Cerebral venous sinus thrombosis: a complication of nitrous oxide abuse

Abstract

Nitrous oxide (NO) is an inhalant that has become increasingly popular as a recreational drug. While it is presumed to be harmless, a number of adverse effects of NO have been described. We discuss the case of a 24-year-old man with no medical history, who initially presented to the emergency department with progressive polyneuropathy caused by vitamin B₁₂ deficiency after NO abuse. Two days after being discharged with hydroxocobalamin supplementation, the patient returned with a severe headache, blurry vision and slurred speech. Imaging revealed cerebral venous sinus thrombosis. Hypercoagulability workup showed slightly elevated homocysteine and normalised vitamin B₁₂ after supplementation. Genetic testing showed a heterozygous prothrombin G20210A mutation. He was treated with low-molecular-weight heparin followed by dabigatran. We hypothesise that NO use may increase the risk of developing cerebral venous thrombosis, especially in patients with multiple risk factors and elevated homocysteine levels.

Background

Nitrous oxide (NO) is a low-priced, readily available recreational drug, which has gained popularity among adolescents and young adults.¹ Compared with 2014, worldwide, the use of NO has almost doubled, with 11.9% of respondents to the global drug survey in 2019 admitting they had used NO in the last year compared with 6.3% in 2014.^{2 3} Increased use of NO has shed light on a range of complications with regular use of NO, including neurological symptoms, like neuropathy and myelopathy, as well as hyperpigmentation of the skin and cytopenia.^{1 4} Few case reports have explored thrombosis as a side effect of NO abuse.^{5 6} In this report, we present a case illustrating the potential relationship between NO abuse and its effect on vitamin B₁₂ metabolism, blood coagulation and cerebral venous sinus thrombosis (CVST).

Case presentation

A 24-year-old man presented to the emergency department (ED) with 4 days of progressive hypoesthesia and weakness of distal upper and lower limbs. Neurological examination also showed reduced deep tendon reflexes and impaired vibration sense of the lower limbs up to the knee. The patient took no medication and had no relevant medical or family history. A lumbar puncture (LP) was performed for signs of Guillain-Barré syndrome or demyelinating myelopathy. Cerebrospinal fluid analysis showed no pleioctyosis and normal protein levels. MRI of the spine was performed, which did not show any signs of myelopathy. A post contrast series did not show any enhancement after contrast. Blood analysis for causes of polyneuropathy showed low vitamin B₁₂ of 81 pmol/L (145–569 pmol/L), with elevated methylmalonic acid of 26.200 nmol/L (50–340 nmol/L). Nerve conduction studies were not performed since myelopathy was ruled out by MRI, symptoms had been present for a week and had not progressed during admission; thus, electromyography at this stage could provide false negative results.

During hospital admission, the patient developed a postdural puncture headache, which resolved spontaneously within days. On further inquiry during admission, the patient admitted regular use of NO. He had shared cylinders filled with 10 L of liquid NO on a weekly basis with a few friends for multiple weeks, mainly in the weekends (a 10 L cylinder of NO fills approximately 925 balloons). The patient was discharged with a treatment of 1000 mg intramuscular hydroxocobalamin injections every 3 days for a total of 10 times to treat his neuropathy caused by vitamin B₁₂ deficiency.

Two days after discharge, he presented at the ED with a headache, blurry vision and slurred speech. According to his relatives, he had not used any illicit drugs since discharge and had last used NO before his first hospitalisation (more than 2 weeks ago). Urine analysis was negative for drugs.

On presentation at the ED, he had a blood pressure of 150/95 mmHg, a heart rate of 88 beats/min with temperature of 36.5°C and oxygen saturation of 94%. Neurological examination showed mixed non-fluent aphasia, dysarthria, right-sided central facial nerve palsy, hemianopia and hemiparesis. Ophthalmological examination showed optic nerve pallor. The patient’s second ED presentation and subsequent hospital admission will be discussed further in this report.

Investigations

Initial imaging at the ED included a CT scan (before and after intravenous contrast) of the brain, which showed a CVST at the superior sagittal sinus (figure 1).

Figure 1.

CT images with and without intravenous contrast on presentation in the emergency department. (A) CT without intravenous contrast showing an abnormally dense aspect of the superior sagittal sinus. (B) CT with intravenous contrast showing an empty delta sign indicating thrombosis of the superior sagittal sinus. (C) CT with intravenous contrast showing complete filling defect of the superior sagittal sinus.

He was readmitted to the hospital where he developed multiple secondary generalised tonic-clonic seizures during the first days of his hospitalisation. The seizures were successfully treated with valproic acid. A cerebral MRI was performed, which showed subacute ischaemia in the left frontoparietal region (figure 2). During hospital admission, the patient developed diplopia. Repeated ophthalmological evaluation showed bilateral papilloedema.

Figure 2.

MRI of the brain showing a subacute infarction in the left frontoparietal lobe on different sequences, with an arrow pointing to the infarction. (A) T1 showing a left frontoparietal hypointense lesion. (B) T1 with contrast showing the same hypointense lesion without contrast enhancement. (C) T2 fluid-attenuated inversion recovery showing a left frontoparietal hyperintense lesion. (D, E) Diffusion-weighted imaging (suboptimal) showing a left frontoparietal hyperintense lesion and apparent diffusion coefficient showing a hypointense lesion indicating subacute ischaemia. (F) Susceptibility weighted imaging showing a left frontoparietal hypointense signal indicating blood products in the lesion, thus showing that there is haemorrhagic transformation of the infarction.

Extensive coagulability analysis was performed (after starting anticoagulants). Genetic analysis revealed a heterozygous mutation for the prothrombin G20210A factor II gene, which is associated with a two to three times increased risk for thrombosis.⁷ Coagulation laboratory tests and autoimmune factors were found to be normal except for elevated fibrinogen: 6.3 g/L (2.0–5.0 g/L), which was not considered clinically relevant.

Since vitamin B₁₂ supplementation was started during the first hospitalisation, coagulability and follow-up analysis during the second hospitalisation showed elevated vitamin B₁₂ level of >1476 pmol/L (145–569 pmol/L) and normal serum homocysteine of 11.2 μmol/L (<15 umol/L).

Treatment

The patient was started on therapeutic low-molecular-weight heparin (LMWH). This was preferred over vitamin K antagonists due to the shorter half-life of LMWH compared with vitamin K antagonists. This gives the benefit of being able to perform a LP to treat potential intracranial hypertension while only having to stop treatment with LMWH for a short amount of time. Since the patient did develop signs of intracranial hypertension (headache and papilloedema), which is a known complication of a CVST, he was advised to undergo a LP. The previously performed CT ruled out risk for cerebral herniation or other causes of intracranial hypertension other than CVST. However, the patient opted for medical treatment of intracranial hypertension symptoms with acetazolamide.

He was referred to a vascular medicine specialist for further evaluation of risk factors for hypercoagulability and to assess the need for lifelong treatment with dabigatran. He was also referred to an ophthalmologist to evaluate the papilloedema. After discharge, he was monitored in our outpatient clinic. He was referred for ambulatory physical rehabilitation and a psychiatry consultation for NO abuse.

Outcome and follow-up

On discharge, the patient only had issues with headache and diplopia, which improved during ambulatory follow-up. The patient finished his ambulatory physical rehabilitation 2 months after discharge. Since the patient showed motivation to discontinue his NO use, the psychiatrist did not see any indication to further follow-up on the patient. Nine months after the event, he reported short-term memory issues and fatigue following moderate physical or mental effort.

The vascular medicine specialist switched LMWH for dabigatran a few weeks after discharge. Since the test for lupus anticoagulant was inconclusive, this test will be repeated in 6 months. The patient will be using dabigatran until re-evaluation with the results of the subsequent lupus anticoagulant analysis test.

Four months after discharge, the papilloedema had completely recovered. The patient discontinued using acetazolamide. Six months after discharge, the papilloedema had recurred, suggesting the development of chronic intracranial hypertension. Acetazolamide was restarted.

The patient has not experienced any epileptic seizures since discharge. The valproic acid was successfully tapered and the patient has stopped using this medication.

Discussion

This is one of only a few cases describing the potential relationship between NO use, vitamin B₁₂ deficiency, polyneuropathy and CVST. The effect of NO on vitamin B₁₂ homeostasis may provide an explanation for this.

NO is known to oxidise cobalamin to its inactive form and thus decrease present methylcobalamin. Since methylcobalamin functions as a cofactor for methionine synthase, low methylcobalamin will inhibit this enzyme. Methionine synthase catalyses two reactions: the reaction from 5-methyl-tetrahydrofolate to tetrahydrofolate and from homocysteine to methionine using the methyl group produced in the first reaction. Inhibited methionine synthase by insufficient levels of methylcobalamin will lead to decreased plasma levels of methionine and increased levels of homocysteine.^{8 9}

Since NO oxidises cobalamin, the risk of complications (such as polyneuropathy or CVST) will increase if vitamin B₁₂ levels are lower. This means that having risk factors for low vitamin B₁₂, such as following a vegetarian diet or abusing alcohol, will increase the chance of developing complications by NO use. The patient in this report did not have such risk factors.

It was found that the risk of complications due to NO use increases with a higher amount of NO use in a short period of time or when NO is used daily. Infrequent use of 50–100 bulbs within 3 hours would increase the risk of complications, as would use of 10–20 bulbs on a daily basis.¹⁰ Since the patient in our report repetitively used a high amount of NO in a short amount of time (since he mostly used during the weekends), he was at risk of developing complications due to NO use.

The vitamin B₁₂ deficiency following NO use is one mechanism by which NO causes neuropathy. Methionine is needed in the methylation of myelin. Since vitamin B₁₂ is needed to catalyse the reaction from homocysteine to methionine, low levels of vitamin B₁₂ will cause demyelination.^{1 9}

A recent study has suggested that NO use may also lead to peripheral nerve toxicity by a separate mechanism.¹¹ In this study, the authors compared neuropathy in patients with vitamin B₁₂ deficiency caused by NO use and vitamin B₁₂ deficiency by other causes. They found a difference in patterns in nerve conduction studies between these two groups of patients. Nerve conduction studies in patients who had used NO showed that motor axons were more affected. For the patients with polyneuropathy caused by a vitamin B₁₂ deficiency due to other causes, nerve conduction studies showed that sensory axons were mostly affected. While the pathophysiological mechanism that explains this difference is not yet understood, this does suggest that there is a separate mechanism by which NO causes neuropathy.¹¹ This finding may also explain why patients with a polyneuropathy after NO use can present differently; presenting with more motor issues than are found with polyneuropathy caused by vitamin B₁₂ deficiency. Unfortunately, no nerve conduction studies were performed in this case and while the patient in this report showed both sensory and motor issues, the progressive distal limb weakness was the precipitating factor to visit the ED.

The increased levels of homocysteine found with vitamin B₁₂ deficiency could be used to explain associated risk of NO use with CVST. Homocysteine is known to have prothrombotic properties due to inhibition of both protein C and thrombomodulin activity in both veins and arteries, thereby hampering a key pathway preventing thrombus formation.¹² Previous studies have shown an increased risk for venous thromboembolic events (VTEs) in patients with hyperhomocysteinaemia.¹³ However, while mildly elevated homocysteine has been associated with increased risk of VTE in patients, Oger et al have also shown this association in patients with low vitamin B₁₂ independent of hyperhomocysteinaemia.¹⁴ In addition, further studies have shown that the associations between VTE and mild hyperhomocysteinaemia had not been adjusted for confounders, such as body mass index and smoking status.¹⁵

One limitation of our case report is that homocysteine was measured 9 days after the start of vitamin B₁₂ supplementation. However, our understanding of the physiological mechanism of vitamin B₁₂ deficiency and significantly elevated methylmalonic acid levels are highly suggestive of elevated homocysteine levels before vitamin B₁₂ supplementation was begun.

Furthermore, studies report controversial results regarding homocysteine lowering therapy and the reduction in the incidence and recurrence rates of VTE and stroke.^{16 17} This may suggest that reduced homocysteine levels after 9 days of supplementation may not yet have affected the patient’s risk of developing a VTE. However, study populations used in these studies were older and had significant cardiovascular risk factors, suggesting possible confounding and poor generalisability to this clinical case. Also, these studies did not include CVST as an outcome. Furthermore, studies have not conclusively shown that hyperhomocysteinaemia is associated with higher risk for VTE; this may be the reason homocysteine-lowering therapies fail to show clinical effect.

Few case reports have described thrombotic events in the context of NO abuse. A report by Pratt et al describes CVST as an adverse effect of NO abuse in a female patient with additional risk factors, including first trimester pregnancy and a mutation of the MTHFR gene, involved in homocysteine metabolism.⁵ Bajaj et al described a case of ischaemic stroke in a patient with decreased vitamin B₁₂ and elevated homocysteine levels after NO abuse.¹⁸ Pulmonary embolism and deep brain thrombosis have also been reported in a case of NO abuse in a 29-year-old man.¹⁹ A case report published by den Uil et al describes a 32-year-old male patient with chronic abuse of NO who presented with an aortic arch embolism, leading to axillary artery occlusion and subsequent medial cerebral artery stroke. This patient had a heterozygous (prothrombin G20210A) factor II gene, vitamin B₁₂ deficiency and hyperhomocysteinaemia with no other coagulation abnormalities. In this single patient study, they used a proof-of-principle approach showing normalised homocysteine and vitamin B₁₂ in periods without NO abuse, and recurrent increases in homocysteine along with VTE on relapsing into NO use.⁶ In addition, a case report by Liu et al shows a case of cortical vein thrombosis after NO use in a patient with a history of chronic NO use, with no elevated homocysteine reported. However, she did use an oral contraceptive.²⁰ These case reports highlight the complex interaction between predisposing genetic mutations or risk factors, hyperhomocysteinaemia and NO abuse in both arterial thromboembolism and VTE.

CVST is reported to be a rare complication of LP, and LP is reported in clinical guidelines as a mechanical precipitant of CVST. There have been multiple studies regarding the mechanism by which way a LP may influence the occurrence of CVST. Canhao et al showed that a LP results in a decrease of mean blood flow velocity by an average of 47% in the straight sinus immediately following LP. A decrease of 29% was found more than 6 hours after LP.²¹ An alternative mechanism suggested in a case report by Alblas et al is that postdural puncture intracranial hypotension may reduce blood flow in the intracranial veins through vein dilation. This may lead to progressive thrombus formation.²² Our patient reported postdural puncture headache during his first admission, which resolved within a few days. Intracranial hypotension may have occurred and maintained (asymptomatically) for several days after, which they may have been another risk factor for developing CVST. However, the patient in the case report by Alblas et al developed CVST 4 days after the LP and had an additional risk factor (intravenous prednisone use).²²

The presentation of CVST in this patient indicates that NO abuse could increase the risk of CVST, particularly in the presence of additional risk factors, such as recent LP and factor II G20210A heterozygous mutation. Chronic NO abuse has been associated with myelopathy and polyneuropathy, and recently several case reports have reported hyperhomocysteinaemia associated with NO abuse, in turn, leading to both arterial thromboembolism and VTE. We suggest that this may be driven by the effect of NO on vitamin B₁₂ metabolism and the resulting hyperhomocysteinaemia, which proposes a risk associated with the use of this recreational drug. This report aims to contribute to the awareness of risks associated with NO abuse among the general public.

Learning points.

• This is one of the few cases linking nitrous oxide (NO) abuse to thrombosis.

• NO can cause a vitamin B₁₂ deficiency, in turn, leading to hyperhomocysteinaemia.

• NO abuse may thus increase the risk of developing a cerebral venous sinus thrombosis.

Ethics statements

Patient consent for publication

Obtained.