Hemiplegic migraine: neurophysiological, neurovegetative and clinical correlates

Migraine is a highly prevalent neurological disease present in around 12% of the general population, with a trifold prevalence in women [1]. The disorder is usually characterised by moderate-to-severe throbbing unilateral headache episodes, recurring with a variable frequency. The pain may last from 4 to 72 hours and may be associated with various symptoms which include physical exercise intolerance, nausea, photo- or phonophobia. Before or during an attack, a portion of patients (around 10-20%) may sometimes manifest transient negative or positive focal neurological symptoms (i.e., migraine aura) lasting usually up to one hour each. This configures the so-called migraine with aura (MwA). Such patients usually show some exacerbated characteristics compared to migraine without aura (MwoA) ones. The most frequent aura involves the visual system, but any system can be affected [2].A rare subtype of MwA is hemiplegic migraine (HM) where the most relevant clinical manifestations are motor auras that may last up to several days [3,4]. The disease may be sporadic (SHM) or familial (FHM) if 1st- or 2nd-degree relatives are affected too. In the case of FHM, it is sometimes possible to recognise pathogenic mutations involving genes of some ion channel proteins, leading to an autosomal dominant inheritance of the disease. Studies on murine models of FHM demonstrated how one of the main pathogenetic alterations was constituted by an increased cortical excitability [5]. This result is due to increased glutamatergic activity in addition to a dysfunction of intracortical inhibitory mechanisms [6]. Such hypotheses may be broadly transferred to MwA and even to MwoA, but clinical studies on HM patients are needed to increase the understanding of this disease. Clinical neurophysiology with non-invasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation (TMS) allow researchers to study cortical excitability. There are several TMS protocols, such as single-pulse, paired-pulse, or repeated TMS (rTMS) that can study different neurophysiological responses. The experiments using NIBS confirm that migraine shows an increased cortical excitability and a dysfunction in intracortical inhibitory patterns [7,8]. Another aspect which is altered in people with migraine (PwM) is multisensory integration (i.e., the cortical integration of stimuli from different sensory modalities). This process can be evaluated by presenting visual and auditory stimuli at the same time (i.e., generating sound-induced flash illusions – SIFI) [9,10]. Studies revealed how migraineurs show a lesser extent of SIFI, thus indicating an increased visual cortical excitability [11]. Migraineurs often complain of symptoms that resemble an involvement of the autonomic nervous system (ANS – i.e., the system that regulates responses to stimuli from the environment without the subject’s awareness, such as the automatic regulation of blood pressure or heart rate). Patients may complain of these symptoms both during the attacks or among them. Local autonomic symptoms may include flushing, rhinorrhoea, eyelid oedema, red eye, and lacrimation, while systemic ones are nausea, vomiting, palpitations, syncope, and light-headedness. An easy-accessible tool for the evaluation of ANS is represented by the study of heart rate variability (HRV). Heart rate is not fixed, but constantly changes dynamically, responding to internal and external stimuli. Migraineurs seem to show alterations in HRV, but the evidence is still conflicting. Thus, it is not clear whether the main alterations rely on the sympathetic or the parasympathetic nervous system [12–14]. The aim of the present research is to study the neurophysiological, neurovegetative and clinical correlates of HM patients. Particularly, patients would provide clinical information based on their headache diaries, and they should undergo an extensive neurophysiological and autonomic evaluation. Before discussing about the results of the present work, there will be an introduction regarding the main neurophysiological techniques and their implications in different clinical disorders in addition to an introduction to migraine and to the study of HRV.