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Original Research: Diffuse Lung Disease |

Lymphangioleiomyomatosis and Tuberous Sclerosis Complex in QuebecLAM and TSC: Prevalence and Health Burden: Prevalence and Health-care Utilization FREE TO VIEW

Arnold S. Kristof, MD; Pei Zhi Li, MSc; Philippe Major, MD; Jennifer S. Landry, MD
Author and Funding Information

From the Department of Critical Care (Dr Kristof), Meakins-Christie Laboratories, McGill University Health Centre; Department of Medicine, Respiratory Division (Dr Kristof), Respiratory Epidemiology and Clinical Research Unit (Ms Li and Dr Landry), McGill University Health Centre; and Department of Neurosciences (Dr Major), Sainte-Justine Hospital, University of Montreal, Montreal, QC, Canada.

CORRESPONDENCE TO: Arnold S. Kristof, MD, McGill University Health Centre, Royal Victoria Hospital, 687 Pine Ave W, L3.05, Montreal, QC, H3A 1A1, Canada; e-mail: arnold.kristof@mcgill.ca


Drs Major and Landry are senior coauthors of this article.

Part of this article has been presented in abstract form at the 17th LAMposium, March 28-30, 2014, Chicago, IL.

FUNDING/SUPPORT: This work was funded by unrestricted donations from Tuberous Sclerosis Canada and Fondation Charles-Guindon.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(2):444-449. doi:10.1378/chest.14-3095
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Published online

BACKGROUND:  Lymphangioleiomyomatosis (LAM) is a manifestation of tuberous sclerosis complex (TSC) that causes destruction of the lung and chronic respiratory failure. Population-based estimates of demographics, clinical outcomes, and health-care utilization are lacking for TSC and LAM.

METHODS:  Data on demographics, clinical outcomes, and health-care utilization in the Quebec ministerial provincial health-care database were analyzed for their association with TSC and LAM.

RESULTS:  A total of 1,004 subjects with TSC were identified using International Classification of Diseases, Ninth and 10th Revisions, codes for a prevalence of one in 7,872 people. There were 38 subjects with LAM, nine of whom also had TSC. Mean ages as well as the mean age at death were lower in the LAM and TSC group than in the control group. Mortality rates were higher in subjects with LAM than in those with TSC or in control subjects. Subjects with LAM experienced more medical visits and hospitalizations than did those with TSC and control subjects; these were associated with higher health-care costs. Frequently prescribed drugs in TSC or LAM included anticonvulsants, antidepressants, and sedatives; the use of mammalian target of rapamycin inhibitors was uncommon.

CONCLUSIONS:  The prevalence of TSC in Quebec, Canada, is similar to estimates from previously published surveys. LAM is likely underreported, perhaps due to suboptimal case identification or referral. Health-care utilization and mortality for LAM are high, suggesting that timely diagnosis and therapy could be beneficial. Mental health disorders may be an unrecognized clinical feature of LAM. These results provide a population-based background for policymakers and researchers to better address the needs of patients with TSC and LAM.

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome caused by inherited or spontaneous heterozygous germline mutations in the TSC1 or TSC2 genes.1 Clinical manifestations include neurodevelopmental disorders and hamartomatous tumors in multiple organs. Neurologic manifestations begin in childhood and can include mental retardation, epilepsy, and autism spectrum disorder.2,3 In contrast to children, new or progressive tumors account for much of the morbidity of TSC during adulthood. These include hamartomatous tumors of the skin and kidneys as well as low-grade neoplasias in the lung, brain, and lymphatic system.4 Lymphangioleiomyomatosis (LAM) is a manifestation of TSC caused by proliferating nodules in the lung interstitium and develops only during adulthood.1 LAM causes progressive destruction of the lung parenchyma, respiratory failure, and the need for lung transplantation. LAM can occur sporadically, but screening studies indicate a frequency of up to 30% in patients with TSC.5,6

The chronicity of TSC and LAM as well as their attributable morbidity may account for a significant burden on the health-care system, and little is known regarding the associated use of health-care resources. Current estimates addressing the frequency of disease manifestations in patients with TSC and LAM and their relative impacts on clinical outcomes are derived from regional natural history studies or institutional surveys.7 These reports are likely subject to patient identification and referral bias. To facilitate the prioritization of research and health-care policy, we assessed the prevalence, distribution of disease manifestations, and health-care resource utilization in a comprehensive population-based survey of patients with TSC and LAM in Quebec, Canada.

Study Design and Selection of Subjects

This study was performed using a retrospective cohort of subjects with LAM, TSC, or both and control subjects in the province of Quebec (Canada) between 1996 and 2011 and contained in the Régie de l’Assurance-Maladie du Québec (RAMQ) (Quebec Health Care Insurance Board) database. The RAMQ is a centralized, single-payer system that insures all residents in the province of Quebec for physician, pharmacist, and hospital reimbursement for health-care services. Using International Classification of Diseases (ICD) codes, RAMQ databases were searched to identify all subjects with TSC (ICD, Ninth Revision, code 759.5 or ICD, Tenth Revision, code Q85.1). Because there was no ICD code for LAM at the time, subjects were identified by searching either “LAM” or “lymphangioleiomyomatosis” in the diagnosis section of the medical services database or in the diagnosis section (principal, admitting, death, or secondary diagnoses) associated with any hospital admission. The cohort was separated into four groups: (1) TSC only, (2) LAM only, (3) TSC with LAM, and (4) control. Data from January 1, 1996, to December 31, 2011, were extracted. The control group was randomly selected from the RAMQ database and matched for sex and year of birth. Access to the RAMQ database was approved by the Commission d’accès à l’information du Québec, and the study protocol (#13-050 GEN) was approved by the research ethics board (Genetics and Population research - Biomedical D panel) of the McGill University Health Centre.

Administrative Databases

Four provincial databases administered by the RAMQ were used in this study. (1) The MED-ECHO database8 contains information on acute care hospitalizations and day surgeries. Each record contains demographic information along with the primary diagnosis on admission and 15 possible secondary diagnoses.9 Details on hospitalization, date of admission, and length of stay, as well as on the admission, principal, and secondary diagnoses and cause of death, were obtained. (2) The Medical Services database includes data on medical billing, including type of service performed, diagnosis, specialty of claimant, setting where the service was provided (eg, outpatient, private, ED), number of claims, date on which the service was performed, and fee paid by the RAMQ to the billing physician. (3) A database administered by Statistics Canada contains demographic information on all insured patients in Canada, including date of birth, sex, and date of death, if applicable. (4) The Quebec Prescription Drug database includes data on all drugs dispensed (date of service, Drug Identification Number, American Hospital Formulary class, dosage, and duration), length of use, and associated fees. This database is complete for all children aged < 18 years in Quebec since January 1, 1997, but not for adults who have a private insurance plan. The data have been validated and found to be accurate and reliable.10

Statistical Analyses

Intergroup comparisons of the four subject groups (TSC only, LAM only, LAM with TSC, and control) were made by univariate approach. One-way analysis of variance or Student t test was used to compare means of continuous variables. Mantel-Haenszel χ2 tests were used for ordinal variables. Tests based on the Poisson distribution were used for count and rate outcomes. P ≤ .05 was considered significant for intergroup heterogeneity. For multivariable analysis, variables significantly associated with the outcome in univariate analyses were included, except for age, which was used for adjustment despite the univariate analyses. Variables were selected using a stepwise forward method, with the cutoff for significance set at P ≤ .05.11,12 A multivariate Poisson regression model11 was used to determine the association between clinical factors and the number of admissions and outpatient and ED visits. Statistical analyses were conducted using SAS 9.4 software (SAS Institute Inc).

Prevalence and Mortality in Patients With TSC and LAM

A total of 1,004 subjects with TSC were identified in the database for a prevalence of one in 7,872 people (Table 1). Thirty-eight were identified as having LAM, nine of whom also had TSC. The proportion of deaths in patients with TSC and LAM over the 16-year study period was 13% and 28%, respectively, compared with 15% in the control group; however, mean age at death was 15 and 18 years younger than control subjects, respectively. Crude mortality rates (deaths/1,000 patient-years) were also highest in patients with LAM (Table 1). Only one death was attributed to patients with both TSC and LAM. TSC was listed as the cause of death in 7.5% of deaths (Table 2); the most frequent cause of death (10.5%) in the TSC group was aspiration pneumonia. In patients with LAM, LAM or acute respiratory failure was the documented cause of death in 33% (Table 2).

Table Graphic Jump Location
TABLE 1 ]  Characteristics of the Study Subjects

Data are presented as mean ± SD or No. (%). LAM = lymphangioleiomyomatosis; TSC = tuberous sclerosis complex.

a 

Mortality rate was calculated as the number of deaths (n) divided by the number of patients (%) during the study period or as the number of deaths per person-y of follow-up.

Table Graphic Jump Location
TABLE 2 ]  Causes of Death Documented in Fatal Cases of TSC and LAM

See Table 1 legend for expansion of abbreviations.

Health-care Resource Utilization

Patients with TSC and those with LAM had more hospital admissions and longer hospital stays than control subjects; there was an apparent additive effect in patients with TSC and LAM (Table 1). Epilepsy was the most frequent documented cause for hospital admission in TSC, whereas the disease itself (ie, LAM) and pneumothorax were the most common causes in patients with LAM (Table 3). Medical visits to both primary care physicians and specialists were also more frequent in patients with LAM or TSC than in control subjects; in agreement, the physician visit fees per patient-year were higher in patients with TSC or LAM than in control subjects (Table 1). Patients with LAM were more likely to see a nephrologist and pulmonologist than those with TSC or in the control group. The rarity of lung transplantation, which was performed in only four patients with LAM, precluded an accurate analysis of its effect on clinical outcomes or resource utilization. Of note, 5.4% of visits in patients with TSC were to a psychiatrist compared with 1.8% in those with LAM and 2.5% in control subjects. When corrected for age, a diagnosis of LAM alone or of TSC and LAM was associated with increased medication costs, medical visits, and hospital admissions when compared with a diagnosis of TSC alone (Table 4).

Table Graphic Jump Location
TABLE 3 ]  Most Frequent Medical Diagnosis at Hospital Discharge

See Table 1 legend for expansion of abbreviations.

Table Graphic Jump Location
TABLE 4 ]  The Effects of LAM Compared With TSC on Outcome and Additive Effects of LAM and TSC

Data are presented as parameter estimate (95% CI) from regression analysis unless otherwise indicated. See Table 1 legend for expansion of abbreviations.

a 

TSC was used as reference group in linear regression models, except logistic regression and Poisson regression.

b 

Poisson regression data present as rate ratio (95% CI).

Patterns of Prescription Drug Use

In patients with TSC, anticonvulsant drugs (18.3% of total prescriptions), benzodiazepines (10.4%), and antipsychotics (7.8%) were the most commonly prescribed. A high rate of antidepressant use was found in both patients with TSC and LAM (4.2% and 4.4%, respectively); benzodiazepines were also commonly prescribed in patients with LAM (5.9%). In contrast to TSC, the frequency of antipsychotic drug use in patients with LAM did not exceed that observed in control subjects. No prescriptions for rapamycin (sirolimus) were recorded in patients with LAM, likely because the study period preceded its routine use. In contrast, 135 prescriptions for rapamycin were written for patients with TSC, perhaps reflecting its emerging use for intractable epilepsy.

Few studies have systematically estimated the prevalence of TSC or LAM in a large population, and little is known regarding the related use of health-care resources.7 In this diagnosis-based interrogation of a provincial health-care database, the prevalence of TSC was similar to that reported in other survey-based population or natural history studies.13 Although its prevalence was low in this cross-sectional study, LAM accounted for significant morbidity and mortality. Health-care resource utilization was increased in patients with TSC or LAM. Of note, visits to psychiatrists and the use of psychotropic medications were frequent in patients with TSC or LAM, suggesting that psychiatric illness might significantly affect their quality of life as well as health-care resource utilization.

Because all residents of Quebec are registered in a single-payer health-care system, outcome rates inferred from the associated databases reflect the entire population, and many biases associated with population-based surveys are avoided (eg, selection, recall). In addition, the control subjects were matched for age and sex, and exhibited comorbidities characteristic of the overall population. However, misclassification, failure to identify cases, and missing data may have influenced the results. Although misclassification could lead to underestimation of the prevalence of TSC or LAM, the rate of TSC was similar to that found in other studies.13 The low prevalence of LAM was likely due to suboptimal case identification partly because of a lack of formal ICD codes for LAM but more likely resulting from a lack of clinical recognition. Based on studies, LAM, as assessed by CT imaging of the chest, should have been detected in approximately 30% of patients with TSC.5,14 However, radiologic screening for LAM in patients with TSC in Quebec was likely low during the study period because guideline-based recommendations for screening became available in 2010,15 and these patients would have likely exhibited mild or absent clinical manifestations.5 As a result, patients with LAM identified in the Quebec databases were likely those with greater morbidity, mortality, and health-care resource utilization. The impact of LAM on clinical outcomes and resource use may be better estimated once radiologic screening in patients with TSC becomes routine.

Although the study period ended in 2011, interpretation of the results may be limited by recent and rapid changes in the standard of care for TSC and LAM. During the study period, transplantation or the use of rapamycin for TSC or LAM was rare. However, indications for transplantation in LAM have subsequently been refined, and the results of a multicenter trial for the effectiveness of rapamycin were published.16 If routinely instituted, these interventions may have since prolonged survival and reduced morbidity, thereby altering health-care utilization and prescription patterns. Similarly, the use of rapamycin in TSC for intractable seizures might have reduced the need for anticonvulsant medications, hospitalizations, or surgery for epilepsy.17 To address the utility of recently introduced interventions, follow-up studies in the Quebec cohort are needed, as well as the collection of comprehensive prospective data by research consortia.

An increase in hospital admissions and medical visits was observed in patients with TSC, especially in those with LAM (Table 1). This was accompanied by greater cost; however, the total cost of prolonged hospital admissions seen with LAM and TSC was likely underestimated because the cost related to hospitalization was not included in the current analysis. When compared with TSC, there was a strong association between LAM and health-care resource utilization by multivariable analysis (Table 4). As expected from the high frequency of pulmonary (eg, pneumothorax, respiratory failure) and renal (eg, angiomyolipomas) manifestations, patients with LAM commonly visited pulmonologists and nephrologists. Of particular note, there was a significant number of visits to psychiatrists, and the use of psychotropic medications (ie, antidepressants, benzodiazepines) was common, suggesting a high prevalence of affective disorders. According to a systematic review on published studies on TSC, approximately 30% of patients experience depressive or anxiety disorders, and these are most common in patients aged > 18 years.7 Psychiatric manifestations in LAM warrant further investigation and may represent targets for interventions that alter morbidity and quality of life.

Results from the current study can likely be generalized to other large populations in North America or Europe. Potential threats to generalizability include differences in race distribution, access to care, and payer systems. Nonetheless, it is likely that LAM is underdiagnosed in the general population and that both TSC and LAM account for significant health-care resource utilization. In patients with TSC, screening for LAM with emerging biomarkers18 or imaging protocols6 may permit earlier diagnosis and intervention. Moreover, targeting specific domains of resource utilization, such as that attributed to psychiatric manifestations, may mitigate the burden on patients, families, and the health-care system. Now that mammalian target of rapamycin inhibitors are routinely used for the treatment of LAM, and lung transplantation is likely more common, their impacts on clinical outcomes and resource utilization can be better assessed in future studies.

Author contributions: A. S. K. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. A. S. K., P. Z. L., P. M., and J. S. L. contributed to the study design, data analysis and interpretation, and writing of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Major is the local principal investigator for the EXIST (Efficacy and Safety of Everolimus for Subependymal Giant Cell Astrocytomas Associated With Tuberous Sclerosis Complex)-1 and EXIST-3 trials; is an invited speaker for and has participated in advisory committees on tuberous sclerosis complex sponsored by Novartis AG; and has participated in an advisory committee on epilepsy sponsored by Eisai Co, Ltd. Drs Kristof and Landry and Ms Li have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

ICD

International Classification of Diseases

LAM

lymphangioleiomyomatosis

RAMQ

Régie de l’Assurance-Maladie du Québec

TSC

tuberous sclerosis complex

Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355(13):1345-1356. [CrossRef] [PubMed]
 
Kandt RS. Tuberous sclerosis complex and neurofibromatosis type 1: the two most common neurocutaneous diseases. Neurol Clin. 2003;21(4):982-1004. [CrossRef]
 
Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008;372(9639):657-668. [CrossRef] [PubMed]
 
Orlova KA, Crino PB. The tuberous sclerosis complex. Ann N Y Acad Sci. 2010;1184:87-105. [CrossRef] [PubMed]
 
Moss J, Avila NA, Barnes PM, et al. Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med. 2001;164(4):669-671. [CrossRef] [PubMed]
 
Cudzilo CJ, Szczesniak RD, Brody AS, et al. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest. 2013;144(2):578-585. [CrossRef] [PubMed]
 
Hallett L, Foster T, Liu Z, Blieden M, Valentim J. Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review. Curr Med Res Opin. 2011;27(8):1571-1583. [CrossRef] [PubMed]
 
Cadre normatif du système MED-ÉCHO, 1987. Santé et Services sociaux Québec website. http://publications.msss.gouv.qc.ca/acrobat/f/documentation/2000/00-601.pdf. Accessed March 1, 2015.
 
Ministère de la Santé et des Services Sociaux du Québec. Les banques de données du MSSS. Numéro 1: Données sur la clientèle hospitalière (MED-ÉCHO). Quebec, 1986. Réseau Santécom website. http://www.santecom.qc.ca/Bibliothequevirtuelle/santecom/35567000024304.pdf. Accessed March 1, 2015.
 
Tamblyn R, Lavoie G, Petrella L, Monette J. The use of prescription claims databases in pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription claims database in Québec. J Clin Epidemiol. 1995;48(8):999-1009. [CrossRef] [PubMed]
 
King TE Jr. Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am J Respir Crit Care Med. 2005;172(3):268-279. [CrossRef] [PubMed]
 
Armitage P, Berry G, Matthews J. Statistical Methods in Medical Research.4th ed. Malden, MA: Blackwell Science; 2005.
 
Northrup H, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4):243-254. [CrossRef] [PubMed]
 
Meraj R, Wikenheiser-Brokamp KA, Young LR, McCormack FX. Lymphangioleiomyomatosis: new concepts in pathogenesis, diagnosis, and treatment. Semin Respir Crit Care Med. 2012;33(5):486-497. [CrossRef] [PubMed]
 
Johnson SR, Cordier JF, Lazor R, et al; Review Panel of the ERS LAM Task Force. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J. 2010;35(1):14-26. [CrossRef] [PubMed]
 
McCormack FX, Inoue Y, Moss J, et al; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011;364(17):1595-1606. [CrossRef] [PubMed]
 
Curatolo P. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol. 2015;52(3):281-289. [CrossRef] [PubMed]
 
Young L, Lee HS, Inoue Y, et al; MILES Trial Group. Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med. 2013;1(6):445-452. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
TABLE 1 ]  Characteristics of the Study Subjects

Data are presented as mean ± SD or No. (%). LAM = lymphangioleiomyomatosis; TSC = tuberous sclerosis complex.

a 

Mortality rate was calculated as the number of deaths (n) divided by the number of patients (%) during the study period or as the number of deaths per person-y of follow-up.

Table Graphic Jump Location
TABLE 2 ]  Causes of Death Documented in Fatal Cases of TSC and LAM

See Table 1 legend for expansion of abbreviations.

Table Graphic Jump Location
TABLE 3 ]  Most Frequent Medical Diagnosis at Hospital Discharge

See Table 1 legend for expansion of abbreviations.

Table Graphic Jump Location
TABLE 4 ]  The Effects of LAM Compared With TSC on Outcome and Additive Effects of LAM and TSC

Data are presented as parameter estimate (95% CI) from regression analysis unless otherwise indicated. See Table 1 legend for expansion of abbreviations.

a 

TSC was used as reference group in linear regression models, except logistic regression and Poisson regression.

b 

Poisson regression data present as rate ratio (95% CI).

References

Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355(13):1345-1356. [CrossRef] [PubMed]
 
Kandt RS. Tuberous sclerosis complex and neurofibromatosis type 1: the two most common neurocutaneous diseases. Neurol Clin. 2003;21(4):982-1004. [CrossRef]
 
Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008;372(9639):657-668. [CrossRef] [PubMed]
 
Orlova KA, Crino PB. The tuberous sclerosis complex. Ann N Y Acad Sci. 2010;1184:87-105. [CrossRef] [PubMed]
 
Moss J, Avila NA, Barnes PM, et al. Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med. 2001;164(4):669-671. [CrossRef] [PubMed]
 
Cudzilo CJ, Szczesniak RD, Brody AS, et al. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest. 2013;144(2):578-585. [CrossRef] [PubMed]
 
Hallett L, Foster T, Liu Z, Blieden M, Valentim J. Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review. Curr Med Res Opin. 2011;27(8):1571-1583. [CrossRef] [PubMed]
 
Cadre normatif du système MED-ÉCHO, 1987. Santé et Services sociaux Québec website. http://publications.msss.gouv.qc.ca/acrobat/f/documentation/2000/00-601.pdf. Accessed March 1, 2015.
 
Ministère de la Santé et des Services Sociaux du Québec. Les banques de données du MSSS. Numéro 1: Données sur la clientèle hospitalière (MED-ÉCHO). Quebec, 1986. Réseau Santécom website. http://www.santecom.qc.ca/Bibliothequevirtuelle/santecom/35567000024304.pdf. Accessed March 1, 2015.
 
Tamblyn R, Lavoie G, Petrella L, Monette J. The use of prescription claims databases in pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription claims database in Québec. J Clin Epidemiol. 1995;48(8):999-1009. [CrossRef] [PubMed]
 
King TE Jr. Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am J Respir Crit Care Med. 2005;172(3):268-279. [CrossRef] [PubMed]
 
Armitage P, Berry G, Matthews J. Statistical Methods in Medical Research.4th ed. Malden, MA: Blackwell Science; 2005.
 
Northrup H, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4):243-254. [CrossRef] [PubMed]
 
Meraj R, Wikenheiser-Brokamp KA, Young LR, McCormack FX. Lymphangioleiomyomatosis: new concepts in pathogenesis, diagnosis, and treatment. Semin Respir Crit Care Med. 2012;33(5):486-497. [CrossRef] [PubMed]
 
Johnson SR, Cordier JF, Lazor R, et al; Review Panel of the ERS LAM Task Force. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J. 2010;35(1):14-26. [CrossRef] [PubMed]
 
McCormack FX, Inoue Y, Moss J, et al; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011;364(17):1595-1606. [CrossRef] [PubMed]
 
Curatolo P. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol. 2015;52(3):281-289. [CrossRef] [PubMed]
 
Young L, Lee HS, Inoue Y, et al; MILES Trial Group. Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med. 2013;1(6):445-452. [CrossRef] [PubMed]
 
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