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Epilepsy Board Review
Epilepsy Board Review
Koubeissi
Nabil J. Azar Editors
Epilepsy
Board Review
A Comprehensive Guide
123
Epilepsy Board Review
Mohamad Z. Koubeissi
Nabil J. Azar
Editors
123
Editors
Mohamad Z. Koubeissi Nabil J. Azar
Epilepsy Center Associate Professor of Neurology
George Washington University Epilepsy Division
Washington, DC Vanderbilt University Medical Center
USA Nashville, TN
USA
vii
viii Contents
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
Contributors
xi
xii Contributors
the cell membrane. Table 1.1 shows the intracel- This triggers a cascade of events leading to the
lular and extracellular concentrations of these ions fusion of presynaptic vesicles with the membrane
and their equilibrium potentials in a typical of the presynaptic terminal, thereby releasing
mammalian neuron. The membrane potential at neurotransmitter molecules into the synaptic
which there is no net flow of ions across the cell cleft. Binding of neurotransmitters to the recep-
membrane is the resting membrane potential tors on the postsynaptic terminal activates ion
which can be calculated using the Goldman– channels associated with them, allowing the
Hodgkin–Katz equation. The major contributor of passage of ions leading to local changes in
resting membrane potential is the potassium leak membrane potential (Fig. 1.1). Such local chan-
channels with a net outward flow of potassium ges in membrane potential are known as post-
ions (K+) under resting conditions. An action synaptic potentials (PSPs) which are
potential is generated when the negativity in the nonpropagated small-amplitude potentials lasting
interior of the neuron, i.e., the resting membrane 10–100 ms. PSPs can be excitatory (excitatory
potential, decreases to a critical point (typically postsynaptic potential (EPSP)) or inhibitory (in-
around −40 mV). The voltage-gated sodium hibitory postsynaptic potential (IPSP)) depending
channels play a major role in the generation and on the type of ion channel activated and the
propagation of action potential by allowing electrochemical gradient for ions that can pass
sodium to enter into the soma. Once generated, the through the channel. EPSPs generally result from
action potential—a short duration (usually less an inward flow of positive ions such as sodium or
than 2 ms) high-amplitude wave of depolarization calcium and cause depolarization (excitation),
—travels through the neuronal processes and thus decreasing the threshold for triggering an
reaches synapse, a specialized contact between action potential in the postsynaptic terminal. On
neurons usually between axons and dendrites. the other hand, IPSPs result from an inward flow
Synaptic transmission is the major mode of of negative ions (e.g., chloride) or outward flow
transmission of information from one neuron to of positive ions (e.g., potassium) and cause
another. Each synapse has a presynaptic terminal hyperpolarization (inhibition), thus increasing the
containing neurotransmitters in vesicles and a threshold for triggering an action potential in the
postsynaptic terminal containing receptors for the postsynaptic terminal.
neurotransmitters. Neurotransmitters are released A single EPSP or IPSP is not sufficient
from the presynaptic terminal when an action enough to move the membrane potential of the
potential causes sufficient change in the voltage postsynaptic terminal to or away from the
(depolarization) at the presynaptic terminal to threshold for triggering of action potential.
activate voltage-gated calcium channels allowing Summation of several PSPs is necessary for that
calcium to enter into the presynaptic terminal. purpose. Such summation can be spatial
Table 1.1 Intracellular and extracellular concentrations of ions that play a major role in determining the resting
membrane potential in a mammalian neuron
Ion Intracellular (mM) Extracellular (mM) Equilibrium potential (mV)
Potassium (K*) 140–150 5 –90
Sodium (Na*) 5–15 145 +60
Chloride (Cl) 4–30 110–125 –70
1 Physiologic Basis of EEG and Epilepsy 5
secondary phenomenon resulting from the electrode at a distance would record negativity
development of potential gradients between areas because of an outflow of negative ions (or an
of localized membrane potential change and the inflow of positive ions) associated with the cur-
remaining areas of the neuronal membrane. rent flowing through the extracellular space.
A ‘sink’ is generated at the site of an EPSP Therefore, polarity of extracellular field
because of an inflow of positive ions into the potentials recorded by surface electrodes on EEG
localized area of the neuron, and there is a cor- depends on the direction of current flow as well
responding ‘source’ at a distance where positive as on the position of the electrode relative to the
ions come out of the neuron; current flows from location of the generator. This translates to the
the ‘source’ to the ‘sink’ in the extracellular fact that superficial EPSPs and deep IPSPs will
space giving rise to the extracellular field show the same polarity (negative) on a surface
potential. Thus, a recording electrode close to the recording electrode. Likewise, superficial IPSPs
synapse receiving an excitatory input (EPSP) and deep EPSPs will show the same polarity
would record a negative potential because of an (positive) on a surface recording electrode
inward flow of positive ions causing negativity in (Fig. 1.3). Thus, orientation of neurons and their
the extracellular space nearby, whereas a deep processes, as well as location of synaptic contacts
recording electrode at a distance would record with respect to the cortical surface, are important
positivity because of an outflow of positive ions determinants of extracellular field potentials
associated with the current flowing through the recorded by EEG electrodes.
extracellular space. The reverse is true for an Pyramidal neurons in the cerebral cortex are
inhibitory input (IPSP): A recording electrode arranged in vertical columns with their cell
close to the synapse receiving an inhibitory input bodies typically in the layer III or V and their
(IPSP) would record a positive potential because processes (dendrites and axons) spanning the
of an inward flow of negative ions (or an outward entire column and receiving thousands of
flow of positive ions), whereas a recording synaptic contacts. This allows for summated
Fig. 1.2 Basic mechanisms underlying the generation description is based on the assumption that an extended
of potentials (electroencephalogram (EEG)) and of mag- neuronal process, e.g., a dendrite, is locally depolarized
netic fields (magnetoencephalogram (MEG)) in the by the activation of an excitatory synapse. Adapted
extracellular space of central nervous system. The from [1]
1 Physiologic Basis of EEG and Epilepsy 7
(a) (c)
EPSP IPSP
(b)
Fig. 1.3 Membrane potential (MP) changes and field deeper recording (E2). a(2) The activation of a deep
potentials (FPs) elicited by the activation of excitatory excitatory synapse elicits a current flow with inverse
and inhibitory synapses in the central nervous system. direction as compared with a(1). Therefore, the extracel-
The elementary processes are explained by means of a lular FP consists in a positive deflection at the surface and
neuronal element (hatched area), the one end of which in a negative one at the depth. b(1) The outward current
contracts the surface of a structure in the central nervous at S generates an IPSP in the region of ME2, as well as in
system. The MP of the neuron element is recorded at both that of ME1. Due to the direction of the extracellular
ends by the microelectrodes ME1 and ME2. The extra- current flow, the FP generated consists in a positive
cellular field is picked up at the surface of the neuronal fluctuation in the depth (E2) and in a negative one in the
structure by the electrode E1, as well as in the vicinity of surface recording (E1). b(2) The current flow during the
ME2 by the electrode E2. Active excitatory and inhibitory activation of a superficial inhibitory synapse is inverse as
synapses are marked by open triangles and black trian- compared with b(1). Therefore, the FP recorded from the
gles (S), respectively. a(1) The inward current at S surface consists of a positive fluctuation. Differences in
generates an EPSP that appears in the region of ME1, the time course of the various potentials are caused by the
as well as in that of ME2. Because S is located electrical properties of the tissue. c Schematic summary
superficially, the FP generated, due to the direction of of the polarity of the potential recorded on the scalp with
the extracellular current flow (arrows), is of negative an EEG recording electrode based on the occurrence of
polarity at the surface (E1) and of positive polarity in the (superficial vs. deep) EPSP or IPSP. Adapted from [1]
potentials with a vertical dipole or a dipole ori- the electrode. Most of the cortical activity
ented at an angle to the recording electrodes recorded from subdural or depth electrodes is not
(discussed further below) which can be recorded evident in the scalp EEG due to the attenuation
on EEG. On the other hand, summated potentials by the intervening scalp and skull.
resulting in horizontal dipoles (oriented parallel The EEG pattern is thought to depend on
to the recording electrodes) cannot be generally numerous areas of the cerebral cortex with
recorded on EEG. Subcortical structures have an opposite electrical poles (dipoles) that constantly
indirect influence on scalp EEG. Of note, to fluctuate. Thus, the EEG signal at a scalp elec-
produce a scalp EEG signal, 6 cm2 or more of trode can be viewed as a result of currents gen-
synchronously active area of cortex is required. erated by a negative and a positive dipole layer in
Scalp electrodes record volume-conducted the electrode ‘view.’ The potential recorded at the
potentials. Signal decreases proportionally to electrode is proportional to the solid angle sub-
the square of the distance between the source and tended by the dipole layer as shown in Fig. 1.4.
8 S. Bandyopadhyay et al.
Fig. 1.4 Use of the solid angle rule to ascertain the electrode A is actually lower than that measured by the
signal measured on the scalp surface relative to the more distant electrode B because of the arrangement of
orientation of the dipole. Top Surface electrode B sees a the dipoles in the discharging region. The smaller solid
large electrical potential because of the orientation and angle, ΩA, is proportional to the voltage measured on the
proximity of the dipole layer, as borne out by the solid scalp. Adapted from [2]
angle ΩB. Bottom In this case, the potential seen by the
1 Physiologic Basis of EEG and Epilepsy 9
Fig. 1.5 There are unusual sources wherein both the middle row of illustrations, the positions of the electrodes
negative and the positive poles are recorded on the on the scalp, relative to the discharging cortex, are shown.
surface. The bottom row of figures shows a patch of cortex The top row illustrates the voltage that would be recorded
containing gyri and sulci. The darker areas represent the on the EEG as a function of the distance along the scalp
cortical mantle that is activated by an epileptic discharge, right below it. Adapted from [2]
with negative and positive poles highlighted. In the
If adjacent active regions of the cortex have the bursts giving rise to fluctuating field poten-
voltage fields with different dipole orientations, tials. When recording from surface is done with
they summate in relation to their representative an amplifier with a finite time constant (as in
field vectors. For example, if two cortical areas conventional EEG), such fluctuations in field
have an opposite dipole orientation such as the potential are recorded as waveforms (Fig. 1.6).
two sides of a sulcus, cancelation occurs, and no Sustained firing of the afferent fiber leads to
voltage field is evident at the scalp. When the sustained depolarization of the apical dendrites
dipole is vertical and the electrode is directly causing a depolarization shift which is not
above it, the electrode records the field maximum reflected on the surface in conventional EEG
(Fig. 1.5). As the orientation of the dipole recorded with an amplifier with a finite time
becomes progressively less radial and more tan- constant. Sustained changes in field potential
gential to a recording electrode, the electrode (baseline shifts) can be recorded using a direct
records a voltage field of lesser amplitude. If the current or DC amplifier that has an infinite time
dipole is directly below the electrode but it is constant (Fig. 1.7). Such recordings are not done
perfectly tangential, the electrode records no from the scalp because of technical difficulties
potential because of its location on the zero and are usually performed in experiments in
isopotential line of the source scalp field. animal models. Of note, not only baseline shifts
are generated by neurons; but glial cells also
contribute to its generation. Increased firing of a
Wave Generation and Baseline Shifts deep-seated neuron causes rise in extracellular
potassium concentration which in turn leads to
When an afferent fiber forming an excitatory depolarization of glial cell superficial to it. Such
synapse on an apical dendrite near the surface depolarization of the glial cell electrotonically
produces bursts of action potentials interrupted spreads to the glial cell network coupled by gap
by periods of quiescence, EPSPs sum up during junctions.
10 S. Bandyopadhyay et al.
Fig. 1.6 Wave generation in the electroencephalogram action potentials in the afferent fiber generate wavelike
(EEG) at the surface of the cerebral cortex. A perpendic- excitatory postsynaptic potentials (EPSPs) in the dendritic
ular pyramidal neuron is shown. An afferent fiber formed region and corresponding waves in the EEG recording.
an excitatory synaptic contact at the superficial part of the Tonic activity in the afferent fiber results in long-lasting
apical dendrite. Simultaneous recordings of the membrane EPSP with only small fluctuations. The long-lasting
potentials (MPs) of the afferent fiber and the dendritic depolarization is not reflected on the conventional EEG
element, as well as of the EEG, are displayed. Groups of recording. Adapted from [2]
Fig. 1.7 Sustained shifts in the electroencephalogram of the apical dendrite. The membrane potentials (MPs) of
(EEG) at the surface of the cerebral cortex resulting from the afferent fiber and the dendritic element were recorded
sustained neuronal activities. If recordings are performed simultaneously, as was the EEG/DC. Increased and
with a direct current (DC) amplifier (EEG/DC), sustained decreased sustained activity in the afferent fiber generated
potentials can also be recorded at the surface. In the sustained depolarizations and hyperpolarizations of the
perpendicular pyramidal neuron depicted, an afferent fiber dendritic region and corresponding negative and positive
formed an excitatory synaptic contact at the superficial part shifts of the EEG/DC recording. Adapted from [2]
1 Physiologic Basis of EEG and Epilepsy 11
Fig. 1.8 EEG (a) and membrane potential (MP) changes of penicillin to the cortical surface (hatched area in a).
of a pyramidal tract neuron and extracellular field potential Drawings of original tracings from experiments in the rat.
(FP) recorded in the vicinity of the impaled neuron The sweep speed in b is five times that in a. The recording
(b) during focal interictal activity elicited by the application sites are shown in the schematic drawings. Adapted from [1]
12 S. Bandyopadhyay et al.
Fig. 1.9 Simultaneous recordings of EEG and (Drawings after original tracings from experiments in
DC/EEG (a) and of DC/EEG and membrane potential the cat’s motor cortex. The sweep speed in b is 10 times
(MP) of a pyramidal tract neuron (b) during generalized that in a.) Adapted from [1]
tonic–clonic seizures elicited by pentylenetetrazol.
Theta rhythms: Theta rhythms are in the upon stimulation of brain stem structures. Epi-
4–7 Hz frequency range which is conspicuous in sodes of cortical oscillations faster (100–600 Hz)
limbic regions in various animal species and in than beta–gamma frequency called ripples (100
humans. It is thought to represent a dynamic state to 200 Hz), or fast ripples (>200 Hz) have been
arising from neuronal networks in the described under both normal conditions and
hippocampus associated with spatial navigation epileptic seizures. Ripples probably reflect syn-
and memory processes. chronized IPSPs, whereas fast ripples appear to
Alpha rhythms: Alpha rhythm represents the represent bursts of population spikes. While
frequency range of 8–13 Hz. Aside from occip- high-frequency oscillations like ripples and fast
ital cortex, alpha rhythm can be recorded from ripples may be normal, recent studies indicate
the somatosensory cortex (also called mu that they may be the marker of epileptogenic
rhythm) and temporal cortex (also called tau region.
rhythm). Alpha rhythms are mainly generated
from the cortex with only moderate dependence
on the thalamus. Further Reading
Spindle (sigma) rhythms: Spindles (7–14 Hz)
originate from the thalamus and are considered to be 1. Schomer DL, Lopes da Silva FH, editors. Neider-
the first signs of EEG synchronization during early meyer’s electroencephalography: basic principles,
stages of sleep. The reticular nucleus of the thala- clinical applications, and related fields. Philadelphia,
PA: Lippincott Williams & Wilkins; 2011.
mus is regarded as the pacemaker of the spindles. 2. Wyllie E, Cascino DC, Gidal BE, Goodkin HP,
Faster rhythms: Beta and gamma rhythms are editors. Wyllie’s treatment of epilepsy: principles and
faster rhythms associated with wakeful state or practice. Philadelphia, PA: Lippincott Williams &
REM sleep. They arise when spindle and slower Wilkins; 2011.
3. Duabe JR, Rubin DI, editors. Clinical neurophysiol-
EEG rhythms are suppressed (probably mediated ogy. New York, NY: Oxford University Press; 2009.
by acetylcholine, serotonin, and norepinephrine)
EEG Instrumentation, Montage,
Polarity, and Localization 2
Krikor Tufenkjian
Montages
Fig. 2.5 Bipolar montage with anterior-to-posterior chains (longitudinal bipolar or double-banana montage)
18 K. Tufenkjian
generated by both the brain and the environment. Filtering the EEG signal: Conventional EEG
Filtering out the surrounding noise is done with a interpretation requires the exclusion of very low
differential amplifier, which excludes the signals frequencies using a high-pass (or low frequency)
recorded by both electrodes in a channel and filter, very high frequencies using a low-pass (or
amplifies the differences in between. This func- high-frequency filter) filter, or a specific band of
tion is also known as common mode rejection. frequencies using a high-pass filter.
2 EEG Instrumentation, Montage, Polarity, and Localization 19
Fig. 2.8 To the left is a representation of a negative adjacent electrodes in the same chain. The highest
potential and its field as recorded from the scalp. Right negative potential is recorded from contact C; this would
upper is a representation of that potential as represented lead to B–C to have a positive value (down-going tracing
on a referential montage. Note that the amplitude of the on EEG), while C–D will have a negative value
spike corresponds to the proximity of the recording (up-going). This would result in the so-called phase
electrode to the negative filed maximum. Right lower is reversal on a bipolar montage, where the common
the same potential as recorded from the same electrodes electrode is closest to the maximum negative potential
but arranged in a longitudinal bipolar montage. Each as recorded from the scalp and within that chain
channel represents the difference in potential between two
A signal-filtering device is made from a cir- an alternating current (AC) source, then once the
cuit containing a capacitor and a resistor. A ca- polarity of the source is reversed a new current
pacitor contains two conducting surfaces may pass in the circuit until the plates of the
separated by non-conducting material. When capacitor are once more saturated, though with
placed as a part of a circuit, opposing charges opposite polarity. Increasing the frequency of the
will accumulate on each plate until each plate is AC current above the limit of the saturation of a
“crowded” and the current stops (Fig. 2.9). If this capacitor will allow for a current to pass con-
is a part of a circuit with a direct current (DC), tinuously through the circuit.
then no further current may pass once the In the past, EEGs were obtained using analog
capacitor is saturated. If, however, the circuit has recorders. Frequency filtering in these machines
was done with devices that utilize resistor/
capacitor circuits. Such filters are characterized
by their time constant, which determines what
frequencies will pass through.
The time constant is determined by the
amount of resistance and capacitance in the cir-
cuit. It is defined as the time needed to discharge
the capacitor in the circuit to 36.8% of its initial
full charge. Its value is inversely related to the
frequency that will pass through the filter. For
example, using a filter with a higher time con-
stant will allow the lower frequencies to pass
Fig. 2.9 Resistor–capacitor circuit through. With the more recent digital machines,
20 K. Tufenkjian
the EEG signal from each electrode is digitized than a certain value to pass. The low-pass filter
first and frequency filtering is done using soft- is set to 70 Hz in the usual scalp EEG reading
ware processing. settings. Changing this to 35 Hz will allow only
A low-pass filter (also known as frequencies lower than 35 Hz to pass through.
high-frequency filter) allows frequencies lower This will filter out a lot of the faster myogenic
Fig. 2.10 a High-frequency filter set at 70 Hz. Note the b The high-frequency filter is changed to 15 Hz. Most of
abundant myogenic artifact in the first three seconds of the myogenic artifacts are removed. There is a concurrent
the recording. A high-amplitude spike is also noted. reduction in the amplitude of the spike
2 EEG Instrumentation, Montage, Polarity, and Localization 21
Fig. 2.11 a EEG with the low-frequency filter set to activity. c Low-frequency filter changed to 5 Hz. Only
1 Hz. b Same EEG with the low-frequency filter changed frequencies above 5 Hz pass. Note that there has been no
to 2 Hz. Note the reduction of the amplitude of the slow effect on the fast frequency myogenic artifact
artifact and will also slightly reduce the ampli- A high-pass filter (also known as low-
tude of signals with a steep rise time, such as frequency filter) allows higher frequencies to
epileptiform spikes and sharp waves pass, usually set to about 1 Hz (corresponds to a
(Fig. 2.10). time constant of about 0.16 s) for routine scalp
22 K. Tufenkjian
Fig. 2.12 a High-frequency oscillations at 250 Hz—the onset represents magnification of the boxed area. b Slow
baseline shift at the beginning of a seizure recorded with grid electrodes
24 K. Tufenkjian
Fig. 2.13 High-frequency signal is sampled at a rate below the Nyquist rate. The resulting waveform remarkably
misrepresents the original waveform, resulting in aliasing
sampling rate falls below a certain point, then the outlet. The third prong ensures shunting of
resulting waveform would no longer represent excess current from the EEG machine to the
the original one. This erroneous representation is earth ground. All electrical devices in the EEG
called aliasing. The Nyquist sampling theorem room should be connected to a common earth
determines that the sampling rate should be at ground.
least twice the frequency of the original signal to A single ground electrode is placed any-
avoid aliasing, or distortion of waveforms. where on the patient and connects to the
The ACNS guidelines recommend a sampling appropriate jack in the input jackbox of the
rate at 3 times or more the frequency of the EEG machine. The patient should not be
original signal (Fig. 2.13). A filter is used on the connected to the earth ground. In ICU setting,
signal prior to digitizing to exclude all frequen- a patient may be connected to another elec-
cies above a certain frequency determined by the trical device with a ground connection. Double
Nyquist theorem (anti-aliasing filter). grounding should be avoided in these situa-
Another important aspect is the monitor dis- tions [2].
play. Most LCD monitors can display 1920 dots
(pixels) horizontally. The sampling rate on the
EEG machine may actually exceed the capacity EEG Artifacts
of the monitor display. Low-definition monitors
will give a “grainy” tracing, and this could be a Artifacts will be discussed in Chap. 3, but in the
particular concern with high-frequency activity remaining part of this chapter we will provide
(Fig. 2.14). some EEG examples with the purpose of further
training of the reader’s artifact pattern recogni-
tion. Artifacts may arise from the electrical
EEG and Patient Safety environment as well as bioelectrical sources
originating from the patient (Figs. 2.15, 2.16,
Proper grounding during EEG is an important 2.17, 2.18, 2.19, 2.20, 2.21, 2.22, 2.23 and
patient safety issue. The EEG machine should 2.24).
be connected to a three-pronged hospital grade
2 EEG Instrumentation, Montage, Polarity, and Localization 25
Fig. 2.14 Effect of reducing the display resolution from 1920 by 1080 pixels (top record) to 1280 by 1024
pixels (bottom record)
26 K. Tufenkjian
Fig. 2.15 a Electrode pop artifact. Poor contact at the P3 contact with the scalp. The difference in impedance
and C4 electrodes resulted in an isolated potential at these compared with the other electrodes interferes with the
two contacts (60-Hz notch filter on). b The notch filter is ability of the differential amplifier to reject the 60 cycle
removed and the 60-Hz artifact is now seen at the P3 and noise which actually gets amplified [3]
C4 electrodes, which have higher impedance due to poor
2 EEG Instrumentation, Montage, Polarity, and Localization 27
Fig. 2.16 Movement artifact. The disorganized EEG potentials do not have the typical field seen in brain-generated
waveforms
Fig. 2.18 Sweat artifact. Slow undulation (less than 1 Hz) of the EEG tracing is seen in a diaphoretic patient
Fig. 2.19 Myogenic artifact. These high-frequency activities are generated by the frontalis and temporalis muscles;
therefore, these are seen maximally in the anterior midline and temporal chains
2 EEG Instrumentation, Montage, Polarity, and Localization 29
Fig. 2.21 Blink artifact. The cornea has a slightly electrodes. This is represented as a down-going wave-
positive potential compared to the retina. During a blink, form, which falls in amplitude exponentially from the
the eyelid makes contact with cornea allowing for that front to the back
positive potential to be recorded from the anterior frontal
30 K. Tufenkjian
Fig. 2.22 Lateral eye movement artifact and lateral (arrows). This is followed by a slow rightward movement
rectus spike. In this example, the patient is reading a of the eyes with the potentials slowly shifting to the
book, the rapid saccade to the left brings the positive opposite direction (ovals). A small spike preceding the
potential of the cornea closer to the left frontal channels saccade is noted which is generated from the left lateral
producing a positive phase reversal at F7 and away from rectus muscle (arrowhead)
the right with a resulting negative phase reversal at F8
2 EEG Instrumentation, Montage, Polarity, and Localization 31
Fig. 2.23 Glossokinetic artifact. The difference in potential between the tip and the base of the tongue produces
diffuse, slow waves with a frontal maximum
32 K. Tufenkjian
Fig. 2.24 ECG artifact. Small sharp transient can be seen time locked to the ECG QRS potentials. The lower tracing
shows this ECG contamination during an EEG performed for the evaluation of electrocerebral inactivity
Accurate EEG interpretation greatly relies on • Reactive to eye opening and closure.
pattern recognition of normal EEG variants and • Fast alpha variant is similar to beta rhythms
artifacts. Several of these normal patterns may except that it is located in occipital rather than
mimic pathologic EEG findings, leading to in frontal, central, and parietal regions.
potential misinterpretation of normal EEG trac- • Slow alpha variant is more difficult to discern
ings. Some of these normal patterns may even without clear reactivity to eye closure and
mimic ictal discharges, leading to overtreatment. opening.
This chapter covers the electrographic features of
common normal EEG variants and artifacts [1–3]. Alpha Squeak (Fig. 3.3):
Normal EEG variants often present with dis- • Transient increase in frequency immediately
tinctive electrographic features that include after eye closure.
morphology, distribution, and occurrence in • Assessment of the frequency of the posterior
specific stages (wakefulness, drowsiness, or background rhythm should not include the
sleep). Some benign EEG variants are better first 0.5–1 s after eye closure in order to avoid
visualized when using a preferred EEG montage. overestimation.
Fast Alpha (Fig. 3.1) and Slow Alpha Vari-
ants (Fig. 3.2): Rhythmic Mid-Temporal Theta Bursts of
Drowsiness (RMTTBD) (Fig. 3.4):
• Harmonics of the posterior background
rhythm: twice as fast (fast alpha variant) or • Also known as Rhythmic Mid-Temporal
half as fast (slow alpha variant). Discharges (RMTD) and psychomotor
• Notched appearance can resemble Rhythmic variant.
Mid-Temporal Theta Bursts of Drowsiness • Composed of rhythmic bursts or trains of
(RMTTBD) except that it occurs over the theta waves (5–7 Hz) usually with a notched
posterior head regions. appearance that is maximal in mid-temporal
regions.
• Occurs bilaterally with a shifting emphasis
from side to side.
R. Azzam M.Z. Koubeissi N.J. Azar (&)
• It is monomorphic and monorhythmic and
Department of Neurology, Vanderbilt University does not evolve into other waveforms or
Medical Center, 1161 21st Ave. South, a-0118 frequencies.
Medical Center North, Nashville, • Occurs during relaxed wakefulness and
TN 37232-2551, USA
e-mail: nabil.azar@vanderbilt.edu
drowsiness.
M.Z. Koubeissi
e-mail: koubeissi@gmail.com
Midline Theta Rhythm (Fig. 3.5):
Fig. 3.1 Fast alpha variant (arrow); sensitivity 7 lV/mm, low frequency filter (LFF) 1 Hz, high-frequency filter (HFF)
70 Hz
Fig. 3.2 Slow alpha variant (arrows); sensitivity 7 lV/mm, LFF 1 Hz, HFF 70 Hz
3 Normal EEG Variants and Artifacts 35
Fig. 3.3 Alpha squeak (arrows); sensitivity 7 lV/mm, LFF 1 Hz, HFF 70 Hz
Fig. 3.4 Rhythmic Mid-Temporal Theta Bursts of Drowsiness (RMTTBD) (arrows); sensitivity 7 lV/mm, LFF 1 Hz,
HFF 70 Hz
36 R. Azzam et al.
Fig. 3.5 Midline theta rhythm (arrow); sensitivity 7 lV/mm, LFF 1 Hz, HFF 70 Hz
Fig. 3.6 Consecutive EEGs showing subclinical rhythmic electrographic discharge in adults (SREDA)
38 R. Azzam et al.
Fig. 3.7 14- and 6-Hz positive bursts (arrow); sensitivity 7 lV/mm, LFF 1 Hz, HFF 70 Hz
Fig. 3.8 6-Hz spike-and-wave bursts (arrow); sensitivity 7 lV/mm, LFF 1 Hz, HFF 70 Hz
Fig. 3.9 Benign sporadic sleep spikes (BSSS) (arrows); sensitivity 7 lV/mm, LFF 1 Hz, HFF 70 Hz
• Occurs during relaxed wakefulness and • Usually do not have a slow-wave component
drowsiness disappearing with deep sleep and do not occur in repetitive trains.
(unlike spike-and-wave discharges which • Commonly occur unilaterally but can inde-
persist during sleep). pendently involve the opposite hemisphere.
• Usually occurs bilaterally and synchronously.
• Two types have been described: FOLD Wickets (Fig. 3.10):
(Female Occipital Low-amplitude and
Drowsiness) and WHAM (Wake • Intermittent trains of monophasic arciform
High-amplitude Anterior and Male). waveforms or single spike-like waveforms.
• FOLD is considered to be benign, whereas • Occur exclusively on one side (left > right) or
WHAM is more likely to be associated with bilaterally with shifting predominance.
seizures. • Frequency of 6–11 Hz and possibly represent
fragments of temporal alpha activity or the
Benign Sporadic Sleep Spikes or (BSSS) third rhythm.
(Fig. 3.9): • Seen during wakefulness, drowsiness, and
light sleep, and disappear in deeper sleep.
• Also known as small sharp spikes (SSS) or • Should not be mistaken for a temporal seizure
benign epileptiform transients of sleep (BETS). discharge or spikes; if a single spike is found,
• Seen in adults during drowsiness and light it should be compared with a train of wicket
sleep and disappear with deeper sleep. spikes on other pages.
• Low-voltage (<50 µV) and short-duration • Not associated with a slow wave and do not
(<50 ms) monophasic or diphasic spike with distort the background.
abrupt ascending limb and a steep descending
limb. The Third Rhythm (Fig. 3.11):
3 Normal EEG Variants and Artifacts 41
Fig. 3.10 Left wicket rhythm (arrows); sensitivity 7 lV/mm, LFF 0.5 Hz, HFF 70 Hz
Fig. 3.11 The third rhythm (arrows); sensitivity 7 lV/mm, LFF 1 Hz, HFF 70 Hz
Fig. 3.12 Frontal arousal rhythm (FAR) (arrows); sensitivity 7 lV/mm, LFF 1 Hz, HFF 70 Hz
Frontal Arousal Rhythm (FAR) (Fig. 3.12): • Resemble the Greek letter k with monophasic
or diphasic waveforms with prominent
• Trains of 7–20 Hz waveforms that occur surface-positive waveform.
predominantly over the frontal regions lasting • Occurs over the occipital regions when sub-
up to 20 s. ject is visually scanning.
• May be notched in appearance with varying • Bilateral and synchronous but may be
harmonics. asymmetric.
• Seen mainly in children following arousal • Possibly represent an evoked cerebral
from sleep and disappears with full response to visual stimuli.
wakefulness.
Positive Occipital Sharp Transients (POSTs)
Mu-Rhythm (Fig. 3.13): (Fig. 3.15):
Fig. 3.14 Lambda waves (arrows); sensitivity 7 lV/mm, LFF 1 Hz, HFF 70 Hz
• Consists of fast-wave and slow-wave com- of a spindle and the hand portion by the
ponents and resembles a mitten with the slower wave component.
thumb of the mitten formed by the last wave • Variant of a vertex wave or K-complex.
44 R. Azzam et al.
Fig. 3.15 Positive occipital sharp transients (POSTs) (arrows); sensitivity 7 lV/mm, LFF 1 Hz, HFF 70 Hz
Fig. 3.16 Frontal mitten pattern (arrows); sensitivity 7 lV/mm, LFF 1 Hz, HFF 70 Hz
3 Normal EEG Variants and Artifacts 45
Fig. 3.17 Breach rhythm in the left centro-parietal region (arrows); sensitivity 7 lV/mm, LFF 1 Hz, HFF 70 Hz
Breach Rhythm (Fig. 3.17): • All eye movements are generated by corneal
and retinal potentials.
• High-voltage activity over a skull defect. • It is a direct current represented by a dipole
• Consists of a spiky appearance and sharply whose positive pole localizes to the cornea
contoured arciform 6–11 Hz waveforms. and negative pole localizes to the retina.
• Most prominent in temporal and central • The electrodes involved are closest to the
regions and can usually represent wickets and eyeball: Fp1, Fp2, F7, and F8.
mu-rhythms depending on the location of the • The electrodes surrounding the eyeball detect
skull defect. a positive potential which voltage is usually
greater than the cerebral potential.
EEG artifacts are activity recorded by the • For example, when the eyes are closed, the
EEG that is usually not cerebral in origin. Several eyeballs move upward to their natural
sources of artifacts exist and can be divided into position (Bell’s phenomenon) and this
physiologic and non-physiologic. upward movement is detected by a positive
potential recorded at Fp1 and Fp2
(Fig. 3.21). This activity is then followed
Physiologic EEG Artifacts by a falloff recorded at the next electrodes:
F3 and F4. When the eyes are open again,
Eye movements—vertical (Fig. 3.18), horizontal the inverse occurs. If these movements
(Fig. 3.19), oblique (Fig. 3.20), flutter, and happen repetitively, they will result in a
nystagmus: blink artifact.
46 R. Azzam et al.
Fig. 3.18 Vertical eye movements: (a) up gaze, (b) down gaze; sensitivity 7 lV, LFF 1 Hz, HFF 70 Hz
Fig. 3.19 Horizontal eye movements: (a) left gaze, (b) right gaze; sensitivity 7 lV, LFF 1 Hz, HFF 70 Hz
• Another example is when eyes move to the electrode F7 and it becomes more positive
left, the activity at Fp1 and Fp2 remains than other electrodes. Because the eyes move
steady, with no change in potential. However, conjugately, the cornea is moving away from
the positive potential is detected by the F8 and it becomes less positive, or more
3 Normal EEG Variants and Artifacts 47
Fig. 3.20 Oblique eye movement: up and to the left (arrow); sensitivity 7 lV, LFF 1 Hz, HFF 70 Hz
negative, because the retina is now closer to generate an equal positive potential recorded
this electrode. This horizontal movement to in a bipolar montage recording from elec-
the left produces a positive phase reversal trodes Fp1–F7 and a large upward deflection
with a maximal positive potential at F7 and a on the channel recording Fp2–F8. This
negative phase reversal with a maximal neg- occurs because the positive potential
ative potential recorded at F8. involves both Fp1 and F7 relatively equally,
• Oblique eye movements are more difficult to and the potential difference recorded with
interpret and constitute a combination of the differential amplifier approximates to
both vertical and horizontal movements. An zero. The potential difference recorded from
eye movement upward and to the left would Fp2–F8 is negative at Fp2 and positive at
48 R. Azzam et al.
Fig. 3.21 Upward movement of the eyeball brings the positively charged cornea closer to Fp1 and the negatively
charged retina farther from Fp1, resulting in a positive or downward deflection
F8, creating an upward deflection in that • Single motor units appear as repetitive or
channel. This is due to the rules of local- single negative or positive deflections that
ization (if input 1 is more negative than have a comb-like appearance.
input 2, an upward deflection will be • The frontalis electromyogram (EMG) is seen
recorded). in frontal electrodes, as when tightly closing
• Eyelid flutter produces low-voltage slow eyes. This can also be seen during photic
activity and is often limited to Fp1 and Fp2 stimulation, a photomyoclonic response. The
electrodes. temporalis EMG is recorded from F7, F8, T7,
• Horizontal nystagmus is usually detected T8, P7, and P8. This is typically seen with
unilaterally, and the movement is recorded by jaw clenching or chewing.
the electrode on the side of the fast phase of • High-frequency filters should not be used to
the nystagmus because of the larger positive eliminate the EMG artifact because they alter
voltage of the cornea near that electrode. its appearance from a sharp wave to a more
Vertical nystagmus is rarely detected because sinusoidal frequency that resembles cerebral
of the low voltage and the distance of these beta activity.
electrodes from the eyeball.
Electrocardiographic—QRS complex
Electromyographic—lateral rectus, single (Fig. 3.23), pulse, cardioballistic:
motor units, frontalis, temporalis, swallowing,
and chewing: • The QRS complex is easily monitored by
applying electrodes to the chest. The gener-
• The lateral rectus artifact (Fig. 3.22) is a ated signal is high voltage generated by the
low-voltage motor unit potential recorded heart. This activity when recorded at the scalp
from the F7 and F8 electrodes. It appears as a constitutes a far-field potential. It is often
sharp positive deflection of very short dura- picked up by montages using ear electrodes
tion with a slow falloff as the muscle relaxes. as a reference. It is prevalent in obese
3 Normal EEG Variants and Artifacts 49
Fig. 3.22 Lateral rectus spike (arrow); sensitivity 7 lV, LFF 1 Hz, HFF 70 Hz
Fig. 3.23 Electrocardiographic artifact (arrows); sensitivity 7 lV, LFF 1 Hz, HFF 70 Hz
50 R. Azzam et al.
Fig. 3.24 Glossokinetic and chewing artifacts; sensitivity 7 lV, LFF 1 Hz, HFF 35 Hz
patients, and patients with short necks and tongue movements, such as la-la-la or
babies. ta-ta-ta. This artifact may resemble gener-
• Pulse artifact is usually confined to a single alized spike-and-wave discharges when
electrode and appears as a slow-wave poten- filtered.
tial. It occurs when an electrode is placed
over a surface artery. The electrocardiogram Galvanic (Fig. 3.25):
signal will be time locked to the slow wave
and always occurs at the same location. • This artifact is secondary to perspiration and
• A cardioballistic artifact is rhythmic delta results in high-amplitude slow-wave
activity, usually widespread in distribution, potentials.
which represents head movement with each • Standard low-frequency filters reduce this
pulse. The relationship between the cardiac artifact.
signal and these pulsations is not always • A salt bridge may be formed shorting two
time locked to any particular phase of the electrodes contacting the perspiration.
signal.
Physiologic movements—tremor (Fig. 3.26)
Glossokinetic (Fig. 3.24): and jerks:
• Movement of the tongue creates a direct • Tremor is often between 4 and 6 Hz and
current potential where the tip of the ton- localized to the body region involved. It is
gue is negative with respect to its base. often seen in the head and upper limbs.
They are frequently recorded as slow • Jerks produce enough body movement to
activity from the temporal electrodes. This move the electrodes or the head creating a
can be reproduced by having the patient potential in the recording.
repeat words or phrases that produce active
3 Normal EEG Variants and Artifacts 51
Fig. 3.25 Diffuse sweat artifact; sensitivity 7 lV, LFF 1 Hz, HFF 70 Hz
Neonatal Montage
Fig. 4.2 Trace discontinue. Trace discontinue pattern seen in 26–28 weeks of PCA (Picture source Atlas of neonatal
encephalography—Third Edition Lippincott Williams and Wilkins A Wolters Kluwer Company)
newborns frequently show the patterns that may PCA <30 weeks. It is characterized by
be normal for a baby of a lesser PCA. Such high-amplitude (50–300 µV) bursts of mixed
patterns are described as dysmature patterns and frequency (theta and alpha riding over delta)
indicate encephalopathy in the appropriate set- which are seen simultaneously on both the
ting. This may improve rapidly with the hemispheres followed by low-amplitude
improvement in encephalopathy. Developmental periods of quiescence (<25 µV) which can
landmarks are best categorized in 3 phases: <30 last anywhere between few seconds and
weeks, 30–37 weeks, and >37 weeks. 1 min (inter-burst interval—IBI) (Fig. 4.2).
Fig. 4.3 Trace alternant. Trace alternant pattern seen in quiet sleep in 38–30 weeks of PCA (Picture source Atlas of
neonatal encephalography—Third Edition Lippincott Williams and Wilkins A Wolters Kluwer Company)
ranges anywhere between 6 and 10 s and has For these reasons, the abnormalities are most
higher voltage >25 µV. frequently seen in the quiet sleep phase.
• Prolonged IBI is seen in acute encephalopa- Trace alternant: These are characterized by
thy secondary to any type of brain injury, but high-amplitude (50–150 µV) synchronous burst
is also commonly seen in moderate-to-severe of mixed frequencies predominantly delta activ-
hypoxic ischemic encephalopathy. ity for 3–10 s followed by 3–5 s of
low-amplitude burst (25–50 µV) of predominant
theta activity. This patterns replaces the trace
discontinue with advanced PCA. This pattern is
PCA Between 30 and 37 Weeks seen only in quiet sleep in neonates between
PCA of 36 and 38 weeks (Fig. 4.3).
EEG starts showing variation in different
behavioral states around 35 weeks of PCA. • TA usually starts appearing in neonates >35
Identifying different sleep stages in a newborn’s weeks and can be seen until 42 weeks but no
EEG is critical for optimal interpretation. EEG longer than 44 weeks of PCA.
maturational changes occur first in active sleep; • In active sleep (and later in wakefulness), TA
after a lag of about 2 weeks, the awake periods is replaced by more continuous pattern char-
start showing more mature patterns. Quiet sleep acterized by uninterrupted, low-to-medium
is the last stage to show more mature changes. amplitude, mixed EEG activity with <2 s of
4 Neonatal EEG and Neonatal Seizures 59
voltage attenuation (<25 µV), and seen in In certain conditions like non-ketotic hyper-
mostly neonates with PCA >30 weeks. glycinemia, the EEG bursts may be accompanied
• TA pattern is replaced by medium-to-high by myoclonic jerks (Fig. 4.5).
voltage delta slow wave sleep after PCA of Synchrony: Burst of morphological similar
44–48 weeks (Fig. 4.4a, b). activity in the homologous head regions is sep-
arated by <1.5 s.
• They usually appear in the central region first Frontal sharps (Encoches Frontales): These
followed by temporal and occipital and also are blunt isolated biphasic broad sharp transients
disappear in the same order. (0.5–0.75 s) seen in the frontal region with initial
• Most commonly seen during 24–34 weeks smaller negativity followed by prominent posi-
and starts to disappear first in the active sleep tivity phase.
after 30 weeks. They can be present in the
quiet sleep up to 38 weeks. • They are usually symmetric and synchronous;
• Abnormal findings: Delta brushes are often • Frequently seen in the transitional stage of
asynchronous, but when consistently absent sleep;
on one side, a concern for some cerebral • Usually seen between 33 and 46 weeks of
dysfunction is raised; if it is persistently pre- PCA with peak around 35 weeks;
sent beyond 44 weeks then it is consistent • Mostly associated with rhythmic bi-frontal
with dysmaturity (Fig. 4.7). delta; and
4 Neonatal EEG and Neonatal Seizures 61
Fig. 4.7 Delta brushes in 29–30 weeks of PCA: Delta encephalography—Third Edition Lippincott Williams and
brushes seen in the bilateral central regions in a discon- Wilkins—A Wolters Kluwer Company)
tinuous background (Picture source Atlas of neonatal
Fig. 4.8 Frontal sharps in 34–35 weeks of PCA (Picture source Atlas of neonatal encephalography—Third Edition
Lippincott Williams and Wilkins—A Wolters Kluwer Company)
62 K. Velayudam and A.N.V. Moosa
Fig. 4.10 Sharp electrographic transients (Picture source Levin and Luders Comprehensive Clinical Neurophysiol-
ogy W.B. Saunders Company)
Table 4.2 Etiology—neonatal seizures. Modified from Chapter Neonatal seizures in Volpe J Neurology of Newborn.
5th ed
Etiology Key features % Patients
with normal
development
Hypoxic Prenatal: toxemia, fetal distress, abruptio – Common cause both in term and 50%
ischemic placentae, cord compression preterm infants
encephalopathy Perinatal: iatrogenic, maternal – Usually within 4 days of life
(*32%) hemorrhage, fetal distress – Focal clonic or multifocal clonic
Postnatal: hyaline membrane disease, seizures
congenital heart disease, Pulmonary – Severity of seizures parallel with
hypertension grade of the encephalopathy.
Intracranial Intraventricular, intraparenchymal Tonic seizures are common IVH: 10%
hemorrhage subarachnoid subdural hemorrhage SAH: 90%
(*17%)
Stroke (*7%) Arterial stroke, venous infarction due to Focal clonic seizures in the setting of –
venous sinus thrombosis hemiparesis
Trauma Subdural and subarachnoid hemorrhage – SAH: 90%
Infections Beta-hemolytic streptococci, E. coli, HSV infections—PLEDS seen in *50%
(*14%) Herpes simplex, HIV, coxsackievirus B, temporal regions
torch mycoplasma infection HSV DNA PCR—more sensitive test
Cerebral Migration disorders, neurocutaneous Usually occur within 1 week 0%
malformations disorders Peroxisomal disorders—
polymicrogyria.
Early myoclonic epileptic
Encephalopathy—burst suppression
pattern
Poor prognosis
Metabolic Transient: Usually occur within first 2 days Transient:
disorders hypoglycemia, hypocalcemia Seizures common with late onset 50–100%
(*9%) hyponatremia, hypernatremia hypocalcemia, hypomagnesemia with
Persistent: hypocalcemia in premature infants
inborn errors of metabolism Good prognosis
IEM—Infantile spasms, tonic spasms,
myoclonic seizures
Poor prognosis
Unknown – – –
(*10%)
4 Neonatal EEG and Neonatal Seizures 65
Fig. 4.12 Alpha seizures (Picture source Atlas of neonatal encephalography—Third Edition Lippincott Williams and
Wilkins—A Wolters Kluwer Company)
• Neonatal seizures due to acute encephalopa- 4. Riviello J, et al. Pharmacology review: drug therapy
thy usually improve in 7–14 days. for neonatal seizures: part 1. Neoreviews. 2004;5:
e262.
5. Slaughter L, Patel A, Slaughter J, et al. Pharmaco-
logical treatment of neonatal seizures: a systematic
review. J Child Neurol. 2013;28:351.
References 6. Mizrahi E, Hrachovy R, Kellaway P. Atlas of
neonatal electroencephalography. 3rd ed. Houston,
TX: Lippincott Williams &Wilkins; 2004.
1. Tsuchida T, Wusthoff C, Shellhaas R, et al. Amer- 7. Clancy R, Bergqvist C, Dlugos, D. Neonatal
ican clinical neurophysiology society standardized encephalography. In Ebersole J, Pedley T, editors.
EEG terminology and categorization for the descrip- Current practice of clinical electroencephalography.
tion of continuous EEG monitoring in neonates: 3rd ed. Lippincott Williams &Wilkins; 2003.
report of the American clinical neurophysiology 8. Hrachovy R. Development of the normal electroen-
society critical care monitoring committee. J Clin cephalogram. In: Levin K, Luders H, editors. Com-
Neurophysiol. 2013;30:161–73. prehensive clinical neurophysiology. 5th ed.
2. Shellhaas R, Chang T, Tsuchida T, et al. The Cleveland, OH: W. B. Saunders Company; 2000.
American clinical neurophysiology society’s guide- 9. Volpe J. Neurology of the newborn. 5th ed. Boston,
line on continuous electroencephalography monitor- Massachusetts: Saunders Elsevier; 2008.
ing in neonates. J Clin Neurophysiol. 2011;28:611–7. 10. Fenichel G. Neonatal neurology. 4th ed. Nashville,
3. Riviello J, et al. Pharmacology review: drug therapy TN: Churchill Livingstone Elsevier; 2007.
for neonatal seizures: part 1. Neoreviews. 2004;5:
e215.
Multiple Choice Questions for Part I
1. Neurons in the cerebral cortex are organized 4. Resting membrane potential of a neuron is
in: around:
A. Three horizontal layers A. +90 mV
B. Four horizontal layers B. –70 mV
C. Six horizontal layers with layer IV C. +70 mV
receiving inputs from thalamus D. –70 µV
D. Six horizontal layers with layer VI E. –20 µV
being the most superficial
E. Six vertical layers 5. Choose the one incorrect statement from the
following:
2. What is the predominant pattern seen in a A. At least 6 cm2 of synchronous cortical
<30 weeks PCA preterm infants? activation is necessary to detect an
A. Trace discontinue individual epileptic spike on scalp
B. Trace alternant electrodes.
C. Trace continue B. Epileptic spikes are exclusively sur-
D. Electrocerebral silence face negative.
E. Burst-suppression pattern C. EEG potentials recorded from the
scalp are produced by the summation
3. Which of the following is true about of the excitatory and inhibitory post-
GLUT1 deficiency? synaptic potentials of pyramidal
neurons.
A. High CSF glucose levels D. At the cortical layers III, V, and
B. Ketogenic acid is the treatment of VI, the pyramidal neurons are aligned
choice in a perpendicular fashion to the
C. Macrocephaly is common cortex.
D. Responds fairly well to sodium chan- E. EEG potentials are not mere represen-
nel blockers tations of neuronal action potentials.
E. All of the above
72 Multiple Choice Questions for Part I
6. The EEG of 2-year-old male with Canavan 10. A 2-week-old boy is having daily seizures
disease will likely show: characterized by brief multifocal jerks,
at times with apnea. The boy is alert
A. Multifocal epileptiform discharges and acting normal in between seizures. His
B. LPDs father and paternal grandfather had similar
C. Burst-suppression pattern seizures that resolved after several months
D. Amplitude attenuation from birth. The likely mutation is:
E. Polymorphic delta activity
A. SCN1A, encoding the sodium channel
7. Which of the following is false about a1 subunit
myoclonic epilepsy of infancy? B. CACNA1G, encoding the T-type
voltage-gated calcium channel
A. Males are more affected than females C. CHRNA4, encoding the a4 subunit of
B. Valproate is the treatment of choice the neuronal nicotinic acetylcholine
C. Positive family history of febrile sei- receptor
zures or epilepsy D. GABRG2, encoding the c2 subunit of
D. Developmental delay is seen in the c-aminobutyric acid A receptor
majority of patients E. KCNQ2, encoding a voltage-gated
E. EEG can show generalized polyspike- potassium channel
and-wave
11. The recommended length of a neonatal
8. Which of the following is incorrect about EEG is:
Dravet syndrome?
A. 20 min
A. Progressive neurological regression B. 30 min
B. Overall poor prognosis C. 60 min
C. SCN1A gene mutation D. 90 min
D. Respond to lamotrigine E. 120 min
E. All of the above is true
12. In the following image which of the fol-
9. Resting membrane potential of a cell can be lowing represents the artifact generated
calculated by the following equation: from the left lateral rectus muscle:
13 In full-term infants, sleep spindles are seen C. If the difference in potential between
at the age of: two electrodes is negative this is rep-
resented by a downward deflection.
A. Birth D. Each channel in an EEG recording
B. 1–3 months represents the difference in potential
C. 6–12 months between two electrodes.
D. 12–24 months E. None of the above
E. Not until adolescence
15. Which of the following is the correct order
14. Choose the one incorrect statement from the in which the maturational changes in
following: neonatal EEG develop?
29. Choose the incorrect statement regarding A. They require the use of an additional
“common mode rejection”: electrode used as the machine
reference.
A. Helps to filter out the environmental B. The signal from each channel is sam-
electrical noise. pled and stored at regular intervals.
B. Requires the use of a differential This sampling rate in most machines
amplifier. ranges from 256 to 1024 Hz.
C. Involves exclusion of the signals C. The Nyquist sampling theorem deter-
recorded by both electrodes and mines that the sampling rate should at
amplifying the differences in between. least match double the frequency of
D. Is unable to reject the 60 Hz artifact the original signal to avoid aliasing.
since the latter is also recorded by the D. The ACNS guidelines recommend a
ground electrode. sampling rate at 3 times or more the
E. None of the above. frequency of the original signal.
E. All of the above are correct.
30. The minimal surface area of the postsy-
naptic action potential required for record- 33. Which of the following statements con-
ing of a spike on scalp EEG is: cerning EEG grounding is correct:
35. Changing the filter settings on the EEG B. Ictal discharges are often generalized,
allows for all of the following, except: due to immaturity of the brain
C. Absence seizures are most common
A. Passing of signals above a certain D. Urgent surgery is the treatment of
frequency. choice
B. Exclusion of signals below a certain E. VNS is usually helpful early-onset
frequency. infantile spams
C. Allowing viewing high-frequency
oscillations in intracranial EEG.
D. Stopping a narrow band of Answers
frequencies.
E. Preferential amplification of epilepti- 1. (C). The cerebral cortex is organized in six
form discharges. horizontal layers with layer I being the most
superficial underneath the pial surface, and
36. If 60 Hz sine wave is sampled at 100 Hz, layer VI being the deepest overlying the
the result is: subcortical white matter. Layer IV (Internal
Granular Layer) receives input from
A. Electromagnetic gain
thalamus.
B. Digital filtering
2. (A). At a gestational age below 30 weeks,
C. Aliasing
the EEG activity consists of burst of mixed
D. Sub-harmonic wave
frequency (mostly delta) in a discontinuous
E. Amplification delay
fashion interspaced with periods of EEG
attenuation lasting for few seconds to 1–
37. West syndrome is characterized by:
2 min. The higher amplitude of the bursts
A. Myoclonic seizures occurs in the posterior region This EEG
B. Infantile spasms pattern is referred as to trace discontinue. At
C. Absence seizures this age, there is no distinction between
D. Dialeptic seizures sleep and awake states.
E. All of the above 3. (B). GLUT1 deficiency syndrome is caused
by impaired glucose transport across the
38. Which of these options represents an blood–brain barrier and is linked to low
advantage of a bipolar montage over a ref- CSF glucose levels. Clinically, patients
erential montage: present with acquired microcephaly, and
early-onset epilepsy that is refractory to
A. Ability to detect both local (near field) standard AEDs. Most patients carry muta-
and distant (far field) potentials tions of the SLC2A1 gene. The ketogenic
B. Provides a closer representation of the diet is the treatment of choice as conven-
absolute potential at an electrode tional AEDs are not effective.
C. Makes the visual detection of differ- 4. (B). The resting membrane potential of a
ences in local potential easier neuron is typically −70 mV, the inside of
D. Requires placement of fewer electrodes the neuron being negative in relation to the
E. All of the above outside. The resting membrane potential is
determined by movement of potassium,
39. Which of the following is true about sodium, and chloride ions along their elec-
neonatal seizures: trochemical gradient across the cell
membrane.
A. Majority of ictal discharges originate 5. (B). Epileptic spikes are most commonly
in the central regions surface negative. However, on occasions
78 Multiple Choice Questions for Part I
where the spike is generated in a sulcus seizures persisting beyond 5 years of age to
perpendicular to the scalp, the dipole will be myoclonic-astatic epilepsy, some cases of
parallel to the scalp and surface positivity temporal lobe epilepsy to Dravet Syndrome
can be recorded. Positive epileptiform dis- at the severe end of this spectrum. Seizures
charges are also seen after brain surgery and include absence, myoclonic, atonic, and
in infants with germinal matrix hemorrhage. generalized tonic–clonic and tend to lessen
6. (E). Canavan disease like all leukodystro- by late childhood and adolescence. 10% of
phies affects the white matter. Since Canavan familial GEFS+ cases have mutations in the
disease affects diffusely the white matter, it SCN1A gene; a few have GABA channel
typically produces diffuse EEG slow activity mutations in the GABRG2.
such as polymorphic delta activity. 9. (C). Equilibrium potential for an ion is the
7. (D). Benign myoclonic epilepsy of infancy is membrane potential at which there is no net
a rare disorder occurring in children between movement of that ion across the cell mem-
the age of 5 months to 5 years. Males are brane. Equilibrium potential for an indi-
more affected than females, and a family vidual ion can be calculated using the
history of febrile seizures or epilepsy is pre- Nernst equation. The membrane potential at
sent in 30–40% of cases. Myoclonus is the which there is no net flow of ions across the
most common seizure type followed by cell membrane is the resting membrane
absence and generalized tonic–clonic sei- potential which can be calculated using the
zures. EEG can be normal but most com- Goldman–Hodgkin–Katz equation which
monly show generalized polyspike-and-wave takes multiple ions into account. The Hen-
discharges and valproate is the treatment of derson–Hasselbalch equation describes the
choice. Overall development is usually nor- derivation of pH as a measure of acidity.
mal except for some learning disability. 10. (E). The clinical picture is typical of benign
8. (D). Dravet syndrome is a form of severe familial neonatal seizures. This condition
infantile-onset epilepsy that usually pre- has been linked to mutations of the KCNQ2
sents between 5–15 months of age with or KCNQ3 gene, encoding for a voltage-
generalized, hemiclonic convulsions, or gated potassium channel that has a major
status epilepticus. Common triggers include role in regulating neuronal excitability.
acute illness, fever, or vaccination. Devel- 11. (C). The recommended length of a neonatal
opment is initially normal but then regresses EEG recording is 60 min. In a full-term
slowly afterward. Majority of patients neonate, this will allow the sampling of all
(>70%) have de novo mutations in the the neonatal sleep stages that approximately
voltage-gated sodium channel gene, include 25 min of active sleep, 20 min of
SCN1A. Seizures are worsened by sodium quiet sleep, and 15 min of intermediate
channel modulating drugs such lamotrigine. sleep. Neonatal EEG recording during
The ketogenic diet is a common treatment wakefulness has a low yield due to exces-
modality but the overall outcome is typi- sive artifacts. Unlike neonates, adults have a
cally poor. The term GEFS+ originally typical sleep cycle of 80–120 min.
called generalized epilepsy with febrile 12. (B). The short spike at F7 from the lateral
seizures plus but now has been revised to rectus muscle is immediately followed by a
genetic epilepsy with febrile seizures plus positive phase reversal resulting from the
(as some patients also have partial seizures). positive charge of the cornea moving closer
The GEFS+ spectrum includes several to the electrodes on the left.
entities ranging from typical febrile seizures 13. (B). Sleep spindles are formed at the age of
at the mild end, patients with fever related 1–3 months in term infants, maximal in the
Multiple Choice Questions for Part I 79
central regions. They are initially bilateral interictal correlate of infantile spasm is the
but asynchronous until the age of 2 years chaotic hypsarrhythmia with seizures con-
when they become synchronous. sisting of electrodecremental pattern.
14. (C). By convention, if the difference in 22. (A). The polarity of extracellular field
potential between two electrodes is nega- potentials recorded by surface electrodes on
tive, then it is represented by an upward EEG depends on the direction of the current
deflection. flow as well as on the position of the elec-
15. (B). EEG maturational changes occur first in trode relative to the location of the genera-
active sleep, EEG maturational changes tor. Thus, superficial EPSPs and deep IPSPs
occur first in active sleep; after a lag of about will show the same polarity (negative) on a
2 weeks the awake periods start showing surface recording electrode. Likewise,
more mature patterns. Quiet sleep is the last superficial IPSPs and deep EPSPs will show
stage to show more mature changes. For this the same polarity (positive) on a surface
reasons, the abnormalities are most fre- recording electrode. Therefore, orientation
quently seen in the quiet sleep phase. of neurons and their processes as well as
16. (D). Sodium and chloride ions have a location of synaptic contacts with respect to
higher extracellular concentration while the cortical surface are important determi-
potassium concentration is higher in the nants of extracellular field potentials recor-
intracellular compartment. ded by EEG electrodes.
17. (E). The rhythmic myogenic artifact in the 23. (E). Most common etiology of neonatal
first four and last one-second represent seizures is hypoxic ischemic encephalopa-
chewing artifact. In addition, isolated thy. Tonic seizures are typically seen in
myogenic artifact can be seen in seconds 7– preterm neonates with intraventricular
8–9, blink artifact can be seen in second 5, hemorrhage and focal seizures with hemi-
and lateral eye movement to the left on paresis are typically seen in neonates with
second 7 of this epoch. ischemic infarcts.
18. (A). The voltage-gated sodium channels 24. (C). Sleep spindles (7–14 Hz) originate
play a major role in generation and propa- from the thalamus and are considered to be
gation of action potential by allowing the first signs of EEG synchronization
sodium to enter into the soma. during early stages of sleep. The reticular
19. (D) A large number of EPSPs and IPSPs nucleus of the thalamus is regarded as the
generated in a complex network of neurons pacemaker of the spindles.
generate an extracellular field potential that 25. (E). Episodes of cortical oscillations (100–
changes over time which is believed to be 600 Hz) called ripples (100–200 Hz) or fast
the basis of potentials recorded on EEG. ripples (>200 Hz) have been described both
20. (D). Frontal sharps (or Encoches Frontales) under normal conditions and epileptic sei-
are blunt isolated biphasic broad sharp zures. Ripples probably reflect synchro-
transients (0.5–0.75 s) seen in the frontal nized IPSPs whereas fast ripples appear to
region. They are usually symmetric and represent bursts of population spikes.
synchronous, frequently seen in transitional 26. (D). The paroxysmal depolarizing shift
stage of sleep, between 33 weeks–46 weeks (PDS) is an intracellular mechanism that is
PCA with peak around 35 weeks. If con- not recorded by scalp EEG. It represents the
sistently absent or asymmetrical on one intracellular electrophysiological correlate
side, structural lesion on the that side will of focal epileptiform discharges such as
be highly suspected. sharp waves and spikes. It consists of
21. (C). Infantile spasms are brief epileptic abnormal synchronous activation of multi-
tonic contractions affecting infants and ple neurons at the cellular level causing a
children, seen in West syndrome. The wave of depolarization. It is primarily due
80 Multiple Choice Questions for Part I
to the activation of high-frequency fast 34. (C). In neonatal EEGs, multifocal epilepti-
sodium channel potentials. form discharges (spikes or sharp waves) do
27. (B). Slow activity (slowing) is a function of not necessarily imply potential epilepto-
white matter disturbance while voltage or genicity like in adults. In prematures, mul-
amplitude reduction (attenuation) is a func- tifocal sharp transients can be normal when
tion of cortical disturbance. The mechanism they are rare and random. When multifocal
of focal slowing is likely due to partial cor- discharges are frequent as in this case, they
tical deafferentation from subcortical struc- are often indicative of non-specific
tures. This could be due to functional or encephalopathy.
anatomic deafferentation of the cortex as 35. (E). It is not possibly to preferentially “filter
may be seen in toxic-metabolic encephalo- in” epileptiform discharges. At best, filters
pathies or structural brain lesions. allow to remove some artifacts to allow for
28. (B). Small leakage currents, short cord easier visual detection of epileptiform
connections, people not connected to the discharges.
ground, high-resistant contacts (dry skin), 36. (C). The Sampling Theorem states that if a
and one common ground are all measures signal contains component frequencies
that minimize the risk of electrocution. ranging from 0 to fN, then the minimum
29. (D). The differential amplifier can reject the sampling frequency that can be used for a
60 Hz artifact as long as it is recorded digitized data to adequately represent the
equally by both electrodes in each channel. frequency content of the original signal is
If there is significant difference in the 2 fN called the Nyquist frequency (equal to
impedance between two electrodes, then the two times of the original frequency sam-
60 cycle signal will be recorded unequally pled). Aliasing refers to the distortion of a
and the artifact will appear on the EEG. signal caused by sampling frequency lower
30. (D). The postsynaptic action potential than the Nyquist frequency. In this case, to
should involve at least 6 cm2 of cortex to be avoid aliasing, a minimal sampling rate of
detected as an epileptiform discharge on 120 Hz is needed.
scalp EEG. 37. (B). West syndrome consists of a triad of
31. (E). The time constant equals the time infantile spasms, developmental delay, and a
needed to discharge the capacitor in the grossly abnormal EEG pattern termed hyp-
circuit to 36.8% of its initial full charge. Its sarrythmia. It usually affects infants between
value is inversely related to the frequency the ages of 4–8 month. In the majority of
that will pass through the filter. cases, West syndrome is associated with
32. (C). If the sampling rate falls below a cer- serious neurological abnormalities being
tain point, the resulting waveform would no genetic, structural, metabolic, or infectious.
longer represent the original one (aliasing). 38. (C). In a bipolar montage, external noise
Per the Nyquist sampling theorem the can easily be canceled out as it measures the
sampling rate should be at least twice the difference in potential between adjacent
frequency of the original signal to avoid electrodes and hence amplifies local
aliasing. potentials.
33. (B). A three pronged hospital grade outlet 39. (A). Neonatal seizures often arise from the
should be used. There is no need to connect central region followed by the temporal
the EEG machine to the bed. When a region. In the exception of myoclonic sei-
patient is connected to more than one zures, all neonatal seizures are unifocal or
electrical device a common ground should multifocal at onset, frequently associated
be utilized. with an abnormal EEG background.
Part II
The Abnormal EEG
Ictal and Interictal EEG
5
Mohamad Z. Koubeissi and Nabil J. Azar
one contact, but not on neighboring ones, it Frequent comorbidities of individuals with mul-
is often more suggestive of an artifact. tifocal IEDs include cognitive and motor deficits.
Fig. 5.2 Periodic lateralized epileptiform discharges (PLEDs) over the left frontal region in an adult patient after
resolution of prolonged focal status epilepticus over the same region
Ictal EEG
Fig. 5.3 Spike-and-slow wave complex in a patient with
JME. Note the phase reversals over F3 and F4 Recording the ictal EEG is an essential part of
the surgical evaluation of patients with intract-
able epilepsy [9]. In such patients, it is important
voltage without a prominent after going that the recorded seizures are semiologically
slow-wave component and may occur singly. typical of the patient’s habitual episodes before
They are best seen with a referential ear montage. surgical decisions are made. In addition, record-
Slow spike-and-wave complexes present with ing the patient’s habitual episodes is essential for
a frequency that is slower than the 3-Hz pattern characterization of paroxysmal events in indi-
of absence epilepsy. They are a typical electro- viduals with questionable nonepileptic episodes.
graphic feature of Lennox-Gastaut syndrome. Ictal EEG represents a clear deviation from
Their typical frequency is around 1.0–2.5 Hz, the baseline of a pattern that shows some evo-
with wider (less spiky) sharp component than in lution. By evolution, it is meant that the pattern
absence epilepsy. Sleep activates trains of such changes in terms of its frequency, amplitude,
slow complexes in the extent that they may field, or morphology as the seizure occurs. This
appear continuous as in electrical status epilep- applies most typically to focal seizures, espe-
ticus during sleep (ESES). cially temporal lobe seizures, but may start with a
semi-rhythmic delta activity over one temporal
region and soon evolves into a theta range spike
PhotoEpileptiform Discharges discharge over the same distribution that is typ-
(Photoparoxysmal Response) ical of mesial temporal generators. However,
even in generalized epilepsies, such as absence
Photoepileptiform discharges are IEDs that are epilepsy, an evolution pattern can be noted
elicited by photic stimulation. The elicited dis- whereby the initial frequency of the
charges can be generalized (most common), spike-and-slow-wave discharge is higher than 3,
bilateral posterior, or unilateral predominant often 3.5 Hz, whereas toward the end of the
(least common). They may occur within the burst, the frequency slows down to 2.5 Hz.
5 Ictal and Interictal EEG 87
Ictal EEG in Focal Epilepsy whereas the opposite scenario suggests a lateral
neocortical origin.
Only 22% of all focal seizures that are not In extratemporal lobe seizures, a
associated with alteration of consciousness (for- fast-frequency ictal discharge may be more
merly named simple partial seizures) have an common than in temporal lobe epilepsy, but, in
EEG correlate. In the subset of such seizures general, extratemporal seizures are not associated
where a motor component is present, the elec- with a clear ictal discharge as often as seizures of
trographic yield increases to 33% versus only temporal origin [11]. For example, only half of
15% of those that have no motor manifestations frontal lobe seizures have a localizing EEG pat-
[10]. On the other hand, seizures that are asso- tern [13]. Similarly, parietal lobe seizures often
ciated with alteration of awareness (dyscognitive have no clearly localizing EEG [14]. Occipital
seizures, formerly termed complex partial sei- lobe seizures commonly show an ictal discharge
zures) are almost always associated with EEG over the occipital region. Both occipital and
changes. Rare exceptions may apply to seizures parietal lobe seizures tend to propagate to the
originating from the parietal or frontal lobe [11]. temporal lobes, where seizures become semio-
When ictal discharges are present in seizures that logically and electrographically indistinguishable
do not cause alteration of awareness, they are from temporal lobe seizures. Occipital lobe sei-
morphologically indistinguishable from focal zures can also propagate to frontal and insular
ictal discharge in dyscognitive seizures, mani- regions.
festing as focal repetitive spike discharge,
low-voltage fast activity, or focal rhythmic
slowing, among others. In general, when the ictal Ictal EEG in Generalized Epilepsy
discharge consists of fast frequencies, it indicates
proximity of the recording electrode to the sei- In generalized seizures, the earliest clinical and
zure focus. On the other hand, slow discharges, EEG changes typically are not lateralizing and
for example in the delta range, typically represent indicate diffuse brain involvement [15]. A more
propagated activity from distant sites. recent definition of generalized seizures is “sei-
In temporal lobe epilepsy, simultaneous scalp zures originating at some point within, and
and depth electrode recordings show that no scalp rapidly engaging, bilaterally distributed net-
EEG changes are seen when seizure discharges works. These networks can include cortical and
are limited to the hippocampus (Fig. 5.4). As the subcortical structures, but do not necessarily
seizure propagates outside of the mesial temporal involve the entire cortex,” and “they can be
structures into neocortical regions, it is then asymmetric” [16]. In idiopathic generalized
detected by scalp EEG. A 5–9-Hz temporal ictal epilepsies, the baseline EEG is within normal
discharge is highly associated with seizures of limits, and the interictal epileptiform and ictal
hippocampal onset (Fig. 5.5) [12], while neo- discharges are typically bilateral and maximal
cortical seizures often are associated with poly- over the frontal head regions. In contrast, the
morphic, 2–5-Hz On the other hand, seizures EEG background is slow in symptomatic gener-
originating at the temporal neocortex are often alized epilepsy.
associated with irregular, polymorphic, 2–5-Hz
ictal discharge (Figs. 5.6 and 5.7). The main use
of sphenoidal electrodes is not only to increase Idiopathic Generalized Epilepsy
the overall yield of detecting epileptiform EEG
abnormalities, but also to further localize inter- The ictal discharge has an abrupt onset and ter-
ictal and ictal discharges. For example if a dis- mination, and, although widespread, it is often
charge is of higher voltage over the sphenoidal maximum over the frontal regions with phase
electrodes than mid-temporal electrodes (T3 or reversals seen over F3 and F4. In absence sei-
T4), it signifies more inferior and mesial origin, zures, rhythmic spike-and-slow-wave runs that
88 M.Z. Koubeissi and N.J. Azar
Fig. 5.4 Right hippocampal ictal discharge from the same d Further evolution 40 s later. Note the amplitude discrep-
patient in Fig. 5.1 recorded with depth electrodes. a Note the ancy between MH2 and MH3, 4, and 5, despite the proximity
initial high-voltage spike that marks the seizure onset, of these electrodes to one another (5-mm inter-electrode
followed by high-frequency low-voltage activity. b Evolu- distance), which reflects the closed-field nature of the
tion of the seizure with slower rhythms now seen in the hippocampus and the importance of recording with depth
anterior hippocampus. c Further evolution 25 s later, with electrodes in order to detect its activity. AH anterior
highly organized ictal discharge in the middle hippocampus. hippocampus; MH middle hippocampus
Fig. 5.6 Left frontal seizure from the same patient with PLEDs in Fig. 5.2
Fig. 5.7 Right hemispheric seizure in a patient who presented with acute stroke and altered mental state that prompted
an EEG to rule out subclinical seizures
last longer than 3 s often have clinical correlates epilepsy is that of 3/s spike-and-slow-wave
and may be termed “ictal” as opposed to shorter complexes, usually starting at 3.5 Hz and end-
runs, often termed: “interictal”. However, due to ing at 2.5 Hz. Occasionally polyspikes may be
the difficulty of assessing subtle, brief alteration seen.
of awareness, and the distinction between inter- In juvenile myoclonic epilepsy (JME), bursts
ictal and ictal is not straightforward. If absence of diffuse, bi-frontal maximum
seizures are associated with automatisms, they polyspike-and-slow-wave discharges are seen
are called complex absence seizures [17]. The interictally or with myoclonic jerks. These are
classic ictal pattern of childhood absence typically faster than in absence epilepsies,
90 M.Z. Koubeissi and N.J. Azar
commonly around 5–6 Hz. One third of indi- corresponds to the brief muscle relaxation. Longer
viduals with JME show a photoparoxysmal postictal phases can be expected after longer sei-
response. An ictal discharge of 10–16 Hz fre- zures and in younger individuals.
quency can be seen in association with some
myoclonic seizures. When absence seizures
occur in individuals with JME, they manifest Symptomatic Generalized Epilepsies
electrographically as 3-Hz spike-and-slow
waves, like in other absence epilepsies. The ictal discharge in symptomatic tonic–clonic
Tonic seizures are often associated with voltage seizures is similar to that of idiopathic general-
attenuation with superimposed high-frequency ized seizures. Tonic seizures are typically asso-
activity of 20–40 Hz. In tonic–clonic seizures, ciated with an electrodecremental pattern or
this pattern evolves to patterns with higher paroxysmal fast activity of 10–25 Hz frequency.
amplitude with slower frequencies, followed by This is often followed within 5 s by sharp-and-
yet a slower pattern with intermittent slow waves. slow wave complexes. The vast majority of such
Another ictal pattern in tonic–clonic seizures is discharges are bilateral and frontal maximum.
that of initial fast activity of about 10 Hz that Atypical absence seizures often occur in
gradually increases in voltage before it starts patients with developmental and cognitive delay
mixing up with rhythmic slow waves yielding and are one seizure type in Lennox-Gastaut
polyspike-and-slow wave complexes [17]. What syndrome (LGS), which also includes tonic sei-
marks the switch from the tonic to the clonic phase zures, atonic seizures, and myoclonic seizures.
of the seizure is when the slow-rhythm frequency The EEG in LGS is marked generalized, frontal
reaches 4 Hz. Clonic jerks correspond to bursts of maximum slow spike-and-slow waves (1.5–
multiple spikes separated by a slow wave that 2.5 Hz) (see Fig. 5.8). Tonic, as well as atonic,
5 Ictal and Interictal EEG 91
seizures are associated with a low-voltage fast electroencephalogrpahy: a study of 374 seizures in
pattern. As mentioned previously, the baseline 48 patients. Brain. 1975;98:427–40.
8. Koubeissi MZ, et al. Scotosensitive myoclonic
EEG is slow and disorganized. seizures in MERRF. Neurology. 2009;72(9):858.
9. Koubeissi MZ, et al. Medically intractable seizures
originating from the primary somatosensory hand
References area. Epileptic Disord. 2008;10(4):339–48.
10. Devinsky O, et al. Clinical and electroencephalo-
graphic features of simple partial seizures. Neurol-
1. Sam M, So E. Significance of epileptiform discharges ogy. 1988;38(9):1347–52.
in nonepileptic patients in the community. Epilepsia. 11. Williamson PD, et al. Complex partial seizures of
2001;42:1273–7. frontal lobe origin. Ann Neurol. 1985;18(4):497–
2. Chatrian G, et al. A glossary of terms most 504.
commonly used by clinical electroencephalogra- 12. Ebersole JS, Pacia SV. Localization of temporal lobe
phers. In: International Federation of Societies for foci by ictal EEG patterns. Epilepsia. 1996;37
Electroencephalographers and Clinical Neurophysi- (4):386–99.
ology: recommendations for the practice of clinical 13. Laskowitz DT, et al. The syndrome of frontal lobe
neurophysiology. Elsevier Science Publishers: Ams- epilepsy: characteristics and surgical management.
terdam; 1983. p. 11–27. Neurology. 1995;45(4):780–7.
3. Marret S, et al. Positive rolandic sharp wave and 14. Williamson PD, et al. Parietal lobe epilepsy: diag-
periventricular leukomalacia in the newborn. Neuro- nostic considerations and results of surgery. Ann
pediatrics. 1986;17:199–202. Neurol. 1992;31(2):193–201.
4. Kellaway P. The incidence, significance, and natural 15. Proposal for revised classification of epilepsies
history of spike foci in children. In: Henry C, editor. and epileptic syndromes. Commission on Classifica-
Current clinical neurophysiology: update on EEG tion and Terminology of the International
and evoked potentials. Amsterdam: Elsevier; 1980. League Against Epilepsy. Epilepsia. 1989;30(4):
p. 171–5. 389–99.
5. Slatter K. Some clinical and EEG findings in patients 16. Berg AT, et al. Revised terminology and concepts for
with migraine. Brain. 1968;91:85–91. organization of seizures and epilepsies: report of the
6. Kellaway P, Bloxom A, McGregor M. Occipital ILAE commission on classification and terminology,
spike foci associated with retrolental fibroplasia and 2005–2009. Epilepsia. 2010;51(4):676–85.
other forms of retinal loss in children. EEG Clin 17. Panayiotopoulos CP, Obeid T, Waheed G. Differen-
Neurophysiol. 1955;7:469–78. tiation of typical absence seizures in epileptic
7. Penry J, Porter R, Dreifuss F. Simultaneous record- syndromes. A video EEG study of 224 seizures in
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EEG and Semiology in Generalized
Epilepsies 6
Nandakumar Bangalore-Vittal
1. For the purpose of discussion in this chapter, Primary generalized tonic–clonic seizures are
the proposed ABPN content outline for sei- seen in juvenile absence epilepsy, juvenile myo-
zure classification (based on semiology) will clonic epilepsy, epilepsy with generalized tonic–
be followed [1]. clonic seizures only, as well as in provoked sei-
Generalized seizures are divided as follows: zures, including alcohol withdrawal seizures. The
semiology discussed below is mainly based on
A. Tonic–clonic observations in the video-EEG setting.
B. Absence
(i) The entire tonic–clonic event typically lasts
a. Typical 1–2 min and patients have no recollection of
b. Atypical the event.
c. Absence with special features
Prodrome: This is a state where some
i. Myoclonic absences patients might feel a sense of uneasiness, irri-
ii. With eyelid myoclonia tability, or difficulty concentration and occur
hours to a day before the actual seizure.
C. Myoclonic
Tonic phase:
a. Myoclonic • Brief flexion spasm of axial and arm muscles is
b. Myoclonic–atonic associated with the loss of consciousness.
Involvement in respiratory muscles leads to
vocalization (the ictal cry), and patients
become apneic. During the initial closing of the
N. Bangalore-Vittal (&)
Department of Neurology, Nashville General
jaw, tongue biting can happen, more com-
Hospital at Meharry, Vanderbilt University Medical monly on the side of the tongue or the inner
Center, 1161 21st Avenue S, Nashville, TN 37232, cheek. The normal position of the tongue does
USA not include protrusion for biting to affect the
e-mail: nandakumar.bangalore.vittal@vanderbilt.edu
tip. Falls can occur if the patient is standing. body, or muscle aches are also commonly
The eyes move up and the pupils dilate. reported. The entire postictal state can last
Autonomic signs consist of increase in heart minutes to hours and is proportional to the
rate and blood pressure, sweating, and tra- duration of the seizure and the age of the
cheobronchial secretions. Foaming at the patient, lasting longer in children. Focal face or
mouth can occur due to involvement of the limb weakness (Todd’s paresis) is less com-
glottic muscles and prolonged seizures can mon than in secondary generalized seizures.
cause cyanosis.
Trauma from falls on hard objects, tongue bit-
Clonic phase: ing, vertebral compression fractures, aspiration
• Starts as a tremor, progressing to 4 Hz pneumonia, and neurogenic pulmonary edema can
activity (which denotes the onset of the clonic occur. The last complication in addition to central
phase) and slower. This phase involves cycles apnea and cardiac arrest can play a role in sudden
of inhibition interspersed by brief muscle unexplained death in epilepsy or SUDEP [5].
activity. Each spasm is associated with
pupillary contraction and dilation. (ii) EEG correlation: (Figs. 6.1, 6.2, 6.3, 6.4,
6.5, 6.6, 6.7, and 6.8)
Post-ictal state: • Interictally waking EEG is often normal
• Respiratory activity resumes with slower and and the yield of interictal epileptiform
deeper phases at times mimicking deep sleep discharges is increased by hyperventila-
with snoring. The muscles are relaxed, tion and sleep. Photosensitivity
including the sphincters, which can lead to (photic-stimulus-induced generalized
bowel or bladder incontinence. Variable epileptiform discharges) can be seen in up
degrees of confusion typically follow the per- to 25 % of cases where there is also a
iod of stupor or sleep. Headache, generalized family history of epilepsy.
Fig. 6.2 Representation of ictal discharge during generalized tonic–clonic seizure which lasted for 1 min and 45 s.
Figure 6.1 shows generalized spike-and-wave discharges that gain rhythmicity as shown in Fig. 6.2
Fig. 6.7 Representation of post-ictal state at 1 min showing generalized voltage attenuation and generalized slow
activity
Fig. 6.8 Representation of post-ictal state at 5 min showing continued generalized slow activity
• Nonepileptiform activities such as gen- and slow waves), then corresponding EEG ictal
eralized excessive low-voltage rhythms can be seen.
beta-activity or mild-generalized slow The tonic phase onset is predominated by
activity can be seen secondary to anti- muscle artifact obscuring the EEG. If neuromus-
seizure medications. Chronic therapy cular blockers are used, the EEG shows higher
with valproate and benzodiazepines can amplitude and decreasing frequency discharge in
abolish epileptiform discharges. Frontal the range of 9–10 Hz called the “epileptic
intermittent rhythmic delta activity recruiting rhythm.” Small side-to-side delay can
(FIRDA) has also been reported. be noted with computer analysis, but this delay is
inconsistent. Slower mixed frequency discharges
Generalized spike-and-wave discharges can with increasing amplitude rhythmic spikes are
be seen in patients with no history of seizures, seen bilaterally followed by repetitive complexes
indicating a familial epilepsy trait. Similar dis- of high-amplitude spike-and-slow-wave activity
charges can also be seen in metabolic encepha- in association with the tremor. Slowing of repe-
lopathies or drug-withdrawal states where they titions occurs with the start of violent jerks of the
present as generalized tonic–clonic seizures. clonic phase, as cortical inhibition progresses.
During the postictal state, an isoelectric EEG
Ictal EEG in Generalized Tonic–Clonic Seizures: followed by diffuse slow activity can be seen,
which corresponds to neuronal hyperpolarization.
If generalized tonic–clonic seizures are pre- Focal abnormalities during postictal states are not
ceded by absence (3 Hz spike-and-slow-wave) or expected and might suggest focal epilepsy with
myoclonic jerks (theta-range spikes or polyspikes secondary generalization.
6 EEG and Semiology in Generalized Epilepsies 99
Fig. 6.9 Absence seizure. This 10 s EEG clip shows ictal discharge—typical 3 Hz generalized high-voltage rhythmic
spike-and-wave discharge train during which the patient demonstrated delayed responsiveness
100 N. Bangalore-Vittal
Fig. 6.10 Absence seizure in a patient with juvenile myoclonic epilepsy. Note the polyspike-and-wave discharge at the
onset of ictal discharge (center of the EEG clip) that lasts *3 s
• At the onset the discharge can be of higher (3–4 Hz) than in CAE. About 80 % of
frequency *3.5 Hz and slows down over patients also have generalized tonic–clonic
time. Occasionally, generalized polyspike- and myoclonic seizures.
and-wave discharges, even bilateral indepen-
dent focal frontal spikes, can occur in typical (iii) Atypical Absence: This is an important
absence. These discharge trains often last seizure type in patients with Lennox–
5–15 s but can last up to 30 s. Hyperventi- Gastaut syndrome. Seizures occur lifelong
lation often precipitates longer trains of and are more resistant to treatment, and
discharges. photosensitivity is not a feature.
• During non-REM sleep, single or multiple
Semiology:
spike-and-wave discharges are frequent.
Onset and end of seizures is more gradual and
eyelid myoclonus is not rhythmic. Forward head
(ii) Juvenile Absence Epilepsy (JAE,
movement, perioral myoclonus, and drooling are
Fig. 6.10): JAE has a typical age of onset
notable. The seizure is usually less than 10 s in
between 9 and 13 years. Absence seizures
duration and the child can continue simple
typically occur in clusters upon awakening,
activities during an event.
and ocular retropulsive movements are less
often seen. Seizures are less frequent than in EEG in atypical absence:
CAE. EEG during absences shows gener- The ictal EEG shows 2–2.5 Hz slow
alized high-voltage spike-and-wave spike-and-wave discharge, which can be irregu-
discharge, which may be slightly faster lar. Interictal EEG shows an abnormal
6 EEG and Semiology in Generalized Epilepsies 101
background with diffuse slowing and multifocal 10–60 s. Falls from seizures are uncommon, and
interictal spikes. postictal state is not seen. Respiratory arrest and
urinary incontinence can occur.
(iv) Absence with special features [6]: EEG in myoclonic absence (Fig. 6.11): Ictal
EEG consists of generalized rhythmic 3 Hz
Myoclonic absence: The mean age of onset is spike-and-wave discharges coinciding with the
seven years with boys more often affected than rhythmic jerking of arms and can last 10–60 s.
girls. Cognition and development are abnormal Occasionally, the classic discharges are inter-
in two-thirds of patients who can have other mixed with polyspike-and-wave discharges.
seizure types such as generalized tonic–clonic
seizures. These seizures are very frequent, can
occur in sleep, and tend to be resistant to therapy. Myoclonic Seizures [7]
Fig. 6.11 A 20 s EEG clip of a 9-year-old boy with spike-and-wave discharges. Also note the delayed respon-
staring and rhythmic symmetric shoulder abduction siveness—command given to touch the nose was fol-
movements synchronous with generalized 3 Hz lowed 7 s later when the discharge had ended
102 N. Bangalore-Vittal
Fig. 6.12 A 10 s EEG clip showing generalized polyspike-and-wave discharge in a patient with juvenile myoclonic
epilepsy with myoclonic seizures
and sometimes during nocturnal awakenings or remember these jerks and are sometimes only
when tired in the evenings. At times, ideation of perceived internally as “mild electrical shock.”
the jerks can induce myoclonic jerks. Patients Objects in the hands tend to be thrown off and
Fig. 6.13 Generalized tonic seizure in a patient with attenuation. Tonic arm posturing was accompanied by
LGS. The EEG clip initially shows background slow generalized low-voltage fast activity (middle 1/3 of EEG
activity with intermixed periods of relative voltage clip) lasting 4–5 s
6 EEG and Semiology in Generalized Epilepsies 103
Fig. 6.15 A 10 s EEG clip of atonic seizure in a patient with head drop in sitting posture. Head drop coincides with the
high-amplitude slow wave during the third second of the EEG clip below
myoclonic epilepsy—higher (upon awakening) precede generalized 4–5 Hz S&W or the above-described
seizures or incidence of GTCSz PS&W discharges discharge for tonic–clonic seizure
all three photosensitivity
together
Absence None Childhood absence Very frequent staring High-voltage 2.5–3.5 Hz rhythmic Runs of described Interictal discharges
epilepsy—more than episodes lasting *10 s, can S&W discharges for longer than 3 s more likely cause
90 % undergo be associated with ocular clinical events
remission with age myoclonic movements
Atypical Tonic Lennox–Gastaut Gradual onset and end of Slow background with Interictal 2–2.5 Hz slow irregular S&W
absence seizures syndrome = seizures head movements with spikes discharges
Atonic are lifelong and perioral myoclonia and
photosensitivity is not drooling last <10 s
a feature Can perform simple activities
during seizure
Myoclonic Absence Absence with special Frequent arm abduction, with High-voltage 3–4 Hz S&W High-voltage 3–4 Hz S&W discharges
absence features—myoclonic perioral myoclonia lasting discharges time locked with myoclonic jerks and
absence 10–60 s without postictal delayed responsiveness when tested
state
(continued)
105
Table 6.1 (continued)
106
The ictal patterns tend to occur in series and definition have alteration in consciousness or
last for minutes with seizures occurring every alteration in awareness.
20–30 s.
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These are also predominantly seen in symp- with epileptic seizures and with epilepsy: report of
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nology. Epilepsia. 2001;42(6):796–803.2.
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tive impairment as in Lennox–Gastaut syndrome. Carlen PL, Wennberg R. Video-EEG evidence of
Semiology: Brief atonia can be limited to the lateralized clinical features in primary generalized
head or can involve all postural muscles. Loss of epilepsy with tonic-clonic seizures. Epileptic Disord.
2003;5(3):149–56.
consciousness is extremely brief and patients can 3. Usui N, Kotagal P, Matsumoto R, Kellinghaus C,
stand up immediately after a fall. When atonia is Lüders HO. Focal semiologic and electroencephalo-
prolonged, patients will lay motionless on the graphic features in patients with juvenile myoclonic
floor. Falls occur on the body axis. The arms are epilepsy. Epilepsia. 2005;46(10):1668–76.
4. Epilepsy: a comprehensive textbook, vol 1. 2nd edn.
not involved by tonic or myoclonic phenomenon. Generalized tonic clonic seizures (Chap. 47). Wolters
In mild cases, only upper body is involved, and Kluwer, Lippincott & Williams and Wilkin.
in severe cases, the lower body can be involved. 5. Langan Y, Nashef L, Sander JW. Case-control study
EEG correlation (Figs. 6.15 and 6.16): The of SUDEP. Neurology. 2005;64(7):1131–3.
6. Epilepsy: a comprehensive textbook, vol 1. 2nd ed.
interictal EEG is not specific and can show slow Typical and atypical absences (Chap. 49). Wolters
spike-and-wave activity. EMG when recorded Kluwer, Lippincott & Williams and Wilkin.
shows silence for *400 ms or 7. Epilepsy: a comprehensive textbook, vol 1. 2nd edn.
polyspike-and-wave activity. The ictal EEG Generalized myoclonic seizures (Chap. 50). Wolters
Kluwer, Lippincott & Williams and Wilkin.
shows generalized polyspike-and-wave activity 8. Epilepsy: a comprehensive textbook, vol 1. 2nd ed.
with atonia coinciding with slow activity (this Generalized clonic seizures (Chap. 48). Wolters
pattern is most often seen). Other ictal patterns Kluwer, Lippincott & Williams and Wilkin.
can be seen, including low- or high-voltage fast 9. Epilepsy: a comprehensive textbook, vol 1. 2nd ed.
Tonic seizures (Chap. 52). Wolters Kluwer, Lippin-
activity, and flattening or burst of cott & Williams and Wilkin.
polyspike-and-waves followed by generalized 10. Epilepsy: a comprehensive textbook, vol 1. 2nd ed.
slow wave activity. Atonic and myoclonic-atonic seizures (Chap. 51).
Wolters Kluwer, Lippincott & Williams and Wilkin.
11. Gastaut H, Tassinari CA. Handbook of electroen-
Summary: Table 6.1 summarizes the gener- cephalography and clinical neurophysiology, Part A:
alized seizure types, other seizures that can occur Epilepsies (vol 13). Ictal discharges. Amsterdam:
in the same patient and recognized epileptic Elsevier Scientific Publishing Company; 1975. P. 29.
syndromes. Emphasis has been placed on clinical 12. Gastaut H, Tassinari CA. Handbook of electroen-
cephalography and clinical neurophysiology, Part A:
seizure semiology along with interictal and ictal Epilepsies (vol 13). Ictal discharges. Amsterdam:
EEG findings. All generalized seizures by Elsevier Scientific Publishing Company; 1975. P. 34.
EEG and Semiology in Focal Epilepsy
7
Amir M. Arain
The majority of seizures could be divided into ciated observable motor or autonomic compo-
generalized or focal (also known as partial) sei- nents or involving subjective sensory or psychic
zures based on ictal EEG onset. Generalized phenomenon only. These seizures are also
seizures, as the name implies, appear to have a known as simple partial seizures or auras;
bilateral onset on the EEG since the seizure (2) focal seizures with impairment of awareness,
discharge is believed to rapidly involve bilateral also called dyscognitive, implying a larger cere-
networks. In contrast, focal seizures arise within bral involvement. These seizures are also known
networks limited to one hemisphere. As electro- as complex partial seizures; and (3) secondary
graphic seizure onsets may be discretely local- generalized seizures, which are focal seizures
ized or widely distributed, the clinical semiology that evolve to a bilateral convulsive seizure.
complements the electrographic findings in con-
cluding seizure localization. While historical
description of seizures may help in semiology, Temporal Lobe Seizures
video-EEG monitoring of habitual seizures is key
in analyzing details of seizure semiology. Temporal lobe seizures may arise from mesial and
Scalp EEG fails to detect seizure onset in many lateral temporal regions. This distinction is
patients. Scalp EEG fails to lateralize seizures in important in the surgical evaluation of refractory
about 25% of seizures in patients with unilateral epilepsy. Mesial temporal lobe seizures will often
mesial temporal lobe epilepsy and as high as 33– be abolished after standard temporal lobectomy or
50% of seizures in patients with extratemporal selective amygdalohippocampectomy, while lat-
epilepsy [1–3]. In these cases, seizure semiology eral temporal lobe seizures will often require
is often very helpful. invasive video-EEG monitoring in order to map
Some semiological features are useful for eloquent cortex and tailor a surgical resection. The
lateralizing seizure onset zone to a hemisphere clinical features favoring mesial temporal lobe
(Table 7.1), and others can help in further lobar epilepsy include early age of onset, history of
or sublobar localization (Table 7.2). Focal sei- complex febrile seizures, congenital brain mal-
zures can be divided into (1) seizures without formations, CNS infections, tumors, head trauma,
impairment of awareness with or without asso- perinatal injury, stuttering course of seizure con-
trol, and typically with well-controlled seizures in
early childhood but re-emergence of refractory
epilepsy in adolescence or early adulthood and
A.M. Arain (&) infrequent or rare secondarily generalized sei-
Department of Neurology, Vanderbilt University zures. In contrast, lateral temporal lobe epilepsy is
Medical Center, A-0118 Medical Center North,
Nashville, TN 37232, USA typically characterized by later age of onset of
e-mail: amir.arain@vanderbilt.edu seizures, absence of early risk factors, absence of
hippocampal atrophy, and more common negative followed within 30 s by 5–7 Hz sphenoidal
structural or functional brain imaging. maximum theta activity [5]. At times, sudden
Mesial temporal lobe seizures often have an generalized or lateralized suppression or attenu-
aura—with rising epigastric discomfort or inap- ation is also seen [6]. Interictal EEG abnormali-
propriate fear or olfactory feeling and or auto- ties consist of frequent spikes or sharp waves
nomic signs like; pallor, flushing, mydriasis, predominantly in the inferomesial (sphenoidal
irregular respiration or respiratory arrest, electrodes) and anterior temporal regions.
abdominal borborygmi, and eructation. These Lateral temporal lobe seizures are relatively
seizures often exhibit contralateral dystonic pos- less common than mesial temporal lobe seizures.
turing of the hand (and ipsilateral hand automa- However, these seizures may be associated with
tisms), preserved ictal language if the focus is in an aura of vertigo, or with auditory or visual
nondominant temporal lobe, ictal speech arrest if hallucinations. These seizures often evolve early
the focus is in dominant temporal lobe, postictal to a unilateral clonic activity and early head
nose wiping with ipsilateral hand, ictal vomiting turning. On scalp EEG, lateral temporal lobe
or retching behavior, and head version in transi- seizures have a high incidence of repetitive
tion to secondary generalization. epileptiform discharges at ictal onset [6]. Also if
Mesial temporal lobe seizures are often asso- present, a transitional sharp wave at ictal onset
ciated with a rhythmic theta-range ictal discharge favors a neocortical rather than hippocampal
on scalp EEG [4]. Typically, an initial focal seizure onset [7]. Neocortical seizures often start
temporal rhythmic activity of <5 Hz frequency is with higher frequency activity (alpha or beta
7 EEG and Semiology in Focal Epilepsy 111
range) on scalp EEG, but may also be associated They often occur in clusters and may present as
with irregular, polymorphic, 2–5 Hz lateralized bizarre attacks that appear hysterical with fencing
activity [4]. Interictal EEG abnormalities in and posturing [9], prominent motor automatisms
neocortical temporal epilepsy may be absent or (hypermotor), usually complex, aggressive sex-
consist of occasional spikes or sharp waves pre- ual automatisms, and vocalizations with variable
dominantly in the anterior or mid-temporal complexity [10]. Frontal lobe seizures can be
regions [8]. grouped into four based on their origin in the
While certain semiological features can help frontal lobe.
lateralize the seizure onset zone and, further, Supplementary motor seizures may occur
localize it to the temporal lobe, they cannot dis- without alteration of consciousness, representing
criminate between mesial and lateral temporal simple partial seizures. Typical characteristics
onsets. These include ictal emeticus, ictal urinary include prominent tonic posturing, usually of the
urge, and ictal spitting, which often localize to contralateral upper extremity, contraversive head
the right temporal lobe, and piloerection, which and eye deviation, preservation of consciousness
localizes to the left temporal lobe. in some patients, and postictal Todd’s paresis.
Anterior cingulate seizures are characterized
by sudden changes in mood and elaborate
Extratemporal Lobe Seizures gestural frequent tonic/dystonic posturing, rare
changes of facial expression of fear, vocaliza-
Extratemporal lobe seizures can mimic temporal tion, complex motor automatisms that are often
lobe seizures semiologically and electrographi- hypermotor, and autonomic features.
cally (1). These are often referred to as temporal Orbitofrontal seizures are characterized by
plus epilepsies (TPE) (2). They are often difficult sudden complex gestural automatism, hypermo-
to differentiate simply by using general clinical tor activity, olfactory fear and prominant facial
features. However, early ictal signs and symp- expression of fear hallucinations, illusions, and
toms that suggest involvement of the perisylvian prominent autonomic features.
region, the orbitofrontal cortex, or the Dorsolateral frontal seizures are often char-
temporo-parieto-occipital junction should acterized by unilateral clonic activity involving
heighten the suspicion of temporal plus epilep- face and spreading to the arm and leg. These
sies (2). This is of clinical importance since seizures often occur without the alteration of
misdiagnosis as temporal lobe epilepsy and rec- consciousness [11]. They often involve forced
ommending temporal lobectomy will result in head turning to the contralateral side with lateral
surgical failure and persistence of seizures. deviation of the eyes indicating activation of
contralateral frontal eye field [12, 13]. In domi-
nant frontal lobe convexity seizures, aphasia is
Frontal Lobe Seizures often seen.
In frontal lobe seizures, the ictal EEG often
Although they constitute the second most com- shows excessive generalized muscle artifact at
mon focal seizures after temporal lobe seizures, the onset, and the ictal discharge is typically brief
frontal lobe seizures can pose a diagnostic chal- and delayed. The ictal EEG can also be falsely
lenge. They do not always produce loss of localizing. The Interictal EEG is commonly
awareness, and when they do, they usually have normal, though multifocal epileptiform dis-
brief or no postictal confusion. Thus, frontal lobe charges may be seen in mesial frontal lobe sei-
seizures can be mistaken for psychogenic zures. In dorsolateral frontal epilepsy, the
nonepileptic seizures, movement disorders, or interictal EEG may show focal interictal epilep-
parasomnias. Frontal lobe seizures are typically tiform discharges localizing to the epileptogenic
characterized by stereotypical pattern, frequent focus. Frontal lobe seizures may also be char-
nocturnal occurrence, and brief duration [9]. acterized by bilateral synchronous interictal
112 A.M. Arain
epileptiform discharges representing secondary when the seizure focus is in the mesial or basal
bilateral synchrony. Alternatively, focal epilep- occipital regions. False localization can also be
tiform discharges are seen in the ipsilateral or seen in occipital lobe seizures [6]. Ictal EEG may
contralateral temporal or frontal lobes. become more evident as a low-voltage fast
Parietal and occipital lobe seizures can often activity progressively followed by a rhythmic
present with temporal or frontal symptomatology epileptiform discharge. Ictal EEG in occipital
because of spread of their locus of origin. They seizures may vary with the pathway of propa-
are often the cause for pseudotemporal and gation, typically spreading to the temporal or
pseudofrontal seizures. frontal region or bilaterally. At times, the initial
occipital onset is missed while the ictal discharge
rapidly becomes predominant in the temporal
Parietal Lobe Seizures region giving a false localization.
The interictal EEG in occipital lobe epilepsy
The symptomatogenic zone of parietal lobe sei- is typically abnormal. Posterior temporal
zures may be distant from the seizure onset zone, epileptiform discharges are the most common
with the seizure semiology representing ictal patterns. Centrotemporal spikes are frequently
propagation beyond the parietal association cor- seen with occipital paroxysms. Other patterns
tex. Propagation pathways can be from the include random unilateral or bilateral occipital
parietal lobe to the sensorimotor cortex, premotor spikes, often with fixation-off sensitivity.
eye field, supplementary motor, or temporolim- Fixation-off sensitivity is characterized by pos-
bic region. These seizures can be characterized terior or generalized epileptiform discharges that
by focal motor clonic activity contralateral to the consistently occur after eye closure and last as
epileptogenic zone, tonic posturing of extremi- long as the eyes are closed. It may represent an
ties, oral–gestural automatisms, complex ictal or interictal phenomenon. Some patients
automatisms, painful or thermal or sexual/groin may also have occipital spikes exclusively dur-
paresthesia, head deviation, Todd’s paralysis, or ing sleep, while others may consistently have
postictal aphasia. normal EEG.
The ictal EEG may be poorly informative and
falsely localizing [6]. It may show diffuse voltage
suppression followed by sharp waves spreading Insular Lobe Seizures
either anteriorly or posteriorly to the frontal or
parietal operculum. Interictal epileptiform dis- The insula is an island of cerebral cortex folded
charges, if present, are typically seen in the deep within the lateral sulcus. It has extensive
temporal region. connections with temporal, occipital, opercular,
and orbitofrontal regions, and with the triangular
and opercular parts of the inferior frontal gyrus.
Occipital Lobe Seizures Seizures restricted to the insular lobe do not
result in impairment of consciousness and may
Occipital lobe seizures are often characterized by manifest as laryngeal discomfort with thora-
elementary visual hallucinations consisting of coabdominal constriction or dyspnea, vomiting,
flashing or steady spots or simple geometric hypersalivation, laryngeal constriction, followed
forms. Other manifestations include repeated eye by unpleasant paresthesias or warmth in the
blinking and tonic eye and head deviation, either perioral region or involving larger somatic areas,
ipsilateral or contralateral to the ictal discharge. dysarthria or dysphonia, ending with focal motor
Occipital seizures are often associated with such manifestations.
vegetative phenomena as vomiting. The ictal The distance of the insular cortex from the
EEG in occipital lobe epilepsy may be normal surface makes scalp recordings imprecise.
7 EEG and Semiology in Focal Epilepsy 113
Ictal EEG often is marked by muscle artifacts and 6. Foldvary N, Klem G, Hammel J, Bingaman W,
can show ictal discharges in the temporal Najm I, Luders H. The localizing value of ictal EEG
in focal epilepsy. Neurology. 2001;57:2022–8.
regions. Interictal epileptiform discharges on 7. Azar NJ, Lagrange AH, Abou-Khalil BW. Transi-
scalp EEG are usually absent. tional sharp waves at ictal onset—a neocortical ictal
pattern. Clin Neurophysiol. 2009;120:665–72.
8. Pfander M, Arnold S, Henkel A, Weil S, Wer-
hahn KJ, Eisensehr I, Winkler PA, Noachtar S.
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interobserver reliability of scalp ictal EEG. Neurol- Novelly RA, Mattson RH. Complex partial seizures
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Sharbrough FW, Marsh WR, Meyer FB, Jack CR, Wyllie E, Luders H. Frontal lobe seizures: electro-
O’Brien PC. Factors predictive of the outcome of clinical syndromes. Epilepsia. 1995;36:16–24.
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2000;41:843–9. izing value of unilateral motor and somatosensory
4. Ebersole JS, Pacia SV. Localization of temporal lobe manifestations in frontal lobe seizures. Epilepsy Res.
foci by ictal EEG patterns. Epilepsia. 1996;37:386– 2001;43:125–33.
99. 13. Wyllie E, Luders H, Morris HH, Lesser RP, Din-
5. Risinger MW, Engel J Jr, Van Ness PC, Henry TR, ner DS. The lateralizing significance of versive head
Crandall PH. Ictal localization of temporal lobe and eye movements during epileptic seizures. Neu-
seizures with scalp/sphenoidal recordings. Neurol- rology. 1986;36:606–11.
ogy. 1989;39:1288–93.
Status Epilepticus
8
Pavel Klein
Definition Classification
P. Klein (&)
Department of Neurology, Mid-Atlantic Epilepsy
and Sleep Center, 6410 Rockledge Drive, Suite 410,
Bethesda, MD 20817, USA
e-mail: kleinp@epilepsydc.com
age <18 years, history of prior epilepsy and electrographic seizure versus 5% of
convulsive seizures prior to monitoring were the non-comatose patients. Prevalence of NCSE by
risk factors for electrographic seizures. Seizures diagnosis is shown in Table 8.3 [3].
were detected during the first 24 h of CEEG The diagnosis of non-convulsive status
monitoring in 88% of patients, during day 2 of epilepticus in patients with altered mental status
monitoring in another 5%, and after 48 h of and ambivalent EEG can be aided with intra-
monitoring in 7%. 20% of comatose patients venous benzodiazepine bolus injection, e.g.,
required >24 h of monitoring to detect the first lorazepam 1 mg, which may abolish the
8 Status Epilepticus 117
Adult % Pediatric %
– Paraneoplastic etiology, with associated
CVA 25 Fever/infection 35 autoantibodies (i) Hu, (ii) Ma2, and
ASM change 19 ASM change 20 (iii) CRMP-5—all of them target intracellular
EtOH/recr. drugs 12 Unknown 9 antigens. Most common associated neo-
Anoxia 11 Metabolic 8 plasms are small cell lung carcinoma (asso-
Metabolic 9 Congenital 7 ciated with all of the above antibodies),
testicular germ call carcinoma (Ma2), and
Unknown 8 Anoxia 5
thymoma (CRMP5). In these conditions, SE
Fever/infection 5 CNS infection 5
may be refractory and respond to tumor
TBI 5 4
removal.
Tumor 4 CVA 3 – Autoimmune diseases including Hashimoto’s
CNS infection 2 EtOH/recr. drugs 2 thyroiditis, SLE, Rasmussen’s encephalitis
Congenital 1 Tumor 1 syndrome, with associated thyroid microso-
mal antibodies, voltage-gated K channels
antibodies, NMDA-receptor antibodies, all of
epileptiform discharges, sometimes with associ- which are extracellular antigens. Rasmussen’s
ated paradoxical improvement of the patient’s encephalitis syndrome is associated with
level of consciousness. anti-NR2A antibody (NMDA-receptor sub-
Etiology of SE for adults and children is unit GluRepsilon2).
shown in Table 8.4 [4]. – Infectious, ill-defined include the recently
A variable proportion of patients with status described new-onset refractory SE (NORSE)
have preceding the history of epilepsy, in some in adults and febrile infection-related epilepsy
studies estimated up to approximately 45%. In syndrome (FIRES) in previously normal
approximately 50% of patients with preceding children.
epilepsy, the epilepsy is acute symptomatic. It is – Chromosomal, genetic, or congenital
remote symptomatic in 20% cases, idiopathic in dysplastic and inborn errors of metabolism,
14%, and unclassified in 17%. all covered elsewhere in this book.
118 P. Klein
Fig. 8.1 Increased T2 signal (FLAIR protocol) in epilepsia partialis continua arising from the right hemisphere (a),
with resolution after i.v. anesthesia (b)
Fig. 8.2 MR images, FLAIR sequences. a Arrow shows hemisphere seizures. c Axial DWI showing expanded
left-sided region of change (shown only on the left side and hyper-intense splenium during bitemporal SE.
for clarity, but bilateral change is present). b Axial DWI d Axial DWI images showing gyral pattern of restricted
showing gyral pattern of restricted diffusion and ipsilateral diffusion and crossed cerebellar diaschisis in a right
thalamic (pulvinar) change in a patient with left hemispheric SE
hypoxia. The regional hyperperfusion serves as a Table 8.9 Treatment of early SE (first-line treatment)
(adapted from Ref. [2])
compensatory mechanism, but is insufficient to
prevent the stimulation of anaerobic glycolysis Route Adult Pediatric dose
dose
due to the prolonged ictal activity.
Lorazepam iv 4 mg 0.1 mg/kg
Midazolam im 5–10 mg 0.15–0.3 mg/kg
Table 8.10 Comparative efficacy of diazepam, loraze- Phenobarbital may be more effective than
pam, and midazolam in the treatment of SE before arrival phenytoin in suppressing SE, but is less used in
in the hospital. Response = seizure termination prior to
arrival in ER without rescue treatment [9, 10] practice, possibly because of greater potential for
respiratory depression and intubation, particu-
Dose/route Response %
larly in combination with benzodiazepines.
Midazolam 10 mg im 73 Comparison of efficacy of lorazepam, pheno-
Lorazepam 4 mg iv 59–63 barbital, and phenytoin with or without benzo-
Diazepam 10 mg iv 43 diazepam is shown in Table 8.12.
Placebo Im 21 Phenytoin has the advantage of lack of seda-
tion or respiratory depression. Maximum CNS
concentration is reached in 20 min. Its potential
depression and sedation. Seizure recurrence is side effects include bradycardia (7%) and
common after benzodiazepine administration, hypotension (27%) [11]. Phenytoin is alkaline
especially in acute symptomatic SE. and with extravasation causes skin irritation and
In a study comparing the efficacy of intra- “purple glove syndrome” which occurs in 1–2%
muscular midazolam with intravenous lorazepam of patients [11]. Phenytoin needs to be adminis-
for children and adults in status epilepticus tered in normal saline as it precipitates in dex-
treated by paramedics outside the hospitals, sei- trose. Infusion rate is 50 mg/min for adults,
zures were stopped prior to arrival in the hospital 20 mg/min for the elderly, and 25 mg/min for
in 73% subjects treated with midazolam 10 mg i. children. The elderly have a higher risk for car-
m. and 63% subjects treated with lorazepam diovascular complications. Heart rate and blood
4 mg i.v. with 4.5 and 6.5 min to the cessation of pressure should be monitored with the reduction
convulsions, respectively. Seizures recurred in of infusion rate if hypotension occurs. Total
11% in both groups. Adverse-event rates were blood level and free phenytoin level should be
similar in the two groups [10]. checked at the end of the infusion, within 30 min
Secondary treatment includes phenytoin or of infusion if seizures persist or 1–2 h after
phenobarbital (Table 8.11). It should be admin- infusion if seizures stop, in order to help with
istered at the same time as the benzodiazepine. timing of maintenance treatment.
Table 8.12 Comparison of efficacy of SE treatment parameters phenytoin, phenobarbital, and lorazepam [11]
Response rate % (Sz Dose Maximal admin rate Infusion time
end 20 min) (mg/kg) (mg/min) (min)
Lorazepam 65 0.1 2 4.7
Phenobarbital 58 15 100 16.6
Phenytoin + diazepam 56 18 50 42
0.15 5
Phenytoin 44 18 50 33
122 P. Klein
Table 8.13 Use of valproate and levetiracetam in Stage 2 status epilepticus (adapted from Ref. [2])
Route Adult dose Pediatric dose
Valproate iv infus rate 15–30 mg/kg 20–40 mg/kg
10–15 min 10–25 mg/kg neonates
Levetiracetam iv infus rate Not established; 2000–4000 used 5–15 min Not established
Table 8.14 Refractory SE treatment with iv anesthetics propofol, midazolam, and pentobarbital
Dose, bolus mg/kg Followed by infusion mg/kg/h SE control rate (%) [14]
Propofol 1–2 5–10 mg/kg/h 68
Midazolam 0.1–0.3 (at 25 mg/min) 0.05–0.4 mg/kg/h 78
Pentobarbital 5–20 0.1–3 64
European guidance recommends titration of It has a rapid onset of action: Seizure control
propofol and barbiturate to EEG burst suppres- occurs in 2–3 min versus 123 min with pento-
sion, and midazolam to seizure suppression, barbital. It often requires high doses (e.g., 50–
maintained for at least 24 h [15]. 100 mcg/mg/kg/min) to induce burst suppres-
Therapeutic coma lowers metabolic activity of sion, often with associated hypotension requiring
brain tissue, removes the energy mismatch i.v. pressor support. It has common and poten-
between brain tissue energy use and supply, and tially lethal side effects, chiefly hypotension,
allows neuronal recovery, including recovery of metabolic acidosis, pneumonia, and the “propo-
normal neuronal synaptic receptor function. fol infusion syndrome” (PRIS). PRIS occurs at
The three most commonly used i.v. anesthetics high doses with prolonged infusion, e.g.,
are shown in Table 8.14, together with dosing and >4 mg/kg/h for more than 24 h, more so with
infusion rate. Following initial bolus injection, the co-treatment with catecholamines and steroids. It
rate of infusion/dose of the chosen agent should consists of unexplained lactic acidosis, rhab-
be titrated quickly up to electrographic seizure domyolysis with elevated creatinine kinase,
suppression and then EEG burst suppression. hypertriglyceridemia, and widespread ECG
The optimal duration of the treatment has not changes, including cardiac arrest. Prolonged
been determined in controlled studies. Different propofol infusion is associated with other serious
centers use variably 24–48 h of EEG burst sup- systemic complications, most commonly pneu-
pression on the i.v. anesthetic before attempting a monia. In one study of adults with RSE, there
taper. i.v. anesthetic is restarted if seizures recur. was 57% mortality with propofol treatment ver-
During i.v. anesthesia, non-anesthetic ASMs sus 17% with midazolam.
should be optimized in preparation for with- Midazolam rapidly enters brain tissue. It has a
drawal of the i.v. anesthetic. The duration of i.v. powerful short duration. 0.4 mg/kg/h infusion
anesthesia is empirical. Side effects are common, rate is more effective in RSE than 0.2 mg/kg/h
include hypotension, pneumonia, gastric paresis, infusion rate, with lower mortality of 40% versus
and immunosuppression, and contribute inde- 62%. There is a risk of development of acute
pendently to poor outcome and death. Mortality tolerance with risk of seizure relapse. Break-
and functional outcome is similar in those with through seizures may occur in 50% of patients.
and without EEG suppression. Side effects include hepatic and renal impair-
Propofol is the first-line intravenous anes- ment, respiratory, and cardiac depression,
thetic agent for RSE in many centers because its although the latter is less pronounced than with
rapid onset and short duration of action, even barbiturates.
after prolonged infusion, allow a greater control Pentobarbital has longer half-life, making
of the depth of anesthesia than with pentobarbital quick adjustments and evaluation of mental sta-
or midazolam [14]. Its t1/2 is 2 h, but its effect is tus after discontinuation of the infusion more
shorter (minutes) because of its rapid distribution difficult [16]. It is associated with the greatest
into peripheral tissues. 1–2 mg/kg load is fol- incidence of systemic complications, particularly
lowed by infusion at 5–120 mcg/kg/min, with hypotension, splanchnic hypoperfusion (leading
up-titration in increments of 10 mcg/kg/min to gastric, pancreatic, and hepatic sequelae),
every 10–15 min to EEG response/side effects. immunosuppression, with attendant risks of
124 P. Klein
infections most commonly pneumonia, but also TBI, encephalitis, and other infectious, inflam-
nosocomial iv sepsis via catheter, or UTI; and matory and paraneoplastic causes in previously
reduced GI motility. The side effects may limit non-epileptic patients—with RSE duration of
treatment dose and duration. >1 h. Good treatment response occurs in idio-
Inhalational agents: Inhalational halogenated pathic SE in previously non-epileptic patients;
anesthetics such as isoflurane and desflurane SE is associated with ASM non-compliance in
have been used successfully to control seizures in epileptic patients and SE duration of <1 h [13].
small numbers of patients who do not respond to SE prognosis: Overall mortality is 3–6% in
intravenous agents [14]. The logistical and safety children, 14% in young adults, 38% in the
implications of providing inhalational anesthesia elderly. It is 3% with SE duration of 30–60 min
in the ICU are substantial, and such treatment is and 32% with duration of >1 h. It is higher with
not a realistic option in most circumstances. an acute precipitant, in acute symptomatic epi-
Other agents are used in clinical practice in lepsy, after anoxic brain injury, in the elderly,
RSE. They include valproate, topiramate, leve- and in SE duration of >24 h. It is low in the
tiracetam, lacosamide, ketamine, and i.v lo- context of alcohol withdrawal or ASM
razepam infusion. Evidence of efficacy of VPA, non-compliance in an epilepsy patient. Approx-
TPM, LEV, LCM, and ketamine is based on imately 15% of patients have severe and 15% of
uncontrolled studies, retrospective reviews, and patients have mild neurological deficit. 35% of
case series reports. patients recover to baseline [14].
Other ancillary treatments used in continued In children with convulsive SE, mortality is
refractory status epilepticus unresponsive to 3–5% short term and further 3% long term, with
standard treatments have included hypothermia, similar risk factors for poor and favorable out-
ketogenic diet, immunotherapy—including IVIG come as with adults. 25–40% of children with SE
and plasmapheresis—resective surgery, and develop subsequent epilepsy. This is highest with
vagal nerve stimulation. Their use is based on acute symptomatic convulsive SE. 35% children
anecdotal and case series evidence only. with SE > 30 min go on to have neurodevelop-
RSE treatment monitoring includes monitor- mental decline.
ing of electrolytes, calcium, magnesium, blood RSE outcome: RSE has mortality of 39–48%
gases, and pH, and monitoring for and treatment in adults and 16–44% in children. 28% adults
of concurrent infection, fever, rhabdomyolysis, and 32% children return to baseline.
hypotension, and bradycardia, all of which may
worsen RSE outcome.
Refractory NCSE: Because the side effects of References
treatment might outweigh its potential benefits in
NCSE, there remains debate about whether 1. DeLorenzo RJ, Hauser WA, Towne AR, Boggs JG,
NCSE should be treated as aggressively as Pellock JM, Penberthy L, Garnett L, Fortner CA,
GCSE. Administration of anesthetic agents is Ko D. A prospective, population-based epidemio-
logic study of status epilepticus in Richmond, Vir-
often postponed until a trial of a third-line ginia. Neurology. 1996;46(4):1029–35.
non-anesthetic anticonvulsant has been com- 2. Shorvon S, Baulac M, Cross H, Trinka E. Walker M
pleted [15]. (for the Task Force ILAE Commission on European
Affairs. Gray Matters Epilepsia. 2008;49:1277–88.
3. Claassen J, Mayer SA, Kowalski RG, Emerson RG,
Hirsch LJ. Detection of electrographic seizures with
SE Treatment Outcome continuous EEG monitoring in critically ill patients.
Neurology. 2004;62:1743–8.
The two factors that best predict SE treatment 4. DeLorenzo RJ, Towne AR, Pellock JM, Ko D. Status
epilepticus in children, adults, and the elderly.
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caused by acute structural lesions such as CVA, sequence of electroencephalographic changes during
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6. Wasterlain CG, Liu H, Naylor DE, Thompson KW, generalized convulsive status epilepticus. Veterans
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ing status epilepticus: the receptor trafficking hypoth- 12. Trinka E. What is the evidence to use new
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Colling C, Rowan AJ, Handforth A, Faught E,
EEG in Encephalopathy and Coma
9
Mohamad Z. Koubeissi, Nabil J. Azar and Peter W. Kaplan
The EEG is a very important part of the eval- may be detected within the first day of moni-
uation of patients with acutely altered mental toring, but in those with coma, the first seizure
status. Many of these patients are referred from is typically recorded after the first 24 h. Pre-
intensive care settings, and a routine initial step dictors of seizures on continuous EEG moni-
often involves obtaining a 20-min record to toring in the ICU include coma, age <18 years,
screen for seizures, status epilepticus, history of epilepsy, convulsive seizures prior to
encephalopathy, or even hypersomnolence. monitoring [1], CNS infection, brain tumor,
More recently, there has been a move to pro- recent neurosurgery, and periodic epileptiform
longed monitoring with continuous EEG moni- discharges [5].
toring (cEEG) also being made available in the Status epilepticus is discussed in Chap. 8 and
intensive care setting with the possibility of will not be discussed in this chapter. Rather, we
remote reviewing of the record. The exact place will explore the principal EEG findings in
for extended recordings remains under consid- encephalopathic patients and their clinical rele-
eration, but a recent study has revealed that vance. EEGs may be done for diagnosis, moni-
about 20% of comatose ICU patients have toring of the effects of treatment, or for
non-convulsive seizures [1]. There are some prognosis. Regarding the latter, there is an
data to suggest that non-convulsive seizures and increasing body of work that supports the notion
non-convulsive status epilepticus (NCSE) are that prognosis depends heavily on the etiology of
associated with worse outcome in patients with confusion and coma. For example, a particular
subarachnoid hemorrhage, or following head coma pattern due to medication toxicity may
trauma [1–4]. In 88% of ICU patients, seizures prove to be reversible, while conversely, it may
herald a very poor prognosis if due to hypoxic–
ischemic brain injury. Other EEG patterns may
predict outcome, independent of etiology. For
M.Z. Koubeissi (&)
Department of Neurology, George Washington example, EEG reactivity during which there may
University, Foggy Bottom South Pavilion, be a change in EEG amplitude, frequency, or the
22nd and I Street, NW, 7th Floor, appearance of other patterns following noxious
Washington DC 20037, USA
stimulation, noise or eye opening may indicate a
e-mail: koubeissi@gmail.com
more favorable prognosis. Spontaneous vari-
N.J. Azar
ability along the course of a recording typically
Vanderbilt University, Nashville, TN, USA
suggests a better prognosis than when the EEG is
P.W. Kaplan
suppressed, monotonous, and unreactive.
Department of Neurology and Pediatrics, Johns
Hopkins Medicine, Baltimore, MD, USA
Intermittent Rhythmic Delta Activity disturbances and with structural lesions, but did
(IRDA) not correlate with epilepsy [8]. More recently, a
large retrospective study found significant sta-
IRDA refers to diffuse, synchronous 2–3 Hz tistical correlations with strokes and noted its
sinusoidal waves that are often maximal anteri- favorable prognostic significance [9].
orly. It often occurs on a background of delta- or While IRDA is not associated with epilepsy,
theta-range slowing and can be occasionally OIRDA in children can have either an
asymmetric. As the term “intermittent” implies, it encephalopathic or epileptiform significance, as
often has an abrupt onset and offset, and is typ- it has been described in association with focal
ically a reactive pattern that is blocked by eye epilepsy and generalized epilepsy, especially
opening. In children, it may be maximum in the absence seizures [10].
posterior head regions and termed occipital
intermittent rhythmic delta activity, or OIRDA.
IRDA was long believed to be a pattern Triphasic Waves
indicative of deep-midline dysfunction originally
seen in children with midline tumors and raised As the name implies, triphasic waves consist of
intracranial pressure [6], and latter with structural three phases of increasing duration and decreas-
lesions involving both the cortical gray matter ing slopes. The initial phase is negative, brief,
and deep nuclei [7]. With time, it came increas- and steep, and is followed by a second positive
ingly to be seen in the elderly, typically with a trough of longer duration and slightly slower
frontal predominance (FIRDA), associated with slope. The magnitude of this second positive
background slowing. It signifies cerebral dys- phase is the largest, generally higher than 70 µV.
function, commonly diffuse encephalopathy, It is followed by a third phase that is negative and
although it can be seen with focal lesions. It is largest in duration. The duration of the triphasic
seen early in coma, soon after loss of the poste- wave is 150–500 ms. The distribution is gener-
rior basic rhythm, but is non-specific in terms of ally anterior-dominant, although they may be
pathology. As for all encephalopathic patterns, posterior-dominant in some cases. On the longi-
the prognosis of IRDA depends largely on the tudinal bipolar montage, the positive trough may
underlying pathology. show an anterior-to-posterior lag (Fig. 9.1).
Building on the work of others, Accolla and When they are maximal in the occipital region, a
colleagues in a prospective study noted that posterior to anterior lag may be seen (Fig. 9.2).
FIRDA occurred with toxic-metabolic Triphasic waves often occur with a frequency of
Fig. 9.1 Triphasic waves in an encephalopathic patient. Notice the anterior-to-posterior lag in the second (positive)
component of the triphasic wave (boxed)
9 EEG in Encephalopathy and Coma 129
Fig. 9.2 Notice the posterior-to-anterior lag in the second (positive) component of the triphasic wave (boxed)
once or twice per second on a slow background. in PDA becomes slower and loses its reactivity to
They can be bilaterally synchronous or appear stimulation.
independently on either side. PDA is believed to be generated in pyramidal
The cause of triphasic waves has classically neurons in cortical layers II, III, and V. Schaul
been attributed to metabolic encephalopathy such and colleagues found that this pattern was largely
as liver or kidney failure. However, they have also seen in dysfunctions of the subcortical white
been described in the other toxic and metabolic matter or with lesions which partially deaffer-
conditions, including lithium toxicity and ented white matter [12, 13]. Further studies
hyponatremia, or even with subcortical white revealed that it could be seen with metabolic,
matter disease [11]. Interestingly, they may toxic, or infectious encephalopathies [14], and
decrease upon administration of benzodiazepines less commonly with infratentorial lesions
without an improvement in sensorium, making the involving the thalamus and rostral brainstem [15,
distinction from epileptiform discharges difficult. 16]. Occasionally, PDA or more frequently
continuous RDA occurs with deep-seated
epileptic foci that are remote from the scalp
Continuous High-Voltage surface, with limbic encephalitis and with limbic
Polymorphic Delta (PDA) status epilepticus.
Figure 9.3 shows bilateral waxing and waning
PDA is 1–2 Hz, high-amplitude, arrhythmic medium-to-high voltage 1–3 Hz delta activity
slow-wave activity that is generally seen in the with some interspersed lower voltage theta fre-
later stages of coma than IRDA and triphasic quencies. There is little alpha or beta activity.
waves, but may still attenuate with stimulation. The patient had severe head trauma and remains
As the coma deepens, the predominant frequency alive but with little functional recovery.
130 M.Z. Koubeissi et al.
Fig. 9.3 Medium-to-high-voltage 1–3 Hz polymorphic delta activity in a patient with severe head trauma who had
little functional recovery
Low-Voltage Slow Non-reactive EEG types of artifacts, such as EKG, respiration, and
intravenous drips. The record must be run so as to
Low-voltage records (<20 lV) without variabil- conform to the Guidelines of the American Clin-
ity or reactivity occur with anoxia or less fre- ical Neurophysiology Society (ACNS) (http://
quently with severe metabolic and ischemic www.acns.org/pdf/guidelines/Guideline-3.pdf):
disturbances. Following cardiac arrest, it carries a
zero percent prognosis for return to conscious- – Minimum of 8 scalp electrodes and earlobe
ness, but care must be taken to exclude signifi- references
cant hypothermia and sedative or anesthetic – Electrode Impedance must be between 100
agents. Low-voltage fast patterns conversely may and 10,000 X
be seen in *5% of the normal population and – Interelectrode distance should exceed 10 cm
with alcoholism and sometimes with benzodi- – EEG must be read with sensitivity of
azepine use, but will also possess normal vari- 2 lV/mm and a
ability and reactivity. – s = 0.3–0.4 s
– Integrity of the whole system should be tested
– Monitoring techniques (EKG, Ventilator, etc.)
Electrocerebral Inactivity should be kept in mind as sources of artifact
– Reactivity to pain and loud sound must be
Electrocerebral inactivity (ECI) (Fig. 9.6) repre- checked
sents an EEG pattern where no activity of cortical – Assessment of adequate core body tempera-
origin can be seen. The EEG often shows many ture is required
– Recording should last for at least 30 min, and spindles occur in concert with generalized slow
done by qualified technologists negative waves constituting K-complexes. The
– Electroencephalographers should read the spindles may be prolonged and exceed 2 s Typ-
EEG at the bed side, and are advised to ically, the EEG tracing of sleep architecture is
repeat the following day if they suspect unreactive to external stimuli or at least returns to
electrocerebral silence. this pattern without a clinical return to
consciousness.
Once these criteria are satisfied, and if the First described by Jasper and Van Buren [17]
presence of anesthetic or suppressant drugs is in a patient with a midbrain tumor near the 3rd
excluded, the finding of ECI in concert with an ventricle, it has since been reported in >250
appropriate clinical examination (demonstrating patients with an aggregate prognosis for death
the lack of brainstem reflexes) indicates “brain of *25%. Spindle coma pattern is seen with
death.” These recordings are usually obtained head injury, anoxic encephalopathy, viral
after cardiorespiratory arrest, severe head trauma, encephalitis, drug intoxication, metabolic
and intractable malignant raised intracranial encephalopathy, and post-ictal states. It also may
pressure. be due to lesions in the pontomesencephalic
junction. Prognosis is often favorable, but gen-
erally depends on associated features, particu-
Spindle Coma larly reactivity. Studies have also shown the
prognosis to depend on the etiology of coma, and
Spindle coma is a pattern of sleep architecture in to be about 73% with structural abnormalities of
which bilateral bursts of fronto-central 9–14 Hz the brainstem, a third after hypoxia, about 15%
“spindles” are recorded (Fig. 9.7). If the coma after head trauma, and negligible when with
deepens, the spindle frequency slows. Often the following seizures or with drugs [18].
Fig. 9.7 Sleep-like bursts of spindles that are non-reactive to external stimuli. The patient recovered
134 M.Z. Koubeissi et al.
Fig. 9.8 Low-voltage recording of a patient after car- Following noxious stimulation, there is no evidence of
diorespiratory arrest with alpha frequencies seen diffusely EEG reactivity. The patient died
bilaterally and prevalent in the frontal head regions.
9 EEG in Encephalopathy and Coma 135
frequently encountered excessive fast activity in stupor, coma, worsening rigidity, and progres-
the EEG non-comatose patients receiving ben- sion to death. The EEG shows slowing and dis-
zodiazepines or barbiturates. Beta coma or organization of the background rhythms in the
encephalopathy (Fig. 9.9) produces an EEG with first stage (Fig. 9.10). In the second stage, there
high-frequency spindle-like bursts at *20– are periodic bilaterally synchronous discharges
25 Hz, often diffusely, but typically involving of diphasic or triphasic morphology with volt-
the fronto-central regions. Waking background is ages reaching 300 µV. With more disease pro-
often seen, as is theta activity, and the patient is gression, multiphasic discharges or polyspikes
rarely deeply unresponsive. The beta activity is may appear. Classically, the frequency of these
usually little reactive to external stimuli. Causes periodic discharges is 1 per second, and they
include benzodiazepines and barbiturates. may be associated with myoclonic jerks. These
Excess EEG beta activity can be seen in awake or periodic discharges persist into the third stage
confused patients with alcohol or other with- with gradual increase in the interdischarge
drawal states. interval, gradually evolving into further attenua-
tion of the background activity.
diphasic or triphasic discharges of CJD, the 4. Vespa PM, et al. Nonconvulsive seizures after
periodic complexes of SSPE are often slow traumatic brain injury are associated with hippocam-
pal atrophy. Neurology. 2010;75(9):792–8.
waves with or without sharply contoured wave- 5. Hirsch LJ. Continuous EEG monitoring in the
form components. They are generalized often intensive care unit: an overview. J Clin Neurophys-
with frontal predominance. Interestingly, these iol. 2004;21(5):332–40.
periodic discharges may initially appear while 6. Daly D, et al. The electroencephalogram in cases of
tumors of the posterior fossa and third ventricle.
the background is still within normal limits. This Electroencephalogr Clin Neurophysiol. 1953;5
is in contrast to CJD when the background dis- (2):203–16.
organizes invariably prior to the appearance of 7. Gloor P. Generalized cortico-reticular epilepsies.
the periodic discharges. Some considerations on the pathophysiology of
generalized bilaterally synchronous spike and wave
discharge. Epilepsia. 1968;9(3):249–63.
8. Accolla EA, et al. Clinical correlates of frontal
References intermittent rhythmic delta activity (FIRDA). Clin
Neurophysiol. 2011;122(1):27–31.
9. Sutter R, Stevens RD, Kaplan PW. Clinical and
1. Claassen J, et al. Detection of electrographic seizures imaging correlates of EEG patterns in hospitalized
with continuous EEG monitoring in critically ill patients with encephalopathy. J Neurol. 2013;260
patients. Neurology. 2004;62(10):1743–8. (4):1087–98.
2. Vespa PM, et al. Increased incidence and impact of 10. Watemberg N, et al. Clinical correlates of occipital
nonconvulsive and convulsive seizures after trau- intermittent rhythmic delta activity (OIRDA) in
matic brain injury as detected by continuous elec- children. Epilepsia. 2007;48(2):330–4.
troencephalographic monitoring. J Neurosurg. 11. Kaplan PW, Rossetti AO. EEG patterns and imaging
1999;91(5):750–60. correlations in encephalopathy: encephalopathy part
3. Claassen J, et al. Continuous EEG monitoring and II. J Clin Neurophysiol. 2011;28(3):233–51.
midazolam infusion for refractory nonconvulsive 12. Ball GJ, Gloor P, Schaul N. The cortical electromi-
status epilepticus. Neurology. 2001;57(6):1036–42. crophysiology of pathological delta waves in the
9 EEG in Encephalopathy and Coma 137
7. Which of the following is true about the 9. Clinical features of mesial temporal lobe
following EEG? epilepsy include all except:
A. It suggests a seizure focus in the left A. Early age of onset
inferior parietal region B. History of complex febrile seizures
B. It is consistent with the previous brain C. Stuttering course of seizure control
surgery D. Clonic movements
E. Hippocampal atrophy
C. It is indicative of encephalopathy 10. All of the following are true about initial
D. It shows triphasic waves investigation into patient with seizure in ER
E. C & D except:
Multiple Choice Questions for Part II 141
A. CK levels obtained between 6 and 13. In treatment of refractory status epilepticus all
12-h post-event show elevated levels of the following statements are true except:
in convulsive seizures and not in
PNES A. Continuous propofol infusion of
B. Prolactin level should be drawn within >50 mcg/kg/min is associated with a
20 min of event to differentiate risk of hypotension
organic event with the loss of con- B. Hypothermia may be used as adjunc-
sciousness with PNES tive treatment
C. Lactic acid levels drawn soon after an C. Levetiracetam dose used should not be
episode will show elevated levels after less than 2000 mg/day
convulsive seizure D. Mortality rate is higher with i.v.
D. Repeat EEG should be performed in midazolam than with i.v. propofol
patients with alcohol withdrawal sei- E. Lacosamide may be effective adjunc-
zures and EEG showing generalized tive treatment
spike-and-waves
E. All of the above are true 14. Seizures with generalized onset are seen in
which of the following genetic epilepsies?
11. Which of the following is true about
recurrence of febrile seizures? A. Benign childhood epilepsy with cen-
trotemporal spikes
A. Phenytoin is effective in preventing B. Autosomal dominant nocturnal frontal
recurrences. lobe epilepsy
B. The risk of recurrence is increased if C. Temporal lobe epilepsy with auditory
the temperature was high at the time of features
the seizure. D. Dravet syndrome
C. The older the age, the more likely the E. None of the above
febrile seizure is to recur.
D. Complex febrile seizures are more 15. Among the following factors, the one that is
likely to recur than simple febrile associated with the most favorable outcome
seizures. in SE is:
E. Frequency of febrile illness is directly
correlated with recurrence risk. A. Early treatment initiation
B. Non-compliance with anticonvulsant
12. During carotid endarterectomy, intraopera- medications in patients with estab-
tive EEG monitoring can help avoid: lished epilepsy
C. Epilepsy onset in the elderly
A. Seizures D. Early arrival in the hospital
B. Carotid clamping E. None of the above
C. Hypotension
D. Shunting 16. Which of the following is false about idio-
E. EEG is useless pathic generalized epilepsy (IGE)?
142 Multiple Choice Questions for Part II
A. Failure of presynaptic synthesis of 28. Which of the following is not true about the
GABA following EEG?
144 Multiple Choice Questions for Part II
32. Which of the following is true about the A. Associated with clinical seizures
EEG shown above: B. The most common cause is drug
overdose
A. Pathognomonic of liver failure C. The outcome is very poor in <30%
B. Left hemispheric seizure focus D. Distinct from the typical EEG of CJD
C. Normal sleep EEG E. Distinct from the typical EEG of SSPE
D. Caused by medication toxicity
E. Requires prophylaxis with antiseizure 37. Metabolic consequences of convulsive sta-
medications tus epilepticus may include all of the fol-
lowing except:
33. Parietal lobe seizures are characterized by
all except: A. Hypoglycemia
B. DIC
A. Focal motor clonic activity C. Renal alkalosis
B. Tonic posturing of extremities D. Hypotension
C. Painful or thermal paresthesia E. Hyponatremia
D. Sexual paresthesia
E. Prominent autonomic features 38. A progressive change (increase or decrease)
in which of the following will help identify
34. According to the guidelines of the Ameri- ictal discharges on the EEG?
can Clinical Neurophysiology Society
A. Frequency
(ACNS), which of the following is needed
B. Amplitude
for the recording of electrocerebral
C. Field
inactivity?
D. Morphology
E. All of the above
A. Minimum of 12 scalp electrodes and
earlobe references
39. Celiac disease has been associated with:
B. Interelectrode distance should be less
than 10 cm
A. Thalamic bleeds
C. Reactivity to pain and loud sound
B. Occipital calcifications
must be checked
C. Chiari malformation
D. Electrode Impedance must be between
D. Optic Glioma
10 and 1000 X
E. Any of the above
E. Time constant must be 0.3–0.4 ms
40. Which of the following is true about sei-
35. The incidence of SE in the USA has been
zures in patients undergoing dialysis?
estimated to approximately
A. Previous history of epilepsy does not
A. 0.9% of population
increase risk of seizures in peritoneal
B. 0.01% of population
dialysis
C. Between 18 and 40 per 100,000
B. Hypocalcemia in these patients is a
population
significant cause of seizures
D. 6–7 per 100,000 population
C. Seizures can occur in patients who
E. None of the above
develop dialysis-associated dementia/
chronic dialysis encephalopathy
36. Which of the following is true about gen-
eralized periodic epileptiform discharges
(GPEDs)?
146 Multiple Choice Questions for Part II
41. Which of the following is not true about A. Occurs with toxic disturbances
triphasic waves? B. Occurs in liver failure
C. Correlates with epilepsy
A. May occur in lithium toxicity D. Occurs in stroke
B. May occur in renal failure E. Associated with good prognosis
C. Do not correlate with epilepsy
D. Worsen with administration of 46. Insular lobe seizures are characterized by all
benzodiazepines except:
E. May occur in white matter disease
A. Dysarthria
42. MRI scan of the brain during or after status B. Perioral warmth feeling
epilepticus may show an increase in T2 C. Hypersalivation
signal in D. Laryngeal constriction
E. Complex gestural automatisms
A. The cerebellum contralateral to the
side of ictus 47. The following is not true regarding gener-
B. The ipsilateral hippocampus alized epilepsies.
C. The ipsilateral posterior thalamus
D. The splenium A. Vagal nerve stimulator and discon-
E. All of the above nection of the two hemispheres are
options in certain refractory cases
43. The EEG target pattern during continuous B. Many patients with JME have seizure
EEG monitoring in refractory status relapse if antiepileptics are stopped
epilepticus (RSE) includes: even after years of seizure freedom
C. Almost half of the cases of childhood
A. Burst-suppression pattern with inter- absence epilepsy outgrow the seizures
burst intervals of at least 10 s by adulthood
B. Any burst-suppression pattern D. Prognosis of JAE is similar to CAE
C. Burst-suppression pattern with sup-
pression intervals of at least 3 s 48. In burst-suppression pattern:
D. Burst suppression with burst duration
of no longer than 2 s A. Suppression phases have voltage of
E. None of the above less than 10 µV
B. Bursts contain mixed frequency activity
44. Occipital seizures are characterized by all C. Bursts contain spikes
except: D. Pattern is reversible in hypothermia
E. All of the above
A. Complex visual hallucinations
B. Repeated eye blinking
Multiple Choice Questions for Part II 147
49. The incidence of photosensitivity is highest 54. Myoclonic absences differ from absence
in which of the following: seizures in childhood absence epilepsy by
all of the following except:
A. Juvenile myoclonic epilepsy
B. Juvenile absence epilepsy A. Faster frequency of ictal discharges
C. Childhood absence epilepsy B. Not precipitated by hyperventilation
D. Epilepsy with myoclonic absence C. Occur in older patients
E. Epilepsy with grand mal seizures upon D. Response to treatment is incomplete as
awakening in CAE
E. Patients more often have abnormal
50. Auras associated with mesial temporal lobe cognition
seizures are characterized by all except:
55. Ictal emeticus lateralizes the seizure focus
A. Déjà vu to:
B. Rising epigastric discomfort
C. Pallor A. Right temporal region
D. Vertigo B. Left temporal region
E. Borborygmi C. Right parietal region
D. Right occipital region
51. Ictal EEG with focal right temporal rhyth- E. Right frontal region
mic activity that evolves to 5–7 Hz rhythm
within 30 is consistent with an ictal focus in 56. Frontal lobe seizures are characterized by
the: all except:
A. 10% Answers
B. 20%
C. 50% 1. (A). Risk factors for developing epilepsy
D. 75% after of febrile seizures include complex
E. 100% febrile seizures (i.e., lasting >15 min,
focal-onset seizures, and more than one
53. Hypermotor seizures with prominent seizure in 24 h), family history of epilepsy,
expression of fear localize the seizure focus abnormal development, and the presence of
to the: a post-ictal Todd’s weakness.
2. (E). Inappropriate fear is commonly seen
A. Supplementary motor region with mesial temporal lobe seizures because
B. Orbitofrontal region of the involvement of amygdala. The lead-
C. Cingulate region ing role of the amygdala, as well as that of
D. Dorsolateral frontal convexity the hippocampus and the parahippocampal
E. Parietal region gyrus, in the mechanisms of inducing a
148 Multiple Choice Questions for Part II
14. (D). The common seizure types in Dravet occipital spikes that are best brought out by
syndrome that is associated with a mutation darkness but other types of epileptiform
of the alpha 1 subunit of the voltage-gated activity have been noted, as well. Because
sodium channel gene (SCA1) are general- the frequency of seizures is low, many
ized tonic–clonic and myoclonic seizures. patients do not need to be treated with
The remaining genetic epilepsy syndromes antiseizure medicines.
are characterized with focal-onset seizures. 19. (B). In atonic seizures, the slow wave cor-
Rolandic epilepsy presents with facial responds to atonia. The loss of muscle tone
motor seizures and has complex inheritance usually lasts for *400 ms. The ictal EEG
patterns. As the name implies, seizures in can have multiple patterns, including gen-
autosomal dominant nocturnal frontal lobe eralized polyspike-and-wave activity, bursts
epilepsy (associated with mutations in the of polyspike-and-wave followed by gener-
nicotinic acetylcholine receptor) are noc- alized slow activity, and low- or
turnal frontal lobe seizures. Seizures in high-voltage fast activity (this pattern can
temporal lobe epilepsy with auditory fea- be seen with tonic seizures).
tures or autosomal dominant lateral tempo- 20. (A). Ictal EEG is characterized by evolu-
ral lobe epilepsy (associated with the tion, rather than being monomorphic. By
leucine-rich, glioma inactivated-1 or LGI1 evolution, it is meant that the pattern
gene) are marked by auditory changes in terms of its frequency, ampli-
hallucinations. tude, field, or morphology as the seizure
15. (B). In SE, good response to treatment is occurs.
seen in idiopathic SE in previously 21. (E). Please refer to Chap. 5.
non-epileptic patients—SE associated with 22. (D). This patient has infantile spasms, one
medication non-compliance in epileptic of the most malignant (and frequently
patients and SE duration of less than an under-recognized) forms of epilepsy in
hour. infancy. Approximately 75% of patients
16. (D). The background in IGE is typically have an underlying cause of the syndrome,
normal. Myoclonic seizures tend to occur including structural, genetic, metabolic,
upon awakening. In generalized epilepsy post-ischemic, or post-infectious problems.
with febrile seizures plus (GEFS+) patients Developmental outcomes for patients with
experience febrile seizures early in child- these underlying abnormalities are very
hood and other types of seizures later in life. poor.
17. (B). Slow spike-and-wave complexes pre- 23. (D). The clinical significance of spikes of
sent with a typical frequency of 1.0–2.5 Hz, different locations is not the same. Seizures
with wider (less spiky) sharp component occur in 90% of children with anterior
than in the absence epilepsy frequency. temporal spikes, but in only 40% of those
They are a typical of Lennox–Gastaut syn- with rolandic spikes or occipital spikes.
drome. Sleep activates trains of such slow Occipital spikes can be in children with
complexes in the extent that they may congenital blindness. In BECTS, spikes are
appear continuous as in electrical status equally negative over the central and tem-
epilepticus during sleep (ESES). They are poral derivations with the positive end of
associated with slow EEG background. the dipole appearing typically in the frontal
18. (E). The patient has benign occipital epi- regions. Multifocal spikes are often associ-
lepsy or idiopathic childhood occipital epi- ated with background slowing and comor-
lepsy (most likely Panayiotopoulos bidities including cognitive and motor
syndrome). The symptoms and signs deficits.
described in the question are classic for this 24. (D). Pharmacoresistance in SE is due to
diagnosis. The EEG classically shows seizure-induced internalization of synaptic
150 Multiple Choice Questions for Part II
GABA-A receptor (subunits b2-3, ɤ2) and Cognitive and psychiatric comorbidities are
simultaneous externalization of common in temporal lobe epilepsy.
AMPA/NMDA receptors to the synapse. As 29. (D). Olfactory hallucinations/auras are not
a result, there is decreased response to seen with dorsolateral frontal convexity
GABA and GABA potentiating medica- seizures. Mesial temporal structures espe-
tions such as benzodiazepine. cially the amygdala play an important role
25. (A). This patient has early infantile epileptic in the genesis of olfactory auras. Selective
encephalopathy (EIEE), also known as amygdalectomy has a dramatic effect on the
Ohtahara syndrome. Age of onset typically olfactory aura in some patients.
is within the first few months and patients 30. (D). Seizures that do not cause alteration of
can have tonic spasms, partial seizures, and awareness will have EEG changes in only
myoclonus. The EEG shows a suppression- 21% of the cases. This increases to 33% if
burst pattern. A wide variety of structural, the seizures include motor phenomena and
metabolic, and genetic etiologies are asso- drops to 15% if they don’t.
ciated with EIEE. Although seizures may 31. (C). In a study comparing the efficacy of
resolve in up to 50% of survivors, the intramuscular midazolam with intravenous
prognosis for normal psychomotor devel- lorazepam for children and adults in status
opment is very poor. Many patients progress epilepticus treated by paramedics outside
to developing infantile spasms and Lennox– hospitals, seizures were stopped prior to
Gastaut syndrome. arrival in the hospital in 73% subjects
26. (B). Postictal aphasia in complex partial treated with midazolam 10 mg i.m. and
seizures is seen if the ictal focus is in the 63% subjects treated with lorazepam 4 mg
dominant temporal lobe while preserved i.v. with 4.5 and 6.5 min to cessation of
ictal language in complex partial seizures is convulsions, respectively. Seizures recurred
seen if the focus is in nondominant tem- in 11% in both groups. Adverse-event rates
poral lobe. were similar in the two groups.
27. (B). Fos-phenytoin, a phosphate ester pro- 32. (D). The EEG shows triphasic waves,
drug of phenytoin, has replaced phenytoin in which can occur in a variety of clinical
many institutions. Fos-phenytoin is given as settings including lithium toxicity, white
phenytoin equivalent (PE), with the dose of matter disease, hyponatremia, and meta-
20 mg/kg. It can be given in dextrose or bolic encephalopathy, among others. There
normal saline. It is water soluble and can be is no correlation with increased seizure risk.
given i.m. as well as i.v. Its bioavailability is 33. (E). Prominent autonomic features are
100% compared with phenytoin. It is rapidly commonly seen with insular cortex stimu-
converted to PHT by serum and tissue alka- lation and seen with insular seizures.
line phosphatases. Its conversion half-life to Autonomic features are not a feature of
phenytoin is 7–15 min. Phenytoin levels parietal lobe seizures.
should be checked 2 h after infusion. 34. (C). The ACNS guidelines include:
28. (A). The EEG shows a right temporal spike – Minimum of 8 scalp electrodes and
and slow wave and evidence of right tem- earlobe references
poral slowing before and after the spike, – Electrode Impedance must be between
compared with the left temporal tracings. 100 and 10,000 X
The slowing is indicative of regional dys- – Interelectrode distance should exceed
function. There are no other spike popula- 10 cm
tions to suggest multifocal epilepsy. – EEG must be read with sensitivity of
Postictal aphasia localizes to the dominant, 2 lV/mm and a
commonly left, hemispheric seizures. – s = 0.3–0.4 s
Multiple Choice Questions for Part II 151
– Integrity of the whole system should be 40. (F). Unlike hemodialysis, peritoneal dialy-
tested sis does not increase the risk of seizure
– Monitoring techniques (EKG, Ventila- occurrence.
tor, etc.) should be kept in mind as 41. (D). Triphasic waves have been classically
sources of artifact associated with metabolic encephalopathy
– Reactivity to pain and loud sound must such as liver or kidney failure. However, they
be checked are also seen in the other toxic and metabolic
– Assessment of adequate core body conditions, including lithium toxicity and
temperature is required hyponatremia, or even with subcortical white
– Recording should last for at least 30 min matter disease. Interestingly, they may
and done by qualified technologists decrease upon the administration of benzo-
– Electroencephalographers should read diazepines without an improvement in sen-
the EEG at the bedside and are advised sorium, making the distinction from
to repeat the following day if they sus- epileptiform discharges difficult.
pect electrocerebral silence. 42. (E). In SE, MRI may be focally abnormal
35. (C). The incidence of SE in the USA is showing increased FLAIR, T2 signal
between 18 patients per 100,000 popula- hyperintensity and high-intensity signal
tion, according to a retrospective epidemi- DWI (diffusion-weighted imaging), both
ological study in Rochester, MN, and local at seizure focus and remote, com-
41/100,000 population (with 50 SE monly in the ipsilateral posterior thalamus
episodes/year/100,000) in a prospective (pulvinar), contralateral cerebellum, and
epidemiological study in Richmond, VA. bilateral splenium of the corpus callosum.
36. (A). There is a high association clinical 43. (B). The treatment goal during RSE is
seizures or electrographic seizures before or electrographic seizure suppression and EEG
after the recording of GPEDs. The most burst-suppression pattern or electrocerebral
frequent cause is cerebral anoxia after car- inactivity. Optimal parameters of burst
diorespiratory arrest. A poor outcome suppression such as duration of interburst
(mortality or vegetative state) is >97%. interval have not been determined. Some
Severe metabolic disease and overdoses of investigators believe that an interburst
lithium and baclofen may also cause interval of 5 s is desirable.
GPEDs. The EEG should raise the suspi- 44. (A). Occipital lobe seizures are associated
cion of CJD. Patients with later stages of with simple visual hallucinations. Complex
subacute sclerosing encephalitis (SSPE) can visual hallucinations are commonly origi-
have GPEDs with longer inter-GPED nated in visual association cortex at tem-
interval. poro–occipital junction.
37. (C). Complications of SE include hypona- 45. (C). A prospective study noted that FIRDA
tremia, hypoglycemia, acidosis, acute renal occurred with toxic-metabolic disturbances
failure, acute hepatic failure, and DIC, and with structural lesions, but did not
among others. correlate with epilepsy. More recently, a
38. (E). Seizures are marked by evolution in large retrospective study found significant
any of the mentioned criteria. statistical correlations with strokes, and
39. (B). Celiac disease has been associated with noted its favorable prognostic significance.
bilateral occipital calcifications. This can 46. (E). Complex gestural automatisms are not
potentially result in visual symptoms and seen in insular seizures rather they are
occipital seizures. manifested in complex partial seizures from
152 Multiple Choice Questions for Part II
frontal lobe seizures (cingulated, orbito- indicated mesial temporal onset. In this case,
frontal) or temporal pole. it would mean right mesial temporal region.
47. (D). The prognosis of CAE is better than 52. (D). The overall mortality for the aggregate
JAE as patients with JAE have other seizure 335 cases with alpha coma was 76%, with
types and might not outgrow their seizures. mortality varying according to etiology.
Treatment response is incomplete compared Brainstem infarction and anoxia after car-
to CAE where most patients respond to diorespiratory arrest was *90%, while
ethosuximide or valproic acid. other causes, including drug intoxication,
48. (E). Burst-suppression pattern consists of were much less (<10%).
bursts of high-voltage, mixed frequency and 53. (C). Hypermotor seizures with prominent
spike activity, separated by the periods of facial expression of fear are primarily
EEG suppression to less than 10 µV. Eti- associated with a ventral-prefrontal epilep-
ologies include anoxic encephalopathy, drug tic zone (cingulate region), whereas those
intoxication, anesthetics, and hypothermia. presenting with lower agitation and
This pattern is generally reversible if tonic/dystonic posturing are associated with
induced by hypothermia or anesthetics, but a mesial premotor epileptic zone.
is indicative of poor prognosis in the setting 54. (B). In myoclonic absences, the frequency
of anoxic encephalopathy. of the ictal discharge is 3–5 Hz and dis-
49. (A). Incidence of photosensitivity is highest charges are time-locked to myoclonic jerks.
in patients with juvenile myoclonic Similar to seizures in CAE, myoclonic
epilepsy. absences are precipitated by hyperventila-
50. (D). Auras of vertigo and dizziness are tion. They occur in older patients—mean
more frequent in patients with extratempo- age of 7—and two-thirds of the times have
ral complex partial seizures than in patients abnormal cognition, and treatment response
with mesial temporal epilepsy. is incomplete.
51. (B). Risinger et al. tested the reliability and 55. (A). Ictal vomiting results from the activa-
accuracy of scalp ictal EEG with sphenoidal tion of nondominant mesial temporal
electrodes, as a predictor of seizure localiza- structures. Intense nausea and vomiting can
tion in 110 patients with suspected temporal occur with insular stimulation in animals.
lobe epilepsy who subsequently underwent Fiol et al. suggested that insular areas trig-
intracerebral EEG monitoring. Unilateral ger ictal vomiting but require the mesial
5-Hz or greater temporal or sphenoidal temporal cortex for completion.
rhythm was the first discernible ictal activity 56. (C). Nocturnal enuresis is not typically seen
or was evident within 30 s after seizure onset with frontal lobe seizures.
Part III
Specific Epilepsy Syndromes
Electro-Clinical Syndromes by Age
of Onset—Childhood, Adolescence, 10
and Adult
Tesfaye Zelleke
Pathophysiology:
Childhood Absence Epilepsy (CAE)
According to the cortical focus theory, spikes
are generated at a cortical focus and propagate
Childhood absence epilepsy occurs in children
rapidly via cortico-cortical networks to both
4–8 years of age with peaks around 6 years. It is
hemispheres resulting in rapid synchronization.
more frequent in girls. CAE is characterized by
Paroxysmal oscillation in the cortico-thalamic
very frequent absence seizures (pyknolepsy).
loops amplifies and sustains the spike-wave
Hyperventilation induces the absence seizures.
discharges.
Based on clinical and electrographic features,
Genetics:
absence seizures are classified as typical and
Genetic mutations currently account for a
atypical absence seizures.
small proportion of patients with absence epi-
Typical absence seizures are associated with
lepsy. Mutations in GABA receptor (GABRG2,
transient impaired consciousness (behavioral
GABRA1), calcium channels, and non-ion
arrest, staring) with or without eye fluttering and
channel proteins have been identified in CAE.
automatisms. Onset and cessation are abrupt.
Glut-1 transporter deficiency is described in
Ictal EEG shows >2.5 Hz generalized spike and
about 10% of children with early-onset (under
wave lasting >3 s (average <10 s).
the age of 4 years) absence epilepsy.
Atypical absence seizures tend to have less
Animal models (generalized epilepsy/
abrupt onset and cessation, greater change in
absence epilepsy):
tone, longer duration, and variable impairment of
Several animal models are available for gen-
consciousness. Interictally, the EEG shows gen-
eralized epilepsy and absence epilepsy, which
eralized irregular and asymmetric slow spike and
include acute pharmacologic models
waves (1.5–2.5 Hz). The ictal EEG is similar to
[pentylenetetrazole (PTZ), penicillin, THIP,
the interictal discharges but may be associated
GBL], chronic models [genetic absence epilepsy
with diffuse fast activity.
rats from Strasbourg (GAERS), Wistar Albino
Glaxo/Rijswijk (WAG/Rij)] and other models
[AY-9944, MAM-AY].
Treatment options:
These include ethosuximide, lamotrigine, and
valproate [1]. A double-blinded, randomized,
comparative clinical trial compared the three
T. Zelleke (&) medications in CAE and found that ethosuximide
Department of Neurology, Children’s National
provided the best combination of seizure control
Medical Center, 111 Michigan Avenue, NW,
Washington, DC. 20010, USA and fewest attentional side effects, making it the
e-mail: tzelleke@cnmc.org optimal initial monotherapy in CAE.
Ethosuximide provided better seizure control A mix of generalized seizures occurs including
compared to lamotrigine and fewer attentional myoclonic, atonic, absence, GTC, and tonic (less
effects compared to valproic acid. Although CAE common). Non-convulsive status epilepticus may
is often perceived as “benign”, many children occur on awakening from sleep or nap. GTC is
with CAE have cognitive deficits and long-term usually the first seizure and is seen in 75–95% of
psychosocial problems. patients. Prognosis for seizure and cognitive
outcome is variable.
EEG shows bursts of 2–3 Hz generalized
Epilepsy with Myoclonic Absences spike wave and polyspike waves, which increase
with sleep. 4–7 Hz rhythmic theta activity over
The majority (70%) of children with epilepsy the central regions and vertex is a specific find-
with myoclonic absences are boys. The average ing. Myoclonic-atonic seizures are electrograph-
age of onset is 7 years. In about one-third of ically associated with a single generalized
patients a specific cause is identified. Family spike/polyspike wave (unlike LGS which shows
history of epilepsy is reported in 20%. Neu- secondary bilateral synchrony) or 3–4 Hz activ-
roimaging abnormalities, mainly some degree of ity lasting 2–6 s.
diffuse atrophy, are seen in 17% of patients. Neuroimaging is normal. Glut-1 deficiency
Patients have variable impairment of con- syndrome is identified in about 5 % of children
sciousness. Myoclonic jerks involving shoulders, with Doose syndrome. SCN1A mutation is
arms, and legs are seen. Tonic contractions, reported as a cause. Treatment options include
particularly elevation of the arms, are often valproate, lamotrigine, ethosuximide, topiramate,
noted. At times, the tonic activity may be levetiracetam, and the ketogenic diet.
asymmetric. Arrest of respiration and urinary
incontinence may occur. Seizures last 10–60 s
and frequent seizures may occur on awakening. Lennox-Gestaut Syndrome (LGS)
Other seizure types such as GTC, absence, and
drop seizures may also occur. Some children may LGS is characterized by the triad of 1. multiple
evolve to Lennox-Gastaut syndrome (LGS), and seizure types: tonic (nocturnal tonic seizures are
cognitive impairment may occur. characteristic), atonic, atypical absence, GTC,
The ictal EEG shows 3 Hz rhythmic, bilateral, and partial seizures; 2. EEG features of slow
synchronous, and symmetric spike-wave dis- background with generalized slow spike-wave
charges. Intermixed polyspikes may be seen. discharges at 1.5–2 Hz, multifocal discharges,
Bilateral myoclonias occur at same frequency as and generalized fast activity at 10–25 Hz in
spike waves, i.e., 3/second. Treatment options sleep; and 3. cognitive dysfunction and intellec-
include valproate and ethosuximide [2]. tual disability.
The peak age of onset is 3–5 years. Infantile
spasms precede LGS in 10–25%. LGS results
Epilepsy with Myoclonic-Atonic from structural/metabolic causes in 70–78%,
Seizures including meningo-encephalitis, cortical dys-
plasia, hypoxia, and traumatic brain injury,
[Also known as Doose syndrome, or Epilepsy among others. In 22–30% of children the cause is
with myoclonic astatic epilepsy] unknown. Family history of epilepsy is reported
Age of onset is 1–5 years, and the child is in 3–30%.
normal at onset. There is strong family history of Several medications are used in the treatment
idiopathic epilepsy in 15–32%. Myoclonic and of LGS, but seizure control is usually inadequate
atonic seizures with falls suggest the diagnosis. [3].
10 Electro-Clinical Syndromes by Age of Onset—Childhood, Adolescence, and Adult 157
JAE, unlike CAE, is associated with less frequent Progressive Myoclonic Epilepsy
absence seizures (one to a few per day) and is (PME)
more frequently associated with GTC seizure (in
80%). The impairment of consciousness is less PME is a group of disorders presenting with
severe in JAE. The age of onset ranges from 10– severe myoclonic seizures (and tonic–clonic
17 years. seizures) with progressive neurologic
158 T. Zelleke
deterioration (ataxia, dementia). EEG shows seizure with automatisms. The mean age
progressive slowing, generalized and multifocal of onset is 10 years. Asymptomatic
discharges, and photosensitivity typically at family members may have hippocampal
lower flash frequency. sclerosis. The course is benign in the
PME includes Lafora disease, Myoclonus majority.
Epilepsy with Ragged Red Fibers (MERRF). C. FMTLE associated with febrile seizures
Neuronal Ceroid Lipofuscinoses, Sialidosis, and starts in the first to second decade of life
Unverrricht-Lundborg Disease. Dentatorubral- and has a benign course.
pallidoluysian atrophy (DRPLA) may also cause
PME [4]. 2. Familial lateral temporal lobe epi-
lepsy (Autosomal Dominant Partial
Epilepsy with Auditory Features
Autosomal Dominant Nocturnal (ADPEAF)):
Frontal Lobe Epilepsy (ADNFLE) ADPEAF is associated with focal sei-
zures. Elemental or complex auditory
ADNFLE is caused by mutation of genes coding aura is prominent in 64% of patients.
for neuronal nicotinic acetylcholine receptor The epilepsy has a benign course.
subunits (CHRNA4, CHRNB2, CHRNA2). Sei- Leucine-rich glioma-inactivated 1
zure onset is in childhood with mean age of (LGI1) gene mutation is identified in
11.7 years, and seizures persist into adulthood. 50% of families.
The typical seizure manifests with sudden arou-
sal from NREM sleep (stage II) with hyperkinetic
or tonic movements. Seizures may cluster.
Awareness is usually retained. Auras, which may Familial Focal Epilepsy with Variable
be specific with sensory and psychic symptoms Foci
or non-specific, are frequently reported. Neu-
roimaging is normal. Interictal EEG is usually Different focal epilepsies are seen in different
normal. Ictal EEG may show bifrontal family members. Seizures and EEG abnormali-
discharges. ties are consistent in each affected family mem-
ber. Frontal lobe seizures predominate. Features
that help to differentiate from ADNFLE include
Familial Temporal Lobe Epilepsy less frequent seizures, daytime seizures, more
(Autosomal Dominant frequent secondary generalization, and rare
with Incomplete Penetrance) clusters and auras. Seizure foci may also be
temporal or occipital. Inheritance pattern is
1. Familial mesial temporal lobe epilepsy autosomal dominant with 70% penetrance;
(FMTLE): FMTLE may occur with or with- mapped to chromosome 22q12 [5].
out hippocampal sclerosis.
In this syndrome, development is initially nor- Myoclonic Epilepsy in Infancy (MEI) [2]
mal, and then seizure starts between 1 week and
7 mos (mean = 3 mos). Initially, there are spo- With an onset of 4 mos–3 yo, this syndrome is
radic focal motor seizures but eventually they eventually outgrown in most patients. Clinically,
become prolonged or occur in clusters and may there are axial or upper extremity myoclonic
secondarily generalize. The interictal EEG ini- jerks with head drops; trunk flexion or extension
tially shows multifocal slowing, which pro- has been noted, and the lower extremities are
gresses and later includes a disruption of sleep only involved rarely. The EEG shows general-
architecture. The ictal EEG shows multifocal ized spike/polyspikes lasting 1–3 s. This syn-
origins of seizures with migration to different drome is associated rarely with antecedent febrile
regions (morphologically, including rhythmical seizures. Reflex myoclonic seizures are a sub-
delta or sharp waves/spikes). There are associ- group (induced by auditory, tactile stimuli); some
ated extrapyramidal signs and tone worsens over patients are photosensitive. The differential
time. There is early intractability but seizure diagnosis includes infantile spasms and benign
control may improve with age in survivors. Early myoclonus. The EEG and normal development
deaths may be associated with respiratory differentiate MEI from infantile spasms (hypsar-
difficulties. rhythmia) and benign myoclonus (normal EEG).
Neurodevelopmental prognosis in survivors Neurodevelopment generally is normal but
generally is poor. The list of genetic mutations patients may develop other seizures later in life.
associated with this syndrome is expanding Treatment typically is with VPA, LEV, or CZP.
rapidly.
been noted (there likely are others). The prog- seizures are the most commonly noted one. By
nosis is good for both seizures and development. definition, there is no evidence of intracranial
infection or defined cause for the seizure. The
incidence is 3–5% of the US population. The
Myoclonic Encephalopathy median age of presentation is 18 mos and half of
in Nonprogressive Disorders patients present between 12 and 30 mos. In terms
of genetics, 10–20% of siblings also have these
Three forms of this epilepsy syndrome have been seizures.
described [5]: Recurrence of febrile seizure is:
1. Absence + myoclonic seizures. The EEG *33% will have a second FS (range in studies is
shows theta–delta or delta with spikes. Typ- 23–42%);
ically, this is diagnosed in the 1st year of like. *½ of those will have a 3rd FS (range in studies
There usually is a genetic etiology (Angel- is 7–30%);
man, Prader–Willi, Rett, others). Treatment in *50% recur in 1st 6 months; 75–90% recur in
combination with ESM-VPA may work in 1st year.
some patients.
2. Alternating bilateral positive and negative Recurrence risk is influenced by: age (<1 year
myoclonus. The EEG shows diffuse rhythmic doubles the risk), FS in 1st degree relative (up to
slow spike-waves or multifocal spike-waves double the risk), low-grade fever at seizure onset,
or theta–delta. There may be dyskinetic and illness frequency. Risk factors for develop-
movements. The onset usually is 6 yo. ing epilepsy after a FS include a positive family
Seizures are medically intractable seizures, history of epilepsy, abnormal neurodevelopment,
and infants show poor neurodevelopment. occurrence of a complex febrile seizure, a pos-
Structural brain malformations have been tictal Todd’s paralysis, number of febrile seizures
noted in some patients. (more seizure = greater risk), and duration of
3. Mild onset with focal facial (then limbs) sei- febrile seizure (longer seizure = greater risk).
zures. Onset in this form typically is 7 mos–5
yo. The EEG shows generalized spike-waves
or bilateral continuous slow activity and then Genetic Epilepsy and Febrile Seizures
EEG and clinical deterioration (with both Plus (GEFS+) [7]
pyramidal and extrapyramidal signs, as well
as myoclonus). This form may be associated FS+ is defined as a FS after 6 yo or occurrence of
with neonatal anoxia. Seizures are medically other seizure types. Almost any type of seizure
intractable. has been documented for FS+. FS+ is associated
with mutations in SCN1A, SCN1B, or GABRG2
Because the prognosis is somewhat different, but importantly, mutations only are seen in 10–
this syndrome should be distinguished from the 20% of those with GEFS+ (so genetic testing
progressive myoclonus epilepsies. generally is not advised).
(8% of patients have an onset <3 yo). Develop- of spikes in sleep, fast spikes or polyspikes, or a
ment is normal early and then deteriorates clini- suggestion of burst suppression following spikes.
cally (including pyramidal signs and ataxia). In terms of prognosis, BECTS typically is out-
The EEG shows spike and wave or polyspike and grown by age 16. Nearly 80% of patients have
waves. Approximately 70–80% of patients have <6 seizures so treatment is not recommended for
mutations in SCN1A, so genetic testing generally most patients. There are concerns about language
is indicated for prognosis and to obviate the need development, which should be specifically
for further diagnostic workup. The so-called screened even if school performance is average
SMEI “borderland” (SMEB) lacks certain core (high-functioning students may not need this).
features of SMEI but has been documented in Occasionally, BECTS resolves only to have
various pedigrees but is no longer believed to be other types of seizures develop after 18 years of
a separate entity. Treatment with Na-channel age. Treatment, if needed, has included CBZ,
medications (e.g., carbamazepine, lamotrigine) OXC, LEV, VPA, GPN, and sulthiame.
may worsen seizures in these patients. Some
patients have clear seizure exacerbations when
exposed to extrinsic (or even generating intrinsic) Panayiotopoulos Syndrome
heat—thus, these environmental stimuli should (Early Childhood Onset “Occipital”
be avoided when possible and practical. Epilepsy) [8]
seen anywhere. There is an increased frequency Treatment initially is with antiseizure medici-
of epileptiform activity during sleep and with eye nes, although seizures become refractory to
closure. Because seizures are fairly frequent, this treatment. Immunomodulators such as corticos-
epilepsy syndrome usually requires treatment but teroids, intravenous immunoglobulin, and certain
seizures tend to remit 2–7 years after onset. chemotherapeutic agents (e.g., cyclophos-
phamide) have been used to mitigate the impact
Rasmussen Syndrome of the progressive nature of this disease, with only
limited success. Unfortunately, most patients
With an onset typically between 3 and 14 years, eventually need a hemispherectomy for seizure
patients are almost always neurodevelopmentally control (the unihemispheric nature of the disease,
normal prior to the onset of seizures. On occa- which remains unexplained, makes this surgery
sion, there will be an antecedent nonspecific an option). Prognosis is largely determined by
febrile illness days to weeks before the first sei- preoperative level of function. Postoperative
zure. Rarely, this syndrome will develop in rehabilitation is necessary to optimize outcomes.
patients with other autoimmune diseases. There
likely is an immune-mediated etiology but a
specific organism or trigger has not been identi- References
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phenotypes of KCNQ-related epilepsy. Epilepsia.
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5. Elia M. Myoclonic status in nonprogressive encepha-
3. MRI: Unihemispheric focal cortical atrophy lopathies: an update. Epilepsia. 2009;50(Suppl 5):41–
and at least one of the following: 4. doi:10.1111/j.1528-1167.2009.02119.x.
– Gray or white matter T2/FLAIR hyperin- 6. Patel N, Ram D, Swiderska N, Mewasingh LD, New-
ton RW, Offringa M. Febrile seizures. BMJ. 2015;351:
tense signal
h4240.
– Hyperintense signal/atrophy of ipsilateral 7. Catterall WA. Sodium channel mutations and epi-
caudate head lepsy. In: Noebels JL, Avoli M, Rogawski MA,
Olsen RW, Delgado-Escueta AV, editors. Jasper’s
basic mechanisms of the epilepsies, 4th ed. Bethesda
Part B:
(MD): National Center for Biotechnology Information
4. Clinical: Epilepsia partialis continua or pro- (US); 2012.
gressive unilateral cortical deficit(s). 8. Sánchez Fernández I, Loddenkemper T. Pediatric focal
epilepsy syndromes. J. Clin. Neurophysiol. 2012;29
5. MRI: Progressive unihemispheric focal cor-
(5):425–40. doi:10.1097/WNP.0b013e31826bd943.
tical atrophy. 9. Bien CG, Granata T, Antozzi C, et al. Pathogenesis,
6. Histopathology: T-cell-dominated encephali- diagnosis and treatment of Rasmussen encephalitis: a
tis w/activated microglial cells (typically, but European consensus statement. Brain. 2005;128(Pt
3):454–71. doi:10.1093/brain/awh415.
not necessarily forming nodules) and reactive
astrogliosis.
Imitators of Epilepsy
12
Dewi Frances T. Depositario-Cabacar and Nabil J. Azar
List of the common nonepileptic paroxysmal • Behavioral disorders (rage attacks, inat-
disorders by age: tentiveness), and
• Syncope.
A. Infants and neonates: C. Adolescences and adults:
• Sandifer syndrome, • Nonepileptic psychogenic seizures (also
• Self-gratification syndrome, known as pseudoseizures),
• Benign myoclonus of early infancy, • Syncope,
• Shuddering attacks, • Panic attacks and hyperventilation,
• Startle disease or hyperekplexia, • Migraines, and
• Benign neonatal myoclonus, • Parasomnias and sleep disorders (such
• Jitteriness, head banging and body as narcolepsy and cataplexy).
rocking,
• Spasmodic torticollis, and Sandifer syndrome: This syndrome consists of
• Apnea. intermittent abnormal posturing such as stiffen-
B. Older children: ing and opisthotonic posturing usually primarily
• Breath-holding spells, due to gastroesophageal reflux. It is usually
• Movement disorders (tics, paroxysmal associated with feedings. It can be mistaken as
kinesigenic choreoathetosis, etc.), paroxysmal dystonia, epileptic spasms, or tonic
• Parasomnias and sleep disorders, seizures. This usually improves with antireflux
• Migraine headaches, medications.
• Psychogenic nonepileptic seizures, Self-gratification syndrome: This is also
referred to as infantile masturbation. This occurs
in infants and young children. It involves rubbing
of the thighs against each other, thrusting of the
pelvis associated with sweating, grunting, or
flushing of the face with variable degree of
D.F.T. Depositario-Cabacar responsiveness. After the event, the child is back
Department of Neurology and Pediatrics,
Children’s National Medical Center, to baseline. Treatment involves reassuring the
George Washington University, family of its self-limiting and benign nature.
111 Michigan Avenue, Washington Benign myoclonus of infancy: This usually
DC 20010, USA occurs in the first year of life, mostly seen
e-mail: Dcabacar@childrensnational.org
between the age of 3–8 months. It consists of
N.J. Azar (&) brief tonic or myoclonic contractions involving
Department of Neurology, Vanderbilt University
Medical Center, Nashville, TN 37212, USA the axial muscles. These spasms usually occur in
e-mail: dr.nabil.azar@gmail.com cluster and are different from benign neonatal
sleep myoclonus. Neurological examination, Bradycardia or asystole may occur. Main treat-
EEG, and development are all normal. Treatment ment is also parental reassurance, with some
involves reassurance since myoclonus usually studies suggesting a role for atropine.
resolves by 2 years of age. Migraines: Migraines are common causes of
Shuddering attacks: These usually occur recurrent headaches. The dilemma occurs if the
between the ages of 4–6 months. The events neurological event occurs without significant
consist of tremor in the head, arms, and trunk headaches and the event can be mistaken for
with adduction and flexion of the elbows. Com- seizures, such as in the case of confusional
munication and responsiveness are usually migraine or migraine with aura.
impaired. They can be triggered by emotions For example, confusional migraines are epi-
such as fear, anger, or frustration. They tend to sodes of confusion, agitation/hyperactivity, par-
gradually subside with age and completely tial or total amnesia, disorientation, lethargy, or
resolve by 10 years of age. Reassurance of the vomiting that may last for several minutes or
family is usually enough. hours. Headache and visual complaints may
Hyperekplexia: This is also referred as stiff occur but are not prominent symptoms. These
baby syndrome or startle disease. It appears more may be mistaken for temporal lobe seizures but
like an exaggerated startle response and may other etiologies such as encephalitis, substance
result in falling. It usually occurs at the age of abuse, metabolic causes, and vasculitis should be
6 months to 6 years and peaks at the age of 2– considered.
3 years old. It consists of a triad of generalized On the other hand, migraines with aura can
stiffness, nocturnal myoclonus, and tonic spasms appear as focal seizures if the visual disturbances
with auditory or tactile stimuli. In affected neo- are more prominent than the headache, such as
nates, tapping the tip of the nose or glabella may “Alice in wonderland” syndrome where visual
elicit a typical response. It is secondary to gene micropsia, macropsia, and distortions can all
mutations affecting inhibitory glycine receptor occur. This can be easily mistaken for temporal
(GLRA1 and GLRB). Commonly used treat- or occipital lobe seizures.
ments are clonazepam, followed by valproic acid Parasomnias and sleep disorders: Some sleep
or levetiracetam. disorders can be mistaken for complex partial
Breath-holding spells: Breath-holding spells seizures, commonly of frontal lobe origin due to
commonly occur between the ages of 6 and their hypermotor features and nocturnal occur-
18 months. Spells are divided as cyanotic or rence. These mostly include night terrors (oc-
pallid. curring in non-REM sleep) and REM behavior
Cyanotic breath-holding spells are usually disorder (occurring in REM sleep).
precipitated by an emotional cause such as frus- In the case of night terrors, the child wakes up
tration. The child cries and then holds the breath from sleep, appears terrified and agitated, is
in expiration resulting in cyanosis and may be inconsolable, and has no recollection of the
followed by loss of consciousness and loss of event. They occur around the age of 4 years and
tone. The precipitating event can be from the typically resolve by 8 years.
child being upset. If the apnea is prolonged, While in REM behavior, excessive and vio-
clonic jerks may be observed. Treatment is usu- lent motor activity with no recollection of events
ally reassurance and behavioral modification of is frequent. Polysomnography (with EEG normal
parental response. If recurrent, then screening for recording) is the gold standard diagnostic tool.
iron deficiency anemia can be done. On the other hand, narcolepsy is characterized
Pallid breath-holding spells usually occur in by a tetrad of cataplexy, sleep paralysis, hypna-
response to a minor trauma or fright. The child gogic hallucinations, and excessive daytime
stops breathing, becomes pale, may have a brief sleepiness. Cataplexy is a sudden loss of muscle
cry followed by loss of consciousness. Clonic tone precipitated by touch, emotional excitement,
jerks and incontinence may also occur. or laughter. It may occur several times during the
12 Imitators of Epilepsy 169
day and may often be mistaken for atonic sei- Psychogenic nonepileptic seizures (PNES):
zures. Two tests that are commonly used in PNES are by far the most common imitators of
diagnosing narcolepsy are the polysomnogram epilepsy. It has been reported that 25–40% of all
and multiple sleep latency test (MSLT). admissions to inpatient video-EEG studies end
Syncope: Syncope is very common and up to up with the diagnosis of PNES. However, despite
10% of the population will experience it at least the ability to diagnose PNES with high confi-
one time during their life. It is caused by a dence using video-EEG monitoring, the delay in
transient interruption of cerebral blood flow to diagnosis is long, averaging about 7–10 years.
the brain resulting in loss of consciousness. The patient’s history may suggest the diag-
Neurocardiogenic syncope (or vasovagal nosis. Several clues are useful in clinical practice
syncope) is the most common type of syncope. and should raise the suspicion that seizures may
The event is often preceded by prodromal be psychogenic rather than epileptic. One of the
symptoms of feeling of warmth, nausea, blurring first clues is resistance or worsening of seizures
or tunnel vision, diaphoresis, and lightheaded- to antiepileptic drug trials. The presence of
ness. Events are usually provoked by emotions prominent comorbid psychiatric conditions
(pain, anxiety, blood drawing) particular situa- should also raise the suspicion of PNES, partic-
tions (crowded environment, hot weather, pro- ularly the presence of depression, anxiety, or
longed standing, fatigue). It may be caused by PTSD (mainly secondary to physical or sexual
decreased blood volume or venous return, or abuse). Psychiatric comorbidities are found in the
parasympathetic cardioinhibitory response caus- majority of patients with PNES, with depression
ing vasodepression. Common reflex causes of being the most common.
syncope are coughing, micturition, and swal- In addition, several specific triggers that are
lowing. Tilt table tests are occasionally done in atypical for epilepsy may suggest the diagnosis
recurrent syncopal cases. Diagnosis is made by of PNES, such as emotional triggers (whether
history, orthostatic measurements, or tilt table positive or negative stress), headache or pain,
testing. Treatment includes reassurance, avoiding specific sounds or lights. Also, certain situations
precipitating factors, increasing fluid and salt may trigger PNES, for example, the presence of
intake. If needed, beta-blockers, alpha-adrenergic specific audience and occurrence in the physi-
agonists, anticholinergics, and mineralocorti- cian’s office or waiting room.
coids (such as fludrocortisone) can be used. A detailed description of events by witnesses
In contrast, cardiogenic syncope is less com- is always helpful since specific clinical features
mon but may be more life threatening. In such have been shown to favor the diagnosis of PNES.
case, syncopal episodes occur without warning Some of these clinical features include eye clo-
or prodromal symptoms and may occur during sure, side-to-side head or body shaking, bilateral
physical exertion. Common causes include asynchronous and often discontinuous move-
structural cardiac diseases (such as hypertrophic ments, crying, speech stuttering, and arching of
cardiomyopathy, aortic stenosis), or dysrhyth- the back. With convulsive attacks, rapid or short
mias. An initial cardiology workup including postictal recovery, shallow irregular, and soft
cardiac echocardiography and Holter monitoring postictal breathing pattern also favor PNES.
is warranted. Despite the fact that urinary incontinence, tongue
Convulsive syncope refers to syncope that is biting, bodily injuries can be commonly seen in
followed by brief tonic or rarely clonic activity, both epileptic and nonepileptic seizures, serious
which may occur in prolonged cerebral hypop- injuries and tongue biting at the side are more
erfusional states. typical for epileptic seizures.
During syncopal episodes, the EEG typically PNES diagnosis requires video-EEG recording
show transient high-voltage delta activity or of typical events. Withdrawal of antiepileptic
complete voltage attenuation. drugs is also essential for excluding a concomitant
170 D.F.T. Depositario-Cabacar and N.J. Azar
diagnosis of epilepsy, which can be seen in up to Successful treatment and seizure freedom may
10% of patients suffering from PNES. A formal be a challenging task, and in several instances
psychiatric evaluation with additional neuropsy- hard to reach. Some of the common treatment
chological testing is also an integral part of the obstacles include effective delivery of the diag-
initial assessment. nosis, acceptance of the diagnosis and patient
Treatment of PNES is targeted toward specific commitment to therapy and follow-up. In gen-
psychiatric conditions and is often very individ- eral, patients who accept their diagnosis and
ualized. Therapy typically includes psychother- follow through with therapy are more likely to
apy and the use of adjunctive medications to treat experience a successful outcome.
coexisting depression or anxiety.
Genetic Analysis of Epilepsies
13
Sara K. Inati
multiplex ligation probe amplification (MLPA), are genetic change that is identified. When a muta-
also widely used [1]. tion in a single gene produces different epilepsy
phenotypes in different individuals, this is refer-
red to as variable expressivity and reduces the
Utility of Genetic Testing in Epilepsy positive predictive value of the test. For example,
missense mutations in SCN1A can be associated
When ordering genetic testing, it is important to be with phenotypes ranging from no seizures or
aware of factors that may affect the clinical validity simple febrile seizures (GEFS+) to severe
and utility of a given test in a specific clinical sit- epileptic encephalopathy (Dravet syndrome) [7].
uation. Clinical validity describes the ability of a Genetic (or locus) heterogeneity occurs when
test to determine whether a person is or will a single clinical phenotype can result from
become affected with a given disorder. Clinical mutations in different genes (e.g., in GEFS+ due
utility of a test refers to the risks and benefits of a to different sodium and/or GABA receptor
positive or negative test on patient care. mutations), or when different genetic mecha-
Clinical validity is determined by many fac- nisms can produce the same disease (e.g., IGE
tors. Genetic testing may be performed in several can show autosomal dominant or complex
types of laboratories. Clinical laboratories in the inheritance). Additionally, families with a given
USA that are certified under the Clinical Labora- syndrome may not have mutations in any previ-
tory Improvement Act (CLIA) are required to ously identified genes. Patients without affected
meet federal quality standards. Tests can also be relatives are also less likely to have a mutation in
carried out in research laboratories, which do not previously identified genes [2]. In such cases, a
require CLIA certification and perform analyses positive result may be informative, but a negative
for research only. There is also direct-to-consumer result is not helpful clinically.
genetic testing, usually ordered over the Internet Reduced penetrance describes when individ-
for a fee. This has the advantage of easy access uals with a mutation remain unaffected. Pene-
and privacy, but is not subject to the same quality trance for AD epilepsy is usually approximately
control measures as clinical laboratories, and 70% [2]. This lowers the positive predictive
generally does not include genetic counseling or value of testing and can present significant dif-
adequate epidemiological data about baseline ficulties in predictive testing in asymptomatic
genetic variation to assist with interpretation of individuals. Also, gene–environment interactions
the results [2]. may play a role in the expression of a trait. Each
The appropriate type of test must also be of these factors may lead to decreased clinical
ordered, as a given test will miss changes that it validity of a genetic test.
is not designed to detect (a mutation in a given Clinical utility depends on the clinical validity
gene may not affect a test for a particular SNP or of a test, but also on specific features of a given
CNV but still contribute to a disease). For each clinical situation. The relative risks and benefits
test, a negative result is most definitive if a of testing depend on the availability of an
positive result was obtained from an affected effective treatment, cost and accessibility of
family member. Additionally, the source of DNA testing, severity of the disease, age of onset
affects the validity of a test. A germ-line mutation (particularly as it may affect reproductive choi-
may be absent in a parent’s somatic cells (leading ces), family history and the implications of test-
to negative genetic testing), but can still be pas- ing on other family members, and potential
sed on to offspring. Somatic mosaicism (more ethical, legal, and social implications of genetic
than one genotype in the body) may lead to testing. The Federal Genetic Information
negative testing from one tissue and positive Non-Discrimination Act (GINA) passed in May
testing from another [2]. 2008 prohibits discriminatory use of genetic
Clinical validity is also impacted by the sen- information by employers and health insurers,
sitivity and specificity of the test and the type of but does not extend to life insurance, disability
13 Genetic Analysis of Epilepsies 173
insurance, or long-term case insurance [8]. All of in vitro fertilization). Of note, for women carry-
these issues should be addressed in pretest and ing a mitochondrial mutation, the risk of recur-
posttest genetic counseling, and informed con- rence cannot be accurately predicted and prenatal
sent should be obtained before ordering a genetic testing is not accurate. The only way to guarantee
test [2]. avoidance of recurrence is the use of a donor egg
[1].
In order to perform appropriate genetic test-
Clinical Application of Genetic ing, a full history must be obtained, including a
Testing in Epilepsy three-generation pedigree focused on seizures
and other seizure mimics, neurodevelopmental
Genetic testing in patients with epilepsy can be and psychiatric conditions, ancestral origins,
diagnostic or predictive. Diagnostic testing is outcomes of all pregnancies, and consanguinity.
done in a patient with epilepsy to clarify the Full neurologic examination, developmental
diagnosis and/or prognosis, to save a patient assessment, and appropriate further testing such
from further evaluation/testing, and rarely to as EEG, MRI, and/or metabolic workup can also
affect clinical management. It can also provide contribute to appropriate genetic counseling and
families with information about the risks of test selection [1].
recurrence and can help with reproductive For the epilepsies, the total number of genes
decision-making. Ideally, this testing may also in a differential diagnosis is often large and
lead to targeted therapy. available tests are rapidly changing, so it is
Predictive testing is performed to predict the important to know genetic diseases with a high
onset of epilepsy in asymptomatic patients risk for epilepsy and to become familiar with
(usually offspring or siblings of patients with online references such as GeneTests and OMIM
epilepsy). This also includes prenatal diagnostic [2]. Gene panels are also becoming more widely
testing. The risk of epilepsy in relatives of available. Tables 13.1 and 13.2 are a selected list
patients with epilepsy is increased if there is an of genes that have been identified in idiopathic
earlier age of onset (<35 years old), idiopathic and symptomatic epilepsies. These represent a
epilepsy, an increased number of affected rela- synthesis of information from the referenced
tives, and if a parent is affected, particularly the articles, and the reader is referred to epilepsy
mother [9]. Particularly for prenatal diagnostic textbooks and the references at the end of this
testing, epilepsy risk is increased if a parent is a section if a more complete list is desired.
carrier of a balanced chromosomal translocation, The clinical utility of performing these tests
if the mother is a carrier of an X-linked or remains highly variable. Identification of muta-
mitochondrial mutation, if both parents are car- tions in patients with early-onset epileptic ence-
riers for an autosomal recessive condition, or if a phalopathies such as Dravet syndrome (SCN1A),
parent carries an autosomal dominant disorder epilepsy limited to females with mental retarda-
[1]. Many severe pediatric neurogenetic condi- tion (EFMR) (PCDH19), and infantile spasms
tions result from de novo or spontaneous muta- (ARX in boys, CDKL5 in girls) can be very
tions. If parents have negative genetic testing, the useful, as they can limit further (often invasive)
risk of recurrence in future offspring is <1% and diagnostic testing, inform the prognosis, at times
would likely be attributable to undetectable guide treatment, and provide useful information
gonadal mosaicism [1]. for genetic counseling for the family [3].
Options for parents at high risk who desire In other clinical situations, genetic testing has
additional children include adoption, use of a less clinical utility. Although very useful in the
donor egg or sperm (depending on which parent setting of a baby with possible Dravet syndrome,
carries the mutation), prenatal testing (chorionic testing for SCN1A mutations in a family with
villous sampling or amniocentesis), or preim- GEFS+ has limited clinical utility due to the
plantation genetic diagnosis (which requires widely variable phenotype, so that testing cannot
174 S.K. Inati
accurately predict prognosis or necessarily 3. Scheffer IE. Genetic testing in epilepsy: what should
inform treatment or genetic counseling. Testing you be doing? Epilepsy Curr. 2011;11:107–11.
4. Engel J, Pedley TA, Aicardi J, Bonkowsky et al.
for KCNQ2 and 3 in benign familial neonatal Genetic diseases associated with epilepsy, Epilepsy.
seizures, although highly accurate, is also of Philadelphia, PA: Lippincott Williams & Wilkins;
limited usefulness clinically. The diagnosis is 2007 (Chapter 17 ).
often clear based on the history, as this disorder 5. Miller DT, et al. Consensus statement: chromosomal
microarray is a first-tier clinical diagnostic test for
is autosomal dominant with high penetrance. In individuals with developmental disabilities or congen-
addition, the prognosis is favorable, so diagnosis ital anomalies. Am J Hum Genet. 2010;86:749–64.
is unlikely to alter reproductive choices [2]. 6. Mefford HC, et al. Rare copy number variants are an
important cause of epileptic encephalopathies. Ann
Neurol. 2011;70:974–85.
7. Harkin LA, et al. The spectrum of SCN1A-related
References infantile epileptic encephalopathies. Brain.
2007;130:843–52.
8. Hampton T. Congress passes bill to ban discrimination
1. Pong AW, Pal DK, Chung WK. Developments in
based on individuals’ genetic makeup. JAMA.
molecular genetic diagnostics: an update for the
2008;299:2493.
pediatric epilepsy specialist. Pediatr Neurol.
9. Winawer MR, Shinnar S. Genetic epidemiology of
2011;44:317–27.
epilepsy or what do we tell families? Epilepsia.
2. Ottman R, et al. Genetic testing in the epilepsies-report
2005;46(Suppl 10):24–30.
of the ILAE Genetics Commission. Epilepsia.
2010;51:655–70.
Epilepsy Secondary to Specific
Mechanisms 14
Amar Bhatt
Brain Tumors and Epilepsy correlation is the absence of LGI1 gene product
in GBM, due to gene translocation [5]. This is a
Intracranial tumors are a common cause of adult tumor suppressor gene, but two non-neoplastic
—and childhood-onset epilepsies. In general, the epilepsies relate to LGI1: autosomal dominant
following tumors are more epileptogenic: lateral temporal lobe epilepsy with auditory fea-
adult-onset tumors (which tend to be supraten- tures caused by LGI1 gene mutation and
torial, as opposed to pediatric tumors), lower autoimmune epilepsy related to antibodies
grade tumors, cortical tumors, and tumors closer against an LGI1 gene product (VGKC complex).
to sensitive networks, such as hippocampus or The American Academy of Neurology
motor cortex [5]. Parietal tumors have the (AAN) guidelines recommend strongly against
strongest association with seizures, followed AED prophylaxis in brain tumor patients without
closely by temporal tumors. a history of seizures, since prophylaxis does not
Seizure semiology depends on tumor location, prevent the first seizure [7]. AED prophylaxis
but certain pathologies have stronger association may be used peri- and post-operatively, but
with seizures. Nearly all dysembryoplastic neu- usually only for one week. Once seizures have
roepithelial tumors will cause seizures, followed occurred, AEDs must be chosen carefully due to
by gangliogliomas and low-grade astrocytomas; interactions with chemotherapy and corticos-
higher grade or fast-growing tumors (such as teroids, as well as additive risk of bone marrow
glioblastoma multiforme [GBM] or primary CNS suppression. Thus, agents such as levetiracetam
lymphoma) do not cause seizures as often [6]. and lacosamide may be preferred.
A characteristic GBM is shown in Fig. 14.1. The goal of seizure freedom must be balanced
Additionally, hypothalamic hamartomas cause with tumor prognosis; seizure freedom may not
gelastic seizures. Regardless of tumor type, a be a goal with unresectable tumors. Surgical
seizure as the initial symptom of tumor presen- treatment must be divided into “tumor surgery”
tation may increase the risk of recurrent seizures (curative) or “epilepsy surgery” (palliative). Poor
and refractory seizures, possibly independent of prognostic factors for seizure control include
treatment. longer epilepsy duration, lower tumor grade,
Epileptogenicity may relate to both peritu- seizures at time of tumor diagnosis, and incom-
moral (non-neoplastic) tissue as well as genetic plete resection. Surgery can be considered even
factors. Higher grade tumors may have central in low-grade tumors with resistant epilepsy, even
necrosis and be electrically silent, whereas sur- if stable on imaging. Imaging alone should not
rounding hemosiderin or edematous tissue may guide surgery, since peritumoral tissue can be
be epileptogenic. One example of a genetic epileptogenic. Video-EEG, electrocorticography,
and functional mapping (e.g., language or motor has important implications; males have the more
function) should be used to guide resection. severe phenotype of LIS, whereas females have
the milder phenotype of SBH (e.g., mild devel-
opmental delay and seizure onset in teenage
Malformations of Cortical years).
Development Polymicrogyria (PMG) is characterized by
excessive, small gyri. It may present as bilateral
Classification and understanding of malformations perisylvian polymicrogyria syndrome, consisting
of cortical development (MCDs) continues to of seizures, aphasia, and oromotor dysfunction.
evolve. Most definitions are based on genetics, Schizencephaly (SCZ) and porencephaly
imaging, molecular biology, and pathology [8, 9]. (POR) are both characterized by parenchymal
Stem cells not only differentiate into neurons and “clefts”; SCZ typically has gray matter along the
glia, but they also migrate radially outward from the clefts (which is often PMG), whereas POR has a
germinal matrix in the deep forebrain and white matter lining. When SCZ is associated with
periventricular regions. They also organize into optic nerve hypoplasia and absence of the septum
“cytoarchitectonic” patterns, creating the six layers pellucidum, this is known as septo-optic dys-
of neocortex. Any disruption in this process can plasia (de Morsier syndrome), and screening for
lead to MCDs (i.e., normal cells in the wrong place, hypopituitarism is important.
or abnormal cells in the right place). Periventricular nodular heterotopia (PVNH)
Many MCDs are named based on descriptive consists of gray matter nodules along the lateral
anatomic terms and do not indicate a specific ventricles due to failed neuronal migration
disease or genetic cause per se; in fact, many (Fig. 14.2), often causing intractable focal sei-
have overlapping pathology. Some occur in iso- zures. PVNH may be associated with abnormal
lation as well as in the context of larger syn- overlying cortex; there is debate as to whether
dromes, such as hemimegalencephaly (HMEG). both the nodule and cortex should be resected.
HMEG is characterized by a triad of intractable PVHN must be differentiated from the
partial seizures from infancy, hemiparesis, and subependymal nodules of TSC (Table 14.2).
developmental delay; imaging readily identifies
an enlarged, dysmorphic cerebral hemisphere.
HMEG may occur in neurocutaneous syndromes,
such as tuberous sclerosis complex (TSC) or
neurofibromatosis. Functional hemispherectomy
can improve seizure control and quality of life.
Lissencephaly (LIS) and subcortical band
heterotopia (SBH) are two distinct phenotypes
that may share similar genetic features. LIS is
characterized by a “smooth brain” with absent or
decreased convolutions (so-called agyria or
pachygyria). SBH consists of an extra band of
gray matter within the white matter (also known
as “double cortex”). The classical form of LIS
has a thickened, four-layer cortex and may have
associated SBH. The autosomal dominant form
of LIS is caused by LIS1 gene mutation and is
typically more severe posteriorly, whereas the
X-linked form is usually caused by DCX
(“doublecortin”) gene mutation and is typically Fig. 14.2 Bilateral periventricular nodular heterotopia,
more severe anteriorly. The X-linked inheritance as seen on T2-weighted MRI
14 Epilepsy Secondary to Specific Mechanisms 181
Head trauma may be classified as mild, though maintaining first-week seizure freedom
moderate, or severe (Table 14.3). The presence does not reduce mortality, disability, or late sei-
of early seizures in combination with moderate zures [18]. There is no evidence for the use of
or severe head trauma increases the risk of steroids to prevent seizures.
developing epilepsy [15]. Early seizures in mild
head trauma do not necessarily increase that risk.
In fact, there may be an association between mild Stroke and Epilepsy
head trauma and PNES. In children under five
years of age, early seizures after head trauma are Pediatric and adult epilepsy related to cere-
more common, but these are less predictive of brovascular disease differs in many regards.
epilepsy as compared to adults. Seizure as the presenting symptom of stroke is
Assuming that a past head injury is the cause very common in neonates (about 80%), relatively
of seizures can be detrimental; one may miss common in children (about 30%), and rare in
non-epileptic events or a diagnosis of adults; epilepsy risk after pediatric stroke can be
idiopathic/genetic generalized epilepsy. The cost up to 40%, whereas the risk in adults is less than
may be more severe in veterans; PNES is asso- 5% [19].
ciated with significantly more cumulative AED Post-stroke seizures are classified as early
exposure and delay in diagnosis in veterans as (within the first week) or late (after the first
compared to civilians [16]. Epileptiform dis- week), similar to post-traumatic seizures. Even
charges on EEG are not necessarily predictive of one late unprovoked post-stroke seizure has a
epilepsy and can be misleading, particularly high recurrence rate (>50%), and AED treatment
when events are unwitnessed or the history is should strongly be considered. Therefore, as in
vague. Video-EEG remains the gold standard in head trauma, late post-stroke seizures are nearly
the diagnosis of post-traumatic seizure-like synonymous with epilepsy.
events, and it should be considered in any Predictors of post-stroke epilepsy in adults
patient who is medication-resistant after one year include cortical location, presence of hemor-
of treatment. Video-EEG with AED withdrawal rhage, and stroke severity (based on examination
is important, since some patients have both and NIH stroke scale) [19]. The EEG is not
epileptic seizures and PNES. consistent in predicting epilepsy after stroke.
Prophylactic treatment is only recommended Lateralized periodic discharges (LPDs, formerly
in certain situations, and the evidence is strongest known as periodic lateralized epileptiform dis-
for prevention of early seizures in adults; data in charges or PLEDs) are considered a classic
children is insufficient. The AAN guidelines finding in stroke and may be predictive of sei-
recommend phenytoin prophylaxis in adults with zures, but they are not common, and may only
severe brain injury, but only for the first week; predict early seizures and not necessarily later
evidence does not suggest benefit of longer epilepsy. The most common finding is slow
duration of prophylaxis in preventing late sei- activity (focal or generalized), which is
zures [17]. Per a Cochrane review, the number non-specific and not predictive of seizures. A re-
needed to treat in preventing early seizures is ten, cent Cochrane review [20] has not found strong
evidence that treating early post-stroke seizures thin cut imaging (Fig. 14.4) [24]. When com-
prevents the development of epilepsy, although paring hippocampal volumes, asymmetry of the
only one of the studies reviewed met inclusion temporal horns of the lateral ventricle should not
criteria as a randomized controlled trial designed be over-interpreted as MTS. Additionally, even if
to address this question. MRI is normal, PET may show temporal hypo-
metabolism suggestive of MTS. A recent study
found good surgical outcomes after temporal
Mesial Temporal Sclerosis lobectomy in patients with PET-positive,
MRI-negative temporal lobe lesions [25], com-
Mesial temporal sclerosis (MTS), also known as parable to the typical MRI-positive MTS
hippocampal sclerosis, is one of the most com- patients.
mon causes of adult-onset epilepsy, especially The cause of MTS is unclear. There may be a
refractory epilepsy. However, it has been found relationship between MTS, early complex febrile
in up to 14% of adults without epilepsy [21]. seizures, and childhood head trauma, but cause
Classic semiology can include abdominal auras and effect remain controversial. Often there is a
(nausea, pressure, butterflies, and epigastric ris- latent period between the injury and seizure
ing), fear, an unpleasant taste or smell, oroali- onset, but it is not clear whether the MTS noted
mentary or (ipsilateral) limb automatisms, and on imaging was either not previously present, not
autonomic phenomenon. The typical ictal EEG apparent since the brain was still developing, or
pattern consists of anterior temporal rhythmic not able to be studied by current imaging
theta or alpha activity, which often exceeds 5 Hz techniques.
within 30 s of seizure onset [22, 23]. Though Histopathology in MTS usually involves
many cases may have bilateral temporal onset on neuronal loss and gliosis in the CA1, CA3, and
scalp (bisynchronous or independent), this does CA4 hippocampal regions, with relative sparing
not necessarily rule out surgery. However, since of CA2. Surgical experience has noted two
seizures may start elsewhere and spread to the important areas outside the hippocampus that
mesial temporal region, a primary extratemporal usually require resection to achieve a good sei-
localization may be the source of seizures, even zure outcome: the parahippocampal gyrus and
when semiology and ictal EEG patterns are pre- the amygdala. Because MTS is so common, and
dominantly temporal. so amenable to surgical resection, new-onset
The most common MRI finding in MTS is temporal lobe epilepsy at any age warrants
hippocampal hyperintensity on T2-weighted evaluation for MTS. Dual pathology (MTS with
sequences (e.g., FLAIR). However, this is not coexistent neoplasms, MCDs, or vascular
very reliable. Hippocampal atrophy is the most lesions) may require resection of both lesions for
specific finding, usually noted on T1-weighted, a good outcome.
6. van Breemen MS, Wilms EB, Vecht CJ. Epilepsy in 18. Schierhout G, Roberts I. Antiepileptic drugs for
patients with brain tumours: epidemiology, mecha- preventing seizures following acute traumatic brain
nisms, and management. Lancet Neurol. 2007;6 injury. Cochrane Database Syst Rev. 2012;6:
(5):421–30. CD000173.
7. Glantz MJ, Cole BF, Forsyth PA, et al. Practice 19. Hantus S, Friedman N, Pohlmann-Eden B. Epilepsy
parameter: anticonvulsant prophylaxis in patients in the setting of cerebrovascular disease (Chap. 30).
with newly diagnosed brain tumors. Neurology. In: Wyllie E, editor. Wyllie’s treatment of epilepsy:
2000;10(54):1886–993. principles and practice. 5th ed. Philadelphia: Lippin-
8. Leventer RJ, Guerrini R, Dobyns WB. Malforma- cott Williams and Wilkins; 2011.
tions of cortical development and epilepsy. Dialog 20. Sykes L, Wood E, Kwan J. Antiepileptic drugs for
Clin Neurosci. 2008;10(1):47–62. the primary and secondary prevention of seizures
9. Mirzaa G, Kuzniecky R, Guerrini R. Malformations after stroke. Cochrane Database Syst Rev. 2014;1:
of cortical development and epilepsy. In: Wyllie E, CD005398.
editor. Wyllie’s treatment of epilepsy: principles and 21. Benbadis SR, Wallace J, Reed Murtagh F. MRI
practice (Chap. 27). 5th ed. Philadelphia: Lippincott evidence of mesial temporal sclerosis in subjects
Williams and Wilkins; 2011. without seizures. Seizure. 2002;11(5):340–3.
10. Blümcke I, Thom M, Aronica E, et al. The clinico- 22. Risinger MW, Engel J Jr, Van Ness PC, Henry TR,
pathologic spectrum of focal cortical dysplasias: a Crandall PH. Ictal localization of temporal lobe
consensus classification proposed by an ad hoc Task seizures with scalp/sphenoidal recordings. Neurol-
Force of the ILAE Diagnostic Methods Commission. ogy. 1989;39(10):1288–93.
Epilepsia. 2011;52(1):158–74. 23. Ebersole JS, Pacia SV. Localization of temporal lobe
11. Krsek P, Maton B, Korman B, et al. Different foci by ictal EEG patterns. Epilepsia. 1996;37
features of histopathological subtypes of pediatric (4):386–99.
focal cortical dysplasia. Ann Neurol. 2008;63 24. Cendes F. Neuroimaging in investigation of patients
(6):758–69. with epilepsy. Continuum (Minneap Minn). 2013;19
12. Lerner JT, Salamon N, Hauptman JS, et al. Assess- (3):623–42.
ment and surgical outcomes for mild type I and 25. LoPinto-Khoury C, Sperling MR, Skidmore C, et al.
severe type II cortical dysplasia: a critical review and Surgical outcome in PET-positive, MRI-negative
the UCLA experience. Epilepsia. 2009;50(6):1310– patients with temporal lobe epilepsy. Epilepsia.
35. 2012;53(2):342–8.
13. Haltiner AM, Temkin NR, Dikmen SS. Risk of 26. Van Gompel JJ, Rubio J, Cascino GD, Worrell GA,
seizure recurrence after the first late posttraumatic Meyer FB. Electrocorticography-guided resection of
seizure. Arch Phys Med Rehabil. 1997;78(8):835–40. temporal cavernoma: is electrocorticography war-
14. Annegers JF, Hauser WA, Coan SP, Rocca WA. ranted and does it alter the surgical approach? J
A population-based study of seizures after traumatic Neurosurg. 2009;110(6):1179–85.
brain injuries. N Engl J Med. 1998;338(1):20–4. 27. Josephson CB, Leach JP, Duncan R, Roberts RC,
15. Schuele S. Post-traumatic epilepsy (Chap. 29). In: Counsell CE, Al-Shahi Salman R; SAIVMs steering
Wyllie E, editor. Wyllie’s treatment of epilepsy: committee and collaborators. Seizure risk from
principles and practice. 5th ed. Philadelphia: Lippin- cavernous or arteriovenous malformations: prospec-
cott Williams and Wilkins; 2011. tive population-based study. Neurology. 2011;76
16. Salinsky M, Spencer D, Boudreau E, Ferguson F. (18):1548–54.
Psychogenic nonepileptic seizures in US veterans. 28. Hon JM, Bhattacharya JJ, Counsell CE, et al. SIVMS
Neurology. 2011;77(10):945–50. collaborators. The presentation and clinical course of
17. Chang BS, Lowenstein DH. Practice parameter: intracranial developmental venous anomalies in
antiepileptic drug prophylaxis in severe traumatic adults: a systematic review and prospective,
brain injury. Neurology. 2003;60:10–6. population-based study. Stroke. 2009;40(6):1980–5.
Multiple Choice Questions for Part III
1. Which of the following is shared by Dravet 4. Which of the following is true about
syndrome and generalized epilepsy with familial lateral temporal lobe epilepsy with
febrile seizures plus (GEFS+)? auditory features?
D. Focal slowing on EEG is not predictive 18. Which of the following is true regarding
of epilepsy after stroke seizures after traumatic brain injury?
E. Strokes are not correlated with seizures
A. Prophylaxis of seizures should continue
15. Which of the following is true about Doose for one month after severe brain injury
syndrome? B. Risk of epilepsy decreases with time after
the injury, especially after the first two
A. Positive family history of idiopathic years
generalized epilepsy C. At least two late seizures are necessary
B. Grand mal seizures are rare to diagnose post-traumatic epilepsy and
C. Brain MRI often shows abnormalities consider treatment
D. Glut-1 deficiency is identified in 50% D. A history of mild head trauma and
of cases abnormal EEG warrants anticonvulsant
E. Dietary therapies are not effective treatment
E. All of the above are correct
16. A 6-year-old male is seen for occasional
nocturnal seizures consisting of strange 19. Which of the following is true about Len-
throaty noise and contraction of the left face. nox–Gastaut syndrome (LGS)?
The yield of the EEG will be highest during:
A. Infantile spasms precede LGS in >50%
A. Photic stimulation of cases
B. Sleep B. The EEG shows spike-wave discharges
C. Wakefulness at 3–5 Hz
D. Hyperventilation C. Sleep normalizes the EEG
E. Studying D. EEG background is often normal
E. 70% of the patients have structural/
17. Which of the following does not have an metabolic causes
autosomal dominant inheritance?
20. A 26 year old lady with two-year history of
A. Early-onset absence epilepsy (due to diarrhea and weight loss, presented with
GLUT-1) new onset seizures. Which of the following
B. Juvenile myoclonic epilepsy (due to can help most with the diagnosis?
GABA-A receptor)
C. Lateral temporal lobe epilepsy with A. Pelvic CT scan
auditory features (due to LGI1) B. D-Xylose test
D. Dentatorubral-pallidoluysian atrophy C. Sural biopsy
(due to trinucleotide repeats) D. Urine epinephrine test
E. Sialidosis (due to Increased urinary E. None of the above, EEG is the only
oligosaccharides) helpful test
190 Multiple Choice Questions for Part III
21. A 16-year-old girl with intractable partial 25. A 17-year-old high school student presented
epilepsy has a brain MRI which reveals with recurrent weekly episodes of odd
periventricular lesions. Which of the fol- behavior at night. During these episodes, he
lowing radiologic features is more likely to would wake up 3 h after falling asleep,
suggest periventricular nodular heterotopia, walk through the dormitory, or be sitting
rather than the subependymal nodules of quietly in the kitchen room. His classmates
tuberous sclerosis complex? report that he would appear confused and
clumsy and afterward has no recollection of
A. Unilateral lesion the event. Which of the following is the
B. Calcified lesion most likely diagnosis?
C. Homogenous lesion
D. White matter intensity lesion A. Nocturnal absence seizures
E. Ventricular lesion B. Confusional arousal disorder
C. Frontal hypermotor seizures
22. Which of the following is an identifiable D. Sleep-induced syncope
pathology in continuous spike-and-wave E. Early-onset dementia
during sleep (CSWS)?
26. Which of these tumor types is most likely to
A. Polymicrogyria be associated with seizures?
B. Porencephaly
C. Thalamic lesions A. Primary CNS lymphoma (PCNSL)
D. Migrational disorders B. Dysembryoplastic neuroepithelial
E. All of the above tumor (DNET)
C. Meningioma
23. A 6-month-old boy has epileptic spasms, D. Astrocytoma
hypotonia, and difficulty feeding. His MRI E. Schwannoma
reveals lissencephaly. Which genetic muta-
tion is also known to be responsible for a 27. Which of the following is true about juve-
milder phenotype, especially in girls? nile myoclonic epilepsy (JME)?
24. Which of the following would NOT be an 28. A 65-year-old male is referred for the
appropriate treatment for this patient (in evaluation of frequent nocturnal stereotyped
question 23), if started within the first events of brief violent motor activity. EEG
4 days of onset? recording during these events is normal. His
brain MRI is also normal. Which neuro-
A. Vigabatrin logical condition is likely associated with
B. Carbamazepine this sleep disorder?
C. Ketogenic diet
D. Oral corticosteroids A. Alzheimer’s dementia
E. ACTH B. Parkinson’s disease
Multiple Choice Questions for Part III 191
48. A 4-month-old full-term baby has periodic 2. (C). For the diagnosis of nonepileptic psy-
episodes of arching of the back and stiff- chogenic seizures, several clinical features
ening every 2–3 h. His neurological exam- are helpful in confirming this diagnosis.
ination and EEG between attacks is normal. Highly predictive features include eye clo-
He has not been gaining weight at the sure, out of phase or discontinuous motor
expected pace and has occasional vomiting. activity, and forward pelvic thrusting, among
The treatment of choice is: others. Confusion is not helpful in distin-
guishing epileptic from nonepileptic seizures.
A. Pyridoxine 3. (B). Most cases of absence epilepsies of
B. Vigabatrin childhood have complex inheritance. In one
C. ACTH study, only 12% of screened patients with
D. Omeprazole early-onset absence epilepsy had mutations
E. Observe in SLC2A1, the gene encoding the GLUT1
glucose transporter. Some mutations are
49. A 35-year-old woman without a history of familial and others are de novo.
epilepsy is hospitalized with confusion and 4. (D). Familial lateral temporal lobe epilepsy
psychosis. EEG reveals frequent partial with auditory features is autosomal dominant
seizures, resistant to four anticonvulsants. with seizure onset in adolescence or early
She is noted to have choreiform movements adult life. Typical aura is a simple auditory
on examination. Which test is most likely to hallucination with the evolution to dyscog-
provide a specific diagnosis? nitive and grand mal seizures. It is associated
with mutations in the leucine-rich glioma-
A. PET-CT of abdomen and pelvis inactivated (LGI) gene on chromosome 10q.
B. LGI1 antibody (voltage-gated potas- 5. (A). This is a classical description of an
sium channel complex) infant with Dravet syndrome, also known as
C. MRI of the brain with contrast severe myoclonic epilepsy of infancy
D. Continuous video-EEG monitoring (SMEI). More than 70% of patients have
E. Lumbar puncture mutations in SCN1A, although girls with
negative testing should undergo analysis of
PCDH19. Seizures are very difficult to con-
Answers trol. Many recommend avoidance of seizure
medicines that act on sodium channels.
1. (B). Dravet syndrome presents in infancy Nonconvulsive status epilepticus is not
with convulsive seizures often triggered uncommon. Deterioration in gait patterns
by fever. It also includes other seizure types has been noted in studies of older patients.
such as myoclonic, atonic, focal dyscognitive Vaccinations (especially those containing
seizures, and nonconvulsive status epilepti- whole-cell pertussis) have been reported as a
cus. Development slows in the second year. trigger in case series.
Intellectual disability and intractable seizures 6. (E). Mutations in CHRNA2, CHRNA4, and
ensue. In Dravet, *75% of subjects have CHRNB2, genes encoding the nicotinic
mutations in the voltage-gated sodium acetylcholine receptor, are seen in patients
channel gene, SCN1A (95% of which are de with autosomal dominant nocturnal frontal
novo). Sodium channel agents, such as lam- lobe epilepsy. Please refer to Table 12.1 for
otrigine, tend to worsen the seizures. In 10% other details.
of familial GEFS+, there are mutations in the 7. (D). The risk of Sudden Unexpected Death
SCN1A gene; others have GABRG2 muta- in Epilepsy (SUDEP) in patients with
tions affecting the GABA channel. drug-resistant epilepsy is about 1/100, while
Multiple Choice Questions for Part III 195
injury. Recurrence risk of seizures after one and thalamic lesions. Family history of sei-
late post-traumatic seizure is high; therefore, zure is reported in 10–15%.
this is essentially considered to be epilepsy, 23. (B). LIS1 gene mutation causes the autoso-
and treatment should be strongly considered. mal dominant form of lissencephaly; the
Early seizures in combination with moderate DCX gene mutation has an X-linked inher-
or severe head trauma increase risk of itance pattern which may present with
developing epilepsy, but mild head trauma in (milder) subcortical band heterotopia phe-
combination with abnormal EEG is not notype in girls. FLNA is related to periven-
diagnostic of epilepsy, particularly if tricular nodular heterotopia, and TSC2 is
the clinical events are not convincingly related to tuberous sclerosis complex.
epileptic by history. Video-EEG monitoring 24. (B). A recent evidence-based guideline out-
should be considered in such cases, as lined the evidence for different treatments for
non-epileptic events are in the differential infantile spasms (Go et al., Neurol
diagnosis. 2012;78:1974). Of all the treatments listed,
19. (E). The peak age of onset of LGS is 3– carbamazepine would not be expected to lead
5 years, and infantile spasms precede LGS to resolution of the spasms. Earlier onset of
in 10–25%. EEG features of slow back- treatment is associated with better outcomes.
ground with generalized slow spike-wave 25. (B). The history of stereotyped nocturnal
discharges at 1.5–2 Hz, multifocal dis- odd behavior occurring during the first half
charges, and generalized fast activity at 10– of the night, and amnesia of the events is
25 Hz in sleep. LGS results from suggestive of confusional arousal disorder.
structural/metabolic causes in 70–78%. Sleep deprivation, excessive stress, or alco-
20. (B). Common clinical signs and symptoms hol intake can trigger these episodes. EEG
of Whipple’s disease include diarrhea, recording during these events may be normal
steatorrhea, abdominal pain, weight loss, and or show generalized slowing of background
migratory arthropathy. In about 10–30% of activity.
patients, CNS symptoms of dementia, 26. (B). Of the primary brain tumors, DNET has
movement disorders or seizures may occur. the highest association with seizures (nearly
D-Xylose test can help with confirming 100%), followed by gangliogliomas and
intestinal malabsorption syndrome. Overall, astrocytomas. Higher grade or fast-growing
duodenal biopsy is considered the gold tumors such as glioblastoma or PCNSL have
standard for diagnosis. a lower association with seizures.
21. (C). Both tuberous sclerosis complex 27. In JME, photosensitivity is noted in about
(TSC) and periventricular nodular hetero- 30% of patients. Family history of epilepsy
topia (PVNH) can present with seizures and is reported in 40–50%. Inheritance is
periventricular lesions. The lesions of PVNH unclear, likely polygenic, but both autoso-
are typically not calcified, are homogenous, mal dominant and recessive inheritance have
are gray matter (by definition), and may be been reported. Gene mutations identified in
bilateral (particularly in familial cases, which some families include GABRA1 (GABA-A
are usually X-linked). receptor gene on chromosome 5q34),
22. (E). CSWS manifests as global regression in CLCN2 (chloride channel 2 gene on chro-
cognition and behavior. The majority of mosome 3q26), and myoclonin1/EFHC1
patients have seizures. CSWS is sometimes (EH-hand motif protein on chromosome
associated with identifiable pathology, e.g., 6p12; found in 9% of JME).
neuronal migrational disorders, polymicro- 28. (B). The clinical description is most consis-
gyria, shunted hydrocephalus, porencephaly, tent with REM behavior disorder. This sleep
Multiple Choice Questions for Part III 197
disorder has been closely linked to the which LGI1 is a common target. NMDA-R
development of Parkinson’s disease. antibody-mediated disease often presents
29. (B). Hypothalamic hamartoma is usually with associated movement disorder and
sporadic but is rarely associated with auto- ovarian teratoma; GAD antibody-mediated
somal dominant Pallister–Hall syndrome disease may also present with type I diabetes
(GLI3 gene mutation). mellitus or stiff-person syndrome; anti-
30. (E). Glut1 is found in microvessels and Amphiphysin antibody-mediated disease
astrocytes, and it facilitates glucose transport often presents with neuropathy and can be
into the brain. Initial patients with Glut1 DS associated with small cell lung cancer or
had refractory epilepsy (infantile onset), breast adenocarcinoma.
encephalopathy, acquired microcephaly, 35. (D). There is no evidence that treating early
cognitive impairment, and motor abnormal- post-traumatic seizures lowers the risk of
ities (spasticity, ataxia, and dystonia). Clin- developing epilepsy/late seizures, although
ical features include seizures, movement/gait treating and preventing early seizures may
disorders, and cognitive/behavioral distur- help with acute recovery, as early seizures
bances. Seizure starts in infancy (average could lead to further brain injury. Although
age of onset 8 months). GTC, absence, multivariate analyses have shown that early
myoclonic, and focal seizures may occur. seizures do not themselves increase risk of
Only 8% will be seizure free with medica- late seizures, early seizures are associated
tions alone. with development of late seizures due to
31. (B). Longer duration of illness, abnormal confounding factors that increase risk for
neuropsychological testing, and presence of both early and late seizures (brain contusion,
psychiatric comorbidities are the predictors subdural hematoma, and loss of conscious-
of negative outcome in psychogenic ness or amnesia > 24 h).
nonepileptic seizures. 36. (E). The patient has benign occipital epilepsy
32. (D). Tumors in adults, tumors near sensitive or idiopathic childhood occipital epilepsy
or irritable structures and networks (limbic (most likely Panayiotopoulos syndrome).
pathways, motor cortex), and tumors that are The symptoms and signs described in the
low grade (e.g., those without central question are classic for this diagnosis.
necrosis) are more likely to be associated The EEG classically shows occipital spikes
with seizures. that are best brought out by darkness but
33. (E). Patients with history of migraines may other types of epileptiform activity have been
have normal EEGs or nonspecific EEG chan- noted, as well. Because the frequency of
ges including generalized slowing (or focal in seizures is low, many patients do not need to
hemiplegic migraines), loss of normal alpha be treated with antiseizure medicines.
rhythm, enhanced photic drive, and attenuated 37. (A). Age and clinical description are consis-
beta activity. Occipital spikes can also be seen tent with the diagnosis of hyperekplexia or
in basilar migraines. In the absence of suspi- stiff baby syndrome. It consists of a triad of
cion for epilepsy, there is no justification in generalized stiffness, nocturnal myoclonus,
obtaining EEGs for migraineurs. and tonic spasms that are usually triggered by
34. (B). The presence of rapid cognitive decline auditory or tactile stimuli. It is caused by
and myoclonus could suggest Creutzfeldt– gene mutations affecting the inhibitory gly-
Jacob disease, but new-onset intractable cine receptor (GLRA1 and GLRB). The
seizures more strongly suggest autoimmune treatment of choice is clonazepam.
epilepsy. Hyponatremia is typical of VGKC- 38. Glut1 deficiency is associated with spastic or
complex antibody-mediated disease, of ataxic gait, dystonia, chorea, tremor,
198 Multiple Choice Questions for Part III
exertional dyskinesia, and episodic weak- 41. (A). During convulsions, tongue biting
ness (triggered by fasting and exercise). (especially at the side of tongue) is more
Cognitive and behavioral disturbances likely to occur with epileptic seizures. The
including learning/intellectual disability, remaining features are highly suggestive of
language deficit (predominantly expressive), psychogenic nonepileptic seizures.
and dysarthria are common. The diagnosis of 42. (A). This is a classic description of bilateral
Glut1 DS is based on hypoglycorrhachia perisylvian polymicrogyria syndrome; the
with normoglycemia and low-to-normal CSF perisylvian localization explains the symp-
lactate. CSF glucose is <40 mg/dl toms, EEG findings, and imaging abnormal-
(2.2 mmol/L); in all reported cases, CSF ities. Schizencephaly can be seen with
glucose is <60 mg/dl (3.3 mmol/L). CSF: polymicrogyria but is not typically part of this
blood glucose ratio is <0.4 (fasting state). syndrome; the MRI would show parenchy-
Gene mutation (SLC2A1 gene on chromo- mal clefts in schizencephaly. Pachygyria and
some 1p35-31.3) is identified in about 90% lissencephaly are seen in combination with
of patients. 90% is de novo mutation; *10% each other, and the MRI description is
AD; rare AR. Erythrocyte glucose uptake inconsistent with these two options.
assay may be used to confirm the diagnosis. 43. (D). Anti-NMDA receptor encephalitis may
The ketogenic diet is effective. Only 8% will present with a prodrome of viral-like syn-
be seizure free with medications alone. drome precedes psychiatric and behavioral
39. (A). The initial symptoms are suggestive of problems. The symptoms progress to altered
presyncope but the associated change in mental state, seizures, dyskinesia, choreoa-
awareness and the partial relief on lacosa- thetosis, and breathing and autonomic insta-
mide are both suggestive of epileptic sei- bility. CSF shows signs of inflammation in
zures. Normal routine EEG and brain over 90% of patients. Lymphocytic pre-
imaging do not exclude the diagnosis of dominant pleocytosis, mildly elevated pro-
epilepsy. An inpatient video-EEG monitor- tein, and oligoclonal bands may be present.
ing with lacosamide withdrawal is the gold The diagnosis of anti-NMDA receptor
standard test, in addition to full cardiac encephalitis is made by the demonstration of
telemetry will be valuable too. anti-NMDA receptor antibodies in serum and
40. (D). The constellation of partial blindness, CSF. The level of antibody in CSF correlates
epilepsy, schizencephaly, and an absent with symptom and outcome. Anti-NMDA
septum pellucidum suggests septo-optic receptor encephalitis may be associated with
dysplasia (de Morsier syndrome). Optic ovarian teratoma in females.
nerve hypoplasia may also be seen. This is 44. (E). Propofol infusion syndrome is a rare
typically associated with hypopituitarism, syndrome which affects patients undergoing
and the events described are probably syn- long-term treatment with high doses of
cope and not seizures. Therefore, a serum propofol. This can lead to cardiac failure,
cortisol level is most likely to give a specific metabolic acidosis, rhabdomyolysis, and
diagnosis. Although the remaining answer kidney failure, and is often fatal. The syn-
choices may suggest a cause of syncope, drome occurs more commonly in children,
screening for pituitary dysfunction should and critically ill patients receiving glucocor-
not be overlooked. ticoids and catecholamines.
Multiple Choice Questions for Part III 199
45. (B). Several characteristics were shown to be Pyridoxamine 5′-phosphate oxidase (PNPO)
associated with good outcomes (event reso- deficiency, caused by mutation of PNPO on
lution) in psychogenic nonepileptic seizures. chromosome 17q21.32 and inherited as
These include male gender, younger age at autosomal recessive trait, results in the
onset, short duration of illness, higher edu- decreased synthesis of PLP and clinically
cational and socioeconomic status, and manifests with severe refractory neonatal
minimal motor involvement during events. epileptic encephalopathy with prenatal sei-
46. (C). The American Academy of Neurology zures. EEG may show burst-suppression
guidelines recommend anticonvulsant treat- pattern. CSF neurotransmitter metabolite
ment only after a seizure has occurred. Pro- levels are abnormal: low HVA and 5-HIAA
phylaxis in brain tumor patients without a concentration (degradation products of
history of seizures is only recommended for dopamine and serotonin, respectively), and
one week post-operatively; longer-term high L-dopa (precursor of dopamine),
prophylaxis in patients (regardless of oper- 5-hydoxytryptophan (precursor of sero-
ative history) has not been shown to prevent tonin), and 3-ortho-methyldopa concentra-
the first seizure. tions. CSF PLP level is reduced. Patients
47. (E). Glycine encephalopathy (also known as respond to pyridoxal phosphate but not to
nonketotic hyperglycinemia) is an autosomal pyridoxine.Primary cerebral folate deficiency
recessive condition caused by defect in the results from defect in transport of folate
glycine cleavage system (intramitochondrial across blood-CSF/blood–brain barrier. There
enzyme complex) resulting in excess glycine are 2 possible causes for the transport defect:
in all tissues, especially CNS. Glycine is both blocking auto-antibodies against folate
excitatory (cortex) and inhibitory (brainstem receptors of the choroid plexus and folate
and spinal cord) neurotransmitter in the CNS. receptor gene mutation (FOLR1). Clinically
Infants presented with neonatal hypotonia, symptoms start at 4–6 months of age with
seizures (often myoclonic), encephalopathy irritability and disturbed sleep. Slow head
or coma, and hiccups. The diagnosis of gly- growth, ataxia, choreoathetosis, and ballistic
cine encephalopathy is confirmed by elevated movements are additional features. By
glycine in plasma and CSF, and CSF to 2 years of age, mental retardation, ataxia,
plasma glycine ratio >0.08. Seizures occur in involuntary movements, and spastic diplegia
35–60% of patients with mitochondrial dis- will ensue. Later visual disturbance and
order. Examples include MERRF (myoclonic progressive sensorineural hearing loss occur.
epilepsy and red ragged fibers), Alpers syn- About a third of patients have seizures which
drome [POLG1 (polymerase gamma) muta- includes myoclonic-atonic, absence, and
tion: explosive focal epilepsy, EPC or status GTC seizures.
epilepticus, and predominant occipital dis- 48. (D). The clinical description is most consis-
charges on EEG may suggest the diagnosis], tent with the diagnosis of Sandifer syndrome
and MELAS (mitochondrial myopathy or infantile gastroesophageal reflux disease.
encephalopathy, lactic acidosis and stroke- Since he has been losing weight and vom-
like episodes). Elevated plasma and/or CSF iting, a trial of antacids such is omeprazole is
lactate suggests mitochondrial disorder but needed. This condition usually resolves after
normal lactate does not rule out the diagno- the age of 6 months.
sis. Elevated alanine level may indicate 49. (A). The patient most likely has anti-NMDA
mitochondrial disorder. Pyridoxal 5′ phos- receptor encephalitis, characterized by
phate (PLP) is an essential cofactor in the new-onset refractory seizures, prominent
synthesis of dopamine and serotonin. psychiatric features, and a movement
200 Multiple Choice Questions for Part III
work-up of a first unprovoked seizure. MRI is Table 15.1 Seizure recurrence rates
usually preferred over CT scans because of its Recurrence
higher resolution for soft tissue and malforma- rate (%)
tions. In one pooled analysis of 928 subjects with After first unprovoked seizure 40
brain MRI after first seizure, 15 % were found to After two unprovoked seizures 73
have brain MRI abnormalities. In the same study, After three unprovoked seizures 76
51 % of 1766 patients (pooled analysis) had an
After treating first unprovoked seizure 15
abnormal initial routine EEG. An additional 35 %
were identified to have abnormalities on the sec-
ond sleep-deprived EEG. An abnormal EEG
predicts a higher recurrence rate, and a normal FIRST Trial (Italy) in 1993 found a 51 %
EEG predicts a lower recurrence rate but does not recurrence by two years.
rule out epilepsy. On average, about 50 % of UK (MESS Trial) in 2005 found 39 %
individuals clinically diagnosed with a seizure recurrence by two years.
have a normal first routine EEG. Laboratory The recurrence rates were higher years after a
testing, such as complete blood counts, blood remote symptomatic and after having two or
glucose, and electrolyte panels (particularly more seizures (Tables 15.1 and 15.2). Treatment
sodium), cerebrospinal fluid analysis, and toxi- after the first seizure decreases the recurrence rate
cology screening may be helpful as determined by 30–60 % but does not eliminate the risk
by the specific clinical scenario based on history, completely (Table 15.3).
physical, and neurologic examination, but there
v. Seizure recurrence after the first unpro-
are insufficient data to support or refute recom-
voked seizure according to etiologic factors
mending any of these tests for the routine evalu-
and EEG findings Berg and Shinnar [4]:
ation of adults presenting with an apparent first
unprovoked seizure (Krumholz et al.).
Etiology
In one study by King et al., brain MRI
Idiopathic 32 %
abnormalities were seen in 14 % (38 of 277) of
Symptomatic 57 %
patients with a first unprovoked seizure. Tumors
EEG
were the most commonly identified etiology for
Normal 27 %
seizures followed by developmental anomalies
Epileptiform 58 %
then hippocampal pathologies and vascular
Etiology + EEG
malformations King et al. [2]. In another similar
Idiopathic + Normal 24 %
study done 15 years later, 23 % (177 of 764) of
Symptomatic + Abnormal EEG 65 %
patients had MRI abnormalities. This time
Focal onset seizures had higher risk of
developmental anomalies were equally common
recurrence than generalized-onset seizures.
as tumors. The higher yield was attributed to the
A first seizure occurring during sleep also had
use of 3 T MRIs as opposed to 1.5 T in the
higher risk for recurrence than a seizure occur-
original study Hakami et al. [3].
ring during wakefulness. The other risk factors
for seizure recurrence included status epilepticus
iv. Seizure recurrence after first unprovoked
as first seizure, abnormal interictal neurological
seizure:
examination, abnormal brain imaging, multiple
The recurrence rate after the first unprovoked or clustered seizures at onset, and strong family
seizure averages around 40 % within the first two history of seizures.
years. This was concluded based on three large Treatment decision after first seizure
pivotal studies: This subject has always been controversial as
Meta-analysis (USA) in 1991 which found a scholars usually differ in their practices of treat-
36 % recurrence by the two years. ing or not treating the first seizure. In general,
15 Principles of Epilepsy Diagnosis and Management 205
about 60 % of the patients who had their first epilepsies. On the contrary, some narrow spec-
seizure will never have another one. In this case, trum AEDs could cause worsening of seizures if
it is appropriate to give the facts to the patient given to a patient with generalized-onset seizures
and let them make their decisions. If the patient (see Table 15.4).
prefers not to be treated and understands the risk Mechanism of action (MOA) is another factor
of receiving no treatment, it is perfectly accept- that may influence the selection of an AED
able not to treat. Some patients will insist on (Table 15.5). However, the role of MOA is very
being treated since they do not want to risk limited, and the existing data do not support
another seizure. In this case, treatment is offered consideration of MOA as a major criterion in
for these patients provided that they understand choosing an AED. Many AEDs have multiple
the seizure recurrence risk is decreased but not MOAs, and some have unknown MOAs. This
necessarily eliminated with treatment. After an makes it even more difficult to make a judgment
acute or remote symptomatic (cerebral insult) based on MOA alone [5, 6]. According to a study
seizure in a clinically unstable patient, treatment by Deckers CL et al., there is some evidence
is usually indicated without waiting for a second showing that AED polytherapy based on MOA
seizure. Selecting an appropriate antiepileptic may enhance effectiveness. In particular, com-
(AED) is quite challenging task in most cases. bining a sodium channel blocker with a drug
This is due to the presence of multiple AED enhancing GABAergic inhibitor could be an
options and very little predictability of good advantageous combination. Combining two
response. In addition, efficacy and tolerability of GABA mimetic drugs or combining an AMPA
AEDs may strongly differ among individuals. antagonist with an NMDA antagonist may
There are several available factors that could enhance efficacy, but tolerability may be reduced
help us make an educated decision of what AED with this combination.
would be best to start with. The spectrum of a
particular AED (narrow or broad) is one of these
factors (Table 15.4). In general, narrow spectrum Other Factors Influencing AED
AEDs are reserved for seizures with known. Selection
When seizure classification is unclear, it is wiser
to initiate a broad spectrum agent AED. The • Seizure type/classification
reason for this approach is that most narrow • Epilepsy syndrome
spectrum AEDs will not benefit patients • Established drug efficacy for a particular sei-
with generalized-onset seizures or generalized zure type or epilepsy syndrome
206 H.H. Sonmezturk et al.
The classic AEDs include Phenobarbital, Pheny- Drug trials primarily aim to prove superiority
toin, Primidone, Ethosuximide, Benzodiazepines, over placebo, or no inferiority (conversion to
Carbamazepine, and Sodium Valproate. There monotherapy studies). Drug trials tend to use
15 Principles of Epilepsy Diagnosis and Management 207
Table 15.6 Commonly used abbreviations, brand names, and most frequent side effects of AEDs
ABR Generic Brand Watch for
Older (Classic) AEDs
PHB Phenobarbital (Luminal) Sedation, rash, liver failure, aplastic anemia, osteopenia, CT d/o
PHT Phenytoin (Dilantin) SJS, blood dyscrasia, liver failure, gingival hyperplasia, hirsutism,
osteopenia
PRM Primidone (Mysoline) Metabolized to phenobarbital
ESX Ethosuximide (Zarontin) Stomach upset, abdominal pain/cramps
CLZ Clonazepam (Klonopin) Somnolence, lethargy, sexual dysfunction, tolerance is an issue
CZP Clorazepate (Tranxene) Somnolence, lethargy
DZM Diazepam (Valium) Not for prevention, can be used as abortive medication (watch for resp
suppression)
LRZ Lorazepam (Ativan) Not for prevention, can be used as abortive medication (resp
suppression)
CBZ Carbamazepine (Tegretol) Sedation, #WBC, #Na, bradycard, SJS, agranulo, hepatic fail,
pancreatitis
VPA Valproate (Depakote) Weight gain, tremor, #Plt, pancreatitis, liver failure, "ammonia, hair
loss
Newer AEDs
VGB Vigabatrin (Sabril) Permanent visual field deficit 30–40 %, reversible subcortical edema
ZNS Zonisamide (Zonegran) Cross reacts with sulfa, hypohidrosis, renal stones
LTG Lamotrigine (Lamictal) Nonsedating, insomnia, SJS (needs very slow titration), myoclonus
FBM Felbamate (Felbatol) Aplastic anemia, liver failure, weight loss, "PHT, VPA, PHB
GBP Gabapentin (Neurontin) Sedation, weight gain, myoclonus
TPM Topiramate (Topamax) Weight loss, severe cognitive slowing, dysesthesias, glaucoma, renal
stones
TGB Tiagabine (Gabitril) Sedation, cognitive slowing, worsens gen szs (myoclonic, absence)
OXC Oxcarbazepine (Trileptal) #Na in elderly, #OCP levels, sedation, rash
LEV Levetiracetam (Keppra) Irritability (hateful, anger issues, Vit B6 100 mg/day may help),
depression
PGB Pregabalin (Lyrica) Sedation, swelling in lower extremities, blurred vision
RFM Rufinamide (Banzel) Loss of appetite, aggravated seizures, status epilepticus
LCM Lacosamide (Vimpat) Dizziness, fatigue
ESL Eslicarbazepine (Aptiom) Nausea, Dizziness, diplopia, hyponatremia (1–2 %)
CLB Clobazam (Onfi) 1, 5-benzodiazepine, somnolence, lethargy, (less addiction potential)
EZG Ezogabine (Potiga) Urinary retention, tremors, bluish skin coloration
PER Perampanel (Fycompa) Ataxia, severe mood issues (hostility, homicidal ideation, aggression)
Table 15.7 Summary of studies and level of evidence for each seizure type and epilepsy syndrome
Seizure type or epilepsy syndrome Class I Class Class Level of efficacy and effectiveness
studies II III evidence
studies studies (in alphabetical order)
Adults with partial-onset seizures 4 1 34 Level A: CBZ, LEV, PHT, ZNS
Level B: VPA
Level C: GBP, LTG, OXC, PHB,
TPM, VGB
Level D: CZP, PRM
Children with partial-onset seizures 1 0 19 Level A: OXC
Level B: None
Level C: CBZ, PHB, PHT, TPM,
VPA, VGB
Level D: CLB, CZP, LTG, ZNS
Elderly adults with partial-onset 1 1 3 Level A: GBP, LTG
seizures Level B: None
Level C: CBZ
Level D: TPM, VPA
Adults with generalized-onset tonic– 0 0 27 Level A: None
clonic seizures Level B: None
Level C: CBZ, LTG, OXC, PHB,
PHT, TPM, VPA
Level D: GBP, LEV, VGB
Children with generalized-onset tonic– 0 0 14 Level A: None
clonic seizures Level B: None
Level C: CBZ, PB, PHT, TPM, VPA
Level D: OXC
Children with absence seizures 1 0 7 Level A: ESM, VPA
Level B: None
Level C: LTG
Level D: None
Benign epilepsy with centrotemporal 0 0 3 Level A: None
spikes (BECTS) Level B: None
Level C: CBZ, VPA
Level D: GBP, LEV, OXC, STM
Juvenile myoclonic epilepsy (JME) 0 0 1 Level A: None
Level B: None
Level C: None
Level D: TPM, VPA
(SGTCS). This was a multi-center double-blind (Mattson et al. 1992). Glauser et al. compared
trial for initiation monotherapy. A total of 622 ESX, VPA, and LTG monotherapies for the
adult epilepsy patients were recruited. Treatment treatment of childhood absence epilepsy in a
success was highest with CBZ or PHT, inter- double-blind randomized controlled trial. This
mediate with PHB, and lowest with PRM study was done on 453 children with newly
(Mattson et al. 1985). In another multi-center diagnosed absence epilepsy. ESX and VPA had
double-blind study, VPA was compared to CBZ similar efficacy which was better than LTG. ESX
for the treatment of complex partial seizures and had fewer attentional dysfunction than VPA.
SGTCS in adult patients. Both drugs were ESX was re-established as the first choice drug in
equally effective in controlling SGTCS. For the childhood absence epilepsy despite the
complex partial seizures, outcome measures availability of multiple newer AEDs. No
favored CBZ which also had less adverse effects prospective double-blind controlled study
210 H.H. Sonmezturk et al.
showed superior efficacy of newer drugs com- highest with OXC and TPM and lowest with
pared to the older ones. Several studies showed GBP and LEV Costa et al. [8]. Table 15.8
better tolerability and less discontinuation rates summarizes ideal AED(s) selection based on
with newer AEDs. In one study, PGB had similar seizure type and comorbidities.
tolerability but inferior efficacy to LTG for the
treatment of newly diagnosed partial seizures in
adults Kwan et al. [7]. Another study demon- Drug-Resistant Epilepsy
strated PGB to be non-inferior to LTG in the and Polytherapy
treatment of refractory partial seizures. In a
meta-analysis by Costa J. et al., clinical compa- Drug resistant epilepsy is defined as failure to
rability of the newer AEDs in refractory partial achieve seizure freedom after adequate trials of
epilepsy was analyzed. A total of 62 randomized two appropriately chosen AEDs used as thera-
controlled trials comparing a new AED to a peutic levels in monotherapy or combination
placebo as adjunctive therapy, and 8 randomized therapy (2010 consensus document by ILAE,
controlled trials comparing a new AED to Kwan et al. 2010). Overall, about one third of all
another AED as add were reviewed. In this epilepsies prove to be drug resistant. Among all
meta-analysis, LEV shined as the AED with high epilepsies, symptomatic or cryptogenic epilepsies
responder rate as well as low withdrawal rate. have higher rate of drug resistance compared to
Looking at the results overall, TPM and LEV had idiopathic epilepsies Kwan et al. [9]. Drug
the highest responder rates. GBP and TGB had resistance also tends to be higher in patients who
the lowest responder rates. Withdrawal rate was had more than 20 seizures prior to starting
15 Principles of Epilepsy Diagnosis and Management 211
treatment. When the initial AED fails, adding a study, 1617 seizure-free epilepsy patients on
second AED or switching to another AED did polytherapy were identified. The majority of
not differ statistically; however, common practice seizure-free patients (81.3 %) on polytherapy
favors the combination therapy Kwan et al. [9]. were on two AEDs only. With 64 effective dual
Wide range of combinations of two or perhaps therapy regimens, VPA and LTG combination
three AEDs can be effective in some patients. was the most commonly successful combination
With the available 25 different AEDs, about 300 at 24.3 %. About 17.5 % of seizure-free patients
possible double therapy regimen and more than were on three AEDs. There were 57 effective
2000 triple therapy regimens can be achieved. triple therapy regimens, and the most commonly
While choosing an appropriate AED combina- successful combinations were (LTG + TPM +
tion, drug-drug interactions should be avoided. VPA) or (LEV + LTG + VPA) Stephen et al.
Enzyme inducing AEDs will increase their own [10].
clearance as well as most of the other AEDs One should also consider the specific rash
(Table 15.10). For example, combining PHB and cross-sensitivity rates among AEDs (Table 15.9).
VPA would increase sedation and weight gain; There is no known specific cross-sensitivity
combining PHT and CBZ would result in between LTG and other AEDs. AEDs with low
increased side effects such as dizziness and risk of rash include VPA, GBP, PGB, LEV, and
diplopia and bidirectional induction of metabo- TPM.
lism would make it difficult to maintain thera- Eliminating AEDs which are deemed inef-
peutic blood levels. VPA may triple LTG blood fective is necessary to decrease the drug burden,
levels and result in increased chances of allergic to allow higher doses of more effective drugs,
reactions. If used cautiously, VPA and LTG and also to avoid drug-drug interactions. There
combination therapy is shown to be one of the may be certain patients who would have
most successful combinations in generalized increased seizures even when an ineffective drug
epilepsy. Also it is recommended to avoid com- is decreased or stopped. These patients usually
bination of AEDs with similar side effects such end up on multiple AEDs up to six or seven
as dizziness, imbalance, and diplopia common to without seizure control. Withdrawal seizures
sodium channel blockers. In particular, these should not discourage clinician to simplify AED
combinations include CBZ + LTG, CBZ + regimens. If needed, epilepsy monitoring unit
LCM, OXC + LCM, or LTG + LCM. In one could be used to safely taper the ineffective AED.
Table 15.10 P450 Enzyme inducing AEDs (strong) Enzyme inhibiting AEDs (strong)
enzyme modulation of
several AEDs Phenobarbital Valproic acid
Primidone Topiramate (weak)
Phenytoin
Carbamazepine
Oxcarbazepine (doses > 900 mg)
Lamotrigine (weak)
80–90 % of all existing medications will be affected by the enzyme inducing AEDs
above. In particular efficacies of steroids, estrogens, digoxin, warfarin, furosemide, and
doxycycline will be decreased
212 H.H. Sonmezturk et al.
Stopping AEDs When Seizure these patients. Young women with 2–3 year
Freedom Achieved seizure freedom could prefer drug withdrawal
during pregnancy. Some patients have intolerable
About 70 % of epilepsy patients will eventually side effects which may necessitate drug with-
achieve seizure freedom with AEDs. There is drawal. Some patients have difficulty finding a
often an illusion of cure after seizures are con- job while on AEDs, and we may chose to taper
trolled for long term. However, this is not the AEDs off in these patients. In general 2–5 years
case in most patients. In general, depending on of seizure freedom is needed. And the tapering of
the seizure or epilepsy and etiology, 11–41 % of the AEDs should be slowly spread over
patients will relapse after the AED discontinua- 6–12 months.
tion. The relapse rate tends to be lower in chil-
dren (* 20 %) and higher in adults (* 40 %).
In one large study, patients in long-term remis- References
sion were randomized either to withdraw or
continue the treatment. In the first two years, 1. Hauser et al. Rochester Minnesota 1955–1984. 1993.
41 % of the patients coming off the treatment 2. King, et al. Lancet. 1998;352(9133):1007–11.
relapsed versus 22 % of the patients continuing 3. Hakami, et al. Neurology. 2013;81(10):920–7.
4. Berg and Shinnar Neurology. 1991;41(7):965–72.
on medication. Most relapses occurred within the 5. Dodrill CB, et al. Epilepsy Res. 2000;42(2–3):123–
first year of treatment reduction or AED with- 32.
drawal. The more severe and long lasting a 6. Biton V, et al. Epilepsia. 1998;39(suppl 6):125.
patient’s active epilepsy was before remission, 7. Kwan, et al. Lancet Neurol. 2011;10(10):881–90.
8. Costa J, et al. Epilepsia. 2011;52:1280.
the greater the risk of relapse. Diagnosis of 9. Kwan P, Brodie MJ. N Engl J Med. 2000;342
Juvenile myoclonic epilepsy (JME) or the pres- (5):314–9.
ence of a structural lesion underlying the epi- 10. Stephen LJ, et al. Epilepsy Res. 2012;98(2–3):194–8.
lepsy also increased the relapse risk (MRC 11. Krumholz et al. Neurology. 2007;69(21):1996–2007.
12. First Seizure Trial Group Neurology. 1993;43(3 Pt
Antiepileptic Drug Withdrawal Group (1991). 1):478–83.
Clinicians should choose a patient specific 13. Marson A et al. Lancet. 2005;365(9476):2007–2013.
approach in discontinuing AED therapy. Also, 14. Hesdorffer DC, et al. Epilepsia. 2009;50(5):1102–8.
the epilepsy classification and seizure type 15. Deckers CL, et al. Epilepsia. 2000;41(11):1364–74.
16. Tracy Glauser et al. Special Report Epilepsia, **
should be considered. Relapse rate in rolandic (*):1–13, 2013.
epilepsy is about 2 %, so the threshold to with- 17. Baulac M, et al. Epilepsy Res. 2010;91(1):10–9.
draw the treatment after long-term remission 18. Hirsch LJ, et al. Neurology. 2008;71(19):1527–34.
should be low. On the other hand, the relapse rate 19. MRC Antiepileptic Drug Withdrawal Group. Lancet.
1991;337:1175–1180.
in JME is about 85 %, so there should be a much
higher threshold to withdraw the treatment in
Old Generation Antiepileptic Drugs
16
Bassel Abou-Khalil
the only affordable antiepileptic drug in much of unchanged in the urine. In the presence of
the developing world. enzyme induction, only about 40% is excreted
unchanged. In monotherapy, primidone half-life
is 10–15 h; it is shorter (6.5–8.3 h) in the pres-
Primidone ence of enzyme inducers.
In the presence of inducers, particularly
Primidone is converted to phenobarbital and phenytoin, the ratio of primidone-to-
phenylethylmalonamide (PEMA), which is also phenobarbital is reduced due to the acceleration
an active metabolite. Unlike phenobarbital, of primidone-to-phenobarbital conversion.
primidone does not have a direct effect on Primidone and phenobarbital are potent enzyme
GABA receptors. Primidone and phenobarbital inducers, decreasing the efficacy of drugs
may act synergistically to reduce sustained metabolized by the p450 enzymes system. Since
high-frequency repetitive firing, at clinically rel- phenobarbital will be present when primidone is
evant concentrations. This is an effect on the used, all phenobarbital interactions are also pre-
sodium channel that neither drug has when used sent by necessity.
alone. As mentioned earlier, phenobarbital acts at Primidone has acute toxic reactions that are
the GABA-A receptor to prolong the opening of different from phenobarbital. It can produce
the chloride channel. The mechanism of action of transient drowsiness, dizziness, ataxia, nausea,
PEMA is unknown, and its anti-seizure activity is and vomiting that can be debilitating. These
modest. Primidone is available only as an oral reactions are present even before phenobarbital
preparation. It is poorly soluble, precluding an IV has appeared as a metabolite. Therefore, a slow
preparation. titration of primidone is necessary. Tolerance to
Primidone oral bioavailability is fairly com- these acute adverse experiences develops rapidly
plete. Its volume of distribution is *0.7 L/kg. Its within hours to days. Otherwise, primidone has
protein binding is low, less than 10% for primi- similar adverse experiences to phenobarbital,
done and for PEMA. including adverse experiences from long-term
Primidone is metabolized in the liver. PEMA use.
is the first detected metabolite. When used in Primidone is effective against the same seizure
monotherapy, about 25% of oral primidone is types as phenobarbital. The recommended
converted to phenobarbital. After one dose, primidone therapeutic plasma concentration is 5–
approximately 64% of primidone is excreted 12 mg/L. A phenobarbital level should also be
16 Old-Generation Antiepileptic Drugs 215
monitored. Since about 25% of oral primidone is lead to phenytoin accumulation. Similarly, some
converted to phenobarbital, the dose of primi- alleles are associated with decreased activity
done required for a certain level is about 4–5 leading to accumulation.
times the dose of phenobarbital required for that The phenytoin half-life is dependent on the
same level. Primidone was found to have equal serum concentration. The initial half-life is
efficacy but lower tolerability in comparison with approximately 22 h (with the range of 8–60 h).
phenobarbital, phenytoin, and carbamazepine. The half-life increases as the serum concentration
increases within and above the recommended
therapeutic range (10–20 mg/L).
Phenytoin The mechanism of the nonlinear elimination
kinetics is that enzymes responsible for most of
Phenytoin has been used since 1938 when phenytoin elimination are partially saturated with
Houston and Merritt discovered its efficacy in the concentrations within the recommended range
maximum electroshock animal model. Phenytoin (with individual variation as to the concentration
acts by binding to active state of the sodium at which this phenomenon first appears). These
channel and reducing high-frequency firing (as enzymes are not able to increase their activity in
might occur during a seizure), while allowing proportion to phenytoin concentration, as the
normal action potentials to occur. concentration increases in the recommended
Phenytoin is available as oral preparations and therapeutic range. Therefore, steady-state
parenteral solution. There is also a phenytoin phenytoin level increases disproportionately as
prodrug for parenteral administration, the maintenance dose is increased within and
fosphenytoin. above the recommended therapeutic range.
Phenytoin absorption is variable. The rate and Below are two examples of the consequences of
extent of absorption may also differ among for- phenytoin nonlinear kinetics.
mulations and is affected by a variety of factors Example 1: A daily dose of 300 mg per day
including age and food. While oral bioavailabil- results in a concentration of 9 mg/L, with some
ity can be greater than 90% in adults, it is residual seizures. Increasing the dose to 400 mg
decreased in neonates and is also decreased in the per day, a 30% increase in dose would have been
presence of nasogastric feedings, calcium, and expected to increase the steady-state concentra-
antacids. There is limited absorption in the tion by 30%, to 12 mg/L, if phenytoin were to
stomach. Absorption is primarily in the duode- follow linear elimination kinetics. However, with
num where the higher pH increases the phenytoin its nonlinear kinetics, the concentration increases
solubility. The time to maximal concentration is disproportionately, by more than 300%, to
shorter with immediate release preparations and 31 mg/L, with associated toxicity. Therefore,
longer with extended-release formulations. The when increasing phenytoin dose within the
volume of distribution is approximately therapeutic range, small increments should be
0.75 L/Kg. Protein binding is approximately used (e.g., 30–60 mg).
90%. Example 2: A patient presents with phenytoin
The major pathway of elimination of pheny- toxicity and a serum concentration of 40 mg/L.
toin is hydroxylation, mediated mainly by the The half-life was previously estimated at 24 h
cytochrome p450 enzymes CYP 2C9 and to a when the serum concentration was 13 mg/L.
lesser extent CYP 2C19. Phenytoin follows However, after phenytoin was stopped, it took
nonlinear kinetics. Small changes in CYP 2C9 3 days for the serum concentration to drop below
activity may have clinically significant effects. 20 mg/L. The reason for this is that the half-life
Some CYP 2C9 alleles are associated with was markedly prolonged in the presence of
reduced clearance of phenytoin. The importance toxicity.
of CYP 2C19 increases with higher levels. Some Phenytoin is affected by drugs that decrease
inhibitors such as ticlopidine and isoniazid may absorption (e.g., nasogastric tube feedings) drugs
216 B. Abou-Khalil
that compete for protein binding (such as val- A phenytoin level of 15 mg/L may actually be
proate) and by enzyme inducers or inhibitors. toxic with a free level of 3–4.5 mg/L, equivalent
Drugs that cause phenytoin accumulation include to a total level of 30–45 mg/L in the presence of
amiodarone, azoles, fluoxetine/fluvoxamine, and normal protein binding.
isoniazid. Phenytoin is a potent enzyme inducer When a low-protein state is present as the
that reduces the efficacy of other drugs metabo- only factor affecting protein binding, the total
lized by the p450 enzyme system, including a phenytoin level can be corrected using the fol-
number of other antiepileptic drugs. lowing formula: Cn = Co/[(0.02 albu-
Phenytoin protein binding plays an important min) + 0.1], where Cn is the normal total level
role in some phenytoin interactions. The and Co is the observed total level.
protein-free phenytoin level is responsible for its Phenytoin concentration-dependent adverse
therapeutic effect and for its toxicity. The free effects include nystagmus, ataxia, incoordination,
fraction increases in the presence of low-protein diplopia, dysarthria, and drowsiness. In addition,
state, renal failure, hepatic failure, old age, or exacerbation of seizures may occur with con-
with co-administration of valproate. Therapeutic centrations above 30 mg/L. Some individuals
decisions are usually made based on the total may experience prominent adverse effects within
phenytoin level, assuming that 10% is free. the recommended therapeutic range, including
However, a free level should be obtained in cognitive adverse effects.
clinical situations where an increase in the free Idiosyncratic reactions may be related to the
fraction is expected. formation of an arene oxide, the active metabo-
As an example of the potential consequences lite that forms due to inadequate epoxide
of altered protein binding of phenytoin, a patient hydrolase activity. Allergic rash occurs in up to
with epilepsy and renal impairment may be 8.5% of patients. Serious severe rash such as
having uncontrolled seizures with a total Stevens–Johnson syndrome or toxic epidermal
phenytoin concentration of 15 mg/L. The deci- necrolysis are much less common. A hypersensi-
sion has to be made whether the dose should be tivity syndrome may occur rarely, with rash,
increased to improve seizure control or should be fever, lymphadenopathy, eosinophilia, elevated
decreased because of toxicity causing a para- liver enzymes, and renal failure.
doxical increase in seizure frequency. The Phenytoin also has long-term adverse effects
protein-free concentration turns out to be including gingival hyperplasia, hirsutism, acne,
4.5 mg/L, equivalent to a total phenytoin con- cerebellar atrophy (which may also occur after
centration of 45 mg/L under the condition of acute intoxication), reduced bone density,
normal protein binding. In this case, holding reduced folate levels, anemia, and macrocytosis.
phenytoin was the correct approach. While renal Phenytoin also has potential teratogenicity and is
and hepatic failures are frequently associated classified with pregnancy category D.
with the decreased albumin concentration, the The IV preparation is associated with local
reduction in protein binding may also occur as a reactions such as pain and burning at the infusion
result of small molecules that compete for protein site, phlebitis, cellulitis, or necrosis from
binding. extravasation, and the purple glove syndrome
Valproate competes with phenytoin for pro- with discoloration then petechial rash. Cardio-
tein binding. In monotherapy, each of phenytoin vascular adverse experiences include hypoten-
and valproate are approximately 90% sion, conduction abnormality, and arrhythmia.
protein-bound, and the free phenytoin level is They are related in part to the vehicle, propylene
about 10% of the total level. With concomitant glycol. They can be avoided with the slowing of
use, each 1 mg/L of valproate increases the free the infusion rate, which should not exceed
fraction of phenytoin by approximately 50 mg/m.
0.1–0.2%. At a valproate level of 100 mg/L, the Phenytoin is effective against partial onset
free phenytoin fraction may increase to 20–30%. (focal seizures) and generalized tonic–clonic
16 Old-Generation Antiepileptic Drugs 217
seizures. Efficacy against tonic and atonic sei- rapidly after the end of infusion. It is not seen
zures is less well established. Phenytoin is not with intramuscular administration.
effective against generalized myoclonic or gen-
eralized absence seizures and may even exacer-
bate these seizures. Carbamazepine
Phenytoin can be loaded orally (18 mg/kg
divided into 3 doses given 2–3 h apart). IV Carbamazepine is a related structure to tricyclic
loading dose for status epilepticus is 18– antidepressants. Its mechanism of action is
20 mg/kg. Phenytoin should be evaluated in reducing high-frequency neuronal firing through
normal saline, not dextrose 5% in water. It the blocking of the sodium channel in a voltage
should be administered into a large vein with a and use dependent fashion.
maximum rate not exceeding 50 mg/min. It has good bioavailability of 80–90%, and it
Intramuscular injection is not recommended is lipophilic but poorly water-soluble, making
due to slow and erratic absorption as well as parenteral formulation difficult. Its protein bind-
crystallization at the injection site causing pain ing is about 75%, usually not of clinical
and a sterile abscess. importance.
Carbamazepine is cleared almost entirely via
hepatic metabolism. The most important meta-
Fosphenytoin bolic product is carbamazepine-10,11-epoxide,
produced via oxidation through CYP 3A4 and
Fosphenytoin is a water-soluble phenytoin pro- CYP 2C8. It is an active metabolite which is also
drug. It can be given intravenously or intramus- responsible for some adverse effects. Carba-
cularly. It is rapidly and completely converted to mazepine induces its own metabolism. This
phenytoin by the cleavage of the phosphate process, known as autoinduction, causes
group by nonspecific phosphatases. Its conver- increased clearance, shortened half-life, and
sion half-life is 8–18 min, and the conversion is lower serum concentration of carbamazepine
completed in a little more than 1 h. It is highly over time. The process typically takes 2–
bound to serum albumin (95–99%). It displaces 4 weeks. As a result, carbamazepine cannot be
phenytoin from protein-binding sites after IV started at the target maintenance dose. It has to be
administration, increasing unbound phenytoin titrated gradually.
concentrations as a function of fosphenytoin Carbamazepine is a potent inducer of p450
concentration. It is indicated for a replacement of enzyme system (particularly CYP 3A4, CYP
oral fosphenytoin or for intravenous or intra- 2C9, CYP 2C19, and CYP 1A2), increasing the
muscular loading. It is marketed in phenytoin clearance of agents metabolized by these
equivalents, so the loading dose is the same as enzymes. The list of drugs affected includes
phenytoin. The maximum rate of intravenous hormonal contraceptives, warfarin, and several
infusion is much higher, at 150 mg/min, in view antiepileptic drugs, including valproate and
of the absence of propylene glycol. A therapeutic lamotrigine.
phenytoin level is usually reached within 10 min Carbamazepine is affected by agents that
after IV loading and within 30 min after intra- induce or inhibit CYP 3A4. The list includes
muscular administration. erythromycin and other macrolide antibiotics
Fosphenytoin has a lower incidence of local (except azithromycin), fluoxetine, propoxyphene,
reactions. However, intravenous administration and grapefruit juice among others. The level of
in the awake individual is commonly associated carbamazepine epoxide is increased by the con-
with paresthesias and itching, most often in the comitant use of valproate, felbamate, oxcar-
groin and perianal region, as well as the trunk bazepine, and zonisamide.
and the back of the head. This adverse experi- The most common adverse experiences with
ence is related to infusion rate and subsides carbamazepine are nausea, GI discomfort,
218 B. Abou-Khalil
headache, dizziness, incoordination, unsteadi- until the drug failed due to uncontrolled seizures
ness, vertigo, sedation, tiredness, blurred vision, or unacceptable side effects. The overall treat-
diplopia, nystagmus, and tremor. Benign ment success was highest with carbamazepine
leukopenia is common, occurring in 10–20% of and phenytoin, intermediate with phenobarbital
instances. It is most often transient and may be and lowest with primidone. The drugs had
persistent though not progressive. This is to be overall equal efficacy, and the difference in
distinguished from the more serious but very rare treatment success was related to tolerability.
aplastic anemia. Carbamazepine can cause Primidone caused more intolerable acute toxic
hyponatremia. Cognitive impairment has been effects, mainly nausea, vomiting, dizziness,
reported on neuropsychological testing. sedation, decreased libido, and impotence. When
Long-term use is associated with weight gain and specific seizure types were analyzed, control of
decreased bone density. Carbamazepine has been secondarily generalized tonic–clonic seizures did
found to increase sex hormone binding globulin not differ significantly with the 4 drugs, but
and decrease testosterone concentration. carbamazepine provided complete control of
Idiosyncratic adverse experiences include partial seizures more often than primidone or
rash, rare Stevens–Johnson syndrome and toxic phenobarbital. As a result, carbamazepine
epidermal necrolysis, as well as very rare became the drug against which new antiepileptic
hypersensitivity syndrome with fever, rash, end drugs were compared.
organ involvement. Lupus-like syndrome is rare,
as are hepatotoxicity and aplastic anemia (esti-
mated at 1 in 200,000). There is a strong asso- Oxcarbazepine
ciation between the HLA-B1502 allele and
carbamazepine-induced Stevens–Johnson syn- Even though oxcarbazepine was first introduced
drome in Asian populations and individuals of in the USA in 2000, it is listed with the
Asian descent. The FDA has issued an alert and old-generation drugs since it was introduced in
updated product labeling recommending genetic some European countries as early as 1963.
testing of HLA-B polymorphisms to predict Oxcarbazepine is structurally related to carba-
carbamazepine-induced serious skin reactions in mazepine, but different from carbamazepine in its
individuals of Asian descent. metabolism and in the induction of metabolic
Carbamazepine has been assigned pregnancy pathways. Oxcarbazepine has a similar mecha-
category D due to increased risk of spina bifida nism of action to carbamazepine, inhibiting
when used in polytherapy. high-frequency repetitive neuronal firing by
Carbamazepine is effective against partial blocking voltage-gated sodium channels. It also
onset (focal) seizures and against generalized modulates high-voltage-activated calcium
tonic–clonic seizures. However, it may exacer- channels.
bate absence and myoclonic seizures as well as Oxcarbazepine absorption is almost complete
atonic seizures. The recommended therapeutic with a bioavailability of about 99%. It is very
range is 4–12 mg/L. rapidly metabolized to a monohydroxy deriva-
The efficacy and tolerability of carba- tive, an active metabolite responsible for oxcar-
mazepine, phenobarbital, phenytoin, and primi- bazepine activity. Oxcarbazepine protein binding
done were compared in a large, multicenter, is about 60% while the monohydroxy derivative
double-blind, cooperative veterans administra- protein binding is about 40%. The oxcarbazepine
tion trial [9]. Six hundred and twenty-two adults half-life is 1–3.7 h. The monohydroxy derivative
with partial and secondarily generalized tonic– is further metabolized and has a half-life of 8–
clonic seizures were randomly assigned to one of 10 h. Oxcarbazepine does not induce its own
the four drugs and were followed for two years or metabolism.
16 Old-Generation Antiepileptic Drugs 219
diazepam course can be used in some syndromes be used orally to stop mild seizure clusters/acute
such as Landau–Kleffner syndrome and electrical repetitive seizures.
status epilepticus during sleep (ESES). Clorazepate is a prodrug, as it is rapidly
Lorazepam is metabolized in the liver through decarboxylated in the stomach to form the active
glucuronidation and excreted by the kidneys. It desmethyldiazepam (DMD). It is FDA-approved
does not have active metabolites. Its clearance is for management of anxiety disorders and as
reduced by valproate and other inhibitors. It is adjunctive therapy in the management of partial
available in oral and parenteral forms. It is not seizures. It is available in oral form only, in
appropriate for chronic use. Its main use is for immediate and extended-release preparations.
status epilepticus. It has a longer duration of Clobazam was only approved in the USA in
action than diazepam despite its shorter half-life, 2009, but is listed with the old-generation
as a result of less lipid solubility and less redis- antiepileptic drugs because it has been used
tribution to adipose tissue. Lorazepam can also in Europe since 1975. It is the only
16 Old-Generation Antiepileptic Drugs 223
The new-generation antiepileptic drugs (AEDs) half-life in monotherapy is 20–23 h. The half-life
became available in the USA after 1993, fol- is shorter in children and also shorter in the
lowing a 15-year hiatus during which no new presence of enzyme inducers. Felbamate has
drugs were introduced for the treatment of epi- many interactions. It is an inhibitor of CYP
lepsy. In general, the newer AEDs have not 2C19, CYP 1A2, and beta-oxidation. As a result,
improved on the efficacy of carbamazepine, the it inhibits the metabolism and increases the
AED to which they have been most often com- serum concentration of phenobarbital, phenytoin,
pared. However, many of the newer antiepileptic valproate, carbamazepine epoxide, and warfarin.
drugs have advantages in terms of pharmacoki- On the other hand, felbamate induces CYP 3A4
netics (Table 17.1), interactions, and tolerability and thus decreases carbamazepine level and also
[1, 2]. The new drugs will be discussed in the reduces oral contraceptive efficacy.
order that they were introduced to the US market. Felbamate is affected by enzyme-inducing
The exceptions are oxcarbazepine and clobazam, antiepileptic drugs which accelerate felbamate
which were discussed in the previous chapter. clearance and reduce its serum concentration.
Common adverse effects of felbamate are
anorexia, nausea, vomiting, and weight loss.
Felbamate Stomach irritation can be improved by adminis-
tration with food and by the use of H2 blockers
Felbamate was first approved in the USA in or proton pump inhibitors. Felbamate may also
1993. Felbamate has several mechanisms of cause insomnia, irritability, and headache.
action, including NMDA antagonism, enhancing Felbamate was discovered to have serious
GABA, blocking sodium channels, and blocking idiosyncratic potential adverse effects. It may
high-voltage activated calcium channels. cause aplastic anemia with an estimated risk of 1
It has excellent oral bioavailability, greater in 5000–8000 patients. Aplastic anemia has not
than 90%. It is only 25% protein-bound, which is been reported below age 13. The onset of aplastic
not clinically significant. It is metabolized via anemia is after 2.5–6 months of treatment. It is
CYP 3A4. Between 40 and 50% of the absorbed highly unlikely to occur after one year of treat-
dose appears unchanged in the urine and the rest ment. It has risk factors including prior cytope-
as inactive metabolites and conjugates. Its nia, allergy to or significant toxicity with other
antiepileptic drugs, and underlying autoimmune
disease [3]. Another serious idiosyncratic
potential adverse effect is hepatic failure, with an
B. Abou-Khalil (&)
estimated risk of 1 26,000-1 and 54,000. The
Department of Neurology, Vanderbilt University
Medical Center, Nashville, TN, USA
e-mail: bassel.abou-khalil@vanderbilt.edu
onset of this toxicity has been after 25–959 days adjunctive therapy in the treatment of partial sei-
of treatment, with a mean of 217 days. Neither zures, with or without generalization, in adults
aplastic anemia nor liver failure can be prevented with epilepsy and adjunctive therapy in the treat-
by monitoring of CBC and liver enzymes. Nev- ment of partial and generalized seizures associated
ertheless, it is recommended to check CBC and with Lennox-Gastaut syndrome in children.”
liver function tests prior to starting felbamate, The FDA indication specifies that “felbamate is
then every 2 weeks for 6 months, then every 2– not indicated as a first-line treatment; it is rec-
3 months after 6 months, and then every ommended only in those who respond inade-
6 months after the first year. quately to alternative treatments and whose
Felbamate is a wide-spectrum antiepileptic epilepsy is so severe that the risk of aplastic ane-
drug, although its efficacy in generalized seizure mia and/or liver failure is deemed acceptable.” A
types of idiopathic generalized epilepsy has not written informed consent is needed.
been evaluated in class I studies. The official The suggested felbamate therapeutic range is
FDA indications are: “Either monotherapy or 40–100 mg/L.
17 New-Generation Antiepileptic Drugs 227
Gabapentin Lamotrigine
Gabapentin was first approved in the USA in 1994. Lamotrigine was first approved in the USA in
The mechanism of action is binding to the alpha-2 1995, but was licensed in Europe in 1991. Its
delta subunit of voltage-gated calcium channels. mechanism of action is blocking sodium chan-
This binding reduces the influx of calcium and nels. This secondarily results in blocking the
reduces neurotransmitter release under hyperex- release of glutamate. Lamotrigine also inhibits
citable conditions. Despite its name, gabapentin high-voltage activated calcium channels.
does not interact with GABA receptors. Lamotrigine has an excellent oral bioavail-
Gabapentin bioavailability is low, with con- ability of about 98%. The time to maximum
siderable inter-subjective variability. In addition, concentration is 1–1.5 h with the immediate
oral bioavailability decreases with increasing release preparation and 4–11 h with the
gabapentin dose. For example, bioavailability is extended-release preparation. Its protein binding
60% after a single 300 mg dose, but only 29% is only 55%.
for 1600 mg t.i.d. and 36% for 1200 mg p.o. q.i. Lamotrigine is extensively metabolized in the
d. (bioavailability improves with dividing the liver, predominantly by glucuronidation (to lam-
dose) [4]. The reason for the above is that otrigine 2–N-glucuronide), then excreted by the
gabapentin is transported from the gut into the kidney. About 94% is eliminated in the urine,
bloodstream by the L-amino acid transport sys- about 10% as unchanged drug, and 90% as glu-
tem, which is saturable. Gabapentin protein curonide conjugates. The half-life is about 24 h in
binding is minimal at less than 50%. monotherapy, 48–60 h when used with valproate,
Gabapentin is not metabolized in humans. It is and 12 h when used with an enzyme inducer.
eliminated unchanged in the urine as a result Lamotrigine is associated with a mild autoin-
requires dose reduction with renal impairment. duction. It is a weak inhibitor of dihydrofolate
Its half-life is 5–7 h. reductase (not clinically relevant). Lamotrigine
Gabapentin has no known interactions, which slightly increases topiramate level and slightly
is predicted by the absence of metabolism, the decreases valproate level. However, it is mark-
absence of enzyme induction or inhibition, and edly affected by some other drugs. Its clearance is
the absence of protein binding. However, antacids increased in the presence of enzyme-inducing
including aluminum hydroxide or magnesium drugs, estrogen containing oral contraceptives,
hydroxide may reduce gabapentin bioavailability and pregnancy. On the other hand, lamotrigine
if taken within 2 h from gabapentin intake. clearance is markedly decreased by valproate.
Gabapentin adverse effects include sedation, Dose-related adverse effects include dizziness,
dizziness, ataxia, asthenia, and weight gain. It ataxia, blurred vision, diplopia, nausea, and
may cause myoclonus. It may be associated with vomiting. Headache and tremor may also occur.
cognitive slowing in the elderly, and emotional Rash is seen in about 3%, but the risk is higher in
lability or hostility in children. It has been children, with coadministration of valproate, with
assigned pregnancy category C. faster titration, and with higher doses. As a result
Gabapentin is a narrow-spectrum agent of increased risk of rash with faster titration,
against focal seizures. It failed clinical trials lamotrigine has to be titrated very slowly. The rate
against absence and primary generalized tonic– of titration is slower in the presence of valproate.
clonic seizures [5, 6]. It may cause exacerbation Rare serious idiosyncratic adverse effects
of myoclonus [7]. The official FDA indication is include Stevens–Johnson syndrome, toxic epi-
for adjunctive therapy for partial seizures. It is dermal necrolysis, or hypersensitivity syndrome
also approved for the treatment of postherpetic (1 in 4000). It is assigned pregnancy category C.
neuralgia. An extended-release preparation Lamotrigine is a wide-spectrum antiepileptic
(gabapentin enacarbil) has been approved for the drug effective against partial–onset as well as
treatment of restless leg syndrome. generalized tonic–clonic seizures. It is FDA
228 B. Abou-Khalil
indicated as adjunctive therapy or for conversion word-finding difficulty, and cognitive slowing.
to monotherapy for partial seizures, adjunctive There may be depression. Kidney stones occur in
therapy for generalized tonic–clonic seizures, and about 1.5% of individuals. Acute myopia and
adjunctive therapy for Lennox–Gastaut syndrome. secondary angle-closure glaucoma are reported
Efficacy against generalized absence seizures is rarely. Paresthesias in the hands and feet may
less than valproate and ethosuximide. Its efficacy occur as a result of the carbonic anhydrase activ-
against myoclonic seizures is variable, and lam- ity. Oligohydrolysis, hyperthermia, and metabolic
otrigine may exacerbate myoclonic seizures in acidosis are more common in children. Weight
some individuals. The recommended therapeutic loss may occur.
range for lamotrigine is 2–20 mg/L [8]. Topiramate is assigned pregnancy category D
Lamotrigine is also FDA indicated for main- due to increased risk of oral clefts in exposed
tenance treatment of bipolar I disorder to delay a infants [9].
mood episode. Topiramate is a wide-spectrum antiepileptic
drug. However, it is not effective against general-
ized absence seizures as demonstrated in a ran-
Topiramate domized controlled clinical trial [10]. The FDA
indications are for initial monotherapy or adjunc-
Topiramate is a sulfamate-substituted monosac- tive therapy for partial–onset or primary general-
charide. It was approved in the USA in 1996. It has ized tonic–clonic seizures in adults and children
multiple mechanisms of action including blocking 2 years or older, and as adjunctive therapy for adult
of voltage-gated sodium channels, augmentation and pediatric patients with seizures associated with
of GABA activity, antagonism of AMPA/kainate Lennox–Gastaut syndrome. Topiramate is also
receptors, inhibition of high-voltage activated indicated for prophylaxis of migraine. Topiramate
calcium channels, and weak inhibition of carbonic requires a slow titration to improve tolerability.
anhydrase activity.
Topiramate has a good oral bioavailability of
80–95%. Its protein binding is only 15–40%. Tiagabine
Topiramate is not extensively metabolized.
About 70% is eliminated unchanged in the urine. Tiagabine was first approved in the USA in 1997.
Its hepatic metabolism by the p450 enzyme It is a designer drug, the mechanism of which is
system is via hydroxylation, hydrolysis, and inhibition of GABA reuptake at the synapse.
glucuronidation, to form inactive metabolites. Tiagabine has an excellent oral bioavailabil-
There is evidence of renal tubular reabsorption. ity. It is highly protein-bound (96%). It is
The half-life is about 21 h. extensively metabolized in the liver mainly by
Drug interactions are minimal. Topiramate is CYP 3A4. Only 2% is excreted unchanged; 63%
a mild inhibitor of CYP 2C19, so that it may is excreted in the feces and 25% in the urine. The
increase phenytoin levels when used at a higher half-life is 7–9 h in monotherapy and 2–5 h in
dose. It is also a mild inducer of CYP 3A4, so the presence of enzyme inducers. As a result of
that it may reduce the efficacy of the oral con- the short half-life, it requires t.i.d. dosing.
traceptive when used at a dose of 200 mg per day Tiagabine does not affect other medications.
or more. Hyperammonemia may occur when Even though it is highly protein-bound, its serum
topiramate is used in conjunction with valproate. concentration is low and it is unlikely to compete
Enzyme-inducing antiepileptic drugs may reduce for protein binding; in addition, tiagabine dosing
topiramate levels by up to 50%. decisions are not usually based on serum con-
Topiramate adverse effects include sedation, centration. Tiagabine metabolism, however, is
fatigue, dizziness, and ataxia, which are helped by accelerated by enzyme-inducing drugs.
slower titration. Topiramate may cause cognitive The most commonly reported tiagabine
difficulties including memory disturbance, adverse effects were dizziness, asthenia,
17 New-Generation Antiepileptic Drugs 229
nervousness, tremor, depression, and emotional levetiracetam titration [13]. There have been rare
lability. Adverse effects are more common dur- reports of psychosis [14].
ing titration, and slow titration is thus required. Levetiracetam is a wide-spectrum drug. The
Tiagabine may be associated with dose-related official FDA indications are adjunctive therapy
episodes of nonconvulsive status epilepticus or for partial–onset seizures in adults and children
encephalopathy, which may occur even in the 4 years or older; adjunctive therapy for myo-
absence of epilepsy [11, 12]. It has been assigned clonic seizures in adults and adolescents 12 years
pregnancy category C. or older with juvenile myoclonic epilepsy; and
Tiagabine is a narrow-spectrum agent effec- adjunctive therapy for primary generalized tonic–
tive against focal seizures only. It is not effective clonic seizures in adults and children 6 years or
against and may exacerbate generalized absence older with idiopathic generalized epilepsy.
or myoclonic seizures. Its FDA indication is for Levetiracetam is not FDA approved for
adjunctive therapy only. It is used off label in the monotherapy in the USA, but it is approved for
treatment of addiction, to increase proportion of initial monotherapy in Europe. The optimal
deep sleep, and in the management of spasticity therapeutic level is unknown. One study sug-
in multiple sclerosis. gested that 11 mg/L may be a threshold con-
centration for therapeutic response [15]. The
upper limit of the therapeutic range is unknown.
Levetiracetam
irritability, and anorexia. Weight loss may occur. particularly with higher doses. Pregabalin is
Cognitive slowing and difficulty with concen- classified with pregnancy category C.
tration may be seen, particularly at higher doses. Pregabalin is a narrow-spectrum drug against
Kidney stones occur as frequently as 4%. Rarely, partial–onset seizures. The official FDA epilepsy
depression and psychosis may occur. Serious indication is an adjunctive therapy for adult
rash such as Stevens–Johnson syndrome and patients with partial–onset seizures. Pregabalin is
toxic epidermal necrolysis occur rarely. Oligo- also indicated for neuropathic pain associated
hydrolysis, hyperthermia, and metabolic acidosis with diabetic peripheral neuropathy, postherpetic
may occur, more often in children. Zonisamide neuralgia, and fibromyalgia.
was assigned pregnancy category C.
Zonisamide is a wide-spectrum antiepileptic
drug but has undergone class I trials only for Lacosamide
partial–onset seizures. The official FDA indica-
tion is for adjunctive therapy in the treatment of Lacosamide was first approved in the USA in
partial seizures in adults with epilepsy. In Eur- 2008. Its mechanism of action is enhancing slow
ope, it is indicated as initial monotherapy for inactivation of sodium channels. This is to be
partial seizures. In Japan, it is also indicated as distinguished from other antiepileptic drugs that
monotherapy for generalized seizures. The sug- interact with the sodium channel, all of which
gested therapeutic range is 10–14 mg/L. enhance fast inactivation of sodium channels.
Lacosamide is available in oral and intra-
venous formulations. The oral bioavailability is
Pregabalin about 100%. Protein binding is less than 15%.
Lacosamide is metabolized by demethylation
Pregabalin was first approved in USA in 2005. in the liver to inactive O-desmethyl metabolite
Its mechanism of action is similar to gabapentin. via CYP 2C19. Approximately 95% is excreted
It binds to the alpha-2 delta subunit of voltage- in the urine, 40% as unchanged drug, and 30% as
gated calcium channels, reducing the influx of O-desmethyl metabolite. The half-life is
calcium and reducing neurotransmitter release approximately 13 h.
under hyperexcitable conditions. Lacosamide has no known pharmacokinetic
Unlike gabapentin, pregabalin has very good interactions despite the CYP 2C19 metabolism.
oral bioavailability, greater than 90%. The However, it does have pharmacodynamic inter-
bioavailability is also independent of dose. The actions with other antiepileptic drugs that act on
time to maximum concentration is 1 h, but is the sodium channel.
delayed up to 3 h when ingested with food. It has The dose-related adverse effects include
no protein binding. dizziness, headache, nausea, diplopia, and seda-
Pregabalin is not metabolized in humans. It is tion. All these are more likely when lacosamide
excreted unchanged in the urine, thus requiring is used in conjunction with other sodium channel
dose reduction in patients with renal impairment. blockers. It may also cause a small asymptomatic
Pregabalin half-life is about 6 h. increase in the PR interval.
Pregabalin has no known pharmacokinetic Lacosamide is a narrow-spectrum antiepilep-
interactions, which is predicted by the absence of tic drug against partial–onset seizures. The offi-
metabolism, the absence of enzyme induction or cial FDA indication is for adjunctive therapy of
inhibition, and the absence of protein binding. partial–onset seizures in patients 17 years or
Pregabalin can cause increased appetite and older. The parenteral formulation is indicated as
weight gain. There may be peripheral edema. short-term replacement when oral administration
Myoclonus may occur in some individuals, is not feasible in patients taking oral lacosamide.
17 New-Generation Antiepileptic Drugs 231
30% as the glucuronide conjugates, and 10% as frequency of administration in adult patients with
other metabolites. The half-life of eslicarbazepine epilepsy. Epilepsy Res. 1998;31:91–9.
5. Chadwick D, Leiderman DB, Sauermann W, et al.
is 13–20 h in plasma and 20–24 h in CSF, justi- Gabapentin in generalized seizures. Epilepsy Res.
fying once daily dosing used in clinical trials. 1996;25:191–7.
Eslicarbazepine is not subject to autoinduc- 6. Trudeau V, Myers S, LaMoreaux L, et al. Gabapentin
tion. However, it can induce CYP 3A4, thus in naive childhood absence epilepsy: results from two
double-blind, placebo-controlled, multicenter studies.
decreasing plasma concentrations of estrogen and J Child Neurol. 1996;11:470–5.
drugs metabolized by this enzyme. It also has a 7. Perucca E, Gram L, Avanzini G, et al. Antiepileptic
moderate inhibitory effect on CYP 2C19, drugs as a cause of worsening seizures. Epilepsia.
potentially increasing plasma concentration of 1998;39:5–17.
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phenytoin and other drugs metabolized by this lamotrigine serum concentrations with tolerability in
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The most common eslicarbazepine adverse in pregnancy: preliminary experience from the UK
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Dietary Therapies
18
Amy Kao
Ketone bodies can cross the blood–brain barrier carbohydrates. The MCT diet provides 60–70%
and so are used instead of glucose for energy [2]. calories from fat. The downside of the MCT diet
The “classic” KD utilizes long-chain fatty is gastrointestinal side effects including diarrhea,
acids (as opposed to medium-chain fatty acids) vomiting, and abdominal pain [4]. However, a
and is the most widely used dietary treatment. randomized controlled trial comparing the toler-
The composition of the diet is calculated using a ability and efficacy of the MCT diet versus
ratio of the weight of fat (in grams) to the sum of classical KD showed no significant differences in
the weight of protein and carbohydrates. Typical either [5].
ratios are 3:1 or 4:1 (compared to the ratio in a
standard North American diet which is 0.3:1). In a
3:1 ratio, there are 3 grams of fat for every 1 g of Modified Atkins Diet (MAD)
protein plus carbohydrate combined. The amount
of protein is calculated to meet dietary reference The MAD was developed at Johns Hopkins
intake which is 1 g per kilogram body weight, so Hospital, first reported in 2003, and aimed at
a 3:1 ratio is typically used for older children with children with behavioral difficulties, adolescents,
greater body mass. Calories are also measured, and adults [6]. The standard Atkins diet has a
such that they are sufficient to support growth but goal of weight loss and includes an induction
controlled to prevent excessive weight gain. phase in which there is limitation of carbohy-
Roughly 90 % of the calories are obtained from drates to induce ketosis. In the MAD, this initial
fat consumption in the classic KD. phase of carbohydrate restriction is continued,
Historically, caloric restriction, fluid restric- and weight loss is not encouraged unless nutri-
tion, and an initial fasting period of 24–48 h, tionally indicated.
until large ketones are demonstrated, have been The fat to protein plus carbohydrate ratio of
features of the KD, but there is limited evidence the MAD is 0.9:1, providing approximately 60–
that these are necessary. Initial fasting seems to 65% of calories from fat, 30% from protein
shorten the time to the first reported seizure (higher than the KD and “normal” diet), and 10%
reduction, but long-term outcomes are not from carbohydrates (higher than the KD). Based
impacted. A randomized controlled trial com- upon the protocol at Johns Hopkins, in children,
paring fasting versus gradual initiation (gradually initial carbohydrate restriction is to 10 grams per
increasing ratios from 1:1 to 2:1 to 3:1 to 4:1) day for a month, with liberalization to 15 g, then
showed equivalent efficacy at 3 months, with 20–30 g per day. Adults are started at 15 g of
decreased weight loss, decreased episodes of carbohydrates per day and then increased to
hypoglycemia, and decreased treatment neces- 20–30 g per day after a month. This initial
sary for acidosis or dehydration in those children stricter period is based upon data from a ran-
initiated without fasting [3]. domized, prospective cross-over design study
which showed higher incidence of >50% seizure
reduction at 3 months in patients who initially
Medium-Chain Triglyceride consumed 10 grams per day (60%) versus 20 g
(MCT) Diet per day (10%). The glycemic index of carbohy-
drates is not controlled. Fiber is subtracted from
In 1971, Peter Huttenlocher at the University of the total carbohydrate count.
Chicago introduced the MCT Diet. Whereas the Initiation of the MAD is done as an outpatient
classic KD uses standard foods as source of fat, process and no weighing of foods is required,
this utilizes MCT oil as a source of although counting carbohydrates is required.
medium-chain fatty acids, which is more easily Low-carbohydrate multivitamin and calcium
absorbed and delivered directly to the liver; supplementation is prescribed. Medications may
thereby, more efficiently generating ketones and be changed to lowest carbohydrate formulations.
allowing greater consumption of protein and Urine ketones are checked twice per week and
18 Dietary Therapies 237
may be elevated to the “large” level, but some- breadth of issues regarding the KD including the
times are lower than those generated by the KD. practical details of management.
Monitoring includes phone follow-up in a month This consensus statement states that the “KD
and clinic follow-up at 3 and 6 months, with should be strongly considered in a child who has
complete blood count (CBC), complete meta- failed 2–3 anticonvulsant therapies, regardless of
bolic panel (CMP), fasting lipid profile at base- age or gender, and particularly in those with
line, 3 and 6 months [7]. symptomatic generalized epilepsies.” In addition,
the committee members reviewed publications
on efficacy in particular conditions. For the KD
Low-Glycemic-Index Treatment to be considered as having probable benefit in
(LGIT) that condition, the existence of at least 2 publi-
cations was required; those included myoclonic
This is the least restrictive dietary therapy pre- astatic epilepsy, Dravet syndrome, tuberous
sently used in epilepsy management and, thus, sclerosis, Rett syndrome, and infantile spasms.
may be seen as more palatable and better toler- Formula feeding through gastrostomy tube or
ated than the other diets. It is also initiated in the bottle would also be a favorable factor, as it
outpatient setting, without weighing of foods. It would simplify food preparation and minimize
was first reported in 2005 at Massachusetts chances of intolerance.
General Hospital, based upon the theory that one Also, based upon specific metabolic abnor-
mechanism of the KD could be stabilization of malities, there are 2 conditions in which the KD
blood sugar levels. This arose from observations could be considered treatment of choice, to be
that seizure control of children on the KD can be used before 2 or 3 antiseizure medications have
very sensitive to intake of extra carbohydrates, failed. Those would be glucose transporter defi-
and that blood glucose levels are extremely ciency syndrome, in which glucose transport
stable in children on the KD. The LGIT allows across the blood–brain barrier is impaired, and
higher carbohydrate intake than the other 2 diets pyruvate dehydrogenase deficiency in which
but limits the type of carbohydrates to those that pyruvate cannot be metabolized into acetyl-coA.
are low in glycemic index, foods that result in Other conditions in which the KD may pos-
lower postprandial blood sugar and insulin pro- sibly be beneficial (based upon single case report
files. Larger particle size, less gelatinization of a or case series) include such conditions as Landau
starch, presence of fat, higher acidity, and Kleffner syndrome, Lafora body disease, suba-
increased fiber content lead to lower glycemic cute sclerosing panencephalitis, mitochondrial
indices. The type of starch is also a factor. respiratory chain complex disorders, phospho-
In LGIT, fat contributes 60% of calories, protein fructokinase deficiency, febrile infection-related
20–30%, and carbohydrates are limited to 40– epilepsy syndrome (FIRES)/status epilepticus,
60 g per day. All carbohydrates are foods with Lennox-Gastaut syndrome, hypoxic-ischemic
glycemic index less than 50 [8]. encephalopathy, and focal malformations of
cortical development.
Contraindications are essentially disorders
Patient Selection that involve fatty acid metabolism defects due to
various enzyme deficiencies. Long-chain fatty
In December 2006, the Charlie Foundation acids are shuttled across the outer and inner
commissioned a panel of 26 pediatric epileptol- mitochondrial membranes by carnitine, facili-
ogists and dietitians from 9 countries with tated by first carnitine palmitoyltransferase I,
expertise in the KD, to create a consensus then carnitine translocase, then CPT2, after
statement on the clinical management of the KD. which beta oxidation occurs within the mito-
It was endorsed by the Child Neurology Society chondrion, generating acetyl-coA, which then
and serves as an excellent reference for a wide enters the Krebs cycle or forms ketones. Pyruvate
238 A. Kao
carboxylase converts pyruvate to oxaloacetate, so model studies, has investigated this. Proposed
deficiency impairs Krebs cycle function. Thus, mechanisms have included numerous processes,
contraindications include primary carnitine defi- such as direct anticonvulsant effect of ketones/
ciency, carnitine palmitoyltransferase I or II free fatty acids, antioxidant/anti-inflammatory
deficiency, carnitine translocase deficiency, effects by decreasing reactive oxygen species,
Beta-oxidation defects (medium-chain acyl action on mitochondrial uncoupling proteins,
dehydrogenase deficiency or MCAD, long-chain increase of mitochondrial biogenesis, decrease of
acyl dehydrogenase deficiency or LCAD, glutamate, and increase of GABA.
short-chain acyl dehydrogenase deficiency or
SCAD), and pyruvate carboxylase deficiency.
The lack of carbohydrates in the KD can also Duration
exacerbate acute intermittent porphyria. Relative
contraindications include “failure to thrive,” an When the KD is the effective, evidence of benefit
identifiable surgical focus, and predictors of occurs fairly quickly. The range of time until
noncompliance such as lack of supervision, benefit is 1–65 days and is typically within the
access to or tendency toward forbidden foods, first 2 weeks after initiation. Similarly, in a
and lack of parental readiness and commitment prospective study in adults on the MAD, median
[9]. time to improvement was 2 weeks (range 1–8
Typically, an outpatient clinic visit is where weeks) [10]. Based on these data, continued KD
screening and patient selection takes place. administration for 3 months is encouraged before
Nutritional history is obtained, complicating deciding if the KD should be resumed or
medical factors and other potential barriers to discontinued.
success are identified, education regarding the If seizure freedom is obtained on the KD,
particular diet is given, and expectations and weaning and discontinuation of the KD is con-
goals are discussed. Laboratory testing is per- sidered after 2 years, similar to the approach with
formed to screen for metabolic contraindications; antiseizure medications. If seizure freedom is not
these may include complete blood count, elec- obtained, but improved seizure control occurs,
trolytes, magnesium, phosphorous, zinc, sele- the balance between benefit and long-term risks
nium, liver and kidney function tests, fasting needs to be considered when discussing duration
lipid profile, urinalysis, urine calcium/creatinine, of the KD.
urine organic acids, serum amino acids, and
acylcarnitine profile.
The concomitant use of carbonic anhydrase Complications
inhibitors is not a contraindication. Topiramate
and zonisamide may increase the likelihood of Short-term complications of the KD may include
profound acidosis and associated lethargy and vomiting, dehydration, hypoglycemia, and
vomiting during the period of initiation of the excessive acidosis. Therefore, patients are typi-
KD. However, they do not need to be discon- cally hospitalized for initiation of the KD. Con-
tinued before initiation of the KD. Daily enteral stipation is a frequent side effect, which is treated
citrate may be administered to counteract this by increasing hydration, giving conducive foods
acidosis. such as avocado, or using bulk-forming laxatives.
Monitoring for long-term side effects of the
KD must take place on a standard basis, at least
Mechanisms every 3 months. This includes measurements and
laboratory testing for weight and height, hyper-
The exact mechanisms by which dietary thera- lipidemia (fasting lipid profile), nutritional and
pies treat seizures have not been precisely electrolyte deficiencies (electrolytes with bicar-
delineated. Much research, including animal bonate, calcium, magnesium, phosphorous,
18 Dietary Therapies 239
complete blood count with platelets, free and 90% seizure reduction and 28% with >90% sei-
total carnitine, zinc selenium, liver function tests, zure reduction. In an adult study, efficacy was
vitamin D), and kidney stones (urinalysis, urine quick if present (median 2 weeks), with 47%
calcium and creatinine). Also, as urine ketone experiencing >50% seizure reduction by
testing is less accurate than serum testing, serum 3 months and 33% by 6 months [7(p39)].
beta-hydroxybutyrate levels may be drawn to
correlate with home urine results. Bone mineral
density scan, to assess for osteopenia/ Low-Glycemic-Index Treatment
osteoporosis, may be considered, particularly in
patients who are high risk (immobile, multiple Review of 60 patients has shown 38% of patients
antiseizure medications, history of fractures) and with a >50% decrease in seizures at 1 month,
on the KD longer than 2 years. with 24% having >90% seizure decrease. Of the
Evidence of longer-term adverse events with patients who continued on LGIT through
the MAD is limited. In theory, risk of growth 6 months, 60% had a >50% seizure decrease,
limitation, kidney stones, dyslipidemia, and and 38% had a >90% decrease in seizures [8
gastroesophageal reflux would be less common (p43)].
than with the KD. Approximately, 25–50 mg/dl
increases in total cholesterol have been noted.
Blood urea nitrogen also has been shown to Future Directions
increase, likely related to increased protein intake
[7(p39)]. The use of the KD is being investigated in sev-
eral neurologic conditions beyond epilepsy, and
in traumatic brain injury, Alzheimer’s disease,
Outcomes amyotrophic lateral sclerosis, autism, glial
tumors, diabetic nephropathy, and Parkinson’s
A Cochrane Review in 2012 yielded 4 random- disease. In addition, in development is 2-deoxy-
ized controlled trials (versus no randomized (D)-glucose (2-DG), an agent which is a non-
controlled trials in a similar review in 2003). metabolizable glucose analog that inhibits
These trials were heterogeneous, namely one glycolysis.
compared 3:1 and 4:1 ratios of the KD, one
compared MCT and classical KD, one KD versus
no diet, one fasting versus gradual initiation, and Further Reading
one MAD with 10 versus 20 grams of carbohy-
drates. However, taken together, all showed that Lee PR, Kossoff EH. Dietary treatments for epilepsy:
at least 38% of patients had a 50% decrease in Management guidelines for the general practitioner.
seizures at 3 months, with the benefit maintained Epilepsy and Behavior 2011; 21:115–121.
Nangia S, Caraballo RH, Kang HC, Nordli DR, Schef-
at 1 year. fer IE. Is the ketogenic diet effective in specific
epilepsy syndromes? Epilepsy Research 2012;
100:252–257.
Modified Atkins Diet Levy RG, Cooper PN, Giri P, Pulman J. Ketogenic diet
and other dietary treatments for epilepsy. Cochrane
Database of Systematic Reviews 2012, Issue 3. Art
Efficacy of the MAD may be comparable to the No:CD001903.
KD in children and adults. In two studies
including children, 43–65% had at least >50%
reduction of seizures at 6 months, with 35–36% References
having >90% seizure reduction [7(p38)].
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4. Zupec-Kania BA, Spellman E. An overview of the Optimal clinical management of children receiving
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2008;23:589–96. tional Ketogenic Diet Study Group. Epilepsia.
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ized trial of classical and medium-chain triglyceride 10. Kossoff EH, Rowley H, Sinha SR, Vining EPG.
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epilepsy. Epilepsia. 2009;50(5):1109–17. intractable epilepsy in adults. Epilepsia. 2008;49
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Other Pharmacological Therapies:
Investigational Antiepileptic Drugs, 19
Animal Models of Epilepsy,
Hormonal Therapy, Immunotherapy
Bassel Abou-Khalil
cannabis, is undergoing early trials in epilepsy initially produced only subclinical after dis-
after a media campaign based on anecdotal charges eventually result in full-fledged gener-
reports of efficacy in various epilepsy syndromes, alized tonic-clonic seizures [10]. Though
including Dravet syndrome [8]. Intravenous laborious, this model has been increasingly used
allopregnanolone, a neurosteroid that modulates in the preclinical testing of candidate drugs.
synaptic and extrasynaptic GABAA receptors, is However, this model has also been criticized for
undergoing testing in super-refractory status the absence of spontaneous seizures that are
epilepticus, where there is a decreased synaptic typical of human epilepsy.
expression of benzodiazepine-sensitive GABAA True animal models of epilepsy should have
receptors [31]. spontaneously recurrent seizures. Such models
may have genetic or acquired epilepsy. Com-
monly used genetic models are DBA/2 mice with
Animal Models of Epilepsy audiogenic seizures and the genetic absence
epilepsy rats from Strasbourg (GAERS) [22, 23].
The development of AEDs has depended con- Efficacy in DBA/2 mice with audiogenic seizures
siderably on animal models of epilepsy helps predict efficacy against human generalized
(Table 19.1). Perhaps, the most important appli- tonic-clonic seizures, while efficacy on GAERS
cation was historically screening of compounds helps predict efficacy against human generalized
for anti-seizure activity. The two main animal absence seizures. Animal models of acquired
models used in the screening of antiepileptic chronic epilepsy include post-status epilepticus
drug candidates were the maximal electroshock models, in which chemically or electrically
(MES) model and the subcutaneous pentyl- induced status epilepticus is followed by spon-
enetetrazole (PTZ) model [21]. In the MES taneously recurring seizures.
model, electrical stimulation is applied, usually Because newly introduced AEDs have had
through the cornea, with an intensity sufficient to limited impact on the proportion of patients with
elicit tonic hind limb extension in all control drug-resistant epilepsy, it is now recognized that
animals [4]. The electrical stimulus is 50–60 Hz there is a need for animal models of epilepsy that
in frequency, 0.6 ms in pulse width, and 0.2 s in are drug-resistant [21]. One such model is the
stimulus train duration. The usual intensity nee- 6-Hz psychomotor seizure model in mice. In this
ded is 50 mA for mice and 150 mA for rats. In model, 6-Hz pulses of 0.2-ms duration are
the PTZ model, PTZ is injected subcutaneously delivered through the cornea for 3 s, resulting in
at a dose known to induce at least 5 s of clonic a seizure that resembles limbic seizures in
seizure activity in 97% of the animals. The MES humans. At an intensity of 44 mA (twice that
model has been said to be predictive of efficacy necessary to produce seizures in 97% of mice),
against generalized tonic-clonic seizures, many AEDs become ineffective [21]. The
whereas the PTZ model has been thought to be methylazoxymethanol acetate (MAM) rat model
predictive of efficacy against absence seizures. of cortical dysplasia can also serve as a model of
However, these models may miss some effective pharmacoresistant epilepsy. In this model, MAM
AEDs, most notably levetiracetam. In addition, in utero exposure to results in a cortical
these models have been criticized for being dysplasia-like lesion, and seizures induced in
models of seizures in healthy animals, rather than these rats by kainate are resistant to several
models of epilepsy. AEDs. Pharmacoresistant epilepsy can also be
One animal model that is predictive of effi- produced by exposure to low doses of lamotrig-
cacy against partial (focal) seizures is the kin- ine during kindling or by selection of subgroups
dling model. In this model, repeated electrical of rats that are resistant to specific AEDs from a
stimuli are applied to the amygdala or hip- large group of epileptic rats.
pocampus of rats, resulting in permanent lower- All the currently marketed AEDs are used as
ing of the seizure threshold, so that stimuli that symptomatic treatment to suppress seizures.
19 Other Pharmacological Therapies: Investigational … 243
Table 19.1 Select animal models of seizures/epilepsy and the proposed corresponding human seizure/epilepsy type
that is modeled
Animal model MES PTZ Kindling DBA/2 mice GAERS rats
Human Generalized Generalized Partial Generalized Generalized
seizure/epilepsy tonic-clonic absence seizures tonic-clonic, reflex absence
type seizures seizures (limbic) seizures, SUDEP seizures
Animal model 6-Hz psychomotor seizure MAM seizure model Post-status epilepticus
model in mice model in rats
Human Pharmacoresistant limbic Pharmacoresistant seizures, Chronic focal epilepsy
seizure/epilepsy seizures cortical dysplasia
type
There is no clear evidence that any current AED cycle [14]. Synthetic progestins and clomiphene
is effective in the prevention of epilepsy. There is citrate have also been reported beneficial as
increasing interest in the identification of disease treatments for catamenial epilepsy in small
modifying treatments that could prevent the studies.
development of epilepsy after an insult or pre- Ganaxolone is a derivative of allopreg-
vent the progression of epileptogenesis. Chronic nanolone that lacks hormonal activity. It has been
animal models of epilepsy can be used to study tested in a number of clinical trials. There was a
potential anti-epileptogenic treatments. The most suggestion that women with catamenial epilepsy
commonly used models in this setting are the were a subgroup that benefited in particular [30].
kindling model and the post-status epilepticus Ganaxolone was also tested in infantile spasms
model [21]. and found helpful in some patients [19]. It is not
known if this compound will eventually be
available for clinical use.
Hormonal and Immunological ACTH and steroids are first-line short-term
Treatment treatments for infantile spasms/West syndrome.
They help control seizures and improve behavior
Hormonal therapy may be considered in women and EEG. They are most effective in the idio-
with catamenial epilepsy, in whom seizures seem pathic syndrome. A high dose seems to be more
to follow a cyclical pattern related to the men- effective. When it comes to ACTH, one approach
strual cycle [13, 15]. Three patterns of catamenial is to begin with 40 IU per day for 1–2 weeks and
epilepsy have been described: C1 pattern where increase to 60 or 80 IU per day thereafter if the
seizures increase in frequency just before and response is incomplete. If it is effective, it is then
during menses, C2 pattern where seizures tapered over 1–4 months. ACTH and steroids are
increase around the time of ovulation, and C3 less commonly used to treat Lennox–Gastaut
pattern where seizures occur with anovulatory syndrome and Landau–Kleffner syndrome.
cycles. Catamenial epilepsy is thought to be Steroids and IVIG may be considered in the
related to progesterone and estrogen fluctuations. treatment of Rasmussen’s syndrome and other
Estrogen appears to be proconvulsant, and pro- epilepsies suspected to be of immune origin, to
gesterone appears to be anticonvulsant. In cata- treat the underlying cause of epilepsy. Limbic
menial epilepsy, seizures are more likely to occur encephalitis, usually autoimmune, is increasingly
when the ratio of progesterone to estrogen recognized as a cause of chronic epilepsy. An
decreases, as seen around the time of menstrua- immune basis of epilepsy should be considered
tion and the time of ovulation. The C1 pattern of when there is no other clear etiology, the onset
catamenial epilepsy responds to progesterone was acute or subacute, and there is a prior history
200 mg tid administered on days 14–28 of the of autoimmunity (or autoimmunity is present in a
244 B. Abou-Khalil
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tration in epilepsy patients: effects of race and sex. feasibility and pharmacokinetics by seizure type and
Clin Pharmacol Ther. 2012;91:483–8. status, and tolerability of intranasal diazepam in
25. McKnight K, Jiang Y, Hart Y, et al. Serum adults with epilepsy. Epilepsy Currents. 2014;14
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Epilepsy Management in Special
Populations 20
Amir M. Arain
that can be readily diagnosed. Moreover, the favorable pharmacokinetic profiles. Medications
extratemporal lobe seizures with subtle features must be initiated at a low dose and slowly titrated
and prominent postictal confusion are more up. Older AEDs with enzyme-inducing proper-
common in elderly. Misdiagnosis may also result ties should be avoided, and newer generation
from difficulties in history taking, comorbidities, AEDs with significant cognitive adverse events,
polypharmacy, and the fact that the EEG is less including topiramate and zonisamide, should also
helpful for diagnosis than in younger individuals. be avoided [25]. Valproate may be a good choice
Epilepsy in elderly can be delayed because of in elderly, but one has to keep in mind the
these factors. Physicians treating elderly patients potential side effects of parkinsonism (which is
should have epilepsy in their differential usually reversible) and dementia [26]. Lamot-
diagnosis. rigine, gabapentin, and levetiracetam are appro-
Once the diagnosis of epilepsy is established, priate medications to be started as monotherapy
then the treatment should be started as the risk of in elderly patients with epilepsy [27, 28]. Sei-
recurrence after the first unprovoked seizure is zures in the elderly can often be well controlled
*80% [22]. Clinicians should have a low with monotherapy. In patients with refractory
threshold in starting AEDs. Physiological chan- epilepsy, epilepsy surgery must be considered.
ges of aging may affect AED pharmacokinetics.
These include decreased albumin, decreased liver
metabolism, and decreased glomerular filtration Women with Epilepsy
and excretion. These changes result in longer
half-lives of the medication and greater risks of Women with epilepsy have some unique char-
drug–drug interactions [23]. Several AEDs acteristics that can significantly affect the course
including carbamazepine, phenytoin, and val- and management of epilepsy. Epilepsy and
proate are highly protein bound and will compete female hormones reciprocally influence one
with other medications, including digoxin, for another. Similarly, AEDs and female hormones
adherence to serum proteins resulting in toxicity. also influence one another. Such interactions can
Changes in protein binding result in misleading affect seizure control and medication adverse
measurements of total AED concentration. events. The specific issues in women with epi-
Checking free levels of phenytoin and valproate lepsy warrant special attention to their menstrual
is recommended to the elderly. Elderly patients cycle regularity, fertility and ovulatory function,
are more sensitive to side effects of AEDs, sexuality, hormonal contraception, pregnancy
including peak toxicity. Thus, extended release and breast-feeding, and bone health. Unfortu-
formulations can be helpful as they result in nately, the awareness to these issues is not
lower peaks. prevalent among healthcare providers [29].
Older generation AEDs have higher incidence Estrogen and progesterone have different
of drug–drug interactions with other medications. effects on epilepsy. Estrogen may be procon-
Many AEDs induce liver enzymes, thus lowering vulsant as it may reduce inhibition at the GABAA
the levels of other medications. Administration receptor and also inhibits the synthesis of
of carbamazepine, for example, can lower sim- GABA. On the other hand, progesterone may be
vastatin level [24]. Newer AEDs have relatively anticonvulsant as it enhances inhibition at the
better pharmacokinetics profile with less poten- GABAA receptor and increases the GABA syn-
tial for drug–drug interactions. Grapefruit juice thesis [30]. Progesterone also may attenuate the
can increase the level of many medications, action of the brain’s major excitatory neuro-
including carbamazepine, resulting in dizziness, transmitter, glutamate, in the hippocampus. Thus,
lack of coordination, sedation, and other side the hormonal fluctuations of the menstrual cycle
effects. may result in fluctuation in seizure frequency.
It is recommended that newer AEDs be started This pattern is seen in catamenial epilepsy, which
in elderly patients with epilepsy because of their is present in approximately half of all women
250 A.M. Arain
with epilepsy. In these patients, exacerbations of of cognitive teratogenicity with valproic acid. In a
seizure frequency occur at certain points in the study that assessed cognition in 3- and 6-year-old
menstrual cycle, either before the start of their children who were exposed in utero to AEDs,
menstruation, during menses, or around the time those who were exposed to valproate had signif-
of ovulation possibly because of higher icantly lower IQ scores than those exposed to
estrogen-to-progesterone ratios [31]. other medications [36, 37]. Thus, valproate must
Some AEDs may affect the female hormones be avoided in monotherapy or polytherapy during
and contraception. Enzyme-inducing AEDs, such the first trimester of pregnancy. However, other
as phenytoin, carbamazepine, phenobarbital, authors suggest that if it is imperative to use
primidone (and at higher doses, oxcarbazepine valproate during pregnancy, then a low dose of
>900 mg/day and topiramate >200/day), can the extended release formulation should be used,
reduce the levels of contraceptives [32, 33]. In starting with 500 mg per day and not exceeding
such situations, alternative or supplementary 1000 mg per day [38]. It is recommended to use
contraceptive methods should be used. On the AEDs in monotherapy rather than polytherapy as
other hand, estrogen decreases lamotrigine level the risk of major congenital malformations is
by about 50%. Dosage adjustments of lamotrig- increased by polytherapy. Based on the data, the
ine may be necessary to maintain appropriate probable safest medications are lamotrigine,
response when starting or stopping estrogen— levetiracetam, oxcarbazepine, zonisamide, gaba-
containing oral contraceptives in these women. pentin followed by carbamazepine and phenytoin
Fertility issues are common in women with [39]. Folic acid supplementation is recommended
epilepsy. In epidemiologic studies, women with to women with epilepsy prior to pregnancy. There
epilepsy are approximately two-thirds less likely is still controversy on the optimal dose of folic
to have children than women without epilepsy. acid. For healthy women, a dose of 0.4 mg/day is
Factors that may contribute to the lower fertility optimal, while for high-risk patients, especially
rates in women with epilepsy include decreased ones with the previous history of major congenital
libido, reduced marriage rates, increased anovu- malformations, a dose of 4–5 mg/day is recom-
latory menstrual cycles, menstrual disorders such mended [40]. Prenatal testing, at 14–20 weeks of
as amenorrhea or oligomenorrhea, and increased gestation, should be considered in pregnant
early miscarriages. AEDs, specifically women with epilepsy. Since then by seizure
enzyme-inducing ones, may also have an effect medication levels drop during pregnancy, check-
on fetal survival. Moreover, women with epi- ing the levels on a monthly basis is recommended.
lepsy are more likely to have polycystic- Breast-feeding risks and benefits should be
ovary-syndrome-like ovulatory dysfunction with assessed for every individual patient. AED
clinical evidence of hyperandrogenemia, a risk excretion into breast milk is adversely propor-
that is increased by valproic acid treatment [34]. tional to the degree of protein binding, with
Pregnancy can affect seizures, and although it higher protein binding resulting in less excretion
is a high progesterone state, some women may into breast. Phenobarbital and other AEDs may
have worsening of seizures during pregnancy. cause sedation or poor feeding. The American
This worsening could be an effect of pregnancy Academy of Neurology encourages breast-
itself or because of decreasing AED levels as the feeding in conjunction with close observation
pregnancy progresses. The risk of congenital for any excessive sedation or irritability [41].
malformations may be increased by epilepsy. Bone health is another important aspect of epi-
Teratogenicity can be worsened by AEDs, and the lepsy in women. AEDs, especially enzyme-
rates of major congenital malformations (ranging inducing ones, can worsen bone health and pre-
from 4.6% with carbamazepine to 10.7% with dispose to fractures [42]. Valproate, although not an
valproate monotherapy) are 2–3 times higher than enzyme inducer, can cause osteopenia [43–45].
in untreated women with epilepsy (*3%) [35]. Among newer generation AEDs, oxcarbazepine
Besides anatomical teratogenicity, there is a risk and topiramate at high doses can adversely affect
20 Epilepsy Management in Special Populations 251
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absorptiometry scan can be used to diagnose epilepsy in Rochester, Minnesota: 1940–1980.
Epilepsia. 1991;32:429–45.
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women with epilepsy at risk. Women at risk should rural Iceland: a population-based study. Epilepsia.
be counseled to take vitamin D and calcium sup- 1999;40:1529–34.
plementation. If female patients are on AEDs that 13. Hauser WA. Seizure disorders: the changes with age.
Epilepsia. 1992;33(Suppl 4):S6–14.
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primary care providers for possible institution of multicenter study. Arch Neurol. 2000;57:1617–22.
15. Kilpatrick CJ, Davis SM, Hopper JL, Rossiter SC.
bisphosphonates or calcitonin. Early seizures after acute stroke. Risk of late seizures.
Arch Neurol. 1992;49:509–11.
16. Hauser WA, Morris ML, Heston LL, Anderson VE.
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Multiple Choice Questions for Part IV
1. Which of the following antiepileptic drugs C. The audiogenic seizure model in mice
would be the best initial choice in an adoles- predicts efficacy against focal seizures
cent girl with juvenile myoclonic epilepsy? D. Levetiracetam was effective in both MES
and PTZ models
A. Carbamazepine
E. The 6 Hz model is predictive of efficacy
B. Pregabalin
against absence seizures
C. Lacosamide
D. Valproic acid
4. The cooperative VA studies showed:
E. Levetiracetam
A. Carbamazepine and phenytoin were
2. A 26-year-old female had frequent episodes
overall more efficacious than phenobar-
of focal left hand shaking followed by gen-
bital and primidone
eralized tonic–clonic seizure activity. On
B. Phenobarbital and primidone were less
two occasions, she broke her jaw and her
well tolerated than carbamazepine and
right shoulder. Routine EEG is normal, and
phenytoin
brain imaging is unremarkable. Which
C. Phenobarbital was more efficacious than
would be most appropriate antiepileptic drug
primidone
for this patient?
D. Primidone was better tolerated than
A. Oxcarbazepine phenobarbital
B. Lamotrigine E. Primidone was more efficacious than
C. Topiramate phenobarbital
D. Phenobarbital
E. Valproate 5. Which of the following is not a 1,4
benzodiazepine?
3. Which is true about animal models of
epilepsy? A. Diazepam
B. Clonazepam
A. The PTZ model helps predict efficacy C. Lorazepam
against absence seizures D. Clobazam
B. The kindling model typically has spon- E. Clorazepate
taneously recurring seizures
254 Multiple Choice Questions for Part IV
6. Which of the following benzodiazepines has 11. Urinary retention is most likely to occur with
important active metabolites?
A. Perampanel
A. Clonazepam B. Levetiracetam
B. Clobazam C. Ezogabine
C. Diazepam D. Felbamate
D. B and C E. Pregabalin
E. All the above
12. Which is not likely to happen with the
7. Dupuytren’s contractures and plantar fibro- addition of felbamate?
matosis are chronic adverse effects of
A. Increased phenobarbital level
A. Tiagabine B. Increased phenytoin level
B. Phenobarbital C. Increased carbamazepine level
C. Vigabatrin D. Increased valproate level
D. Clobazam E. Toxicity related to carbamazepine epoxide
E. Clorazepate
13. A 4-month-old infant is diagnosed with
8. Simvastatin efficacy is reduced with: infantile spasms. He did not respond to
2-week course of ACTH at 150 units/m2.
A. Lamotrigine Which of the following antiepileptic medi-
B. Carbamazepine cations would you use next?
C. Levetiracetam
D. Pregabalin A. Vigabatrin
E. Ezogabine B. Levetiracetam
C. Topiramate
9. An adolescent boy with epilepsy presents D. Clobazam
with overheating and fever following exer- E. Tiagabine
cise. The likely cause is as follows:
14. Irritability is most common with the fol-
A. Levetiracetam lowing AEDs:
B. Lamotrigine
C. Zonisamide A. Lamotrigine and oxcarbazepine
D. Valproate B. Perampanel and levetiracetam
E. Phenobarbital C. Felbamate and zonisamide
D. Phenobarbital and primidone
10. The following antiepileptic drug is FDA E. Valproate and ethosuximide
approved for once-daily dosing:
15. Insomnia is most likely with which of the
A. Perampanel following?
B. Zonisamide
C. Ethosuximide A. Gabapentin
D. Clobazam B. Pregabalin
E. Topiramate C. Ezogabine
D. Perampanel
Multiple Choice Questions for Part IV 255
36. Which of the following is unlikely to exac- 41. Screening for potential psychosocial barriers
erbate absence seizures? to the safety and success of the ketogenic
diet should take place before initiation of
A. Carbamazepine therapy. Which of the following features
B. Oxcarbazepine makes the ketogenic diet a better/easier
C. Valproate treatment option?
D. Tiagabine
E. Vigabatrin A. Presence of a gastrostomy tube
B. Severe failure to thrive/inability to
37. Which of the following antiepileptic drug is maintain adequate nutrition
not known to modulate GABA? C. Potential surgically resectable seizure
focus
A. Phenobarbital D. Multiple siblings in an unstructured
B. Tiagabine home environment
C. Clonazepam E. Available premanufactured formulas
D. Pregabalin
E. Topiramate 42. Prolonged episodes of altered responsive-
ness are most likely with:
38. For which of the following conditions is the
ketogenic diet indicated? A. Tiagabine
B. Perampanel
A. Primary carnitine deficiency C. Vigabatrin
B. Pyruvate carboxylase deficiency D. Clobazam
C. Pyruvate dehydrogenase deficiency E. Pregabalin
D. Porphyria
E. None of the above
258 Multiple Choice Questions for Part IV
43. Screening for disorders of fatty acid meta- D. Deficiency of calcium and vitamin D,
bolism should be performed prior to initia- leading to bone mineralization loss
tion of the ketogenic diet. Specifically, this E. Encephalopathy due to hypoglycemia,
testing could include which of the dehydration, and excessive acidosis
following?
46. Epilepsy is most commonly associated with:
A. Complete blood count and complete
metabolic panel including liver function A. Dementia
tests and BUN and creatinine B. Stroke
B. Acylcarnitine profile, urine organic acids, C. Birth defect
and carnitine D. Bipolar disorder
C. CSF glucose, lactate, folate metabolites, E. Psychosis
amino acids, and neurotransmitters
D. Kidney ultrasound and nephrology 47. There is a need for more research and data
consult regarding the incidence and prevention of
long-term complications in patients who
44. A 23-year-old man with idiopathic general- have been on the ketogenic diet for long
ized epilepsy was initially maintained on durations, for instance greater than 5 years.
lamotrigine. Valproate was added as adjunct Which of the following tests would be rea-
therapy. Which of the following effects sonable to perform in such a patient, who is
may result from interaction between these otherwise asymptomatic?
drugs?
A. Blood draw for amylase, lipase
A. Lamotrigine toxicity because of glu- B. Renal ultrasound looking for renal stone
curonidation inhibition C. Abdominal X-ray for stool
B. Decreased lamotrigine efficacy due to D. Blood draw for 25-hydroxy-vitamin D
inhibition of cytochrome 2C9 and 2C19 and consideration of bone density scan
C. Decreased valproate efficacy due to E. CRP
induction of CYP2C9
D. Increased risk of liver disease 48. The literature supports the probable benefit
E. Valproate toxicity due to inhibition of its of the ketogenic diet in which of the fol-
b-oxidation lowing conditions?
45. With rare exceptions, the ketogenic diet is A. Benign myoclonus of infancy
initiated during an inpatient hospitalization. B. Juvenile myoclonic epilepsy
Complications during the initiation period C. Glucose transporter protein 1 deficiency
could include all of the below, except: D. Pyruvate carboxylase deficiency
A. Vomiting due to hypoglycemia, dehy- 49. A 36-year-old male from Nepal is evaluated
dration, excessive acidosis, constipation, for a generalized tonic seizure. Few weeks
or exacerbation of gastroesophageal ago, he started taking rifampin and isoniazid
reflux for a positive tuberculin test. His neurolog-
B. Precipitation of deterioration in a patient ical examination, EEG, and brain MRI are
with an undiagnosed disorder of fat all normal. What is the likely mechanism
metabolism responsible for his seizure?
C. Excessive metabolic acidosis in a patient
also treated with a carbonic anhydrase A. Reversible inhibition of GABA reuptake
inhibitor B. Impaired pyridoxine synthesis
Multiple Choice Questions for Part IV 259
76. Which is not true about vigabatrin’s visual 81. Which antiepileptic drug blocks T-type cal-
defect? cium channel:
International Ketogenic Diet Study Group’s epilepsy syndromes showed that only
recommendation? 20% had a greater than 75% decrease in
seizures
A. The ketogenic diet should be considered D. There are currently no randomized con-
in a patient whose epilepsy is controlled trolled trials published on the efficacy of
by a single medication, but whose family dietary therapies in epilepsy treatment
prefers “natural” therapies
B. The ketogenic diet should be considered 88. Which antiepileptic drug should be avoided
only as a last resort, since it is hard to in a patient with known sulfa drug allergy?
administer, is unpalatable, and there is no
data from randomized controlled trials to A. Pregabalin
support it B. Zonisamide
C. The ketogenic diet should be considered C. Carbamazepine
in a child who has failed 2–3 anticon- D. Vigabatrin
vulsant therapies, as long as he/she is E. Lamotrigine
older than 1 year and younger than
12 years of age 89. The following statement is false:
D. The ketogenic diet should be considered
in a child who has failed 2–3 anticon- A. A common ratio of the ketogenic diet is
vulsant therapies, regardless of age or 4 g of fat to 1 g of protein plus carbo-
gender hydrate (4:1)
B. In a 4:1 ratio ketogenic diet, approxi-
86. Brivaracetam has the following mechanism mately 90% of energy comes from fat
of action: C. A fasting period during initiation of the
ketogenic diet is necessary to achieve
A. Potassium channel opening ketosis
B. Blocking of sodium channels D. The modified Atkins diet is approxi-
C. Binding to the synaptic vesicle protein mately a 1:1 ratio
D. Binding to the GABAA receptor E. In the low glycemic index treatment,
E. Binding to the synaptic vesicle protein foods are chosen which produce
and blocking of sodium channels slower/steadier changes in blood glucose
87. There has been growing interest and confi- 90. A 72-year-old man is seen in clinic for a new
dence in the use of the ketogenic diet and diagnosis of epilepsy, with recurrent partial
subsequently a growing body of literature. seizures secondary to a right MCA ischemic
Which of the following statements is true? infarct. His medical history includes chronic
afib (for which he takes warfarin), osteo-
A. Four randomized controlled trials porosis, and a history of kidney stones.
showed that at least 38% of patients had Which of the following is the most appro-
a 50% reduction in seizures compared to priate antiepileptic medication for this
controls at 3 months, with this response patient?
maintained for up to a year
B. A meta-analysis has shown that a third of A. Carbamazepine
all patients on the ketogenic diet may B. Levetiracetam
become seizure-free C. Primidone
C. A recent retrospective, multicenter study D. Ethosuximide
assessing the ketogenic diet for various E. Zonisamide
264 Multiple Choice Questions for Part IV
91. In addition to the traditional ketogenic diet, does not typically have spontaneous sei-
alternative dietary therapies have been zures. The audiogenic seizure model is pre-
developed for epilepsy treatment. Which of dictive of efficacy against generalized tonic–
the following is an alternative dietary ther- clonic seizures. Levetiracetam efficacy was
apy for epilepsy treatment? missed by the maximal electroshock model
(MES) and PTZ models. The 6 Hz model is
A. The low glycemic index treatment a model of pharmacoresistant epilepsy.
B. The Atkins diet 4. (B). In the first VA cooperate, all four
C. The Paleo diet antiepileptic drugs compared had equal effi-
D. The short-chain triglyceride diet cacy, but phenobarbital and primidone were
less well tolerated.
92. The blood levels of which antiepileptic will 5. (D). In contrast to the listed benzodi-
not be altered after the addition of azepines, Clobazam is a 1,5 benzodiazepine;
phenytoin? the brand name “On-fi” is derived from
“One-five.”
A. Felbamate 6. (D). Diazepam and clobazam have important
B. Topiramate active metabolites (desmethyldiazepam and
C. Zonisamide desmethylclobazam). Clonazepam is con-
D. Tiagabine verted to an inactive metabolite.
E. Pregabalin 7. (B). Connective tissue diseases in particular
Dupuytren’s contractures and plantar fibro-
matosis may be seen with long-term phe-
Answers nobarbital use.
8. (B). Enzyme-inducing antiepileptic medica-
1. (E). In this case, levetiracetam is the most tions can induce the metabolism of other
appropriate choice for treating juvenile concomitant medications such as carba-
myoclonic epilepsy in a woman of child- mazepine and phenytoin and can lower the
bearing age. Pregabalin and carbamazepine serum concentration of simvastatin by about
are typically efficacious against partial–onset 50%.
seizures and may potentially exacerbate 9. (C). Both zonisamide and topiramate are
generalized seizures, notably absence and mild carbonic anhydrase inhibitors. The
myoclonic seizures. Lacosamide lacks evi- resulting decreased sweat may lead to over-
dence to support its use in this condition, heating and possible heatstrokes especially
while valproate should be avoided in women in children.
of childbearing age due to significant risk of 10. (A). While some of the other antiepileptic
teratogenicity. drugs have a long half-life (such as zon-
2. (A). The clinical scenario describes partial isamide, clobazam, and ethosuximide), they
seizures with secondarily generalization. do not have FDA approval for once-daily
Oxcarbazepine is an appropriate drug for dosing. The main reasons are the potential
treating this condition. Lamotrigine and sedation and cognitive or gastrointestinal
topiramate would not be a good choice due side effects that may incur from high doses
to the slow titration schedule. Phenobarbital given once daily.
and valproate must be avoided in women of 11. (C). Ezogabine may be associated with uri-
childbearing age. nary retention in about 2% of patients. It is
3. (A). The pentylenetetrazole (PTZ) model is generally reported within the first six months
predictive of efficacy against absence sei- of treatment, but can also be observed later.
zures, although some effective drugs may be 12. (C). Felbamate reduces carbamazepine level
missed by this model. The kindling model through induction of CYP3A4, but may
Multiple Choice Questions for Part IV 265
mechanism in addition to its SV2A binding. tricarboxylic acid cycle, to be used for
In general, it exhibits a similar profile to energy production or ketone body produc-
levetiracetam general but with a higher tion. A shift to use of fats as the primary
potency (about 10 times higher). energy source in disorders of fat metabolism
31. (B). Valproate can produce tremors and would precipitate deterioration. Lack of
Parkinsonism that is usually dose-dependent carbohydrates would exacerbate acute inter-
and more common in the elderly. It is usu- mittent porphyria.
ally reversible with reduction or elimination 39. (D). Incidence of epilepsy increases with the
of the drug. severity of mental retardation (MR), but it
32. (A). Pentylenetetrazole (PTZ) is an animal varies depending on epidemiological
model of absence seizures, while the other methodologies as well. In population-based
listed animal models are specific for partial studies, 21% of those with mild MR had
seizures. epilepsy. Another study reported epilepsy in
33. (C). Vigabatrin visual toxicity is a slowly 11% of subjects with mild MR and in 23%
progressive, usually irreversible retinopathy in those with severe MR. On the other hand,
that is related to dose and duration of in institution-based studies including
treatment. patients with severe MR, the prevalence of
34. (D). Tiagabine has a short half-life; it is a epilepsy varies from 32 to 34%.
narrow-spectrum agent for partial (focal) 40. (B). Vigabatrin use is associated with visual
seizures, approved only as adjunctive ther- field constriction in about one-third of
apy; it increases GABA levels by inhibiting patients. Periodic visual field monitoring is
its reuptake in the synapse. required for the prescription of vigabatrin.
35. (A). Aplastic anemia and hepatic failure are 41. (E). Premanufactured ketogenic formulas are
unlikely within one month of initiating fel- available, ensuring more accuracy of mea-
bamate therapy. Known risk factors include surements and minimizing barriers such as
prior cytopenia, allergy to or significant food refusal or aversions.
toxicity with other antiepileptic drugs, and 42. (A). Prolonged encephalopathy or noncon-
underlying autoimmune disease. vulsive status epilepticus may be seen as a
36. (C). Valproate is a wide-spectrum dose-related adverse effect of tiagabine.
antiepileptic drug effective against absence 43. (B). This should adequately screen for dis-
seizures; the other listed AEDs may exac- orders of fatty acid metabolism including
erbate absence seizures. carnitine deficiency, CPT I or II deficiency,
37. (D). Unlike other listed antiepileptic drugs, carnitine translocase deficiency, and the
pregabalin does not interact with GABA beta-oxidation defects. The other choices are
receptors. also reasonable considerations for preinitia-
38. (C). In pyruvate dehydrogenase deficiency, tion screening, but for other conditions.
pyruvate cannot be metabolized into 44. (A). Valproate inhibits uridine glucosyl
acetyl-coA. The ketogenic diet bypasses this transferase, the enzyme that metabolizes
step and provides ketones as an alternative lamotrigine. Initiation of valproate therapy
fuel for the brain. All of the other choices are will result in lamotrigine toxicity. This
contraindications to the ketogenic diet. addition usually requires immediate reduc-
Long-chain fatty acids are transported across tion of the dose of lamotrigine by about
the mitochondrial membrane by carnitine 50%.
(helped by CPT I and II and carnitine 45. (D). This would be a longer-term compli-
translocase); once in the mitochondrion, cation. Osteoporosis in the ketogenic diet is
fatty acids are beta-oxidized to 2 carbon contributed to by calcium/vitamin D defi-
units of acetyl-CoA that can then enter the ciency as well as acidosis.
Multiple Choice Questions for Part IV 267
46. (B). Most common known etiology for epi- of choice for pure generalized absence
lepsy is cerebrovascular disease at 11%, seizures.
followed by neurologic deficits from birth, 51. (B). Although the benefit on seizure control
mental retardation, or cerebral palsy at 8%. can be seen within 2 weeks after initiation
47. (D). Long-term complications in children on (in 75% of children in one study), it is rec-
the ketogenic diet for >2 years have not ommended that the ketogenic diet be con-
been systematically reviewed. There may be tinued for 3 months before deciding to
increased fractures and kidney stones. continue or discontinue. Gradual weaning
Symptoms, however, would be expected in rather than abrupt discontinuation is pre-
the setting of pancreatitis, renal calculi, or ferred and may assist with determining
severe constipation. Specific guidelines for whether there has been benefit of the keto-
monitoring of bone health, however, still genic diet on seizure control. The recom-
need to be delineated. mendation is to discontinue after 2 years of
48. (C). In GLUT1 deficiency syndrome, glu- seizure freedom, similar to the time period
cose transport across the blood-brain barrier used for anticonvulsant medications.
is impaired. Since the ketogenic diet pro- 52. (C). The likely diagnosis of this patient is
vides ketones that bypass the metabolic neurocysticercosis. Epilepsy is the most
defect, serving as an alternative fuel to the common presentation (70% of patients) fol-
brain, the ketogenic diet is the treatment of lowed by headache, stroke, and psychiatric
choice for this syndrome. Such epilepsy manifestations. It is more common in
treatment is not necessary for benign myo- Southern America due to ingestion of
clonus of infancy. Although the ketogenic uncooked egg-infected pork meat. Brain
diet may be particularly helpful for gener- imaging often reveals several ring-enhancing
alized epilepsies, there has not been data lesions. Treatment consists of anthelminthic
supporting its use in JME as of yet. The medication (such as albendazole) and ster-
ketogenic diet is contraindicated for pyru- oids (e.g., dexamethasone) to suppress the
vate carboxylase deficiency, which would inflammatory response induced by destruc-
impair tricarboxylic acid cycle function and tion of live cysticerci.
energy production in the ketogenic diet. 53. (D). Valproate exposure during pregnancy is
49. (B). Isoniazid is an antibiotic commonly associated with decreased verbal IQ and
used in treating tuberculosis. It may trigger autism in offsprings. The teratogenic effect is
de novo seizures by competing with the dose-dependent and is irrespective of
mechanism of pyridoxine and its metabo- monotherapy or polytherapy use. Supple-
lites. Pyridoxine is an essential cofactor for mentation with folic acid is not sufficient to
many enzymatic reactions, including GABA reverse the teratogenic effect.
an inhibitory neurotransmitter. 54. (C). This patient is suffering from partial–
50. (B). A large, multicenter, double-blind, ran- onset seizures and postherpetic neuralgia for
domized, controlled trial to compare the which pregabalin is FDA indicated for.
efficacy, tolerability, and neuropsychological Topiramate, lamotrigine, and levetiracetam
effects of ethosuximide, valproic acid, and have not yet been proven effective in this
lamotrigine favored ethosuximide. After setting. Carbamazepine could be helpful but
16 weeks of therapy, the has the risk of drug interactions at the level
freedom-from-failure rates for ethosuximide of hepatic metabolism.
and valproic acid were similar and higher 55. (C). Both valproate and phenytoin are highly
than the rate for lamotrigine. However, protein-bound antiepileptic drugs. When
attentional dysfunction was more common used together or added to a highly
with valproic acid than with ethosuximide. protein-bound medication (such as war-
As a result, ethosuximide became the drug farin), they can compete on protein binding,
268 Multiple Choice Questions for Part IV
increasing the free fraction of either drugs. abnormal initial routine EEG. An additional
Valproate free fraction decreases at higher 35% were identified to have abnormalities
concentrations due to protein saturation. on the second sleep-deprived EEG. An
56. (E). The use of the KD is being investigated in abnormal EEG predicts a higher recurrence
several neurologic conditions beyond epi- rate, and a normal EEG predicts a lower
lepsy and in traumatic brain injury, Alzhei- recurrence rate but does not rule out
mer’s disease, amyotrophic lateral sclerosis, epilepsy.
autism, glial tumors, diabetic nephropathy, 64. (E). Maternal use of valproate during preg-
and Parkinson’s disease. In addition, in nancy was associated with a significantly
development is 2-deoxy-(D)-glucose (2-DG), increased risk of autism spectrum disorder
an agent which is a nonmetabolizable glucose and childhood autism in the offspring.
analog that inhibits glycolysis. 65. (B). Lorazepam and clonazepam do not have
57. (B). Lamotrigine does not affect bone health active metabolites; lorazepam has the short-
while phenytoin, phenobarbital, and topira- est half-life.
mate can, because of their enzyme induction 66. (C). Phenytoin has nonlinear (saturable)
properties. kinetics; its half-life becomes longer after
58. (D). Topiramate should be avoided in elderly the saturation point which is usually within
because it has significant cognitive effects. the recommended therapeutic range.
These can significantly limit or compromise 67. (B). Carbamazepine induces its own meta-
their intellectual reserves. bolism so that its half-life becomes shorter
59. (B). Faciobrachial dystonic seizures are fre- with continued use. The process of autoin-
quent brief dystonic seizures, typically duction is completed over 2–4 weeks.
affecting the ipsilateral arm and face found 68. (C). Recurrence rate after the first seizure
in association with LGI1 antibodies. Facio- averages around 30–40% by two years. The
brachial dystonic seizures often precede risk is higher (approaching 50–60%) when
LGI1-antibody encephalitis. Recognition the EEG or brain MRI is positive.
may lead to early diagnosis and early insti- 69. (A). Primidone is converted into phenobar-
tution of immunotherapy, with improved bital and phenylethylmalonamide (PEMA),
outcome. which is also an active metabolite. Primi-
60. (A). Excluding carbamazepine, all the other done has acute toxic reactions that are dif-
four medications (amiodarone, cimetidine, ferent from phenobarbital. It can produce
fluconazole, and felbamate) may inhibit transient drowsiness, dizziness, ataxia, nau-
phenytoin metabolism and may cause sea, and vomiting that can be debilitating.
phenytoin accumulation. These reactions are present even before
61. (B). Excluding ceftriaxone, all the other phenobarbital has appeared as a metabolite.
three medications (erythromycin, fluoxetine, 70. (D). Among the listed antiepileptic drugs,
and propoxyphene) and grapefruit juice may gabapentin is mostly excreted in urine;
inhibit carbamazepine metabolism and may hence, its dose should be reduced according
cause carbamazepine accumulation. to the renal function.
62. (D). Estrogen may be proconvulsant as it 71. (D). Overall, risk factors that carry higher
may reduce inhibition at the GABAA seizure recurrence rate include focal-onset
receptor and also inhibits the synthesis of seizures, status epilepticus or cluster seizures
GABA. On the other hand, progesterone at first seizure, abnormal EEG with epilep-
may be anticonvulsant as it enhances inhi- tiform activity (sharp waves or spikes), and
bition at the GABAA receptor and increases abnormal brain MRI or neurological
GABA synthesis. examination.
63. (B). In one pooled analysis of 1766 subjects, 72. (E). Levetiracetam does not interact with
51% of patients (pooled analysis) had an oral contraceptive medications, while all the
Multiple Choice Questions for Part IV 269
other choices can lower oral contraceptive tend to offer pharmacological advantages in
medication levels. regard to lower protein binding, minimal
73. (B). Antiepileptic drugs with potential oph- drug–drug interaction, and absence or mini-
thalmological adverse effects include topi- mal liver inhibition/induction. They are,
ramate (acute open-angle glaucoma), however, more expensive than older AEDs.
vigabatrin (peripheral visual constriction), 81. (A). Ethosuximide and valproate are both
and ezogabine (photoreceptor damage). known to block T-type calcium channels,
74. (C). Zonisamide and topiramate are mild which conveys efficacy against absence
carbonic anhydrase inhibitors and are known seizures.
to decrease sweat production (causing 82. (C). HLA allele B*1502 is a marker for
anhydrosis or hypohydrosis). This may par- carbamazepine-induced Stevens–Johnson
ticularly be dangerous in patients with high syndrome and toxic epidermal necrolysis,
physical activity, without compensatory particularly in Han Chinese. The FDA rec-
hydration. ommends genotyping all Asians for the
75. (B). Risk of seizure recurrence after first allele before treatment initiation.
symptomatic seizure is about 33% in an 83. (E). St John’s wort (or Hypericum perfora-
acute (less than 7 days) stroke setting and tum) is a popular medicinal herb used for the
70% in a remote setting (more than 7 days). treatment of depression. It is known to
Risk of seizure recurrence after first symp- induce cytochrome P450 affecting the phar-
tomatic seizure is about 13% in the setting of macokinetics of several AEDs such as phe-
acute TBI and 45% in the setting of remote nobarbital, carbamazepine, and phenytoin,
TBI. resulting in adverse events.
76. (B). Vigabatrin’s visual field defect may 84. (A). Overall, 11–41% of patients will relapse
affect about one-third of patients with vari- after antiepileptic drug discontinuation. The
able severity. It primarily consists of relapse rate tends to be lower in children
peripheral visual field constriction. Risk (*20%) and higher in adults (*40).
factors include longer duration of treatment 85. (D). This is the consensus statement made
and higher dosage. by the International Ketogenic Diet Study
77. (C). All of the listed antiepileptic drugs are Group.
considered to be broad-spectrum except 86. (E). Brivaracetam binds to the synaptic
pregabalin which targets focal-onset seizures vesicle protein as well as blocks sodium
and may alternatively worsen generalized channels.
seizures especially myoclonic seizures. 87. (A). Compared to the Cochrane Review
78. (C). Several clinical trials were concluded or performed in 2003, in which no RCTs were
underway for (up to the current writing) the available, the Cochrane Review in 2012
treatment of acute repetitive seizures. This reviewed 4 RCTs, which showed that at least
includes intranasal diazepam and midazo- 38% of patients had a 50% decrease in sei-
lam, intramuscular diazepam (by autoinjec- zures at 3 months, with this positive
tor), and buccal midazolam. response maintained for a year. Hender-
79. (B). Zonisamide does not have an extended son CB et al’s meta-analysis in 2006 showed
release preparation, but has a prolonged 1/3 of patients having a >90% decrease in
half-life, obviating the need for such a seizures. Caraballo R et al’s multicenter
preparation. retrospective study in 2011 showed 22%
80. (C). Overall, when compared to older AEDs, with seizure freedom and 56% with greater
newer AEDs tend to have better safety profile than 75% decrease.
and tolerability (except for felbamate, viga- 88. (B). Zonisamide’s chemical structure
batrin) but comparable efficacy. They also includes a sulfa moiety and thus should be
270 Multiple Choice Questions for Part IV
avoided in patients with known history of exclusively against absence seizures. Car-
sulfa allergy. bamazepine and primidone are liver enzyme
89. (C). Traditionally, the patient would fast for inducers that can decrease warfarin efficacy
24–48 h. Once urine ketones appeared, the and worsen osteoporosis. Zonisamide can
ketogenic diet would then be initiated grad- precipitate kidney stones.
ually. Data support the fact that ketosis 91. (A). The Modified Atkins diet, the medium-
occurs without this initial fasting period and chain triglyceride diet, and the low glycemic
that tolerance of the diet may be higher index treatment are alternative dietary ther-
without this fasting period. apies developed for epilepsy treatment.
90. (B). In this case, levetiracetam is the most 92. (E). Pregabalin is not metabolized and is not
appropriate choice for treating partial sei- affected by phenytoin and other enzyme
zures. Ethosuximide is efficacious inducers.
Part V
Presurgical Evaluation
and Epilepsy Surgery
Neuroimaging in Epilepsy
21
Anuradha Singh, Priyanka Sabharwal
and Timothy Shephard
either standard anterior temporal lobe resection differentiation in the temporal lobe or decreased
or selective amygdalohippocampectomy. A le- white matter in the adjacent temporal lobe (e.g.,
sionectomy of a cavernoma with or without collateral eminence and temporal stem). There
corticectomy is a reasonable option if can be atrophy of the ipsilateral fornix and
anti-seizure medications are not effective in mammillary body (Fig. 21.4). High-resolution
controlling seizures. A more aggressive surgical 3D T1WI are also useful when performing hip-
approach, such as a functional hemispherectomy, pocampal volumetric analyses. However, para-
may be warranted in patients with Sturge Weber central lesions are more evident on axial
syndrome, Rasmussen’s encephalitis, large sequences. Figure 21.5 shows a less common
porencephalic cyst due to previous traumatic or case of temporal lobe seizures from a temporal
ischemic insult, hemimegalencephaly, or Dyke– lobe encephalocele involving the subjacent
Davidoff–Masson syndrome (congenital or sphenoid wing.
acquired). Neuroimaging may have a direct Neuronal migrational disorders: Hetero-
influence on therapeutic options that neurologists topias are neuronal migrational disorders
offer to their patients; e.g., a scan supporting a (NMDs) where gray matter gets arrested as
diagnosis of Tuberous Sclerosis (TS) in an infant neurons migrate from periventricular regions
with infantile spasms may justify the use of toward pia during embryonic stages.
vigabatrin or m-TOR inhibitors over adrenocor- High-resolution 3D T1-weighted volumetric
ticotrophic hormone (ACTH). Not all structural imaging provides superior gray–white contrast
lesions are epileptogenic; therefore, it is prudent that is critical to identify subtle cortical malfor-
to correlate incidental findings on MRI with mations in patients with epilepsy (Fig. 21.6).
clinical history, seizure semiology, and EEG Higher magnetic strengths (3- or 7-Tesla) can
data. Some of the commonly encountered lesions detect very subtle cortical dysplasias.
in patients with epilepsy are described below. Heterotopias can either be focal, nodular, or
Mesial temporal sclerosis: Temporal lobe multifocal (as in TS) or preferentially involve
epilepsy (TLE) is the most common form of focal one hemisphere as in hemimegalencephaly.
epilepsy. Mesial TLE is more prevalent than Subcortical band heterotopias (SBH) are typi-
neocortical epilepsy and often intractable to cally periventricular, bilateral nodular collections
anti-seizure medications. The most common of gray matter with relatively smooth margins,
identifiable lesion on MRI brain is mesial tem- which gives the appearance of a double cortex.
poral sclerosis (MTS; Fig. 21.1). In patients with Pachygyria is abnormal tissue in the right loca-
TLE, subtle anatomic features of the medial tion with abnormal sulcation and gyration of the
temporal lobes and pathologies such as MTS or mantle which is typically > 8 mm thick
incomplete hippocampal inversion (Fig. 21.2) (Fig. 21.7a). Polymicrogyria (PMG) is either
are best appreciated in an oblique coronal plane. two- or four-layered cortex, which is less than 5–
This orientation is orthogonal to the long axis of 7 mm (Fig. 21.7b). PMG is commonly associ-
the temporal lobe and reduces volume averaging ated with hypoxic-ischemic injury, or prenatal
problems for the thin laminar appearance of the cytomegalovirus (CMV) infection.
hippocampus. Oblique coronal temporal FCDs are classified into three categories (Type
high-resolution T2-weighted and FLAIR are the I, II, and III) and further divided into various
best sequences to diagnose MTS. This entity is subtypes (Table 21.1). In a fully myelinated brain,
characterized by (1) hippocampal atrophy, FCD type I may be characterized by subtle blur-
(2) increased T2 signal, and (3) abnormal mor- ring of the gray–white junction with typically
phology or loss of internal architecture of hip- normal cortical thickness, moderately increased
pocampus. In 10% of the cases, MTS can be white matter signal hyperintensities on T2/FLAIR
bilateral (Fig. 21.3). Secondary findings may images and decreased signal intensity on
include dilatation of the temporal horn of the T1-weighted images. FCD Type IIA cortical
lateral ventricle, loss of gray–white matter dysplasias are characterized by marked blurring of
21 Neuroimaging in Epilepsy 275
Fig. 21.1 Axial FLAIR (a) demonstrates enlargement of Companion coronal FLAIR (b) and T2-weighted MRI
the left lateral ventricle temporal horn and the left (c) demonstrate volume loss, hyperintensity, and subtle
hippocampus is relatively smaller and hyperintense com- laminar blurring. These are classic MRI findings for left
pared to the contralateral side. Note that the lateral aspect hippocampal sclerosis. If the amygdala also is involved,
of the left hippocampal body is abnormally smooth, and this can be classified as left mesial temporal sclerosis
hippocampal head digitations are reduced (arrow).
Fig. 21.2 Coronal T2-weighted images demonstrating inversion (IHI). This patient also had left hippocampal
globular left hippocampus (arrow, panel a) more vertical sclerosis, but it remains controversial whether IHI
left collateral sulcus and low-lying left body of the fornix predisposes to sclerosis or is just an incidental association
(arrow, panel b) consistent with incomplete hippocampal
the gray–white junction on T1 and T2-FLAIR (aka the “transmantle sign”) which marks the
images due to hypomyelination or dysmyelination involvement of radial glial neuronal bands. This
of the subcortical white matter with or without radiological feature differentiates FCD from
cortical thickening. Here, the increased white low-grade tumors. Type II lesions are more
matter signal changes on T2, WI, and FLAIR commonly seen outside the temporal lobe with
images frequently tapers toward the ventricles predilection for the frontal lobes. Type III FCD is
276 A. Singh et al.
typically associated with another principal lesion predominantly gyral abnormalities is caused by
such as hippocampal sclerosis, tumor, a vascular mutation in LIS1 gene (Fig. 21.8). Anteriorly
malformation, or other acquired pathology during predominant lissencephaly in heterozygous males
early life. and subcortical band heterotopia (SBH) in
Other important NMDs include lissencephaly, heterozygous females are caused by mutations of
which is characterized by smooth brain surface and the XLIS (double cortex gene on chromosome X).
abnormal gyration, which varies between agyria Schizencephaly is another rare form of MCD
and pachygyria. Lissencephaly with posteriorly which is characterized by the presence of a
21 Neuroimaging in Epilepsy 277
Fig. 21.4 Oblique coronal T2 demonstrates obvious gray matter heterotopia in the lateral wall of the right
volume loss and laminar blurring of the right hippocampal lateral ventricle, best seen on the coronal double-inversion
head (arrow, panel a) consistent with right hippocampal recovery image (arrow, panel c) compared to companion
sclerosis and right fornix atrophy (b). There is a small T2 and T1-weighted MRI (b and d)
Fig. 21.5 Axial and coronal T2-weighted MRI, and abnormality is not always associated with seizures, but
coronal FLAIR demonstrate a small encephalocele that should be considered suspicious. In this case, the finding
involves a focal portion of the fusiform gyrus cortex was concordant with semiology and EEG
extending into the right foramen ovale (arrows). The MRI
transcortical cleft that can extend from ventricles Brain tumors: Approximately 20–40% of the
to the pia with open or fused lips, and often adults with primary brain tumors experience one
polymicrogyria is seen on the lips of the schizen- seizure prior to the tumor diagnosis, and another
cephaly (Fig. 21.9). Hemimegalencephaly is the 20–45% will suffer from seizures during the
unilateral hamartomatous excessive growth of all course of the illness [1]. This incidence rate
or part of one cerebral hemisphere at different varies depending on the tumor type, the grade of
phases of embryologic development. MRI in these the tumor, and its location. Seizures are more
cases reveals an enlarged hemisphere with common in slow growing tumors such as
increased white matter volume, cortical thicken- meningiomas, gangliogliomas (GGs), dysemby-
ing, agyria, pachygyria, polymicrogyria or lissen- oplastic neuroepithelial tumors (DNETs), or dif-
cephaly, and blurring of the gray–white matter fuse low-grade tumors such as Grade II
junction. Often, a large, ipsilateral irregularly astrocytomas, oligodendrogliomas, and oligoas-
shaped ventricle may be seen. trocytomas (Table 21.2). Typically, the low-grade
278 A. Singh et al.
Fig. 21.6 Coronal FLAIR MRI (a) and serial axial anterior cingulate gyrus and adjacent left medial frontal
FLAIR MRI of the frontal lobes (b) demonstrating subtle gyrus (arrows) from a pathologically proven cortical
gray–white blurring and FLAIR hyperintensity in the left dysplasia
Fig. 21.7 a Coronal 3D T1-weighted (A) and axial show abnormal cortex that appears thickened extending
FLAIR MRI (B) demonstrate broad, simplified gyri with from the posterior right Sylvian fissure (arrow). The
relatively shallow sulci in the bifrontal regions compared fissure is lengthened with a vertical orientation toward the
to the temporal and parietal regions consistent with vertex (arrow, panel C). Findings consistent with unilat-
pachygyria. b Coronal and axial FLAIR (A and B), eral polymicrogyria
sagittal, and axial post-contrast 3D T1 (C and D) MRI
tumors do not enhance on Gd-administration. The Gangliogliomas typically present with temporal
most common location is temporal lobe, followed lobe epilepsy, presumably due to the temporal
by the parietal, frontal, and occipital lobes. lobes being a favored location (Fig. 21.10).
21 Neuroimaging in Epilepsy 279
Gangliogliomas are closely related to gangliocy- (60%) followed by temporal lobes (30%).
tomas, which contain essentially only mature Meningiomas are the most common extra-axial
neural ganglion cells, and ganglioneurocytoma, tumors of the central nervous system. They are
which in addition have small mature neoplas- nonglial neoplasms that originate from the
tic neurons. On MRI, these tumors may show arachnoid cap cells of the meninges and have
cystic changes or calcifications. characteristic imaging findings, although there
DNETs are cortically based benign neoplastic are many variants (Fig. 21.12). GBMs are
cortical malformations, which may show sub- aggressive malignant tumors that are associated
cortical extension in approximately 30% of with significant vasogenic edema and heteroge-
tumors giving them a triangular appearance neous enhancement. The overall incidence of
(Fig. 21.11). These tumors appear as seizures in Grade IV glioblastoma multiforme
well-defined lobulated, and solid tumors that are (GBM) patients, without considering the loca-
hyperintense on T2WI and may erode the over- tion, has been reported between 25 and 50% at
lying calvarial bone or show microcystic chan- presentation and another 20–30% during the
ges. The most common location is temporal course of the disease [2]. Metastatic lesions tend
280 A. Singh et al.
Fig. 21.10 Axial FLAIR (a), T2-weighted (b), posteromedial temporal lobe with focal areas of contrast
pre-contrast (c), and post-contrast T1-weighted MRI enhancement most consistent with ganglioglioma. CT
(d) demonstrating solid and cystic mass in the left also often demonstrates focal calcification
to have a smaller risk for seizures, one exception the first pass of a bolus of contrast agent. This
being metastatic melanoma. method allows the radiologist to determine the
Perfusion-weighted imaging is a useful tool, relative cerebral blood volume (rCBV). In gen-
which involves several image acquisitions during eral, the underlying principle is the greater the
21 Neuroimaging in Epilepsy 281
rCBV, the higher the grade of tumor. Lack of malformations (AVMs), which can be
notable flow indicates a nonneoplastic etiology parenchymal, dural, or mixed. In contrast, low
with abnormal signal intensity, such as flow vascular malformations are cerebral cav-
demyelination. Of note, mixed oligoden- ernous malformations (CCMs), developmental
drogliomas can have low rCBV. Besides the venous anomaly (DVA), or mixed vascular
prognostic information it provides, malformations (Fig. 21.15). CCMs have a
perfusion-weighted imaging can increase the unique “popcorn” appearance with hemorrhages
yield of brain biopsy and help in differentiating of different ages. They may be bright on CT due
recurrent neoplasm from radiation necrosis. On to pooling of blood within the cavernoma. The
perfusion MRI, GBMs typically show increased most characteristic feature is blood products of
regional blood flow (Fig. 21.13). different ages with an area of hyperintensity
Another interesting but rare kind of focal representing methemoglobin surrounded by a
congenital tumor is hypothalamic hamartoma hypointense ring of hemosiderin on T2W MRI.
(HH). These tumors are typically associated with Gradient echo (GRE) sequences are useful to
ictal spells of laughter without mirth or gelastic detect CCMs and may show low or minimal
seizures (Fig. 21.14). HH are composed of enhancement on Gd. MRI brain is superior to CT
cytologically normal, small, and large neurons, scan to look for the nidus of an AVM which is
which are organized in poorly demarcated clus- hyperdense compared to adjacent brain
ters of variable size and density. These tumors (Fig. 21.16). It is easier to appreciate fast flow
are categorized by the Delalande classifications voids on T2WI due to fast flow and enlarged
I–IV. Type I has a horizontal orientation and may draining veins may be seen. Phase contrast MR
be lateralized on one side; Type II has a vertical angiography can help subtract the hematoma
orientation and an intraventricular location; components in patients who present with acute
Type III is a combination of types I and II; hemorrhage into an AVM. CTA can demonstrate
Type IV is a giant hamartoma. feeding arteries, nidus, and draining veins visi-
Vascular malformations: Vascular malfor- ble, which resembles a “bag of worm” appear-
mations can be either high flow or low flow. ance. The exact anatomy of feeding vessels and
High flow malformations include arteriovenous draining veins is often difficult to delineate, and
Fig. 21.12 Axial pre-contrast (a) and post-contrast gray matter and shows homogeneous enhancement with
T1-weighted MRI (b) demonstrate an extra-axial mass dural tail consistent with meningioma
overlying the right frontal operculum that is isointense to
Fig. 21.13 MRI brain post-Gd T1-weighted image consistent with glioblastoma multiforme. Perfusion MRI
(a) showing ring enhancement in the right thalamus and (b) shows increased regional cerebral blood flow at the
deep gray structures with associated mass effect, midline tumor margins
shift, and obstructive hydrocephalus. Pathology was
thus angiography remains necessary. Digital brain, both in cortical layers and in blood vessels
subtraction angiography (DSA) remains the gold and identify hemosiderin in CCMs, old infarcts
standard in delineating the location and number or old contusions.
of feeding vessels supplying the central nidus and Infectious/Inflammatory disorders: A common
the pattern of venous drainage (superficial or etiology for seizures in all age groups, both in the
deep). The susceptibility-weighted images (SWI) developing and developed world, includes infec-
are particularly sensitive to iron content in the tions of the nervous system. A wide variety of
21 Neuroimaging in Epilepsy 283
Fig. 21.14 Coronal T2-weighted (a) and sagittal patient with gelastic seizures. Findings support diagnosis
T1-weighted MRI (b) demonstrating ectopic gray matter of hypothalamic hamartoma
along the wall of the 3rd ventricle (arrow) in adolescent
Fig. 21.15 Axial T2-weighted and axial susceptibility- (arrow). Pre- and post-contrast axial MRI (c and
weighted MRI (a and b) demonstrate a popcorn-like T2 d) demonstrate associated developmental venous anomaly
bright lesion with surrounding hypointense susceptibility (arrow) strongly supporting diagnosis of cavernoma
pathogens including viral, bacterial, fungal, para- additional information, which is discussed in rel-
sitic, and other opportunistic pathogens can cause evant sections in this chapter. Briefly, restricted
CNS disease in humans. Though gold standard of diffusion helps in differentiation of progenitor
diagnosis remains either biopsy or CSF analysis, abscesses from ring-enhancing lesions of other
neuroimaging can aid in rapid diagnosis by help- etiology. Also, the presence of lactate and
ing identify typical lesion patterns. While it is cytosolic amino acids and the absence of choline
outside the scope of his chapter to comprehen- on MRS are seen in the cases of pyogenic
sively discuss CNS infections, we have attempted abscesses. Autominnune encephalitides can also
to list typical radiology findings with common be associated with seizures. Figure 21.17 illus-
CNS infections associated with epilepsy in trates an example of progressive volume loss and
Table 21.3. More recent MRI techniques, such as denudation of the overlying cortex Rasmussen’s
DWI and MRS also aid in diagnosis by providing syndrome is one kind of autoimmune encephalitis
284 A. Singh et al.
associated with intractable unilateral seizures, TBI. SWI and DWI are the best sequences to
progressive hemiparesis or weakness on one side, detect DAI. Tong et al. group showed that number
and intellectual dysfunction. of hemorrhagic DAI lesions seen on SWI was six
Neurocutaneous Syndromes (Phacomatoses): times greater than that on conventional
These are a group of inherited disorders charac- T2-weighted 2D GRE imaging and the volume of
terized by hamartomas and neoplasms through- hemorrhage was approximately twofold greater.
out the body along with involvement of the
nervous system and skin. The neuroradiological
features of common phacomatoses, namely, Positron Emission Tomography (PET)
Tuberous sclerosis (TS), Neurofibromatosis
(NF1 and NF2), and Sturge Weber syndrome PET is a noninvasive, diagnostic imaging tech-
(SWS) are summarized in Table 21.4. nique for measuring the metabolic activity of
Figure 21.18 illustrates a few salient neuro- cells in the human body. PET studies character-
radiological features of TS and SWS in patients ize genotype–phenotype interactions because this
with medically refractory seizures. technique directly measures neurometabolic
Trauma: Traumatic brain injury (TBI), espe- changes and receptor binding. PET produces
cially severe closed skull injury and penetrating images of the body by detecting the radiation
dural injury have been well documented to cause emitted from radioactive substances. These sub-
post-traumatic epilepsy [3]. Patients with pro- stances are injected into the body and are usually
longed loss of consciousness, post-traumatic tagged with a radioactive atom (11C, 18Fl, 15O or
13
amnesia, or hemorrhage in the brain (subarach- N) that has short decay time (Table 21.6). The
noid hemorrhage, subdural, epidural, intra- radioactivity localizes in the appropriate areas of
parenchymal, and intraventricular) are at a higher the body and is detected by the PET scanner.
risk of developing immediate (onset within 24 h), Different colors and/or degrees of brightness
early (onset within a week), or late-onset epilepsy. on a PET image represent different levels of tis-
The findings on imaging vary from contusions, sue or organ function. For example, as healthy
with or without diffuse axonal injury (DAI), or tissue uses glucose for energy, it accumulates
hemorrhages in different locations (Table 21.5). some of the tagged glucose, which shows up on
T2WI and the FLAIR images are sensitive to PET images. However, epileptogenic tissue dur-
edema in the brain, while GRE and SWI are very ing interictal phases utilizes less glucose than
sensitive to microhemorrhages. Figure 21.19 healthy normal tissue, and thus, it appears less
shows temporal encephalomalcia as a result of bright than normal tissue on the PET images
21 Neuroimaging in Epilepsy 285
(Fig. 21.20). 18F FDG-PET is particularly helpful transporters (GLUTs). Most low-grade tumors
in identifying subtle FCDs. FDG is useful for have lower concentrations of GLUTs and can
tumor grading because most high-grade tumors, usually be distinguished from high-grade glio-
such as high-grade gliomas, medulloblastoma, mas by the lower FDG uptake on PET [4].
and primary central nervous system lymphoma, FDG-PET is a useful tool in distinguishing
have high concentrations and activity of glucose post-radiation necrosis from tumor progression,
286 A. Singh et al.
Fig. 21.17 Serial coronal FLAIR images of the left progressive volume loss and denudation of the overlying
temporal lobe in an adult patient with autoimmune cortex (arrow). Similar focal lobar volume loss can
encephalitis. Between 2010 and 2015, there was happen in Rasmussen encephalitis
both in high-grade gliomas and brain metastases. tracer injections (typically Tc-99 m) are
In general, recurrent tumor is FDG avid, and administered during an ictal event that allows
radiation necrosis is not FDG avid. computation of variations in rCBF between ictal
and inter-ictal states. Studies by multiple groups
have validated SISCOM as a valuable tool that
Subtraction Ictal SPECT offers improved localization of seizure focus by
Co-registered to MRI (SISCOM) visualization of the region of hyperperfusion
and thus higher neuronal activity (40–86%).
SISCOM is a novel neuroimaging technique Further, SISCOM findings serve as a guide for
that couples MR images with nuclear medicine further intracranial monitoring, electrode place-
SPECT (Single-Photon Emission Computed ment, and in determining the extent of surgical
Tomography) scans to identify areas of resection, which in turn offers a higher proba-
increased perfusion with respect to regional bility of post-surgical seizure freedom
cerebral flow (rCBF). It is commonly used as a [6–8]. Occasionally, incongruous findings have
tool in pre-surgical evaluation to localize the been reported between intracranial vEEG and
seizure focus in both pediatric and adult patients SISCOM in post-surgical patients [5]. These
with refractory epilepsy [5]. Technically, radio likely reflect an altered blood flow pattern in
21 Neuroimaging in Epilepsy 287
Fig. 21.18 Axial FLAIR (a, b) demonstrates focal T2 tubers in the posterior basal left temporal lobe were
hyperintense masses in the cortex and subcortical white responsible for the majority of seizures in this patient with
matter of the basal left temporal lobe and left inferior tuberous sclerosis. Axial CT slice (c) demonstrating
parietal lobule consistent with tubers. Axial pre-contrast cortical tram-track calcification throughout most of the
T1 and coronal T2-weighted MRI demonstrate multiple left cerebral hemisphere consistent with pial angiomato-
ependymal nodules along the bilateral caudo-thalamic sis. There is a volume loss, but with relative sparing of the
grooves. These lesions demonstrate subtle T1 hyperin- left frontal operculum. Findings are consistent with Sturge
tensity (arrow) attributed to calcification that can be seen Weber syndrome
on CT (not shown). Video EEG suggested the adjacent
Fig. 21.20 Simultaneous PET-MRI technology in a lateral left temporal lobe (arrow, panel b). Blended
temporal lobe epilepsy patient. Coronal FLAIR demon- images combining MRI and FDG data can also be
strates volume loss and hyperintensity in the left obtained to assist visual detection of abnormalities (here,
hippocampal head (arrow, panel a). Coronal FDG demon- FLAIR with color FDG map superimposed)
strates hypometabolism that involves both medial and
fields in the range of femto and pica Tesla. Superconducting Quantum Interference Devices
Patient wears a helmet containing an array of (SQUIDS). MEG has a high resolution in both
100+ sensitive magnetic field measurement space (2–3 mm) and time (<1 ms). The skull and
devices. The measurement devices are called the tissue surrounding the brain affect the
21 Neuroimaging in Epilepsy 289
Fig. 21.21 Advanced imaging workup in patient with functional MRI of the patient performing word generation
MRI-negative left temporal lobe epilepsy. task demonstrates left language dominance (b). A re-
Coronal MPRAGE with interictal MEG dipole cluster in gion-of-interest of BOLD signal in the planum temporale
the left middle temporal gyrus (blue arrow, panel a) was (presumably Wernicke’s area) demonstrated a strong
concordant with semiology and EEG. Task-based correlation with performance of the task (arrow, panel c)
magnetic fields measured by MEG much less diffusion coefficient (ADC) maps calculated from
than they affect the electrical impulses measured the diffusion-weighted images, the intensity of
by electroencephalogram. MEG is usually per- pixels is more directly proportional to extent dif-
formed with simultaneous EEG. For Magnet fusion, and the T2 weighting is removed from the
Source Imaging (MSI), information from MEG data. A bright signal on DWI and dark signal on
and MRI is coregistered to form magnetic source ADC supports the evidence of cytotoxic edema
localization images that provide detailed struc- seen with infarctions (Table 21.7). A focus of
tural–unctional information of the brain. MSI increased signal intensity on DWI with a normal
helps in characterization and localization of ADC signal suggests vasogenic edema and refer-
epileptiform activity and pre-operative mapping red to as “T2 shine through.”
of brain areas supporting sensory, motor, and
language function (Fig. 21.21). MSI is compli-
mentary to PET, fMRI, and EEG as it provides Diffusion Tensor Imaging (DTI)
unique information on the spatiotemporal
dynamics of brain activity. DTI is based on the basic principle that the dif-
fusion of water molecules in the brain is
restricted by intracellular and extracellular
Diffusion-Weighted Imaging (DWI) membranes, particularly myelin. The image
intensities are inversely related to the relative
DWI adds spatially encoding magnetic gradients mobility of water molecules in tissue and the
to the standard MRI sequence to make the image direction of motion. Anisotropy is a measure of
sensitive to the translational motion of water the orientation dependent water diffusion within
molecules. In the absence of T2 weighting, the an image voxel, e.g., CSF has a fractional ani-
“bright regions” represent decreased water diffu- sotropy of near zero, whereas highly coherent
sion, and “dark regions” represent increased water white matter has a fractional anisotropy near 1.
diffusion. Hence an acute stroke with cytotoxic The diffusion data can also be given color codes
edema and slow water diffusion will appear very based on principal direction of diffusion, and the
bright. However, a T2-bright tissue, such as edema intensity of color is proportional to the fractional
or gliosis from a late subacute or chronic infarct, anisotropy. The transverse axis (x-axis) is repre-
also can appear bright on a diffusion trace image sented by red color; the green color depicts
(this is called “T2 shine through”). In apparent anterior posterior (y axis), and blue is designated
290 A. Singh et al.
to superior inferior (z-axis). DTI tractography tissue of interest. Though both are based on
then uses fractional anisotropy and the principal similar principles, MRS uses signal from protons
orientation of diffusion with the voxel to char- to estimate the concentration of metabolites,
acterize the coherent white matter bundle 3D chiefly N-acetyl aspartate (NAA), choline (Cho),
orientations with the brain and spinal cord. Thus, creatine (Cr), and lactate in brain tissue. 1H
tractography allows accurate diagnosis of even spectroscopy, most widely used, is useful for
subtle congenital and acquired lesions that might assessment of markers of neuronal loss such as
disrupt the axonal organization. NAA, products of anaerobic metabolism such as
Practical applications of DTI and tractography lactic acid, and direct measures of primary
in epilepsy include precise delineation of white excitatory and inhibitory neurotransmitters. 31P
matter tracts in the brain, especially in identifi- spectroscopy is directed toward the characteri-
cation of eloquent white matter tracts, such as the zation of the bio energetic status of the tissue of
arcuate fasciculus adjacent to neoplasms or interest phosphocreatine (PCr), adenosine
epileptogenic regions [9, 10]. Another area where triphosphate (ATP), and phosphoinositol (Pi).
tractography has significant implications is in Applications of MRS in epilepsy imaging are
mapping of optic radiations during pre-surgical widespread. In patients with hippocampal scle-
planning of anterior temporal lobe resection pro- rosis, the MRS shows evidence of neuronal dys-
cedures. Here, pre-operative tractography can function such as decreased NAA and decreased
demonstrate the anterior extent of Meyer’s loop, NAA/Cho and NAA/Cr ratios and decreased
which is variable between people and cannot be myoinositol (MI) in ipsilateral temporal lobe and
visualized on traditional MRI studies. Thus, one increased lipid and lactate soon after a seizure
can predict the extent of visual field defects that [13]. Conventionally, MRS has been used in
might happen post-surgery. DTI has relatively characterization and differentiation of masses that
poor spatial resolution and is less sensitive to appear equivocal on MRI. MRS can help differ-
injury at crossing fibers and close to gray–white entiate between dysplastic versus neoplastic
matter junction [11, 12]. masses, recurrent brain neoplasm versus radiation
injury, or between an abscess versus a tumor [14].
Further, MRS has also been used to screen for
MR Spectroscopy (MRS) inborn errors of metabolism such as Canavan’s
disease and creatine deficiency. There is a typi-
In the field of epilepsy, MRS acts as a valuable cally decreased NAA/Cr ratio in patients with
tool by complementing MRI. While conventional dysplastic cortex as in hemimegalencephaly.
MRI is very helpful in studying anatomy, MRS Interestingly, multiple studies have now validated
offers a noninvasive means to determine the MRS as a tool in identifying the seizure focus,
biochemical and metabolic characteristics of the thus making it useful in the evaluation of both
21 Neuroimaging in Epilepsy 291
focal and generalized epilepsy. Work by numer- with newly diagnosed brain tumors. Report of the
ous groups has shown specific metabolic abnor- Quality Standards Subcommittee of the American
Academy of Neurology. Neurology. 2000;54
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16]. Inter-ictal changes include increased inor- 2. Moots PL, Maciunas RJ, Eisert DR, Parker RA,
ganic phosphate (Pi), increased pH, and decreased Laporte K, Abou-Khalil B. The course of seizure
phosphomonoesters, a decreased PCr/Pi ratio disorders in patients with malignant gliomas. Arch
Neurol. 1995;52(7):717–24.
together with a decrease in NAA (reduction of 3. Annegers JF, Hauser WA, Coan SP, Rocca WA.
22% ipsilateral to seizure focus). Also, an increase A population-based study of seizures after traumatic
in lactic acid is usually seen post-ictally. brain injuries. N Engl J Med. 1998;338(1):20–4.
While MRS has been reported to have localizing 4. Horky LL, Treves ST. PET and SPECT in brain
tumors and epilepsy. Neurosurg Clin N Am 2011;22
value by numerous groups (65–96% chances of (2):169–84.
lateralization in TLE by proton MRS and 65–75% 5. So EL. Integration of EEG, MRI, and SPECT in
value in TLE by phosphorus MRS), research is localizing the seizure focus for epilepsy surgery.
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6. Bianchin MM, Wichert-Ana L, Velasco TR,
localization of the epileptogenic focus. Martins AP, Sakamoto AC. Imaging epilepsy with
SISCOM. Nat Rev Neurol. 2011;7(4):1–2.
7. Ahnlide JA, Rosén I, Lindén-Mickelsson Tech P,
Functional MRI (F-MRI) Källén K. Does SISCOM contribute to favorable
seizure outcome after epilepsy surgery? Epilepsia.
2007;48(3):579–88.
Functional MRI is a noninvasive imaging tech- 8. Van Paesschen W. Ictal SPECT. Epilepsia. 2004;45
nique that has grown in popularity over the past (Suppl 4):35–40.
two decades. Its role has been increasingly rec- 9. Yogarajah M, Duncan JS. Diffusion-based magnetic
ognized in clinical practice to lateralize language resonance imaging and tractography in epilepsy.
Epilepsia. 2008;49(2):189–200.
and motor functions. The intracarotid sodium 10. Luat AF, Chugani HT. Molecular and diffusion
amobarbital angiographic procedure (the tensor imaging of epileptic networks. Epilepsia.
“Wada”) and intraoperative cortical stimulation 2008;49(Suppl 3):15–22.
mapping procedures are still the clinical gold 11. Duncan JS. Imaging the Brain’s highways—diffusion
tensor imaging in epilepsy. Epilepsy Currents.
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these mapping techniques have their own limita- lobe epilepsy. Epilepsia. 2011;52(Suppl 4):32–4.
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parameter: anticonvulsant prophylaxis in patients
Neuropsychological Evaluation
in Epilepsy 22
Madison M. Berl and Leigh Sepeta
behavior to make inferences about brain function • Although there are some findings that focal
and structure. The history is similar to other epilepsy is associated with focal deficits, this
providers where information is systematically is true for adults more than children likely due
gathered through interview with the patient and to the plasticity of children’s brains. There-
their caregivers/spouses, and record review. fore, children do not follow adult profiles.
Formal testing of abilities and behavioral obser- Moreover, even though focal epilepsy may
vations are conducted over the course of one or result in a deficit related to the location of the
more office visits or, less ideally, on an inpatient epilepsy, this is not the only deficit that the
basis. There are numerous neuropsychological person is contending with. For example, a
measures available. Table 22.1 is not an person with left temporal lob epilepsy may
exhaustive list; however, the measures listed are have verbal memory difficulties, but also has
commonly used both clinically and in research in inattention and slow processing speed.
epilepsy populations. Formal testing refers to a • Seizures (focal or generalized) may impact
standardized method of administration and scor- functioning across any or all domains.
ing of responses. A profile of strengths and • Cognitive difficulties may predate and/or
weaknesses is derived by comparing a person’s persist beyond onset, which may indicate
test scores to a normative population of a similar that cognitive difficulties may share a com-
age across domains. Domains of functioning mon underlying neuroanatomic substrate with
include the following: what is generating the seizures.
• Progressive deterioration of cognitive skills is
• General Cognitive Functioning/Intelligence observed in a minority of individuals. As
Quotient (IQ) such, a plateau and/or regression of skills is a
• Language strong impetus for surgery, in particular for
• Memory and Learning hemispherectomy, but any other resection as
• Attention well. Please see below within specific domain
• Executive-Regulatory Function areas for further discussion.
• Visual/Spatial/Nonverbal processing
• Motor There are multiple factors that combine to
• Academic Achievement determine neuropsychological outcome:
• Adaptive Functioning
• Social/Emotional – Age of onset
• Personality – Seizure type
– Underlying pathology
– Neuronal discharges (ictal and interictal)
– Episodes of status
Neuropsychological Findings – Antiseizure medications (ASMs)
by Domain in Epilepsy – Psychosocial
– Public attitudes/stigma
Overview – Individual attitude (e.g., self-worth; depression)
It is long recognized that persons with epilepsy The challenge has been to unravel this com-
have greater incidence of cognitive and psychi- plex picture due to a lack of quality studies and
atric comorbidities (Gowers 1881). Consistent challenges (e.g., suitable controls, complex
with the heterogeneity of seizure disorders, but interactions; sensitivity of neuropsychological
even often within a single type of epilepsy, no test; small sample sizes/lots of tests; validity).
single cognitive profile exists for epilepsy. Other With that caveat, some general cognitive out-
general considerations are as follows: comes include the following:
22 Neuropsychological Evaluation in Epilepsy 295
– Generalized seizures are worse than focal, Nonetheless, even taking this cohort—excluding
and tonic–clonic seizures are worse than the one-third with IQ < 70)—there is a down-
absence ward shift of IQ with a Mean IQ (≈ 90) which
– Earlier onset is associated with more falls in the low average range compared to the
difficulties normal population where Mean IQ = 100.
– Interictal subclinical discharges are associated Risk factors for ID in epilepsy:
with transient cognitive impairment (TCI).
This has mixed evidence, but fewer studies. • Primary generalized epilepsy, West syndrome,
Lennox–Gastaut syndrome, localization-
related epilepsy, but seizure focus difficult to
Intelligence isolate
• Severe volumetric abnormalities
Approximately one-third of people with epilepsy • Early onset of epilepsy
have IQ scores below 70, which falls in the • Frequent seizures, more episodes of status
Intellectually Deficient (ID—formally MR) epilepticus
range. The majority (≈ 2/3) of people with epi- • Polytherapy
lepsy have average range (or higher) intelligence. • Comorbid diagnoses (e.g., autism)
22 Neuropsychological Evaluation in Epilepsy 297
As such, IQ is considered a proxy for out- associated with verbal memory problems.
come, disease severity, and extent of underlying Similarly, right TLE is associated (but not as
pathology. strongly) with visual memory problems. This
finding is the basis of the utility of presurgical
evaluation by providing evidence for location
Language of seizure focus and determining the risk of
postsurgical cognitive deficits. List learning
Along with memory, language is probably one of measures tend to be the most predictive of
the most studied domains in people with epilepsy hippocampal dysfunction.
given that focal epilepsy is most often in the • Unlike for other areas of functioning, there is
temporal, followed by frontal lobes. evidence for progressive loss with continued
seizures which is consistent with the changes
• Language representation: There is a higher seen on MRI.
incidence (25–30%) of atypical dominance • One hypothesis of why memory deficits are
(right or bilateral) than the normal not specific to TLE is that memory perfor-
right-handed population (5%). mance may also be disrupted due to other
– Atypical language dominance is more skills such as poor organization or attention
likely with large, early in development that rely on frontal lobe functions.
insults (e.g., perinatal stroke), with earlier
onset and with left-handedness.
– If language remains ipsilateral to focus,
a left hemispheric focus may have Attention/Executive Functions
impact on language functions (speeded
naming). Beyond the effects of IQ, attention problems are
• Appropriate simple, single-word knowledge, commonly observed.
untimed language skills.
• Adults with TLE frequently have • Prevalence of ADHD is 20–40%.
word-finding problems, which is found by • ADHD Inattentive Presentation is more
confrontation naming tasks (e.g., Boston common, and the boys and girls are equally
Naming Test), which may be related to the represented, which is different from devel-
hippocampal role in word retrieval. opmental ADHD with no seizures.
• Progressive language impairment is associ- • There may be higher rates of attention prob-
ated with Rasmussen’s encephalitis and Lan- lems with FLE and CAE.
dau–Kleffner syndrome, both of which have a • Associated issues such as nocturnal seizures
period of normal language development. or medication side effects may be the primary
cause of inattention.
• Myth that stimulants used for ADHD symp-
Memory toms would lower seizure threshold; however,
many studies have shown this to be untrue.
Similar to language findings, memory difficulties
are commonly associated with TLE. Executive functioning (EF), a set of skills that
is necessary for efficient and goal-directed
• The presence of mesial temporal pathology behavior is less well studied, but is a common
and degree of hippocampal atrophy is asso- difficulty. Aspects of EF that are shown to be
ciated with greater impairment. impaired in people with epilepsy include shifting,
• “Material specificity” of memory problems is cognitive flexibility, working memory, and
true more so in adults such that left TLE is organization.
298 M.M. Berl and L. Sepeta
• Parent questionnaire of EF was a significant attendance, there may be a larger gap following
predictor of performance and helpful in seizure onset.
identifying an “at-risk” group of children with
new-onset epilepsy.
Psychosocial
• Processing speed deficits are the most com- Mapping cognition is a role that may be under-
mon side effect of ASMs. Slower speed is taken primarily by either the neuropsychologist
associated with polytherapy (defined by load or neurologist or as a shared venture.
or toxicity as well as number) and type of
ASM (topiramate; phenobarbital; • Purpose is that the information is needed to
GABA-ergic inhibition). avoid morbidity of surgical procedure.
• Seizure type has been implicated, particularly • Techniques used to map language, memory,
FLE and benign rolandic epilepsy. and motor functions are changing with
available technology.
• Prior gold standard method was to pharma-
cologically inactivate ipsilateral anterior and
Academic Functioning middle cerebral arteries for several minutes.
This procedure is referred to many ways,
Poor academic achievement is associated with all including the intracarotid amobarbital test
epilepsy types. Outcome is moderated by psy- (IAT)/Wada or etomidate speech and memory
chosocial variables. As with other cognitive test (eSAM), and has no standard protocol.
skills, problems may predate seizure onset; The aims are to 1) lateralize function (lan-
however, should seizure control disrupts school guage and memory) and 2) demonstrate the
22 Neuropsychological Evaluation in Epilepsy 299
forward model. The forward model requires an Source Modeling of Epileptic Activity
anatomical model of the head and the struc- and Evoked Responses
tures from which the electrical activity arises.
This is referred to as the head model. Once a When modeling the sources of epileptic activity,
forward model is defined, it is possible to the recorded MEG data are first reviewed visu-
generate many hypotheses about possible gen- ally by an experienced electroencephalographer
erators of the observed sensor measurements to identify epileptic spike events or ictal activity
and identify the hypothesis that best explains which can then be subjected to source modeling.
the measurements. Different source modeling Epileptic spikes seen in MEG may not always
techniques differ in the nature of the forward be seen in the simultaneous EEG recording, and
modeling and the types of generators likewise, not all EEG spikes are represented in
permitted. MEG. Since MEG sees the magnetic component
Of the various source modeling methods that of an electrical event in the cortex, it is in theory
have been developed over the years, equivalent more sensitive to electrical currents that are tan-
current dipole (ECD) modeling has found wide gential to the head surface—as for instance from
use in clinical applications. ECD modeling the banks of sulci. EEG, on the other hand, is
assumes that the electrical generators of activity more sensitive to radial sources, such as those
measured at MEG sensors are point dipoles: a generated at the crests of gyri. In most instances,
source and sink (positive and negative ends) however, epileptic spikes have generators that
separated by an infinitesimally small distance. are several square centimeters in area and have
Although real generators of electrical activity in both radial and tangential components. However,
the brain are not point sources, ECD modeling the spike may lead in one or the other modality
has proven to be clinically useful in localizing the depending on whether the tangential or radial
sources of epileptic spike activity and evoked sources dominate at the onset of the spike.
potentials. Dipolar models are defined by their Once epileptic spikes are identified in the
locations (x-, y-, and z-coordinates in a frame of MEG sensors, dipolar models are typically
reference to which the patients’ head model has employed to localize the sources in clinical
been co-registered) and orientation (defined by 2 applications. Figure 23.1 shows an example of
parameters). Additional “goodness-of-fit” interictal epileptic spike events whose sources
parameters quantify how well a model dipole localize to the right medial temporal regions. Due
accounts for the observed neuromagnetic fields. to the relatively short duration of MEG record-
Several alternative techniques for source ings compared to long-term EEG monitoring
modeling currently exist, for instance techniques studies, ictal events during MEG are uncommon.
that model the generators as a distributed field of However, when ictal activity is recorded, early
point dipolar sources. These distributed source ictal rhythms that precede any head movements
modeling approaches have predominantly been can be subjected to source modeling to localize
used in research applications thus far. Source seizure onset zones. An example of dipolar
modeling methods can also be applied to the source modeling applied to ictal rhythms is
electrical signals recorded by EEG. However, shown in Fig. 23.2.
because magnetic fields are not affected by CSF, There is ample evidence that magnetic source
meninges, skull and scalp, or skull breaches, the modeling of evoked responses can reliably
head modeling requirements for magnetic source localize primary sensory cortices (visual, audi-
modeling are much simpler. This translates into tory, and somatosensory). Figure 23.3 shows an
higher spatial resolution for an equivalent num- example of source modeling of somatosensory
ber of recording locations around the head for evoked response to median nerve stimulation
magnetic source modeling compared to electrical using dipolar modeling and dSPM [3]. Localiza-
source modeling [2]. tion of primary motor cortex using dipolar
304 M. Raghavan
Fig. 23.1 Dipolar sources of epileptic spikes. The panels topographic representation of the event is shown in the
above show an example of dipolar source models of top right panel, along with dipolar sources of a collection
epileptic spike activity. The panel on the far left shows of such events on axial and coronal planes through the
MEG traces from a subset of magnetometers with the dipole cluster in the bottom right panel
cursor marking an epileptic spike event. A sensor level
modeling of motor preparation potentials is, 87% of patients [6]. Using the same methods,
however, less reliable [4]. Alternative methods to Doss et al. [7] found language representation in
localize changes in beta band oscillatory activity the hemisphere to be treated with a concordance
in the motor cortex have been explored with rate of 86% with the Wada test in 35 patients,
greater success [5], although yet to be widely with a sensitivity of 80% and specificity of
adopted. 100%. Several smaller studies have reported
For lateralizing language, neuromagnetic MEG–Wada concordance rates between 69 and
responses to auditory language stimuli have been 100% using a variety of paradigms and analysis
found to be concordant with the Wada test in methods.
23 Magnetoencephalography and Magnetic Source Modeling 305
Fig. 23.2 Dipolar sources of ictal sharp rhythms. The onset as recorded in a subset of MEG sensors. Dipolar
panels above show an example of ictal source modeling sources of successive peaks of the ictal waveform are
using MEG. The traces on the left panel show seizure shown on planar views in the panels on the right
Fig. 23.3 Dipolar and distributed source models (dSPM) A distributed source model for the same point in time is
for somatosensory evoked responses. The left upper panel shown in the bottom right panel (dSPM with a threshold
shows the evoked responses to somatosensory stimulation of p < 0.001). Both the dipole model and maxima of the
of the right median nerve in a subset of MEG sensors in dSPM activation localize to the post-central gyrus in an
the left central region. Dipolar sources at the peak of the area consistent with anatomically predicted hand
response are shown in the top right and bottom left panels. somatosensory representation
resective brain surgery. Therefore, in these and/or asystole. In most patients, the main vagus
patients, VNS Therapy is a viable palliative nerve is the largest of the three nerves
treatment option. (Figure 24.1).
Patients with documented refractory partial epi- A bipolar lead transmits stimulation from the
lepsy who are not eligible for brain surgery, e.g., generator to the left vagus nerve. The lead consists
having multifocal epilepsy, unclear seizure focus, of a pin that connects to the generator on one end,
overlapping eloquent cortex, or those who are and the helices that contain the stimulation
opposed to are considered potential candidates electrodes and anchor tether on the other end.
for the VNS Therapy. VNS may have a limited
role in patients with previous unsuccessful
resective epilepsy surgery. In a recent series, Initial Clinical Trials—Overview
18.75% of such patients had 50% reduction in
seizure frequency with one case of worsening Adjunctive use of left VNS Therapy in patients
seizures, but it may be an option given its with refractory epilepsy was tried in five
potential antipsychotic and mood-stabilizing acute-phase landmark clinical studies in 45 cen-
effects [5]. ters (40 US, 1 Canada, 4 EU). A total of 454
patients were implanted with VNS with a total
patient exposure of 901 device-years. Individual
Vagus Nerve Anatomy and Lead mean patient exposure was 24 months (8 days–
Placement 7.4 years).
Eligible patients were implanted (baseline
The lead electrodes must be placed below where period 12 weeks) and the generator was activated
the superior and inferior cervical cardiac bran- 2 weeks later. In the two randomized, blinded,
ches separate from the vagus nerve. Stimulation active control trials (E03 and E05), patients were
of either of these two branches during the system randomized to: (1) HIGH group (higher fre-
diagnostics (lead test) may cause bradycardia quency, pulse width, higher duty cycle) and
(2) LOW group (active control) and were fol- in degenerative nerve damage. The ON time
lowed for a 14-week treatment period (E05: [6]). OFF time can be induced by continuous or very
frequent magnet activation (> 8 h) and therefore
should be avoided.
Clinical Trials: Efficacy and Safety
The HIGH group showed significant seizure Suggested Initial Dosing Settings
frequency reduction compared with the baseline
and the LOW group (24.5% vs. 6.1%, p = 0.01). The VNS is activated 2 weeks after implan-
In the HIGH group, 31% experienced 50% tation and when the healing process is com-
seizure reduction as opposed to 13% in the LOW pleted. The initial recommended parameters are
group (p = 0.02). The most common adverse as follows:
events were voice alteration and dyspnea. The
treatment was well tolerated and 97% patients – Output current of 0.25 mA,
(306 of 314) continued into the long-term – ON time 30 s/OFF time 5 min,
follow-up phase of the study (Fig. 24.2). – Signal frequencies of 20–30 Hz, and
– Pulse width 250–500 µs.
Stimulation Parameters and Safety It is recommended to keep all AEDs stable for
the first 3 months of VNS before any changes are
VNS Therapy is based on: attempted. The current intensity can be increased
by 0.25 mA every 2–4 weeks, to reach a mini-
– output current, mum of 1 mA over a 6–8 week period, or as
– signal frequency, tolerated. It is also recommended to give the
– pulse width, and patient enough time to adapt before leaving the
– ON/OFF time. office, and before the next increment.
Fig. 24.2 Left median seizure reduction (%) of patients 2 years of follow-up (intent-to-treat analysis). Right
participating in E03 (n = 114) and E05 (n = 105) ran- proportion of patients with 50% seizure reduction in
domized placebo-controlled trials, and all VNS studies the same groups (Ben-Menachem, Lancet Neurol. 2002)
combined (E01–E05, N = 440) at 3 months, 1 year, and
312 G.K. Motamedi
– Hoarseness: up to 60% and may indicate population. Therefore, the recorded rates of
device malfunction, nerve constriction (ap- SUDEP did not seem to have been increased
parent within a few days), nerve fatigue with significantly by VNS Therapy.
intense stimulation parameters (turn off for – Manipulation of pulse generator and lead by
several days until hoarseness subsides), and patients through the skin (Twiddler’s syn-
persistent hoarseness not associated with drome): may damage or disconnect the lead
stimulation suggests nerve irritation (requires from the generator (Cyberonics.com, Physi-
immediate investigation). cian’s manual).
– Dysphagia and aspiration: there is higher risk
with preexisting swallowing difficulties.
– Dyspnea: higher risk with underlying COPD
or asthma. Precautions
– Obstructive sleep apnea (OSA): higher risk of
apneic events during the stimulation with Cardiac evaluation: in case of family history,
OSA (lower stimulus frequency of 2 Hz or past medical history, or EKG indications of
longer “OFF” time recommended). Since new dysfunctional cardiac conduction systems (reen-
onset cases of OSA have been reported, prior try pathway).
evaluation in high-risk patients should be Serum electrolytes: Mg2+, Ca2+ levels to be
considered. checked before implantation.
– Nerve damage with device malfunction: may Postoperative bradycardia: can occur in
cause painful stimulation (tape magnet over patients with cardiac arrhythmias; consider
the generator to stop stimulation if suspect a postimplant EKG and Holter monitoring.
malfunction; evaluate for possible surgical Bradycardia (<40 bpm) and/or asystole:
intervention). may occur during intraoperative system diag-
– Laryngeal irritation: more common in nostics (lead test). In such patients cardiac
smokers. monitoring at the time of device activation is
– Lead break: may prevent patients from recommended.
receiving efficient therapy. If diagnostics
suggest a fracture, turn the pulse to 0 mA
output current (to prevent possible dissolution Optimizing Parameters
of the conductor material hence pain, and Alleviating Side Effects
inflammation, and vocal cord dysfunction).
– Trauma to the vagus nerve: can occur during Optimizing Results
surgery and can result in permanent vagal
nerve dysfunction. This can be achieved by increasing output cur-
– Sudden unexplained death in epilepsy rent and/or modifying ON/OFF times (duty
(SUDEP): through August 1996, 10 cycle).
(definite/probable and possible) cases were
recorded among 1000 VNS patients (2017
patient-years of exposure) indicating an inci- Managing Side Effects
dence rate of 5/1000 patient-years. However,
estimates for non-VNS epilepsy patients The following steps may be taken as needed to
range from 1.3 to 3.5 in the epilepsy popu- alleviate side effects: decreasing signal frequency
lation and 9.3 in surgical candidate (from 30 to 20 Hz) or decreasing output current
24 Vagus Nerve Stimulation and Other Neuromodulation 313
(by 0.25 mA). If decreasing the output current closed-loop responsive neurostimulation
does not achieve tolerability, lowering the pulse (RNS) of intracranial structures [8]. The DBS
width (from 500 to 250 ls) may be considered. (thalamic stimulation) has not yet been approved
by the FDA, but it has been recently approved in
Europe [3]. The RNS system (NeuroPace device)
VNS Warning with MRI has been FDA approved in late 2014. There are
also early reports of potential benefits of stimu-
The VNS is MRI compatible including 1.5T and lating other extracranial sites (e.g., trigeminal
3T scanners. Head and extremity scans are nerve) ([9–11]).
allowed using a transmit and receive type of RF
coil. Before patient enters into the MR system
room, both output current and magnet current Responsive Cortical Stimulation
should be set to 0 mA since MRI-induced mag-
netic field may cause magnet-mode activation and Besides VNS, the other FDA-approved neu-
stimulation. After the MRI is done, reprogram- rostimulation intervention is the responsive neu-
ming is needed to restore the setting parameters. rostimulator (RNS), NeuroPace®. The idea of
MRI should not be performed on patients with RNS is based on studies that showed short trains
lead breaks, see product labeling for all condi- of electrical stimulation can stop afterdischarges
tions. Diathermy (shortwave, microwave, thera- [12, 13]. Eligible candidates are patients with
peutic—not diagnostic—ultrasound) should not focal epilepsy with a well-defined but
be used on VNS Therapy patients. non-resectable epileptogenic zone such as elo-
quent cortex or bilateral mesial temporal foci.
A multicenter, double-blinded, randomized trial
Mechanism(s) of Action of VNS involving 191 patients with partial epilepsy was
conducted ( 3 seizures/month, 1 or 2 seizure
The precise mechanism of action of VNS foci). Responsive neurostimulator detecting
remains unknown. In animal models (maximum abnormal EEG connected to depth or subdural
electroshock, PTZ, alumina gel, strychnine, kin- leads was placed at 1 or 2 seizure foci. The pulse
dling), VNS prevented seizures or seizure spread generator connects with the electrodes and is
(except for the alumina gel model). A series of placed in the skull. One month after implanta-
facts have been considered to play a role in its tion, the subjects were randomized to receive or
function, e.g., VNS affects heart and respiratory not receive (sham) stimulation. After a 12-week
rates, vagus-initiated activity in the brain has blinded phase, all patients received unblinded
been localized through use of fos1 immunoreac- stimulation for 84 weeks. By the end of the
tivity, regional brain glucose metabolism (in blinded phase, stimulated group had a 37.9%
animals), and via PET imaging in human. The seizure reduction compared to the sham group at
newest version of VNS labeled Aspire adds the 17.3% (p = 0.012) [8].
advantage of cardiac rhythm detection of At 5 months postimplantation, 41.5% seizure
seizures. reduction was seen in the stimulation group
compared to a 9.4% reduction in the sham
group. The seizure reduction continued to
Investigational Neurostimulators improve during a subsequent open-label phase
where both arms received stimulation. A 50%
In recent years, two pivotal trials of neurostim- responder rate (those who achieved 50% or more
ulation in humans with drug-resistant epilepsy reduction of seizure frequency) was seen in 55%
have been conducted: deep brain stimulation after two years. The median percentage seizure
(DBS) via chronic programmed bilateral stimu- reduction was seen in 44% (at 1 year), and 53%
lation of anterior thalamus (SANTE trial) [7] and (at 2 years) of patients. Intracranial hemorrhages
314 G.K. Motamedi
and infections each occurred in about 2% of population-based studies from Rochester, Minnesota.
implanted patients, but neither mood nor cogni- Mayo Clin Proc. 1996;71(6):576–86.
2. Sillanpää M, Jalava M, Kaleva O, Shinnar S.
tive function worsened, and quality of life Long-term prognosis of seizures with onset in
improved. Similar to the findings in VNS Ther- childhood. N Engl J Med. 1998;11;338(24):1715–22.
apy, seizure reduction appeared to further 3. Bergey GK. Neurostimulation in the treatment of
improve over time (p < 0.0001) and the RNS epilepsy. Exp Neurol. 2013;244:87–95.
4. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ,
was well tolerated with acceptable safety [14]. et al. Definition of drug resistant epilepsy: consensus
proposal by the ad hoc Task Force of the ILAE
Commission on Therapeutic Strategies. Epilepsia.
Electrical Stimulation of the Anterior 2010;51(6):1069–77.
5. Koutroumanidis M, Binnie CD, Hennessy MJ, et al.
Nucleus of the Thalamus (SANTE Trial) VNS in patients with previous unsuccessful resective
epilepsy surgery: antiepileptic and psychotropic
A multicenter, double-blind, randomized clinical effects. Acta Neurol Scand. 2003;107(2):117–21.
trial including 110 patients with partial epilepsy 6. DeGiorgio CM, Schachter SC, Handforth A, et al.
Prospective long-term study of vagus nerve stimula-
(baseline seizure frequency 19.5/month) was tion for the treatment of refractory seizures. Epilep-
conducted. After a 3-month blinded phase half of sia. 2000;41(9):1195–200.
the patients received stimulation and the other 7. Fisher R, Salanova V, Witt T, et al. Electrical
half received no stimulation. Then, all patients stimulation of the anterior nucleus of thalamus for
treatment of refractory epilepsy. Epilepsia. 2010;51
received unblinded stimulation. In the last month (5):899–908.
of the blinded phase, the stimulated group had a 8. Morrell MJ, RNS System in Epilepsy Study
29% greater seizure reduction compared with the Group. Responsive cortical stimulation for the treat-
control group (p = 0.002) [7] (Fig. 24.3). ment of medically intractable partial epilepsy. Neu-
rology. 2011;27;77(13):1295–304.
9. DeGiorgio CM, Murray D, Markovic D, White-
hurst T. Trigeminal nerve stimulation for epilepsy:
References long-term feasibility and efficacy. Neurology.
2009;10;72(10):936–8.
10. DeGiorgio CM, Soss J, Cook IA, et al. Randomized
1. Hauser WA, Annegers JF, Rocca WA. Descriptive controlled trial of trigeminal nerve stimulation for
epidemiology of epilepsy: contributions of drug-resistant epilepsy. Neurology. 2013;26;80
(9):786–91.
24 Vagus Nerve Stimulation and Other Neuromodulation 315
11. Pop J, Murray D, Markovic D, DeGiorgio CM. 13. Motamedi GK, Lesser RP, Miglioretti DL, et al.
Acute and long-term safety of external trigeminal Optimizing parameters for terminating cortical after-
nerve stimulation for drug-resistant epilepsy. Epi- discharges with pulse stimulation. Epilepsia. 2002;43
lepsy Behav. 2011;22(3):574–6. doi: 10.1016/j. (8):836–46.
yebeh.2011.06.024. 14. Heck CN, King-Stephens D, Massey AD, et al.
12. Fernández IS, Loddenkemper T. Electrocorticogra- Two-year seizure reduction in adults with medically
phy for seizure foci mapping in epilepsy surgery. intractable partial onset epilepsy treated with respon-
J Clin Neurophysiol. 2013;30(6):554–70. sive neurostimulation: final results of the RNS
System Pivotal trial. Epilepsia. 2014;55(3):432–41.
Epilepsy Surgery Assessment
and Testing 25
Gholam K. Motamedi
Presurgical Evaluation
tapered down in order to record electrographic function of each temporal lobe separately to
and clinical seizures for the above purposes. determine whether the nonepileptic side would
Patients also need appropriate neuroimaging be capable of handling memory function by itself
studies including high-resolution epilepsy proto- after the affected temporal lobe is surgically
col MRI and other available imaging technologies removed. The test also can assist with seizure
as indicted or available such as MR spectroscopy onset side since there is typically concordance
(MRS), positron emission tomography (PET), between the seizure onset side and poor memory
single-photon emission computed tomography function on that side (upon contralateral
(SPECT), or magneto-encephalography (MEG). injection).
In case the scalp recording is of limited value,
patients who are considered potential candidates
for surgical treatment may need invasive Case Presentation #1
recordings using strips, grids, or depth electrodes
and possibly cortical mapping before an appro- A 28-year-old woman with past medical history
priate surgical procedure could be planned. After of seizures since age 9 years presented with the
lateralization and localization of the seizure onset episodes of staring and left-hand clenching before
focus, potential surgical candidates should convulsion (focal dyscognitive seizures with
undergo a series of tests for further evaluation to secondary generalization). These events occur
define their final candidacy for an appropriate twice a week on average. She had been on mul-
surgical treatment including neuropsychological tiple ASMs in the past without much improve-
testing and functional MRI or intracarotid amo- ment. She has given up college and her previous
barbital procedure (IAP, Wada test). jobs since she could not concentrate, drive a car,
or work. Currently, she suffers from tremor, and
memory and concentration problems. Her serum
Neuropsychology analysis shows high levels of phenytoin and val-
proate. A routine EEG and high-resolution brain
The main questions that are addressed by a neu- MRI were obtained (Figs. 25.1 and 25.2).
ropsychological test include determining parts of Her presurgical evaluation indicated that she
the brain that are impaired. In particular, higher was a good candidate for a right anterior tem-
cognitive functions such as verbal and visual poral lobectomy (Fig. 25.3). During the presur-
memory and language are studied. The test also gical evaluation, she was started on
helps establish a baseline for future comparison. levetiracetam, and her phenytoin and valproate
This helps predict potential postsurgical deficits. were tapered off. Later, prior to her surgery, she
Studies have shown that the best predictor of responded better to combination therapy with
postoperative adequacy is the preoperative cog- levetiracetam and lamotrigine; i.e., her seizures
nitive and psychosocial status; i.e., the lower the were less frequent and her side effects improved
preoperative cognitive and psychosocial status, significantly. The patient became seizure free
the lower the risk for further decline [2, 3]. after a right anterior temporal lobectomy and was
kept on a lower dose of monotherapy with one of
her ASMs (follow-up >4 years).
Intracarotid Amobarbital Procedure
(Wada Test)
Is Epilepsy Surgery Warranted?
This test “imitates” the prospective temporal
lobectomy by temporarily inhibiting unilateral Randomized, controlled trials (RCT) to assess
brain functions using a drug. Therefore, it helps the efficacy and safety of epilepsy surgery were
lateralizing language dominance and memory missing till 2001. In the first such study [4], 80
function. The Wada test evaluates memory patients with temporal lobe epilepsy (TLE) were
25 Epilepsy Surgery Assessment and Testing 319
study confirmed that in TLE, surgery is superior (1) continued ASM (n = 23), or (2) anterior
to prolonged medical therapy. This RCT also mesial temporal lobectomy (AMTR) plus ASM
showed that randomized trials of surgery for treatment (n = 15) and were followed for two
epilepsy are feasible and appear to yield precise years. The primary outcome was seizure freedom
estimates of treatment effects. during the second year of follow-up, and the
secondary outcome was health-related quality of
life (QOL), cognitive function, and social
Early Randomized Surgical Epilepsy adaptation.
Trial (ERSET) Seizure freedom during the second year of
follow-up was reported in 11 of 15 patients in the
It has been well established that years of active surgical group versus none of the 23 in the
epilepsy predict cognitive impairment in children medical group (P < 0.001). Also, improvement
and adolescents [5, 6]. Therefore, in order to of QOL was higher in the surgical group
investigate the effects of early surgery, i.e., (P = 0.01). Memory decline occurred in 4
whether it would be superior to continued med- patients (36%) after surgery. Adverse events
ical management, Engel et al., conducted a included one stroke in a surgical case versus 3
multicenter, parallel-group RCT soon after the cases of status epilepticus in the medical group. It
failure of 2 ASM trials in patients with temporal was concluded that resective surgery plus ASM
lobe epilepsy [7]. Thirty-eight patients (18 M/20 in patients with new refractory MTLE results in
F; age 12 years) with MTS and refractory lower probability of seizures during second year
MTLE who were within 2 consecutive years of of follow-up than continued ASM treatment
adequate trials of 2 ASMs were randomized to alone.
25 Epilepsy Surgery Assessment and Testing 321
to be the predictor of excellent long-term seizure but no memory decline in the right SAH group
control, while less disparity in the memory score was seen while some even showed improvement
between the sides was the predictor of persistent [20].
seizures.
SAH in TLE patients with MTS results in Standard Versus Selective Temporal
seizure-free outcomes comparable to procedures Lobe Surgery
with more extensive temporal neocortical resec-
tions [17]. Although this method was introduced A meta-analysis of standard anterior temporal
to minimize the neurocognitive side effects of lobectomy (ATL) versus selective SAH for sei-
temporal lobectomy, interestingly, at this point zure control in TLE included 11 studies (1203
there is more controversy regarding postopera- patients) and concluded that ATL is more likely
tive neuropsychological outcomes, rather than to achieve an Engel Class I outcome compared
seizure-free outcome, when compared to stan- with SAH (p < 0.01). Standard ATL confers
dard ATL. Some studies have suggested that better chance of achieving freedom from dis-
SAH results in better cognitive function com- abling seizures in patients with TLE [23].
pared to ATL [10], while others have shown no
evidence of a clear neurocognitive benefit and in
fact SAH might cause significant verbal memory Right Versus Left Temporal Lobectomy
deficits in dominant temporal lobe resection [18, (RTL vs. LTL)
19].
In another study, 76 adult patients with SAH Comparison of neuropsychological outcome
for MTLE via the trans-middle temporal gyrus following RTL versus LTL shows postoperative
approach reported 92% Engel Class I or II with decline in verbal memory after LTL, perfor-
very low surgical morbidity and no mortality. mance intelligence decline after LTL (depending
Postoperative neuropsychological testing showed on infero-lateral and basal region removal), and
verbal memory decline in the left SAH group, visuospatial memory outcome after RTL
25 Epilepsy Surgery Assessment and Testing 323
(depending on basal and hippocampal region foci while preserving the language and sensory
removal). More resection is associated with cortex as depicted above. He had no language
worse functioning and vice versa [24]. deficits after the resection. He has been com-
pletely seizure free since the surgery while con-
tinuing only one of his ASMs at minimal dose
Case Presentation #2 (he had one breakthrough seizure 5 years later
after stopping his ASM but has remained seizure
A 43-year-old man developed seizures two years since resuming the ASM (follow-up since
after surviving a left temporal aneurysm rupture. surgery >6 years)).
Following the surgery and aneurysm resection,
he did well until the seizures started. Multiple
ASMs were tried but he continued having partial Case Presentation #3
seizures with secondary generalization about
twice a month. His brain MRI findings were A 35-year-old woman presented with seizures
consistent with his history of prior surgery and an since age 5 years. She described her seizures as
encephalomalacia involving the posterior tem- “day dreaming, head turning, lip smacking,
poral lobe. His video-EEG monitoring localized right-hand posturing and at times convulsions.”
his seizure onset focus to the left temporal area In the past, she had been on phenobarbital since
including the posterior regions. His Wada test childhood, as well as several other ASMs. Her
lateralized language to the left side and showed a current seizure frequency is about 3 times per
significantly better memory function on the right. week. She lives with her family, has never
He was admitted for subdural grid placement in worked, and does not drive. Her mother reports
order to accurately localize the epileptogenic behavioral problems (outbursts). After the first
zone and perform language mapping prior to a visit, while starting her presurgical evaluation,
prospective left temporal resective surgery her ASM was changed to levetiracetam that
(Figs. 25.4, 25.5, and 25.6). resulted in some improvement in seizure fre-
Cortical mapping defined the language cortex quency, but later she responded better to the
next to the seizure focus. The patient underwent a combination therapy of levetiracetam and lam-
left temporal lobectomy including the seizure otrigine (i.e., her seizures decreased to 1–2 per
Fig. 25.5 Ictal discharges mainly limited to electrodes 23 and 31 (red), before spreading and secondary generalization;
patient aware
Fig. 25.7 Buildup of rhythmic ictal discharges in few left mesial–basal temporal electrodes. The patient underwent a
standard left ATL and has been completely seizure free since the surgery with no new deficits (follow-up >5 years)
month). Her high-resolution brain MRI was (complex-partial): 237 (59%), GTCS: 119 (30%),
normal. A routine EEG showed left temporal focal without alteration of awareness
spikes and video-EEG monitoring revealed left (simple-partial seizures): 26 (6%), and mixed: 17
temporal ictal onset, but there were a few sei- (4%). Of these 372 (93%) had temporal lobe, and
zures with indeterminate localization. An inva- 27 (7%) extra-temporal lobe resections. The
sive monitoring using subdural strip electrodes pathology showed MTS in 113 patients (28%),
was performed to confirm the localization gliosis in 237 (59%), and normal tissue in 49
(Fig. 25.7). Resective surgery was curative. (12%). The overall Engel Class I outcome is
given as follows:
92% probability of seizure remission at 10 years. The negative predictors (risk factors) were
Negative risk factors included (1) extra-temporal (1) higher baseline seizure frequency and
seizure focus (p < 0.001), (2) previous surgery (2) preoperative generalized tonic–clonic sei-
(p < 0.001), (3) male gender (p = 0.035), and zures. Memory decline was reported with domi-
(4) normal tissue in pathology (p = 0.038). nant hippocampus resections [26].
Fig. 25.9 Clinical seizure; arousal from sleep; movement artifact with no clear epileptiform discharges
Fig. 25.11 Bilateral subdural strips placed through burr holes for seizure onset focus lateralization (Phase 2a). From
left: frontal, left oblique, and left lateral views
Fig. 25.12 Left temporal rhythmic delta discharges recorded 10 s from seizure onset, indicating a far-field recording
from a remote focus (such as frontal lobe) that had spread to the temporal lobe
After lateralizing the seizure onset of the left yellow) indicating the epileptogenic zone located
hemisphere in Phase 2a through bilateral strips, on the edge of the fronto-polar electrode grid.
the patient underwent a second surgery by plac- Cortical mapping was performed on the most
ing more extensive grid electrodes to cover the anterior row of the superior posterior frontal grid
medial inter hemispheric, fronto-polar, superior and did not reveal any eloquent cortex.
posterior, and inferior posterior frontal lobes on Figure 25.14 shows the 3D reconstruction of
the left for accurate seizure localization as well as the seizure onset electrodes (red) and those to
cortical mapping as indicated. EEG recording which seizures rapidly spread (brown and yel-
(not shown) indicated the seizure onset elec- low). Since the seizure onset zone was located on
trodes shown in red along with electrodes to the edge of the grid, the resection included the
which the seizures rapidly spread (brown and colored electrodes in the top two rows of the grid
25 Epilepsy Surgery Assessment and Testing 329
Fig. 25.13 Location of the seizure onset zone and interictal discharges on the intracranial electrodes
(Engel Class I outcome) in 45.1%. Significant indicated supplementary motor area (SMA)-type
predictors of long-term seizure freedom included seizures. Her high-resolution MRI showed a
lesional origin, abnormal MRI, and localized small area of increased signal intensity in the
frontal resection (vs. more extensive lobectomy). bottom of a gyrus in the right mesial frontal area
In patients with lesional FLE, improved outcome at the convexity, corresponding to the distal
was more likely to be achieved after gross-total lower extremity on the left. Therefore, she
resection rather than subtotal lesionectomy [27]. underwent invasive recording using subdural
In another study, 25 patients with history of grid electrodes covering the right frontal and
resective surgery after intracranial EEG record- temporal regions including motor and sensory
ing were reviewed. A seizure-free (Engel Class cortex, and a dual-sided 2 8 strip to record
1) outcome was seen in 15 patients (60%), while directly from the SMA. Her invasive recording
10 patients (40%) continued to have seizures revealed very frequent interictal spikes and sei-
(Classes II, III, and IV). Risk factors for lack of zures onset zone at the juncture of motor cortex,
seizure freedom included: pre-SMA but less in the SMA proper, with
spread anteriorly. Of note, the ictal discharges
– Left frontal lobe epilepsy surgery; consisted of very high-frequency (beta and
– Dominant hemisphere; gamma) discharges. After discussing the options,
– Patients without aura; the patient underwent an awake surgery for a
– Interictal epileptiform discharges in scalp limited resection including the pre-SMA and part
EEG; of the SMA proper preserving the motor (foot
– Intracranial EEG widespread (>2 cm) in and leg) cortices. Pathology confirmed focal
contrast to focal seizure onset; cortical dysplasia. She had a transitory left-sided
– Shorter latency to onset of seizure spread; and paresis following the surgery with excellent
– Ictal involvement beyond frontal lobe. recovery following rehabilitation. She remained
seizure free for one year after which her noctur-
Lack of seizure freedom is likely because of nal seizure resumed but at a significantly lower
widespread epileptogenicity (as indicated by frequency (90% of decrease) and was milder in
rapid spread of ictal activity). Early resection severity. She had no more diurnal seizures for
may improve seizure outcomes of FLE surgery, 3 years but has had rare seizures during the day
particularly in children [28, 29]. over the last 2 years (follow-up since sur-
gery >6 years). Given her condition and the
Case #5 presence of comorbidities (obstructive sleep
A 52-year-old woman presented with seizures apnea and asthma requiring steroids and resultant
since age seven; she attributed her seizures to an weight gain complicating her apnea manage-
accident two years earlier when an axe fell on her ment), her medications have not been tapered.
head. Her seizures presented as sudden arm and
leg extension with no clear loss of awareness that
happened up to 10 times day (mostly nocturnal). Supplementary Motor Area
She had tried all available ASMs (had a preg- (SMA) Seizures
nancy on phenytoin and phenobarbital with fetal
in utero exposure and congenital defects in the These seizures presented with tonic posturing of
baby). At the time of presentation, she was on 4 the extremities, usually bilateral, and may appear
ASMs at high doses. Her EEGs had been always as “fencer posturing.” Awareness is typically
normal, and in the past she had been diagnosed retained during these seizures. The primary
with “pseudoseizures” by her neurologist. epileptogenic zone is usually outside the SMA
Her scalp monitoring showed no interictal or with rapid spread to the SMA, hence the semi-
ictal EEG discharges while numerous typical ology. The interictal, and even ictal, EEG is often
seizures were recorded. The seizure semiology unrevealing. If the seizure onset focus is outside
25 Epilepsy Surgery Assessment and Testing 331
the SMA, resection of epileptogenic zone alone, manent deficits in about one-third of patients
leaving the SMA intact, might be enough [30]. with MST performed in eloquent cortex. There-
Synchronous interictal/ictal discharges in SMA fore, MST surrounding a lesionectomy may
and primary cortex with a time lag of 25/100 ms. minimize the excised volume and improve sei-
have been reported [31]. Resecting the EEG zure control [35].
onset zone within the SMA while sparing pri- However, a meta-analysis of data from 6
mary motor cortex may result in >90% seizure major epilepsy centers (211 patients, 53 with
reduction [32]. Following the SMA resection, MST alone) reported similar results between the
while preserving primary motor cortex, a transi- MST plus resection and MST alone procedures:
tory paresis or severe deficits without permanent The MST plus resection resulted in >95% seizure
loss of motor or speech functions may be seen reduction (GTCS 87%, CPS 68%, SPS 68%),
(typically lasting 24 h), but favorable surgical compared to >95% seizure reduction (GTCS
outcome is common [33]. 71%, CPS 62%, SPS 63%) in MST alone group.
The outcome seemed to be independent of
factors such as EEG localization, MST location,
Multiple Subpial Transection (MST) age at onset, or duration of epilepsy. These results
suggest that MST may be efficient by itself, with
This technique was introduced to spare the minimal neurologic compromise, and should be
eloquent cortex in patients in whom the epilep- investigated as a stand-alone procedure [36].
togenic zone lies in eloquent cortex. The NST is
based on the notion that epileptogenic dis-
charges require side-to-side (horizontal) interac- Overall Seizure-Free Outcome
tion of cortical neurons while the major
functional properties of cortical tissue depend The overall seizure-free rates following different
upon the vertical fibers. Therefore, severing the types of surgery in different brain regions are
tangential intracortical fibers in the seizure focus reported as follows:
using a small blade is performed, while vertical
fiber connections and blood vessels are pre- Temporal lobectomy: 55–80%
served [34]. Frontal lobe resections: 5–18%
In a report of 21 patients (18 intractable epi- Frontal lobectomy: 23–68%
lepsy and 3 Landau–Kleffner syndrome (LKS)) Parietal lobe resections: 45%
who underwent either resection plus MST (12) or Occipital resections: 46–88%
MST alone, in precentral and postcentral regions Hemispherotomy: 60%
(follow-up: *1–5 years), significant seizure
reduction was seen in 11 of 18 patients (61%)
and 3 LKS patients. The latter group who were
mute before operation showed significant speech Epilepsy Surgery—Long-term
recovery. There were no chronic neurological Outcome ( 5 Years)
deficits. Other studies have reported up to 56%
seizure freedom and 95% seizure reduction in Excellent short-term results of resective epilepsy
patients with intractable epilepsy arising from surgery have been well established. Therefore,
eloquent cortex following combined resection review and meta-analysis of long-term outcomes
and MST versus no seizure freedom and >50% of largest case series of patients of any age after
seizure reduction in those treated with MST resective or non-resective epilepsy surgery have
alone. Predictor of complete seizure freedom been attempted. After a mean follow-up of
appears to be the disappearance of epileptiform 5 years, resective surgery resulted in the fol-
discharges in the post-op EEG. Subtle, but per- lowing seizure freedom rates:
332 G.K. Motamedi
Temporal lobe resections: 66% Scalp ictal EEG is rarely localizing. Parietal
Occipital and parietal resections: 46% lobe seizures have more variable scatter of
Frontal lobe resections: 27% interictal EEG discharges and less localizing ictal
Multiple subpial transections: 16% discharges compared to temporal or frontal lobe
Callosotomy (free of most disabling seizures): seizures. Overall, the semiology is of less value
35% in these patients. High-frequency oscillations
(HFOs) may be useful for localization as they
Therefore, long-term seizure-free rate follow- more concentrated in seizure focus.
ing temporal lobe resective surgery appears to be Postoperative sensory deficits such as tempo-
favorable similar to that of short-term-controlled rary partial hemisensory or Gerstmann syndrome
studies, but it is consistently lower after may be seen when corticectomy involves
extra-temporal or palliative surgeries [37]. post-central gyrus. However, resective surgery
can result in seizure freedom or significant sei-
zure reduction especially when a lesion is pre-
Failed Epilepsy Surgery sent. The most common pathologies include
and Reoperation low-grade tumors, cortical dysplasia, gliotic
scars, or cavernous vascular malformations.
Reoperation following a failed previous surgery Complete or nearly complete seizure freedom
can be an efficacious and reasonably safe has been reported in 65–67.5% of patients with
approach. Successful reoperation has been favorable outcome factor being the absence of
reported in patients with concordance between post-resection epileptiform discharges on the
their postsurgical imaging and electroclinical EEG [40–43].
findings, and no brain trauma or infection before
their seizure onset. A review of 15 case series
including 402 adult patients reoperated 2–
5.5 years later (reoperation rate: 3.8–14%; Occipital Lobe Epilepsy
follow-up of 6 months–4 years) post-reoperation
seizure freedom was reported at 36.6% and Auras are reported in 88% of these patients. The
complications rate at 13.5% [38]. auras consist of elementary visual hallucina-
It is also safe to use subdural grid electrodes tions, ictal amaurosis, eye movement sensations,
in patients with prior craniotomy with favorable early forced blinking or eyelid flutter, and con-
long-term seizure-free outcomes. In these tralateral visual field deficits. There is often
patients, ictal onset at the edge of original sur- eye/head deviation (usually contralateral to the
gical bed (more with lesional epilepsy) seems to side of seizure origin), loss of awareness, vari-
be a predictor of seizure freedom [39]. ous types of automatism, fumbling (typical for
temporal lobe seizures), and at times asymmet-
rical tonic or focal clonic motor patterns (char-
Parietal Lobe Epilepsy acteristic of frontal lobe seizures). Medial or
lobar lesions are more likely to cause visual field
Auras are commonly present in these seizure; 94% defects. The scalp EEG is rarely localizing [44,
of patients report somatosensory auras (painful 45]. Intracranial EEG recording correctly iden-
dysesthesias), vertigo, aphasia, or disturbances of tifies occipital lobe seizure origin in most, but
one’s body image. The ictal propagation to the not all of these patients. The variability in
SMA may result in hypermotor manifestations semiology depends on seizure spread patterns,
while propagation to the temporo-limbic regions i.e., medially, laterally, above/below the sylvian
may result in complex visual or auditory halluci- fissure, both ipsilateral and contralateral to the
nations and automatisms. seizure origin.
25 Epilepsy Surgery Assessment and Testing 333
After, focal resection seizure freedom is seen significant and long-term improvement in their
in 46–88% of patients. The most common cognitive processing speed, in particular those
pathologies include dysplasia, tumors, and glio- who were on no ASM [48].
sis. Following resection, about 50% of patients
will not experience any new visual deficits while
new quadrantanopia or hemianopia has been Extra-temporal Epilepsy Surgery
reported in 17%. Tailored resections (e.g., in in Children
lateral occipital lesions) may help preserve intact
vision in about 38% of patient [46]. In general, surgical outcomes for extra-temporal
lobe epilepsy (ETLE) are worse than those for
TLE. A meta-analysis of the available literature
Insular-Opercular Seizures (17 studies, 95 patients) reported that pathology
(cortical dysplasia) and seizure type (CPS) were
These seizures usually present as nocturnal the positive outcome predictors. Factors con-
complex motor seizures. The auras include vis- tributing to less favorable outcome seem to be
cerosensitive or somatosensory symptoms. Ictal diffuse nature of pathology involved in ETLE,
semiology consists of asymmetric tonic–dystonic difficulty localizing the seizure focus in young
posturing and/or hyperkinetic automatisms children, and involvement of “eloquent” cortex
(bimanual/bipedal activity and ballistic move- [49].
ments). Simultaneous insular and opercular ictal
discharges are present. Complex motor mani-
festations are seen when the seizure spreads to Ictal Onset High-Frequency
frontomesial regions (cingulum, superior frontal Oscillations
gyrus, and SMA) and/or mesial and neocortical
temporal lobe structures. Retrospective review of high-frequency oscilla-
Favorable outcome can be achieved with tions (HFOs > 80 Hz; sampling rate: 2000 Hz)
insular-opercular cortical resections. The most recorded in intracranial EEG in pediatric patients
common underlying pathology is focal cortical suggest a high prevalence of ictal HFO zones in
dysplasia [47]. 93% of patients. Complete resection of ictal
HFOs, regardless of the frequency bands, is highly
correlated with a favorable surgical outcome. In
Epilepsy Surgery in Children one series, complete resection resulted in 82%
seizure freedom versus 21% after incomplete
Epilepsy surgery is commonly performed in resection. The most common pathology in these
children. The long-term outcome (5–21 years) patients was cortical dysplasia [50].
studied in 47 children with age at surgery ranging
from 0.5 to 18.7 years (mean 8) reported 49%
(23/47) seizure freedom and >75% seizure References
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Procedures and Outcomes
in Epilepsy Surgery 26
Ronald P. Lesser
Although surgery has risks, there are several nearby might react in way that could add addi-
reasons to consider it for patients with epilepsy. tional harm or danger.
First is the possibility of harm to the patient if Fourth are risks related to side effects of
surgery is not done, because of continued sei- anticonvulsants, particularly if patients have fre-
zures. In a study in 1997, Buck and coworkers quent seizures with the need for higher doses or
[1] found that of 300 patients with at least one for additional numbers of medications. Addi-
seizure in the previous year, 24% had sustained a tionally, for women of childbearing age, anti-
head injury, 16% had burned or scalded them- convulsants impose risks on a developing fetus,
selves, 14% had a seizure while bathing or and, for young children, seizures and medica-
swimming with the risk of drowning, 10% had a tions impose risks on development.
dental injury, and 6% had a fracture. Over the last several decades, there have been
Second, beyond actual injury is the important a number of new medications which can be used,
entity SUDEP (sudden unexpected death in epi- but unfortunately, many patients continue to
lepsy patients), an entity that may be more have seizures despite these. Overall, only 2/3–3/4
common in patients with more generalized con- of patients can be seizure-free on medication [2].
vulsive seizures and in patients in their third Studies have shown that patients with intractable
through fifth decades of life. The reason for death seizures undergoing surgery are significantly
in these patients is not known, but it is clear that more likely to be seizure-free after surgery than if
patients with seizures, particularly with intract- they continue on medication alone [3].
able seizures, can be found dead without a clear Before operating, however, we need to
explanation other than the fact that they have determine whether surgery is appropriate for the
epilepsy. particular patient, and, if so, which. Less invasive
Third are the effects that ongoing seizures, evaluations should be performed first, with
particularly those affecting consciousness, have questions to answer including the following:
on a person’s daily life. One cannot drive. One What do the clinical symptoms suggest about
may have a seizure in public or in an unfamiliar region of seizure onset? Is there a focal lesion
situation and be unable to care for oneself. Those that can be resected? Is there a focus that can be
found on EEG? Is the focus accessible surgi-
cally? Is the focus surgically separate from
regions controlling important functions? Would a
procedure other than focal resection be better?
R.P. Lesser (&) Because the symptoms of seizures can vary and
Department of Neurology, Johns Hopkins University
because of the possibility of seizures beginning
School of Medicine, 600 North Wolfe Street, 2-147
Meyer Building, Baltimore, MD 21287-7247, USA in one place but projecting to another, it is
e-mail: rl@jhmi.edu important to correlate the behaviors with the
EEG findings during the episodes, and for this eye, head, or body turning with tonic or dystonic
reason, patients should be referred for video EEG posturing. Orbital frontal seizures can include
monitoring so that actual seizures can be recor- unusual behaviors including hypermotor activity
ded and patient behaviors during the seizures such as rapid leg kicking or bicycling and can
analyzed. have autonomic findings, behavior arrest, and
automatisms of other types. These characteristi-
cally occur frequently during sleep and last a
Symptoms relatively short period of time. Seizures from the
frontal operculum can include salivation and
Temporal lobe seizures are the most commonly swallowing. Inferior frontal onset can include
evaluated for surgery. Onsets of seizures from findings referable to the face or to speech. Dor-
the temporal lobe can include epigastric, olfac- solateral or dorsomedial onset seizures can
tory, and gustatory sensations, emotional chan- include contralateral motor findings, premotor
ges, sense of familiarity or strangeness, area seizures tonic version, and supplementary
hallucinations, staring, and automatisms, among motor area seizures speech arrest, fencing pos-
others. One review [4] concluded that with tures, bilateral motor findings, and head version.
temporal lobe epilepsy, abdominal aura had a It is important to note that frontal lobe regions
52% sensitivity and 90% specificity for localiz- can produce seizures that are similar to one
ing seizures to the temporal lobe. Seizures arising another.
from temporal neocortex can have similar Seizures from the insula can include visceral,
symptoms. For example, basal but not mesial gustatory, and somatosensory symptoms,
temporal seizures can present with behavioral including laryngeal constriction or paresthesias
arrest or motor changes. Ictal theta activity was [4]. Parietal lobe seizures can begin with
found to have an 85% probability for temporal somatosensory phenomena, and occipital lobe
lobe epilepsy and was 80–94% correct with seizures can begin with visual auras and phe-
respect to the side of seizure onset. Lateralized nomena. However, both parietal and occipital
interictal spikes and possibly contralateral hand lobe seizures can be locally silent, with symp-
dystonia also were helpful. The authors thought toms related to the area of projection. For
that some of these also might help differentiate example, parietal lobe seizures can imitate
mesial from lateral temporal lobe epilepsy. superior frontal lobe seizures or can have sen-
Febrile seizures are thought to have a rela- sorimotor symptoms.
tionship with mesial temporal sclerosis, as is
found with mesial temporal lobe epilepsy; one
report [5] found that only 2/21 patients with Noninvasive Evaluations
neocortical temporal lobe epilepsy had a history
of febrile seizures. Seizure-free intervals were Neuropsychological evaluation is important both
found to be less common with neocortical tem- in assessing baseline functioning and in deter-
poral lobe epilepsy than with mesial onset tem- mining whether there are aspects of function,
poral lobe epilepsy. Despite neocortical onset, which are below expectations. At times, these
there nonetheless could be mild hippocampal functions can be localized to specific regions of
atrophy. Patients could have tumors or hetero- the brain, which in turn might be the sites of
topias. About half could have decreased memory origin of the patient’s seizures.
function on the Wada test. Independent con- The intracarotid sodium amobarbital or Wada
tralateral spikes were rare. Some patients had test is performed less frequently now than had
experiential auras or motionless stares. been the case in the past. When used, it has two
Frontal lobe epilepsy symptoms vary with the purposes. With the test, a medication, which
site of seizure onset [4]. With superior or inter- traditionally had been amobarbital, but now can
hemispheric onsets, there can be contralateral be another such as midazolam, is injected so as to
26 Procedures and Outcomes in Epilepsy Surgery 339
“anesthetize” one hemisphere for a few minutes describe the occurrence of two potentially
while the other is tested. One looks for language epileptogenic lesions regardless of type.
function during the period of “anesthesia,” to see Causes of extra temporal seizures in a series
whether speech remains while the hemisphere is of 133 consecutive cases included [7] cortical
not functioning, and one presents items for the dysplasia in 38% and tumor in 28%. They
patient to remember. One also tests recall mem- reported that 10/50 patients with cortical dys-
ory after the effects of the medication wear off, to plasia also had tumors; 11/50 had infarcts or
see whether new memories could be encoded remote ischemic lesions. They found four with
during the period of hemisphere inactivation. The arteriovenous malformations, 3 with Sturge–
idea is that if a function is intact during the Weber malformations, and 2 with Rasmussen’s
period of drug-induced inactivation, the tested encephalitis. 17% had no significant findings.
function is likely to be supported by the Positron-emission tomography (PET) scans
non-inactivated hemisphere. can point to areas of decreased metabolic func-
Imaging is increasingly important in evaluat- tion which in turn can be area of epileptogenesis.
ing patients with intractable seizures, with mag- Single-photon emission computed tomography
netic resonance imaging (MRI) being the most (SPECT) studies can point to areas of altered
important; one should always be performed if function in a similar way with similar inferences
possible. Important findings include evidence of regarding whether these might indicate where
mesial temporal sclerosis or other abnormality, as seizures are originating. Magnetic resonance
well as evidence of tumor, dysplasia, vascular spectroscopy (MRS) can point to areas with
anomaly, developmental defects, or other chan- altered chemistry. fMRI is being developed as a
ges. For patients with temporal lobe epilepsy, it possible alternative to the Wada test, using it to
is important to keep in mind that there can be localize language, which has been relatively
bilateral atrophy on MRI in some patients, per- successful, as well as memory, which has not
haps 20% [4]. Sometimes, surgery can nonethe- been as successful thus far.
less be performed on one side, if seizures only
originate on that side, but it adds a consideration
before deciding whether to operate and a con- Invasive Evaluations
sideration when counseling the patient with
respect to possible postoperative memory prob- Often noninvasive evaluation is sufficient to
lems. Neuroimaging [4] can show amygdala determine how and where to operate, but some
abnormalities in 55% of patients and changes in patients need implanted electrodes as well.
the enterorhinal cortex in 25% and in the fornix Depth and subdural electrodes are the ones
in 86%. In one study of patients with temporal principally used. Depth electrodes are thin
lobe epilepsy and tumors [6], astrocytomas were “tubes,” each usually containing several elec-
found in 46%, gangliogliomas in 21%, oligo- trodes and electrode wires, and which are
dendrogliomas in 18%, dysembryoplastic neu- directed through the skull and through the outer
roepithelial tumors in 6%, anaplastic cerebral tissues, aiming at more medial locations
astrocytomas in 6%, and meningiomas in 3%. such as mesial temporal lobes. However, there
Dual pathology can occur in 15–52% of are electrodes along the tube so that more lateral
patients with hippocampal sclerosis, with eti- locations including neocortex are recorded at the
ologies including heterotopias, cortical dysplasia, same time. Subdural electrodes are flat disks,
and tumors. Vascular lesions including cav- usually a few millimeters in diameter, imbedded
ernous malformations and arteriovenous malfor- in Silastic or other plastics and placed over and
mations can occur in about 5% of patients [4]. around areas of interest. Both depth and subdural
Although the term has often been used to electrodes are used to localize the area of seizure
describe the combination of hippocampal scle- onset. Subdural electrodes are commonly, and
rosis plus another lesion, it also is used to depth electrodes less commonly, stimulated
340 R.P. Lesser
electrically to determine the relationship of the important to emphasize that the reliability of
area of seizure onset to regions controlling results can depend on the intensity of stimulation.
important functions such as movement, sensa- If you stimulate at too low an intensity, you can
tion, and language. get a false-negative result. If you stimulate at too
Complications of depth electrodes include high an intensity, you can get afterdischarges
asymptomatic subdural bleeding gliosis, degen- which can produce false positives because of the
eration, and microabscesses along electrode tract spread of the afterdischarges and also can cause
[8–10]. The incidence of bleeding or infection is seizures. One should begin at a low intensity,
between 0.5 and 5%. There can be a 25% overall 0.5–1 mA, and increase in increments of 0.5–
rate of complications with subdural electrodes 1 mA. Keep in mind that the above is in mil-
[11], including 12% infection, 11% transient liamps, but the important parameter is charge
neurological deficits, 2.5% epidural hematoma, density, which depends on not only current but
2.5% increased intracranial pressure, 1.5% also electrode surface area.
infarction, and 0.5% death. Cerebrospinal fluid It is also important to emphasize that stimu-
leakage also was common. The authors found lation only assesses the cortex directly under the
that complications were more likely if there were stimulated electrodes. Charge density drops rel-
more than 60 electrodes and if the grid was left in atively rapidly with increased distance from the
more than 10 days. Other risks included older actual location of the electrodes. Also, 7/8 of the
patients, left-sided placement, and additional burr current is shunting through the cerebrospinal
holes. They observed that complication risk fluid [13, 14].
likely was less now with improved technique. In addition to stimulation, one can analyze the
brain function with a variety of methods based on
frequency or power analysis. In summary, one
Testing the Brain—Functional asks the patient to perform an activity which can
Localization be something simple such as moving the tongue,
making a fist, or wiggling the toes. One then
Functional localization can be performed in one records brain activity before during and after this
of two ways. One can alter the brain, for example activity and sees whether there are changes in
with cortical stimulation, and assess the behav- particular regions of the brain which might point
iors that occurred during the alteration. An to the area participating in controlling this
example would be to see whether there is hand or activity. There [15, 16] is a relatively good cor-
other movement during stimulation. One also can relation between the results of such analyses and
alter behavior and then assess the brain during the results of cortical stimulation, but the two
the behavior. An example might be asking the methods are slightly different so that the regions
patient to begin to read and then seeing whether localized with one technique or the other might
there is reading arrest during stimulation. Corti- be expected to, and in fact do, differ.
cal stimulation is generally performed with
recurrent pulses. These should be alternating in
polarity, so that the resulting stimulation is Temporal Lobe Surgical Resections
charge-balanced, to avoid complications due to
metal deposit on an electrode. We [12] have used Seizure Control
0.3-ms duration alternating polarity square wave
pulses, delivered at 50 pulses per second, with There are controversies regarding what to
stimulation duration varying but generally 1–2 s remove. For example, for anterior temporal
initially and then up to about 5 s for language lobectomy, some perform the same standard
testing. Intensities that are needed to obtain resection on each patient, while others tailor the
stimulation-induced changes vary; with the resection based upon the specific findings during
device we use, they can go up to 17.5 mA. It is evaluation, particularly evaluation with
26 Procedures and Outcomes in Epilepsy Surgery 341
implanted electrodes. Some surgeons perform an seizures. If patient has a normal MRI, outcome
amygdalohippocampectomy with lateral tempo- can be good if there are ipsilateral interictal EEG
ral structures left relatively intact. Some will do a discharges and a history of febrile seizures. Out-
hippocampectomy alone. There has been interest come can be worse in patients with tumors, cor-
in the use of radiosurgery and laser surgery as tical dysplasia, vascular disease, and a longer
noninvasive ways of resecting only mesial tem- duration of epilepsy [4].
poral structures. One review [4] concluded that after surgery
In a prospective study [17], Wiebe et al. com- for temporal lobe tumors, 65% of patients
pared 40 patients who underwent temporal became seizure-free and 82–86% of patients
lobectomy to 40 who were on a surgical waiting were free of disabling seizures. For mesial tem-
list for a year. The surgery was an en bloc resec- poral sclerosis, 75% of patients became
tion of 4–4.5 cm of the dominant and 6–6.5 cm of seizure-free with 41–79% free of disabling sei-
the non-dominant, temporal lobe, with removal of zures. Among patients with normal MRIs, 56–
amygdala and 1–3 cm hippocampus. One year 62% of patients became seizure-free. For patients
later, 58% of patients with surgical treatment but with cortical dysplasia, 38–54% became seizure-
only 8% of patients with medical treatment alone free. For patients with dual pathology, in this
were free of episodes with loss of consciousness. case mesial temporal sclerosis plus another
Quality of life also improved in patients who had lesion, 73% became free of disabling seizures if
surgery. However, simple partial seizure may both pathological areas were removed but only
continue: This group previously found [18] that 20% if only one of the areas was removed.
93% of surgical and 13% of medical patients had a Schmidt et al. [20] reviewed previous reports
90–100% reduction of seizures after 6 months but of a total of 1658 patients who had been off
only 35% of the surgical patients (and 6% of the medication for 5 years. They found that 25% of
medicine alone patients) were completely adults and 31% of children became seizure-free
seizure-free. Also, seizures can recur over time. In and remained off medication for 5 years.
one review [19] of patients seizure-free at one Surgery outcome has long been classified
year, 87–90% were seizure-free at 2 years, 74– using a system devised by Engel [21]. In this,
82% at 5 years, and 67–71% at 10 years. Among Class I is for patients “free of disabling seizures,”
patients who were seizure-free at 2 years, 95% but the subcategories include completely seizure-
were seizure-free of 5 years, 82% at 10 years, and free since surgery, non-disabling simple partial
68% at 15 years. Therefore, with time, seizure seizures only, some disabling seizures but none
control decreases, but the longer the patient was for 2 years, and generalized convulsive seizures
seizure-free, the better the outcome. This review with medication discontinuation. Class II was for
noted that more than half of the patients would patients with rare disabling seizures, with sub-
have their seizure recurrence in the first 6 months categories of initially free of disabling seizures,
and 95% in the first 5 years. They found that rare seizures now, rare disabling seizures since
incomplete resection was more likely in patient surgery, more than rare disabling seizures but
with seizure recurrence. They also noted the rare for the last two years, and nocturnal seizures
possibility of a “running-down” phenomenon only. Class III was defined as worthwhile
with initial seizure recurrence followed by seizure improvement, with subcategories of worthwhile
control. Good prognostic factors included early seizure reduction and prolonged seizure-free
onset of seizures, mesial temporal sclerosis with intervals of greater than half the follow-up per-
ipsilateral interictal EEG discharges, unilateral iod and at least two years. Class IV was for
MRI, PET, and SPECT findings with a single patients with no worthwhile improvement, with
lesion, and greater than 90% of the interictal EEG subcategories of significant seizure reduction, no
findings originating in one place. Poor prognostic change, or worsening of seizures. The classifi-
factors included a long duration of seizures and cation system was revised by a committee of the
the occurrence of generalized tonic–clonic International League Against Epilepsy [22]. In
342 R.P. Lesser
this classification, Class 1 was for patients Adverse effects [4] after temporal lobe epi-
completely seizure-free with no auras beginning lepsy surgery can occur in about 2% of patients
one month after surgery, Class 2 for patients with including quadrantanopsia and memory prob-
auras only, and class 3 for patients with 1–3 lems. There can be other field deficits as well as
seizure days per year. Class 4 was for patients motor, sensory, or speech deficits. With anterior
with seizures ranging from 4/year to 50% choroidal artery or other occlusions, there can be
decrease in days with seizures. Class 5 was for significant problems including strokes. Some
patients with a 50% reduction to 100% increase patients have had cerebellar hemorrhages. Death
in days with seizures. Class 6 was for patients has been reported to occur in 0.24% of patients.
with a greater than 100% increase. Classes 3–6 One review [25] found less than 1% morbidity
included patients with or without auras. including hemorrhage, infarction, pulmonary
embolus, and pseudogout. There was a 2.4%
incidence of hemiparesis and 50% incidence of
Other Outcomes visual field defects with 2–4% hemianopia. Less
than 2% of patients had infection and epidural
Memory often can be worse [23]: (a) after a hematoma or transient third nerve palsy, 20%
dominant hemisphere temporal lobe resection, transient anomia, 1–3% persistent dysphagia, and
(b) if the MRI does not show exclusive unilateral 2–20% transient psychosis or depression.
mesial temporal sclerosis, and (c) if preoperative Depression is commonly present prior to
immediate and delayed recall memory is intact. temporal lobectomy and is more common after-
In particular, there can be declines in object ward if present prior to surgery. Patients with a
naming and similar functions. Memory can history of depression are less likely to become
improve, however, if a nondominant resection is seizure-free after surgery. Moreover, there is a
performed. Surgery can be successful [19] if risk of postsurgery suicide, with an age- and
depth recordings show a unilateral ictal onset, if sex-adjusted mortality ratio of 13.3 compared to
there is ictal spiking but not a rhythmic fast the US population as a whole [26]. On the other
pattern, if there is no evolution to a distinct hand, a study found that 45% of a group of
contralateral seizure pattern, and if there is an patients experienced remission of psychiatric
interhemispheric propagation time greater than symptoms, no longer needing psychotropic
8 s. As expected from the last of these, a longer medication, after epilepsy surgery [27].
duration of ictal EEG activity before clinical
onset may at times point to a more successful
surgical result. Also, results of temporal lobe Other Surgical Resections
surgery are better if the onset of the seizure is not
diffuse on the recordings and does not begin in In one survey [19] of frontal lobe surgery patients,
the posterior temporal regions where resection is at one year 49.5% of patients had Class I onsets
more difficult [19]. With bilateral ictal onset, with 55.7% of these patients seizure-free. In
surgery can still be successful if greater than 50% 5 years, 47% had Class I seizure control and
of seizures originate from the resected side, and 30.1% of these were seizure-free. At 10 years,
if the Wada test shows adequate memory on the 41.9% had Class I outcome. 80% of recurrences
other side with no extra temporal focus [24]. In were in the first 6 months. If there were recur-
this study, 9/11 operated patients had no seizures rences, patients were less likely to become
and one of 11 had a 75% reduction in seizure seizure-free. The running-down phenomenon was
frequency. Explanations for the findings included less frequent. Good prognostic factors included
the possibility of a mirror focus, disconnection, MRI lesions and complete resection. With these,
or bilateral disease which was nonetheless the likelihood of good prognosis was 72% versus
responsive to unilateral surgery. 41% if these were not present.
26 Procedures and Outcomes in Epilepsy Surgery 343
The same authors concluded that with parietal or lesions such as porencephaly with seizures that
and occipital lobe seizures, 73.1% of patients have become intractable to medication [32].
were seizure-free in 6 months, 68.5% in one Often, these patients have multiple seizures per
year, and 54.8% in 6 years. Circumscribed day and have a complete or progressive hemi-
lesions conveyed a good prognosis. The authors paresis. There are widespread areas of potential
noted that side effects such as dysphagia or epileptogenesis in a single hemisphere. The entire
Gerstmann’s syndrome could occur and they hemisphere is removed in the classic procedure,
discuss the importance of sparing the calcarine but there are modifications including a functional
cortex and speech areas. hemispherectomy, in which the hemisphere is left
Patients with bilateral temporal lobe onsets in place but disconnected from the opposite
were discussed above. In addition, several hemisphere by section of pathways such as the
authors have commented on the importance of corpus callosum. To avoid postoperative compli-
considering that some patients with infantile cations, some surgeons will collapse the subdural
spasms and apparent bilateral ictal onset on EEG space by fixing the dura to the falx. Corticectomy
may show unilateral PET hypometabolism and plus disconnection has been performed as well as
then may be found to be the candidates for focal corticectomy plus lobectomy. 70–80% of patients
surgery. Similar situations may occur with become seizure-free. Because of the reduction in
patients with focal hamartomas or other unilat- seizures, intellectual function often improves.
eral MRI lesions but apparently multifocal sei- Despite removal of a hemisphere, patients can
zures. In many cases, the lesions are congenital walk or even run although they may need an ankle
or acquired early [28]. brace. The hand contralateral to the resected
When a region of seizure onset cannot be hemisphere has no fine finger and has little wrist
removed completely, multiple subpial transec- movement but can function as a “helper hand.”
tions can be considered [29, 30]. This involves Possible complications include subarachnoid
separating the superficial cortical horizontal bleeding, hemosiderosis, cerebrospinal fluid
connections within a gyrus while preserving the block, and hydrocephalus.
vertical pathways. Often, this is performed Multilobe resections can be performed as
adjacent to an area of resection. Transections are well. For example, this can be done in patients
typically performed at approximately 5-mm with Sturge–Weber syndrome, or with cortical
intervals, with the cuts extending 1–3 mm. The dysplasia, with the dysplasia removed as an
concept is that this disrupts “horizontal” epilep- addendum to temporal lobe resection. These
togenic propagation while preserving “vertical” methods have not been helpful in patients with
axonal connections. One should keep in mind Rasmussen’s syndrome; hemispherectomy is the
that this affects the gyral crown but not the sulci surgical treatment of choice. As expected, func-
because of the way this is done. Reports describe tional complications of hemispherectomy or
that 1/3–2/3 of patients become seizure-free, but multilobar resection often relate to the location of
later recurrences also are possible. Although the the area of surgical removal. In particular,
major gyral sulci are well known, it is important removal of the perirolandic area is more likely to
to realize that there are microsulci throughout the result in a permanent motor deficit. (But patients
cortex which are not readily seen from the cor- with Rasmussen’s syndrome often are already
tical surface and that fibers in the microsulci are hemiparetic when surgery is performed.)
not affected by this technique. Also, microscopy Corpus callosotomy has been particularly
shows that transections produce not only fiber helpful for atonic, “falling,” seizures as well as
separations but also microlesions [31]. for tonic seizures, with electrodecrement at sei-
Hemispherectomy is a useful for seizure zure onset, and for generalized tonic–clonic sei-
control in a small group of patient who have zures. While “falling” seizures may benefit, other
problems such as Rasmussen’s syndrome, seizure types may remain, so generally this
hemimegalencephaly, Sturge–Weber syndrome, should be thought of as a palliative rather than
344 R.P. Lesser
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more severe after section, and in experimental Surgical pathologic findings of extratemporal-based
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Quality of Life in Epilepsy
27
Patsy J. Ramey, Mohamad Z. Koubeissi and Nabil J. Azar
Restrictions: Patients at risk for seizures should Driving: Without a doubt, the loss of driving
be warned that all environments or situations that privileges has the greatest overall impact on
could cause harm to the patient or others, should those with epilepsy. Each state has regulations
a seizure occur, must be avoided. Specifically: and some leave the decision to the discretion of
the provider. Driving restriction typically ranges
• No working at “unprotected” heights, between three and 12 months. Tennessee, for
including roofs and ladders. example, requires six months of seizure freedom,
• No working around heavy machinery with whereas Kentucky requires three months. The
moving parts. loss of driving means relying on others for
• No construction equipment use. transportation whether this is to school, work,
• No use of manufacturing equipment, includ- shopping, or to go on a date! The loss of a license
ing, among others, fork lifts, heavy presses, may mean the loss of employment for those that
and conveyor belt systems. drive a truck or captain a boat for a living.
• Avoid known environmental triggers: heat, Commercial Truck Drivers: The restrictions
cold, humidity, dust, and fumes. are placed by the Federal Motor Carrier Safety
• Shower or bathe in minimal amounts of water Administration:
in order to avoid drowning in case of loss of Current recommendations are that restrictions
consciousness. should be determined on an individualized basis.
• Swim only when supervised by someone who The nature of the seizure and risk of recurrence
is aware of seizure history and is capable of should be considered when determining fitness
helping should a seizure occur. for specific job requirements.
• No cooking or working around open flames.
• NO DRIVING! • Persons with diagnosed epilepsy who are
seizure-free and off medication for 10 years
These restrictions stay in effect until released may be considered for licensure to operate a
at the discretion of the provider or the stipula- commercial vehicle.
tions of the state. • Onetime event thought to be nonepileptic and
requiring no antiseizure medication will pos-
sibly allow for return to driving after six
months of seizure freedom.
P.J. Ramey M.Z. Koubeissi N.J. Azar (&)
• Single unprovoked seizure with no recurrence
Department of Neurology, Vanderbilt University
Medical Center, Nashville, TN 37212, USA may be considered for reinstatement follow-
e-mail: dr.nabil.azar@gmail.com ing a five-year period off medication.
M.Z. Koubeissi A waiver to this determination may be made
e-mail: koubeissi@gmail.com
if the individual has a normal EEG and has possible if a satisfactory explanation can be
been evaluated by a neurologist that special- established.
izes in epilepsy. Guide for Aviation Medical Examiners:
• Acute symptomatic seizures in the presence
of acute structural insults to the central ner- • A disturbance of consciousness without sat-
vous system with low risk for recurrence; isfactory medical explanation of the cause
there should be no restriction after they have must submit all pertinent medical records,
been seizure-free for two or more years off current neurological report, to include name
antiepileptic drugs. and dosage of medication(s) and side effects.
• Persons that have undergone any procedure This requires Federal Aviation Administra-
that penetrates the dura should not be con- tion (FAA) decision.
sidered eligible for commercial licensure [1]. • Rolandic seizure must submit all pertinent
medical records, current status report, to
Merchant Mariners Including Riverboat include name and dosage of medication(s) and
Captains: According to the US Department of side effect. Rolandic seizures may be eligible
Homeland Security and the United States Coast for certification if the applicant is seizure-free
Guard under COMDTMOTE 16700.4, NVIC for 4 years and has a normal EEG.
04-08, Enclosure (8) Mariners, including com- This requires FAA decision.
mercial ship captains and riverboat captains, are • Febrile seizure (single episode) must submit all
controlled by the Coast Guard. pertinent medical records and a current status
report if occurred prior to age 5, without recur-
• Those mariners that have seizure(s) deter- rence and off medications for 3 years of issue.
mined to be low risk of recurrence may be Otherwise, this requires FAA decision.
considered for a waiver to return to duty • Transient loss of nervous system function(s)
when they have been seizure-free and off without satisfactory medical explanation
medication for a minimum of one year. of the cause, e.g., transient global amnesia
• Those with seizures considered as high risk of must submit all pertinent medical records,
seizure recurrence must be seizure-free for a current status report, to include name
minimum of eight years [on or off medica- and dosage of medication(s) and side effects.
tion]. If they continue on medication their This requires FAA decision.
dose regimen must be stable for two years. If • Unexplained syncope, single seizure. An
they are off medication, they must be applicant who has a history of epilepsy, a
seizure-free for eight years from the time they disturbance of consciousness without satis-
stopped the medication [2]. factory medical explanation of the cause, or a
transient loss of control of nervous system
Aircraft Pilots: Neurological disorders: epi- function(s) without satisfactory medical
lepsy, seizures, stroke, paralysis, etc. The appli- explanation of the cause must be denied or
cant should provide history and treatment, deferred by the examiner. Consultation with
pertinent medical records, current status report, FAA is required.
and medication. The Examiner should obtain • Infrequently, the FAA has granted an autho-
details about such a history and report the results. rization under the special issuance section of
An established diagnosis of epilepsy, a transient part 67 14 CFR 67.401 when a seizure dis-
loss of control of nervous system function(s), or a order was present in childhood, but the indi-
disturbance of consciousness is a basis for denial vidual has been seizure-free for a number of
no matter how remote the history. Like all other years. Factors that would be considered in
conditions of aeromedical concern, the history determining eligibility in such cases would be
surrounding the event is crucial. Certification is age at onset, nature, and frequency of
27 Quality of Life in Epilepsy 349
4. United States Department of Labor. Secretary of 5. Social Security Official Website. SSR 87-6:
Labor Thomas E. Perez. Disability resources. Job TITLES II AND XVI: THE ROLE OF
accommodations. http://www.dol.gov/dol/topic/ PRESCRIBED TREATMENT IN
disability/jobaccommodations.htm. Accessed 22 Oct THE EVALUATION OF EPILEPSY. http://www.
2015. socialsecurity.gov/OP_Home/rulings/di/01/SSR87-
06-di-01.html Accessed 22 Oct 2015.
8. Epilepsy Foundation. Stronger Together. http://www.
epilepsyfoundation.org/resources/newsroom/
pressreleases/Epilepsy-Foundation-And-Epilepsy-
Therapy-Project-Finalize-Merger-To-Create-Strong-
Websites—Further Reading Unified-Organization-To-Support-People-With-
Epilepsy.cfm.
9. Centers for Disease Control and Preventions. CDC:
6. Adult Epilepsy News—Get Adult Epilepsy Info. Life Saving Lives, Protecting People. Epilepsy. http://
between the lines. http://www.lifebetweenthelines. www.cdc.gov/epilepsy/projects.htm.
com/plan-ahead.html. 10. Epilepsy Foundation Middle & West Tennessee.
7. Epilepsy.com. An Epilepsy Therapy Project Initiative http://epilepsytn.pmhclients.com/index.php/
of the Epilepsy Foundation. http://www.epilepsy. programs/.
com/epilepsy/main_epilepsy.
Multiple Choice Questions for Part V
D. Better but seizure freedom chances than C. Architectural dysplasia is the subtype of
temporal lobectomy FCD that is most often missed on MRI
E. Worse but seizure freedom chances than imaging
temporal lobectomy D. FCD is seldom seen with dual pathology
of HS
7. All of the following is true about E. In neonates, FCD is usually hyperintense
hemimegalencephaly, except? in T2-weighted images and hypointense
in T1-weighted images
A. White matter volume in enlarged hemi-
sphere is normal
12. Intracarotid amobarbital procedure (Wada
B. Hemispheric growth is hamartomatous
test) can be helpful in terms of:
C. There is agyria
D. There is polymicrogyria
A. Lateralizing seizure focus
E. There is lissencephaly
B. Lateralizing memory
C. Lateralizing language dominance
8. Where in the hippocampus are sclerotic
D. Predicting surgical outcome
changes typically found in MRI-negative
E. All of the above
(1.5T) temporal lobe epilepsy?
A. CA1 13. Which of the following is true regarding
B. Hippocampal tail diffusion MRI findings in the epileptogenic
C. CA3 zone during the ictal phase?
D. CA4
E. Subiculum A. During the ictal period, diffusion MRI
abnormalities are found equally in both
9. Neuromagnetic signals from the brain are of the gray and the white matter
the order of: B. Ictal onset is followed by an immediate
increase in the ADC signal
A. Nanoteslas
C. Following the short initial phase of ictal
B. Milliteslas
onset, the ADC signal is highest due to
C. Microteslas
vasogenic edema
D. Femtoteslas
D. With continued seizure activity, there is
E. Picoteslas
eventual cytotoxic edema and the ADC
signal increases
10. Which of the following is true about driving
E. During the postictal phase, if there is
restrictions in the USA?
irreversible injury due to seizure activity,
A. Uniform across all states the ADC signal decreases compared to
B. Minimal seizure freedom is 3 months neighboring tissue
C. Does not apply to provoked seizures
D. Excludes brief absence seizures 14. In drug-resistant epilepsy, deep brain stim-
E. None of the above ulation targets which of the following
structures?
11. Which of the following best characterizes
MRI findings in focal cortical dysplasia? A. Cingulate gyrus
B. Reticular formation of the thalamus
A. MRI findings can be detected in 90% of
C. Anterior nucleus of the thalamus
patients with FCD
D. Hippocampus
B. Transmantle sign is seen in patients with
E. Outer globus pallidus
cytoarchitectural dysplasia
Multiple Choice Questions for Part V 355
15. The antiepileptic effects of vagus nerve 18. Free consulting service on workplace
stimulation (VNS): accommodations is provided by:
A. FDA
A. Increases indefinitely over time until
B. Job accommodation network (JAN)
complete seizure freedom is achieved
C. “No epileptic left behind” association
B. Reaches its peak in 3 months
D. Accommodation for all office
C. Remains the same throughout the course
E. This service is not free
of treatment
D. Shows improvement over a 2 year
19. A patient who continues to have focal and
course as compared to the initial 3
secondary generalized seizures despite trying
months
7 different antiseizure medications
E. Is highest initially
A. Is likely to become seizure-free after
16. Which of the following is associated with trying more ASMs
poor verbal memory outcome after left B. Is unlikely to become seizure-free after
temporal lobectomy? trying more ASMs
C. Must be referred for presurgical
A. Left mesial temporal sclerosis on MRI evaluation
B. Adult seizure onset D. Is very likely to become seizure-free with
C. Left temporal hypometabolism on deep brain stimulation (DBS) therapy
FDG-PET E. 2 and 3
D. Poor preoperative scores on the Rey
Auditory Verbal Learning Test 20. Which of the following MRI techniques has
E. Poor preoperative scores on Boston the highest relative sensitivity for detection
Naming Test of mesial temporal sclerosis?
B. Ipsilateral to the seizure foci, there is 26. All of the following are common pitfalls in
increased l-opiate receptor binding, erroneously diagnosing epileptic lesions in
decreased r-opiate receptor binding, and normal hippocampi except?
decreased К-opiate receptor binding
C. Increased D2/D3 binding in the epilep- A. Vertically oriented hippocampus erro-
togenic temporal lobe neously suggests hippocampal dysplasia
D. Decreased benzodiazepine receptor B. The hippocampus is normally hyperin-
binding ipsilateral to the temporal tense on T1, misleading to a diagnosis of
epileptic foci bilateral MTS
E. Increased serotonin-1A (5-HT1A) C. Artifactual size asymmetry can easily be
receptor binding ipsilateral to the tem- caused by head rotation as the hip-
poral epileptic foci pocampus is large anteriorly and tapers
progressively posteriorly
23. All of the following are true about neu- D. Hippocampal sulcus remnant is a normal
ropsychological tests, except: variant that occurs in 10–15% of normal
hippocampi
A. Working memory can be assessed by
E. A choroid fissure cyst expands the
Digit Span Backwards
choroidal fissure and compresses the
B. Grooved Pegboard Test or Purdue Peg-
hippocampus, erroneously suggesting
board Test assesses visual memory
hippocampal atrophy
C. Set-shifting can be assessed by Trail
Making Test
27. Which of the following statements about
D. Stroop Color Word Test assesses exec-
MEG source modeling is incorrect?
utive function
E. Rey–Osterrieth Complex Figure Test
A. The problem of determining the cortical
assesses planning
generators of MEG activity is considered
an “ill-posed” inverse problem
24. Most common adverse events of vagus nerve
B. “Ill-posed” inverse problems have a
stimulation (VNS) includes:
unique solution
A. Tachycardia C. “Ill-posed” inverse problems have an
B. Bradycardia infinite number of possible solutions
C. Cough D. The “forward model” is a physical model
D. Hoarseness of neural sources in the brain and how
E. Asystole these sources generate electromagnetic
fields outside the head
25. All of the following are MRI findings of the E. The “head model” is a component of the
affected side in mesial temporal sclerosis forward model
except?
28. Which of the following is the most common
A. Loss of internal architecture of the
neoplastic lesion associated with new onset
hippocampus
seizures in older adults?
B. Collateral white matter atrophy of the
temporal lobe
A. DNET
C. Extratemporal enlargement of the
B. Ganglioglioma
caudate
C. Low-grade glioma
D. Extratemporal atrophy of the fornix
D. High-grade glioma
E. Dilation of the temporal horn
E. Cerebral metastasis
Multiple Choice Questions for Part V 357
29. Which of the following is true about efficacy D. Can be recorded with scalp EEG in the
of responsive neurostimulation (RNS)? absence of muscle artifact
E. Are seen only ictally
A. Seizure reduction in the 12 week blinded
phase of RNS is 17.3%
33. Which of the following is an appropriate use
B. Seizure reduction 5 months postimplan-
of CT in patients with epilepsy?
tation of RNS is 25%
C. 50% responder rate is 55% after two A. Acute emergency for evaluation of new
years onset seizures in patients with symp-
D. Seizure freedom reaches 75% tomatic causes.
E. None of the above B. Postoperative follow-up for tumor
recurrence.
30. All of the following are true regarding pos- C. Defining topographic relationships of
tictal diffusion changes except? epileptogenic lesions to functional cortex
and cortical white matter tracts.
A. If ictal activity subsides without causing
D. Detection of mesial temporal lobe
irreversible injury, a complete resolution
sclerosis.
with no residual diffusion change is
E. Pediatric new onset seizures without
noted.
apparent symptomatic cause.
B. During the immediate postictal period,
there is a decrease in the ADC.
34. A 45-year-old pilot experiences a brief epi-
C. ADC is increased with continued seizure
sode of “losing track of conversation” after a
activity due to neuronal cell death, acute
prolonged flight. His routine EEG reveals
inflammatory changes, and gliosis.
occasional left temporal rhythmic delta
D. During the immediate postictal period,
activity but is otherwise normal. His brain
there is decreased DWI signal in the
MRI is normal. The most appropriate coun-
epileptogenic area.
seling step is to:
E. If injury due to seizure activity pro-
gresses, the ADC increases compared to A. Have the pilot continue the regular flight
the preictal state and to the neighboring schedule
normal tissue. B. Restrict the pilot from long flights for at
least 6 months
31. Which of the following intracranial vascular C. Indefinitely stop piloting
malformations is most commonly associated D. Refer to psychiatry for possible malingering
with seizures? E. Offer few weeks of rest before resuming
regular flight schedule
A. Arteriovenous malformations
B. Cavernous hemangiomas 35. Which of the following is not true about
C. Epidural hematoma ADHD in individuals with epilepsy?
D. Venous angiomas
A. ADHD is seen in 20–40%
E. Capillary telangiectasias
B. In epilepsy, ADHD affects males and
females equally
32. Recent studies suggest that high-frequency
C. Temporal lobe epilepsy is associated
oscillations (HFOs) are:
with higher rates of attention problems
A. Most abundant in the frontal lobes than frontal lobe epilepsy
B. Are present in the epileptogenic zone D. Nocturnal seizures exacerbate inattention
C. Signify functional cortex and must not E. Stimulants do not lower the seizure
be resected threshold
358 Multiple Choice Questions for Part V
36. At present, MEG has an approved clinical C. May have an MRI after turning off the
indication for all of the following, except: magnet mode
D. May have an MRI after turning off the
A. Localizing cortical generators of interic-
normal and magnet mode
tal epileptic spikes in patients being
E. Refer for CT scan instead
evaluated for epilepsy surgery
B. Lateralizing language dominance prior to
40. For lateralizing language, what is the con-
brain surgery
cordance rate between neuromagnetic
C. Localizing somatosensory cortex prior to
responses to auditory language stimuli and
brain surgery
the Wada test?
D. Confirming a diagnosis of epilepsy in a
patient with negative EEG studies A. <10%
E. Localizing primary auditory cortex prior B. 25%
to brain surgery C. 50%
D. >70%
37. Magnetic source modeling refers to
41. Which of the following is true about side
A. Modeling the cortical generators of
effects of responsive neurostimulation
neuromagnetic events
(RNS)?
B. Modeling the microscopic neural cir-
cuitry that generates brain electrical A. Intracranial hemorrhages occurred at a
signals rate of 10%
C. Modeling the various sources of inter- B. Mood worsening was noted
ference in the MEG system C. Cognitive function worsened
D. Modeling the anatomy of the brain from D. Quality of life improved
MRI E. None of the above
E. Modeling the magnetic properties of the
head and brain tissue 42. Very frequent VNS magnet activation in the
setting of high-frequency stimulation
38. Which of the following statements represents ( 50 Hz) can result in:
a limitation of MEG in the presurgical
evaluation of patients for epilepsy surgery? A. ON time OFF time that does not
result in degenerative nerve damage in
A. MEG cannot accurately localize primary
laboratory animals and is safe
sensory cortices for functional mapping
B. ON time OFF time is not technically
B. In patients with multifocal spikes, mag-
possible to induce
netic source modeling cannot accurately
C. ON time OFF time that can result in
localize the events
degenerative nerve damage in laboratory
C. In some patients, no interictal spikes or
animals and therefore should be avoided
ictal events may be captured during the
D. OFF time ON time that would be
MEG study
ineffective and therefore should be
D. Ictal rhythms cannot be localized using
avoided
magnetic source modeling methods
E. No effect
39. Which statement is correct about patients
43. A 34-year-old woman started having epi-
with vagal nerve stimulation (VNS)?
sodes of confusion and lip smacking.
A. May not have an MRI Her EEG showed left temporal spikes. She
B. May have an MRI after turning off the was initially started on levetiracetam but
normal mode failed to achieve good seizure control. In
Multiple Choice Questions for Part V 359
spite of adding lamotrigine, she continued to 47. A patient with history of prior left temporal
have occasional disabling seizures. Her hemorrhage and refractory left temporal
antiepileptic blood levels are therapeutic. lobe epilepsy may undergo temporal
The best next step is to: lobectomy:
51. Patients with extratemporal lobe epilepsy: 55. When comparing results of temporal lobec-
tomy to medical treatment in intractable
A. More likely need invasive recording
epilepsy, patients treated with surgery are
before epilepsy surgery
how many times more likely to be
B. More likely to be surgical candidates
seizure-free?
without invasive recording
C. More likely to need subdural recording A. 3 times
unless there are frontal lobe discharges B. 7 times
consistent with frontal lobe epilepsy C. 15 times
D. More likely to be surgical candidates D. 20 times
without invasive recording, only if brain E. 25 times
MRI shows a frontal lobe lesion
E. More likely to be surgical candidates 56. Which of the following is true about
without invasive recording, only if brain hemispherectomy?
MRI shows a parietal lobe lesion
A. About 25% of patients become
seizure-free after hemispherectomy, but
52. Which of the following is true regarding
intellectual function worsens
abdominal aura?
B. About 25% of patients become
A. It has a sensitivity of 90% for localizing seizure-free after hemispherectomy, and
seizures to the temporal lobe intellectual function improves
B. It has a specificity of 90% for localizing C. About 75% of patients become
seizures to the temporal lobe seizure-free after hemispherectomy, but
C. It indicates insular seizure onset intellectual function worsens
D. It is non-specific in localizing seizure D. About 75% of patients become
onset seizure-free after hemispherectomy, and
E. None of the above intellectual function improves
E. About 50% of patients become
53. Stimulation of either of superior and inferior seizure-free after hemispherectomy, with
cervical cardiac branches of the vagus nerve no change in intellectual function
during system diagnostics (lead test) may
cause: 57. When ictal theta activity is recorded, tem-
poral lobe epilepsy is present in:
A. Bradycardia and/or asystole
B. Tachypnea A. Less than 10%
C. Hiccups B. 10–25% of cases
D. Respiratory distress C. 25–50% of cases
E. Diarrhea D. 50–75% of cases
E. More than 75% of cases
54. Which antidepressant is least likely to
aggravate seizures? 58. Extrahippocampal abnormalities in patients
with temporal lobe epilepsy
A. Bupropion
B. Citalopram A. Are rare
C. Clomipramine B. Include atrophy of lateral temporal
D. Amoxapine structures
E. Venlafaxine C. Often include cortical dysplasia
Multiple Choice Questions for Part V 361
D. Correlate with favorable surgical out- achieve seizure freedom with the second
come if hippocampal atrophy is not antiepileptic drug?
present on presurgical MRI
A. 5%
E. None of the above
B. 15%
C. 25%
59. Which of the following is false about Ras-
D. 40%
mussen encephalitis?
E. 50%
A. Bilateral disease is rare
B. May present in adolescents or adults 64. Stimulation of the region anterior to the
C. Developmental delays do not precede premotor cortex will likely cause:
presentation
A. Salivation
D. Multilobar resections are a useful alter-
B. Eye deviation
native to hemispherectomy
C. Sensory derangement
E. Progressive hemiparesis will ensue
D. Behavioral change
E. Tinnitus
60. Which of the following psychiatric condi-
tions is most common in patients with
epilepsy?
A. Bipolar II Answers
B. Attention deficit disorder
C. Paranoid delusions 1. (C). CT scans provide better details about
D. Depression bony structures and can easily detect hem-
E. Post-traumatic stress disorder orrhages, calcifications, strokes after 24 h,
and large tumors. However, CT may fail to
61. Lifting driving restrictions of epilepsy recognize commonly encountered lesions in
patients operating large commercial vehicles patients with epilepsy such as hippocampal
require: atrophy, hippocampal sclerosis, cortical
dysplasias, or low-grade gliomas (LGGs).
A. Same rule as for private car
2. (A). Magnetic source modeling or magnetic
B. A minimum of two-year seizure freedom
source imaging (MSI) refers to the process of
C. A minimum of ten-year seizure freedom
generating best-fitting hypotheses about the
D. Being off antiepileptic drugs
cortical generators of recorded neuromag-
E. C and D
netic signals. Source modeling does not
attempt to model the microscopic neural
62. All of the following may exclude patients
circuitry that generates brain signals, but
from disability benefits except:
assumes elementary sources comprised of
A. Chronic alcohol consumption one or many current dipoles. Structural
B. Low antiepileptic blood levels models of the head and brain are requisites
C. Twice-weekly minor motor seizures for source modeling but not the objective.
D. Seizure freedom for more than three 3. (C). Unlike general psychological practice, a
months neuropsychologist does not necessarily
E. Nocturnal seizures diagnose psychiatric conditions or provide
treatment and may not assess specific voca-
63. In the newly diagnosed epilepsy, almost half tional skills (driving, interest inventory, etc).
patients will have seizure freedom with the 4. (B). Dyke–Davidoff–Masson syndrome
first antiepileptic drug. What percentage will (DDMS) presents with seizures, facial
362 Multiple Choice Questions for Part V
16. (B). Early age of onset increases the chances there is increased l-opiate receptor binding,
that the brain will functionally rearrange. increased r-opiate receptor binding, and
Mesial temporal lobe sclerosis on MRI and decreased К-opiate receptor binding. There
hypometabolism on PET suggest poor is decreased D2/D3 binding in the epilepto-
functioning and thus less risk of decline after genic temporal lobe. C-flumazenil PET is
surgery. Poor preoperative performance on very sensitive in MRI-negative temporal
naming and verbal memory makes suggest lobe epilepsy given reduced benzodiazepine
lower chances of further postoperative receptor binding. There is decreased
decline serotonin-1A receptor binding in patients
17. (A). During the ictal state, there is ipsilateral with TLE.
temporal hyperperfusion with surrounding 23. (B). Please refer to the table in Chap. 22.
severe hypoperfusion. In the peri-ictal state, 24. (D). The most common adverse effect of
there is a “postictal switch” during which VNS is hoarseness. Most of the VNS
there is severe ipsilateral hypoperfusion adverse effects have a negligible impact on
throughout the temporal lobe, with the the quality of life of treated patients and are
exception of persistent hyperperfusion in the reported as mild in most instances.
mesial temporal region. Bilateral temporal 25. (C). There is extratemporal atrophy of the
lobe hyperperfusion is only seen in seizures caudate.
of lateral temporal origin. 26. (B). The hippocampus is normally hyperin-
18. (B). The job accommodation network (JAN), tense on FLAIR, misleading to a diagnosis
a service of the Office of Disability of bilateral MTS. Amygdala and hippocam-
Employment Policy (ODEP), provides free pus are isointense on all other MR pulse
consulting services on workplace accom- sequences.
modations. Accommodations may be needed 27. (B). The problem of MEG or EEG source
at work or school depending on classic sei- modeling is considered an “ill-posed”
zure triggers, recommendations, and inverse problem. “Ill-posed” inverse prob-
restrictions. lems do not have unique solutions, but rather
19. (E). Medically intractable epilepsy is defined an infinite number of possible solutions.
as failure of two adequate trials of anti- 28. (E). Metastatic lesions are the most frequent
seizure medications to achieve seizure free- epileptogenic neoplasms in older adults.
dom. Patients who have failed to 29. (C). Seizure reduction in the 12-week blin-
medications must be referred for surgical ded phase of RNS was 37.9% compared with
evaluation since additional medication regi- 17.3% for sham. At 5 months postimplan-
mens will have very low chances of tation, 41.5% seizure reduction was seen in
achieving seizure freedom. the stimulation group compared to a 9.4%
20. (E). Hippocampal volumetry, sensitivity of reduction in the sham group. Two years after
97%. implantation of RNS, 50% responder rate
21. (A). Unrecognized ictal activity during FDG was reported in 55%.
injection could make temporal lobe con- 30. (D). During the immediate postictal period,
tralateral to the focus appear falsely depres- the DWI signal is increased in the epilepto-
sed. Prior depth electrode implantation could genic zone.
lead to contralateral hypometabolism. 31. (A). Seizures occur in 24–69% of arteri-
Increased interictal metabolism ipsilateral to ovenous malformations and 34–51% of
an epileptic focus has been described in large cavernous hemangiomas. The vast majority
cortical malformations. of capillary telangiectasias and venous
22. (D). Monoamine oxidase-B binding increa- angiomas are clinically silent. Epidural
ses with increasing gliosis in temporal lobe hematomas are not considered intracranial
epilepsy. Ipsilateral to the seizure focus, vascular malformations.
364 Multiple Choice Questions for Part V
32. (B). HFOs are oscillation in the gamma band 39. (D). Patients with vagal nerve stimulators
that are recorded with intracranial electrodes can undergo MRI imaging if both normal
at high digital sampling frequencies. They and magnet modes are turned off.
have been studied and found to be abundant 40. (D). For lateralizing language, neuromag-
in the epileptogenic zone ictally and interi- netic responses to auditory language stimuli
cally. Resection of the areas where HFOs are were found to be concordant with the Wada
seen correlated with better surgical outcome. test in 87% of patients. Other investigators
33. (A). MRI is indicated for all of the other found a concordance rate of 86% with the
answer choices. Wada test in 35 patients with a sensitivity of
34. (C). The clinical history and the described 80% and specificity of 100%. Several smal-
EEG abnormality (rhythmic temporal delta ler studies have reported MEG–Wada con-
activity) are both suggestive of partial (focal) cordance rates between 69 and 100% using a
epilepsy. Piloting an aircraft, either private variety of paradigms and analysis methods.
or commercial, is completely prohibited for 41. (D). In a 2-year follow-up study of RNS,
anyone with a history of seizures. 50% responder rate was reported in 55% of
35. (C). Prevalence of ADHD in epilepsy is 20– patents. Intracranial hemorrhages and infec-
40%. Inattentive presentation is more com- tions each occurred in about 2% of implan-
mon, and the boys and girls are equally ted patients, neither mood nor cognitive
represented, which is different from devel- function worsened, and quality of life
opmental ADHD with no seizures. There improved.
may be higher rates of attention problems 42. (C). When using high-frequency stimulation
with FLE and CAE. Associated issues like (>50 Hz), frequent VNS magnet activation
nocturnal seizures or medication side effects can result in nerve damage and thus should
may be the primary cause of inattention. be avoided.
Studies have shown that stimulants used for 43. (D). This patient likely has drug-resistant
ADHD symptoms do not lower seizure partial epilepsy of left temporal lobe origin.
threshold. He has failed two antiepileptic drugs at
36. (D). MEG is not clinically indicated at this therapeutic doses and appropriate drug
point for the evaluation of a patient with new levels. The next step is to consider epilepsy
onset seizures, or to confirm a diagnosis of surgery for which an inpatient video EEG
epilepsy. MEG and source modeling of study is part of the workup.
epileptic spikes or evoked responses is 44. (B). Temporal lobe resection has been
indicated as part a presurgical evaluation shown to be superior to continued medical
prior to epilepsy, tumor, or vascular surgery. therapy in refractory temporal lobe epilepsy
37. (A). Modeling the cortical generators of in a controlled trial. The rate of seizure
neuromagnetic event freedom with vagus nerve stimulation or
38. (C). MEG studies aimed at localizing inter- response for stimulation is much less than
ictal epileptic spikes may sometimes fail to that of lobectomy.
record any epileptic events for source mod- 45. (B). Although the surgical outcomes in
eling (*20% of cases) given the relatively non-lesional epilepsy are generally less
short duration of the recording. In these sit- optimal than those of lesional epilepsy, this
uations, it may not contribute to localizing must not deter the epileptologist from per-
epileptic dysfunction. Multifocality of spikes forming the surgical evaluation. In these
does not undermine the accuracy of the patients, sometimes intracranial monitoring
source modeling. Ictal MEG recordings are may help localize the seizure focus, and the
relatively infrequent, but early ictal rhythms surgical outcomes are often favorable. Hip-
can be modeled with good accuracy to pre- pocampal seizures occur in patients with
dict seizure onset zones. normal MRI, which can be confirmed with
Multiple Choice Questions for Part V 365
depth electrode recordings. In these patients, with akinetic mutism, incontinence, apraxia,
the pathology often shows neuronal loss in or the alien hand syndrome. It is thought that
the CA4 region of the Ammon’s horn. this is more likely if the entire corpus cal-
46. (A). Patients with epilepsy have higher risks losum is sectioned initially. For this reason,
of suicidality than the normal population. many prefer to do an anterior 2/3 section
This is mainly due to the coexistent depres- first.
sion. Antiepileptic adverse events have also 51. (A). In extratemporal lobe epilepsy, invasive
been linked to higher suicidal ideations in recordings are often used for localizing the
patients with epilepsy. seizure focus and mapping the brain, thus
47. (A). In such a patient, right hemispheric defining the surgical borders in a manner that
verbal memory lateralization improves sur- maximizes tissue resection and minimizes
gical candidacy in terms of memory out- functional deficits. While in frontal lobe
come, but is not enough because of the risk epilepsy the ictal EEG can be
language deficits if language is on the left. non-lateralizing, a lateralizing EEG or sei-
Ictal scalp EEG is not totally localizing. zure semiology is helpful primarily in guid-
Functional neuroimaging is important but ing the implantation of the intracranial
will not provide the details as regards the electrodes for further localization and map-
relationship of the seizure onset zone to the ping. Similarly, lesions are helpful in this
eloquent cortex as with intracranial regard, but do not obviate the need for
monitoring. monitoring as the seizure focus often is close
48. (C). Seizures from the insula can include to, though not within, the lesion, and nearby
visceral, gustatory, and somatosensory cortex can be eloquent.
symptoms, including laryngeal constriction 52. (B). Abdominal aura had a 52% sensitivity
or paresthesias. and 90% specificity for localizing seizures to
49. (C). This presentation is typical of frontal the temporal lobe (Velasco, T. R. and
lobe epilepsy. Insular and temporal lobe Mathern, G. W. in Wyllie’s Treatment of
epilepsy may have similar presentations, but Epilepsy: Principles and Practice (ed Cas-
they are much less frequent causes of this cino GD Wyllie E, Gidal BE, Goodkin HP)
seizure semiology. Although non-REM Ch. 82, 922–936 (Wolters Kluwer/
parasomnias may have similar presenta- Lippincott Williams & Wilkins, 2011).
tions, REM sleep behavior disorder presents 53. (A). The VNS lead electrodes must be placed
differently. The brief duration of the seizure, below where the superior and inferior cervi-
its stereotypical nature, nocturnal occur- cal cardiac branches separate from the vagus
rence, and the full recovery make psy- nerve. Stimulation of either of these two
chogenic seizures less likely. branches during the system diagnostics (lead
50. (B). Corpus callosotomy has been particu- test) may cause bradycardia and/or asystole.
larly helpful for atonic, “falling,” seizures as 54. (B). Selective serotonin reuptake inhibitors
well as for tonic seizures, with elec- (such as citalopram) are the preferred
trodecrement at seizure onset, and for gen- first-line antidepressant therapy for patients
eralized tonic–clonic seizures. While with epilepsy. The other listed drugs may
“falling” seizures may benefit, other seizure aggravate seizures especially at higher doses.
types may remain, so generally this should 55. (B). In the controlled trial of temporal
be thought of as a palliative rather than lobectomy versus continued medical treat-
curative procedure. Focal seizures can ment in intractable temporal lobe epilepsy,
become more severe after section, and in one year later 58% of patients with surgical
experimental models, kindling can occur treatment but only 8% of patients with
more rapidly. There can be an acute dis- medical treatment alone were free from epi-
connection syndrome after callosal section, sodes with loss of consciousness.
366 Multiple Choice Questions for Part V
56. (D). After hemispherectomy, 70–80% of bidirectional, and depression may precede
patients become seizure-free. Because of the epilepsy and is considered to be a risk factor
reduction in seizures, intellectual function for epilepsy. In addition, depression is often
often improves. associated with anxiety symptoms or
57. (E). Ictal theta range organized spike dis- full-blown anxiety disorder.
charge was found to have an 85% probabil- 61. (E). A diagnosis of epilepsy and the use of
ity for temporal lobe epilepsy and was 80– antiepileptic medications (AEDs) preclude
94% correct with respect to side of seizure the individual from driving a commercial
onset. motor vehicle. In order to even be consid-
58. (B). Quantitative analysis of MRIs in ered for reinstatement of commercial dri-
patients with temporal lobe epilepsy shows ver’s licensing (CDL), an individual with
frequent atrophy in medial as well as lateral epilepsy has to be off AED(s) and
temporal structures. A non-sclerotic hip- seizure-free for at least 10 years.
pocampus correlated with less optimal sur- 62. (C). Patients with epilepsy may be granted
gical outcome after lobectomy than short- or long-term disability if their seizures
hippocampal sclerosis. remain uncontrolled despite appropriate
59. (D). Rasmussen encephalitis (RE) is a rare, therapy, strict compliance, and absence of
progressive, chronic disease characterized by known controlled triggers such as alco-
seizures, progressive hemiparesis, and cog- holism. In the particular case of motor sei-
nitive loss. It occurs mainly in children with zures, major motor seizures must be
a peak of incidence at the age of 6–7 years. occurring more frequently than once a month
However adolescent and adult cases have and minor motor seizures must be occurring
been reported accounting for about 10% of more frequently than once weekly.
all cases of RE. RE occurs usually in healthy 63. (B). The first antiepileptic drug achieves
children, adolescents, and adults. RE usually seizure freedom in 47% of patients, and the
affects only one hemisphere of the brain; second antiepileptic drug achieves seizure
bilateral disease is very rare. freedom in only 14%.
60. (D). Depression affects at least one-third of 64. (B). During electrocorticography, stimula-
patients with epilepsy and is considered to be tion of the frontal eye fields (Brodmann area
the most common psychiatric comorbidity 8) which is situated just anterior to the pre-
that needs early identification and treatment. motor cortex, will likely cause contralateral
The relationship of seizure and epilepsy is eye deviation.
Index
Note: Page numbers followed by f and t indicate figures and tables, respectively.
surgery assessment and testing for, 331–332 inhibitory (see Inhibitory postsynaptic potential
Ohtahara syndrome. See Early infantile epileptic (IPSP))
encephalopathy (EIEE) Post-traumatic epilepsy, 181
Oligodendroglioma, 280t Pregabalin, 230
Orbitofrontal seizures, 111 Pregnancy, seizure and, 250
Oxcarbazepine, 218–219, 241 Presurgical evaluation, 317–318
pharmacokinetic parameters of, 214t Primary CNS lymphoma (PCNSL), 179
Primidone, 214–215
Progesterone, 249–250
P Progressive Myoclonic Epilepsy (PME), 157–158, 163,
Pallister–Hall syndrome, 159 175t, 188, 196
Parasomnias, 168–169 Propofol, for refractory status epilepticus, 123, 123t
Parietal lobe epilepsy, 112, 145 Psychogenic Nonepileptic Seizures (PNES), 169–170,
surgery assessment and testing for, 332 182
Paroxysmal Depolarization Shift (PDS), 11, 83 Psychogenic seizures
Pentobarbital, for refractory status epilepticus, 123–124, convulsive, 163, 191
123t nonepileptic, 169, 195
Pentylenetetrazole (PTZ) model, 123, 123t remission in, 191
Perampanel, 232, 241 Psychomotor/reaction time, neuropsychological
Periodic Lateralized Epileptiform Discharges (PLEDs), evaluation of, 298
84–85, 85f, 182 Psychosocial domain, neuropsychological evaluation of,
Periventricular nodular heterotopia (PVNH), 180–181, 298
181t Pyridoxine-dependent seizures, 65
Phacomatoses, magnetic resonance imaging for, 284,
286t, 286f
Phantom spike-and-wave bursts. See 6-Hz Q
spike-and-wave bursts Quality of life, 347–352
Pharmacodynamics, 223 accommodations, 349–350
Pharmacokinetics, 225, 249 aircraft pilots, 348–349
Pharmacoresistant epilepsy, 317, 319 commercial truck drivers, 347
Phenobarbital, 213–214 disability, 350
pharmacokinetic parameters of, 214t driving, 347
for status epilepticus, 122, 122t medical record, need of documentation for, 350–351
Phenylethylmalonamide (PEMA), 214 medications affordability, 351
Phenytoin, 246–248 merchant mariners, 348
pharmacokinetic parameters of, 214t restrictions, 347
for status epilepticus, 122–123, 122t seizure triggers, 349
Photoepileptiform discharges, 86
Photoparoxysmal response, 86
Physiologic EEG artifacts, 45–51, 46–51f R
Physiologic movements artefact, 50–51, 52f Rabies encephalitis, 285t
Pleiomorphic xanthoastrocytoma (PXA), 280t Reflex epilepsies, 158
Polymicrogyria (PMG), 180, 274 Refractory epilepsy
Polymorphic delta (PDA), continuous high voltage, 129, defined, 309–310
130f partial, treatment options for, 317
Polytherapy, 210–211 surgery assessment and testing for, 317
Porencephaly (POR), 180 Refractory Status Epilepticus (RSE)
Positive Occipital Sharp Transients (POSTs), 42, 44f evaluation of, 122
Positron Emission Tomography (PET), 284–286, 288f, pathophysiology of, 122
288t treatment for, 120–122
Postconceptional age (PCA), 55, 56 Relative cerebral blood volume (rCBV), 280
less than 30 weeks of gestation, 57 Remission, in psychogenic seizures, 192
between 30 and 37 weeks, 58–59, 58f, 59f Responsive cortical stimulation, 313–315
between 38 and 44 weeks, 62 Restrictions, 347
Postictal aphasia, 143, 150 Retigabine. See Ezogabine
Postsynaptic potential (PSP), 3–5 Rhythmic Mid-Temporal Discharges (RMTD). See
excitatory (see Excitatory postsynaptic potential Rhythmic mid-temporal theta bursts of drowsiness
(EPSP)) (RMTTBD)
374 Index
V
Vagus nerve anatomy, 318 Y
Vagus nerve stimulation (VNS) therapy, 317–322 Yale Group approach, modified, 321
adverse effects of, 319–320 Yield, electrographic, 87
approved indications of, 317
clinical indications of, 318
dosing settings, 319 Z
efficacy and safety of, 319, 319f Zonisamide, 229–230
electrode polarity and pulse stimulus, 310