Department of Pathophysiology, School of Medicine, National University of Athens and 1 Department of Nephrology, Laikon General Hospital, Athens, Greece
Correspondence to: M. Voulgarelis, Department of Pathophysiology, Medical School, University of Athens, 75, M. Asias St., 115 27, Athens, Greece. E-mail: mvoulgar{at}med.uoa.gr
SIR, PV, a 38-yr-old patient with a 13-yr history of SLE, was admitted to our hospital because of occipital headache, blurring of vision and seizures after treatment with the second weekly course of intravenous infusion with rituximab (monoclonal antibody against CD20) for recurrence of renal disease. A similar episode had occurred after the first infusion, which was uneventfully resolved 24 h later.
The patient was diagnosed with SLE in 1995. For 6 yr she had had a mild disease, expressed mainly as skin rashes and arthralgias. In February 2001 she presented with nephrotic syndrome, active urinary sediment and pancytopenia. Immunology testing revealed high anti-DNA and low complement levels, while a bone marrow biopsy was consistent with peripheral destruction. Renal biopsy revealed the presence of diffuse proliferative glomerulonephritis (WHO IV). The patient was placed on intravenous pulses of cyclophosphamide, and responded efficiently with resolution of proteinuria and haematuria and complete haematological recovery.
In December 2001 a small brain infarct was detected on MRI scan after an episode of diplopia and blurring of vision. Anticardiolipin antibodies of the immunoglobulin G type were increased and oral anticoagulation therapy with a therapeutic international normalized rescue (INR) ranging from 2.5 to 3.0 was instituted.
In June 2003, while on quarterly intravenous infusions with cyclophosphamide, a recurrence of renal disease had occurred and weekly infusions with rituximab were started (375 mg/m2), without prior steroid prophylaxis.
On her current admission, one day after the second rituximab infusion, blood pressure was 210120 mmHg. An S3 gallop was present. Funduscopic examination revealed chronic hypertensive changes without evidence of papilloedema. No focal neurological signs were present. Laboratory evaluation revealed the presence of thrombotic microangiopathy. Renal function was deteriorating and soon anuria developed, requiring haemodialysis. Increased levels of anti-DNA antibodies and low levels of complement were present, consistent with increased lupus activity.
Six days later, a third scheduled infusion with rituximab was given. Six hours after the medication was administered, headache, severe hypertension, blurring of vision and seizures developed. An MRI scan revealed the presence of high-intensity signal in the cortical and subcortical white matter of the parietal lobes and the lateral posterior and lateral portions of the temporal lobes, consistent with the radiological findings of reversible posterior leucoencephalopathy syndrome (RPLS) (Fig. 1) [1].
|
Therefore, we present a case of RPLS in a patient with SLE and secondary antiphospholipid syndrome, after rituximab therapy.
RPLS, first recognized in 1996, is characterized by the presence of reversible white matter oedema involving predominantly the posterior part of the cerebral hemispheres. Clinically, it presents with headache, blurring of vision and seizures and commonly occurs in cases of acute hypertension in the context of fluid overload, renal insufficiency and treatment with immunosuppressive drugs [1, 2]. Although not well understood, it seems that a focal disruption of the bloodbrain barrier causes the shifting of fluid from the intravascular compartment and the white matter oedema [3].
Our patient presented with typical clinicoradiological findings of RPLS. Known causes of RPLS, such as uraemia, fluid overload and hypertension, were present. However, what was impressive was the temporal correlation of the above symptoms with the administration of rituximab. On all three occasions, 68 h after the infusion of rituximab, a constellation of symptoms typical of RPLS appeared, which subsided approximately 24 h later. Interestingly, 45 days later all MRI abnormalities had completely abated.
Rituximab is a monoclonal antibody against CD20, initially used in the treatment of lymphoproliferative disorders and recently in refractory lupus cases [4, 5]. Although central nervous system complications have not yet been reported, hypertensive crisis occasionally occurs, which could be a possible explanation for the precipitation of RPLS in this patient [6]. On the other hand, it is known that activated endothelial cells, possibly in an active lupus environment, express CD20 antigen. Therefore, one could speculate that there is another putative mechanism of rituximab-induced endothelial activation through CD20 binding [7].
Finally, it seems possible that the syndrome was precipitated by the release of cytokines into the circulation as a consequence of therapy, due to the effects of cytokines on nerve conduction, as has been described in patients with multiple sclerosis receiving Campath-1H. Such effects may be compounded by the presence of renal failure [8].
Although the occurrence of RPLS in patients with SLE has been described [9, 10, 11, 12], this is the first case of RPLS reported in the literature to occur after the infusion of rituximab on a hypertensive, uraemic background in a patient with SLE. Practising clinicians should be aware of such a complication, which is, fortunately, completely reversible after discontinuation of the offending medication and correction of hypertension and renal dysfunction.
We are indebted to Professor H. M. Moutsopoulos for his continuous inspiration, guidance and support.
The authors have declared no conflicts of interest.
References