eMedicine Specialties > Neurology > Inflammatory and Demyelinating Diseases

Systemic Lupus Erythematosus: Differential Diagnoses & Workup

Author: Tarakad S Ramachandran, MBBS, FRCP(C), FACP, Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital
Coauthor(s): James Santiago Grisolia, MD, Active Staff, Scripps Mercy Hospital
Contributor Information and Disclosures

Updated: Oct 30, 2008

Differential Diagnoses

Other Problems to Be Considered

Aseptic meningitis
Devic syndrome
Abducens (VI) nerve palsy
Granulomatous angiitis of the central nervous system
Neuromuscular diseases
Mechanistic similarities between SLE and multiple sclerosis might have lead to the term "lupoid sclerosis". Although, at times, neuro-SLE might mimic multiple sclerosis very closely, pathologic studies clearly show them to be very distinct disorders.⁷

Workup

Laboratory Studies

• 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. 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 in a certain percentage of the general population (especially the elderly). Anti-DNA antibody testing is positive in only about 70% of 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.
• Of particular interest are the serum antiribosomal P antibody (which is positive in 60% of cases of lupus psychosis) and the family of antibodies known collectively as antiphospholipid antibodies (including the anticardiolipin antibody, [ACLA]). These may be positive in hypercoagulable states, myelopathy, and LSE. APA were present in 16-60% of the reported cases.⁸
• Complement studies (C3, C4, CH50) may be useful to determine disease activity in patients known or thought to have SLE.
• Antiphospholipid syndrome was first described in association with SLE but also may occur independently. This should be searched for in patients with known to have SLE with neurologic complications, especially myelopathy or cerebrovascular events, whether embolic, thrombotic, or hemorrhagic.
• In addition to testing serum ACLA, hematologic studies 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 report that lupus anticoagulant (LA) is the strongest test to determine the risk of thrombosis in SLE-antiphospholipid antibodies (aPL).⁹ The presence of lupus nephritis (LN) and Raynaud phenomenon (RP) strongly predicts thrombosis, while lymphopenia and antimalarials are protective. These findings help to identify patients who may benefit from prophylactic therapy.
• AlSaleh et al report a high prevalence of positive anti-Ro antibodies (52.3%) among their Arab patients, which they feel probably reflects a character, that is, commonly seen in SLE patients of Middle East origin.¹⁰
• CSF abnormalities were seen in 30-40% of patients reported. The frequency of CSF oligoclonal bands has varied between reports, 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, CSF can reflect increased CNS lupus activity by showing elevated levels of white cells, protein, immunoglobulin synthesis, or absolute immunoglobulin G (IgG). Antineuronal nuclear antibodies (ANNA) have some value in confirming CNS disease when performed on CSF but are less specific or sensitive than a serum test.
• Conventional blood studies have varying utility in diagnosing SLE, depending on associated conditions and manifestations.
  • 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 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 may be followed more roughly by the 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.
  • The CBC in SLE may demonstrate a hemolytic anemia with reticulocytosis or reductions of neutrophils, lymphocytes, or platelets.
  • Liver function studies are rarely affected by SLE per se. (Lupoid hepatitis is not part of the SLE spectrum.) Elevations of hepatocellular enzyme levels more likely point to a 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 clinical or biopsy-proven disease. Normal creatine kinase levels, therefore, do not reliably distinguish between SLE myositis and drug-related (steroid, hydroxychloroquine) myopathy.

Imaging Studies

• Joseph et al (2007) in their study have reported that 35% of CT brain scans were abnormal and 65% of MR scans, but CT remains valuable in identifying hemorrhages and larger infarcts.³ Neuroradiologic evaluation favors MRI over CT scans 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 vessel involved and the mechanism of stroke.
• Other vague areas of patchy cortical or subcortical abnormality (lucency on CT, T2 signal intensity on MRI) may correspond to small vessel vasculitis or cerebritis, but distinction from opportunistic infection (eg, toxoplasmosis, progressive multifocal leukoencephalopathy) often cannot be made on radiographic grounds, requiring other studies, including cerebral biopsy. With either CT 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 gray matter of cortex or deep nuclei when the lesions are rounded or patchy in shape. If the lesions are radially oriented along white matter tracts, favor the periventricular white matter, and involve the corpus callosum, then multiple sclerosis is a more likely diagnosis.
• Perisulcal cortical atrophy is reported as a frequent finding on CT.¹¹
• CT scanning may detect calcifications in patients with long-standing cerebritis.
• Castellino et al (2008) report that combining SPECT and MRI appears more useful than the two techniques alone and may help the clinician in the assessment of patients with neuropsychiatric (NP) involvement since normal findings contemporarily detected by these two techniques have been rarely observed in patients with NP involvement, especially in those with focal manifestations where MRI and SPECT were never simultaneously normal.¹²  
  • Dural sinus thrombosis is a rare complication of SLE-associated hypercoagulability and is often seen in association with antiphospholipid antibodies. Radiologically, flow defects in one or more venous sinuses may be imaged on MRI, MR venous angiography, conventional angiography, or radionuclide brain scan. Associated edema or hemorrhagic infarcts may be obvious on MRI or CT scans.
  • PET scanning and magnetic resonance 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.
• When embolic stroke occurs in patients with proven or suspected SLE, echocardiography is mandatory to assess for valvular and other intracardiac lesions. In the patient known to have SLE who presents with an apparently nonembolic 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.
• Strokes and leukoaraiosis were more common in the APLS group, consistent with the idea of an APLS-induced prothrombotic state.¹³
  • The carotid bifurcation may be conveniently imaged by ultrasound.
  • Magnetic resonance angiography (MRA) or transcranial Doppler ultrasound confirm thrombotic lesions of extracranial or intracranial vessels.
  • Cerebral vasculitis can only be detected by conventional contrast angiography. However, even this study often misses the predominantly small vessel involvement of lupus vasculopathy.
  • In the presence of a clear stroke with positive 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.
  • In the patient with SLE who has risk factors for conventional small-vessel cerebrovascular disease (eg, 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 CNS inflammation, ANAs, or intrathecal IgG synthesis may support a diagnosis of SLE over atherosclerotic small vessel disease. Clinical–radiologic correlations are not always obvious; more importantly, MRI lesions may resolve completely within days in keeping with clinical improvement or persist despite clear remission.
• Meningeal or brain biopsy should only be considered in situations where the benefits (eg, preventing unnecessary immunotherapy, excluding opportunistic infections) outweigh the surgical risks.
• In patients with SLE who have myelopathy, spinal 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, CSF should be obtained prior to contrast introduction to assess for SLE disease activity, cytology, or evidence of opportunistic infection as appropriate.

Other Tests

• Electroencephalography (EEG) may be helpful to confirm the focal point of an apparently diffuse encephalopathy. It is most useful in patients with seizures whose cases are difficult to manage.
  • EEG also provides a measure of recurrence risk when anticonvulsant therapy is withdrawn. An active spike 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 CNS lupus.
  • Reported selective left temporolimbic region changes¹⁴  are not always observed.
• EMG and nerve conduction studies (NCS) provide useful data in the clinical assessment of peripheral complications of SLE.
  • Muscle weakness in patients with SLE may result from inflammatory myopathy, medication-induced myopathy, neuromuscular junction dysfunction, neuropathies, or from other musculoskeletal disturbances. While much of the clinical decision-making relies on examination and historical evidence (especially time course of drug therapy with steroids or hydroxychloroquine), EMG may be useful in distinguishing inflammatory from noninflammatory myopathy.
  • Lupus myositis resembles dermatomyositis or polymyositis on EMG findings, including increased insertional activity, fibrillations 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 on 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.

Procedures

• 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 value of the procedure. When more than one potential etiology is present in the case of a disabling polyneuropathy, biopsy may determine the predominant pathology, serving as a potential alternative to empiric treatment for one or more etiologies. Findings are discussed in Histologic Findings.
• 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. 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. Histologic findings are discussed below.
• Brain biopsy is sometimes necessary when 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, meningeal biopsy is necessary to diagnose chronic meningitis that cannot be diagnosed through conventional serology, cultures, or other methods.

Histologic Findings

At times, the only findings are nonspecific demyelination or nerve fiber dropout.

Muscle biopsy most commonly reveals similar findings, 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 may demonstrate the protean findings of opportunistic infections or neoplasm, but uncomplicated SLE cerebritis typically demonstrates the small vessel vasculopathy discussed in Organic encephalopathies, with or without an inflammatory infiltrate. Since much of clinically apparent so-called cerebritis proves to result from cardiac embolism, typical findings of acute, subacute, or chronic embolic infarction may be found.

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