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Case Reports

Posterior Reversible Encephalopathy Syndrome Following Infliximab Infusion

Zamvar, Veena*; Sugarman, Ian D; Tawfik, Rihab F; Macmullen-Price, Jeremy§; Puntis, John WL*

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Journal of Pediatric Gastroenterology and Nutrition: January 2009 - Volume 48 - Issue 1 - p 102-105
doi: 10.1097/MPG.0b013e31818aedb4
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Infliximab is a chimeric antitumour necrosis factor (TNF) monoclonal antibody with potent anti-inflammatory effects. It is highly effective in severe active and fistulating Crohn disease. The most commonly reported side effects are infections (including tuberculosis) and hypersensitivity reactions; there is a small risk of lymphoproliferative disorders. We report the case of a young boy with severe Crohn colitis who developed visual symptoms and seizures postinfliximab infusion with abnormal magnetic resonance imaging (MRI) of the brain. This showed extensive high signal abnormalities affecting cerebellar hemispheres, occipital poles, medial parietal lobes and peripheral frontal lobes, consistent with extensive posterior reversible encephalopathy syndrome (PRES). This rare “encephalopathic” process has been reported in preeclampsia, hypertensive encephalopathy, and in association with immunosuppressive agents such as cyclosporine A and tacrolimus; to our knowledge an association with infliximab has not previously been reported.


A 14-year-old boy presented with a 6-month history of central abdominal pain associated with diarrhoea (no blood or mucus) and an urgent need to defecate. On examination he appeared pale, was slightly tender in the left iliac fossa, and had a perianal fissure and skin tag; haemoglobin was 11.3 g/dL (normal range 11.5–15 g/dL), inflammatory markers were raised with platelets 411 × 109/L (normal range 150–400 × 109/L), C-reactive protein (CRP) was 19.2 mg/L (normal <10 mg/L), and plasma viscosity was 1.99 mPa · s (normal range 1.5–1.72). At colonoscopy, he was found to have extensive pan proctocolitis with large ulcers and contact bleeding, more marked in the descending colon and rectum; upper gastrointestinal endoscopy was normal. Histological examination showed active granulomatous inflammation in the colon with focal ulceration fully consistent with active Crohn disease. Treatment with prednisolone, metronidazole, and mesalazine was followed by a dramatic improvement in symptoms and he remained in remission for 1 year. On relapsing, steroid was reintroduced with some improvement in clinical condition, but with deterioration as the dose was reduced. Symptoms included retrosternal pain, vomiting, diarrhoea with occasional blood on toilet paper and severe left-sided abdominal pain with urgency, weight loss, and nighttime waking to the extent that he began missing a lot of time from school. Azathioprine was commenced (initially at a dose of 1 mg/kg) and liquid diet therapy was also instituted in an attempt to bring about remission; the exclusion diet was stopped after several days, when he developed profuse diarrhoea with blood. Inflammatory markers were mildly elevated at this time, with haemoglobin 12.4 g/dL, white cell count 7.54 × 109/L (normal range 4–11 × 109/L), platelet count 497 × 109/L, and CRP 29 mg/L. A barium meal and follow through showed no evidence of small bowel involvement. His symptoms worsened and he became increasingly unwell. Following admission to the hospital, he was commenced on intravenous fluid and hydrocortisone. Investigations revealed low serum albumin of 27 g/L (normal range 34–48 g/L), high CRP at 131 mg/L, haemoglobin of 10.8 g/dL, white cell count of 4.77 × 109/L, and platelets of 467 × 109/L. Abdominal radiograph showed no signs of obstruction or of colonic dilatation, and colonic wall thickening was readily apparent on abdominal ultrasound scan. At colonoscopy, he was found to have a deep anal fissure, marked inflammation with pseudopolyps and deep ulceration in the recto sigmoid, the descending colon was strictured, and an attempt to pass the colonoscope was abandoned. Parenteral nutrition was commenced together with bowel rest. In view of his continuing poor clinical state despite these measures infliximab therapy was discussed with the child and his parents; following informed consent for this treatment he was given a dose of 5 mg/kg. There was a clear response during the next 2 days with a reduction in diarrhoea and abdominal pain. On day 5, he complained of visual disturbance (seeing increasingly large blobs of red and white light) and of vertigo, at which time it was noted that his eyes were deviated to the right and his eyelids were flickering; his blood pressure was not elevated. Repeated episodes occurred, each lasting about 1 minute and were diagnosed as probable occipital lobe seizures by the paediatric neurologists; these short episodes were followed by several periods of generalised tonic clonic seizures lasting more than 6 minutes. Treatment with phenytoin, cefotaxime, acyclovir, and erythromycin was given to control seizures and treat any possible underlying infection. Investigations at this stage included normal urea and electrolytes, calcium, magnesium and phosphate, liver function tests, full blood count, clotting, CRP (<5 mg/L), and plasma viscosity (1.55 mPa · s). Electro encephalogram showed mild excess slow wave activity thought to be postictal. Computed tomography scan of the brain showed a focal area of hypoattenuation in the medial left parietal lobe with no evidence of any extraaxial collection, acute haemorrhage, hydrocephalus, or abnormal parenchymal enhancement. MRI of the brain revealed abnormal T2 and fluid-attenuated inversion recovery signal hyperintensities in a broadly symmetrical distribution affecting the cerebellar hemispheres, occipital poles, medial parietal lobes, and peripheral frontal lobes (Fig. 1). The signal abnormalities were predominantly subcortical, but also involved the cortex and some deep white matter. There was no enhancement following gadolinium. The findings were consistent with either extensive PRES or progressive multifocal leukoencephalopathy. On lumbar puncture cerebrospinal fluid (CSF) pressure was normal as were blood and CSF protein, glucose, lactate, and microscopy. Blood, urine, and CSF culture were negative for pathogens, including enterovirus, JC virus, varicella zoster, cytomegalovirus, Epstein-Barr virus and herpes simplex; mycoplasma immuno globulin M and cryptococcal antigens were also negative. Stool culture was negative for Clostridium difficile toxin, norovirus, Salmonella, Shigella, Escherichia coli, Campylobacter, and Cryptosporidium. Immunoglobulins were normal and autoantibodies including anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies were negative.

FIG. 1:
Axial fluid-attenuated inversion recovery MRI images of the brain at presentation. Abnormal high signal is seen in (A) right frontal and medial parietal lobes, (B) occipital lobes, and (C) within both cerebellar hemispheres.

Visual symptoms resolved after a few days and formal assessment by an ophthalmologist was reported to be normal. His bowel symptoms resolved and parenteral nutrition was discontinued after 2 weeks; following this he was discharged home on oral prednisolone and azathioprine (2.5 mg/kg). Repeat MRI performed 4 weeks later showed complete resolution of the extensive parenchymal lesions, allowing a firm diagnosis of PRES (Fig. 2). For the next 6 months his Crohn disease remained in remission with bowel movements once per day, normal stool, and no abdominal pain; he achieved a normal weight for his age, had plenty of energy, and went back to full-time schooling. Unfortunately, he experienced another major relapse, culminating in colectomy and ileostomy.

FIG. 2:
Axial fluid-attenuated inversion recovery brain images after treatment showing complete resolution of the high signal abnormalities in (A) right frontal and medial parietal lobes, (B) occipital lobes, and (C) within both cerebellar hemispheres.


Inflammatory bowel disease is a chronic, idiopathic condition in which TNF-α is thought to play a role. Infliximab, a potent anti-TNF-α monoclonal antibody, has been found to be a highly effective therapeutic agent (1). It is approved for use in patients with moderate to severe Crohn disease or fistulising Crohn disease that is unresponsive to conventional therapy. The most commonly reported side effects are the risk of developing severe infections, opportunistic infections including tuberculosis, and lymphoproliferative disorders such as non-Hodgkin lymphoma and recently reported hepatosplenic T cell lymphoma; with increasing use further side effects are likely to be encountered (2–4). Neurological complications (demyelinating polyneuropthy), although rare, have also been reported (5). Our patient developed occipital lobe seizures followed by generalised tonic clonic seizures 5 days after his first dose of infliximab. In view of his immunosupression the possibility of infection was considered and he was treated with antibiotics; subsequently no evidence for bacterial or viral infection was found. His clinical course, findings on neuroimaging, and subsequent complete recovery are fully consistent with the diagnosis of PRES.

PRES is a clinical syndrome of insidious onset of headache, confusion, or decreased level of consciousness, visual changes, and seizures with characteristic findings on neuroimaging of posterior cerebral white matter edema (6). Occipital lobe seizures may be the only major neurological manifestation of PRES (7). Its causes are diverse, but common precipitants are hypertension, renal decompensation, fluid retention, or treatment with immunosuppressive drugs (6). Those most commonly implicated are cyclosporine A (8,9), tacrolimus (10), cisplatin (11), corticosteroids (12), bevacizumab (13,14), and other cytotoxic agents, whilst natalizumab has been associated with progressive multifocal leukoencephalopathy, a demyelinating disease of the central nervous system (15). The pathogenesis of PRES is unclear and it appears to be related to disordered cerebral autoregulation and endothelial dysfunction. In hypertensive encephalopathy there is autoregulatory failure of cerebral vasculature resulting in edema, and once the blood pressure is lowered there is complete resolution. The mechanism by which immunosuppressives cause this syndrome is less clear, but it is thought to be due to endothelial dysfunction from a direct toxic effect on the vascular endothelium, leading to capillary leakage, disruption of the blood-brain barrier, and then triggering of vasogenic edema. This can occur in normotensive individuals and with nontoxic levels of these drugs (6). Neuroimaging is essential for diagnosis and the typical findings are that of symmetrical white matter edema in the posterior cerebral hemispheres, particularly the parieto-occipital lobes, although variations do occur (16). With prompt recognition and early treatment, lowering of blood pressure, dose reduction, or drug withdrawal complete recovery can be expected within days or weeks. In a small number of patients residual neurological deficit and even death have been reported (6,17).

The clinical symptoms in this case, typical neuroimaging findings, and subsequent resolution confirm the diagnosis of PRES. The absence of hypertension and other known etiologies, and our patient's complete recovery whilst still taking high-dose corticosteroids and azathioprine clearly implicate infliximab. Infliximab acts at the cellular level by binding to membrane-bound TNF-α, facilitating cell destruction by antibody-dependent cellular toxicity or complement-dependent cytotoxicity (1). Hence, we speculate that it may have induced endothelial dysfunction by direct toxic effects with resultant vasogenic edema.

This report emphasises the possibility of serious and unexpected side effects of infliximab, whilst demonstrating its efficacy in the management of Crohn disease. The importance of counselling patients and families regarding the known and unknown side effects of novel interventions is highlighted.

Our patient remained in remission on azathioprine for 6 months after his single dose of infliximab. Unfortunately, he had another major relapse, culminating in colectomy and ileostomy; we believed that further treatment with biologicals or thalidomide (because this also has an anti-TNF action) would be contraindicated, and that colectomy was the most appropriate treatment option.


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