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Childhood and adolescent migraine: A neuropsychiatric disorder?
Medical Hypotheses 76 (2011) 778–781
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Childhood and adolescent migraine: A neuropsychiatric disorder? Umberto Balottin a,b, Matteo Chiappedi b,e,⇑, Maura Rossi b, Cristiano Termine c,d, Giuseppe Nappi c a
Headache Science Center and Department of Child Neurology and Psychiatry, IRCCS ‘‘C. Mondino National Institute of Neurology’’ Foundation, Pavia, Italy Child Neuropsychiatry Unit, University of Pavia, Pavia, Italy c Headache Science Center, IRCCS ‘‘C. Mondino National Institute of Neurology’’ Foundation, Pavia, Italy d Child Neuropsychiatry Unit, Department of Clinical and Biological Sciences, University of Insubria, Varese, Italy e Don Carlo Gnocchi ONLUS Foundation, Rehabilitation Unit, ‘‘Santa Maria alle Fonti’’ Medical Center, Salice Terme (PV), Italy b
a r t i c l e
i n f o
Article history: Received 24 November 2010 Accepted 6 February 2011
a b s t r a c t Migraine is a neurological disorder characterized by unilateral head pain, nausea and/or vomiting and altered sensory perception (particularly phono- and/or photophobia). It is a common and disabling condition in children and adolescents, just as it is in adults; its origins, pathophysiology and long-term course are still not fully understood. Biological factors are currently held to be crucial in the aetiopathogenesis of primary headaches, such as migraine. In children and adolescents, we hypothesize that for migraine to develop, life events and their psychological processing are fundamental and can act in two different ways: either as a predisposing factor, inducing a chronic state of anxiety or depression (even subclinical), or as a trigger factor, activating a cascade of psychological events which, in turn, activate the biological mechanisms that produce the migraine attack. According to our hypothesis, psychological processing of life events (i.e. how the child perceives and mentally processes them) is the main factor in migraine aetiopathogenesis. This hypothesis has important implications in terms of diagnostic and therapeutic choices for children and adolescents with migraine. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Headache can occur as a primary condition with migraine characteristics, or it can be secondary to many neurological and nonneurological disorders (e.g. all conditions accompanied by fever or alterations of the hydroelectrolytic balance). Migraine is a paroxysmal disorder characterized by unilateral head pain, nausea and/or vomiting, and altered sensory perception (particularly phono- and/or photophobia). It is both a common and a disabling condition, but there is no consensus about its origin, pathophysiology and long-term course, particularly in the pediatric population. It has been proposed that a better knowledge of the natural history of headache and of the role of prognostic factors could be useful for identifying children at risk of migraine headache, and guiding their evaluation and treatment [1]. In the field of migraine, the evidence-based medicine literature tends to focus on biological factors, using models borrowed from other neurological paroxysmal disorders (such as epilepsy) to explain the disease. This biological view, which may be seen as a form of scientific reductionism, remains deeply rooted, even though Anttila et al. [2], in a population-based study, showed that children ⇑ Corresponding author at: Don Carlo Gnocchi ONLUS Foundation, Rehabilitation Unit, ‘‘Santa Maria alle Fonti’’ Medical Center, Viale Mangiagalli 52, 27052 Salice Terme (PV), Italy. Tel.: +39 0383 945612; fax: +39 0383 945678. E-mail address: [email protected] (M. Chiappedi). 0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.02.016
with migraine ‘‘had significantly higher levels of total, internalizing, and somatic symptoms, as well as social and family problems, than those without headache and had higher levels of somatic symptoms than children with tension-type headache’’. However, the authors base this psychiatric comorbidity on shared aetiopathogenetic factors, and on the assumption that emotional disturbances are a consequence of the pain and disability experienced by children with migraine. Moreover, they underline that, in their study, most children with headache did not report high levels of psychiatric symptoms. The biological model is borrowed almost exactly from studies conducted in adults and has also been used to interpret data from recent, methodologically sound studies [3]. However, an alternative explanation has been proposed by other authors, such as Fearon and Hotopf [4], who studied a large number of children and found that those with a high frequency of headache attacks had a higher risk, in adulthood, of developing headache or other somatic complaints (Odds Ratio: 1.75) or psychiatric disorders (OR: 1.41). Their suggestion that ‘‘underlying psychosocial adversity’’ may play a role in headache opens up the way for alternative (non-biological) explanations and interventions in childhood and adolescent headache. Biological findings and theories in migraine The biological basis of migraine at a molecular level is uncertain, so that different aetiopathogenetic theories remain open.
U. Balottin et al. / Medical Hypotheses 76 (2011) 778–781
The vascular theory attributed the phenomenon of pain in migraine attacks to vasodilatation, on the basis of experimental observations of increased extracranial artery diameters in migraine patients [5]. Instead, the neurological theory linked migraine attacks to neuronal events, occurring in different brain areas and mediated by neurotransmitter imbalances. Central to this theory is the phenomenon of cortical spreading depression (CSD), a term coined by Leão to describe a wave of complete neuronal and glial depolarization that, once triggered by a sufficiently strong stimulus, propagates centrifugally through grey matter, irrespective of functional divisions and arterial territories [6]. The unusually long duration of the depolarization (up to a minute or more) and its extremely slow propagation (approximately 3 mm per minute) compared with action potentials (lasting milliseconds and propagating at a rate of meters per second) distinguish CSD from normal neuronal activity [7]. Because it often travels across the part of the brain that processes vision, CSD may constitute the neurological substrate of migraine with aura, while its role in migraine without aura is still very much questioned [8,9]. Efforts to reconcile the vascular and neuronal hypotheses led to the modern, integrated pathophysiological view of migraine as a neurovascular disorder. In this context, a major pathogenic step is thought to be the release of inflammatory neuropeptides from trigeminal sensory afferents, prompting dilatation of the meningeal vessels [10]. Another possibly relevant factor, recently proposed, is neurogenic inflammation, i.e. inflammation caused by the release of vasoactive peptides from perivascular axons in response to unknown triggers [11]. This mechanism is thought to be mediated by calcitonin gene-related peptide (CGRP) and substance P, which in turn increase pro-inflammatory, vasoactive and algogenic substances including cytokines, 5-HT, histamine and nitric oxide (NO). These substances activate endothelial cells, mast cells and platelets to increase extracellular levels of amines, arachidonate metabolites, peptides and ions, but also CGRP synthesis and release [12]. Peripheral and central sensitization, i.e. facilitation of the transmission of impulses in nociceptive nerve fibers, has been demonstrated in migraine [13]. Whereas peripheral sensitization is related to the vasodilatation of the meningeal blood vessels that can, in turn, trigger neurogenic inflammation, central sensitization causes altered processing of sensory input in the brainstem, principally in the trigeminal nucleus caudalis and in the periacqueductal grey matter [14]. It can however be discussed if these are aetiopathogenetic factors or possibly sequelae of migraine itself. It has also been hypothesized that migraine is a channellopathy, involving mainly calcium channels [15]. However, caution is warranted when attempting to establish a pathogenic link between sporadic hemiplegic migraine (the model on which this theory is based) and migraine with or without aura, since it is impossible, on the basis of the still insufficient available evidence, to demonstrate that these conditions share the same genetic predisposition [16]. Finally, several brain neurotransmitter systems have been suggested to be involved in migraine. Although the serotoninergic system has been more extensively studied – a decrease in 5-HT descending pain inhibitory tone has been suggested to be an important factor predisposing to the activation of the trigemino– vascular nociceptive pathway [17] –, a role for glutamate, dopamine, noradrenaline and for neuromodulators such as tyrosine (possibly mediated by their action on CGRP synthesis and secretion) is increasingly being proposed [18].
Psychological findings and theories in migraine Given that child neuropsychiatry is our specific area of interest, we here discuss psychological findings and theories in migraine so-
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lely with reference to the available data in children and adolescents. It must be pointed out, however, that significant levels of psychiatric comorbidity (i.e. the co-occurrence of psychiatric symptoms or disorders) have been demonstrated in adult migraine patients – 22–32% will meet criteria for major depression and 51– 58% for at least one anxiety disorder at some point in their lifetime [19] – and it is our belief that, with some caveats, most of our considerations here could be extended to adults. As shown by Bruijn et al. in a recent systematic review of clinical studies [20], somatic complaints and internalizing disorders are frequent in children with migraine, but the authors conclude that this is ‘‘a consequence of the nature of their disease rather than a sign of psychological dysfunctioning’’; hence, ‘‘children with migraine at referral to a specialist do not exhibit more psychological dysfunctioning and (to a lesser extent) do not exhibit more psychiatric comorbidity compared with healthy controls’’. This conclusion seems somewhat biased, however, as the authors seem to consider only externalizing disorders among the ‘‘psychological dysfunctions’’. This is certainly questionable, given that internalizing symptoms are the core of emotional disorders, a category that, somewhat similar to the old clinical concept of neurosis is central to understanding of many aspects of child psychopathology. In this field, the evidence emerging from five high-quality studies [21–25], identified in the review by Bruijn, is rather striking. Mazzone et al. [21] found that up to 33% of children with migraine have internalising disorders and/or hyperactivity. Similar findings were reported by Galli et al. [22] and Vannatta et al. [23], while the study by Cooper et al. [24] is an outlier that, however, was conducted 15–20 years before the others and used different questionnaires to investigate only anxious and depressive symptoms. Moreover, Pakalnis, Gibson and Colvin [25] found that children with migraines have a significantly higher prevalence of oppositional defiant disorder and of psychiatric symptoms in different domains (that include internalising disorders). These authors suggest that psychological interventions such as ‘‘stress counselling, biofeedback, relaxation therapy (. . .) may be an important part of the therapeutic treatment plan to achieve optimal success in decreasing headache burden in children and their families’’. Psychiatric comorbidity is often reported in population-based studies, confirming clinical evidence. Anttila et al. [2] studied 1135 Finnish children and found a significant prevalence of family functioning difficulties, of impaired social relationships and of internalising and global behaviour disorders among primary headache patients. These findings are consistent with those obtained by Fearon and Hotopf [4] in their study of 17,414 children; these authors concluded that headaches (including migraine) could be read as ‘‘signs of underlying psychosocial adversity’’. Cahill and Cannon [26], on the other hand, in a longitudinal, population-based study in New Zealand, showed that the risk of having migraine or migraine and tension-type headache at the age of 26 is two or three times higher in children recording higher levels of anxiety at the age of nine and/or 15 years. They conclude that ‘‘migraine should be a headache subtype of particular interest to psychiatrists’’, given the significant association between stress, personality traits, psychiatric disorders and migraine. Marmorstein et al. [27], analyzing a sample drawn from the Minnesota Twin Family Study (a community-based study of adolescents and their families) found that ‘‘parental depression, antisocial behavior and drug dependence were associated with offspring migraine’’. This idea is confirmed by the findings of a meta-analysis of the efficacy of treatments for idiopathic headaches (including migraine). Eccleston et al. [28] found that ‘‘there is very good evidence that psychological treatments, principally relaxation and cognitive behavioral therapy, are effective in reducing the severity and frequency of chronic headache in children and adolescents’’;
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furthermore, the recent updated and expanded version of this meta-analysis showed that this beneficial effect is maintained over time [29]. These findings are in line with results obtained by Trautmann et al. [30]. Conversely, the efficacy of preventive drug therapy does not seem to be sufficiently proven, which is why the FDA has decided, for now, not to approve any drug for the prevention of pediatric migraine [31]. Although this lack of evidence probably has many different reasons, at present a psychological intervention is better supported than preventive pharmacological therapy. These findings appear particularly important when one considers the increasing doubts now being raised over the use of questionnaires as the only method of assessing psychopathology. Indeed, the psychometric properties of these instruments are often insufficiently tested, a fact often pointed out as a limitation of published studies [32]; according to Pauschardt et al. integration of a face-to-face clinical psychiatric examination is fundamental in order to reduce the risk of missing relevant data [33]. This point is supported by our own everyday experience working with children with migraine: it can be extremely difficult, using only psychological questionnaires, to probe life events and situations such as tensions within the family, parental separation or divorce, and deaths of emotionally significant people. A questionnaire can hardly be deemed comparable to clinical psychiatric interviews as means of detecting the subtle interplay between real life events and a frail personality organization, especially when both parents and child are concentrating on somatic symptoms and complaints and tending to ignore emotional aspects [34,35]. Moreover, most authors believe that ‘‘it is often found that although patients with headache report elevated symptom levels, both the headache and non-headache group means typically fall within the ‘‘normal range’’, indicating that although children with headache are considered to be statistically more depressed than children without headache, most are not clinically maladjusted’’ [36]. As for anxiety, the same authors note that ‘‘although children with migraine do not experience more anxiety than their nonheadache peers, they appear to be less able to cope with stress and anxiety, resulting in increased headaches’’. Authors such as Kandel [37], however, have shown that a bidirectional interaction exists between our mind and our brain: our thoughts, emotions, beliefs, anxieties and anguishes can influence the functioning of our brain, which in turn is the key component in integrating facts about and views of the external world into our personal ‘‘internal world’’ [38]. But if this mechanism is not working correctly, because the child is unable to process his emotional reactions [39] or unconsciously prefers to avoid this mental operation [40], the result might be a somatic symptom, a worsening of a pre-existing somatic disorder, or a predisposition to a disorder. As well as external or internal stimuli (triggers), there also exist ‘‘mental stimuli’’, evoked by memory and by life events [41]. The result, from a psychological point of view, is similar to what is termed alexithymia, i.e. impairment of the ability to recognise and make sense of emotions that have somehow been moved into the body [42]. In other cases, difficulty managing an overwhelming affective experience, when the ability to express the emotion is lacking, leads to the ‘‘désaffectation’’ described by McDougall [39]. These psychological mechanisms could account, in part, for the frequently reported differences between the parents’ and patient’s views on the child’s psychological status [43]. This, again, is confirmed by our own clinical experience and is even more understandable when one considers that the child’s/adolescent’s mind, since it is still developing, risks being unable to tolerate stress factors (in this case, psychological factors); in this situation, these factors are more likely to induce damage (here, the transformation of emotional distress into a somatic complaint).
Our hypothesis Biological factors are thought to be crucial in the aetiopathogenesis of childhood and adolescent migraine. For the disorder to develop, however, a crucial role is played by life events and their psychological processing. These may intervene either as a predisposing factor, inducing a chronic state of anxiety or depression (even subclinical), or as a trigger factor, activating a cascade of psychological events which, in turn, activate the biological mechanisms that produce the migraine attack. As discussed above, current findings seem to allow migraine in children and adolescents to be regarded as a psychiatric disorder: this can explain at least in part why psychological treatments show more evidence of utility in the short- and long-term than do prophylactic drugs. More specifically, migraine can be considered a psychosomatic disorder as defined by McDougall, i.e. as an attack to health and/or body integrity in which a psychological factor plays a role [39]. This hypothesis offers scope for overcoming the mind versus body dualism in this field (which may be translated as the psychological versus biological origin of primary migraine) [44]. Other authors have sought to explain the role of stress as a trigger factor in headache by hypothesizing a biological route leading from stress to headache (see, for example, the work of Cathcart [45] examining stress-induced tension-type headache). Our hypothesis, however, is more radical because it considers the main factor in migraine aetiopathogenesis to be not the life events as such, but rather how the child perceives and mentally processes them. It thus refers to a particular modality of mental functioning and organization in which the interior mental world, with all its emotions, fantasies, desires, fears and sorrows, or a part of this world, is temporarily sealed off, consigned to a separate area of the mind (and brain) where it cannot be thought about and mentally processed. It must be stressed, however, that these psychological factors are to be seen as part of a cascade, whose end is represented by the sensation of pain: therefore our hypothesis integrates the fundamental role of biological and genetical factors in the aetiopathogenesis of migraine, underlining the role of psychological functioning style and of life events psychic processing. We have no reliable data to define exactly at which level of the cascade psychological factors act and it is also possible that they have multiple actions. Therefore, our hypothesis is not in contrast with the well known efficacy of drugs used to treat migraine attacks (such as triptans): it states that at the end of the cascade somatic pain is produced by the activation of one or more common biological mechanisms, which drugs are supposed to block. This hypothesis is both testable and possibly useful for treatment purposes. If migraine derives from both biological and psychological factors, the latter being fundamental in determining its course, any intervention able to reduce the contribution of psychological factors will likely improve the child’s long-term outcome. This view is supported by studies in adult patients [19] and, as mentioned, the usefulness of psychological interventions is already well established [28–30]. Psychological interventions can, however, be planned in different ways. Broadly speaking, they may aim to reduce psychosocial stressors, e.g. providing more social support for families [46], or to help the patient improve his coping abilities and strategies (vis-à-vis both migraine attacks and life events generally that constitute sources of negative emotions and feelings) and become, as far as possible, accepting and aware of his own emotions and deep inner feelings. A direct comparison between these forms of intervention could make it possible to evaluate whether personal or psychosocial fac-
U. Balottin et al. / Medical Hypotheses 76 (2011) 778–781
tors really play a role and to establish the exact contribution of each to the course of childhood migraine. Moreover, if psychological aspects are important in determining the number and severity of attacks, drugs used to treat or to prevent migraine episodes should have differentiated effects based on psychological status. Given the already quoted disappointing data available for pharmacological prophylactic interventions [47], this consideration could lead to a significant improvement in our treatment schedules. In conclusion, our hypothesis has important implications for the organization of services dealing with children affected by migraine. Indeed, should it be proven valid, it would become necessary for such services to focus not only on the somatic complaints of the child and his parents, but also on their psychological functioning, in order to improve or possibly resolve these children’s complaints. Conflict of Interest The authors have no conflict of interest to disclose. No grants or funding were used for this paper. References [1] Guidetti V, Galli F, Termine C. Headache in children. In: Aminoff MJ, Boller F, Swaab DF, editors. Headache handbook of clinical neurology. Amsterdam: Elsevier; 2010. [2] Anttila P, Aromaa H, Sillanpää M. Psychiatric symptoms in children with primary headache. J Am Acad Child Adolesc Psychiatry 2004;43(4):412–9. [3] Beghi E, Bussone G, D’Amico D, et al. Headache, anxiety and depressive disorders: the HADAS study. J Headache Pain 2010;11(2):141–50. [4] Fearon P, Hotopf M. Relation between headache in childhood and physical and psychiatric symptoms in adulthood: national birth cohort study. BMJ 2001;322(7295):1145. [5] Graham JR, Wolf HG. Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry 1938;39:737–63. [6] Leao AAP. Spreading depression of activity in cerebral cortex. J Neurophysiol 1944;7:359–90. [7] Leao AAP, Morison RS. Propagation of spreading cortical depression. J Neurophysiol 1945;8:33–45. [8] Ayata C. Cortical spreading depression triggers migraine attack: pro. Headache 2010;50(4):725–30. [9] Charles A. Does cortical spreading depression initiate a migraine attack? Maybe not. Headache 2010;50(4):731–3. [10] Moskowitz MA. Genes, proteases, cortical spreading depression and migraine: impact on pathophysiology and treatment. Funct Neurol 2007;22:133–6. [11] Dalkara T, Zervas NT, Moskowitz MA. From spreading depression to the trigeminovascular system. Neurol Sci 2006;27:S86–90. [12] Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache 2006;46:S3–8. [13] Goadsby PJ. Migraine pathophysiology. Headache 2005;45:S14–24. [14] Galletti F, Cupini LM, Corbelli I, Calabresi P, Sarchielli P. Pathophysiological basis of migraine prophylaxis. Prog Neurobiol 2009;89:176–92. [15] Russell MB. Is migraine a genetic illness? The various forms of migraine share a common genetic cause. Neurol Sci 2008;29:S52–4. [16] Wessman M, Terwindt GM, Kaunisto MA, Palotie A, Ophoff RA. Migraine: a complex genetic disorder. Lancet Neurol 2007;6:521–32. [17] Panconesi A. Serotonin and migraine: a reconsideration of the central theory. J Headache Pain 2008;9(5):267–76. [18] D’Andrea G, Leon A. Pathogenesis of migraine: from neurotransmitters to neuromodulators and beyond. Neurol Sci 2010;31(Suppl 1):S1–7. [19] Smitherman TA, Maizels M, Penzien DB. Headache chronification: screening and behavioral management of comorbid depressive and anxiety disorders. Headache 2008;48:45–50.
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Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Childhood and adolescent migraine: A neuropsychiatric disorder? Umberto Balottin a,b, Matteo Chiappedi b,e,⇑, Maura Rossi b, Cristiano Termine c,d, Giuseppe Nappi c a
Headache Science Center and Department of Child Neurology and Psychiatry, IRCCS ‘‘C. Mondino National Institute of Neurology’’ Foundation, Pavia, Italy Child Neuropsychiatry Unit, University of Pavia, Pavia, Italy c Headache Science Center, IRCCS ‘‘C. Mondino National Institute of Neurology’’ Foundation, Pavia, Italy d Child Neuropsychiatry Unit, Department of Clinical and Biological Sciences, University of Insubria, Varese, Italy e Don Carlo Gnocchi ONLUS Foundation, Rehabilitation Unit, ‘‘Santa Maria alle Fonti’’ Medical Center, Salice Terme (PV), Italy b
a r t i c l e
i n f o
Article history: Received 24 November 2010 Accepted 6 February 2011
a b s t r a c t Migraine is a neurological disorder characterized by unilateral head pain, nausea and/or vomiting and altered sensory perception (particularly phono- and/or photophobia). It is a common and disabling condition in children and adolescents, just as it is in adults; its origins, pathophysiology and long-term course are still not fully understood. Biological factors are currently held to be crucial in the aetiopathogenesis of primary headaches, such as migraine. In children and adolescents, we hypothesize that for migraine to develop, life events and their psychological processing are fundamental and can act in two different ways: either as a predisposing factor, inducing a chronic state of anxiety or depression (even subclinical), or as a trigger factor, activating a cascade of psychological events which, in turn, activate the biological mechanisms that produce the migraine attack. According to our hypothesis, psychological processing of life events (i.e. how the child perceives and mentally processes them) is the main factor in migraine aetiopathogenesis. This hypothesis has important implications in terms of diagnostic and therapeutic choices for children and adolescents with migraine. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Headache can occur as a primary condition with migraine characteristics, or it can be secondary to many neurological and nonneurological disorders (e.g. all conditions accompanied by fever or alterations of the hydroelectrolytic balance). Migraine is a paroxysmal disorder characterized by unilateral head pain, nausea and/or vomiting, and altered sensory perception (particularly phono- and/or photophobia). It is both a common and a disabling condition, but there is no consensus about its origin, pathophysiology and long-term course, particularly in the pediatric population. It has been proposed that a better knowledge of the natural history of headache and of the role of prognostic factors could be useful for identifying children at risk of migraine headache, and guiding their evaluation and treatment [1]. In the field of migraine, the evidence-based medicine literature tends to focus on biological factors, using models borrowed from other neurological paroxysmal disorders (such as epilepsy) to explain the disease. This biological view, which may be seen as a form of scientific reductionism, remains deeply rooted, even though Anttila et al. [2], in a population-based study, showed that children ⇑ Corresponding author at: Don Carlo Gnocchi ONLUS Foundation, Rehabilitation Unit, ‘‘Santa Maria alle Fonti’’ Medical Center, Viale Mangiagalli 52, 27052 Salice Terme (PV), Italy. Tel.: +39 0383 945612; fax: +39 0383 945678. E-mail address: [email protected] (M. Chiappedi). 0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.02.016
with migraine ‘‘had significantly higher levels of total, internalizing, and somatic symptoms, as well as social and family problems, than those without headache and had higher levels of somatic symptoms than children with tension-type headache’’. However, the authors base this psychiatric comorbidity on shared aetiopathogenetic factors, and on the assumption that emotional disturbances are a consequence of the pain and disability experienced by children with migraine. Moreover, they underline that, in their study, most children with headache did not report high levels of psychiatric symptoms. The biological model is borrowed almost exactly from studies conducted in adults and has also been used to interpret data from recent, methodologically sound studies [3]. However, an alternative explanation has been proposed by other authors, such as Fearon and Hotopf [4], who studied a large number of children and found that those with a high frequency of headache attacks had a higher risk, in adulthood, of developing headache or other somatic complaints (Odds Ratio: 1.75) or psychiatric disorders (OR: 1.41). Their suggestion that ‘‘underlying psychosocial adversity’’ may play a role in headache opens up the way for alternative (non-biological) explanations and interventions in childhood and adolescent headache. Biological findings and theories in migraine The biological basis of migraine at a molecular level is uncertain, so that different aetiopathogenetic theories remain open.
U. Balottin et al. / Medical Hypotheses 76 (2011) 778–781
The vascular theory attributed the phenomenon of pain in migraine attacks to vasodilatation, on the basis of experimental observations of increased extracranial artery diameters in migraine patients [5]. Instead, the neurological theory linked migraine attacks to neuronal events, occurring in different brain areas and mediated by neurotransmitter imbalances. Central to this theory is the phenomenon of cortical spreading depression (CSD), a term coined by Leão to describe a wave of complete neuronal and glial depolarization that, once triggered by a sufficiently strong stimulus, propagates centrifugally through grey matter, irrespective of functional divisions and arterial territories [6]. The unusually long duration of the depolarization (up to a minute or more) and its extremely slow propagation (approximately 3 mm per minute) compared with action potentials (lasting milliseconds and propagating at a rate of meters per second) distinguish CSD from normal neuronal activity [7]. Because it often travels across the part of the brain that processes vision, CSD may constitute the neurological substrate of migraine with aura, while its role in migraine without aura is still very much questioned [8,9]. Efforts to reconcile the vascular and neuronal hypotheses led to the modern, integrated pathophysiological view of migraine as a neurovascular disorder. In this context, a major pathogenic step is thought to be the release of inflammatory neuropeptides from trigeminal sensory afferents, prompting dilatation of the meningeal vessels [10]. Another possibly relevant factor, recently proposed, is neurogenic inflammation, i.e. inflammation caused by the release of vasoactive peptides from perivascular axons in response to unknown triggers [11]. This mechanism is thought to be mediated by calcitonin gene-related peptide (CGRP) and substance P, which in turn increase pro-inflammatory, vasoactive and algogenic substances including cytokines, 5-HT, histamine and nitric oxide (NO). These substances activate endothelial cells, mast cells and platelets to increase extracellular levels of amines, arachidonate metabolites, peptides and ions, but also CGRP synthesis and release [12]. Peripheral and central sensitization, i.e. facilitation of the transmission of impulses in nociceptive nerve fibers, has been demonstrated in migraine [13]. Whereas peripheral sensitization is related to the vasodilatation of the meningeal blood vessels that can, in turn, trigger neurogenic inflammation, central sensitization causes altered processing of sensory input in the brainstem, principally in the trigeminal nucleus caudalis and in the periacqueductal grey matter [14]. It can however be discussed if these are aetiopathogenetic factors or possibly sequelae of migraine itself. It has also been hypothesized that migraine is a channellopathy, involving mainly calcium channels [15]. However, caution is warranted when attempting to establish a pathogenic link between sporadic hemiplegic migraine (the model on which this theory is based) and migraine with or without aura, since it is impossible, on the basis of the still insufficient available evidence, to demonstrate that these conditions share the same genetic predisposition [16]. Finally, several brain neurotransmitter systems have been suggested to be involved in migraine. Although the serotoninergic system has been more extensively studied – a decrease in 5-HT descending pain inhibitory tone has been suggested to be an important factor predisposing to the activation of the trigemino– vascular nociceptive pathway [17] –, a role for glutamate, dopamine, noradrenaline and for neuromodulators such as tyrosine (possibly mediated by their action on CGRP synthesis and secretion) is increasingly being proposed [18].
Psychological findings and theories in migraine Given that child neuropsychiatry is our specific area of interest, we here discuss psychological findings and theories in migraine so-
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lely with reference to the available data in children and adolescents. It must be pointed out, however, that significant levels of psychiatric comorbidity (i.e. the co-occurrence of psychiatric symptoms or disorders) have been demonstrated in adult migraine patients – 22–32% will meet criteria for major depression and 51– 58% for at least one anxiety disorder at some point in their lifetime [19] – and it is our belief that, with some caveats, most of our considerations here could be extended to adults. As shown by Bruijn et al. in a recent systematic review of clinical studies [20], somatic complaints and internalizing disorders are frequent in children with migraine, but the authors conclude that this is ‘‘a consequence of the nature of their disease rather than a sign of psychological dysfunctioning’’; hence, ‘‘children with migraine at referral to a specialist do not exhibit more psychological dysfunctioning and (to a lesser extent) do not exhibit more psychiatric comorbidity compared with healthy controls’’. This conclusion seems somewhat biased, however, as the authors seem to consider only externalizing disorders among the ‘‘psychological dysfunctions’’. This is certainly questionable, given that internalizing symptoms are the core of emotional disorders, a category that, somewhat similar to the old clinical concept of neurosis is central to understanding of many aspects of child psychopathology. In this field, the evidence emerging from five high-quality studies [21–25], identified in the review by Bruijn, is rather striking. Mazzone et al. [21] found that up to 33% of children with migraine have internalising disorders and/or hyperactivity. Similar findings were reported by Galli et al. [22] and Vannatta et al. [23], while the study by Cooper et al. [24] is an outlier that, however, was conducted 15–20 years before the others and used different questionnaires to investigate only anxious and depressive symptoms. Moreover, Pakalnis, Gibson and Colvin [25] found that children with migraines have a significantly higher prevalence of oppositional defiant disorder and of psychiatric symptoms in different domains (that include internalising disorders). These authors suggest that psychological interventions such as ‘‘stress counselling, biofeedback, relaxation therapy (. . .) may be an important part of the therapeutic treatment plan to achieve optimal success in decreasing headache burden in children and their families’’. Psychiatric comorbidity is often reported in population-based studies, confirming clinical evidence. Anttila et al. [2] studied 1135 Finnish children and found a significant prevalence of family functioning difficulties, of impaired social relationships and of internalising and global behaviour disorders among primary headache patients. These findings are consistent with those obtained by Fearon and Hotopf [4] in their study of 17,414 children; these authors concluded that headaches (including migraine) could be read as ‘‘signs of underlying psychosocial adversity’’. Cahill and Cannon [26], on the other hand, in a longitudinal, population-based study in New Zealand, showed that the risk of having migraine or migraine and tension-type headache at the age of 26 is two or three times higher in children recording higher levels of anxiety at the age of nine and/or 15 years. They conclude that ‘‘migraine should be a headache subtype of particular interest to psychiatrists’’, given the significant association between stress, personality traits, psychiatric disorders and migraine. Marmorstein et al. [27], analyzing a sample drawn from the Minnesota Twin Family Study (a community-based study of adolescents and their families) found that ‘‘parental depression, antisocial behavior and drug dependence were associated with offspring migraine’’. This idea is confirmed by the findings of a meta-analysis of the efficacy of treatments for idiopathic headaches (including migraine). Eccleston et al. [28] found that ‘‘there is very good evidence that psychological treatments, principally relaxation and cognitive behavioral therapy, are effective in reducing the severity and frequency of chronic headache in children and adolescents’’;
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furthermore, the recent updated and expanded version of this meta-analysis showed that this beneficial effect is maintained over time [29]. These findings are in line with results obtained by Trautmann et al. [30]. Conversely, the efficacy of preventive drug therapy does not seem to be sufficiently proven, which is why the FDA has decided, for now, not to approve any drug for the prevention of pediatric migraine [31]. Although this lack of evidence probably has many different reasons, at present a psychological intervention is better supported than preventive pharmacological therapy. These findings appear particularly important when one considers the increasing doubts now being raised over the use of questionnaires as the only method of assessing psychopathology. Indeed, the psychometric properties of these instruments are often insufficiently tested, a fact often pointed out as a limitation of published studies [32]; according to Pauschardt et al. integration of a face-to-face clinical psychiatric examination is fundamental in order to reduce the risk of missing relevant data [33]. This point is supported by our own everyday experience working with children with migraine: it can be extremely difficult, using only psychological questionnaires, to probe life events and situations such as tensions within the family, parental separation or divorce, and deaths of emotionally significant people. A questionnaire can hardly be deemed comparable to clinical psychiatric interviews as means of detecting the subtle interplay between real life events and a frail personality organization, especially when both parents and child are concentrating on somatic symptoms and complaints and tending to ignore emotional aspects [34,35]. Moreover, most authors believe that ‘‘it is often found that although patients with headache report elevated symptom levels, both the headache and non-headache group means typically fall within the ‘‘normal range’’, indicating that although children with headache are considered to be statistically more depressed than children without headache, most are not clinically maladjusted’’ [36]. As for anxiety, the same authors note that ‘‘although children with migraine do not experience more anxiety than their nonheadache peers, they appear to be less able to cope with stress and anxiety, resulting in increased headaches’’. Authors such as Kandel [37], however, have shown that a bidirectional interaction exists between our mind and our brain: our thoughts, emotions, beliefs, anxieties and anguishes can influence the functioning of our brain, which in turn is the key component in integrating facts about and views of the external world into our personal ‘‘internal world’’ [38]. But if this mechanism is not working correctly, because the child is unable to process his emotional reactions [39] or unconsciously prefers to avoid this mental operation [40], the result might be a somatic symptom, a worsening of a pre-existing somatic disorder, or a predisposition to a disorder. As well as external or internal stimuli (triggers), there also exist ‘‘mental stimuli’’, evoked by memory and by life events [41]. The result, from a psychological point of view, is similar to what is termed alexithymia, i.e. impairment of the ability to recognise and make sense of emotions that have somehow been moved into the body [42]. In other cases, difficulty managing an overwhelming affective experience, when the ability to express the emotion is lacking, leads to the ‘‘désaffectation’’ described by McDougall [39]. These psychological mechanisms could account, in part, for the frequently reported differences between the parents’ and patient’s views on the child’s psychological status [43]. This, again, is confirmed by our own clinical experience and is even more understandable when one considers that the child’s/adolescent’s mind, since it is still developing, risks being unable to tolerate stress factors (in this case, psychological factors); in this situation, these factors are more likely to induce damage (here, the transformation of emotional distress into a somatic complaint).
Our hypothesis Biological factors are thought to be crucial in the aetiopathogenesis of childhood and adolescent migraine. For the disorder to develop, however, a crucial role is played by life events and their psychological processing. These may intervene either as a predisposing factor, inducing a chronic state of anxiety or depression (even subclinical), or as a trigger factor, activating a cascade of psychological events which, in turn, activate the biological mechanisms that produce the migraine attack. As discussed above, current findings seem to allow migraine in children and adolescents to be regarded as a psychiatric disorder: this can explain at least in part why psychological treatments show more evidence of utility in the short- and long-term than do prophylactic drugs. More specifically, migraine can be considered a psychosomatic disorder as defined by McDougall, i.e. as an attack to health and/or body integrity in which a psychological factor plays a role [39]. This hypothesis offers scope for overcoming the mind versus body dualism in this field (which may be translated as the psychological versus biological origin of primary migraine) [44]. Other authors have sought to explain the role of stress as a trigger factor in headache by hypothesizing a biological route leading from stress to headache (see, for example, the work of Cathcart [45] examining stress-induced tension-type headache). Our hypothesis, however, is more radical because it considers the main factor in migraine aetiopathogenesis to be not the life events as such, but rather how the child perceives and mentally processes them. It thus refers to a particular modality of mental functioning and organization in which the interior mental world, with all its emotions, fantasies, desires, fears and sorrows, or a part of this world, is temporarily sealed off, consigned to a separate area of the mind (and brain) where it cannot be thought about and mentally processed. It must be stressed, however, that these psychological factors are to be seen as part of a cascade, whose end is represented by the sensation of pain: therefore our hypothesis integrates the fundamental role of biological and genetical factors in the aetiopathogenesis of migraine, underlining the role of psychological functioning style and of life events psychic processing. We have no reliable data to define exactly at which level of the cascade psychological factors act and it is also possible that they have multiple actions. Therefore, our hypothesis is not in contrast with the well known efficacy of drugs used to treat migraine attacks (such as triptans): it states that at the end of the cascade somatic pain is produced by the activation of one or more common biological mechanisms, which drugs are supposed to block. This hypothesis is both testable and possibly useful for treatment purposes. If migraine derives from both biological and psychological factors, the latter being fundamental in determining its course, any intervention able to reduce the contribution of psychological factors will likely improve the child’s long-term outcome. This view is supported by studies in adult patients [19] and, as mentioned, the usefulness of psychological interventions is already well established [28–30]. Psychological interventions can, however, be planned in different ways. Broadly speaking, they may aim to reduce psychosocial stressors, e.g. providing more social support for families [46], or to help the patient improve his coping abilities and strategies (vis-à-vis both migraine attacks and life events generally that constitute sources of negative emotions and feelings) and become, as far as possible, accepting and aware of his own emotions and deep inner feelings. A direct comparison between these forms of intervention could make it possible to evaluate whether personal or psychosocial fac-
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tors really play a role and to establish the exact contribution of each to the course of childhood migraine. Moreover, if psychological aspects are important in determining the number and severity of attacks, drugs used to treat or to prevent migraine episodes should have differentiated effects based on psychological status. Given the already quoted disappointing data available for pharmacological prophylactic interventions [47], this consideration could lead to a significant improvement in our treatment schedules. In conclusion, our hypothesis has important implications for the organization of services dealing with children affected by migraine. Indeed, should it be proven valid, it would become necessary for such services to focus not only on the somatic complaints of the child and his parents, but also on their psychological functioning, in order to improve or possibly resolve these children’s complaints. Conflict of Interest The authors have no conflict of interest to disclose. No grants or funding were used for this paper. References [1] Guidetti V, Galli F, Termine C. Headache in children. In: Aminoff MJ, Boller F, Swaab DF, editors. Headache handbook of clinical neurology. Amsterdam: Elsevier; 2010. [2] Anttila P, Aromaa H, Sillanpää M. Psychiatric symptoms in children with primary headache. J Am Acad Child Adolesc Psychiatry 2004;43(4):412–9. [3] Beghi E, Bussone G, D’Amico D, et al. Headache, anxiety and depressive disorders: the HADAS study. J Headache Pain 2010;11(2):141–50. [4] Fearon P, Hotopf M. Relation between headache in childhood and physical and psychiatric symptoms in adulthood: national birth cohort study. BMJ 2001;322(7295):1145. [5] Graham JR, Wolf HG. Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry 1938;39:737–63. [6] Leao AAP. Spreading depression of activity in cerebral cortex. J Neurophysiol 1944;7:359–90. [7] Leao AAP, Morison RS. Propagation of spreading cortical depression. J Neurophysiol 1945;8:33–45. [8] Ayata C. Cortical spreading depression triggers migraine attack: pro. Headache 2010;50(4):725–30. [9] Charles A. Does cortical spreading depression initiate a migraine attack? Maybe not. Headache 2010;50(4):731–3. [10] Moskowitz MA. Genes, proteases, cortical spreading depression and migraine: impact on pathophysiology and treatment. Funct Neurol 2007;22:133–6. [11] Dalkara T, Zervas NT, Moskowitz MA. From spreading depression to the trigeminovascular system. Neurol Sci 2006;27:S86–90. [12] Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache 2006;46:S3–8. [13] Goadsby PJ. Migraine pathophysiology. Headache 2005;45:S14–24. [14] Galletti F, Cupini LM, Corbelli I, Calabresi P, Sarchielli P. Pathophysiological basis of migraine prophylaxis. Prog Neurobiol 2009;89:176–92. [15] Russell MB. Is migraine a genetic illness? The various forms of migraine share a common genetic cause. Neurol Sci 2008;29:S52–4. [16] Wessman M, Terwindt GM, Kaunisto MA, Palotie A, Ophoff RA. Migraine: a complex genetic disorder. Lancet Neurol 2007;6:521–32. [17] Panconesi A. Serotonin and migraine: a reconsideration of the central theory. J Headache Pain 2008;9(5):267–76. [18] D’Andrea G, Leon A. Pathogenesis of migraine: from neurotransmitters to neuromodulators and beyond. Neurol Sci 2010;31(Suppl 1):S1–7. [19] Smitherman TA, Maizels M, Penzien DB. Headache chronification: screening and behavioral management of comorbid depressive and anxiety disorders. Headache 2008;48:45–50.
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