R. Swamy Venuturupalli, M.D.,F.A.C.R.
Allan L Metzger, M.D.,F.A.C.P., F.A.C.R.
What is CNS lupus?
Central nervous system (CNS) lupus refers to several different neurological and/or behavioral clinical syndromes in patients with systemic lupus erythematosus (SLE). The neuropsychiatric manifestations of lupus, which are frequent, vary from mild to severe and are often difficult to distinguish from other conditions and etiologies. Any location within the central nervous system (brain and spinal cord) may be affected with a variety of presentations from mild cognitive dysfunction to seizures, stroke or coma. Table 1 summarizes the major manifestations of CNS lupus. (adapted from “The Lupus Book”- Daniel J Wallace, M.D.)
Table 1: Major manifestations of CNS lupus.
Cognitive dysfunction (not thinking clearly, memory deficits)
Altered mental alertness (e.g. stupor or coma)
Aseptic meningitis (inflammation of the covering of the brain)
Stroke (disturbance of the blood supply to different parts of the brain)
Peripheral neuropathy (e.g. numbness, tingling, burning of the hands and feet)
Myelitis (disruption) of the spinal cord.
Autonomic neuropathy (e.g., flushing reaction or mottled skin)
Until recently, only those syndromes with specific neuropathology were considered to be part of the CNS lupus syndrome (for e.g., seizures, strokes, paralysis), and these conditions were thought to affect about 25% of lupus patients. In the last decade with early detection (through CT, MRI and PET scans) and improved aggressive treatment the incidence of these conditions has decreased. However, the overall incidence of CNS lupus has increased because of the recognition of conditions such as cognitive dysfunction and lupus headaches as discrete entities even though there is no specific pathology that can be found in the brain to explain these conditions. Thus, CNS lupus is now considered as being present in many patients with SLE at some point during the disease.
What causes CNS Lupus?
A variety of pathological processes may be involved in CNS lupus. The blood supply to a particular part of the brain can be disrupted due to autoimmune vasculitis (blood vessel inflammation), or clots formed as a result of antiphospholipid antibodies, or emboli that travel from a cardiac source. In some lupus patients, the thickness of their blood is increased causing hyperviscosity and this may disrupt blood flow. Anti-neuronal antibodies also may be produced in some lupus patients; these can have direct effects on the cells of the brain (neurons) and alter their function. The choroid plexus, a part of the brain that is the source of cerebrospinal fluid (CSF- a fluid bathing brain and spinal cord) may be involved thus causing diffuse problems. Several cytokines such as interleukin-1, interleukin-6 and interferon-γ are increased in CNS lupus and these have a direct effect on the neurons and can interfere with their function. Abnormalities of the hormones produced in the hypothalamus, pituitary and adrenal glands (the HPA axis) are common in lupus due to the disease itself as well as the effects of steroids and these abnormalities can cause some of the CNS disturbances lupus.
In addition, a number of secondary factors lead to the manifestations of CNS lupus such as infection (lupus patients are more prone to certain types of infections), medications (several drugs such as corticosteroids have significant CNS toxicity), hypertension, electrolyte imbalances, uremia (renal failure), thyroid disease, atherosclerotic strokes, and subdural hematomas. The concomitant presence of fibromyalgia in lupus patients is associated with an increase in functional neurological problems such as anxiety and cognitive dysfunction.
What are the clinical manifestations of CNS lupus?
The spectrum of clinical presentations in CNS lupus is broad. The major clinical syndromes seen in CNS lupus are:
CNS vasculitis: This is an inflammation of the brain’s blood vessels due to lupus activity. This is the most serious syndrome associated with lupus, and is one of the two specific CNS syndromes that are part of the American College of Rheumatology’s criteria for defining lupus. It usually occurs early in the course of disease (over 80% of episodes occur within the first five years of disease), being seen in about 10% of lupus patients. The typical patient presents with fevers, seizures, meningitis like stiffness of the neck, and psychotic or bizarre behavior. Brain MRI may demonstrate multiple or single areas with infarcts. A spinal tap may be needed to diagnose this condition (and exclude infection), and usually shows a high number of cells, high protein level and a high synthesis rate of immunoglobulins. Anti-neuronal antibodies may be present in the serum and/or the CSF. Usually, high dose steroids and/or cytoxan are needed to treat this syndrome.
The Antiphospholipid syndrome: Anyone who has antiphospholipid antibodies as part of their lupus syndrome is at risk to develop blood clots, which could form in vessels supplying the brain, or travel to the brain after forming in the heart or elsewhere in the body. Blood clots to the brain (called thromboembolic events) can occur suddenly, and are usually painless. Patients may have sudden onset of paralysis, or loss of speech. Lupus does not have to be “active”, for a clot to be formed. MRI and CT scans may show a blood clot. Treatment includes the usual management of a stroke, and perhaps immunosuppresant medication; but all patients who have high levels of antiphospholipid antibodies in significant amounts should be given prophylactic blood thinners (aspirin and/or coumadin) to prevent strokes and other blood clot complications.
Lupus Headache: Headaches are common in lupus patients, occurring in up to 45-50% of patients. Most investigators feel that headache as a manifestation of CNS lupus occurs as an acute presentation during a lupus flare in association with other neurologic complications. Usually abnormal laboratory tests are seen, and usually lupus headaches resolve with corticosteroid therapy as lupus disease activity improves. However, many lupus patients have headaches, which are not related to disease activity or other manifestations of lupus. Amazingly, in one well controlled study, the overall incidence of headaches, migraine and tension type were similar to the general population. Thus, there is some controversy whether there is an increase in headache incidence in lupus. Older studies reported that migraine headaches were more common in lupus patients, and the headaches were usually associated with Raynaud’s phenomenon, antiphospholipid antibodies, and/or thrombotic events. However, more recent controlled studies have not confirmed these associations. Thus lupus headache as a distinct entity remains controversial and unless the headaches are associated with other neurological complications suggestive of CNS lupus, (in which case they are treated with steroids) they are usually treated symptomatically with anti-migraine medications, or anti-inflammatories such as naproxen, or ergot derivatives.
Lupus myelitis: Myelitis refers to dysfunction of the spinal cord. This is a serious complication of lupus that causes paralysis or weakness and ranges from difficulty in moving one limb to paraplegia. It is caused either by inflammation (lupus vasculitis) of the sac that surrounds the spinal cord, or by clots in the arteries supplying the spinal cord (usually caused by antiphospholipid antibodies). Steroids and/or immunosuppresants are usually used to treat inflammation from vasculitis, and anticoagulants such as heparin and coumadin are usually added on. Chronic inflammatory demyelinating polyneuropathy (CIDP) and post-infectious Guillain-Barre syndrome are other conditions that can cause spinal cord dysfunction, which have a higher prevalence in SLE and may be responsive to intravenous immunoglobulin therapy.
Autonomic nervous system dysfunction: The autonomic nervous system is that part of the nervous system which controls involuntary body functions such as regulating the heart beat, breathing, sweating etc. Although this has been poorly studied, the autonomic nervous system may function abnormally in many lupus patients. Examples of autonomic dysfunction
include Raynaud’s phenomenon, cognitive impairment, livedo reticularis (a mottled skin rash), and tingling and numbness of the extremities. Other causes for these symptoms usually need to be ruled out, and this syndrome is usually treated symptomatically.
Cognitive dysfunction: Lupus patients frequently complain of confusion, profound fatigue, difficulty in articulating thoughts, and memory impairment. While blood testing confirms the presence of Lupus, other laboratory tests are usually normal. Conventional imaging and CSF examination are usually normal. A superficial mental state exam performed in a physicians office usually does not reveal any abnormalities, but more detailed neuropsychiatric testing usually reveals abnormalities in focusing, attention span, task completion, memory and decreased problem solving capabilities. A SPECT scan (a radionuclear brain scan) usually shows some abnormalities. Currently, cognitive dysfunction is thought to be caused by circulating chemicals called cytokines, and blood flow abnormalities to different parts of the brain. Cognitive dysfunction must be differentiated from depression, fibromyalgia, and behavioral alterations due to medication, infections, strokes, sleep disorders and other brain abnormalities. Usually, the symptoms of cognitive dysfunction are intermittent. Corticosteroids are have not been shown to be effective, but anti-malarials such as plaquanil and quinacrine could be helpful. Tricyclic antidepressants, or selective serotonin uptake inhibitors (prozac, zoloft, lexapro, effexor, cymbalta etc.) may be helpful, and cognitive behavioral therapy, and EEG or regular biofeedback may be very useful. Lastly, DHEA, St. John’s Wort and gingko biloba are complementary medicine alternatives.
Organic Brain syndrome: When lupus patients have a stroke or lupus vasculitis insult, these lesions may heal with scarring, which results in a permanent motor, sensory or mental deficit or even seizures. This condition resulting from a permanent damage to the CNS is known as organic brain syndrome. Its importance lays in its recognition, since there is no need to treat these lesions with immunosuppressive medicines, but they are treated symptomatically or with anti-seizure medications.
Other manifestations of CNS lupus: Abnormalities of the peripheral nerves are seen with frequency in lupus patients. This leads to painful neuropathy with tingling and numbness of the extremities. Pharmaceutical agents used to treat lupus may affect the CNS. For example, the non-steroidal anti-inflammatory drugs such as indomethacin, tolmectin, sulindac and ibuprofen have been associated with headaches. Very high doses of anti-malarials have been associated with manic behavior and psychosis as have corticosteroids. Infections of the CNS can mimic CNS lupus. Infections such as TB, meningococcus, staphylococcus, and streptococcus are common in SLE. Lastly, opportunistic infections (they occur in patients being treated with high doses of steroids or immunosuppressive medications, by pathogens that are not normally harmful), can mimic lupus and need to be excluded when considering a diagnosis of CNS lupus.