Shared mechanisms of epilepsy, migraine and affective disorders

Since the nineteenth century several clinical features have been observed in common between migraine and epilepsy (such as episodic attacks, triggering factors, presence of aura, frequent familiarity), but only in recent years researchers have really engaged in finding a common pathogenic mechanism. From studies of disease incidence, we understand how either migraine among patients with epilepsy or epilepsy among migraine patients are more frequent than in the general population. This association may result from a direct causality, by the same environmental risk factors and/or by a common genetic susceptibility. Ischemic events are the most frequent direct causes, especially among women and elderly people: migraine can lead to silent or clinically considerable strokes, and these ones could explain the increased risk of developing epilepsy in people with a history of migraine. Head injuries can lead headache, often with migraine characteristics, and seizures. But there are also many idiopathic cases. The comorbidity migraine–epilepsy might be explained in these cases by a neuronal hyperexcitability, which increases the risk of both diseases: a higher concentration of extracellular glutamate, the main excitatory neurotransmitter, leads in fact as a result a Cortical Spreading Depression (the pathophysiological mechanism at the base of aura) and convulsions; antiepileptic drugs such as topiramate are, therefore, used also in migraine prophylaxis. A genetic link between these two diseases is particularly evident in familial hemiplegic migraine: mutations of ATP1A2, SCN1A and CACNA1A genes, identified in this disease, have also been involved in different types of epilepsy and febrile seizures. The channelopathies, especially engaging sodium and potassium ions, can be the common pathogenic mechanism of migraine and epilepsy. Both migraine and epilepsy also have, compared to the general population, a higher prevalence and incidence of affective disorders such as anxiety, depression and suicidal ideation. Anxiety and depression can be part of symptoms that accompany migraine or seizures. Female patients with a long history of illness and frequent attacks are the most at risk. The impact of these diseases on the quality of life is the most obvious cause of these disorders, furthermore some antiepileptic drugs can have depressive effects on mood; the anxious–depressive disorders often result from the interaction between iatrogenic and psychosocial factor with common neurobiological pathogenesis. A chronic lowering of 5-HT (serotonin) levels has been demonstrated both in migraineurs and in depressed patients; amitriptyline and venlafaxine are the most indicated drugs in the treatment of migraine with comorbid depression currently. Likewise imbalance in dopamine levels has been also demonstrated: a D2 receptor genotype has been directly related to comorbidity migraine–depression. In women, hormonal fluctuations are also crucial, especially in the post-partum and late luteal phase, when the estrogenic reduction, associated with up-regulation of SNPs and down-regulation of serotonergic and GABAergic systems, increases the risk of migraine and depression. Furthermore, central sensitization phenomena have been highlighted in both diseases, and result in a progressive increase in the frequency of attacks up to chronicity and the consequent development of drug resistance and overuse. Further studies will be necessary to deepen the close relationship between these three diseases.