CNS Syndromes of Systemic Lupus Erythematosus
- According to the American College of Rheumatology, the following are central nervous system (CNS) manifestations of systemic lupus erythematosus (SLE):
- Acute confusional state.
- Anxiety disorder.
- Aseptic meningitis.
- Cerebrovascular disease.
- Cognitive dysfunction.
- Demyelinating disease.
- Headache.
- Mood disorder.
- Movement disorder (chorea).
- Myelopathy.
- Psychosis.
- Seizure disorder.
- Acute confusional state.
The general term “neuropsychiatric lupus” is being superseded by the understanding that lupus can affect the nervous system in diverse ways, each with distinctive clinical findings, pathogenesis, prognosis, and treatment. The American College of Rheumatology distinguished 12 central neurologic manifestations of SLE. Neurologists subdivide these in greater detail, noting, for example, many different mechanisms and localizations of strokes or seizures. Neurologic manifestations of lupus often occur early in the disease. The CNS syndromes discussed below are presented in approximate order of prevalence; however, prevalences are inexact due to variations of definition and clinical sampling. Patients with SLE are also at risk for peripheral nervous system disease (Table 73–1).
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Cognitive dysfunction, especially in domains such as visual or verbal memory, attention, executive function, and psychomotor speed, is the most common neuropsychiatric aspect of lupus. These disturbances can range from subtle to severe. Prevalence figures vary greatly, depending on diagnostic criteria and extent of psychometric testing. Mild cognitive dysfunction typically waxes and wanes without clear correlation to other aspects of disease activity. Patients with antiphospholipid antibodies have increased risk of developing cognitive dysfunction.
Severe cognitive dysfunction, including acute confusional states or delirium, affects only a small percentage of lupus patients and can overlap with other neuropsychiatric aspects of lupus, such as psychosis and affective disorders. Patients with these more severe neuropsychiatric presentations usually have serum and cerebrospinal fluid (CSF) antibodies against the NR2-NMDA receptor. These antibodies are probably not solely responsible for the mental changes because titers often remain elevated in the CSF months after symptoms have resolved. Moreover, these antibodies are less likely to be elevated in lupus patients with focal neurologic syndromes. Other autoantibodies, such as those directed against antiribosomal P, can occur in patients with neurologic manifestations of lupus, but none is particularly helpful in diagnosing whether or not a patient has lupus or if new neurologic findings are due to SLE or other etiology.
In 50% or more of patient with lupus, brain MRI shows T2-bright lesions in the white matter. These lesions can be present in patients without clinical CNS disease. However, the lesions are more common among patients with cognitive impairment, seizures, hypertension, or antiphospholipid antibodies, and become more common as the disease progresses.
Patients with severe cognitive dysfunction merit laboratory testing for alternative metabolic causes, brain imaging, electroencephalography, and lumbar puncture. Cognitive dysfunction in SLE is sometimes a reflection of other neurologic effects of lupus, such as strokes or seizures. The differential diagnosis includes medication effects and other metabolic disturbances, hypertensive or uremic encephalopathy, and opportunistic infections.
Most instances of mild cognitive dysfunction need no specific treatment. Cognitive behavioral therapies may help. Once other treatable systemic causes are excluded, patients with severe confusional states including psychosis can be treated with acute immunosuppression, usually starting with intravenous high-dose glucocorticoids.
Recurrent tension or migraine headaches affect more than half of patients with lupus. However, there is no distinctive severe intractable “lupus headache”, and whether headache is more common in patients in lupus than in the general population is debatable. Most recurrent headaches in patients with lupus do not require extensive imaging or other neurologic investigations.
Important causes of headache include stroke, meningitis, posterior reversible leukoencephalopathy, and pseudotumor cerebri. When a patient with lupus has a new type of headache or other warning signs (such as fever, seizures, an altered mental status, or focal neurologic findings), a thoughtful and thorough evaluation is required.
Tension and migraine headaches in patients with lupus can be treated by avoiding precipitating factors, using analgesics or triptans for acute attacks, and considering migraine prophylactic drugs for patients with frequent and disabling headaches. These are the same tactics used for such complaints in patients without lupus. Headache alone is not due to active inflammation and is not an indication for immunosuppressive therapies.
Patients with lupus have an increased incidence of anxiety, depression, and even mania compared with age and gender matched controls. Perhaps one-fifth of patients with lupus have an episode of major depression during the course of their illness.
Affect can also be influenced by the severity of illness, medications (eg, glucocorticoids and anticonvulsants), or other manifestations of disease, such as depression or a complication of stroke.
The treatment of affective disorders in SLE differs little from that of the general treatment of these conditions. Small studies have suggested that cognitive behavioral therapy can ameliorate depression, anxiety, and cognitive dysfunction.
Seizures or psychosis are the only two neuropsychiatric syndromes that are included among the American College of Rheumatology classification criteria for lupus. Nearly one-tenth of patients with lupus have a seizure sometime during the course of their lives. The seizures can take a variety of forms (eg, focal or generalized, single or recurrent).
Every patient with SLE and seizures needs careful evaluation for type and cause of seizure, including an electroencephalogram and MRI of the brain, and an evaluation for potential metabolic causes. Seizures can accompany a number of other lupus manifestations, such as strokes, other focal brain lesions, psychosis, uremia, hypertensive encephalopathy, or posterior reversible leukoencephalopathy. Seizures can be caused by electrolyte disturbances or opportunistic CNS infections. Patients with elevated antiphospholipid or anti-Smith antibodies have increased risk of seizures.
Seizures in patients with lupus are treated with the same anticonvulsants used in epilepsy of other causes. Seizures are not an indication for increased immunosuppression unless brain imaging or examinations of the CSF demonstrate evidence of brain inflammation.
Psychosis affects only a small percentage of lupus patients. The psychosis presents as delusions, often paranoid, and hallucinations, more often auditory than visual or olfactory. Lupus psychosis most often occurs within the first year of presentation of the disease, accompanied by other systemic manifestations of disease activity and by affective or cognitive changes.
Lupus psychosis must be distinguished from psychosis caused by glucocorticoids, other drugs, or metabolic disturbances. Patients with glucocorticoid-induced psychosis are usually taking more than 40 mg daily of prednisone (or equivalent dose of other glucocorticoids), often have had a recent increase in glucocorticoid dose, and are more likely than patients with lupus psychosis to be alert, cognitively intact, and free of other active neurologic complications (such as seizures).
Patients with lupus psychosis need aggressive immunosuppressive therapy, usually starting with high-dose glucocorticoids (eg, intravenous methylprednisolone). They also commonly need treatment with typical or atypical antipsychotic drugs until the immunosuppression becomes effective.
Most patients with lupus psychosis have excellent psychiatric recovery within months of increasing or beginning immunosuppressive treatment. Many patients are able to stop taking antipsychotic medication but continue taking immunosuppressive agents, which are titrated according to other lupus manifestations. A minority of patients have a recurrent episode of psychosis, which can occur many years after the first episode.
The timing and focal clinical signs of stroke in lupus are similar to those of cerebrovascular accidents in the general population. Most strokes in patients with lupus are due to atherosclerosis or hypertensive cardiovascular disease. Patients who have antiphospholipid antibodies have an important additional risk factor for thrombotic strokes. Strokes due to Libman-Sacks endocarditis are much less common, and those caused by true cerebral vasculitis are quite rare.
The treatment of acute stroke in patients with lupus is similar to that of stroke in the general population. Stroke is not an indication for immunosuppression except in the rare instances of CNS vasculitis. Because of their general increased stroke risk, patients with lupus should be attentive to primary stroke prevention: avoiding smoking; controlling blood pressure, diabetes, and lipids; and taking low-dose aspirin if not contraindicated by other factors. These measures are also important for secondary stroke prevention. Oral anticoagulation with warfarin is reserved for patients with cardiogenic causes of embolic stroke or for those with antiphospholipid antibodies. The optimal international normalized ratio (INR) during warfarin therapy in patients with antiphospholipid antibodies is controversial; some experts favor an INR of 2.0–3.0, while others favor an INR of 3.0–4.0.
Aseptic meningitis presents with fever, headache, or stiff neck and is diagnosed by the finding of a CSF pleocytosis. The pleocytosis is usually mononuclear, and cultures are negative. Aseptic meningitis develops in less than 1% of patients with SLE.
Patients with meningitis must have CSF cultures and serology to exclude opportunistic or other infectious causes of meningitis. Nonsteroidal anti-inflammatory drugs can also cause aseptic meningitis, and therefore constitute a potential confounder in patients with SLE.
The aseptic meningitis of lupus usually resolves spontaneously without specific treatment.
Chorea is the most common movement disorder that complicates lupus, affecting about 1% of patients. It can be unilateral or bilateral and occur early or late in the disease. Chorea is sensitive to levels of female hormones; the incidence is increased in women during menses, during pregnancy, and in those who take oral contraceptives. Hence, lupus is a risk factor for the development of chorea gravidarum. Patients with lupus and chorea often have antiphospholipid antibodies, but the chorea is not due to antibody-associated thrombosis. MRI usually does not implicate any focal lesion in this setting and is typically normal in the absence of other baseline neuropathology related to SLE or comorbid conditions. Other movement disorders, such as reversible parkinsonism, can also occur as a manifestation of lupus.
The differential diagnosis of chorea in patients with lupus includes Huntington disease, rheumatic fever, and medications.
Typically, lupus chorea progresses over weeks, then resolves. There is no proof that immunosuppression aids recovery. Antidopaminergic drugs, such as haloperidol or tetrabenazine, might help suppress choreiform movements.
