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What’s New, What’s Hot:
The 2015 AES Hot Topics
Symposium
Emily L. Johnson, MD
Johns Hopkins School of Medicine, Baltimore, Maryland
A REPORT FROM THE 69th ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY
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1
Importance of Genetics in Epilepsy
A growing body of evidence is emerging for the
importance of genetics in epilepsy:
» Results of twin studies have shown that monozygotic twins
»
»
»
have a higher rate of concordance than do dizygotic twins.
Family studies have shown that the risk of generalized
epilepsy is 10% in siblings of a patient with the same
condition, and the risk of focal epilepsy is 5% in siblings of
patients with focal epilepsy.
Phenotypic studies have identified families with inherited
epilepsy syndromes, such as generalized epilepsy with
febrile seizures plus (GEFS+).
Genetic studies of these families using copy-number
variants, linkage analysis, and positional cloning have
produced discoveries of associated genes.
Vadlamudi L et al. Neurology. 2014;83:1042; Hartmann C et al. Epilepsia. 2015;56:e26–e32.
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2
History of Epilepsy Genetics
Discoveries related to epilepsy genetics have increased
exponentially over the past few years:
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3
History of Epilepsy Genetics continued

Before 2001, the “channelopathy era” saw the
discovery of specific channel mutations.

From 2001 to 2009 (the “dark ages” of epilepsy
genetics) more than 100 association studies yielded
negative or irreproducible results.

Since 2009, the study of microdeletions, microduplications, and next-generation sequencing has led to
an exponential increase in epilepsy genetics.
» Example: a recent study of 805 children with epilepsy
found that 40 patients (5%) had microdeletions or
microduplications that explained the patient’s epilepsy
phenotype.
Olson H et al. Ann Neurol. 2014;75:943
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4
Patterns of Genetic Epilepsy

Patterns of genetic epilepsy include inherited genes,
de novo mutations, and de novo postzygotic
mutations.

Inherited genes may be autosomal dominant or
autosomal recessive.

In genome-wide association studies of patients with
infantile spasms or Lennox-Gastaut syndrome (LGS)
and their parents, de novo causative mutations can
be identified; increasing the size of these studies
allows better identification of enriched de novo
mutations in patients with epileptic encephalopathy
when compared with the general population.
Poduri A, Lowenstein D. Curr Opin Genet Dev. 2011;21:325; EuroEPINOMICS-RES Consortium, Epilepsy
Phenome/Genome Project, and Epi4K Consortium. Nature. 2013;501:217; Am J Hum Genet. 2014;95:360.
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5
Which Patients Should Be Tested?
Genetic testing should be undertaken when diagnostic
certainty and prognosis are important; identifying
genetic causes of epilepsy can help to improve patient
care by leading to clinically relevant models, preclinical
trials, and precise treatment:
» For example, a 6-month-old boy with new-onset infantile
spasms and hypsarrhythmia (with negative MRI findings)
who has a specific mutation in a gene associated with
epilepsy or infantile spasms could forgo further workup
(eg, metabolic testing, lumbar puncture).
» Likewise, a teenage patient with a history of juvenile
myoclonic epilepsy and a family history of generalized
seizures can be reassured that the disease is benign and
nonprogressive after genetic test results are gathered.
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Which Patients Should Be Tested? continued
Another reason to perform genetic testing is when
information on specific genes can guide specific
treatments to pursue or avoid, such as mutations
in the following genes:
» SCN1A, in which lamotrigine and phenytoin should be
avoided;
» SCN2A, in which high-dose phenytoin therapy may be
helpful;
» SLC2A1, in which the ketogenic diet may be useful;
» ALDH7A1, in which response to pyridoxine may be
expected; and
» PNPO, in which patients may respond to pyridoxal-5phosphate.
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7
Which Patients Should Be Tested? continued

Other mutations may be related to promising
off-label use of specific treatments, although more
information is needed; they include mutations of:
» KCNQ2, in which ezogabine therapy could be considered;
» KCNT1, in which quinidine use could be helpful; and
» GRIN2A, in which memantine could be prescribed.

For patients with epilepsy and tuberous sclerosis,
treatment with everolimus could be considered.
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8
Which Patients Should Be Tested? continued

Patients with “epilepsy plus” syndromes—the
combination of epilepsy with dysmorphic features,
intellectual disability, infantile spasms, or autism—
also should undergo genetic testing.

The clinical picture may suggest a classic syndrome
associated with a single gene:
» For example, Down syndrome suggests trisomy 21 (verified
with a karyotype);
» Dravet syndrome suggests a SCN1A mutation (tested with
SCN1A sequencing for deletion or duplication); and
» Rett syndrome suggests a MECP2 mutation (which can be
sequenced for deletion or duplication).
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9
Which Patients Should Be Tested? continued

Patients with refractory epilepsy that affects
treatment should also be tested, particularly if
surgery is considered.

Examples are patients with early-onset epileptic
encephalopathy, patients < 4 years of age with earlyonset absence seizures, and patients with familial
focal epilepsy.

In refractory cases, an identifiable genetic cause may
influence the consideration of surgical treatment.
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10
Options for Genetic Testing

Available options for genetic testing include:
» Chromosomal microarray analysis;
» Single-gene testing (sequencing, duplication, deletion
testing);
» Panel testing, including an “epilepsy panel” or “autism
panel”; and
» Whole-exome sequencing.

When a phenotype highly suggests the diagnosis of a
specific syndrome, testing for that syndrome should
be performed.
» For example, when pyridoxine-related epilepsy is suspected,
testing for a mutation in ALDH7A1 should be done.
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11
Options for Genetic Testing continued

A patient with a history and examination suggesting
Angelman syndrome should undergo chromosomal
microarray analysis.
» If the results of UBE3A sequencing are negative, an
epilepsy panel for Angelman-like genes should be
considered.
» If all results are negative, whole-exome sequencing should
be performed, since the syndrome is highly likely to be
genetic.

For early-onset absence seizures that occur before
the age of 4 years, the SLC2A1 gene should be tested,
and determination of glucose levels in cerebrospinal
fluid (CSF) can be considered.
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12
Options for Genetic Testing continued

For patients with “epilepsy plus” or early-onset
refractory epilepsy, a chromosomal microarray
analysis and epilepsy gene panel are recommended,
with progression to whole-exome sequencing if
initial tests are negative.

If the results of all genetic tests are negative, patients
can be referred to a registry of people with specific
genetic epilepsies (eg, Dravet syndrome), individual
research studies, the Rare Epilepsy Network
(https://ren.rti.org/), or the Epilepsy Genetics
Initiative (http://www.cureepilepsy.org/egi/).
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13
Autoimmune Epilepsy

Immune epilepsy is said to be present when there is
evidence of autoimmune-mediated inflammation of
the central nervous system (CNS), according to the
International League Against Epilepsy.
» Examples of immune-mediated epilepsy include anti-LGI1
encephalitis and anti-NMDA receptor encephalitis.

Similarly, autoimmune epilepsy is autoimmune
encephalitis with a predominant epileptic phenotype.

Approximately 80% of people with autoimmune
encephalitis have epilepsy or seizures, and some 2%
of all epilepsies have an autoimmune etiology.
International League Against Epilepsy. ILAE Revised Terminology for Organization of Seizures and Epilepsies,
2011–2013; Irani SR et al. Curr Opin Neurol. 2011;24:146
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14
Autoimmune Epilepsy continued

Antibodies causing autoimmune epilepsy are
immunoglobulin-G (IgG) complexes directed against
extracellular or intracellular central nervous system
(CNS) antigens.

Extracellular antigens include AChR (GlyR),
NMDAR, LGI1, and CASPR2.

Intracellular antibodies include GAD65 and VGKC.

Rates of association with systemic malignancies vary,
depending on the autoantibody.
Vincent A et al. Lancet Neurol. 2011;10:759
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15
Autoimmune Epilepsy continued

In a study of 300 patients, epilepsy was the second
most common cause of autoantibody testing (22%)
after encephalitis or encephalopathy (42%).

Autoantibodies were less often tested for in patients
with cognitive or psychiatric disorders (9%) or
peripheral neurologic disorders (4%).

The frequency of positive antibodies identified in
that laboratory was 4.7% (out of 6,893 patients).

The most commonly detected antibody was GAD65
(27.9%); the next most common were NMDAR
(23.4%) and LGI1 (18.1%).
Dogan Onugoren M et al. J Neurol Neurosurg Psychiatry. 2015;86:965
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16
Suggestive Clinical Features

Specific syndromes, including limbic encephalitis,
faciobrachial dystonic seizures, and encephalopathy,
raise the possibility of autoimmune epilepsy.

Young women with epilepsy and patients with other
autoimmune diseases also are at increased risk.

Other seizure types and patterns that raise the
possibility of autoimmune epilepsy include:
» Pilomotor seizures;
» Unexplained new-onset epilepsy in adult life; and
» New-onset epilepsy with status epilepticus or with a very
high frequency of seizures.
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17
Suggestive Diagnostic Features

The presence of an “extreme delta brush” (which has
been associated with NMDAR encephalitis) on an
electroencephalogram (EEG)

An elevated cell count in the CSF

Unmatched oligoclonal bands in the CSF but not in
the serum

Encephalitic lesions on MRI, especially in the
mediotemporal areas

Histopathology showing “chronic encephalitis”
Dogan Onugoren M et al. J Neurol Neurosurg Psychiatry. 2015;86:965; Bien CG. Epilepsia. 2013;54(Suppl
2):48; Schmitt SE et al. Neurology. 2012;79:1094
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18
Incidence of Autoimmune Epilepsy

The incidence of antibody-confirmed autoimmune
epilepsy may be surprisingly high.

In one study of 19 women (age, 15–45 years) with
new-onset epilepsy and no obvious preceding cause
or syndrome, 5 (26%) had NMDAR antibodies.
» Of those five women, four (80%) had prominent psychiatric
symptoms.

In a series of 13 patients with new-onset status
epilepticus, 8 (62%) had NMDAR antibodies;
9 (69%) had oligoclonal bands in the CSF; and
additional patients had GAD65, Ri, and neuropil
antibodies.
Niehusmann P et al. Arch Neurol. 2009;66:458; Holzer FJ et al. Eur Neurol. 2012;68:310
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19
Which Tests Should Be Ordered?

Although CSF-only antibodies are found in < 25% of
cases, antibody testing of the CSF is more sensitive
than serum testing for NMDAR antibodies.

In a study of 250 patients with confirmed NMDAR
encephalitis, CSF antibodies were detected in all 250
patients, but serum antibodies were detected in only
214 patients on both immunohistochemical and cellbased assays.

Serum-only LGI1 and ampiphysin antibodies are
common.

Consequently, paired CSF and serum specimens
should be sent to the laboratory whenever possible.
Gresa-Arribas N et al. Lancet Neurol. 2014;13:167
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20
Significance of Antibody Testing

Positive antibody test results must be compared with
the clinical response of patients.

The specificity of some tests are not confirmed (eg,
the significance of NMDAR antibodies in serum
only; CASPR2 at < 1:200; VGKC complex antibodies
other than those directed to LGI1/CASPR2).

Positive findings on nonspecific tests should be
treated with caution.

Non-IgG antibodies have no proven clinical
significance.
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21
Treatment of Autoimmune Epilepsy
If the presence of
autoantibodies is
confirmed by
testing, a suggested
treatment approach
using several drugs
off label may be
tried.
Bien CG, Bien C. Z Epileptol. 2015;28:201; Dalmau J et al. Lancet Neurol. 2011;10:63
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22
Treatment of Autoimmune Epilepsy continued

If the antibody test is not confirmatory (“gray
cases”), 80 mg/d of prednisolone for 4 weeks can be
tried, followed by tapering the dosage by 10 mg/d
each week to 10 mg/d.

If no clinical improvement is noted after 3 months,
discontinue prednisolone.

If the patient shows partial improvement, increase
the dosage of prednisolone or switch to rituximab
and/or cyclophosphamide.

If the patient has had a clinical remission, continue
giving 5 mg/d of prednisolone for 6 months.
Bien CG, Bien C. Z Epileptol. 2015;28:201
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23
Treatment of Autoimmune Epilepsy continued

Treatment responses to immunotherapy can be high.

One study of 30 patients with autoimmune epilepsy,
including 21 patients (69%) with daily seizures, who
had been treated with monthly methylprednisolone
or intravenous immunoglobulin found that 62% of
the patients had a  50% reduction in seizure
frequency, including 10 patients (33%) who were
seizure-free.
Toledano M et al. Neurology. 2014;82:1578
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24
Valproate Safety in Women

The European Medicines Agency in 2014 advised
doctors in the EU not to prescribe valproate “for
epilepsy or bipolar disorder in pregnant women, in
women who can become pregnant, or in girls unless
other treatments are ineffective or not tolerated.”

This followed a drug safety announcement issued by
the FDA in 2013 stating that “valproate products
should only be prescribed if other medications are
not effective in treating the condition or are otherwise
unacceptable…. All non-pregnant women of
childbearing age taking valproate products should
use effective birth control.”
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25
Valproate Safety in Women continued

However, many providers in the epilepsy community
are concerned that the alternatives to valproate in
treating generalized idiopathic/genetic epilepsies may
not be as effective.

The risk of uncontrolled seizures is not considered,
and women may be encouraged to rapidly discontinue
valproate during pregnancy, with potentially serious
consequences.

In a recent study, epilepsy-related deaths, mainly
sudden unexplained death in epilepsy patients
(SUDEP), accounted for 4%–7% of maternal deaths—
10-fold higher than expected—in the United Kingdom.
Edey S et al. Epilepsia. 2014;55:e72
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26
Risks of Taking Valproate
The risk of major
congenital
malformations
(MCMs) among
pregnant women
taking valproate is
higher than that
associated with
other antiepileptic
drugs (AEDs) and
is dose dependent.
Tomson T et al. Lancet Neurol. 2011;10:609; Hernandez-Diaz S et al. Neurology. 2012;78:1692; Tomson T,
Battino D. Lancet Neurol. 2012;11:803
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27
Risks of Taking Valproate continued

Adding other AEDs to valproate has no major impact
on the frequency of MCMs.

In utero exposure to valproate negatively impacts
neurodevelopmental/cognitive outcomes and IQ
when measured at 3 and 6 years of age.

These cognitive findings are also most significant
when high doses of valproate (> 800 mg/d) are used.

In addition, there is an increased absolute risk of
autism spectrum disorder after valproate exposure in
utero.
Tomson T et al. Neurology. 2015;85:866; Meador K et al. N Engl J Med. 2009;360:1597; Meador K et al. Lancet
Neurol. 2013;12:244; Baker GA et al. Neurology. 2015;84:283; Wood AG et al. Epilepsia. 2015;56:1047
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28
Task Force Recommendations

In 2015, the ILAE Commission on European Affairs
and the European Academy of Neurology jointly
recommended that “whenever possible, valproate
should be avoided in the treatment of girls and
women of childbearing potential.”

The task force recommended that women with
epilepsy be informed about the teratogenic risks of
valproate, and the drug should not be used to treat
focal epilepsy; if valproate is used in women of
childbearing potential, it should be given at the
lowest effective dose, and women not planning
pregnancy should use effective birth control.
Tomson T et al. Epilepsia. 2015;56:1006
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29
Task Force Recommendations continued

In cases of newly diagnosed generalized epilepsies,
the risks and benefits of valproate versus those of
alternative therapies should be carefully weighed.

Valproate is a reasonable choice provided that the
woman is fully informed about its risks and benefits
and is not planning pregnancy.

Valproate is also appropriate therapy for girls with
epilepsy when there is a high likelihood of seizure
remission and AED discontinuation before puberty.

Valproate treatment also may be considered in
patients with severe or disabling epilepsies for whom
the likelihood of pregnancy is extremely low.
Tomson T et al. Epilepsia. 2015;56:1006
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30
Task Force Recommendations continued

For women already taking valproate who are not
planning pregnancy, use of a different AED should
be considered if seizure control is suboptimal.

For women with seizures that did not respond to
other AEDs before valproate therapy was started,
continuation of valproate is reasonable.

If seizures are controlled, valproate withdrawal or a
change in therapy should be considered if the risk of
relapse is acceptable to the patient.

Because the risk of major congenital malformations
is dose dependent, total daily doses should be
reduced to below 600 mg if valproate is continued.
Tomson T et al. Epilepsia. 2015;56:1006
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31
Task Force Recommendations continued

In patients with generalized genetic epilepsies,
patients and clinicians together may agree that
continuing valproate is reasonable after carefully
weighing the risks and benefits.

When possible, the lowest effective dose of valproate
should be established before conception.

If seizures are well controlled on low doses of
valproate (< 600 mg/d), and if the patient considers
the risk of withdrawal or switching to another AED
unacceptable, continued low-dose valproate therapy
may be considered.
Tomson T et al. Epilepsia. 2015;56:1006
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32
Task Force Recommendations continued

Women already on valproate who become pregnant
should try to reduce their dose below 600 mg/d if
the risk is acceptable to the patient (usually when the
history suggests that the patient does not need a high
dose for seizure control).

Pregnant women with epilepsy should consider
withdrawing from valproate therapy if they agree
that they do not need the drug for seizure control or
are willing to switch to another AED.
Tomson T et al. Epilepsia. 2015;56:1006
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33
Cannibinoids: Preclinical Studies

Tetrahydrocannabinol demonstrated anticonvulsant
effects in a majority of preclinical studies and
proconvulsive effects in a minority of those studies.

Cannabidiol (CBD), by comparison, demonstrated
anticonvulsant effects in the majority of studies and
no proconvulsant effects.
CBD has multiple molecular targets, including ion
channels and enzymes; many of these targets have
been demonstrated only in vitro.
Animal studies of cannabinoids have shown promise
in protecting mice and rats from cocaine- and kainic
acid-induced seizures.


Fezza F et al. Mol Cell Neurosci. 2014;62:1; Whalley B. American Herbal Pharmacopoeia. 2014; Ibeas Bih C et al.
Neurotherapeutics. 2015;12:699; Vilela LR et al. Toxicol Appl Pharmacol. 2015;286:178
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34
Cannibinoids: Clinical Studies
In a survey of
families with
children taking
CBD for infantile
spasms, LennoxGastaut syndrome
(LGS), and severe
myoclonic epilepsy
of infancy (Dravet
syndrome), the
majority of families
reported a decrease
in seizure frequncy.
Hussain SA et al. Epilepsy Behav. 2015;47:138
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35
Cannibinoids: Clinical Studies continued

In a retrospective study of 75 patients in Colorado
(mean age, 7 years), one third of the families
reported at least a 50% decrease in seizures, and two
families reported seizure freedom in their children.

Families that had children with LGS reported the
highest decrease in seizures.

Eleven families (15%) discontinued CBD, mostly due
to inefficacy.

Although 44% of families reported adverse effects of
CBD, 33% of families reported seeing improved
alertness or behavior, and 11% saw improvements in
motor and language skills.
Press CA et al. Epilepsy Behav. 2015;45:49
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36
Cannibinoids: Clinical Studies continued

Efficacy and safety data from 261 patients treated for
3 months in a CBD expanded-access program
showed a mean decrease in seizure frequency of
45%, while patients with Dravet syndrome
experienced a decrease of 62.7% in seizure frequency
and those with LGS, a drop of 71.1%.

Seizure freedom was achieved by 9% of the patients.

Somnolence and diarrhea were the most common
side effects of CBD (23%), and serious side effects
occurred in 106 patients, including death in seven
gravely ill patients.
Devinsky O et al. AES 2015, Poster 3.397
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37