Carlo Colosimo, MD, Francesco E.
Pontieri, MD, Rome, Italy
To the Editor : We read with interest the
clinical/scientific Note by Drs. Goren and
Friedman on levodopa-induced yawning in PD. They
state that "yawning has not been associated with
treated or untreated PD" and they suggest that
"if yawning is a dopamine mediated phenomenon in
humans it should be seen in PD patients treated
with levodopa and dopamine agonists". Indeed,
this is the case. If is well known that
apomorphine, a direct Dl-D2 dopamine receptor
agonist, frequently induces yawning just before
the onset of the motor effect, both in
experimental animals and in patients with PD.
Yawning was clearly described since the early
clinical trials with apomorphine in the 1950. A
More recently this effect was confirmed in the
larger clinical series that have marked the
revival of this drug as an adjunct therapy for
advanced PD, either as intermittent boluses or
as a continuous subcutaneous infusion via
portable minipumps. Interestingly, the
widespread reintroduction of apomorphine in the
therapeutic arsenal for PD is due to the
observation that pretreatment with the
peripheral dopamine receptor blocking agent
domperidone could prevent apomorphine-induced
nausea, drowsiness, and arterial hypotension,
but not yawning. This would confirm that this
side effect has a central origin related to
dopamine receptor stimulation in the basal
ganglia. However, as pointed out by the authors,
the pathogenesis is far more complex involving
the stimulation of other neurotransmitters in
the forebrain.
Virgilio GH.
Evidente, MD, Scottsdale, AZ;
Katrina Gwinn Hardy, MD, Jacksonville,
FL
To the Editor: We read with interest the
article by Drs. Goren and Friedman on yawning in
PD. The authors state that yawning has not been
associated with treated or untreated PD and that
it is most likely a dopamine-mediated
phenomenon. We wish to point out that idiopathic
PD is not the first parkinsonian syndrome
reported to be associated with yawning. Yawning
was described by Dr. von Economo not only in the
acute encephalitic ,"somnolent" stage of
encephalitis lethargica (EL) along with
sleepiness, but also in postencephalitic
parkinsonian (PEP) patients without any
accompanying sleep disturbance or somnolence. In
the latter case, the yawning was often rhythmic
and repetitive, and was viewed as a form of
automatism or compulsive tic. We recently
published a video collection of early
cinematographic cases of PEP seen at the Mayo
Clinic in the 1920s, with one case showing a
woman with paroxysmal yawning. Like
idiopathic PD, PEP is associated with neuronal
loss that is most distinct in the substantia
nigra and less so in the basal ganglia . Given
the neuropathologic involvement of the
nigrostriatal system in PEP, the parkinsonism
was likely due to dopaminergic dysfunction. We
believe that the compulsive yawning in
PEP could also possibly be dopamine-mediated, as
this symptom or sign often remitted in the few
cases of PEP that spontaneously improved.
John D. O'Sullivan, FRACP, Andrew J. Lees,
NID, London, UK; Andrew J. Hughes, IMD,
Victoria, Australia
To the Editor: We read with interest the
report by Drs. Goren and Friedman describing a
parkinsonian patient for whom yawning heralded
"on" phases after oral levodopa, but were
surprised that the same effect following
administration of the dopamine agonist
apomorphine was not mentioned. The majority of
our PD patients who are administered
subcutaneous apomorphine to test dopaminergic
responsiveness or intermittently to treat
parkinsoman motor fluctuations experience
yawning, usually coincident with the onset of
the motor response. Sedation, wich is also
common after apomorphine injections, sometimes
but not always accompanies the yawning. The
hypothalamic paraventricular nucleus receives
afferent projections from the midbrain
dopaininergic neurons, and oxytocin release from
this area in response to dopaminergic
stimulation is thought to mediate both yawning
and penile erections in rats following
apomorphine. We recently described five patients
with PD who experienced apomorphine-induced
penile erections, three of whom also yawned
after apomorphine administration supporting a
similar link in man. Like yawning, the erections
were usually transient and occurred as the
patients switched from "off"' to "on" suggesting
the postsynaptic dopamine receptor mechanisins
involved differ from those mediating the more
prolonged motor response. Yawning and erections
appear to be dose-related and may depend on the
number of hypothalamic neurons producing
Ocytocin, which have been shown to be reduced in
PD. Effects such as yawning and erections
associated with dopaminergic agents may be
considered irrelevant or embarrassing by
patients and go unrecognized without specific
questioning. We agree with Drs. Goren and
Friedman that such observations may be important
to our understanding of the dopaminergic system
in PD.
Joseph H. Friedman, MD, Pawtucket,
RI; Jessica Goren, PharmD, Kingstown,
RI
Reply from the Authors : We appreciate the
interest our letter generated. Since reporting
the two cases, we have subsequently observed
another PD patient who yawned in conjunction
with turning "on." He had never made the
connection between yawning qnd responding to
L-dopa, but in the office he was initially
"Off," then began to yawn, and was shortly
thereafter able to walk, which had net been the
case earlier. The patient, in retrospect,
reported that this was a common phenomenon. We
acknowledge that yawning occurred in PEP. This,
of course, occurred in the absence of medication
and was therefore inherent in the condition, as
were a number of other movement and behavior
disorders. We are unaware that unmedicated
patients with PD yawn when not sleepy or bored.
The possibility that dopamine is involved is
consistent with our report.
Although our letter stated that dopamine
agonists and apomorphine in particular have been
associated with yawning, we failed to note that
apomorphine is known to induce yawning in PD
patients. We appreciate this fact being brought
to our attention. Because yawning is not
keynoted in any of these articles, and
apomorphine is not used in the United States, we
were unable to retrieve this information from
Medline searches and did not know this from
personal experience. We do not have a hypothesis
to explain why apomorphine induces yawning so
commonly whereas L-dopa and the oral dopamine
agonists do not.
