Vibhangini S. Wasade, Indranil Balki, Susan
M. Bowyer, Shaila Gaddam, Ali-reza
Mohammadi-Nejad, Mohammad-Reza Nazem-Zadeh,
Hamid Soltanian-Zadeh, Andrew Zillgitt, Marianna
Spanaki-Varelas
Excessive yawning was described in some
neurological conditions as part of periictal or
ictal manifestations of epilepsy, most commonly
temporal lobe. We present the first case of
controllable yawning as a primary seizure
semiology with dominant frontal lobe involvement
in a 20-year-old man. Video
electroencephalography recorded 8 yawning
episodes accompanied with right arm movement
correlating with rhythmic diffuse theta range
activity with left hemispheric predominance.
Magnetoencephalography coherence source imaging
was consistent with persistent neuronal networks
with areas of high coherence reliably present
over the left lateral orbitofrontal region.
Epileptogenic areas may have widespread networks
involving the dominant frontal lobe in unique
symptomatogenic areas.
1. Introduction
Yawning is a physiological response defined
by a sequence of involuntary mouth opening, deep
inspiration, brief apnea, and slow expiration
[1]. The James&endash;Lange theory
suggests that feedback of afferent signals from
muscles and viscera integrates at the brain to
create arousal, with yawning as a manifestation
of bodily consciousness [2]. Certain
emotional states and drowsiness are
physiological events that have been shown to be
associated with excessive yawning [3],
as have pathological conditions such as stroke
and frontal lobe/brain stem tumors [4],
[5], [6] and [7]. There
are only a few cases in the literature where
yawning has been described as a symptom of
epilepsy. While such cases are rare, they
describe yawning as a periictal phenomenon or as
an ictal manifestation of epilepsy, most
commonly temporal lobe epilepsy (TLE)
[8], [9], [10],
[11], [12] and [13].
Based on the current review of the literature,
we present the first case of controllable
yawning as a primary seizure semiology due to
dominant frontal lobe involvement.
2. Case report
A 20-year-old right-handed man presented
with brief episodes of strange symptoms with
yawning noted since age 18 years. He described
these as brief episodes of yawning lasting a few
seconds, with associated light headedness, at
times with muscle spasms over his arms or neck
without loss of awareness. These usually
occurred upon waking up in the morning or when
sitting at a computer, also when tired or
sleep-deprived. He added that he could restrain
his urge to yawn.
To characterize his spells, an 8-hour video
electroencephalography (VEEG) was performed with
a repeat study after 6 months for follow-up. The
initial 8-hour VEEG did not show any interictal
epileptiform activity. However, 8 typical
yawning episodes were recorded, which at times
were accompanied by right arm movement and
showed rhythmic diffuse theta range activity
with left-hemispheric predominance lasting for
up to 7 s on EEG (Fig. A.1). A follow-up study
performed after 6 months recorded episodes when
he restrained his yawn with no ictal correlates
on EEG. Stronger yawning episodes showed similar
ictal patterns as recorded in the previous
study.
Magnetoencephalography (MEG) was also
completed with a 148-channel neuromagnetometer
system (4D Neuroimaging) with 32 channels of
simultaneous digital EEG. No interictal
epileptiform activity was present in the MEG for
dipole analysis. Overall functional brain
connectivity was imaged with MEG coherence
source imaging (MEG-CSI). Results were encoded
as a color spectrum for values between 1
(entirely coherent) and 0 (no coherence) and
overlaid on the patient's MRI with the solutions
restricted to the gray matter. The MEG-CSI
exclusively lateralized high coherence to the
left hemisphere, and persistent neuronal
networks were most reliably present in the left
lateral orbitofrontal gyrus (Fig. A.2).
Cortical thickness of the brain was
evaluated based on the T1-weighted magnetic
resonance images (MRI), acquired on a 1.5T
Philips healthcare scanner and processed using
the FreeSurfer software (version 5.3.0;
http://www.surfer.nmr.mgh.harvard.edu). The
processing steps were the following. The
intensities of the T1-weighted images were
bias-corrected using the nonparametric
nonuniform intensity normalization implemented
in the N3 v1.10 package along with their default
parameters. Then, skull stripping was performed
using a hybrid watershed algorithm. The cortical
regions of the brain were extracted, and the
surface of each hemisphere was registered to the
surface of the FreeSurfer's atlas. This
registration generated the same number of
vertices in the two hemispheres. Finally, the
cortical thickness of the left hemisphere (LH)
was subtracted from the cortical thickness of
the right hemisphere (RH) point-by-point. The
results are graphically displayed on the LH
using a color-coding scheme. A smoothed version
of the "LH&endash;RH" map, spatially smoothed
using a 5-mm FHWM Gaussian kernel, is also shown
on the patient's LH surface, using the same
thresholding and color-coding scheme. Left
lateral orbitofrontal and medial orbitofrontal
(marked in red color) regions showed thicker
cortex (Fig. A.3).
The patient was started on lacosamide, and
seizures were better controlled with dose
optimization to 200 mg twice daily. In addition,
he could control the progression of his seizures
by consciously restraining his yawn.
3. Discussion
Our case demonstrates controllable yawning
as a novel primary seizure semiology in dominant
frontal lobe epilepsy as diagnosed with VEEG and
MEG and supported by MRI-based cortical
thickness analysis. This suggests that
epileptogenic areas could also be intricate with
widespread networks involving the dominant
frontal lobe symptomatogenic areas.
Physiologic yawning is thought to be
primarily controlled by the paraventricular
nucleus of the hypothalamus, the locus
coeruleus, and reticular activating system
[14]. One theory proposes that nerve
endings of the incertohypothalamic dopaminergic
system project into oxytocinergic neurons that,
in turn, connect to the hippocampus, pons, and
medulla oblongata, stimulating yawning. Several
neurotransmitters and neuropeptides have been
shown to modulate oxytocinergic neurons
[12]. It would seem that any
interference in this pathway could lead to
pathological yawning.
Yawning is still seldom reported in
connection with epilepsy, since first described
by Penfield and Jasper [15]. The
majority of the literature exists in the form of
case reports [14]. A review of the
literature by Specchio et al. [14] found
12 patients, with associated periictal or ictal
yawing: in 2 patients as preictal, in 4 patients
as exclusively ictal, and in 6 patients as
postictal manifestation of the seizures.
Mechanisms have been proposed to explain
periictal yawning, namely brainstem activation
due to changes in alertness, activation due to
epileptic discharge, or seizure-mediated release
of neurohormonal substances [14].
Yawning as an ictal phenomenon has been
reported, although rarely, as a pathological
condition in the elderly originating from
diencephalic/brain stem structures [2].
Three other case reports reveal ictal yawning as
a manifestation of TLE [10],
[11] and [15], while others
displayed either focal spike-and-waves
[8] or diffuse attenuation [9]
on EEG.
As a postictal phenomenon, yawning occurred
in 5 of 6 patients with TLE reviewed by Specchio
et al. [14], of which 4 had nondominant
TLE with histopathology showing hippocampal
sclerosis, ganglioglioma, cavernous angioma, and
dsyembryoplastic neuroepithelial tumor
[13]. Another patient with postictal
irresistible, forceful yawning had nondominant
hemisphere epilepsy with right centroparietal
discharges on EEG [12].
In contrast, our patient appears to be a
rare case with yawning occurring as an ictal
manifestation of dominant frontal lobe epilepsy.
Occasionally associated symptom of right arm
jerk could explain contralateral frontal lobe
involvement as well. A study involving slow
event-related fMRI experiments in volunteers
suggested that ventromedial prefrontal cortex
(vmPFC) activation is associated with the urge
to yawn by contagion, independently of mirror
neuron network [16]. Similarly, the urge
to control yawning in our patient could possibly
indicate executive function being accessed from
the involved frontal lobe.
In addition, it is not uncommon to encounter
a paucity of interictal epileptiform discharges
on EEG in frontal lobe epilepsy. After obtaining
VEEG findings that correlated yawning with ictal
left-hemispheric predominant slow activity,
further investigation with MEG-CSI confirmed an
area of high coherence within the epileptiform
network over the left lateral orbitofrontal
regions. Although the routine MRI of the brain
was unremarkable, advanced analysis examining
the cortical thickness showed increased gray
matter in the same area as MEG-CSI. This is the
first report showing left frontal lobe
involvement in ictal yawning diagnosed with
functional testing by VEEG and MEG and
structural brain mapping by MRI cortical
thickness analysis.
The functional differences between vmPFC and
orbitofrontal regions are not yet well
understood. Although the exact mechanism for our
patient's seizure semiology is unclear, it is
possible that neural networks within vmPFC and
the lateral orbitofrontal region activated by
epileptic discharges somehow trigger the reflex
in brainstem leading to yawning. Although our
patient appeared to be a rare case, it is
possible that many cases go unreported,
especially if seizures are controllable.
In conclusion, the case we described expands
our view on the possibilities of localization
for ictal yawning that could also be present
with dominant frontal lobe epilepsy. Our
understanding in such cases is still inadequate,
and further studies with advanced diagnostic
investigative modalities will likely help better
define such epilepsies with intricate neuronal
networks.
