Potential association of sildenafil administration with third (III) cranial nerve palsy in pulmonary arterial hypertension patient

PVRI Member Authors: Aikaterini Flevari, Iraklis Tsagkaris, Stylianos Argentos, Dimitros Konstantonis, Irini Mavrou, Stylianos Orfanos, Ioannis Lekakis, Apostolos Armaganidis

Abstract

We present the case of a 71 year old man with pulmonary arterial hypertension (PAH), atrial fibrillation, and monoclonal gammopathy of undetermined significance (MGUS), who experienced sudden left periorbital headache, left eyelid ptosis and ophtalmoplegia, with intact pupillary reflexes. The patient was treated with bosentan and sildenafil citrate. The sildenafil dosage had been recently doubled to 40 mg tid. Thorough laboratory and radiologic investigation for the cause of the palsy was negative. Sildenafil was withdrawn and six months later there was complete resolution of symptoms and signs. Sildenafil might have been a potential cause of reversible III cranial nerve palsy in this PAH patient.

Introduction

Sildenafil citrate is a selective phosphodiesterase type-5 (PDE-5) inhibitor, and has a proven therapeutic efficacy in male erectile dysfunction (ED). In 2005 it was shown to be effective in and gained approval for pulmonary arterial hypertension (PAH) treatment.1 Despite the fact that 20 mg per os tid is the approved regimen, the optimal dose for PAH is titrated and often a higher dosage of sildenafil is prescribed in numerous countries.2 Pupil sparing III cranial nerve (oculomotor) palsy has been twice reported in men with occasional use of sildenafil for ED.3,4 To our knowledge, we present the first case of pupil sparing oculomotor nerve palsy in a patient with PAH who was taking sildenafil on a regular basis. The patient’s medical history was positive for monoclonal gammopathy of undetermined significance (MGUS), a disease with documented risk for arterial and venous thrombosis5,6,7 and with occasional reports of cranial as well as peripheral nerve palsy.6,7

 

Case Report

 A 71 year old man with a previous diagnosis of atrial fibrillation and PAH presented in our clinic claiming sudden onset of diplopia, left eyelid ptosis and ipsilateral periorbital headache, two weeks after having doubled sildenafil’s dosage. Two years before the incident, the patient was referred to our PH service due to deteriorating dyspnea on exertion (New York Heart Association functional status - NYHA III). A detailed diagnostic work-up was performed and after right heart catheterization [RHC, mean pulmonary artery pressure (mPAP): 35mmHg, pulmonary arterial wedge pressure (PAWP): 10mm Hg, pulmonary vascular resistance (PVR): 5 Wood units] and a thorough exclusion of other causes of pulmonary hypertension (with emphasis on left heart and thromboembolic disease), the diagnosis of pulmonary arterial hypertension (PAH) was confirmed, and treatment with bosentan initiated. During the diagnostic work-up, a single protein band in the gamma region of serum protein electrophoresis was revealed (IgG kappa chains). Bone marrow biopsy was positive for low grade plasmatocytosis (<10%);hematological, biochemical and radiological investigation excluded Multiple Myeloma (MM) and the diagnosis of monoclonal gammopathy of undetermined significance (MGUS) was also set. Although the patient initially responded well to treatment, a year later he was re-admitted due to deterioration of clinical status (NYHA status late III and leg edema), while his hematological disease was stable. A new RHC was performed (mPAP: 43mmHg, PAWP: 7mm Hg, PVR: 8 Wood units) and sildenafil (20mg per os tid) was then added. Four months later due to poor clinical response, the dose of sildenafil was doubled (40mg tid) and fifteen days later the patient experienced a dull left periorbital pain, which was mildly relieved with paracetamol. The following day, he had blurred vision, diplopia and gradually PVRI Chronicle: Volume 2 Issue 1, January - June 2015 deteriorating ptosis of the left eyelid. He was then admitted to our clinic. On admission, his vision was clear and near visual acuity was normal. There was ptosis and slight abduction of the left eye (Figure 1) with a deficit in adduction beyond midline (Figure 2). There was also complete limitation of left eye elevation and depression. Pupils were equal in size and pupillary direct and indirect reflexes in dim and bright light were normal. An anterior segment exam, a dilated fundus exam and a neurological exam all revealed normal results. Likewise, the arterial blood pressure and pulse rate were within normal range. Both brain computed tomography (CT) scan and magnetic resonance imaging (MRI) tests were negative. His hematological condition revealed a mildly elevated glycosylated haemoglobin, (HbA1c: 6.4% with upper limit 5.6%), but fasting glucose and plasma lipid profile were within normal limits (glucose: 85mg/dl, cholesterol: 150 mg/dl, triglycerides: 130 mg/dl, LDL: 102mg/dl and HDL: 32mg/dl). Atherogenic Plasma Index (AIP=0.07) revealed a low cardiovascular risk. Lumbar puncture showed normal cerebrospinal fluid protein electrophoresis and normal cytology. Sildenafil was gradually withdrawn and three months later the patient had an important improvement in eyelid ptosis and in all ophthalmic movements but adduction. Six months later, left ophthalmoplegia was fully restored.

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 Figure 1: At initial presentation the patient exhibited ptosis and slight abduction of the left eye.

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Figure 2: On examination, there was limitation in performing adduction beyond midline.

Discussion

Sildenafil citrate causes selective PDE-5 enzyme inhibition, thus maintaining high values of intracellular cyclic guanosine monophosphate (cGMP), the second messenger of nitric oxide (NO) and principal mediator of smooth muscle vascular relaxation, especially in penile and pulmonary vasculature.8 It thus regulates blood flow in these regions, minimally affecting other areas of the body.8 Since 2005, it joined prostanoids and endothelin receptor antagonists in the therapeutic armamentarium of PAH. Sildenafil’s most common side effects include flushing, headache, dyspepsia and nasal congestion, which occur in 6-18% of subjects depending on dose, and which result from systemic vasodilation, secondary to PDE- 5 inhibition of vascular smooth muscle.9 Major ocular adverse events are associated with the increase in retinal and choroidal blood flow, due to the wide expression of PDE-5 in these tissues,9 Also due to co-inhibition of PDE-6 enzyme, in rod and cone photoreceptors, the retinal phototransduction pathway is impaired and it may be responsible for mild and transient visual effects, such as blue tinged vision or increased photosensitivity.9

 Third (III) cranial nerve palsy has been reported in association with PDE-5 use in two cases. The first reported case was a 56 year old man, who developed a complete pupil-sparing III nerve palsy 36 hours following a single sildenafil dose intake (50mg) for erectile dysfunction.3

 The second reported case was a 44 year old man, with uncontrolled type I diabetes mellitus, who also developed pupil-sparing III nerve palsy, 12 hours after ingestion of a single dose of sildenafil (50mg).4 In both cases, authors considered that sildenafil might have caused transient hypoperfusion of the III cranial nerve. In all cases, including ours, pupillary light reflexes were intact, which indicates that parasympathetic fibers controlling sphincter pupillae muscle via the ciliary ganglion were not damaged. This can be attributed to the anatomical arrangement of its fibers, as fibers controlling pupillary function travel on the superficial area and are spared from ischemic injuries. Indeed, in the majority of ophthalmic neuropathies of vascular etiology (e.g. diabetes mellitus), centrally located fibers are affected, while pupillary fibers are spared.

Although there was a temporal association of sildenafil dosage increase with the nerve palsy followed by full recovery after sildenafil discontinuation, we cannot exclude that other conditions might have played a role. For example MGUS, a premalignant usually asymptomatic plasma cell disorder that affects at least 3% of adults older than 50 years5 carries an augmented risk for both arterial and venous thrombosis.5 There have been a few reported cases connecting MGUS to cranial nerve palsies4 , specifically Bell’s.7 In these reports, blood flow in the nutrient vessels of the nerves (vasa nervorum) was considered impaired due to blood hyperviscosity caused by the circulating abnormal protein.

Conclusion

Sildenafil may be a potential etiologic factor for reversible third cranial nerve palsy. Although it cannot be explicitly proven that sildenafil was the cause of this patient’s neuropathy, the close temporal relationship between the drug’s dose augmentation and patient’s symptoms, as well as the full recovery after sildenafil withdrawal, strongly suggests this possibility.

 

References

1.Galiè N, Ghofrani HA, Distler O, Gerhardt F, Gorenflo M, Grünig E, Haefeli WE et al. Sildenafil citrate therapy for pulmonary arterial hypertention. N Engl J Med 2005; 353:2148-2157

2. Ghofrani HA, Distler O, Gerhardt F, Gorenflo M, Grünig E, Haefeli WE et al Treatment of pulmonary arterial hypertension (PAH): updated Recommendations of the Cologne Consensus Conference 2011. Int J Cardiol 2011;154 Suppl 1:S20-33.

3. Donahue SO, Taylor RJ. Pupil-sparing third nerve palsy associated with sildenafil citrate (Viagra). Am J Ophthalmol. 1998;126:476-477

4. Acaroglu G, Akinci A, Zilelioglu O. Sildenafil associated pupil-sparing third nerve palsy. Neuro-Ophthalmology 2006;30:117–119

5. Kristinsson SY, Pfeiffer RM, Bjorkholm M, Goldin LR, Schulman S, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood 2010;115:4991-4998

6. Yoshida T, Yazaki M, Gono T, Tazawa K, Morita H, Matsuda M, Funakoshi K, Yuki N, Ikeda S. Severe cranial nerve involvement in a patient with monoclonal anti-MAG/SGPG IgM antibody and localized hard palate amyloidosis. J Neurol Sci 2006;244:167-71

7. Korczyn AD, Pick AI, Schreibman S. Bell’s Palsy with Monoclonal Gammopathy. Z. Neurol 1973;203:337-340

8. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral Sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998;338:1397-1404.

9. Foresta C, Caretta N, Zuccarello D, Poletti A, Biagioli A, Caretti L, Galan A. Expression of the PDE5 enzyme on human retinal tissue: new aspects of PDE5 inhibitors ocular side effects Expression of the PDE5 enzyme on human retinal tissue: new aspects of PDE5 inhibitors ocular side effects. Eye 2008;22:144–149.

10. Lapresle J, Lasjaunias P. Cranial nerve ischaemic arterial syndromes. Brain 1986;109:207-215 

Topics

Pulmonary Arterial Hypertension

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PVRI Chronicle Vol 2: Issue 1 cover image

January 2015

PVRI Chronicle Vol 2: Issue 1

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