Resolution of papilledema associated with cyclosporine use after change to tacrolimus

Abstract

Use of medications including vitamin A derivatives and tetracyclines have been associated with papilledema and raised intracranial pressure. A 46-year-old woman was referred to neuro-ophthalmology for bilateral optic disc oedema and had a 7-year history of cyclosporine use after renal transplantation. She had preserved visual function and moderate bilateral optic disc oedema. Magnetic resonance imaging and magnetic resonance venography of the brain were normal apart from signs of raised intracranial pressure. Lumbar puncture revealed an elevated opening pressure of 40 cm of water with normal cerebrospinal fluid contents. Nephrology was consulted and cyclosporine was switched to tacrolimus and she was treated with acetazolamide. The papilledema resolved within 1 month of her initial visit. It is important to recognise the role that cyclosporine plays in raising intracranial pressure, especially in patients requiring immunosuppression, such as transplant patients. Tacrolimus is a suitable alternative in these cases.

Background

Papilledema refers to optic disc oedema secondary to raised intracranial pressure (ICP) and may result in irreversible vision loss if not treated in a timely fashion.¹ Neuroimaging is required to rule-out intracranial mass lesions and venous sinus thrombosis. Use of medication including vitamin A derivatives and antibiotics such as tetracyclines is also associated with raised ICP, emphasising the importance of reviewing the patient’s list of medications and past medical history.² We present a case of papilledema and raised ICP in a patient with a 7-year history of cyclosporine use after renal transplant that rapidly resolved after switching cyclosporine to tacrolimus.

Case presentation

A 46-year-old woman was referred to ophthalmology for a 6-month history of flashing lights and floaters in her right eye. She had a medical history of end-stage renal disease secondary to focal segmental glomerulosclerosis and had a renal transplant 15 years prior to presentation. She also had a history of hypertension. Her current medications included cyclosporine 75 mg two times per day (started 7 years prior to presentation), mycophenolic acid 1000 mg two times per day, prednisone 5 mg/ day and diltiazem 240 mg/day. Further questioning revealed low-grade headaches and pulsatile tinnitus over the past several months. She was overweight (body mass index (BMI) 28 kg/m²), but denied recent weight gain. On examination, she had a visual acuity of 20/20 in both eyes and normal colour vision. Her pupils were equal and reactive to light with no relative afferent pupillary defect. Dilated fundus examination revealed moderate bilateral optic disc oedema (figure 1). There was also a right posterior vitreous detachment. Humphrey visual field testing showed nonspecific depressed points with questionable reliability and a mean deviation of −5.03 dB in the right eye and −1.15 dB in the left eye. She had bilateral optic disc oedema with preserved visual function consistent with papilledema and underwent further investigations on admission to hospital.

Figure 1.

Optic disc photographs of the right and left eye showing moderate bilateral optic disc oedema at presentation.

Investigations

Magnetic resonance imaging (MRI) and magnetic resonance venography (MRV) of the brain were normal apart from signs of raised ICP including an empty sella and bilateral narrowing of the distal transverse sinuses (figure 2). She underwent a lumbar puncture in the left lateral decubitus position, which revealed normal cerebrospinal fluid contents and an elevated opening pressure of 40 cm of water.

Figure 2.

T1-weighted MRI image showed an empty sella turcica (yellow arrow). Magnetic resonance venography of the brain showed bilateral narrowing of the distal transverse sinuses (red arrows). There was no evidence of venous sinus thrombosis or space-occupying lesions.

Differential diagnosis

The differential diagnosis for raised ICP in this setting included intracranial mass lesions and venous sinus thrombosis, both of which were excluded with MRI and MRV. Infectious etiologies like meningitis may also cause elevated ICP, but our patient was systemically well and had normal cerebrospinal fluid contents.³ Drug-induced intracranial hypertension was the most likely diagnosis since the patient was on cyclosporine, a medication associated with raised ICP. Idiopathic intracranial hypertension (IIH) is a diagnosis of exclusion and a better explanation was available in this case (association with cyclosporine).

Treatment

The nephrology service was consulted and cyclosporine was changed to extended-release tacrolimus 4 mg/day. She was also started on acetazolamide 500 mg two times per day.

Outcome and follow-up

At the 1-month neuro-ophthalmology follow-up appointment, she continued to have normal visual function. There was minimal optic disc oedema in the right eye and resolved optic disc oedema in the left eye (figure 3). Thus, acetazolamide was discontinued. At her 3-month follow-up appointment, her ocular examination was normal and the papilledema had completely resolved. This rapid resolution confirmed the diagnosis of cyclosporine-associated raised ICP. Such a rapid resolution would not be expected in IIH.

Figure 3.

The optic disc oedema substantially improved after cessation of cyclosporine, as seen in the 1-month follow-up images. There is minimal optic disc oedema in the right eye and no disc oedema in the left eye.

Discussion

Papilledema refers to optic disc oedema due to raised ICP, which may be secondary to intracranial mass lesions, venous sinus thrombosis or medication use. Commonly implicated medications are retinoids, antibiotics (eg, tetracyclines) and lithium.² It is therefore important to perform a comprehensive medication review when evaluating any patient with suspected papilledema. When no known cause is identified, a diagnosis of IIH can be made according to the modified Dandy criteria.⁴ There are characteristic neuroimaging findings that suggest intracranial hypertension and these include a partially empty sella, flattening of the posterior globes and distal transverse sinus stenosis.⁵ Transverse sinus stenosis is likely secondary to the raised ICP, but is also thought to contribute to intracranial hypertension secondarily, resulting in a vicious cycle.⁶ This is the basis for the proposed treatment of venous sinus stenting in IIH.⁶ However, when a secondary cause of intracranial hypertension is suspected, treatment should first be directed at addressing the underlying cause. Prompt recognition and management of patients with papilledema is important to avoid permanent, irreversible vision loss.¹

Cyclosporine has previously been associated with papilledema and raised ICP in patients after bone marrow transplant, renal transplant, cardiac transplant, nephrotic syndrome, atopic dermatitis, psoriasis, tubulointerstitial nephritis and Crohn’s disease.^7–25 The exact mechanism of cyclosporine-induced intracranial hypertension remains unclear, and there is no established correlation between serum cyclosporine levels and the presence of papilledema.⁷ The appearance of papilledema after initiation of cyclosporine is also variable, occurring as early as within 30 days and as late as within 5 years.^{8 9} Papilledema occurring at 7 and 8 years after initiation of cyclosporine have been reported but both cases involved the additional use of minocycline, an antibiotic associated with drug-induced intracranial hypertension.¹⁰ Our patient presented with papilledema after 7 years of cyclosporine use with no other identifiable causes. To our knowledge, this case had the longest delay of onset of cyclosporine-induced papilledema reported in the literature. However, the variable onset of papilledema may be due to its asymptomatic presentation. Many cases of cyclosporine-induced papilledema were discovered on routine examination, while others presented with symptoms of elevated ICP including, but not limited to, headaches, decreased vision, diplopia, and nausea/vomiting.^7–17

There is no consensus in the management of cyclosporine-induced papilledema. Cessation of cyclosporine appears to be effective in managing symptoms and improving ocular complications.7 8 12–16 18 25 In certain cases where cyclosporine was not stopped after the discovery of papilledema, procedures such as cerebrospinal fluid shunting procedures were required in treatment of refractory elevated ICP. However, despite this aggressive intervention, optic atrophy and vision loss still occurred in these cases.^{9 22} Other treatment options include use of acetazolamide, prednisone, glycerol and therapeutic lumbar punctures, which are all treatment regimens used in the treatment of intracranial hypertension.7 8 10 12 20 21 Some patients can have lasting clinical remission after a single lumbar puncture, but this is not thought to be a reliable treatment option.²⁶ In addition to cessation of cyclosporine, some reports successfully transitioned patients to other immunosuppression medications like mycophenolate mofetil, tacrolimus and sirolimus without recurrence of papilledema.8 15 16 25 Our case demonstrates the rapidity of resolution of papilledema using a combination of a diagnostic lumbar puncture, transition from cyclosporine to tacrolimus and initiation of acetazolamide. At her 1-month follow-up appointment, acetazolamide was discontinued given the near-complete resolution of her papilledema. At 3 months, her fundus examination was normal with complete resolution of papilledema.

Learning points.

• In a suspected case of papilledema, a thorough medication review should be performed to identify potential medications that may be responsible for raised intracranial pressure.

• Patients with cyclosporine-induced papilledema can be asymptomatic or present with symptoms such as headaches and visual changes.

• Cessation of cyclosporine is key for reversing cyclosporine-induced papilledema, which can resolve in as early as 1 month. This should be carried out together with the patient’s nephrologist and suitable alternatives such as tacrolimus should be considered.