Vertebral Artery Dissection and Hyperhomocysteinemia: A Case Report

In young adults, cervical artery dissection (CAD) is recognized as the second cause of stroke [1, 2, 3], justifying approximately 20% of acute cerebrovascular events before 45 years [4–7].The cause of CAD is still unknown in most cases. Except in anecdotal case reports, the most recognized predisposing factors are traumas and primary diseases of the arterial wall [8].In 1969 McCully [9]hypothesized a possible link between increased plasma level of homocystein and vascular disease. Nowadays, we know that mild hyperhomocysteinemia, i.e. 12–14 µmol/l, is also an independent risk factor for vascular disease [10, 11, 12].Among factors contributing to mild hyperhomocysteinemia the thermolabile form of the enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) is a quite common genetic abnormality that occurs in 4–10% of the general population as homozygous form [12, 13, 14, 15].The genetic base of thermolability has been detected as a C to T substitution at nucleotide 677 [12, 15]of the MTHFR gene. Homozygotes for the thermolabile form have a specific activity of ∼50% of normal while heterozygotes have ∼75% of normal subjects.We describe a case of vertebral artery dissection associated to hyperhomocysteinemia and homozygosity for the thermolabile form of MTHFR.A 43 year-old man was admitted to our Stroke Unit for acute cerebrovascular disorder. At the neurological examination he showed left ptosis and miosis, anhydrosis of the left upper part of the face, horizontal nystagmus, paralysis of the gaze on the left side, left deviation at Romberg sign, pain, tactile and thermic hypoesthesia at the right part of the body. Two weeks before he had complained sudden pain on the back of the neck followed by vomiting, ataxia on walking, blurring of bilateral vision and left ptosis. He underwent both CT scan and MRI of the brain which were negative for focal lesions. We performed a duplex color-flow examination which showed high-resistance signal flow on the left vertebral artery in the proximal segment in the absence of stenosis and normal carotid and right vertebral artery flow. We suspected a vertebral dissection; in this context angiography showed a very low flow on the extracranial part on the left vertebral artery caused by a thight stenosis of the last part of the vessel.Heparin was immediately started (24,000 IU daily) by continuous intravenous infusion. After 10 days MRI showed a thrombus on the left vertebral artery. Duplex color-flow examination was carried out once a week; after 1 month we found normal flow on the left vertebral artery.Angiographic studies performed after 2 and 7 months confirmed the good flow of the vessel. After intravenous heparin, the treatment was continued with warfarin for 6 months.Neither major vascular risk factors nor previous head trauma were documented. The only abnormal finding was a high total homocysteine level (38 µmol/l) which was confirmed twice. Folate level (2.51 ng/ml) as well vitamin B12 levels (172 pg/ml) were slightly below the normal range.The patient presented a family history for cardiovascular disease, so we carried out the genotype for the thermolabile form of MTHFR in the patient and all of his family (fig. 1) and measured homocysteine in the family members, except for his sister. His mother and brother had normal values for homocysteine (10.0 and 8.00 µmol/l), while homozygosity for the thermolabile form of MTHFR was found in the whole family.In our patient there is a correlation between increased total plasma homocysteine level and CAD. Until now there is no clinical evidence about mild hyperhomocysteinemia as risk factor for CAD, although it has been implicated as a pathogenetic factor in the development of vascular disease [11, 12].The importance of hyperhomocysteinemia in inducing endothelial damage is well documented by different studies both in vitro and in vivo [16, 17, 18, 19]. In cell culture experiments, addition of homocysteine to the cell medium induces cell detachment from endothelial cell monolayers [17]and functional abnormalities in the release of endothelium-derived NO [20].In non-human primates, a continuous homocysteine infusion for 3 months has resulted in patchy endothelial desquamation amounting to 10% of the aortic surface, and moderate hyperhomocysteinemia has led to abnormal vasomotor activity [19], which means that endothelial damage results in impaired endothelial function [21, 22].Woo et al. [22]have demonstrated that in subjects with hyperhomocysteinemia there is an impaired reaction of endothelium-dependent flow-mediated-dilation. The pathophysiological mechanism has not been elucidated until now; probably there is a physical injury with cell desquamation [16, 17], abnormal interaction between NO [18]and homocysteine related generation of reactive oxygen species [19, 20]. This kind of endothelium dysfunction can be the key for early events of atherogenesis [23]; we also suppose that it could be responsible for a weakness of the arterial wall (vascular stress in minor traumas) in patients with CAD.In our family study we created a link between mild Hcy as an independent risk factor for cardiovascular disease [9, 10, 11, 12]and as a new risk factor for CAD, leading to endothelial damage and artery dissection.Mild hyperhomocysteinemia can be due to genetic alteration responsible for the thermolabile form of MTHFR [13, 14, 15]. Different studies confirm that 677 C-T mutation is linked to vascular diseases, particularly coronary artery disease [24], carotid atherosclerosis [25]and silent brain infarction [26]. We think that a genetic mutation may contribute to hyperhomocysteinemia leading to endothial damage and artery dissection. In our patient and his family members there was a homozygosity for MTHFR, but only him presented hyperhomocysteinemia, so other pathogenetic factors may possibly trigger the increase of homocysteinemia.Hyperhomocysteinemia and genetic polymorphism may represent a risk factor for arterial dissection, where genetic and environmental factors could interact in the cascade of pathogenetic events leading to arterial wall damage.