Katherine Shoults, MD Case report: Neurological complications of nitrous oxide abuse A patient who presented with limb paresthesia and B12 deficiency was eventually diagnosed with subacute combined degeneration neuropathy secondary to nitrous oxide abuse. Case data ABSTRACT: A 34-year-old female ary to nitrous oxide (“laughing gas”) A 34-year-old female presented with with a history of alcohol and crystal abuse that had affected B12 activa- a 2-week history of progressive bilat- methamphetamine abuse presented tion. The patient was continued on eral limb paresthesia and tenderness, to the emergency department with B12 therapy, neurology follow-up as well as an inability to balance. She limb paresthesia and difficulty walk- was arranged, and addiction coun- had been well previously, although ing. At a primary care visit a week seling services were recommended. she did have a history of alcohol and earlier her progressive neurological Unfortunately, the patient was lost crystal methamphetamine abuse. She compromise had been viewed in the to follow-up after discharge from the had abstained from crystal metham- context of anemia and she was start- hospital. Physicians should be aware phetamine for 5 years and from alco- ed on daily B12 injections. Further that nitrous oxide is easy to acquire hol for 2 months. She was working as a investigations in hospital revealed in the form of commercially available care aid and denied using illegal drugs diminished proprioception, hyperal- cartridges or whipped cream canis- currently, but reported she had been gesia with pinprick and temperature ters called “whippits” and abuse of inhaling nitrous oxide (“laughing tests, a wide-based high-steppage nitrous oxide is increasingly com- gas”) for 6 months, with an escalation gait, elevated levels of B12 and ho- mon. Physicians should also be of use over the previous 2 months. mocysteine, and normocytic ane- aware that a high B12 level is diffi- She reported using 10 to 12 nitrous mia. Magnetic resonance imaging cult to interpret because nitrous ox- oxide cartridges (“whippits”) a day. A revealed abnormal cord signal inten- ide inhibits B12 activation yet does week earlier, she had visited a prima- sity in bilateral dorsal columns C1- not lower B12 levels. Patients pre- ry care clinic where her progressive C2 through C6-C7 and T4-T5 through senting with limb paresthesia, sen- neurological compromise was viewed T9-T10. Eventually the patient was sory loss, and B12 deficiency should in the context of anemia related to a diagnosed with subacute combined be asked about nitrous oxide use. low B12 level of 114 pmol/L. She degeneration neuropathy second- Abstinence is key to treatment. was diagnosed with B12 deficiency of unknown cause and started on daily B12 injections. Unfortunately, she did not refrain from nitrous oxide use fol- lowing this preliminary diagnosis and her symptoms continued. Dr Shoults is an internal medicine resident This article has been peer reviewed. at the University of British Columbia. 192 BC MEDICAL JOURNAL VOL. 58 NO. 4, MAY 2016 bcmj.org Case report: Neurological complications of nitrous oxide abuse In the emergency department her ing toes found on physical examina- physical examination revealed di- tion suggested corticospinal tract in- minished proprioception, diminished volvement, despite normal motor and vibration perception, and diminished reflex findings. Although there were light touch perception in the hands also clinical findings of a peripheral and lower limbs, with sensory loss in neuropathy in association with the pa- a glove and stocking pattern. She had tient’s spinal cord disease, nerve con- hyperalgesia with pinprick and tem- duction studies and electromyography perature tests. She had extensor plan- were not done to confirm this. tar reflex responses bilaterally and a Common causes of B12 deficien- wide-based high-steppage gait. Her cy were considered—malabsorption, Romberg test result was positive. Her pernicious anemia, and nutritional motor strength, reflexes, and cranial deficiency—in order to explain the Figure. T2-weighted MRI scan of the C4-C5 spine reveals signal hyperintensity in nerve findings were normal. patient’s initially low B12 levels. the dorsal columns (arrow). The patient’s blood work revealed Malabsorption was determined to be an elevated B12 level of 1069 pmol/L unlikely given the patient’s lack of can present with a megaloblastic an- (normal range 150 to 600 pmol/L) GI symptoms. Pernicious anemia is emia and subacute combined degen- and an elevated homocysteine level of rare but could not be ruled out in this eration syndrome similar to that seen 14.5 µmol/L (normal range less than case in the absence of the Schilling in pernicious anemia. Serum B12 lev- 12.9 µmol/L). Methylmalonic acid test. Nutritional deficiency was iden- els may be low, normal, or high, de- levels were not measured. A normo- tified as a likely contributor, given the pending on the extent of nitrous oxide cytic anemia was also identified, with patient’s iron deficiency and history abuse and B12 supplementation. This normal iron and ferritin levels but a of alcohol abuse. case highlights the fact that a high low transferrin saturation and a red The patient continued on daily B12 level is difficult to interpret be- cell distribution width (RDW) in the 1000-µg B12 injections for a total cause nitrous oxide inhibits B12 acti- upper range of normal (14.4%). Test of 10 days and then transitioned to vation yet does not reduce B12 levels. results for infectious diseases con- weekly injections for 2 months. A Inactive B12 will cause homocysteine sidered in the differential diagnosis, plan was made to transition to month- to be elevated because it is a substrate including HIV, hepatitis, and syphilis, ly injections depending on clinical re- for methionine synthase in the pro- were negative. Autoimmune condi- sponse, and neurology follow-up was duction of methionine. Methylmal- tions and demyelinating conditions arranged. The patient was counseled onic acid is also a precursor and can were also considered. Guillain-Barré on the importance of abstaining from likewise be elevated. and multiple sclerosis were excluded nitrous oxide and provided with in- Postoperative subacute combined based on history, physical examina- formation on addiction services in the degeneration and peripheral neuropa- tion, and imaging. Magnetic reso- community. Unfortunately, the pa- thy in susceptible patients treated with nance imaging revealed abnormal tient was lost to follow-up after dis- nitrous oxide anesthesia have been cord signal intensity in bilateral dor- charge from the hospital. reported in the literature for over 2 sal columns C1-C2 through C6-C7 decades. For example, Holloway and and T4-T5 through T9-T10 consistent Discussion colleagues described neurological with subacute degeneration ( Figure ). Nitrous oxide use can result in a sub- deterioration after nitrous oxide anes- The patient was eventually diag- acute combined degeneration of the thesia in 1990.2 Multiple cases since nosed with subacute combined degen- spinal cord and a peripheral neurop- have described patients with subclini- eration neuropathy secondary to ni- athy by converting B12 from an active cal B12 deficiency for reasons such trous oxide abuse that interfered with monovalent to an inactive bivalent. as pernicious anemia, irritable bowel B12 utilization. Subacute combined Active B12 is a coenzyme for me- disease, or dietary restrictions who degeneration refers to involvement thionine synthase, which plays a cru- experience neurological symptoms of both the posterior columns and the cial role in the generation of methyl immediately following surgery until lateral corticospinal tract. The MRI groups for the synthesis of several about 2 months after surgery. In these results highlighted the involvement of products, including DNA, RNA, and cases, duration of nitrous oxide expo- the posterior columns and the up-go- myelin.1 Clinically, this inactivation sure (40% to 66% concentrations) BC MEDICAL JOURNAL VOL. 58 NO. 4, MAY 2016 bcmj.org 193 Case report: Neurological complications of nitrous oxide abuse ranged from 1 to 11 hours.3 A recent to nitrous oxide, including dentists Competing interests systematic review analyzed adverse and anesthesiologists, have also been None declared. effects associated with nitrous oxide identified as being at increased risk use in labor and delivery.4 Maternal for misuse, abuse, and dependence on References adverse effects to the drug included nitrous oxide.8 1. Alt R, Morrissey R, Gang M, et al. Severe nausea, vomiting, and dizziness. The Abstinence is key in treatment. myeloneuropathy from acute high-dose study sizes were inadequate to assess Our patient did not abstain from use nitrous oxide (N2O) abuse. J Emerg Med more rare and serious effects such as and perceived no improvement in her 2011;41:378-380. neurological compromise.4 However, symptoms with B12 supplementa- 2. Holloway KL, Alberico AM. Postoperative it may be that pregnant women expe- tion alone. In the majority of cases, myeloneuropathy: A preventable compli- rience fewer serious side effects than patients improve with abstinence cation in patients with B12 deficiency. J the general population because the and B12 supplementation, although Neuro-surg 1990;72:732-736. B12 and folic acid they consume in symptoms can be slow to resolve and 3. Singer M, Lazaridis C, Nations S, et al. Re- prenatal supplements are protective. patients are not always deficit-free at versible nitrous oxide-induced myeloneu- Neurological effects related to the end of treatment. Serum B12 level ropathy with pernicious anemia: Case re- recreational nitrous oxide abuse have does not seem to correlate with treat- port and literature review. Muscle Nerve also been described in case reports. ment response.3 2008;37:125-129. Like our patient, most patients in Physicians should be aware that 4. Likis FE, Andrews JC, Collins MR, et al. these cases have subclinical B12 defi- patients may fail to mention nitrous Nitrous oxide for the management of la- ciency and symptoms that only devel- oxide when asked about drug use, and bor pain: A systematic review.