Table 2 Overview of studies reporting burden of illness by health care resource use, direct costs or mortality in TSC patients

Shepherd et al. 1991 [100]

Retrospective chart review, bottom-up

Mayo Clinic/ USA

all TSC

all

Clinical diagnosis of TSC according to 1988 Gomez criteria

355

0

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

yes

only via mortality

n. r.

Liang et al. 2019 [101]

Prospective, single-center

Capital Epilepsy Therapy Center Beijing/ China

TSC + E

all

Pharmacoresistant epilepsy, surgery in year 2007

25

N/A

2007

1

1

14.3 (R 6–23)

n. r.

n. r.

8 (32)

100

N/A

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

Quality of life in epilepsy inventory-31 (QOLIE-31)

n. r.

Lennert et al. 2012 [24]

Retrospective chart review, bottom-up

Minnesota Epilepsy Group/ USA

only TSC + E

all

Inclusion: TSC–related seizure disorder within the first 6 months after tuberous sclerosis complex diagnosis

exclusion: TSC–unrelated seizure disorder

95 (only children)

0

1973–2010

37

0.5 to 5

3.1 (SD 7.8)

N/A

3.1 (SD 7.8)

48 (51.0)

91 (95.8)

N/A

yes

yes

n. r.

n. r.

n. r.

n. r.

only via clinical information and HCRU

n. r.

Graffigna et al. 2013 [102]

Qualitative interview

survey of patients from 15 TSC centers/ Italy

Caregivers of children with TSC + SEGA

all

Caregivers of children with TSC + SEGA

0

48

2011–2012

1

N/A

47 (SD 6.3) (caregiver)

N/A

N/A

62.5 (caregiver)

N/A

100

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

Qualitative statements

Krueger et al. 2013 [103]

Prospective, multicenter,open-label, phase!/ II clinical trial

TSC clinics at Cincinnati Children’s Hospital Medical Center (CCHMC) and Texas Children’s Hospital/ USA

Pharmacoresistant epilepsy

brain

> = 2 years of age, confirmed diagnosis of TSC (1998 clinical diagnostic criteria or identified disease-causing mutation, pharmacoreistant epilepsy)

23

N/A

16 months

16 months

8 (R 2–21)

n. r.

n. r.

50

n. r.

N/A

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

Quality of Life for Children with Epilepsy (QOLCE), Nisonger Child Behavioral Rating Form (NCBRF)

n. r.

Eijkemans et al. 2015 [86]

Retrospective observational, bottom-up

University Medical Center Utrecht (UMCU)/ Netherlands

all TSC/ TSC + AML

kidney

Diagnosis of TSC according to the modified Gomez criteria and aged 18 years or older

351^* (only adults)

0

1990–2012

22

median 15.8

39.8 (R 18–89)

39.8 (R 18–89)

N/A

175 (49.8)

N/A (0)

N/A

yes

n. r.

n. r.

n. r.

n. r.

yes

only via HCRU

n. r.

Kristof et al. 2015 [104]

Retrospective cohort study, top-down

Régie de l’Assurance-Maladie du Québec (RAMQ; Quebec Health Care Insurance Board) database/ Canada

all TSC/ TSC + LAM/ LAM/ controls

lung

LAM and/or TSC and controls

1004 (children and adults)

0

1996–2011

15

n. r.

39.5 (SD 24.4)

n. r.

n. r.

555 (55.3)

n. r.

N/A

yes

yes

yes

n. r.

n. r.

yes

only via HCRU

n. r.

Rentz et al. 2015a [56]

Cross-sectional, non-interventional, bottom-up

web-based survey/ USA

paediatric/ adult TSC patients/ caregivers

all

Inclusion: age 18 years or older, TSC diagnosis (or care for individual with TSC), read English and ability to participate, and consent

exclusion: patients with cognitive impairment or other health impairment that interfere w/ survey completion

676^** (children and adults)

275 (179 adult caregiver, 96 pediatric caregiver)

2012

N/A

2 months (May and June 2012)

29.8 (SD 17.7)

38 (SD 12.8)

7.1 (SD 4.6)

400 (59.2)

197 (26.5)

40.7

yes

yes

n. r.

n. r.

n. r.

n. r.

Short Form (12) Health Survey (SF-12), Hamilton Depression Rating Scale-Short Form (HDI-SF)

SF-12,HDI-SF

Rentz et al. 2015b [105]

Cross-sectional, non-interventional, bottom-up

web-based survey/ USA

TSC caregivers

all

See Rentz et al. 2015a

275^** (children and adults)

275^**

2012

0

2 months (May and June 2012)

n. r.

n. r.

n. r.

217 (79)

0

100

yes

yes

n. r.

n. r.

n. r.

n. r.

SF-12, HDI-SF

SF-12, HDI-SF

Skalicky et al. 2015 [106]

Cross-sectional, non-interventional, bottom-up

web-based survey/ USA

paediatric/ adult TSC patients

all

See Rentz et al. 2015 a

116^** (children and adults)

69^**

2012

0

2 months (May and June 2012)

25.5 (SD 16.6)

36.8 (SD 11.5)

9 (SD 5.0)

n. r.

47 (40.5)

59.5

yes

yes

yes

n. r.

n. r.

n. r.

SF-12, HDI-SF, Work Productivity and Activity Impairment plus Classroom Impairment Questions: Special Health Problem (WPAI CIQ-SHP), version 2

SF-12, HDI-SF, WPAI CIQ-SHP-version 2

Sun et al. 2015 [107]

Retrospective cohort study, top-down

National claims databases (MarketScan commercial and Medicaid, Pharmetrics commercial)/ USA

all TSC + SEGA surgery

brain (SEGA)

TSC patients with first SEGA surgery claim in study period

47 (children and adults)

0

2000–2011

11

n. r.

11.6

n. r.

n. r.

16 (34)

n. r.

N/A

yes

yes

yes

yes

n. r.

n. r.

only via HCRU

n. r.

Vekeman et al. 2015 [35]

Retrospective, longitudinal cohort study, bottom-up

University Medical Center Utrecht (UMCU)/Netherlands

CKD stage/ AML size

kidney, lung

Diagnosis of TSC according to the revised 1998 TSC criteria

369^* (children and adults)

0

1990–2012

22

mean 14.3

32.4 (SD 23.7) CKD stage I

n. r.

n. r.

n. r.

n. r.

N/A

yes

yes

yes

yes

n. r.

n. r.

only via clinical information and HCRU

n. r.

Crall et al. 2016 [108]

Cross-sectional, bottom-up

web-based survey and survey of out-patients/USA

TSC with AF and caregivers

skin

Inclusion: clinical or genetic diagnosis of TSC, age > 6 years at enrollment /caregiver of a patient exclusion: uncertain diagnosis of TSC/ severe neurologic deficits/ survey noncompletion

219 (children and adults)

161

2014–2015

N/A

N/A

n. r.

n. r.

n. r.

94 (42.9)

n. r.

73.5

n. r.

yes

n. r.

n. r.

n. r.

n. r.

Children’s Dermatology Life Quality Index (CDLQI)

Childhood Atopic Dermatitis Impact Scale (CADIS)

Fallah et al. 2016 [109]

Cost-utility analysis, bottom-up and top-down

literature search (clinical data), Tufts CEA registry, Agency for Healthcare Research and Quality (AHRQ) Medical Expenditure Panel Survey/ USA

TSC + E only (model)

brain (seizures)

N/A

N/A

N/A

2000–2015

15

15 for clinical outcomes, cost data updated to 2016 USD

N/A

N/A

N/A

N/A

N/A (100)

N/A

n. r.

n. r.

yes

yes

n. r.

n. r.

n. r.

n. r.

Kingswood et al. 2016a [110]

Retrospective cohort study, bottom-up and top-down

National Health Service (NHS) databases CPRD (clinical practice research datalink) and CPRD-HES (hospital event statistics)/ UK

all TSC/ general population comparator

all

Diagnosis of TSC between 1 January 1987 and 30 June 2013 and at least 3 years of continuous data prior to the last available record

278^*** (children and adults)

0^***

1987–2013

26

at least 3

31.5 (SD 18.7)

n. r.

n. r.

147 (53)

n. r.

N/A

yes

yes

yes

yes

n. r.

n. r.

only via HCRU

n. r.

Kingswood et al. 2016b [111]

Retrospective cohort study, bottom-up and top-down

National Health Service (NHS) databases CPRD (clinical practice research datalink) and CPRD-HES (hospital event statistics)/ UK

TSC + renal manifestations/ general population comparator

kidney

See Kingswood et al. 2016a

79^*** (children and adults)

0^***

1987–2013

26

at least 3

38,3 (SD 17.1)

n. r.

n. r.

37 (46.7)

8 (11.3)

N/A

yes

yes

yes

yes

n. r.

n. r.

only via HCRU

n. r.

Kingswood et al. 2016c [42]

Retrospective cohort study, bottom-up and top-down

National Health Service (NHS) databases CPRD (clinical practice research datalink) and CPRD-HES (hospital event statistics)/ UK

all TSC/ general population comparator

all

Diagnosis of TSC between 1 January 1987 and 30 June 2013

334^*** (children and adults)

0^***

1987–2013

26

mean 17.4 (SD 6.4)

30.3 (SD 18.6)

n. r.

n. r.

177 (53)

n. r. (29)

N/A

n. r.

n. r.

n. r.

n. r.

n. r.

yes

only via mortality

n. r.

Wilson et al. 2016 [112]

Retrospective, top-down

Agency for Healthcare Research and Quality (AHRQ) National Inpatient Sample (NIS) database/ USA

all TSC

all

All TSC patients in the database

5655 (hospital admissions) (children and adults)

0

2000–2010

10

n. r.

22.3 (SD 19.5)

n. r.

n. r.

n. r. (52.5)

n. r.

N/A

yes

n. r.

yes

n. r.

n. r.

n. r.

only via HCRU

n. r.

Amin et al. 2017 [113]

Retrospective chart review, bottom-up

Bath TSC clinic database/ UK

all TSC

all

Definite diagnosis of TSC (International TSC Consensus Group)

284 (children and adults)

0

1981–2015

34

median 8 (IQR 3–17)

w/ ID 25 (IQR 15–36), wo/ ID 28 (IQR 17–43)

n. r.

n. r.

142 (50)

n. r.

N/A

n. r.

n. r.

n. r.

n. r.

n. r.

yes

only via mortality

n. r.

Shepherd et al. 2017 [23]

Retrospective cohort study, bottom-up and top-down

National Health Service (NHS) databases (EMR, HES, clinical practice research datalink)/ UK

all TSC/ TSC + E, TSC + E/ general population comparator

all

Recorded diagnosis of TSC in study period and at least 3 years of continuous data prior to the last available record

209 (children and adults)

0

1997–2012

15

at least 3

26.8 (SD 17.8)

N/A

N/A

102 (48.8)

81 (38.8)

N/A

yes

yes

yes

yes

n. r.

n. r.

only via clinical information and HCRU

n. r.

Song X. et al. 2017 [114]

Cross-sectional, top-down

Truven Commercial Claims and Medicaid database/ USA

TSC + AML/ controls in Commercial/ Medicaid databases

all

Patients diagnosed with TSC-renal AML in the databases

743 (children and adults)

0

2000–2013

13

37.0 (SD 31.1) to 87.2 (SD 42.9)

n. r.

36.9 (SD 13.0)

9.7 / 6.9 (SD 5.2)

n. r.

256 (34.5)

N/A

yes

yes

yes

n. r.

n. r.

n. r.

only via HCRU

n. r.

Welin et al. 2017 [27]

Retrospective, top-down

National Board of Health and Welfare (NBHW) national registers/ Sweden

all TSC

all

All patients with TSC diagnosis in national register

551 (children and adults)

0

2004–2014

10

mean 8.8

n. r.

n. r.

n. r.

339 (45.1)

238 (61.6) at first observation

N/A

yes

yes

n. r.

n. r.

n. r.

yes

only via HCRU

n. r.

Both et al. 2018 [115]

Qualitative study using semistructured interviews

Dutch Foundation for patients with TSC, healthcare providers/ Netherlands

TSC patients/ parents

all

Adolescent TSC patients 18–30 years old with a definitive TSC diagnosis; parents of children with TSC of 18 years, or older, or younger and having transitioned into adult care

28 (children and adults)

12

n. r.

n. r.

n. r.

R 17–30

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

TSC-related themes, categorized by the ICF

TSC-related themes, categorized by the ICF

Hamer et al. 2018 [116]

Retrospective, multi-center cohort study (12), bottom-up

survey of patients from 12 German epilepsy centers/ Germany

all TSC

all

Patients aged ≥18 years with a confirmed TSC diagnosis according to clinical Gomez criteria and/or genetic testing

262 (only adults)

0

2010–2015

5

5

36.2 (SD 9)

36.2 (SD 9)

N/A

122 (46.6)

0

N/A

yes

yes

n. r.

n. r.

n. r.

n. r.

only via HCRU

n. r.

Kopp et al. 2018 [117]

Retrospective observational, bottom-up

Carol and James Herscot Center for Tuberous Sclerosis Complex, Massachusetts General Hospital (MGH)/ USA

all TSC

all

All patients under the age of 18 with TSC

99 (only children)

0

2001–2007

6

n. r.

N/A

7.7 (SD 4.2)

7.7 (SD 4.2)

54 (54.5)

99 (100)

N/A

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

Symptom Checklist-90—Revised (SCL-90-R), Parenting Stress Index (Short Form)

Mowrey et al. 2018 [118]

Cross-sectional, bottom-up

web-based survey/ USA

all TSC

all

Having a diagnosis of TSC, age of 18 years or older, ability to independently complete a 30-min electronic survey.

71 (only adults)

0

2017–2018

N/A

3 months

43.7 (SD 13.2)

43.7 (SD 13.2)

N/A

52 (73)

0

N/A

yes

yes

n. r.

n. r.

n. r.

n. r.

Brief-Illness Perceptions Questionnaire (Brief-IPQ), Beck Anxiety Inventory (BAI), and Beck Depression Inventory-II (BDI-II).

n. r.

Rentz et al. 2018 [119]

Cross-sectional, non-interventional, bottom-up

web-based survey/USA

paediatric/ adult TSC + AML patients/ caregivers

kidney

see Rentz et al. 2015a

182^** (110 AML) (children and adults)

59^**

2012

N/A

2 months (May and June 2012)

29.1 (SD 16.6)

36.4 (SD 13.6)

10.6 (SD 4.7)

n. r.

31 (28.2)

54

yes

yes

n. r.

n. r.

n. r.

n. r.

SF-12, HDI-SF

SF-12, HDI-SF

Skalicky et al. 2018 [119]

Cross-sectional, bottom-up

web-based survey/ USA

paediatric/ adult TSC patients/ caregivers

all

see Rentz et al. 2015a

609^** (children and adults)

275^**

2012

N/A

2 months (May and June 2012)

28.9 (SD 18)

38 (SD 13.1)

7.1 (SD 4.6)

n. r.

179 (29.4)

45.2

yes

yes

yes

n. r.

yes

n. r.

WPAI CIQ-SHP version 2

WPAI CIQ-SHP version 2; out-of-pocket indirect healthcare spending related to time and money spent for TSC-related medical care travel and childcare expenses

Song J. et al. 2018 [120]

Retrospective, bottom-up and top-down

National Tuberous Sclerosis Association (NTSA), TSC Natural History Database/ USA, Belgium

TSC + E only

all

All TSC patients in the database

1110(children and adults)

0

2006–2014

8

4.3

n. r.

n. r.

n. r.

535 (48.2)

n. r.

N/A

yes

yes

n. r.

n. r.

n. r.

n. r.

only via HCRU

n. r.

Amin et al. 2019 [121]

Cross-sectional, non-interventional

Bath TS clinic/ UK

All TSC

all

TSC, as defined by the International Tuberous Sclerosis Complex Consensus Group

91

n. r.

2014

N/A

n. r.

n. r.

34

12

50%

35 (38.5)

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

Pediatric Quality of Life Inventory (PedsQL) (children)

SF-36 (adults)

n. r.

Bar et al. 2019 [53]

Cross-sectional, bottom-up

Written questionnaire/ network of the reference center for rare epilepsies and TSC (Necker-Enfants Malades and university hospitals of Saint-Etienne, Lille and Lyon) and the French association for TSC (ASTB), France

TSC patients in transition from pediatric care

all

Age > 18 years and confirmed diagnosis of TSC before the age of 16

60 (only adults)

30

2014

N/A

n. r.

32 (range 18–55)

32 (range 18–55)

N/A

29 (49%)

N/A

50

yes

yes

n.r.

n.r.

yes

n.r.

Quality of Life Scale (QOLS), Multidimensional Fatigue Inventory-20 (MFI-20)

n.r.

Tritton et al. 2019 [122]

Cross-sectional, bottom-up

Web-based survey/ USA and Europe

TSC + epilepsy

all

Clinical diagnosis of TSC and epilepsy

186

N/A

2017–2018

N/A

N/A

27.3

n. r.

n. r.

82 (44.1)

70 (37.6)

N/A

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

European quality of life (EQ – 5 dimensions – 3 levels)

n. r.

Vergeer et al. 2019 [123]

Single-center retrospective chart review, bottom-up

University Medical Center Utrecht (UMCU)/Netherlands

TSC with AML, SEGA and/or epilepsy

all

Diagnosis of TSC according to the revised 1998 TSC criteria

363^*

0

1990–2015 (2012)

16

N/A

n. r.

n. r.

n. r.

n. r

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

Health Utility Index version 3 (HUI-3)

n. r.

Zak et al. 2019 [124]

Retrospective chart review, bottom-up

Cincinnati Children’s Hospital Medical Center TSC clinic/ USA

all TSC

all

All patients who attended the CCHMC TSC clinic during the study period, National Death Index (NDI)

567 (children and adults)

0

1998–2016

18

n. r.

n. r.

n. r.

n. r.

247 (> 18) (%n. r.)

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

n. r.

yes

only via mortality

n. r.