Nitrous Oxide Anesthesia Associated Myelopathy

OBSERVATION Nitrous Oxide Anesthesia–Associated Myelopathy

Rose-Marie Marie´, MD, PhD; Eric Le Biez, MD; Philippe Busson, MD; Ste´phane Schaeffer, MD; Lydia Boiteau, MD; Benoit Dupuy, MD; Fausto Viader, MD

Background: The role of nitrous oxide exposure in neu- cious anemia. Results of electrophysiologic examina- rologic complications of subclinical cobalamin defi- tions showed a diffuse demyelinating neuropathy. ciency has been reported, but few cases are well docu- Magnetic resonance imaging of the spinal cord dis- mented. closed hyperintensities of the dorsal columns on T2- weighted images. Observation: Two weeks after surgery for prosthetic adenoma, a 69-year-old man developed ascending par- Conclusions: Pernicious anemia can result in severe neu- esthesia of the limbs, severe ataxia of gait, tactile sen- rologic symptoms with only mild hematologic changes. sory loss on the 4 limbs and trunk, and absent tendon The role of nitrous oxide anesthesia in revealing sub- reflexes. After a second surgical intervention, the pa- clinical B12 deficiency must be emphazised. Magnetic reso- tient became confused. Four months after onset, the pa- nance imaging of the spinal cord might be helpful in mak- tient had paraplegia, severe weakness of the upper limbs, ing the diagnosis. cutaneous anesthesia sparing the head, and confusion. Moderate macrocytosis, low serum B12 levels, and a posi- tive Schilling test result led to the diagnosis of perni- Arch Neurol. 2000;57:380-382

UBACUTE COMBINED degen- the trunk and upper limbs. Two months eration of the spinal cord1 later he had severe gait ataxia, with loss caused by pernicious ane- of position sense and pallesthesia, and ab- mia (PA) is characterized by sent tendon reflexes. Paraparesis devel- combined involvement of py- oped thereafter with a bilateral Babinski Sramidal tracts and posterior columns of the sign; sensory loss became complete in the spinal cord, sometimes associated with pe- lower limbs, and the upper limbs became ripheral neuropathy, optic atrophy, and en- ataxic. He again underwent surgery for cephalopathy.2 Diagnosis might be diffi- cholecystitis and became confused. Four cult when anemia or macrocytosis are months after onset, the patient had com- lacking or in the presence of normal se- plete flaccid paraplegia, urine retention, rum cobalamin (Cbl) levels.3 Nitrous ox- fecal incontinence, severe ataxia and mod- ide exposure may trigger development of erate weakness of the upper limbs, and neurologic complications in patients with complete loss of all sensory modalities be- subclinical Cbl deficiency (see Green and low the C2 level. He was also time and Kinsella4 and Schilling5). We describe a pa- place disorientated, with impaired memory tient with previously unrecognized PA who and visual hallucinations. Visual acuity was developed an extremely severe and long- 12/20 in both eyes. Fundi and visual fields lasting neurologic disease after 2 expo- were normal. sures to nitrous oxide during anesthesia. Electrophysiologic testing 2 months From the Service de Neurologie, after onset detected a generalized slow- Centre Hospitalier REPORT OF A CASE ing of sensory conduction velocities (26 Universitaire de Caen, Caen, m/s; amplitude of the right superficial per- France (Drs Marie´, Busson, A 69-year-old retired butcher underwent oneal nerve potential, 10 µV), normal mo- Schaeffer, and Viader), and the Services de Radiologie surgery for benign prostate hypertrophy tor conduction, and no denervation on (Dr Boiteau) and Neurologie under 40% nitrous oxide anesthesia (3.2 electromyography. Four months after on- (Drs Le Biez and Dupuy), L/min) for 1 hour. Two weeks later he set, mild denervation and slowing of mo- Hopital Pasteur, started having distal paresthesias of the tor conduction velocities were found in the Cherbourg, France. lower limbs that extended progressively to upper limbs (right median nerve, 40 m/s).

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Sensory evoked potentials could not be recorded; visual evoked potentials were delayed on both sides (right, 134.4 milliseconds; left, 131.2 milliseconds). Results of a complete blood cell count 1 month after onset were normal (patient being free from folic acid treatment) except for an increased mean corpuscular volume (101 fL); 3 months later the results were as fol- lows: hemoglobin level, 10.7 g/dL; red blood cell count, 2.99 ϫ 1012/L; mean corpuscular volume,103.6 fL; red blood cell distribution width, 19%; white blood cell count, 5.30 ϫ 109/L; and platelet count, 2.72 ϫ 109/L. Results of bone marrow aspiration were normal. The serum Cbl level was less than 37 pmol/L (reference range, 130-700 pmol/L), and the serum folic acid level was 30 nmol/L Cervical magnetic resonance image (sagittal and coronal) showing a (reference range, 5-30 nmol/L). T2-weighted hypersignal in the posterior and lateral parts of the medulla. Anti–intrinsic factor antibodies were detected (13 U/mL [reference range, Ͻ8 U/mL]), and intrinsic factor Visual impairments are uncommon (0.5%). Although our in gastric fluid was low (3.7 U [reference range, 30-40 patient had no visual complaints, he had bilateral alter- U]). Gastric mucosa appeared macroscopically normal, ation of visual evoked potentials. Severe peripheral and but fundic biopsy specimens disclosed atrophy and in- central nervous system damage might thus occur in Cbl testinal metaplasia. The Schilling test confirmed the di- deficiency despite relatively mild hematologic changes.8 agnosis of PA: Cbl excretion after intrinsic factor, 12.7% Magnetic resonance imaging of the spinal cord dem- (reference range, 14%-40%; PA Ͼ9); without intrinsic onstrated conspicuous changes in posterior and lateral factor, 3.2% (reference range, 14%-40%; PA Ͻ10); ra- columns, in accordance with the anatomical lesions of tio, 4.0 (reference range, 0.7-1.2; PA Ͼ1.7). subacute combined degeneration of the spinal cord.9 Pre- Spinal magnetic resonance imaging (Figure) re- vious studies also reported T2 hyperintensities of the spi- vealed hyperintensity of the posterior two thirds of the nal cord, either diffuse10,11 or confined to the dorsal col- spinal cord on sagittal T2-weighted images involving umns,12-14 or involving both lateral and dorsal columns. mainly the posterior and lateral columns on axial slices Even in the latter case, however, the dorsal columns are from the cervical level to T10 and only the posterior col- the first to be involved and the most altered. Most au- umns from T10 to the terminal cone. Use of gadolinium thors have reported axonal degeneration of peripheral did not enhance the signal. Brain magnetic resonance im- nerves with or without associated demyelination. Heal- ages were normal. ton et al6 observed decreased mean corpuscular vol- Three months after the first symptoms appeared the umes, absent or reduced sensory evoked potentials, and patient received intramuscular cyanocobalamin, 1000 µg/d fibrillations in distal muscles, indicating a mixed senso- for 5 days, and then 5000 µg every other day for 6 months. rimotor axonal demyelinating pattern. McCombe and A short course of intravenous hydroxocobalamin was McLeod2 found axonal degeneration by electromyogra- given (5000 µg/d), which did not seem to hasten recov- phy and sural nerve biopsy examination in 3 patients. ery. Improvement was delayed and slow, starting with In our patient, findings of electrophysiologic examina- the disappearance of disorientation and hallucinations. tions initially suggested a demyelinating sensory neu- Six months after introduction of cobalamin supplemen- ropathy that eventually progressed to a mixed axonal tation, the patient was well oriented but still chair- demyelinating pattern. bound, with spastic paraparesis, proprioceptive sensory In most patients, the diagnosis of Cbl deficiency de- loss of the lower limbs, incomplete urinary retention, and pends on serum Cbl measurements, as in our patient, who mild ataxia of the upper limbs. Results of a complete blood also had anti–intrinsic factor antibodies and fundic at- cell count were normal. Magnetic resonance imaging rophy, which suggests PA rather than a hereditary de- showed persistent dorsal column hyperintensities but fect.15-17 Our patient’s neurologic symptoms started shortly sparing of lateral columns. During the next 6 months he after nitrous oxide exposure and worsened after a sec- continued receiving 5000 µg of intramuscular cyanoco- ond surgical procedure under nitrous oxide anesthesia. balamin weekly. After 1 year of treatment the patient could Kondo et al18 showed that exposure to nitrous oxide causes walk unaided for short distances with mild ataxia. He died multiple defects in Cbl metabolism. Kinsella and Green19 of intestinal occlusion. An autopsy was not performed. described 2 patients similar to ours with unsuspected Cbl deficiency who developed acute Cbl deficiency symp- COMMENT toms after a single exposure to nitrous oxide during a surgical procedure. Nitrous oxide is a potent oxidant18 that Untreated Cbl deficiency might result in neuropathy, sub- disrupts the methionine synthetase reaction by causing acute combined degeneration of the spinal cord, and en- oxidation of Cob(I)alamin to Cob(II)alamin, which blocks cephalopathy, in isolation or in various combinations. regeneration of the cobalamin coenzyme methylcobala- Of 143 patients with Cbl deficiency reviewed by Heal- min, produces a condition simulating Cbl deficiency, in- ton et al,6 41% had combined neuropathy and myelopa- hibits methylation of myelin phospholipids, and alters thy. Our patient also had encephalopathy, a complica- incorporation of fatty acids into the myelin sheaths.20 In tion observed in only 8.1% of patients in other studies.6,7 patients with normal stores of Cbl, a sufficient quantity

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 of unoxidized Cbl may be available to maintain enzyme 4. Green R, Kinsella LJ. Current concepts in the diagnosis of cobalamin deficiency. function; in patients with borderline Cbl stores, even short Neurology. 1995;45:1435-1440. 5. Schilling RF. Is nitrous oxide a dangerous anesthetic for vitamin B12–deficient exposures to nitrous oxide may be sufficient to precipi- subjects? JAMA. 1986;255:1605-1606. tate a Cbl deficiency syndrome. 6. Healton EB, Savage DG, Brust JCM, Garrett TJ, Lindenbaum J. Neurologic as- pects of cobalamin deficiency. Medicine. 1991;70:229-244. 7. Karnaze DS, Carmel R. Low serum cobalamin levels in primary degenerative de- CONCLUSIONS mentia: do some patients harbor atypical cobalamin deficiency states? Arch In- tern Med. 1987;147:429-431. Pernicious anemia may lead to extremely severe neuro- 8. Karnaze DS, Carmel R. Neurologic and evoked potential abnormalities in subtle logic complications despite few hematologic changes. It cobalamin deficiency states, including deficiency without anemia and with nor- might also be more frequent than usually thought be- mal absorption of free cobalamin. Arch Neurol. 1990;47:1008-1012. cause using serum Cbl levels below 200 pmol/L as the 9. Ducken LW, Jacobs JM. Nutritional deficiencies and metabolic disorders, vitamin B12. In: Adams JH, Corsellis JAN, Ducken LW, eds. Greenfield’s Neuropathology. indicator of deficiency, its prevalence ranges from 7% to 4th ed. London, England: Edward Arnold; 1984:585-592. 4 16%. Exposure to nitrous oxide during anesthesia is an 10. Berger JR, Quencer R. Reversible myelopathy with pernicious anemia: clinical/MR underrecognized and potentially important factor in trig- correlation. Neurology. 1991;41:947-948. gering and worsening the neurologic consequences of Cbl 11. Tracey JP, Schiffman FJ. Magnetic resonance imaging in cobalamin deficiency. Lancet. 1992;339:1172-1173. deficiency. The subacute onset of a sensory neuropathy, 12. Murata S, Naritomi H, Sawada T. MRI in subacute combined degeneration. Neu- myelopathy, encephalopathy, or any combination of these roradiology. 1994;36:408-409. in the days or weeks after undergoing a surgical proce- 13. Timms SR, Cure JK, Kurent JE. Subacute combined degeneration of the spinal dure should raise the question of Cbl deficiency even in cord: MR findings. AJNR Am J Neuroradiol. 1993;14:1224-1227. the absence of hematologic changes. 14. Wolansky LJ, Goldstein G, Gozo A, Lee HJ, Sills I, Chatkupt S. Subacute combined degeneration of the spinal cord: MRI detection of preferential involvement of the posterior columns in a child. Pediatr Radiol. 1995;25:140-141. Accepted for publication September 7, 1999. 15. Carmel R,Watkins D, Goodman SJ, Rosenblatt D. Hereditary defect of cobala- Reprints: Rose-Marie Marie´, MD, PhD, Service de Neu- min metabolism (chlG mutation) presenting as a neurologic disorder in adult- rologie De´jerine, Centre Hospitalier Universitaire de Caen, hood. N Engl J Med. 1988;30:1738-1739. 16. Reynolds EH, Bottiglieri T, Laundy M, et al. Subacute combined degeneration Avenue de la Coˆte de Nacre, 14000 Caen, France. with high serum vitamin B12 level and abnormal vitamin B12 binding protein. Arch Neurol. 1993;50:739-742. REFERENCES 17. Sigal SH, Hall CA, Antel JP. Plasma R binder deficiency and neurologic disease. N Engl J Med. 1987;317:1330-1332. 18. Kondo H, Osborne ML, Kolhouse F, et al. Nitrous oxide has multiple deleteri- 1. Russell JSR, Batten FE, Collier J. Subacute combined degeneration of the spinal ous effects on cobalamin metabolism and causes decreases in activities of cord. Brain. 1900;23:39-110. both mammalian cobalamin-dependent enzymes in rats. Clin Invest. 1981;67:

2. McCombe PA, McLeod JG. The peripheral neuropathy of vitamin B12 deficiency. 1270-1283. J Neurol Sci. 1984;66:117-126. 19. Kinsella LJ, Green R. “Anesthesia paresthetica”: nitrous oxide–induced cobala- 3. Carmel R. Pernicious anemia: the expected findings of very low serum cobalamin deficiency. Neurology. 1995;45:1608-1610. min levels, anemia, and macrocytosis are often lacking. Arch Neurol. 1988;48: 20. Frenkel EP. Abnormal fatty acid metabolism in peripheral nerves of patients with 1712-1715. pernicious anemia. J Clin Invest. 1973;52:1237-1245.

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