Central retinal artery occlusion and subsequent amaurosis fugax in the contralateral eye associated with the G20210A prothrombin gene (F2) variant: a case report.

PURPOSE: Report the case of a patient with a history of central retinal artery occlusion in her right eye and amaurosis fugax associated with acute ischemic changes in her left eye related to a prothrombin G20210A gene variant, in which OCT-A was used as a diagnostic and therapeutic tool. CASE PRESENTATION: 55-year-old woman with a history of central retinal artery occlusion in her right eye and prothrombin gene G20210A (F2) variant diagnosis. She presented to our consultation with amaurosis fugax in her left eye. As medical history, she had an episode of bilateral posterior scleritis diagnosed asynchronously with the current episode. Vascular, autoimmune, and metabolic prothrombotic diseases were ruled out. OCT-A showed areas suggesting acute ischemia consistent with macular retinopathy in her left eye. Anticoagulant therapy with Apixaban was initiated, considering the risk for her vision. Control OCT-A showed perfusion improvement in the previous site of the occlusive vascular event. We also considered the extent of the inflammatory response due to posterior scleritis as a differential diagnosis. Nevertheless, it is less likely, considering the temporality between scleritis and the retinal-vascular episodes. CONCLUSIONS: While the G20210A prothrombin gene (F2) variant is a rare cause of retinal artery occlusion, it is important to consider it a differential diagnosis. Good visual outcomes can be achieved with prompt initiation of antithrombotic treatment. In addition, OCT-A is useful for diagnosing ischemic retinal changes that cannot be observed with other diagnostic methods and monitoring them.

DNA methylation dynamics in human carotid plaques after cerebrovascular events.

OBJECTIVE: To understand whether cerebrovascular events, a major complication of atherosclerosis, are associated with any specific DNA methylation changes in the carotid plaque. APPROACH AND RESULTS: We profiled the DNA methylomes of human symptomatic carotid plaques obtained from patients who had cerebrovascular events (n=19) and asymptomatic counterparts (n=19) with a high-density microarray (≈485 000 CpG sites, Illumina), and crossed DNA methylation data with RNAseq-based expression data from an independent symptomatic carotid plaque set (n=8). Few (30) CpGs showed a significant (P<0.05; absolute Delta-Beta, >0.20) differential methylation between the 2 groups. Within symptomatic carotid plaques, DNA methylation correlated significantly with postcerebrovascular event time (range, 3-45 days; r-value range, -0.926 to 0.857; P<0.05) for ≈45 000 CpGs, the vast majority of which became hypomethylated with increasing postcerebrovascular event time. Hypomethylation was not due to erasure of the gene-body and CG-poor region hypermethylation that accompany the progression of stable lesions, but rather targeted promoters and CpG islands. Noticeably, promoter hypomethylation and increased expression of genes involved in the inhibition of the inflammatory response, defense against oxidative stress, and active DNA demethylation were observed with increasing postcerebrovascular event time. Concomitantly, histological changes consistent with phagocyte-driven plaque healing were observed. CONCLUSIONS: Weak changes in the DNA methylome distinguish symptomatic from asymptomatic plaques, but a widespread demethylation resulting in permissive transcriptional marks at atheroprotective gene promoters is established in plaques after a cerebrovascular event, thus mirroring previous observations that ruptured plaques tend to revert to a stable structure. The identified loci are candidate targets to accelerate the pace of carotid plaque stabilization.

Atypical erythrocytes and platelets in a patient with a pro-thrombin mutation.

Prothrombin mutation G20210A, anti-phospholipid syndrome as well as iron overload has previously been shown to cause thrombotic events. The main reason for this is the involvement of these anomalies in causing hypercoagulability of the coagulation system, which frequently leads to venous and arterial thrombotic events. We report the case of a 37-year-old white female with prothrombin mutation G20210A, anti-phospholipid syndrome, as well as an increased serum ferritin level, who experienced two transient ischemic attacks and suffers from regular amaurosis fugax. We present an ultrastructural depiction of erythrocytes, platelets, and the fibrin network, to explain the clinical manifestations of the thrombotic state seen in this patient.

Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations.

OBJECTIVE: Familial hemiplegic migraine (FHM) is a genetically heterogeneous disorder in which three genes, CACNA1A, ATP1A2, and SCN1A, are currently known to be involved. FHM is occasionally associated with other neurologic symptoms such as cerebellar ataxia or epileptic seizures. A unique eye phenotype of elicited repetitive daily blindness (ERDB) has also been reported to be cosegregating with FHM in a single Swiss family. METHODS: We report an additional family in whom the proband had, in addition to FHM, typical ERDB. In this family and the previously reported Swiss family, the whole coding region of the SCN1A gene was screened after exclusion of mutation in CACNA1A and ATP1A2 genes. RESULTS: We identified two novel SCN1A mutations (c.4495T>C/p.Phe1499Leu and c.4467G>C/p.Gln1489His missense substitutions) in exons 24 and 23, respectively, segregating with the disease in all living affected members. Both mutations were absent from 180 healthy Caucasian controls and were located in an intracellular loop highly conserved throughout evolution. CONCLUSION: We report new clinical data supporting cosegregation of familial hemiplegic migraine and the new eye phenotype of elicited repetitive daily blindness and two novel SCN1A mutations as the underlying genetic defect in two unrelated families. SCN1A encodes the voltage-gated sodium channel Nav1.1 that is highly expressed in the CNS including the retina. This remarkably stereotyped new eye phenotype has clinical characteristics of abnormal propagation of the retinal electrical signal that may be a retinal spreading depression. These results suggest that SCN1A mutations, which alter neuronal brain excitability, may occasionally alter retinal cell excitability.

Ocular vascular thrombotic events: a diagnostic window to familial thrombophilia (compound factor V Leiden and prothrombin gene heterozygosity) and thrombosis.

In a 12-member, 3-generation kindred with conjoint inheritance of G1691A factor V Leiden (FVL) and G20210A prothrombin gene (PTG) mutations, identified through a proband with amaurosis fugax and his father with nonarteritic ischemic optic neuropathy (NAION), the authors' hypothesis was that ocular thrombosis was a diagnostic window to familial thrombophilia-thrombosis. The authors used polymerase chain reaction (PCR) measures for thrombophilia (FVL, PTG, C677T-A1298C methylenetetrahydrofolate reductase [MTHFR], platelet glycoprotein PLA1A2) and hypofibrinolysis (plasminogen activator inhibitor-1 4G4G). The 39-year-old white male proband, with amaurosis fugax and transient ischemic attacks (TIA), was found to be a compound heterozygote for FVL and PTG mutations. His symptoms resolved only after coumadin. His 44-year-old brother (deep venous thrombosis [DVT]) and 46-year-old sister (DVT, pulmonary embolus [PE]) were compound FVL-PTG gene heterozygotes. Of 4 asymptomatic children born to these 3 siblings, 2 were FVL heterozygotes and 2 PTG heterozygotes. The proband's 69-year-old father, with NAION and ischemic stroke, had PTG heterozygosity, familial high factor VIII, and compound MTHFR C677T-A1298C mutation with homocysteinemia. The proband's 61-year-old aunt had PTG heterozygosity, recurrent DVT, and mesenteric artery thrombosis. The proband's 67-year-old mother, free of thrombotic events, was a FVL heterozygote, had high factor VIII, and PAI-1 4G4G homozygosity. In this extended kindred, ocular thrombotic events (amaurosis fugax, NAION) were associated with variegated thrombotic events, including TIA, ischemic stroke, DVT, PE, and mesenteric artery thrombosis, and opened a diagnostic window to family screening and treatment for complex thrombophilias, which had previously been undiagnosed.

Novel mouse model of monocular amaurosis fugax.

BACKGROUND AND PURPOSE: Retinal ischemia is a major cause of visual impairment and is associated with a high risk of subsequent ischemic stroke. The retina and its projections are easily accessible for experimental procedures and functional evaluation. We created and characterized a mouse model of global and transient retinal ischemia and provide a comprehensive chronologic profile of some genes that display altered expression during ischemia. METHODS: Ischemia and reperfusion were assessed by observing flat-mounted retinas after systemic fluorescein injection. The temporal pattern of gene expression modulation was evaluated by quantitative reverse transcription-polymerase chain reaction from the occurrence of unilateral 30-minute pterygopalatine artery occlusion until 4 weeks after reperfusion. Electroretinograms evaluated functional sequelae 4 weeks after the ischemic episode and were correlated with histologic lesions. RESULTS: This model is the first to reproduce the features of transient monocular amaurosis fugax resulting from ophthalmic artery occlusion. The histologic structure was roughly conserved, but functional lesions affected ganglion cells, inner nuclear layer cells, and photoreceptor cells. We observed an early and strong upregulation of c-fos, c-jun, Cox-2, Hsp70, and Gadd34 gene expression and a late decrease in Hsp70 transcript levels. CONCLUSIONS: A murine model of transient retinal ischemia was successfully developed that exhibited the characteristic upregulation of immediate-early genes and persistent functional deficits. The model should prove useful for investigating mechanisms of injury in genetically altered mice and for testing novel neuroprotective drugs.

Amaurosis fugax: associations with heritable thrombophilia.

The aim of this study was to prospectively assess associations between amaurosis fugax, inherited thrombophilia, and acquired thrombophilia. Thrombophilia and hypofibrinolysis were studied in 11 cases (eight women, three men; all white) with amaurosis fugax, 57 +/- 17 years old, selected by the absence of abnormal brain magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), magnetic resonance venography (MRV), ipsilateral internal carotid artery plaque, atrial fibrillation, or cardiac thrombus. Cases were compared to 78 healthy adult white controls (53 +/- 18 years old) for serologic measures, and by polymerase chain reaction to 248 healthy white controls (78 adults, 170 children) for gene mutations. All 11 cases had one or more familial thrombophilic coagulation disorder including one heterozygous for the G1691A factor V Leiden mutation, two with low free protein S, four with high factor VIII, three with resistance to activated protein C, three homozygous for the C677T methylenetetrahydrofolate reductase (MTHFR) mutation, two compound C677T-A1298C MTHFR heterozygotes, and three with hypofibrinolytic 4G4G homozygosity for the PAI-1 gene. The case with factor VIII of 160% had two other thrombophilias (compound MTHFR C677T-A1298C heterozygosity, resistance to activated protein C), and hypofibrinolytic high Lp(a). Thrombophilic C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity was present in five of 10 (50%) cases vs. 30 of 248 (12%) controls, Fisher's p (p(f)) = .005. Thrombophilic factor VIII was high in four of 10 (40%) cases vs. 0 of 38 controls, p(f) = .001. Thrombophilic hyperestrogenemia in five of the eight women (four exogenous estrogen, one pregnant) may have interacted with inherited thrombophilia-hypofibrinolysis, promoting thrombus formation. In cases selected by the absence of abnormal brain magnetic resonance imaging, significant ipsilateral internal carotid artery plaque, atrial fibrillation, or cardiac thrombus, we speculate that amaurosis fugax can be caused by reversible (by anticoagulation) retinal artery thrombi associated with heritable thrombophilia and/or hypofibrinolysis, often augmented by estrogen-driven acquired thrombophilia.

Elicited repetitive daily blindness: a new familial disorder related to migraine and epilepsy.

The authors report a family affected by multiple daily episodes of transient visual loss, elicited repetitive daily blindness (ERDB); the onset was early in life, and the disease followed a benign course. ERDB is associated with childhood epilepsy and familial hemiplegic migraine, apparently segregating as a monogenic, autosomal dominant condition with variable expression. Genetic linkage to CACNA1A was excluded.