Syed Husain1 and Diya Baker2
1FY2 doctor, Sandwell and West Birmingham Hospitals Birmingham
2ST2 Ophthalmology trainee, West Midlands Deanery
– There is an increasing incidence of patients presenting to emergency departments with history of nitrous oxide use and neurological symptoms.
– A detailed drug history is imperative as part of any ophthalmology/neurology history taking to ensure significant differentials are considered e.g. link between N2O inhalation and raised ICP.
-There should be a low threshold for CT venogram in patients with headaches and nitrous oxide use to exclude CVST.
-Patients presenting with a history of nitrous oxide use and headaches should be assessed with fundoscopy as part of the overall neurological evaluation, and if any visual disturbance is reported they should undergo a complete ophthalmological assessment.
Described as an epidemic, recreational nitrous oxide (N2O) use has risen more than 40% over the past decade in 16-24 year olds, and poses significant risk to their health including death (1,2,3). Common initial symptoms include headache, visual hallucinations and paraesthesia in the distal limbs. Reported morbidity includes; bone marrow suppression, cytopenia, skin hyperpigmentation and myeloneuropathies including sub-acute combined degeneration of the spinal cord (4). Evidence suggests these sequelae are the result of a functional Vitamin B12 deficiency induced by N2O (5). There have also been few reports of arterial and venous thrombosis attributed to N2O usage, with rare accounts of cerebral venous sinus thrombosis (6,7).
Despite the health risks associated with N2O abuse, it is sought after for its short-lived euphoria and widely presumed to be a safe ‘legal high,’ particularly in the United Kingdom and Netherlands, where it is cheap and readily accessible (8). Additionally, it is easy to administer via ‘whippets’- small metal canisters designed for release of N2O into whipped cream, yet can be discharged into balloons from which the gas is inhaled. With an increasing number of emergency admissions related to N2O abuse, governmental and media campaigns are seeking to curb its use through raising awareness of its dangers (1).
Herein, we present a case report of a young male with worsening headaches and visual disturbance who was found to have papilloedema. Through exclusion, there is a high index of suspicion that this was related to N2O abuse. Therefore, we hope clinicians will adopt a low threshold for taking a detailed drug history and investigation for raised intracranial pressure (ICP) in this patient population, including ophthalmological assessment.
A normally fit and well, 21 year old gentleman presented to the eye casualty with worsening occipital headaches for 2 weeks, followed by blurring of vision with a pressure-like sensation behind both eyes. This was accompanied by intermittent paraesthesia in the upper left arm. The headache was worse on lying flat, indicative of raised intracranial pressure, and reported occasional persistent tinnitus in his left ear. He noted no other neurological symptoms or visual complaints. In the past he was using Cannabidiol oil vape and cigarettes, equating to approximately 4 pack-years. On further questioning, he admitted to inhaling N2O intermittently for four months, followed by increasing amounts of inhalation during the three weeks prior to presentation, approximately 0.5L per day.
There were grossly reduced visual fields bilaterally on visual confrontation. Slit lamp biomicroscopy revealed bilateral Frisen Grade V papilloedema, suggesting a high risk of visual crash. Visual acuity and colour vision was normal. Neurological examination was otherwise unremarkable.
CT head/CT venogram showed an empty sella with distortion of the optic nerves with narrowing of the lateral transverse sinuses, indicating raised intracranial pressure. There did not appear to be any obvious cerebral venous sinus thrombosis (CVST). A lumbar puncture was performed for diagnostic and therapeutic purposes. Opening pressure was 51cmH2O and reduced to 22cmH2O accompanied by immediate relief of the headache. However, the headache returned after 4 hours. CSF results were normal. Whilst awaiting B12/homocysteine levels, he was administered a prophylactic intramuscular B12 injection.
Common causes of bilateral optic disc swelling include papilloedema (optic disc swelling secondary to raised intracranial pressure), infiltrative optic neuropathy, toxic optic neuropathy and malignant hypertension. CT head excluded any obvious space occupying lesions or intracranial bleeding, and CT venogram excluded any obvious thrombi, although it is possible microthrombi were not visualised. Lumbar puncture showed raised intracranial pressures. The patient’s vital signs were within normal parameters as were his full blood count and electrolyte profiles. Optic disc atrophy is known to occur with Vitamin B12 deficiency, which can occur as a result of chronic N2O use, however this patient had optic disc swelling. He denied consuming any substances known to cause toxic optic neuropathy. Similarly, the patient was otherwise systemically well with no signs of malignancy. It is likely this patient’s visual decline is multifactorial due to; raised ICP and an element of ischaemic optic neuropathy. Objectively, with no obvious CVST, the modified diagnostic criteria for idiopathic intracranial hypertension (IIH) was fulfilled and therefore managed as an atypical IIH patient (9).
The patient was immediately transferred to a regional neurosurgical centre where a therapeutic lumbar drain was inserted. After lumbar drain removal, the optic disc swelling was improving, confirmed by OCT, and high dose acetazolamide was initiated (from 500mg BD to 500mg QDS) on discharge. As such, there was no requirement for a ventriculoperitoneal shunt.
At 6-week follow-up, the patient’s optic disc swelling was continuing to improve and he reported no symptoms. He was counselled that he may not be able to drive again as the range of his visual field was unlikely to improve in the context of ischaemic damage to the optic nerve. However at 6 month follow-up the patient reported complete subjective return of normal field of vision.
Our case report indicates a novel relationship between recreational N2O inhalation and raised ICP. Much of the research into the effects of N2O is derived from the anaesthetic literature, having previously been widely popular as an anaesthetic agent due to its rapid onset/offset, low volatility and analgesic properties5. Early physiological studies have reported a dose-dependent effect of increasing N2O concentrations leading to cerebral vasodilation and therefore raised intracranial pressures10. These effects were reversed on removal of the N2O. However, to our knowledge, there are no reports of recreational N2O use leading to papilloedema, in the absence of another cause for the papilloedema, e.g. CVST. The patient described herein was overweight, however, possessed none of the other established risk factors for IIH. In light of the actions of N2O on intracranial pressure, it is possible there is a relationship between chronic/high dose N2O inhalation and papilloedema, rather than the raised ICP being idiopathic in nature.
Thromboembolic phenomena have been widely reported in the literature following chronic or high doses of N2O. A recent systematic review highlighted six cases of arterial thrombosis and nine cases of venous thrombosis, four of which were intracranial (median age=26 years, males formed 71% of all cases) (11). Although these patients presented following recreational N2O use, few had confounding factors such as Coronavirus disease (COVID) and methylenetetrahydrofolate reductase (MTHFR) gene mutations. MTHFR gene mutations result in hyperhomocysteinaemia thereby predisposing to arterial thrombosis, with meta-analysis of case-control studies demonstrating a link with venous thrombosis too (12). The patient described herein had no obvious thrombi therefore did not undergo testing for thrombogenic mutations. The majority of patients reported by Oulkadi et al. had elevated levels of homocysteine and all those whose Vitamin B12 levels were measured prior to supplementation had normal levels, which is expected since the function of the Vitamin B12 molecule is impaired- not its concentration. The patient described herein was prophylactically given Vitamin B12 injection before his levels were measured making any meaningful association between Vitamin B12 and papilloedema difficult in this case.
Vitamin B12 is a vital cofactor in enzymatic pathways necessary for methylation of the central nervous system (CNS) nerve fibres. As such, the functional Vitamin B12 deficiency caused by N2O can result in neurological symptoms such as paraesthesia, as reported in this case,and rarely subacute combined degeneration of the spinal cord (5).
Recreational N2O usage has sharply increased over the years with an associated rise in morbidity and mortality. It is imperative clinicians are aware of the multisystem effects from N2O inhalation, especially its potential for raised ICP, to manage and prevent long-term sequelae, and educate the public on its risks.
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- Drug misuse: findings from the 2018 to 2019 CSEW [Internet]. GOV.UK. [cited 2022 Sep 25]. Available from: https://www.gov.uk/government/statistics/drug-misuse-findings-from-the-2018-to-2019-csew
- Office for National Statistics. Drug-related deaths involving nitrous oxide in England and Wales, 1993 to 2017. 2018. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/adhocs/009096drugrelateddeathsinvolvingnitrousoxideinenglandandwales1993to2017.
- Garakani A, Jaffe RJ, Savla D, Welch AK, Protin CA, Bryson EO, et al. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: A systematic review of the case literature. Am J Addict. 2016 Aug;25(5):358–69.
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- de Valck L, Defelippe VM, Bouwman NAMG. Cerebral venous sinus thrombosis: a complication of nitrous oxide abuse. BMJ Case Rep. 2021 Aug 16;14(8):e244478.
- Van Amsterdam J, Nabben T, van den Brink W (2015) Recreational nitrous oxide use: prevalence and risks. Regul Toxicol Pharmacol 73(3):790–796. https://doi.org/10.1016/j.yrtph.2015.10.017
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- Oulkadi S, Peters B, Vliegen AS. Thromboembolic complications of recreational nitrous oxide (ab)use: a systematic review. J Thromb Thrombolysis [Internet]. 2022 Jun 27 [cited 2022 Sep 25]; Available from: https://doi.org/10.1007/s11239-022-02673-x
- den Heijer M, Rosendaal FR, Blom HJ, Gerrits WB, Bos GM. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost. 1998 Dec;80(6):874–7.