History
Among the neurologic manifestations of systemic lupus erythematosus (SLE), the most common are the organic encephalopathies (35–75% of case series), which comprise all potential variations of acute confusion, lethargy, or coma; chronic and subacute dementias. They can also manifest as psychiatric symptoms, including depression, mania, psychosis, or other affective disturbances.
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. These patients are generally on immunosuppressive drugs, have had episodes of relative hypertension, and have renal involvement. Magnetic resonance image (MRI) findings are characteristic, typically involving the occipital lobes, which differentiates PRES from other central nervous systems (CNS) complications of SLE. Clinical and radiographic resolution of abnormalities within 1–4 weeks is typically seen. Despite this, patients with PRES can sometimes present with dramatic signs and symptoms. [13]
Seizures
Seizures are already known to occur in 14–25% of patients with lupus compared with 0.5–1% in the general population. [14] Seizures may result from cerebral vasculitis (ischemic or hemorrhagic manifestations), cardiac embolism, opportunistic infections, drug intoxication, or associated metabolic derangements. A seizure focus may result from an acute insult or from the development of an epileptogenic focus in an area of previous brain insult. Partial or secondarily generalized seizures are most common, but various other seizure types have also been reported.
While evaluating these patients, electrolyte disturbance and medication effects should be excluded, especially those resulting from antidepressants, psychostimulants, or withdrawal from sedatives or alcohol. Opportunistic infections should be considered in patients on 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). 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. [15]
Cranial nerve involvement
Cranial nerve involvement is also relatively uncommon and usually transient, [16] occurring in 10% of patients with SLE. Visual disturbances tend to be bilateral (80%) and occur late in the disease course (77%). Ocular involvement includes 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. [15, 17, 18]
Lee et al reported a case of SLE with recurrent laryngeal palsy resulting in vocal cord paresis. [19]
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.
The ischemic stroke should be differentiated from a 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 a 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 myopathy must be differentiated from myopathy induced by steroid usage or antimalarial therapy or arthralgias and other musculoskeletal sequelae of SLE. Distinction from arthralgias and other musculoskeletal conditions is based on symmetrical, proximal muscle weakness (more than what is expected for painful giveaway), 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 can be devastating. Transverse myelitis, subacute-to-chronic demyelinating syndromes, and abrupt vascular occlusive events (e.g., 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 (e.g., epidural abscess).
Fatigue
Chronic fatigue is a common symptom in SLE and usually does not relate to the objective muscular effort (i.e., walking upstairs may seem no more challenging than walking on level ground). [20] Fatigue may contribute to both self-perceived and 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 a nocturnal sleep disorder, and systemic conditions (e.g., 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 and chorea has been reported in fewer than 4% of patients. [21]
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:
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Young patients with new-onset confusional or psychiatric states, stroke, or parkinsonism
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Patients presenting with a multifocal process affecting the CNS, especially if both CNS (e.g., patients carrying the presumptive diagnosis of multiple sclerosis) and peripheral nervous systems (PNS) are affected
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Patients with cranial neuropathies
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Patients with non-compressive myelopathies
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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. [22] Cerebral embolism is further speculated to be implicated in the pathophysiology of SLE with neuropsychiatric syndrome.
Physical Examination
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 (e.g., 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 idiopathic immune-mediated polyneuropathy (Guillain-Barré syndrome) should always be considered. The 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 (i.e., myelography or magnetic resonance imaging [MRI]) to exclude compressive lesions. If myelography is performed, the 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, 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 an 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 accompanying pain) support myopathy, whereas distal symmetric weakness (with distal sensory loss) implicates 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 giveaway weakness without organic muscle weakness supports arthralgia or other musculoskeletal etiology. Fatigue from autoimmune disorder is rarely accompanied by objective muscular weakness.
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This axial, T2-weighted brain magnetic resonance image (MRI) demonstrates an area of ischemia in the right periventricular white matter of a 41-year-old woman with longstanding systemic lupus erythematosus (SLE). She presented with headache and subtle cognitive impairments but no motor deficits. Faintly increased signal intensity was also seen on T1-weighted images, with a trace of enhancement following gadolinium that is too subtle to show on reproduced images. The distribution of the abnormality is consistent with occlusion of deep penetrating branches, such as may result from local vasculopathy, with no clinical or laboratory evidence of lupus anticoagulant or anticardiolipin antibody. Cardiac embolus from covert Libman-Sacks endocarditis remains less likely due to the distribution.
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- Overview
- Presentation
- DDx
- Workup
- Approach Considerations
- Serum Chemistry Studies
- Hepatocellular and Muscle Enzyme Levels
- Antinuclear Antibody Test
- Lupus Anticoagulant Test
- CSF Studies
- Brain Imaging Studies
- Spinal Imaging Studies
- Echocardiography and Ultrasonography
- Electroencephalography
- EMG and Nerve Conduction Studies
- Biopsies and Histologic Features
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- Treatment
- Medication
- Questions & Answers
- References
