AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Systemic lupus erythematosus (SLE) is an autoimmune disorder that affects many organ systems, including the central and peripheral nervous systems and muscles. SLE is in the differential diagnosis for many neurological conditions. A variety of neurologic complications may arise in patients with known SLE.

Pathophysiology

General principles

The pathophysiology of SLE has not been defined fully, although many genes that affect immune function, particularly the human leukocyte antigen (HLA), may augment susceptibility to clinical disease. Most monozygotic (identical) twins are discordant for clinical SLE, strongly suggesting that additional factors, probably environmental, trigger the widespread development of autoimmunity in susceptible individuals.

Certain medications (eg, phenytoin, hydralazine, procainamide, and isoniazid) may produce drug-induced lupus, but this disorder differs from classic SLE in its autoantibody profile (eg, antihistone antibody positive) and in sparing the kidneys and central nervous system (CNS). Once triggered, SLE's autoimmune reaction affects many sites through multiple mechanisms such as deposition of immune complexes, effects of cytokines and other chemical neuromodulators, direct attack by autoantibodies or activated leukocytes, and others.

Non-neurologic sites of damage include the renal glomeruli, joints, pleural or pericardial serosa, integument, cardiac or vascular endothelium, cardiac valves, and the oral and conjunctival mucosa. Multiple sites may be involved within the nervous system.

Organic encephalopathies

Among the neurologic manifestations of SLE, the most common are the organic encephalopathies. These diffuse syndromes correlate poorly with the extent of vasculitis or frank thromboembolism. Functional studies such as positron emission tomography (PET), functional magnetic resonance imaging (MRI), or single photon emission computerized tomography (SPECT) demonstrate patchy areas of dysfunction in brain areas unaffected on conventional MRI, findings that suggest an uncoupling of metabolic processes independent of obstruction to cerebral blood flow. The mechanism of these apparent metabolic alterations is unknown.

In areas of apparent vasculitis, histology demonstrates degenerative changes in small vessel walls, often with minimal or no inflammatory infiltrates. Chronic effects of immune complex deposition offer one potential mechanism for SLE vasculopathy; cytokine-mediated effects on vascular endothelium or local brain parenchyma are another. Inflammatory and noninflammatory SLE vasculopathies may be clinically indistinguishable. The terms cerebritis and vasculitis are well embedded in the literature and will be used in this article, keeping in mind the evolving understanding of the underlying processes.

In addition to small vessel vasculopathy, inflammatory changes may occur in large- to medium-sized vessels, giving a more classic vasculitis, sometimes with clinical stroke syndromes resulting from local thrombosis or artery-to-artery emboli. Other potential stroke etiologies include local thrombosis from antiphospholipid antibodies, which may involve small or medium-sized arteries or veins, including the venous sinuses. Emboli can occur as a result of Libman-Sacks endocarditis (LSE), a sterile endocardial inflammation that produces vegetations on the heart valves, seen in greater frequency in the presence of antiphospholipid antibodies. LSE also may cause a diffuse microembolization pattern that is clinically hard to distinguish from vasculitis or cerebritis. In focal clinical syndromes, overt or covert cardiac emboli are more frequently responsible than focal vasculitic or thrombotic processes.

Antiphospholipid antibodies comprise one category of the multiple autoantibodies that may be associated with SLE. In addition to their association with LSE and local arterial or venous thrombosis, these antibodies also may be associated with a hemorrhagic diathesis, myelopathy, and non-neurologic manifestations such as spontaneous abortion.

Neuromuscular manifestations

Peripheral manifestations of SLE include peripheral nerve injury, myopathy, or disturbances of the neuromuscular junction, which may clinically duplicate myasthenia or myasthenic syndrome. Peripheral neuropathy may result from vasculitic insult to the vasa nervorum (clinically resulting in mononeuritis multiplex or a more confluent polyneuropathy) or from a demyelinating pathology (which clinically results in a chronic sensory or sensorimotor polyneuropathy or, more rarely, in an acute motor presentation resembling acute inflammatory demyelinating polyradiculoneuropathy).

Myopathy in SLE most commonly results from vasculitis of the small vessels feeding the muscle, with pathology reminiscent of dermatomyositis, although on rare occasions the pathophysiology more closely resembles polymyositis with inflammatory involvement of muscle fibers themselves. These findings may be distinguished pathologically from medication-associated myopathy resulting from steroids or hydroxychloroquine sulfate therapy.

Frequency

United States

Incidence is 14.6-50.8 cases per 100,000 people.

International

Incidence is 12-39 cases per 100,000 people. Estimates of incidence and prevalence are hampered by inconsistencies in application of diagnostic criteria and selection bias.

Mortality/Morbidity

• With full access to medical care, overall survival for SLE is 85% at 5 years and 63% at 15 years.
• Stroke, cerebral vasculitis, spinal cord injury, and infection all increase the risk of mortality.

Race

• SLE is found in all ethnic groups and races; referral bias complicates any assessment of relative prevalence.
• Susceptibility genes, which may increase the risk of SLE, vary across ethnic populations.

Sex

As with most autoimmune disorders, SLE shows a strong female predominance (as high as 5:1 during childbearing years).

Age

All age groups are affected; however, peak incidence is in young adulthood. Clinical onset often coincides with menarche, pregnancy, postpartum, or menopause.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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History

• Among the neurologic manifestations of SLE, the most common are the organic encephalopathies (35-75% of case series), which basically comprise all potential variations of acute confusion, lethargy, or coma; chronic dementias; depression, mania, or other affective disturbances; or psychosis. Acute or subacute mental status changes may be secondary to diffuse cerebritis but should be differentiated from focal cortical dysfunction resulting from thromboembolic cerebrovascular accident (CVA) or from diffuse changes resulting from electrolyte or metabolic derangements (accentuated by concomitant renal failure); medication effects including steroid psychosis (most problematic with high dosages and long durations); aseptic meningitis (seen especially with nonsteroidal anti-inflammatory drugs [NSAIDs]); or opportunistic infections that result in meningitis, encephalitis, brain abscess, or systemic infection with a secondary toxic encephalopathy.
• Seizures occur in 15-20% of patients with SLE and may result from cerebral vasculitis (ischemic or hemorrhagic manifestations), cardiac embolism, opportunistic infection, drug intoxication, or associated metabolic derangements. A seizure focus may result from an acute insult or from the development of a seizure focus in an area of prior brain insult.
• • Partial or secondarily generalized seizures are most common, but all seizure types have been reported.
  • Electrolyte disturbance and medication effects should be excluded, especially those resulting from antidepressants, stimulant medications used to treat fatigue, or withdrawal from sedatives or alcohol. Opportunistic infections should be considered in patients receiving immunosuppressive therapy. Steroid therapy, especially high dose pulse therapy, has been associated with status epilepticus.

• Cranial nerve abnormalities (most prominently, optic neuritis) occur in 10% of patients with SLE. Oculomotor nerve palsies and all other cranial neuropathies have been reported.
• Stroke is clinically evident in 5-10% of most series and may involve small, medium, or large vessels by a variety of mechanisms as discussed earlier. Subacute evolution or any premonitory symptoms suggest a thrombotic or vasculitic mechanism, whereas an abrupt onset with maximum deficit initially supports an embolic mechanism. Ischemic stroke should be differentiated from brain hemorrhage, brain abscess, and other structural lesions. Parenchymal brain hemorrhage may result from bleeding into an ischemic vascular bed, particularly following cardiac emboli or dural sinus thrombosis.
• Peripheral neuropathy occurs in as many as 18% of patients. A sensory or sensorimotor predominantly distal polyneuropathy is most common; however, the patchy deficits and subacute time course of mononeuritis multiplex and the rapidly progressive course of acute demyelinating polyneuropathy have been reported. The neuromuscular junction may be affected, mimicking the weakness patterns (and physiology) of myasthenia gravis or myasthenic syndrome (ELS). Myositis is clinically apparent as proximal weakness and myalgias in 3-5% of patients but, if assiduously sought, may be found in as many as 50%.

• Autoimmune-mediated myopathy must be differentiated from myopathy induced by steroid or antimalarial therapy as well as arthralgias and other musculoskeletal sequelae of SLE. Distinction from arthralgias and other musculoskeletal conditions is based on symmetrical, proximal muscle weakness (in excess of that weakness explained by painful give way), elevated creatine kinase, and absence of other musculoskeletal findings. Distinguishing SLE-induced myopathy from medication-induced myopathy is dependent on the time course of the weakness in relation to changes in medical therapy. In difficult cases, clinical response to increasing or decreasing the suspected medication may settle the issue.
• Spinal cord involvement is rare but devastating. Transverse myelitis, subacute-to-chronic demyelinating syndromes, and abrupt vascular occlusive events (eg, spinal artery thrombosis) have been described.

• Slowly progressive lesions may result from demyelination or compression by tumor or central disc herniation. Rapid onset suggests transverse myelitis, infarction, or compression by a rapidly expanding lesion (eg, epidural abscess).
• Chronic organic encephalopathy may mimic degenerative dementia.
• • In any patient with SLE with slowly progressive cognitive loss, inquiry for other clinical evidence of SLE activity, electrolyte disturbance, medication effect, vitamin B-12 or thyroid deficiency, or opportunistic infection in the immunosuppressed patient, is indicated.
  • Prior steroid therapy may provoke an adrenocortical deficiency state.

• Chronic fatigue is a common symptom in SLE and usually does not relate to objective muscular effort, ie, walking up stairs may seem no harder than walking on level ground. Fatigue may contribute to both self-perceived and to measurable cognitive impairment, chiefly by impairing frontal lobe attentional functions. This may relate to metabolic dysfunction of brain parenchyma, as discussed in Organic encephalopathies. Depression, myopathy, excessive daytime fatigue due to nocturnal sleep disorder, and systemic conditions (eg, electrolyte disturbance, fluid overload, pulmonary insufficiency) remain in the differential diagnosis. Many patients with mild orthostatic hypotension present with symptoms resembling chronic fatigue and may not complain of the usual presyncopal symptoms.
• Less common neurologic syndromes presenting in the patient known to have SLE include movement disorders (chorea, ataxia, parkinsonism), pseudotumor cerebri, and venous sinus thrombosis.
• Acute aseptic meningitis is rarely described in association with NSAID therapy but must be differentiated from infectious etiologies, especially in immunosuppressed patients.
• Neurologic syndromes often are present at SLE presentation and SLE should be considered in the following individuals:
  • Young patients with new-onset confusional or psychiatric states, stroke, or parkinsonism

  • Patients presenting with a multifocal process affecting the CNS, especially if both CNS (eg, patients carrying the presumptive diagnosis of multiple sclerosis) and peripheral nervous systems are affected

  • Patients with cranial neuropathies

  • Patients with noncompressive myelopathies

  • Patients with chorea, unexplained ataxia, myopathy, or polyneuropathy
• With systemic or other organ system involvement suggestive of autoimmune dysfunction (eg, low-grade fevers, fatigue, arthralgias or arthritis, renal dysfunction, malar or other skin rashes) laboratory evaluation should include at minimum antinuclear antibody (ANA) testing and anti-DNA binding to confirm a positive ANA result. Other autoantibody testing is dependent on clinical judgment and test availability.

Physical

• Abrupt or subacute onset of any focal neurologic deficit may result from local vasculitis with thrombosis, distant artery-to-artery embolization, or cardiac emboli.
• Mass lesions (eg, subdural or parenchymal hemorrhages) or brain abscess remain in the differential diagnosis.
• Paraparesis implicates cauda equina, thoracic-lumbar spinal cord, partial lesions of the cervical cord, brainstem lesions, or parasagittal cerebral lesions.
• • Extensor toe signs localize to the cord or above, excluding cauda equina. Acute lesions at either cauda or cord levels may be associated with hyporeflexia, areflexia, or sphincter disturbances.
  • If an areflexic paraparesis is unaccompanied by a sensory level or spreads to the arms, acute demyelinating polyneuropathy (Guillain-Barré syndrome) should be considered.
  • Sensory loss to pain and temperature with sparing of posterior column function (position sense, graphesthesia with or without vibration sense) suggests an anterior spinal artery syndrome.
  • Clinically involved cord levels require immediate imaging (ie, myelography or MRI) to exclude compressive lesions.
  • If myelography is performed, spinal fluid should be collected for analysis prior to introducing contrast media.

• Cranial neuropathies most commonly result from lupus vasculitis affecting the vasa nervorum supplying the involved nerve. Although optic neuritis (painful or painless subacute loss of visual acuity, usually accompanied by visible inflammation of the optic nerve head) is most common, any cranial nerve may be affected. Imaging studies can exclude compressive lesions that result from opportunistic infection, tumor, or aneurysm.
• Diffuse weakness may result from polyneuropathy, myopathy, neuromuscular junction disease, or systemic fatigue.
• Examination findings of objective, symmetric proximal muscle weakness (with or without concomitant pain) support myopathy, while distal symmetric weakness (with distal sensory loss) implicates a peripheral polyneuropathy. Myopathy should never be accompanied by sensory loss, but may at times be asymmetric.
• Mononeuritis multiplex results in patchy, asymmetric weakness, sensory loss, or both in the distribution of multiple peripheral nerves or roots. Clinical distinction between proximal myopathy and polyradiculopathy or proximal mononeuritis multiplex may be difficult, requiring electromyogram (EMG) or nerve conduction velocity (NCV) studies or even nerve and muscle biopsies for an accurate diagnosis.
• Weakness that improves or worsens with repetitive testing suggests a neuromuscular junction defect.
• Painful give way weakness without organic muscle weakness supports arthralgia or other musculoskeletal etiology.
• Fatigue from autoimmune disorder is rarely accompanied by objective muscular weakness. Orthostatic hypotension should be excluded.

Causes

As with most autoimmune disorders, the cause of SLE is unknown. Sex, genetic, and other risk factors are discussed in the Introduction.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
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• Differentials
• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Aseptic meningitis
Devic syndrome
Abducens (VI) nerve palsy
Granulomatous angiitis of the central nervous system
Neuromuscular diseases

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• In previously undiagnosed patients thought to have SLE, the principal diagnostic study is the ANA test.
• • Although many rheumatologists consider this test to be 100% sensitive for diagnosis, a positive ANA 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).

• 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.
• 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.
• Cerebrospinal fluid (CSF) exam is most useful to exclude infection, especially in immunocompromised patients. However, CSF can reflect increased CNS lupus activity by showing elevated 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 enzymes more likely point to a medication-related or viral hepatitis, and obstructive patterns point to medications or to biliary obstruction.
  • Muscle enzymes (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

• 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.
• CT scanning may detect calcifications in patients with long-standing cerebritis.
• • 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.
• • 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.

• 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.

• EMG and nerve conduction studies (NCS) provide useful data in the clinical assessment of peripheral complications of SLE.
• • Muscle weakness in patients with SLE patient 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

In nerve biopsies, 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 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.

TREATMENT

Section 6 of 11  

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• Follow-up
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Medical Care

Treatment of SLE should be provided in cooperation with a consulting rheumatologist. Therapeutic intensity correlates with the severity of an acute attack. NSAIDs and other symptomatic agents are used for less threatening symptoms. Corticosteroids are used in low-dose oral, high-dose oral, or high-dose IV regimens according to the severity of potential organ damage.

Clinical studies supporting this approach were generally performed in lupus nephritis because of its frequency, severity, and quantifiable improvement or deterioration, but the same treatment approaches are generally applied to other organ systems, including the central and peripheral nervous systems and muscular disease. This overall treatment approach should be familiar to neurologists who are accustomed to the evaluation and treatment of other autoimmune conditions such as multiple sclerosis, myasthenia gravis, or polymyositis.

• High-dose IV corticosteroid regimens consist of methylprednisolone 1-2 g daily for 3-6 doses, followed by oral prednisone 60 mg daily, then tapering according to clinical recovery. Less threatening flare-ups may be treated with as much as 100 mg or as little as 10 mg prednisone PO qd (or other agents in equivalent dosage), again tapering gradually according to clinical symptoms, with an increase of 10-20% during the taper if clinical disease flares again. Tapering to an every other day steroid regimen reduces adverse effects substantially but probably will not be successful until clinical disease is quite stable. In acute high dosage, steroids may provoke status epilepticus, psychosis, hypokalemia, hyperglycemia, or hypertension and clinical evidence of any intercurrent infection may be reduced.
  • With chronic use, steroids cause familiar adverse effects including weight gain, diabetes mellitus, cataracts, immunocompromise, and osteoporosis. Calcium supplementation (1 g daily for men or premenopausal women, 1.5 g daily for postmenopausal women) should be initiated early and continued even when steroids are tapered successfully to qod.

  • Thrush and herpetic outbreaks may be treated symptomatically or prophylactically.
• Various steroid-sparing strategies have evolved for chronic use, including cyclophosphamide 0.5-2 mg/kg/d, azathioprine 1-2 mg/kg/d, and methotrexate 10-15 mg given once weekly with folate rescue, permitting gradual reduction or elimination of chronic steroid therapy. Higher dose ranges or dosing based on body surface area may be used for these medications based on the experience of individual clinicians.

• All chronic cytotoxic regimens present substantial risks and should be followed only by physicians familiar with these agents. In acute, life-threatening illness, one option is to initiate cyclophosphamide PO or a single dose of 8-20 mg/kg IV, along with IV methylprednisolone.
• Antimalarials, especially hydroxychloroquine in dosage of 100-400 mg daily, are used as alternatives to steroids or as supplements to accelerate steroid taper. They have not been studied in central or peripheral nervous system disease. Antimalarials generally require months to become effective and, therefore, they are not used in the acute treatment of organ-threatening disease.
• Generally, mild myopathy or polyneuropathy may be treated with NSAIDs and other symptomatic medications (eg, anticonvulsants, tricyclics, other medications used for neurogenic or musculoskeletal pain). Symptoms may be caused by medications (eg, steroids, antimalarials) or other etiologies in addition to SLE. If alternative explanations are unlikely and symptoms are more bothersome, low to medium-dose prednisone may be tried, possibly with a longer-term transfer to antimalarial therapy.
• If a patient with SLE patient presents with acute polyradiculopathy resembling Guillain-Barré syndrome or chronic relapsing polyradiculopathy resembling chronic inflammatory demyelinating polyneuropathy, treatment with IV immunoglobulin (IVG) in conventional doses should be considered. When IVG is unavailable or poorly tolerated, plasma exchange should be considered as an alternative. Unfortunately, few therapeutic studies exist on these rare presentations of SLE.

• Seizures are common sequelae of SLE and may result from acute or chronic disease. Acute electrolyte disturbance, response to high-dose steroids, or other acute disturbance may only require temporary anticonvulsant treatment, while more chronic epileptogenic foci may require lifetime prophylaxis. Anticonvulsants may be used in a conventional fashion, emphasizing medications most effective for focal onset or secondarily generalized seizures. Phenytoin and other agents associated with drug-induced lupus are unlikely to actually increase disease activity in SLE, but with chronic use may cause diagnostic confusion for physicians.
• Treatment of the antiphospholipid syndrome remains controversial, with therapy based predominantly on anecdotal experience. Although many authorities recommend full anticoagulation with Coumadin (warfarin) possibly in conjunction with immunosuppressant therapy to suppress production of the antibody, other authorities support antiplatelet therapy initially, with stronger measures reserved for repeated stroke, progressive myelopathy, or other clear-cut, clinical treatment failure.

Consultations

• Generally, new-onset SLE diagnosed based on neurologic symptoms should be managed in conjunction with a rheumatologist or internist.
• If neurologic signs or symptoms present in a patient with SLE that is well established, the need for additional consultations beyond the treating internist or rheumatologist is determined by the presence and severity of concomitant organ disease. For example, in patients with severe lupus nephritis, renal consultation may be needed for initiation of hemodialysis.

Diet

A special diet may be required for renal, cardiac, or SLE complications but is generally not required for the neurologic aspects of SLE.

Activity

• The usual activity restrictions (eg, driving, operating machinery, swimming) that apply to patients with seizures apply to patients with SLE who have seizures.
• • Regulations for driving vary by state in the United States.
  • Recommendations may be tailored to the individual based on frequency, seizure type, duration of aura (if any), and concomitant morbidity (including dementia or psychosis).

• Activity restrictions also may apply to patients with organic brain impairment in the absence of seizures or to patients with myelopathy, visual disturbance, or neuromuscular syndromes.

MEDICATION

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The goal of therapy is to suppress the autoimmune activity.

Drug Category: Immunosuppressants

Used for disease modification and reduction of organ-threatening or life-threatening damage. Often needed on acute and chronic bases, these drugs should be used by physicians who are familiar with their use and potential complications (eg, opportunistic infections and common adverse effects).

Drug Name	Prednisone (Deltasone)
Description	Used for acute CNS or PNS disease that is not deemed sufficiently dangerous to warrant acute IV methylprednisolone. Also used to follow IV therapy for a gradual outpatient taper.
Adult Dose	Varies from 20-100 mg PO qd, usually every am or bid, depending on severity of disease. Gradually taper to qod when possible, eventually tapering off entirely (if possible without disease recurrence)
Pediatric Dose	0.5-2 mg/kg/d PO qd or bid/qid; taper as disease course permits
Contraindications	Documented hypersensitivity; uncontrolled infections; uncontrolled GI bleeding; perforated viscus; viral, fungal, or tubercular skin infections.
Interactions	May affect hepatic metabolism or serum protein binding of other medicines (this effect is least important with short courses or rapid taper); corticosteroid clearance may also decrease when used concurrently with estrogens; when used concomitantly with digoxin, it may increase digitalis toxicity secondary to hypokalemia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Because this formulation is usually used for long-term therapy, chronic issues of GI bleeding, glucose intolerance, osteoporosis, aseptic necrosis, weight gain, and cataract formation become critically important; prophylactic GI protection and calcium supplementation are generally indicated with appropriate coverage for candidal, herpetic, or other infections in selected patients

Drug Name	Cyclophosphamide (Cytoxan, Neosar)
Description	This antineoplastic agent is used acutely for life-threatening symptoms, generally in combination with IV corticosteroids. Various PO and IV protocols exist for long-term management of active disease. Physicians who are comfortable in follow-up of this agent should manage patients.
Adult Dose	8-20 mg/kg IV as a single dose for acute disease 0.5 mg/kg/d PO for chronic disease, adjusting the dose for disease modification and blood studies
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone marrow function; uncontrolled infections
Interactions	Allopurinol may increase the risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may also potentiate doxorubicin-induced cardiotoxicity; conversely, digoxin serum levels may be reduced; antimicrobial effects of quinolones may be reduced; chloramphenicol may increase cyclophosphamide half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; rate of metabolism and leukopenic activity are increased by chronic administration of high doses of phenobarbital; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and the neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor carefully prn for leukemia, bone marrow suppression, hemorrhagic cystitis, and covert sepsis; other long-term risks include teratogenesis, carcinogenesis, and infertility; clinical monitoring should be accompanied by frequent CBC and urinalysis monitoring, the latter for hematuria

Drug Name	Azathioprine (Imuran)
Description	Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.
Adult Dose	1-2 mg/kg/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; low levels of serum thiopurine methyltransferase (TPMT)
Interactions	Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Pregnancy	D - Unsafe in pregnancy
Precautions	Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check TPMT level prior to therapy and follow liver, renal, and hematologic function; pancreatitis rarely associated

Drug Name	Methotrexate (Folex, Rheumatrex)
Description	Antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. Satisfactory response seen in 3-6 wk following administration.
Adult Dose	10-15 mg PO/IM given once weekly; adjust dose gradually to attain satisfactory response
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency
Interactions	Oral aminoglycosides may decrease absorption and blood levels of concurrent oral methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX; coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor CBCs monthly, and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts; aspirin, NSAIDs, or low dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs including salicylates has not been tested)

Drug Category: Antimalarial

Used as alternative to steroids or as supplements to accelerate steroid taper.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

In/Out Patient Meds:

• Acute treatment with immunosuppressants is followed by a prolonged outpatient taper, usually with PO prednisone.
• • Gradual dosage reduction may result in a disease flare-up at some point, which is usually handled by a 10-20% increase in prednisone dosage with gradual taper again as the disease stabilizes and improves.
  • GI protective agents and calcium supplementation (1.5 g daily in postmenopausal women, 1 g daily in all others) is routine.

• Symptomatic medication depends on specific disease manifestations. From a neurologic standpoint, treatment may include anticonvulsants, antipsychotics, antidepressants, stimulants for fatigue, NSAIDs, or muscle relaxants, and various medications for neurogenic pain.

Transfer:

• Patients with an acute neurologic presentation generally require an intensive care unit and neuroimaging facilities. Hemodialysis may be needed if acute renal failure occurs.
• Physician comfort and access to experienced multispecialty consultation are usually more of a problem than medical equipment limitation.

Complications:

• Potential complications include (but are not limited to) sepsis, paralysis, acute renal failure, additional embolic or thrombotic events, and hemorrhage induced by lupus anticoagulants or therapeutic anticoagulation.
• Pericarditis, pleuritis, and myopathy resulting from steroid or antimalarial use may occur.

Prognosis:

• Overall, prognosis for SLE patients has improved dramatically in recent decades, with 70% now living 10 years after diagnosis.
• Neurologic complications worsen prognosis, especially in the presence of refractory seizures, encephalopathy, or paralysis from stroke or myelopathy.
• CNS-specific statistics are not available.

Patient Education:

• The principle obstacle in long-term management is patient compliance with immunosuppressive, anticonvulsant, or other prophylactic regimes.
• Clear explanation of treatment goals and the consequences of poor compliance is essential. Ideally, such communication should be offered during the mid to late phases of acute illness when appropriate concern promotes maximal compliance.
• • If appropriate, a translator for patient or family conferences should be utilized. Tailor communication to consider the patient's disease process, culture, and socioeconomic background.
  • Consequences on work, family life, and childbearing should be explored.

• Possible adverse effects of medications should be listed without undue emphasis. Long-term issues (eg, adverse effects of chronic immunosuppression, other medication adverse effects, what to monitor that is symptomatic of opportunistic infection, SLE recurrence) may be deferred to subsequent follow-up visits at the discretion of the physician.
• For excellent patient education resources, visit eMedicine's Immune System Center. Also, see eMedicine's patient education article Lupus (Systemic Lupus Erythematosus).

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• In previously undiagnosed patients with SLE, the typical legal issue is delay in diagnosis that may or may not have contributed to irreversible progression of brain, spinal cord, or systemic organ damage, or death.
• • Judicious ordering of an ANA analysis in the appropriate clinical setting is the best defense. As discussed above, confirmation that SLE is responsible for organ damage may still be problematic, given issues of sensitivity and specificity of the available diagnostic tests.
  • If clinical presentation is especially atypical, explain this clearly to the family during the acute course. Clear communication with patient and family prevents most medicolegal problems.

• In the previously diagnosed patient with SLE, the major medicolegal risks involve the complexity of management. This chronic disease affects multiple organ systems. Therapy can be dangerous, and multiple, unforeseen complications may arise.
• • The physician may have to trade benefit to one organ system for risk to another.
  • Ongoing family education is essential to ensure that the general goals of therapy are understood. The patient and family should be consulted at appropriate choice points and must realize the overall risks and hazards of a critical situation. Try to correct unrealistic hopes or fears.

• A negative outcome in any patient, whether newly or previously diagnosed, always presents medicolegal risk.
• • Poor communication with the family, treating a younger patient, and economic devastation of the family all enhance the likelihood of a lawsuit, independent of any actual negligence.
  • Complex, critical care management still permits second-guessing by a resourceful plaintiff's expert.
  • The best defense is good medicine and documentation, appropriate consultation outside one's own area of expertise, and good family communication. Even if these factors fail to prevent a lawsuit, they will improve the odds of a successful defense. Never alter documentation ex post facto, especially once a suit is filed. Late memoranda to preserve one's recollection should be addressed to the attorney. Do not append this to the patient record, since modifications inevitably appear self-serving and raise questions of the integrity of the chart.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  This axial, T2-weighted brain 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. 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 distribution.
	View Full Size Image
Media type:  MRI

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Brooks WM, Sabet A, Sibbitt WL, et al. Neurochemistry of brain lesions determined by spectroscopic imaging in systemic lupus erythematosus. J Rheumatol. Dec 1997;24(12):2323-9. [Medline].
• Bruyn GA. Controversies in lupus: nervous system involvement. Ann Rheum Dis. Mar 1995;54(3):159-67. [Medline].
• Calabrese LV, Stern TA. Neuropsychiatric manifestations of systemic lupus erythematosus. Psychosomatics. Jul-Aug 1995;36(4):344-59. [Medline].
• Futrell N. Inflammatory vascular disorders: diagnosis and treatment in ischemic stroke. Curr Opin Neurol. Feb 1995;8(1):55-61. [Medline].
• Futrell N, Schultz LR, Millikan C. Central nervous system disease in patients with systemic lupus erythematosus. Neurology. Sep 1992;42(9):1649-57. [Medline].
• Garton MJ, Isenberg DA. Clinical features of lupus myositis versus idiopathic myositis: a review of 30 cases. Br J Rheumatol. Oct 1997;36(10):1067-74. [Medline].
• Hess DC. Cerebral lupus vasculopathy. Mechanisms and clinical relevance. Ann N Y Acad Sci. Aug 14 1997;823:154-68. [Medline].
• Isshi K, Hirohata S. Differential roles of the anti-ribosomal P antibody and antineuronal antibody in the pathogenesis of central nervous system involvement in systemic lupus erythematosus. Arthritis Rheum. Oct 1998;41(10):1819-27. [Medline].
• Kourbeti IS, Boumpas DT. Biological therapies of autoimmune diseases. Curr Drug Targets Inflamm Allergy. Feb 2005;4(1):41-6. [Medline].
• Roldan CA, Shively BK, Crawford MH. An echocardiographic study of valvular heart disease associated with systemic lupus erythematosus. N Engl J Med. Nov 7 1996;335(19):1424-30. [Medline].
• Steinlin MI, Blaser SI, Gilday DL, et al. Neurologic manifestations of pediatric systemic lupus erythematosus. Pediatr Neurol. Oct 1995;13(3):191-7. [Medline].
• Tan EM, Feltkamp TE, Smolen JS, et al. Range of antinuclear antibodies in "healthy" individuals. Arthritis Rheum. Sep 1997;40(9):1601-11. [Medline].
• Uramoto KM, Michet CJ, Thumboo J, et al. Trends in the incidence and mortality of systemic lupus erythematosus, 1950-1992. Arthritis Rheum. Jan 1999;42(1):46-50. [Medline].
• West SG, Emlen W, Wener MH, Kotzin BL. Neuropsychiatric lupus erythematosus: a 10-year prospective study on the value of diagnostic tests. Am J Med. Aug 1995;99(2):153-63. [Medline].
• Williams R, Harmon ME, Burlingame R, Du Clos T. Studies of serum C-reactive protein in systemic lupus erythematosus. J Rheumatol. Mar 2005;32(3):454-61. [Medline].

Article Last Updated: Mar 28, 2005