Lupus and the Nervous System

36  Lupus and the Nervous System: Clinical Aspects, Psychopathology, and Imaging Sterling G. West and John G. Hanly

OUTLINE Classification, 434 Clinical Presentations, 435 Frequency and Attribution of Neuropsychiatric Events in SLE Patients, 435 Etiopathogenesis, 435 Clinical Manifestations, 436 Central Nervous System, 436 Acute Confusional State, 436 Cognitive Dysfunction, 436 Headache, 437 Aseptic Meningitis, 438 Cerebrovascular Disease, 438 Myelopathy, 438 Movement Disorders, 440 Demyelinating Syndrome, 440 Seizures, 440 Psychiatric Disorders, 441 Psychosis, 441 Mood Disorders, 441 Anxiety Disorders, 441 Peripheral Nervous System, 442 Cranial Neuropathies, 442 Peripheral Polyneuropathies, 442 Autonomic Disorders, 443 Myasthenia Gravis and Related Disorders, 443 Neuropsychiatric SLE in Children and Older Adults, 443 Secondary Causes of Central Nervous System Dysfunction in SLE, 443 Clinical and Laboratory Evaluation, 443 Clinical Laboratory Tests, 444

Autoantibodies, 444 Antiphospholipid Antibodies, 444 Antiribosomal P Antibodies, 445 Antineuronal and Neural Antigen-Specific Antibodies, 446 Cerebrospinal Fluid Tests, 447 Routine Cerebrospinal Fluid Tests, 447 Cerebrospinal Fluid Immunologic Tests, 447 Cerebrospinal Fluid Antineuronal Antibodies, 447 Miscellaneous Determinations, 447 Summary, 447 Electroencephalography, 447 Neuropsychometric Tests, 447 Neuroimaging Studies, 448 Computed Tomography, 448 Magnetic Resonance Imaging, 448 Positron-Emission Tomography and Single-Photon Emission Computed Tomography, 448 Transcranial Color Doppler Sonography, 449 Nonconventional Magnetic Resonance Imaging, 449 Functional Magnetic Resonance Imaging, 449 Magnetic Resonance Relaxometry, 449 Magnetization Transfer Imaging, 449 Diffusion Tensor Imaging, 450 Magnetic Resonance Spectroscopy, 450 Angiography, 450 Treatment, 450 Central Nervous System Manifestations, 450 Difficult Clinical Situations, 451 Peripheral Nervous System Manifestations, 452 Prognosis, 452

Neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) are frequent, vary from mild to severe, and are often difficult to diagnose and distinguish from those of other diseases. Any location in the nervous system may be affected, with symptoms and signs ranging from mild cognitive dysfunction to seizures, strokes, and coma. At the initial development of neuropsychiatric (NP) manifestations, many patients have other medical conditions or are receiving medications that can affect the central nervous system (CNS) or the peripheral nervous system (PNS). The challenge to the clinician is to determine the exact cause of the nervous system dysfunction and to institute the

appropriate therapy. This chapter describes the classification, clinical signs and symptoms, laboratory and neuroimaging findings, differential diagnosis, and treatment of systemic lupus erythematosus (SLE) involving the nervous system.

434

CLASSIFICATION The prevalence of NP manifestations in adult SLE ranges from 4% to 91%, depending on the ascertainment methodology.1-3 The lower percentages are from studies that reported only patients with NPSLE

CHAPTER 36  Lupus and the Nervous System who developed major objective NP manifestations as a result of lupus, whereas the higher percentages come from studies reporting patients with SLE who have either subjective or objective complaints including both major and minor manifestations of NP dysfunction. However, comparing past studies of NPSLE is often impossible, because many reports are cross-sectional studies that include patients with varying disease durations and do not use a standardized definition or classification system for NP manifestations. In 1999 an international, multidisciplinary committee of the American College of Rheumatology (ACR) developed case definitions, including diagnostic criteria and important exclusions, for 19 NP syndromes known to occur in SLE patients4 (Table 36.1). This nomenclature is the current standard used to help clinicians classify NPSLE, as well as help investigators in research studies. It is helpful clinically to segregate these syndromes into central (diffuse [neurologic versus psychiatric] and focal events) and peripheral neurologic presentations5 (see Table 36.1).

TABLE 36.1  Neuropsychiatric Syndromes

of SLE

Manifestation Central Nervous System (Diffuse) • Acute confusional state • Cognitive dysfunction • Severe (dementia) • Headache • Pseudotumor cerebri • Aseptic meningitis • Psychiatric disturbances • Psychosis • Mood disorders • Anxiety disorders

a

Frequency (%)a 4–7 17–59b 3–5 24–72b <1 <1 2–11 12–43b 24–57b

Central Nervous System (Focal) • Cerebrovascular disease • Myelopathy • Movement disorders • Demyelinating syndromes • Seizures

5–18 1–1.5 <1–2 <1 7–20

Peripheral Nervous System • Cranial neuropathy • Peripheral neuropathy • Inflammatory demyelinating polyradiculopathy • Mononeuropathy, single or multiplex • Plexopathy • Autonomic neuropathy • Myasthenia gravis

1 2–21 <1 <1 <1 <1 <1

Estimated cumulative frequencies are based on published studies and reviews. b Estimated frequency includes nonlupus causes. Adapted from American College of Rheumatology Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature: The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 42(4): 599–608, 1999; Bertsias GK, Ioannidis JP, Aringer M, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis 69(12): 2074–2082, 2010.

435

Since the publication of the ACR nomenclature for NPSLE syndromes, several investigators have used these criteria. In a recent meta-analysis of 10 prospective studies (2049 total SLE patients), the overall prevalence of NP syndromes using the ACR nomenclature was estimated to be 56.3%.3 However, these studies included both major and minor clinical manifestations. In a cross-sectional, population-based study from Finland, Ainala and others found that 42 of 46 (91%) patients with SLE met criteria for NPSLE using the ACR nomenclature.6 Many of these were mild syndromes including cognitive dysfunction, headaches, and mood disorders. When these patients were compared with well-matched non-SLE control subjects, 56% of the latter fulfilled at least one of the ACR criteria, suggesting the criteria had a high sensitivity (91%) but low specificity (46%).6 However, if the ACR criteria were revised to exclude syndromes without objective findings, such as anxiety, headaches, mild depression, subjective cognitive complaints, and polyneuropathy symptoms with a negative electromyogram and nerve conduction velocities, then the specificity improved to 93%. Therefore the ACR nomenclature is useful for major NPSLE syndromes but problematic when applied to subjective syndromes that are common in patients without SLE.

CLINICAL PRESENTATIONS Frequency and Attribution of Neuropsychiatric Events in SLE Patients The cumulative frequencies of the various NP presentations are reported in Table 36.1 and can be divided into CNS (diffuse [neurologic versus psychiatric] and focal events) and PNS presentations. Notably, an individual patient can have more than one neurologic manifestation concurrently or sequentially. The attribution of NP events to SLE per se or to an alternative etiology is determined case by case on the basis of exclusion using available clinical, laboratory, and imaging data. Depending on the stringency of attribution rules, the proportion of NP events attributed to SLE in newly diagnosed SLE patients has varied from 19% to 38% of NP events in 6% to 12% of patients over the first year of the illness. Seizure disorders, cerebrovascular disease (CVD), acute confusional states, and neuropathies were the most common NP syndromes attributed to SLE. The cumulative occurrence of NP events increases over time, although the proportion of events attributed to SLE and non-SLE causes remains the same.7 Studies using these attribution rules have shown differences in clinical outcomes for NP events attributed to SLE and non-SLE causes, stronger associations with some lupus autoantibodies, and stronger associations between patient- and physician-reported outcomes for NP events attributed to SLE.8,9 Regardless of attribution, the impact of cumulative NP events in SLE patients is evident from the significant reduction in virtually all domains of health-related quality of life instruments.10

Etiopathogenesis Several autopsy series have reported detailed neuropathologic analyses of patients with NPSLE.11-15 Many of these studies are hampered by the inclusion of patients with secondary causes of CNS dysfunction, as well as patients with prolonged intervals between NPSLE manifestations and death. Despite the limitations, these studies provide important insights into the pathogenesis of NPSLE and agree on several important points. First, there is no distinct or pathognomonic lesion that NPSLE causes in the brain that is diagnostically specific, similar to the “wire loop” lesion of the kidney or the “onionskin” lesion of the spleen. Notably, vasculitis is unusual (3%–5%) at autopsy. The most common finding is a small-vessel, bland, noninflammatory, proliferative vasculopathy characterized by hyalinization. These degenerative and proliferative

436

SECTION 5  Clinical Aspects of Lupus Erythematosus

changes in the small cerebral vessels are seen in all SLE patients but are more diffuse in patients with NPSLE and frequently associated with microthrombi and microinfarction. These neuropathologic lesions vary in age from region to region, rather than appearing to have occurred simultaneously. Notably, clinical manifestations may not be readily explained by pathologic findings and brain magnetic resonance imaging (MRI) frequently will not demonstrate many of the microscopic lesions found at autopsy.14 Some patients with NPSLE, particularly those with diffuse manifestations, may have relatively unremarkable brain pathology.13 Despite these autopsy findings, the pathogenesis of NPSLE remains unknown. However, it is unlikely that a single pathogenic mechanism is responsible for the myriad of NP manifestations observed in NPSLE (see Table 36.1). Diffuse cerebral manifestations (e.g., acute confusional state, psychosis, etc.) that are often transient, reversible on therapy, and not consistently associated with brain pathologic abnormalities, most likely have a different pathogenesis from the focal symptoms (e.g., strokes, others), which are usually acute in onset, permanent even with therapy, and frequently associated with pathologic lesions at autopsy. Many investigators believe that cerebrovascular endothelial dysfunction plays a pivotal role.13,14 Primary NPSLE events tend to occur during active lupus, supporting complement activation as an important contributor to this endothelial dysfunction.16 Endothelial dysfunction and its associated microvasculopathy can disrupt the blood-brain barrier, allowing an influx of cells, autoantibodies, and cytokines into the CNS, which can cause diffuse NP manifestations. Additionally, procoagulant factors (e.g., antiphospholipid antibodies, etc.) can augment endothelial cell activation by further predisposing the patient to thrombosis and emboli leading to strokes and other focal manifestations. In any single patient with NPSLE, a combination of these mechanisms likely contributes to clinical manifestations (see Chapter 23 for a more complete discussion).

BOX 36.1  Secondary (Nonlupus) Causes of

Neuropsychiatric Manifestations in SLE Infection Medications Thrombotic thrombocytopenia purpura Hypertension Posterior reversible encephalopathy syndrome Metabolic disturbances Hyperglycemia or hypoglycemia Electrolyte imbalances (Na+2, Ca+2) Uremia Hypoxemia Fever Thyroid disease Vitamin B12 deficiency Atherosclerotic strokes Subdural hematoma Berry aneurysm or cerebral hemorrhage Cerebral lymphoma Fibromyalgia Reactive depression Sleep apnea Other primary neurologic or psychiatric diseases

Adapted from American College of Rheumatology Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature: The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 42(4): 599–608, 1999; Bertsias GK, Ioannidis JP, Aringer M, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis 69(12): 2074–2082, 2010.

CLINICAL MANIFESTATIONS NPSLE can involve the CNS, PNS, the autonomic nervous system, and/ or the myoneural junction (see Table 36.1). Patients with NPSLE can exhibit diffuse, focal, or a combination of NP symptoms. Clinical signs and symptoms range from mild and transient dysfunction to severe presentations, resulting in permanent neurologic sequelae and/or death. This diversity of manifestations and severity are the result of several different immunopathogenic mechanisms, which can affect various areas of an anatomically and physiologically complex nervous system. The clinician must always be aware that neurologic abnormalities in SLE may not be the result of primary NPSLE but can be secondary to infection, electrolyte abnormalities, medication side effects, or numerous other causes (Box 36.1). In the Systemic Lupus International Collaborating Clinic (SLICC) inception cohort study of 1206 patients with early lupus followed prospectively over a mean follow up of 1.9 years, 486 (40.3%) developed at least one NP event of which 93% affected the CNS and 7% involved the PNS.7 Of those with NP events, 79% were diffuse and 21% were focal manifestations. Notably, less than one-third of the events could be attributed to SLE with the majority secondary to a nonlupus cause. Various models have been proposed to improve the accuracy of attributing a NP event to primary NPSLE.7,17,18 The onset of a major NP event (e.g., seizures, psychosis, severe alterations of consciousness, cerebrovascular accidents, cranial nerve neuropathy, myelopathy) early in the course of active SLE (within 1 year of diagnosis) without another readily identifiable etiology is most likely caused by primary NPSLE. SLE patients with active disease and those with previous episodes of NPSLE are more likely to have a subsequent NP event.

Central Nervous System Acute Confusional State

This condition, synonymous with “acute encephalopathy” or “delirium,” occurs in 4% to 7% of all SLE patients, and up to 30% of patients are hospitalized for NPSLE.19 It is characterized by a disturbance of attention that develops over hours and fluctuates with variable impairment of other cognitive abilities. NPSLE may progress to severe reduction in level of arousal or coma. Other features include a disturbed sleep–wake cycle and changes in psychomotor behavior, of which hyperactivity is most easily recognized, whereas lethargy may mask other symptoms. Distinguishing acute confusional states from persistent cognitive impairment is assisted by a history of an acute onset of new symptoms and fluctuations in attention and level of arousal. Attribution to SLE is challenging because this requires exclusion of CNS infection, metabolic disturbances, thrombotic thrombocytopenia purpura (TTP), substance abuse, or drug-induced causes.4 Regardless of its cause or attribution to SLE, acute confusion is more likely to occur if there is preexisting cognitive impairment.

Cognitive Dysfunction Cognition is the sum of mental processes that result in observed behavior. Cognitive dysfunction (previously called chronic organic brain syndrome) may be mild (e.g., lupus fog) and limited to aspects of particular domains of function or may be more severe and diffuse and consistent with dementia. The diagnosis and attribution of cognitive impairment, which is frequently significant in SLE patients, remains challenging. Self-reported measures of perceived cognitive impairment are poorly correlated with

CHAPTER 36  Lupus and the Nervous System objective cognitive assessment in SLE patients, show low sensitivity, and are associated with concurrent anxiety and depression.20-22 Thus formal neuropsychological assessment remains the gold standard. The ACR case definition of cognitive impairment identifies eight domains of cognitive functioning of particular importance: simple attention, complex attention, memory, visuospatial processing, language, reasoning/ problem solving, psychomotor speed, and executive functions.4 Using formal neuropsychological assessment, 16 cross-sectional studies in SLE revealed cognitive impairment in 17% to 59% that was considered subclinical in 11% to 54% of patients.23 The pattern of cognitive impairment in SLE patients is neither specific nor unique. Impairments include slowed information processing speed, reduced working memory, and executive dysfunction (e.g., difficulty with multitasking, organization, and planning), which is a pattern associated with pathology affecting subcortical brain regions.24 A similar “subcortical” pattern of cognitive impairments is seen in multiple sclerosis (MS).25 Computerized neuropsychological assessment of cognitive efficiency, using the Automated Neuropsychological Assessment Metrics (ANAM),26 identified cognitive impairment in 69% of adult SLE patients and 59% in a study of childhood-onset SLE.27 In another study of adult SLE patients studied within 9 months of diagnosis, Petri and colleagues found cognitive impairment in 21% to 61% of cases, depending on the stringency of the definition of impairment.28 Hanly and colleagues also found a range of cognitive impairment, from 11% to 50% compared with locally recruited healthy controls, which again depended on the stringency of the definition of impairment.29 Moreover, this frequency was comparable to that seen in patients with rheumatoid arthritis (RA; 9%–61%) and lower than in MS patients (20%–75%) from the same center. Although it seems clear that computerized tests such as ANAM are sensitive to identifying reduced cognitive efficiency, this may arise from many causes (see Box 36.1). Computerized testing facilitates efficient screening of SLE patients by nonexperts but may fail to identify higher level cognitive impairment in SLE.29 Prospective studies have generally not found increasing point prevalence in cognitive impairment.30-32 In a 5-year prospective study of 70 patients Hanly and colleagues found a decline in overall cognitive impairment from 21% to 13% with most either never impaired or with resolution of cognitive impairment and only a minority demonstrating emergent, fluctuating, or persistent impairment.30 Similar trajectories of cognitive impairment have been reported in other prospective studies ranging from 2 to 5 years’ duration.31,32 Patients who are at the highest risk of a decline in cognitive function on repeat testing are those with a history of clinical NP events, abnormal MRI with multiple strokes and cerebral atrophy, and persistently elevated antiphospholipid antibodies.33,34 Cognitive decline is not associated with corticosteroid use. The pathogenesis of cognitive dysfunction in SLE is unknown. An association has been reported between cognitive abnormalities and certain autoantibodies in the serum or cerebrospinal fluid (CSF) or both. As mentioned previously, the strongest agreement is the association between cognitive dysfunction, cognitive decline, and persistently positive antiphospholipid antibodies. Faust and colleagues have reported that a subset of anti–double-stranded DNA (anti-dsDNA) antibodies that cross-react with the anti-N-methyl-d-aspartate receptor subunit 2A (NR2A) and anti-N-methyl-d-aspartate receptor subunit 2B (NR2B) of the N-methyl-d-aspartate receptor (NMDAR) is associated with diffuse CNS manifestations including cognitive dysfunction and emotional distress, particularly when present within the CSF.35 This association is notable because this subset of NMDARs is increased in both the hippocampus (learning and memory) and the amygdala (fear-conditioning response). They are receptors for glutamate, the major excitatory neurotransmitter of the brain. Notably, the expression of these receptors is altered in major psychoses, and receptor antagonists

437

cause hallucinations and paranoia.36,37 In both murine and human SLE, the anti-NR2 antibodies have been shown to bind to a pentapeptide consensus sequence (“DWEYS”) contained in the extracellular ligand binding domain of NR2 receptors.38,39 Enhanced permeability of the blood-brain barrier is critical for the anti-NR2 antibodies to gain access to the neuronal cells.38 The blood-brain barrier may be permeabilized by SLE (e.g., immune complex deposition, cytokines) and non-SLE (e.g., smoking, hypertension, epinephrine) factors. In contrast to previous antineuronal antibodies, anti-NR2 antibodies induce apoptotic cell death in vitro and in vivo causing cell injury akin to excitatory amino acid toxicity by enhancing calcium influx into the neuron resulting in mitochondrial stress and caspase activation. Such neuronal cell injury/ death could lead to clinical NP manifestations. This effect is mediated via the antigen binding portion of the antibody and is inhibited by memantine, an NMDA receptor antagonist.38 In human lupus the association between circulating anti-NR2 antibodies and NPSLE is less clear. Omdal and colleagues found an association between serum anti-NR2 antibodies and depression, decreased short-term memory, and impaired learning.40 Apart from another report of an association with depression, four cross-sectional studies did not confirm these findings.41-44 Yoshio and colleagues studied both serum and CSF samples from 80 SLE patients (53 with NPSLE) and found the strongest association between NP events and anti-NR2 antibodies in the CSF.45 Another study of CSF samples from 53 SLE patients found anti-NR2 antibodies in 44% and 82% of patients with focal and diffuse NPSLE, respectively.46 These data suggest that access of anti-NR2 antibodies to brain neuronal antigens can cause clinical NP events, although a permeabilized blood-brain-barrier may be required for this to occur. Most studies of cognitive impairment have used adult study subjects with SLE but not pediatric patients, because no validated battery of neuropsychological tests for children with SLE has been available. Recently a pediatric version of the ANAM (Ped-ANAM) has been validated in a pediatric lupus population and showed neurocognitive impairment in childhood patients with lupus without a history of NPSLE.47 The future impact of cognitive dysfunction on a child’s academic achievement and activities of daily living is unknown, but it is likely to be significant as the maturing adolescent brain is more vulnerable to disease-associated injury. An additional concern is the potential effect of maternal antineuronal antibodies, such as anti-NR2, on a fetus whose brain lacks a competent blood-brain barrier for much of the gestation period.

Headache Headaches (migraine and tension) are common in SLE patients, reportedly occurring in 24% to 72%, but the association with NPSLE is controversial.2,3,7 Some investigators have described a headache (i.e., lupus headache) characterized by an acute presentation during a serologically active lupus flare with or without other neurologic manifestations that resolves with corticosteroid therapy as the lupus disease activity improves. A recent large prospective study of 1732 SLE patients found headaches occurred in 17% at enrollment and 58% of patients after 10 years of disease.48 However, the headaches in this cohort were not associated with SLE disease activity or specific autoantibody and resolved independent of other treatment for SLE, which suggests a nonlupus cause. Furthermore, a meta-analysis of multiple studies has found no increase in the frequency of headache in SLE patients compared with control groups.49 Indeed, headache is a common occurrence in the general population, especially in women with up to 62% prevalence in 1 year.50 This has led to the conclusion that headache is so prevalent in the general population that, in isolation, it is not possible to attribute it to SLE. Some have suggested that headache is not a primary manifestation of NPSLE and should not be a variable in SLE global disease activity

438

SECTION 5  Clinical Aspects of Lupus Erythematosus

indices.51,52 Treatment of isolated headaches in patients with SLE should be similar to patients without lupus. In an individual SLE patient with disabling headaches, many etiologies must be considered. Previous studies have suggested that migraine headache in patients with SLE is associated with Raynaud phenomenon, antiphospholipid antibodies, and/or thrombotic events. However, controlled studies of over 275 patients have failed to confirm these observations.53 Despite the lack of confirmation, some clinicians will administer a 2-week trial of low-molecular-weight heparin to determine whether treatment-resistant headaches improve in a patient with antiphospholipid antibodies who is not on anticoagulation. Another cause of severe headache is benign intracranial hypertension (i.e., pseudotumor cerebri), which can occasionally be a manifestation of NPSLE.54 Presenting signs include refractory headaches, papilledema, and no focal neurologic symptoms. Lumbar puncture reveals increased intracranial pressure (>250 mm H2O), normal protein, and no white blood cells in the CSF. Although pseudotumor cerebri can occur in adults for multiple reasons (e.g., obesity, sleep apnea, medications), most SLE patients are young, adolescent women with severe disease. Several patients have had a history of rapid corticosteroid withdrawal, and 50% had cerebral venous sinus thrombosis as a result of hypercoagulability (e.g., nephrotic syndrome, antiphospholipid antibodies) as a potential cause. Headache can also be a component of other NP events attributed to SLE including CNS vasculitis, cerebral vein thrombosis, intracranial hemorrhage, and aseptic meningitis. In all SLE patients with headache, nonlupus secondary causes must always be ruled out before ascribing a severe headache to primary NPSLE regardless of disease activity. The most common or important secondary causes include severe hypertension, infection, nonsteroidal antiinflammatory medications (e.g., aseptic meningitis), antimalarial therapy, sleep apnea, cerebral venous sinus thrombosis, and subdural hematoma.

Aseptic Meningitis Aseptic meningitis in SLE is rare (<1%). Patient symptoms include fever, headache, meningeal signs, and CSF pleocytosis with normal CSF glucose and protein usually less than 100 mg/dL. The pleocytosis is most commonly less than 200 to 300 cells/mm3 and predominantly (>50%) lymphocytes. Rarely, significantly higher cell counts with a neutrophil predominance can occur in patients who are severely ill. Infectious meningitis of any cause, subarachnoid hemorrhage, carcinomatous meningitis, sarcoidosis, and medication effects from nonsteroidal antiinflammatory drugs (NSAIDs; e.g., ibuprofen, others), as well as from intravenous gamma globulin (IVIG) and azathioprine, must be excluded. The cause of aseptic meningitis in NPSLE is unclear, but patients usually respond to corticosteroid therapy.

Cerebrovascular Disease CVD occurs in 5% to 18% of patients with SLE and can affect any area of the brain.55-57 Ischemic strokes account for 80% of the CVD observed. Hemorrhagic strokes from intraparenchymal or subarachnoid bleeding can also occur. Overall, the risk of stroke is approximately two times the age- and sex-matched controls. For premenopausal women with SLE, the stroke standardized incidence ratio is reported to be 8 to 22 times that of aged-matched controls.58 Strokes caused by primary NPSLE usually occur within the first 5 years of the onset of SLE. Several risk factors have been identified including antiphospholipid antibodies, active SLE (SLEDAI > 6), previous stroke or transient ischemic attack (TIA), cigarette smoking, hypertension, dyslipidemia, diabetes mellitus, cardiac valvular disease, and advanced age.5,57 Common presentations include TIAs, hemiplegia, aphasia, cortical blindness, or other deficits of cerebral function. Seizures, movement disorders, and cognitive impairment can also result from CVD. Strokes are frequently severe,

and between 13% and 64% of patients will have a recurrent stroke resulting in significant morbidity and mortality (12%–28%).55,59 Strokes can be from large-vessel or small-vessel disease. Large-vessel strokes can be the result of thrombosis from a coagulopathy, cardiogenic emboli, vasculitis, and/or accelerated atherosclerosis.60 An acute presentation favors an embolic source, whereas subacute presentations are seen more commonly with in situ thrombosis or vasculitis. Small-vessel strokes and TIAs can be from antiphospholipid antibody–associated thrombosis, noninflammatory vasculopathy, emboli, vasculitis, or leukothrombosis. Patients with stroke from antiphospholipid antibodies frequently have evidence of livedo reticularis (Sneddon syndrome). Patients with CNS vasculitis typically present with fever, headache, and confusion with or without seizures and/or coma in combination with active SLE and cutaneous vasculitis. The diagnosis of CVD is made clinically and supported by neuroimaging studies. A computed tomography (CT) scan of the brain is capable of detecting cerebral hemorrhage and large infarctions, making it a useful study in screening patients with SLE who have acute neurologic deterioration. Cranial MRI with contrast is superior to CT scanning in detecting smaller and frequently transient lesions. An MRI typically shows hyperintense gray and white matter lesions on T2-weighted images, which account for the patient’s clinical symptoms. Additional lesions in clinically silent areas are also frequently observed (Fig. 36.1A). Magnetic resonance angiography (MRA), carotid Doppler ultrasound, echocardiogram, and transcranial color Doppler sonography (TCDS) are noninvasive procedures that can be useful in detecting large-vessel vasculitis, thrombosis, microemboli, or sources of emboli, leading to vascular occlusion and stroke. Angiograms are more likely to show abnormalities in patients with large infarctions. CSF examination may show pleocytosis and high protein in patients with cerebral vasculitis or blood in patients with subarachnoid hemorrhage. Otherwise, the CSF examination is usually normal or demonstrates nonspecific abnormalities, such as a few cells or high protein or both. Primary prevention of CVD in SLE patients includes risk factor modifications such as smoking cessation and control of hypertension, hyperlipidemia, hyperglycemia, and elevated homocysteine levels. Most patients with antiphospholipid antibodies should receive low-dose aspirin or other antiplatelet therapy. Many physicians also prescribe hydroxychloroquine for its antithrombotic and lipid-lowering effects. In patients who present with a large-vessel stroke, acute management is similar to patients without SLE and requires a stroke specialist to identify patients who would benefit from thrombolysis/thrombectomy. Otherwise, treatment of strokes in patients with SLE is based on the suspected pathogenesis.5 Patients with suspected vasculitis are treated with corticosteroids and cytotoxic drugs, whereas those with a thrombosis from a coagulopathy, antiphospholipid antibodies, or cardiac emboli are treated by anticoagulation therapy with or without antiplatelet agents. Treatment of patients with strokes as a result of a noninflammatory vasculopathy is difficult because the pathogenesis of these vascular lesions is unclear. Most clinicians prescribe low-dose aspirin or other platelet inhibitors and hydroxychloroquine while aggressively treating stroke risk factors. The value of corticosteroids with or without other immunosuppressive medications is uncertain, but they are often given to patients who are serologically active or to control other accompanying lupus manifestations.61

Myelopathy Myelopathy occurs in approximately 1% to 1.5% of patients and can be the initial presentation of SLE. Most patients (80%) are young women between 20 and 40 years of age, although childhood cases have also been reported.62 Investigators have reported that lupus patients can present with one of two distinct transverse myelitis syndromes.63 Patients

CHAPTER 36  Lupus and the Nervous System

A

439

B Figure 36.1  Axial brain magnetic resonance imaging (fluid-attenuating inversion recovery sequence). (A) Brain atrophy, multiple infarcts, and white matter hyperintensities in a 36-year-old woman with systemic lupus erythematosus (SLE) with antiphospholipid antibodies presenting with cognitive decline and neurologic deficits. (B) Vasogenic edema caused by posterior reversible encephalopathy syndrome in a 42-year-old woman with SLE presenting with headache, cortical blindness, isolated seizure, and severe hypertension.

with myelitis affecting predominantly gray matter present with the acute onset (<6 hours) of lower extremity flaccidity, hyporeflexia, and urinary retention with a preserved sense of needing to void. Patients typically have active SLE accompanied by fever, nausea, and vomiting. CSF is abnormal with a neutrophilic pleocytosis (80%), elevated protein (100%), and decreased glucose (50%). Relapses are uncommon but any delay in treatment results in poor if any neurologic recovery. Patients with myelitis affecting predominantly white matter present with the subacute onset (>72 hours) of progressive weakness (paraparesis, quadriparesis), bilateral sensory deficits, spasticity, hyperreflexia, and impaired sphincter control. White matter myelitis can occur in patients without active SLE. CSF is abnormal in the majority of patients, although the levels of pleocytosis, elevated protein, and decreased glucose are much less pronounced compared with patients with gray matter myelitis. Relapses are common and can lead to permanent disability. An MRI of the spinal cord should be done on all patients with suspected myelitis. It can help confirm the diagnosis and exclude other causes of spinal cord compression, which may benefit from surgery. An MRI of lupus myelopathy typically shows edema with abnormalities of T2-weighted images (up to 93%), which may be accompanied by spinal cord enlargement in 75% of patients. Any level of the spinal cord can be involved, with gray matter myelitis more typically involving the thoracolumbar spinal cord and white matter myelitis involving the cervicothoracic cord. Notably, some patients may have a normal MRI, especially if the examination is delayed (longer than 5 days) or if the patient has received treatment. The differential diagnosis includes compressive myelopathy (e.g., tumor, abscess, hematoma), epidural lipomatosis, vertebral compression fracture, anterior spinal artery syndrome, infection (e.g., tuberculosis, multiple viruses), sarcoidosis, and Guillain–Barré syndrome. The cause of lupus myelopathy is multifactorial. Vasculitis during an acute exacerbation of lupus leading to ischemic necrosis of the cord has been pathologically documented in a few cases. Some investigators

have reported that patients with SLE myelopathy frequently have antiphospholipid antibodies and thrombosis, whereas other investigators have not. Recently anti-neuromyelitis optica (NMO) IgG (anti–NMOIgG) antibodies have been associated with transverse myelitis.64 The antigenic target of these antibodies is aquaporin-4, which is the most abundant water channel in the CNS. These patients have several features in common, including the development of longitudinally extensive transverse myelitis involving at least three vertebral segments on MRI. This abnormality is distinct from other causes of myelopathy that typically involve a single segment. Additional features that may be present include a history of optic neuritis, coexistent Sjögren’s, and anti-Sjögren’s antigen A (anti-SSA/Ro) antibodies.65 Identification of this subset of white matter myelitis is important because the presence of anti–NMO-IgG antibodies indicates a severe disease course with frequent relapses. Lupus myelopathy tends to have a poor prognosis. Several reports have emphasized that pulsed methylprednisolone and cyclophosphamide may improve the prognosis of these patients. This therapy must be used early, because all patients with gray matter myelitis will reach their peak severity of myelopathy symptoms within 6 to 24 hours, and 50% of patients with white matter myelitis will reach their symptom nadir within 3 to 5 days of onset. Early use of aggressive therapy has resulted in the reversal of symptoms and stabilization in the majority of patients with white matter myelitis, with 50% having a complete recovery and 29% having a partial recovery.62 Plasma exchange and/or rituximab has also been successfully used, especially in patients with anti–NMO-IgG antibodies.65,66 In patients with significant titers of antiphospholipid antibodies, both immunosuppressive and anticoagulation therapy should be used, although studies are limited and have not proven that anticoagulation has any added benefit.67 Maintenance immunosuppressive therapy is needed after the initial induction regimen because recurrences of myelopathy, particularly in patients with anti–NMO-IgG antibodies, are common (50%–60%). Rehabilitation measures to prevent pressure

440

SECTION 5  Clinical Aspects of Lupus Erythematosus

sores; preserve range of motion, strength, and mobility; and institute appropriate bladder management should be initiated early.

ganglia. Treatment with immunosuppressive agents and dopamine-agonist drugs can lead to recovery.69

Movement Disorders

Demyelinating Syndrome

Chorea, hemiballismus, cerebellar ataxia, choreoathetosis, dystonia, and parkinsonian-like rigidity or tremors are rare manifestations. Chorea is the most common, occurring in less than 1% to 2% (adults) to 4% (pediatric) of patients with SLE.68 Chorea is characterized by rapid, brief, involuntary, and irregular movements and may be generalized or limited to the extremities, trunk, or face. Choreoathetosis is diagnosed when chorea is accompanied by slow, writhing movements of the affected extremity. Chorea occurs most commonly in young women, children, and during pregnancy (chorea gravidarum) or the postpartum period. It may be the initial presentation of SLE or precede other manifestations of SLE by years. Chorea usually occurs early in the course of SLE, can be unilateral or bilateral, can be recurrent (35%), and is frequently associated with other NPSLE symptoms such as strokes and psychiatric manifestations. Antiphospholipid antibodies are frequently found and may be responsible for basal ganglia infarction. Blood-brain barrier disruption allowing entry of antineuronal antibodies directed against unknown neuronal antigens in the basal ganglia has also been postulated. The CSF examination and brain MRI are frequently unremarkable. Functional imaging shows basal ganglia hyperactivity. The symptoms of chorea usually last for several weeks and rarely can last for up to 3 years. A long differential diagnosis of illnesses is rarely associated with chorea. Sydenham chorea secondary to rheumatic fever is the most common and can be ruled out by obtaining antistreptococcal antibodies (anti-DNase B). However, the onset of chorea in a young woman with a positive antinuclear antibody (ANA) test result should strongly suggest SLE. The recommended treatment of chorea is dopamine receptor antagonists combined with antiplatelet therapy if antiphospholipid antibodies are present.5 Immunosuppressive therapy is used in patients with generalized lupus activity or who fail to respond to conservative treatment. Many patients spontaneously recover or improve on treatment, whereas others fail to respond to immunosuppressive therapy. Patients with evidence of thrombosis with or without antiphospholipid antibodies should receive anticoagulation. Infarction of the subthalamic nucleus can result in hemiballismus, which has rarely been reported in SLE. Ballismus may be steroid responsive or related to antiphospholipid antibodies. Cerebellar ataxia is reported in less than 1% to 2% of patients with SLE. Patients have an inability to stop or end purposeful movements. The abnormalities may involve the trunk or extremities. Dysarthria and nystagmus are common. The cause is uncertain, but some cases may be caused by cerebellar or brainstem infarction or antiphospholipid antibodies, or may be associated with Purkinje cell antibodies. In patients with cerebellar atrophy associated with antibodies against Purkinje cells, a paraneoplastic syndrome must be ruled out before attributing it to NPSLE. Aggressive immunosuppressive therapy is recommended coupled with anticoagulation in patients with thrombotic infarctions caused by antiphospholipid antibodies. Tremor of all types has been reported in up to 5% of patients with SLE during the course of their disease. However, parkinsonian-like symptoms caused by alterations of the substantia nigra are an extremely rare manifestation of NPSLE. Patients present with behavioral alterations (e.g., irritability, apathy), rigidity and progressive bradykinesia, and/or akinetic mutism. Vascular infarction caused by antiphospholipid antibodies and antidopaminergic antibodies are proposed as pathogenetic mechanisms. MRI shows hyperintensities in the thalamus and basal ganglia in 50% of patients. Single-photon emission CT (SPECT) cerebral scanning can detect decreased regional cerebral blood flow to the basal

Syndromes similar to MS, sometimes called lupoid sclerosis, have rarely (<1%) been described in patients with SLE.70 Interestingly, both MS and NPSLE share many features including clinical presentation, Lhermitte sign, a positive ANA test result (2%–27% of patients with MS), abnormal CSF with elevated IgG index and oligoclonal bands, and abnormal brain MRIs. Whether both diseases can coexist in one patient or whether lupoid sclerosis is simply an unusual presentation of NPSLE is unclear. Notably antiphospholipid antibodies have been demonstrated in a number of patients with an MS-like illness, suggesting these antibodies may be pathogenic in lupoid sclerosis and transverse myelitis. Another MS-like presentation is Devic disease (NMO spectrum disorder).64,65 These patients present with optic neuritis and longitudinally extensive transverse myelitis either simultaneously or separately. They have anti–NMO-IgG antibodies (75%); however, unlike patients with MS, they frequently have anti-SSA/Ro antibodies (see previous discussion in the section Myelopathy). Patients with SLE with antiphospholipid antibodies can mimic this presentation with optic nerve and spinal cord infarction. The therapy of patients with lupoid sclerosis differs from MS therapy. Both patient populations may respond to immunosuppressive therapy. However, patients with SLE who have lupoid sclerosis or optic nerve or spinal cord infarction caused by vascular occlusion from antiphospholipid antibodies are best treated with anticoagulation therapy. Patients with SLE with NMO spectrum disorder should receive aggressive immunosuppressive therapy and in some cases plasma exchange.

Seizures Seizures occur in 4% to 20% of patients with SLE and are more frequent in patients with African ancestry.3,71 They may occur before the development of other symptoms of SLE or at any time during its course, with 50% occurring during the first year after SLE diagnosis.72 The seizures can be an isolated neurologic event but are more commonly associated with active generalized multisystem lupus activity with or without other NP manifestations. Generalized major motor (67%–88%) and partial complex seizures are most common, although any kind of seizure can occur. Seizure episodes are usually self-limited, although status epilepticus can occur and frequently signals a preterminal event. The cause of seizures in NPSLE is multifactorial. Antineuronal antibodies, focal ischemia, and infarctions caused by vascular occlusion from thrombosis and emboli, hemorrhage, and cytokine or neuroendocrine effects on the seizure threshold have all been implicated. Several studies have shown an association between antiphospholipid antibodies and seizures in patients with SLE.73 An increased risk of seizures, seizures with strokes, and recurrence of seizures exists in patients with higher titers of antiphospholipid antibodies. Some investigators have demonstrated a direct effect of these antibodies on neurons, possibly leading to neuronal dysfunction and seizure by a nonthrombotic mechanism.74 However, most seizures in patients with antiphospholipid antibodies are probably the result of cerebral ischemia from cerebral microinfarctions. Secondary causes of seizures include infections, medication effects, metabolic disturbances, hypoxemia, and hypertension, which must be ruled out in all patients with SLE who have seizures. The majority of seizures attributed to SLE have a favorable prognosis, resolving without the use of long-term antiseizure drugs, no discernable effect on health-related quality of life, and a low rate of recurrence.71 Two studies have reported a lower risk of seizures in SLE patients on antimalarial drugs, even after adjusting for confounding variables.71,75 Risk factors for recurrent seizures requiring anticonvulsant therapy

CHAPTER 36  Lupus and the Nervous System include antiphospholipid antibodies, high disease activity, focal neurologic signs, abnormal brain MRI, and an epileptiform electroencephalogram (EEG). Although some anticonvulsant medications have been shown to cause a positive ANA test result and rarely clinical SLE, this presentation is no reason to withhold these medications when they are indicated for patients with established lupus.5 Seizure control is important because recurrent seizures increase the vulnerability of neurons to additional injury. Consequently, corticosteroids and other immunosuppressive medications should be used in patients with status epilepticus, recurrent seizures, or other neurologic manifestations. Patients with SLE with high-titer antiphospholipid antibodies and seizures should also receive anticoagulation therapy, especially if the brain MRI shows areas of microinfarction.

Psychiatric Disorders Psychosis

Psychosis occurs in up to 11% of patients with SLE (2%–4% in most series) with the initial episode occurring within the first year after the diagnosis of SLE in the majority (60%–80%).5,76 The predominant symptoms are delusions and/or hallucinations (usually auditory in NPSLE). Most patients have evidence of globally active lupus. Therefore the sudden onset of psychosis in a patient with clinically and serologically active SLE without a psychiatric history or precipitating cause is usually indicative of NPSLE. Some investigators have reported an association between antiribosomal P antibodies and psychosis.77 Titers of these antibodies reportedly rise with an exacerbation of psychosis and decrease in response to corticosteroid therapy. Other studies have not found a correlation between these antibodies and psychosis.78,79 Other causes of psychosis must be ruled out including high-dose corticosteroids (recent increase of prednisone to >30–40 mg/d), nonprescribed drug abuse, schizophrenia, depression, and other immune-mediated encephalopathies. Generally lupus psychosis has a favorable prognosis.76

Mood Disorders The ACR case definitions for mood disorders consist of major depressivelike episodes, mood disorder with depressive features, mood disorder with manic features, and mood disorder with mixed features.4 Some previous studies have included patients with particularly severe mood disorders under the category of lupus psychosis. Mood disorders are one of the most common NP events reported in SLE cohorts and are usually among the top three of all NP events.3,7 The reported frequency of mood disorders has been up to 43% but more typically is between 6% and 17%.2,3 A recent study reported that mood disorders occurred in 12.7% of 1827 patients followed over the first 5 years of their disease, and the estimated cumulative incidence of any mood disorder after 10 years was 17.7%.80 However, most of these psychiatric issues are the result of nonlupus causes such as medications, a reaction to a chronic illness, or other psychosocial factors. The most frequent types of mood disorders are major depressive-like episodes and mood disorder with depressive features, which occur in equal proportions.80 The frequency of mood disorders in SLE patients is comparable to the general population and to patients with other chronic diseases. For example, depressive disorders were detected in 8.6% of 8764 randomly selected individuals in the general populations of five European countries, with the highest prevalence in women at 10.1% compared with 6.6% among men.81 The frequency of major depressive episodes in the United States over 1 year was 10%. The frequency of depression in East Asian countries is considerably lower (e.g., South Korea 2.9%) than that in Western countries, which is also the case for SLE patients from the same geographic region.82 Whether this lower frequency can be attributed to cultural or biological factors is unknown. A systematic review of 13,189 patients with RA showed

441

depression in 34.2% to 38.8% of the patients (using two self-reporting questionnaires) and a frequency of major depressive disorder in 16.8% of the patients.83 The use of depression symptom questionnaires to screen for mood disorders is problematic. Commonly used instruments often include symptoms such as fatigue, sleep disturbance, loss of appetite, and worries about health, all of which overlap with symptoms for medical conditions. This poor specificity can result in poor positive predictive value when depression screening instruments are used in SLE cohorts. For example, Petri and colleagues reported an 8.1% prevalence of mood disorder according to ACR case definition criteria but a 31% prevalence of depression on the basis of their screening instrument.84 Using the latter, they found depression to be associated with the presence of fibromyalgia and with poorer cognitive test performance, although not with other demographic or clinical characteristics. For these reasons the use of screening questionnaires is not recommended by the Canadian Task Force on Preventive Health Care for the detection of mood disorders in place of face-to-face clinical screening. The etiology of mood disorders in SLE and specifically the attribution of this common NP event to SLE or non-SLE causes may be challenging in individual patients. Antiribosomal P antibodies and anti-NR2 antibodies have been associated with severe mood disorders in some but not all studies.85 A recent study with a systematic approach to attribution using a clinical algorithm reported that 38% of mood disorders were attributable to SLE, but the lack of association with global SLE disease activity, cumulative organ damage, and a panel of lupus autoantibodies traditionally associated with NPSLE implies that the majority of mood disorders are not primary manifestations of the disease.80 In addition, although dysregulated production of type I interferon (IFN) is a frequent occurrence in SLE and has been associated with several events, including mood disorders, at least one study did not demonstrate an association between elevated production of type I IFN and depression and fatigue in patients with SLE.86 Finally, the association between mood disorders and treatment with high-dose prednisone has been inconsistent.80 The occurrence of mood disorders in SLE patients has a number of consequences, including a reduced health-related quality of life, even after adjustment for multiple potential confounders including SLE disease activity, cumulative organ damage, and medications. The cooccurrence of mood disorders with other NP events may complicate their assessment. For example, cognitive symptoms, but not necessarily impaired cognitive function, are more frequent in both SLE and non-SLE patients with depression, which should be treated before the formal assessment of cognitive function. Furthermore, the occurrence of mood disorders is associated with a higher frequency of nonadherence to recommended therapies, scheduled clinic appointments, and recommended lifestyle modifications, all of which are critical to the optimal management of SLE.

Anxiety Disorders Anxiety, which can co-occur with or be a symptom of depression, is common in SLE, occurring in 24% to 57% of patients, although there is often uncertainty about their etiology and attribution.2,3,7 Anxiety disorders represent prominent generalized anxiety or panic attacks, or obsessions or compulsions that result in significant distress or impaired function. However, it can be extremely challenging to attribute an anxiety disorder to physiologic changes of the CNS caused by SLE rather than the side effects of pharmacologic treatment or an adjustment reaction in which anxiety symptoms result from the stress of having this medical condition. As with data derived from self-report instruments for mood and anxiety symptoms, it is important to distinguish between anxiety symptoms and anxiety disorders. Based on a prospective study of 23

442

SECTION 5  Clinical Aspects of Lupus Erythematosus

SLE patients, Ward and colleagues found that anxiety symptoms varied with global SLE disease activity, whereas Segui and colleagues reported that a decline in anxiety symptoms accompanied the change from active to quiescent disease. This suggested that distress resulting from active lupus may increase anxiety symptoms.87,88 Ishikura and colleagues found that anxiety symptoms were associated with lack of knowledge about SLE and its management at the start of treatment, suggesting that improved knowledge about SLE and its treatment may reduce the likelihood of future emergence of anxiety symptoms.89

Peripheral Nervous System Cranial Neuropathies

Cranial neuropathy occurs in 1% of patients with SLE during the course of the disease. It usually occurs during active SLE, can be transient, and usually responds to corticosteroid therapy. Ptosis, third and sixth nerve palsies, internuclear ophthalmoplegia, trigeminal neuralgia, and facial nerve palsies are the most common. Optic neuropathy causing blindness, anosmia, tinnitus, vertigo, and sensorineural hearing loss are less common symptoms. The causes of cranial neuropathies include vascular occlusion and focal meningitis. Autopsy studies have demonstrated lesions in the brainstem, as well as the peripheral part of the cranial nerves. Some of these neuropathies have been associated with vasculitis and others with thrombosis associated with antiphospholipid antibodies. All patients with optic neuritis should be tested for anti–NMO-IgG antibodies.64,65 Concurrent Lyme disease, sarcoidosis, myasthenia gravis, and brainstem or base-of-skull lesions must be ruled out before attributing a cranial neuropathy to NPSLE. Treatment is initially with corticosteroids. Cytotoxic medications are reserved for those who do not respond or those who present with optic nerve involvement. Anticoagulation is instituted if antiphospholipid antibodies are the suspected cause of cranial nerve infarction.

Peripheral Polyneuropathies Peripheral nerve involvement occurs in 1.5% to 27% of patients with SLE, depending on diagnostic criteria used.90,91 Other studies report that 5% to 14% of SLE patients have a peripheral neuropathy with approximately 60% of those caused by lupus and the rest caused by a nonlupus cause.7,92-94 Symptoms can be severe or subtle and overlooked by the clinician. The most common presentation is a sensory or sensorimotor axonal polyneuropathy (55%–60% of patients). Recently a small-fiber neuropathy has been reported in up to 17% of patients with a lupus-associated peripheral neuropathy.93,95 Less commonly, patients can have a mononeuritis multiplex; acute or chronic demyelinating polyradiculopathy; and, rarely, a plexopathy. Peripheral neuropathy can be an initial or later manifestation of SLE and does not always correlate with disease activity. Alternative nonlupus causes for the peripheral neuropathy including nerve root compression, uremia, diabetes mellitus, drug toxicities, vitamin deficiencies, heavy metal or solvent exposure, cancers and paraproteinemias, viral and other infections, sarcoidosis, alcohol and other toxins, and hereditary neurologic diseases must always be excluded. Patients with distal, symmetric or asymmetric, peripheral polyneuropathy can present with mild to severe sensory or sensorimotor fiber involvement. Patients usually complain of numbness and dysesthesias. Neurologic testing shows cutaneous hypesthesia to pinprick, light touch, and temperature stimuli. Most of these patients have a length-dependent peripheral neuropathy supported by abnormal neurodiagnostic studies showing an axonal polyneuropathy. Less commonly (<1%), a large, myelinated afferent fiber is involved, which exhibits deficits of vibratory and proprioceptive sense, areflexia, and sensory ataxia with variable motor dysfunction. When motor axons are affected, weakness and muscle atrophy are seen. Electrodiagnostic studies usually show features of a

mixed axonal and demyelinating neuropathy. The pathogenesis of the peripheral neuropathy is unclear. Antineuronal antibodies and vasculitis from deposition of immune complexes have both been implicated. Patients with significant paresthesias and/or weakness and abnormal nerve conduction tests are treated with glucocorticoids with or without other immunosuppressive medications and neuroleptic agents. SLE patients with symptoms suggestive of a peripheral neuropathy but with normal nerve conduction studies may have a small-fiber neuropathy.93,95 Notably this neuropathy is not included in the ACR NPSLE case definitions.4 Patients can present with a length-dependent small-fiber neuropathy manifested by burning pain in the feet or stockingglove distribution. Examination can show allodynia or hyperalgesia; decreased sensation to pinprick and temperature; and normal reflexes, motor strength, and proprioception. Vibratory sensation may or may not be affected in the toes. Immunohistologic staining of skin biopsies demonstrates a decreased density of the intradermal, small-diameter, nonmyelinated C fiber nerves of the feet compared with a skin biopsy of a more proximal part of the leg suggesting distal neuronal involvement. Alternatively, some patients have burning dysesthesias involving their torso and/or proximal extremities with abnormal skin biopsies of the affected areas while skin biopsies of their distal extremities are normal. These patients have a non–length-dependent small-fiber neuropathy that is postulated to be caused by dorsal root ganglia involvement. Because of the nonanatomic nature of these patients’ symptoms, their pain is oftentimes erroneously diagnosed as psychogenic. Patients with small-fiber neuropathy are treated symptomatically with neuroleptic medications. Most (67%) will not deteriorate on follow up. Mononeuritis multiplex is the multifocal and random dysfunction of individual, noncontiguous nerve trunks. Patients frequently develop sensorimotor deficits in the upper or lower extremities (wrist drop or foot drop) with an asymmetric distribution. Occasionally, it can be widespread and mimic a distal, symmetric, sensorimotor polyneuropathy. Mononeuritis multiplex typically occurs in the setting of active SLE, often with other neurologic abnormalities. Neurodiagnostic studies usually show an axonal pattern with a reduction in amplitude of evoked compound action potentials with relative preservation of nerve conduction velocities. The cause is believed to be a vasculitis of the vasa nervorum, although this can only be demonstrated on sural nerve biopsy in 50% of cases. Aggressive therapy with corticosteroids and pulse IV or daily oral cyclophosphamide with or without plasma exchange is recommended.96 Rituximab or IVIG therapy has also been effectively used. Recovery of nerve function takes up to 1 year. Few cases of patients with SLE with an inflammatory polyradiculoneuropathy have been reported.97 There are two forms: the acute form resembles Guillain–Barré syndrome and the chronic form resembles chronic, inflammatory, demyelinating polyradiculoneuropathy. Patients with acute presentation have an ascending, predominantly areflexic motor paralysis, which peaks in 10 to 14 days. Little or no sensory loss occurs because small, nonmyelinated fibers are not involved. Involvement of large myelinated afferent fibers leads to the loss of proprioception and vibratory sensation. An associated autonomic dysfunction can develop in some patients. No sphincter disturbance occurs, which helps separate it from transverse myelitis. CSF examination reveals an elevated total protein level with a white blood cell count less than 50 cells/mm3. Electrodiagnostic studies reveal a demyelinating pattern with a slowing of nerve conduction velocities, dispersion of evoked compound action potentials, conduction block, and significant prolongation of distal latencies. The pathogenesis is unknown, but most cases occur early in the course of a patient with active SLE. Unlike in Guillain–Barré syndrome without SLE, patients have been successfully treated with corticosteroids with or without cyclophosphamide. Experience with

CHAPTER 36  Lupus and the Nervous System

443

the use of plasmapheresis or IVIG is limited but is frequently used in conjunction with immunosuppressive agents in SLE patients with this presentation. Recovery can occur within weeks if no neuronal damage has occurred. Patients with SLE who exhibit chronic demyelinating polyradiculopathy resembling chronic inflammatory demyelinating polyneuropathy (CIDP) can experience recurrent episodes of acute symptoms similar to those with Guillain–Barré syndrome, a mononeuritis multiplex-like pattern, or a symmetric polyradiculopathy evolving over weeks to months.98 Electrodiagnostic studies frequently are confusing, showing a mixed axonal-demyelinating pattern. Nerve biopsy is usually not helpful but may show inflammation. Therapy includes corticosteroids, plasmapheresis, cyclophosphamide, rituximab, and IVIG.

NPSLE was present in twice as many hospitalized patients, compared with SLE outpatients. In those with NP manifestations, over 70% occur within the first year of diagnosis of SLE. Headaches, psychosis, and cognitive dysfunction are the most common presentations. Chorea is a more common manifestation in pediatric NPSLE than adults and is associated with antiphospholipid antibodies. Additionally, adolescent patients with SLE with antiphospholipid antibodies, particularly the lupus anticoagulant, are most at risk for strokes and need lifelong anticoagulation therapy to prevent recurrences.101 Overall survival in pediatric patients with primary NPSLE is 95%, but at least 25% have evidence of permanent NP damage. In older age groups (>50 years), CNS involvement is reported to be less frequent (6%–19%), is milder, and has a better prognosis.104

Autonomic Disorders

SECONDARY CAUSES OF CENTRAL NERVOUS SYSTEM DYSFUNCTION IN SLE

Acute severe autonomic neuropathy with profound dysfunction of the parasympathetic or sympathetic nervous system or both has rarely (<1%) been reported. Gastrointestinal (constipation), cardiovascular (orthostatic hypotension), genitourinary (sphincter control, sphincteric action, erectile or ejaculatory dysfunction), sweating (anhidrosis and heat intolerance), and pupillary abnormalities are evident and, when severe, respond to corticosteroids. Sensitive tests of autonomic function show that mild dysfunction may be present, although clinically unappreciated, in up to 20% of patients with lupus.99 This dysfunction does not correlate with disease duration, lupus activity, or the presence of peripheral neuropathy. Some of these patients have a small-fiber neuropathy. The clinical significance, prognosis, and treatment for these mild abnormalities are unknown.

Myasthenia Gravis and Related Disorders Myasthenia gravis and SLE may coexist in the same patient. Over 70 cases have been reported.100 Myasthenia typically precedes the onset of SLE in the majority of these patients. In some cases, SLE develops after thymectomy for the treatment of myasthenia gravis. Patients have typical manifestations of myasthenia with neuromuscular fatigue and a weakness of bulbar or other voluntary muscles with repetitive muscular contractions. No impairment of sensation or loss of reflexes occurs. Antibodies to the acetylcholine receptor can be demonstrated in 85% of patients with myasthenia and are believed to cause neuromuscular symptoms by reducing the number of acetylcholine receptors at the neuromuscular junction. Diagnosis is made clinically and confirmed with electromyography (EMG), and repetitive peripheral nerve stimulation at a rate of two per second shows a characteristic decremental response that is reversed by the acetylcholinesterase drugs. Few patients with SLE and Lambert–Eaton myasthenic syndrome have been reported. Presenting symptoms include weakness and hyporeflexia, which improves with exercise. Neurodiagnostic studies show a myopathic EMG with low-amplitude compound muscle action potential, which increases in amplitude after exercise. High-frequency, repetitive stimulation demonstrates a 50% or more increment in the amplitude of the compound motor action potential. No improvement of clinical or EMG findings occurs with anticholinesterase drugs. The etiopathogenesis is suspected to be an IgG antibody against the voltagegated calcium channels in the presynaptic neuromuscular junction. Plasmapheresis and immunosuppressive medications are effective therapy.

Neuropsychiatric SLE in Children and Older Adults As in adults, the prevalence of NP manifestations in pediatric SLE varies from 20% to 95%.101-103 A 6-year prospective study of 75 pediatric patients with SLE found that 95% had evidence of NPSLE at some time using the ACR NPSLE nomenclature.103 If only serious manifestations were considered, then the prevalence of NPSLE fell to 76%. Not surprisingly,

Secondary causes of CNS dysfunction in patients with SLE must always be ruled out before attributing symptoms to primary NPSLE (see Box 36.1). Prospective studies point out that 50% to 69% of neurologic events are caused by secondary factors.7 The most common secondary causes include infections, medications, metabolic disturbances, TTP, and sleep apnea. Equally as important, the clinician must realize that the presence of an ANA in a patient with neurologic symptoms does not imply that the patient has NPSLE or, for that matter, SLE at all. Over the last decade, posterior reversible encephalopathy syndrome (PRES) has been recognized as an important secondary cause of neurologic dysfunction.105 Some investigators think it is a manifestation of primary NPSLE, whereas others consider it a secondary cause. It can occur at any time during the course of SLE. Patients typically present with seizures (50%–95%), accelerated hypertension (70%–85%), renal disease (80%–90%), headache (70%), blurred vision (45%–50%), and/ or cortical blindness (30%). Notably, over 75% have had augmentation of their immunosuppressants (IV methylprednisolone, IV cyclophosphamide) within an average of 7 days before the development of PRES. The majority (61%) have evidence of brain MRI abnormalities involving the posterior circulation caused by vasogenic edema (see Fig. 36.1B). Other areas of the brain can also be affected. Hemorrhage can be a complication affecting up to 15% of patients with PRES. Therapy is supportive and includes prompt control of the blood pressure and control of seizures if present. Further increase in immunosuppressive therapy is contraindicated and potentially detrimental unless the patient’s SLE disease activity warrants more aggressive treatment. Long-term anticonvulsants are rarely needed once neuroimaging abnormalities resolve after an average of 20 to 25 days. With early recognition and prompt therapy, full neurologic recovery usually occurs.

Clinical and Laboratory Evaluation No single test can diagnose NPSLE. After excluding secondary causes, the diagnosis of NPSLE can only be confirmed if a patient’s NP symptoms can be corroborated with objective abnormalities in the neuropsychological examination, CSF analysis, neuroimaging studies, EEG, and/or biopsy. Therefore a methodologic workup is essential for the patient with SLE who complains of NP symptoms.4,5,18,19 A careful and thorough history and physical examination, including a complete neurologic and mental status evaluation, must be performed on each patient. In addition, a variety of laboratory, CSF, microbiological, and neurodiagnostic studies must be performed to assess disease activity and to exclude other diseases that can cause neurologic symptoms. Earlier studies emphasized that certain clinical signs, such as retinal and dermal vasculitis or livedo reticularis, were more common in patients with NPSLE, particularly those with strokes. Furthermore, although NPSLE can be the initial or

444

SECTION 5  Clinical Aspects of Lupus Erythematosus TABLE 36.2  Frequency of Abnormal

BOX 36.2  Laboratory Evaluation and

Laboratory Tests Commonly Used in the Evaluation of Neuropsychiatric Lupus Erythematosus

Diagnostic Imaging of Patients With SLE and Neuropsychiatric Manifestations Complete blood count and peripheral blood smear Chemistries: electrolytes, creatinine, glucose Liver-associated enzymes Thyroid function tests Urinalysis C3/C4 and/or CH50 Double-stranded DNA (anti-dsDNA) antibodies Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti–β2-GPI) Cerebrospinal fluid: cell count, protein, glucose, Q-albumin, IgG index, oligoclonal bands, Venereal Disease Research Laboratory, cultures, and India ink; fungal antigens (cryptococcal, histoplasma), Lyme disease PCR and viral (HSV, VZV, JC virus) PCR when indicated Brain and/or spinal cord MRI (T1/T2, fluid-attenuated inversion recovery, diffusionweighted imaging, gadolinium-enhanced T1) Electroencephalogram Other tests when indicated: C-reactive protein Urine screen for illicit drugs Serum and CSF antineuronal antibodies Anti-neuromyelitis optica (anti–NMO-IgG) or antiaquaporin-4 antibodies Antiribosomal P antibodies CT of brain Echocardiogram CT angiogram or magnetic resonance angiogram Cerebral angiography Tests for hypercoagulability: protein C, protein S, serum antithrombin III (SAT III), prothrombin 20210A mutation, factor V Leiden, homocysteine Cryoglobulins

Test Serologic Antineuronal antibodies Neuromyelitis optica (anti–NMO-IgG) antibodies Antiribosomal P antibodies Antiphospholipid antibodies Cerebrospinal Fluid Routine Pleocytosis

sole active manifestation of SLE, many studies have reported that NPSLE frequently occurs when SLE is clinically and serologically active.5,18 However, in all patients with SLE who have NP dysfunction, additional tests will be necessary to confirm an NPSLE diagnosis and to exclude other causes (Box 36.2) (Tables 36.2 and 36.3). Recommendations of the basic laboratory evaluation and diagnostic imaging that should be obtained for patients suspected of having NPSLE have been published4,5 (see Box 36.2) (Fig. 36.2).

Clinical Laboratory Tests A complete blood count and urinalysis should be obtained for disease activity and to rule out infection. If thrombocytopenia is present, the blood smear should be examined for schistocytes to exclude TTP. Biochemistry tests including electrolytes, creatinine, glucose, liverassociated enzymes, and thyroid function tests are obtained to exclude metabolic abnormalities that can cause neurologic dysfunction. Complement (C3/C4 or CH50) determinations and anti-dsDNA antibodies should be obtained to assess disease activity. The presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, anti–β2-glycoprotein I [GPI] antibodies) should be determined. Tests for other causes of hypercoagulability should be performed in patients with a family history of clotting. Most patients with SLE will have an elevated erythrocyte sedimentation rate and a normal or mildly elevated C-reactive protein. A significantly elevated C-reactive protein (>6 mg/

Diffuse manifestations Transverse myelitis and/or optic neuritis

24–90

Psychosis

45–80

Strokes and focal manifestations

6–34 22–50 3–8

Special Antineuronal antibodies (IgG)

30–95

Elevated IgG index Oligoclonal bands (≥2 bands)

Comment

30–92 75

Increased protein Low glucose

Elevated Q-albumin

CSF, Cerebrospinal fluid; HSV, herpes simplex virus; CT, computed tomography; MRI, magnetic resonance imaging, PCR, polymerase chain reaction; VZV, varicella-zoster virus.

Frequency of Abnormal Test Result Range (%)a

8–33

25–66 15–50

Rule out infection and NSAID meningitis Nonspecific Rule out infection, transverse myelitis Diffuse manifestations (90%–95%), focal manifestations (25%–30%) Break in blood-brain barrier, more common with focal manifestations Diffuse manifestations Diffuse manifestations

a

Frequencies based on those reported in various studies and reviews. NSAID, Nonsteroidal antiinflammatory drug.

dL) may indicate systemic vasculitis, polyserositis, or infection. A fasting lipid profile and homocysteine levels are obtained to establish vascular risk factors. Urine tests for illicit drug use may be indicated in selected patients.

Autoantibodies Over 20 autoantibodies in the serum and CSF have been reported to be associated with NPSLE.106-108 They have been detected by a variety of methods using multiple different substrates. Over 50% of them are autoantibodies that react to brain antigens, whereas the remaining are systemic autoantibodies. Many of these autoantibodies are not clinically available and remain investigational. However, the four that are clinically available (antiphospholipid, antiribosomal P, antineuronal, and anti– NMO-IgG antibodies) and one that is investigational (anti-NR2) deserve further discussion.

Antiphospholipid Antibodies Antiphospholipid antibodies, directed against phospholipid-binding proteins such as β2-GPI and prothrombin, induce a procoagulant state

CHAPTER 36  Lupus and the Nervous System

445

TABLE 36.3  Frequency of Abnormal Diagnostic Tests Commonly Used in the Evaluation of

Neuropsychiatric Lupus Erythematosus Test

Frequency of Abnormal Test Results, Range (%)

Electroencephalogram

60–91

No specific abnormality is present; patients with SLE without CNS symptoms can have an abnormal EEG

29–59 (atrophy) 10–25 (infarction or hemorrhage)

Atrophy may be the result of corticosteroids; CT scans miss 20%–25% of definite clinical infarctions

Neuroimaging Procedures CT scan

Comment

MRI Scan All patients with NPLE Patients with NPLE; diffuse symptoms only Patients with NPLE; focal symptoms Patients with SLE; no NP manifestations SPECT

20–76 <50

No specific lesion is present; atrophy is common Are more likely abnormal if obtained within 48 hours of treatment

Up to 80–100 18–40 44–88

Angiography Echocardiography

10 40

T2-weighted lesions >10 mm in size are mostly diagnostic Small (2–5 mm) periventricular and subcortical WMHI are present Up to 67% of patients with SLE who have CNS events unrelated to NPLE; 50% of patients with SLE without a history of NP events have abnormal scans Are more likely abnormal in embolic or large strokes Definite valvular lesions are more common in patients who have had a stroke; may have an association with antiphospholipid antibodies

CNS, Central nervous system; CT, computed tomography; EEG, electroencephalogram; MRI, magnetic resonance imaging; NP, neuropsychiatric; NPLE, neuropsychiatric lupus erythematosus; SLE, systemic lupus erythematosus; SPECT, single-photon emission computerized tomography; WMHI, white matter hyperintensities.

and are associated predominantly with focal manifestations of NPSLE. The lupus anticoagulant, anticardiolipin, and anti–β2-GPI antibodies are the ones best characterized. In a meta-analysis of 21 retrospective studies made up of more than 1000 patients with SLE and other autoimmune disorders, the average prevalence of lupus anticoagulant and anticardiolipin antibodies was 34% and 44%, respectively.109 NP manifestations occurred in 38% to 49% of patients with antiphospholipid antibodies compared with 12% to 21% of patients without antiphospholipid antibodies. Most were vascular events such as stroke and seizures. Many studies combine primary antiphospholipid antibody syndrome patients and SLE patients with antiphospholipid antibodies, making interpretation of these studies difficult to apply to patients with SLE only. Several neurologic syndromes have been associated with antiphospholipid antibodies in patients with SLE.5 The most common are stroke (OR [odds ratio] 2–7), cerebral venous sinus thrombosis, dementia (OR 2–5) seizures (OR 3–6), chorea (OR 10), transverse myelopathy (OR 10), ocular ischemia, and sensorineural hearing loss. Each one is believed to be caused by a thromboembolic event resulting in vascular occlusion. SLE patients with the greatest risk for cerebral infarction are those who have the lupus anticoagulant in addition to high-titer anticardiolipin and anti–β2-GPI antibodies (i.e., triple positive) compared with patients with only a single antiphospholipid antibody. Clinically, patients with antiphospholipid antibodies who have had a prior thromboembolic event, livedo reticularis, thrombocytopenia, or active lupus (e.g., vasculitis, hypocomplementemia, elevated anti-dsDNA antibodies) are at increased risk for thrombosis (stroke, OR 16). Furthermore, approximately one-third of patients with antiphospholipid antibodies have abnormal echocardiograms that demonstrate left ventricular valvular lesions, which are a potential source for an embolic stroke. Up to 30% of patients with SLE who develop a thromboembolic event are likely to develop a recurrent episode within 1 year of the initial occurrence although not usually in the same vascular territory.110,111

The ability of antiphospholipid antibodies to cause thrombosis within vessels of different calibers is the result of a complex interaction among these antibodies, complement activation, brain endothelial cells, and cerebral hemostasis, which is only partially understood.13,14,16,112 Brain endothelial cells display different functional and phenotypic characteristics compared with endothelial cells at other anatomic sites and therefore may be more prone to thromboses. Other cerebrovascular risk factors can add to the thrombotic risk conferred by antiphospholipid antibodies, including cigarette smoking, hyperlipidemia, hypertension, diabetes mellitus, and hyperhomocysteinemia, which are correctable risk factors that need to be identified and treated. Alternatively, antiphospholipid antibodies may cause some NP manifestations (e.g., seizures) through nonthrombotic mechanisms, such as modulation of neuronal cell function, which has been demonstrated in vitro.113

Antiribosomal P Antibodies Antibodies to the C-terminal region of cytoplasmic ribosomal P protein are found in 12% to 20% of patients with SLE, and their determination is among the most specific tests for SLE.114 The antibodies may be more prevalent in patients with SLE who are Asian compared with patients with SLE who are Caucasian or African American. Cross-sectional studies have both supported and refuted an association of antiribosomal P antibodies with psychosis and severe depression.77-79 More recent prospective studies and two meta-analyses have confirmed that SLE patients with antiribosomal P antibodies are more likely to develop psychosis or severe depression.107,108 Serum levels of the antibody may correlate with the severity of the psychosis in selected patients, but they also can vary widely over time without any clinical event. The antibody may become undetectable with successful therapy. Notably, patients with SLE who have mild depression or cognitive dysfunction or both do not have elevated serum antiribosomal P antibody levels.

446

SECTION 5  Clinical Aspects of Lupus Erythematosus Diffuse Manifestations

Seizures

Focal Manifestations

History, physical examination, complete blood count, chemistries, urinalysis, appropriate cultures, complement, anti-dsDNA Must rule out secondary causes of CNS dysfunction Routine cerebrospinal fluid analysis (cell count, protein, glucose, culture, VDRL)

May need screening CT scan prior to lumbar puncture

Electroencephalogram (seizures) Cranial MRI scan

CSF special tests - Antineuronal antibodies - IgG index - Oligoclonal bands

Antiphospholipid antibodies Echocardiogram (cerebral emboli)

Antiribosomal P antibodies (psychosis/depression) Antiphospholipid antibodies (aPLs) (dementia, seizures) Neuropsychiatric tests (mild cognitive dysfunction) Further workup as clinically indicated Mild symptoms—treat symptomatically Major or progressive symptoms Corticosteroids Progressive symptoms

Cytotoxics Biologics Plasmapheresis

Recurrent seizures Antiepileptics Corticosteroids + Anticoagulation (if aPLs) Investigational therapies

Vasculitis

Antiphospholipid antibodies

Corticosteroids + Cytotoxics Biologics

Aspirin Anticoagulation

Figure 36.2  Algorithm for the evaluation and treatment of patients with systemic lupus erythematosus with neuropsychiatric systemic lupus erythematosus.

Antiribosomal P antibodies have been demonstrated in the CSF of patients with NPSLE. The mechanism explaining how an antibody against a cytoplasmic antigen can cause CNS dysfunction is unclear. Matus and others have demonstrated that antiribosomal P antibodies recognize a neuronal surface P antigen (NSPA) that is preferentially distributed in areas of the brain involved in memory, cognition, and emotion.115 Binding of this antibody to NSPA caused an increase in calcium influx into the neuron, leading to apoptosis and suggesting this as a mechanism. Subsequent work in a murine model demonstrated that antiribosomal P antibodies induced apoptosis of neuronal cells when injected directly into the hippocampus and that circulating antiribosomal P also penetrated the brain in animals given lipopolysaccharides (LPS) and produced behavioral changes.116

Antineuronal and Neural Antigen-Specific Antibodies Serum antineuronal antibodies are more common in patients with NPSLE (30%–92%) than in patients with SLE without CNS lupus (4%–20%).108,117 They are neither as sensitive nor as specific as CSF antineuronal antibody measurements. Neuroblastoma-binding serum

and CSF autoantibodies are particularly frequent in patients with NPSLE with diffuse presentations such as encephalopathy and severe cognitive dysfunction.19 Human studies of antineuronal antibodies in NPSLE have demonstrated a temporal relationship with NP events, their presence in CSF, and identification in neuronal tissues from patients succumbing to NPSLE.118-120 Autoantibodies in the CSF are caused by passive transfer from the circulation through enhanced permeability of the blood-brain barrier and, independently, by intrathecal production. The antigenic specificity of these serum antineuronal antibodies has not been fully investigated. Two autoantibodies whose cognate neuronal antigens have been determined are the anti–NMO-IgG antibody and the anti-NR2 antibody. The anti–NMO-IgG antibody reacts with aquaporin-4 and is associated with manifestations of NMO spectrum disorder (see previous discussion in the section Myelopathy). The anti-NR2 antibody is a subset of anti-dsDNA antibodies that cross-react with the NR2A and NR2B subunits of the NMDA receptor and has been associated with psychiatric and cognitive difficulties, particularly when present in the CSF (see previous discussion in the section Cognitive Dysfunction).

CHAPTER 36  Lupus and the Nervous System

447

Cerebrospinal Fluid Tests

Miscellaneous Determinations

CSF analysis is useful in all patients with SLE who have had a change in neurologic status, particularly to exclude infection or other secondary causes of CNS dysfunction. In some patients with NPSLE, CSF results may be unremarkable (50%). However, other patients with NPSLE may have abnormalities helpful in confirming the diagnosis and guiding management. Consensus panels recommend that routine CSF tests, IgG index, and oligoclonal bands be determined on all patients suspected of having NPSLE.4,5

Several cytokines (interleukin [IL]-6, IL-8, IP-10, MCP-1, G-CSF, IFN-α), CC chemokine ligands (CCL2, CCL5), CX3CL chemokines (CXCL1, CXCL8, CXCL10), and matrix metalloproteinase (MMP-9) have been reported to be elevated in the CSF of active patients with NPSLE and may be important in the pathogenesis.123,124 Additionally, levels of glial fibrillary acidic protein and neurofilament-triplet protein are three to seven times higher in the CSF of patients with NPSLE compared with control subjects. These levels correlated with the degree of abnormalities found on a brain MRI. Measurements of these mediators may be useful in the future for diagnosis and to monitor immunologic activity and neuronal damage.

Routine Cerebrospinal Fluid Tests Routine CSF tests include cell count with differential; protein; glucose; Gram stain; other special stains including India ink (Cryptococcus) and acid-fast bacillus (AFB); Venereal Disease Research Laboratory (VDRL) test; and bacterial, fungal, and mycobacterial cultures. Tests for cryptococcal and histoplasma antigen and polymerase chain reaction (PCR) for herpes simplex virus (HSV), varicella-zoster virus (VZV), and JC virus and Lyme disease (if indicated) should be performed. Assays using nucleic acid amplification can rapidly detect Mycobacterium tuberculosis. Pleocytosis (<100–300 cells per high-power field) and elevated protein (70–110 mg/dL) are found in some patients with active NPSLE. Protein abnormalities are more common (22%–50%) than pleocytosis (6%–34%). Neutrophilic pleocytosis with elevated protein suggests cerebral vasculitis with ischemia if infection is ruled out. Patients with antiphospholipid antibodies and neurologic thromboembolic events frequently have elevated protein levels with mild or no pleocytosis. The CSF glucose level is rarely (3%–8%) decreased (30–40 mg/dL) in NPSLE. Patients with acute transverse myelopathy have been reported to have hypoglycorrhachia (50%) more often than patients with other manifestations of NPSLE. CSF pleocytosis, elevated protein levels, and low glucose should always raise suspicion of an acute or chronic infection before attributing these abnormalities to NPSLE.

Cerebrospinal Fluid Immunologic Tests CSF IgG levels are elevated in 69% to 96% of patients with NPSLE, and a level greater than 6 mg/dL almost always indicates NPSLE, although it is present in only 40% of patients with NPSLE. An elevated CSF Q-albumin ratio, indicating a break in the blood-brain barrier, has been noted in up to one-third of patients, especially those with progressive encephalopathy, transverse myelitis, and strokes.19 Several groups have now confirmed that an elevated IgG index or oligoclonal bands or both are observed in 15% to 50% of patients, particularly in those with diffuse manifestations, such as encephalopathy and psychosis.19,121,122 Patients with focal manifestations, such as stroke from antiphospholipid antibodies, typically do not have an elevated IgG index or oligoclonal bands, unless they also have a coexistent encephalopathy (complex presentation).19 These abnormalities have been shown to normalize in some patients after successful therapy.19,122

Cerebrospinal Fluid Antineuronal Antibodies Using neuroblastoma cells as the antigen source, antineuronal antibodies have been detected in the CSF of 30% to 95% of patients with NPSLE, compared with only 11% of patients with lupus without CNS disease.108,119 Furthermore, 90% of the patients with diffuse manifestations of psychosis, encephalopathy, or generalized seizures had elevated IgG antineuronal antibodies, compared with only 25% of patients with focal manifestations of hemiparesis or chorea. Notably, the antineuronal antibody was concentrated eightfold in the CSF, relative to its concentration in paired serum samples.

Summary When a lumbar puncture is performed in patients with SLE who have CNS dysfunction, the CSF tests that should be ordered are cell count with differential, glucose and protein levels, VDRL, and Gram stain and cultures. In addition, CSF should be sent for antineuronal antibodies and a “multiple sclerosis” panel, which includes a CSF IgG level, Q-albumin ratio, IgG index, oligoclonal bands, and a calculated IgG synthesis rate. Patients with diffuse manifestations frequently have elevated antineuronal antibodies or an elevated IgG index and oligoclonal bands, suggesting immunologic activity. Patients with only focal manifestations do not usually have antineuronal antibodies, elevated IgG index, or oligoclonal bands, but they may have an elevated Q-albumin ratio caused by a disruption of the blood-brain barrier. Patients who have CSF pleocytosis and elevated protein levels with negative cultures may have acute inflammation from vasculitis causing their focal symptoms. In contrast, patients with antiphospholipid antibodies, causing thrombosis and focal symptoms, usually have elevated protein levels but mild or no pleocytosis in their CSF. Infection must be ruled out in all patients with CNS dysfunction.

Electroencephalography Conventional EEG is abnormal in 60% to 91% of adult and pediatric patients with NPSLE. The most common finding is diffuse slowing with increased beta and delta background activity.125 Focal abnormalities and seizure activity can also be seen. The most common neuroanatomic site of seizure activity on EEG occurs in the left hemisphere.126 Unfortunately, the EEG findings are not specific for NPSLE, and other disorders, including metabolic encephalopathies and drug effects, can give similar findings. Furthermore, up to 50% of patients with SLE without active NPSLE can have abnormal EEGs. Consequently, a single abnormal EEG has limited diagnostic value for NPSLE. On occasion, however, an EEG may be very helpful in revealing unsuspected seizure activity, which was not otherwise clinically apparent, as the cause of other neurologic presentations (e.g., coma).

Neuropsychometric Tests Although cognitive complaints are more frequent in SLE patients, the use of self-report measures of perceived cognitive impairment correlate poorly with objective measures and are influenced by comorbid conditions. Thus formal neuropsychological assessment remains the gold standard but takes several hours to administer.4 A 1-hour ACR neuropsychological battery of tests has been developed and is a standardized, validated instrument (sensitivity 80%, specificity 81%) to document cognitive dysfunction.127 However, it must be administered by a trained neuropsychologist.127 It examines eight domains of cognitive functioning: simple attention, complex attention, memory, visuospatial processing, language, reasoning/problem solving, psychomotor speed, and executive functions. In patients with NPSLE causing disturbances of cognition,

448

SECTION 5  Clinical Aspects of Lupus Erythematosus

the pattern of cognitive impairment in SLE patients is neither specific nor unique to SLE. Computerized testing of cognitive function (e.g., ANAM) is also available and facilitates efficient screening of SLE patients by nonexperts but may fail to identify higher level cognitive impairment in SLE.26,29

NEUROIMAGING STUDIES Computed Tomography CT is used primarily in emergency settings to rule out a large infarct or hemorrhage in an SLE patient with an acute neurologic deterioration. In stable patients, CT is sensitive to cerebral atrophy, which has been detected in 29% to 59% of the patients with NPSLE, and calcifications most frequently found in the basal ganglia.128 Other pathology, such as infarction, hemorrhage, and meningeal thickening as a consequence of inflammation may be detected as well. Although relatively insensitive, CT may detect white matter abnormalities reflecting edema as well as diffuse neuropathology associated with NPSLE, including chronic white matter demyelination and small infarcts. However, CT does not reliably distinguish damage from reversible inflammatory disease within the nervous system.

Magnetic Resonance Imaging Conventional MRI is the preferred method of structural imaging in SLE (see Fig. 36.1).15,129 It offers a higher spatial resolution than CT, and it is more sensitive to relatively minor changes in brain tissue. MRI also has the advantage of generating a variety of images, depending on the acquisition sequence used. T1 images are best for differentiating fat from water, with tissue rich in water (e.g., gray matter) appearing darker than tissue rich in fat (i.e., white matter). Abnormalities on MRI scanning have been reported in 19% to 70% of SLE patients with cortical atrophy on T1 images, which is the most commonly reported finding. Correlation between atrophy and cognitive impairment in NPSLE is well established, highlighting the significance of this finding.130 On T2 images, tissues rich in water are brighter than tissues rich in fat, making T2 images particularly sensitive to edema. Applying a fluid-attenuating inversion recovery (FLAIR) pulse to a T2 sequence dampens the CSF signal, further highlighting areas of edema. In subcortical regions, increased signal intensity on T2 imaging is known as “white matter hyperintensities” (WMHIs). These WMHIs occur in 20% to 50% of SLE patients regardless of clinical NP disease and in up to 75% of SLE patients with antiphospholipid syndrome (APS). In an unselected SLE population, the volume of such T2 image lesions was associated with patient age, overall disease severity, and disease duration.131 Notably, in the normal general population, individuals over age 50 and those with a history of migraine headaches and multiple cardiovascular risk factors (smoking, hypertension, hyperlipidemia, diabetes mellitus) are more likely to have WMHI. No MRI finding is specific for NPSLE. However, lesion location and appearance can help differentiate NPSLE from certain other autoimmune disorders, such as MS. Large WMHIs, present in the corpus callosum or periventricular regions, that are also seen as areas of damage on T1-weighted images are more characteristic of MS than SLE. Other abnormalities that may help distinguish damage from active inflammatory disease include acute and reversible lesions that lack clear borders, have a filamentous pattern, and that follow the gray–white matter junction along sulci and gyri. Hyperintensities in the gray matter provide further evidence of inflammatory disease. Enhancement of lesions on T1-weighted images following IV gadolinium can also be used as an indication of breakdown of the blood-brain barrier and active inflammation.128

In SLE, structural changes on MRI may be used as an indication of treatment effects in addition to disease activity. For example, gray matter edema may resolve over 2 to 3 weeks following an acute NP event, especially in patients undergoing corticosteroid therapy. However, the course of clinical symptoms and response to treatment may differ from MRI changes. Although conventional structural imaging with MRI may identify active nervous system disease in SLE, this is not universally the case. Patients with active NPSLE often show MRI results similar to those not in the active stage of the disease and not uncommonly have normal MRI images, even when NP symptoms are clearly present.15,128,129 NPSLE syndromes that are frequently accompanied by normal structural imaging are more likely diffuse manifestations such as acute confusion, psychosis, mood disorders, and headaches. Importantly, a recent study showed that patients dying with NPSLE have abnormal brain histopathology showing diffuse microvascular disease even with a normal brain MRI.14 Neither CT nor MRI reliably differentiate SLE from non-SLE disorders that have similar behavioral and neurologic presentations, including vascular incidents unrelated to SLE, infectious meningitis, noninflammatory edema, or non–SLE-related infarcts and trauma-related hemorrhage.131 These limitations are not trivial, since decision-making regarding treatment often depends on determining whether the presenting symptoms are caused by active lupus, by preexisting but currently quiescent SLE, or by non-SLE factors.

Positron-Emission Tomography and Single-Photon Emission Computed Tomography Positron-emission tomography (PET) is based on the assumption that blood supply and glucose/oxygen metabolism within a region of the brain vary with changes in neuronal activity in that anatomic region.129 PET is an effective method of detecting diffuse abnormalities in brain function and for localization of pathology. It uses two technologies that allow for in vivo measurement and localization of neurologic processes: examination of radiologic tracer kinetics and CT. The former provides information about the compartmental kinetics of glucose metabolism, oxygen metabolism, and blood flow, and can even assist in mapping white matter fibers and axonal projections. The PET scanner is also designed to provide a CT image of the brain combined with concentration distributions of tracer-labeled products. The disadvantages of PET include exposure of patients to large doses of radiation, the potential limited availability of radiopharmaceuticals, and cost. SPECT operates on similar principles, and is a more readily available method of studying brain function, but it too has its drawbacks.129 As with PET, SPECT requires exposure to radioactive substances via injection or inhalation. Radiotracers used in SPECT often lead to the underestimation of regional cerebral blood flow, and the image resolution is inferior to other computed tomographic techniques, including CT and PET. As is the case with other functional imaging modalities, SPECT does not provide a direct measure of brain activity; instead, it measures concurrent physiologic changes in brain tissue that are correlated with such activity. Komatsu and colleagues used PET to compare 12 SLE patients with and without psychiatric symptoms.132 Those with active psychiatric symptoms showed decreased metabolic rates for glucose in prefrontal and inferior parietal lobes and in the anterior cingulated regions bilaterally, whereas those with active SLE but without psychiatric symptoms had normal PET scan results. Similar results have been reported by others using SPECT. Huang and colleagues examined 78 SLE patients: 48 with NP symptoms and 30 SLE patients without NP symptoms. They found that 90% of patients with NP symptoms had regions of hypoperfusion compared with 20% of patients without such symptoms.133 These hypoperfused areas were seen mostly in the parietal lobe, and to a lesser extent in the frontal and temporal lobes, within the regions of

CHAPTER 36  Lupus and the Nervous System

449

distribution of the middle cerebral artery. Generally the literature on SPECT scanning in SLE has found areas of diminished uptake in 86% to 100% of patients with major NP events (e.g., stroke, seizures, psychosis), in 33% to 85% of patients with minor NP events (e.g., headache, subjective memory loss), and in 10% to 50% of patients without apparent NP disease.129,134 However, just as with all other imaging techniques, the data obtained using PET and SPECT must be interpreted with caution because abnormalities in glucose absorption, oxygen use, and blood flow may not be indicative of active CNS disease. Chronic nervous system damage associated with SLE may cause cell death and consequent decreases in neuronal density that will produce similar results on PET and SPECT to those of active NPSLE. Furthermore, changes in blood flow and metabolism can also occur in sites distant from those of the pathologic lesion. This phenomenon, known as diaschisis, occurs when local neuronal activity is diminished in normal-appearing brain tissue because of a loss of afferent input from a remote brain region. Thus PET may provide valuable functional information about NPSLE but has relatively high associated hazards and costs. It also requires parallel anatomic imaging to be useful on a routine basis. Although SPECT may overcome the issue of cost, abnormalities observed using SPECT have not been found to differentiate patients with major NPSLE features, such as stroke, seizures, or psychosis, from patients with milder NPSLE features, such as headaches, dizziness, and mild cognitive impairments. Furthermore, SPECT abnormalities can be seen in SLE patients without NP disease, and it may be chronic in some and reversible in others.15,128,129 Therefore a normal PET or SPECT may indicate no evidence of NPSLE, whereas an abnormal study must be put in the clinical context.

included those associated with working memory and executive function. Moreover, the BOLD signal diminished in those SLE patients with clinical evidence of cognitive impairment and in those with longer disease. One of the implications from these preliminary studies is that brain compensatory responses maintain cognitive function for a time but may eventually be overcome at which point the patient becomes cognitively impaired. Although fMRI has considerable potential, it also has limitations that have to be resolved before its introduction into widespread clinical practice. The signal changes generated by shifts in cognitive states or tasks are relatively small, and, to detect them, numerous MRI acquisitions and long scanning sessions can be required. Another limitation of fMRI is the absence of clear standards for interpreting hemodynamic responses as indirect measures of neuronal activity. Contributing to this is our lack of knowledge about the exact mechanisms regulating regional blood flow. There is no clear and consistent relationship between excitatory synaptic activity and increased fMRI signal, perhaps because the contribution of inhibitory synaptic activity to the fMRI signal is variable and still poorly understood.

Transcranial Color Doppler Sonography

Magnetization Transfer Imaging

TCDS is a noninvasive method used to measure basal cerebral artery blood flow as well as microvascular tone, endothelial function, and blood flow resistance and impedance. Results in SLE patients with and without NP symptoms have been conflicting.135 However, TCDS has the ability to detect cerebral microembolism, which has been demonstrated in 15% of SLE patients.136 This is most common in patients with antiphospholipid antibodies and valvular heart disease. Therefore detection of a high cerebral microembolic signal by TCDS may identify patients at increased risk for strokes and other NP manifestations.137

MTI is a structural imaging modality that measures the integrity of white matter tracks, which cannot be easily visualized using conventional MRI.129 The technique is based on quantification of the magnetization exchange between macromolecule-bound protons in myelin and water protons by the generation of a magnetization transfer ratio (MTR), which uses two conventional MRI images: one proton density or T2 image and another with a saturation pulse. An MTR is directly influenced by the amount of bound protons, which is proportional to the amount of myelin within a specific region of interest (e.g., a specific fiber bundle or the entire brain). A decrease in the average MTR within a region of interest usually signifies demyelination in that region, whereas the distribution of MTR values for individual image pixels can be used as an indicator of tissue integrity. A distribution of MTR values within a region that consists of a single, narrow, high peak indicates homogeneity of the MTR and uniformly healthy tissue. When demyelination is present, the peak on the MTR histogram becomes wider and lower because of increased pixels with lower MTR values. Studies that have used MTI in SLE patients have reported global damage in patients with NPSLE, even in those who are no longer in the active stages of the disease, with normal conventional MRI scans.140,141 MTI indices have been found to correlate with indices of neurologic, psychiatric, and cognitive functioning. However, MTI measures continue to demonstrate tissue damage when clinical indicators normalize or improve. Although psychiatric, cognitive, and neurologic symptoms of NPSLE may resolve, the brain pathology underlying them may not.142 MTI may assist in detecting brain abnormalities not seen with conventional MR imaging and may also be useful in measuring neuropathologic functions resulting from NPSLE, even after acute NP symptoms and signs resolve. However, because of a lack of standard interpretation guidelines MTI is not currently used for clinical purposes.

Nonconventional Magnetic Resonance Imaging Although conventional MRI is the most frequently used imaging technique, there are many other experimental imaging modalities based on the principles of MR that provide unique information about brain structure, function, and biochemistry. These include functional magnetic resonance imaging (fMRI), magnetic resonance relaxometry (MRR), magnetization transfer imaging (MTI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS).129

Functional Magnetic Resonance Imaging An fMRI provides information about brain function by measuring changes in blood flow either at rest or while performing cognitive tasks. Because of the presence of iron atoms in hemoglobin, blood has magnetic properties and the change in blood concentrations within tissues can be detected using MR techniques. More specifically it records blood-oxygenlevel dependent (BOLD) signals as a measure of neuronal metabolism. This technique can be used to inform the “functional connectivity” of brain regions, and the loss of connectivity can be indicative of pathology. Relatively few studies have used fMRI in SLE.138 Generally the BOLD signals were increased during cognition tasks in anatomic areas that

Magnetic Resonance Relaxometry MRR is a method of quantifying T1-weighted or T2-weighted relaxation times in brain tissue. Relaxation times reflect changes in tissue density or chemical composition; thus, relaxometry can add sensitivity to conventional MRI scans and detect abnormalities not observed on conventional images. MRR has been studied in patients with SLE who have active major NP events, such as seizures, psychosis, or coma, with findings of increased T2-weighted relaxation time of otherwise normalappearing gray matter, suggesting gray matter edema in such patients compared with patients with minor NPSLE events.139

450

SECTION 5  Clinical Aspects of Lupus Erythematosus

Diffusion Tensor Imaging DTI provides an additional method for examining white matter homogeneity and connectivity.129 DTI is based on the principle of isotropy (Brownian motion), which refers to the unrestricted, chaotic movement of proton-containing molecules in free water. In the highly structured tissue of the brain, particularly in white matter fiber tracks, molecules can easily move in the same direction as the myelinated axons, creating preferential diffusion or anisotropy. Pathologic conditions that disturb the highly structured integrity of the white matter fibers cause a loss of anisotropy and change the diffusion behavior of the water molecules. The level of fractional anisotropy (FA) can be calculated for individual MRI image pixels in a region of interest or for the entire brain. These results are presented as a histogram with lower FA peaks, indicating more pixels with higher diffusion values that reflect damage or degeneration in white matter tracks. In studies using DTI, patients with NPSLE have been found to have more pixels with low FA values than healthy controls, particularly in the internal capsule and in the limbic regions.143 The clinical relevance of these findings is, as yet, unclear. However, some evidence suggests that mean diffusivity for the entire brain as well as diffusion parameters in the frontal lobe, corpus callosum, left arm forceps major, left anterior corona radiata, and thalamus can differentiate SLE patients with and without NPSLE.144 In addition, DTI appears to be useful in detecting early alterations in normal-appearing white matter in NPSLE patients.145 With further study, DTI changes may conceivably assist in the early diagnosis of NPSLE and help determine the pathogenesis of NP symptoms.141

Magnetic Resonance Spectroscopy MRS provides information about the neurochemical composition of tissue within a designated region of interest.129 The metabolites detected using this method typically include N-acetylaspartic acid (NAA), choline-containing compounds (Cho), myo-inositol (mI), lactate (L), and creatine (Cre). NAA is considered to primarily indicate neuronal and axonal integrity, and a reduction in NAA is considered indicative of neuronal loss. The Cho peak is associated with cell membrane turnover (loss and replacement of cellular membranes) and with a loss of myelin. It is often elevated in patients who have suffered a stroke, brain inflammation, or acute white matter disease, all of which involve membrane metabolism. Glial density is estimated by mI. Lactate is undetectable in healthy brain tissue, and its presence indicates anaerobic metabolism, which is usually attributable to ischemia. Creatine is a measure of brain energy metabolism and is used as an internal reference standard for calculations of ratios. Biochemical changes that have been noted in SLE and that have been linked to neurocognitive dysfunction include reductions of NAA in T2 lesions and in normal-appearing gray and white matter. Reduction of NAA has also been associated with seizures, psychosis, and confusional states.131 Although recovery of NAA levels has been observed, the circumstances governing the reversibility of changes in this neurochemical are poorly understood.131,146 It is clear, however, that reduced NAA is not only seen in active NPSLE but also is seen in irreversible chronic brain injury. The Cho peak has also been found to be elevated in NPSLE in the absence of obvious structural abnormalities on conventional imaging.147 It has been suggested that elevation in choline-containing compounds can be a prognostic indicator because it often reflects disease activity or inflammation.131 Elevation in choline, combined with reduction in NAA, has been linked to cognitive impairment in SLE patients.131 Although MRS cannot be used to diagnose NPSLE or to reliably differentiate it from disorders with comparable clinical presentations, it

may be helpful in characterizing brain tissue damage, particularly in the presence of otherwise normal imaging results.128,145

Angiography Cerebral angiography is frequently normal in patients with NPSLE, including those with cerebral infarction on MRI. This lack of sensitivity may be explained by the small size of vessels affected by lupus vasculopathy. Occasionally, vasculitis of large-sized arteries or cerebral emboli can be documented, especially in those with large infarcts. Angiography can also be used for localization before thrombolysis and thrombectomy in a patient with an early stroke. However, angiograms are an invasive procedure with possible morbidity. CTA and MRA are noninvasive alternatives that can demonstrate abnormalities in medium to large vessels. In patients with suspected emboli, carotid Doppler and echocardiographic techniques (including transesophageal) should be performed to determine an embolic source.

TREATMENT The therapy of NPSLE differs, depending on the clinical presentation and suspected pathogenesis.5,148,149 A thorough clinical and diagnostic evaluation of any patient with SLE with new NP symptoms is important to establish the extent of neurologic impairment and brain injury to assess future progression and response to therapy. Secondary causes of CNS dysfunction should be excluded quickly, and all unnecessary medications should be stopped. Therapy should not be delayed pending test results. If it is unclear whether the CNS dysfunction is the result of primary NPSLE or a secondary cause, then the patient should be treated for both until diagnostic test results return. Recommendations for the treatment of NPSLE have been published5 (see Fig. 36.2).

Central Nervous System Manifestations The treatment of NPSLE is empiric because few controlled clinical trials have been conducted.150 The therapy should be tailored to the severity of the presentation and suspected etiologic variables. Patients with mild, diffuse manifestations such as headaches, anxiety or dysphoria, paresthesias, or an infrequent seizure may only need analgesics, psychotropic medications and psychological support, neuroleptic agents, or antiseizure medications, respectively, and to be observed closely for any neurologic progression. A particularly difficult clinical situation is the patient with SLE who complains of cognitive dysfunction but has a clinically normal mental status examination. In these patients, serial formal psychometric testing may be helpful in establishing the presence, extent, and progression, if any, of impairment. Secondary causes such as medications, thyroid disease, depression, and especially sleep apnea need to be excluded. Treatment should be supportive, including memory aids, and immunosuppressive therapy avoided unless progression can be documented. Adult and pediatric patients with NPSLE who have severe or progressive, diffuse or nonthrombotic presentations such as acute confusional state, psychosis, severe depression, aseptic meningitis, and coma may benefit from immunosuppressive medications in addition to their symptomatic therapy (e.g., psychotropic medications). Most clinicians recommend 1 mg/kg per day of prednisone in divided doses. For the most severe cases, pulse IV methylprednisolone (pediatric [30 mg/kg]; adults [500 mg to 1 g daily] for 3 days) followed by daily prednisone may be beneficial.148,149 Failure to respond within a few days may necessitate doubling the prednisone dose or switching from prednisone to dexamethasone (12–20 mg, once a day), which penetrates the blood-brain barrier more effectively than other corticosteroid preparations. Continued failure to respond is an indication to add cytotoxic medications or a trial of plasmapheresis or both, particularly for a comatose patient. In

CHAPTER 36  Lupus and the Nervous System patients who are corticosteroid unresponsive, azathioprine and mycophenolate mofetil are less effective than cyclophosphamide. Pulse IV cyclophosphamide (0.75–1.0 g/m2) given every 3 to 6 weeks has been reported to be beneficial in both adult and pediatric patients.148-151 Another potential method of IV cyclophosphamide administration, which may have fewer side effects, is the Euro-Lupus regimen (500 mg IV every 2 weeks for six doses), although the use of this regimen in severe NP lupus presentations is limited. Some patients with NPSLE may not tolerate this regimen or will have contraindications to aggressive immunosuppressive therapy. In these patients, intrathecal methotrexate combined with dexamethasone (10 mg of each, weekly for 3 weeks) has been used successfully in a few patients.152 Patients with NPSLE with focal or thrombotic manifestations demand an immediate and aggressive evaluation. If vasculitis is suspected, then high-dose corticosteroids and cyclophosphamide are used similar to patients with severe, diffuse, or nonthrombotic manifestations. Clinical experience suggests that cyclophosphamide is more effective than other immunosuppressive medications. Plasmapheresis may be beneficial during the first week to allow time for the corticosteroids and cyclophosphamide to take effect. Once the patient’s vasculitis is controlled with cyclophosphamide, another cytotoxic medication (azathioprine, mycophenolate mofetil) may be substituted to maintain remission. Whether chronic antiplatelet and statin therapies prevent thrombosis or atheroma formation in the damaged vessel is unknown, but they are often used. Most strokes caused by NPSLE are the result of thrombosis associated with antiphospholipid antibodies and not vasculitis. Some are caused by emboli from damaged heart valves. The acute management of CVD requires a stroke specialist to direct management of thrombolytic therapy or thrombectomy if indicated (stroke <4–6 hours’ duration). In patients with large or cardioembolic strokes, aspirin and prophylactic dose heparin are used for the first few days because therapeutic dose heparin may cause hemorrhage into the infarcted area. Later the heparin dose is increased to therapeutic and the patient is followed with serial brain CT scans to monitor for intracranial bleeding. The heparin levels should be followed using an antifactor Xa assay, especially in patients with an elevated partial thromboplastin time (PTT) caused by the lupus anticoagulant. After estimating bleeding risk from long-term anticoagulation, the patient is switched to warfarin. The intensity of warfarin therapy is debated. International guidelines recommend lifelong warfarin at an international normalized ratio (INR) of 3.0 to 3.5 or a combined antiaggregant–anticoagulation regimen with aspirin or other antiplatelet drug combined with warfarin at an INR of 2.0 to 3.0.153 Certainly, patients with recurrent stroke, despite warfarin therapy, should have warfarin titrated to maintain the higher INR goal (3.0–4.0) and/or be started on combination therapy with an antiplatelet agent. In addition, any patient with recurrent strokes and a lupus anticoagulant treated with warfarin should also have chromogenic factor X levels followed and maintained at less than 20% of normal to ensure adequate anticoagulation. Patients who continue to thrombose on appropriate anticoagulation therapy may respond to IV immunoglobulin or plasmapheresis with immunosuppressive therapy. The new oral anticoagulants (e.g., factor IIa and Xa inhibitors) have not been adequately studied in this patient population but are an interesting alternative. All patients should have their generalized lupus disease activity controlled with hydroxychloroquine with corticosteroids and immunosuppressive agents if necessary to help prevent further thrombotic events.61,149 Statin therapy is also recommended. Patients with NPSLE with recurrent seizures should be treated with antiseizure medications. Patients with status epilepticus or frequent seizures should also be treated with high-dose prednisone. Patients with seizures, cerebral infarctions, and moderate to high titers of

451

antiphospholipid antibodies should be started on anticoagulation therapy once seizures are controlled, although they are at increased risk for falls and cerebral trauma. Patients with SLE and seizures should remain on antiseizure medications for at least 1 year. If they have no recurrence of seizures, a normal MRI, and normal EEG, then antiseizure medications can be withdrawn and the patient closely followed. Vehicle driving restrictions should be enforced. Some patients with NPSLE will fail to respond or have contraindications to standard immunosuppressive and anticoagulant therapies. In steroid-unresponsive NPSLE, B-cell depletion therapy with anti-CD20 (rituximab) has been reported to be successful in uncontrolled trials.66,154,155 Belimumab trials excluded patients with severe NPSLE; consequently, its effectiveness is unknown. Plasma exchange (PLEX) has also been reported to be effective in 75% of patients with severe NPSLE.156,157 One protocol recommends the first three exchanges be done every other day followed by weekly PLEX for another three exchanges.156 If the patient has not already received cytotoxic medications, IV cyclophosphamide may be given 24 hours after the third PLEX (synchronization protocol). Hematopoietic stem cell transplantation or high-dose cyclophosphamide therapy may be considered for patients with severe and resistant NPSLE.148,149

Difficult Clinical Situations Several difficult clinical situations warrant further comment. First is the patient who has SLE and is taking corticosteroids who presents with NP symptoms that could be NPSLE or steroid psychosis.158 A few caveats concerning steroid psychosis may be clinically helpful: (1) patients are typically not psychotic and usually exhibit a change in mood (mania), (2) most patients are adults because this condition rarely occurs in children, and (3) steroid psychosis is more likely if the prednisone dose has been increased to more than 30 to 40 mg/day in the previous 2 to 6 weeks. In the absence of these clinical clues, doubling the dose of corticosteroids for 3 days while awaiting test results is one approach. If the psychotic episode is the result of NPSLE, it should respond to this therapy. Failure to improve lessens the likelihood of NPSLE, and the corticosteroids should be tapered to one-half the original dose. If corticosteroids cannot be tapered, then psychotropic medications such as haloperidol or lithium can be used. Tricyclic antidepressants should be avoided. A second situation is the young patient (<40 years) with SLE and mild cognitive complaints who is found to have a few (or several) small lesions in the cerebral white matter on T2-weighted brain MRI. Patients in whom cognitive dysfunction is confirmed by formal NP testing should receive antiplatelet therapy (aspirin 75–100 mg/day) or hydroxychloroquine or both, especially if antiphospholipid antibodies are present. Patients with antiphospholipid antibodies who fail to respond to this therapy as evidenced by the progression of cognitive dysfunction or the accumulation of brain lesions on an MRI may benefit from oral anticoagulation therapy with warfarin. Another difficult situation is SLE with dementia from prior NPSLE or from infarctions related to antiphospholipid antibodies.159 The dementia in these patients will not respond to corticosteroids and, in fact, may worsen. Patients with SLE with stable dementia should not be automatically assumed to have active NPSLE; therefore, they should not be treated aggressively with immunosuppressive medications. Another difficult clinical situation is a patient presenting with acute transverse myelitis. These patients should receive IV pulse methylprednisolone, followed by high-dose prednisone. Further treatment is determined by the suspected cause of the myelitis. In patients with probable vasculitis, cyclophosphamide should be instituted and prednisone continued. Patients with myelopathy as a result of thrombosis associated with antiphospholipid antibodies should receive

452

SECTION 5  Clinical Aspects of Lupus Erythematosus

anticoagulation, prednisone, and immunosuppressive agents, whereas patients with myelitis as a result of anti-NMO antibodies may benefit from PLEX, prednisone, and rituximab. Several other neurologic syndromes, including stroke, transverse myelitis, chorea, seizures, and MS-like syndromes, have been associated with antiphospholipid antibodies and other pathogenic mechanisms. When a patient exhibits one of these manifestations, the antiphospholipid antibody results may take a few days to return. In the interim, these patients can be treated with corticosteroids and antiplatelet drugs until the results of antiphospholipid antibodies return, particularly because vasculitis can coexist with antiphospholipid antibody–associated thrombosis. If the antiphospholipid antibodies are positive, then the next decision is whether to continue with antiplatelet drugs or to treat with anticoagulants. One approach has been to anticoagulate those patients with the lupus anticoagulant or high-titer (greater than 40–50 IgG phospholipid units) IgG anticardiolipin/anti–β2-GPI antibodies, and/or other manifestations of the antiphospholipid antibody syndrome, including livedo reticularis, previous miscarriages, previous thrombotic episodes, and mild thrombocytopenia. Hydroxychloroquine, corticosteroids, and immunosuppressive agents are used to control lupus disease activity, which may contribute to the vasculopathy and risk of thrombosis.

Peripheral Nervous System Manifestations Patients with SLE and mild, nonprogressive paresthesias require only symptomatic therapy with neuroleptic medications. Patients with cranial or severe peripheral or autonomic neuropathy are initially treated with high-dose corticosteroids. Patients with Guillain–Barré syndrome or CIDP frequently have IVIG or PLEX as additional therapy.157,160 Patients with mononeuritis multiplex as a result of vasculitis should also receive cytotoxic therapy such as cyclophosphamide. When using cyclophosphamide in patients with PNS or autonomic nervous system involvement, determining whether the patient has a neurogenic bladder is important; failure to eliminate the cyclophosphamide metabolites will lead to hemorrhagic cystitis. Patients with SLE and myasthenia gravis are treated with medications that increase the concentration of acetylcholine at the neuromuscular junction. Other therapy such as IVIG for severe disease is similar to that for patients without SLE who have myasthenia. The role of thymectomy is controversial because SLE has been reported to flare after the thymus has been removed.

PROGNOSIS The prognosis for patients with NPSLE remains guarded. Recent studies have shown that the overall clinical impact of NPSLE has a negative impact on the quality of life as indicated by lower scores on subscales of the Short Form (SF)-36, higher damage index scores, and more disability compared with patients with SLE without a history of NPSLE.161,162 Although many patients with NPSLE who have major diffuse symptoms appear to recover, studies using psychometric testing demonstrate that many patients are left with cognitive dysfunction, suggesting residual CNS damage. Patients with focal manifestations may stabilize but usually do not reverse their deficits during therapy. Notably, individual NP manifestations differ in their prognostic implications. Few studies have prospectively studied patients with NPSLE over time. Several studies have shown that mild cognitive deficits detected by formal testing do not appear to progress or adversely affect the quality of life or work capacity over time in the majority of patients.30 However, those patients with the highest number of cognitive domains impaired were more likely to become unemployed. Patients with major NPSLE manifestations have a less optimistic prognosis. Recurrences of NPSLE episodes occur in 20% to 40% of pediatric and adult patients

with NPSLE, leading to more residual dysfunction. Residual NP damage was found in 25% of children who had a history of NPSLE. Patients with seizures, cerebrovascular events, and recurrent episodes of NPSLE were most at risk for persistent deficits. In a 2-year study of 32 adults with NPSLE, Karassa and colleagues163 reported residual deficits in 31%, whereas another prospective study of 44 adult patients with NPSLE found a higher frequency of work disability compared with patients without a history of NPSLE.161 Patients with recurrent episodes of NPSLE and those with antiphospholipid antibodies generally did worse. Using the ACR-SLICC damage index, several investigators have reported that NP damage from any cause accumulates over time and develops in 33% to 51% of patients. Notably, the occurrence of NP events, regardless of whether or not they are the result of NPSLE or a nonlupus cause, is associated with a poorer health-related quality of life.162 Some studies have found an increased mortality in adults (7%–19%) and children (3%–10%) with NPSLE, whereas others have not.164 Status epilepticus, stroke, and coma are poor prognostic signs, demanding aggressive evaluation and treatment to help prevent residual neurologic damage or death. Whether the therapy of NPSLE improves or contributes to long-term morbidity and mortality from conditions such as atherosclerosis and cancer is unclear. Consequently, the clinician must make every effort to limit the toxicities of therapy by controlling hypertension, treating hyperlipidemia and hyperglycemia, using osteoporosis prophylaxis, administering vaccinations, advising against smoking, treating hyperhomocysteinemia, and using medications for Pneumocystis jiroveci prophylaxis.

REFERENCES 1. Kampylafka EI, Alexopoulos ML, Kosmidis DB, et al. Incidence and prevalence of major central nervous system involvement in systemic lupus erythematosus: a 3-year prospective study of 370 patients. PLoS ONE. 2013;8(2):e55848. 2. Ainiala H, Loukkola J, Peltola J, et al. The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. Neurology. 2001;57(3): 496–500. 3. Unterman A, Nolte JE, Boaz M, et al. Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin Arthritis Rheum. 2011;41(1):1–11. 4. ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 1999;42(4): 599–608. 5. Bertsias GK, Ioannidis JPA, Aringer M, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis. 2010;69(12): 2074–2082. 6. Ainiala H, Hietaharju A, Loukkola J, et al. Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation. Arthritis Care Res. 2001;45(5):419–423. 7. Hanly JG, Urowitz MB, Su L, et al. Prospective analysis of neuropsychiatric events in an international disease inception cohort of patients with systemic lupus erythematosus. Ann Rheum Dis. 2010;69(3):529–535. 8. Hanly JG, Urowitz MB, Su L, et al. Short-term outcome of neuropsychiatric events in systemic lupus erythematosus upon enrollment into an international inception cohort study. Arthritis Rheum. 2008;59(5):721–729. 9. Hanly JG, Urowitz MB, Su L, et al. Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus. Ann Rheum Dis. 2011;70(10):1726–1732. 10. Hanly JG, Urowitz MB, Sanchez-Guerrero J, et al. Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: an

CHAPTER 36  Lupus and the Nervous System international inception cohort study. Arthritis Rheum. 2007;56(1): 265–273. 11. Johnson RT, Richardson EP. The neurological manifestations of systemic lupus erythematosus. Medicine (Baltimore). 1968;47(4):337–369. 12. Ellis SG, Verity MA. Central nervous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, 1955–1977. Semin Arthritis Rheum. 1979;8(3):212–221. 13. Devinsky O, Petito CK, Alonso DR. Clinical and neuropathological findings in systemic lupus erythematosus: the role of vasculitis, heart emboli, and thrombotic thrombocytopenic purpura. Ann Neurol. 1988;23(4):380–384. 14. Cohen D, Rijnink EC, Nabuurs RJA, et al. Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement. Rheumatology. 2017;56(1):77–86. 15. Sibbitt WL, Brooks WM, Kornfeld M, et al. Magnetic resonance imaging and brain histopathology in neuropsychiatric systemic lupus erythematosus. Semin Arthritis Rheum. 2010;40(1):32–52. 16. Mahajan SD, Parikh NU, Woodruff TM, et al. C5a alters blood-brain barrier integrity in a human in vitro model of systemic lupus erythematosus. Immunology. 2015;146(1):130–143. 17. Monov S, Monova D. Classification criteria for neuropsychiatric systemic lupus erythematosus: Do they need a discussion? Hippokratia. 2008;12(2):103–107. 18. Bortoluzzi A, Scire CA, Bombardieri S, et al. Development and validation of a new algorithm for attribution of neuropsychiatric events in systemic lupus erythematosus. Rheumatology (Oxford). 2015;54(5):891–898. 19. West SG, Emlen W, Wener MH, et al. Neuropsychiatric lupus erythematosus: a 10-year prospective study on the value of diagnostic tests. Am J Med. 1995;99(2):153–163. 20. Hanly JG, Su L, Omisade A, et al. Screening for cognitive impairment in systemic lupus erythematosus. J Rheumatol. 2012;39(7):1371–1377. 21. Kozora E, Ellison MC, West S. Depression, fatigue, and pain in systemic lupus erythematosus (SLE): relationship to the American College of Rheumatology SLE neuropsychological battery. Arthritis Rheum. 2006;55(4):628–635. 22. Julian LJ, Yazdany J, Trupin L, et al. Validity of brief screening tools for cognitive impairment in rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2012;64(3):448–454. 23. Denburg SD, Denburg JA. Cognitive dysfunction and antiphospholipid antibodies in systemic lupus erythematosus. Lupus. 2003;12(12): 883–890. 24. Leritz E, Brandt J, Minor M, et al. “Subcortical” cognitive impairment in patients with systemic lupus erythematosus. J Int Neuropsychol Soc. 2000;6(7):821–825. 25. Shucard JL, Parrish J, Shucard DW, et al. Working memory and processing speed deficits in systemic lupus erythematosus as measured by the paced auditory serial addition test. J Int Neuropsychol Soc. 2004;10(1):35–45. 26. Reeves DL, Kane R, Winter K. Automated neuropsychological assessment metrics (ANAM V3.11a/96) user’s manual: clinical and neurotoxicology subset. (Report No. NCRF-SR-96-01). San Diego, CA: National Cognitive Foundation; 1996. 27. Brunner HI, Ruth NM, German A, et al. Initial validation of the Pediatric Automated Neuropsychological Assessment Metrics for childhood-onset systemic lupus erythematosus. Arthritis Rheum. 2007;57(7):1174–1182. 28. Petri M, Naqibuddin M, Carson KA, et al. Cognitive function in a systemic lupus erythematosus inception cohort. J Rheumatol. 2008;35(9):1776–1781. 29. Hanly JG, Omisade A, Su L, et al. Assessment of cognitive function in systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis by computerized neuropsychological tests. Arthritis Rheum. 2010;62(5):1478–1486. 30. Hanly JG, Cassell K, Fisk JD. Cognitive function in systemic lupus erythematosus: results of a 5-year prospective study. Arthritis Rheum. 1997;40(8):1542–1543.

453

31. Hay EM, Huddy A, Black D, et al. A prospective study of psychiatric disorder and cognitive function in systemic lupus erythematosus. Ann Rheum Dis. 1994;53(5):298–303. 32. Waterloo K, Omdal R, Husby G, Mellgren SI. Neuropsychological function in systemic lupus erythematosus: a five-year longitudinal study. Rheumatology (Oxford). 2002;41(4):411–415. 33. Menon S, Jameson-Shortall E, Newman SP, et al. A longitudinal study of anticardiolipin antibody levels and cognitive functioning in systemic lupus erythematosus. Arthritis Rheum. 1999;42(4):735–741. 34. Hanly JG, Hong C, Smith S, Fisk JD. A prospective analysis of cognitive function and anticardiolipin antibodies in systemic lupus erythematosus. Arthritis Rheum. 1999;42(4):728–734. 35. Faust TW, Chang EH, Kowal C, et al. Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms. Proc Natl Acad Sci USA. 2010;107(43):18569–18574. 36. Akbarian S, Sucher NJ, Bradley D, et al. Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. J Neurosci. 1996;16(1):19–30. 37. Jentsch JD, Roth RH. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology. 1999;20(3):201–225. 38. Kowal C, DeGiorgio LA, Nakaoka T, et al. Cognition and immunity; antibody impairs memory. Immunity. 2004;21(20):179–188. 39. DeGiorgio LA, Konstantinov KN, Lee SC, et al. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med. 2001;7(11):1189–1193. 40. Omdal R, Brokstad K, Waterloo K, et al. Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur J Neurol. 2005;12(5):392–398. 41. Lapteva L, Nowak M, Yarboro CH, et al. Anti-N-methyl-D-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus. Arthritis Rheum. 2006;54(8):2505–2514. 42. Hanly JG, Robichaud J, Fisk JD. Anti-NR2 glutamate receptor antibodies and cognitive function in systemic lupus erythematosus. J Rheumatol. 2006;33(8):1553–1558. 43. Harrison MJ, Ravdin LD, Lockshin MD. Relationship between serum NR2a antibodies and cognitive dysfunction in systemic lupus erythematosus. Arthritis Rheum. 2006;54(8):2515–2522. 44. Steup-Beekman G, Steens S, van Buchem M, Huizinga T. Anti-NMDA receptor autoantibodies in patients with systemic lupus erythematosus and their first-degree relatives. Lupus. 2007;16(5):329–334. 45. Yoshio T, Onda K, Nara H, Minota S. Association of IgG anti-NR2 glutamate receptor antibodies in cerebrospinal fluid with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 2006;54(2):675–678. 46. Arinuma Y, Yanagida T, Hirohata S. Association of cerebrospinal fluid anti-NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1130–1135. 47. Brunner HI, Klein-Gitelman MS, Zelco F, et al. Validation of the Pediatric Automated Neuropsychological Assessment Metrics in childhood-onset systemic lupus erythematosus. Arthritis Care Res. 2013;65(3):372–381. 48. Hanly JG, Urowitz MB, O’Keeffe AG, et al. Headache in systemic lupus erythematosus: results from a prospective, international inception cohort study. Arthritis Rheum. 2013;65(11):2887. 49. Mitsikostas DD, Sfikakis PP, Goadsby PJ. A meta-analysis for headache in systemic lupus erythematosus: the evidence and the myth. Brain. 2004;127(Pt 5):1200–1209. 50. Stovner LJ, Andree C. Prevalence of headache in Europe: a review for the Eurolight project. J Headache Pain. 2010;11(4):289–299. 51. Lockshin MD. Editorial: splitting headache (off). Arthritis Rheum. 2013;65(11):2759–2761. 52. Davey R, Bamford J, Emery P. The validity of the inclusion of “lupus headache” in the Systemic Lupus Erythematosus Disease Activity Index. Arthritis Rheum. 2007;56(8):2812–2813. 53. Fernandez-Nebro A, Palacios-Munoz R, Gordillo J, et al. Chronic or recurrent headache in patients with systemic lupus erythematosus: a case control study. Lupus. 1999;8(2):151–156.

454

SECTION 5  Clinical Aspects of Lupus Erythematosus

54. Green L, Vinker S, Amital H, et al. Pseudotumor cerebri in systemic lupus erythematosus. Semin Arthritis Rheum. 1995;25(2):103–108. 55. Futrell N, Millikan C. Frequency, etiology, and prevention of stroke in patients with systemic lupus erythematosus. Stroke. 1989;20(5):583–591. 56. Mok CC, Ho LY, To CH. Annual incidence and standardized incidence ratio of cerebrovascular accidents in patients with systemic lupus erythematosus. Scand J Rheumatol. 2009;38(5):362–368. 57. Mikdashi J, Handwerger B, Langenberg P, et al. Baseline disease activity, hyperlipidemia, and hypertension are predictive factors for ischemic stroke and stroke severity in systemic lupus erythematosus. Stroke. 2007;38(2):281–285. 58. Schoenfeld SR, Kasturi S, Costenbader KH. The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systemic review. Semin Arthritis Rheum. 2013;43(1):77–95. 59. Bernatsky S, Clarke A, Gladman DD, et al. Mortality related to cerebrovascular disease in systemic lupus erythematosus. Lupus. 2006;15(12):835–839. 60. Roldan CA, Gelgand EA, Qualls CR, et al. Valvular heart disease by transthoracic echocardiography is associated with focal brain injury and central neuropsychiatric systemic lupus erythematosus. Cardiology. 2007;108(4):331–337. 61. Fanouriakis A, Pamfil C, Sidiropoulos L, et al. Cyclophosphamide in combination with glucocorticoids for severe neuropsychiatric systemic lupus erythematosus: a retrospective, observational, two-centered study. Lupus. 2016;25(6):627–636. 62. Kovacs B, Lafferty TL, Brent LH, et al. Transverse myelopathy in systemic lupus erythematosus: an analysis of 14 cases and review of the literature. Ann Rheum Dis. 2000;59(2):120–124. 63. Birnbaum J, Petri M, Thompson R, et al. Distinct subtypes of myelitis in systemic lupus erythematosus. Arthritis Rheum. 2009;60(11): 3378–3387. 64. Pittock SJ, Lennon VA, de Seze J, et al. Neuromyelitis optica and non-organ specific autoimmunity. Arch Neurol. 2008;65(1):78–83. 65. Kolfenbach JR, Horner BJ, Ferucci ED, et al. Neuromyelitis optica spectrum disorder in patients with connective tissue disease and myelitis. Arthritis Care Res. 2011;63(8):1203–1208. 66. Narvaez I, Rios-Rodriguez V, de la Fuente D, et al. Rituximab therapy in refractory neuropsychiatric lupus: current clinical evidence. Semin Arthritis Rheum. 2011;41(3):364–372. 67. Katsiari CG, Giavri DD, Mitsikostas KG, et al. Acute transverse myelitis and antiphospholipid antibodies in lupus. No evidence for anticoagulation. Eur J Neurol. 2011;18(4):556–563. 68. Cervera R, Asherson RA, Font J, et al. Chorea in the antiphospholipid syndrome. Clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature. Medicine (Baltimore). 1997;76(3):203–212. 69. Baizabal-Cavallo JF, Bonnet C, Jankovic J. Movement disorders in systemic lupus erythematosus and the antiphospholipid antibody syndrome. J Neural Transm (Vienna). 2013;120(11):1579–1589. 70. Magro Checa C, Cohen D, Bollen ELEM, et al. Demyelinating disease in SLE: is it multiple sclerosis or lupus? Best Pract Res Clin Rheumatol. 2013;27(3):405–424. 71. Hanly JG, Urowitz MB, Su L, et al. Seizure disorders in systemic lupus erythematosus results from an international, prospective, inception cohort study. Ann Rheum Dis. 2012;71(9):1502–1509. 72. Appenzeller S, Cendes F, Costallat LTL. Epileptic seizures in systemic lupus erythematosus. Neurology. 2004;63(10):1808–1812. 73. Cimaz R, Meroni PL, Schoenfeld Y. Epilepsy as part of systemic lupus erythematosus and systemic antiphospholipid syndrome (Hughes syndrome). Lupus. 2006;15(4):191–197. 74. Caronti B, Calderaro C, Alessandri C, et al. Serum anti-beta2glycoprotein I antibodies from patients with antiphospholipid antibody syndrome bind central nervous system cells. J Autoimmun. 1998;11(5):425–429. 75. Andrade RM, Alarcon GS, Gonzalez LA, et al. Seizures in patients with systemic lupus erythematosus: data from LUMINA, a multiethnic cohort (LUMINA LIV). Ann Rheum Dis. 2008;67(6):829–834.

76. Pego-Reigosa JM, Isenberg DA. Psychosis due to systemic lupus erythematosus: characteristics and long-term outcome of this rare manifestation of the disease. Rheumatology. 2008;47(10):1498–1502. 77. Briani C, Lucchetta M, Ghirardello A, et al. Neurolupus is associated with anti-ribosomal P protein antibodies: an inception cohort study. J Autoimmun. 2009;32(2):79–84. 78. Karassa FB, Afeltra A, Ambrozic A, et al. Accuracy of anti-ribosomal P protein antibody testing for the diagnosis of neuropsychiatric systemic lupus erythematosus: an international meta-analysis. Arthritis Rheum. 2006;54(1):312–324. 79. Gerli R, Caponi L, Tincani A, et al. Clinical and serological associations of ribosomal P autoantibodies in systemic lupus erythematosus: prospective evaluation in a large cohort of Italian patients. Rheumatology (Oxford). 2002;41(12):1357–1366. 80. Hanly JG, Su L, Urowitz MB, et al. Mood Disorders in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study. Arthritis Rheumatol. 2015;67(7):1837–1847. 81. Ayuso-Mateos JL, Vazquez-Barquero JL, Dowriick C, et al. Depressive disorders in Europe: prevalence figures from the ODIN study. Br J Psychiatry. 2001;179:308–316. 82. Mok CC, Lau CS, Wong RW. Neuropsychiatric manifestations and their clinical associations in southern Chinese patients with systemic lupus erythematosus. J Rheumatol. 2001;28(4):766–771. 83. Matcham F, Rayner L, Steer S, Hotopf M. The prevalence of depression in rheumatoid arthritis: a systemic review and meta-analysis. Rheumatology (Oxford). 2013;52(12):2136–2148. 84. Petri M, Naqibuddin M, Carson KA, et al. Depression and cognitive impairment in newly diagnosed systemic lupus erythematosus. J Rheumatol. 2010;37(10):2032–2038. 85. Stojanovich L, Zandman-Goddard G, Pavlovich S, et al. Psychiatric manifestations in systemic lupus erythematosus. Autoimmun Rev. 2007;6(6):421–426. 86. Kellner ES, Lee PY, Li Y, et al. Endogenous typie-1 interferon activity is not associated with depression or fatigue in systemic lupus erythematosus. J Neuroimmunol. 2010;223(1–2):13–19. 87. Ward MM, Marx AS, Barry NN. Psychological distress and changes in the activity of systemic lupus erythematosus. Rheumatology (Oxford). 2002;41(2):184–188. 88. Segui J, Ramos-Casals M, Garcia-Carrasco M, et al. Psychiatric and psychosocial disorders in patients with systemic lupus erythematosus: a longitudinal study of active and inactive stages of the disease. Lupus. 2000;9(8):584–588. 89. Ishikura R, Morimoto N, Tanaka K, et al. Factors associated with anxiety, depression and suicide ideation in female outpatients with SLE in Japan. Clin Rheumatol. 2001;20(6):394–400. 90. Omdal R, Loseth S, Torbergsen T, et al. Peripheral neuropathy in systemic lupus erythematosus—a longitudinal study. Acta Neurol Scand. 2001;103(6):386–391. 91. Xianbin W, Mingu W, Dong X, et al. Peripheral neuropathies due to systemic lupus erythematosus in China. Medicine (Baltimore). 2015;94(11):e625. 92. Florica B, Aghdassi E, Su J, et al. Peripheral neuropathy in patients with systemic lupus erythematosus. Semin Arthritis Rheum. 2011;41(2): 203–211. 93. Oomatia A, Fang H, Petri M, Birnbaum J. Peripheral neuropathies in systemic lupus erythematosus. Arthritis Rheumatol. 2014;66(4): 1000–1009. 94. Toledano P, Orueta R, Rodriguez-Pinto I, et al. Peripheral nervous system involvement in systemic lupus erythematosus: prevalence, clinical and immunological characteristics, treatment and outcome of a large cohort from a single centre. Autoimmun Rev. 2017;16(7): 750–755. 95. Goransson LG, Tjensvoll AB, Herigstad A, et al. Small-diameter nerve fiber neuropathy in systemic lupus erythematosus. Arch Neurol. 2006;63(3):401–404. 96. Matthew L, Talbot K, Love S, et al. Treatment of vasculitic peripheral analysis: a retrospective analysis of outcome. QJM. 2007;100(1): 41–51.

CHAPTER 36  Lupus and the Nervous System 97. Li X, Wang Y. Systemic lupus erythematosus with acute inflammatory demyelinating polyneuropathy: a case report and review of the literature. J Clin Med Res. 2016;8(7):555–559. 98. Vina ER, Fang AJ, Wallace DJ, Weisman MH. Chronic inflammatory demyelinating polyneuropathy in patients with systemic lupus erythematosus: prognosis and outcome. Semin Arthritis Rheum. 2005;35(3):175–184. 99. Shalimar, Handa R, Deepak KK, et al. Autonomic dysfunction in systemic lupus erythematosus. Rheumatol Int. 2006;26(9):837–840. 100. Jallouli M, Saadoun D, Eymard D, et al. The association of systemic lupus erythematosus and myasthenia gravis: a series of 17 cases, with a special focus of hydroxychloroquine use and review of the literature. J Neurol. 2012;259(7):1290–1297. 101. Muscal E, Brey RL. Neurologic manifestations of systemic lupus erythematosus in children and adults. Neurol Clin. 2010;28(1): 61–73. 102. Benseler SM, Silverman ED. Neuropsychiatric involvement in pediatric systemic lupus erythematosus. Lupus. 2007;16(8):564–571. 103. Sibbitt WL Jr, Brandt JR, Johnson CR, et al. The incidence and prevalence of neuropsychiatric syndromes in pediatric onset systemic lupus erythematosus. J Rheumatol. 2002;29(7):1536–1542. 104. Tomic-Lucic A, Petrovic R, Radak-Petrovic M, et al. Late-onset systemic lupus erythematosus: clinical features, course, and prognosis. Clin Rheumatol. 2013;32(7):1053–1058. 105. Barber CE, Leclerc R, Gladman DD, et al. Posterior reversible encephalopathy syndrome: an emerging disease manifestation in systemic lupus erythematosus. Semin Arthritis Rheum. 2011;41(3): 353–363. 106. Zandman-Goddard G, Chapman J, Shoenfeld Y. Autoantibodies involved in neuropsychiatric SLE and antiphospholipid syndrome. Semin Arthritis Rheum. 2007;36(5):297–315. 107. Hanley JG, Urowitz MB, Siannis F, et al. Autoantibodies and neuropsychiatric events at the time of systemic lupus erythematosus diagnosis: results from an international inception cohort study. Arthritis Rheum. 2008;58(3):843–853. 108. Ho RC, Thiaghu C, Ong H, et al. A meta-analysis of serum and cerebrospinal fluid autoantibodies in neuropsychiatric systemic lupus erythematosus. Autoimmun Rev. 2016;15(2):124–138. 109. Love PE, Santora SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med. 1990;112(9):682–698. 110. Levine SR, Brey RL, Joseph CLM, et al. Risk of recurrent thromboembolic events in patients with focal cerebral ischemia and antiphospholipid antibodies. Stroke. 1992;23(supplI):I29–I32. 111. Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2015;74(6): 1011–1018. 112. Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid antibody syndrome. N Engl J Med. 2013;368(11):1033–1044. 113. Chapman J, Cohen-Armon M, Shoenfeld Y, Korczyn AD. Antiphospholipid antibodies permeabilize and depolarize brain synaptoneurosomes. Lupus. 1999;8(2):127–133. 114. Mahler M, Kessenbrock K, Szmyrka M, et al. International multicenter evaluation of autoantibodies to ribosomal P proteins. Clin Vaccine Immunol. 2006;13(1):77–83. 115. Matus S, Burgos PV, Bravo-Zehnder M, et al. Antiribosomal-P autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosis. J Exp Med. 2007;204(13):3221–3234. 116. Bravo-Zehnder M, Toledo EM, Segovia-Miranda F, et al. Anti-ribosomal p protein autoantibodies from patients with neuropsychiatric lupus impair memory in mice. Arthritis Rheumatol. 2015;67(1):204–214. 117. Kang EH, Shen GQ, Morris R, et al. Flow cytometric assessment of anti-neuronal antibodies in central nervous system involvement of systemic lupus erythematosus and other autoimmune diseases. Lupus. 2008;17(1):21–25.

455

118. Weiner SM, Klein R, Berg PA. A longitudinal study of autoantibodies against central nervous system tissue and gangliosides in connective tissue diseases. Rheumatol Int. 2000;19(3):83–88. 119. Bluestein HG, Williams GW, Steinberg AD. Cerebrospinal fluid antibodies to neuronal cells: association with neuropsychiatric manifestations of systemic lupus erythematosus. Am J Med. 1981;70(2):240–246. 120. Zvaifler NJ, Bluestein HG. The pathogenesis of central nervous system manifestations of systemic lupus erythematosus. Arthritis Rheum. 1982;25(7):862–866. 121. Mok MY, Chan EY, Wong WS, Lau CS. Intrathecal immunoglobulin production in patients with systemic lupus erythematosus with neuropsychiatric manifestations. Ann Rheum Dis. 2007;66(6):846–847. 122. Hirohata S, Taketani T. A serial study of changes in intrathecal immunoglobulin synthesis in a patient with central nervous system systemic lupus erythematosus. J Rheumatol. 1987;14(5):1055–1057. 123. Okamoto H, Kobayashi A, Yamanaka H. Cytokines and chemokines in neuropsychiatric syndromes of systemic lupus erythematosus. J Biomed Biotechnol. 2010;2010:268436. 124. Yoshio T, Okamoto H, Kurasawa K, et al. IL-6, IL-8, IP-10, MCP-1, and G-CSF are significantly increased in cerebrospinal fluid but not in sera of patients with central neuropsychiatric lupus erythematosus. Lupus. 2016;25(9):997–1003. 125. Lampropoulos CE, Koutroumanidis M, Reynolds PPM, et al. Electroencephalography in the assessment of neuropsychiatric manifestations in antiphospholipid syndrome and systemic lupus erythematosus. Arthritis Rheum. 2005;52(3):841–846. 126. Glanz BI, Laoprasert P, Schur PH, et al. Lateralized EEG findings in patients with neuropsychiatric manifestations of systemic lupus erythematosus. Clin Electroencephalogr. 2001;32(1):14–19. 127. Kozora E, Ellison MC, West S. Reliability and validity of the proposed American College of Rheumatology neuropsychological battery for systemic lupus erythematosus. Arthritis Rheum. 2004;51(5):810–818. 128. Sibbitt WL, Sibbitt RR, Brooks WM. Neuroimaging in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 1999;42(10):2026–2038. 129. Zardi EM, Taccone A, Marigliano B, et al. Neuropsychiatric systemic lupus erythematosus: tools for diagnosis. Autoimmun Rev. 2014;13(8):831–839. 130. Appenzeller S, Pike GB, Clarke AE. Magnetic resonance imaging in the evaluation of central nervous system manifestations in systemic lupus erythematosus. Clin Rev Allergy Immunol. 2008;34(3):361–366. 131. Sibbitt WL Jr, Jung RE, Brooks WM. Neuropsychiatric systemic lupus erythematosus. Compr Ther. 1999;25(4):198–208. 132. Komatsu N, Kodama K, Yamanouchi N, et al. Decreased regional cerebral metabolic rate for glucose in systemic lupus erythematosus patients with psychiatric symptoms. Eur Neurol. 1999;42(1):41–48. 133. Huang WS, Chiu PY, Tsai CH, et al. Objective evidence of abnormal regional cerebral blood flow in patients with systemic lupus erythematosus on Tc-99m ECD brain SPECT. Rheumatol Int. 2002;22(5):178–181. 134. Govoni M, Castellino G, Padovan M, et al. Recent advances and future perspective in neuroimaging in neuropsychiatric systemic lupus erythematosus. Lupus. 2004;13(3):149–158. 135. Zardi EM, Vernieri F, Navarini L, et al. Systemic lupus erythematosus with and without neuropsychiatric manifestations: a neck and transcranial duplex sonography study. Int J Immunopathol Pharmacol. 2012;25(4):1157–1165. 136. Baizabal-Carvallo JF, Samson Y. Microembolic signals in systemic lupus erythematosus and other cerebral small vessel diseases. J Neurol. 2010;257(4):503–508. 137. Dahl A, Omdahl R, Waterloo K, et al. Detection of cerebral signals in patients with systemic lupus erythematosus. J Neurol Neurosurg Psychiatry. 2006;77(6):774–779. 138. Mikdashi JA. Altered functional neuronal activity in neuropsychiatric lupus: a systemic review of the fMRI investigations. Semin Arthritis Rheum. 2016;45(4):455–462. 139. Petropoulos H, Sibbitt WL Jr, Brooks WM. Automated T2 quantitation in neuropsychiatric lupus erythematosus: a marker of active disease. J Magn Reson Imaging. 1999;9(1):39–43.

456

SECTION 5  Clinical Aspects of Lupus Erythematosus

140. Bosma GP, Middelkoop HA, Rood MJ, et al. Association of global brain damage and clinical functioning in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 2002;46(10):2665–2672. 141. Ercan E, Ingo C, Tritanon O, et al. A multimodal MRI approach to identify and characterize microstructural brain changes in neuropsychiatric systemic lupus erythematosus. Neuroimage Clin. 2015;8:337–344. 142. Bosma GP, Rood MJ, Zwinderman AH, et al. Evidence of central nervous system damage in patients with neuropsychiatric systemic lupus erythematosus, demonstrated by magnetization transfer imaging. Arthritis Rheum. 2000;43(1):48–54. 143. Emmer BJ, Veer IM, Steup-Beekman GM, et al. Tract-based spatial statistics on diffusion tensor imaging in systemic lupus erythematosus reveals localized involvement of white matter tracts. Arthritis Rheum. 2010;62(12):3716–3721. 144. Jung RE, Caprihan A, Chavez RS, et al. Diffusion tensor imaging in neuropsychiatric systemic lupus erythematosus. BMC Neurol. 2010;10:65. 145. Zimny A, Szmyrka-Kaczmarek M, Szewczyk P, et al. In vivo evaluation of brain damage in the course of systemic lupus erythematosus using magnetic resonance spectroscopy, perfusion-weighted, and diffusion-tenor imaging. Lupus. 2014;23(1):10–19. 146. Steens SC, Bosma GP, ten Cate R, et al. A neuroimaging follow up study of a patient with juvenile central nervous system systemic lupus erythematosus. Ann Rheum Dis. 2003;62(6):583–586. 147. Appenzeller S, Li LM, Costallat LT, Cendes F. Neurometabolic changes in normal white matter may predict appearance of hyperintense lesions in systemic lupus erythematosus. Lupus. 2007;16(12):963–971. 148. Sanna G, Bertolaccini ML, Khamashta MA. Neuropsychiatric involvement in systemic lupus erythematosus: current therapeutic approach. Curr Pharm Des. 2008;14(13):1261–1269. 149. Govoni M, Bortoluzzi A, Padovan M, et al. The diagnosis and clinical management of the neuropsychiatric manifestation of SLE. J Autoimmun. 2016;74:41–72. 150. Braile-Fabris L, Ariza-Andraca R, Olguin-Ortega L, et al. Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. Ann Rheum Dis. 2005;64(4):620–625. 151. Trevsani VF, Castro AA, Neves Neto JF, et al. Cyclophosphamide versus methylprednisolone for the treatment of neuropsychiatric involvement in systemic lupus erythematosus. Cochrane Database Syst Rev. 2000;(3):CD002265. 152. Valesini G, Priori R, Francia A, et al. Central nervous system involvement in systemic lupus erythematosus: a new therapeutic

approach with intrathecal dexamethasone and methotrexate. Springer Semin Immunopathol. 1994;16(2–3):313–321. 153. Erkan D, Aguiar CL, Andrade D, et al. 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev. 2014;13(6):685–696. 154. Tokunaga M, Saito K, Kawabata D, et al. Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system. Ann Rheum Dis. 2007;66(4):470–475. 155. Tsanyan M, Soloviev S, Aleksandrova E, Nasonov E. Efficacy and safety of rituximab in the treatment of neuropsychiatric systemic lupus erythematosus during long-term follow-up. Ann Rheum Dis. 2015;74:1076–1077. 156. Bortoluzzi A, Padovan M, Farina I, et al. Therapeutic strategies in severe neuropsychiatric systemic lupus erythematosus: experience from a tertiary referral centre. Reumatismo. 2012;64(6):350–359. 157. Kronbichler A, Brezina B, Quintana LF, Jayne DRW. Efficacy of plasma exchange and immunoadsorption in systemic lupus erythematosus and antiphospholipid syndrome: a systemic review. Autoimmun Rev. 2016;15(1):38–49. 158. Bhangle SD, Kramer N, Rosenstein ED. Corticosteroid-induced neuropsychiatric disorders: review and contrast with neuropsychiatric lupus. Rheumatol Int. 2013;33(8):1923–1932. 159. Gómez-Puerta JA, Cervera R, Calvo LM, et al. Dementia associated with the antiphospholipid syndrome: clinical and radiological characteristics of 30 patients. Rheumatology. 2005;44(1):95–99. 160. Patwa HS, Chaudhry V, Katzberg H, et al. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology. Neurology. 2012;78(13):1009–1015. 161. Jonsen A, Bengtsson AA, Nived O, et al. Outcome of neuropsychiatric systemic lupus erythematosus within a defined Swedish population: increased morbidity but low mortality. Rheumatology. 2002;41(11): 1308–1312. 162. Hanly JG, Su L, Farewell V, et al. Prospective study of neuropsychiatric events in systemic lupus erythematosus. J Rheumatol. 2009;36(7): 1449–1459. 163. Karassa FP, Ioannidis JP, Boki JA, et al. Predictors of clinical outcome and radiologic progression in patients with neuropsychiatric manifestations of systemic lupus erythematosus. Am J Med. 2000;109(8):628–634. 164. Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1000 patients. Medicine (Baltimore). 2003;82(5):299–308.