View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector J Headache Pain (2006) 7:222–230 DOI 10.1007/s10194-006-0300-8 TUTORIAL Simona Sacco Comorbid neuropathologies in migraine Luigi Olivieri Stefano Bastianello Antonio Carolei Received: 20 April 2006 Abstract The identification of cause, and migraine associated Accepted in revised form: 16 May 2006 comorbid disorders in migraineurs with subclinical vascular brain Published online: 15 June 2006 is important since it may impose lesions. therapeutic challenges and limit treatment options. Moreover, the study of comorbidity might lead to improve our knowledge about S. Sacco • L. Olivieri • A. Carolei Department of Neurology, causes and consequences of University of L’Aquila, migraine. Comorbid neuropatholo- 67100 L’Aquila, Italy gies in migraine may involve mood disorders (depression, S. Bastianello IRCCS C. Mondino mania, anxiety, panic attacks), Pavia, Italy epilepsy, essential tremor, stroke, and white matter abnormalities. A. Carolei (౧) Particularly, a complex bidirection- Neurologic Clinic, al relation exists between migraine Department of Internal Medicine and stroke, including migraine as a and Public Health, risk factor for cerebral ischemia, University of L’Aquila, migraine caused by cerebral Piazzale Salvatore Tommasi 1, I-67100 L’Aquila-Coppito, Italia ischemia, migraine as a cause of Key words Migraine • Depression • e-mail: [email protected] stroke, migraine mimicking cere- Epilepsy • Tremor • Stroke • White Tel.: +39-0862-64153 bral ischemia, migraine and cere- matter lesions • Patent foramen Fax: +39-0862-64153 bral ischemia sharing a common ovale bidity may arise by coincidence or selection bias, one con- Introduction dition may cause the other, both conditions may be relat- ed to shared environmental genetic risk factors, and the Comorbidity may be defined as the presence of any addi- same environmental or genetic risk factors may determine tional coexistent condition in a patient with an index dis- a brain state that gives rise to both conditions. ease or as an association between two disorders that is Comorbid neuropathologies in migraine, as shown in more than coincidental [1]. The presence of a comorbidi- Table 1, may involve mood disorders (depression, mania, ty may complicate diagnosis because of overlapping anxiety, panic attacks), epilepsy, essential tremor, stroke symptoms. As stated by Lipton and Silberstein [2], comor- and white matter abnormalities [1]. 223 Table 1 Comorbid neuropathologies in migraine Table 3 Antiepileptic drugs used for migraine prevention Psychiatric disorders Gabapentin Epilepsy Levetiracetam Essential tremor Topiramate Stroke Valproate White matter abnormalities Zonisamide sy represent distinct families of neurological disorders Migraine and psychiatric disorders with typical constellations of symptoms. Migraine is characterised by recurrent attacks of pain and associat- The prevalence of behavioural disorders such as major ed symptoms. Epilepsy is characterised by recurrent depression, mania or hypomania, generalised anxiety and attacks of positive neurological symptoms, often pro- social phobia is higher in subjects with migraine than in gressing to altered or lost consciousness and, at times, those without migraine [3]. Epidemiologic studies report an by convulsive features. The sensory, motor and cogni- association between migraine headache and major depres- tive characteristics of migraine and epilepsy often over- sion [3–6]. The association might be noncausal, reflecting lap. Auras, hallucinations, changes in mood and behav- shared genetic or environmental pathogenic determinants. iour or consciousness, and focal sensory or motor symp- Alternatively, migraine might cause major depression or toms may occur in both conditions. Both disorders may might be caused by it. The hypothesis that depression in present with headache. Furthermore, as migraine and persons with migraine may reflect a psychological response epilepsy are highly comorbid, many individuals have to the stress of recurrent severe headaches would predict an both disorders, further complicating accurate diagnosis. influence only from migraine to depression but not from Many patients complain of headaches after seizures and depression to migraine. In contrast, the hypothesis of in some cases the migraine aura can trigger seizures, as shared causes would predict that each disorder might anticipated by Andermann and Andermann [9], who increase the risk of first-time occurrence of the other. Some coined the term migralepsy specifically referring to this studies suggested bidirectional influences between condition. However, in many patients, migraine and migraine and major depression, with each disorder increas- epileptic attacks are not temporally related. According ing the risk of first onset of the other [6, 7]. Moreover, the to Lipton et al. [10], the risk of migraine is more than fact that prevention of migraine attacks might benefit from twice as high in persons with epilepsy, whether treatments with some antidepressant agents (Table 2) sup- probands or relatives, than in persons without epilepsy. ports the presence of shared mechanisms. Besides, the risk of migraine is increased in persons Besides, the association between migraine and depres- with epilepsy caused by head trauma and is present in sion is better proven for migraine with aura than for every subgroup of epileptic patients, defined by seizure migraine without aura [8]. type, age at onset, aetiology or family history. The prevalence of epilepsy in patients with migraine ranges from 1% to 17%, with a median of 5.9%. This percent- age greatly exceeds that found in the general population, Migraine and epilepsy which is approximately 0.5% [11]. In contrast, the prevalence of migraine in patients with epilepsy ranges Migraine and epilepsy are both chronic neurologic dis- from 8% to 15% [12]. Additionally, the therapeutic orders with episodic attacks. Both migraine and epilep- options for the two disorders overlap, as antiepileptic drugs such are currently used also for migraine preven- Table 2 Antidepressants used for migraine prevention tion (Table 3). Amitriptyline Fluvoxamine Paroxetine Sertraline Migraine and tremor Phenelzine Bupropion As reported by Biary et al. [13], unexplainably, essential Mirtazapine tremor and migraine occur together more frequently than Trazodone just by chance alone. Accordingly, the prevalence of Venlafaxine migraine in patients with essential tremor is 36% com- 224 pared with a prevalence of 18% in normal controls. migraineurs with aura with respect to migraineurs with- Similarly, essential tremor occurs in about 17% of patients out aura indicating a low absolute risk increase, with 3.8 with migraine, compared with only 1% of controls. additional cases per year per 10,000 women [21]. This fact might be due to a higher cardiovascular risk profile of migraineurs with respect to controls and particularly of migraineurs with aura. The GEM population-based Migraine and stroke study reported that, compared to controls, migraineurs were more likely to smoke, less likely to drink alcohol A complex bidirectional relationship exists between and more likely to report a parental history of early migraine and stroke (Table 4), including migraine as a risk myocardial infarction. Migraineurs with aura were more factor for cerebral ischaemia, migraine caused by cerebral likely to have an unfavourable cholesterol profile, to ischaemia, migraine as a cause of stroke, migraine mimic- have elevated blood pressure and to report a history of king cerebral ischaemia, migraine and cerebral ischaemia early onset coronary heart disease or stroke; female sharing a common cause, and migraine associated with migraineurs with aura were more likely to be using oral subclinical vascular brain lesions [14–16]. contraceptives [22]. Migraine as a risk factor for cerebral ischaemia Migraine caused by cerebral ischaemia The fact that migraine might be considered as a risk fac- Migraine caused by cerebral ischaemia is also referred to tor for cerebral ischaemia has long been debated [17]. as symptomatic migraine. It is diagnosed when an estab- To speak of this possibility, a clearly clinically defined lished structural central nervous system lesion produces stroke syndrome must occur remotely in time from a typical episodes of migraine with or without neurologic typical attack of migraine [18]. History of migraine may aura. This is the case of migraine-like headaches that are contribute to the risk of stroke through an unspecified attributed to ischaemic stroke or transient ischaemic mechanism. Several case-control studies investigated attack but also the case of migraine-like headaches attrib- the relationship between migraine and stroke: the odds uted to nontraumatic intracranial haemorrhage, which are ratio was 4.3 (1.2–16.3; 95% CI) in women under 45 extensively described in Chapter 6 of The International years of age according to Tzourio et al. [19] and 3.7 Classification of Headache Disorders, second edition (1.5–9.0; 95% CI) according to Carolei et al. [20]. (ICHD-II) (Table 5) [23]. Besides, odds ratios were higher in patients with a his- The close temporal relation between the stroke and the tory of migraine with aura than in patients with a histo- onset of the headache is the main factor supporting the ry of migraine without aura. According to Carolei et al. diagnosis as well as the resolution of the headache after [20],