Abstract
Objective. To clarify the relationship between initial assisted ventilation duration and outcome for patients with congenital myotonic dystrophy (CDM).
Methods. A retrospective chart review was conducted of cases of CDM that presented to the Children’s Hospital of Eastern Ontario (Ottawa, Ontario, Canada) between 1980 and 2000. Inclusion criteria were conclusive testing for CDM and clinical presentation in the first 30 days of life. Duration of assisted ventilation, morbidity, mortality, and developmental outcome were measured.
Results. A total of 23 children met the inclusion criteria. One child died at 5 days of age, and 2 others had withdrawal of ventilation. The remaining 20 children were divided into 2 groups on the basis of whether they needed > or <30 days of ventilation. In the first year of life, 25% mortality was noted in the children with prolonged ventilation, whereas no child in the short ventilation duration group died. After 1 year of age, 1 child in each group died with follow-up of 2 to 16 years. The children with prolonged ventilation needed more hospitalizations. Delays were noted in development in both groups of children at ages 1, 3, and 6 years; however, there was an improvement in motor and language scores over time in all children. Children who required ventilation for <30 days had better motor, language, and activities of daily living scores at all ages.
Conclusions. Children with CDM with prolonged ventilation experienced 25% mortality in the first year. The use of a specific time period of ventilation to decide on withdrawal of therapy must be reconsidered given these findings. Prolonged ventilation was followed by greater morbidity and developmental delay than children with shorter ventilation duration.
Myotonic dystrophy is a multisystem disorder characterized by muscle weakness and myotonia manifesting in early adulthood.1 Two loci for the disease are known and described as DM1 and DM2. At both loci, inheritance is autosomal dominant. DM1 is associated with a CTG trinucleotide expansion on chromosome 19q13.3, and DM2 is associated with a CCTG tetranucleotide expansion at 3q21.2 Although the contribution of disruptions of these genes coding for the myotonic dystrophy protein kinase and the zinc finger 9 protein, respectively, may contribute to the symptoms of the disease, the primary pathogenesis is believed to be related to the effect of large accumulations of mutant mRNA in the nucleus of cells.3,4
In DM1, a more severe clinical phenotype and earlier age of onset can occur over subsequent generations as the unstable trinucleotide repeat carried by the parent can expand further during gametogenesis. This phenomenon is known as genetic anticipation and, in this context, leads eventually to an infant with congenital myotonic dystrophy (CDM). The incidence of CDM is 1 in every 3500 to 16 000 births.5 Although there can be a wide spectrum of symptoms, the child often has evidence of hypotonia, weakness, feeding difficulties, and mechanical respiratory failure requiring intubation and ventilation immediately after birth.6 Several published reports list pediatric mortality rates in the range of 17% to 41% for patients with CDM.7–9 The cause of death is generally respiratory insufficiency.
Decisions regarding child bearing or predicting outcome for families with an affected child can be difficult on the basis of genetic information alone as the genotypic-phenotypic correlation is variable.10,11 Rarely do families feel comfortable using only genetic information to decide about child bearing given this phenotypic variability.12 A more pragmatic approach to prognostication focuses on clinic status of the child once she or he is born. The duration of ventilation has been examined as an indicator of outcome in a few studies.13–15 This approach has advantages in that the child may be the index case, so genetic information is not immediately available, and also, it takes into consideration other physiologic parameters that affect children with CDM. Furthermore, ventilatory support is often used as a focal point regarding decisions of treatment withdrawal in ill children. One frequently quoted study suggests uniform mortality for children who require ventilation for >30 days on the basis of results from 4 children.13 More recently, however, a number of case reports are suggesting reasonable survival in children who are ventilated for >30 days.16,17
The objectives of the current study were to clarify the relationship between initial ventilation duration and outcome for patients with CDM. The hypothesis was that although medical morbidity will be greater in children who require prolonged ventilation, early mortality will not be universal and long-term medical and developmental status will be similar regardless of ventilation status. On the basis of the previous literature, the hypothesis was generated using 30 days or longer of ventilation as a definition of prolonged ventilation.
METHODS
A retrospective chart review was performed for all cases of myotonic dystrophy from 1980 to December 2000 followed at the Children’s Hospital of Eastern Ontario. Cases were identified by the examination of charts coded as myotonic dystrophy by the Health Records Department. In addition, the records of 1 of the authors (M.B.) and all patients seen in the Neuromuscular Clinic at Children’s Hospital of Eastern Ontario by a second author (P.J.) were reviewed for accuracy and completeness.
Inclusion criteria were 1) conclusive testing for CDM by gene testing, electromyography, and/or muscle biopsy in child or parent and 2) presentation in the first 30 days of life with feeding difficulties, hypotonia, and/or respiratory problems attributable to myotonic dystrophy. This included not only neonatal intensive care admissions but also inpatient admissions and clinic visits.
Descriptive factors and outcomes including demographic features, antenatal information, and medical and developmental outcomes were gathered through chart review by a single person with confirmation of a portion of records by 1 of the authors (R.S.). Demographic information included maternal age and parity, gender, gestational age, birth weight, and the method of diagnostic testing. Information on CTG expansion size was collected using the common classification: E0 = 50 to 200 repeats, E1 = 200 to 500, E2 = 500 to 1000, E3 = 1000 to 1500, and E4 = >1500. Medical information collected included the details of neonatal resuscitation, Apgar scores, cord gases, the duration of assisted ventilation, associated pulmonary complications, the number of hospitalizations after discharge, and mortality including the age at and the cause of death. Assisted ventilation was defined as the need for mechanical ventilation (excluding continuous positive airway pressure [CPAP]) for any part of a 24-hour period. A resuscitation score was developed for this study and ranged on a scale from 0 (no intervention needed) to 6 (medications needed). See Appendix A for details.
Developmental assessments within 3 months (in either direction) closest to ages 1, 3, and 6 years were obtained from physiotherapy, occupational therapy, or physicians’ notes when available. Scores were generated for expressive language skills, motor skills, and activities of daily living (ADL) using commonly obtained developmental skills and based on information that the authors believed would be most likely to be documented in the charts in an objective manner (eg, expressive vs receptive language). One point was assigned for each developmental skill obtained. See Appendix B for details.
The data are presented through descriptive measures, and, where appropriate, means are compared with t tests assuming independent samples. Statistical significance was considered for P < .05.
RESULTS
A total of 23 children met the inclusion criteria. Figure 1 outlines the natural history of the identified children. Three children were not included in the evaluation of the groups, 1 because the child died at 5 days of persistent pulmonary hypertension of the newborn and thus could not be assigned to a ventilation duration group and 2 others whose natural history where unknown as ventilation was withdrawn at 30 days and 52 days. These last 2 children had few problems other than chronic mechanical respiratory failure, and decision to withdraw was based on previous medical literature. Twelve children were ventilated for <30 days, including 4 who required no ventilation at all. The second group consisted of 7 children who were ventilated for >30 days. The duration of ventilation for all of the children is presented in Fig 2. In 1 child, the duration of ventilation is truncated at 90 days as the exact duration of ventilation is not available because of a transfer to another institution. This child, however, did have follow-up visits at our hospital, and so developmental status was assessed.
Flow diagram of outcome of children identified with CDM.
Duration of assisted ventilation.
The demographic characteristics of the 2 groups are compared in Table 1. No significant differences were found between the 2 groups with respect to these factors. Several resuscitation factors were compared between the groups and are shown in Table 1. Infants who required >30 days of ventilation required significantly more resuscitation than those with shorter-term ventilation as represented by the resuscitation scores. Cord gas pH and base excess was available on only 7 children, mostly in the prolonged ventilation group, and none showed substantial abnormality. Similarly, the next available pH and base excess did not show marked acidosis in any child. Apgar scores were available on 18 children and showed a significant difference between infants who required <30 days of ventilation and those who progressed to longer-term ventilation needs.
Demographic and Resuscitation Characteristics of Children With CDM
The percentage mortality at each stage is demonstrated in Table 2. Two children died in the first year, and both were in the group of children who required prolonged ventilation. One child died at 8 months from a cardiac arrest during a presumed viral respiratory infection. The child had been ventilated initially for 3 months (109 days) and was reventilated 1 month later after a presumed viral respiratory illness. He was never again able to ventilate independently and was still admitted at the time of death. The second child, also being ventilated from birth, died at 10 months, after a 1-week period of respiratory deterioration and several seizures. Two children, 1 from each group, died in the follow-up period, which ranged from 1 to 16 years (group-specific ranges in Fig 1). One child died at age 1 year 9 months during cardiac surgery for mitral and pulmonary stenosis (short ventilation group), and the second was found without vital signs during a hospital admission for a bowel obstruction at 11 years of age.
Postnatal Medical Characteristics of Children With CDM
Acquired pulmonary disease such as pneumothorax and pneumonia were more frequent in the group of children with prolonged ventilation. These complications as well as endogenous pulmonary factors such as hypoplasia and raised hemidiaphragm were combined to demonstrate the burden of pulmonary complications and are reported in Table 2. Six children required tracheostomy placement, and all were in the prolonged ventilation group. The other significant morbidity that was examined was the number of hospitalizations per year of age, and this is also given in Table 2.
In our sample, it was determined that 11 infants with CDM were the index cases for their families. Expansion size was available for 10 children in this study. Figure 3 illustrates how ventilation duration varied with expansion number.
Expansion size and duration of ventilation. (See Methods for trinucleotide expansion number corresponding to E0–E4).
Table 3 demonstrates the developmental scores by age and group. Children who required ventilation for <30 days had better motor scores at all ages, and these differences reached statistical significance at age 1 and 3 years. There was a trend in all children with CDM toward improvement in motor scores over time. Language skills also improved in all children between ages 3 and 6 years and seemed to be better at all ages in the short ventilation group. The ADL scores remained static in the prolonged ventilation group between 3 and 6 years, whereas the scores improved in children who were ventilated for <30 days during this same time period
Developmental Outcome
DISCUSSION
Children who had CDM and were ventilated for >30 days experienced a 25% mortality in the first year and a 17% mortality beyond this. This is in contrast to the children who were ventilated <30 days, who had no deaths recorded in the first year and an 8% death rate later in the pediatric age range. The children who require longer ventilation also experience greater morbidity as demonstrated by the longer initial hospital stays and the greater number of hospitalizations per year of age. All children who survived the first year improved and eventually became ventilator independent. Developmental progress was seen in both groups of children, with those who were ventilated for >30 days having more developmental lag than the comparators, especially in the area of motor skills.
Although there is a much higher rate of death for children who require prolonged ventilation, the figure is much less than 100%, as has been suggested in previous studies. Previous literature has documented universal fatality in children who are ventilated for >30 days.13,14 Rutherford described a series of 14 children with CDM, 3 of whom were ventilated for >month, and all died by the age of 15 months. Because of the perceived poor prognosis, a fourth child in this series who required ventilation for >30 days had a withdrawal of ventilatory support and died. In the literature, numerous references are made to this article and suggest that progressing with ventilation beyond 30 days is futile and justification for withdrawal of care.7,9,16,17 In another series of 17 newborns with various congenital myopathic diseases, including 7 children with CDM, all children who were ventilated for >21 days died.14 The ages and causes of death were not specified.
Recently, several case reports have documented that survival is possible despite prolonged ventilation. One child, who was 19 months of age (2870 repeats, or E4) and ventilated for 127 days followed by 14 days of CPAP, was reported to have evidence of marked developmental delay particularly of motor skills.17 A child with a ventilation duration of 55 days and a week of CPAP was reported to be delayed in motor skills but without respiratory issues at 1 year of age.16 The cases presented here record much greater follow-up times than that available currently in the literature, allowing a more complete examination of morbidity and mortality.
Documenting the mortality related to ventilation duration is very important. The main reason that we sought to clarify the relationship between ventilation duration and outcome resides in the understanding that the pathophysiology of CDM is distinct from the latter onset myotonic dystrophy. In CDM, muscle immaturity is the main culprit leading to hypotonia and respiratory muscle weakness.18,19 This immaturity improves over time both pathologically20 and by parental and clinical reports.9,12 Thus, it is expected that if a child escapes the complications of prolonged ventilation, then he or she will eventually have the strength to support independent ventilation. This was clear in our population that all those who survived the first year were able to maintain independent ventilation.
Other reasons exist for clarifying the relationship between ventilation duration and outcome. First, predicting outcome simply from the child or maternal genetic information is often impractical as the child in many cases is the index case and medical therapy is under way before diagnosis, forcing treatment decisions to be focused on ventilation duration and other medical complications. In this study, more than half of the children were the index case. Furthermore, a great deal of variability exists in the clinical presentations and the genotype.10,11,21 This was the case in this series of patients, as shown in Fig 3, in which children with the highest degrees of expansion size had ranges of ventilation from 0 to 180 days. Information was not available in this series to determine how many parents with known DM had prenatal counseling, but the literature suggests that this is not well received by many families12 because of the phenotypic variability. In fact, this variability has led to the International Myotonic Dystrophy Consortium to caution against using repeat length as a prognosticator.11
Finally, ventilation is a very tangible life support measure and cessation will often lead to a rapid death in the setting of respiratory failure, so this often becomes the focal point for decisions around withdrawal of care. As supportive care improves over time, one might expect more children to survive prolonged ventilation, thus giving time for muscle maturation to occur. This may help to explain why earlier studies found such pessimistic results. For these reasons, this study attempted to provide physicians and caregivers with a longitudinal perspective on outcome in children with CDM placed in the context of ventilation needs. To clarify the outcome better, we also included medical and developmental parameters that will help both health professionals and caregivers to understand better the life of a child with CDM.
Medical complications in this study did not include significant intrapartum asphyxial injury. Although this study found that the Apgar scores at both 1 and 5 minutes were much lower in the children with prolonged ventilation, relying on the Apgar scores to characterize asphyxia is likely to be misleading in children with CDM because of the score’s reliance on muscle tone and activity. Low cord gas pH and base excess are indicators of intrapartum compromise. Although the group of children who went on to have a longer duration of ventilation had a lower cord and first gas pH, the values were not in a range usually associated with significant encephalopathy. The worst cord gas pH obtained on a child was 7.16, and the base excess was −7.8. A greater initial resuscitative effort was needed in the prolonged ventilation group, but this likely reflects that 4 children in the other group did not require any intubation. In the follow-up period, it was believed that the number of hospitalizations per year of age would be a reflection of the morbidity experienced by these children, and it was evident that the children who needed longer duration of ventilation had more reason for later admissions. Causes of hospitalization were generally related to respiratory illness or gastrointestinal dysmotility in both groups; however, respite care, orthopedic procedures, and in 3 children revisions of ventriculoperitoneal shunts also contributed.
The developmental data presented in this study show that children do improve over time. This is particularly evident in the motor skills, which is consistent with our understanding of the pathophysiology of CDM. Pathologic reports have demonstrated an improvement in muscle histology over time,20 and the findings of this study demonstrate the clinical correlate. That the difference in motor skills between our 2 groups is greater at younger ages also supports the process of a gradual improvement in muscle immaturity. The cognitive impairments in CDM are believed to be more static and attributable to organizational differences in brain development.22,23 Neuroimaging and central nervous system pathology studies support this observation.20,24 Central nervous system involvement is marked most often by static ventriculomegaly and cerebral white matter lesions on magnetic resonance imaging scans.20,23,24 Pathologically, cortical organizational features are seen. The data presented in this study on language and ADL function give some insight into the cognitive status of these children. All children gained skills over time with a suggestion that those who were ventilated longer were more impaired, reflecting the more severe disease process. More objective measures of cognitive function were not available on any of the children presented here, but in the literature, objective cognitive testing on children with CDM has shown intelligence quotients ranging from 24 to 79.9,23–25
The retrospective nature of this study compromised the ability to make strong observations on the developmental progress; however, it should remain accurate for the mortality findings. Difficulty is encountered when trying to elicit developmental information from chart review, and the unvalidated developmental scores used are recognized as being less than ideal. The developmental data must be interpreted with caution but are important in informing decisions about which developmental scales may need to be used in future work. The groups are also small, and, as such, the statistical comparisons should be viewed with this in mind.
Given the findings of this investigation, it becomes evident that the use of a specific time period of ventilation to decide on withdrawal of therapy must be reconsidered. We have demonstrated that mortality is not universal in children who require prolonged ventilation and that most children will eventually become independent of the ventilator as their muscles become more mature. This study provides information to assist caregivers and physicians in making decisions when confronted with the difficult choices associated with the care of a child with CDM. Future initiatives that would help in understanding the outcome of children with CDM would include a prospective database dedicated to myotonic dystrophy presenting in the neonatal period with follow-up examining developmental progress in more objective ways. Assessments of health-related quality of life and development of disease-specific measures of health-related quality of life could be conducted in this setting. Information of this nature would be useful for families who are trying to understand better the future of their child with CDM and to help physicians in prognosticating at the early stages of the disease.
APPENDIX A: RESUSCITATION SCORE
Nothing = 0
Oxygen only = 1
CPAP = 2
Bag and mask positive pressure ventilation = 3
Intubation and ventilation = 4
Cardiac compressions = 5
Resuscitative medications used = 6
APPENDIX B: DEVELOPMENTAL SCORES
Expressive Language
Range 0 to 5
No expressive language = 0
Noises only = 1
Speaks 1 to 10 words = 2
Sign language = 3
Picture board use = 4
Speaks >10 words = 5
Motor Score
No motor skills = 0
Rolling = 1
Sitting = 2
Creeping =3
Crawling = 4
Independent standing = 5
Walking with aid = 6
Walking independently = 7
Running = 8
Stairs = 9
Bicycle/tricycle = 10
Activities of Daily Living Score
Range 0 to 3
One point for each of the following: feeds independently, toilets independently, and dresses independently. A score of 0 was given for complete dependence in all areas.
Acknowledgments
Financial support for the project was obtained through a grant from the Children’s Hospital of Eastern Ontario Research Institute.
Dr Campbell was responsible for the study concept, methods, data management, and analysis. In addition, Dr Campbell produced the draft manuscript. Dr Sherlock supervised data collection and was involved in the production of the draft manuscript. Drs Jacob and Blayney provided comments in the planning of the project and made revisions to the manuscript. Data entry was completed through the Chalmers Research Group.
We thank Karen Lortie for help with data collection and the Chalmers Research Group for consultation on data management and analysis.
Footnotes
- Received April 14, 2003.
- Accepted October 10, 2003.
- Reprint requests to (C.C.) Section of Pediatric Neurology, Children’s Hospital of Western Ontario, 800 Commissioners Rd E, London, Ontario, Canada. E-mail: craig.campbell{at}lhsc.on.ca
REFERENCES
- Copyright © 2004 by the American Academy of Pediatrics
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