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Amin et al. Orphanet Journal of Rare Diseases (2024) 19:89
https://doi.org/10.1186/s13023-023-02994-x Orphanet Journal of Rare
Diseases
*Correspondence:
S. Amin
sa0118@bristol.ac.uk
Full list of author information is available at the end of the article
Abstract
Background Rett syndrome (RTT) and tuberous sclerosis complex (TSC) are two rare disorders presenting with a
range of dierent epileptic seizures. Seizure management requires careful therapy selection, thereby necessitating
development of high-quality treatment guidelines. This targeted literature review (TLR) aimed to characterise country-
specic and international treatment guidelines available for pharmacological management of seizures in RTT and TSC.
Methods A TLR was performed between 25-Jan and 11-Mar 2021. Manual searches of online rare disease and
guideline databases, and websites of national heath technology assessment bodies were conducted for the
following countries: Australia, Canada, France, Germany, Israel, Italy, Japan, Spain, Switzerland, UK, and US as dened
by pre-specied eligibility criteria. Search terms were developed for each condition and translated into local
languages where appropriate. Eligible publications were dened as guidelines/guidance reporting pharmacological
management of seizures in patients with RTT and TSC. Guideline development methodology, geographical focus,
author information and treatment recommendations were extracted from guidelines. An author map was generated
using R version 3.5.1 to visualise extent of collaboration between authors.
Results 24 total guidelines were included, of which three and six contained only recommendations for RTT and TSC,
respectively (some provided recommendations for ≥ 1 condition). Guideline development processes were poorly
described (50% [12 guidelines] had unclear/absent literature review methodologies); reported methodologies were
variable, including systematic literature reviews (SLRs)/TLRs and varying levels of expert consultation. Most (83%
[20/24]) were country-specic, with guideline authors predominantly publishing in contained national groups;
four guidelines were classied as ‘International,’ linking author groups in the US, UK, Italy and France. High levels of
heterogeneity were observed in the availability of treatment recommendations across indications, with 13 and 67
recommendations found for RTT and TSC, respectively. For RTT, all treatment recommendations were positive and
sodium valproate had the highest number of positive recommendations (Khwaja, Sahin (2011) Curr Opin Pediatr
23(6):633–9). All TSC treatments (21 medications) received either exclusively negative (National Organization for Rare
Treatment guidelines for rare, early-onset
conditions associated with epileptic seizures:
a literature review on Rett syndrome
and tuberous sclerosis complex
S.Amin1* , B.Ruban-Fell2, I.Newell2, J.Evans3, K.Vyas4, C.Nortvedt4 and R. F.Chin5,6
Page 2 of 14Amin et al. Orphanet Journal of Rare Diseases (2024) 19:89
Background
Rett syndrome (RTT) and tuberous sclerosis complex
(TSC) are rare, single-gene disorders that can present
with autism, epilepsy and intellectual disability [1–3].
RTT is a progressive, developmental impairment disor-
der that almost exclusively affects females, with symp-
toms varying dramatically between patients [1]. TSC
is a multi-system disorder characterised by formation
of benign tumours in several organs and is associated
with developmental delay and cognitive dysfunction [2].
Despite these distinct aetiologies, both conditions are
known to cause epileptic treatment-resistant seizures
from an early age [4], with a range of different seizure
types observed in both cases [5, 6]. Many individuals
with TSC initially manifest infantile spasms, although
most other seizure types, including both focal and gen-
eralised, have also been associated with TSC [2]. Age
of onset of epilepsy in RTT is typically later than TSC,
with a mean age of 5 years [7], compared to < 2 years in
TSC [8], with a cumulative risk of developing epilepsy of
approximately 90% over the lifespan. e occurrence and
remission of these seizures are highly heterogeneous [9],
and it is very common for children with RTT to experi-
ence more than one seizure type, thereby complicating
treatment decision-making [10]. In addition to epilepsy,
severe breathing disturbances and non-epileptic events
such as non-epileptic myoclonic jerks are also frequently
present [11, 12].
e management of seizures in RTT and TSC is an
important aspect of the overall management strategy of
these conditions [7, 13–17]. erapies must be chosen
carefully to optimise seizure control, to reduce the risk
of preventable injuries and complications associated with
seizures and to improve patient quality of life (QoL) [18].
Early control of seizures is especially important in TSC
as it is thought to prevent subsequent developmental
epileptic encephalopathy and to reduce cognitive behav-
ioural consequences [19, 20]. Pharmacological manage-
ment with long-term anti-seizure medications (ASM)
remains the primary seizure treatment for these disor-
ders, but can be associated with significant side effects [2,
21–24]. Furthermore, there is a general lack of compara-
tive studies examining the efficacy and safety of different
ASMs used in monotherapy or combination treatment
for these disorders [5, 25], and it is known that the effi-
cacy of different ASMs in controlling seizures in RTT and
TSC varies among individuals [5, 6, 26, 27]. Alongside
medical treatments, non-pharmacological management
of seizures, including ketogenic diets and vagus nerve
stimulation may also be used in RTT [23], while in TSC,
epilepsy surgery can be used [26]. Mammalian target of
rapamycin (mTOR) inhibitors have also been highlighted
as potential pharmacological treatments for TSC [27].
Given that seizures in RTT and TSC are often resistant
to treatment (in that they are not adequately controlled
despite the use of two or more appropriately chosen
ASMs), treatment of these conditions often requires a
combination of different medications [5, 6]. Treatment
choice is therefore carefully considered and informed by
a number of factors, including seizure type, the affected
individual’s age, the severity of symptoms (as well as spe-
cific organ system involvement for TSC), presence or
absence of learning disabilities in TSC and other comor-
bidities such as kidney angiomyolipomas [1, 2].
e selection of appropriate ASMs to manage the sei-
zures attributed to these complex disorders is both chal-
lenging yet potentially highly beneficial for patients, and
the development of appropriate treatment guidelines, in
both national and international contexts, helps to provide
clinicians with a clear and optimised management strat-
egy that can be shared between specialists [28]. More-
over, these treatment recommendations often inform
health technology assessment (HTA), regulatory body
guidance, and payer coverage for treatments in some
geographies, and thereby influence treatment licensing
whilst affecting patients’ access to novel treatments [29,
30].
However, due to a lack of evidence within the literature,
treatment guidelines for rare diseases are frequently dif-
ficult to find and of varying quality, [31, 32] despite their
recognised contribution to improvements in quality of
patient care [33]. Furthermore, as rare conditions are
encountered infrequently by clinicians, rigorous treat-
ment guidelines are particularly important to guide the
management of seizures and co-morbidities in RTT and
TSC [31]. Even if treatment guidelines are available, often
they are not specific to the treatment of seizures within
the rare condition in question, and may either provide
Disorders (2019)) or positive (Chu-Shore et al. (2010) Epilepsia 51(7):1236–41) recommendations; vigabatrin received
the highest number of positive recommendations (Kaur, Christodoulou (2019)).
Conclusions This review highlights the need for the development of international high-quality and comprehensive
consensus-based guidance for the management of seizures with pharmacological therapy in RTT and TSC.
Trial registration Not applicable.
Keywords Seizures, Guidelines, Treatment, Rett syndrome, Tuberous sclerosis complex, Literature review, Rare
diseases
Page 3 of 14Amin et al. Orphanet Journal of Rare Diseases (2024) 19:89
guidance on the condition in general with a brief descrip-
tion of managing seizures, or conversely, may focus on
seizure management in a wide range of conditions. A
clear demand for robust, treatment guidelines has been
highlighted in a user satisfaction survey undertaken by
the Orphanet website (an online initiative which aims
to provide high-quality information on rare diseases). In
this survey, respondents reported interest in both having
access to more clinical guidelines and review articles than
were currently available and an expanded availability of
resources from a wider geographical range [34].
Clinicians stand to benefit from the pooled expertise
and evidence shared through author collaborations based
on methods of robust evidence generation, such as sys-
tematic literature reviews (SLRs) and rigorous forms of
expert consensus. However, national and international
collaboration between guidelines developers is needed to
develop high-quality recommendations and avoid dupli-
cation of effort [35, 36].
is targeted literature review (TLR) aimed to provide
a multinational overview of available treatment guide-
lines for the pharmacological management of seizures in
RTT and TSC, and their treatment recommendations. A
TLR was chosen in order to search less standard sources
than those typically seen in a systematic review in light of
the fact that not all guidelines are published in traditional
medical journals. More specifically, we aimed to:
1. Investigate the availability of region/country-specic
and international treatment guidelines for RTT and
TSC;
2. Describe guideline development methodologies;
3. Evaluate the extent of author collaboration through
the development of an author network using
included guidelines; and
4. Report the frequency of existing positive and
negative treatment recommendations for RTT and
TSC.
Methods
Search strategy
A TLR was performed between 25th January and 11th
March 2021 to identify relevant treatment guidelines.
e dates of searches and strategies used for each infor-
mation source, which have been previously reported [35],
were adapted for RTT and TSC and are summarised in
Table S1, Additional File 1. Briefly, the following online
information sources were manually searched in accor-
dance with a pre-specified protocol: Google, Guide-
line Central, Orphanet, National Organisation for Rare
Disorders (NORD), American Academy of Neurology
(AAN), American Epilepsy Society (AES) and Inter-
national League Against Epilepsy (ILAE). In addition,
national HTA body websites for the following countries
were also searched: Australia (Pharmaceutical Benefits
Scheme), Canada (Canadian Agency for Drugs and Tech-
nologies in Health), France (Haute Autorité de Santé),
Germany (Gemeinsamer Bundesausschuss), Israel (State
of Israel – Ministry of Health), Italy (Agenzia Italiana del
Farmaco [AIFA]), Japan (Ministry of Health, Labour and
Welfare), Spain (Ministerio de Sanidad, Consumo y Bien-
estar Social), Switzerland (Bundesamt für Gesundheit),
and United Kingdom (UK) (National Institute for Health
and Care Excellence [NICE]. When searching the data-
bases, search terms suitable for the database functionality
were used, specific database features were accounted for,
searches were filtered for guidelines where possible, and
combinations of free-text and terms for each of the indi-
cations of interest were used as search terms.
Review process
Criteria defined using a PICOS (Population, Interven-
tion, Comparators, Outcomes, Study design) approach
were used to screen identified records for eligibility and
are presented in Table1. ese criteria were defined a
priori in the review protocol, in order to reduce bias in
the review and selection of records by reviewers. e
review process has been previously reported [35]. In
brief, guidelines or guidance publications were deemed
eligible for inclusion if they reported on the pharmaco-
logical management of seizures in patients with RTT or
TSC in the countries of interest.
Publications which were informed by rigorous meth-
ods, had multiple authors or explicitly indicated that
certain treatments were ‘recommended’ were defined as
guidelines. e review also captured technology appraisal
guidance developed following HTAs, as well as guidelines
produced by HTA bodies. e review was conducted
in accordance with a pre-specified protocol in order to
ensure a comprehensive review of all relevant sources
and to reduce sources of bias in screening and extraction.
Search results were screened, using the pre-specified
protocol, by a single reviewer, except where applicabil-
ity of the search criteria was unclear, in which case the
record was assessed by a second reviewer.
Data extraction and analyses
A pre-defined extraction grid was used to extract rel-
evant data from the guidelines that were included in this
review, as described previously [35]. In brief, the follow-
ing information was extracted: author names and affili-
ations; publication date and planned revision date; the
methodology of guideline development; population(s)
addressed; pharmacological treatment recommenda-
tions; references to other treatment recommendations.
Eligible publications were classified as “International” if
they were developed either for multiple countries or did
Page 4 of 14Amin et al. Orphanet Journal of Rare Diseases (2024) 19:89
not specify to which countries they pertained. If neither
of these criteria were fulfilled, regional author affiliations
were used to determine nationality of the guideline.
e country-specificity of identified guidelines, meth-
odology of guideline development, references made to
treatment recommendations in other sources and the
cross-referencing of treatment recommendations made
within other guidelines were analysed descriptively in
Microsoft Excel®.
e extent of collaboration between authors who had
authored > 1 guideline both at a national and interna-
tional level was measured by mapping and visualising the
authors involved in the development of each guideline
into a network. is visualisation was developed using
the programming language R version 3.5.1.
An individual ASM that was recommended for use in
a specific indication, irrespective of the line of treatment
or whether the treatment was adjunctive was defined as a
positive recommendation. An individual ASM treatment
that was highlighted as a potential option by a guideline
but whose use was recommended against (for any rea-
son) in a specific indication, irrespective of the line of
treatment or whether the treatment was adjunctive, was
considered a negative recommendation.
Results
Characteristics of included guidelines
A total of 24 eligible records with publication dates rang-
ing between November 2005 and January 2021 were
identified following removal of duplicate results (Fig.1;
Table S2, Additional File 1). Most guidelines were coun-
try-specific (i.e. recommendations were intended for
patients in a specific country), with only four guidelines
(17%) considered to be “International” (Fig. 2). Guide-
lines were identified in 7/11 (64%) of regions that were
pre-defined in the review criteria (‘International’ guid-
ance was included as one region in this case). Other-
wise, the individual countries with the highest number
of identified guidelines were the UK (17% [4/24]), Spain
(17% [4/24]), Italy (13% [3/24]) and Japan (13% [3/24]).
No guidelines were identified for use in Israel, Switzer-
land, Germany or Australia. Of the guidelines identified,
five were specifically developed for regions within one
of the countries of interest (21% [5/24]): Two Canadian
guidelines were developed specifically for the provinces
of British Columbia [37] and Ontario [38], one UK guide-
line was created for use in Scotland [39], one Italian
guideline was developed for the region of Tuscany [40]
and one of the four Spanish guidelines identified was cre-
ated specifically for the region of Andalusia [41]. None of
the US guidelines identified (8% [2/24]) were for use at
the state level.
Evidence base and methodology for guideline
development
Among the 24 identified guidelines, 10/24 (42%) did not
specify whether guideline development was informed
using literature reviews. Notably, none of the guidelines
for RTT detailed a guideline development methodology.
Additionally, 4/24 guidelines (17%) explicitly did not use
Table 1 Eligibility criteria
Modied PICOS domain Inclusion criteria Exclusion criteria
Population Patients with the following epileptic conditions:
• Rett syndrome
• Tuberous sclerosis complex
Conditions other than those
listed
Intervention Any None
Outcomes The document must have discussed the management of the conditions of inter-
est in terms of pharmacological treatment pathways for routine seizure control
• Documents that did not discuss
the management in terms of
pharmacological treatment
pathways
• Emergency medication and
surgical guidelines
Publication type Guidelines or guidance documents Publications other than
guidelines
Other considerations Specically produced for use in:
• EU5 countries (UK, Germany, Spain, Italy, France)
• Japan
• Australia
• Switzerland
• Israel
• US
• Canada
International guidelines (i.e. guidelines produced for multiple countries that
included or potentially included the countries of interest, or guidelines that did
not specify which countries they pertained to)
Produced specically for use
in countries that were not of
interest
PICOS, Populatio n, Intervention, Comp arators, Outcomes, Stu dy design; UK, United Ki ngdom; US, United States
Page 5 of 14Amin et al. Orphanet Journal of Rare Diseases (2024) 19:89
a literature review to develop their recommendations. Of
the remaining guidance documents, 7/21 involved litera-
ture searches (2/24 [8%] SLR; 5/24 [21%] TLR); of these,
3/24 (12%) used a combination of both methods (Fig.3).
No details regarding use of expert consultation to develop
recommendations were reported by 11/24 guidelines
(46%). A Delphi panel (a structured and iterative survey
technique used to gather consensus on specific issues
from a group of experts) was used to inform the develop-
ment of 1/24 (4%) guidelines, while 6/24 (25%) guidelines
were based on formal consensus group exercises. Other
forms of expert consultation, including working groups
or targeted expert interviews, were used to develop the
remaining five guidelines (21%; Fig.4). While the use of
a combined development approach consisting of a litera-
ture review and expert consultation was reported by 9/24
(38%) of guidelines, none explicitly utilised the combina-
tion of an SLR and a Delphi panel.
e included guidelines mainly cited other treatment
guidelines for TSC and RTT (31/65 citations; 48%) or
Fig. 2 Geographies of identied guidelines. *No guidelines were identied for use in Israel, Switzerland, Germany or Australia. The geography of guideline
use refers to the country for which the guidance was specically developed. UK, United Kingdom; US, United States
Fig. 1 Literature review owchart. *Online information sources included: Guideline Central, National Organization for Rare Disorders (NORD), American
Academy of Neurology (AAN), American Epilepsy Society (AES), International League Against Epilepsy (ILAE), Orphanet, Google, National Institute for
Health and Care Excellence (NICE), Pharmaceutical Benets Scheme (PBS), Canadian Agency for Drugs and Technologies in Health (CADTH), Ministerio de
Sanidad, Consumo y Bienestar Social (MSCBS), Agenzia Italiana del Farmaco (AIFA), Haute Autorité de Santé (HAS), Gemeinsamer Bundesausschuss (G-BA),
Bundesamt für Gesundheit (BAG), State of Israel – Ministry of Health, Ministry of Health, Labour and Welfare (MHLW)
Page 6 of 14Amin et al. Orphanet Journal of Rare Diseases (2024) 19:89
other compiled literature sources such as literature
reviews (19/65; 29%). e referenced literature reviews
largely consisted of SLRs included in the Cochrane
Database of Systematic Reviews (13/19; Fig. 5). Regu-
latory body recommendations comprised 13/65 of the
citations; of these, two were made to HTA body recom-
mendations. e UK’s NICE guidance on the diagno-
sis and management of epilepsies (CG137) [42], an SLR
from the Cochrane Database of Systematic Reviews on
the treatment of infantile spasms [43] and an SLR from
the Cochrane Database of Systematic Reviews on the
treatment of Lennox-Gastaut syndrome were the most
frequently referenced documents (five, five and six times,
respectively) [44].
Extent of author collaboration
A visualisation of the network of authors involved in
developing each of the guidelines identified in this study
(including those developed for both RTT and TSC) was
developed to determine the extent of national and inter-
national collaboration. Using this author map, connec-
tions were identified between authors involved in the
development of international treatment guidelines and
US, UK, French and Italian guideline author groups
Fig. 4 Types of expert consultation performed to inform guideline development. ‘None’ refers to guidelines in which expert consultation was explicitly
not used; ‘Other’ refers to working groups or targeted expert interviews. NR, not reported
Fig. 3 Types of literature review performed to inform guideline development. ‘None’ refers to guidelines in which a literature review was explicitly not
used. NR, not reported; SLR, systematic literature review; TLR, targeted literature review
Page 7 of 14Amin et al. Orphanet Journal of Rare Diseases (2024) 19:89
(Fig.6). Other regional guidelines were developed within
contained national groups.
Treatment recommendations for Rett syndrome
Only three guidelines were identified that made recom-
mendations for the symptomatic treatment of seizures in
RTT, and among these, a total of 13 individual treatment
recommendations were made (irrespective of the line of
treatment; see Fig.7), all of which were positive. Overall,
seven different medications were included in treatment
recommendations for RTT, of which sodium valproate
had the highest number of positive recommendations (3;
Fig.7). No recommendations for a specific line of treat-
ment were made for use in RTT; however, two recom-
mendations for specific seizure types were made, both of
which were positive recommendations for the treatment
of myoclonic seizures (one for levetiracetam and one for
topiramate).
Treatment recommendations for tuberous sclerosis
complex
A total of 67 individual treatment recommendations,
irrespective of the line of treatment, were made within
the 22 guidelines identified for TSC (Fig. 8). e vast
majority of treatment recommendations for TSC were
positive (65/67 [97%]). Vigabatrin had the highest num-
ber of positive recommendations (21/65 [32%]) and was
recommended for infantile spasms. e other medica-
tions which received a high number of positive recom-
mendations were adrenocorticotropic hormone (ACTH;
10), topiramate [6], prednisolone [4] and sodium val-
proate [4]. Cannabidiol and sirolimus both received one
negative recommendation each based on a lack of cur-
rent evidence regarding their use.
e vast majority (65/67) of treatment recommenda-
tions for TSC were positive. Of these, 65% (42/65) were
treatment line-specific (23 for first-line, 19 for second-
line; Table S3, Additional File 1). e highest number of
positive recommendations specific to first-line treatment
was received by vigabatrin [15], while ACTH received the
highest number of positive recommendations specific to
second-line treatments [6]. ere were no negative rec-
ommendations specific to treatment lines made for TSC.
Additionally, 90% of the total treatment recommenda-
tions (60/67) for TSC were specific to seizure type. Of
these, 59 were positive recommendations and the major-
ity (46; including 17 recommendations for vigabatrin and
10 for ACTH) were related to infantile spasms. Positive
seizure type-specific recommendations were also made
for focal seizures [9] and treatment-refractory [2] seizure
types. One negative seizure type-specific recommen-
dation was made for sirolimus in relation to treatment-
refractory TSC.
Discussion
is review provides a geographically diverse over-
view of available guidelines and their treatment recom-
mendations for seizure management in RTT and TSC,
with guidance documents from eleven countries across
Europe, North America and Asia Pacific. In summary,
the review identified a paucity of international guidelines;
a limited use of ‘gold standard’ methodologies used in
guideline development; a lack of international collabora-
tion between author groups; and a low number of overall
treatment recommendations for RTT.
Fig. 5 Guideline cross-referencing to other treatment guidelines and regulatory/HTA recommendations. Cross-referencing refers to the number of dif-
ferent treatment guidelines, regulatory body recommendations, HTA body recommendations or other references that were cited within the guidelines
identied in this study, either in the body of the guideline text or in accompanying reference lists. ’Other’ references included a Cochrane systematic
literature review, and informational websites about RTT or TSC. HTA, health technology assessment; RTT, Rett syndrome; TSC, Tuberous sclerosis complex
Page 8 of 14Amin et al. Orphanet Journal of Rare Diseases (2024) 19:89
Interestingly, the majority of guidelines were country-
specific (four guidelines were classified as ‘International’).
In addition, a reasonable proportion of the guidelines
were specifically developed for a particular region within
a given country, which may reflect differing geographical
medication availabilities. However, despite this find-
ing, there was no major divergence in recommenda-
tions between countries, suggesting a general consensus
amongst guideline developers across the globe.
Fig. 7 Treatment recommendations for Rett syndrome. N = 13 (13 positive and 0 negative recommendations) from three guidelines. Positive recommen-
dation: use of an individual ASM treatment that was recommended for use in a specic indication, irrespective of the line of treatment (e.g. rst line) or
whether the treatment was adjunctive; Negative recommendation: an individual ASM treatment that was highlighted as a potential option by a guideline
but not recommended by a guideline for use (for any reason) in a specic indication, irrespective of the line of treatment or whether the treatment was
adjunctive
Fig. 6 Map of collaboration between the author groups of included guidelines. Each individual circle represents one author of a guideline. Each ‘cluster’
represents the group of authors that developed one guideline. Each cluster is labelled with the names of its respective rst author(s). Guidelines which
share one or more authors between them are connected by grey lines, with single circles between guideline clusters representing the individuals who
authored both guidelines in question. Guidelines were classied as “International” if they were developed either for multiple countries or did not specify
to which countries they pertained. Guidelines for which author names were not reported have not been included in this gure. NICE, National Institute
for Health and Clinical Excellence; SIGN, Scottish Intercollegiate Guidelines Network
Page 9 of 14Amin et al. Orphanet Journal of Rare Diseases (2024) 19:89
SLRs are considered the ‘gold standard’ for evidence
synthesis, and the Delphi methodology is recommended
for use in healthcare settings as a reliable means of
determining consensus for defined clinical problems
[45–47]. Despite this, this review identified a lack of
guideline development approaches combining these two
approaches in addition to a wide variety of methodolo-
gies used in general. Fewer than 50% of the guidelines
specified that their development process was informed
by literature reviews (42% [10/24]), and only half of the
guidelines were developed through expert consultation
(50% [12/24]), which highlights a need for further clarity
and standardisation in the reporting and development of
additional guidance using rigorous methodological pro-
cesses. In addition, available tools to improve guideline
reporting, such as the AGREE checklist [48], could be
utilised more frequently to align and improve guideline
development practice for these rare diseases [32].
Notably, detail on the methodology of guideline devel-
opment was entirely absent for the three RTT guidelines,
which is of particular concern given the limited literature
available for treating this rare disease [49]. Conversely,
most TSC guidelines were developed using a SLR or TLR,
in combination with ‘other’ forms of expert consultation
(such as working groups or targeted expert interviews),
as opposed to the preferred combination of an SLR and
Delphi panel. is may reflect the relatively large time
and resource burden associated with these study types,
problems which are likely to be more pronounced in the
context of rare diseases [50].
Links between author groups who published the four
International guidelines (Curatolo et al., Krueger and
Northrup, Wheless et al. and Wilmshurst et al.) [24, 51–
53] and author groups who published guidelines from the
US, UK, Italy and France were identified. is suggests
a reasonably well-defined network for TSC between the
US and Europe, whilst highlighting the need for outreach
and inclusion of author groups outside these regions, as
international guidelines written solely by authors in high-
income countries are unlikely to be suitable for most cli-
nicians and patients around the world. Further, only one
guideline (Bahi-Buisson et al.) [54] within this author
collaboration network was for RTT. Despite the general
consensus observed among the included guidelines, addi-
tional communication between national expert groups
by pooling clinical expertise, e.g. via supra-national bod-
ies, could potentially help to address the current lack of
international guidelines for these disorders, particularly
for RTT [55]. Similarly, further international and national
guidance could benefit regions where no national guide-
lines are available to help inform the development of
local guidelines.
is review highlighted the relatively limited number
of treatment guidelines for RTT and TSC, which may
reflect the critical need for treatments and the difficulty
of developing treatment guidelines for rare diseases in
general, due to low disease prevalence and patient popu-
lation heterogeneity [56–58]. Consequently, there is an
urgent need to develop additional up-to-date treatment
guidelines for both RTT and TSC. e particularly low
number of available treatment guidelines for RTT may
Fig. 8 Treatment recommendations for tuberous sclerosis complex. N=67 (65 positive and two negative treatment recommendations) from 22 guide-
lines. Positive recommendation: use of an individual ASM treatment that was recommended for use in a specic indication, irrespective of the line of
treatment (e.g. rst line) or whether the treatment was adjunctive; Negative recommendation: an individual ASM treatment that was highlighted as a
potential option by a guideline but not recommended by a guideline for use (for any reason) in a specic indication, irrespective of the line of treatment
or whether the treatment was adjunctive. ACTH, adrenocorticotropic hormone
Page 10 of 14Amin et al. Orphanet Journal of Rare Diseases (2024) 19:89
reflect the difficulty in identifying the most appropriate
ASM treatment according to seizure type and a patient’s
individual needs [5]. is issue is compounded by a lack
of comparative studies and the large number of different
ASMs that must be evaluated, which is highlighted by the
conflicting results found in previously conducted retro-
spective analyses.
For TSC, the most positively recommended treatment
in the review reported here (vigabatrin) aligned with the
ASM treatment recommendations made by the NICE
guidance CG137 for infantile spasms [59]. However,
there was no specific guidance in this document for the
use of ASMs in RTT [59]. Similarly, the low number of
available treatment guidelines for TSC may reflect the
complexity of seizure management in this disorder, given
that the efficacy of different ASMs can vary in different
individuals and subsequently a combination of different
medications is often required [2]. However, patients with
TSC may have access to alternative treatment options to
control seizures, such as surgery and vagal nerve stimu-
lation [2]. Notably, there was a lack of negative recom-
mendations for both of these disorders; only two such
recommendations were identified (one each for the use
of cannabidiol and sirolimus in TSC), which were due to
lack of current evidence rather than a lack of efficacy.
e lack of recommendations for specific lines of treat-
ment for RTT suggests a need to provide further clar-
ity on the most suitable ASM regimen for patients with
this disorder, and further guidance on which treatments
should be prioritised or preferred over others. is find-
ing may be due to a paucity of randomised controlled tri-
als, the high cost of developing rare disease medicines,
and the ethical challenges of conducting such studies on
the developing brain [60]. e five most frequently rec-
ommended ASMs for RTT in this review are consistent
with findings from other studies [7, 61–63]. However, as
only a small number of patients have been included in
reports addressing the effectiveness of newer ASMs, such
as lamotrigine, levetiracetam, and topiramate (combined
with the fact that new ASMs are likely to be developed)
the number of available treatment recommendations for
these medications may increase as further research is
conducted [5].
Other key areas in which guidance was not identified
included management of Sudden Unexpected Death in
Epilepsy (SUDEP). Children with RTT in particular are at
higher risk of sudden death, due to developmental delay,
generalised seizures and use of polypharmacy in treating
the condition [64]. Despite this, we did not find any dis-
cussion or guidance around SUDEP in this review, which
suggests that further guidance is needed on this topic.
e high proportion of treatment recommendations
for TSC that were seizure type-specific (88% [59/67]) may
reflect the varied seizure types that can be experienced
by patients with this disorder, such as infantile spasms,
which often require different treatment approaches [65].
In contrast, only 15% (2/13) of recommendations for
RTT were seizure type-specific (these were both myo-
clonic), despite the fact that generalised tonic-clonic and
complex partial seizures are considered to be the most
common seizure type in patients with RTT.
Notably, vigabatrin received exclusively positive treat-
ment recommendations in TSC, and a comparatively
large proportion of these were treatment line- and seizure
type-specific. However, the consensus identified around
positive recommendation for vigabatrin in TSC, despite
known safety concerns (such as drowsiness, fatigue, nau-
sea, behaviour, mood changes, and visual field defects in
some adults), highlights an unmet need with regard to
patient QoL [66].
Despite the approval of the mTOR inhibitor, everoli-
mus, as adjunctive therapy for TSC-associated partial
onset seizures, this medication received a low number of
recommendations in this review [67]. is is most likely
due to the fact that guidelines can take time to develop
following marketing authorisation of a medication. How-
ever, additional positive treatment recommendations
may be expected for everolimus managing seizures, as a
phase III, randomised, double-blind, placebo-controlled
study in 2016 has shown that adjunctive treatment signif-
icantly reduces seizure frequency with a tolerable safety
profile compared with placebo in patients with TSC and
treatment-resistant seizures [68]. Indeed, the 2021 guide-
lines from the International TSC Consensus Group,
which were recently updated from the 2013 guidelines
included in this review, recommend both everolimus
and cannabidiol as adjunctive therapies for non-infantile
seizures in TSC. Moreover, these recommendations are
based on Category I (e.g. defined as highest quality) evi-
dence [69].
In addition, many of the treatments that were widely
recommended in this review have no specific licence
for RTT or TSC. For example, the ASMs that received
positive recommendations for RTT are either licensed
for treating all forms of epilepsy (e.g. sodium valproate
[70]) or for specific seizure types (e.g. carbamazepine,
[71] lamotrigine [72], topiramate [73], and levetiracetam
[74]), rather than specifically for treating seizures in this
disorder. For sodium valproate specifically, safety con-
cerns have been published by NICE and the AIFA since
development of the guidelines identified in this review
[75, 76], (specifically for girls and young women of child-
bearing age around the risk of polycystic ovarian syn-
drome), suggesting clinicians are moving away from use
of this treatment. In TSC, apart from everolimus and an
oral solution of cannabidiol, which have been approved
by the Food and Drug Administration (FDA) [77, 78]
and the European Medicines Agency (EMA) [79, 80]
Page 11 of 14Amin et al. Orphanet Journal of Rare Diseases (2024) 19:89
as adjunctive treatments for seizures, other ASMs that
received a high number of positive recommendations
for TSC are licensed more generally for specific seizure
types, but not for this specific indication (e.g. vigabatrin,
[66] topiramate [73], and carbamazepine [71]).
Some limitations were identified as a result of the tar-
geted nature of the review. A single reviewer assessed
the eligibility of all records; when the applicability of
the inclusion criteria was unclear, a second independent
reviewer adjudicated the decision. Use of an additional
reviewer when assessing eligibility may have helped
to reduce bias and inaccurate application of inclu-
sion/exclusion criteria [81]. Additionally, this literature
review searched sources not typically used in a system-
atic review, including those found using Google, medical
society and guideline developer websites. e decision
to focus on these sources minimised the risk of missing
indexing local guidelines, given that not all guidelines are
published in traditional medical journals or in the Eng-
lish language. Despite these sources being less standard
for a literature review, they returned a large number of
specific records and provided a multinational overview of
the available guidelines and their treatment recommen-
dations in the absence of previously conducted analyses.
is review further aimed to report on guidance docu-
ments from a broad sample of countries likely to be influ-
ential in the development of treatment guidelines. Due to
focus of this review on Australia, Canada, France, Ger-
many, Israel, Italy, Japan, Spain, Switzerland, the UK and
the US only, the results may not fully represent the inter-
national landscape of treatment guidelines for RTT and
TSC.
Another limitation of the review was that additional
detail on ASM efficacy by patient age group was not
captured, which previous research has shown to be rel-
evant in the treatment of RTT; sodium valproate and
carbamazepine were effective in patients who presented
seizures within the typical age range (4–5 years), while
lamotrigine (LTG) was effective for patients in whom epi-
lepsy started later [16]. In addition, the time period of the
review meant that treatment guidelines published after
March 2021 were not captured. For example, further rec-
ommendations in Rett Syndrome have been published,
such as the Rett Syndrome Health Checklist, published
in 2021, by the patient advocacy and research organisa-
tion Reverse Rett [82]. e treatment recommendations
identified in this review should therefore be interpreted
in the context and date that they were made (all identified
papers were published between December 2005 – Janu-
ary 2021), as new research and medication approvals may
necessitate updates to treatment guidelines. Additional
reviews could also be conducted to investigate the wider
management of these disorders, including emergency
treatment of seizures and surgical interventions for TSC.
Conclusion
is review highlights the need for the development of
further international, high-quality and comprehensive
consensus-based guidance, influenced by a more diverse
range of geographical regions, for the management of sei-
zures with pharmacological therapy in RTT and TSC. In
addition, the lack of treatment line-specific and seizure
type-specific treatment recommendations for RTT high-
lights an urgent need for further guidance on selecting an
appropriate ASM regimen for this disorder to optimise
the management of seizures.
Supplementary Information
The online version contains supplementary material available at https://doi.
org/10.1186/s13023-023-02994-x.
Additional le 1: Supplementary tables
Acknowledgements
The authors would like to acknowledge Carolyn Walsh, PhD, and Eleanor
Thurtle, MChem, Costello Medical for medical writing support and publication
coordination. This study was funded by GW Pharmaceuticals, Cambridge, UK.
Authors contributions
Substantial contributions to study conception and design: BRF, IN, JE, KV;
substantial contributions to analysis and interpretation of the data: RC, BRF,
IN, JE, KV, CN, SA; drafting the article or revising it critically for important
intellectual content: SA, BRF, IN, JE, KV, CN, RC; nal approval of the version of
the article to be published: SA, BRF, IN, JE, KV, CN, RC.
Funding
This study was sponsored by GW Global Services (International) Ltd.
Support for third-party writing assistance for this article, provided by Eleanor
Thurtle, MChem, Costello Medical, UK, was funded by GW Global Services
(International) Ltd in accordance with Good Publication Practice (GPP3)
guidelines (http://www.ismpp.org/gpp3).
Data availability
The data supporting the conclusions of this article are included within the
article and its additional les.
Declarations
Ethics approval and consent to participate
Not applicable to this manuscript.
Consent for publication
Not applicable to this manuscript.
Competing interests
This study was funded by GW Global Services (International) Ltd. Editorial
and medical writing services were provided by Costello Medical. S. Amin,
has provided consultancy and speaker services, and has participated in
events and studies, for GW Global Services (International) Ltd; Medtronic
Limited, Boston Scientic, Novartis, PTC therapeutics and Desitin; I. Newell,
employee of Costello Medical; B. Ruban-Fell, employee of Costello Medical;
J. Evans, employee of Costello Medical; K. Vyas, employee of GW Global
Services (International) Ltd; C. Nortvedt, employee of GW Global Services
(International) Ltd; R.F.M. Chin, has provided consultancy and speaker
services, and has participated in events and studies, for GW Global Services
(International) Ltd, Eisai, Zogenix, Neopharm Group and The Rize Medical
Cannabis and Life Sciences UCITS ETF.
Page 12 of 14Amin et al. Orphanet Journal of Rare Diseases (2024) 19:89
Author details
1Bristol Royal Hospital for Children, Research and Education Centre, Upper
Maudlin St, Bristol BS2 8AE, UK
2Costello Medical, London, UK
3Costello Medical, Cambridge, UK
4GW Pharmaceuticals, London, UK
5Royal Hospital for Children and Young People, Edinburgh, UK
6Muir Maxwell Epilepsy Centre, Centre for Clinical Brain Sciences,
Edinburgh, UK
Received: 23 February 2022 / Accepted: 13 December 2023
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