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Atreatment for neurally mediated syncope (Don't) hold your breath.

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A Treatment for Neurally
Mediated Syncope? (Don’t)
Hold Your Breath
Neurally mediated syncope is among the most prevalent of neurological disorders; up to 35% of individuals
have experienced a syncopal event.1 Yet, despite this
high prevalence, many aspects of this disorder remain
The syncopal episode is characterized by paroxysmal
vasodilation with bradycardia that results in hypotension and decreased cerebral perfusion. The event is typically accompanied by premonitory features such as
blurred or tunnel vision, muffled hearing, lightheadedness, weakness, diaphoresis, hyperventilation, pallor,
and nausea, and is often preceded by an increase in
heart rate and blood pressure.2,3
This hemodynamic profile resembles the defense reaction in animals, induced by stimulation of limbic
structures including the “defense area” in the hypothalamus. A similar response occurs in humans and conscious animals in reaction to arousing stimuli such as a
loud noise or an air jet.4 The increase in heart rate and
blood pressure is followed by the sudden appearance of
hypotension with bradycardia of varying degree, ranging from a relative slowing of heart rate to prolonged
asystole. This vasodepressor-bradycardic response has
some features in common with the “playing dead” response or extreme immobility that occurs in many species as a reaction to an inescapable threat.5 The behavior may avert the attack of a predator and lends
support to the notion that the reflex is a relic of a
physiological response that conferred a selective advantage.
Alternately, several recent reports have drawn attention to stress myocardiopathy that is associated with
increased sympathetic activity after emotional stress.
Patients with this disorder present with acute left ventricular dysfunction accompanied by symptoms suggesting myocardial ischemia, which is most likely due
to high levels of circulating catecholamines.6,7 It is
conceivable that a predisposition to an alternate and
less physiologically demanding response to stress, the
hypotension and bradycardia of neurally mediated syncope, conferred survival benefit on those with that
Although some predisposing factors and provocative
stimuli are well established, for example, motionless
upright posture, warm ambient temperature, intravascular volume depletion, pain, and intense emotion, the
underlying basis for the widely different thresholds for
syncope among individuals exposed to the same provocative stimulus is not known. The disorder typically
occurs in persons with an essentially normal somatosensory nervous system, autonomic nervous system,
and cardiovascular system, highlighting the question:
Why are some individuals habitual fainters whereas
others have never fainted?
A genetic basis for neurally mediated syncope may
exist; several studies have reported an increased incidence of syncope in first-degree relatives of fainters,
but no gene or genetic marker has been identified, and
environmental, social, and cultural factors have not
been excluded by these studies.8 –10
Studies of autonomic cardiovascular and neuroendocrine function have not provided to date a consistent
mechanistic explanation for the susceptibility to neurally mediated syncope. It is against this background
that, in this issue of the journal, Norcliffe-Kaufmann
and colleagues11 propose that vascular sensitivity to hypocarbia may underlie the predisposition to neurally
mediated syncope. They report that individuals predisposed to recurrent neurally mediated syncope show
greater cerebral vasoconstriction and forearm vasodilation in response to different levels of hypocarbia than
do healthy control subjects. Although they show that
cerebrovascular and peripheral vascular sensitivity to
hypocarbia are significantly greater in neurally mediated syncope patients than control subjects, considerable overlap in sensitivity between control subjects and
patients is present. Nonetheless, because hyperventilation is a common premonitory feature of neurally mediated syncope (indeed, some have suggested the “thoracoabdominal pump” is a compensatory mechanism
to increase venous return to the heart12,13), it appears
reasonable to speculate that this enhanced but discordant sensitivity of the cerebral and peripheral vasculature to hypocarbia may contribute to the susceptibility
to syncope in some patients. If replicated, controlled
trials with interventions to minimize hypocarbia should
be considered in patients with recurrent neurally mediated syncope.
Most patients presenting after a single uncomplicated syncopal event require reassurance, education
about the disease, and advice as to how to recognize
prodromal symptoms and avoid provocative situations.
There is, however, a group of patients who require additional interventions. This includes patients with recurrent neurally mediated syncope (some patients faint
several times a day) and patients with episodic syncope
in a high-risk situation. Syncope in these patients leads
to impaired quality of life, psychological distress, and
substantial morbidity, and necessitates therapeutic attention.
Physical countermaneuvers are a first-line intervention that has been shown to increase blood pressure
and delay or abort the onset of neutrally mediated syn-
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
cope under laboratory conditions14,15 and in a multicenter, controlled trial.16 Patients should be instructed
to isometrically contract limb and trunk muscles at the
onset of prodromal symptoms. Rapid ingestion of tap
water may also help avert syncope.17
Pharmacotherapeutic interventions have produced
inconsistent results. Fludrocortisone, anticholinergic
agents, theophylline, ␤-adrenoreceptor antagonists, selective serotonin reuptake inhibitors disopyramide, and
␣-adrenoreceptor agonists are frequent therapeutic interventions.18 There are few large-scale, randomized,
clinical trials using these agents. Serial tilt-table testing
has been used in some trials to assess a therapeutic response, but this may not be an adequate surrogate
model for the prediction of a therapeutic response in
spontaneous syncope.19 ␤-Adrenoreceptor antagonists
are the most extensively used agents, based initially on
small uncontrolled trials and the widely held theory
that neurally mediated syncope is provoked by mechanical activation of cardiac afferent nerve fibers in
the ventricular wall by forceful ventricular contractions.20 The evidence in support of this mechanism is
wanting, and several multicenter randomized trials using different ␤-adrenoreceptor antagonists have failed
to show efficacy over placebo.18,21
Similarly, two randomized, placebo-controlled, dualchamber pacemaker trials were both negative.22,23 A
proportion of patients have cardioinhibitory asystole as
their primary syncopal mechanism and, therefore, may
obtain some benefit from pacemaker insertion,24 but
this has not been demonstrated in a prospective, randomized, controlled trial. Thus, studies to date continue to support the view put forth so lucidly by Sir
Thomas Lewis in 1932: “Undoubtedly the main cause
of the fall in blood pressure in these attacks, and the
enfeeblement loss of pulse, is independent of the vagus,
and lies in the blood vessels.”25
So, what is a clinician to do when treating a patient
with recurrent syncope given this impoverished therapeutic landscape. Based on the data that NorcliffeKaufman and colleagues11 present, it is not flippant
and may well be sound medical advice to say, “Hold
your breath.”
Roy Freeman, MD
Department of Neurology
Beth Israel Deaconess Medical Center
Boston, MA
1. Ganzeboom KS, Colman N, Reitsma JB, et al. Prevalence and
triggers of syncope in medical students. Am J Cardiol 2003;91:
1006 –1008, A8.
2. van Lieshout JJ, Wieling W, Karemaker JM, et al. The vasovagal response. Clin Sci (Lond) 1991;81:575–586.
Annals of Neurology
Vol 63
No 3
March 2008
3. Julu PO, Cooper VL, Hansen S, et al. Cardiovascular regulation in the period preceding vasovagal syncope in conscious humans. J Physiol 2003;549:299 –311.
4. Dampney RA, Coleman MJ, Fontes MA, et al. Central mechanisms underlying short- and long-term regulation of the cardiovascular system. Clin Exp Pharmacol Physiol 2002;29:
5. Gabrielsen GW, Smith EN. Physiological responses associated
with feigned death in the American opossum. Acta Physiol
Scand 1985;123:393–398.
6. Tsuchihashi K, Ueshima K, Uchida T, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a
novel heart syndrome mimicking acute myocardial infarction.
Angina Pectoris-Myocardial Infarction Investigations in Japan.
J Am Coll Cardiol 2001;38:11–18.
7. Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress.
N Engl J Med 2005;352:539 –548.
8. Camfield PR, Camfield CS. Syncope in childhood: a case control clinical study of the familial tendency to faint. Can J Neurol Sci 1990;17:306 –308.
9. Mathias CJ, Deguchi K, Bleasdale-Barr K, et al. Frequency of
family history in vasovagal syncope. Lancet 1998;352:33–34.
10. Serletis A, Rose S, Sheldon AG, et al. Vasovagal syncope in
medical students and their first-degree relatives. Eur Heart J
11. Norcliffe-Kaufmann LJ, Kaufmann H, Hainsworth R. Enhanced vascular responses to hypocapnia in neurally mediated
syncope. Ann Neurol 2008;63: 288 –294.
12. Miller JD, Pegelow DF, Jacques AJ, et al. Skeletal muscle pump
versus respiratory muscle pump: modulation of venous return
from the locomotor limb in humans. J Physiol 2005;563:
13. Thijs RD, Wieling W, van den Aardweg JG, et al. Respiratory
countermaneuvers in autonomic failure. Neurology 2007;69:
14. Krediet CT, van Dijk N, Linzer M, et al. Management of vasovagal syncope: controlling or aborting faints by leg crossing
and muscle tensing. Circulation 2002;106:1684 –1689.
15. Wieling W, Colman N, Krediet CT, et al. Nonpharmacological
treatment of reflex syncope. Clin Auton Res 2004;14(suppl 1):
16. van Dijk N, Quartieri F, Blanc JJ, et al. Effectiveness of physical counterpressure maneuvers in preventing vasovagal syncope:
the Physical Counterpressure Manoeuvres Trial (PC-Trial).
J Am Coll Cardiol 2006;48:1652–1657.
17. Lu CC, Diedrich A, Tung CS, et al. Water ingestion as prophylaxis against syncope. Circulation 2003;108:2660 –2665.
18. Brignole M, Alboni P, Benditt DG, et al. Guidelines on management (diagnosis and treatment) of syncope—update 2004.
Europace 2004;6:467–537.
19. Kaufmann H, Freeman R. Pharmacological treatment of reflex
syncope. Clin Auton Res 2004;14(suppl 1):71–75.
20. Mark AL. The Bezold-Jarisch reflex revisited: clinical implications of inhibitory reflexes originating in the heart. J Am Coll
Cardiol 1983;1:90 –102.
21. Sheldon R, Connolly S, Rose S, et al. Prevention of Syncope
Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Circulation
2006;113:1164 –1170.
22. Connolly SJ, Sheldon R, Thorpe KE, et al. Pacemaker therapy
for prevention of syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a
randomized trial. JAMA 2003;289:2224 –2229.
23. Raviele A, Giada F, Menozzi C, et al. A randomized, doubleblind, placebo-controlled study of permanent cardiac pacing for
the treatment of recurrent tilt-induced vasovagal syncope. The
vasovagal syncope and pacing trial (SYNPACE). Eur Heart J
24. Brignole M. International study on syncope of uncertain aetiology 3 (ISSUE 3): pacemaker therapy for patients with asystolic neurally-mediated syncope: rationale and study design. Europace 2007;9:25–30.
25. Lewis T. A lecture on vasovagal syncope and the carotid sinus
mechanism with comments on Gowers’s and Nothangel’s syndrome. Br Med J 1932;1:873– 876.
DOI: 10.1002/ana.21368
Are Adenosine Antagonists,
Such as Istradefylline,
Caffeine, and Chocolate,
Useful in the Treatment of
Parkinson’s Disease?
Adenosine, a purinergic modulator located on the corticostriatal glutamate terminals, normally stimulates the
indirect GABAergic inhibitory striatopallidal pathway
and may be involved in the normal center surrounding
inhibition, suppressing unwanted motor activity.1 In
Parkinson’s disease (PD), striatopallidal neurons are
hyperactive; therefore, inhibition of adenosine’s action
by pharmacological manipulation should ameliorate
parkinsonian symptoms, as Fuxe and Ungerstedt2 first
reported in 1974. Subsequent research has provided
further evidence that foods containing caffeine, such as
brewed coffee, tea, cola, and even dark chocolate, exert
antiparkinsonian effects, probably mediated by blocking adenosine A2A receptors.3 These receptors consist
of a heterotrimeric guanosine triphosphate–binding
protein, linked to cyclic adenosine 3⬘,5⬘ monophosphate (cAMP). Acting via cAMP as second messenger,
caffeine influences downstream targets through
dopamine- and cAMP-regulated phosphoprotein of 32
KD (DARP-32).3 Thus, it appears that the antiparkinsonian (as well as attention-enhancing) effects of caffeine that are mediated through adenosine A2A receptor
blockade and A2A receptor antagonists may be regarded
as potential therapies for parkinsonian and attentiondeficit disorders.4 Furthermore, several studies have
demonstrated that caffeine consumption is inversely
correlated with the risk for development of PD,5 which
has led to the proposition that adenosine antagonists
may also have neuroprotective effects.6,7
The discovery that enhancement of behavioral effects
of dopaminergic drugs correlated with their ability to
block adenosine receptors created a new class of antiparkinsonian drugs.8 The observed antiparkinsonian effects of adenosine antagonists appear to be mediated by
antagonistic interaction between adenosine A2A and
dopamine D2 receptors; the A2A/D2 heterome is thus
responsible for the enhancement of D2 signaling in the
striatopallidal neurons.7,9 Adenosine A2A antagonists
potentiate the effects of low-dose L-dopa on locomotor
and rotational activity in rats, and augment the motor
effects of L-dopa in MPTP primates, leading to the
proposal that A2A antagonists might be useful antiparkinsonian drugs by improving motor symptoms,
smoothing out L-dopa–related motor complications,
ameliorating dyskinesias, and possibly exerting diseasemodifying or neuroprotective effects.7–12
Based on its high affinity for the striatal A2A receptors (Ki ⫽ 12 ⫾ 1.7nM) and long half-life (approximately 47 hours), the adenosine A2A receptor antagonist istradefylline (KW-6002) has been studied
extensively in various animal models and in humans.7,9
The drug has been studied also in patients with PD
experiencing L-dopa–related motor fluctuations and
peak-dose dyskinesias in clinical trials.13–15 In the 12week, double-blind, randomized, placebo-controlled pilot, the PD patients were randomized to treatment
with placebo (n ⫽ 29), istradefylline up to 20mg/day
(n ⫽ 26), or istradefylline up to 40mg/day (n ⫽ 28).
Using home diaries, patients assigned to the istradefylline group were found to have a mean reduction in the
proportion of awake time spent in the “off” state by
7.1 ⫾ 2.0% compared with an increase of 2.2 ⫾ 2.7%
in the placebo group ( p ⫽ 0.008); the “off” time decreased by 1.2 ⫾ 0.3 hours in the istradefylline group
compared with an increase of 0.5 ⫾ 0.5 hour in the
placebo group ( p ⫽ 0.004). In this issue of Annals,
LeWitt and colleagues15 report the results of a much
larger, double-blind, placebo-controlled trial and found
that patients randomized to istradefylline (40mg/day)
had a mean reduction of 1.2 hours (18%) in “off” time
while awake as compared with those treated with placebo, from the baseline of mean 6.4 and 6.2 hours
“off” time in the istradefylline and placebo groups, respectively. This benefit, however, was offset by a mild,
but statistically significant, increase in “on” time with
dyskinesia in the istradefylline group, although there
was no increase in “troublesome dyskinesia.” The Clinical Global Impression-Improvement scores favored istradefylline at weeks 4 and 8, but not at end point (12
weeks). This study, similar to the above exploratory
study by Hauser and coworkers,14 reported no significant benefit of istradefylline on parkinsonian symptoms as measured by the Unified Parkinson’s Disease
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
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