Center for Rare Diseases
Göttingen, University Medical Center
Göttingen
Abstract
A 59-year-old man presented for care who,
for 8 years, had had recurrent attacks of
yawning and severe fatigue initiated by
relatively mild exercise of his right leg
(Figure). In 2011, he had a herniation of the
L4-5 disc, which affected the right L4 root.
Conservative treatment noticeably reduced the
sciatic pain on the right side within a few
months. However, after this event, he would
promptly experience attacks of yawning and
fatigue each time he engaged in mod rate
exercise of the right leg (eg, going upstairs,
riding a bi- cycle, or repeatedly pushing
certain weights only with his right leg).
Attacks were not associated with a headache or
body temperature change, and similar exercises
of the other 3 limbs did not provoke yawning and
fatigue.
Résumé
Un homme de 59 ans présente depuis 8
ans des crises récurrentes de
bâillements et une fatigue intense
déclenchée par un exercice
relativement modeste de sa jambe droite comme la
marche. En 2011, il a une hernie du disque L4-5,
qui affecte la racine droite L4. Un traitement
conservateur a sensiblement réduit la
douleur sciatique du côté droit en
quelques mois. Cependant, après cet
événement, il ressent rapidement
des attaques de bâillements et de fatigue
chaque fois qu'il commence un exercice
modéré de la jambe droite (par
exemple, monter à l'étage, faire
du vélo ou pousser plusieurs fois
certains poids uniquement avec sa jambe droite).
Les attaques ne sont pas nécessairement
associées à un mal de tête
ou à un changement de température
corporelle, et des exercices similaires des 3
autres membres ne provoquent pas de
bâillement ni de fatigue.
Le patient a été traité
avec succès en prenant plusieurs fois par
semaine l'agoniste du récepteur
opioïde oral tilidine (50 mg, plus 4 mg de
naloxone) avant chaque exercice. Avec ce
traitement, la mobilisation de sa jambe droite
n'a pas déclenché de
bâillement ni de fatigue.
A 59-year-old man presented for care who,
for 8 years, had had recurrent attacks of
yawning and severe fatigue initiated by
relatively mild exercise of his right leg. In
2011, he had a herniation of the L4-5 disc,
which affected the right L4 root. Conservative
treatment noticeably reduced the sciatic pain on
the right side within a few months. However,
after this event, he would promptly experience
attacks of yawning and fatigue each time he
engaged in mod rate exercise of the right leg
(eg, going upstairs, riding a bicycle, or
repeatedly pushing certain weights only with his
right leg). Attacks were not associated with a
headache or body temperature change, and similar
exercises of the other 3 limbs did not provoke
yawning and fatigue.
Neurological, endocrine, and cardiopulmonary
investigations, including brain magnetic
resonance imaging, echocardiography,
polysomnography, and right-leg
electrophysiology, yielded no crucial
pathological findings. Video 1 shows an attack
of yawning and fatigue symptoms while walking on
a treadmill, immediately after an increase of
the incline to 3%.
Yawning rarely occurs as a main feature in
neurological disorders. Various neurotransmitter
systems interact to regulate yawning, with
dopamine playing a key role. Dopamine elicits
yawning via the activation of oxytocin
production in the hypothalamic paraventricular
nucleus, through D3 dopamine receptors and
subsequent cholinergic transmission,
particularly in the hippocampus.
In rats, application of the nonselective
dopamine agonist apomorphine increases yawning
frequency. Yawning also is an adverse effect of
apomorphine use in humans. Video 2 shows that,
under resting conditions, subcutaneous injection
of a low dose (2 mg) of apomorphine within a few
minutes induced the same clinical symptoms in
this patient as were observed at earlier points
during exercise of his right leg.
Hypothetically, the patient's initial
clinical condition with severe sciatic pain in
the right leg induced an associative,
movement-specific, and recurrent activation of
his apparently sensitive hypothalamic
dopaminergic system.
Opioid agents seem to inhibit yawning
through opioid receptor activation, particularly
in the paraventricular nucleus. After
subcutaneous injection of the opioid receptor
agonist piritramide (3.75 mg), the same exercise
on the treadmill as in Video 1 did not trigger
yawning and fatigue (Video 3). This was the case
not only after increase of the treadmill incline
to 3% but also after subsequent increases up to
7%, applied stepwise every 5 minutes (Video
3).
During similar exercise on the treadmill,
the patient's oxygen saturation, heart rate,
blood pressure, and body temperature did not
change after injection of piritramide compared
with the untreated condition (data not
shown).
The patient has now been successfully
treated several times per week by the oral
opioid receptor agonist tilidine (50 mg, plus 4
mg of naloxone) before each bout of exercise.
Under this treatment regimen, strain of his
right leg did not trigger yawning and
fatigue.
While we are not able to directly assess
dopaminergic neurotransmission in corresponding
hypothalamic regions, these observations are
consistent with the conditioning of an
apparently hypersensitive hypothalamic
dopaminergic system in the patient. Application
of an oral _-opioid receptor agonist presents a
reasonable treatment option for patients with a
similar disorder.
REFERENCES
1. Teive HAG, Munhoz RP, Camargo CHF,
Walusinski O. Yawning in neurology: a review.
Arq Neuropsiquiatr. 2018;76(7):473-480.
2. Collins GT, Eguibar JR. Neurophamacology
of yawning. Front Neurol Neurosci.
2010;28:90-106.
3. Dey S, Singh RH. Modification of
apomorphine-induced behaviour following chronic
swim exercise in rats. Neuroreport. 1992;3(6):
497-500.
4. KollerW,StacyM.Otherformulationsandfuture
considerations for apomorphine for subcutaneous
injection therapy. Neurology. 2004;62(6)(suppl
4): S22-S26. doi:10.1212/WNL.62.6_suppl_4.S22
Another explanation
This man is suffering from sciatica.
The endogenous opioid system consists of
widely scattered neurons that produce three
opioids: beta-endorphin, the met- and
leu-enkephalins, and the dynorphins. These
opioids act as neurotransmitters and
neuromodulators at three major classes of
receptors, termed mu, delta, and kappa, and
produce analgesia. Like their endogenous
counterparts, the opioid drugs, or opiates, act
at these same receptors to produce both
analgesia and undesirable side effects. During
his algic stress, this man releases endogenous
opioids which contribute to analgesia.
All opioids inhibit yawning, so it is not
endogenous opioid system that trigger his yawns.
Microinjection studies suggest that the
inhibitory effects of morphine result from the
activation of _-opioid receptors on
oxytocinergic neurons within the PVN.
Enkephalins, being endogenous opioids, are found
in magnocellular and parvocellular PVN
divisions, and the paraventriculo-hypophyseal
tract may also contain enkephalins. To note,
yawning is a prevalent sign of the opiate
withdrawal syndrome in human opiate
addicts.
The sciatica can play as an inflammatory
stress and then triggers release of
Corticotrophin R factor (CRF),
corticotrophin-like intermediate lobe peptide
and others molecules (dynorphins, POMC,
adenosine, anandamide). Adenosine and opiate
systems were shown to modulate each other,
resulting in a withdrawal syndrome including
yawning. The levels of these molecules increase
in the cerebrospinal fluid during his algic
stress. In my theory, yawning reduce (increase
the clearance of these molecules) their
concentration in CSF. Yawning appear as an
homeostatic process, in your clinical case,
which help decrease of some molecules discharged
during his lumbar spine injurie (conflict).
