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Nitrous oxide myelopathy in an abuser of whipped cream bulbs
Nitrous oxide myelopathy 73
Nitrous oxide myelopathy in an abuser of whipped cream bulbs Helmut Butzkueven1 MBBS, John O. King2 MD, FRACP 1
Neurology Registrar, 2Senior Neurologist, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
Summary A 23 year old man presented with a severe posterior column myelopathy related to prolonged nitrous oxide abuse obtained from whipped cream bulbs. The site of pathology was identified by magnetic resonance imaging (MRI) and somatosensory evoked potentials. The mechanism of toxicity involves inactivation of vitamin B12 dependent enzymes. Appropriate treatment with methionine and vitamin B12 was instituted quickly with good neurological outcome. There are major concerns regarding the availability of nitrous oxide in supermarkets. © 2000 Harcourt Publishers Ltd Journal of Clinical Neuroscience (2000) 7 (1), 73–75 © 2000 Harcourt Publishers Ltd DOI: 10.1054/ jocn.1999.0149, available online at http://www.idealibrary.com on
Keywords: nitrous oxide toxicity, myelopathic disorders, substance abuse, anaesthetic toxicity Received 20 December 1998 Accepted 16 February 1999 Correspondence to: Helmut Butzkueven, 61 Gower Street, Kensington, Victoria 3031, Australia. Tel: + 613 9376 3595; E-mail: [email protected]
INTRODUCTION Nitrous oxide, a common analgesic and anaesthetic agent, is occasionally abused by dental and medical personnel. Neurological sequelae of prolonged exposure include potentially irreversible axonal peripheral neuropathy and myelopathy. Recharging bulbs for whipped cream dispensers contain nitrous oxide and are freely available at supermarkets in Australia. We wish to report a patient with a severe myelopathy resulting from prolonged abuse of these cartridges. There are two previous reports in the literature of neurological sequelae using such cartridges, but this is the first to provide clinical and imaging evidence of the site of toxicity in the posterior columns of the spinal cord.1,2
limbs, there was a mild increase in tone, with normal power and reflexes. Pain and temperature sensation were preserved, as was vibration sense, but there was a gross disturbance of proprioception including severe difficulty in detecting the direction of passive movement of his wrists and elbows. There were no cerebellar signs. In the legs, there was a mild increase in tone with brisk reflexes but flexor plantar responses and normal power. Again, sensory testing revealed abnormalities only of proprioception – at the toes, ankles, knees and even at the hips; this was so severe that the patient, with his eyes closed, was completely unable to tell whether his hips and knees were being flexed or extended passively. He was unable to walk, even with support, and Romberg’s test was predictably positive. General examination was normal. Initial investigations revealed a mild macrocytic anaemia with a haemoglobin of 122 g/l and a mean cell volume of 100 fl. The vitamin B12 level was borderline at 130 mcmol/l, with normal red cell folate. The spinal fluid was acellular with a protein of 0.76 g/l (normal < 0.45 g/l), and a normal glucose level. Routine nerve conduction studies of the lower limb were normal. Somatosensory evoked responses from tibial nerve stimulation revealed normal conduction to the lumbar spine, but slow conduction to the cortex, indicative of a central nervous system cause for his severe proprioceptive abnormalities. INVESTIGATIONS MRI scan of the brain was normal. A T-2 weighted MRI scan of the cervical spine showed increased signal in the posterior cervical cord, and transverse images demonstrated posterior column pathology (Figs 2 & 3). The patient was treated with daily vitamin B12 injections (hydroxycobalamin 1000 mcg i.m.) and methionine one gram orally t.d.s. After two weeks, he still required the assistance of another person to walk and was discharged to an inpatient rehabilitation facility. At outpatient review three months later, he was walking independently with only minor proprioceptive abnormalities on examination. He had gained 10 kg and his mood appeared normal. DISCUSSION Mechanism of toxicity Nitrous oxide interacts in vivo with vitamin B12 by converting the monovalent cobalt ion of the vitamin to its bivalent form. This reaction irreversibly inactivates B12 and enzymes in which it is a cofactor, specifically methionine synthase.
Case report A 23 year old man was admitted to the neurology unit of The Royal Melbourne Hospital in August 1997 with a history of increasing gait disturbance over the preceding 5 days, mainly due to inco-ordination. In addition, the patient complained of tingling and numbness in the fingers and, to a lesser degree, in the feet. He had used heroin intranasally on a weekly basis for 3 years, but not in the preceding month. He gave a history of nitrous oxide abuse using approximately 40–60 whipped cream bulbs per day during the last 6 months. He obtained these at three local supermarkets, at a cost of approximately $A30 per day (Fig. 1). There was no other significant past history. On examination, he was malnourished, easily distractable and hypomanic. The cranial nerves were normal. In the upper
© 2000 Harcourt Publishers Ltd
Fig. 1 Whipped cream bulbs containing nitrous oxide.
Journal of Clinical Neuroscience (2000) 7(1)
74 Butzkueven and King
Fig. 4 Methionine synthase catalyses the generation of tetrahydrofolate (THF) and methionine from homocysteine and methyltetrahydrofolate. Methionine is metabolised to S-adenosylmethionine (SAM). SAM is both a vital one carbon donor for methylation reactions and it also generates 10formyl THF in conjunction with THF. 10-formyl THF is required for DNA synthesis.
Fig. 2 Sagittal T2-weighted MRI of the cervical spine showing diffuse high signal in the posterior cord.
activity in patients using nitrous oxide during labour show a reduction in the activity of this enzyme. The percentage reduction is heavily dependent on pre-exposure maternal blood B12 level, so that pre-existing borderline B12 deficiency results in a profound loss of activity.6 Anaesthetic toxicity
Fig. 3 Axial T2-weighted MRI of the mid-cervical spine delineating the posterior columns as the anatomical site of this high signal.
It has been shown that methionine synthase activity is inhibited by exposure to nitrous oxide in the mouse, rat and human. Recovery of this activity takes several days, consistent with the time period required to replace the irreversibly inactivated enzyme. Methionine synthase is of central importance for both DNA synthesis and to replenish the one carbon donor pool (Fig. 4).3 Measurements of in vivo placental methionine synthase
Journal of Clinical Neuroscience (2000) 7(1)
Clinically, one major concern is related to possible adverse effects of nitrous oxide use in anaesthetic practice, in particular exposure during prolonged operations or long labour. It is known from animal data that continuous exposure for 24 h leads to megaloblastic changes in the bone marrow and 5 days of exposure to agranulocytosis. Therefore, patients could suffer haematological or neurological complications. Indeed, a 1986 case report details the development of a megaloblastic marrow in a seriously ill patient with B12 deficiency given a total of 2 h of anaesthetic exposure.7 This megaloblastic change and agranulocytosis are preventable by administration of folinic acid, which is converted to 10 FormylTHF (Fig. 4).4,5 In terms of neurological toxicity, Scott et al. reported that chronic 15% nitrous oxide exposure in monkeys resulted in mixed combined degeneration of the spinal cord, and that this was fully preventible by concomitant administration of 2 g of oral methionine per day.9 In two obstetric patients, Schilling reported the development of subacute combined degeneration of the spinal cord within eight weeks of nitrous oxide exposure during labour; pre-existing subclinical B12 deficiency was demonstrated in both cases.8 © 2000 Harcourt Publishers Ltd
Nitrous oxide myelopathy 75
Abuse of nitrous oxide
CONCLUSION
Up to 20% of medical and dental students in the USA admitted to recreational use in an anonymous survey.10 Neurological sequelae of nitrous oxide abuse are occasionally reported in the literature, mainly in anaesthetic personnel and dentists. The usual manifestation is an axonal peripheral neuropathy which gradually improves with abstinence.11 There are also several clinical descriptions of a myeloneuropathy12,13 but there are no case reports of a pure myelopathy, and no direct MRI evidence of spinal cord involvement has been published to date. Occasionally, the neurological toxicity can be permanent and lead to severe disability. There are only two previous case reports describing neurological toxicity from recreational use of whipped cream bulbs. One patient, initially diagnosed with a conversion disorder and admitted to a psychiatric service, was noted to have signs of a myeloneuropathy.2 The patient received vitamin B12 and recovered within one week. The second patient presented with a recurrent peripheral neuropathy, with axonal degeneration demonstrated on sural nerve biopsy. Gas chromatography analysis of the bulb contents in this case revealed the presence, beside, nitrous oxide, of 26 other volatile, potentially neurotoxic compounds; these included toluene, trichlorethylene and phenol.1
We report this case in order to raise awareness of a potentially serious form of abuse of nitrous oxide, which is freely available in the form of bulbs for recharging whipped cream dispensers. The neurological toxicity includes a myelopathy, which can be irreversible or, as in this case, require substantial health resource commitments over a prolonged period. Early recognition is vital and institution of combination therapy with methionine and vitamin B12 is recommended.
TREATMENT Given the above anaesthetic and animal data, possible therapeutic options might include parenteral folinic acid, intramuscular vitamin B12 injection or oral methionine. Evidence is scant and anecdotal, but one case report highlights the usefulness of coadministration of methionine and vitamin B12.14 Two patients were initially treated with vitamin B12 alone but the neurological symptoms worsened. One of the patients was commenced on oral methionine and this arrested the progression and accelerated recovery. The patient reported here has made a full recovery and thus, in the absence of other data, it seems prudent to recommend this combination therapy for the treatment of acute neurological toxicity.
© 2000 Harcourt Publishers Ltd
REFERENCES 1. Sahenk Z, Mendell J R, Couri D, Nachtman J. Polyneuropathy from inhalation of N2O cartridges through a whipped-cream dispenser. Neurology 1978; 28: 485–487. 2. Brett A. Myeloneuropathy from whipped cream bulbs presenting as conversion disorder. Aust NZ J Psychiatry 1997; 31: 131–132. 3. Nunn J F. Clinical aspects of the interaction between nitrous oxide and vitamin B12. Br J Anaesth 1987; 59: 3–13. 4. Amess J A et al. Megaloblastic haemopoiesis in patients receiving nitrous oxide. Lancet 1978; 2: 339–342. 5. Ablett J J L. Tetanus and the Anaesthetist. Br J Anaesth 1956; 28: 258. 6. Landon M J, Creagh-Barry P, McArthur S, Charlett A. Influence of vitamin B12 status on the inactivation of methionine synthase by nitrous oxide. Br J Anaesth 1992; 69: 81–86. 7. Nunn J F, Chanarin I, Tanner A G, Owen E R. Megaloblastic bone marrow changes after repeated nitrous oxide anaesthesia. Br J Anaesth 1986; 58: 1469–1470. 8. Schilling R F. Is nitrous oxide a dangerous anesthetic for vitamin B12 deficient subjects? JAMA 1986; 255: 1605–1606. 9. Scott J M, Dinn J J, Wilson P, Weir D G. Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet 1981; 2: 334–337. 10. Rosenberg H, Orkin F K, Springstead J. Abuse of nitrous oxide. Anesth Analg 1979; 58: 104–106. 11. Layzer R B, Fishman R A, Schafer J A. Neuropathy following abuse of nitrous oxide. Neurology 1978; 28: 504–506. 12. Layzer R B. Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet 1978; 2: 1227–1230. 13. Heyer E J et al. Nitrous oxide: clinical and electrophysiologic investigation of neurologic complications. Neurology 1986; 36: 1618–1622. 14. Stacy C B, Di Rocco A, Gould R J. Methionine in the treatment of nitrousoxide induced neuropathy and myeloneuropathy. J Neurol 1992; 239(7): 401–403.
Journal of Clinical Neuroscience (2000) 7(1)
Nitrous oxide myelopathy in an abuser of whipped cream bulbs Helmut Butzkueven1 MBBS, John O. King2 MD, FRACP 1
Neurology Registrar, 2Senior Neurologist, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
Summary A 23 year old man presented with a severe posterior column myelopathy related to prolonged nitrous oxide abuse obtained from whipped cream bulbs. The site of pathology was identified by magnetic resonance imaging (MRI) and somatosensory evoked potentials. The mechanism of toxicity involves inactivation of vitamin B12 dependent enzymes. Appropriate treatment with methionine and vitamin B12 was instituted quickly with good neurological outcome. There are major concerns regarding the availability of nitrous oxide in supermarkets. © 2000 Harcourt Publishers Ltd Journal of Clinical Neuroscience (2000) 7 (1), 73–75 © 2000 Harcourt Publishers Ltd DOI: 10.1054/ jocn.1999.0149, available online at http://www.idealibrary.com on
Keywords: nitrous oxide toxicity, myelopathic disorders, substance abuse, anaesthetic toxicity Received 20 December 1998 Accepted 16 February 1999 Correspondence to: Helmut Butzkueven, 61 Gower Street, Kensington, Victoria 3031, Australia. Tel: + 613 9376 3595; E-mail: [email protected]
INTRODUCTION Nitrous oxide, a common analgesic and anaesthetic agent, is occasionally abused by dental and medical personnel. Neurological sequelae of prolonged exposure include potentially irreversible axonal peripheral neuropathy and myelopathy. Recharging bulbs for whipped cream dispensers contain nitrous oxide and are freely available at supermarkets in Australia. We wish to report a patient with a severe myelopathy resulting from prolonged abuse of these cartridges. There are two previous reports in the literature of neurological sequelae using such cartridges, but this is the first to provide clinical and imaging evidence of the site of toxicity in the posterior columns of the spinal cord.1,2
limbs, there was a mild increase in tone, with normal power and reflexes. Pain and temperature sensation were preserved, as was vibration sense, but there was a gross disturbance of proprioception including severe difficulty in detecting the direction of passive movement of his wrists and elbows. There were no cerebellar signs. In the legs, there was a mild increase in tone with brisk reflexes but flexor plantar responses and normal power. Again, sensory testing revealed abnormalities only of proprioception – at the toes, ankles, knees and even at the hips; this was so severe that the patient, with his eyes closed, was completely unable to tell whether his hips and knees were being flexed or extended passively. He was unable to walk, even with support, and Romberg’s test was predictably positive. General examination was normal. Initial investigations revealed a mild macrocytic anaemia with a haemoglobin of 122 g/l and a mean cell volume of 100 fl. The vitamin B12 level was borderline at 130 mcmol/l, with normal red cell folate. The spinal fluid was acellular with a protein of 0.76 g/l (normal < 0.45 g/l), and a normal glucose level. Routine nerve conduction studies of the lower limb were normal. Somatosensory evoked responses from tibial nerve stimulation revealed normal conduction to the lumbar spine, but slow conduction to the cortex, indicative of a central nervous system cause for his severe proprioceptive abnormalities. INVESTIGATIONS MRI scan of the brain was normal. A T-2 weighted MRI scan of the cervical spine showed increased signal in the posterior cervical cord, and transverse images demonstrated posterior column pathology (Figs 2 & 3). The patient was treated with daily vitamin B12 injections (hydroxycobalamin 1000 mcg i.m.) and methionine one gram orally t.d.s. After two weeks, he still required the assistance of another person to walk and was discharged to an inpatient rehabilitation facility. At outpatient review three months later, he was walking independently with only minor proprioceptive abnormalities on examination. He had gained 10 kg and his mood appeared normal. DISCUSSION Mechanism of toxicity Nitrous oxide interacts in vivo with vitamin B12 by converting the monovalent cobalt ion of the vitamin to its bivalent form. This reaction irreversibly inactivates B12 and enzymes in which it is a cofactor, specifically methionine synthase.
Case report A 23 year old man was admitted to the neurology unit of The Royal Melbourne Hospital in August 1997 with a history of increasing gait disturbance over the preceding 5 days, mainly due to inco-ordination. In addition, the patient complained of tingling and numbness in the fingers and, to a lesser degree, in the feet. He had used heroin intranasally on a weekly basis for 3 years, but not in the preceding month. He gave a history of nitrous oxide abuse using approximately 40–60 whipped cream bulbs per day during the last 6 months. He obtained these at three local supermarkets, at a cost of approximately $A30 per day (Fig. 1). There was no other significant past history. On examination, he was malnourished, easily distractable and hypomanic. The cranial nerves were normal. In the upper
© 2000 Harcourt Publishers Ltd
Fig. 1 Whipped cream bulbs containing nitrous oxide.
Journal of Clinical Neuroscience (2000) 7(1)
74 Butzkueven and King
Fig. 4 Methionine synthase catalyses the generation of tetrahydrofolate (THF) and methionine from homocysteine and methyltetrahydrofolate. Methionine is metabolised to S-adenosylmethionine (SAM). SAM is both a vital one carbon donor for methylation reactions and it also generates 10formyl THF in conjunction with THF. 10-formyl THF is required for DNA synthesis.
Fig. 2 Sagittal T2-weighted MRI of the cervical spine showing diffuse high signal in the posterior cord.
activity in patients using nitrous oxide during labour show a reduction in the activity of this enzyme. The percentage reduction is heavily dependent on pre-exposure maternal blood B12 level, so that pre-existing borderline B12 deficiency results in a profound loss of activity.6 Anaesthetic toxicity
Fig. 3 Axial T2-weighted MRI of the mid-cervical spine delineating the posterior columns as the anatomical site of this high signal.
It has been shown that methionine synthase activity is inhibited by exposure to nitrous oxide in the mouse, rat and human. Recovery of this activity takes several days, consistent with the time period required to replace the irreversibly inactivated enzyme. Methionine synthase is of central importance for both DNA synthesis and to replenish the one carbon donor pool (Fig. 4).3 Measurements of in vivo placental methionine synthase
Journal of Clinical Neuroscience (2000) 7(1)
Clinically, one major concern is related to possible adverse effects of nitrous oxide use in anaesthetic practice, in particular exposure during prolonged operations or long labour. It is known from animal data that continuous exposure for 24 h leads to megaloblastic changes in the bone marrow and 5 days of exposure to agranulocytosis. Therefore, patients could suffer haematological or neurological complications. Indeed, a 1986 case report details the development of a megaloblastic marrow in a seriously ill patient with B12 deficiency given a total of 2 h of anaesthetic exposure.7 This megaloblastic change and agranulocytosis are preventable by administration of folinic acid, which is converted to 10 FormylTHF (Fig. 4).4,5 In terms of neurological toxicity, Scott et al. reported that chronic 15% nitrous oxide exposure in monkeys resulted in mixed combined degeneration of the spinal cord, and that this was fully preventible by concomitant administration of 2 g of oral methionine per day.9 In two obstetric patients, Schilling reported the development of subacute combined degeneration of the spinal cord within eight weeks of nitrous oxide exposure during labour; pre-existing subclinical B12 deficiency was demonstrated in both cases.8 © 2000 Harcourt Publishers Ltd
Nitrous oxide myelopathy 75
Abuse of nitrous oxide
CONCLUSION
Up to 20% of medical and dental students in the USA admitted to recreational use in an anonymous survey.10 Neurological sequelae of nitrous oxide abuse are occasionally reported in the literature, mainly in anaesthetic personnel and dentists. The usual manifestation is an axonal peripheral neuropathy which gradually improves with abstinence.11 There are also several clinical descriptions of a myeloneuropathy12,13 but there are no case reports of a pure myelopathy, and no direct MRI evidence of spinal cord involvement has been published to date. Occasionally, the neurological toxicity can be permanent and lead to severe disability. There are only two previous case reports describing neurological toxicity from recreational use of whipped cream bulbs. One patient, initially diagnosed with a conversion disorder and admitted to a psychiatric service, was noted to have signs of a myeloneuropathy.2 The patient received vitamin B12 and recovered within one week. The second patient presented with a recurrent peripheral neuropathy, with axonal degeneration demonstrated on sural nerve biopsy. Gas chromatography analysis of the bulb contents in this case revealed the presence, beside, nitrous oxide, of 26 other volatile, potentially neurotoxic compounds; these included toluene, trichlorethylene and phenol.1
We report this case in order to raise awareness of a potentially serious form of abuse of nitrous oxide, which is freely available in the form of bulbs for recharging whipped cream dispensers. The neurological toxicity includes a myelopathy, which can be irreversible or, as in this case, require substantial health resource commitments over a prolonged period. Early recognition is vital and institution of combination therapy with methionine and vitamin B12 is recommended.
TREATMENT Given the above anaesthetic and animal data, possible therapeutic options might include parenteral folinic acid, intramuscular vitamin B12 injection or oral methionine. Evidence is scant and anecdotal, but one case report highlights the usefulness of coadministration of methionine and vitamin B12.14 Two patients were initially treated with vitamin B12 alone but the neurological symptoms worsened. One of the patients was commenced on oral methionine and this arrested the progression and accelerated recovery. The patient reported here has made a full recovery and thus, in the absence of other data, it seems prudent to recommend this combination therapy for the treatment of acute neurological toxicity.
© 2000 Harcourt Publishers Ltd
REFERENCES 1. Sahenk Z, Mendell J R, Couri D, Nachtman J. Polyneuropathy from inhalation of N2O cartridges through a whipped-cream dispenser. Neurology 1978; 28: 485–487. 2. Brett A. Myeloneuropathy from whipped cream bulbs presenting as conversion disorder. Aust NZ J Psychiatry 1997; 31: 131–132. 3. Nunn J F. Clinical aspects of the interaction between nitrous oxide and vitamin B12. Br J Anaesth 1987; 59: 3–13. 4. Amess J A et al. Megaloblastic haemopoiesis in patients receiving nitrous oxide. Lancet 1978; 2: 339–342. 5. Ablett J J L. Tetanus and the Anaesthetist. Br J Anaesth 1956; 28: 258. 6. Landon M J, Creagh-Barry P, McArthur S, Charlett A. Influence of vitamin B12 status on the inactivation of methionine synthase by nitrous oxide. Br J Anaesth 1992; 69: 81–86. 7. Nunn J F, Chanarin I, Tanner A G, Owen E R. Megaloblastic bone marrow changes after repeated nitrous oxide anaesthesia. Br J Anaesth 1986; 58: 1469–1470. 8. Schilling R F. Is nitrous oxide a dangerous anesthetic for vitamin B12 deficient subjects? JAMA 1986; 255: 1605–1606. 9. Scott J M, Dinn J J, Wilson P, Weir D G. Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet 1981; 2: 334–337. 10. Rosenberg H, Orkin F K, Springstead J. Abuse of nitrous oxide. Anesth Analg 1979; 58: 104–106. 11. Layzer R B, Fishman R A, Schafer J A. Neuropathy following abuse of nitrous oxide. Neurology 1978; 28: 504–506. 12. Layzer R B. Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet 1978; 2: 1227–1230. 13. Heyer E J et al. Nitrous oxide: clinical and electrophysiologic investigation of neurologic complications. Neurology 1986; 36: 1618–1622. 14. Stacy C B, Di Rocco A, Gould R J. Methionine in the treatment of nitrousoxide induced neuropathy and myeloneuropathy. J Neurol 1992; 239(7): 401–403.
Journal of Clinical Neuroscience (2000) 7(1)