NDT Advance Access originally published online on October 30, 2007
Nephrology Dialysis Transplantation 2008 23(1):417-419; doi:10.1093/ndt/gfm594
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Posterior reversible encephalopathy induced by intravenous immunoglobulin
Email: f.bridoux{at}chu-poitiers.fr
Sir,
Intravenous immunoglobulin (IvIg) is commonly used in nephrology units for the treatment of auto-immune diseases, antibody-mediated renal allograft rejection and immune deficiencies. Minor adverse effects, such as myalgia, headache, shiver, nausea, vomiting or fever occur in <20% of patients. Major reactions including renal failure, thromboembolism, aseptic meningitis and anaphylaxis are less common. Whereas osmotic nephropathy resulting from maltose and saccharose toxicity is well-known to nephrologists, posterior reversible encephalopathy syndrome (PRES) is a rare and potentially severe adverse event of IvIg therapy.
A 42-year-old man was admitted for end-stage renal failure secondary to myeloma cast nephropathy in the context of plasma cell leukaemia, diagnosed 2 months previously. His past medical history was otherwise unremarkable. Haematological tests showed increased white blood cells (12380/mm3) with 27% of circulating plasma cells. Immunoelectrophoresis revealed a serum monoclonal IgG-
with a urine- Bence–Jones protein and serum levels of -free light chains of 9760 mg/l. Gammaglobulin level was 13 g/l. Bone marrow smears and biopsy demonstrated massive plasma cell infiltration (67%). X-ray examination revealed diffuse osteolytic bone lesions. Serum creatinine was 450 µmol/l with severe hyperkalaemia requiring periodic haemodialysis. Vincristine, adriamycin and dexamathazone therapy was initiated. One month after the first course of chemotherapy, circulating plasma cells were no longer detected, while bone marrow plasmacytosis (10%) and serum-free -light chain levels (1,220 mg/l) had decreased. Because of persistent hypogammaglobulinaemia (5 g/l), 0.5 g/kg of IvIg (Octagam ®, Octapharma SAS, France) was slowly administered. IvIg infusion was stopped after 2 h, as the patient developed headache, nausea, fever (38°C), visual loss with horizontal nystagmus and hypertension (170/80 mmHg). Four hours later, confusion and generalized seizures occurred, which required intravenous clonazepam and phenytoin and assisted ventilation. A plasmapheresis session with serum albumin was performed. After 24 h, complete resolution of neurological symptoms was achieved.
At the onset of neurological symptoms, laboratory data showed: glucose 1 g/l, sodium 140 mmol/l, potassium 3.5 mmol/l, serum creatinine 450 µmol/l, total protein 66 g/l, albumin 28 g/l, calcium 2.2 mmol/l, phosphorus 1.53 mmol/l, CRP 7 mg/l, white blood cell 14 500/mm3, haemoglobin 9.7 g/dl, haematocrit 30% and platelet 379 000/mm3. Fundoscopic examination was normal. Brain MRI revealed increased signal in the white matter of left parieto-occipital lobe on T2 weighted sequences. Unfortunately, lumbar puncture and plasma viscosity was not performed. One month later, neurological examination and brain MRI were normal.
PRES, initially described by Hinchey et al. in 1996 [1], is defined by the association of neurological signs (headache, vomiting, visual disturbance, confusion and seizures) and radiological abnormalities of occipital white matter, usually bilateral, characterized by cerebral oedema with hypodense signals on CT scan and hyperintense signals on T2 weighted images by MRI. Electroencephographic examination shows non-specific slow wave activity, while lumbar puncture reveals raised protein concentration with mononuclear pleocytosis [2,3]. The most commonly reported causes of PRES are immunosuppressive drugs (cyclosporin A and tacrolimus), interferon-
, malignant hypertension with encephalopathy and eclampsia. By definition, clinical neurological and radiological signs are reversible after resolution of the underlying cause.
Neurological complications of IvIg therapy include mainly aseptic meningitis, cerebral infarction and PRES [2]. In our case, the presence of suggestive neurological signs with unilateral parieto-occipital changes on MRI, strongly suggested the diagnosis of PRES. IvIg was first implicated as a cause of PRES in 1996 [4]. Since then, four additional cases have been reported [2,3,5,6], two of them with unilateral occipital white matter changes on MRI [3,5]. Although a latency of 3 [4] to 4 [5] days between IvIg infusion and onset of PRES has been reported, neurological signs may appear in the first hours of treatment, as in our case [2,3]. Complete recovery of neurological symptoms occurs within 2 days [2,3,5] to several weeks [1,6]. Little is known about the pathophysiology of IvIg-induced PRES. A role for hypertensive encephalopathy is unlikely in our case. Vasogenic oedema, cerebral vasospasm and serum hyperviscosity [2,4] have been proposed as probable mechanisms of PRES. Unfortunately, in previous and present cases, plasma viscosity was not measured. In our patient, although hyperviscosity secondary to myeloma was ruled out by evidence of low serum protein, albumin and gammaglobulin levels, we postulated that a brutal change of plasma viscosity induced by IvIg perfusion might be involved in the sudden occurrence of PRES. However, a role for cerebral vasospasm or vasogenic oedema was not excluded. Two previously reported patients were treated successfully with intravenous corticosteroids [4,5], but evidence for their use remains uncertain, as withdrawal of the offending agent may be sufficient for neurological recovery. Whether or not plasmapheresis had a beneficial effect on clinical symptoms remains also unproven in the present case.
In summary, PRES should be suspected in patients with neurological signs, especially visual disturbance after IvIg infusion and adequately confirmed by MRI. Nephrologists need to be aware of this unusual neurological complication, as early recognition may improve prognosis.
Conflict of interest statement. None declared.
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1Department of Nephrology
2Department of Radiology
Hôpital Jean Bernard
CHU Poitiers, France
Notes
See http://www.oxfordjournals.org/our_journals/ndtplus/
References
- Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med (1996) 334:494–500.
[Abstract/Free Full Text] - Mathy I, Gille M, Van Raemdonck F, Delbecq J, Depre A. Neurological complications of intravenous immunoglobulin (IVIg) therapy: an illustrative case of acute encephalopathy following IVIg therapy and a review of the literature. Acta Neurol Bel (1998) 98:347–351.
- Harkness K, Howell SJL, Davies-Jones GAB. Encephalopathy associated with intravenous immunoglobulin treatment for Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry (1996) 60:586.
[Free Full Text] - Voltz R, Rosen FV, Yousry T, Beck J, Hohlfeld R. Reversible encephalopathy with cerebral vasospasm in a Guillain-Barre syndrome patient treated with intravenous immunoglobulin. Neurology (1996) 46:250–251.
[Abstract/Free Full Text] - Nakajima M. Posterior reversible encephalopathy complicating intravenous immunoglobulins in a patient with Miller-Fisher Syndrome. Eur Neurol (2005) 54:58–60.[CrossRef][Web of Science][Medline]
- Attarian S, Trebuchon A, Azulay J-Ph, Pouget J. Encéphalite aiguë compliquant une polyradiculonévrite aiguë. Rev Neurol (2002) 158:470–472.[Web of Science][Medline]
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