LUPUS: A GP Guide to Diagnosis
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. Conventional tests give the incidence of neurological abnormalities in lupus as 50%. However, with the recognition of the antiphospholipid (Hughes) 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.
The recognition that many neurological features such as seizures, memory loss, transitory ischaemic attacks (TIAs), psychosis or paraplegia can occur in relative isolation and the increasing recognition of lupus itself both serve to underline the clinical importance of this neurological diagnosis.
There is a wide spectrum of clinical presentations, including neurologic, psychiatric and behavioural abnormalities. They encompass a diversity of symptoms such as: headaches, focal and generalised seizures, ischaemic cerebral vascular 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) and myasthenia gravis.
Any of these neurological or psychiatric features can appear in isolation or in combination and may be a first presentation of the disease.
Headaches are a very common complaint in lupus. They may be migrainous and can 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.
Neurocognitive dysfunction is also a common feature in lupus and may be present in up to 80% of the patients with active neuropsychiatric manifestations and in 42% 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 antiphospholipid antibodies (aPL) is a well-known cause of ischaemic 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 reports include cerebral vein thrombosis, hemiballismus and hemichorea.
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 histopathology at post-mortem examination includes vasculitis, perivascular lymphocytic infiltration, thrombosis of small and large vessels, ischaemic necrosis of the cord, microhaemorrhages and myelomalacia of the cord. The presentation of acute transverse myelopathy usually occurs early in the course of lupus. Serologic parameters of disease activity are not always remarkable. Magnetic Resonance Imaging (MRI) or CT/Myelogram should be performed to exclude any surgical cord compression. 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, sensorineuronal hearing loss, trigeminal neuropathy, may be presenting symptoms of cranial neuropathies.
Acute ascending motor paralysis, indistinguishable from Guillain-Barré; autonomic neuropathy; narcolepsy; aseptic meningitis; pseudotumour cerebri; normal pressure hydrocephalus; myasthenia gravis; saggital sinus thrombosis and chorea are many of the rare CNS manifestations described in patients with lupus.
The diagnosis of neuropsychiatric lupus is primarily clinical and follows exclusion of other possible aetiologies such as sepsis, drug effects, metabolic disturbances and severe hypertension. Evidence of active disease in other organs is helpful but not always present.
The pathogenetic mechanisms remain unknown, but certainly a single pathogenetic mechanism cannot explain the large spectrum and diversity of neuropsychiatric manifestations seen in lupus.
Post-mortem studies of the brain in neuropsychiatric lupus frequently indicate small vessel vasculopathy and occasionally vasculitis, with infarcts in both grey and white matter. Arterioles and capillaries are mainly affected, though changes may be seen in arteries. Capillary prominence occurs in almost all cases which is attributed to cytoplasmatic swelling.
The variety of lesions found in neuropsychiatric lupus indicate a variety in the mechanism of damage. Several hypotheses have been suggested to explain CNS manifestations in lupus. Since the affected tissue cannot be sampled, current research focuses upon the role of vascular injury, effects of autoantibodies on neuronal cells and the consequence of pro-inflammatory cytokine expression within the CNS.
Diffuse cerebral manifestations are often transient, reversible on therapy, and not consistently associated with specific brain pathology. Conversely, focal symptoms are usually acute and permanent and associated with pathologic lesions at autopsy. It has been speculated that many diffuse symptoms result from mechanisms (antineuronal antibodies, cytokines) that interfere with neural impulses or neuro-transmitters, whereas focal manifestations are due to vascular events (predominantly thrombosis) that result in nerve cell death. A combination of mechanisms probably occurs in many patients.
Occlusive vasculopathy causing both arterial and venous occlusion is relatively common in lupus. Anticardiolipin antibodies and the lupus anticoagulant have a well-established association with macro/micro thrombosis, as well as thromboembolism. Vascular abnormalities, due to increased endothelial cell adhesiveness, may be a further factor to be taken into account in the thrombotic vasculopathy seen in lupus.
Certainly, a single mechanism is unlikely to account for all the clinical syndromes, but much attention is focused on abnormalities of the immune system and the thrombotic and inflammatory events involving the cerebral vasculature.
While some studies suggest an increase in the intrathecal synthesis of autoantibodies, others have focused on a possible increased permeability of the blood-brain barrier (BBB) to give access of substances normally excluded by it, including circulating toxins and antibodies. Increased permeability of the BBB has been demonstrated by Gd-DTPA enhanced MRI and CSF analysis in some patients with CNS lupus.
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.
Imaging tools may aid in the diagnosis of neuropsychiatric lupus. However, despite many different types of neuroimaging tests 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 hypertension or other cardiovascular risk factors.
Single-photon emission computed tomography (SPECT) uses tomographic reconstruction of single photons emitted by radiolabelled 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 (33%) in CNS lupus patients. Clearly, non-lupus causes of neuropsychiatric disturbances can result in an abnormal SPECT scan. Conversely, a normal SPECT scan may provide evidence against active neuropsychiatric 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 on 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.
There have been no controlled trials of any treatment strategies in CNS lupus. The three major advances in management have been: firstly, the recognition of the APS with its emphasis on the use of anticoagulants; secondly, the more conservative use of steroids (doses of over 80 mg daily result in little benefit and a massive increase in opportunistic infections) and thirdly, in diffuse (non-thrombotic) CNS lupus, the use of pulse cyclophosphamide.
In a study at St. Thomas' Hospital, London, of IV pulse cyclophosphamide regimes in aCL-negative CNS lupus patients, improvement was often surprisingly quick, occasionally in days.
Patients with mild diffuse manifestations like headache and depression may only need symptomatic treatment with analgesics, antidepressants and antimigraine management
Perhaps the most important advance in CNS lupus has come with the recognition of the antiphospholipid (Hughes) syndrome and the importance of thrombotic mechanisms in the development of brain symptoms.
Many patients with CNS lupus who have aPL and focal MRI lesions are being successfully treated with warfarin, whereas previously they would have received steroids.
Dr. Lais L.F. Mendonça |
Dr. Munther A. Khamashta |