Journal of Pediatric Rehabilitation Medicine: An Interdisciplinary Approach 6 (2013) 227–233 DOI 10.3233/PRM-140257 IOS Press
227
Cerebral palsy patients discovered dead during sleep: Experience from a comprehensive tertiary pediatric center Ali F. Karatas, Elissa G. Miller, Freeman Miller, Kirk W. Dabney, Steven Bachrach, Justin Connor, Kenneth Rogers and Laurens Holmes, Jr.∗ Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
Accepted 14 October 2013
Abstract. OBJECTIVES: It is not uncommon for children with cerebral palsy (CP) to be discovered dead during sleep (DDDS); however, the factors associated with this pattern of mortality remain unknown. The current study aims to describe the mortality associated with children with CP from a single, tertiary care center who were DDDS. METHODS: A retrospective (case-only) design to examine proportionate mortality and patient characteristics and comorbidities that may be related to children DDDS between 1993 and 2011. RESULTS: There were 177 patients with CP whose deaths were reported to our institution during the study period, of which 19 were DDDS at home. The period proportionate mortality (PPM) was 114.5 per 1000. The average age at time of death was 17 years and 6 months (minimum, 6 years; maximum, 25 years). All but one of the DDDS patients had gastrointestinal feeding tubes, seizure disorders, respiratory disorders, and were non-ambulatory. Very importantly, our DDDS patients manifested clusters of respiratory disorders, namely recurrent aspiration pneumonia (10/19), asthma pneumonitis (4/19), food/vomitius inhalation (6/19), reactive airway disease (16/19), respiratory failure (14/19), chronic bronchitis (7/19), chronic obstructive lung disease (9/19), and nocturnal respiratory insufficiency (16/19). CONCLUSIONS: Respiratory disorders, severe motor disability, seizures, and intellectual status are possible co-morbidities that may be associated with DDDS. There is a need for further study in order to understand what type of monitoring and care (if any) may help prevent DDDS related to these co-morbidities and sleep disorders/abnormalities. Keywords: Cerebral palsy, proportionate mortality, respiratory disorders, mortality, co-morbidities
1. Introduction Cerebral palsy (CP) is characterized by motor impairment that may present as global physical and psycho-motor dysfunction. This condition involves brain impairment as well as locomotor dysfunction. Most cerebral palsies occur during early development, including the prepartum, intra-partum, or early post∗ Corresponding author: L. Holmes, Jr., Orthopedic Department, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA. Tel.: +1 302 377 3550; Fax: +1 302 651 5951; E-mail: [email protected].
partum period. Cerebral palsy is non-progressive, but the signs and symptoms may vary with the child’s maturation. An epidemiologic study on CP in England and Scotland found its prevalence to be 2.5 per 1000 live births [1]. 2001 data on the prevalence of CP in the United States estimated this to be 764,000 children and adults [2]. An estimated 70–80% of CP cases are said to be prenatally related with the majority described as unknown in terms of etiology. However, birth complications have been associated with an estimated 6% of cases of congenital CP [3]. Some of the postulated causes are hydrocephalus, cranial hemorrhage, prolonged asphyxia, head trauma from shaken
c 2013 – IOS Press and the authors. All rights reserved 1874-5393/13/$27.50
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A.F. Karatas et al. / Cerebral palsy patients discovered dead during sleep
baby syndrome, bacterial and viral infection (such as cytomegalovirus), and lead poisoning [4]. Individuals with CP are more likely to have a higher mortality rate compared to the general population [5–7]. A 10-year study (1986–1995) of CP mortality in California indicated mortality of 90 per 1,000 person-years [8]. In this study, children (under 15 years) contributed 136 757 person–years of follow-up, and the adults contributed 271 138 person–years, for a total of 407 895 person–years. During this period, 4,408 participants died, for an overall mortality rate of 11 deaths per 1000 person–years. Also, mortality in other populations has been shown to be 50% by age 20 years among patients with CP who have seizures, severe mental retardation (MR), and are non-ambulatory [7–9]. However, there was variability in median survival within the group of non-ambulatory children, with medians being greater than 20 years for some sub-groups. For the most severely impaired children at age 2 years, median survival to age 20 years or greater is unusual. Children with CP who were discovered dead during sleep (DDDS) have been specifically reported in literature, but related mechanism had been used in a few studies [7,10]. In one of these studies, the etiology of death could not be identified in 25 children; five of these patients were found dead in bed by their caregivers [10]. In another study, some CP children were discovered dead in bed [7]. Despite being mentioned, these studies presented little or no information regarding this phenomenon, and no study to date has investigated the phenomenon more fully. The mechanism of death associated with these specific patients remains unknown, and there is no reported literature on this phenomenon, especially risks and predisposing factors. We aimed, in the current study, to examine all patients DDDS from 1993–2011, thus evaluating treatment received during lifetime, co-morbidities, CP topography, and prognostic factors in an attempt to better understand the phenomenon of DDDS and to generate hypotheses on contributing factors to DDDS.
2. Patients and methods This study was institutional review board (IRB) approved. We conducted a retrospective descriptive study (case-only) to assess the pattern, characteristics, and possible trends among our patients with CP who were DDDS. The CP program at our institution maintains reliable patient records comparable to most disease registries.
Data were extracted from our medical records on demographics (sex, year of birth, age at death), topographical pattern of CP (hemiplegic/diplegic/triplegic/ quadriplegic), motor severity (Gross Motor Function Classification System [GMFCS] level I–V), and intellectual status (none/moderate/severe MR). Other data extracted in the presence or absence of the following were gastrostomy/jejunostomy tube, scoliosis hip dysplasia/hip dislocation, long bone fracture, and hydrocephalous/shunt. The co-morbidity data were extracted from the electronic medical records and included the presence or absence of the following: gastrointestinal (GI) bleeding, anemia, decubitus ulcer, seizure, GI feeding tube, respiratory disorder, recurrent aspiration pneumonia, food/vomitus inhalation, reactive airway disease, respiratory failure, chronic bronchitis, chronic obstructive lung disease, and nocturnal insufficiency. The salivagram history was extracted as positive or negative, and the last radiograph data were extracted as normal versus non-normal. The year of surgeries, demographics, co-morbidities, and prognostic factors were tabulated in order to observe common patterns and characteristics among the patients who were DDDS. 2.1. Statistical analysis A descriptive statistics was used in this study. The proportionate mortality was estimated using the total number of patients DDDS as a numerator, death from all causes during the study period as the denominator, and 1000 as a multiplier. Quantitatively proportionate mortality was given by: DDDS / all deaths during the study period X 1000.
3. Results Of 177 patients known to have died during the study period, a total of 19 children (11 male, 8 female) were DDDS between 1993 and 2011 in our patient population (pediatric CP). The proportionate mortality, which is the proportion of deceased CP patients DDDS relative to all CP patients who died during the study, was 114.5 per 1000. All patients DDDS died between age 6 and 25 years. The mean age at death was 17 years and 6 months (SD, 4.7). Table 1 describes the demographic, CP topography, and clinical features observed in these patients. Of those DDDS, 11 were male, 18 had spastic quadriplegia, 11 had severe MR, and eight had hydrocephalus.
A.F. Karatas et al. / Cerebral palsy patients discovered dead during sleep Table 1 Demographic and clinical features of patients discovered dead during sleep Variable Sex Female Male Cognitive level Severe MR Moderate MR Hydrocephalus Yes No Place of death Hospital Home CP subtype Spastic diplegic Quadriplegic Ambulation Yes No
Frequency
%
8 11
42 58
11 8
58 42
8 11
42 58
− 19
− 100
1 18
5 95
1 18
5 95
CP, cerebral palsy; MR; mental retardation. Table 2 Variable Scoliosis Yes No Scoliosis surgery Yes No Hip dysplasia/dislocation Yes No Hip surgery Yes No Long bone fracture Yes No Gastrointestinal bleeding Yes No Anemia Yes No Decubitus ulcer Yes No Gastric tube obstruction Yes No Salivagram history Positive None
Frequency
%
13 6
68.5 31.5
10 9
52.7 47.3
9 10
47.4 52.6
7 12
41.2 58.8
9 10
47.4 52.6
4 15
21 79
5 14
27 73
9 10
47 53
8 11
43 57
5 14
27 73
Table 2 demonstrates the co-morbidities in patients DDDS. Thirteen were diagnosed with scoliosis, and 10 of these patients underwent surgery for curve deformity correction. Nine of the patients in the study were
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Table 3 Respiratory manifestations and disorders in patients discovered dead during sleep Variable Recurrent aspiration pneumonia Yes No Asthma pneumonitis Yes No Inhalation Yes No Reactive airway disease Yes No Respiratory failure Yes No Nocturnal respiratory insufficiency Yes No Chronic bronchitis Yes No Chronic obstructive lung disease Yes No
Frequency
%
10 9
53 47
4 15
21 79
6 13
31.5 68.4
16 3
84 16
14 5
74 26
16 3
84 16
7 12
36 64
9 10
47 53
diagnosed with either hip dysplasia or hip dislocation, while seven underwent surgery for hip reduction and normalization. GI bleeding is sometimes seen when patients are fed with gastric or jejunal feeding tubes. All of the patients had GI feeding tubes; GI bleeding was observed in four, while anemia was seen in five study patients. In addition, eight patients had gastric tube obstruction, and their tubes were replaced. Decubitus ulcer may be associated with non-ambulation; 18 of our patients were non-ambulatory, and nine had decubitis ulcer. Table 3 illustrates respiratory manifestations and disorders in patients DDDS. A history of recurrent aspiration pneumonia was observed in 10 patients, inhalation (food and vomitius) in six, reactive airway disease in 16, respiratory failure in 14, nocturnal respiratory insufficiency in 16, chronic bronchitis in seven, and chronic obstructive lung disease in nine.These conditions were observed in the patients during the management/care period. 3.1. Selective case presentation We present the case of one of our patients DDDS. This patient had spastic, quadriplegic CP, chronic seizure disorder (generalized tonic clonic seizures), scoliosis, and a history of weight loss and intermittent
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respiratory distress. In 1998, he had a spinal fusion, tendon release surgery, and multiple other orthopedic surgeries for his deformities. He had a learning disability but could read at grade-school level. The patient had a history of recurrent pneumonia and was frequently treated with antibiotics. His weight dropped from 44 kg to 33 kg over three years in his mid teens. He had open placement of a gastric tube six weeks prior to death and gained 5.45 kg with overnight feeds without problem. He was coughing less, and he perceived his health to be good. During the work up for his weight loss, he was diagnosed with respiratory distress, tracheal stenosis, right main-stem bronchus stenosis, seizure, obstructive sleep apnea (OSA), and gastroesophageal reflux disease (GERD). He had a positive salivagram and was started on glycopyrrolate. His respiratory complaints were treated with one liter per minute oxygen and the use of a pulse oximeter. On his last visit, two months prior to his death, he reported overall respiratory improvement and longer and better quality sleep. His oral feeding at home was going well with adequate time spent. There was no complaint of fever or other signs of illness reported on his last visit. A full autopsy was obtained and found no explanation for his death. However, the chronic changes related to his previous respiratory condition were noted.
3.2. Temporal survival pattern and trends The 19 patients DDDS exhibited some common patterns. All patients had gastrostomy-jejunostomy feeding tube and seizures. Nearly all patients had respiratory problems, including chronic respiratory failure or recurrent aspiration pneumonia. Whereas orthopedic manifestations, mainly scoliosis and hip dislocation, were found in most deceased patients during the study period, there was no pattern established relating these orthopedic manifestations to mortality. We examined our population for any relationship between recent orthopedic surgical procedure and timing of death and no pattern or relationship was observed, as none of the deceased patients died within three years following surgery. Respiratory issues, seizures, and GI pathologies were the most common co-morbidities among our 19 patients.
4. Discussion This study was designed to describe the demographic and clinical pathologic features that may be associated with DDDS. We examined medical records on all 19 patients in our CP program DDDS over an 18-year period. Specifically, we assessed all organ system pathologies, surgical treatment received, and medications during their lifetime. As a retrospective assessment, there are some relevant patterns that could be used in generating hypotheses regarding these deceased patients. First, all but one patient had respiratory pathology. Second, these patients had enteral feeding tubes, which is indicative of possible potential for gastric tube obstruction. Third, all but one of these patients had seizures and were non-ambulatory. Lastly, all patients had either mild or severe MR manifested as moderate or severe cognitive impairment, which has been repeatedly implicated in CP survival. 4.1. Respiratory pathology We have shown in this study that seizures and respiratory disorders or pathology tend to be the most common factors among our patients that were DDDS. Children with CP often have lung disease, which tends to reduce their survival. This pathology is due to impaired respiratory muscle function associated with severity of CP. Consequently, it is reasonable to expect that death among these patients may be linked to respiratory pathology as well as to chronic aspiration due to food or saliva [11–13]. Our finding is supported by previous studies in similar settings: one in which 4.5% of CP deaths were associated with unexpected death during sleep [7], and one in which an estimated 13.9% of the children with CP were DDDS [10]. Although these patients had been in good health prior to being DDDS, they presented with histories of recurrent aspiration pneumonia, reactive airway disease, asthma pneumonitis, chronic obstructive lung disease, chronic bronchitis, respiratory failure, and nocturnal respiratory insufficiency. Since all of our deceased patients had seizure disorders, and since association has been established between recurrent, uncontrolled seizures and food and vomitus inhalation as well as aspiration pneumonitis, it is reasonable to expect that respiratory pathology may play some role in the mechanism of death of these patients. Besides respiratory pathologies, since all of our DDDS patients had seizure/epilepsy, it is also expected that this condition
A.F. Karatas et al. / Cerebral palsy patients discovered dead during sleep
might play a substantial role in this phenomenon [14, 15]. An association between CP and sleep apnea has been demonstrated [11,12,16]. Patients with CP are more likely to present with obstructive sleep apnea syndrome (OSAS) and sleep-related breathing disorders (SRBD) relative to the general population, according to polysomnography (PSG); these conditions tend to increase morbidity and mortality. Unfortunately we were unable to observe any pattern with PSG in our patients who were DDDS. In our sample, there were no PSG tests performed. These data could have allowed us to examine the possible contributions of OSAS and SRBD to the mortality of the patients in this study. An approximated four of our 19 patients who were DDDS had asthma pneumonitis (hypersensitivity pneumonitis), while all except one had reactive airway disease (RAD). Asthma is common in patients with CP, but it is normally due to some other contributors to lung disease development, including (but not limited to) pulmonary aspiration, bronchiectasis, impaired mucociliary clearance, kyphoscoliosis, and airway obstruction [17,18]. The consistent bronchopulmonary co-morbidity in patients who were DDDS is indicative of the need for recommendation for adequate management of these conditions. Specifically, GERD should be reduced and salivation should be addressed by placing these patients on medications that are effective in reducing salivation, such as anticholinergic agents. Bachrach et al. observed that anticholinergics such as benztropine and glycopyrrolate are effective in decreasing salivation in patients with CP [4]; however, given the side effects, glycopyrrolate is preferred to benztropine. In addition, to avoid GERD and its possible pulmonary manifestations such as aspiration pneumonia,Nissen fundoplication, which is a surgical procedure to treat GERD is often needed [19]. This procedure reinforces the lower esophageal sphinter, reducing the likelihood of acid backup in the esophagus. Because CP is associated with several co-morbidities, it has been suggested that the management of respiratory infections, such as recurrent aspiration pneumonia, should be treated with not only antibiotics but also with bronchoalveolar lavage when necessary [13]. In addition, antibiotic selection should be based on sputum culture results and should follow a prolonged course between three and four weeks [13]. Finally, to prevent pneumonia and influenza, patients with CP should receive routine immunizations, including yearly influenza vaccination.
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4.2. Seizures Seizure disorder or epilepsy was observed in all patients who were DDDS in this study. Excess seizure activitiy has been shown to occur significantly in neurodevelopmental disorders such as CP. Remarkably, sudden unexpected death has been shown as well in patients with seizures, but not with idiopathic seizures [15] A study by Hesdorffer DC et al. found sudden unexplained death in epilepsy (SUDEP) to be common in idiopathic epilepsy as well [25]. SUDEP may provide some insight into the underlying mechanism and predisposition to being DDDS. Another recent study has suggested cardiac arrhythmia and central apnea as possible mechanisms for excess mortality in neurodevelopment seizures [14]. In our sample, DDDS reflects unexplained death, and, given the high prevalence of seizures, it is not unrealistic to expect that cardiac arrhythmia and sleep apnea may have played a role in our sample as well. 4.3. Scoliosis Thirteen of our 19 patients had scoliosis, and 10 had surgeries for correction of spinal curve deformities. Among patients with CP, kyphoscoliosis is quite common and has been shown to affect an estimated 13/19 of children with CP [10]. Baikie reported that the contributing effects of scoliosis to GERD are pulmonary aspiration, impaired mucociliary clearance, airway obstruction, and respiratory failure [18]. Therefore, while surgery benefits curve deformities, we must balance between the benefits and the potential risk, especially in children with pulmonary disorders [10,19]. From our data none of the DDDS cases occurred within twelve months of scoliosis surgery. 4.4. Aspiration A study assessing the use of various tests for aspiration found salivagram to correlate more positively with aspiration [21]; however there was poor agreement between the tests, namely salivagram, barium video fluoroscopy, and radionuclide scan. Nevertheless, the study concluded that salivagram remains the most preferred test and is useful in predicting the risk of aspiration among patients with CP. Among our DDDS sample, five patients tested positive for aspiration with salivagram. 4.5. Decubitus ulcers Some of our deceased patients presented with decubitus ulcers, which, in some cases, may result in sep-
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ticemia and bacteremia, thus decreasing survivability. Since decubitus ulcers are very difficult to cure in this patient population, we recommend a complete prevention of decubitus ulcers by using special padding in the wheelchair and beds, as well as using special beds designed to alternate pressure during sleep. 4.6. Sleep abnormalities The relatively high prevalence of CP patients DDDS suggests the need to provide an objective evaluation of sleep problems and disorders in these patients, especially those with quadriplegia and other CP topography who present with noisy breathing and disturbed nocturnal sleep. In other, similar neurological conditions, the following sleep studies have been used to assess sleep conditions/disorders (these are the studies that generally comprise PSG): overnight electroencephalogram (EEG), electromyography (EMG), electrooculogram (EOG), electrocardiogram (ECG), pulse oxymetry (PO), arterial oxygen saturation (SpO2 ), chest wall and abdomen motion, oral and nasal airflow, and end-tidal PCO2 (PETCO2 ). Evidence suggests that the use of PSG in combination with clinical assessment is effective in identifying the underlying causes of sleep problems and disorders, and should be used to provide effective treatment to narrow morbidity and mortality associated with OSAS and SRBD. Given the benefits of PSG, we recommend this test for patients with CP, especially those with disturbed nocturnal sleep and noisy breathing. A study clearly indicated the benefits of lateral airway radiographs in assessing the size of adenoidal tissue in children who snore. Also, in patients with a long history of apnea, venous blood gas or high serum bicarbonate is recommended in screening for CO2 retention. Therefore when PSG is not feasible, CO2 retention screening becomes a feasible alternative. In addition, clinical assessment/judgment, lateral airway radiographs, and PO applied during sleep should be performed [13, 22]. Quadriplegic patients with sleep disorders should be managed with surgical treatments, mainly adenotonsilectomy, if indicated [23], and continuous positive airway pressure, which is a non-surgical procedure to enhance the airway and breathing. In treating central apnea, methylxanthines, oxygen therapy, and nasal positive pressure ventilation are recommended [24]. Finally, we recommend that for those families who choose not to pursue surgical intervention or ventilatory support for a severely affected CP child with an abnormal PSG, adequate counseling should be provided regarding the phenomenon of DDDS.
4.7. Study limitations This study provides substantial information on children DDDS. However, there are some limitations. First, this study is retrospective in nature. We critically assessed our medical records with intent of increasing the precision and unbiased extraction of information. Despite this critical appraisal, there is a possibility of information bias and misclassification influencing the data collected in this study. Secondly, we were unable to examine the sleep architecture of the study patients to determine the EEG, EOG, ECG, and PO patterns that may reflect prolonged sleep apnea as seen in OSAS and SBRD. Thirdly, there were no data on hypoxia, which might have supported respiratory involvement in these patients who were DDDS. Unfortunately, these data remain unavailable since all of our patients died at home.
5. Conclusion In summary, this study represents the characteristics of all patients in our CP program who were DDDS between 1993 and 2011. It suggests that respiratory disorders, severe motor disability, seizures, and intellectual status are possible co-morbidities that may be associated with DDDS. Based on reviewed literature, patients with CP, especially those with quadriplegia, are more likely to develop sleep problems and disorders and to die due to OSAS and SRBD. While we were unable to directly implicate sleep disorders/abnormalities in our patients who expired due to DDDS mechanism, monitoring and surveillance of these patients is essential and may minimize mortality associated with DDDS. In addition, given our limitations in assessing variables that may have enhanced our understanding of this phenomenon, we recommend development and validation of a national CP registry.
Conflict of interest No sources of funding exist to report. The authors report no conflicts of interest.
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227
Cerebral palsy patients discovered dead during sleep: Experience from a comprehensive tertiary pediatric center Ali F. Karatas, Elissa G. Miller, Freeman Miller, Kirk W. Dabney, Steven Bachrach, Justin Connor, Kenneth Rogers and Laurens Holmes, Jr.∗ Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
Accepted 14 October 2013
Abstract. OBJECTIVES: It is not uncommon for children with cerebral palsy (CP) to be discovered dead during sleep (DDDS); however, the factors associated with this pattern of mortality remain unknown. The current study aims to describe the mortality associated with children with CP from a single, tertiary care center who were DDDS. METHODS: A retrospective (case-only) design to examine proportionate mortality and patient characteristics and comorbidities that may be related to children DDDS between 1993 and 2011. RESULTS: There were 177 patients with CP whose deaths were reported to our institution during the study period, of which 19 were DDDS at home. The period proportionate mortality (PPM) was 114.5 per 1000. The average age at time of death was 17 years and 6 months (minimum, 6 years; maximum, 25 years). All but one of the DDDS patients had gastrointestinal feeding tubes, seizure disorders, respiratory disorders, and were non-ambulatory. Very importantly, our DDDS patients manifested clusters of respiratory disorders, namely recurrent aspiration pneumonia (10/19), asthma pneumonitis (4/19), food/vomitius inhalation (6/19), reactive airway disease (16/19), respiratory failure (14/19), chronic bronchitis (7/19), chronic obstructive lung disease (9/19), and nocturnal respiratory insufficiency (16/19). CONCLUSIONS: Respiratory disorders, severe motor disability, seizures, and intellectual status are possible co-morbidities that may be associated with DDDS. There is a need for further study in order to understand what type of monitoring and care (if any) may help prevent DDDS related to these co-morbidities and sleep disorders/abnormalities. Keywords: Cerebral palsy, proportionate mortality, respiratory disorders, mortality, co-morbidities
1. Introduction Cerebral palsy (CP) is characterized by motor impairment that may present as global physical and psycho-motor dysfunction. This condition involves brain impairment as well as locomotor dysfunction. Most cerebral palsies occur during early development, including the prepartum, intra-partum, or early post∗ Corresponding author: L. Holmes, Jr., Orthopedic Department, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA. Tel.: +1 302 377 3550; Fax: +1 302 651 5951; E-mail: [email protected].
partum period. Cerebral palsy is non-progressive, but the signs and symptoms may vary with the child’s maturation. An epidemiologic study on CP in England and Scotland found its prevalence to be 2.5 per 1000 live births [1]. 2001 data on the prevalence of CP in the United States estimated this to be 764,000 children and adults [2]. An estimated 70–80% of CP cases are said to be prenatally related with the majority described as unknown in terms of etiology. However, birth complications have been associated with an estimated 6% of cases of congenital CP [3]. Some of the postulated causes are hydrocephalus, cranial hemorrhage, prolonged asphyxia, head trauma from shaken
c 2013 – IOS Press and the authors. All rights reserved 1874-5393/13/$27.50
228
A.F. Karatas et al. / Cerebral palsy patients discovered dead during sleep
baby syndrome, bacterial and viral infection (such as cytomegalovirus), and lead poisoning [4]. Individuals with CP are more likely to have a higher mortality rate compared to the general population [5–7]. A 10-year study (1986–1995) of CP mortality in California indicated mortality of 90 per 1,000 person-years [8]. In this study, children (under 15 years) contributed 136 757 person–years of follow-up, and the adults contributed 271 138 person–years, for a total of 407 895 person–years. During this period, 4,408 participants died, for an overall mortality rate of 11 deaths per 1000 person–years. Also, mortality in other populations has been shown to be 50% by age 20 years among patients with CP who have seizures, severe mental retardation (MR), and are non-ambulatory [7–9]. However, there was variability in median survival within the group of non-ambulatory children, with medians being greater than 20 years for some sub-groups. For the most severely impaired children at age 2 years, median survival to age 20 years or greater is unusual. Children with CP who were discovered dead during sleep (DDDS) have been specifically reported in literature, but related mechanism had been used in a few studies [7,10]. In one of these studies, the etiology of death could not be identified in 25 children; five of these patients were found dead in bed by their caregivers [10]. In another study, some CP children were discovered dead in bed [7]. Despite being mentioned, these studies presented little or no information regarding this phenomenon, and no study to date has investigated the phenomenon more fully. The mechanism of death associated with these specific patients remains unknown, and there is no reported literature on this phenomenon, especially risks and predisposing factors. We aimed, in the current study, to examine all patients DDDS from 1993–2011, thus evaluating treatment received during lifetime, co-morbidities, CP topography, and prognostic factors in an attempt to better understand the phenomenon of DDDS and to generate hypotheses on contributing factors to DDDS.
2. Patients and methods This study was institutional review board (IRB) approved. We conducted a retrospective descriptive study (case-only) to assess the pattern, characteristics, and possible trends among our patients with CP who were DDDS. The CP program at our institution maintains reliable patient records comparable to most disease registries.
Data were extracted from our medical records on demographics (sex, year of birth, age at death), topographical pattern of CP (hemiplegic/diplegic/triplegic/ quadriplegic), motor severity (Gross Motor Function Classification System [GMFCS] level I–V), and intellectual status (none/moderate/severe MR). Other data extracted in the presence or absence of the following were gastrostomy/jejunostomy tube, scoliosis hip dysplasia/hip dislocation, long bone fracture, and hydrocephalous/shunt. The co-morbidity data were extracted from the electronic medical records and included the presence or absence of the following: gastrointestinal (GI) bleeding, anemia, decubitus ulcer, seizure, GI feeding tube, respiratory disorder, recurrent aspiration pneumonia, food/vomitus inhalation, reactive airway disease, respiratory failure, chronic bronchitis, chronic obstructive lung disease, and nocturnal insufficiency. The salivagram history was extracted as positive or negative, and the last radiograph data were extracted as normal versus non-normal. The year of surgeries, demographics, co-morbidities, and prognostic factors were tabulated in order to observe common patterns and characteristics among the patients who were DDDS. 2.1. Statistical analysis A descriptive statistics was used in this study. The proportionate mortality was estimated using the total number of patients DDDS as a numerator, death from all causes during the study period as the denominator, and 1000 as a multiplier. Quantitatively proportionate mortality was given by: DDDS / all deaths during the study period X 1000.
3. Results Of 177 patients known to have died during the study period, a total of 19 children (11 male, 8 female) were DDDS between 1993 and 2011 in our patient population (pediatric CP). The proportionate mortality, which is the proportion of deceased CP patients DDDS relative to all CP patients who died during the study, was 114.5 per 1000. All patients DDDS died between age 6 and 25 years. The mean age at death was 17 years and 6 months (SD, 4.7). Table 1 describes the demographic, CP topography, and clinical features observed in these patients. Of those DDDS, 11 were male, 18 had spastic quadriplegia, 11 had severe MR, and eight had hydrocephalus.
A.F. Karatas et al. / Cerebral palsy patients discovered dead during sleep Table 1 Demographic and clinical features of patients discovered dead during sleep Variable Sex Female Male Cognitive level Severe MR Moderate MR Hydrocephalus Yes No Place of death Hospital Home CP subtype Spastic diplegic Quadriplegic Ambulation Yes No
Frequency
%
8 11
42 58
11 8
58 42
8 11
42 58
− 19
− 100
1 18
5 95
1 18
5 95
CP, cerebral palsy; MR; mental retardation. Table 2 Variable Scoliosis Yes No Scoliosis surgery Yes No Hip dysplasia/dislocation Yes No Hip surgery Yes No Long bone fracture Yes No Gastrointestinal bleeding Yes No Anemia Yes No Decubitus ulcer Yes No Gastric tube obstruction Yes No Salivagram history Positive None
Frequency
%
13 6
68.5 31.5
10 9
52.7 47.3
9 10
47.4 52.6
7 12
41.2 58.8
9 10
47.4 52.6
4 15
21 79
5 14
27 73
9 10
47 53
8 11
43 57
5 14
27 73
Table 2 demonstrates the co-morbidities in patients DDDS. Thirteen were diagnosed with scoliosis, and 10 of these patients underwent surgery for curve deformity correction. Nine of the patients in the study were
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Table 3 Respiratory manifestations and disorders in patients discovered dead during sleep Variable Recurrent aspiration pneumonia Yes No Asthma pneumonitis Yes No Inhalation Yes No Reactive airway disease Yes No Respiratory failure Yes No Nocturnal respiratory insufficiency Yes No Chronic bronchitis Yes No Chronic obstructive lung disease Yes No
Frequency
%
10 9
53 47
4 15
21 79
6 13
31.5 68.4
16 3
84 16
14 5
74 26
16 3
84 16
7 12
36 64
9 10
47 53
diagnosed with either hip dysplasia or hip dislocation, while seven underwent surgery for hip reduction and normalization. GI bleeding is sometimes seen when patients are fed with gastric or jejunal feeding tubes. All of the patients had GI feeding tubes; GI bleeding was observed in four, while anemia was seen in five study patients. In addition, eight patients had gastric tube obstruction, and their tubes were replaced. Decubitus ulcer may be associated with non-ambulation; 18 of our patients were non-ambulatory, and nine had decubitis ulcer. Table 3 illustrates respiratory manifestations and disorders in patients DDDS. A history of recurrent aspiration pneumonia was observed in 10 patients, inhalation (food and vomitius) in six, reactive airway disease in 16, respiratory failure in 14, nocturnal respiratory insufficiency in 16, chronic bronchitis in seven, and chronic obstructive lung disease in nine.These conditions were observed in the patients during the management/care period. 3.1. Selective case presentation We present the case of one of our patients DDDS. This patient had spastic, quadriplegic CP, chronic seizure disorder (generalized tonic clonic seizures), scoliosis, and a history of weight loss and intermittent
230
A.F. Karatas et al. / Cerebral palsy patients discovered dead during sleep
respiratory distress. In 1998, he had a spinal fusion, tendon release surgery, and multiple other orthopedic surgeries for his deformities. He had a learning disability but could read at grade-school level. The patient had a history of recurrent pneumonia and was frequently treated with antibiotics. His weight dropped from 44 kg to 33 kg over three years in his mid teens. He had open placement of a gastric tube six weeks prior to death and gained 5.45 kg with overnight feeds without problem. He was coughing less, and he perceived his health to be good. During the work up for his weight loss, he was diagnosed with respiratory distress, tracheal stenosis, right main-stem bronchus stenosis, seizure, obstructive sleep apnea (OSA), and gastroesophageal reflux disease (GERD). He had a positive salivagram and was started on glycopyrrolate. His respiratory complaints were treated with one liter per minute oxygen and the use of a pulse oximeter. On his last visit, two months prior to his death, he reported overall respiratory improvement and longer and better quality sleep. His oral feeding at home was going well with adequate time spent. There was no complaint of fever or other signs of illness reported on his last visit. A full autopsy was obtained and found no explanation for his death. However, the chronic changes related to his previous respiratory condition were noted.
3.2. Temporal survival pattern and trends The 19 patients DDDS exhibited some common patterns. All patients had gastrostomy-jejunostomy feeding tube and seizures. Nearly all patients had respiratory problems, including chronic respiratory failure or recurrent aspiration pneumonia. Whereas orthopedic manifestations, mainly scoliosis and hip dislocation, were found in most deceased patients during the study period, there was no pattern established relating these orthopedic manifestations to mortality. We examined our population for any relationship between recent orthopedic surgical procedure and timing of death and no pattern or relationship was observed, as none of the deceased patients died within three years following surgery. Respiratory issues, seizures, and GI pathologies were the most common co-morbidities among our 19 patients.
4. Discussion This study was designed to describe the demographic and clinical pathologic features that may be associated with DDDS. We examined medical records on all 19 patients in our CP program DDDS over an 18-year period. Specifically, we assessed all organ system pathologies, surgical treatment received, and medications during their lifetime. As a retrospective assessment, there are some relevant patterns that could be used in generating hypotheses regarding these deceased patients. First, all but one patient had respiratory pathology. Second, these patients had enteral feeding tubes, which is indicative of possible potential for gastric tube obstruction. Third, all but one of these patients had seizures and were non-ambulatory. Lastly, all patients had either mild or severe MR manifested as moderate or severe cognitive impairment, which has been repeatedly implicated in CP survival. 4.1. Respiratory pathology We have shown in this study that seizures and respiratory disorders or pathology tend to be the most common factors among our patients that were DDDS. Children with CP often have lung disease, which tends to reduce their survival. This pathology is due to impaired respiratory muscle function associated with severity of CP. Consequently, it is reasonable to expect that death among these patients may be linked to respiratory pathology as well as to chronic aspiration due to food or saliva [11–13]. Our finding is supported by previous studies in similar settings: one in which 4.5% of CP deaths were associated with unexpected death during sleep [7], and one in which an estimated 13.9% of the children with CP were DDDS [10]. Although these patients had been in good health prior to being DDDS, they presented with histories of recurrent aspiration pneumonia, reactive airway disease, asthma pneumonitis, chronic obstructive lung disease, chronic bronchitis, respiratory failure, and nocturnal respiratory insufficiency. Since all of our deceased patients had seizure disorders, and since association has been established between recurrent, uncontrolled seizures and food and vomitus inhalation as well as aspiration pneumonitis, it is reasonable to expect that respiratory pathology may play some role in the mechanism of death of these patients. Besides respiratory pathologies, since all of our DDDS patients had seizure/epilepsy, it is also expected that this condition
A.F. Karatas et al. / Cerebral palsy patients discovered dead during sleep
might play a substantial role in this phenomenon [14, 15]. An association between CP and sleep apnea has been demonstrated [11,12,16]. Patients with CP are more likely to present with obstructive sleep apnea syndrome (OSAS) and sleep-related breathing disorders (SRBD) relative to the general population, according to polysomnography (PSG); these conditions tend to increase morbidity and mortality. Unfortunately we were unable to observe any pattern with PSG in our patients who were DDDS. In our sample, there were no PSG tests performed. These data could have allowed us to examine the possible contributions of OSAS and SRBD to the mortality of the patients in this study. An approximated four of our 19 patients who were DDDS had asthma pneumonitis (hypersensitivity pneumonitis), while all except one had reactive airway disease (RAD). Asthma is common in patients with CP, but it is normally due to some other contributors to lung disease development, including (but not limited to) pulmonary aspiration, bronchiectasis, impaired mucociliary clearance, kyphoscoliosis, and airway obstruction [17,18]. The consistent bronchopulmonary co-morbidity in patients who were DDDS is indicative of the need for recommendation for adequate management of these conditions. Specifically, GERD should be reduced and salivation should be addressed by placing these patients on medications that are effective in reducing salivation, such as anticholinergic agents. Bachrach et al. observed that anticholinergics such as benztropine and glycopyrrolate are effective in decreasing salivation in patients with CP [4]; however, given the side effects, glycopyrrolate is preferred to benztropine. In addition, to avoid GERD and its possible pulmonary manifestations such as aspiration pneumonia,Nissen fundoplication, which is a surgical procedure to treat GERD is often needed [19]. This procedure reinforces the lower esophageal sphinter, reducing the likelihood of acid backup in the esophagus. Because CP is associated with several co-morbidities, it has been suggested that the management of respiratory infections, such as recurrent aspiration pneumonia, should be treated with not only antibiotics but also with bronchoalveolar lavage when necessary [13]. In addition, antibiotic selection should be based on sputum culture results and should follow a prolonged course between three and four weeks [13]. Finally, to prevent pneumonia and influenza, patients with CP should receive routine immunizations, including yearly influenza vaccination.
231
4.2. Seizures Seizure disorder or epilepsy was observed in all patients who were DDDS in this study. Excess seizure activitiy has been shown to occur significantly in neurodevelopmental disorders such as CP. Remarkably, sudden unexpected death has been shown as well in patients with seizures, but not with idiopathic seizures [15] A study by Hesdorffer DC et al. found sudden unexplained death in epilepsy (SUDEP) to be common in idiopathic epilepsy as well [25]. SUDEP may provide some insight into the underlying mechanism and predisposition to being DDDS. Another recent study has suggested cardiac arrhythmia and central apnea as possible mechanisms for excess mortality in neurodevelopment seizures [14]. In our sample, DDDS reflects unexplained death, and, given the high prevalence of seizures, it is not unrealistic to expect that cardiac arrhythmia and sleep apnea may have played a role in our sample as well. 4.3. Scoliosis Thirteen of our 19 patients had scoliosis, and 10 had surgeries for correction of spinal curve deformities. Among patients with CP, kyphoscoliosis is quite common and has been shown to affect an estimated 13/19 of children with CP [10]. Baikie reported that the contributing effects of scoliosis to GERD are pulmonary aspiration, impaired mucociliary clearance, airway obstruction, and respiratory failure [18]. Therefore, while surgery benefits curve deformities, we must balance between the benefits and the potential risk, especially in children with pulmonary disorders [10,19]. From our data none of the DDDS cases occurred within twelve months of scoliosis surgery. 4.4. Aspiration A study assessing the use of various tests for aspiration found salivagram to correlate more positively with aspiration [21]; however there was poor agreement between the tests, namely salivagram, barium video fluoroscopy, and radionuclide scan. Nevertheless, the study concluded that salivagram remains the most preferred test and is useful in predicting the risk of aspiration among patients with CP. Among our DDDS sample, five patients tested positive for aspiration with salivagram. 4.5. Decubitus ulcers Some of our deceased patients presented with decubitus ulcers, which, in some cases, may result in sep-
232
A.F. Karatas et al. / Cerebral palsy patients discovered dead during sleep
ticemia and bacteremia, thus decreasing survivability. Since decubitus ulcers are very difficult to cure in this patient population, we recommend a complete prevention of decubitus ulcers by using special padding in the wheelchair and beds, as well as using special beds designed to alternate pressure during sleep. 4.6. Sleep abnormalities The relatively high prevalence of CP patients DDDS suggests the need to provide an objective evaluation of sleep problems and disorders in these patients, especially those with quadriplegia and other CP topography who present with noisy breathing and disturbed nocturnal sleep. In other, similar neurological conditions, the following sleep studies have been used to assess sleep conditions/disorders (these are the studies that generally comprise PSG): overnight electroencephalogram (EEG), electromyography (EMG), electrooculogram (EOG), electrocardiogram (ECG), pulse oxymetry (PO), arterial oxygen saturation (SpO2 ), chest wall and abdomen motion, oral and nasal airflow, and end-tidal PCO2 (PETCO2 ). Evidence suggests that the use of PSG in combination with clinical assessment is effective in identifying the underlying causes of sleep problems and disorders, and should be used to provide effective treatment to narrow morbidity and mortality associated with OSAS and SRBD. Given the benefits of PSG, we recommend this test for patients with CP, especially those with disturbed nocturnal sleep and noisy breathing. A study clearly indicated the benefits of lateral airway radiographs in assessing the size of adenoidal tissue in children who snore. Also, in patients with a long history of apnea, venous blood gas or high serum bicarbonate is recommended in screening for CO2 retention. Therefore when PSG is not feasible, CO2 retention screening becomes a feasible alternative. In addition, clinical assessment/judgment, lateral airway radiographs, and PO applied during sleep should be performed [13, 22]. Quadriplegic patients with sleep disorders should be managed with surgical treatments, mainly adenotonsilectomy, if indicated [23], and continuous positive airway pressure, which is a non-surgical procedure to enhance the airway and breathing. In treating central apnea, methylxanthines, oxygen therapy, and nasal positive pressure ventilation are recommended [24]. Finally, we recommend that for those families who choose not to pursue surgical intervention or ventilatory support for a severely affected CP child with an abnormal PSG, adequate counseling should be provided regarding the phenomenon of DDDS.
4.7. Study limitations This study provides substantial information on children DDDS. However, there are some limitations. First, this study is retrospective in nature. We critically assessed our medical records with intent of increasing the precision and unbiased extraction of information. Despite this critical appraisal, there is a possibility of information bias and misclassification influencing the data collected in this study. Secondly, we were unable to examine the sleep architecture of the study patients to determine the EEG, EOG, ECG, and PO patterns that may reflect prolonged sleep apnea as seen in OSAS and SBRD. Thirdly, there were no data on hypoxia, which might have supported respiratory involvement in these patients who were DDDS. Unfortunately, these data remain unavailable since all of our patients died at home.
5. Conclusion In summary, this study represents the characteristics of all patients in our CP program who were DDDS between 1993 and 2011. It suggests that respiratory disorders, severe motor disability, seizures, and intellectual status are possible co-morbidities that may be associated with DDDS. Based on reviewed literature, patients with CP, especially those with quadriplegia, are more likely to develop sleep problems and disorders and to die due to OSAS and SRBD. While we were unable to directly implicate sleep disorders/abnormalities in our patients who expired due to DDDS mechanism, monitoring and surveillance of these patients is essential and may minimize mortality associated with DDDS. In addition, given our limitations in assessing variables that may have enhanced our understanding of this phenomenon, we recommend development and validation of a national CP registry.
Conflict of interest No sources of funding exist to report. The authors report no conflicts of interest.
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