Neurologic Manifestations of Systemic Lupus Erythematosus 

Neurologic manifestations are among the features of systemic lupus erythematosus (SLE), a multisystem autoimmune connective tissue disorder with various clinical presentations. SLE affects many organ systems, including the central and peripheral nervous systems and muscles.^[1]

Central nervous system (CNS) lupus is a serious but potentially treatable illness, which still presents very difficult diagnostic challenges (see the following image). This condition is in the differential diagnosis for many neurologic conditions. Thus, neurologists and other clinicians need to be aware of the various presentations and neurologic complications of SLE; patients with SLE often have neurologic symptoms, and SLE is sometimes diagnosed after patients present for treatment of a neurologic event.^{[2, 3]}

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 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.

See also Pediatric Systemic Lupus Erythematosus, Neonatal Lupus and Cutaneous Lupus Erythematosus in Children, Systemic Lupus Erythematosus and Pregnancy, Discoid Lupus Erythematosus, Bullous Systemic Lupus Erythematosus (BSLE), Acute Cutaneous Lupus Erythematosus (ACLE), Subacute Cutaneous Lupus Erythematosus (SCLE), and Physical Medicine and Rehabilitation for Systemic Lupus Erythematosus.

Among the neurologic manifestations of systemic lupus erythematosus (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) scanning, functional magnetic resonance imaging (MRI), or single photon emission computerized tomography (SPECT) scanning demonstrate patchy areas of dysfunction in brain areas not demonstrable 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. (See CT Scanning and MRI.)

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 may also 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. (See Biopsies and Histologic Features.)

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.

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 with MRI, MR venous angiography, conventional angiography, or radionuclide brain scanning. Associated edema or hemorrhagic infarcts may be obvious on MRI or CT scans.

Peripheral manifestations of systemic lupus erythematosus (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.

Drug-induced myopathy

The most common type of drug-induced myopathy is steroid-induced myopathy. It usually presents with progressing painless muscle weakness, fatigability, and muscle atrophy, and is an adverse effect of glucocorticoid use (though fluorinated glucocorticoid has a higher chance of causing this).

Muscle biopsy often reveals slight variation in fiber size with type 2b atrophy, with little or no fiber necrosis and no inflammatory cells. Biopsy also often reveals slight myofibrillar loss with accumulations of glycogen, lipids, and aggregates of mitochondria. (See Biopsies and Histologic Features.)

Amphiphilic drug myopathies

Amphiphilic drug myopathies are often caused by drugs with hydrophobic moiety and hydrophilic region containing amine group. They produce multisystem disorders including neuropathy, myopathy, and cardiomyopathy. Chloroquine and hydroxychloroquine cause vacuolar myopathy, often given in a 500 mg daily dose of chloroquine for 1 year or longer. At extracellular pH, this drug is poorly ionized and penetrates membranes. With acid pH in lysosome, cationic region interacts with polar materials.

Muscle biopsy reveals vacuoles with lipid and membranous material, with strong acid phosphatase staining in muscle fibers and normal periodic acid-Schiff (PAS) staining for glycogen. (See Biopsies and Histologic Features.)

Among the neurologic manifestations of systemic lupus erythematosus (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.

Mental status changes

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

Posterior reversible encephalopathy syndrome (PRES) has been described in SLE. Patients are generally on immunosuppressive drugs, have had episodes of relative hypertension, and have renal involvement. Magnetic resonance image (MRI) findings are characteristic, involving the occipital lobes in particular, which differentiates PRES from other central nervous system (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.^[4]

Seizures

Seizures are already known to occur in 14-25% of patients with lupus compared with 0.5-1% in the general population.^[5] 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 previous 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 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).^[6] The investigators found a higher overall frequency of seizures (42%), as an early manifestation in 27% of patients, and, in 10%, seizures were the first SLE symptom. Previous to this, there had been no case reports of myoclonus in SLE as a presenting feature.^[6]

Cranial nerve involvement

Cranial nerve involvement is also relatively uncommon and usually transient,^[7] 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.^[6]

Lee et al reported 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.^[8]

Stroke

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

Peripheral neuropathy occurs in as many as 18% of patients with SLE. 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. 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%.

Myopathy

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

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).

Fatigue

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.

Other neurologic syndromes

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 American College of Rheumatology (ACR) criteria. Chorea has been seen in fewer 4% of patients.^[9]

Acute aseptic meningitis is rarely described in association with NSAID therapy, but this condition must be differentiated from infectious etiologies, especially in immunosuppressed patients.

Neurologic syndromes are often 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 (PNS) are affected
• Patients with cranial neuropathies
• Patients with noncompressive myelopathies
• Patients with chorea, unexplained ataxia, myopathy, or polyneuropathy

Microembolic signals have been well recognized in SLE with CNS involvement. Azarpazhooh et al reported microembolic signals in patients with SLE at risk for neuropsychiatric syndromes.^[10] Cerebral embolism is further speculated to be implicated in the pathophysiology of SLE with neuropsychiatric syndrome.

Abrupt or subacute onset of any focal neurologic deficit in systemic lupus erythematosus (SLE) 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 magnetic resonance imaging [MRI]) to exclude compressive lesions. If myelography is performed, spinal fluid should be collected for analysis before 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) and retrobulbar neuritis are 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, whereas distal symmetric weakness (with distal sensory loss) implicates a peripheral polyneuropathy. Myopathy should never be accompanied by sensory loss, but it 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.

Chronic organic encephalopathy may mimic degenerative dementia. In any patient with systemic lupus erythematosus (SLE) with slowly progressive cognitive loss, a search 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.

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.^[11]

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. Concomitant SLE and antiphospholipid syndrome has been shown to increase the risk of nervous system involvement.^[1]

Complement studies (C3, C4, CH50) may be useful to determine disease activity in patients known or thought to have SLE.

Other conditions that should be considered when evaluating a patient with suspected of central nervous system (CNS) lupus include neuromuscular diseases, aseptic meningitis, Devic syndrome, Lambert-Eaton myasthenic syndrome, abducens (cranial nerve VI) nerve palsy, granulomatous angiitis of the CNS, acute and chronic inflammatory demyelinating polyradiculoneuropathy.

The following are considered in the differential diagnosis of CNS lupus:

• Acute Disseminated Encephalomyelitis
• Blood Dyscrasias and Stroke
• Brainstem Gliomas
• Confusional States and Acute Memory Disorders
• HIV-1 Associated CNS Complications (Overview)
• Lyme Disease
• Myasthenia Gravis
• Neurological Sequelae of Infectious Endocarditis
• Spinal Cord Infarction
• Vasculitic Neuropathy

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 (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.

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 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 a 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 results suggested that FcgammaRIIIb polymorphism might not be a susceptibility gene for SLE and lupus nephritis.^[12]

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.^[13]

Serum chemistry studies

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 may be 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.

Hepatocellular and muscle enzyme levels

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.

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 in 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.^[14] Additionally, the investigators determined that dsDNA titer by ELISA and BILAG score for severity index are the best markers for follow-up.^[14]

Antiphospholipid 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 (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.^[15]

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).^[16] The presence of lupus nephritis and Raynaud 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

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).^[6]

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 vessel involved and the mechanism of stroke. See the image below for an example of ischemia visible on MRI.

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 (eg, 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 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. 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%)onproton-density and T2-weighted MRIs of the brain.^[17]

Perisulcal cortical atrophy is reported as a frequent finding on CT scans.^[18] 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 2 techniques alone and may help the clinician in the assessment of patients with neuropsychiatric involvement, because normal findings contemporarily detected by these 2 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.^[19]

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 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 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 embolic stroke occurs in patients with proven or suspected systemic lupus erythematosus (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.

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.^[20]

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 be helpful to 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 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 central nervous system (CNS) lupus.

Reported selective left temporolimbic region changes^[21] are not always observed.

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 from other musculoskeletal disturbances. Although 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.

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 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.

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.

Histologic evaluation most commonly reveals similar findings to those of 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 (eg, 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, 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 demonstrates the small vessel vasculopathy discussed in Organic Encephalopathies, with or without an inflammatory infiltrate. Because 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.

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.

Treatment of systemic lupus erythematosus (SLE) should be provided in cooperation with a consulting rheumatologist. Therapeutic intensity correlates with the severity of an acute attack. Nonsteroidal anti-inflammatory drugs (NSAIDs) and other symptomatic agents are used for less threatening symptoms. Corticosteroids are used in low-dose oral, high-dose oral, or high-dose intravenous (IV) regimens according to the severity of potential organ damage. Previous steroid therapy may provoke an adrenocortical deficiency state.

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.

With little evidence base to the therapeutic modalities, a logical approach to the treatment of cerebral lupus is to build a treatment strategy around the various possible pathogeneses: (1) ischemia due to thromboses secondary to the antiphospholipid syndrome, (2) small-vessel noninflammatory proliferative vasculopathy due to cell-mediated immune mechanisms, and (3) antibody-mediated damage to spinal cord and optic nerve—akin to Devic disease.^[22]

Seropositive findings for neuromyelitis optica (NMO)–immunoglobulin G (IgG) antibody occurring with SS/SLE (Sjogren syndrome/SLE overlap) or non–organ-specific antibodies favors coexisting NMO (Devin syndrome) rather than a vasculitic process. Antibodies against the aquaporin 4 channel is an important evaluation for this common confusing situation.^[23]

The standard treatment for the nonthrombotic syndromes associated with systemic lupus erythematosus (SLE) is immunosuppression, first with corticosteroids and with early recourse to cyclophosphamide. A Cochrane Database Systematic Review found no randomized controlled trials comparing these 2 treatments and concluded there was no evidence of a treatment advantage of cyclophosphamide.^[24]

Corticosteroids

High-dose intravenous (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 orally (PO) daily (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 the 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.

Antimalarial agents

The discovery that Toll-like receptor signaling and interferon-alpha abundance are central elements of the systemic lupus erythematosus (SLE) disease process has led to a new appreciation for hydroxychloroquine as an essential baseline medication. Modulation of the immune system via B-cell depletion is entering clinical practice.

Antimalarials, especially hydroxychloroquine in dosage of 100-400 mg daily, are used as alternatives to steroids or as supplements to accelerate steroid taper. These agents 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.

Cytotoxic agents

Various steroid-sparing strategies have evolved for long-term use in systemic lupus erythematosus (SLE), 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.

Jonsdottir et al reported that the majority of patients improved following rituximab plus cyclophosphamide.^[25] The differential downregulation of anti-DNA of the immunoglobulin (Ig) G and IgA but not the IgM isotypes supports the hypothesis that cells producing pathogenic autoantibodies are preferentially targeted by the treatment. The fact that greater absolute numbers of CD19⁺ cells at baseline predict a less impressive clinical and serologic response suggests that more flexible dosing could be advantageous.

Investigational pharmacologic approaches

Mycophenolate mofetil is an effective and safer alternative to cyclophosphamide for patients with lupus nephritis. Other therapeutic approaches under development include anticytokine therapies, costimulatory blockade, antigen-specific immune modulation, and hematopoietic stem cell transplantation.^[26]

Epratuzumab, a monoclonal antibody against the B-cell surface antigen CD22, and atacicept, a chimeric molecule formed by a receptor for B-cell–activating factor and a proliferation-inducing ligand with immunoglobulin G (IgG), have both been promising in initial small trials; larger clinical trials are under way.^[27] Clinical trial data have shown that B-cell targeting therapies are beginning to fulfill their promise as treatments for systemic lupus erythematosus (SLE), and there are good reasons to hope for further progress in the near future.

The treatment of Devic syndrome (neuromyelitis optica) in isolated myelopathy or optic neuropathy associated with the antiphospholipid syndrome (APLS) or lupus needs further study. In view of their lack of pathologic similarity to classical multiple sclerosis, treatments such as interferon-beta cannot be justified. Also, there is no hard evidence to support the use of anticoagulation, in the absence of evidence for progressive ischemia of isolated anatomic sites. Therefore, therapy is generally aimed at circulating pathogenic antibodies, with steroids and cyclophosphamide. Plasma exchange has proven effective in nonlupus Devic disease. Because of the analogy with nonlupus Devic disease, plasma exchange is also an attractive alternative in systemic lupus erythematosus (SLE)–Devic disease.^[28]

Generally, mild myopathy or polyneuropathy may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and other symptomatic medications (eg, anticonvulsants, tricyclics [TCAs], other medications used for neurogenic or musculoskeletal pain). Symptoms may be caused by medications (eg, steroids, antimalarials) or other etiologies in addition to systemic lupus erythematosus (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 systemic lupus erythematosus (SLE) presents with acute polyradiculopathy resembling Guillain-Barré syndrome or chronic relapsing polyradiculopathy resembling chronic inflammatory demyelinating polyneuropathy, treatment with intravenous immunoglobulin (IVIg) in conventional doses should be considered. When IVIg 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 systemic lupus erythematosus (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, whereas 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 (APLS) remains controversial, with therapy based predominantly on anecdotal experience. Although many authorities recommend full anticoagulation with warfarin (Coumadin) (despite there being no randomized clinical trial to prove this), other authorities support antiplatelet therapy initially, with stronger measures reserved for repeated stroke, progressive myelopathy, or other clear-cut, clinical treatment failure.

It is clear that aiming for an international normalized ratio (INR) of 2.0–3.0 is as good at reducing the risk of further events as more intensive anticoagulation.^[29] This could be done possibly in conjunction with immunosuppressant therapy to suppress production of the antibody.

A special diet is generally not required for the neurologic aspects of systemic lupus erythematosus (SLE), but it may be required for patients with renal, cardiac, or SLE complications.

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.

Generally, new-onset systemic lupus erythematosus (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.

Cerebral lupus, like the neurologic vasculitides, is best managed jointly by neurologists, clinical immunologists, renal physicians, rheumatologists, and the primary physicians.

The overall outcome of central nervous system (CNS) lupus, quality of life, and prognosis can be enhanced with close follow-up and coordination between the individual's neurologist, rheumatologist, and primary care physician. Neurologists and rheumatologists usually do not act as primary care physicians and leave healthcare maintenance to practitioners who need to be reminded to screen for various comorbidities associated with inflammation and complications of medication. Rheumatologists need to take the responsibility to ensure that their patients with lupus have optimal primary care access, which includes a working relationship with them.^[30]

Central nervous system (CNS)-specific statistics are not available, however, neuropsychiatric events in systemic lupus erythematosus (SLE) have a more favorable outcome than events secondary to non-SLE causes. Events attributed to SLE generally occur during the early course of the illness, do have a negative impact on the quality of life of the patient, and do vary in severity and frequency.^[31]

Neurologic complications worsen prognosis, especially in the presence of refractory seizures, encephalopathy, or paralysis from stroke or myelopathy.

Taddio et al concluded that presence of atypical manifestations of pediatric SLE at presentation and early kidney disease correlated with poor outcome. Similarly, during follow-up, kidney and CNS diseases were associated with worse outcome.^[32]