- Email: [email protected]
Is neurally mediated hypotension an unrecognised cause of chronic fatigue?
Although this was not a clinical trial, but a natural experiment dictated by field conditions, it provides useful insights. Delay in giving the third hepatitis B vaccine dose for up to 2 years is unlikely to have a negative impact on immune response. Thus, delay of the third dose, even for several months, does not necessitate restarting the vaccine series R
or
confirmation of the final response
Mangione,
Health District
T Stroffolini, M E Tosti, D
to
the vaccine.
the essential feature of chronic fatigue syndrome, since functional impairment is an integral part of all case definitions. Prolonged inactivity, and in particular bed rest, is strongly associated with fatigue and postural hypotension.5 Simple rehabilitation and activity management programmes might thus be more appropriate than further unproven pharmacological interventions, and could also have a lower risk of side-effects.
Fragapani, *A Mele
(USL) 13, Licata, Agngento; Ospedale
Civile di Montefiascone,
Viterbo, *Istltuto Superiore di Samtà, reparto di Epidemiologia Clmica, 00161 Roma, Italy; and Ospedale S Giacomo D’Alto Passo, Licata, Agrlgento
Simon Wessely Chronic Fatigue Syndrome Research Unit, King’s Institute of Psychiatry, London SE5 9RS, UK
1 1 2
3
Jilg W, Schmidt M, Deinhardt F. Immune responses to late booster doses of hepatitis B vaccine. J Med Virol 1985; 17: 249-54. Hadler SC, Monson MA, Lugo DR, Perez M. Effect of timing of hepatitis B vaccine dose on response to vaccine in Yucpa Indians.
2
Vaccine 1989; 7: 106-10. Committee on Infectious Diseases. Update on timing of hepatitis B vaccination for premature infants and for children with lapsed immunization. Pediatrics 1994; 94: 403-04.
4
Is
neurally mediated hypotension an unrecognised cause of chronic fatigue? SIR-1 am astonished by Rowe and colleagues’ conclusions and suggest that these workers could usefully have included some controls. My experience has been that young healthy volunteers drop their blood pressure and may faint if tilted to 60° or 70° from the horizontal for longer than 10 min. Rowe’s subjects were tilted for as long as 30 min. It is even more surprising that Rowe and co-workers should choose to help their patients by the use of atenolol or disopyramide. &bgr;adrenoceptor blocking drugs decrease exercise tolerance, increase fatigue, and can produce depressed mood; and disopyramide is not without its drawbacks. Properly programmed exercise training should be beneficial and eliminate the need for powerful drugs in patients with a selflimiting condition, chronic fatigue syndrome, and normal hearts. R J Walden Pharmacology, Rayne Institute, University College London,
Clinical
London WC1, UK
SIR-On the basis of a small selected case series Rowe and colleagues report an association between chronic fatigue, chronic fatigue syndrome, and hypotension. British and American physicians have long rejected any association between low blood pressure and symptoms such as fatigue and dizziness, by contrast with their German colleagues.’1 Yet before we dismiss such observations out of hand, it is noteworthy that two large-scale population-based surveys provided support for an association between low blood pressure and fatigue in younger age groups.2,3 Nevertheless, the same workers who reported this association were also at pains to point out the absence of evidence that raising blood pressure is either effective or desirable, or to support the widespread use of pharmaceutical agents prescribed for this purpose. Such caution is even more appropriate for the contentious subject of chronic fatigue syndrome. Are there alternative explanations for Rowe and colleagues’ findings? The first possible confounder is depression. One of the two epidemiological studies I mention3 showed that the association between fatigue and low blood pressure was related to low mood, which is a common finding in chronic fatigue syndrome,4 but no information is provided in the current report concerning the psychological status of the subjects. The second is inactivity, 1112
3
5
College School of Medicine and
Donner-Banzhoff N, Kreienbrock L, Baum E. Hypotension: does it make sense in family practice? Fam Pract 1994; 11: 368-74. Wessely S, Nickson J, Cox B. Symptoms of low blood pressure: a
population study. BMJ 1990; 301: 362-65. Pilgrim J, Stansfield S, Marmot M. Low blood pressure, low mood? BMJ 1992; 304: 75-78. David A. Postviral fatigue syndrome and psychiatry. Br Med Bull 1991; 47: 966-88. Saltin B, Blomquist G, Mitchell J, Johnson R, Wildenthal K, Chapman C. Response to exercise after bed rest and training: a longitudinal study of adaptive changes in oxygen transport and body composition. Circulation 1968; 38 (suppl 7): 1-55.
Authors’
reply
SIR-It
should
be surprising that atenolol and used to treat our 7 patients with chronic disopyramide and mediated fatigue neurally hypotension. These drugs have been among the recommended therapies for neurally mediated hypotension for years. Symptom-free individuals occasionally will have abnormal responses to upright tilt, but to suggest that a hypotensive response is the norm would not be correct. Such abnormal responses occur in about 7-5% of controls during stage 1 of tilt testing, and in up to 27% when those who receive isoprenaline are included.’1 Prolonged bed rest might have been a more reasonable explanation for our findings if any of our patients had been confined to bed. They had not. All spent periods of each day moving about, and 3 continued to attend school. Similarly, none was clinically depressed. Symptoms improved within two weeks in 4 of the adolescents, which is an improbably short time for physical reconditioning to occur or for there to be spontaneous recovery from depression. The pace of improvement, along with the return of the tilt test response to normal in 1 patient whose fatigue improved and the persistence of an abnormal response in 1 child who did not improve, would be more consistent with a causal association than a confounder effect between neurally mediated hypotension and chronic fatigue. We did not describe an association between chronic fatigue and simple low blood pressure, as Wessely suggests, but between chronic fatigue and neurally mediated hypotension (also called vasodepressor syncope). The hypotension was confirmed only during upright tilt; before tilt testing, all patients had normal supine and standing blood pressures for age. We have not endorsed the use of any medication for the treatment of chronic fatigue syndrome, because such a recommendation would need to be based on data from randomised trials. Our report merely points to the potential for chronic fatigue to be more treatable, and with different drugs, than had been assumed in the past. Whether intentionally or not, Walden and Wessely imply that chronic fatigue syndrome is usually self-limited and that patients in some way could walk it off. There are no data suggesting that physical rehabilitation exercises are effective as primary treatments for neurally mediated hypotension or chronic fatigue syndrome. Indeed, patients with chronic not
were
fatigue syndrome typically feel much worse after modest physical exertion. Similarly, we are not aware of data suggesting a high rate of spontaneous resolution of chronic fatigue syndrome in the short term when patients satisfy strict criteria for this diagnosis. In a large study by Wilson and colleagues/ the mean duration of illness was 9-2 years, and a substantial proportion of patients continued to have impaired function with a further 3 years of follow-up. Against this background, the term self-limited loses meaning. *Peter C Rowe, Issam
Bou-Holaigah,
Jean S Kan,
Hugh Calkins
"Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
1 Kapoor WN, Smith MA, Miller NL. Upright tilt testing in evaluating syncope: a comprehensive literature review. Am J Med 1994; 97: 78-88. 2 Wilson A, Hickie I, Lloyd A, et al. Longitudinal study of outcome of chronic fatigue syndrome. BMJ 1994; 308: 756-59.
SIR-Rowe and colleagues incorrectly state that neurally mediated hypotension has not previously been implicated as a cause of chronic fatigue. In a paper published in 1992,’ we described 7 patients whose clinical features, apart from their ages, were strikingly similar to those of the patients reported by Rowe et al. They, too, presented with severe chronic fatigue associated with orthostatic lightheadedness. We attributed both these symptoms to orthostatic hypotension of a delayed type, described in a previous publication2 which became evident in these patients between 13 and 30 min after they had assumed the upright posture. In our patients, diagnosis was based on a precise duplication of the circumstances that they described as leading to their lightheadedness-ie, prolonged standingrather than on the more artificial use of a tilt table sometimes with isoprenaline infusion, used by Rowe and colleagues. Like these workers, we speculated that the relief of the fatigue by treatment that reduced or corrected the orthostatic hypotension in 5 of the patients might indicate that "the ’chronic fatigue syndrome’ might result, at least in part or in some individuals from the failure to maintain blood pressure in the upright posture". We are glad that Rowe’s observations are in accord with our findings. However, we warn that it is not always possible, despite the use of various therapeutic measures, to alleviate either the orthostatic hypotension or the fatigue. This finding, too, would tend to support the view that delayed orthostatic hypotension is an important pathogenetic mechanism leading to chronic fatigue syndrome. It may also be relevant to point out that the chronic fatigue syndrome has been attributed to impaired functional activity of the hypothalamic-pituitary-adrenal axis,3,4 in which the prevalence of orthostatic hypotension is known to be very high, though, of course, other consequences of hormonal deficiency might be contributing to fatigue in these patients. *David H P Streeten, Gunnar H Anderson Department of Medicine, College of Medicine, State University
Psychiatric manifestations in girl with ornithine transcarbamylase deficiency SiR-Deficiency of ornithine transcarbamylase (OTC) is an X-linked inborn error of urea synthesis. In male patients, the disease usually causes lethal ammonia intoxication during the neonatal period. Reflecting the random X-inactivation of the normal X-chromosome, female patients heterozygous for the disease have a wide range of clinical manifestations with a phenotype varying from apparent normality to a clinical pattern usually seen in male hemizygotes.’-3 We report a girl with OTC deficiency in whom the main clinical manifestations were psychiatric symptoms. The patient was the first child of unrelated French parents. At 6 months of age, she had vomiting related to gastro-oesophageal reflux. Thereafter, during the first 8 years of life, she had many episodes of behavioural problems: temper tantrums, aggression, feeding difficulties, and sleeplessness associated with vomiting. Her symptoms were attributed to difficulties in her relationship with her mother. At 8 years of age, because of lack of improvement in her psychiatric condition, she was admitted to a psychiatric hospital with new crises including aggression to herself and others, delirium with phobias, agitation, and anxiety. This episode coincided with the birth of a younger sister. The diagnosis of personality disorder and possible psychosis was made. In fact, between crises, the child’s behaviour was almost normal. 8 months after she was institutionalised in the psychiatric hospital, she had an attack of confusion, severe vomiting, and sudden blindness for which she was transferred to the regional hospital. On admission, she was comatose with pyramidal tract signs. Biological investigation revealed a plasma ammonia of 239 )J.moI/L, then 1270 µmol/L (normal <50), and glutamine 1236 µmol/L (normal <600). Urinary organic acid a showed high quantity of uracil, and chromatography was 326 urinary orotic acid µmol/mmol creatinine (normal <3). These two elements were very suggestive of OTC deficiency, confirmed by measurement of hepatic enzyme activity (13-5% of control values; D Rabier, Hopital des Enfants-Malades, Paris). Despite intensive therapy, the child died. The diagnosis of OTC deficiency in this patient was delayed because psychiatric disorders are rarely reported in this disease, although behavioural problems are frequently encountered.4,5 The possibility of an inborn error of metabolism should be considered in patients with episodes of neuropsychiatric problems especially when associated with vomiting. In these cases, an inherited disorder of the urea cycle has to be considered and could lead to an effective treatment based on a restricted protein diet. Claude Largillière Service de Pédiatrie, Hôpital Huriez, 59037 Lille, France
1
2 of New York,
Health Science Center, Syracuse, NY 13210, USA
3
1 Streeten DHP, Anderson GH Jr. Delayed orthostatic intolerance.
Arch Intern Med 1992; 152: 1066-72. 2
Streeten DHP. Orthostatic disorders of the circulation. New York: Plenum Publishing, 1987; 174: 180. 3 Poteliakhoff A. Adrenocortical activity and some clinical findings in acute and chronic fatigue. J Psychosomat Res 1981; 25: 91-95. 4 Demitrack MA, Dale JK, Straus SE, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 1991; 73: 1224-34.
4
5
Rowe PC, Newman SL, Brusilow SW. Natural history of symptomatic partial ornithine transcarbamylase deficiency. N Engl J Med 1986; 314: 541-47. Largillière C, Houssin D, Gottrand F, et al. Liver transplantation for ornithine transcarbamylase deficiency in a girl. J Pediatr 1989; 115: 415-17. Hawks Arn P, Hauser ER, Thomas GH, Herman G, Hess D, Brusilow SW. Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus: a cause of postpartum coma. N Engl J Med 1990; 322: 1652-55. Spade M, Guardamagna O, Rabier D, et al. Recurrent episodes of bizarre behaviour in a boy with ornithine transcarbamylase deficiency: diagnostic failure of protein loading and allopurinol challenge tests. J Pediatr 1994; 125: 249-51. DiMagno EP, Lowe JE, Snodgrass PJ, Jones JD. Ornithine transcarbamylase deficiency: a cause of bizarre behavior in a man. N Engl J Med 1986; 315: 744-47.
1113
or
confirmation of the final response
Mangione,
Health District
T Stroffolini, M E Tosti, D
to
the vaccine.
the essential feature of chronic fatigue syndrome, since functional impairment is an integral part of all case definitions. Prolonged inactivity, and in particular bed rest, is strongly associated with fatigue and postural hypotension.5 Simple rehabilitation and activity management programmes might thus be more appropriate than further unproven pharmacological interventions, and could also have a lower risk of side-effects.
Fragapani, *A Mele
(USL) 13, Licata, Agngento; Ospedale
Civile di Montefiascone,
Viterbo, *Istltuto Superiore di Samtà, reparto di Epidemiologia Clmica, 00161 Roma, Italy; and Ospedale S Giacomo D’Alto Passo, Licata, Agrlgento
Simon Wessely Chronic Fatigue Syndrome Research Unit, King’s Institute of Psychiatry, London SE5 9RS, UK
1 1 2
3
Jilg W, Schmidt M, Deinhardt F. Immune responses to late booster doses of hepatitis B vaccine. J Med Virol 1985; 17: 249-54. Hadler SC, Monson MA, Lugo DR, Perez M. Effect of timing of hepatitis B vaccine dose on response to vaccine in Yucpa Indians.
2
Vaccine 1989; 7: 106-10. Committee on Infectious Diseases. Update on timing of hepatitis B vaccination for premature infants and for children with lapsed immunization. Pediatrics 1994; 94: 403-04.
4
Is
neurally mediated hypotension an unrecognised cause of chronic fatigue? SIR-1 am astonished by Rowe and colleagues’ conclusions and suggest that these workers could usefully have included some controls. My experience has been that young healthy volunteers drop their blood pressure and may faint if tilted to 60° or 70° from the horizontal for longer than 10 min. Rowe’s subjects were tilted for as long as 30 min. It is even more surprising that Rowe and co-workers should choose to help their patients by the use of atenolol or disopyramide. &bgr;adrenoceptor blocking drugs decrease exercise tolerance, increase fatigue, and can produce depressed mood; and disopyramide is not without its drawbacks. Properly programmed exercise training should be beneficial and eliminate the need for powerful drugs in patients with a selflimiting condition, chronic fatigue syndrome, and normal hearts. R J Walden Pharmacology, Rayne Institute, University College London,
Clinical
London WC1, UK
SIR-On the basis of a small selected case series Rowe and colleagues report an association between chronic fatigue, chronic fatigue syndrome, and hypotension. British and American physicians have long rejected any association between low blood pressure and symptoms such as fatigue and dizziness, by contrast with their German colleagues.’1 Yet before we dismiss such observations out of hand, it is noteworthy that two large-scale population-based surveys provided support for an association between low blood pressure and fatigue in younger age groups.2,3 Nevertheless, the same workers who reported this association were also at pains to point out the absence of evidence that raising blood pressure is either effective or desirable, or to support the widespread use of pharmaceutical agents prescribed for this purpose. Such caution is even more appropriate for the contentious subject of chronic fatigue syndrome. Are there alternative explanations for Rowe and colleagues’ findings? The first possible confounder is depression. One of the two epidemiological studies I mention3 showed that the association between fatigue and low blood pressure was related to low mood, which is a common finding in chronic fatigue syndrome,4 but no information is provided in the current report concerning the psychological status of the subjects. The second is inactivity, 1112
3
5
College School of Medicine and
Donner-Banzhoff N, Kreienbrock L, Baum E. Hypotension: does it make sense in family practice? Fam Pract 1994; 11: 368-74. Wessely S, Nickson J, Cox B. Symptoms of low blood pressure: a
population study. BMJ 1990; 301: 362-65. Pilgrim J, Stansfield S, Marmot M. Low blood pressure, low mood? BMJ 1992; 304: 75-78. David A. Postviral fatigue syndrome and psychiatry. Br Med Bull 1991; 47: 966-88. Saltin B, Blomquist G, Mitchell J, Johnson R, Wildenthal K, Chapman C. Response to exercise after bed rest and training: a longitudinal study of adaptive changes in oxygen transport and body composition. Circulation 1968; 38 (suppl 7): 1-55.
Authors’
reply
SIR-It
should
be surprising that atenolol and used to treat our 7 patients with chronic disopyramide and mediated fatigue neurally hypotension. These drugs have been among the recommended therapies for neurally mediated hypotension for years. Symptom-free individuals occasionally will have abnormal responses to upright tilt, but to suggest that a hypotensive response is the norm would not be correct. Such abnormal responses occur in about 7-5% of controls during stage 1 of tilt testing, and in up to 27% when those who receive isoprenaline are included.’1 Prolonged bed rest might have been a more reasonable explanation for our findings if any of our patients had been confined to bed. They had not. All spent periods of each day moving about, and 3 continued to attend school. Similarly, none was clinically depressed. Symptoms improved within two weeks in 4 of the adolescents, which is an improbably short time for physical reconditioning to occur or for there to be spontaneous recovery from depression. The pace of improvement, along with the return of the tilt test response to normal in 1 patient whose fatigue improved and the persistence of an abnormal response in 1 child who did not improve, would be more consistent with a causal association than a confounder effect between neurally mediated hypotension and chronic fatigue. We did not describe an association between chronic fatigue and simple low blood pressure, as Wessely suggests, but between chronic fatigue and neurally mediated hypotension (also called vasodepressor syncope). The hypotension was confirmed only during upright tilt; before tilt testing, all patients had normal supine and standing blood pressures for age. We have not endorsed the use of any medication for the treatment of chronic fatigue syndrome, because such a recommendation would need to be based on data from randomised trials. Our report merely points to the potential for chronic fatigue to be more treatable, and with different drugs, than had been assumed in the past. Whether intentionally or not, Walden and Wessely imply that chronic fatigue syndrome is usually self-limited and that patients in some way could walk it off. There are no data suggesting that physical rehabilitation exercises are effective as primary treatments for neurally mediated hypotension or chronic fatigue syndrome. Indeed, patients with chronic not
were
fatigue syndrome typically feel much worse after modest physical exertion. Similarly, we are not aware of data suggesting a high rate of spontaneous resolution of chronic fatigue syndrome in the short term when patients satisfy strict criteria for this diagnosis. In a large study by Wilson and colleagues/ the mean duration of illness was 9-2 years, and a substantial proportion of patients continued to have impaired function with a further 3 years of follow-up. Against this background, the term self-limited loses meaning. *Peter C Rowe, Issam
Bou-Holaigah,
Jean S Kan,
Hugh Calkins
"Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
1 Kapoor WN, Smith MA, Miller NL. Upright tilt testing in evaluating syncope: a comprehensive literature review. Am J Med 1994; 97: 78-88. 2 Wilson A, Hickie I, Lloyd A, et al. Longitudinal study of outcome of chronic fatigue syndrome. BMJ 1994; 308: 756-59.
SIR-Rowe and colleagues incorrectly state that neurally mediated hypotension has not previously been implicated as a cause of chronic fatigue. In a paper published in 1992,’ we described 7 patients whose clinical features, apart from their ages, were strikingly similar to those of the patients reported by Rowe et al. They, too, presented with severe chronic fatigue associated with orthostatic lightheadedness. We attributed both these symptoms to orthostatic hypotension of a delayed type, described in a previous publication2 which became evident in these patients between 13 and 30 min after they had assumed the upright posture. In our patients, diagnosis was based on a precise duplication of the circumstances that they described as leading to their lightheadedness-ie, prolonged standingrather than on the more artificial use of a tilt table sometimes with isoprenaline infusion, used by Rowe and colleagues. Like these workers, we speculated that the relief of the fatigue by treatment that reduced or corrected the orthostatic hypotension in 5 of the patients might indicate that "the ’chronic fatigue syndrome’ might result, at least in part or in some individuals from the failure to maintain blood pressure in the upright posture". We are glad that Rowe’s observations are in accord with our findings. However, we warn that it is not always possible, despite the use of various therapeutic measures, to alleviate either the orthostatic hypotension or the fatigue. This finding, too, would tend to support the view that delayed orthostatic hypotension is an important pathogenetic mechanism leading to chronic fatigue syndrome. It may also be relevant to point out that the chronic fatigue syndrome has been attributed to impaired functional activity of the hypothalamic-pituitary-adrenal axis,3,4 in which the prevalence of orthostatic hypotension is known to be very high, though, of course, other consequences of hormonal deficiency might be contributing to fatigue in these patients. *David H P Streeten, Gunnar H Anderson Department of Medicine, College of Medicine, State University
Psychiatric manifestations in girl with ornithine transcarbamylase deficiency SiR-Deficiency of ornithine transcarbamylase (OTC) is an X-linked inborn error of urea synthesis. In male patients, the disease usually causes lethal ammonia intoxication during the neonatal period. Reflecting the random X-inactivation of the normal X-chromosome, female patients heterozygous for the disease have a wide range of clinical manifestations with a phenotype varying from apparent normality to a clinical pattern usually seen in male hemizygotes.’-3 We report a girl with OTC deficiency in whom the main clinical manifestations were psychiatric symptoms. The patient was the first child of unrelated French parents. At 6 months of age, she had vomiting related to gastro-oesophageal reflux. Thereafter, during the first 8 years of life, she had many episodes of behavioural problems: temper tantrums, aggression, feeding difficulties, and sleeplessness associated with vomiting. Her symptoms were attributed to difficulties in her relationship with her mother. At 8 years of age, because of lack of improvement in her psychiatric condition, she was admitted to a psychiatric hospital with new crises including aggression to herself and others, delirium with phobias, agitation, and anxiety. This episode coincided with the birth of a younger sister. The diagnosis of personality disorder and possible psychosis was made. In fact, between crises, the child’s behaviour was almost normal. 8 months after she was institutionalised in the psychiatric hospital, she had an attack of confusion, severe vomiting, and sudden blindness for which she was transferred to the regional hospital. On admission, she was comatose with pyramidal tract signs. Biological investigation revealed a plasma ammonia of 239 )J.moI/L, then 1270 µmol/L (normal <50), and glutamine 1236 µmol/L (normal <600). Urinary organic acid a showed high quantity of uracil, and chromatography was 326 urinary orotic acid µmol/mmol creatinine (normal <3). These two elements were very suggestive of OTC deficiency, confirmed by measurement of hepatic enzyme activity (13-5% of control values; D Rabier, Hopital des Enfants-Malades, Paris). Despite intensive therapy, the child died. The diagnosis of OTC deficiency in this patient was delayed because psychiatric disorders are rarely reported in this disease, although behavioural problems are frequently encountered.4,5 The possibility of an inborn error of metabolism should be considered in patients with episodes of neuropsychiatric problems especially when associated with vomiting. In these cases, an inherited disorder of the urea cycle has to be considered and could lead to an effective treatment based on a restricted protein diet. Claude Largillière Service de Pédiatrie, Hôpital Huriez, 59037 Lille, France
1
2 of New York,
Health Science Center, Syracuse, NY 13210, USA
3
1 Streeten DHP, Anderson GH Jr. Delayed orthostatic intolerance.
Arch Intern Med 1992; 152: 1066-72. 2
Streeten DHP. Orthostatic disorders of the circulation. New York: Plenum Publishing, 1987; 174: 180. 3 Poteliakhoff A. Adrenocortical activity and some clinical findings in acute and chronic fatigue. J Psychosomat Res 1981; 25: 91-95. 4 Demitrack MA, Dale JK, Straus SE, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 1991; 73: 1224-34.
4
5
Rowe PC, Newman SL, Brusilow SW. Natural history of symptomatic partial ornithine transcarbamylase deficiency. N Engl J Med 1986; 314: 541-47. Largillière C, Houssin D, Gottrand F, et al. Liver transplantation for ornithine transcarbamylase deficiency in a girl. J Pediatr 1989; 115: 415-17. Hawks Arn P, Hauser ER, Thomas GH, Herman G, Hess D, Brusilow SW. Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus: a cause of postpartum coma. N Engl J Med 1990; 322: 1652-55. Spade M, Guardamagna O, Rabier D, et al. Recurrent episodes of bizarre behaviour in a boy with ornithine transcarbamylase deficiency: diagnostic failure of protein loading and allopurinol challenge tests. J Pediatr 1994; 125: 249-51. DiMagno EP, Lowe JE, Snodgrass PJ, Jones JD. Ornithine transcarbamylase deficiency: a cause of bizarre behavior in a man. N Engl J Med 1986; 315: 744-47.
1113