Introduction - Central Nervous System Involvement in Lupus and Antiphospholipid (Hughes) Syndrome

Central nervous system (CNS) involvement has been emphasised as one of the major lupus manifestations since the first descriptions of the disease and is among the leading causes of morbidity and mortality. Its recognition and treatment continue to represent a major diagnostic and therapeutic challenge. Conventional tests give the prevalence of neurological abnormalities in lupus as 40-50%. However, with the recognition of the antiphospholipid syndrome (APS) and its striking array of neurological manifestations and the more penetrating studies of neuropsychiatric and cognitive changes in lupus, this percentage might become higher.

Clinical Manifestations

The spectrum of CNS involvement is wide and encompasses almost the whole spectrum of neurological diseases (Table 1). By far the most frequent manifestations are headache, depression, psychiatric illness ranging from mild affective disorder to full blown psychosis and generalised seizures. The neuropsychiatric events are unpredictable and can occur at any time in the course of the disease, occasionally even preceding the onset of systemic disease. A neurological disorder may occur as an isolated event or in association with other signs of systemic disease activity. Multiple neurological events may occur together.

Headaches are a very common complaint in lupus. They may be migrainous and last for days or weeks. The headaches are often intractable, unresponsive to narcotic analgesics and can antedate the diagnosis by many years. Epilepsy is an important complication of lupus patients and can present as generalised "grand mal", focal, temporal lobe or "petit mal". Seizures can be a primary event resulting from the direct effect of active lupus on the CNS, or may also occur as a consequence of infection or metabolic abnormality.Ten per cent of lupus patients develop seizures and a strong association between the presence of antiphospholipid antibodies (aPL) and seizures is now well established.

Neurocognitive dysfunction is also a common feature in lupus and may be present in up to 80% of the patients with active CNS manifestations and in 40% of overall lupus patients. The various studies of cognitive function suggest considerable diversity in the type of cognitive impairment, including attention and concentration, various aspects of verbal and non-verbal memory including working memory, verbal fluency, visuo-spatial skills, psychomotor speed and cognitive flexibility.
Psychosis, depression and anxiety are the most frequently cited psychiatric disorders in lupus, although both frequency and pathophysiological relationship to the disease remain controversial.

Vasculopathy due to thrombotic events in the presence of aPL is a well known cause of ischemic cerebral disease. Often the features (as well as the MRI lesions) are widespread and frequently mis-diagnosed as "vasculitis". Several cases of focal neurologic manifestations associated with aPL in lupus patients have been reported. These include cerebral vein thrombosis and chorea. Thrombosis of microvessels in the retina and the inner ear causing amaurosis fugax, blindness and sensorineural hearing loss, respectively, are features associated with the presence of aPL.

Transverse myelitis is a rare manifestation of lupus, estimated as less than 1% of complications. The presentation of acute transverse myelopathy usually occurs early in the course of lupus. Serologic parameters of disease activity are not always remarkable. MRI or CT/Myelogram should be performed to exclude any cord compression requiring surgery. Neurogenic bladder may persist despite motor recovery. There is a strong association between transverse myelitis and the presence of aPL.

Less common in lupus than in primary vasculitis, peripheral neuropathy may present as sensory polyneuropathy (stocking-glove distribution), mononeuritis multiplex and mixed motor and sensory polyneuropathy, while ocular motor abnormalities, facial palsy and trigeminal neuropathy,may be presenting symptoms of cranial neuropathies. Acute ascending motor paralysis, indistinguishable from Guillain-Barre, narcolepsy, aseptic meningitis, pseudotumour cerebri, normal pressure hydrocephalus and myasthenia gravis are many of the rare CNS manifestations described in patients with lupus.

Diagnosis

The diagnosis of CNS lupus is primarily clinical and follows exclusion of other possible causes such as sepsis, drug effects (steroids), metabolic disturbances (uraemia) and severe hypertension. Evidence of active disease in other organs is helpful but not always present. There is no single test that is diagnostic. A careful history and physical examination coupled with routine laboratory studies (including coagulation) may help distinguish CNS lupus from neuropsychiatric dysfunction due to other causes. CSF examination has proved disappointing, apart from its use in the exclusion of infection. Elevated CSF IgG, IgM or IgA and the presence of oligoclonal bands have been observed in CNS lupus.

Neuroimaging

Imaging tools may aid in the diagnosis of CNS lupus. However, despite many different types of neuroimaging test abnormalities described in CNS lupus, there is no specific finding that is diagnostic. Indeed, the heterogeneous nature of the disease could explain the inconsistent association between clinical symptoms and neuroimaging studies.
The MRI has been shown to be superior to CT scanning in detecting lesions in CNS lupus. However, the finding of focal lesions on brain MRI must be interpreted with caution. Previous studies have reported that a few asymptomatic lupus patients without a history of CNS disease will show focal white matter lesions. This is more likely to occur in patients with aPL, hypertension or other cardiovascular risk factors.

Single-photon emission computed tomography (SPECT) uses tomographic reconstruction of single photons emitted by radio-labelled tracer for the determination of cerebral blood flow. Abnormal SPECT scans are frequently observed in subjects with focal and diffuse CNS lupus and in children with lupus in whom the diagnosis is especially difficult to document. In general, SPECT scans have shown a high sensitivity (90%) but low specificity (30%) in CNS lupus patients. Clearly, non-lupus causes of CNS disturbances can result in an abnormal SPECT scan. Conversely, a normal SPECT scan may provide evidence against active CNS lupus.

Positron emission tomography (PET) is a radionuclide technique that uses unstable isotopes for measuring cerebral glucose uptake or consumption, cerebral oxygen uptake or blood flow. PET has been found to show abnormalities in milder CNS disorder, such as cognitive dysfunction, which do not show up in MRI.

Other manifestations of lupus neuroimaging include cerebral atrophy, venous thrombosis, venous infarction and intracranial calcification. Sulcal enlargement with or without ventricular enlargement is common in CNS lupus and seems related to disease duration and long term steroid therapy, rather than an intrinsic manifestation of CNS lupus.

Treatment

Due to the lack of controlled randomised trials, there is a desperate need to assess the efficacy of various therapeutic interventions in CNS lupus, where the treatment is still empirical and based on clinical experience.

Focal CNS Manifestations

One of the most important advances in the treatment of CNS lupus has come from the recognition of the APS and the importance of thrombotic mechanisms in the development of a number of CNS manifestations in lupus patients. The presence of aPL is strongly associated with thrombotic CNS events. The most common manifestations of focal CNS disease in lupus patients are transient ischemic attacks and ischemic stroke. Many lupus patients with cerebral ischemia and aPL, who would have previously received high dose of corticosteroids and/or immunosuppression, are today being successfully treated with anticoagulation. Immunosuppression should only be used in patients with active lupus disease. There is no evidence so far to support its use in patients with APS. Minimum treatment requires antiaggregant therapy as a prophylactic measure, but longterm anticoagulation with warfarin is mandatory in patients with APS-associated stroke. Other focal CNS manifestations, such as demyelinating syndrome, transverse myelitis, chorea, migraine and seizures, when associated with aPL, may also benefit from anticoagulation.

Severe diffuse CNS manifestations

Acute confusional state, generalized seizures, major depression and psychosis, and severe cognitive dysfunction generally require corticosteroids in the first instance. High dose of corticosteroids may only be used in severe cases and preferably for short terms. Pulse intravenous cyclophosphamide therapy may help when more severe manifestations are refractory to corticosteroids and other immunosuppressive agents. Plasmapheresis, IVIG, intrathecal methotrexate and dexamethasone,mycophenolate mofetil and rituximab deserve further studies to confirm their usefulness in the treatment of CNS lupus.

Table 1. Major neuropsychiatric syndromes in Systemic Lupus Erythematosus

• Headaches
• Focal and generalised seizures
• Ischemic cerebrovascular accidents
• Organic brain syndrome (delirium, cognitive impairment, impaired memory or concentration)
• Psychiatric disorders (psychosis, depression, phobias, schizophrenia, catatonia)
• Peripheral neuropathy (radiculopathy, plexopathy, mononeuritis, polyneuropathy, autonomic neuropathy)
• Transverse myelitis
• Movement disorders (particularly chorea)
• Myasthenia gravis


Prof Munther A Khamashta
Consultant & Head of Lupus Clinic
Dubai Hospital
United Arab Emirates