Posterior reversible encephalopathy syndrome after first rituximab transfusion for treatment of granulomatosis with polyangiitis

Abstract

A woman in her 60s developed acute onset headache, blurry vision and encephalopathy a few hours after rituximab infusion, given to treat granulomatosis with polyangiitis. CT scan showed oedema in the posterior circulation area suggesting the diagnosis of posterior reversible encephalopathy syndrome, and an MRI confirmed it. After being treated with aggressive blood pressure control and other supportive measures, her symptoms improved over 3–4 days. This case highlights the need for awareness and early recognition of this rare but serious adverse effect of rituximab. CT scan can be helpful in diagnosis (also to rule out bleeding), but the MRI provides the most accurate diagnosis.

Background

Posterior reversible encephalopathy syndrome (PRES) is characterised by a collection of symptoms caused by vasogenic oedema, usually reversible, primarily involving the posterior central nervous system circulation.¹ Patients may experience headaches, altered level of consciousness, visual disturbances and seizures.^{1 2} Risk factors for PRES include a variety of diseases that cause uncontrolled hypertension, immunosuppressed conditions, use of immunosuppressants such as calcineurin inhibitors and renal insufficiency.³ PRES has rarely been described after rituximab therapy.⁴ Rituximab is a monoclonal antibody that depletes CD20+ B cells and is the standard of care along with corticosteroids for systemic autoimmune diseases such as granulomatosis with polyangiitis (GPA).⁵

We report a case of acute headache, encephalopathy, acute hypoxic respiratory failure secondary to pulmonary oedema with brain imaging findings consistent with PRES occurring a few hours after the first rituximab transfusion in a patient recently diagnosed with rapidly progressive glomerulonephritis (RPGN) secondary to perinuclear antineutrophil cytoplasmic antibody (p-ANCA) vasculitis.

Case presentation

A woman in her 60s with hypothyroidism and pernicious anaemia presented to the hospital with nausea, diarrhoea and fatigue that had been progressively worsening for 3 weeks. She denied fevers, chills, chest pain, shortness of breath, blood in urine or stools and any specific muscle weakness. Her home medications included levothyroxine and vitamin B₁₂ and D supplements. On presentation, she appeared comfortable in no acute distress. Her vitals were: blood pressure of 135/74 mm Hg, heart rate 95 beats per minute, temperature 36.6°C, respiratory rate 22 breaths per minute and SpO2 99% on room air. Cardiac, respiratory and neurological exams were within normal limits. She had sores on the gums, upper lips and upper palate but did not have any skin lesions or rash. Complete blood count testing showed leucocytosis of 21.6×10⁹/L with an absolute neutrophil count of 18.8×10⁹/L, anaemia with a haemoglobin of 5.6 g/L and thrombocytosis with a platelet count of 761×10⁹/L. Serum chemistries revealed elevated blood urea nitrogen and creatinine of 81 mg/dL and 5.4 mg/dL, respectively. She had no history of renal disease, and renal function had been normal on routine testing a few weeks ago. Urinalysis showed significantly elevated protein (100 mg/dL) and blood (>1000 red blood cells).

In the setting of acute kidney injury and a nephritic picture on urinalysis, a workup for autoimmune diseases was performed and revealed positive serum p-ANCA. Due to a high likelihood for vasculitis and low suspicion for infection, pulse dose steroids (intravenous methylprednisolone 1000 mg daily for 3 days) were started along with performing a renal biopsy. Due to worsening metabolic derangements and developing fluid overload, the patient was started on haemodialysis. Kidney pathology revealed severe crescentic necrotising glomerulonephritis. Immunofluorescence microscopy studies showed positive staining for fibrinogen in areas of necrosis and crescentic formation with no dense deposits confirming RPGN secondary to p-ANCA vasculitis.

After confirmation of the diagnosis, the patient was started on rituximab therapy. At the infusion initiation, she was awake, alert, oriented and breathing comfortably on 2 L of oxygen through a nasal cannula. Five hours following the infusion, she complained of a headache, blurry vision and became confused and somnolent shortly after. The blood pressure had increased to 177/86 mm Hg, her breathing got worse with hypoxia, and she had to be placed on a non-rebreather mask. She withdrew to painful stimuli, but her words were difficult to understand, and she struggled to follow commands. She did not have any unilateral deficits, and the pupillary and corneal reflexes were intact. However, as her respiratory status and lethargy progressively worsened, she was intubated a few hours later.

Investigations

An urgent CT of the brain was performed and revealed bilateral occipital and inferior right cerebellar hypodensities (figure 1). CT angiography and perfusion of the head and neck showed no thrombosis but revealed decreased perfusion in the bilateral temporal and occipital lobes compatible with a diagnosis of PRES.⁶ MRI showed diffuse hyperintensity throughout the supratentorial and infratentorial subcortical white matter, most severe in the bilateral occipital lobes confirming PRES (figure 2).

Figure 1.

Hypodensities in the bilateral occipital lobes (A) and cerebellum (B) seen on CT during initial presentation for headache and encephalopathy.

Figure 2.

Diffuse hyperintensity on T2 fluid-attenuated inversion recovery MRI sequence seen in supratentorial and infratentorial subcortical white matter, most severe in the bilateral occipital lobes (A) and cerebellum (B).

A bedside chest X-ray revealed pulmonary oedema and small pleural effusions. An echocardiogram showed an ejection fraction (EF) of 20%–25%, and the imaging pattern was concerning for stress-induced cardiomyopathy. All infectious workups, including respiratory and cultures, were negative.

Differential diagnosis

In this patient who experienced sudden onset headache and decreased level of consciousness who recently started rituximab infusion, the differential diagnosis was broad and included acute stroke, intracranial haemorrhage, hypertensive encephalopathy and PRES. An urgent CT of the brain was able to rule out bleeding.

The differential diagnosis was narrowed down to PRES and basilar artery thrombosis with the CT findings of bilateral occipital and cerebellar hypodensities (figure 1). CT angiography and perfusion studies ruled out basilar artery thrombosis and supported a diagnosis of PRES which was later confirmed on an MRI (figure 2). PRES was attributed to rituximab due to the sequential timeline of events between infusion and onset of symptoms 5 hours later.

The differential diagnosis for acute respiratory failure included diffuse alveolar haemorrhage (DAH) due to vasculitis, pulmonary oedema secondary to heart failure, hypertensive emergency and renal failure.

A chest X-ray with bilateral alveolar pattern (figure 3), an echocardiogram showing an EF of 20%–25% and bronchoscopy not characteristic of DAH made the diagnosis of acute pulmonary oedema most likely.

Figure 3.

Chest X-ray showing bilateral pleural effusions in the lower lung fields.

Treatment

After intubation, the patient was transferred to the intensive care unit for aggressive blood pressure control and ventilator management. Glucocorticoids and haemodialysis were continued. With the help of fluid removal by haemodialysis, aggressive blood pressure control and other supportive care, the patient’s neurological and respiratory status improved over the next 72 hours, and she was successfully extubated. She was weak but was able to follow commands and reported improvement in headache and blurry vision.

Outcome and follow-up

The oxygen requirements slowly improved, and she was weaned down to nasal cannula and then room air after a few days. She was discharged home 10 days later on prednisone and remained haemodialysis.

As an outpatient, she was started on oral cyclophosphamide, and the steroids were gradually tapered down. The rheumatology and nephrology teams continue to see her regularly and have placed her on the kidney transplant list. A follow-up brain MRI 6 weeks postdischarge showed complete resolution of the areas of hyperintensity on T2 fluid-attenuated inversion recovery images (figure 4). In the past 2 years, since the initial presentation, there has been no reoccurrence of PRES following discontinuation of rituximab.

Figure 4.

Follow-Up MR T2 fluid-attenuated inversion recovery sequence showed resolution of hyperintensity in the bilateral occipital lobes (A) and cerebellum (B).

Discussion

PRES occurs due to the failure of autoregulation in the posterior cerebral circulation in response to acute changes in blood pressure.² One of the proposed mechanisms is cerebral hyperperfusion and vasogenic oedema due to high arterial pressure, which disrupts the blood-brain barrier and causes plasma leakage through the tight-junction proteins.¹ PRES affects 8% of patients on immunosuppressants after bone marrow transplant and 0.4%–6% of patients after solid organ transplant.¹ An autoimmune disorder is present in 45% of patients who develop PRES.⁶ PRES in patients on immunosuppressive and cytotoxic medications is believed to be caused by circulating toxins that lead to acutely high arterial pressure triggering vascular leakage and oedema. For example, calcineurin inhibitors have been shown to release vasoactive substances and may cause increased vascular permeability.³ GPA itself may contribute to the development of PRES,^{7 8} as it results in renal insufficiency and immunosuppression, which are established risk factors for PRES.²

Only a few cases of PRES associated with rituximab have been reported in the literature. A review of rituximab-associated PRES identified 15 cases and reported another.⁴ The majority (81%) of patients were women, ranging from 17 to 72 years. In these patients, rituximab was most commonly used to treat lupus nephritis and lymphoma. To our knowledge, ours is the first reported case of PRES in a patient with ANCA-associated vasculitis treated with rituximab. In many of these cases, the onset of PRES after rituximab was variable. Only one case reported symptoms immediately after the first transfusion occurring in a 61-year-old woman treated for diffuse large B cell lymphoma.⁹ Notably, this patient subsequently underwent seven cycles of rituximab treatment with no relapse of PRES. Even though a definite cause and effect relationship is hard to establish in case reports; however, based on a few prior reports of PRES after rituximab, such as above and given the onset of clinical symptoms immediately after the infusion in our patient, makes rituximab the most likely cause.

Cyclophosphamide can also be used to treat ANCA-associated vasculitides, and it is non-inferior to rituximab for these indications.¹⁰ Cyclophosphamide has also rarely been reported to cause PRES in patients with renal failure.^{11 12} The patient in the current case tolerated it with no adverse effects, indicating that it is an acceptable alternative for a patient who develops PRES after rituximab. The case adds to this growing body of literature highlighting the need to closely monitor the neurological and haemodynamic status of patients who are started on rituximab.

Learning points.

• Rituximab can rarely be associated with posterior reversible encephalopathy syndrome (PRES).

• It should be considered in any patient presenting with acute onset of neurological symptoms such as headache, blurry vision and/or encephalopathy.

• Urgent imaging studies to differentiate between stroke versus PRES is paramount in establishing the correct diagnosis.

• Neurological status and haemodynamics should be monitored in patients starting rituximab infusion.

• Patients being considered for rituximab should be informed of PRES as a possible side effect.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).