction and abnormal scan. Her case also suggests that the absence of inflammatory markers in the CSF may not rule out an immune-mediated cause for CNS dysfunction.
FDG-PET may provide a biomarker for NPSLE, and may thus assume a role in both the diagnosis of NPSLE and the monitoring of response to therapy. Future studies should examine the correlation of FDG-PET findings and NPSLE, to establish the procedure’s value as a marker.
Neuroimaging modalities other than FDG-PET have also shown distinctions among groups of patients with NPSLE, patients with SLE who do not have neuropsychiatric symptoms, and healthy controls. Using diffusion tensor imaging, Jung et al (2010a) found that, compared with controls and patients with uncomplicated SLE, patients with NPSLE had significantly reduced white matter integrity of the left arm of the forceps major, the left anterior corona radiata, and the body of the corpus callosum; further, impaired cognitive performance in the patients with NPSLE correlated with fractional anisotropy changes along specific white matter tracts.
Using volumetric MRI, Jung et al (2010b) found cortical thinning in the left frontal, bilateral parietal, and right occipital lobes in patients with NPSLE compared with controls, after adjusting for age; compared with patients with uncomplicated SLE, those with NPSLE showed atrophy of the right frontal and temporal cortices, thalamus, caudate nucleus, and putamen.
In Fitzgibbon et al’s (2008) study using blood oxygen level-dependent functional MRI during working memory tasks, patients with NPSLE had much greater cortical activation in the supplementary motor regions and both posterior inferior parietal lobules than did healthy controls.
These studies have shown that patients with NPSLE have both structural and functional changes in the brain. Like FDG-PET, these other imaging modalities may eventually contribute to the diagnosis of NPSLE and to monitoring the disease course, offering considerable benefits over conventional MRI.
The neurologic and psychiatric syndromes associated with SLE have been defined (“The American College of Rheumatology nomenclature,” 1999). However, there are no accepted criteria for these syndromes’ specific clinical features that would make it possible to determine whether the features are in fact a primary manifestation of SLE and not a medication side effect, complication of SLE, or comorbid disease. Consequently, we cannot yet know the true incidence and prevalence of NPSLE.
The addition of FDG-PET imaging to the assessment of new-onset psychiatric and neurologic symptoms in patients with SLE may improve the recognition and diagnosis of SLE-related psychiatric and neurologic syndromes. FDG-PET should be considered for patients in whom conventional MRI shows no acute abnormality and whose CSF analysis is normal. Large-scale studies are needed to facilitate the development of well-defined biological markers that can be used in the diagnosis and measurement of disease activity in NPSLE.
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