CNS Lupus Workup

Conventional blood studies have varying utility in diagnosing systemic lupus erythematosus (SLE), depending on the associated conditions and manifestations. With systemic or other organ system involvement suggestive of autoimmune dysfunction (e.g., low-grade fevers, fatigue, arthralgias or arthritis, renal dysfunction, malar or other skin rashes) laboratory evaluation should include antinuclear antibody (ANA) testing and anti-DNA binding to confirm a positive ANA result. Other autoantibody testing should be based on clinical judgment and test availability.

In the patient with SLE who has risk factors for conventional small-vessel cerebrovascular disease (e.g., diabetes, hypertension), the clinical distinction between SLE and atherosclerotic (lipohyalinoid) disease as a cause of a given stroke may be difficult. Under these circumstances, additional studies such as lumbar puncture for evidence of central nervous system (CNS) inflammation, antinuclear antibodies (ANAs), or intrathecal immunoglobulin (IgG) synthesis may support a diagnosis of SLE over atherosclerotic small vessel disease. Clinical–radiologic correlations are not always obvious; more importantly, magnetic resonance imaging (MRI) lesions may resolve completely within days in keeping with clinical improvement or persist despite clear remission.

The complete blood cell (CBC) count in SLE may demonstrate hemolytic anemia with reticulocytosis or reductions of neutrophils, lymphocytes, or platelets.

Although Fcgamma receptor genes have been suggested to play an important role in the pathogenesis of SLE and lupus nephritis, Yuan et al's study suggested that FcgammaRIIIb polymorphism might not be a susceptibility gene for SLE and lupus nephritis. ^[24]

AlSaleh et al reported a high prevalence of positive anti-Ro antibodies (52.3%) among their Arab patients, which they felt probably reflected a common characteristic in SLE patients of Middle East origin. ^[25]

Electrolytes, glucose, and calcium are especially worth checking in the setting of new-onset generalized seizures or acute encephalopathy. Acid-based disturbances may be obvious on review of electrolytes, but an arterial blood gas (ABG) analysis may be useful to assess or follow such a disturbance, especially in the obtunded, acutely ill patient.

Lupus nephritis activity is customarily followed by assessing casts in the urine and proteinuria measured by dipstick or 24-hour collection but maybe followed more roughly by the blood urea nitrogen (BUN) and creatinine levels. Acute increases in BUN may produce metabolic encephalopathy, but on a chronic basis, very high BUN elevations may be surprisingly well tolerated.

Liver function studies are rarely affected by SLE disease activity (lupoid hepatitis is not part of the SLE spectrum.) Elevations of hepatocellular enzyme levels more likely point to medication-related or viral hepatitis and obstructive patterns point to medications or to biliary obstruction.

Muscle enzyme levels (creatine kinase, aldolase) may be moderately or severely elevated with lupus myopathy, although normal levels also may be seen with the clinical or biopsy-proven disease. Normal creatine kinase levels, therefore, do not reliably distinguish between SLE myositis and drug-related (steroid, hydroxychloroquine) myopathy.

The classic finding of a low C-reactive protein (CRP) level but an elevated erythrocyte sedimentation rate (ESR) or plasma viscosity was seen in about 40% of patients with systemic lupus erythematosus (SLE). In previously undiagnosed patients thought to have SLE, the principal diagnostic study is the antinuclear antibody (ANA) test.

Although many rheumatologists consider this test to be 100% sensitive for diagnosis, a positive ANA result alone is not sufficient for diagnosis. Positive test results are seen in other autoimmune conditions and a certain percentage of the general population (especially the elderly). Anti-DNA antibody testing is positive in only about 70% of central nervous system (CNS) episodes.

When a positive ANA result is thought to be clinically relevant, follow up with an antibody to native, double-stranded DNA (dsDNA antibody) to confirm the diagnosis of SLE. An autoantibody panel should be checked for related pathogenic antibodies.

ANA and immunofluorescence

El-Chennawi et al concluded that in patients with clinical features of SLE, ANA detection by immunofluorescence is a more sensitive and effective screening. ^[26] Additionally, the investigators determined that dsDNA titer by ELISA and BILAG score for severity index are the best markers for follow-up. ^[26]

Antiphospholipid antibodies

Of particular interest are the serum anti-ribosomal P antibody (which is positive in 60% of cases of lupus psychosis) and the family of antibodies known collectively as antiphospholipid antibodies (APAs, aPLs) (including the anticardiolipin antibody, [ACLA]). These may be positive in hypercoagulable states, myelopathy, and LSE. APAs were present in 16-60% of the reported cases. ^[27]

In addition to testing serum anticardiolipin antibody (ACLA), hematologic studies in patients with systemic lupus erythematosus (SLE) may reveal a circulating anticoagulant (originally called the lupus anticoagulant). Prolongation of the activated partial thromboplastin time (aPTT) only identifies 30% of circulating anticoagulants. Sensitivity may be enhanced by the Russell viper venom test, the kaolin clotting time, or variations using hexagonal phase phospholipids or other adsorbents.

Choojitarom et al reported that lupus anticoagulant (LA) is the strongest test to determine the risk of thrombosis in SLE-antiphospholipid antibodies (APAs, aPLs). ^[28] The presence of lupus nephritis and raynaud's phenomenon strongly predicts thrombosis, whereas lymphopenia and antimalarials are protective. These findings help to identify patients who may benefit from prophylactic therapy.

Cerebrospinal fluid (CSF) abnormalities have been seen in 30-40% of patients with systemic lupus erythematosus (SLE) reported. The frequency of CSF oligoclonal bands has varied between reports, with a lower range generally around 20%. An abnormal CSF is generally associated with a poor prognosis.

Cerebrospinal fluid (CSF) examination is most useful to exclude infection, especially in immunocompromised patients. However, the CSF can reflect increased central nervous system (CNS) lupus activity by showing elevated levels of white cells, protein, immunoglobulin synthesis, or absolute immunoglobulin G (IgG). Antineuronal nuclear antibodies have some value in confirming CNS disease when performed on CSF, but these are less specific or sensitive than a serum test.

In the presence of a clear stroke with positive antinuclear antibody (ANA) and anti-DNA binding studies, a presumptive diagnosis of lupus cerebritis may be considered, even in the absence of positive imaging studies, provided that other causes of stroke have been reasonably excluded.

CT scanning and MRI

MRI has greater sensitivity to endogenous contrast procedures than CT and detects abnormalities in 75% of SLE patients. ^{[29, 30]}

Joseph et al reported that 35% of computed tomography (CT) brain scans were abnormal and 65% of magnetic resonance (MR) scans, but CT scanning remains valuable in identifying hemorrhages and larger infarcts in patients with systemic lupus erythematosus (SLE). ^[15]

Neuroradiologic evaluation favors magnetic resonance imaging (MRI) over CT scanning, because subtle ischemia or cerebritis may be seen with greater sensitivity. The most common findings with either study are ischemic zones that may correspond to cortical or subcortical infarcts and may be large or small according to the size of the vessel involved and the mechanism of stroke. See the image below for an example of ischemia visible on MRI.

This axial, T2-weighted brain magnetic resonance image (MRI) demonstrates an area of ischemia in the right periventricular white matter of a 41-year-old woman with longstanding systemic lupus erythematosus (SLE). She presented with headache and subtle cognitive impairments but no motor deficits. Faintly increased signal intensity was also seen on T1-weighted images, with a trace of enhancement following gadolinium that is too subtle to show on reproduced images. The distribution of the abnormality is consistent with occlusion of deep penetrating branches, such as may result from local vasculopathy, with no clinical or laboratory evidence of lupus anticoagulant or anticardiolipin antibody. Cardiac embolus from covert Libman-Sacks endocarditis remains less likely due to the distribution.

Other vague areas of patchy cortical or subcortical abnormality (lucency on CT scan, T2 signal intensity on MRI) may correspond to small vessel vasculitis or cerebritis, but distinction from opportunistic infection (e.g., toxoplasmosis, progressive multifocal leukoencephalopathy) often cannot be made on radiographic grounds, requiring other studies, including cerebral biopsy. With either CT scanning or MRI, contrast enhancement increases the sensitivity for acute and subacute cerebral lesions.

A frequent clinical problem occurs when the MRI reveals multiple, small T2 signal intensities in the white matter, making it difficult to distinguish between multiple sclerosis and SLE or other vasculitides. Although many clinical and laboratory factors assist in this differential diagnosis, the MRI appearance is more supportive of SLE when the lesions are not confined to periventricular white matter but favor the gray-white junction or even involve the gray matter of cortex or deep nuclei with lesions assuming a rounded or patchy shape. If the lesions are radially oriented along white matter tracts, favor the periventricular white matter, and involve the corpus callosum, multiple sclerosis is a more likely diagnosis. Using the Fazekas criteria, at least 3 areas of increased signals, and 2 of the following features—lesion abutting body of lateral ventricles, infratentorial lesion location, and lesions larger than 5 mm—led to a further highly significant improvement of specificity (96%) on proton-density and T2-weighted MRIs of the brain. ^[31]

Perisulcal cortical atrophy is reported as a frequent finding on CT scans. ^[32] CT scanning may also detect calcifications in patients with long-standing cerebritis.

SPECT scanning and MRI

Castellino et al reported that combining single-photon emission computed tomography (SPECT) scanning and MRI appears more useful than the two techniques alone and may help the clinician in the assessment of patients with neuropsychiatric involvement, because normal findings contemporarily detected by these two techniques have been rarely observed in patients with neuropsychiatric involvement, especially in those with focal manifestations wherein MRI and SPECT scanning were never simultaneously normal. ^[33]

PET scanning and MRS

Positron emission tomography (PET) scanning and MR spectroscopy (MRS) promise greater sensitivity for cerebritis. However, the greatest utility of imaging studies remains the exclusion of unexpected mass lesions or opportunistic infectious processes.

MR angiography

MR angiography (MRA) or transcranial Doppler ultrasonography confirms thrombotic lesions of extracranial or intracranial vessels.

A cerebral angiogram is more sensitive than a CT angiogram of the brain in detecting changes in vasculitis. However, even this study often misses the predominantly small-vessel involvement of lupus vasculopathy. 

Magnetic Transfer Imaging (MTI)

Magnetic transfer imaging (MTI) is used to measure the transfer of energy between bound and unbound hydrogen molecules, and the results are expressed as MT ratio. ^[34] Demyelination causes a decrease in the bound molecules and edema causes an increase in the unbound molecules, decreasing the MT ratio. ^{[35, 36]}

Diffusion-weighted MRI (DWI)

Diffusion-weighted MRI (DWI) assesses the changes in the stochastic movement of water in the brain. Increased diffusivity and MTI changes are seen either because of demyelination or cerebral atrophy, increasing the CSF volume, or a combination of both. In acute stroke, cytotoxic edema leads to intracellular swelling, thus causing decreased diffusivity. ^{[34, 35, 37]}

Diffusion tensor imaging (DTI)

Diffusion tensor imaging (DTI) applies the DWI data to envision the neural tracts and chart the white matter connections. Abnormalities like demyelination and altered network connectivity are detected, which are not observed in MRI. ^[36]

Blood-oxygen-level-dependent functional MRI (BOLD-fMRI)

Blood-oxygen-level-dependent functional MRI (BOLD-fMRI) is used to measure the local brain deoxyhemoglobin levels, which acts as an indirect scale of brain function within the grey matter. ^[38]

In patients with systemic lupus erythematosus (SLE) who have myelopathy, spinal magnetic resonance (MRI) or myelography is mandatory to exclude compressive lesions. MRI also may demonstrate intramedullary spinal lesions, with variable sensitivity that depends on imaging sequences and technical factors related to the MRI equipment. If myelography is elected, cerebrospinal fluid (CSF) should be obtained before introducing contrast medium to assess for SLE disease activity, cytology, or evidence of opportunistic infection as appropriate.

When an embolic stroke occurs in patients with proven or suspected systemic lupus erythematosus (SLE), echocardiography is mandatory to assess valvular and other intracardiac lesions. In the patient known to have SLE who presents with an apparently non-embolic stroke syndrome or apparent so-called focal cerebritis, cardiac emboli remain the most likely etiology, mandating echocardiography in these settings as well. Transesophageal echocardiography may be helpful in selected cases.

In one study, strokes and leukoaraiosis were more common in the group with antiphospholipid syndrome (APLS) than in the group without APLS, which is consistent with the idea of an APLS-induced prothrombotic state. ^[39]

The carotid bifurcation may be conveniently imaged by ultrasonography.

As noted previously, magnetic resonance angiography (MRA) can confirm thrombotic lesions of extracranial or intracranial vessels in systemic lupus erythematosus (SLE), as can transcranial Doppler ultrasonography.

Electroencephalography (EEG) may help confirm the focal point of an apparently diffuse encephalopathy in patients with systemic lupus erythematosus (SLE). This study is most useful in patients with seizures whose cases are challenging to manage.

EEG also provides a measure of recurrence risk when anticonvulsant therapy is withdrawn. An active focus (especially with multiple loci), frequent discharges, or localization to the frontotemporal region predicts a likely recurrence of seizures after anticonvulsant cessation.

A normal EEG., even with sleep deprivation, does not exclude the possibility of recurrent seizures. It generally is associated with a reduced recurrence risk, although this has not been studied specifically in central nervous system (CNS) lupus. ^[40]  

Electromyography (EMG) and nerve conduction studies provide useful data in the clinical assessment of peripheral complications of systemic lupus erythematosus (SLE).

Muscle weakness in patients with SLE may result from inflammatory myopathy, medication-induced myopathy, neuromuscular junction dysfunction, neuropathies, or other musculoskeletal disturbances. Although much of the clinical decision-making relies on examination and historical evidence (especially the time course of drug therapy with steroids or hydroxychloroquine), EMG may help distinguish inflammatory from noninflammatory myopathy.

Lupus myositis resembles dermatomyositis or polymyositis on EMG findings, including increased insertional activity, fibrillation and positive sharp waves, and myopathic motor unit potentials and recruitment patterns, as well as complex repetitive discharges. Lupus myositis may present with normal EMG findings, especially (but not exclusively) if partially treated so that a normal needle examination does not exclude inflammatory myositis in SLE.

Repetitive stimulation studies may be used to search for neuromuscular junction pathology analogous to that seen with either myasthenia or myasthenic syndrome. (This is rare in SLE but has been reported.)

Peripheral nerve dysfunction in SLE presents clinically as mononeuritis multiplex, symmetrical distal polyneuropathy (sensory or sensorimotor), or acute demyelinating polyradiculopathy. The typical findings of each of these conditions may be demonstrated in conventional nerve conduction studies. As with other causes of acute polyradiculopathy, proximal nerve conduction studies or F and H wave studies may be needed to demonstrate proximal dysfunction, especially early in the course of the disease.

Nerve, muscle, and brain biopsies and their respective histologic features in systemic lupus erythematosus (SLE) are briefly reviewed in this section.

Nerve biopsy

Nerve biopsy may be helpful in determining an initial diagnosis of active vasculitis when clinical findings are ambiguous because of the relatively high yield of nerve biopsy in early clinical vasculitis. However, in many cases of clinically confluent, symmetric polyneuropathy, the predominant pathology may be nonspecific demyelination, reducing the clinical utility of the procedure. When more than one potential etiology is present in the case of a disabling polyneuropathy, a biopsy may determine the predominant pathology, guiding the clinician to initiate the treatment. 

On histologic examination, active necrotizing vasculitis may involve epineurial arterioles. Often perivascular infiltrates are found without frank arterial necrosis. Immunofluorescent staining may demonstrate immunoglobulin or complement deposition on vessel walls. At times, the only findings are nonspecific demyelination or nerve fiber dropout.

Muscle biopsy

Muscle biopsy may provide the only reliable differentiation between inflammatory and medication-induced myopathy. Clinical evolution and medication history are most reliable, as creatine kinase is usually, but not always, elevated in inflammatory myopathy. Electromyography (EMG) is usually, but not always, abnormal in inflammatory myopathy, and both are usually normal in medication-induced myopathy. When other factors are ambiguous and empiric therapy is impractical, then muscle biopsy is appropriate.

The histologic evaluation most commonly reveals similar findings to nerve biopsies, emphasizing vascular and perivascular inflammation, similar to the muscle pathology in dermatomyositis. Less frequently, a pathology analogous to classic polymyositis is found, with inflammatory and other changes centered more on the muscle fibers, including frank necrosis, phagocytosis, and degeneration and regeneration of type I and II fibers.

Brain biopsy

Meningeal or brain biopsy should only be considered in situations in which the benefits (e.g., preventing unnecessary immunotherapy, excluding opportunistic infections) outweigh the surgical risks. Brain biopsy is sometimes necessary when magnetic resonance imaging (MRI) findings fail to distinguish SLE cerebritis from an opportunistic infection or neoplasm, balancing the risks and benefits of biopsy against the risks and benefits of empiric therapy. Rarely, a meningeal biopsy is necessary to diagnose chronic meningitis that cannot be diagnosed through conventional serology, cultures, or other methods.

Brain biopsy may demonstrate the protean findings of opportunistic infections or neoplasm, but uncomplicated SLE cerebritis typically shows the small-vessel vasculopathy discussed in organic encephalopathies, with or without an inflammatory infiltrate.