- Email: [email protected]
Life with Spina Bifida: The Role of Quality of Life in Decision-Making
THE JOURNAL OF PEDIATRICS
www.jpeds.com
nonphenylalanine LNAAs on melatonin synthesis as a treatment for PKU. In a double-blinded crossover study, the patients were given either a protein-controlled meal alone or this meal plus an LNAA supplement. The patients who received the meal alone had markedly elevated plasma phenylalanine levels and significantly reduced ratios of both tyrosine and tryptophan levels to the other LNAAs (including phenylalanine), as well as significantly reduced levels of plasma melatonin and urine sulfatoxymelatonin. When given LNAAs, which are thought to increase the levels of tyrosine and tryptophan in the brain, the level of plasma tryptophan and the levels of both plasma melatonin and urinary sulfatoxymelatonin improved in a statistically significant manner. The tyrosine level also rose with an increase in urinary dopamine, its metabolite, but the significance of this finding is muted by the fact that it is produced in the periphery and cannot be used to infer specificity of central nervous system dynamics. Although the response of these metabolites to treatment with LNAAs may imply efficacy of this treatment, the effect was relatively limited and the changes or improvements, although statistically meaningful, did not approach normal levels. However, the possibility of defining a peripheral marker that implies central nervous system benefit of therapy as well as brain toxicity is exciting. These findings require validation. Can they be reproduced in a larger PKU population, and will reduced melatonin synthesis be a true and linear reflection of the danger of elevated phenylalanine levels? Will these findings be corroborated at the tissue level in the mouse model for PKU? Will in vitro studies further corroborate the findings at a tissue and cellular level? Most importantly, will these findings lead to alteration in the way PKU is followed or treated? If the answer to these questions is in the affirmative, Yano et al will have provided us with a new way to study PKU and its treatments.
Vol. 162, No. 5 This work is admirable in is its simplicity and directness. It required no substantial funding, no new techniques, and no expensive molecular studies. Instead, it required insight and ingenuity—hallmarks of science. Whether it is a lasting advance or a “shooting star whose glow rapidly fades,” it does indicate that the age of originality and imagination is not dead. n Stephen Cederbaum, MD Departments of Psychiatry, Pediatrics, and Human Genetics University of California Los Angeles, California Harvey L. Levy, MD Department of Medicine/Genetics Boston Children’s Hospital Department of Pediatrics Harvard Medical School Boston, Massachusetts Reprint requests: Stephen Cederbaum, MD, 635 Charles E Young Dr S, Los Angeles, CA 90095-7332. E-mail: [email protected]
References 1. Scriver CR, Clow CL. Phenylketonuria: epitome of human biochemical genetics. N Engl J Med 1980;303:1336-42. 1394-1400. 2. Belanger-Quintana A, Burlina A, Harding CO, Muntau AC. Up-to-date knowledge on different treatment strategies for phenylketonuria. Mol Genet Metab 2011;104(suppl):S19-25. 3. Lou HC. Dopamine precursors and brain function in phenylalanine hydroxylase deficiency. Acta Paediatr Suppl 1994;407:86-8. 4. Yano S, Moseley K, Azen C. Large neutral amino acid supplementation increases melatonin synthesis in phenylketonuria: a new biomarker. J Pediatr 2013;162:999-1003. 5. Baskett JJ, Cockrem JF, Antunovich TA. Sulphoxymelatonin in older people: relationship to plasma melatonin and renal function. J Pineal Res 1998;24:58-61.
Life with Spina Bifida: The Role of Quality of Life in Decision-Making During the 1950s and early 1960s, perinatal anesthesiology improved, as did perinatal surgery, and Sharrard et al2 then –World Health Organization1 wrote that early surgery on such infants decreased morbidity and increased survival. Surgery shortly after birth became the n the 1950s, anesthesia for newborn surgery was risky, new practice standard. shunt technology for hydrocephalus Several years later Lorber,3 reviewing his See related article, p 993 was poor, and the pre-eminent pediatric 521 cases, wrote that only 18% of survivors neurosurgeons, Ingraham and Matson, wrote that they who had early surgery had normal intelligence and mild-towould only embark on therapy of the infant with spina bifida moderate motor handicaps. Most had severe handicaps, and if the unoperated child survived until age one. Most unoperated children died of sepsis or uncontrolled hydrocephalus. “Health: A state of complete physical, mental, and social
well-being and not just the absence of sickness or frailty.”
I
The author declares no conflicts of interest.
HR-QoL
Health-related quality-of-life
0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.11.065
894
EDITORIALS
May 2013 40% had died. To spare children and families prolonged suffering, Lorber “proposed criteria for ‘selecting’ those for nontreatment” and stated that those untreated would die “quickly.” As director of the Birth Defects Center at Johns Hopkins, this was not my experience.4 In the US, no phenobarbital was given, and children were fed every 4 hours. In the British system, infants were given phenobarbital “to prevent seizures” and fed on demand. Thus, British infants slowly starved to death. During the late 1960s, and early 1970s, prenatal detection of spina bifida became available via the use of maternal alphafetoprotein levels and ultrasonography. Abortion of an affected fetus also became optional, and informed parental consent for surgery became required. Thus, far fewer infants with spina bifida were born, and the ethical scene for decision-making regarding surgery changed. In 2004, having left the field, I was asked to write a chapter on the ethics of decision-making in this new ethical milieu. In preparation, I interviewed 2 young women in their early 20s whom I presumed to be my most successful patients. Both were living at home, wheelchair-bound, with high paraplegias. Both were community college graduates and employed by the Social Security Administration. When I asked them what I should tell parents delivering a newborn with spina bifida, each replied, “I wish I had never been born.”5 I was shocked but did not pursue the conversation further. Was this the response of young females living at home with few social prospects? Or was this the outcome for those with high paraplegia? In this issue of The Journal, Young et al7 have once again determined that adolescents and young adults with spina bifida rate their health as excellent or very good, although the health-related quality-of-life (HR-QoL) scores of respondents were very low. The reader should be concerned about the biases introduced when only 39% of individuals with spina bifida responded to the request to participate in the study: only 52% of those agreed to participate in the survey, and only 87% of those who agreed to participate actually did so. Were respondents those with greater or less disability? Were the respondents more or less intellectually impaired? What was the family role in the responses? The question asked was, “In general would you say your health is: excellent, very good, good, fair or poor.” As the authors state, “self-rated health scores reflect acute health issues more than their underlying chronic conditions” (eg, “given that I have spina bifida, my health is good”). What aspect of health did the participants think they were answering? What was health to them? Was it the absence of current disease, of pain? Did it include their physical disability? Participants in the Para-Olympics would all be in excellent states of health, although each was physically impaired to varying degree.
The greatest differences in the HR-QoL scores varied with the level of the lesion and were in the domains of ambulation, pain, and cognition. The most important single factor in quality-of-life was the level of the lesion at birth. This accounted for 40% of the variance in Health Utilities Index 3 score. Older age was also a factor in lowering HR-QoL scores. Should these results be used in determining treatments at birth or prebirth?6 Should parents of infants with higher lesions be encouraged not to have their children treated? If nontreatment were encouraged, what should be done to mitigate suffering—of the child and family? Most families of newborns with spina bifida have little or no concept of what the child’s future holds. What is the physician’s role in educating them? What role should the physician play in influencing their decision regarding treatment? What can or should be done to mitigate the suffering of the child, the parent, and the medical staff if nontreatment is selected? I will not presume to have answers to these questions but propose further discussion of the quality-of-life issues in these children and of the impact of these issues on decisions regarding early treatment of spina bifida. Perhaps Lorber was correct in his selection criteria. But if an infant is “selected,” then what? Should future HR-QoL scores be used to determine life? n John M. Freeman, MD Professor (emeritus) Neurology and Pediatrics Johns Hopkins University School of Medicine Baltimore, Maryland Reprint requests: John M. Freeman, MD, 1026 Rolandvue Road, Baltimore, MD 21204. E-mail: [email protected]
References 1. World Health Organization. Preamble to the Constitution of the World Health Organization as adopted by the International Health Conference, New York, 19-22 June, 1946; signed on 22 July 1946 by the representatives of 61 States (Official Records of the World Health Organization, no 2, p 100). and entered into force on 7 April 1948. 2. Sharrard WJW, Zachary RB, Lorber J. Survival and paralysis in open myelomeningoceles with special reference to the time of repair of the spinal lesion. Dev Med Child Neurol 1967;9(Supp 13):35-50. 3. Lorber J. Results of treatment of myelomeningocele. an analysis of 524 unselected cases, with special reference to possible selection for treatment. Dev Med Child Neurol 1971;13:279-303. 4. Freeman JM. To treat or not to treat: ethical dilemmas of treating the infant with a myelomeningocele. Clin Neurosurg 1973;20:134-46. 5. Freeman JM. On learning humility: a thirty-year journey. Hastings Cent Rep 2004;34:13-6. 6. Adzick NS, Thom EA, Spong CY, Brock JW III, Burrows PK, Johnson MP, et al., MOMS Investigators. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Eng J Med 2011; 364:993-1004. 7. Young NL, Sheridan K, Burke TA, Mukherjee S, McCormick A. Health outcomes among youth and adults with spina bifida. J Pediatr 2013; 162:993-8.
895
www.jpeds.com
nonphenylalanine LNAAs on melatonin synthesis as a treatment for PKU. In a double-blinded crossover study, the patients were given either a protein-controlled meal alone or this meal plus an LNAA supplement. The patients who received the meal alone had markedly elevated plasma phenylalanine levels and significantly reduced ratios of both tyrosine and tryptophan levels to the other LNAAs (including phenylalanine), as well as significantly reduced levels of plasma melatonin and urine sulfatoxymelatonin. When given LNAAs, which are thought to increase the levels of tyrosine and tryptophan in the brain, the level of plasma tryptophan and the levels of both plasma melatonin and urinary sulfatoxymelatonin improved in a statistically significant manner. The tyrosine level also rose with an increase in urinary dopamine, its metabolite, but the significance of this finding is muted by the fact that it is produced in the periphery and cannot be used to infer specificity of central nervous system dynamics. Although the response of these metabolites to treatment with LNAAs may imply efficacy of this treatment, the effect was relatively limited and the changes or improvements, although statistically meaningful, did not approach normal levels. However, the possibility of defining a peripheral marker that implies central nervous system benefit of therapy as well as brain toxicity is exciting. These findings require validation. Can they be reproduced in a larger PKU population, and will reduced melatonin synthesis be a true and linear reflection of the danger of elevated phenylalanine levels? Will these findings be corroborated at the tissue level in the mouse model for PKU? Will in vitro studies further corroborate the findings at a tissue and cellular level? Most importantly, will these findings lead to alteration in the way PKU is followed or treated? If the answer to these questions is in the affirmative, Yano et al will have provided us with a new way to study PKU and its treatments.
Vol. 162, No. 5 This work is admirable in is its simplicity and directness. It required no substantial funding, no new techniques, and no expensive molecular studies. Instead, it required insight and ingenuity—hallmarks of science. Whether it is a lasting advance or a “shooting star whose glow rapidly fades,” it does indicate that the age of originality and imagination is not dead. n Stephen Cederbaum, MD Departments of Psychiatry, Pediatrics, and Human Genetics University of California Los Angeles, California Harvey L. Levy, MD Department of Medicine/Genetics Boston Children’s Hospital Department of Pediatrics Harvard Medical School Boston, Massachusetts Reprint requests: Stephen Cederbaum, MD, 635 Charles E Young Dr S, Los Angeles, CA 90095-7332. E-mail: [email protected]
References 1. Scriver CR, Clow CL. Phenylketonuria: epitome of human biochemical genetics. N Engl J Med 1980;303:1336-42. 1394-1400. 2. Belanger-Quintana A, Burlina A, Harding CO, Muntau AC. Up-to-date knowledge on different treatment strategies for phenylketonuria. Mol Genet Metab 2011;104(suppl):S19-25. 3. Lou HC. Dopamine precursors and brain function in phenylalanine hydroxylase deficiency. Acta Paediatr Suppl 1994;407:86-8. 4. Yano S, Moseley K, Azen C. Large neutral amino acid supplementation increases melatonin synthesis in phenylketonuria: a new biomarker. J Pediatr 2013;162:999-1003. 5. Baskett JJ, Cockrem JF, Antunovich TA. Sulphoxymelatonin in older people: relationship to plasma melatonin and renal function. J Pineal Res 1998;24:58-61.
Life with Spina Bifida: The Role of Quality of Life in Decision-Making During the 1950s and early 1960s, perinatal anesthesiology improved, as did perinatal surgery, and Sharrard et al2 then –World Health Organization1 wrote that early surgery on such infants decreased morbidity and increased survival. Surgery shortly after birth became the n the 1950s, anesthesia for newborn surgery was risky, new practice standard. shunt technology for hydrocephalus Several years later Lorber,3 reviewing his See related article, p 993 was poor, and the pre-eminent pediatric 521 cases, wrote that only 18% of survivors neurosurgeons, Ingraham and Matson, wrote that they who had early surgery had normal intelligence and mild-towould only embark on therapy of the infant with spina bifida moderate motor handicaps. Most had severe handicaps, and if the unoperated child survived until age one. Most unoperated children died of sepsis or uncontrolled hydrocephalus. “Health: A state of complete physical, mental, and social
well-being and not just the absence of sickness or frailty.”
I
The author declares no conflicts of interest.
HR-QoL
Health-related quality-of-life
0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.11.065
894
EDITORIALS
May 2013 40% had died. To spare children and families prolonged suffering, Lorber “proposed criteria for ‘selecting’ those for nontreatment” and stated that those untreated would die “quickly.” As director of the Birth Defects Center at Johns Hopkins, this was not my experience.4 In the US, no phenobarbital was given, and children were fed every 4 hours. In the British system, infants were given phenobarbital “to prevent seizures” and fed on demand. Thus, British infants slowly starved to death. During the late 1960s, and early 1970s, prenatal detection of spina bifida became available via the use of maternal alphafetoprotein levels and ultrasonography. Abortion of an affected fetus also became optional, and informed parental consent for surgery became required. Thus, far fewer infants with spina bifida were born, and the ethical scene for decision-making regarding surgery changed. In 2004, having left the field, I was asked to write a chapter on the ethics of decision-making in this new ethical milieu. In preparation, I interviewed 2 young women in their early 20s whom I presumed to be my most successful patients. Both were living at home, wheelchair-bound, with high paraplegias. Both were community college graduates and employed by the Social Security Administration. When I asked them what I should tell parents delivering a newborn with spina bifida, each replied, “I wish I had never been born.”5 I was shocked but did not pursue the conversation further. Was this the response of young females living at home with few social prospects? Or was this the outcome for those with high paraplegia? In this issue of The Journal, Young et al7 have once again determined that adolescents and young adults with spina bifida rate their health as excellent or very good, although the health-related quality-of-life (HR-QoL) scores of respondents were very low. The reader should be concerned about the biases introduced when only 39% of individuals with spina bifida responded to the request to participate in the study: only 52% of those agreed to participate in the survey, and only 87% of those who agreed to participate actually did so. Were respondents those with greater or less disability? Were the respondents more or less intellectually impaired? What was the family role in the responses? The question asked was, “In general would you say your health is: excellent, very good, good, fair or poor.” As the authors state, “self-rated health scores reflect acute health issues more than their underlying chronic conditions” (eg, “given that I have spina bifida, my health is good”). What aspect of health did the participants think they were answering? What was health to them? Was it the absence of current disease, of pain? Did it include their physical disability? Participants in the Para-Olympics would all be in excellent states of health, although each was physically impaired to varying degree.
The greatest differences in the HR-QoL scores varied with the level of the lesion and were in the domains of ambulation, pain, and cognition. The most important single factor in quality-of-life was the level of the lesion at birth. This accounted for 40% of the variance in Health Utilities Index 3 score. Older age was also a factor in lowering HR-QoL scores. Should these results be used in determining treatments at birth or prebirth?6 Should parents of infants with higher lesions be encouraged not to have their children treated? If nontreatment were encouraged, what should be done to mitigate suffering—of the child and family? Most families of newborns with spina bifida have little or no concept of what the child’s future holds. What is the physician’s role in educating them? What role should the physician play in influencing their decision regarding treatment? What can or should be done to mitigate the suffering of the child, the parent, and the medical staff if nontreatment is selected? I will not presume to have answers to these questions but propose further discussion of the quality-of-life issues in these children and of the impact of these issues on decisions regarding early treatment of spina bifida. Perhaps Lorber was correct in his selection criteria. But if an infant is “selected,” then what? Should future HR-QoL scores be used to determine life? n John M. Freeman, MD Professor (emeritus) Neurology and Pediatrics Johns Hopkins University School of Medicine Baltimore, Maryland Reprint requests: John M. Freeman, MD, 1026 Rolandvue Road, Baltimore, MD 21204. E-mail: [email protected]
References 1. World Health Organization. Preamble to the Constitution of the World Health Organization as adopted by the International Health Conference, New York, 19-22 June, 1946; signed on 22 July 1946 by the representatives of 61 States (Official Records of the World Health Organization, no 2, p 100). and entered into force on 7 April 1948. 2. Sharrard WJW, Zachary RB, Lorber J. Survival and paralysis in open myelomeningoceles with special reference to the time of repair of the spinal lesion. Dev Med Child Neurol 1967;9(Supp 13):35-50. 3. Lorber J. Results of treatment of myelomeningocele. an analysis of 524 unselected cases, with special reference to possible selection for treatment. Dev Med Child Neurol 1971;13:279-303. 4. Freeman JM. To treat or not to treat: ethical dilemmas of treating the infant with a myelomeningocele. Clin Neurosurg 1973;20:134-46. 5. Freeman JM. On learning humility: a thirty-year journey. Hastings Cent Rep 2004;34:13-6. 6. Adzick NS, Thom EA, Spong CY, Brock JW III, Burrows PK, Johnson MP, et al., MOMS Investigators. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Eng J Med 2011; 364:993-1004. 7. Young NL, Sheridan K, Burke TA, Mukherjee S, McCormick A. Health outcomes among youth and adults with spina bifida. J Pediatr 2013; 162:993-8.
895