EDITORIAL
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.048926 on 16 December 2004. Downloaded from http://jnnp.bmj.com/ on August 24, 2022 by guest. Protected by
.......................................................................................
New year…
M N Rossor, M G Hanna
...................................................................................
L
ast year we said goodbye to Ian
Whittle whom we thank for all his
hard work and welcome Peter
Warnke from Liverpool as our new
Associate Editor for Neurosurgery. We
also say goodbye to many members of
the editorial board and welcome new
faces. The vitality of the journal rests
with its reviewers and authors. We
listed our reviewers in the December
issue and reiterate our thanks to them.
With over two thousand submissions a
year the burden on unpaid reviewers
forever increases. In order to reduce the
EDITORIAL
.......................................................................................
Migraine2anxiety related dizziness
(MARD): a new disorder?
J M Furman, C D Balaban, R G Jacob, D A Marcus
...................................................................................
D
izziness is a common complaint
that can result from abnormalities
of the vestibular apparatus of the
inner ear and of those portions of the
central nervous system (CNS) that
process information from the peripheral
vestibular system and other senses,
particularly vision and somatosensation.
Recently, two CNS disorders, migraine
and anxiety, have been recognised as
being commonly associated with dizzi-
ness.1 2 These associations may be an
expression of an aetiological relation-
ship, for example, dizziness caused by
migraine, or dizziness caused by anxi-
ety; alternatively, migraine or anxiety
may influence the presentation of a
balance disorder. For example, chronic
dizziness may become more disabling
during the added stress of a migraine
headache or panic attack. In addition,
dizziness occurs comorbidly with both
migraine headache and anxiety disor-
ders.3 4 Finally, there is increased comor-
bidity between anxiety and migraine.5
burden we have tried to make an early
decision on priority for the journal with
the result that over a third of papers do
not go out to review. This will include
many papers that are well conducted
and worthy of publication but which we
consider are not best suited to the JNNP,
usually because they are too specialised.
In order to assist authors with the
decision of whether to submit to the
journal we have revised the web-
site guidelines. In summary we wish
to attract papers of general interest
to the multi-disciplinary readership of
Thus, it is not surprising that some
patients with dizziness may suffer from
a combination of a balance disorder,
migraine, and an anxiety disorder, a
symptom complex that we propose to
name migraine2anxiety related dizzi-
ness (MARD) (fig 1). The general
recognition of MARD may be limited
because of the fragmented nature of our
healthcare system, where specialists in
one field, such as psychiatry or neurol-
ogy, fail to recognise phenomena known
to specialists in other fields, such as
otoneurology.
This editorial will focus on the patho-
physiology and clinical issues relating to
MARD, including the interfaces among
balance disorders, migraine, and anxi-
ety. We use current epidemiological data
and studies of pathogenesis to develop
comorbidity models. These models serve
as hypotheses that may lead to possible
treatment options for many patients
with dizziness, including those with
MARD.
1
Neurologists, Psychiatrists, and Neuro-
surgeons. Papers should be of direct
clinical relevance and so we will not
generally publish papers on normal
brain function nor on animal studies.
We hope that these changes will provide
a quick decision for our authors whilst
reducing the burden on reviewers.
Nevertheless prioritising between good
papers remains very difficult and to
assist this we have established a weekly
editorial meeting.
As we enter 2005 we reiterate our
thanks to reviewers and authors and
hope to continue to attract similar high
quality manuscripts to those we have
handled over the last year.
J Neurol Neurosurg Psychiatry 2005;76:1
......................
Authors’ affiliations
Martin N Rossor, Michael G Hanna, Institute
of Neurology, Queen Square, London WC1N
3BG, UK
Correspondence to: Professor Martin Rossor;
mrossor@dementia.ion.ucl.ac.uk
copyright.
Migraine Anxiety disorders
Balance disorders
Figure 1 Venn diagram of the interfaces
among migraine, anxiety, and balance
disorders. The central sector, which denotes the
three way interface, represents an hypothesised
new ailment, migraine2anxiety related
dizziness (MARD).
DEFINITIONS: DISORDER,
SYNDROME, DEFINING
SYMPTOMS, AND ASSOCIATED
SYMPTOMS
Medical conditions are diagnosed by a
variety of signs and symptoms. Specific
constellations of signs and symptoms
are usually called syndromes, whereas a
disorder is ideally identified by specific
pathophysiological mechanisms. Some
diagnostic systems distinguish between
symptoms necessary for the diagnosis of
the disorder (defining symptoms),6 and
those that are associated but not defin-
ing (associated symptoms). Although
associated symptoms occur with
increased prevalence in a disorder, they
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2 EDITORIAL

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.048926 on 16 December 2004. Downloaded from http://jnnp.bmj.com/ on August 24, 2022 by guest. Protected by
but not in patients with tension-type
Spreading headache.13 Conversely, migraine was
depression reported by 38% of 200 consecutive
patients with the primary complaint of
Pain and aura dizziness, compared with 24% in a
comparison group of orthopaedic
Neocortex
patients.1 A similar study evaluating
Vertigo
migraine in patients with isolated ver-
tigo (n = 72) compared with orthopae-
Passive coping dic controls identified migraine in 61%
Thalamus of the vertigo patients but only 10% of
orthopaedic patients.14 Clinical labora-
tory vestibular tests in migraineurs
unselected for the presence or absence
of dizziness show a variety of abnorm-
alities, including both peripheral and
Sterile
central abnormalities;12 13 15 however,
"Trigeminovascular reflex"
inflammation these vestibular abnormalities are more
(extravasation) prominent in patients with migraine
associated with dizziness.9 13 16–20
Vasodilation PAG The link between vestibular symp-
of cerebral and toms and migrainous symptoms and the
labyrinthine increased prevalence of vestibular test
vessels abnormalities in migraineurs suggests
Ophthalmic that migraine related dizziness is based
Activate division Trigeminal on a specific pathophysiology—that is,
trigeminal Nuc. caudalis
that migraine related dizziness is a bona
afferents C1/C2 dorsal horn
fide disorder. In fact, Neuhauser, et al
Peptide have established specific diagnostic cri-
release into teria for migraine related dizziness,
inner ear and which they term ‘‘migrainous vertigo’’.1
interstitial fluid Activate Vestibular A validated structured diagnostic inter-
vestibular nuclei view for migrainous vertigo using these
afferents

copyright.
criteria may help to identify this condi-
tion.21 Using the Neuhauser criteria,
Modulate sensitivity of: migrainous vertigo was diagnosed in
1. "Trigeminovascular reflex" 9% of migraine headache patients. In
2. Pain pathways DRN RMag 45% of these patients, migraine head-
3. Affective reactivity (5-HT ) (5-HT ) ache episodes were regularly accompa-
LC (NE ) LTeg (NE ) nied by vestibular symptoms, and in
another 48%, vestibular symptoms co-
occurred irregularly.1 The influence, if
any, of migraine aura on the link
Figure 2 Pathogenetic model for migraine related dizziness. The core of the diagram represents between migraine and vestibular symp-
pathogenetic mechanisms in migraine related pain, shown as unshaded boxes. The vestibular toms is unknown. We speculate that
linkages to migraine mechanisms are shaded. Adapted from Furman et al.4 5-HT, 5-
some episodes of vertigo in patients
hydroxytryptamine (serotonin); DRN, dorsal raphe nucleus; LC, locus ceruleus; LTeg, lateral
tegmental noradrenergic neurones; NE, norepinephrine; PAG, periacqueductal grey; RMag, with MARD represent migraine aura
nucleus raphe magnus. without headache.

do not in themselves identify the dis-
order. For example, dizziness occurs as
an integral or defining symptom in
Meniere’s disease7 and panic disor-
der—that is, dizziness during a panic
attack.8 Dizziness can also be considered
an associated symptom for migraine9 or
generalised anxiety disorder.6
MIGRAINE RELATED DIZZINESS
The term ‘‘migraine’’ refers to both a
syndrome and a disorder. The diagnosis
of migraine syndrome requires the pre-
sence of a neurological aura associated
with headache or a mixture of symp-
toms including unilateral, disabling,
throbbing pain associated with sensitiv-
ity to noise and light or with nausea.10 In
addition, migraine is characterised by
interictal alterations in neurochemicals
(including serotonin, norepinephrine
(noradrenaline), and dopamine) and
cutaneous allodynia, representing aber-
rant neurophysiology during migraine.11
In addition to these defining features of
migraine, patients often describe a
variety of additional migraine associated
symptoms. One of the most common
migraine accompaniments is dizziness
or balance disturbance. Dizziness occurs
in 28230% and vertigo in 25226% of
patients with a primary complaint of
migraine.9 12 The association tends to be
specific to migraine, rather than head-
ache in general. Dizziness or vertigo
occur in 54.5% of patients with
migraine, compared with 30.2% of
patients with tension-type headache.9
In addition, abnormal posturography
testing is seen in patients with migraine
Pathophysiology of migraine
related dizziness
Reflecting the uncertainty regarding the
pathophysiology of migraine headache,
the pathophysiology of migraine related
dizziness is largely unknown. In fig 2,
we provide a framework that integrates
the possible neuroanatomical pathways
with the clinical manifestations of
migrainous vertigo. Fundamental to
the pathophysiology of migraine is the
trigeminovascular reflex. This is a para-
sympathetic reflex that can produce
vasodilation of large cranial vessels.
The vasodilation of large cranial vessels
is a consequence of activation mediated
by the trigeminal nucleus caudalis (Vc)
and C1-C2 dorsal horn neurones.22 23
In addition to the parasympathetic
effects of the trigeminovascular reflex,

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EDITORIAL
vasodilation may be induced or aug-
mented by direct vasodilator effects of
neurokinin A (NKA), calcitonin gene
related peptide (CGRP), and substance P
(SP) release from trigeminal sensory
terminals.22
Vestibular pathways can contribute to
both central and peripheral migraine
mechanisms.4 The reciprocal connec-
tions between the inferior, medial, and
lateral vestibular nuclei and trigeminal
nucleus caudalis suggest that vestibular
and trigeminal information processing
may be altered concurrently during
migraine attacks, and that vestibular
signals may directly influence trigemi-
novascular reflex pathways. In addition,
central vestibular activation can affect
activity in monoaminergic pathways
through direct connections from the
vestibular nuclei to the dorsal raphe
nucleus, nucleus raphe magnus, locus
coeruleus, and lateral tegmental region.
These changes in monoaminergic activ-
ity due to vestibular activation may both
trigger migraine related symptoms and
modulate activity in both pain related
and anxiety related pathways. Con-
versely, regionally specialised noradre-
nergic24 and serotonergic25 inputs are
potential substrates for altering central
vestibular information processing dur-
ing and between26 migrainous episodes.
Finally, two possible mechanisms may
be related to vertigo as a migraine aura.
Short duration vertigo symptoms have
been suggested to be a ‘‘brainstem aura’’
that may be accompanied by changes in
blood flow.19 Alternatively, direct con-
nections from the posterior parietal
cortex to the vestibular nuclei may
provide a direct access for cortical
mechanisms underlying migraine aura
to reach areas important for vesti-
bular information processing and reflex
performance.
The vestibular periphery may also
influence migraine pathways. Vass et al27
have demonstrated that there is a
significant trigeminal sensory innerva-
tion of the stria vascularis, spiral
modiolar blood vessels, and dark cell
region of the cristae ampularis. They
have shown also that electrical stimu-
lation of the trigeminal ganglion pro-
duces extravasation from the basilar,
anterior inferior cerebellar, and
cochlear arteries of albino guinea pigs,
and that round window application of
capsaicin produces extravasation in the
former two sites.28 The powerful vaso-
dilators SP and NKA are present in the
eighth nerve afferent terminals in the
organ of Corti and vestibular sensory
epithelia.29 SP and NKA may be released
during nerve activation in the same
manner as vasodilatory peptides are
released by peripheral trigeminal nerve
terminals as a neurogenic mechanism in
migraine. As CGRP is present in efferent
projections to cochlear and vestibular
epithelia,30 31 release is expected during
efferent activation. Thus, it is possible
that released SP, NKA, and CGRP from
trigeminal and eighth nerve fibres could
contribute to migraine related dizziness
via hormone-like actions on neural and
vascular elements.
ANXIETY RELATED DIZZINESS
Numerous studies have confirmed that
anxiety and dizziness are interrelated.6 32
For example, among 268 patients
recruited from a tertiary otolaryngology
clinic, panic disorder was identified in
17.2% and major depressive disorder in
11.2%.33 Furthermore, patients recruited
in an anxiety clinic setting, particularly
those with agoraphobia, have an
increased rate of balance dysfunc-
tion.34–37 Consequently, recent studies
have moved away from the previously
held assumption that the presence of
anxiety automatically implies a ‘‘psy-
chogenic’’ cause for dizziness.38 In a
study by Eckhardt-Henn et al,39 patients
with dizziness recruited at a neurologi-
cal clinic underwent both psychiatric
and otoneurological evaluations. Based
on the findings, the 189 patients were
divided into the following groups: (a)
organic (27%), (b) mixed ‘‘psycho-
organic’’ (16%), (c) psychiatric (52%),
and (d) idiopathic (5%). The most
common psychiatric diagnosis was an
anxiety disorder, followed by somatisa-
tion and depressive disorders. There
were no differences between the psy-
chiatric and psycho-organic groups with
respect to the distribution of psychiatric
diagnoses, suggesting that the presence
of a particular diagnosis does not rule
out a vestibular disorder. Based on a
retrospective chart review of 132 (77%)
of 172 patients at a tertiary dizziness
clinic who had been referred for psy-
chiatric evaluation, Staab et al40 classi-
fied patients into three groups: (a)
psychiatric disorder causing dizziness,
(b) primary otoneurological disorder
with secondary anxiety, and (c) pre-
existing anxiety or prodromes escalating
as a result of the neurotological dis-
order. Patients were nearly equally
divided among the three categories. A
diagnosis of panic disorder predicted
membership in the psychiatric dizziness
group, whereas membership in the
primary neurotological group was asso-
ciated with an elevated prevalence of
spatial phobias. The fact that panic
disorder appeared preferentially in the
psychiatric group40 is consistent with a
definition of ‘‘psychiatric dizziness’’
previously proposed by our group.2
These criteria include: (a) the dizziness
is a defining or associated symptom of
a psychiatric disorder, and (b) the
3
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dizziness is not correlated with vestibu-
lar function test abnormalities. The only
psychiatric disorder for which dizziness
is a defining symptom is panic disorder.
Furthermore, we have found that dizzi-
ness that occurs only during panic
attacks is not correlated with vestibular
dysfunction,36 whereas dizziness as an
isolated symptom occurring between
panic attacks is correlated.35 36
Anxiety seems to be a particular
problem in patients with acute vestibu-
lar disorders. In a recent study,41 17
(57%) of 30 patients with acute vertigo
reported that anxiety symptoms seemed
disproportionate to the seriousness of
the disorder. Only 23% had no anxiety.
The increase in anxiety was not just a
general reaction to having an acute
illness, because the comparison group
of patients with other acute neurological
conditions without dizziness reported
significantly less anxiety (17%). In
patients with chronic dizziness, anxiety
is present but less pronounced. In a
study of 112 patients with Meniére’s
disease who remained symptomatic
despite treatment, clinically significant
anxiety was found in only 17%.42
Pathophysiology of anxiety related
dizziness
Three partially overlapping modes of
copyright.
interaction between anxiety and vesti-
bular dysfunction have been proposed:
somatopsychic, psychosomatic, and
linkage.43 A somatopsychic explanation
would be that the perception of vesti-
bular dysfunction, for example, dizzi-
ness or vertigo, causes anxiety. The
initial high anxiety reactions to a ves-
tibular disorder is an example of soma-
topsychic effects. Psychosomatic effects
imply that anxiety causes dizziness. The
psychiatric dizziness of panic is an
example. Anxiety or hyperventilation
may also reactivate a vestibular disorder
by interfering with central compensa-
tion44 or by altering somatosensory
input.45 The linkage model suggests a
common underlying disorder that man-
ifests as both anxiety and balance
problems. The underlying neural circui-
try includes the parabrachial nucleus,
the vestibulothalamocortical and ceruleo-
vestibular pathways, and serotonergic
neurotransmission. In addition, the
periaqueductal grey (PAG) is an area
involved in dizziness, pain, and anxi-
ety, and will be discussed in the next
section. The pathophysiology of anxiety
related dizziness is outlined in fig 3,
which provides a framework for the
three modes of pathogenesis of this
condition, and incorporates informa-
tion concerning both anatomical path-
ways and clinical manifestations.
The parabrachial nucleus (PBN) pro-
vides a key interface between anxiety
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4 EDITORIAL
Neocortex
Vertigo
association
Postural instability
Prefrontal
and
Agoraphobic infralimbic cortex
SMD
Central
amygdaloid
nucleus network
Parabrachial
nucleus DRN (5-HT )
(m, em, el, KF) LC (NE)
Vestibular
nuclei
Figure 3 Pathogenetic model for anxiety
related dizziness. This simplified representation
of the neurological bases of the
balance2anxiety interface is updated from
recent reviews.67 102 These balance–anxiety
linkages appear to involve integrated activity of
at least four neural circuits: (a) a
vestibuloparabrachial nucleus (PBN) network,
(b) a vestibulothalamocortical network, (c) a
ceruleovestibular network, and (d) a raphe
nuclear-vestibular network. 5-HT, 5-
hydroxytryptamine (serotonin); DRN, dorsal
raphe nucleus; LC, locus ceruleus; NE,
norepinephrine; m, em, el, KF, medial, external
medial, external lateral, and Kölliker-Fuse
nucleus subdivisions; SMD, space and motion
discomfort.
related circuitry and central vestibu-
lar pathways. The discovery of the
vestibulo-PBN pathway emerged from
neuroanatomical tracer studies of
vestibuloautonomic pathways. These
studies indicated sparse direct vestibular
nucleus connections to the ventrolateral
medulla, nucleus of the solitary tract,
nucleus ambiguus lateral tegmental
area,46–49 and the anteromedian/
Edinger-Westphal nuclei,50 and robust
projections from the vestibular nuclei to
the medial, external medial, and exter-
nal lateral subnuclei of the PBN and the
Kölliker-Fuse nucleus.48 49 51 The neu-
rones in this vestibulorecipient PBN
region respond to whole body rotation
in alert primates,51 and some PBN cells
project to a wide region in the vestibular
nuclei.52 Reciprocal connections between
the PBN and the central amygdaloid
nucleus, the hypothalamus, and the
infralimbic cortex are consistent with
the role of the PBN as an integral
component of circuitry that mediates
formation of conditioned fear and anxi-
ety responses.53–55 Thus, the PBN appears
to be an important node for linking
vestibular information with the neural
substrates for panic disorders and
anxiety.
The vestibulothalamocortical pathway
links the vestibular nuclei with discrete
fields within the neocortex (including
portions of parietoinsular cortex, areas
3a, 7, and 2v, and the posterior sylvian
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cortex) containing neurones that
Visual
respond to vestibular stimulation.56 57
cortex These responses are mediated by projec-
tions from thalamic regions58 that
Vestibular
cortex receive direct projections from the ves-
tibular nuclei59–63 and show activation in
functional imaging studies.64 This corti-
Thalamus cal pathway is regarded as an important
substrate for perceptions of vertigo,
imbalance, and instability in patients
and might be a pathway for somato-
psychic effects.
The ceruleovestibular pathway arises
from the caudal pole of the locus
ceruleus (LC) and the adjacent nucleus
subceruleus.24 65 There are four quanti-
tatively distinct density levels of nor-
adrenergic fibres in the vestibular
nuclei, with the highest innervation
densities in regions that probably
increase postural sway and alter vesti-
bular evoked eye movements during
anxiety and changes in alertness.24 The
caudal locus ceruleus/nucleus subceru-
leus complex also contains cells that are
known to project by collaterals to: (a)
the hypothalamus, hippocampus, neo-
cortex, and cerebellum; (b) the spinal
cord, cerebellum, neocortex, and hypo-
thalamus; or (c) the spinal cord and
cerebellum.66 As locus ceruleus projec-
tions are also highly collateralised, we
have proposed24 67 that the ceruleoves-
tibular pathway may be one branch of
fibres that co-activate (or co-modulate)
neurones in the vestibular nucleus and
other motor pathways, contributing to
the known effects of the state of arousal
on vestibular reflex performance.68–71
The actions of selective serotonin
reuptake inhibitors (SSRIs) have pro-
vided compelling evidence for a role of
serotonergic transmission in vestibular
function. Recent evidence indicates that
SSRIs are efficacious in the treatment of
vertigo;18 32 72 furthermore, the beneficial
effect of benzodiazepines such as clona-
zepam on both dizziness and anxiety
may be mediated by their serotonergic
effects.73–75 In addition, the vestibular
manifestations of the SSRI discontinua-
tion syndrome (acute onset of dizziness,
vertigo, and uncoordination) are exa-
cerbated by head and eye move-
ments,76 77 which is consistent with
direct effects on vestibular information
processing. Serotonergic projections to
the vestibular nuclei originate from both
the dorsal raphe nucleus and a caudal
region spanning the nucleus raphe
obscurus and nucleus raphe pallidus.25
These pathways also contain a signifi-
cant non-serotonergic component. As
individual raphe neurones often project
to multiple sites via axon collaterals,78–81
we have suggested67 that collateralised
raphe2vestibular projections may co-
modulate activity in the vestibular
nuclei and sites such as the parabrachial
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.048926 on 16 December 2004. Downloaded from http://jnnp.bmj.com/ on August 24, 2022 by guest. Protected by
nucleus, neocortex, and central amyg-
daloid nucleus.79 82 83
MIGRAINE2ANXIETY RELATED
DIZZINESS
The link between migraine and balance
disorders and the link between anxiety
and balance disorders suggests that a
subgroup of such patients will manifest
migraine, anxiety, and a balance dis-
order. MARD is unlikely to be simply the
chance combination of a balance dis-
order, migraine headache, and anxiety.
This notion is supported by the
increased prevalence of panic disorder
in migraine patients with and without
aura. In a recent study, the lifetime
prevalence of panic disorder was 19.6%
in migraine patients with aura and
14.3% in migraine patients without
aura.84 In addition, the presence of
anxiety in patients with migraine sug-
gests a worse prognosis.85 In an 8 year
follow up study, Guidetti et al found that
anxiety disorders were predictive of
headache persistence 8 years later.
Specifically, among patients with
migraine and anxiety, 75% had endur-
ing migraines and anxiety 8 years later,
19% changed to tension headaches, and
only 6% were headache free. By com-
parison, among migraine patients with-
out anxiety, only 30% had enduring
copyright.
migraines, 42% changed to tension
headaches, and 27% were headache
free.
Pathophysiology of MARD
In fig 4, we present a schematic diagram
of the pathophysiology of MARD that
draws from material regarding migraine
related dizziness, illustrated in fig 2, and
anxiety related dizziness, illustrated in
fig 3. In fig 4, we highlight particularly
the role of the PAG. Note that the
superior vestibular nucleus projects to
the ventrolateral and ventral columns of
the PAG. These PAG regions receive
projections from the medial, dorsolat-
eral, and ventrolateral orbital cortex and
from the posterior and dorsal agranular
insular cortex.86 The ventrolateral and
ventral PAG are also connected recipro-
cally with the central amygdaloid
nucleus.87 88 Therefore, the ventrolateral
and ventral PAG appear to be at the
nexus of loops linking vestibular,
migraine, and anxiety related pathways.
This PAG related network appears to
constitute a linkage between the affec-
tive and behavioural responses to bal-
ance disorders and migraine. Both
ventral and ventrolateral PAG are com-
ponents of ‘‘emotional motor’’ pathways
that mediate passive emotional coping
in response to deep or chronic pain or
traumatic injury.89 The activation of
pathways linking the vestibular system
with anxiety and migraine mechanisms
EDITORIAL 5

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.048926 on 16 December 2004. Downloaded from http://jnnp.bmj.com/ on August 24, 2022 by guest. Protected by
and anxiety related circuits on percep-
Unconditioned perceptions
tions of pain, vertigo, postural instabil-
ity, passive coping, visual dependence,
Neocortex and space and motion discomfort
Visual
Pain and aura (SMD) are subject to considerable indi-
association
cortex vidual variations. These variations may
Vertigo
be an important factor in understanding
Postural instability
individual differences in susceptibility to
the development of avoidance beha-
Sopite syndrome viour, including agoraphobia.
Passive coping
Prefrontal and
infralimbic
"Visual Clinical implications of MARD
cortex
dependence" Somatosensory Vestibular The clinical implications of the overlap
SMD cortex cortex between migraine, anxiety, and balance
disorders in MARD relate to diagnosis,
clinical course, and treatment. Because
Conditioned response the care of these patients tends to be
distributed among primary care physi-
Agoraphobia
Thalamus cians, neurologists, otolaryngologists,
and psychiatrists, the initial diagnosis
may reflect the background of the
Central "Trigemino- examining doctor in addition to the
amygdaloid vascular symptoms of the patient. Furthermore,
nucleus network reflex" patients may self select to a particular
PAG
(v and vl) specialist depending on which com-
ponent predominates. Patients with
MARD may be misdiagnosed if one or
Caudal
Trigeminal more components go unrecognised. In
parabrachial
Trigeminal afferents our experience, balance symptoms in
nucleus
nuc. caudalis patients with a clinically significant
anxiety disorder are most likely to be
overlooked, as their symptoms are often
C1/C2 dorsal
horn
attributed entirely to anxiety. An aware-

copyright.
ness of the existence of MARD will
enable physicians not only to appreciate
the predominant complaint but also
stimulate them to look for the other
Superior
vestibular
components.
nucleus A common feature in MARD is visual
dependence—that is, an excessive reli-
ance on visual cues for balance. Visual
dependence and its symptomatic
Head motion expression, SMD, affect many patients
Caudal medial
and inferior
with migraine, anxiety, or a balance
Somatosensory
vestibular disorder. Patients with SMD often have
(via SC )
nuclei discomfort in visual environments that
Optic flow
are overly complex or devoid of visual
DRN (5-HT) (via AOS ) orientation cues. Migraine patients are
LC (NE) Vestibular nuclei also known to be sensitive to certain
visual aspects of the environment, per-
haps independent of vestibular mechan-
Figure 4 Pathogenetic model for migraine2anxiety related dizziness (MARD) showing the three
isms. In certain anxiety disorders,
way interface among migraine, anxiety, and dizziness. The interactions between the
balance2migraine and the balance2anxiety interfaces are shown schematically as a fusion of particularly in height phobia, patients
figs 2 and 3. Neuronal activity in the vestibular nuclei, particularly the superior vestibular nucleus, is have an increased tendency to manifest
a first major integrative site for the balance2migraine2anxiety linkage. As this activity is a function discomfort in certain visual environ-
of (a) afferent input regarding head motion from the inner ear, somatosensation from the spinal ments. As noted in figs 224, visual
cord (SC) and optic flow information from the accessory optic system (AOS); (b) trigeminal sensory dependence and SMD may be seen in
inputs; and (c) descending inputs from the neocortex, it has the potential to participate in the
patients with migraine related or anxi-
triggering, buildup, and perseverence of episodic dysfunction. The effects of noradrenergic and
serotonergic modulation of vestibular, anxiety, and migraine pathways may be viewed as parallel ety related dizziness, and in MARD.
operations of the mechanisms described in figs 2 and 3. 5-HT, 5-hydroxytryptamine (serotonin); Despite our knowledge concerning
AOS, accessory optic system; DRN, dorsal raphe nucleus; LC, locus ceruleus; NE, norepinephrine; CNS pathways that are important for
PAG (v and vl), periaqueductal grey (ventral and ventrolateral columns); SC, superior colliculus; MARD (see fig 4), the relative impor-
SMD, space and motion discomfort. tance of the different components of
MARD is unknown. The effect of treat-
may produce additive effects in terms of physical cause, they may serve as ments may shed light on the nature of
perceptions, affective changes, and cop- unconditioned stimuli for development MARD, including the inter-relationships
ing strategies. Because these perceptions of phobic avoidance. Further, it is among its components. For example,
and affective changes are not easily important to note that the additive if MARD represents a disorder in which
attributed by a patient to a specific central effects of migraine, vestibular, the three manifestations constitute

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6 EDITORIAL

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.048926 on 16 December 2004. Downloaded from http://jnnp.bmj.com/ on August 24, 2022 by guest. Protected by
Reploeg and Goebel found a reduction
Diagnosis of MARD of at least 75% in the frequency of
attacks of dizziness in 72% of patients
with migraine related dizziness who
were treated with either a tyramine
Vestibular symptoms Migraine Anxiety restrictive diet alone or diet in combina-
predominate predominates predominates tion with nortriptyline or atenolol.95 The
calcium channel blocker dotarizine has
also been reported to be effective in
Acute therapy Acute therapy Acute therapy relieving both migraine and peripheral
vertigo.96 With respect to the combina-
tion of migraine and anxiety, no study
Vestibular Triptan Benzodiazepine has specifically addressed the simulta-
suppressants, Clonazepam or
e.g., Meclizine Diazepam
neous treatment of these components.
Promethazine However, migraine preventive medica-
Prochlorperazine tions such as antidepressants and anti-
Preventive Preventive epileptics are also effective for the
therapy therapy management of anxiety disorders.72 97
Triptan
At this time, the clinical treatment for
MARD is largely speculative (fig 5).
Maintenance therapy Antidepressant plus
However, in our opinion, each compo-
Benzodiazepine nent of the disorder should be consid-
Preventive ered when making treatment decisions.
therapy The choice of treatment or treatments
should be influenced by clinical impres-
First-line Paroxetine plus sions regarding cause and effect rela-
antidepressant Clonazepam tionships, if any, and by the relative
Antidepressant
Imipramine or
plus severity of the various comorbidities.
Sertraline
Benzodiazepine In our experience, patients with
MARD in whom balance symptoms
Second-line
antiepileptic predominate should be treated with a
Imipramine or combination of an antidepressant, such
Topiramate
Sertraline
Clonazepam or
as imipramine, and a benzodiazepine,

Diazepam
Third-line
calcium channel
blocker
Verapamil
Rescue therapy
(short-term during
preventive therapy
initiation)
Benzodiazepine
Clonazepam or
Diazepam
Figure 5 Flowchart for the treatment of migraine2anxiety related dizziness (MARD).
different symptomatic expressions of benzodiazepines, are used to treat both
the same pathological substrate, a treat- conditions. Treatment with SSRIs may
ment directed at that underlying com- reduce both dizziness90 and posturo-
mon pathological substrate should graphic abnormalities in agoraphobia.91
result in improvement of all three Dizziness limited to panic attacks in
components. However, treatment direc- panic disorder (psychiatric dizziness)92
ted at a component that constitutes a resolves as panic frequency is reduced
superficial manifestation of the condi- with treatment of this condition. In our
tion (symptomatic treatment) should laboratory, we have found that vestibu-
result in improvement of that compo- lar rehabilitation therapy can be of value
nent but not the others. for patients with agoraphobia with
Although empirical information on vestibular dysfunction who did not
the simultaneous effects of treatment respond to behaviourally oriented ther-
on the three components of MARD is apy.93 With respect to the combination
lacking, studies that focus on two of of dizziness and migraine, both abortive
the three components have been con- and prophylactic migraine medications
ducted. With respect to the combina- effectively control headache and balance
tion of dizziness and anxiety, several symptoms in patients with both
drugs, including antidepressants and migraine and balance complaints.94
copyright.
such as clonazepam. Sertraline and
diazepam are alternates. For patients
in whom vertigo is considered a
migraine aura or migraine equivalent,
a triptan may be beneficial94 for acute
attacks. Patients with MARD in whom
migraine predominates may also benefit
from treatment with an antidepressant.
Our preferred medication is imipramine.
This type of patient may also benefit
from treatment with an anticonvulsant
such as topiramate or a calcium channel
blocker such as verapamil. Note that in
our experience, beta blocking agents do
not appear to be helpful for patients
with MARD. Rescue therapy includes
short term benzodiazepines. For
patients with MARD in whom anxiety
symptoms predominate, an SSRI such
as paroxetine98 99 or sertraline90 is pre-
ferred. Benzodiazepines such as clona-
zepam are valuable, particularly for
those patients with both prominent
anxiety and pronounced balance symp-
toms or SMD, and may be used chroni-
cally. As vestibular rehabilitation
therapy has been shown to be effica-
cious for balance disorders,100 migraine
related dizziness,101 and anxiety related
dizziness,93 all patients with MARD,
especially those with SMD, may benefit
from vestibular rehabilitation therapy.
CONCLUSION
Migraine and anxiety are two condi-
tions that are frequently associated

www.jnnp.com
EDITORIAL
with dizziness and balance disorders.
Moreover, migraine and anxiety are
comorbid, occurring concomitantly
more frequently than would be expected
by chance alone. Thus, it is not surpris-
ing that a subgroup of dizzy patients
presents with both migraine and anxi-
ety. MARD is a newly defined condition
wherein a patient presents with a
combination of a balance disorder,
migraine, and anxiety. The relative
severity of each component and the
functional relationships between each
component may differ from one patient
to another and may change over time.
The pathophysiology of MARD probably
relates primarily to monoaminergic
pathways important for migraine, anxi-
ety, the central vestibular system, and
their interconnections. Recognising
MARD is important, as management
requires amelioration of each of the
underlying conditions, preferably by
implementing treatments that benefit
more than one component of the dis-
order.
J Neurol Neurosurg Psychiatry 2005;76:1–8.
doi: 10.1136/jnnp.2004.048926
......................
Authors’ affiliations
J M Furman, C D Balaban, R G Jacob,
University of Pittsburgh School of Medicine,
Department of Otolaryngology
R G Jacob, University of Pittsburgh School of
Medicine, Department of Psychiatry
D A Marcus, University of Pittsburgh School of
Medicine, Department of Anesthesiology
Correspondence to: Dr J M Furman, Eye & Ear
Institute Building, Suite 500, 200 Lothrop Street,
Pittsburgh, PA 15213; furman@pitt.edu
Received 5 July 2004
In revised form 19 August 2004
Accepted 20 August 2004
There are no competing interests. This is an
editorial, not a study. All of our studies have
passed institutional review board approval.
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EDITORIAL COMMENTARIES
Parkinson’s disease
.......................................................................................
Long duration asymmetric postural
tremor in the development of
Parkinson’s disease
D G Grosset, A J Lees
...................................................................................
Long term asymmetric postural tremor is likely to predict
development of Parkinson’s disease and not essential tremor
P
atients presenting with essen-
tial tremor who later develop
Parkinson’s disease (PD) are re-
called by most practising neurologists,
but there remains debate around the
relationship of the two diagnoses. In
this issue the paper by Chaudhuri et al
(pp 115) reports long term clinical
follow-up of patients with asymmetric
or unilateral postural tremor, where the
diagnosis evolved from essential tremor
to PD. The case against coincidental
dual diagnosis is well argued, but
ascertainment bias limits application of
the conclusions to prospective patient
management. Selected patients in their
series had abnormal presynaptic dopa-
minergic single photon emission com-
puted tomography (SPECT) imaging
confirming degenerative parkinsonism,
but this was conducted only after
parkinsonian features emerged. The
next requirement is to image such cases
earlier to determine whether dopamine
deficiency is present, and whether this
accurately predicts later evolution into
PD. Cases identified in such a manner
would expand the concept of benign
tremulous PD, and could be considered
a postural equivalent of monosympto-
matic rest tremor. It would be beneficial
to record family history (considering
monogenetic parkinsonism with essen-
tial tremor features), and olfactory test
results in such work. Functional dopa-
minergic imaging also results in revision
of diagnosis from early PD largely to
essential tremor,1 with normal SPECT or
positron emission tomography (PET)
presynaptic imaging in 4 to 14% of cases
depending on the population studied
and the duration of symptoms.1 2 In
both settings, functional dopaminergic
imaging gives insights to diagnosis in
the more benign tremulous patient, akin
to the increased understanding of dif-
ferential diagnosis of degenerative par-
kinsonism in the classic brain bank
studies.3
The time profile of evolving rest
tremor (around 2–3 years) in the
reported series of 13 cases, on a back-
ground of asymmetric postural tremor
at least five times longer, raises inter-
esting possibilities in relation to early
detection of PD, and application of
potential neuroprotective drugs. If
asymmetric postural tremor without
rest tremor is an early disease marker,
does this variant of PD have a longer
time course than akinetic-rigid parkin-
sonism or is the early clinical presenta-
tion simply because the patient notices
early tremor much sooner than early
bradykinesia or rigidity? Earlier testing
with presynaptic dopaminergic imaging
could be confounded if there is an extra
striatal or non-dopaminergic compo-
nent in the early phase of PD, at a
time when postural tremor is the only
manifestation.
In the specialist movement disorder
clinic of Chaudhuri et al, less than 3% of
patients evolved from essential tremor
9
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.048926 on 16 December 2004. Downloaded from http://jnnp.bmj.com/ on August 24, 2022 by guest. Protected by
to PD. Based on the community pre-
valence of essential tremor at least 10
times higher than PD, the risk of a
patient with an initial essential tremor
diagnosis needing to be revised to PD is
low. Because of the study design, we do
not know whether symmetrical postural
tremor sometimes evolves into PD. Until
we have further data, it remains appro-
priate for such patients with probable
essential tremor to be reassured, but
asked to return should they develop
worsening motor disability. Given the
very long latency period of such cases
before PD develops, and considering the
diagnostic criteria for essential tremor,4
it seems reasonable to label such cases
isolated tremor (when postural tremor
is unilateral) and atypical essential
tremor (when features are markedly
asymmetrical), until such times as
parkinsonian features emerge.
J Neurol Neurosurg Psychiatry 2005;76:9.
doi: 10.1136/jnnp.2004.053116
......................
Authors’ affiliations
D G Grosset, Southern General Hospital,
Glasgow, UK
A J Lees, Weston Institute of Neurological
Sciences and National Hospital for Neurology
and Neurosurgery, Queen Square, London,
UK
copyright.
Correspondence to: Donald G Grosset, Institute
of Neurological Sciences, 3rd floor, Southern
General Hospital, Glasgow, UK; d.grosset@
clinmed.gla.ac.uk
REFERENCES
1 Whone AL, Watts RL, Stoessl AJ, et al. Slower
progression of Parkinson’s disease with ropinirole
versus levodopa: The REAL-PET study. Ann Neurol
2003;54:93–101.
2 Benamer HT, Oertel WH, Patterson J,
et al. Prospective study of presynaptic
dopaminergic imaging in patients with mild
parkinsonism and tremor disorders: part 1.
Baseline and 3-month observations. Mov Disord
2003;18:977–84.
3 Hughes AJ, Daniel SE, Blankson S, et al. A
clinicopathologic study of 100 cases of
Parkinson’s disease. Arch Neurol
1993;50:140–8.
4 Findley L, Koller WC. Definitions and behavioural
classifications. In: Findley L, Koller WC, eds. In:
Handbook of tremor disorders, edn. New York:
Marcel Dekker, 1994:1–5.
www.jnnp.com
10
Viral CNS infections
.......................................................................................
Molecular diagnosis of CNS viral
infections
L E Davis, K L Tyler
...................................................................................
Diagnostic CSF PCR assays in viral CNS infections
I
dentifying the agent responsible for
suspected cases of viral central ner-
vous system (CNS) infection poses
tremendous diagnostic challenges, and a
specific organism is identified in only
,30% of cases of suspected viral ence-
phalitis.1 Traditionally, definitive diag-
nosis has depended on: 1) culture of
virus from cerebrospinal fluid (CSF) or
brain tissue; 2) identification of viral
particles, inclusions, antigen, or nucleic
acid in brain tissue; or 3) demonstration
of virus specific intrathecal antibody
synthesis.
The ability to amplify small amounts
of viral nucleic acid from CSF using the
polymerase chain reaction (PCR) tech-
nique has revolutionised the diagnosis
of viral CNS infections. CSF PCR is
rapid, inexpensive, and only minimally
invasive. Unfortunately, validation of
the sensitivity and specificity of CSF
PCR by comparison to a ‘‘gold standard’’
such as brain biopsy, is only rarely
available.2 3 False positive CSF PCR
results are rare when tests are per-
formed according to strict standards in
experienced laboratories, with rigorous
attention to procedures designed to
avoid specimen contamination and to
verify the specificity of amplification
products. The sensitivity of CSF PCR
varies with different viruses, and can be
dramatically influenced by the timing of
specimen collection in relation to onset
of illness. For example, in herpes sim-
plex virus (HSV) encephalitis false
negative CSF PCR results may occur
when specimens are collected either too
early or too late.2 4 In the study by
Davies et al (this issue, pp 82–7)5 the
prevalence of positive CSF PCR results
was maximal when specimens were
obtained at 3–14 days (16%–19% posi-
tive) after symptom onset and signifi-
cantly lower when specimens were
obtained earlier (6%) or later (2%).
Clinicians are still faced with the
daunting task of ordering individual
PCR tests for each virus of potential
interest. Recently, ‘‘multiplex’’ CSF PCR
assays have been developed that utilise
multiple primers simultaneously in a
single reaction mixture to amplify
www.jnnp.com
nucleic acid from a group of viruses.
Davies and colleagues5 used this tech-
nology to evaluate 787 CSF samples
from patients with suspected CNS infect-
ions for the presence of HSV 1 and 2,
cytomegalovirus, Epstein-Barr virus
(EBV), varicella-zoster virus, human
herpes virus (HHV)-6, JC virus, and
enteroviruses. CSF PCR was positive in
30% of patients with ‘‘likely’’ CNS viral
infection—a result similar to other
recent studies.1 6 7 The 70% of cases in
which a viral agent was suspected but
never discovered may be due to: 1)
unknown infectious agents; 2) unusual
infectious agents not covered in the tests
employed; 3) known agents missed
because of false negative PCRs; or 4)
non-infectious CNS diseases mimicking
encephalitis.1
There were several surprising results
in the study by Davies et al.5 In 9 of 88
(10%) positive first CSF samples, nucleic
acid from two or more viruses—includ-
ing EBV in 6 cases—was detected. Four
of the five patients with dual positive
CSF PCRs for whom detailed clinical
information was available were human
immunodeficiency virus (HIV) positive.
Multiple positive CSF PCRs on the same
CSF specimen is fortunately uncom-
mon, but may occur in immunocompro-
mised patients. CSF PCR may detect
latent lymphotrophic viruses such as
EBV in CSF inflammatory cells, or such
latent viruses may reactivate in the CNS
producing ‘‘dual’’ infections.8 Another
unexpected result was that CSF PCR
was positive in 15 of 291 (5%) patients
classified as ‘‘unlikely’’ to have CNS
viral infection. 53% of those with a
positive PCR had a normal CSF cell
count and 34% had both a normal cell
count and protein level. The clinical
significance of these PCR positive tests
is currently unclear. Clinical judgment
must be used both in determining when
to order diagnostic CSF PCR assays and
in the interpretation of the findings.
Technical refinements of the basic
PCR procedures—including use of
real-time PCR and quantitative PCR—
and PCR amplification to identify
viral genes associated with resistance
EDITORIAL COMMENTARIES
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.048926 on 16 December 2004. Downloaded from http://jnnp.bmj.com/ on August 24, 2022 by guest. Protected by
to antimicrobial chemotherapy have
already entered clinical practice. An
exciting research development is the
availability of large scale microarrays
that allow simultaneous detection of the
expression of thousands of genes in
single specimens. Microarrays could be
used to quantify the expression of each
gene in a viral genome to provide
invaluable information about epide-
miology, virulence determinants, and
susceptibility to drugs.9 10 Chips using
multi-viral gene probe sets will facilitate
future pathogen discovery and may lead
to discovery of viral aetiologies in both
established and novel CNS diseases.
J Neurol Neurosurg Psychiatry 2005;76:10.
doi: 10.1136/jnnp.2004.051698
......................
Authors’ affiliations
L E Davis, Neurology Service, New Mexico
VA Health Care System, Albuquerque, NM,
USA
K L Tyler, Department of Neurology,
University of Colorado Health Sciences
Center, Denver, CO, USA
Correspondence to: Dr L E Davis, Neurology
Service, New Mexico VA Health Care System,
1501 San Pedro Dr SE, Albuquerque, NM
87108, USA; LEDavis@unm.edu
REFERENCES
copyright.
1 Glaser CA, Gilliam S, Schnurr D, et al.
California Encephalitis Project, 1998–2000. In
search of encephalitis etiologies: diagnostic
challenges in the California Encephalitis
Project, 1998–2000. Clin Infect Dis
2003;36:731–42.
2 Lakeman FD, Whitley RJ. Diagnosis of herpes
simplex encephalitis: application of polymerase
chain reaction to cerebrospinal fluid from brain-
biopsied patients and correlation with disease.
National Institute of Allergy and Infectious
Diseases Collaborative Antiviral Study Group.
J Infect Dis 1995;171:857–63.
3 McGuire D, Barhite S, Hollander H, et al. JC virus
DNA in cerebrospinal fluid of human
immunodeficiency virus-infected patients:
predictive value for progressive multifocal
leukoencephalopathy. Ann Neurol
1995;37:395–9.
4 Weil AA, Glaser CA, Amad Z, et al. Patients
with suspected herpes simplex encephalitis:
rethinking an initial negative polymerase
chain reaction result. Clin Infect Dis
2002;34:1154–7.
5 Davies NWS, Brown LJ, Gonde J, et al. Factors
influencing PCR detection of viruses in
cerebrospinal fluid of patients with suspected viral
infections. J Neurol Neurosurg Psychiatry
2005;76:82–7.
6 Studahl M, Bergstrom T, Hagberg L. Acute viral
encephalitis in adults—a prospective study.
Scand J Infect Dis 1998;30:215–20.
7 Koskiniemi M, Rantalaiho T, Piiparimen H, et al.
Infections of the central nervous system of
suspected viral origin: a collaborative study from
Finland. J Neurovirol 2001;7:400–8.
8 Weinberg A, Bloch KC, Li S, et al. Dual infections
of the central nervous system with Epstein-Barr
virus. J Infect Dis 2004, in press.
9 Kato-Maeda M, Gao Q, Small PM. Microarray
analysis of pathogens and their interaction with
hosts. Cell Microbiol 2001;3:713–9.
10 Striebel HM, Birch-Hirschfeld E, Egerer R, et al.
Virus diagnostics on microarrays. Curr
Pharmaceut Biotechnol 2003;4:401–15.