Isolated cortical vein thrombosis after nitrous oxide use in a young woman: a case report

Nitrous oxide has been widely used as an anesthetic agent in the medical field. However, previous studies have found its use is associated with various medical conditions including macrocytic anemia, peripheral neuropathy, subacute combined degeneration, deep vein thrombosis, pulmonary embolism, aortic thrombosis and cerebral venous sinus thrombosis [1‐20]. Here for the first time we report a young woman with isolated cortical vein thrombosis related to nitrous oxide use.

In this report we described a young Chinese woman with isolated cortical vein thrombosis [21] related to nitrous oxide use. Her history of peripheral neuropathy and subacute combined degeneration was most probably also attributed to nitrous oxide. To our knowledge this is the first case report on the association between nitrous oxide use and isolated cortical vein thrombosis in the existing literatures.

Nitrous oxide has gained its popularity among young people worldwide for many years [22] and also among Chinese people in recent years. Nitrous oxide produces analgesic and anxiolytic effects upon inhalation [22] and has abuse potential [13]. Nitrous oxide could potently change cobalamin from reduced to oxidized state [23]; the lack of bioavailable cobalamin disrupts the normal function of methionine synthase which requires both reduced cobalamin and folate as cofactors [24]. Reduced methionine further leads to reduced S-adenosylmethionine production, which is associated with defective DNA maturation, megaloblastic changes of red blood cells [24] and abnormal myelination of nerve fibers [25]. This is supported by numerous previous individual reports and systematic reviews on the incidence of megaloblastic anemia, peripheral neuropathy and subacute combined degeneration related to nitrous oxide [1‐16], and also in line with a history of peripheral neuropathy and subacute combined degeneration of our patient.

Much less frequently reported were incidences of thrombotic events related to chronic use of nitrous oxide. Den Uil et al. reported a 32-year-old male with aortic arch thrombus formation, increased homocysteine and decreased vitamin B level, and a heterozygous factor II mutation [19]. Bajaj et al. described a 32-year-old male with ischemic stroke, decreased vitamin B12 and folate level, and increased homocysteine level [20]. Sun et al. reported a 29-year-old male with deep vein thrombosis, pulmonary embolism and homocysteinemia [18]. Pratt et al. presented a 21-year-old female with a large cerebral venous sinus thrombosis with elevated homocysteine and methylmalonic acid level, normal cobalamin and folate levels. The patient was also pregnant and had significant MTHFR polymorphisms [17]. Previous studies showed that MTHFR genotype polymorphisms including C677T and A1298C were associated with elevated homocysteine levels [26, 27]; homocysteinemia was again associated with increased risk of venous thrombosis [28, 29]. Furthermore, oral contraceptive has been associated with increased thrombotic risk in women [30, 31]. While in all the above mentioned case reports there was consistent elevation of homocysteine level, our patient only had a high normal homocysteine level. Our patient had normal protein C, protein S and beta-HCG levels; Factor V Leiden mutation was not found. Thus, it cannot be excluded that the use of nitrous oxide by our patient in the preceding week of stroke still increased the homocysteine level (homocysteine level was 9 umol/L one year ago when the diagnosis of subacute combined degeneration was made) and contributed to a hypercoagulable state [32] together with oral contraceptive use. Our patient also had PAI-1 4G/5G polymorphism. However, it is to note that a recent study did not find a higher risk of venous thrombosis related to PAI-1 4G/5G polymorphism [33], and it is uncertain what role it played in the thrombotic event in our patient.

A major limitation is that we could not screen for all types of hereditary thrombophilia to exclude effects of other unknown conditions. However, considering the close temporal relationship between nitrous oxide use and the incidence of isolated cortical vein thrombosis in our patient who had a clear past history of medical conditions associated with nitrous oxide use, we believe nitrous oxide use had at least partly contributed to the formation of isolated cortical vein thrombosis in our patient despite of scare reports from existing literatures [17‐20].

In conclusion, nitrous oxide use could be associated with thrombotic events including isolated cortical vein thrombosis, especially in individuals with other factors predisposing to a hypercoagulable state apart from diseases of the hematological and neurological systems. Early recognition and treatment of isolated cortical vein thrombosis is critical. Considering its easy accessibility among young people, it is of great importance to raise public consciousness of the potential negative effects of nitrous oxide use on young individuals.