Journal of the Neurological Sciences 391 (2018) 104–108

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Journal of the Neurological Sciences

journal homepage: www.elsevier.com/locate/jns

Epilepsy treatment patterns among patients with tuberous sclerosis complex T

a a,⁎ b a a
Jinlin Song , Elyse Swallow , Qayyim Said , Miranda Peeples , Mark Meiselbach ,
James Signorovitcha, Michael Kohrmanc, Bruce Korfd, Darcy Kruegere, Michael Wongf,
Steven Sparaganag
a
Analysis Group, Inc., 111 Huntington Ave, Floor 14, Boston, MA 02199, United States
b
Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover, NJ 07936, United States
c
Akron Children's Hospital, 1 Perkins Square, Akron, OH 44308, United States
d
University of Alabama at Birmingham, 1720 2nd Ave S, Birmingham, AL 35294, United States
e
Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, United States
f
Washington University in Saint Louis, 1 Brookings Dr, St. Louis, MO 63130, United States
g
Texas Scottish Rite Hospital for Children, 2222 Wellborn St, Dallas, TX 75219, United States

A R T I C LE I N FO A B S T R A C T

Keywords: Introduction: Tuberous sclerosis complex (TSC) is a rare congenital disorder often associated with epilepsy.
Tuberous sclerosis complex However, real-world treatment patterns for epilepsy in patients with TSC are not yet well categorized.
Epilepsy Methods: This study included patients with TSC and epilepsy from fifteen clinics in the United States and one in
Treatment patterns Belgium who were enrolled in the TSC Natural History Database (2006–2014). Patient demographics and epi-
Tuberous Sclerosis Natural History Database
lepsy treatment patterns, including the use of anti-epileptic drugs (AEDs), epilepsy surgeries, and dietary
Anti-epileptic drugs
therapies were assessed.
Results: Of the 1328 patients with TSC in the database, 1110 (83.6%) were diagnosed with epilepsy. The median
age of epilepsy diagnosis was 0.7 years. Of those who received treatment for epilepsy (92.3%), 99.5% were
prescribed AEDs, 25.3% underwent surgery, 7.9% were prescribed special diets, and 1% were prescribed
mammalian target of rapamycin (mTOR) inhibitors. Of the patients receiving AEDs, over half (64.5%) used ≥3
different AEDs, and 22.5% underwent surgical treatment following AED initiation. Of the patients who under-
went surgery, 35.1% had subsequent surgery.
Conclusion: The use of multiple AEDs and surgical interventions may indicate a need for new therapies to reduce
the treatment burden among patients with TSC and epilepsy.

1. Introduction
Tuberous sclerosis complex (TSC) is a rare congenital disorder
present in approximately 1 in 6000 to 1 in 10,000 live births [1–3]. The
clinical features of TSC vary widely, but predominantly involve the
presence of benign tumors (hamartomas) in multiple organ systems,
including the brain (i.e., cortical tubers, subependymal nodules, and
subependymal giant cell astrocytomas [SEGAs]) [4, 5]. Epilepsy is a
common manifestation of these neurological structural abnormalities,
affecting between 79 and 90% of patients with TSC [6, 7], and is as-
sociated with a worse cognitive outcome [8]. For approximately 60% of
patients with TSC, seizures begin before the age of one [6, 9], and a
2010 study of the natural history of TSC reported that 99% of patients
who suffered a single seizure went on to develop epilepsy [10].
The primary goals of TSC treatment are to control its systemic
manifestations, including epileptic seizures, and clinical guidelines in-
dicate the use of broad diagnostics and frequent, long-term monitoring
of disease progression [11]. Possible treatments for epilepsy among TSC
patients include anti-epileptic drugs (AEDs), special diets (e.g., keto-
genic), vagus nerve stimulation (VNS), and surgical interventions such
as tuber resection [11, 12]. AEDs are indicated as the first line treat-
ment, with guidelines suggesting that AED selection follow that of other
epilepsies, including multiple AED options (e.g., valproic acid, viga-
batrin, levetiracetam, and topiramate) available for focal seizures [11,
13]. The International TSC Consensus Group recommends vigabatrin
for infantile spasms, with adrenocorticotropin hormone as an alter-
native [11]. In addition, the mammalian target of rapamycin (mTOR)
inhibitor everolimus has shown efficacy in reducing seizure frequency

Abbreviations: TSC, tuberous sclerosis complex; mTOR, mammalian target of rapamycin; AED, anti-epileptic drug; VNS, vagus nerve stimulation; SEGA, subependymal giant cell
astrocytoma; IQR, interquartile range; SD, standard deviation; PKD1, polycystic kidney disease 1
⁎
Corresponding author at: 111 Huntington Ave, Floor 14, Boston, MA 02199, United States.
E-mail address: elyse.swallow@analysisgroup.com (E. Swallow).

https://doi.org/10.1016/j.jns.2018.06.011
Received 15 March 2018; Received in revised form 1 June 2018; Accepted 13 June 2018
Available online 15 June 2018
0022-510X/ © 2018 Published by Elsevier B.V.
J. Song et al.
in trials of patients with TSC and refractory epilepsy and is approved in
Europe for this indication [14–16].
Despite the multiple AEDs available, epilepsy is often progressive
and refractory to current pharmaceutical therapies in this patient po-
pulation [12, 17]. A 2015 study of children with TSC and epilepsy re-
ported that of the 77% of patients who achieved remission after the first
or second AED, only 38% maintained seizure remission at 24 months
[17]. Furthermore, while the treatment patterns of the overall popu-
lation of patients with epilepsy are reasonably well understood, few
studies have focused on epilepsy treatment patterns among patients
with TSC. To address this gap in the literature and expand upon prior
studies, this study used clinical data from an international natural
history database containing over 1000 patients with TSC to assess
treatment patterns in the management of epilepsy.
2. Materials and methods
2.1. Data source
The demographics and clinical histories of TSC patients were ob-
tained from the multicenter TSC Natural History Database, which was
established in 2006 by the Tuberous Sclerosis Alliance [18]. Patients
included in the database had a diagnosis of TSC based on: (1) genetic
evidence of mutation in either the TSC1 or TSC2 genes, or (2) pre-
sentation of clinical symptoms with a minimum of two major disease
features or one major feature plus two minor features constituting a
positive diagnosis [19]. At the time of analysis, 1328 patients were
enrolled in the database between 2006 and 2014 from 16 clinics in the
United States and Belgium: Birmingham, AL; Boston, MA; Brussels,
Belgium; Chicago, IL; Cleveland, OH; Dallas, TX; Denver, CO; Fairfax,
VA; Houston, TX; Loma Linda, CA; Los Angeles, CA; Miami, FL; New
York, NY; Oakland, CA; Philadelphia, PA; and St. Paul, MN. The data
were captured at visits to participating clinics and included information
about TSC-related care received at the clinic and retrospectively-cap-
tured information about TSC-related care received outside the clinic.
Additionally, the database contained information on patient demo-
graphics, genotypes, clinical features of TSC, diagnostic and follow-up
test results, and treatments. The data were de-identified and compliant
with the Health Insurance Portability and Accountability Act; the da-
tabase received institutional review board approval from each of the
participating clinics.
2.2. Study population and patient selection criteria
The current analysis included patients in the database with a diag-
nosis of epilepsy. Treatments for epilepsy received after the diagnosis of
epilepsy were considered in the analysis, and were divided into surgical
and non-surgical treatments. Surgical treatments included corpus cal-
losotomy, hemispherectomy, tuber resection, and VNS-related proce-
dures (e.g., all device implantation and follow-up procedures). Non-
surgical treatments included AEDs, mTOR inhibitors specifically pre-
scribed for epilepsy (i.e., everolimus and sirolimus), and special diets
(i.e., ketogenic, low glycemic index, or modified Atkins diet).
2.3. Assessment of patient demographics, clinical features, and treatment
patterns
Demographics, including age at TSC diagnosis, age at epilepsy di-
agnosis, age at clinic enrollment, sex, race/ethnicity, number of clinical
features ever diagnosed, and TSC gene mutation, were summarized
among patients with TSC and epilepsy. Patients with missing values for
a characteristic were excluded from the summary calculations for that
characteristic. Additionally, the fifteen most common clinical features
diagnosed at any time among patients with epilepsy were identified,
and the number and proportion of patients with each clinical feature
were summarized. Among patients who received an AED, the following
105
Journal of the Neurological Sciences 391 (2018) 104–108
elements were assessed: age at first AED initiation, the average number
of distinct AEDs initiated, and the percentage of patients who received a
surgical procedure after initiating an AED. Among patients who re-
ceived at least one surgical procedure, age at first surgical procedure
and the number of surgical procedures following epilepsy diagnosis
were determined. Counts and percentages were reported for categorical
variables, and means, standard deviations (SD), medians, and inter-
quartile ranges (IQRs) were reported for continuous variables.
To describe recent treatment trends, the proportions of patients
initiating each type of treatment were calculated for each year between
2000 and 2013. Treatments received prior to the establishment of the
database in 2006 were collected retrospectively. Because data avail-
ability ended in April 2014, data from 2014 were excluded from this
analysis. The proportions for each treatment category in each year were
calculated as the number of patients initiating at least one treatment in
that category and year divided by the number of patients initiating at
least one treatment of any kind during the year.
To minimize the impact of incomplete information in the database,
and reduce ambiguity regarding the treatment end dates (which were
not consistently recorded), analyses were performed based on initiation
dates. No assumptions were made regarding combination therapies.
All analyses were conducted using SAS software version 9.4 (SAS
Institute, Cary, NC).
3. Results
3.1. Patient demographics
Of the 1328 TSC patients recorded in the TSC Natural History
Database, 1110 (83.6%) were diagnosed with epilepsy. The mean ages
at TSC and epilepsy diagnosis were 3.4 years (SD: 7.8) and 3.1 years
(SD: 6.4), respectively; however, the median ages were much younger
(0.7 years for both) (Table 1). A small proportion of patients (3.6%)
were diagnosed with TSC prenatally. Most patients with TSC were di-
agnosed with epilepsy in infancy, with 75.0% of epilepsy diagnoses
occurring before the age of 2.2 years and 59.3% before the age of
1 year. Approximately half (51.8%) of the patients with TSC and epi-
lepsy were male, and the majority were white (74.6%). Information on
TSC gene mutations was available for 584 patients (52.6%). Of these
patients, approximately half (55.3%) had a TSC2 gene mutation, 23.3%
had a TSC1 mutation, and 21.2% had no identified mutation. The
median age at clinic enrollment was 11.1 years old, and patients had a
median follow-up duration of 4.3 years.
Patients included in the analysis had a median of 9.0 (IQR:
7.0–12.0) diagnosed clinical features reported in the database (Table 1).
The fifteen most prevalent clinical features are listed in Table 2. Cor-
tical tuber was the most common feature, reported for 90.2% of pa-
tients, followed by subependymal nodules (87.5%), hypomelanotic or
hypopigmented macule (75.2%), facial angiofibroma (61.8%), devel-
opmental delay (51.7%), renal angiomyolipoma (50.5%), rhabdo-
myoma (41.1%), cystic renal lesion (38.5%), shagreen patch (35.2%),
subependymal giant cell astrocytoma (31.0%), and fibroma (25.7%).
The remaining clinical features were observed in fewer than 20% of
patients.
3.2. Epilepsy treatment patterns
Nearly all (92.3%) of the included patients diagnosed with TSC and
epilepsy received non-surgical and/or surgical treatments to reduce or
prevent epileptic seizures (Table 3). Among patients who received
treatment for epilepsy, AEDs were the most common form of treatment
(99.5%), followed by surgery (25.3%), special diets (7.9%), and mTOR
inhibitors (1.0%).
Among the 1020 patients who received an AED, mean age at AED
initiation was 1.5 years (Table 3). Over half (64.5%) of patients who
received an AED initiated three or more distinct AEDs, and 22.5%
J. Song et al. Journal of the Neurological Sciences 391 (2018) 104–108

Table 1 Table 3
Demographics of patients with TSC and epilepsy. Epilepsy Treatment Patterns among Patients with TSC and Epilepsy.
Characteristic Characteristic

a
Age at TSC diagnosis (years) Patients receiving treatment for epilepsy, n (%) 1025 (92.3%)
Mean (SD) 3.4 (7.8) AED 1020 (99.5%)
Median (IQR) 0.7 [0.2–2.4] mTOR inhibitor 10 (1.0%)
Prenatal diagnosis, n (%) 39 (3.6%) Diet 81 (7.9%)
Age at epilepsy diagnosis (years) Surgery 259 (25.3%)
Mean (SD) 3.1 (6.4) Among patients treated with an AED
Median (IQR) 0.7 [0.3–2.2] Age at initiation of first AED (years)
Diagnosed before age 1, n (%) 658 59.3% Mean (SD) 5.9 (9.0)
Age at clinic enrollment (years) Median [IQR] 1.5 [0.5–7.7]
Mean (SD) 14.5 (12.5) Total number of distinct AEDs, n (%)
Median (IQR) 11.1 [5.0–20.2] 1 183 (17.9%)
Duration of follow-up (years), median [IQR] 4.3 [2.9–5.3] 2 179 (17.5%)
Male, n (%) 575 (51.8%) 3 162 (15.9%)
Race/ethnicity, n (%)b 4 142 (13.9%)
White 828 (74.6%) 5+ 354 (34.7%)
Hispanic 169 (15.2%) Patients receiving a surgical procedure after initiation of 229 (22.5%)
African American 91 (8.2%) an AED, n (%)
Asian 46 (4.1%) Time from initiation of first AED to first surgical
American Indian 9 (0.8%) procedure (years)
Pacific Islander 4 (0.4%) Mean (SD) 4.9 (5.4)
Other 33 (3.0%) Median [IQR] 3.0 [1.4–6.3]
Number of clinical features ever diagnosed Among patients treated with a surgical procedure
Mean (SD) 9.2 (3.5) Age at first surgical procedure (years)
Median (IQR) 9.0 [7.0–12.0] Mean (SD) 9.2 (8.9)
Information available on TSC gene mutation, n (%)c 584 (52.6%) Median [IQR] 6.2 [3.0–12.6]
TSC1 136 (23.3%) Patients receiving surgical procedures, n (%)
TSC2 323 (55.3%) Corpus callosotomy 28 (10.8%)
PKD1 3 (0.5%) Hemispherectomy 6 (2.3%)
None identified 124 (21.2%) Resection 168 (64.9%)
VNS-related procedure 115 (44.4%)
Abbreviations: IQR = interquartile range; n = number; SD = standard devia- Number of surgical procedures received, n (%)
tion; TSC = tuberous sclerosis complex. 1 168 (64.9%)
a
Thirty-five patients with a missing date of TSC diagnosis were excluded 2 64 (24.7%)
3+ 27 (10.4%)
from the calculation of age at TSC diagnosis.
b
Time from first surgical procedure to second surgical
More than one race/ethnicity was reported for some patients. procedure (years)
c
For two patients, both TSC2 and PKD1 mutations were reported. Mean (SD) 3.0 (2.9)
Median [IQR] 2.3 [0.7–5.0]
Table 2
Abbreviations: AED = anti-epileptic drug; IQR = interquartile range; mTOR:
Fifteen most prevalent clinical features diagnosed at any time among patients
Mammalian target of rapamycin; n = number; SD = standard deviation;
with TSC and epilepsy.
TSC = tuberous sclerosis complex; VNS = vagus nerve stimulation.
Clinical feature n %
3.3. Epilepsy treatment trends over time
Cortical Tubers 1001 (90.2%)
Subependymal Nodules 971 (87.5%)
Hypomelanotic or Hypopigmented Macule 835 (75.2%) Between the years of 2000 and 2013, AEDs were the most com-
Facial Angiofibroma 686 (61.8%) monly initiated treatment among patients with TSC and epilepsy,
Developmental Delay 574 (51.7%)
constituting between 47.6% (2011) and 80.0% (2013) of initiated
Renal Angiomyolipoma 560 (50.5%)
Rhabdomyoma 456 (41.1%)
treatments (Fig. 1). Surgeries (resection, corpus callosotomy, and VNS-
Cystic Renal Lesion 427 (38.5%) related procedures) were less common during this timeframe, gen-
Shagreen Patch 391 (35.2%) erally < 20% in any year; similarly, use of special diets was low, under
Subependymal Giant Cell Astrocytoma 344 (31.0%) 10% in any year. In general, treatment initiations were fairly stable
Fibroma 285 (25.7%)
over time. The use of mTOR inhibitors first occurred in 2006; in 2013,
Ophthalmological Hamartoma 204 (18.4%)
Autism 172 (15.5%) 8.0% of patients initiated an mTOR inhibitor specifically for epilepsy.
ADHD 126 (11.4%)
Bone Condition 124 (11.2%)
4. Discussion
Abbreviations: ADHD = attention deficit/hyperactivity disorder; n = number;
TSC = tuberous sclerosis complex. This study expands upon previous analyses to assess epilepsy
treatment patterns among patients with TSC through the TSC Natural
subsequently received surgical treatments. History Database, which includes over one thousand patients with both
Among the 259 patients who received at least one surgical proce- TSC and epilepsy from clinics throughout the United States and in
dure, 64.9% had a tuber resection, 44.4% had a VNS-related procedure, Belgium. In this large cohort of patients, epilepsy was diagnosed in the
10.8% had a corpus callosotomy, and 2.3% had a hemispherectomy majority of patients during infancy, consistent with prior reports [4, 10,
(Table 3). The median age at which patients underwent their first 20, 21]. The majority of patients were prescribed multiple AEDs or
procedure was 6.2 years. Over one-third (35.1%) of patients underwent underwent multiple surgical procedures to manage epileptic seizures.
multiple surgical procedures for epilepsy, with a median of 2.3 years Of the patients prescribed AEDs, over half (64.5%) were prescribed
between the first and second surgical procedures. three or more AEDs after diagnosis of epilepsy, and of the patients who
received surgery for epilepsy, over a third had more than one proce-
dure. In addition, almost a quarter of the patients who were treated

106
J. Song et al.
100%
Proportion of patients initiating ≥1 treatment
80%
60%
40%
20%
0%
Year
n 55
Fig. 1. Epilepsy treatments over time among patients with TSC and epilepsy.
Abbreviations: N = number of patients initiating at least one treatment during the year (i.e., denominator); AED = antiepileptic drug; mTOR = mammalian target of
rapamycin; TSC = tuberous sclerosis complex; VNS = vagus nerve stimulation
with AEDs later underwent surgery.
Patients with TSC and epilepsy experience high treatment burden
relative to the general population of patients with epilepsy. The current
study observed a large proportion of patients who initiated multiple
AEDs, consistent with an earlier report among 291 patients from a
single clinic site that estimated that approximately two-thirds of the
epileptic TSC patient population are refractory [10]. This finding sug-
gests that the rate of refractory epilepsy is much higher than the pro-
portion observed in the general population of patients newly-diagnosed
with epilepsy, where over two-thirds of patients effectively manage the
condition with AEDs and become seizure-free [22]. Similarly, patients
with TSC and epilepsy progress to surgery more quickly. Among pa-
tients in our sample who received surgery, the median age at first
surgical procedure was 6.2 years, remarkably young compared to pa-
tients with other focal epilepsies, who frequently experience decades
between epilepsy diagnosis and surgeries such as temporal lobectomy
[23]. In addition, although surgical interventions have been shown to
reduce the risk of seizure occurrence in patients with focal epilepsy who
were unresponsive to AEDs [24], the benefit of surgery for epilepsy in
patients with TSC is less clear; in our sample, over 35% of patients in
the present cohort received multiple surgical procedures. Given that the
inability to achieve freedom from or reduction in seizures often results
in negative health outcomes and greater economic burden for patients
[22, 25, 26], the present findings further demonstrate a continued
unmet need for epilepsy treatments among patients with TSC.
The molecular etiology of TSC-related epilepsy may offer a target
for new therapies. TSC is caused by either familial (20%) or de novo
(80%) mutations in the TSC1 or TSC2 genes [27], which respectively
encode the widely-expressed proteins hamartin and tuberin [28, 29].
These proteins form hamartin-tuberin complexes, which regulate the
mTOR pathway via upstream inhibition of a G protein, Ras homologue
enriched in brain (Rheb) [30]; alteration of this function via TSC1 or
TSC2 mutations can give rise to potentially epileptogenic brain ha-
martomas in TSC [31, 32]. The proposed role of the mTOR pathway in
the generation of TSC tumors suggested the use of mTOR inhibitors,
such as everolimus or sirolimus, may be effective as a treatment for
TSC-related epilepsy [33, 34]. Although sirolimus is not currently ap-
proved for the treatment of epilepsy among TSC patients, everolimus is
approved in the US and Europe for the treatment of TSC-associated
partial onset seizures [16, 35].
Journal of the Neurological Sciences 391 (2018) 104–108
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
71 81 69 88 101 110 106 114 96 66 42 42 25
AED mTOR inhibitor Diet
Resection Corpus callosotomy Hemispherectomy
VNS-related procedure
The results of this study should be considered in light of its lim-
itations. First, data in the TSC Natural History Database were collected
retrospectively, and therefore information regarding TSC-related care
may not have been fully captured, particularly before the database was
established in 2006. Furthermore, additional treatments that patients
may have received outside the centers of excellence may not be fully
captured in the database. Second, the data captured in the TSC Natural
History Database may not be reflective of the overall patient population
with TSC and epilepsy. The data were collected from specialized TSC
clinics, which may serve more severely affected individuals who are
more likely to have hard-to-treat epilepsy. Finally, this study did not
attempt to directly measure or determine efficacy and adverse events of
different treatments, as these measures are not fully captured in the
current database.
5. Conclusions
This study described epilepsy treatment patterns among a large
cohort of patients from a network of sixteen clinics in the US and
Belgium who were diagnosed with TSC and epilepsy. Among the pa-
tients treated with AEDs, almost half used more than three distinct
AEDs and close to a quarter underwent a surgical procedure subsequent
to AED initiation. In addition, > 35% of patients who received epilepsy
surgery underwent more than one procedure. These findings suggest
that, despite early and aggressive treatment, many TSC patients' epi-
lepsy is refractory to current therapies. New treatment options may be
needed to reduce the number of AEDs and surgeries among patients
with TSC and epilepsy.
Disclaimer
The views expressed in this article are those of the authors and do
not necessarily reflect the opinion of the Tuberous Sclerosis Alliance or
the Tuberous Sclerosis Complex Natural History Database Consortium.
Funding sources
This work was supported by Novartis Pharmaceuticals Corporation.
107
J. Song et al.
Declaration of interest
Qayyim Said is an employee of Novartis and owns stock/stock op-
tions. Steven Sparagana, Michael Kohrman, Bruce Korf, and Darcy
Krueger are independent consultants who received consultancy fees
from Novartis. Michael Wong is an independent consultant who did not
receive consultancy fees from Novartis. Elyse Swallow, Jinlin Song,
Miranda Peeples, Mark Meiselbach, and James Signorovitch are em-
ployees of Analysis Group, Inc., which has received consulting fees from
Novartis.
Acknowledgements
The authors would like to thank Jo Anne Nakagawa, the TS
Alliance, the Pediatric Epilepsy Research Foundation, and all TSC
clinics and patients participating in the TSC Natural History Database
Consortium: Minnesota Epilepsy Group, P.A., St. Paul, MN; Texas
Scottish Rite Hospital for Children, Dallas, TX; New York University
School of Medicine, New York, NY; Massachusetts General Hospital,
Boston, MA; Children's Research Institute, Washington, DC; The
University of Chicago, Chicago, IL; UCSF Benioff Children's Hospital
Oakland, Oakland, CA; University of California Los Angeles, Los
Angeles, CA; The University of Texas Health Science Center at Houston,
Houston, TX; University of Alabama at Birmingham, Birmingham, AL;
University of Alabama at Birmingham, Birmingham, AL; Children's
Hospital Colorado, Aurora, CO; Nicklaus Children's Hospital Miami,
Miami, FL; Loma Linda University, Loma Linda, CA; UZ Brussels,
Belgium; University of Pennsylvania, Philadelphia, PA; Boston
Children's Hospital, Boston, MA; Cincinnati Children's Hospital Medical
Center, Cincinnati, OH; Washington University St. Louis, St. Louis, MO.
Medical writing assistance was provided by Shelley Batts, PhD, an
employee of Analysis Group, Inc.
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