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Atouch of increased pain Cutaneous allodynia in migraine.

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tent with these polarized experiences, and enhances our
understanding of a uniquely human cognitive ability to
distinguish the true from the untrue.
Harris et al. note that reactions of assent are significantly prompter than those of dissent or uncertainty.
This they take to support “Spinoza’s conjecture that
the mere comprehension of a statement entails the tacit
acceptance of its being true,” an almost reflexive, if
provisional, assent, to be followed by a more deliberate
weighing and assessment. Human beings, in other
words, are wired to “accept appearances as reality until
they prove otherwise.” This seems to us to ring true.
The most provocative suggestion made by Harris et
al. relates to their finding that all reactions of assent or
acceptance (or belief, if one prefers) are neurophysiologically identical, whether propositional judgments
are made in the highly charged realm of ethical or religious issues or the seemingly neutral realm of arithmetical statements. If such results can be duplicated,
Harris et al. will have made a fascinating discovery.
But are there different kinds of belief? Is belief in a
simple statement whose truth can be checked (such as
“Jesus spoke 2,467 words in the New Testament”)
comparable to forms of belief which we call “faith” or
conviction, where assent is given to transcendent propositions which lie beyond the realm of evidence (such
as belief in a soul, a god, heaven or hell)?
These are all questions for future research, and one
hopes that such questions will now be addressed by
Harris et al., as well as by other researchers. Harris and
his colleagues have set up an original and elegant series
of experiments, and that they have achieved such clearcut results represents a brilliant beginning to what we
hope will be a whole series of ever deeper and more
probing studies on the neurology of belief, a crucial
aspect of human behavior and identity which has, until
now, been beyond the reach of neuroscience.
Oliver Sacks, MD, FRCP and Joy Hirsch, PhD
Columbia University Medical Center
New York, NY
1. Sanfey AG, Rilling JK, Aronson JA, et al. The neural basis of
economic decision-making in the ultimatum game. Science
2. Breiter HC, Aharon I, Kahneman D, et al. Functional imaging
of neural responses to expectancy and experience of monetary
gains and losses. Neuron 2001;30:619-639.
3. Glimcher PW, Rustichini A. Neuroeconomics: The Consilience
of Brain and Decision. Science 2004;306:447-452.
4. Harris S, Sheth SA, Cohen MS. Functional Neuroimaging of
belief, disbelief and uncertainty. Ann Neurol 2007;63:141-147.
DOI: 10.1002/ana.21378
Annals of Neurology
Vol 63
No 2
February 2008
A Touch of Increased Pain:
Cutaneous Allodynia in
Allodynia is a hot topic in migraine research, with increasing recognition that it may be a quantifiable clinical marker. The phenomenon of cutaneous allodynia,
the perception of discomfort resulting from an ordinarily painless stimulus involving the skin, has long
been recognized as a clinical symptom that some patients experience during their migraine attacks. It was
formally described nearly 50 years ago when Selby and
Lance1 reported scalp tenderness in a significant majority of migraine patients associated with their attacks.
Lipton and colleagues’2 study in this issue of Annals is
the first to characterize allodynia at the population
level, employing a questionnaire to quantify allodynic
symptoms in 11,388 patients. The results solidify cutaneous allodynia as a common clinical symptom in
migraine. They also provide interesting new information about the relation between cutaneous allodynia
and other features of migraine, and highlight some
fundamental questions: What does cutaneous allodynia
tell us about migraine pathophysiology? Should it influence our clinical management of migraine patients?
Several interesting and significant findings are reported in Lipton and colleagues’2 study. First, it finds a
prevalence of allodynic symptoms that is similar to that
reported in a variety of other studies.1,3–7 This is important because most other studies of allodynia have been
performed in headache clinics where the severity of
symptoms is typically much greater. It indicates that allodynia is a common characteristic of migraine not only
in specialized headache clinics but in the general population. The study also finds that the allodynic symptoms
are correlated with defining clinical features of migraine,
and with headache severity, frequency, and associated
disability. There is also an increased number and frequency of allodynic symptoms in patients with increased
body mass, and decreased allodynic symptoms in patients with higher levels of education. There is a substantially increased occurrence of allodynic symptoms in patients with migraine with aura as compared with those
without aura. Another interesting finding is that patients
commonly experience allodynic symptoms that involve
nontrigeminal dermatomes, such as discomfort from
wearing a necklace.
Lipton and colleagues’2 study supports the concept
that a questionnaire approach can document the phenomenon of cutaneous allodynia without having to do
formal quantitative sensory testing, a time-consuming
and costly procedure. Lipton and colleagues2 used a
questionnaire that is a modified version of one that was
validated with quantitative sensory testing.8 However,
the ability of a questionnaire to accurately reflect a sensory phenomenon such as allodynia continues to be a
significant issue. Patients with migraine experience a
wide variety of symptoms other than headache, and
there may be considerable variability in their interpretation and articulation of their symptoms. The inverse
correlation between the reporting of cutaneous allodynia and the level of education of the patient that
Lipton and colleagues2 report may be a reflection of
this variability. The advantage of a large population
study such as that conducted by Lipton and colleagues
is that it is able to overcome variability that may be a
confounding factor in smaller studies.
In considering the pathophysiological implications
of allodynia in migraine, it is important to recognize
that current paradigms of allodynia were developed
primarily based on models of neuropathic pain, where
the primary event is an injury or perturbation of peripheral nerve physiology that leads to a secondary allodynia.9 This secondary process is believed to be
caused by sensitization of second- and/or third-order
neurons in the spinal cord and brain, a phenomenon
known as “central sensitization.” In this setting, allodynia typically reflects a progression of the pain process from a peripheral to central phenomenon and indicates a more chronic state. A number of recent
studies of allodynia in migraine have followed this
model of neuropathic pain, suggesting that allodynia
is a clinical marker of a relatively advanced phase of a
migraine attack, indicating central sensitization as a
later part of a pathophysiological cascade that occurs
as migraine progresses.10 However, a key difference
between migraine and other neuropathic pain is that
activation of the central nervous system in migraine is
a primary event. Patients commonly experience premonitory symptoms or aura (including sensory aura)
indicative of cortical or brainstem dysfunction before
they experience pain. Functional imaging and magnetoencephalographic studies have demonstrated these
changes that precede pain.11 It is therefore conceivable that central sensitization could occur primarily
from the direct activation of the cortex and brainstem, rather than secondarily as a consequence of a
peripheral nerve pathway as in traditional models of
neuropathic pain. In this way, cutaneous allodynia
could represent a primary dysregulation of central
sensory processing similar to that which is responsible
for the increased sensitivity to light, sound, and smell
that is common in migraine patients. The significantly increased prevalence of allodynia in patients
with migraine with aura that is reported in Lipton
and colleagues’2 study, as well as in other studies,3,5,12,13 may be a consequence of this primary central
activation. Cutaneous allodynia has also been reported in
trigeminal autonomic cephalalgias such as SUNCT
(short-lasting unilateral headache with nasal congestion
and tearing).14 In these disorders, it may have an abrupt
onset and resolution, a temporal pattern that is not consistent with a chronic, secondary event. The implications
of allodynia as a clinical marker may therefore be different
for migraine and other headache disorders than for neuropathic pain.
Several investigators have proposed that allodynia
has implications for both acute and chronic therapy.4,15 Burstein and colleagues15 have reported that
the development of allodynia is correlated with decreased responsiveness to the triptans as acute migraine therapy. Because other studies suggest that the
efficacy of different acute migraine therapies such as
antiinflammatories or ergotamines may not be affected by presence or absence of allodynia,16,17 it can
be argued that the choice of acute therapy for migraine should be influenced by the presence or absence of allodynia. However, Landy and coworkers4
report that the pain-free response to sumatriptan was
not affected by the presence of allodynia before treatment as indicated by a questionnaire. An additional
complication in the interpretation of the relation between allodynia and triptan use is the finding that
triptans may, in fact, induce cutaneous allodynia.18
With regard to overall treatment outcome, Young and
coworkers12 found that the presence of brush allodynia did not predict treatment failure in patients
who were hospitalized for headache. At this stage, the
influence that the presence of allodynia should have,
if any, on the approach to acute therapy remains uncertain. For now, the clinical reality is that patients
are counseled to take triptans regardless of whether
they have allodynia because there is insufficient evidence to recommend a different course. With regard
to chronic therapy, Lipton and colleagues2 suggest
that if allodynia is indeed a marker of disease progression, then avoidance of allodynia may be a therapeutic goal in preventing the progression from episodic
to chronic migraine. Although their data do indicate
a correlation between the number and frequency of
allodynic symptoms and severity and duration of migraine, it remains to be determined whether cutaneous allodynia has predictive value as a clinical indicator. The tools that they have developed have the
potential to shed new light on these important questions regarding acute and chronic therapy.
Regardless of the answers, however, Lipton and colleagues’2 study calls attention to cutaneous allodynia as a
key component of the multifaceted phenomenology of
migraine. Their data support the concept that cutaneous
allodynia can be quantified in a relatively simple fashion
and can be rigorously correlated with other clinical and
epidemiological features of migraine. It makes a signifi-
Charles and Brennan: Cutaneous Allodynia
cant contribution to what we know about migraine in
the general population, while at the same time underscoring the large gaps in our understanding of this complex neurophysiological disorder.
A Tale of Two Etiologies:
Loss and Recovery of
Olfactory Function
Andrew Charles, MD and K.C. Brennan, MD
Headache Research and Treatment Program,
Department of Neurology
David Geffen School of Medicine at University of
California Los Angeles
Los Angeles, CA
1. Selby G, Lance J. Observations on 500 cases of migraine and allied
vascular headache. J Neurol Neurosurg Psychiatry 1960;23:23–32.
2. Lipton R, Bigal M, Ashina S, et al. Cutaneous allodynia in the
migraine population. Ann Neurol (in press).
3. Ashkenazi A, Sholtzow M, Shaw JW, et al. Identifying cutaneous allodynia in chronic migraine using a practical clinical
method. Cephalalgia 2007;27:111–117.
4. Landy SH, McGinnis JE, McDonald SA. Clarification of developing and established clinical allodynia and pain-free outcomes. Headache 2007;47:247–252.
5. LoPinto C, Young WB, Ashkenazi A. Comparison of dynamic
(brush) and static (pressure) mechanical allodynia in migraine.
Cephalalgia 2006;26:852– 856.
6. Lovati C, D’Amico D, Rosa S, et al. Allodynia in different
forms of migraine. Neurol Sci 2007;28(suppl 2):S220 –S221.
7. Mathew NT, Kailasam J, Seifert T. Clinical recognition of allodynia in migraine. Neurology 2004;63:848 – 852.
8. Jakubowski M, Silberstein S, Ashkenazi A, Burstein R. Can allodynic migraine patients be identified interictally using a questionnaire? Neurology 2005;65:1419 –1422.
9. Campbell JN, Meyer RA. Mechanisms of neuropathic pain.
Neuron 2006;52:77–92.
10. Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack: clinical evidence for
the sequential recruitment of spinal and supraspinal nociceptive
neurons in migraine. Brain 2000;123:1703–1709.
11. Cutrer FM, Black DF. Imaging findings of migraine. Headache
12. Young WB, Richardson ES, Shukla P. Brush allodynia in hospitalized headache patients. Headache 2005;45:999 –1003.
13. Lovati C, D’Amico D, Rosa S, et al. Allodynia in different
forms of migraine. Neurol Sci 2007;28:S220 –S221.
14. Rozen TD, Haynes GV, Saper JR, Sheftell FD. Abrupt onset
and termination of cutaneous allodynia (central sensitization)
during attacks of SUNCT. Headache 2005;45:153–155.
15. Burstein R, Collins B, Jakubowski M. Defeating migraine pain
with triptans: a race against the development of cutaneous allodynia. Ann Neurol 2004;55:19 –26.
16. Jakubowski M, Levy D, Goor-Aryeh I, et al. Terminating migraine with allodynia and ongoing central sensitization using
parenteral administration of COX1/COX2 inhibitors. Headache 2005;45:850 – 861.
17. Silberstein SD, Young WB, Hopkins MM, et al. Dihydroergotamine for early and late treatment of migraine with cutaneous
allodynia: an open-label pilot trial. Headache 2007;47:878 – 885.
18. Linde M, Elam M, Lundblad L, et al. Sumatriptan (5-HT1B/
1D-agonist) causes a transient allodynia. Cephalalgia 2004;24:
Annals of Neurology
Vol 63
No 2
February 2008
A growing body of evidence suggests that decline in
olfactory function may herald the onset of the clinical
signs of Parkinson’s disease (PD) and Alzheimer’s disease.1 Moreover, pathological studies of brains from
asymptomatic older individuals have identified pathological hallmarks of these diseases in regions involved
in processing olfactory input, suggesting that these
brain regions may be targeted early in the disease process. Two longitudinal studies2,3 reported in this issue
of Annals illustrate the range of responses of the olfactory neural circuit to various pathological insults, from
functional recovery to an early indicator of PD.
In the first population-based study to examine olfactory dysfunction as a clinical risk marker for incident
PD,3 the 12-item Brief Smell Identification Test (BSIT) was administered to 2,906 Japanese-American
men participating in the Honolulu-Asia Aging Study.
Men with prevalent dementia, PD, or nasal congestion
at the time of olfactory testing were excluded, leaving
2,267 men. The incidence of PD was inversely related
to baseline performance on the B-SIT. The relative
odds of developing PD over the first 4 years of
follow-up were 5.2 (95% confidence interval,
1.5–25.6) for subjects in the lowest quartile (B-SIT
0 –5) compared with subjects in the two highest quartiles (B-SIT 8 –12) after adjustment for cognitive impairment, midlife coffee and pack-years of cigarette intake, bowel movement frequency, and daytime
sleepiness. For subjects in the second quartile (B-SIT
6 –7), their relative odds were 3.1 (95% confidence interval, 0.6 –16.1, not significant). No relation was seen
between baseline odor naming performance and incident PD cases during years 4 to 8 of follow-up.
Two small prospective studies4,5 and estimates from
functional imaging6,7 support the possibility that olfactory impairment begins 2 to 7 years before meeting the
diagnostic criteria for PD. Ross and colleagues3 have
previously shown that asymptomatic men in the
Honolulu-Asia Aging Study scoring between 0 and 5
on the B-SIT 3 to 4 years before autopsy were significantly more likely to have incidental Lewy bodies in
the substantia nigra and the locus ceruleus (odds ratio,
11.0; 95% confidence interval, 1.3–526) compared to
the highest tercile, suggesting that olfactory impairment might identify a preclinical state of PD.8 Ross
and colleagues’ study3 does not specifically address the
Braak hypothesis,9 which posits that PD pathogenesis
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cutaneous, pain, atouch, increase, migraine, allodynia
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