The comment below was left on a recent post regarding "Readers' Questions Related to MTHFR Polymorphisms." The reader presents a very unusual complication early in her first pregnancy - retinal arteriole occlusion - and the response to her query does not have a ready answer, but it sure was fun to try to come up with one!
I'm now pregnant with my first child. At 9 weeks I developed an arteriole occlusion in the retina of my right eye with some vision loss. My OB did quite a lot of testing and I was found to be positive for homozygous MTHFR. My homocysteine level (not fasting) was normal and my doc doesn't think I need Lovenox or Heparin. I'm on baby aspirin alone but questioning if I should be on additional therapy or seek a second opinion. Any suggestions? Of note, I'm an otherwise healthy 29 year old with no history of lost pregnancies or other clotting problems.
One of the hardest things about responding to a question like this from afar is inadequate information and the inability to question the patient in person and to perform an adequate examination. The obvious concern is why did a “healthy 29 year old” pregnant woman develop occlusion of a retinal arteriole to begin with. We are told that she had “quite a lot of testing done” but without knowing what tests were done, it is hard to know what other tests should be done so that our reader’s question might be best answered.
Retinal arteriole occlusions are most common in older individuals, typically in their 70’s, and in that group, they are usually the result of embolic events – most often cholesterol emboli from atherosclerotic disease in the aorta or carotid arteries, calcific emboli from valvular disease in the heart or atheromatous plaques, and platelet/fibrin emboli from foci of thrombosus in the heart or vascular tree. It has been estimated that less than 1 in 50,000 patient visits to an ophthalmologist will be for the indication of retinal arteriole occlusion in someone less than 30 years of age (Greven, et al., Am J Ophthalmol. 1995;120:776-83).
Indeed, causes of retinal arteriolar occlusion in younger folks are typically NOT related to embolic events, although there are still circumstances when they still can be. Conditions that may increase the risk in this age group include sickle cell hemoglobinopathies, smoking, diabetes, hypertension, genetic and acquired thrombophilias (e.g., antiphospholipid antibodies, lupus anticoagulant, anti-?-2-glycoprotein-1, factor V Leiden, antithrombin III deficiency, protein C and S deficiencies, prothrombin mutation, hyperhomocysteinemia, and, perhaps MTHFR polymorphisms and plasminogen-activator-inhibitor-1), hyperlipidemia, cocaine and IV drug use, cardiac arrhythmias (e.g. atrial flutter) and valvular disease (e.g., bacterial endocarditis), hyperviscosity syndromes, as well as pregnancy and use of hormonal contraceptives. Other conditions that should also be considered are HIV infection, use of certain herbal products and prescription medications such as sildenafil citrate (Viagra) to increase libido, Behcet’s disease, and a host of less common infectious/inflammatory diseases. A history of migraine headaches is also very common among younger women who develop retinal arteriole occlusion.
So the first thing we need from our reader is a very good history, including family, dietary, and social, to query for risk factors and to select for further evaluation from the myriad of possible causes for this condition in women of her age detailed above. She needs a thorough physical exam with blood pressure, cardiac, vascular, and ophthalmologic evaluation, the latter of which she most likely has already had. Serious consideration should be given to both an electrocardiogram (or Holter monitoring) and an echocardiogram to evaluate the rhythm and structure of her heart. Unless some other physical finding such as carotid bruits dictate, carotid Doppler studies are probably unnecessary at her age. Consideration should be given to screens for syphilis (remember, false-positive results are associated with thrombophilias), general autoimmune disease (e.g., ANA, rheumatoid factor), selected genetic and acquired thrombophilias (choose from above!), homocysteine (although if she is on supplemental folic acid, or was at the time her initial homocysteine level was performed, this will probably be 'normal'), complete blood count with platelet count, hemoglobin electrophoresis, diabetes, lipid profile, HIV, and perhaps even blood cultures for bacteria that might be associated with endocarditis and valvular disease.
Interestingly, despite the association of the thrombophilias with venous and arterial thromboembolic disease, I am not aware of any good study that has correlated MTHFR polymorphisms (even in the homozygous state) with retinal arteriole occlusion. Lowenstein and colleagues (Am J Ophthalmol. 1997;124:840-41) were the first to demonstrate the presence of the MTHFR C677T polymorphism in a patient who presented with retinal vein occlusion. In a subsequent study (Ophthalmology 1999;106:1817-20) they reported that among 59 patients with retinal vein occlusions, 44% were heterozygous and 11% were homozygous for the same polymorphism. Around the same time, Saloman and colleagues (Blood Coagul Fibrinolysis 1998;9:617-622) reported an association between MTHFR C677T homozygosity and retinal vein occlusion in 102 patients (OR 1.9; 95% CI 0.95-3.81). However, a retrospective study of 174 patients in Ireland demonstrated no association between MTHFR homozygosity and either retinal vein or arterial occlusive disease (Cahill, et al., Br J Ophthalmol 2001;85:88-90). I am also unaware of any studies that indicate elevated homocysteine levels are associated with retinal arterial occlusion. Indeed, one study from Scandinavia found no association of either the MTHFR C677T polymorphism or homocysteine levels among 116 patients even with retinal vein occlusion (Larrson, et al., Acta Ophthalmol Scand 2000;78:340-343.
So, how do we counsel our reader. I suppose if nothing other than the homozygous MTHFR C677T polymorphism is found, most likely the baby aspirin, supplemental folic acid and prenatal vitamins may be adequate therapy. If some other risk factor is found upon subsequent evaluation, then her treatment should be adjusted accordingly. Admitting our limitations in current medical understanding due to the ‘unknowns’ that might have led to her retinal arteriole occlusion, and since this is such an unusual condition in young women, her pregnancy should be followed very carefully for evidence of complications related to abnormalities of placentation. Remember, thrombophilias in particular are associated with intrauterine growth restriction, fetal loss, pregnancy-induced hypertensive disorders, and early delivery.
I would suggest she have maternal serum screening done at 16 weeks, a ‘targeted sonogram’ at about 20 weeks, and a follow-up assessment of fetal growth and Doppler flow studies at 26-28 weeks. Understand, there is no standard of care here, but such an approach might help anticipate fetal complications and, thereby, allow for antepartum testing that might reduce her risks for an untoward outcome. She must also be made aware that retinal arteriole occlusion is associated with long-term risks for both cardiovascular disease and stroke and if she does have an underlying thrombophilia as the cause, other thromboembolic complications.
Thanks to our reader for sharing her story and for a most challenging question! Dr T