Received: 12 May 2020 

|
  Revised: 17 June 2020 
|  Accepted: 19 June 2020

DOI: 10.1111/epi.16610

FULL -LENGTH ORIGINAL RESEARCH

A pragmatic algorithm to select appropriate antiseizure

medications in patients with epilepsy

Ali A. Asadi-Pooya1,2   | Sándor Beniczky3,4   | Guido Rubboli5,6   |

Michael R. Sperling2   | Stefan Rampp7,8   | Emilio Perucca9,10
1
Epilepsy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
2
Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA
3
Department of Clinical Neurophysiology, Danish Epilepsy Centre (member of the ERN EpiCARE), Dianalund, Denmark
4
Department of Clinical Medicine, Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus University, Aarhus, Denmark
5
Department of Neurology, Danish Epilepsy Centre (member of the ERN EpiCARE), Dianalund, Denmark
6
University of Copenhagen, Copenhagen, Denmark
7
Department of Neurosurgery, University Hospital Erlangen, Erlangen, Germany
8
Department of Neurosurgery, University Hospital Halle, Halle, Germany
9
Division of Clinical and Experimental Pharmacology, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
10
Clinical Trial Center, IRCCS Mondino Foundation (member of the ERN EpiCARE), Pavia, Italy

Correspondence
Ali A. Asadi-Pooya, Epilepsy Research
Center, Shiraz University of Medical
Sciences, Shiraz, Iran.
Email: aliasadipooya@yahoo.com
Funding information
The development of the algorithm was
supported by the Filadelfia Research
Foundation (Denmark). The study sponsors
had no role in the study design, the
collection, analysis, interpretation of data,
writing of the report, and the decision
to submit the paper for publication. The
corresponding author had full access to
all of the study data, and he had the final
responsibility for the decision to submit the
report for publication.
Abstract
Objective: Antiseizure medications (ASMs) are the first-line treatment for epilepsy.
Many ASMs are available; this offers the opportunity to improve therapy by tailoring
it to individual characteristics, but also increases the possibility of healthcare profes-
sionals making inappropriate treatment choices. To assist healthcare professionals,
we developed a pragmatic algorithm aimed at facilitating medication selection for
individuals whose epilepsy begins at age 10 years and older.
Methods: Utilizing available evidence and a Delphi panel−based consensus pro-
cess, a group of epilepsy experts developed an algorithm for selection of ASMs,
depending on the seizure type(s) and the presence of relevant clinical variables (age,
gender, comorbidities, and comedications). The algorithm was implemented into a
web-based application that was tested and improved in an iterative process.
Results: The algorithm categorizes ASMs deemed to be appropriate for each seizure
type or combination of seizure types into three groups, with group 1 ASMs consid-
ered preferred, group 2 considered second line, and group 3 considered third line.
Depending on the presence of relevant clinical variables, the ranking of individual
ASMs is adjusted in the prioritization scheme to tailor recommendations to the char-
acteristics of the individual. The algorithm is available on a web-based application
at: https://epipi​ck.org/#/.

© 2020 International League Against Epilepsy

Epilepsia. 2020;00:1–10.  |
wileyonlinelibrary.com/journal/epi     1
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2      ASADI-POOYA et al.

Significance: The proposed algorithm is user-friendly, requires less than 2 minutes

to complete, and provides the user with a range of appropriate treatment options from
which to choose. This should facilitate its broad utilization and contribute to improve
epilepsy management for healthcare providers who desire advice, particularly those
who lack special expertise in the field.

KEYWORDS
algorithm, drug, epilepsy, seizure, treatment

1  |   IN TRO D U C T ION
Antiseizure medications (ASMs) are the first-line treat-
ment for epilepsy (the most common serious chronic neu-
rological disorder)1, and many patients attain complete
freedom from seizures when prescribed an appropriate
drug. An increasing number of ASMs have been intro-
duced over the years, with approximately 20 now in com-
mon use.2 Few ASMs are effective for all seizure types,
and some are suboptimal because of patient-specific
characteristics such as age, gender, epilepsy syndrome,
comorbidities, adverse effect profile, and drug interac-
tion potential.2–6 Having alternative choices improves the
opportunity to tailor treatment to the individual and to
select other drugs in case of poor tolerability, but may
also lead to inappropriate or suboptimal drug selection,
particularly when epilepsy is managed by nonspecialist
healthcare professionals.7 This risk is compounded by a
scarcity of neurologists and epilepsy specialists in many
places, particularly in low- and middle-income countries,
but also in wealthier countries.8 Moreover, misdiagnosis
and misclassification of seizures are common, and can
lead to selection of either ineffective or potentially sei-
zure-aggravating treatments.9 In one study of 350 adults
with uncontrolled seizures, 29% were found to have been
prescribed an inappropriate ASM and 18% were taking
suboptimal ASM doses.9 Inappropriate drug choice can
also adversely affect comorbidities and diminish the ef-
ficacy of other drugs.10,11
To assist healthcare professionals in epilepsy manage-
ment, we developed a web-based pragmatic algorithm aimed
at facilitating appropriate ASM selection for monotherapy.
The algorithm takes into consideration several patient-spe-
cific variables and provides a ranking of ASMs in order of
likely appropriateness for an individual based on the best
available scientific evidence complemented by expert judge-
ment. In addition to listing a ranking of individualized treat-
ment options, the web-based application provides a summary
of prescribing information for each of the medications being
suggested.
Key points
• The availability of a large number of antiseizure
medications (ASMs) entails a risk of suboptimal
or inappropriate drug selection.
• We developed a web-based version of a pragmatic
algorithm, which can assist healthcare profession-
als in tailoring ASM choice in a monotherapy
setting.
• The algorithm, intended for patients with seizure
onset ≥10  years, accounts for seizure type(s)
and individual demographic and health-related
variables.
• The instrument provides a selection of suitable
ASMs, arrayed in a hierarchy of preference,
depending upon individual patient and drug
characteristics.
2  |  M ETHODS
The algorithm was developed by utilizing a face-to-face
version of the Delphi process12 and was designed for use
in patients whose seizures begin at age 10 years and older.
Earlier-onset epilepsy was excluded, as some childhood syn-
dromes are more complex with regard to diagnosis and treat-
ment and would not readily fit into a broader diagnostic and
therapeutic scheme designed for adolescents and adults.
Five epileptologists from different regions of the world
participated in the process. The proposed instrument, which
can be applied once seizure types are determined based on the
history and other relevant information and a decision to treat
has been made, incorporates a pragmatic algorithm designed
to identify potential misdiagnosis of epilepsy/seizure types
based on eight screening questions.13 Description of the diag-
nostic part of the app, which is intended to minimize the risk
of the treatment selection algorithm being applied to individ-
uals with an incorrect diagnosis, is beyond the scope of this
ASADI-POOYA et al.
article. Whereas there is little or no evidence that response
to treatment varies across different types of focal seizures,
the type of generalized seizure and specific combinations of
generalized seizures have a major influence on medication
choice, as demonstrated by examples provided in this article.
Therefore, as a second step, the group developed a consen-
sus on level of appropriateness of specific ASMs for different
seizure types or combination of seizure types and categorized
potentially appropriate ASMs into three groups (nesting),
with group 1 ASMs being considered preferred, group 2 con-
sidered second line, and group 3 considered third line. As a
third step, the level of appropriateness of each ASM in the
ranking was adjusted according to clinical variables (modi-
fiers) considered particularly relevant for ASM selection,2–5
as defined by the following questions (additional to age and
gender, already entered as part of the screening questions):
• Is the patient using contraceptive medication other than an
intrauterine device? (Shows up only when gender = female)
• Does the patient take any other medication, apart from
contraceptives, on a regular basis? (Shows up only when
gender = female)
• Does the patient take medication on a daily basis? (Shows
up only when gender = male)
• Does the patient have:
a. Brain tumor requiring chemotherapy and/or radiation
therapy
b. Hepatic failure
c. Obesity (BMI ≥30)
d. Diabetes mellitus
e. Clinically significant thrombocytopenia or coagulation
disorder
f. Neutropenia (ie, neutrophil count of <1500μL)
g. Renal stone
h. Allergy to any drug
i. Depression
j. History of irritability or aggressive behavior
k. Migraine (≥4 headaches per month or ≥8 headache
days per month)14
l. Renal insufficiency
The above questions were finalized through a stepwise
Delphi process, with emphasis on accuracy and efficiency,
aiming for as few questions as feasible to minimize complex-
ity and data entry time. The structured discussion aimed at
highlighting causes of disagreements, and the cyclic voting
process continued until achieving consensus for all items.
It is acknowledged that determining the list of clinical vari-
ables and their relative weight in optimizing the ranking is
inevitably influenced by personal judgment, but the consen-
sus-reaching process relied as much as possible on the best
available evidence and recommendation from clinical guide-
lines.5,6 Having panel members from varied backgrounds
|
     3
minimized biases that might be introduced should all origi-
nate from a single site or school.
The app for electronic application of the algorithm was
implemented with TypeScript (https://www.types​cript​lang.
org/) based on React (https://react​ js.org/) and runs on a
Glassfish 5.1 server (https://javaee.github.io/glass​ fish/) in
a docker container (https://www.docker.com/). After imple-
mentation on the web, the authors tested several cases and
agreed on further adjustments of the weighting assigned to
modifiers in order to optimize the function of the algorithm.
In the final step, more cases were tested by a group of six ex-
pert epileptologists, and based on their feedback a few minor
faults in the algorithm and the app were resolved. Overall, the
authors and the external expert epileptologists tested more
than 150 cases in the fine-tuning process of the app. To en-
sure reliability of the algorithm, the app was run primarily to
test case scenarios that were considerably different from each
other, with additional duplicate cases being tested to ensure
reliability of the algorithm.
3  |  RESULTS
Table 1 shows the proposed nesting of ASMs based on sei-
zure type. Table  2 illustrates the nesting adjustments made
by taking modifiers into consideration, including key refer-
ences provided as a source of evidence to explain adjust-
ments applied for each modifier.15–26 Actions in response
to each modifier may result in either upward or downward
adjustments from the primary designated nesting (Figure 1).
Within each group, ASMs are listed in alphabetical order.
Dosing and prescribing information are provided for each of
the ASMs suggested, in addition to an explanation on how
the algorithm applied the information entered by the user to
determine the final ranking. Links to further resources are
given.
For adjustments, the algorithm uses mathematical calcula-
tions. Accordingly, “upgrade by one level” means an upgrade
by one notch (eg, from group 2 to group 1, ie, to a more desir-
able group), whereas “downgrade by one level” means a down-
grade by one notch (eg, from group 1 to group 2, or from group
2 to group 3, ie, to a less desirable group). After adjusting for
applicable modifiers, all ASMs considered appropriate for that
individual are displayed and categorized into groups 1, 2, and
3. ASMs that were present in the primary step of the nesting
process (based on the seizure type) and were downgraded
below group 3 after adjustment for modifiers are not removed,
but they are displayed as “Least desirable options if the above
drugs are not available.” The purpose of retaining less desirable
options is to facilitate treatment selection in settings such as
resource-poor countries where availability of medications may
be restricted. A normalization process is also applied when no
group 1 option emerges after adjustment for modifiers. In that
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4      ASADI-POOYA et al.

T A B L E 1   Proposed nesting of ASMs

Seizure type(s) Nesting of antiseizure medications
based on seizure types
Absence 1-group: ETS, VPA1
2-group: LTG1
3-group: LEV1, ZNS1, ACT1, CLB1, CLN1
Myoclonic 1-group: CLN, VPA, LEV
2-group: CLB2
3-group: TPM, ZNS, PB, NTR
Primary generalized 1-group: VPA
tonic-clonic 2-group: LTG, LEV
3-group: OXC, CLB, ZNS, LCM, TPM, PB, PER, CBZ,
PHT, BRV
Primary generalized 1-group: VPA
tonic-clonic + myoclonic 2-group: LEV
3-group: CLN3, LTG4, ZNS, CLB, TPM, PB, PER, PHT,
LCS, BRV
Primary generalized 1-group: VPA1
tonic-clonic + absence 2-group: LTG1, LEV1
3-group: TPM1, ZNS1, CLB1
Primary generalized 1-group: VPA1
tonic-clonic + myoclonic 2-group: LTG1,4, LEV1
+absence 3-group: TPM1, ZNS1, CLB1, CLN1
Myoclonic + absence 1-group: VPA1, ETS
2-group: LTG1,4, LEV1
3-group: TPM1, ZNS1, CLB1, CLN1
Focal 1-group: LEV, CBZ, LTG, OXC, ESL, LCM
2-group: TPM, VPA, PER, PHT, BRV, ZNS
3-group: CLB, PB, GBP, PGB
Unknown whether focal 1-group: LEV, CBZ, LTG, OXC, ESL, LCM
or generalized seizure 2-group: VPA, PER, PHT, BRV, CLB2, TPM, ZNS
type + age 21 or older 3-group: PB, GBP, PGB
Unknown whether focal 1-group: VPA, LTG, LEV
or generalized seizure 2-group: CLB2, CBZ, PER, ESL, OXC, LCM
type + age under 21 3-group: PB, TPM, ZNS
Note: Additional, specific rules in the algorithm: 1. The following text will be added when the recommended
ASM groups are displayed to the user: “(ETS can be added to it, if absence seizures persist)”. 2. CLB: For
focal seizures, if CLB comes in groups 1 or 2, move it to group 3; For myoclonic and for unknown seizure
types, if CLB comes in group 1, move it to group 2. 3. CLN is always in group 3 in GTCS + myoclonic and
GTCS + myoclonic +absence, and no further possibility for CLN up-grading. 4. In GTCS + myoclonic,
GTCS + myoclonic +absence, and myoclonic + absence, if LTG is selected, the following text will be added:
“(CLN can be added to LTG, if myoclonic seizures persist)”.
Abbreviations: ACT, acetazolamide; BRV, brivaracetam; CBZ, carbamazepine; CLB, clobazam; CLN,
clonazepam; ESL, eslicarbazepine acetate; ETS, ethosuximide; GBP, gabapentin; GTC, (primary)
generalized tonic-clonic; LCM, lacosamide; LEV, levetiracetam; LTG, lamotrigine; NTR, nitrazepam; OXC,
oxcarbazepine; PB, phenobarbital; PER, perampanel; PGB, pregabalin; PHT, phenytoin; TPM, topiramate;
VPA, valproic acid; ZNS, zonisamide.

event, the highest ranked ASM is automatically upgraded to
group 1. Boxes 1-3 provide examples of the nesting process for
clarification purposes.
4  |   D IS C U S S ION
The proposed algorithm, which incorporates key de-
mographic details and 17 clinical variables, is intended
to assist healthcare professionals who are not expert in
epileptology in selecting ASM monotherapies for pa-
tients with seizure onset at age 10  years and older. The
instrument, implemented in an electronic application
freely available on the internet ((https://epipi​c k.org/#/),
provides several ASM options with different levels of
prioritization (group 1, 2, or 3), and gives the health-
care professional ultimate responsibility to decide which
ASM is most suitable for the individual patient. Because
ASADI-POOYA et al.      5
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T A B L E 2   Influence of modifiers on the nesting of ASMs
For a pre-menopausal female (see reference 15):
• For all seizure types (except focal and GTCS): move VPA to group 3, and no further possibility for VPA upgrading
• For focal seizures: remove VPA completely (no possibility to suggest VPA use for that patient).
• For GTCS: move VPA to group 2 without further possibility for upgrading; move LTG to group 1 without further possibility for up-grading;
move LEV to group 1 without further possibility for upgrading.
If age >65 years2–6,16:
Upgrade by one level for GBP, LCM, LEV, LTG
If co-medications2–6,17 (other than contraceptives) are present and the patient has a generalized epilepsy:
Upgrade by one level for ETS, LCM, LEV, LTG, PER, ZNS
Downgrade by one level for CBZ, PB, PHT
If co-medications2–6,17 (apart from contraceptives) are present and the patient has a focal or uncertain epilepsy:
Upgrade by one level for BRV, GBP, LCM, LEV, LTG, PER, ZNS
Downgrade by one level for CBZ, PB, PHT
If on oral contraceptives2–6,17:
Downgrade by one level for PER, TPM
Downgrade by two levels for ESL, CBZ, OXC, PB, PHT
If a female patient is taking contraceptives and LTG is suggested, the following text is displayed: “While lamotrigine is the suggested choice,
you should be aware that lamotrigine levels are reduced by estrogen containing contraceptives and may vary during the contraceptive-pill
taking cycle. Additionally, lamotrigine may moderately reduce levonorgestrel levels.”
Brain tumor requiring chemotherapy and/or radiation therapy2–6,18:
Downgrade by two levels for ESL, CBZ, OXC, PB, PHT
Hepatic failure2–6,19:
Upgrade by one level for GBP, LCM, LEV
Downgrade by two levels for VPA
Obesity (BMI ≥ 30)2–6,20:
Downgrade by one level for GBP, PGB
For patients with idiopathic generalized epilepsies: Downgrade by one level for VPA
For patients focal or uncertain epilepsies: Downgrade by two levels for VPA
Diabetes mellitus2–6:
Downgrade by one level for CBZ, PER, PHT, VPA
Bleeding disorders2–6,21:
For generalized epilepsies: Downgrade by one level for VPA
For focal or uncertain epilepsies: Downgrade by two levels for VPA
Neutropenia 2–6,21:
Downgrade by one level for CBZ, PHT
Renal stones2–6,22:
Downgrade by one level for ACT, TPM, ZNS
Renal failure2,22:
Upgrade by one level for CLB, ETS, LTG, CBZ, PHT
Downgrade by one level for all other drugs
Allergy to any drug2–6,23:
Downgrade by one level for ESL, CBZ, LTG, OXC, PB, PHT, ZNS
Depression2–6,24:
Upgrade by one level for LTG
Downgrade by one level for CLB, CNZ, LEV, NTZ, PB
History of irritability or aggressive behavior2–6,25:
Downgrade by one level for LEV, PER, PB, TPM
Migraine2–6,26:
Upgrade by one level for TPM, VPA
Note: Important notes: 1. If hepatic failure is present, the following warning will be displayed: “Check product information regarding dose adjustment, because of
hepatic failure.” 2. If renal insufficiency is present, the following warning will be displayed: “Check product information regarding dose adjustment, because of renal
insufficiency.”
Upgrade by one (or two) levels means an increase by one (or two) notches to a more desirable group. Accordingly, downgrade refers to a decrease in the ranking to a
less desirable group. For abbreviations, see Table 1.

the algorithm is designed to facilitate ASM selection, it differs from phenomenological and syndromic classifica-
includes only those clinical variables that we viewed as tions aimed at differentiating seizure types irrespective
most important for treatment decisions, an approach that of therapeutic implications.27
 |
6      ASADI-POOYA et al.
Although, a handful of algorithm-based applications have
been developed to assist healthcare professionals in diagnos-
ing seizures,13,28–31 none so far has addressed the need for pa-
tient-tailored drug selection. Identifying epilepsy syndrome
and seizure type(s) correctly is a necessary first step in clin-
ical practice, but it may not necessarily lead to choice of an
appropriate treatment. Evidence of incorrect or suboptimal
drug selection in patients with epilepsy has been documented
by many studies done in different settings.9,32,33 Our instru-
ment has the potential to reduce inappropriate prescribing, as
BOX 1 A 35-year-old man with focal seizures
since 25 years of age who has diabetes and
hypertension and is receiving medications.*
Nesting of ASMs based on his seizure types (pri-
mary nesting) is as follows:
1-group: LEV, CBZ, LTG, OXC, ESL, LCM
2-group: TPM, VPA, PER, PHT, BRV, ZNS
3-group: CLB, PB, GBP, PGB
Because he takes other medications:
Upgrade by one level for BRV, GBP, LCM, LEV,
LTG, PER, ZNS
Downgrade by one level for CBZ, PB, PHT
Because he has diabetes:
Downgrade by one level for CBZ, PER, PHT, VPA
Therefore, the proposed ASM nesting for this patient
will be as follows:
-1. LCM, LEV, LTG
1. BRV, ZNS, OXC, ESL
2. GBP, PER, TPM
3. CLB, PGB, VPA, CBZ
4. PHT, PB
The proposed ASM nesting for this patient after nor-
malization will be as follows:
1-group: LCM, LEV, LTG
2-group: BRV, ESL, OXC, ZNS
3-group: PER, TPM, GBP
Least desirable options if the above drugs are not
available: CLB, PHT, PB, CBZ, PGB, VPA
* *
Variables acting as modifiers for this case example
are shown in italics. For abbreviations, see Table 1.
F I G U R E 1   The response to modifiers
could move up/down the primary designated
nesting of antiseizure medications
it provides advice not only on drug choice but also on dos-
age and titration schedules. The algorithm is user-friendly,
requiring less than 2 minutes to answer (less than 1 minute
BOX 2 A 22-year-old woman with primary
generalized tonic-clonic + myoclonic +absence
seizures since 15 years of age, who is taking
contraceptives and has migraine headaches
(Figure Case 2).*
Nesting of ASMs based on her seizure types (pri-
mary nesting) is as follows:
1-group: VPA*
2-group: LTG*, LEV*
3-group: TPM*, ZNS*, CLB*, CLN*
Because she is pre-menopausal and female:
for all seizures: move VPA to group-3 and no further
possibility for upgrading
Therefore, adjustment of nesting of her ASMs based
on her seizure types will be as follows:
1-group:
2-group: LEV, LTG
3-group: VPA, CLB, CLN, TPM, ZNS
Because she is taking an oral contraceptive drug
(downgrade by one level for TPM), nesting is further
adjusted as follows:
1-group:
2-group: LEV, LTG
3-group: VPA, CLB, CLN, ZNS
4-group: TPM
Because she has migraine headaches (upgrade by
one level for TPM, VPA), but there is no further pos-
sibility for up-grading VPA, the final proposed ASM
nesting for this patient will be as follows:
1-group: LEV, LTG (ETS can be added to it, if ab-
sence seizures persist).
2-group: CLB, ZNS, TPM (ETS can be added to it,
if absence seizures persist), (CLN can be added to
LTG, if myoclonic seizures persist).
3-group: CLN, VPA (ETS can be added to it, if ab-
sence seizures persist).
Variables acting as modifiers for this case example
are shown in italics. For abbreviations, see Table 1.
ASADI-POOYA et al.
BOX 3 A 67-year-old man with focal seizures
since 65 years of age, who has a brain tumor and
depression and is receiving medications
(Figure 2).*
Nesting of ASMs based on his seizure types (pri-
mary nesting) is as follows:
1-group: LEV, CBZ, LTG, OXC, ESL, LCM
2-group: TPM, VPA, PER, PHT, BRV, ZNS
3-group: CLB, PB, GBP, PGB
Because he takes other medications:
Upgrade by one level for BRV, GBP, LCM, LEV,
LTG, PER, ZNS
Downgrade by one level for CBZ, PB, PHT
Because he has a brain tumor:
Downgrade by two levels for ESL, CBZ, OXC, PB,
PHT
Because he has depression:
Upgrade by one level for LTG
Downgrade by one level for CLB, LEV, PB
Because he is 67-years-old:
Upgrade by one level for GBP, LCM, LEV, LTG
Therefore, the final proposed ASM nesting for this
patient will be as follows:
1-group: LTG
2-group: LCS
3-group: LEV
Least desirable options if the above drugs are not
available: BRV, PER, VPA, TPM, ZNS, OXC,
GBP, CLB, ESL, CBZ, PB, PHT, PGB
*
Variables acting as modifiers for this case example
are shown in italics. For abbreviations, see Table 1.
once familiar with it), and provides the user with a range of
ASMs ranked in order of appropriateness. This should facil-
itate broad use among professionals interested in accessing
simple advice in the management of their patients. Apart
from the drug selection and the links to additional resources,
the explanation of how the algorithm adjusted the ranking
based on individual variables bears a strong educational
component, helping physicians without training in epilepsy
understand important aspects involved in choosing the appro-
priate medication.
Some limitations should be acknowledged. The algo-
rithm is applicable only to patients whose seizures begin at
age 10 years and older and is intended primarily for use in a
monotherapy scenario. Development of a similar tool for a
younger population, or for polytherapy setting, would be far
more complex. Although the algorithm was constructed by
taking into consideration available evidence on the properties
|
     7
of individual ASMs2–4 and recommendations from clinical
guidelines,5,6 adjusting ASM selection to individual char-
acteristics cannot be fully evidence-based and needs to take
into consideration personal judgment, which justified use of
a Delphi approach. The choice of medication in the algorithm
is driven by seizure type rather than epilepsy syndrome, but
combinations of seizures types associated with syndromes
with onset at age ≥10 years are fully accounted for. The clin-
ical variables (modifiers) considered are limited and some
of those are only broadly defined, due to the need to com-
promise between efficiency and practicability. Accordingly,
we are aware that not all information that ideally should be
considered in ASM selection is included in the algorithm,
and this in some cases may lead to less than optimal advice.
In particular, aspects subject to geographical variability such
as availability, labeled indications, cost, and reimbursability
of medications are not considered; furthermore, the algo-
rithm does not assist in determining whether in an individual
person treatment should be initiated or deferred. Because of
these limitations, the instrument is being offered as a tool to
facilitate therapeutic decisions, and cannot be a substitute for
the user's clinical judgment.
One final limitation that needs to be discussed relates to
the lack of formal external validation. To date, the instru-
ment has undergone mostly internal testing. Although the
feedback received from a number of epilepsy specialists who
have tested it has been generally favorable, we acknowledge
the need for formal and broader validation studies. A study
currently in progress is assessing how ASM selections done
by expert epileptologists worldwide compare with the algo-
rithm performance in a variety of case scenarios. This in-
vestigation is expected to confirm our preliminary findings
concerning reliability and external validity within the lim-
itations of using predefined cases. The next step will involve
extending these studies to field testing in the real world, and
obtain from expert users broader feedback on the perfor-
mance and usefulness of the instrument. Finally, we envisage
assessing acceptability and perceived usefulness within the
community for which the instrument is mainly designed, that
is, healthcare professionals who are not expert in epilepsy
management, including (but not limited to) those living in
resource-restricted settings. We regard the algorithm as a tool
that will evolve as experience with its use progresses, new
scientific evidence emerges, and new drugs are developed.
The ultimate goal is to improve the quality of care for people
with epilepsy, and to contribute to ameliorate the “treatment
gap” across the world.
ACKNOWLEDGEMENT
We thank Drs. Jakob Christensen, Stefan Juhl, Maromi Nei,
Joseph Sirven, Carlo Andrea Galimberti, and Christopher
Skidmore for their assistance in the evaluation of the
algorithm.
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8      ASADI-POOYA et al.
CONFLICT OF INTERESTS
AAP reports honoraria from Cobel Daruo, Tekaje, and
RaymandRad; and royalty from Oxford University
Press (Book publication), outside the submitted work.
SB reports personal fees from Brain Sentinel, Philips,
Epihunter, UCB Pharma, GW Pharma, and Eisai, outside
F I G U R E 2   How EpiPick works:
Recommended antiseizure medications in
a 67-year-old man with focal seizures who
has a brain tumor and depression and is
receiving medications
the submitted work. EP reports speaker and/or consul-
tancy fees from Amicus Therapeutics, Arvelle, Biogen,
Eisai, GW Pharma, Intas Pharmaceuticals, Sanofi, Sun
Pharma, Takeda, UCB Pharma, and Xenon Pharma,
and publication royalties from Wiley, Elsevier, Wolters
Kluwers, and Idelson Gnocchi, outside the submitted
ASADI-POOYA et al.
work. GR reports speaker fees from UCB Pharma outside
the submitted work. MRS has research contracts through
the university with the National Institutes of Health,
DARPA, UCB Pharma, Eisai, Takeda, Neurelis, SK
Life Sciences, Engage Therapeutics, Medtronic, Xenon,
consulting through the university with Medtronic, con-
sulting with NeurologyLive, and royalties from Oxford
University Press, outside the submitted work. We con-
firm that we have read the Journal's position on issues
involved in ethical publication and affirm that this report
is consistent with those guidelines.
AUTHOR CONTRIBUTIONS
All authors contributed to the conception and design of the
study. AAP drafted the manuscript. All authors contributed
to editing the final manuscript.
ORCID
Ali A. Asadi-Pooya  https://orcid.
org/0000-0002-2598-7601
Sándor Beniczky  https://orcid.org/0000-0002-6035-6581
Guido Rubboli  https://orcid.org/0000-0002-5309-2514
Michael R. Sperling  https://orcid.
org/0000-0003-0708-6006
Stefan Rampp  https://orcid.org/0000-0002-4826-1520
Emilio Perucca  https://orcid.org/0000-0003-3232-1389
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