eMedicine Specialties > Neurology > Inflammatory and Demyelinating Diseases

Systemic Lupus Erythematosus

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

Introduction

Background

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.

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 more common in certain ethnic groups, such as patients with African or Asian ancestry; referral bias complicates any assessment of relative prevalence. Johnson et al (1995) reported the prevalence of lupus as 27.7 cases per 100,000 and as high as 206 cases per 100,000 in Afro-Caribbean women.
• Susceptibility genes, which may increase the risk of SLE, vary across ethnic populations.

Sex

Systemic lupus erythematosus is prevalent among young women, with a peak age of onset between the late teens and early 40s and a female-to-male ratio of 9:1.  

Age

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

Clinical

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.
  • Posterior reversible encephalopathy syndrome (PRES) has been described in SLE. Patients are generally on immunosuppressive drugs, have had episodes of relative hypertension, and with renal involvement. MRI findings are characteristic, involving the occipital lobes in particular, which differentiates PRES from other CNS complications of SLE. Clinical and radiographic resolution of abnormalities within 1-4 weeks is typically seen. In spite of this, patients with PRES might present with dramatic signs and symptoms.¹
• Seizures are already known to occur in 14-25% of patients with lupus compared with 0.5-1% in the general population.² Seizures 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.
  • Joseph et al (2007) have identified that primary neurologic presentation of SLE was more common than anticipated (10/41 patients) and included both seizures (4 cases) and movement disorders such as parkinsonism and myoclonus (4 cases). They found a higher overall frequency of seizures (42%), as an early manifestation in 27%, and, in 10%, seizures were the first SLE symptom. Prior to this, there have been no case reports of myoclonus in SLE as a presenting feature.³ For a CME activity, see Seizures Usually Seen Early in Lupus.
  • Cranial nerve involvement is also relatively uncommon and usually transient,⁴  occurring in 10% of patients with SLE. Oculomotor nerve palsies and all other cranial neuropathies have been reported. Visual disturbances tend to be bilateral (80%) and to occur late in the disease course (77%); these include optic neuritis, retinopathy, and concurrent migrainous features. Anterior segment findings include keratoconjunctivitis sicca, keratitis, and scleritis. Retinopathy can be associated with cotton wool exudates (indicative of local retinal ischemia) and hemorrhages.³  Lee et al (2008) report a case of SLE with recurrent laryngeal palsy resulting in vocal cord paresis. Laryngeal electromyography (LEMG) on both cricothyroid and thyroarytenoid muscles confirmed a left recurrent laryngeal neuropathy with ongoing processes of denervation and reinnervation.⁵  
• 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. Vasculitis is often seen with SLE but is usually limited to small vessels alone. The primary pathology in SLE-related vasculitis is leukocytoclastic vasculitis. Medium- and large-vessel vasculitis in association with SLE is distinctly uncommon. 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. Movement disorders were not included in the ACR criteria. Chorea has been seen in fewer 4% of patients.⁶
• 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.

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