Methotrexate is a commonly used agent in the treatment of an un-ruptured ectopic pregnancy. Thromboembolic events are rarely seen side effects of such a medicine. We report the case of the 22-year-old woman who underwent Methotrexate therapy for an un-ruptured ectopic pregnancy without any history of thromboembolic risk factors. A second dose (50 mg/m2) was administered to the patient showing a nondecreasing pattern of β-HCG levels after an initial standard dosage of Methotrexate (50 mg/m2). On the 12th day of the treatment, a sudden onset of painless vision loss was seen in the right eye. Fundal imaging and fluorescein angiography revealed an occlusion of the superior temporal branch of the right retinal artery. After a month of hyperbaric oxygen therapy, complete recovery without loss of vision was achieved.
Keywords: Methotrexate, Ectopic pregnancy, Branch retinal artery occlusion. https://doi.org/10.5455/JPMA.14284
Nowadays, systemic Methotrexate is frequently used in the treatment of un-ruptured ectopic pregnancy. Methotrexate is a folic acid antagonist, it inhibits Deoxyribonucleic acid (DNA) and Ribonucleic acid (RNA) synthesis by affecting the growth of rapidly dividing cells, particularly the trophoblasts, myeloid cells and gastrointestinal mucosal cells. Commonly encountered side effects of the drug depend on the duration and dosage of the induced therapy; it commonly includes stomatitis, leukopenia, nausea, vomiting, fever and malaise. While thromboembolic events are rare (<0.1%), ocular side effects such as conjunctivitis, retinopathy, transient blindness and visual loss are very uncommon (<0.01%).1 Treatment regimens prescribed for methotrexate are inclusive of single and multiple dosing. Single-dose is preferred due to the ease of administration, lower cost and no need for folinic acid replacement. However, success rates are similar for both regimens.2 In a single dose regimen, 50 mg/m2 Methotrexate is administered intramuscularly and a β-Subunit human chorionic gonadotropin (β-HCG) level is monitored. If β-HCG values do not reduce adequately, a second dose is then given. Acute occlusion of the retinal artery is an ophthalmologic emergency and an ocular analog of cerebral stroke. Although, branch retinal artery occlusion is a much rarer entity seen than the central retinal artery occlusion, the associated factors are however similar. Here, we present a case of acute occlusion in the superior temporal branch of the retinal artery which developed after a second dosage of systemic Methotrexate given initially for the treatment of a non-ruptured ectopic pregnancy.
A 22-year-old woman, gravida 2 and parity 0 presented with complaints of lower abdominal pain and a history of one anembryonic pregnancy was admitted to Kocaeli University Hospital, Turkey on March, 2018. Her past medical history was insignificant. Her serum β-HCG level was found to be 46,558 IU/L (At 6'th week of pregnancy β-HCG level should not be above 1000 IU/L). Transvaginal ultrasonography revealed a 12 × 12 mm mass in the right adnexal area, which may be consistent with an un-ruptured ectopic pregnancy. No foetal cardiac activity or a yolk sac was visualized. Endometrial thickness was 3.4 mm (>5mm in healthy pregnancy). Patient was admitted to the hospital and was followed with a two-day interval β-HCG level. β-HCG values at two-day intervals were monitored (Figure-1)
and a single dose of 50 mg/m2 (86 mg) methotrexate was administered intramuscularly on the 10th day. Pretreatment haemogram, platelet and liver function tests were all normal. Due to inadequate decrease in serum β-HCG levels, a second dose of Methotrexate was given intramuscularly on the 18th day (8th day after the first dose). Sufficient reductions were achieved following the second dose and the patient was then followed with serial β-HCG. On the 30th day of follow-up (12th day of 2nd dose), a painless sudden loss of vision developed in the right eye. Visual activity was 20/40. Optical coherence tomography and fundus fluorescein angiography were performed by an ophthalmologist, occlusion was detected in the superior temporal branch of the right central retinal artery (Figure-2).
In contrast, the appearance of the left eye was normal. Carotid-vertebral Doppler u l t r a s o n o g r a p h y , electrocardiography and colour doppler echocardiography were all normal. No pathology was assessed on protein C & S, anti-thrombin 3 and factor 5 Leiden mutation analysis. Hyperbaric oxygen therapy was then started for the occluded retinal artery. Patient was discharged with decreasing levels of serum β-HCG and a hyperbaric oxygen therapy was continued for nearly a month. Visual and fundal examinations were normal at one and six month's followup. Also, fundus auto fluorescence imaging revealed no abnormality at six month follow-up (Figure-3).
Informed consent was obtained from the patient.
Treatment options for ectopic pregnancy include expectant, surgical or medical management. Methotrexate is less expensive, minimally toxic and protects fertility, hence, it is widely used in the treatment of ectopic pregnancy. Doses of Methotrexate used for ectopic pregnancy are relatively low compared to its other indications. Results of a meta-analysis3 showed greater effectiveness, however, more side effects were also seen with the multi-dose protocol as compared to the single-dose protocol. A randomized prospective study comparing two protocols in un-ruptured ectopic pregnancy gave similar results with the success rate lower than the single-dose protocol.2 Occlusion of the retinal artery is usually in the form of a central retinal artery occlusion (CRAO) and the incidence is reported to be 1/100,000.4 Branch retinal artery occlusion occurs less commonly than central retinal artery occlusion and the outcome is found to be better than that of the central retinal artery occlusion.5 Embolism is the most common cause of CRAO and the major source is the carotid artery atherosclerotic plaques. Risk factors for retinal artery occlusion include arterial hypertension, diabetes mellitus, carotid artery disease, coronary artery disease, transient ischaemic attacks and tobacco. Other risk factors for patients under 50 years of age are hyperhomocysteinaemia, factor V Leiden, protein C and S and anti-thrombin deficiencies, antiphospholipid antibodies, prothrombin gene mutations, sickle cell disease and paraneoplastic syndromes.6 Our patient had none of the above mentioned risk factors and a haemogram, platelet count, liver function test, urine analysis and hypercoagulability tests performed were all normal. No pathology was identified on the echocardiogram and duplex carotid ultrasound examination. Fundoscopic findings of retinal artery occlusion include retinal opacity, cherry-red spot, cattle trucking, optic disc oedema and pallor. Fundus fluorescein angiography showed delayed filling of the affected vessels, reduced arterial caliber and 'cattle trucking' of the blood column in the retinal branch arteries. An increased inner retinal layer thickness can be detected by optical coherence tomography due to retinal oedema and optic nerve swelling.7 Acute retinal artery occlusion has no standard treatment and many options have been reported in the literature. Some of these are Isosorbide dinitrate, Nitroglycerin, inhalation of Carbogen (vasodilatation), Acetazolamide, Mannitol, anterior chamber paracentesis (intraocular pressure reduction), Pentoxifylline (increased red blood cell deformability), isovolaemic haemodilution, enhanced external counterpulsation (improved retinal perfusion), ND:YAG laser embolysis/embolectomy, ocular massage, surgical removal of the clot (dislodging of an embolus), hyperbaric oxygen therapy (increased retinal oxygenation) and Methylprednisolone (reduction of retinal oedema). In two randomized controlled trials, Pentoxifylline8 and an enhanced external counterpulsation combined with haemodilution9 was used for central retinal artery occlusion which suggested positive effects. Our patient achieved normal vision with hyperbaric oxygen therapy which may be due to a branch artery occlusion and not central artery occlusion. In the literature, atypical central retinal artery occlusion was observed in a patient using oral methotrexate and prednisolone for dermatomyositis.10
Occlusion in the superior temporal branch of the retinal artery in the young patient with no risk factors may be due to methotrexate therapy for ectopic pregnancy. Although methotrexate is a safe drug for the treatment of an unruptured ectopic pregnancy, it may have serious side effects.
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Conflict of Interest: None to declare.
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