EDITORIAL 1 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.048926 on 16 December 2004. Downloaded from

Neurologists, Psychiatrists, and Neuro- ...... surgeons. Papers should be of direct clinical relevance and so we will not generally publish papers on normal New year… brain function nor on animal studies. We hope that these changes will provide M N Rossor, M G Hanna 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. ast year we said goodbye to Ian burden we have tried to make an early As we enter 2005 we reiterate our Whittle whom we thank for all his decision on priority for the journal with thanks to reviewers and authors and Lhard work and welcome Peter the result that over a third of papers do hope to continue to attract similar high Warnke from Liverpool as our new not go out to review. This will include quality manuscripts to those we have Associate Editor for Neurosurgery. We many papers that are well conducted handled over the last year. also say goodbye to many members of and worthy of publication but which we J Neurol Neurosurg Psychiatry 2005;76:1 the editorial board and welcome new consider are not best suited to the JNNP, faces. The vitality of the journal rests usually because they are too specialised...... with its reviewers and authors. We In order to assist authors with the Authors’ affiliations listed our reviewers in the December decision of whether to submit to the Martin N Rossor, Michael G Hanna, Institute issue and reiterate our thanks to them. journal we have revised the web- of Neurology, Queen Square, London WC1N With over two thousand submissions a site guidelines. In summary we wish 3BG, UK year the burden on unpaid reviewers to attract papers of general interest Correspondence to: Professor Martin Rossor; forever increases. In order to reduce the to the multi-disciplinary readership of [email protected]

EDITORIAL ...... copyright. Migraine Anxiety disorders Migraine2anxiety related dizziness (MARD): a new disorder? J M Furman, C D Balaban, R G Jacob, D A Marcus ...... Balance disorders

izziness is a common complaint Thus, it is not surprising that some Figure 1 Venn diagram of the interfaces

that can result from abnormalities patients with dizziness may suffer from http://jnnp.bmj.com/ of the vestibular apparatus of the a combination of a balance disorder, among migraine, anxiety, and balance D disorders. The central sector, which denotes the inner ear and of those portions of the migraine, and an anxiety disorder, a three way interface, represents an hypothesised central nervous system (CNS) that symptom complex that we propose to new ailment, migraine2anxiety related process information from the peripheral name migraine2anxiety related dizzi- dizziness (MARD). vestibular system and other senses, ness (MARD) (fig 1). The general particularly vision and somatosensation. recognition of MARD may be limited Recently, two CNS disorders, migraine because of the fragmented nature of our DEFINITIONS: DISORDER, SYNDROME, DEFINING and anxiety, have been recognised as healthcare system, where specialists in on October 1, 2021 by guest. Protected being commonly associated with dizzi- one field, such as psychiatry or neurol- SYMPTOMS, AND ASSOCIATED ness.12 These associations may be an ogy, fail to recognise phenomena known SYMPTOMS expression of an aetiological relation- to specialists in other fields, such as Medical conditions are diagnosed by a ship, for example, dizziness caused by otoneurology. variety of signs and symptoms. Specific migraine, or dizziness caused by anxi- This editorial will focus on the patho- constellations of signs and symptoms ety; alternatively, migraine or anxiety physiology and clinical issues relating to are usually called syndromes, whereas a may influence the presentation of a MARD, including the interfaces among disorder is ideally identified by specific balance disorder. For example, chronic balance disorders, migraine, and anxi- pathophysiological mechanisms. Some dizziness may become more disabling ety. We use current epidemiological data diagnostic systems distinguish between during the added stress of a migraine and studies of pathogenesis to develop symptoms necessary for the diagnosis of headache or panic attack. In addition, comorbidity models. These models serve the disorder (defining symptoms),6 and dizziness occurs comorbidly with both as hypotheses that may lead to possible those that are associated but not defin- migraine headache and anxiety disor- treatment options for many patients ing (associated symptoms). Although ders.34Finally, there is increased comor- with dizziness, including those with associated symptoms occur with bidity between anxiety and migraine.5 MARD. increased prevalence in a disorder, they

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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 central abnormalities;12 13 15 however, Sterile "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 copyright. afferents 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 4 toms is unknown. We speculate that linkages to migraine mechanisms are shaded. Adapted from Furman et al. 5-HT, 5- some episodes of vertigo in patients

hydroxytryptamine (serotonin); DRN, dorsal raphe nucleus; LC, locus ceruleus; LTeg, lateral http://jnnp.bmj.com/ 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- (including serotonin, norepinephrine Pathophysiology of migraine order. For example, dizziness occurs as (noradrenaline), and dopamine) and related dizziness an integral or defining symptom in cutaneous allodynia, representing aber- Reflecting the uncertainty regarding the Meniere’s disease7 and panic disor- rant neurophysiology during migraine.11 pathophysiology of migraine headache,

der—that is, dizziness during a panic In addition to these defining features of the pathophysiology of migraine related on October 1, 2021 by guest. Protected attack.8 Dizziness can also be considered migraine, patients often describe a dizziness is largely unknown. In fig 2, an associated symptom for migraine9 or variety of additional migraine associated we provide a framework that integrates generalised anxiety disorder.6 symptoms. One of the most common the possible neuroanatomical pathways migraine accompaniments is dizziness with the clinical manifestations of MIGRAINE RELATED DIZZINESS or balance disturbance. Dizziness occurs migrainous vertigo. Fundamental to The term ‘‘migraine’’ refers to both a in 28230% and vertigo in 25226% of the pathophysiology of migraine is the syndrome and a disorder. The diagnosis patients with a primary complaint of trigeminovascular reflex. This is a para- of migraine syndrome requires the pre- migraine.912The association tends to be sympathetic reflex that can produce sence of a neurological aura associated specific to migraine, rather than head- vasodilation of large cranial vessels. with headache or a mixture of symp- ache in general. Dizziness or vertigo The vasodilation of large cranial vessels toms including unilateral, disabling, occur in 54.5% of patients with is a consequence of activation mediated throbbing pain associated with sensitiv- migraine, compared with 30.2% of by the trigeminal nucleus caudalis (Vc) ity to noise and light or with nausea.10 In patients with tension-type headache.9 and C1-C2 dorsal horn neurones.22 23 addition, migraine is characterised by In addition, abnormal posturography In addition to the parasympathetic interictal alterations in neurochemicals testing is seen in patients with migraine effects of the trigeminovascular reflex,

www.jnnp.com EDITORIAL 3 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.048926 on 16 December 2004. Downloaded from vasodilation may be induced or aug- migraine. As CGRP is present in efferent dizziness is not correlated with vestibu- mented by direct vasodilator effects of projections to cochlear and vestibular lar function test abnormalities. The only neurokinin A (NKA), calcitonin gene epithelia,30 31 release is expected during psychiatric disorder for which dizziness related peptide (CGRP), and substance P efferent activation. Thus, it is possible is a defining symptom is panic disorder. (SP) release from trigeminal sensory that released SP, NKA, and CGRP from Furthermore, we have found that dizzi- terminals.22 trigeminal and eighth nerve fibres could ness that occurs only during panic Vestibular pathways can contribute to contribute to migraine related dizziness attacks is not correlated with vestibular both central and peripheral migraine via hormone-like actions on neural and dysfunction,36 whereas dizziness as an mechanisms.4 The reciprocal connec- vascular elements. isolated symptom occurring between tions between the inferior, medial, and panic attacks is correlated.35 36 lateral vestibular nuclei and trigeminal ANXIETY RELATED DIZZINESS Anxiety seems to be a particular nucleus caudalis suggest that vestibular Numerous studies have confirmed that problem in patients with acute vestibu- lar disorders. In a recent study,41 17 and trigeminal information processing anxiety and dizziness are interrelated.632 (57%) of 30 patients with acute vertigo may be altered concurrently during For example, among 268 patients migraine attacks, and that vestibular recruited from a tertiary otolaryngology reported that anxiety symptoms seemed signals may directly influence trigemi- clinic, panic disorder was identified in disproportionate to the seriousness of the disorder. Only 23% had no anxiety. novascular reflex pathways. In addition, 17.2% and major depressive disorder in The increase in anxiety was not just a central vestibular activation can affect 11.2%.33 Furthermore, patients recruited general reaction to having an acute activity in monoaminergic pathways in an anxiety clinic setting, particularly illness, because the comparison group through direct connections from the those with agoraphobia, have an of patients with other acute neurological vestibular nuclei to the dorsal raphe increased rate of balance dysfunc- conditions without dizziness reported nucleus, nucleus raphe magnus, locus tion.34–37 Consequently, recent studies significantly less anxiety (17%). In coeruleus, and lateral tegmental region. have moved away from the previously patients with chronic dizziness, anxiety These changes in monoaminergic activ- held assumption that the presence of is present but less pronounced. In a ity due to vestibular activation may both anxiety automatically implies a ‘‘psy- study of 112 patients with Menie´re’s trigger migraine related symptoms and chogenic’’ cause for dizziness.38 In a disease who remained symptomatic modulate activity in both pain related study by Eckhardt-Henn et al,39 patients despite treatment, clinically significant and anxiety related pathways. Con- with dizziness recruited at a neurologi- anxiety was found in only 17%.42 versely, regionally specialised noradre- cal clinic underwent both psychiatric 24 25 nergic and serotonergic inputs are and otoneurological evaluations. Based potential substrates for altering central on the findings, the 189 patients were Pathophysiology of anxiety related vestibular information processing dur- divided into the following groups: (a) dizziness 26 ing and between migrainous episodes. organic (27%), (b) mixed ‘‘psycho- Three partially overlapping modes of copyright. Finally, two possible mechanisms may organic’’ (16%), (c) psychiatric (52%), interaction between anxiety and vesti- be related to vertigo as a migraine aura. and (d) idiopathic (5%). The most bular dysfunction have been proposed: Short duration vertigo symptoms have common psychiatric diagnosis was an somatopsychic, psychosomatic, and been suggested to be a ‘‘brainstem aura’’ anxiety disorder, followed by somatisa- linkage.43 A somatopsychic explanation that may be accompanied by changes in tion and depressive disorders. There would be that the perception of vesti- blood flow.19 Alternatively, direct con- were no differences between the psy- bular dysfunction, for example, dizzi- nections from the posterior parietal chiatric and psycho-organic groups with ness or vertigo, causes anxiety. The cortex to the vestibular nuclei may respect to the distribution of psychiatric initial high anxiety reactions to a ves- provide a direct access for cortical diagnoses, suggesting that the presence tibular disorder is an example of soma- mechanisms underlying migraine aura of a particular diagnosis does not rule topsychic effects. Psychosomatic effects to reach areas important for vesti- out a vestibular disorder. Based on a imply that anxiety causes dizziness. The bular information processing and reflex retrospective chart review of 132 (77%) psychiatric dizziness of panic is an performance. example. Anxiety or hyperventilation of 172 patients at a tertiary dizziness http://jnnp.bmj.com/ The vestibular periphery may also clinic who had been referred for psy- may also reactivate a vestibular disorder influence migraine pathways. Vass et al27 chiatric evaluation, Staab et al40 classi- by interfering with central compensa- have demonstrated that there is a fied patients into three groups: (a) tion44 or by altering somatosensory significant trigeminal sensory innerva- psychiatric disorder causing dizziness, input.45 The linkage model suggests a tion of the stria vascularis, spiral (b) primary otoneurological disorder common underlying disorder that man- modiolar blood vessels, and dark cell with secondary anxiety, and (c) pre- ifests as both anxiety and balance region of the cristae ampularis. They existing anxiety or prodromes escalating problems. The underlying neural circui-

have shown also that electrical stimu- as a result of the neurotological dis- try includes the parabrachial nucleus, on October 1, 2021 by guest. Protected lation of the trigeminal ganglion pro- order. Patients were nearly equally the vestibulothalamocortical and ceruleo- duces extravasation from the basilar, divided among the three categories. A vestibular pathways, and serotonergic anterior inferior cerebellar, and diagnosis of panic disorder predicted neurotransmission. In addition, the cochlear arteries of albino guinea pigs, membership in the psychiatric dizziness periaqueductal grey (PAG) is an area and that round window application of group, whereas membership in the involved in dizziness, pain, and anxi- capsaicin produces extravasation in the primary neurotological group was asso- ety, and will be discussed in the next former two sites.28 The powerful vaso- ciated with an elevated prevalence of section. The pathophysiology of anxiety dilators SP and NKA are present in the spatial phobias. The fact that panic related dizziness is outlined in fig 3, eighth nerve afferent terminals in the disorder appeared preferentially in the which provides a framework for the organ of Corti and vestibular sensory psychiatric group40 is consistent with a three modes of pathogenesis of this epithelia.29 SP and NKA may be released definition of ‘‘psychiatric dizziness’’ condition, and incorporates informa- during nerve activation in the same previously proposed by our group.2 tion concerning both anatomical path- manner as vasodilatory peptides are These criteria include: (a) the dizziness ways and clinical manifestations. released by peripheral trigeminal nerve is a defining or associated symptom of The parabrachial nucleus (PBN) pro- terminals as a neurogenic mechanism in a psychiatric disorder, and (b) the vides a key interface between anxiety

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cortex) containing neurones that nucleus, neocortex, and central amyg- Neocortex Visual 56 57 79 82 83 Vertigo association respond to vestibular stimulation. daloid nucleus. Postural instability cortex These responses are mediated by projec- Prefrontal tions from thalamic regions58 that and MIGRAINE2ANXIETY RELATED Vestibular Agoraphobic infralimbic cortex receive direct projections from the ves- cortex DIZZINESS SMD 59–63 tibular nuclei and show activation in The link between migraine and balance functional imaging studies.64 This corti- Central disorders and the link between anxiety amygdaloid Thalamus cal pathway is regarded as an important nucleus network and balance disorders suggests that a substrate for perceptions of vertigo, subgroup of such patients will manifest imbalance, and instability in patients migraine, anxiety, and a balance dis- Parabrachial and might be a pathway for somato- nucleus DRN (5-HT) order. MARD is unlikely to be simply the (m, em, el, KF) LC (NE) psychic effects. chance combination of a balance dis- The ceruleovestibular pathway arises order, migraine headache, and anxiety. from the caudal pole of the locus Vestibular This notion is supported by the nuclei ceruleus (LC) and the adjacent nucleus increased prevalence of panic disorder subceruleus.24 65 There are four quanti- in migraine patients with and without tatively distinct density levels of nor- aura. In a recent study, the lifetime Figure 3 Pathogenetic model for anxiety adrenergic fibres in the vestibular prevalence of panic disorder was 19.6% related dizziness. This simplified representation nuclei, with the highest innervation of the neurological bases of the in migraine patients with aura and balance2anxiety interface is updated from densities in regions that probably 14.3% in migraine patients without recent reviews.67 102 These balance–anxiety increase postural sway and alter vesti- aura.84 In addition, the presence of linkages appear to involve integrated activity of bular evoked eye movements during anxiety in patients with migraine sug- at least four neural circuits: (a)a anxiety and changes in alertness.24 The gests a worse prognosis.85 In an 8 year vestibuloparabrachial nucleus (PBN) network, caudal locus ceruleus/nucleus subceru- follow up study, Guidetti et al found that (b) a vestibulothalamocortical network, (c)a leus complex also contains cells that are ceruleovestibular network, and (d) a raphe anxiety disorders were predictive of nuclear-vestibular network. 5-HT, 5- known to project by collaterals to: (a) headache persistence 8 years later. hydroxytryptamine (serotonin); DRN, dorsal the hypothalamus, hippocampus, neo- Specifically, among patients with raphe nucleus; LC, locus ceruleus; NE, cortex, and cerebellum; (b) the spinal migraine and anxiety, 75% had endur- norepinephrine; m, em, el, KF, medial, external cord, cerebellum, neocortex, and hypo- ing migraines and anxiety 8 years later, medial, external lateral, and Ko¨lliker-Fuse thalamus; or (c) the spinal cord and 19% changed to tension headaches, and nucleus subdivisions; SMD, space and motion 66 discomfort. cerebellum. As locus ceruleus projec- only 6% were headache free. By com- tions are also highly collateralised, we parison, among migraine patients with- 24 67

have proposed that the ceruleoves- out anxiety, only 30% had enduring copyright. related circuitry and central vestibu- tibular pathway may be one branch of migraines, 42% changed to tension lar pathways. The discovery of the fibres that co-activate (or co-modulate) headaches, and 27% were headache vestibulo-PBN pathway emerged from neurones in the vestibular nucleus and free. neuroanatomical tracer studies of other motor pathways, contributing to vestibuloautonomic pathways. These the known effects of the state of arousal Pathophysiology of MARD studies indicated sparse direct vestibular 68–71 on vestibular reflex performance. In fig 4, we present a schematic diagram nucleus connections to the ventrolateral The actions of selective serotonin of the pathophysiology of MARD that medulla, nucleus of the solitary tract, reuptake inhibitors (SSRIs) have pro- draws from material regarding migraine nucleus ambiguus lateral tegmental vided compelling evidence for a role of related dizziness, illustrated in fig 2, and area,46–49 and the anteromedian/ serotonergic transmission in vestibular 50 anxiety related dizziness, illustrated in Edinger-Westphal nuclei, and robust function. Recent evidence indicates that fig 3. In fig 4, we highlight particularly projections from the vestibular nuclei to SSRIs are efficacious in the treatment of the role of the PAG. Note that the the medial, external medial, and exter- vertigo;18 32 72 furthermore, the beneficial superior vestibular nucleus projects to http://jnnp.bmj.com/ nal lateral subnuclei of the PBN and the effect of benzodiazepines such as clona- the ventrolateral and ventral columns of 48 49 51 Ko¨lliker-Fuse nucleus. The neu- zepam on both dizziness and anxiety the PAG. These PAG regions receive rones in this vestibulorecipient PBN may be mediated by their serotonergic projections from the medial, dorsolat- region respond to whole body rotation effects.73–75 In addition, the vestibular eral, and ventrolateral orbital cortex and 51 in alert primates, and some PBN cells manifestations of the SSRI discontinua- from the posterior and dorsal agranular project to a wide region in the vestibular tion syndrome (acute onset of dizziness, insular cortex.86 The ventrolateral and 52 nuclei. Reciprocal connections between vertigo, and uncoordination) are exa- ventral PAG are also connected recipro- the PBN and the central amygdaloid cerbated by head and eye move- cally with the central amygdaloid on October 1, 2021 by guest. Protected nucleus, the hypothalamus, and the ments,76 77 which is consistent with nucleus.87 88 Therefore, the ventrolateral infralimbic cortex are consistent with direct effects on vestibular information and ventral PAG appear to be at the the role of the PBN as an integral processing. Serotonergic projections to nexus of loops linking vestibular, component of circuitry that mediates the vestibular nuclei originate from both migraine, and anxiety related pathways. formation of conditioned fear and anxi- the dorsal raphe nucleus and a caudal This PAG related network appears to ety responses.53–55 Thus, the PBN appears region spanning the nucleus raphe constitute a linkage between the affec- to be an important node for linking obscurus and nucleus raphe pallidus.25 tive and behavioural responses to bal- vestibular information with the neural These pathways also contain a signifi- ance disorders and migraine. Both substrates for panic disorders and cant non-serotonergic component. As ventral and ventrolateral PAG are com- anxiety. individual raphe neurones often project ponents of ‘‘emotional motor’’ pathways The vestibulothalamocortical pathway to multiple sites via axon collaterals,78–81 that mediate passive emotional coping links the vestibular nuclei with discrete we have suggested67 that collateralised in response to deep or chronic pain or fields within the neocortex (including raphe2vestibular projections may co- traumatic injury.89 The activation of portions of parietoinsular cortex, areas modulate activity in the vestibular pathways linking the vestibular system 3a, 7, and 2v, and the posterior sylvian nuclei and sites such as the parabrachial with anxiety and migraine mechanisms

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and anxiety related circuits on percep- Unconditioned perceptions tions of pain, vertigo, postural instabil- ity, passive coping, visual dependence, Neocortex Visual and space and motion discomfort Pain and aura association (SMD) are subject to considerable indi- 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 Clinical implications of MARD "Visual 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" PAG patients may self select to a particular (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 afferents our experience, balance symptoms in nucleus Trigeminal nuc. caudalis patients with a clinically significant anxiety disorder are most likely to be overlooked, as their symptoms are often C1/C2 dorsal attributed entirely to anxiety. An aware- copyright. horn 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 components. vestibular 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 with migraine, anxiety, or a balance and inferior Somatosensory disorder. Patients with SMD often have vestibular (via SC) discomfort in visual environments that nuclei http://jnnp.bmj.com/ are overly complex or devoid of visual Optic flow 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 on October 1, 2021 by guest. Protected 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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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 neous treatment of these components. e.g., Meclizine Diazepam Promethazine However, migraine preventive medica- Prochlorperazine tions such as antidepressants and anti- Preventive Preventive epileptics are also effective for the management of anxiety disorders.72 97 Triptan therapy therapy At this time, the clinical treatment for MARD is largely speculative (fig 5). However, in our opinion, each compo- Maintenance therapy Antidepressant plus 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 Antidepressant tionships, if any, and by the relative Imipramine or plus Sertraline severity of the various comorbidities. Benzodiazepine In our experience, patients with MARD in whom balance symptoms Second-line antiepileptic predominate should be treated with a Imipramine or Topiramate combination of an antidepressant, such Sertraline as imipramine, and a benzodiazepine, Clonazepam or copyright. Diazepam such as clonazepam. Sertraline and Third-line diazepam are alternates. For patients calcium channel blocker in whom vertigo is considered a Verapamil migraine aura or migraine equivalent, a triptan may be beneficial94 for acute attacks. Patients with MARD in whom Rescue therapy migraine predominates may also benefit (short-term during from treatment with an antidepressant. preventive therapy Our preferred medication is imipramine. initiation) This type of patient may also benefit from treatment with an anticonvulsant such as topiramate or a calcium channel Benzodiazepine blocker such as verapamil. Note that in Clonazepam or http://jnnp.bmj.com/ Diazepam our experience, beta blocking agents do not appear to be helpful for patients with MARD. Rescue therapy includes Figure 5 Flowchart for the treatment of migraine2anxiety related dizziness (MARD). short term benzodiazepines. For different symptomatic expressions of benzodiazepines, are used to treat both patients with MARD in whom anxiety the same pathological substrate, a treat- conditions. Treatment with SSRIs may symptoms predominate, an SSRI such 98 99 90 ment directed at that underlying com- reduce both dizziness90 and posturo- as paroxetine or sertraline is pre- mon pathological substrate should graphic abnormalities in agoraphobia.91 ferred. Benzodiazepines such as clona- on October 1, 2021 by guest. Protected result in improvement of all three Dizziness limited to panic attacks in zepam are valuable, particularly for components. However, treatment direc- panic disorder (psychiatric dizziness)92 those patients with both prominent ted at a component that constitutes a resolves as panic frequency is reduced anxiety and pronounced balance symp- superficial manifestation of the condi- with treatment of this condition. In our toms or SMD, and may be used chroni- tion (symptomatic treatment) should laboratory, we have found that vestibu- cally. As vestibular rehabilitation result in improvement of that compo- lar rehabilitation therapy can be of value therapy has been shown to be effica- 100 nent but not the others. for patients with agoraphobia with cious for balance disorders, migraine related dizziness,101 and anxiety related Although empirical information on vestibular dysfunction who did not 93 the simultaneous effects of treatment respond to behaviourally oriented ther- dizziness, all patients with MARD, on the three components of MARD is apy.93 With respect to the combination especially those with SMD, may benefit lacking, studies that focus on two of of dizziness and migraine, both abortive from vestibular rehabilitation therapy. the three components have been con- and prophylactic migraine medications ducted. With respect to the combina- effectively control headache and balance CONCLUSION tion of dizziness and anxiety, several symptoms in patients with both Migraine and anxiety are two condi- drugs, including antidepressants and migraine and balance complaints.94 tions that are frequently associated

www.jnnp.com EDITORIAL 7 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.048926 on 16 December 2004. Downloaded from with dizziness and balance disorders. Foundation, Inc. Otolaryngol Head Neck Surg cochlea and vestibular endorgans. Eur J Neurosci 1995;113:181–5. 2002;15:487–97. Moreover, migraine and anxiety are 8 Diagnostic and statistical manual of mental 32 Staab JP. Diagnosis and treatment of comorbid, occurring concomitantly disorders (DSM-IV), 4th ed. Washington DC: psychologic symptoms and psychiatric disorders more frequently than would be expected American Psychiatric Association, 1994. in patients with dizziness and imbalance. by chance alone. Thus, it is not surpris- 9 Kayan A, Hood JD. Neuro-otological Otolaryngol Clin North Am 2000;33:617–36. manifestations of migraine. Brain 33 Persoons P, Luyckx K, Desloovere C, ing that a subgroup of dizzy patients 1984;107:1123–42. Vandenberghe J, Fischler B. Anxiety and mood presents with both migraine and anxi- 10 The International Classification of Headache disorders in otorhinolaryngology outpatients ety. MARD is a newly defined condition Disorders (2nd edition). Cephalagia presenting with dizziness: validation of the self- 2004;24(suppl 1):1–96. administered PRIME-MD Patient Health wherein a patient presents with a 11 Burstein R, Yarnitsky D, Goor-Aryeh I, et al. An Questionnaire and epidemiology. Gen Hosp combination of a balance disorder, association between migraine and cutaneous Psychiatry 2003;25:316–23. migraine, and anxiety. The relative allodynia. Ann Neurol 2000;47:614–24. 34 Perna G, Dario A, Caldirola D, et al. Panic 12 Bayazit Y, Yilmaz M, Mumbuc S, et al. disorder: the role of the balance system. severity of each component and the Assessment of migraine-related J Psychiatr Res 2001;35:279–86. functional relationships between each cochleovestibular symptoms. Rev Laryngol Otol 35 Yardley L, Britton J, Lear S, et al. Relationship component may differ from one patient Rhinol (Bord) 2001;122:85–8. between balance system function and 13 Ishizaki K, Mori N, Takeshima T, et al. Static agoraphobic avoidance. Behav Res Ther to another and may change over time. stabilometry in patients with migraine and 1995;33:435–9. The pathophysiology of MARD probably tension-type headache during a headache-free 36 Jacob RG, Furman JM, Durrant JD, et al. Panic, relates primarily to monoaminergic period. Psychiatry Clin Neurosci agoraphobia, and vestibular dysfunction. pathways important for migraine, anxi- 2002;56:85–90. Am J Psychiatry 1996;153:503–12. 14 Lee H, Sohn SI, Jung DK, et al. Migraine and 37 Jacob RG, Furman JM, Durrant JD, et al. Surface ety, the central vestibular system, and isolated recurrent vertigo of unknown cause. dependence: a balance control strategy in panic their interconnections. Recognising Neurol Res 2002;24:663–5. disorder with agoraphobia. Psychosom Med MARD is important, as management 15 Kuritzky A, Toglia UJ, Thomas D. Vestibular 1997;59:323–30. function in migraine. Headache 38 Nilsson A, Henriksson NG, Magnusson PA, requires amelioration of each of the 1981;21:110–12. et al. Vertigo and dizzines reflecting functional underlying conditions, preferably by 16 Cutrer FM, Baloh RW. Migraine-associated disorders. Adv Otorhinolaryngol implementing treatments that benefit dizziness. Headache 1992;32:300–4. 1979;25:93–9. 17 Cass SP, Furman JM, Ankerstjerne K, et al. 39 Eckhardt-Henn A, Breuer P, Thomalske C, et al. more than one component of the dis- Migraine-related vestibulopathy. Ann Otol Anxiety disorders and other psychiatric order. Rhinol Laryngol 1997;106:182–9. subgroups in patients complaining of dizziness. 18 Johnson GD. Medical management of migraine- J Anxiety Disord 2003;17:369–88. J Neurol Neurosurg Psychiatry 2005;76:1–8. related dizziness and vertigo. Laryngoscope 40 Staab JP, Ruckenstein MJ. Which comes first? doi: 10.1136/jnnp.2004.048926 1998;108:1–28. Psychogenic dizziness versus otogenic anxiety. 19 Dieterich M, Brandt T. Episodic vertigo related to Laryngoscope 2003;113:1714–18...... migraine (90 cases): vestibular migraine? 41 Pollak L, Klein C, Rafael S, et al. Anxiety in the J Neurol 1999;246:883–92. first attack of vertigo. Otolaryngol Head Neck Authors’ affiliations 20 Thakar A, Anjaneyulu C, Deka RC. Vertigo Surg 2003;128:829–34. J M Furman, C D Balaban, R G Jacob, syndromes and mechanisms in migraine. 42 Soderman AC, Bagger-Sjoback D, Bergenius J, University of Pittsburgh School of Medicine, J Laryngol Otol 2001;115:782–7. et al. Factors influencing quality of life in patients Department of Otolaryngology 21 Marcus DA, Kapelewski C, Rudy TE, et al. with Meniere’s disease, identified by a copyright. R G Jacob, University of Pittsburgh School of Diagnosis of migrainous vertigo: validity of a multidimensional approach. Otol Neurotol structured interview. Med Sci Monitor 2002;23:941–8. Medicine, Department of Psychiatry 2004;10:CR197–201. 43 Jacob RG. Panic disorder and the vestibular D A Marcus, University of Pittsburgh School of 22 May A, Goadsby PJ. The trigeminovascular system. Psychiatr Clin North Am Medicine, Department of Anesthesiology system in humans: pathophysiologic implications 1988;11:361–74. for primary headache syndromes of the neural 44 Minor LB, Halswanter T, Straumann D, et al. influences on the cerebral circulation. J Cereb Hyperventilation-induced nystagmus in patients Correspondence to: Dr J M Furman, Eye & Ear Blood Flow Metab 1999;19:115–27. with vestibular schwannoma. Neurology Institute Building, Suite 500, 200 Lothrop Street, 23 Goadsby PJ, Lipton RB, Ferrari MD. Migraine-- 1999;53:2158–68. Pittsburgh, PA 15213; [email protected] current understanding and treatment. 45 Sakellari V, Bronstein AM, Corna S, et al. The N Engl J Med 2002;346:257–70. effects of hyperventilation on postural control Received 5 July 2004 24 Schuerger RJ, Balaban CD. Organization of the mechanisms. Brain 1997;120:1659–73. In revised form 19 August 2004 coeruleo-vestibular pathway in rats, rabbits, and 46 Balaban CD, Beryozkin G. Vestibular nucleus Accepted 20 August 2004 monkeys. Brain Res Brain Res Rev projections to nucleus tractus solitarius and the 1999;30:189–217. dorsal motor nucleus of the vagus nerve: There are no competing interests. This is an 25 Halberstadt AL, Balaban CD. Organization of potential substrates for vestibulo-autonomic editorial, not a study. All of our studies have projections from the raphe nuclei to the interactions. Exp Brain Res 1994;98:200–12. http://jnnp.bmj.com/ passed institutional review board approval. vestibular nuclei in rats. Neuroscience 47 Yates BJ, Grelot L, Kerman IA, et al. 2003;120:573–94. 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Parkinson’s disease 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 Long duration asymmetric postural diagnosis needing to be revised to PD is low. Because of the study design, we do tremor in the development of not know whether symmetrical postural tremor sometimes evolves into PD. Until Parkinson’s disease we have further data, it remains appro- priate for such patients with probable D G Grosset, A J Lees essential tremor to be reassured, but asked to return should they develop ...... worsening motor disability. Given the very long latency period of such cases Long term asymmetric postural tremor is likely to predict before PD develops, and considering the development of Parkinson’s disease and not essential tremor diagnostic criteria for essential tremor,4 it seems reasonable to label such cases isolated tremor (when postural tremor atients presenting with essen- essential tremor,1 with normal SPECT or is unilateral) and atypical essential tial tremor who later develop positron emission tomography (PET) tremor (when features are markedly Parkinson’s disease (PD) are re- presynaptic imaging in 4 to 14% of cases P asymmetrical), until such times as called by most practising neurologists, depending on the population studied parkinsonian features emerge. but there remains debate around the and the duration of symptoms.12 In relationship of the two diagnoses. In both settings, functional dopaminergic J Neurol Neurosurg Psychiatry 2005;76:9. this issue the paper by Chaudhuri et al imaging gives insights to diagnosis in doi: 10.1136/jnnp.2004.053116 (pp 115) reports long term clinical the more benign tremulous patient, akin ...... follow-up of patients with asymmetric to the increased understanding of dif- or unilateral postural tremor, where the ferential diagnosis of degenerative par- Authors’ affiliations D G Grosset, diagnosis evolved from essential tremor kinsonism in the classic brain bank Southern General Hospital, 3 Glasgow, UK to PD. The case against coincidental studies. A J Lees, Weston Institute of Neurological dual diagnosis is well argued, but The time profile of evolving rest Sciences and National Hospital for Neurology ascertainment bias limits application of tremor (around 2–3 years) in the and Neurosurgery, Queen Square, London, the conclusions to prospective patient reported series of 13 cases, on a back- UK management. Selected patients in their ground of asymmetric postural tremor copyright. series had abnormal presynaptic dopa- at least five times longer, raises inter- Correspondence to: Donald G Grosset, Institute minergic single photon emission com- esting possibilities in relation to early of Neurological Sciences, 3rd floor, Southern puted tomography (SPECT) imaging detection of PD, and application of General Hospital, Glasgow, UK; d.grosset@ confirming degenerative parkinsonism, potential neuroprotective drugs. If clinmed.gla.ac.uk but this was conducted only after asymmetric postural tremor without parkinsonian features emerged. The rest tremor is an early disease marker, next requirement is to image such cases does this variant of PD have a longer REFERENCES earlier to determine whether dopamine time course than akinetic-rigid parkin- 1 Whone AL, Watts RL, Stoessl AJ, et al. Slower deficiency is present, and whether this sonism or is the early clinical presenta- progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol accurately predicts later evolution into tion simply because the patient notices 2003;54:93–101. PD. Cases identified in such a manner early tremor much sooner than early 2 Benamer HT, Oertel WH, Patterson J, would expand the concept of benign bradykinesia or rigidity? Earlier testing et al. Prospective study of presynaptic tremulous PD, and could be considered with presynaptic dopaminergic imaging dopaminergic imaging in patients with mild parkinsonism and tremor disorders: part 1. http://jnnp.bmj.com/ a postural equivalent of monosympto- could be confounded if there is an extra Baseline and 3-month observations. Mov Disord matic rest tremor. It would be beneficial striatal or non-dopaminergic compo- 2003;18:977–84. to record family history (considering nent in the early phase of PD, at a 3 Hughes AJ, Daniel SE, Blankson S, et al. A clinicopathologic study of 100 cases of monogenetic parkinsonism with essen- time when postural tremor is the only Parkinson’s disease. Arch Neurol tial tremor features), and olfactory test manifestation. 1993;50:140–8. results in such work. Functional dopa- In the specialist movement disorder 4 Findley L, Koller WC. Definitions and behavioural classifications. In: Findley L, Koller WC, eds. In: minergic imaging also results in revision clinic of Chaudhuri et al, less than 3% of Handbook of tremor disorders, edn. New York:

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Viral CNS infections to antimicrobial chemotherapy have ...... already entered clinical practice. An exciting research development is the availability of large scale microarrays Molecular diagnosis of CNS viral that allow simultaneous detection of the expression of thousands of genes in infections single specimens. Microarrays could be used to quantify the expression of each L E Davis, K L Tyler gene in a viral genome to provide invaluable information about epide- ...... miology, virulence determinants, and susceptibility to drugs.910 Chips using Diagnostic CSF PCR assays in viral CNS infections multi-viral gene probe sets will facilitate future pathogen discovery and may lead dentifying the agent responsible for nucleic acid from a group of viruses. to discovery of viral aetiologies in both suspected cases of viral central ner- Davies and colleagues5 used this tech- established and novel CNS diseases. Ivous system (CNS) infection poses nology to evaluate 787 CSF samples J Neurol Neurosurg Psychiatry 2005;76:10. tremendous diagnostic challenges, and a from patients with suspected CNS infect- doi: 10.1136/jnnp.2004.051698 specific organism is identified in only ions for the presence of HSV 1 and 2, ,30% of cases of suspected viral ence- cytomegalovirus, Epstein-Barr virus ...... phalitis.1 Traditionally, definitive diag- (EBV), varicella-zoster virus, human Authors’ affiliations nosis has depended on: 1) culture of herpes virus (HHV)-6, JC virus, and L E Davis, Neurology Service, New Mexico virus from cerebrospinal fluid (CSF) or enteroviruses. CSF PCR was positive in VA Health Care System, Albuquerque, NM, brain tissue; 2) identification of viral 30% of patients with ‘‘likely’’ CNS viral USA particles, inclusions, antigen, or nucleic infection—a result similar to other K L Tyler, Department of Neurology, University of Colorado Health Sciences acid in brain tissue; or 3) demonstration recent studies.167 The 70% of cases in Center, Denver, CO, USA of virus specific intrathecal antibody which a viral agent was suspected but synthesis. never discovered may be due to: 1) Correspondence to: Dr L E Davis, Neurology The ability to amplify small amounts unknown infectious agents; 2) unusual Service, New Mexico VA Health Care System, of viral nucleic acid from CSF using the infectious agents not covered in the tests 1501 San Pedro Dr SE, Albuquerque, NM polymerase chain reaction (PCR) tech- employed; 3) known agents missed 87108, USA; [email protected] nique has revolutionised the diagnosis because of false negative PCRs; or 4) non-infectious CNS diseases mimicking of viral CNS infections. CSF PCR is REFERENCES copyright. rapid, inexpensive, and only minimally encephalitis.1 1 Glaser CA, Gilliam S, Schnurr D, et al. invasive. Unfortunately, validation of There were several surprising results California Encephalitis Project, 1998–2000. In the sensitivity and specificity of CSF in the study by Davies et al.5 In 9 of 88 search of encephalitis etiologies: diagnostic PCR by comparison to a ‘‘gold standard’’ (10%) positive first CSF samples, nucleic challenges in the California Encephalitis Project, 1998–2000. Clin Infect Dis such as brain biopsy, is only rarely acid from two or more viruses—includ- 2003;36:731–42. 23 available. False positive CSF PCR ing EBV in 6 cases—was detected. Four 2 Lakeman FD, Whitley RJ. 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cerebrospinal fluid of patients with suspected viral on October 1, 2021 by guest. Protected 5 Davies et al (this issue, pp 82–7) the viral infection. 53% of those with a infections. J Neurol Neurosurg Psychiatry prevalence of positive CSF PCR results positive PCR had a normal CSF cell 2005;76:82–7. 6 Studahl M, Bergstrom T, Hagberg L. Acute viral was maximal when specimens were count and 34% had both a normal cell encephalitis in adults—a prospective study. obtained at 3–14 days (16%–19% posi- count and protein level. The clinical Scand J Infect Dis 1998;30:215–20. tive) after symptom onset and signifi- significance of these PCR positive tests 7 Koskiniemi M, Rantalaiho T, Piiparimen H, et al. cantly lower when specimens were is currently unclear. Clinical judgment Infections of the central nervous system of suspected viral origin: a collaborative study from obtained earlier (6%) or later (2%). must be used both in determining when Finland. J Neurovirol 2001;7:400–8. Clinicians are still faced with the to order diagnostic CSF PCR assays and 8 Weinberg A, Bloch KC, Li S, et al. Dual infections daunting task of ordering individual in the interpretation of the findings. of the central nervous system with Epstein-Barr virus. J Infect Dis 2004, in press. PCR tests for each virus of potential Technical refinements of the basic 9 Kato-Maeda M, Gao Q, Small PM. Microarray interest. Recently, ‘‘multiplex’’ CSF PCR PCR procedures—including use of analysis of pathogens and their interaction with assays have been developed that utilise real-time PCR and quantitative PCR— hosts. Cell Microbiol 2001;3:713–9. 10 Striebel HM, Birch-Hirschfeld E, Egerer R, et al. multiple primers simultaneously in a and PCR amplification to identify Virus diagnostics on microarrays. Curr single reaction mixture to amplify viral genes associated with resistance Pharmaceut Biotechnol 2003;4:401–15.

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