Brazilian Committee for
Treatment and Research in Multiple
Sclerosis
Introduction
Neuromyelitis optica (NMO) is an
immune-mediated inflammatory disease of the
central nervous System (CNS), which
predominantly affects the optic nerve and spinal
cord. Since the discovery of NMO-lgG as a highly
specific marker of the disease (Lennon et al.,
2004), a wide variety of brainstem,
hypothalamic, cortical and subcortical symptoms
have been added to the classical association of
optic neuritis (ON) and transverse myelitis (TM)
(Jarius et al., 2012; Poppe et al., 2005; Magana
et al., 2009). In over 60% of NMO patients,
brain MRI may detect lesions, which are often
localized at sites of high AQP4 expression
(Pittock et al., 2006a, 2006b).
The term neuromyelitis optica spectrum
disorders (NMOSD) (Wingerchuk et al., 2007)
includes definite NMO (Wingerchuk et al., 2006)
and limited forms of the disease such as
recurrent ON, bilateral and simultaneous ON, and
longitudinally extensive transverse myelitis
(LETM) in AQP4-lgG-seropositive patients.
Patients with NMOSD who complained of
excessive yawning spells initially drew our
attention to this symptom. The spells were
distressing and embarrassing, and even drew
attention from the patients' family and
caregivers. Most frequently, the yawns occurred
in association with nausea and vomiting, hiccups
and other brainstem or hypothalamic
symptoms.
Some patients also reported recurring spells
of excessive yawning preceding TM or ON for
months or years. Because yawning is a primitive
complex involuntary paroxysmal phenomenon
involved in brainstem and hypothalamic
mechanisms of brain thermorégulation and
homeostasis (Walusinski, 2006; Gallup and
Gallup, 2008), we postulated that excessive
yawning in NMOSD may reflect sleep and
thermoregulatory dysfunction due to brainstem or
hypothalamic involvement. Pathologie yawning has
also been reported in multiple sclerosis
(Postert et al., 1996) and a variety of
conditions as well as an adverse effect of drugs
(Walusinski., 2009). However, it had not been
previously described in NMOSD patients.
Clinical findings
Nine AQP4-lgG-seropositive patients
expen'enced excessive yawning that were not
related to periods of fatigue or sleep debt
(Table 1). AU patients were women aged 19-57
years (médian: 39 years) at disease
onset. Seven patients had ON and TM, whereas two
patients demonstrated LETM as a limited fomn of
NMO. Excessive yawning occurred at disease
présentation in five patients, preceded
ON or TM in three patients, and followed the
présentation in four patients. In one
patent (Case 6) abnormal yawning occurred 15
years after the first attack of optic neuritis
and transverse myelitis which followed a severe
and unexplained épisode of vertigo and
nystagmus for four years. Eight patients
exhibited incoercible nausea and vomiting, and
seven patients had hiccups in association with
abnormal yawning. Although pathological yawning
appeared during the acute phase of disease in
six patients it persisted during remission in
three patients. Yawning occurred in clusters of
three to 10 yawns, which tended to repeat at a
frequency of five to over 20 times a day,
continuously lasting for two to 16 weeks. Two
patients were still experiencing intermittent
abnormal yawning at their last visit, which was
four and 12 years after their onset,
respectively. Brainstem symptoms other than
nausea, vomiting and hiccups, were observed in
six patients whereas hypothalamic symptoms were
observed in five. Five out of six patients who
received high-dosage IV methylprednisolone for
ON/TM attacks observed a relief of the
accompanied pathologie yawning.
MRI findings
Eight patients had brain MRI within 1 month
whereas one patient had it at 32 months
following the onset of excessive yawning. In ail
patients, the brain MRI was abnormal and
atypical forMS. An abnormal hyperintense signal
was found in the optic nerve in eight patients,
in the brainstem in eight patients and in the
hypothalamus in five patients. Figure 1 shows
représentative MRI lésions in two
NMO patients with excessive yawning. Three
patients had lésions in the
periven-tricular région; two patients
demonstrated lésions in the corpus
callosum, and one patient had a large anterior
hemi-spheric lésion. Unspecific small
patches or dots in the deep white matter or
subcortical régions were found in four
patients. In ail patients spinal MRI showed
hyperintense signal in the central part of the
cord contiguously involving three or more
vertébral segments (Table 2).
Discussion
The présent observation suggests that
pathological yawning should be added to the wide
variety of clinical manifestations of NMOSD.
Yawning is a phylogenetically old reflexive
phenomenon involving the activity of motor
nuclei of the cranial nerves V, VII, IX, X, XI
and XII, brainstem reticular formation,
hypothalamic paraventricular nucleus (PVN) and
connections to the frontal lobe and cervical
spinal cord (Walusinski, 2009). The PVN also
plays a rôle in the control of osmolarity,
blood pressure, heart rate and sexuality
(Walusinski, 2009).
Although the ultimate function of yawning is
still a matter of dispute, a number of results
suggest that it may serve multiple purposes.
Yawning may hâve a social and
commu-nicative function and may be related to
complex psychological mechanisms involved in
imitation and boredom (Guggisberg et al., 2011).
In addition, it may also be involved in
intero-ceptiveness via its capacity to increase
arousal and self-awareness. The hypothalamus,
thalamus, locus coeruleus, brainstem reticular
formation, and insula are CNS structures that
are predominantly involved in yawning, which are
also related to the représentation and
régulation of homeostasis (Walusinski,
2007). Moreover, a better understanding of the
physiological sympathetic hypothalamic activity
that accom-panies yawning, such as sharp
increases in lung volume, blood pressure and
heart rate as well as an increase in facial
température and decrease in respiratory
rate, suggests that yawning may play a
rôle in brain cooling mechanisms. An
represent key factors in determining the
température of the brain (Corey et al.,
2012).
Symptoms of hypothalamic dysfunction such as
sleep disturbance, anorexia, disordered
thermorégulation, hypotension and
behavioral disorders may be found in NMO
patients (Poppe et al., 2005). Similarly, 26% of
NMO patients hâve clinical or radiological
évidence of brainstem involvement (Jarius
et al., 2012). Interestingly, MRI may show
abnormal signais in the hypothalamus and
brainstem even in patients with no symptoms
related to damage of thèse structures.
Large lésions involving the anterior
subcortical and deep white matter, as observed
in Case 3, have been attributed to excessive
yawning in patients with an anterior circulation
stroke (Singer et al., 2007).
As pathologie yawning may also occur in MS
(Postent et al., 1996) spinal and brain MRI may
help to differentiate between thèse
conditions. A LETM centrally-located
lésion is the most spécifie
imaging feature of NMOSD and is very rare in MS
(Wingerchuk et al., 1999). "NMO-typical" brain
MRI lésions that are considered
exceptional for MS, such as those in dorsal
medulla oblongata (area postrema),
periaqueductal and perie-pendymal régions
of the third or fourth ventricles, as well as
diencephalic and large tumefactive hemispheric
lésions are found in 7% of NMO patients
(Pittock et al., 2006a). On the other hand, 16%
of NMOSD patients fulfill Barkof MS MRI criteria
(Huh et al., 2013). Brain MRI lésions in
temporal lobe and periventricular région,
similar to those found in Case 3, are frequently
observed in MS. However, Case 3 presented MRI
abnormalities that are highly suggestive of
NMOSD such as LETM lésion on spinal MRI,
and brain lésions in the dorsal aspect of
the medulla oblongata (area postrema) and
periaqueductal région (Wingerchuk et al.,
1999; Pittock et al., 2006a, 2006b; Huh et al.,
2013). Thèse findings in association with
AQP4-seropositive status fulfill NMO diagnostic
criteria (Wingerchuk et al., 2006).
Four of our patients reported hypersomnia
which occurred in association with pathological
yawning at disease présentation in three
of them. In thèse patients excessive
yawning could be attributed to hypersomnia.
However, abnormal yawning spells were observed
on subséquent occasions not related to
periods of hypersomnia.
Some of our patients with associated nausea
and vomiting could hâve used anti-emetic
drugs. It is unlikely, however, that
pathological yawning in our séries could
be related to increased sleepiness as a side
effect of thèse médications as
nausea and vomiting lasted only for a few days
whereas pathological yawning most frequently
lasted for two to three months.
Conclusion
The present series supports the hypothesis
that pathological yawning may not be a rare
symptom in NMOSD. However, because yawning is a
physiological phenomenon, patients may not
associate its increased frequency to illness
and, consequently, do not report thèse
symptoms to their doctors unless they are
markedly disturbed and distressed. However, our
case séries is too small to provide a
définitive answer of defining the
frequency and significance of excessive yawning
in NMOSD. We hâve not performed an active
search of pathologie yawning in our entire
population of NMOSD patients to assess its
frequency and meaning. This present
séries just comprise patients in whom
pathologic yawning was psontaneously reported by
themselves or their relatives. an active survey
of tthe symptom in a lager cohort of NMOSD
patients may clarify the issue.
