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Rheumatology Advance Access originally published online on December 15, 2007
Rheumatology 2008 47(3):256-262; doi:10.1093/rheumatology/kem319
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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Neuropsychiatric lupus and reversible posterior leucoencephalopathy syndrome: a challenging clinical dilemma

A. Mak1, B. P. L. Chan2, I. B. Yeh3, R. C. M. Ho4, M. L. Boey1, P. H. Feng1, D. R. Koh1 and B. K. C. Ong2

1Division of Rheumatology, 2Division of Neurology, Department of Medicine, 3Department of Diagnostic Imaging and 4Department of Psychological Medicine, National University Hospital, National University of Singapore, Singapore.

Correspondence to: A. Mak, Assistant Professor of Medicine, Division of Rheumatology, Department of Medicine, National University Hospital, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074. E-mail: mdcam{at}nus.edu.sg


   Abstract
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 Abstract
Introduction
 Method
 Results
 Conclusion
 References
 
Reversible posterior leucoencephalopathy syndrome (RPLS) has been increasingly recognized and reported in the literature. While the condition has been well described in patients with acute hypertension, pre-eclampsia, eclampsia, post-transplantation and chemotherapy, RPLS has been increasingly identified in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Though experience in the diagnosis and management of RPLS in patients with SLE is likely accumulating, few have systematically worked out the strategy to distinguish RPLS from neuropsychiatric SLE (NPSLE) and lupus-related complications of the central nervous system (CNS). Prompt recognition of, and differentiation between, these conditions is essential since their clinical presentations substantially overlap and yet their management strategy and subsequent outcomes can be entirely different. Indeed, inappropriate treatment such as augmentation of immunosuppression may be detrimental to patients with RPLS. A high index of suspicion of RPLS, prompt magnetic resonance imaging of the brain, including diffusion imaging, exclusion of CNS infection and metabolic derangement, a comprehensive medication review accompanied by timely and aggressive control of blood pressure and seizure are keys to successful management of RPLS. Such treatment strategy ensures a very high chance of total neurological recovery in lupus patients with RPLS.

KEY WORDS: Reversible posterior leucoencephalopathy syndrome, Systemic lupus erythematosus, Neurological, Differentiation, Treatment strategy


   Introduction
Top
 Abstract
 Introduction
Method
 Results
 Conclusion
 References
 
With the advent of modern neuroimaging techniques and heightened awareness amongst physicians, reversible posterior leucoencephalopathy syndrome (RPLS), a clinico-radiological syndrome characterized by a rapid onset of headache, seizure, hypertension, altered mental status, bilateral cortical blindness and recognizable radiological features, has been increasingly identified over the past decade since the condition was first described in 1996 [1]. While the majority of RPLS cases reported were related to conditions such as pre-eclampsia, eclampsia, hypertensive crises, thrombotic thrombocytopenic purpura (TTP), post-chemotherapy and solid-organ transplantation [1–8], RPLS is often recognized in patients with autoimmune conditions such as systemic lupus erythematosus (SLE) and systemic vasculitides [9–12].

SLE is an autoimmune disease characterized by its protean clinical manifestation and multi-system involvements [13]. One of the major manifestations, neuropsychiatric SLE (NPSLE), substantially overlaps with the clinical presentation and course of RPLS. The profound similarities of the clinical manifestations between RPLS, NPSLE and lupus-related complications of the central nervous system (CNS), such as CNS infection and psychiatric conditions, often pose major diagnostic and therapeutic challenges to attending clinicians. Physicians should be well equipped to tackle the challenges for three reasons. First, RPLS is virtually reversible with appropriate supportive measures. Second, early recognition of RPLS avoids unnecessary investigations and augmentation of immunosuppression, which may otherwise further aggravate RPLS. Third, accumulation of clinical and neuroradiological experience in studying RPLS expands our knowledge in the pathogenesis, clinical behaviour and management of the condition.

Despite being a condition with a well-described constellation of symptoms, the exact pathophysiological mechanism of RPLS remains unclear. While the majority of knowledge of RPLS stems from case reports or small case series [1–12], the existing literature scarcely discusses the strategies to differentiate between RPLS, NPSLE and lupus-related complications of the CNS. This review attempts to, on top of comprehensively reviewing the pathophysiology of RPLS, work out the strategies to differentiate and manage the aforementioned conditions from aetiopathological and radiological perspectives, based on the current literature of RPLS.


   Method
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 Abstract
 Introduction
 Method
Results
 Conclusion
 References
 
An intensive search of all medical literature published in the English language from 1966 to January 2007 using MEDLINE and PUBMED was performed with the use of the following keywords: ‘reversible posterior leucoencephalopathy’, ‘posterior reversible leucoencephalopathy’, ‘reversible posterior leukoencephalopathy’, ‘posterior reversible leukoencephalopathy’, ‘posterior reversible encephalopathy syndrome’, ‘lupus’ and ‘systemic lupus erythematosus’. The relevant publications were critically evaluated and data were collected, where available and applicable, for simple descriptive analyses.


   Results
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 Introduction
 Method
 Results
Conclusion
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One hundred and twenty-three case reports and series were retrieved and intensively reviewed. In total, around 170 cases of RPLS have been reported since 1996. Amongst these were 17 patients with pre-existing SLE who had adequate clinical information provided. Table 1 summarizes the demographic features, clinical characteristics, radiological features and outcomes of these lupus patients with RPLS.


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  		TABLE 1. Clinical features of 17 lupus patients with RPLS reported in the literature

 
Literature review
RPLS was first described by Hinchey and co-workers [1] in 1996. They published a series of 15 patients who presented with a completely reversible syndrome of headache, altered mental functioning, seizure, loss of vision and renal decompensation associated with characteristic neuroimaging findings [1]. Among the 15 patients described, 13 (86.7%) were women and the mean age of presentation was 39.5 yrs. Two of the 15 patients were lupus patients with hypertensive encephalopathy. Eight had prior immunosuppressive therapies for aplastic anaemia and liver transplantation, one patient had hypertensive crisis secondary to acute nephritis, one with hepatorenal syndrome and the rest of the three were patients with puerperal eclampsia. Computed tomography (CT) and structural magnetic resonance imaging (MRI) of the brain mainly demonstrated invariably reversible and often symmetrical white matter abnormalities distributed mainly in the posterior regions of the cerebral hemispheres. In total, 54 brain regions were affected in these 15 patients comprising: both occipital lobes 24.1% (13/54), both parietal lobes 14.8% (8/54), left temporal lobe and left frontal lobe each 7.4% (4/54), right temporal and both frontal lobes each 5.6% (3/54) and the rest of the brain, namely the cerebellar hemispheres, right caudate, pons, left occipital lobe, right thalamus, right frontal, left internal capsule, central white matter, left parietal lobe and centrum semiovale, each 1.9% (1/54). Taken together, 57% of the regions involved were those supplied by the posterior circulation. While all patients had posterior brain region involvement, an exception occurred in a post liver-transplant patient on tacrolimus. Her brain MRI showed right frontal lobe, left internal capsule and bilateral central white matter involvement, which was not a characteristic neuroimaging feature of RPLS [1]. Nevertheless, as with the rest of the 14 patients, her neurological deficits fully resolved within 2 weeks following appropriate supportive management and withdrawal of the offending cytotoxic agent [1]. Because of the invariably rapid clinical and radiological improvement, Hinchey and co-workers [1] initiated the postulation that the white matter changes were most likely related to transient cerebral oedema rather than infarction.

Following Hinchey's case series, more than 120 case reports and series have been published over the last decade describing the occurrence of RPLS in patients with a wide range of clinical conditions. Similar to Hinchey et al. [1], the majority of RPLS cases reported were related to hypertensive encephalopathy, pre-eclampsia, eclampsia, post solid-organ transplantation, bone marrow transplantation and cytotoxic chemotherapies for solid and haematological malignancies [2–10]. Interestingly, several RPLS cases have also been reported in unusual clinical contexts. For example, a few cases of RPLS were reported following angiography and cardiac catheterization involving the use of i.v. contrast [14, 15]. Though the underlying mechanisms for angiography-induced RPLS remains speculative, it was postulated that radiocontrast damages the endothelium, which results in disruption of the blood–brain barrier, fluid transudation and subsequent vasogenic brain oedema. It is believed that radiocontrast-induced RPLS is related to endothelin, a peptide synthesized in the endothelium capable of increasing human brain endothelial cell permeability by opening up the tight capillary junction or enhancing endothelial pinocytosis [16]. Upon administration of radiocontrast, endothelin was demonstrated to be elevated in humans [17]. In addition to the effect of endothelin, radiocontrast can also cause direct neurotoxicity that further aggravates cerebral oedema [18, 19]. Besides radiocontrast-induced RPLS, RPLS was also described in patients following left ventricular assist device (LVAD) implantation [20], neurosurgery [21] and measles vaccination [22]. Despite the varied aetiologies and unknown mechanism, subsequent full neurological recovery occurred in all of these rare RPLS cases.

Reversible posterior leucoencephalopathy in SLE
An increasing number of cases of RPLS associated with autoimmune diseases such as SLE have been reported during the past decade [1, 12, 23–31]. At the time of writing, 17 lupus patients with RPLS with adequate clinical information were described in the literature (Table 1). Of the 17 lupus patients reported, 16 (94.1%) were women. The mean age of the patients when they presented with RPLS was 29.8 yrs. All had SLE diagnosed prior to presenting with RPLS. These patients are younger (29.8 vs 40.2 yrs) and with a higher female preponderance (94.1 vs 84.6%) compared with the non-lupus patients reported by Hinchey et al. [1]. These discrepancies are largely due to the disease characteristics intrinsic to SLE. Clinical presentation of RPLS in patients with lupus, on the other hand, is very reminiscent of those reported in the non-SLE populations. At the onset of RPLS, 100% (17/17) of patients presented with seizures, 94.1% (16/17) presented with hypertension, 88.2% (15/17) had acute renal failure, 70.6% (12/17) presented with headache, 47.1% (8/17) had blurring of vision and 29.4% (5/17) presented with bilateral cortical blindness. The mean systolic and diastolic blood pressures on presentation of RPLS were 187.6 and 113.5 mmHg, respectively, while the mean serum creatinine level was 329.7 µmol/l. Acute delirium, vomiting, hemiparesis and vertigo were manifested, respectively, in 17.6, 11.8, 11.8 and 5.9% of the lupus patients with RPLS. Out of 17, 13 (76.5%) of them had recent initiation or augmentation of immunosuppressants before RPLS and the mean duration between initiation or augmentation of immunosuppression and appearance of RPLS was 6.9 days. The major immunosuppressants recently instituted or augmented were i.v. methylprednisolone (8/17 patients), i.v. cyclophosphamide (6/17 patients) and cyclosporin (2/17 patients).

In addition to the clinical presentation and course, the radiological features amongst lupus patients with RPLS were also very similar to those without SLE. Of the total of 51 brain regions involved in these 17 lupus patients, 58.8% of the neuroimaging abnormalities were found in the posterior circulation, very close to the proportion reported in non-lupus patients by Hinchey et al. (61%). The clinical course was also highly favourable and full neurological recovery occurred in all patients upon cessation of the offending immunosuppressive agents, prompt blood pressure and seizure control, and temporary renal replacement therapy. The mean duration leading to full neurological recovery of RPLS after presentation was 7.2 days. Depending on the time when neuroimaging was repeated following full neurological recovery, the average duration of radiological improvement or recovery was 24.5 days (range 14–45 days). Table 2 summarizes the comparisons of demographic, clinical and radiological characteristics of patients with lupus-related and non-lupus-related RPLS.


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  		TABLE 2. Comparisons of demographics, clinical and radiological features between patients with lupus-related and non-lupus-related RPLS

 
As yet, there are no clinical reports or laboratory studies published, which demonstrate the direct effect of lupus on cerebral endothelial damage, and most RPLS cases were associated with secondary conditions. Therefore, it is generally believed that RPLS in patients with lupus is essentially a secondary complication of SLE rather than a direct effect of lupus itself [12].

Radiological features of RPLS
Neuroimaging is the major diagnostic tool for RPLS. The cardinal radiological features of RPLS are bilateral, often somewhat asymmetrically distributed vasogenic oedema involving the white matter in the posterior regions of the cerebral hemispheres, with anatomical predilection for the parieto-occipital regions [1, 38–42]. These lesions are reversible following treatment of the underlying cause [1]. While areas of low attenuation in the posterior cerebral hemispheres can be seen in CT brain scans, MRI of the brain remains the favoured modality of choice for diagnosing RPLS [42, 43]. The recognizable MRI features of RPLS are diffuse hyperintensities on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images in the white matter in the posterior areas of the cerebral hemispheres, which spare the calcarine and paramedian occipital lobe structures and are reversible (Fig. 1) [1]. These essential features help to distinguish RPLS from bilateral posterior cerebral artery (PCA) territory infarcts, which do not spare these structures and are not reversible [1]. Moreover, in patients with embolism to the caudal basilar artery, the resultant bilateral PCA territory infarction is often accompanied by thalamic and mid-brain infarcts [1]. Though the subcortical and deep white matter of the PCA-supplied regions of the brain are usually affected in RPLS, involvement of the brainstem, cerebellum, basal ganglia, frontal and temporal lobes and the cortex has also been reported in up to 56% in patients with clinical features of RPLS [1, 44–46]. Nonetheless, the majority of patients with RPLS who presented with these ‘atypical’ neuroimaging features showed full clinical and radiological recovery following prompt identification and treatment, similar to patients with classical neuroimaging findings in the PCA-supplied areas [1, 38–42].


Figure 1
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  		FIG. 1. MRI of a lupus patient who presented with cortical blindness and hypertension. The initial T2-weighted image (top left) shows slightly asymmetric abnormal high T2 signal in the subcortical white matter and cortex of both posterior temporal and occipital lobes. The corresponding MR image obtained 1 week later (top right) shows near-complete resolution of the abnormalities except for mild residual T2 signal hyperintensity in the left occipital subcortical white matter. The DW image from the first study (bottom left) does not demonstrate significantly restricted diffusion in the affected areas, which is confirmed on the ADC map (bottom right), indicating vasogenic oedema.

 
Diffusion-weighted (DW) MRI can further aid in distinguishing vasogenic oedema in RPLS from the cytotoxic oedema associated with early infarcts [40–43]. At typical b-values of 1000 s/mm2, vasogenic oedema in the white matter from RPLS usually has an isointense appearance on isotropic DW images due to the net result of the opposing effects of T2 signal prolongation and restricted diffusion [42, 43, 47]. The apparent diffusion coefficient (ADC) map derived from DW images provides further assistance to distinguish between cytotoxic and vasogenic oedema [42, 43, 48]. The ADC is elevated in vasogenic oedema in RPLS while it is depressed in regions of cytotoxic oedema in infarcted areas. RPLS lesions that are hyperintense on DW MRI and have low ADC values indicate that underlying acute infarction has occurred and these are not reversible [42]. Regions of restricted diffusion in the setting of RPLS have been noted previously, but only when imaging was performed during or immediately after seizures, and the lesions were reversible, suggesting that the lesions were related to seizures and not ischaemia [49]. These characteristic findings further underscore the pivotal role of vasogenic oedema, rather than infarction, in the pathogenesis of RPLS [40–42].

Additional MRI findings include patchy areas of enhancement and small foci of acute haemorrhage in affected areas on contrast-enhanced scans in RPLS patients [1, 39, 42, 44], although these findings are inconstant and are not specific. Angiographic imaging with MR angiography has also revealed reversible vasospasm of the medium and large intracranial vessels in several RPLS patients [50, 51], but again, this finding is not constant.

Newer neuroimaging techniques such as proton magnetic resonance spectroscopic (MRS) imaging [32, 36, 40, 52, 53] and diffusion tensor imaging (DTI) [39] have shown promise in improving the diagnosis and monitoring of RPLS, although their use has yet to be validated with larger studies. While the usefulness of these newer imaging techniques for the diagnosis and subsequent monitoring of RPLS deserves further study, conventional MRI of the brain with isotropic DW imaging remains the gold standard in the current diagnosis of RPLS in view of its lower cost and wider availability.

Mechanisms of disease
The pathophysiological process of RPLS remains incompletely understood, yet it shares a few common pathophysiological processes with hypertensive encephalopathy [38]. To date, three hypotheses have been proposed, which include: (i) cerebral vasoconstriction with subsequent infarcts of the brain, (ii) failure of cerebral autoregulation with consequent vasogenic oedema, and (iii) endothelial damage with disruption of the blood–brain barrier causing fluid and protein transudation in the brain. Nevertheless, a number of experimental studies, neuroimaging and even post-mortem examinations favour the latter two hypotheses. As early as in the 1950s, an experiment performed by Byrom [54] demonstrated that a sudden increase in arterial blood pressure in rats caused transient cerebral oedema in the posterior part of their brains due to functional vascular changes. The oedema entirely reversed after normalization of blood pressure [54]. In response to sudden elevations in mean arterial pressure (MAP), the vasculature of the brain autoregulates to maintain a constant cerebral perfusion pressure (CPP). This autoregulation is principally achieved by compensatory cerebral vasoconstriction mediated by the sympathetic nervous system. Owing to the relative paucity of sympathetic innervation in the vertebrobasilar vasculature compared with that of the internal carotid artery system, a rapid elevation of MAP that overwhelms the autoregulatory capacity of the cerebral vasculature can result in dilatation of the arterioles [1, 38]. Such arteriolar dilatation, along with possible additive endothelial injury from uraemia and cytotoxic agents, subsequently gives rise to extravasation of plasma, cells and protein and causes posterior cerebral oedema [1, 23, 38]. While oedematous change in the grey matter has been reported [1, 24, 39], predilection for white matter involvement may be related to the fact that the cerebral white matter is structurally less tightly packed and organized than the cerebral cortex [39].

The encouraging and characteristic neuroimaging findings using techniques such as DW imaging, MRS imaging and DTI implicate the possible underlying pathophysiological mechanisms of RPLS [39, 40]. As discussed in the previous section, the neuroimaging features in classic RPLS suggest transient increase in water content predominantly in the posterior areas of the brain, and these observations support the hypothesis that vasogenic oedema secondary to cerebrovascular autoregulatory dysfunction and endothelial damage are the most likely underlying pathophysiological mechanisms of RPLS [38–45].

Besides cerebral autoregulatory failure, a number of other conditions can contribute to endothelial damage with subsequent blood–brain barrier disruption. For example, it is evident that immunosuppressants such as cyclosporin and tacrolimus can lead to RPLS via alternative pathways without inducing significant hypertension [24, 55]. Apart from calcineurin inhibitors, other frequently reported agents that lead to RPLS include cisplatin, i.v. immunoglobulins and cytarabine [56–58]. Less commonly used agents, such as L-aparaginase for treating acute lymphoblastic leucaemia [59], and bevacizumab monoclonal antibody for treating colonic carcinoma, were also described [60]. While the exact pathophysiology of chemotherapy-induced RPLS remains unknown, one of the most widely accepted theories is direct endothelial toxicity due to chemotherapy-mediated release of endothelin and thromboxane from endothelial cells [1, 33]. Withdrawal of the offending chemotherapeutic agents invariably leads to resolution of RPLS and some patients can tolerate chemotherapy rechallenges [1, 34].

Though the majority of RPLS cases are clinically and radiologically reversible, this may not always be the case. A few case reports described patients with RPLS who were left with evidence of residual clinical and radiological damage [35, 37]. In patients with RPLS where their seizures and hypertension are not properly managed, irreversible lesions can result from progression from vasogenic to cytotoxic oedema, indicating transformation into intracerebral haemorrhages and infarcts, which ultimately leave permanent neurological damage.

Differentiation between RPLS, NPSLE and CNS complications of SLE—a suggested strategy
It is often hard to differentiate, especially at the initial stage, between RPLS, NPSLE and CNS complications secondary to lupus because the clinical presentation and disease course substantially overlap between these conditions. Nevertheless, neuroimaging can offer timely diagnosis of RPLS and thus allow attending physicians to institute prompt and appropriate treatment.

While neuroimaging is indispensable in the diagnosis and subsequent management of patients with RPLS, a high index of clinical suspicion is mandatory in differentiating RPLS from other CNS manifestations and complications of SLE because subsequent treatment strategy and prognosis can be entirely different between these conditions. Especially in clinical settings where neuroimaging facilities are not immediately available, timely recognition of the classical symptoms of RPLS with special attention to recent institution or augmentation of immunosuppressive medications substantially raises the suspicion of RPLS in lupus patients presenting with RPLS-like neurological symptoms. Hence, a carefully taken history with enquiries about headache of recent onset, seizures, visual disturbance and recent alterations of medications and a thorough physical examination including checking for neck rigidity, pupillary size and reflexes, visual acuity and field defects, focal neurological deficit and mental state examination are always the foundation in addition to urgent neuroimaging in the identification of RPLS. At the same time, timely and careful exclusion of infection, metabolic dysfunction, drug toxicities and impaired renal function, respectively, with full sepsis workup, metabolic, drug and electrolytes screen are essential before narrowing the diagnostic possibilities to NPSLE and lupus-related RPLS. MRI brain with findings characteristic of RPLS after judicious exclusion of other pathologies leads to the correct diagnosis of RPLS.

In an attempt to exclude CNS pathologies such as CNS infection, lumbar puncture and analysis of cerebrospinal fluid (CSF) are indispensable. However, the role CSF analysis in RPLS is an enigma since CSF data in RPLS are very limited. While some authors reported normal CSF findings in patients with RPLS [28, 61], a few reported slightly elevated total protein and red blood cells [1, 7, 23]. Nevertheless, lumbar puncture and CSF analysis are still warranted to rule out other CNS conditions such as infection, demyelination, cerebral vasculitis or subarachnoid haemorrhage, if these differential diagnoses are clinically suspected, even in the context of RPLS.

For lupus patients presenting with neuropsychiatric symptoms without peculiarly abnormal focal neurological signs, blood screening, CSF analysis and neuroimaging findings, the diagnosis of NPSLE is apparent and immunosuppressive therapy should be instituted or augmented, coupled with appropriate auxiliary treatment such as anti-epileptics or anti-psychotics. In patients who have active lupus with recent institution or augmentation of corticosteroids, the possibility of corticosteroid-induced psychosis should be considered especially if the corticosteroid dose is high [61]. To distinguish between NPSLE and corticosteroid-induced psychosis, reduction in corticosteroid dose with vigilant monitoring of neuropsychiatric symptoms and lupus activity is often helpful [61].

Apart from various CNS pathologies and metabolic derangements, it is always prudent to consider the diagnosis of TTP in lupus patients who present with neurological symptoms, acute renal failure and pyrexia. In fact, TTP has been reported in patients with RPLS [5]. Nonetheless, recognition of the characteristic clinical and neuroradiological patterns with the use of MR and DW imaging accompanied by the absence of microangiopathic haemolytic anaemia helps narrow the differential diagnosis down to RPLS. A suggested algorithm in the management of patients with SLE who present with RPLS-like neurological symptoms is shown in Fig. 2.


Figure 2
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  		FIG. 2. Algorithm of diagnosing RPLS. aBilateral occipital, temporal and parietal T2 and FLAIR hyperintense signal with sparing of calcarine and paramedian occipital lobe structures. DW imaging demonstrates lack of restricted diffusion with increased ADC values due to vasogenic oedema. bCNS infection, CNS vasculitides, stroke, drug intoxication, metabolic dysfunction, neuropsychiatric lupus. RPLS: reversible posterior leucoencephalopathy; CSA: cyclosporin.

 
Treatment of RPLS in lupus
As lupus-related RPLS is unlikely to be due to an autoimmune process, institution or augmentation of immunosuppressive therapy attempting to suppress neuropsychiatric symptoms secondary to RPLS is not recommended. In fact, this is not desirable because inappropriate escalation of immunosuppression may aggravate and perpetuate RPLS, leading to permanent neurological damage. Therefore, management of lupus-related RPLS should follow the same strategy as that for non-lupus patients. As already alluded to the treatment strategy of RPLS in non-lupus patients, the key to effective management includes removal of precipitating factors of RPLS, prompt control of blood pressure, timely abolition of seizures and temporary renal support. Patients with lupus-related RPLS should have their MAP reduced by 10–25% or the diastolic blood pressure below 100 mmHg within the first 2 h. Too rapid a reduction in blood pressure is not encouraged since it precipitates end-organ damage such as cerebral infarction, acute myocardial infarction and renal shutdown. Specific to SLE, the choice of anti-hypertensive agents for patients with lupus-related RPLS should be cautious since a number of existing anti-hypertensive drugs are not suitable for patients with SLE. For example, though commonly used in pre-eclampsia and eclampsia, the use of hydralazine or methyldopa is generally discouraged in patients with SLE due to the possibility of drug-induced lupus. Intravenous anti-hypertensive agents such as nitroprusside and labetalol (with both {alpha}- and β-blockade activity) are preferred and they are best given in intensive care units where close haemodynamic monitoring are readily available. With regard to the treatment of RPLS-related seizures in patients with SLE, long-term anticonvulsant use is seldom indicated because seizures usually stop after resolution of neuroimaging abnormalities. Based on anecdotal experience, the use of phenytoin or carbamazepine may cause drug-induced lupus and complicate the clinical picture of patients’ existing lupus. They should therefore be best avoided in lupus patients if other alternatives are available [62, 63].

In general, immunosuppressive agents should be withheld or reduced in lupus patients with RPLS if the condition is not accompanied by active lupus. However, for patients with concomitant active lupus with major organ involvement such as diffuse proliferative glomerulonephritis (DPGN), overt haemolytic anaemia and acute pulmonary haemorrhage, augmentation of immunosuppression is still strongly warranted so as to reduce lupus-related organ damage and subsequent functional decline and death [64]. Of particular concern is acute nephritic syndrome secondary to DPGN. Acute renal impairment and hypertensive encephalopathy resulted from DPGN are clinically very reminiscent of the manifestations of RPLS. Nevertheless, in the presence of active urinary sediments, low serum complement levels, high anti-dsDNA titre with circumferential evidence of active lupus, prompt immunosuppressive therapies with i.v. corticosteroids and cyclophosphamide or oral mycophenolate mofetil are absolutely warranted even in the context of RPLS because delayed immunosuppressive institution in patients with active lupus can lead to poor outcome [65]. In this situation, special attention to the development of symptoms of RPLS in conjunction with judicious monitoring and prompt control of cardiovascular, renal and neurological parameters are of utmost importance. In lupus patients who present with altered neurological state, fever, microangiopathic haemolytic anaemia and renal impairment, TTP should be suspected and plasmapheresis should be seriously considered.

Similar to RPLS in non-lupus patients, lupus patients with RPLS should demonstrate neurological improvement between 1 and 2 weeks following effective treatment. Complete or partial radiological resolution should accompany clinical improvement. Follow-up MRI brain is hence necessary for patients with lupus-related RPLS since resolution of radiological abnormalities help ascertain the clinical diagnosis of RPLS and confirm the absence of residual structural and functional brain damage. In patients whose neurological symptoms do not improve or deteriorate, repeated structural and functional brain scans are even more important in order to discern the presence of active lesions and/or permanent damage. Failure to achieve clinical and radiological improvement in patients tentatively diagnosed with RPLS alerts attending physicians to reconsider the diagnosis and assess possible structural and functional insults to the brain. If no alternative diagnosis apart from RPLS can be made, especially in those patients whose supportive management for RPLS are insufficient, permanent neurological damage may have set in and the prognosis is often worse. As in patients with stroke, patients with lupus-related RPLS complicated by permanent neurological damage should be jointly assessed by neurologists and rehabilitation physicians for devising individualized management plans that aim at preserving functional activities and quality of life. Meanwhile, if clinically justified, rheumatologists should promptly identify and control any lupus activity and unfavourable cardiovascular risk factors for the sake of preventing further damage, halting functional decline and improving survival.


   Conclusion
Top
 Abstract
 Introduction
 Method
 Results
 Conclusion
References
 
RPLS is being increasingly recognized in patients with SLE. It is mainly due to heightened awareness of the condition accompanied by the advent of modern neuroimaging techniques. With strong clinical suspicion of RPLS, followed by appropriate neuroimaging and timely laboratory investigations, it is not difficult to identify RPLS in patients with SLE. In contrast to lupus-related CNS changes, RPLS necessitates decrement in immunosuppressants and prompt blood pressure and seizure control in order to achieve full neurological recovery. If not properly managed, patients with RPLS may progress to permanent cerebral infarcts, neurological damage, functional decline and even death [35]. In some situations when lupus activity is high, the benefits of immunosuppressant augmentation outweigh the risks of perpetuation of RPLS. Augmentation of immunosuppressants is warranted in these cases while vigilant monitoring of blood pressure, neuropsychiatric status, vision and renal function is necessary to prevent initiation and perpetuation of RPLS.

Formula

Disclosure statement: The authors have declared no conflicts of interest.


   References
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 Abstract
 Introduction
 Method
 Results
 Conclusion
 References
 

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Submitted 10 August 2007; revised version accepted 31 October 2007.
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