Download Optimizing Treatment of Adolescents With Partial

A CME-Certified Supplement to
and
Clinical Neurology News®
Optimizing Treatment of Adolescents
With Partial-Onset Seizures
Introduction........................................................... 3
Epidemiology........................................................ 3
Diagnosis and Classification
of Partial-Onset Seizures..................................... 4
Current Pharmacologic Management
Strategies for Partial-Onset Seizures
in Adolescence..................................................... 8
Role of Nonpharmacologic
Strategies for Treatment-Resistant
Partial-Onset Seizures.......................................10
Monitoring...........................................................11
Investigational Therapies for Inadequately
Controlled Partial-Onset Seizures.....................11
Epilepsy in Adolescence:
Special Considerations......................................13
Conclusions.........................................................17
Post-Test..............................................................20
Faculty
Rinat Jonas, Course Director
Assistant Professor
Boston University School of Medicine
Director, Pediatric Long-Term EEG Monitoring
Division of Pediatric Neurology
Boston Medical Center
Boston, Massachusetts
Carl W. Bazil, MD, PhD
Caitlin Tynan Doyle Professor of Clinical Neurology
Director, Epilepsy and Sleep Division
Columbia University College of Physicians and Surgeons
New York, New York
James W. Wheless, MD
Professor and Chief of Pediatric Neurology
Le Bonheur Chair in Pediatric Neurology
University of Tennessee Health Science Center
Director, Neuroscience Institute and
Le Bonheur Comprehensive Epilepsy Program
Le Bonheur Children’s Hospital
Memphis, Tennessee
Model
is for ill
Date of Original Release: February 2013
Expiration Date: February 2014
Course Code: CEE80512
Estimated Time to Complete Activity: 2.0 hours
This educational activity is supported by an educational grant from Eisai Inc.
Jointly sponsored by
and
ustrati
ve purp
oses o
nly.
Optimizing Treatment of Adolescents
With Partial-Onset Seizures
A CME-Certified Supplement to
and
Clinical Neurology News®
Program Description
Epilepsy is the most common neurological disease in
adolescence. Adolescence is a period of rapid physical,
psychological, and emotional development. The presence
of a chronic disease like epilepsy only adds to the burden
of transitioning to adulthood. Adolescents with epilepsy are
more than twice as likely to repeat a school grade and to
have poorer social competence as are those without
epilepsy. Thus, optimal management is essential for maximizing health-related quality of life and psychosocial and
academic functioning during this sensitive period of development. This supplement addresses issues related to the
diagnosis and management of partial-onset seizures in
adolescents, reviews both evidence-based and expertopinion–based recommendations for pharmacologic and
nonpharmacologic management, and examines data on
emerging therapies for inadequately controlled partialonset seizures in this patient population.
Program Goal
To update neurologists on current issues related to the diagnosis and management of partial-onset seizures in adolescents.
Learning Objectives
At the conclusion of this activity, participants will be better
able to:
• Describe the diagnosis and classification of partialonset seizures
• Discuss issues related to the management of
epilepsy in adolescents, including the impact of
epilepsy and its treatment on driving, academics,
and psychosocial function
• Define the risks and benefits of available therapies
for treating partial-onset seizures in adolescents
• Discuss data from recent clinical trials of emerging
therapies in adolescents and adults with partialonset seizures.
Target Audience
This activity has been developed for neurologists.
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This activity has been planned and
implemented in accordance with the
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Accreditation Council for Continuing Medical Education
(ACCME) through the joint sponsorship of Boston
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education for physicians.
Boston University School of Medicine designates this
enduring material for a maximum of 2.0 AMA PRA
Category 1 Credits™. Physicians should claim only the
credit commensurate with the extent of their participation in the activity.
Faculty
Rinat Jonas, MD, Course Director
Assistant Professor
Boston University School of Medicine
Director, Pediatric Long-Term EEG Monitoring
Division of Pediatric Neurology
Boston Medical Center
Boston, Massachusetts
Carl W. Bazil, MD, PhD
Caitlin Tynan Doyle Professor of Clinical Neurology
Director, Epilepsy and Sleep Division
Columbia University College of Physicians and Surgeons
New York, New York
2
James W. Wheless, MD
Professor and Chief of Pediatric Neurology
Le Bonheur Chair in Pediatric Neurology
University of Tennessee Health Science Center
Director, Neuroscience Institute and Le Bonheur
Comprehensive Epilepsy Program
Le Bonheur Children’s Hospital
Memphis, Tennessee
Faculty Disclosures
Boston University School of Medicine asks all individuals
involved in the development and presentation of Continuing
Medical Education (CME) activities to disclose all relationships with commercial interests. This information is
disclosed to CME activity participants. Boston University
School of Medicine has procedures to resolve any apparent
conflicts of interest. In addition, faculty members are asked
to disclose when any discussion of unapproved use of
pharmaceuticals and devices is being discussed.
This educational activity may contain discussion of published and/or investigational uses of agents that are not
indicated by the US Food and Drug Administration.
Dr Bazil: consultant: Eisai Co., Ltd., Lundbeck, Pfizer Inc.
Dr Jonas has nothing to disclose with regard to commercial interests.
Dr Wheless: consultant/speakers bureau: Cyberonics, Inc.,
Eisai Co., Ltd., Lundbeck, Pfizer Inc, Questcor
Pharmaceuticals, Inc., Sunovian Pharmaceuticals Inc.,
Supernus Pharmaceuticals, Inc., Upsher-Smith
Laboratories, Inc.; grant support: GlaxoSmithKline, National
Institutes of Health, Shainberg Foundation.
The Planning Committee for this activity included Rinat
Jonas, MD, and Ilana Hardesty of Boston University
School of Medicine; and Ruth Cohen and Christine M.
Olsen, PhD, of Continuing Education Alliance. The members of the Planning Committee have no significant
relationships to disclose.
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www.globalacademycme.com/primarycare • Optimizing Treatment of Adolescents With Partial-Onset Seizures
Introduction
Adolescents with epilepsy comprise patients with childhood-onset syndromes that persist
into adulthood and patients with epilepsy syndromes that begin in adolescence. As patients
transition from pediatric to adult neurology care, pediatric and adult neurologists may be
called on to manage epilepsy in adolescents. The management of epilepsy in adolescence poses
several challenges. Issues related to autonomy (eg, self-management of medication, getting
enough sleep, and maintaining a healthy diet) can have a significant impact on seizure control.
Optimal epilepsy management also is essential for maximizing health-related quality of life
(HRQOL), psychosocial development, and academic functioning during adolescence.1–3 This
supplement addresses issues related to the diagnosis and management of partial-onset seizures
in adolescents, reviews evidence-based and expert-opinion–based recommendations for pharmacologic and nonpharmacologic management, and examines data on investigational
therapies for inadequately controlled partial-onset seizures in this patient population.
Epidemiology
Epilepsy affects about 3 million Americans, including 300,000
<18 years of age.4 Of the estimated 200,000 new cases of epilepsy
that occur in the United States each year, about 50,000 are in the
pediatric population.4 In the National Survey of Children’s Health
(NSCH), the lifetime prevalence of epilepsy among US children
aged birth to 17 years is 1%. The current prevalence is 0.6%.3
The adjusted incidence rate of new-onset epilepsy among children,
aged 1 month through 17 years, residing in Olmsted County,
Minnesota, between 1980 and 2004 is estimated at 44.5 cases per
100,000 persons/year.5
Epilepsy is the most common neurologic disease in adolescence.
In the NSCH analysis, the lifetime prevalence of epilepsy/seizure
disorders among those 12 to 17 years of age was 1.4%.3 The
incidence rate of epilepsy per 100,000 persons/year among adolescents is 24.8 (Table 1) and is higher among males (29.5) than
females (19.9).5 Among adolescents and adults, the most common
electroclinical syndromes at initial diagnosis are juvenile absence
epilepsy and juvenile myoclonic epilepsy (JME) (Table 2).5
Table 1. Incidence of Seizure Types in Adolescence and Distribution
of New-Onset Cases by Electroclinical Syndrome
Incidence Rates per 100,000 Persons per Year
All epilepsies
24.8
Mode of onset
Generalized
Partial
Unknown
9.2
13.1
2.4
Wirrell EC, et al.7
Table 2. Distribution of New-Onset Cases by Electroclinical Syndrome
Electroclinical Syndrome
at Initial Diagnosis
(Adolescence/Adulthood)
Juvenile absence epilepsy
JME
Epilepsy with GTC seizures alone
Distribution of
New-Onset Cases
39%
39%
21%
Wirrell EC, et al.7 GTC=generalized tonic-clonic.
Optimizing Treatment of Adolescents With Partial-Onset Seizures • www.globalacademycme.com/primarycare
3
Diagnosis and Classification of Partial-Onset Seizures
Terminology and Classification
of Seizures
Generalized seizures are defined as originating within and rapidly
including bilaterally distributed networks.6 In contrast, partial-onset
seizures originate within brain networks limited to one hemisphere.
Partial-onset seizures typically are highly localized in onset, but there
may be more than one onset area in a given patient. While a patient
may exhibit involvement of more than one network and more than
one seizure type, ictal onset must be consistent for each seizure type.
Generalized seizures are classified as tonic-clonic, absence seizures
(typical, atypical, or absence with special features), myoclonic
(myoclonic, myoclonic atonic, myoclonic tonic), clonic, tonic, and
atonic.6 According to the International League Against Epilepsy’s
revised terminology and concepts for organization of seizures and
epilepsies, classification terms such as simple partial or complex
partial are no longer used because they are considered imprecise.6
However, partial-onset seizures may be described by characteristics
(eg, impairment of consciousness/awareness, localization, progression of ictal events) that may facilitate the evaluation of individual
patients or may be useful for a specific purpose, such as differentiating between epileptic seizures and nonepileptic events or
evaluating for surgery. Among those with nonidiopathic partialonset epilepsy, cryptogenic should be distinguished from probable
symptomatic epilepsy because cryptogenic epilepsy has a significantly
better long-term outcome than symptomatic epilepsy.7
Diagnostic Consultation
During a diagnostic consultation for a teenager with suspected or
established epilepsy, sensitivity to both the patient’s growing need
for autonomy and the parents’ concerns is important. Although the
focus of the initial patient interview and subsequent consultations
should be the adolescent, because the history depends to a high
degree on witness account, it is necessary to interview the parents.8
To appeal to the adolescent’s need for autonomy and help foster a
sense of control:
• Address the adolescent first, before the parents.
• Ask the adolescent to introduce the parents to you.
• Explain to the adolescent what will happen during the
initial consultation.
• Explain to the adolescent why it is necessary to talk to the parents.
• Obtain the history from the adolescent directly, with assistance
from the parent when needed.
• Explain the diagnosis, evaluation, and treatment to the adolescent.
• Provide a strategy for remembering medication (eg, cell phone
alarm) and making up missed or late medication to the adolescent.
• During the evaluation, allow the adolescent an opportunity to
supply information and ask questions without the parents present.
• At the end of each visit, ask whether the adolescent has any
questions (if not, suggest possible questions).
• Provide Internet references and adolescent chat room addresses.
• Address correspondence directly to the adolescent patient, but ask
for permission to send copies of letters to the parents.
The interview and neurological examination are key components of
the initial assessment. For patients with a possible first seizure, it is
important to establish whether an actual seizure has occurred and, if
so, whether it is the first episode.9 A careful, detailed history provided
4
by a reliable observer often can help determine whether a seizure has
occurred. The history should include associated factors (eg, age,
family history, health at seizure onset, precipitating events other than
illness), symptoms immediately before and during the seizure
(eg, subjective sensations, mood or behavioral changes, motor and
vocal symptoms, changes in respiration or other autonomic symptoms, loss of consciousness), and symptoms following the seizure
(eg, amnesia for events, lethargy/sleepiness, headache, transient focal
weakness, nausea or vomiting). The next goal of the assessment is to
identify the cause of the seizure. In some cases, a detailed history and
physical/neurological examination may provide sufficient information to determine the probable cause of the seizure or to establish a
need for other tests, such as neuroimaging.
Recommended Investigations
For the adolescent with a first seizure, basic blood tests (complete
blood cell count; measurement of creatinine, calcium, electrolyte
levels; liver function tests) should be performed. 8 Laboratory tests
should be individualized based on clinical circumstances (eg, vomiting, diarrhea, dehydration, alterations in alertness).9 It is important
to inquire about drug or alcohol exposure during the interview
(preferably without parents present), because many substances or
withdrawal from substances may precipitate seizures in an individual
without epilepsy.8 If drug exposure or substance abuse is a concern,
toxicology screening should be considered. Lumbar puncture is of
little value in a child or adolescent with a first nonfebrile seizure
unless there is concern about meningitis or encephalitis.9
An electroencephalogram (EEG) is recommended for differentiating seizures from other events, classifying the initial seizure, and
predicting risk for seizure recurrence.9 Results of the EEG may influence the counseling of the patient and the decision to perform
neuroimaging studies. In addition, the EEG may provide supportive
evidence for the presence of a specific clinical syndrome.9,10 A sleep
deprivation study or 24-hour ambulatory EEG should be considered
if the routine EEG is normal.10
Positive findings on magnetic resonance imaging (MRI) are found
in 20% to 30% of children with a first seizure.11 However, structural
abnormalities requiring intervention are found in only about 1% of
cases. Table 3 summarizes recommendations for structural imaging
in children and adolescents.12 Repeat structural imaging in adolescents
is recommended if there is a failure to control seizures, worsening
Table 3. Recommendations for Structural Imaging
Imaging Indicated
Imaging Usually Not Indicated
seizuresa
• Localization-related
• Focal history, abnormal exam,
focal EEG abnormalitiesa
• Developmental regression
• <2 years old
• Symptomatic generalized
epilepsy syndrome
• Increased intracranial pressure
• History of status epilepticus
• Atypical course for BECTS/IGE
• Childhood absence epilepsy
• Juvenile absence epilepsy
• JME
• BECTS
Adapted from Gaillard WD, et al.12
Boldface indicates syndromes that may occur during adolescence.
aExcept BECTS.
BECTS=benign epilepsy of childhood with centrotemporal spikes; IGE=idiopathic generalized epilepsy.
www.globalacademycme.com/primarycare • Optimizing Treatment of Adolescents With Partial-Onset Seizures
seizures, or alterations in seizure manifestations.12 Imaging may not
be necessary in adolescents with idiopathic partial or generalized
epilepsy when the clinical presentation is typical, the neurological
examination is normal, and characteristic features are evident on
EEG.12 MRI is the preferred imaging modality because of its superior
anatomic resolution and ability to characterize pathologic processes.9,12 Computed tomography with and without contrast can be
considered when MRI is not available (eg, emergent evaluation),
recognizing that some symptomatic causes (eg, small tumors, mesial
temporal sclerosis) will not be detected.12
Differential Diagnosis of
Partial-Onset Seizures
The differential diagnosis of partial-onset seizures involves distinguishing between epileptic and nonepileptic seizures as well as among
different syndromes. Table 4 highlights the differential diagnosis
between epileptic seizures and nonepileptic events in adolescents.13
The presence of psychogenic nonepileptic attacks (PNEAs) is the most
common (>90%) condition misdiagnosed as epilepsy at epilepsy
referral centers. Although most patients with PNEAs are young
Table 4. Distinguishing Between Seizures and Nonepileptic Events
Differential Diagnosis
Key Differentiating Features
PNEAs
• Historical features favoring PNEA: Resistance to AEDs, very high seizure frequency unaffected by AEDs, specific triggers
that are unusual for epilepsy (eg, getting upset, pain), attacks occur in the presence of an audience (particularly in the
physician’s office), presence of certain comorbid diagnoses (eg, fibromyalgia, chronic pain), positive psychosocial history/
psychiatric diagnoses
• Characteristics of motor features favoring PNEAs: Very gradual onset/termination; discontinuous, irregular, or
asynchronous activity; pseudosleep; side-to-side head movements; pelvic thrusting; opisthotonic posturing; stuttering;
weeping; preserved awareness during bilateral motor activity; persistent eye closure; pleomorphic events
• Detailed description of the spells, often including characteristics inconsistent with epileptic seizures
• Presence of histrionic behaviors favors PNEAs
• Symptoms favoring epileptic seizures: Significant postictal confusion, incontinence, occurs out of sleep, significant injury
(especially tongue-biting for tonic-clonic seizures), stereotyped events
• Presence of repeated normal EEGs favors PNEAs
Panic attacks/panic disorder
• Identification of fear as an aura of mesiotemporal epilepsy is clear if it evolves into a clear seizure
• Panic attacks typically include intense autonomic symptoms (especially cardiovascular and respiratory) that typically peak
within 10 minutes
• Comorbid anxiety or mood disorders favor panic attacks
Migraine
• Migraine symptoms usually evolve in minutes versus seconds for seizure symptoms
• Presence of associated migraine symptoms (eg, headache) or more obvious seizure symptoms
Acute dystonic reactions
• Acute dystonic reactions occur in response to dopamine receptor blockers (eg, antipsychotics, antiemetics); typically
occur within 1 to 4 days of starting medication; characterized by twisting movements
Hemifacial spasm
• Unilateral facial twitching of hemifacial spasm, typically affecting the periorbital muscles then spreading to other
ipsilateral facial muscles over months/years
Hypnic jerks
• Hypnic jerks occur only upon falling asleep
• On video EEG monitoring, hypnic jerks occur in wake to stage 1 transition and have no EEG correlate
Parasomnia/narcolepsy
• Historical features consistent with somnambulism or other parasomnia
• Cataplexy occurs during wakefulness, often induced by emotion, and can occasionally be confused with seizures
• EEG and imaging typically normal
• Occur exclusively in sleep
• Video EEG monitoring may be required to distinguish from nocturnal seizures
Hypoglycemia
• Hypoglycemia rarely is associated with a complete LOC; when it does, it resembles syncope
• Hypoglycemia usually is preceded by prodromes of hunger, weakness, tremulousness, malaise, abnormal behaviors
• Circumstances favoring hypoglycemia include diabetes, use of insulin or oral antihyperglycemics, fasting
Syncope
• Syncope, but not epileptic seizures, can cause a flaccid, motionless episode of LOC lasting from seconds to minutes
• Clonic-like or myoclonic-like motor symptoms associated with syncope tend to last only a few seconds and stop once the
patient is horizontal
• Syncope usually is triggered by clear precipitants
• Features favoring syncope: Presyncopal syndromes, older age, history of cardiovascular disease
• Features favoring epileptic seizures: Tongue biting, head turning, posturing, urinary incontinence, cyanosis, prodromal
déjà-vu, postictal confusion
Tics/tic disorders
• Although they can fluctuate, tics are not episodic and typically occur throughout the day
• Tics are sporadic and stereotyped and tend to disappear during sleep
• Tics are preceded by a temporarily suppressible urge to move or vocalize, and expression of the tic is followed by relief
• Onset of tics/tic disorders is usually between ages 5 and 10 years
TIA
• TIA symptoms are typically negative, whereas seizure symptoms are typically positive
• Focal symptoms in TIA are maximal at onset, whereas partial-onset seizure symptoms tend to evolve over seconds
• TIAs rarely, if ever, cause loss of consciousness
Adapted from Benbadis S.13 AEDs=antiepileptic drugs; LOC=loss of consciousness; TIA=transient ischemic attack.
Optimizing Treatment of Adolescents With Partial-Onset Seizures • www.globalacademycme.com/primarycare
5
Table 5. Epilepsy Syndromes That May Be Present During Adolescence
Childhood-Onset Epilepsy Syndromes That May Persist Into Adolescence
Epilepsy Syndromes That May Begin in Adolescencea
• Late-onset childhood occipital epilepsy (Gastaut type, late onset)
• Reading epilepsy
• Benign myoclonic epilepsy in infancy
• Photosensitive epilepsies
• Lennox-Gastaut syndrome
• Juvenile absence epilepsy
• Generalized epilepsy with febrile seizures plus
• JME
• Childhood absence epilepsy
• Epilepsy with generalized tonic-clonic seizures
• Epilepsy with myoclonic absences (Tassinari syndrome)
• Epilepsy with generalized tonic-clonic seizures on awakening
• Eyelid myoclonia with absences (Jeavons syndrome)
• Progressive myoclonic epilepsies
• Myoclonic atonic epilepsy of early childhood (Doose syndrome)
• Mesial temporal lobe epilepsy
• Autosomal dominant nocturnal frontal lobe epilepsy
• Benign partial seizures of adolescence
• Panayiotopoulos syndrome
• Familial focal epilepsy with variable focib
• Other familial temporal lobe epilepsies
al6;
al14;
al.15
Berg AT, et
Wheless JW, et
Kamate M, et
aOnset also may occur in adulthood for some of these syndromes; bOnset from childhood to adulthood.
Table 6. Syndromes Characterized by Partial-Onset Seizures That May Occur During Adolescence
Syndrome
Clinical Features
EEG
Structural Imaging
ADNFLE
• Clusters of typically brief, nocturnal motor seizures with hyperkinetic/
dystonic features and/or tonic manifestations
Video EEG during sleep: Ictal frontal
discharges or ictal, anterior, rhythmic,
slow-wave activity
Normal
• Interictal EEG: Sharp- or spikeslow–wave focus or normal or mild
and nonspecific abnormalities
• Hippocampal
sclerosis in
MTLE-HS
• Ictal EEG: Often normal at seizure
onset; typical pattern consists of
rhythmic, crescendo-like theta
activity with decreasing frequency
and increasing amplitude
• In MTLE without
HS, anatomical
evidence of
localization
Normal
Normal
• Interictal focal epileptiform
abnormalities with a single focus
over time and location concordant
with clinical symptoms
Normal
• Sleep is interrupted but resumes immediately after seizure
• Seizures may be associated with an aura
• Awareness usually is preserved during seizures
• Secondarily GTC seizures occur infrequently in two thirds of patients
MTLE
• Often a history of febrile seizures, trauma, hypoxia, and intracranial
infections before age 5 years
• Initial nonfebrile seizure types that draw clinical attention include
complex partial-onset seizures or secondarily generalized convulsions;
these have been preceded by a history of simple partial-onset seizures
• Most common ictal symptoms include epigastric aura, fear, and
oroalimentary automatisms
Benign partial
seizures of
adolescence
Familial focal
epilepsy with
variable foci
Other familial
temporal lobe
epilepsies
• Single seizure or cluster of 2–5 partial-onset seizures, with period of
seizures lasting ≤36 h
• Partial motor and somatosensory seizures that may progress to
impaired cognition and/or secondarily GTC seizures
• Family history of partial-onset seizures arising from different cortical
locations (temporal, frontal, centroparietal, and occipital)
• Individual patient has same electroclinical pattern of single location
partial-onset epilepsy
• Seizures often nocturnal • EEG abnormalities frequently
brought on or facilitated by sleep
• Mild partial-onset seizures with mainly auditory hallucinations for
FLTLE and déjà vu or other experimental phenomena or hallucinations
alone or with autonomic disturbances for FMTLE
• FLTLE: Normal or mild and nonspecific abnormalities with rare
interictal epileptiform abnormalities
• Normal or mild
and nonspecific
abnormalities
• Visual, olfactory, vertiginous, or cephalic features also common
for FLTLE
• FMTLE: Usually normal and with
mild, focal slow waves or sparse,
usually unilateral, sharp–slow-wave
complexes in the temporal region
• Hippocampal
atrophy can be
found in severe
cases of FMTLE
• Fear/panic and visual, auditory, or somatosensory hallucinations also
common for FMTLE
• Mainly brief aphasic seizures may occur in FLTLE
• Infrequent GTC seizures
• Excellent response to treatment
Panayiotopoulos CP.16
FLTLE=familial lateral temporal lobe epilepsy; FMTLE=familial mesial temporal lobe epilepsy; HS=hippocampal sclerosis.
6
www.globalacademycme.com/primarycare • Optimizing Treatment of Adolescents With Partial-Onset Seizures
women, PNEAs can occur in children and adolescents. The gender
difference favoring women appears to begin in adolescence. Other
than PNEAs, nonepileptic phenomena that occur in adolescence and
may resemble partial-onset seizures include migraine, hemifacial
spasm, parasomnias, tics/tic disorders, and transient ischemic attacks.
Epilepsy syndromes that may be present during adolescence
include childhood-onset epilepsy syndromes that may persist
into adolescence and epilepsy syndromes with an onset in
adolescence (Table 5).6,14,15 Syndromes characterized by partialonset seizures include autosomal dominant nocturnal frontal
lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy (MTLE),
benign partial seizures of adolescence, familial focal epilepsy with
variable foci, and other familial temporal lobe epilepsies (Table 6).16
JME sometimes is misdiagnosed as partial epilepsy (with or
without secondarily generalized seizures), leading to delays in
diagnosis and appropriate therapy. Confusion arises in part because
lateralized or persistently focal EEG abnormalities may occur in
JME.14,17,18 Absence seizures in JME typically are short with only
mild impairment of consciousness and common automatisms;
mistaking them for partial seizures is relatively common.19
Myoclonic seizures in JME may be misinterpreted as focal clonic
seizures because they may be focally distributed or reported as
such.19 Myoclonic jerks are considered the sine qua non of diagnosis
of JME and occur in 100% of cases. 20 When taking the patient
history, it is critical to ask patients about the occurrence of myoclonic jerks and presence of precipitating factors. Myoclonic jerks
may occur unilaterally, and some may be experienced only as a
sensation of electric shock within the body. Myoclonus may not be
reported spontaneously by the patient, and terms that patients
often use to describe jerks include shakes, clumsiness, twitches, and
nervousness. Sometimes, myoclonic jerks are noticed only by the
patient’s family and not by the patient, so interviewing family
members may be helpful. Table 7 describes additional features of
JME that may aid in differentiating it from partial epilepsy. 21–23
Several partial-onset epilepsy syndromes have a known genetic
component (Table 8). 24 Genetic testing may be useful in clinical
practice to support diagnosis of a specific epilepsy syndrome and
may influence the treatment choice.
Table 7. Key Diagnostic Features of JME Compared With Partial-Onset Seizures
JME
Partial-Onset Seizures
Clinical
• Onset between ages 12 and 18 years
• Presence of myoclonic jerks in all patients
• At onset characterized by early morning myoclonus that primarily
involves both upper extremities (although lower limbs may be involved)
and is precipitated by sleep deprivation, fatigue, or alcohol
• GTC seizures in >90%–95% of patients and often are preceded by a
series of myoclonic jerks of increasing frequency and intensity
• Absence seizures occur in 30% of patients and usually are short with
minimal impairment of consciousness
• Depending on syndrome, onset may occur at any age
• Partial-onset seizures predominate, although secondarily GTC
seizures may be present
• Absence of myoclonic jerks
EEG
• Normal background EEG
• Characteristic interictal findings are generalized by 4- to 6-Hz polyspike
and slow-wave complexes, but many patients have 3- to 4-Hz spike and
slow-wave complexes
• Characteristic ictal EEG for a myoclonic jerk is a bilaterally symmetrical,
frontocentrally accentuated, generalized polyspike (frequency 10–16 Hz)and-wave (frequency 2–5 Hz) complex
• Interictal EEG may be normal
• Varies depending on clinical syndrome, but partial-onset seizures
typically show interictal localized epileptiform discharges
• Focal slowing may be present
• Ictal EEG starts from a localized area of the corresponding region of
epileptogenicity and sometimes may precede clinical symptoms
Imaging
• Structural brain lesions rarely found but do not appear to affect
therapeutic response or prognosis
• Increase in cortical gray matter (especially mesial frontal lobes) apparent
on voxel-based analysis of MRI in 40% of patients
Normal or mild/nonspecific abnormalities or presence of lesion or
mesial temporal sclerosis
Wheless JW, et al14; Panayiotopoulos CP16; Ferrie CD19; Renganathan R 20; Gelisse P, et al21; Janz D22; Woermann FG, et al.23
Table 8. Genetic Partial Epilepsies
Familial Focal Epilepsies
Loci/Genes Involved
Recognized Conditions
ADNFLE
CHRNA4, CHRNA2, and CHRNB2 genes
FMTLE
4q13.2-q21.3, 7p21.3, 1q25-q31 and 18qter, 12q22-q23.3
ADLTE
LGI1 gene
ADPEVF
22q12
Conditions Awaiting Confirmation
Autosomal-dominant rolandic epilepsy with speech dyspraxia
SRPX2 gene (1 family with X-linked transmission)
Familial partial epilepsy with pericentral spikes
4p15 (1 family)
Familial occipitotemporal lobe epilepsy and migraine with visual aura
9q21-q22 (1 family)
Michelucci R, et al.24 Reprinted with kind permission from Springer Science + Business Media.
ADLTE=autosomal dominant lateral temporal lobe epilepsy; ADPEVF=autosomal dominant partial epilepsy with variable foci.
Optimizing Treatment of Adolescents With Partial-Onset Seizures • www.globalacademycme.com/primarycare
7
Current Pharmacologic Management Strategies
for Partial-Onset Seizures in Adolescence
Adolescents with epilepsy may require treatment for an initial diagnosis or may have an epilepsy syndrome continuing from childhood.
As patients continue into adolescence, it may be necessary to reassess
their regimen and switch medications. Older drugs commonly used
to treat partial-onset seizures in adolescents include carbamazepine,
phenobarbital, phenytoin, and valproate. Carbamazepine, 25 phenobarbital, 26 and phenytoin27 are indicated for the treatment of
partial-onset seizures (complex partial seizures for carbamazepine
and phenytoin), but the labeling does not differentiate between
monotherapy and adjunctive treatment. Valproate is indicated as
monotherapy or adjunctive therapy in patients with complex partial
seizures that occur alone or with other seizure types. 28,29 During the
past decade, several new treatments have emerged, and studies have
evaluated pre-existing antiepileptic drugs (AEDs) in adolescents
with partial-onset seizures (Table 9).30–33
Current Recommendations for First-Line
Treatment of Partial-Onset Seizures
The American Academy of Neurology (AAN) guidelines for the
treatment of patients with new-onset epilepsy were published in
2004 and are being revised.34 Recommended first-line pharmacotherapy for partial-onset seizures in adolescents includes
carbamazepine, sodium valproate, phenytoin, gabapentin,
lamotrigine, topiramate, and oxcarbazepine.34,35 However, gabapentin is only approved by the US Food and Drug Administration
(FDA) as adjunctive therapy, and lamotrigine is FDA approved
as adjunctive therapy in addition to monotherapy in patients
≥16 years of age who previously received monotherapy with carbamazepine, phenobarbital, phenytoin, primidone, or valproate
(ie, not indicated as first-line treatment).36,37
According to consensus of European expert opinion for the treatment of pediatric epilepsy published in 2007, carbamazepine and
oxcarbazepine are the treatments of choice for first-line monotherapy
of complex partial seizures. Treatment with valproate also is appropriate.38 If carbamazepine or oxcarbazepine is used first and is not
efficacious or tolerated, then a trial of valproate monotherapy is
recommended; if phenytoin is used first and is not efficacious or
tolerated, carbamazepine or oxcarbazepine is recommended, with
valproate as another option.
A 2005 survey of 43 US pediatric and adult epileptologists
established an expert consensus regarding the initial treatment and
second-line monotherapy of adolescents or adults with symptomatic partial-onset seizures.39 Carbamazepine, oxcarbazepine,
lamotrigine, and levetiracetam were considered appropriate. When
first-line monotherapy failed, the agents most often selected for
monotherapy were carbamazepine, oxcarbazepine, lamotrigine,
levetiracetam, and topiramate.
Actual usage patterns of AEDs may differ from society recommendations and FDA approvals. In our clinical experience, drugs
appropriate for partial seizures as add-on therapy may be used as
monotherapy in select patients. As no one drug is definitely more
effective in seizure control than another appropriate agent, the choice
often is made based on overall tolerability of the drug, drug interactions, and potential to improve or worsen any coexisting conditions,
such as migraine or mood disorders. AEDs commonly used to treat
partial-onset seizures include levetiracetam, oxcarbazepine, lamotrigine, and lacosamide.
Treatment of Refractory Epilepsy
With Partial Seizures
Treatment-resistant epilepsy is defined as a “failure of adequate trials
of two tolerated and appropriately chosen and used AED schedules
(as monotherapy or in combination) to achieve sustained seizure
freedom.”40 This definition implies that the AEDs used must be
appropriate for the patient’s seizure type and administered at a therapeutic dose for a sufficient time to observe a clinical response. It has
Table 9. Newer AEDs Approved by the US FDA for Partial-Onset Seizures in Adolescents (ie, 13–17 Years of Age) and Actual Usage Patterns
Monotherapy
Partial-Onset Seizures
AED
Ezogabine
Adjunctive Therapy
Partial-Onset Seizures
(Potiga)a,112
Gabapentin (Neurontin)36
Lacosamide (Vimpat)49
Lamotrigine
(Lamictal)37
X
(in patients ≥16 y, previously receiving
monotherapy with carbamazepine, phenobarbital,
phenytoin, primidone, or valproate)
Levetiracetam (Keppra)48
Oxcarbazepine (Trileptal)31
X
Perampanel (Fycompa)50
Pregabalin
(Lyrica)a,87
Tiagabine (Gabitril)32
Topiramate (Topamax)30
Zonisamide
aIn
8
(Zonegran)a,47
X
Actual Usage in Clinical Practice
X
Adjunctive
X
Monotherapy/adjunctive
X (≥17 y)
Monotherapy/adjunctive
X
Monotherapy/adjunctive
X
Monotherapy/adjunctive
X
Monotherapy/adjunctive
X
Adjunctive
X
Monotherapy/adjunctive
X
Adjunctive
X
Monotherapy/adjunctive
X
Monotherapy/adjunctive
clinical development for adjunctive therapy in adolescents with treatment-resistant partial-onset seizures but not yet FDA approved for this indication.
www.globalacademycme.com/primarycare • Optimizing Treatment of Adolescents With Partial-Onset Seizures
been estimated that between 10% and 40% of children with epilepsy
have treatment-resistant epilepsy.41
Before concluding that a patient has treatment-resistant epilepsy,
it is important to rule out or correct pseudoresistance. 42
Pseudoresistance refers to the persistence of seizures due to inappropriate or inadequate treatment of the underlying disorder. Some
of the most common reasons for pseudoresistance are an incorrect
diagnosis (of epileptic seizures or type of seizures or syndrome
present), the wrong drug or drugs (eg, inappropriate for seizure
type, pharmacokinetic or pharmacodynamic interactions, inadequate dosing), and lifestyle issues (eg, poor adherence, alcohol or
drug abuse).42,43 When a patient’s seizures are not responding to
therapy, the diagnosis should be revisited by reviewing the accuracy
of the seizure and/or syndrome classification and brain imaging
results.44 Additional interviews with the patient and the parents
may help to better characterize the patient’s clinical symptoms and
precipitating factors. Lifestyle factors, including adherence, substance abuse, and other factors that may impact seizures (eg, sleep,
diet) should be assessed and addressed before treatment-resistant
epilepsy is diagnosed. Video EEG monitoring is indicated for all
patients who continue to have seizures despite medications, with
the aim of recording a seizure episode to determine whether a
change in EEG occurs during the clinical event and whether the
clinical attack is consistent or inconsistent with seizure types that
may be unaccompanied by EEG changes (ie, to establish whether
the patient is having epileptic vs psychogenic nonepileptic
attacks).45 A brain MRI also should be performed or repeated.12,45
In most cases, the combination of video EEG monitoring and highquality MRI will allow the neurologist to confirm the diagnosis of
epilepsy; determine whether the seizures are localization-related or
generalized; distinguish among genetic, structural-metabolic, and
unknown causes of epilepsy; and differentiate among localizationrelated epilepsies. 6,45 Laboratory evaluations should be considered
when indicated (eg, to investigate genetic, metabolic, or infectious/
inflammatory causes of intractable seizures).41
For adults with refractory partial-onset seizures, the AAN recommends monotherapy with oxcarbazepine, topiramate, or lamotrigine,
and add-on therapy with gabapentin, lamotrigine, topiramate,
tiagabine, oxcarbazepine, levetiracetam, or zonisamide.46 However,
lamotrigine is indicated as monotherapy in patients ≥16 years of age,
and zonisamide is approved only in adults.37,47 The AAN recommends gabapentin, lamotrigine, topiramate, or oxcarbazepine for
pediatric patients with refractory partial-onset seizures.46 At the
time of the AAN guidelines, levetiracetam was approved only for
this indication in adults, but it currently is approved as adjunctive
therapy for partial-onset seizures in children aged ≥1 month and
adults.46,48 Following publication of the AAN guidelines, lacosamide was approved for add-on therapy of partial-onset seizures in
patients ≥17 years of age.49
Perampanel was FDA approved in October 2012 and is indicated
as adjunctive therapy for treatment of partial-onset seizures with or
without secondary generalization in epilepsy patients ≥12 years of
age.50 Perampanel is a noncompetitive antagonist of AMPA-type
glutamate receptors and reduces excessive excitatory neurotransmission.51 Three multicenter, randomized, double-blind, placebocontrolled phase III studies have assessed the safety and efficacy of
perampanel as add-on therapy in adolescents and adults ≥12 years of
age with refractory partial-onset seizures.52–54 Each study consisted
of a 6-week baseline phase, a 6-week titration phase during which
perampanel was titrated by 2 mg/d, and a 13-week maintenance
phase. For all three studies, patients eligible for randomization experienced at least five partial seizures during the baseline period, had
failed at least two AED trials in the previous 2 years, and were taking
stable doses of up to three approved AEDs. Studies 30452 (N=388)
and 30553 (N=386) evaluated perampanel dosages of 8 or 12 mg/d,
whereas study 30654 (N=706) evaluated dosages of 2, 4, or 8 mg/d.
Overall, perampanel, at dosages of 4, 8, and 12 mg/d, produced
statistically significant median reductions in seizure frequency compared with placebo (Table 10).52–54 Responder rates in the
perampanel 4, 8, and 12 mg/d groups ranged from 29% to 38%.
Compared with placebo, the 50% responder rates were significantly
greater for perampanel 4 mg/d and 8 mg/d in Study 30654 and
8 and 12 mg/d in Study 305,53 but did not achieve significance at
the 8 or 12 mg/d dosages in Study 30452 (Table 10).
FDA-approved AEDs not currently approved for use as adjunctive
therapy in adolescents with treatment-refractory partial-onset
seizures but that are in phase III development for this indication
include ezogabine, pregabalin, and zonisamide.
Table 10. Adjunctive Treatment With Perampanel in Adolescents and Adults With Refractory Partial-Onset Seizures
Median Reduction in Seizure Frequency
Krauss GL, et
al54;
≥50% Responder Rate
Seizure-Free Rate
Study 306 (13-week maintenance phase)
Perampanel 2 mg/d (n=180)
13.6%
20.6%
1.9%d
Perampanel 4 mg/d (n=172)
23.3%b
28.5%a
4.4%d
Perampanel 8 mg/d (n=169)
30.8%c
34.9%c
4.8%d
Placebo (n=185)
10.7%
17.9%
1.2%d
French JA, et al52; Study 304 (13-week maintenance phase)
Perampanel 8 mg/d (n=133)
26.3%a
37.6%
2.2%
Perampanel 12 mg/d (n=134)
34.5%a
36.1%
1.5%
21.0%
26.4%
0%
Placebo (n=121)
French JA, et al53; Study 305 (13-week maintenance phase)
Perampanel 8 mg/d (n=129)
30.5%c
33.3%b
2.3%
Perampanel 12 mg/d (n=121)
17.6%a
33.9%c
5.0%
9.7%
14.7%
1.5%
Placebo (n=136)
aP<0.05
vs placebo; bP<0.01 vs placebo; cP<0.001 vs placebo; dAmong completers of the maintenance period.
Optimizing Treatment of Adolescents With Partial-Onset Seizures • www.globalacademycme.com/primarycare
9
Role of Nonpharmacologic Strategies for
Treatment-Resistant Partial-Onset Seizures
Nonpharmacologic strategies include dietary therapies, alternative therapies, surgery, and vagus nerve stimulation (VNS). For adults, responsive
cortical stimulation, deep brain stimulation, laser-based ablation
surgery, transcranial magnetic stimulation, and trigeminal nerve
stimulation are possible alternatives that are pending FDA approval.
Dietary Therapies
The ketogenic diet is a high-fat, low-protein, and very low-carbohydrate diet most commonly used for children 5 to 10 years of age with
refractory epilepsy.44,55 Approximately one third to one half of
children achieve a cessation of or marked reduction in seizure activity
with a ketogenic diet.56 Results of a small study suggest that adolescent retention on the ketogenic diet is similar to that of younger
children, but retention may be lower among patients with partialonset seizures.57 The ketogenic diet is similarly effective in children
and adults and in patients with different seizure types, including
partial-onset seizures.58,59 Potential candidates for the ketogenic diet
include patients with medically intractable seizures (including those
being considered for epilepsy surgery), those with poor tolerability
with AEDs, and patients with specific neurologic/neurometabolic
syndromes.56 In addition, the ketogenic diet may be beneficial for
partial epilepsy patients with recent deterioration of seizure control
and neurological status.59
The Atkins diet severely restricts carbohydrates during an initiation phase but does not restrict calorie or protein consumption.55,60
A case series evaluated the Atkins diet in 6 children, adolescents, and
adults with refractory epilepsy.60 Half of the patients (including
patients 7, 10, and 18 years of age) experienced a reduction in seizures
and were able to reduce AED medications, providing preliminary
evidence for a benefit of the Atkins diet in this patient population.
Other dietary therapies being studied include a modified Atkins diet
and a low glycemic index diet.44
Complementary and Alternative Therapies
Complementary and alternative medicine (CAM) therapies include
biologically-based practices (eg, herbs, vitamins), mind-body medicine (eg, meditation, prayer, art or music therapies), manipulative and
body-based practices (eg, acupuncture, chiropractic manipulation),
and energy medicine (eg, infield and electromagnetic therapies).61,62
Whole medical systems (eg, Ayurveda, homeopathy, traditional
Chinese medicine) are recognized separately.62 Although there is
little well controlled evidence to support the use of CAM therapies
in patients with epilepsy,61,62 a few randomized trials of meditation
and yoga suggest possible beneficial effects.63,64 The CAM therapies,
in particular herbal remedies (eg, St John’s Wort, ginseng, Gingko
biloba), commonly are used by patients with epilepsy without their
physician’s knowledge. It is important to ask patients with epilepsy
whether they are using any CAM therapies, especially herbal products, to allow evaluation of possible risks associated with seizure
exacerbation or drug interactions with AEDs.
Vagus Nerve Stimulation
VNS is approved for use as adjunctive therapy in adolescents and
adults with treatment-resistant partial-onset seizures65,66 and should
be considered after two AEDs fail to control seizures or are not tolerated and when epilepsy surgery is not an option.66 This treatment
involves implantation of a device to systematically stimulate the
vagus nerve, which has widespread central and peripheral projections.55
10
In various studies, overall responder rates with VNS were 28% to
68%.65,66 Response to VNS is sustained over long-term treatment
and appears to improve over time.66 Patients who have failed epilepsy
surgery also benefit from VNS.66 This treatment modality is well
tolerated; the most common side effects include voice alteration/
hoarseness, cough, and shortness of breath.66
Surgery
Surgery commonly is considered after the failure of at least two
appropriate AED trials in patients with partial-onset seizures.67 In
appropriately selected patients, seizure freedom is about 70% with
temporal resection and 25% with frontal resection.67 Evidence suggests that surgery performed earlier following a diagnosis of
treatment-resistant epilepsy may offer greater benefit than surgery
performed after several years of intractable seizures.38 Therefore,
surgery should be strongly considered for potential candidates.
Two randomized controlled trials have compared surgery with
continued medical management (CMM) in patients with treatmentresistant temporal lobe epilepsy.68,69 In one study, patients ≥16 years
of age with temporal lobe epilepsy whose seizures were inadequately
controlled despite the use of two or more AEDs (one of which was
phenytoin, carbamazepine, or valproic acid) were randomly assigned
to surgery (n=40) or CMM (n=40); four patients in the surgery
group did not undergo surgery.68 Patients were followed for 1 year,
during which time the AEDs were switched or doses increased in all
patients in the CMM group versus nine (22%) in the surgical group.
At 1 year, the cumulative proportion of patients who were free of
seizures impairing awareness (ie, complex partial or secondarily
generalized seizures) was 58% in the surgical group versus 8% in the
CMM group (P<0.001). Overall, 38% of surgical patients and 3% of
CMM patients were free of all seizures, including auras, at 1 year
(P<0.001). Quality of life improved in both groups but statistically
was significantly better at 1 year among patients who received surgery
versus CMM (P<0.001).
The Early Randomized Surgical Epilepsy Trial was a multicenter,
randomized, parallel-group study that examined whether surgery
soon after the failure of two AEDs is superior to CMM.69 Patients
≥12 years of age with MTLE were randomized to surgery (n=15) or
CMM (n=23); the only two adolescents in the study were in the
CMM group. Fourteen of the patients assigned to surgery underwent
surgery, and seven patients in the CMM group underwent surgery
prior to the 2-year visit. The mean number of AEDs was comparable
in both treatment groups and remained stable throughout the study.
During the 2-year follow-up, 73% of patients in the surgical group
versus none in the CMM group remained seizure-free (P<0.001).
Quality of life was superior in the surgical group compared with the
CMM group at months 6, 12, and 18 (P<0.009), but not at month
24 (P=0.08). However, when patients in the CMM group who had
undergone surgery were excluded from the analysis, the difference
was statistically significant at 2 years (P=0.01). The findings of these
two studies strongly support early consideration of surgery to optimize seizure control and HRQOL in patients with temporal lobe
epilepsy. However, the advantages of surgery must be weighed against
potential risks, such as a long recovery time (with lost work/school
time), neurological complications that may affect postoperative functioning, medical (eg, deep vein thrombosis, wound infection) and
psychiatric (eg, depression) complications, and the formation of a
new brain lesion that may cause seizures.67
www.globalacademycme.com/primarycare • Optimizing Treatment of Adolescents With Partial-Onset Seizures
Monitoring
Patients with epilepsy should be monitored regularly for treatment
effectiveness (ie, occurrence, frequency, and severity of seizures), and
side effects should be assessed at every visit.34,44,70,71 The frequency
of patient visits should be individualized. In our experience, a patient
who is stabilized on a simple regimen and is doing well can be seen
every 6 to 12 months. Patients with a more complex AED regimen
or issues (eg, comorbidities, side effects) may need to be seen every 3
to 4 months. Other patients may require more frequent visits, especially if their seizures are not well controlled.
Adolescents with seizures will likely continue to have seizures as
adults. It is important to select a medication that can be well tolerated without a long-term health impact and to monitor patients for
side effects that may affect their HRQOL or their health. Certain
AEDs (eg, phenytoin, valproate) may have adverse effects on bone
health.72,73 Enzyme-inducing AEDs, such as carbamazepine and
phenytoin, increase levels of serum lipids and C-reactive protein
(CRP) and thus may increase cardiovascular risk.72,73 One study in
adults with partial epilepsy found that switching from carbamazepine or phenytoin to the noninducing AEDs lamotrigine or
levetiracetam resulted in significant decreases in atherogenic cholesterol and CRP.72,73 Weight gain may occur during AED therapy,
especially with valproate, pregabalin, and to a lesser degree with
carbamazepine and high-dose gabapentin.71,74 Lamotrigine, levetiracetam, lacosamide, perampanel, and phenytoin are considered
weight-neutral, whereas felbamate, topiramate, and zonisamide may
induce weight loss.50,51,74 There may be adverse hormonal effects
with AEDs. In particular, valproate treatment has been associated
with an increased risk of polycystic ovary syndrome in adolescents
and young women.72,73
Children and adolescents with epilepsy should be monitored for
cognitive and behavioral/psychiatric well-being, HRQOL, and
psychosocial adjustment. The American Epilepsy Society (AES)
Web site provides a “Cognitive and Behavioral Effects of Epilepsy
Practice Tool,” which can be accessed at: http://www.aesnet.org/
practice/practice-tools.75 The AES recommends assessing sleep
behaviors and the sleep environment and providing adolescents and
their parents with suggested lifestyle changes to improve sleep for
maximizing seizure control and cognitive and behavioral functioning.75 In addition to asking about the patient’s sleep habits, the
Epworth Sleepiness Scale76 can be used to assess the patient’s level of
daytime sleepiness.
While patients taking any AED should be monitored for adverse
events, black box warnings warrant special consideration. The carbamazepine labeling has black box warnings concerning the risk of
serious skin reactions as well as the risk of aplastic anemia and agranulocytosis.25 Black box warnings for valproate include hepatotoxicity,
teratogenicity, and pancreatitis.28,29 A black box warning for lamotrigine warns of the risk of life-threatening serious skin reactions, including
Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rashrelated death.37 The labeling for perampanel carries a black box
warning regarding serious psychiatric and behavioral reactions.50
Reactions such as aggression, hostility, irritability, anger, and homicidal ideation and threats have been reported in patients taking
perampanel, and patients should be monitored closely during the
titration period and at higher doses. Patients and caregivers should be
advised to contact a health care provider immediately should any
changes in mood, behavior, or personality occur during or after treatment with perampanel that are atypical for the patient.
Therapeutic drug monitoring can guide dose adjustments, help to
establish an individual therapeutic drug concentration, aid in the
identification of drug toxicity, and help determine the extent of
adherence.44,70,77 In particular, it is useful to obtain a baseline when
the patient is stable to provide a basis of comparison should efficacy
or tolerability problems arise.
Investigational Therapies for Inadequately Controlled
Partial-Onset Seizures
Investigational therapies for refractory partial-onset seizures in latestage clinical development include brivaracetam, eslicarbazepine
acetate, and rufinamide.
Brivaracetam
Brivaracetam is an analog of levetiracetam and acts by binding to
synaptic vesicle protein 2A (SV2A) and inhibiting voltage-gated
sodium channels.51 In one phase IIb study, brivaracetam (50 mg/d, but
not 5 or 20 mg/d) significantly reduced the weekly frequency of partial-onset seizures compared with placebo in 208 patients, 16 to
65 years of age, with refractory partial-onset seizures.78 However, a
subsequent phase IIb study (N=157) did not demonstrate a statistically
significant difference between brivaracetam (50 or 150 mg/d) and
placebo with regard to change from baseline in weekly partial-onset
seizure frequency.79 Two multicenter, randomized, double-blind,
placebo-controlled trials evaluated adjunctive brivaracetam in patients
(16–70 years of age) with partial-onset epilepsy inadequately controlled with one or two AEDs.80 Both studies consisted of an 8-week
baseline period and a 12-week treatment period. Patients who had at
least eight partial-onset seizures during the baseline period were randomized. In one study, patients were randomized to brivaracetam
(5 mg/d, n=97; 20 mg/d, n=100; 50 mg/d, n=101) or placebo (n=98).
The percentage reduction from baseline in partial-onset seizure frequency/week was significantly greater with brivaracetam 50 mg/d
compared with placebo (12.8% difference, P=0.025). In the second
study, which randomized patients to brivaracetam (20 mg/d, n=99;
50 mg/d, n=99; 100 mg/d, n=100) or placebo (n=100), statistical
significance was not achieved on the primary efficacy end point of
percent reduction over placebo in partial-onset seizures in the 50 mg/d
arm. However, statistical significance was achieved for the brivaracetam 100 mg/d arm (11.7% difference, P=0.037). Notably, a short-term
randomized, controlled study of brivaracetam in healthy volunteers
supports a favorable cognitive profile for brivaracetam, but findings
will need to be confirmed in long-term studies of children and adolescents with epilepsy.81
Eslicarbazepine Acetate
Eslicarbazepine acetate is a prodrug of the S-enantiomer of the active
mono-hydroxy derivative of oxcarbazepine.82 This agent is an antagonist of voltage-gated sodium channels and is believed to act by
stabilizing voltage-gated sodium channels in an inactive state and
preventing rapid firing.51,82 All completed phase III studies of eslicarbazepine acetate in patients with uncontrolled partial-onset
seizures were performed in adults ≥18 years of age.83–85 Randomized
Optimizing Treatment of Adolescents With Partial-Onset Seizures • www.globalacademycme.com/primarycare
11
Table 11. Adjunctive Treatment With Eslicarbazepine Acetate in Adults (≥18 Years) With Refractory Partial-Onset Seizures
ESL 400 mg/d (n=100)
ESL 800 mg/d (n=98)
ESL 1,200 mg/d (n=102)
Placebo (n=102)
ESL 800 mg/d (n=85)
ESL 1,200 mg/d (n=80)
Placebo (n=87)
ESL 400 mg/d (n=96)
ESL 800 mg/d (n=101)
ESL 1,200 mg/d (n=98)
Placebo (n=100)
LS Mean Seizure
Median Reduction in
Frequency/4 Weeks
Seizure Frequency
≥50% Responder Rate
Elger C, et al83 (12-week maintenance phase)
6.73 (P=NS)
26%
23%
5.7b
36%
34%a
5.4c
45%
43%c
7.6
16%
20%
Gil-Nagel A, et al84 (12-week maintenance phase)
5.7a
37.9%
34.5%
5.5a
41.9%
37.7%a
7.3
17.0%
22.6%
85
d
Ben-Menachem E, et al (14-week maintenance phase )
9.3
18.7%
17.0%
7.1c
32.6%c
40.0%c
7.4c
32.8%c
37.1%c
10.9
0.8%
13.0%
Seizure-Free Rate
2%
4%
8%a
2%
4.8%
3.9%
1.2%
1.0%
8.0%a
4.1%
1.0%
aP<0.05 vs placebo; bP<0.01 vs placebo; cP<0.001 vs placebo; d All patients started the maintenance phase at the full maintenance dose, except the ESL 1,200 mg/d group, which started at 800 mg/d for the
first 2 weeks of the maintenance phase before reaching 1,200 mg/d. ESL=eslicarbazepine acetate; LS=least squares.
Table 12. Adjunctive Treatment With Rufinamide in Patients ≥16 Years of Age With Refractory Partial-Onset Seizures
RFN 3,200 mg/d (n=156)
Placebo (n=157)
RFN 3,200 mg/d (n=176)
Placebo (n=181)
aP<0.05
Median Reduction in Seizure Frequency
≥50% Responder Rate
Brodie MJ, et al89 (11-week maintenance phase)
20.4%a
28.2%a
−1.6% (ie, increase)
18.6%
Biton V, et al90 (12-week maintenance phase)
23.3%b
32.5%c
9.8%
14.3%
3.8%
1.9%
Not reported
Not reported
vs placebo; bP<0.01 vs placebo; cP<0.001 vs placebo. RFN=rufinamide.
patients had at least four partial-onset seizures in each of the two
4-week periods of the 8-week baseline despite being on a stable dose
of one to two AEDs83,84 or one to three AEDs.85 Eslicarbazepine
800 and 1,200 mg/d significantly reduced mean seizure frequency
compared with placebo (Table 11). The median reduction in seizure
frequency was greater for eslicarbazepine 800 and 1,200 mg/d compared with placebo, 83–85 although statistical significance was
reported in only one study (Table 11).85 Responder rates generally
were higher for the eslicarbazepine 800 and 1,200 mg/d groups than
the placebo groups, as were the proportion of seizure-free patients,
although statistical significance findings differed among the three
studies (Table 11).83–85 An integrated analysis of safety data from
797 patients found that when used in conjunction with one to three
AEDs, eslicarbazepine acetate was associated with a low incidence
of cognitive treatment-emergent adverse events.86 Ongoing phase III
studies include two studies of eslicarbazepine monotherapy in
patients 16 to 70 years of age, with inadequately controlled partialonset seizures; a study of adjunctive eslicarbazepine acetate in
children and adolescents (2–16 years of age) with refractory partial
seizures; and a trial of adjunctive eslicarbazepine in patients ≥16 years
of age with refractory partial seizures.87
Rufinamide
Although its exact mechanism of action is unclear, rufinamide blocks
voltage-dependent sodium channels.51 Rufinamide is FDA approved
for Lennox-Gastaut syndrome in children ≥4 years of age and in
adults. 88 Two phase III, double-blind, randomized, placebocontrolled studies evaluated rufinamide (up to 3,200 mg/d) as
add-on treatment in adolescents and adults (aged ≥16 years for
the Brodie study and 12–80 years for the Biton study) with inadequately controlled partial-onset seizures.89,90 One study consisted of
12
Seizure-Free Rate
an 8-week baseline phase followed by a 2-week titration period and
an 11-week maintenance phase,89 and the other study comprised an
8-week baseline phase followed by a 12-day titration period and a
12-week maintenance phase.90 Randomized patients experienced at
least six partial seizures during the 8-week baseline period despite
being on a stable dose of one to two AEDs89 or one to three AEDs.90
In both studies, rufinamide reduced the median seizure frequency
by at least 20% compared with placebo (Table 12).89,90 About 30%
of rufinamide-treated patients in both studies demonstrated at least
a 50% decrease in partial seizure frequency. Almost twice as many
rufinamide-treated patients as placebo-treated patients achieved
seizure freedom in the study by Brodie and colleagues (3.8% vs 1.9%),
although the difference was not statistically significant. 89 The
efficacy and safety of adjunctive rufinamide (26.9–48 mg/kg/d) in
children and adolescents with drug-resistant partial-onset seizures is
further supported by a prospective, open-label Italian study that
included 70 patients, 3 to 21 years of age.91 At 1 year, 39% of patients
had a ≥50% reduction in seizure frequency, and 4% of patients were
seizure-free. In addition, a randomized, double-blind, placebocontrolled monotherapy trial of rufinamide (3,200 mg/d) in
104 inpatients, aged ≥12 years, with uncontrolled partial-onset seizures demonstrated a reduction in seizures and a longer time to first,
second, and third seizures with rufinamide versus placebo.92
Rufinamide (200, 400, 800, and 1,600 mg/d) as add-on therapy
appears to have a favorable cognitive profile, as demonstrated in an
international, randomized, double-blind, placebo-controlled,
dose-ranging study in 189 patients, 15 to 64 years of age, with
treatment-resistant partial seizures.93 At all doses tested, rufinamide did not produce impairment on any cognitive test during
12 weeks of treatment, although a higher dosage of rufinamide was
used in subsequent trials.
www.globalacademycme.com/primarycare • Optimizing Treatment of Adolescents With Partial-Onset Seizures
Epilepsy in Adolescence: Special Considerations
Adolescence is a period of great change, both physically and
socially.8,14,94,95 As the adolescent transitions into adulthood, issues
emerge, such as those related to driving, drinking, social/sexual relationships, preparation for college or employment, and the general
increase in responsibility.8,14,94–97 Adolescence is a time during which
individuals are forming their identities, maturing intellectually, preparing for independent living, and striving for autonomy. Transitioning
from childhood into adulthood is complicated by the presence of a
chronic illness, such as epilepsy. Whether an adolescent patient has an
epileptic syndrome continuing from childhood or new-onset epilepsy,
management of epilepsy during this developmental period requires
special attention to the issues intrinsic to adolescence.
Stigma and Self-Esteem
Epilepsy may have a profound impact on an adolescent’s self-esteem.94
Compared with younger children, adolescents tend to be more
embarrassed when seizures occur in public. A fear of social embarrassment may lead to self-restriction of activities and unwillingness
to participate in social events, which may contribute to social isolation. In an international survey of 212 adolescents and young adults
with epilepsy, more than one third of respondents indicated they had
kept their epilepsy a secret from others.96 The main reasons for
secrecy were a fear of being treated differently (particularly by other
children) and the belief that others should not know about their
condition. Areas of concern are shown in Figure 1.
Epilepsy can be particularly stigmatizing among adolescents. An
in-depth interview of 22 adolescents with epilepsy identified peer
acceptance as a major issue.98 Nineteen participants reported being
bullied and feeling socially isolated. Several adolescents related experiences of being rejected by friends because of their epilepsy, and half
of the respondents expressed fears about rejection from peers, especially boyfriends or girlfriends, if they found out about their illness.
Unless the situation is managed well, the stigmatizing effect of a
disorder that involves a loss of control and requires regular medication is likely to have a negative impact on the adolescent. Teenagers
may respond by attempting to hide their condition or by taking risks,
such as refusing to accept medication or ignoring other precautions.8
Because adolescents may view taking an AED as a distinguishing
and stigmatizing feature of their illness, some may avoid taking
daytime doses.94 Once-daily or twice-daily medications may be
helpful in such cases. Cosmetic adverse effects (eg, weight gain,
hirsutism, coarsening of facial features, gingival hyperplasia) may
affect the self-esteem of teenagers who tend to be self-conscious about
their appearance.95 Avoiding medications such as phenytoin that
cause cosmetic adverse effects in teenagers and taking steps to avoid
weight gain with AED treatment (eg, by AED selection, modification of lifestyle factors) may help prevent negative consequences on
self-esteem and adherence. To help patients with self-esteem issues,
clinicians can enlist the support of family members and can help
adolescents develop strategies to deal with other people’s beliefs by
allowing patients to discuss their own fears and concerns about
epilepsy and encouraging them to take responsibility for informing
others about their epilepsy.97 Participating in online communities or
in-person support groups may help adolescents with epilepsy feel less
socially isolated and may provide a resource for learning how to deal
with issues of stigma and self-esteem. The Epilepsy Foundation and
its state chapters offer support groups for adolescents with epilepsy
and day camps for children with epilepsy.99
Achieving and Maintaining Autonomy
Parents may react to their child’s epilepsy diagnosis by smothering
the child, whereas adolescents may rebel against the diagnosis by
ignoring treatment recommendations and activity restrictions.
However, it is most helpful to encourage the patient and parents to
maximize the patient’s autonomy and self-management of epilepsy.
For the adolescent with epilepsy, issues of autonomy involve basic
elements of self-care (eg, eating right, getting enough sleep) as well as
managing the medication regimen. It also is important to educate
teenagers about the possible consequences of alcohol and recreational
drug use. Older adolescents will be particularly concerned about the
impact epilepsy and state laws will have on their ability to drive. Any
recommended activity restrictions need to be communicated to
patients and their parents and tailored to the individual patient, based
on their seizure type and control. For females, issues surrounding
Figure 1. Areas of Regular Concern for Children and Adolescents With Epilepsy 96
I worry about what people at school will think if I have a seizure
I worry about being able to keep up with schoolwork
I am less confident meeting with new people
I find it difficult to make new friends
I avoid trying new activities
I avoid going on school trips
I worry about having/starting a relationship with a boy/girlfriend
0%
5%
10%
15%
20%
25%
30%
% of responses
Reprinted from Baker GA, et al,96 Copyright © 2008, with permission from Elsevier.
Optimizing Treatment of Adolescents With Partial-Onset Seizures • www.globalacademycme.com/primarycare
13
Case Study 1
contraception and possibly pregnancy may
become prominent as they enter into more
mature social relationships.
Adolescents should be informed that
insufficient sleep will lower their seizure
threshold.100,101 Teenagers typically need
about 9 hours of sleep.102 As children enter
adolescence, their body clocks change and
they tend to remain awake later. However,
because many teenagers need to get up early
for school, they do not get enough sleep
during the week and try to catch up on sleep
during the weekend.102 This pattern can
lead to chronic sleep deprivation. Sleep disrupted by seizures or other causes also can
cause sleep deprivation. Adolescents should
be counseled about good sleep hygiene
(eg, avoid playing on the computer or watching television shortly before going to bed,
avoid caffeine after mid-afternoon, limit
naps during the day).102 If patients are
taking seizure medications that may keep
them up or make them drowsy, it may be
helpful to instruct the patients to take such
medications early in the day and shortly
before bedtime, respectively. When poor
sleep habits are suspected of contributing to
seizure activity, adolescents should be asked
to track their seizures in relation to their
sleep habits for a few months and then
encouraged to consider how they can
improve their sleep habits.
Many adolescents experiment with
alcohol and recreational drugs.102 Heavy
drinking or certain drugs may increase
seizure risk, or patients may miss their prescribed AEDs as part of rebellious behavior
or for fear of mixing their medication with
other substances.102,103 Although alcohol
intoxication probably does not cause
seizures, alcohol withdrawal is associated
with an increased risk of seizures.94 Patients
should be made aware that the combination
Allison is an overweight 16-year-old
female with a 7-year history of
ADNFLE. She recently presented to a
new neurology clinic after her family
moved to a different state. Allison is
taking valproic acid, and her seizures
occur about twice a month. They
previously occurred several times a
week. Since she has switched to a
different school, she has not told
new friends about her epilepsy, and
her parents have not shared this
information with the teachers and
administration. Allison has been
invited to a few sleepover parties
but has avoided these because she
is afraid that she may have a seizure.
In addition, Allison recently began
dating another student at her new
school. Her mother wants her to start
using birth control. The neurologist
discussed with Allison switching to a
different AED to try to achieve better
seizure control and help address her
weight problem. He also was concerned about the increased risk of
polycystic ovary syndrome with valproic acid. In addition, he counseled
Allison about the potential interactions between AEDs and oral
contraceptives. A decision was made
to switch to zonisamide 200 mg two
times a day (which may help with
weight loss). She was instructed to
make up any missed doses of
zonisamide, at any time, right up to
the next dose. The neurologist also
advised Allison to begin taking supplemental folic acid. Following the
switch, Allison’s nocturnal seizures
decreased to about once a month.
of alcohol ingestion and sleep deprivation
(ie, staying up late with friends while drinking) may provoke seizures.94,99,103
Adherence with AEDs is critical for
maintaining seizure control. Rebelliousness
and a desire to fit in with peers may drive
nonadherence in adolescents with epilepsy.
Other factors, such as forgetfulness, also
may contribute. Two cross-sectional online
surveys that included 153 US adolescents
with epilepsy and their matched caregivers
(n=153) examined self-reported adherence
rates and other aspects of self-care.104
Overall, 35% of adolescents and 31% of
their caregivers reported the patient had
been nonadherent, defined as having missed
a dose or stopped an AED within the past
month; 55% of adolescents and 58% of
caregivers reported the patient having
missed a dose or stopped taking an AED in
the time period between the past month
and more than 3 months ago. In addition,
39% of adolescents who had missed a dose
of medication or had stopped taking medication had suffered a seizure, presumably as a
consequence of nonadherence. Other negative consequences of missed doses/stopping
medication according to adolescent/caregiver report included missing school
(10%/13%), visiting the emergency department (8%/10%), requiring a doctor visit
(8%/7%), missing a social event (5%/6%),
and being hospitalized (2%/3%). Almost
20% of adolescents indicated they were
fearful of the physician’s anticipated reaction to their admission that they didn’t take
their medication as prescribed. The most
commonly reported reason for nonadherence was forgetfulness or not having
medication on hand (70% adolescent/
66% caregiver report). Other reasons are
shown in Figure 2.
Figure 2. Primary Reasons for Nonadherence Among Adolescents With Epilepsy104
Adolescent (n=87)
Caregiver (n=91)
100%
80%
70%
66%
60%
40%
15%
20%
15%
9%
16%
15%
13%
7%
9%
5%
9%
0%
Forgot/did not
have pills with me
Caregiver-related
issues
Side effects
Not sick/
not having symptoms
Not important
to take everytime
Social issues
Asato MR, et al,104 Copyright © 2009 by PSG Publishing Co. Reprinted by permission of SAGE Publications.
14
www.globalacademycme.com/primarycare • Optimizing Treatment of Adolescents With Partial-Onset Seizures
The findings of this study suggest that
while social reasons do contribute to nonadherence among adolescents, they are not
the most commonly cited reasons.104 The
caregiver was considered responsible for
medication adherence in most families
(~88%). Caregiver/parent reminders were
described as the most common method for
reminding patients to take their medication, and fitting medication into the daily
schedule and using a pillbox were methods
used by about half of the patients. Overall,
these results suggest that simplification of
the AED regimen and increased use of
reminder strategies that don’t depend on
the parents may be useful to improve adherence among adolescents. It is important to
educate patients and their parents about
the need to take epilepsy medication as
directed (including all doses), even when
the patient has been asymptomatic; any
attempts to reduce or discontinue medication should be done under physician
supervision. Clinicians can help patients
feel more comfortable about communicating about adherence by being open, honest,
and direct about health-related behaviors
and engaging with patients more directly
about their condition and other related
issues (eg, comorbidities, social issues).104,105
Notably, results of this survey indicate that
adolescents with epilepsy rely heavily on
their caregivers for medication management and adherence. Although this high
degree of dependence may be viewed as an
adaptive response to prevent seizures and
their negative consequences, this situation
may “impair the transition for adolescents
to independence in managing their medical
condition.”104 Educating adolescent
patients about the need for adherence, providing them with the tools and resources to
manage their medication, and encouraging
them to assume responsibility for their selfcare are important steps for helping
adolescents with epilepsy transition to
adulthood. Part of self-management of
medication involves establishing a strategy
for dealing with a missed dose or doses.
The specifics of such a strategy will depend
on the patient’s regimen, but should be
made clear and ideally should involve a
written plan.
Another important component of selfmanagement is having a seizure plan (ie, a
physician-recommended plan for what to do
when the patient has a seizure).104 In the
survey described previously, about half of
adolescents reported having a seizure plan.104
The seizure emergency plans included a
variety of items, such as taking rescue medication, avoiding injury, monitoring the
seizure duration, relaxing or sleeping after
the seizure, calling parents, and visiting the
emergency department.
As part of self-care, patients with epilepsy
will need to modify or restrict their activity
under certain circumstances. For example,
when bathing, patients should consider
taking a shower rather than a bath, having
an adult be aware of when they are in the
shower, and not locking the bathroom
door.11 To avoid scalding, it is recommended that patients with epilepsy use
safety devices that limit water temperature
and avoid shower levers that can be knocked
out of position easily, increasing water temperature.106 Females with epilepsy should
avoid curling and straightening irons to
prevent burns should a seizure occur.
Regular safety guidelines should be followed when participating in athletic
activities (eg, helmets for biking, swimming
in a supervised area and with a swim buddy).
Learning to drive is a major step in
gaining independence in adolescence.107
Therefore, driving restrictions are an
important concern.108 Being unable to drive
because of epilepsy can interfere with
employment and socialization and make
patients feel different from their peers.97,109
However, seizures that occur while driving
can lead to an accident, potentially resulting
in property damage, injury, and even
death.109 In the United States, patients with
controlled epilepsy usually are allowed to
drive with legal restrictions that vary from
state to state.109 Most states have requirements that necessitate that the patient be
seizure-free for a specified length of time
and require a physician’s statement confirming that seizures are well controlled and that
the patient will not present an unreasonable
risk to public safety if allowed to drive.110
In addition, six states (California, Delaware,
Nevada, New Jersey, Oregon, Pennsylvania)
require physicians to report to the state
patients who have seizures, whether or not
the seizures are well controlled. It is important to communicate with patients openly
about seizure risk and driving and educate
them about legal restrictions in their state.
The Epilepsy Foundation provides legal
information about epilepsy and driving and
includes links to driving laws by state.110
State-specific driving laws can be accessed
at the Epilepsy Foundation Web site.111
Issues around contraception and even
pregnancy may arise for female adolescents
with epilepsy. Several enzyme-inducing
Optimizing Treatment of Adolescents With Partial-Onset Seizures • www.globalacademycme.com/primarycare
Case Study 2
Connor is a 16-year-old male who presented following a partial-onset seizure
that lasted for about 1 minute, occurred
at home shortly before dinner time, and
was witnessed by his parents. The
seizure was preceded by a sense of
déjà vu. A careful history revealed that
the patient had experienced similar
seizures on two other occasions while
by himself. The results of Connor’s
physical and neurological exams were
normal. An EEG revealed right temporal
sharp waves. The neurologist diagnosed Connor with partial-onset
seizures and started him on carbamazepine 200 mg twice daily, with the
dose titrated to 200 mg three times a
day. Connor has had long-standing
learning difficulties in school. He is on
the baseball team, and his parents are
worried about him playing the rest of
the season. In addition, Connor recently
began taking driving lessons and is
looking forward to obtaining his permit.
The neurologist advised Connor and his
parents that he could continue playing
baseball, but he should make sure to
wear his helmet. He also reviewed the
state driving regulations for people with
epilepsy with Connor and his parents.
The neurologist also discussed with
Connor the need to take precautions,
such as letting his parents know when
he is showering. He carefully reviewed
the medication regimen with Connor
and discussed the importance of taking
his medications as directed to prevent
future seizures. At a follow-up visit
4 weeks later, Connor was continuing
to have seizures, and his mother indicated he frequently had been skipping
his mid-day dose to avoid having to go
to the nurse’s office to take his medication. The neurologist switched Connor
to the extended-release formulation of
carbamazepine. Despite adherence to
the new regimen, Connor continued to
experience seizures. Blood tests were
negative and did not reveal any signs of
substance abuse. A routine EEG showed
right temporal epileptiform spikes, and
an MRI revealed mesial temporal sclerosis. At this point, the neurologist
added levetiracetam to Connor’s treatment regimen. Connor was referred for
video EEG monitoring, at which time
medications would be changed and an
evaluation made as to whether he is a
good candidate for epilepsy surgery.
15
AEDs have the potential to lower contraceptive hormone levels
because of pharmacokinetic interactions (Table 13).33,112
If such AEDs are used in adolescent females who are taking contraceptives, then the contraceptive dose may need to be altered to
avoid unwanted pregnancy.113,114 It may be prudent to avoid low-dose
oral contraceptives in patients taking an enzyme-inducing AED,
such as carbamazepine.115 Pharmacokinetic interactions between
AEDs and contraceptives may result in reduced AED concentrations. Specifically, concurrent use of oral contraceptives may increase
lamotrigine clearance, resulting in diminished lamotrigine
levels.37,116,117 For females taking a stable dose of lamotrigine and not
taking other drugs that induce lamotrigine glucuronidation, it may
be necessary to increase the maintenance dose of lamotrigine by as
much as twofold when starting oral contraceptives to maintain a
consistent lamotrigine plasma level.37 The plasma concentration of
lamotrigine may increase substantially during the nonsteroid week
of contraception, resulting in toxic side effects and possibly requiring
dose adjustments to the overall maintenance dose of lamotrigine.37,118
According to the Centers for Disease Control’s US Medical
Eligibility Criteria for Contraceptive Use, theoretical or proven risks
outweigh the advantages of using carbamazepine, oxcarbazepine,
phenytoin, primidone, or topiramate concomitantly with combined
oral contraceptives (COCs), the contraceptive patch or ring, or the
progesterone-only pill (POP).119,120 In addition, theoretical or proven
risks are believed to outweigh the advantages of using lamotrigine in
conjunction with COCs or the contraceptive patch or ring because
of the impact of these contraceptive preparations on lamotrigine
concentrations.119,120
The AAN recommends that females with epilepsy take a folic acid
supplement (at least 0.4 mg/d) before they become pregnant to
reduce the risk of major congenital malformations.121 Folic acid
supplementation of sexually active female adolescents with epilepsy
also should be considered because planned or unplanned pregnancies
can occur.
Education and Behavioral Issues
Cognitive impairment is common in patients with epilepsy and may
occur as a consequence of the disease itself.122 In addition to IQ,
cognitive areas that may be affected include attention, language,
perceptual skills, executive functions (eg, problem solving), verbal
and visual memory, motor speed, dexterity, and coordination.
Because most common partial-onset seizures begin in the temporal
lobe and immediate structures, patients with temporal lobe epilepsy
often have memory problems.122 Cognitive deficits in adolescents
with epilepsy may contribute to academic difficulties, such as problems concentrating, keeping up with schoolwork, understanding
instructions, and retaining information.96
It is important to recognize and treat comorbid disorders, such as
attention-deficit hyperactivity disorder (ADHD), which may impact
academic function122 and impair HRQOL.123 Comorbidities,
especially psychiatric disorders, are strongly associated with impaired
HRQOL in adolescents with epilepsy.123 In a recent nationally
representative survey of US children and adolescents, individuals
with current epilepsy had higher rates of the following disorders
compared with those with no current or previous epilepsy diagnosis:
depression (8.4% vs 1.9%), anxiety (17.4% vs 2.7%), ADHD
(23.1% vs 6.2%), conduct disorder (15.6% vs 3.2%), and learning
disability (56.0% vs 7.3%).3 Behavioral reactions to the diagnosis of
epilepsy, such as acting out and not taking medication, also may be
problematic in adolescence.
16
Table 13. Effects of AEDs on Contraceptive Concentrations
Lowers Hormone Levels
Carbamazepine
Felbamate
Oxcarbazepine
Phenobarbital
Phenytoin
Primidone
Rufinamide
Topiramate (≥200 mg/d)
No Significant Effect
on Hormone Levels
Clonazepam
Ethosuximide
Ezogabine
Gabapentin
Lacosamide
Lamotrigine
Levetiracetam
Pregabalin
Tiagabine
Topiramate (<200 mg/d)
Valproate
Vigabatrin
Zonisamide
Pennell PB113; Potiga PI112; Reddy DS.114
In addition to disease-related problems, AEDs may adversely affect
cognition and behavior. Barbiturates and benzodiazepines have clear
adverse cognitive effects124,125 and may cause inattention and hyperactivity.126 Phenytoin and carbamazepine appear to have more
modest adverse effects on memory and other cognitive functions.124
Tiagabine, topiramate, and zonisamide have been associated with
cognitive slowing and difficulty concentrating.124,126 Gabapentin
treatment has been associated with hyperactivity and aggression in
patients with learning problems.126 Both aggressive behavior and
behavioral improvement have been observed with lamotrigine.124
Depressive symptoms have been associated with several AEDs,
including phenobarbital, levetiracetam, topiramate, tiagabine, and
zonisamide.126 Psychotic reactions may occur with phenytoin, ethosuxamide, vigabatrin, zonisamide, topiramate, lamotrigine, and
felbamate.124,126 Serious psychiatric and behavioral reactions may
occur with perampanel.50
Adolescents who are considering college or other postsecondary
education should be advised that schools cannot deny qualified
candidates admission or limit participation in academic and nonacademic programs based solely on their disability (ie, epilepsy).127 In
addition, students with a disability have the right to reasonable
accommodation. For patients with epilepsy, this may include accommodations such as extended test periods or note-taking services.
Patients and their families can find additional information and
resources at the Epilepsy Foundation Web site.127
Transitioning to Adult Care
Adolescents with epilepsy frequently are caught between pediatric
and adult care, with neither service able to fully address their special
needs.101,128 For older adolescents, there is a need for a more seamless
transition of care from the pediatric setting to an adult care setting
as well as a need for adolescents with epilepsy to function as independently as possible in promoting their own health.129 In 2011, the
American Academy of Pediatrics, American Academy of Family
Physicians, and American College of Physicians jointly published a
clinical report and consensus statement on strategies to support the
health care transition from adolescence to adulthood.129 This process
should ensure that high-quality, developmentally appropriate services are available continuously as the patient transitions from
adolescence to adulthood. While the transition to adult care ideally
should occur between 18 and 21 years of age, the first step in the
process (ie, discussing office transitions policy with the patient and
the parents) should begin at approximately 12 to 13 years of age or
www.globalacademycme.com/primarycare • Optimizing Treatment of Adolescents With Partial-Onset Seizures
when the patient presents during adolescence (Figure 3). Surveillance
should be conducted by age 12 years if possible (or when the patient
is diagnosed) to identify any special health care needs, and transition
planning should be initiated by age 14 years. The transition plan
should be reviewed regularly and updated as needed. In addition, it
is important to assess for changes in the patient’s medical status and
address concerns that may require changes in transition goals. By
16 to 17 years of age, plans for the transition should be well established. During the year before the transfer to adult services, a
pretransfer visit should occur. An adult model of care can be initiated
for most patients at age 18 years, even if no transfer of care occurs.
When the patient transitions to adult care, complete medical records
and a portable summary should be provided to the adult service.
Direct communication between pediatric and adult providers is
essential for adolescents with special health care needs.
Adolescents with epilepsy who fail to successfully transition to
adult care may lack specialty care; may not receive satisfactory adult
services; and may lack adequate follow-up, access to newer therapies,
and appropriate management of comorbid conditions.130 For children and adolescents with epilepsy, the close and comfortable
relationship with the pediatric neurology service and concerns about
quality of care and accessibility of adult health services may discourage a transition to adult care.130 The model of a transition clinic,
attended jointly by pediatric and adult neurologists in the adult
health care setting, has been proposed to facilitate a smooth transfer
to adult services for adolescents with epilepsy.130 Such a model could
increase family comfort and encourage dialogue between pediatric
and adult neurology providers over several visits while permitting
the pediatric neurologist to offer input on the patient’s care in the
adult treatment setting.
Figure 3. Health Care Transition Planning Algorithm for All Youth and Young Adults Within a Medical Home Interaction129
Medical Home Interaction
for Patients ≥12 Years of Age
2a
3a
No
Is the Patient
12–13 Years of Age?
Yes
Row 1: Medical Home Interaction
2b
3b
STEP 1: Discuss Office
Transitions Policy With
Youth & Parents
Is the Patient
14–15 Years of Age?
No
Yes
2c
Is the Patient
16–17 Years of Age?
Yes
3c
STEP 2: Ensure Step 1
Is Complete, Then Initiate a
Jointly Developed Transition
Plan With Youth & Parents
2d
No
Is the Patient
≥18 Years of Age?
Yes
3d
STEP 3: Ensure Steps 1 & 2
Are Complete, Then Review
& Update Transitions Plan &
Prepare for Adult Care
STEP 4: Ensure Steps 1,
2, & 3 Are Complete,
Then Implement
Adult Care Model
4
Yes
Incorporate Transition
Planning in Chronic Condition
Management (CCM)
Row 3: Action Steps for Specific Age Ranges
Row 4: Determination of Special Needs
Does Patient Have Special
Health Care Needs?
5a
Row 2: Age Ranges
No
5c
5b
Have Age-Appropriate Transitions
Issues Been Addressed?
No
Initiate Follow-Up
Interaction
Row 5: CCM and Follow-Up
Yes
Start
Action/process
Decision
Stop
6
Transition
Component
of Interaction
Complete
Row 6: Interaction Complete
Reproduced with permission from American Academy of Pediatrics,129 Copyright © 2011 by the AAP.
Conclusions
Epilepsy is the most common neurological disorder among adolescents.1 The presence of a serious condition such as epilepsy
adds to the challenge of transitioning from childhood to adulthood and can adversely impact the adolescent’s psychosocial
development and HRQOL. Management of epilepsy during this
developmental period is complicated by issues such as nonadherence. The management of patients with partial-onset seizures has
evolved during the last decade, and current treatment guidelines
for epilepsy are in the process of being revised. Despite the introduction of newer AEDs, treatment-resistant epilepsy remains a
significant problem among children and adolescents, affecting
between 10% and 40% of this patient population.41 A national
survey of adolescents with epilepsy and their caregivers revealed
that seizures were inadequately controlled in 32% to 37% of
patients and were poorly or not at all controlled in 10%.104
Surgery should be strongly considered for adolescents with partial-onset seizures who have failed treatment with at least two
AEDs. In addition, emerging pharmacotherapies, including brivaracetam, eslicarbazepine acetate, and rufinamide, are being
evaluated in pediatric and adult populations with inadequately
controlled seizures. Results from phase III trials of these agents
in adolescents and adults with uncontrolled partial-onset seizures
are promising, especially considering the treatment-resistant
nature of these patient populations.
Optimizing Treatment of Adolescents With Partial-Onset Seizures • www.globalacademycme.com/primarycare
17
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19
Optimizing Treatment of Adolescents With Partial-Onset Seizures CME Post-Test Answer Sheet
The Self-Assessment Questions are provided here for preview purposes only.
HOW To Receive Credit: Participants wishing to earn CME credit must: 1. Read the supplement. 2. Relate the content material to the learning objectives.
3. Complete the self-assessment questions and the evaluation form online at: www.cealliance.org/credit/CEE80512.
CME Questions: For each question or incomplete statement, choose the answer or completion that is correct. Circle the most appropriate response.
1. The number of Americans <18 years of age who are affected by
11.Video EEG monitoring is indicated for:
epilepsy is:
a.All adolescent patients with epilepsy
a.50,000
b.All epilepsy patients with a normal EEG pattern
b.100,000
c.All patients who continue to have seizures despite medical therapy
c.300,000
d.All patients with suspected temporal lobe sclerosis d.1 million
12.A high-fat, low-protein, and very low-carbohydrate diet most
2. Among adolescents and adults, the most common electroclinical
commonly used for children 5 to 10 years of age with refractory
syndrome(s) at initial diagnosis is (are):
epilepsy is the:
a.Epilepsy with generalized tonic-clonic (GTC) seizures alone
a.Atkins diet
b.Epilepsy with GTC seizures alone and juvenile absence epilepsy
b.Ketogenic diet
c.Juvenile absence epilepsy and juvenile myoclonic epilepsy (JME)
c.Low glycemic index diet
d.Juvenile absence epilepsy only
d.Modified Atkins diet
3. Partial-onset seizures do not:
13.Both randomized controlled studies comparing surgery with
a.Exhibit involvement of more than one network
continued medical management (CMM) in patients with treatmentresistant temporal lobe epilepsy observed:
b.Always originate within cortical structures
c.Exhibit local or wide distribution within a hemisphere
a.Improved quality of life in the CMM group versus the surgery group
d.Originate within brain networks confined to one hemisphere
b.Statistically significantly greater rates of seizure freedom in the CMM group
c.Statistically significantly greater rates of seizure freedom in the surgery
4. Structural imaging is not usually indicated for patients with:
group
a.Developmental regression
d.The mean number of AEDs decreased over time in the surgery group
b.Increased intracranial pressure
14.An AED that is considered weight-neutral is:
c.JME
a.Levetiracetam
d.Localization-related seizures other than benign childhood epilepsy with
centrotemporal spikes
b.Pregabalin
c.Topiramate
5. The most common condition misdiagnosed as epilepsy at epilepsy
d.Valproate
referral centers is:
a.Migraine
15.A novel FDA-approved AED for a symptomatic childhood epilepsy
b.Psychogenic nonepileptic attacks
syndrome that has been evaluated in phase III trials for treatment of
c.Syncope
inadequately controlled partial-onset seizures in adolescents and
adults is:
d.Transient ischemic attacks
a.Brivaracetam
6. A common epilepsy syndrome that typically begins in adolescence or
b.Eslicarbazepine acetate
adulthood and is characterized primarily by partial-onset seizures is:
c.Perampanel
a.Autosomal dominant nocturnal frontal lobe epilepsy
d.Rufinamide
b.Mesial temporal lobe epilepsy
c.Panayiotopoulos syndrome
16.The proportion of adolescents who do not take their AED medication
d.Reading epilepsy
as directed over 1 month is approximately:
a.15%
7. Which of the following statements about JME is false?
b.35%
a.All patients have myoclonic jerks
c.65%
b.Onset is usually during adolescence
d.85%
c.Patients may also exhibit persistently focal electroencephalogram (EEG)
abnormalities (in addition to typical generalized EEG abnormalities)
17. The most common reason for medication nonadherence among
d.Structural lesions on magnetic resonance imaging in JME are associated
adolescents with epilepsy is:
with poor therapeutic response
a.Forgetfulness/not having medication on hand
b.Side effects
8. An antiepileptic drug (AED) recommended by the American Academy
of Neurology guidelines as a first-line treatment for partial-onset
c.Teenage rebellion
seizures in adolescents is:
d.Worry about stigmatization/wanting to fit in
a.Pregabalin
18.An AED that lowers oral contraceptive hormone levels is:
b.Tiagabine
a.Ezogabine
c.Topiramate
b.Gabapentin
d.Zonisamide
c.Lamotrigine
9. A newer AED indicated by the US Food and Drug Administration
d.Oxcarbazepine
(FDA) as monotherapy for adolescents with partial-onset seizures is:
19.More
than half of children and adolescents with epilepsy are also
a.Lacosamide
affected
by:
b.Levetiracetam
a.Anxiety
c.Oxcarbazepine
b.Attention-deficit hyperactivity disorder
d.Zonisamide
c.Depression
10.Treatment resistance is defined as failure of:
d.Learning disability
a.An adequate trial of one tolerated and recommended first-line AED to
20.The
first step in the process of transitioning to adult care (ie,
reduce seizure frequency
discussing office transitions policy with the patient and the parents)
b.An adequate trial of one tolerated and appropriately chosen and used AED
for patients with chronic disease should ideally begin at age:
to achieve sustained seizure freedom
a.12 to 13 years
c.Adequate trials of two tolerated and appropriately chosen and used AEDs
b.14 to 15 years
(as monotherapies or in combination) to achieve sustained seizure freedom
c.16 to 17 years
d.Adequate trials of two tolerated and appropriately chosen and used AEDs
d.18 to 19 years
(as monotherapies or in combination) to reduce seizure frequency
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