Cardiopulmonary Status in Adults with Osteogenesis Imperfecta: Intrinsic Lung Disease May Contribute More Than Scoliosis.

BACKGROUND: Osteogenesis imperfecta (OI) is a heterogeneous group of collagen-related disorders characterized by osteopenia, bone fractures, spine deformities, and nonskeletal complications. Cardiopulmonary complications are the major cause of morbidity and mortality in adults with OI. The cause of such problems was often attributed solely to the presence of large scoliosis curves affecting pulmonary function and, indirectly, cardiovascular health. However, recent studies suggest this may not be the case. Therefore, determining the relationships and causative agents of cardiopulmonary problems in patients with OI, specifically pulmonary impairment, is important to improving the overall wellbeing, quality of life, and survival of these patients. QUESTIONS/PURPOSES: (1) Is cardiopulmonary fitness in OI solely related to the presence of scoliosis? (2) What is the prevalence of heart and lung complications in this adult population? (3) Does the presence of pulmonary impairment impact quality of life in adults with OI? METHODS: This is a prospective observational cross-sectional study. Within 1 year, each participant (n = 30) completed pulmonary function testing, echocardiogram, ECG, chest CT, AP spine radiography, and quality-of-life assessments (SF-36, St. George's Respiratory Questionnaire, Functional Outcomes of Sleep Questionnaire, and Pittsburgh Sleep Quality Index). In terms of pulmonary function, we differentiated restrictive and obstructive physiology using the ratio of forced expiratory volume over one second to forced vital capacity (FEV1/FVC), with restrictive lung physiology defined as FEV1/FVC > 0.8 and obstructive lung physiology as FEV1/FVC < 0.7. Spine radiographs were evaluated for scoliosis. Chest CT images were reviewed to qualitatively assess the lungs. The statistical analysis involved a Kruskall-Wallis test with Bonferroni's correction and a bivariate correlation analysis using Spearman's rho correlation coefficient (p < 0.05). RESULTS: Sixteen of 23 participants with restrictive lung physiology had scoliosis; their ages ranged from 19 years to 67 years. There was no correlation between the magnitude of the scoliosis curve and deficient pulmonary function (R = 0.08; p = 0.68). Seven participants had normal pulmonary function. The average scoliosis curve was 44 ± 29°. Thirteen participants had abnormal ECG findings while 10 had abnormal echocardiogram results. All but two individuals with abnormal chest CT results were found to have bronchial wall thickening. There were no differences in pulmonary or cardiac findings between OI types, except for FVC and total lung capacity, which were lower in individuals with Type III OI than in those with other types of OI. FEV1/FVC correlated with St. George's Respiratory Questionnaire (R = 0.429; p = 0.02) but not with Functional Outcomes of Sleep Questionnaire (R = -0.26; p = 0.19) or SF-36 scores (physical component summary: R = -0.037, p = 0.85; mental component summary: R = -0.204, p = 0.29). CONCLUSIONS: The lack of a relationship between decreased pulmonary function and the severity of scoliosis suggests that restrictive lung physiology in this population is likely because of factors intrinsic to OI and not entirely because of thoracic cage deformities. The fact that pulmonary impairment influences self-perceived quality of life exemplifies how detrimental such complications may be to everyday functioning. This also reinforces the importance of determining the underlying cause of cardiopulmonary impairment in this population to set clear clinical guidelines of care. LEVEL OF EVIDENCE: Level II, prognostic study.

Joint Replacements in Individuals With Skeletal Dysplasias: One Institution's Experience and Response to Operative Complications.

BACKGROUND: Skeletal dysplasias are a heterogeneous group of >400 genetic disorders characterized by abnormal bone growth. Many individuals experience joint pain and limitation, coming to require joint replacement much earlier than the average-statured population. In addition, prosthesis survival rate is less in the dysplastic population. The purpose of this study is to identify risk factors for surgery and provide recommendations to improve surgical outcomes. METHODS: This a retrospective review of 29 individuals with a skeletal dysplasia who had 64 joint replacements between April 1985 and January 2019 at a single institution. We collected demographics, physical examination, medical history, imaging studies, surgical indication, and complications. RESULTS: Spondyloepiphyseal dysplasia was the most common skeletal dysplasia (7), followed by pseudoachondroplasia (4) and multiple epiphyseal dysplasia (4). Average age of the cohort was 40.6 years (range 14-64). Hip arthroplasty (34) was the most commonly performed surgery. The majority of arthroplasties (75%) required custom components. Complication rate was 37.3%, most commonly pulmonary embolism (3) and pneumonia (3). Most complications (81.8%) occurred in individuals with either a pre-existing cardiopulmonary comorbidity or lumbar/sacral deformity. Body mass index did not correlate with complication severity (R = -0.042, P = .752) or rate (R = 0.006, P = .963). CONCLUSION: Surgical complications are highest in patients with pre-existing cardiopulmonary conditions. Body mass index does not predict complications in this cohort. Preoperative evaluations for individuals with skeletal dysplasias should include comprehensive work-up of spine issues and extraskeletal systems that present an operative risk. Intraoperative protocol should include special consideration for placement on the table, airway maintenance, and spinal cord monitoring in select cases.

Hearing loss in individuals with osteogenesis imperfecta in North America: Results from a multicenter study.

Hearing loss (HL) is an extra-skeletal manifestation of the connective tissue disorder osteogenesis imperfecta (OI). Systematic evaluation of the prevalence and characteristics of HL in COL1A1/COL1A2-related OI will contribute to a better clinical management of individuals with OI. We collected and analyzed pure-tone audiometry data from 312 individuals with OI who were enrolled in the Linked Clinical Research Centers and the Brittle Bone Disorders Consortium. The prevalence, type, and severity of HL in COL1A1/COL1A2-related OI are reported. We show that the prevalence of HL in OI is 28% and increased with age in Type I OI but not in Types III and IV. Individuals with OI Types III and IV are at a higher risk to develop HL in the first decade of life when compared to OI Type I. We also show that the prevalence of SNHL is higher in females with OI compared to males. This study reveals new insights regarding prevalence of HL in OI including a lower general prevalence of HL in COL1A1/COL1A2-related OI than previously reported (28.3 vs. 65%) and high prevalence of SNHL in females. Our data support the need in early routine hearing evaluation in all types of OI that can be adjusted to the severity of the skeletal disease.

Scoliosis and Cardiopulmonary Outcomes in Osteogenesis Imperfecta Patients.

STUDY DESIGN: Retrospective clinical study of individuals with osteogenesis imperfecta (OI). OBJECTIVE: To assess the relationship between severity of scoliosis and pulmonary function, and to assess the relationship between restrictive lung disease and self-reported quality of life in individuals with OI. SUMMARY OF BACKGROUND DATA: OI is a heritable connective tissue disorder characterized by osteopenia and a predisposition to fracture. Respiratory insufficiency is a leading cause of mortality. Literature on pulmonary function in this population has shown a negative correlation between percent-predicted vital capacity and severity of scoliosis. However, it has been suggested that decreased pulmonary function in OI may be due to intrinsic pulmonary disease, in addition to the impact of vertebral compression fractures and scoliosis. METHODS: Anterior-posterior spine radiographs and pulmonary function tests from 30 individuals with OI were reviewed. Radiographs were evaluated for scoliosis, defined as a curve ≥ 10°. If more than one curve was present, the largest curve was used. Pulmonary function was defined as the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio. Restrictive pulmonary disease was defined as FEV1/FVC > 80%, while obstructive disease was defined as FEV1/FVC < 70%. Bivariate correlation analysis was performed, using Spearman rho correlation coefficient (P < 0.05). Quality of life was assessed by SF-36. RESULTS: The mean age was 27.6 years (range: 12-42 yrs). 57.6% were female. OI type IV was the most common (46.7%), followed by OI type III (33.3%), OI type I (10%), OI type IX (6.67% each), and OI type VIII (3.33%). Pulmonary comorbidity was present in 40% of individuals, while 6.67% had a cardiac comorbidity. The correlation between scoliosis and pulmonary function was weak and not significant (R = -0.059, P = 0.747). CONCLUSION: Pulmonary function is not significantly correlated with scoliosis, supporting the hypothesis that decreased pulmonary function is intrinsic to OI and/or chest wall deformities, rather than secondary to scoliosis. LEVEL OF EVIDENCE: 4.

Isoflurane impairs the capacity of astrocytes to support neuronal development in a mouse dissociated coculture model.

BACKGROUND: There is growing concern that pediatric exposure to anesthetic agents may cause long-lasting deficits in learning by impairing brain development. Most studies to date on this topic have focused on the direct effects of anesthetics on developing neurons. Relatively little attention has been paid to possible effects of anesthetics on astrocytes, a glial cell type that plays an important supporting role in neuronal development. METHODS: Astrocytes were exposed to isoflurane and then cocultured with unexposed neurons to test for astrocyte-specific toxic effects on neuronal growth. Axon length was measured in the cocultured neurons to assess neuronal growth. RESULTS: We found that neurons cocultured with astrocytes exposed to isoflurane exhibited a 30% reduction in axon outgrowth. Further experimentation showed that this effect is likely due to reduced levels of brain-derived neurotrophic factor in the coculture media. CONCLUSIONS: Isoflurane interferes with the ability of cultured astrocytes to support neuronal growth. This finding represents a potentially novel mechanism through which general anesthetics may interfere with brain development.