Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can affect almost any organ system, and it is characterized by the presence of antinuclear (ANAs) and other autoantibodies as well as a clinical course of flares and remissions. ANAs are present in >90% of patients with SLE. Approximately 20% of SLE cases begin before age 19 years. Incidence and prevalence rates of SLE vary by ethnicity and are higher in Hispanic, black, North American First Nations, and Southeast and South Asian populations. The mean age of presentation for pediatric SLE is 13 years. The ratio for girls to boys in the pediatric population varies from 4:3 in young children to 5:1 in adolescents. The etiology of SLE is unknown, but is thought to be multifactorial, with both genetic and environmental or acquired factors contributing.1 The clinical presentation of SLE is diverse, ranging from a mild disease characterized by rash and arthritis to a severe life-threatening disease involving multiple organs. Patients who fulfill 4 of the 11 American College of Rheumatology (ACR) classification criteria are considered to have definite SLE.2,3
Neuropsychiatric SLE (NPLE) describes pathology of the central, peripheral, and/or autonomic nervous system, as well as psychiatric syndromes observed in patients with SLE in whom other causes have been excluded. The pathogenesis of NPLE is complex, and has been related to vasculitis,4,5 thrombosis, and autoantibodies including antineuronal,6 antiribosomal P antibodies,7–9 and antiphospholipid antibodies.10,11 In 1999, the ACR developed a new classification system for NPLE that separated neuropsychiatric disease into 19 entities (Table 1).12 Although this classification system was defined in adult cohorts, it is generally useful in pediatric SLE.
Neuropsychiatric Manifestations of Systemic Lupus Erythematosus
Neuropsychiatric involvement is common in pediatric SLE and is a major cause of morbidity and mortality. Prevalence estimates vary widely across studies, but at least 25% of pediatric SLE patients appear to have neuropsychiatric involvement at some point.4,11,13–16 Neuropsychiatric manifestations most commonly occur within 1 year of SLE onset, but may develop at any time. In 70% of children with NPLE, neuropsychiatric involvement occurred within the first year of SLE diagnosis. Neuropsychiatric features may be the initial manifestations of SLE in a previously healthy child. SLE should be considered in the differential diagnosis of a child or adolescent presenting with new-onset severe neurologic or psychiatric disease.17
Neuropsychiatric manifestations of lupus in children most often affect the central nervous system (CNS). Peripheral and autonomic nervous system involvement is rare.14 NP pediatric SLE may manifest with headaches, psychosis, seizures, cerebrovascular disease, cognitive dysfunction, and mood disorders including depression. Transverse myelitis, although rare, may rapidly lead to irreversible paralysis unless treated aggressively. Mononeuritis multiplex typically presents with mixed sensorimotor neuropathy of an extremity. An extraordinarily broad range of other, although less common, neurologic syndromes has also been reported (Table 1).4,14–16
In most cases headache is associated with other manifestations of NPLE. In cases of severe isolated headaches, patients should be thoroughly evaluated to rule-out CNS infection, cerebral vein thrombosis, vasculitis, and other intracranial pathologies.
Psychiatric manifestations are also common among patients with NPLE.4,14,15,17 Psychosis, mood disorders, cognitive dysfunction, acute confusional state, and anxiety disorders are included in the 1999 ACR classification system of NPLE.12 Depression is the most common mood disorder seen in pediatric NP pediatric SLE. However, other causes of depression must also be considered. Reactive depression, triggered by the challenges of living with chronic illness, is common in young people with SLE, as are steroid-induced mood changes.14 In addition to affective disorders, auditory, visual, and rarely tactile hallucinations may develop. Interestingly, insight is usually preserved in patients with NP pediatric SLE affected by hallucinations. This may paradoxically complicate treatment, as patients do not wish to report hallucinations for fear of being stigmatized as having severe mental illness.4,18
Cognitive dysfunction has been reported in up to 55% of NP pediatric SLE patients.4,11,14 Impairment of attention, concentration, memory, and word finding may be observed during neurocognitive testing.12 These symptoms may fluctuate or worsen over time. Among adolescents with SLE, a substantial decline in academic performance may signal cognitive dysfunction due to NP pediatric SLE and should trigger further evaluation. In-office screens such as the Mini-Mental State can be useful for identifying severe deficits, but formal detailed neuropsychologic testing is necessary to identify milder deficits.19 Antiphospholipid antibody positivity may play a pathogenic role in NPLE-related cognitive decline. In adult studies, antiphospholipid antibody positivity increases the risk for cognitive dysfunction in SLE patients.19–21 Longer disease duration also appears to be associated with lower cognition.22
In addition to cognitive deficits, antiphospholipid antibody positivity also increases the risk of seizures in children with SLE.
Seizures are an alarming manifestation of lupus affecting the CNS. SLE patients with cerebrovascular disease and cognitive dysfunction also have a greater propensity for seizures. In some studies, antiphospholipid antibody positivity also increased seizure risk. The majority of seizures, about two-thirds in a 20-year retrospective study, are generalized seizures, with partial seizure the next most common.11,14,15 Electroencephalographic (EEG) abnormalities are common in SLE patients with seizure disorder, but tend to be nonspecific. Typical epileptiform EEG patterns are infrequent, but when present are more predictive of seizure recurrence.
Movement disorders are another dramatic expression of NPLE. Chorea is the most common movement disorder associated with NP pediatric SLE, and may be the initial manifestation of SLE. Of note, patients with NP pediatric SLE presenting with chorea were found to be at higher risk for arterial thrombotic events, suggesting a vasculopathic etiology.23 As chorea is uncommon among previously healthy children, SLE should be considered in the differential diagnosis for any child with unexplained new-onset chorea.
Headaches are among the most frequent manifestations of NPLE in children with SLE.14 Per the 1999 ACR Classification system,12 lupus headaches are subdivided into five categories: migraine, tension, cluster headache, headache from intracranial hypertension (pseudotumor cerebri), and nonspecific intractable headache. Of course, as with mood changes, headaches in children with SLE may be multifactorial. There is currently no test that can reliably distinguish headache caused by SLE activity from other etiologies, including idiopathic migraine, medication adverse effect, CNS infection, and others. The clinician may wonder when to consider SLE as a possible etiology in an adolescent with headaches. Careful history taking is essential. In most cases, headache due to SLE activity is associated with other manifestations of NPLE, or with laboratory or clinical signs of systemic SLE activity. In cases of unusually severe or new-onset headaches, patients should be thoroughly evaluated with brain imaging, and possibly lumbar puncture. Imaging may identify ischemic changes or new inflammatory lesions. Lumbar puncture may be needed to measure opening pressure to evaluate for pseudotumor cerebri, and cerebrospinal fluid (CSF) can be evaluated for signs of infection. Additionally, patients with known SLE are immunosuppressed, so special testing of the CSF for opportunistic infections such as cryptococcal meningitis is often indicated. Mild CSF pleocytosis, usually with normal protein and glucose, is consistent with NPLE.
Pathophysiology and Diagnostic Evaluation
Cerebrovascular disease (CVD) in NP pediatric SLE may affect small or large vessels, and may take the form of thrombosis or inflammatory vasculitis. As in other causes of CVD, thrombosis in NP pediatric SLE typically manifests as stroke or transient ischemic attacks. Imaging, particularly angiogram, is usually diagnostic. Unusually, SLE patients are at risk for both arterial and venous occlusions. Cerebral vein thrombosis may occur in patients who are positive for antiphospholipid antibodies. Small vessel CNS vasculitis is more challenging to identify. Small vessel disease may present with nonspecific symptoms including headaches, seizures, or visual problems, and angiogram is usually normal.11,14,15 Magnetic resonance imaging (MRI) with fluid attenuation inversion recovery sequence may demonstrate multifocal-enhancing lesions in small-vessel vasculitis of the CNS.25
Several antineuronal antibodies have been implicated in the pathogenesis of NPLE. These pathogenic autoantibodies may promote vascular occlusion and also lead to interruption of the blood-brain barrier. Anti-NR2 glutamate receptor antibodies, anti-N-methyl-D-aspartate receptor antibodies, and antiribosomal P antibodies have been identified in the serum and/or CSF of patients with NPLE.19,24 Moreover, an association between antiphospholipid antibody positivity and NPLE has been demonstrated in multiple studies.7,8,24–26 However, no autoantibodies are specific for neuropsychiatric SLE. Thus, autoantibody testing is only of moderate use for the diagnosis of NP pediatric SLE, and results must be interpreted in concert with history, physical examination, other laboratory studies, and imaging results.
Brain imaging may be useful in identifying NPLE, and can be important in eliminating alternative diagnoses such as infections and CNS malignancies. Limited studies in adults have shown that about two-thirds of patients with NPLE have abnormalities on brain MRI. Infarct-like lesions involving gray and white matter, and high-signal lesions on T2-weighted images in the frontal and parietal subcortical white matter, are most frequently noted. Most MRI abnormalities in NPLE are secondary to small vessel involvement, and MRI results of small, multifocal, bilateral high-signal intensity lesions are suggestive of small vessel vasculitis. Compared to MRI, computed tomography (CT) is more valuable in demonstrating acute changes due to hemorrhagic strokes, pseudotumor cerebri, or sinus vein thrombosis. Magnetic resonance angiogram is valuable to diagnose large-vessel vasculitis, with sensitivity comparable to conventional cerebral angiography.27 On the other hand, imaging can also be entirely normal, and thus absence of lesions on MRI or CT cannot exclude NPLE. Treatment decisions must be determined based on the entirety of the clinical information.
EEG abnormalities are common in SLE patients with seizure disorder, but typical epileptiform EEG patterns that are more predictive of seizure recurrence are less common.
Single-photon emission CT (SPECT) provides a means of assessing cerebral blood flow and may reveal subtle areas of decreased perfusion or loss of functioning brain parenchyma. A limited number of pediatric studies with small numbers of patients have demonstrated that most of the children with SLE presenting with neuropsychiatric symptoms have abnormal SPECT scans, even when they had normal CT and MRI scans, EEGs, and normal CSF analysis. Moreover, in patients who had abnormalities, the lesions found on SPECT scans extended into areas that appeared normal on MRI. SPECT is not yet in routine clinical use for evaluation of NPLE but may become an important diagnostic tool in the near future.28,29
Specific treatment of NPLE depends on the nature of the underlying process, ie, inflammatory, thrombotic, or both. In cases where an inflammatory process is apparently responsible for the NPLE manifestation, management with glucocorticoids alone or in combination with other immunosuppressants, such as azathioprine, mycophenolate mofetil, or cyclophosphamide,30 is indicated. In very severe or life-threatening cases, and in cases refractory to other treatments, plasma exchange, intravenous immunoglobulin, and rituximab31 have been used.
Antiplatelet and/or anticoagulant therapy is needed for NPLE with thrombotic manifestations. Anticoagulation is indicated especially for arterial thrombosis manifesting as stroke or transient ischemic attack in antiphospholipid syndrome.
The management of acute stroke in children is similar to that in the general population. Pediatric neurology should be consulted. The need for thrombolytic therapy and surgery should be assessed. Aspirin should be initiated, unless contraindicated.
Patients with seizures due to NPLE are treated with anticonvulsants as well as glucocorticoids or other immunosuppressants. As in other manifestations of NPLE, cyclophosphamide or plasma exchange is used for severe or refractory cases. As with seizures, psychiatric manifestations are treated with a combination of symptomatic therapy with antipsychotics or antidepressants and concomitant immunosuppression. Most patients with chorea experience a single episode that subsides gradually. Symptomatic treatment with dopamine antagonists in combination with oral glucocorticoids is usually effective. Chorea in association with antiphospholipid antibody positivity suggests a thrombotic etiology, and antiplatelet and/or anticoagulation therapy should be initiated.
Secondary prevention measures include reducing general lupus flares by optimizing therapy, reducing flare-inducing factors such as stress and infections, and for patients who have persistently high titers of antiphospholipid antibodies, considering aspirin and/or oral anticoagulation.
Long-term prognosis is fairly good, with overall survival rates reported to be around 90%. One study32 evaluated over 50 children with NPLE characterized by psychiatric symptoms or cognitive deficits. Encouragingly, a large majority (82%–95%) of the patients entered remission. However, attainment of remission was typically delayed, occurring over 1 year from symptom onset. Patients were more likely to respond to cyclophosphamide than to other immunosuppressants such as azathioprine or mycophenolate mofetil.32 In other studies, the presence of seizures or CVD as a manifestation of NPLE was a poor prognostic factor for the development of persistent end-organ damage. Some of this damage accrual, such as persistent seizures or persistent cognitive deficits, was a direct consequence of NPLE activity. Neuropsychiatric disease was also a marker for increased risk of steroid-induced morbidity such as osteoporotic fracture, avascular necrosis, cataracts, or diabetes. However, patients who have seizures or CVD as a manifestation of NPLE have higher cumulative disease activity and damage scores in the long term as determined by Systemic Lupus International Collaborating Clinics/Damage Index SLE damage scoring system.14,33–35
NPLE is common in children with SLE, and it is a major cause of morbidity and mortality. Neuropsychiatric symptoms can be the initial presentation of SLE. A high index of suspicion is essential for timely diagnosis as neuropsychiatric symptoms can be the initial presentation of SLE. SLE should be considered in the differential diagnosis of new-onset neurologic symptoms, especially psychosis, chorea, and cognitive impairment in children. New-onset neurologic symptoms in children, particularly psychosis, chorea, and cognitive impairment, should trigger evaluation for SLE. Prompt initiation of immunosuppressant therapy, and anticoagulation if indicated, is necessary to optimize outcomes.
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Neuropsychiatric Manifestations of Systemic Lupus Erythematosus
|Central Nervous System
| Seizure disorders
| Cerebrovascular disease
| Movement disorder (chorea)
| Demyelinating syndrome
| Aseptic meningitis
| Acute confusional state
| Cognitive dysfunction
|Peripheral Nervous System
| Acute inflammatory demyelinating polyneuropathy
| Autonomic disorder
| Mononeuropathy, single/multiplex
| Myasthenia gravis
| Cranial neuropathy
| Mood disorder/depression
| Anxiety disorder